Compounds containing a cyclohexyl group

Abstract

This application relates to compounds containing a cyclohexyl group, specifically to compounds of formula I-AA, their stereoisomers or pharmaceutically acceptable salts thereof, methods for their preparation, pharmaceutical compositions containing the compounds, and their use in the treatment of related diseases (e.g., cancer). [C1] TIFF2025528193000728.tif42156

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and benefit of Chinese Patent Application No. 202211000005.5 filed on August 19, 2022, Chinese Patent Application No. 202310206412.X filed on January 16, 2023, and Chinese Patent Application No. 202310996368.7 filed on August 8, 2023, with the State Intellectual Property Administration of China, the contents of which are incorporated herein by reference in their entireties. [Technical Field]

[0002] This application relates to compounds containing a cyclohexyl group, methods for their preparation, pharmaceutical compositions containing the compounds, and their use in the treatment of related diseases (e.g., cancer). [Background technology]

[0003] The androgen receptor (AR) is a steroid receptor of the nuclear receptor superfamily. Upon binding to androgens (e.g., testosterone, dihydrotestosterone), the AR is released from a complex formed by heat shock proteins, phosphorylates to form a dimer, and is transported into the nucleus. It then binds to its associated DNA fragments, stimulating the transcription of target genes. The transcriptional activity of the activated androgen receptor is regulated by coactivator proteins. The primary role of AR antagonists is to directly block the binding of testosterone or dihydrotestosterone to the androgen receptor, blocking the effects of androgens on cells, thereby promoting androgen resistance and inhibiting cell proliferation, ultimately inducing cell apoptosis and playing an important role in the treatment of prostate cancer.

[0004] PROTAC (proteolysis targeting chimera) molecules are a series of bifunctional compounds that can simultaneously bind to target proteins and E3 ubiquitin ligases. These compounds induce target proteins to be recognized by the cellular proteasome, leading to their degradation and effectively reducing the amount of target proteins in cells. By introducing ligands that can bind to different target proteins into PROTAC molecules, PROTAC molecule-based technology can be used to treat a variety of diseases, and this technology has attracted considerable attention in recent years. Summary of the Invention [Means for solving the problem]

[0005] In one aspect, the present application relates to a compound of formula I-AA, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, Ring A is absent or C 5~15 selected from a cycloalkenyl group, a 5- to 15-membered heterocycloalkenyl group, a phenyl group, or a 5- to 6-membered heteroaryl group; Ring B is selected from a phenyl group or a 5- to 6-membered heteroaryl group; Ring C is selected from 5- to 6-membered heteroaryl groups (e.g., isoxazolyl or furyl groups), Each R 1 are halogens, -OH, -NH2, -CN, C 1~10 Alkyl groups (e.g., C 1~6 alkyl group), C 1~10 Alkoxy groups (e.g., C 1~6 alkoxy group), or haloC 1~10 Alkyl groups (e.g., haloC 1~6 alkyl group), and 1~10 Alkyl groups (e.g., C 1~6 alkyl group), C 1~10 Alkoxy groups (e.g., C 1~6alkoxy group), or haloC 1~10 Alkyl groups (e.g., haloC 1~6 alkyl group) is optionally substituted by one or more substituents; n is selected from 0, 1, 2 or 3; L is selected from a linking group; X 5 is selected from CH or N, X 6 is -O-, -NH- or -N(C 1~6 alkyl)-, wherein said -NH- or -N(C 1~6 alkyl)- is optionally substituted by one or more substituents; Each R 2 , R 3 and R 4 are halogen, -OH, -NH2, -CN, and C, respectively. 1~10 Alkyl groups (e.g., C 1~6 alkyl group), C 1~10 Alkoxy groups (e.g., C 1~6 alkoxy group), or haloC 1~10 Alkyl groups (e.g., haloC 1~6 alkyl group), and 1~10 Alkyl group, C 1~10 Alkoxy group or haloC 1~10 The alkyl group is optionally substituted by one or more substituents; m, p, and q are each independently selected from 0, 1, 2, 3, or 4; Ring G is C 6~10 an aryl group or a 5- to 10-membered heteroaryl group; Ring E is C 3~10 selected from a cycloalkyl group or a 3- to 10-membered heterocycloalkyl group, Ring F is C 6~10 an aryl group or a 5- to 10-membered heteroaryl group; R t is hydrogen, -OH, C 1~6 Alkyl group, C 3~10 cycloalkyl group or 3- to 10-membered heterocycloalkyl group, 1~6 Alkyl group, C 3~10The cycloalkyl group or 3- to 10-membered heterocycloalkyl group is optionally substituted.

[0006] In some embodiments, ring A is absent or C 5~10 It is selected from a cycloalkenyl group, a 5- to 10-membered heterocycloalkenyl group, a phenyl group, or a 5- or 6-membered heteroaryl group.

[0007] In some embodiments, Ring B is selected from a phenyl group or a 6-membered heteroaryl group.

[0008] In some embodiments, said ring C is selected from a 5-membered heteroaryl group.

[0009] In some embodiments, the ring G is selected from a phenyl group or a 5- to 6-membered heteroaryl group. In some embodiments, the ring G is selected from a phenyl group or a 6-membered heteroaryl group. In some embodiments, the ring G is a phenyl group.

[0010] In some embodiments, ring E is 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 selected from cycloalkyl groups. In some embodiments, Ring E is a cyclohexyl group.

[0011] In some embodiments, ring F is C 6~10In some embodiments, ring F is selected from an aryl group or a 5- to 7-membered heteroaryl group. In some embodiments, ring F is selected from a phenyl group or a 5- to 6-membered heteroaryl group. In some embodiments, ring F is selected from a phenyl group or a 6-membered heteroaryl group. In some embodiments, ring F is selected from a phenyl group, a pyridazinyl group, a pyrimidinyl group, or a pyrazinyl group.

[0012] In some embodiments, R t is hydrogen, -OH, C 1~4 Alkyl group, C 3~6 cycloalkyl group or 3- to 6-membered heterocycloalkyl group, 1~4 Alkyl group, C 3~6 The cycloalkyl group or 3- to 6-membered heterocycloalkyl group is optionally substituted. In some embodiments, R t is hydrogen, -OH, C 1~3 Alkyl group, C 3~4 cycloalkyl group or 3- to 4-membered heterocycloalkyl group, 1~3 Alkyl group, C 3~4 The cycloalkyl group or 3- to 4-membered heterocycloalkyl group is optionally substituted. In some embodiments, R t is hydrogen or C 1~3 It is selected from alkyl groups (methyl, ethyl, propyl, etc.).

[0013] In some embodiments, the above terms "optionally substituted" or "optionally substituted with one or more substituents" refer to optionally being substituted with one or more halogens (e.g., fluorine, chlorine, bromine, or iodine), CN, OH, or NH.

[0014] In one aspect, the present application relates to a compound of formula I-1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, Ring A is absent or C 5~10selected from a cycloalkenyl group, a 5- to 10-membered heterocycloalkenyl group, a phenyl group, or a 5- to 6-membered heteroaryl group; Ring B is selected from phenyl groups; Ring C is selected from an isoxazolyl group or a furyl group; Each R 1 are halogens, -OH, -NH2, -CN, C 1~4 Alkyl group, C 1~4 Alkoxy group or haloC 1~4 independently selected from alkyl groups, n is selected from 0, 1, 2 or 3; L is selected from a linking group; X 1 , X 2 , X 3 , X 4 are each independently selected from N or CH; X 5 is selected from CH or N, X 6 is -O-, -NH- or -N(C 1~6 alkyl)-, Each R 2 , R 3 and R 4 are halogen, -OH, -NH2, -CN, and C, respectively. 1~4 Alkyl group, C 1~4 Alkoxy group or haloC 1~4 independently selected from alkyl groups, m, p, and q are each independently selected from 0, 1, 2, 3, or 4;

[0015] In one aspect, the present application relates to a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, Ring A is absent or C 5~10 selected from a cycloalkenyl group, a 5- to 10-membered heterocycloalkenyl group, a phenyl group, or a 5- to 6-membered heteroaryl group; Ring B is selected from phenyl groups; Ring C is selected from an isoxazolyl group or a furyl group; Each R 1 are halogens, -OH, -NH2, -CN, C 1~4 Alkyl group, C 1~4 Alkoxy group or haloC 1~4 independently selected from alkyl groups, n is selected from 0, 1, 2 or 3; L is selected from a linking group; X 1 , X 2 , X 3 , X 4 are each independently selected from N or CH; X 5 is selected from CH or N, X 6 is -O-, -NH- or -N(C 1~6 alkyl)-, Each R 2 , R 3 and R 4 are halogen, -OH, -NH2, -CN, and C, respectively. 1~4 Alkyl group, C 1~4 Alkoxy group or haloC 1~4 independently selected from alkyl groups, m, p, and q are each independently selected from 0, 1, 2, 3, or 4;

[0016] In some embodiments, ring A is absent or C 5~7 It is selected from a cycloalkenyl group, a 5- to 9-membered heterocycloalkenyl group, a phenyl group, or a 5- to 6-membered heteroaryl group.

[0017] In some embodiments, ring A is absent or C 5~6 It is selected from a cycloalkenyl group, a 5- to 10-membered heterocycloalkenyl group, a phenyl group, or a 5- or 6-membered heteroaryl group.

[0018] In some embodiments, ring A is absent or C 5~6 It is selected from a cycloalkenyl group, a 5- to 9-membered heterocycloalkenyl group, a phenyl group, or a 5- to 6-membered heteroaryl group.

[0019] In some embodiments, ring A is absent or C 5~6 It is selected from a cycloalkenyl group, a 5- to 9-membered heterocycloalkenyl group, a phenyl group, or a 5-membered heteroaryl group.

[0020] In some embodiments, ring A is absent or C 5~6 In some embodiments, ring A is selected from a C cycloalkenyl group, a 5- to 9-membered heterocycloalkenyl group, a phenyl group, a pyrrolyl group, a pyrazolyl group, a furyl group, or an oxazolyl group. In some embodiments, ring A is absent or selected from a C cycloalkenyl group, a C cycloalkenyl group, a 5-, 6-, 7-, 8-, or 9-membered heterocycloalkenyl group, a phenyl group, a pyrrolyl group, a pyrazolyl group, a furyl group, or an oxazolyl group.

[0021] In some embodiments, ring A is absent or is selected from a cyclopentenyl group, a monocyclohexenyl group, a bicyclohexenyl group, a dihydropyrrolyl group, a tetrahydropyridinyl group, a tetrahydroazepinyl group, an azaspirooctenyl group, an azaspirononenyl group, a phenyl group, a pyrrolyl group, a pyrazolyl group, a furyl group, an oxazolyl group, or a dihydrooxazinyl group.

[0022] In some embodiments, ring A is absent or is selected from a cyclopentenyl group, a bicyclohexenyl group, a dihydropyrrolyl group, a tetrahydropyridinyl group, a tetrahydroazepinyl group, an azaspirooctenyl group, an azaspirononenyl group, a phenyl group, a pyrrolyl group, a pyrazolyl group, a furyl group, an oxazolyl group, or a dihydrooxazinyl group. In some embodiments, ring A is selected from a monocyclohexenyl group.

[0023] In some specific embodiments, ring A is C 5~6 In some specific embodiments, ring A is selected from a cycloalkenyl group, a 5- to 10-membered heterocycloalkenyl group, a phenyl group, or a 5-membered heteroaryl group. 5~9It is selected from a cycloalkenyl group, a 5- to 9-membered heterocycloalkenyl group, a phenyl group, or a 5-membered heteroaryl group.

[0024] In some specific embodiments, ring A is C 5~6 It is selected from a cycloalkenyl group, a 5- to 9-membered heterocycloalkenyl group, a phenyl group, or a 5-membered heteroaryl group.

[0025] In some specific embodiments, ring A is C 5~9 In some specific embodiments, ring A is selected from a cycloalkenyl group or a 5- to 9-membered heterocycloalkenyl group. 5~6 In some specific embodiments, ring A is selected from a cycloalkenyl group or a 5- to 9-membered heterocycloalkenyl group. 5~9 In some specific embodiments, ring A is selected from C 5~6 In some specific embodiments, ring A is selected from 5- to 9-membered heterocycloalkenyl groups.

[0026] In some specific embodiments, ring A is selected from a cyclopentenyl group, a dihydropyrrolyl group, a tetrahydropyridinyl group, a tetrahydroazepinyl group, an azaspirononenyl group, an azaspirooctenyl group, a phenyl group, a pyrrolyl group, or a pyrazolyl group.

[0027] In some more specific embodiments, ring A is selected from a cyclopentenyl group, a dihydropyrrolyl group, a tetrahydropyridinyl group, a tetrahydroazepinyl group, an azaspirononenyl group, or an azaspirooctenyl group.

[0028] In some more specific embodiments, ring A is selected from a phenyl group, a pyrrolyl group, or a pyrazolyl group.

[0029] In some specific embodiments, Ring C is an isoxazolyl group. In some specific embodiments, Ring C is a furyl group.

[0030] In some embodiments, the structural fragment [ka] teeth, [ka] or [ka] Selected from.

[0031] In some embodiments, the structural fragment [ka] teeth, [ka] or [ka] In some embodiments, the structural fragment is selected from [ka] teeth, [ka] or [ka] or structural fragments thereof [ka] teeth, [ka] or [ka] or structural fragments thereof [ka] teeth, [ka] Selected from.

[0032] In some embodiments, the structural fragment [ka] teeth, [ka] or [ka] In some embodiments, the structural fragment is selected from [ka] teeth, [ka] or [ka] or structural fragments thereof [ka] teeth, [ka] or [ka] or structural fragments thereof [ka] teeth, [ka] Selected from.

[0033] In some embodiments, the structural fragment [ka] teeth, [ka] or [ka] Selected from.

[0034] In some embodiments, the structural fragment [ka] teeth, [ka] or [ka] In some embodiments, the structural fragment is selected from [ka] teeth, [ka] or [ka] Selected from.

[0035] In some specific embodiments, the structural fragment [ka] teeth, [ka] or [ka] In some specific embodiments, the structural fragment is selected from: [ka] teeth, [ka] or [ka] In some more specific embodiments, the structural fragment is selected from: [ka] teeth, [ka] or [ka] or structural fragments thereof [ka] teeth, [ka] or [ka] or structural fragments thereof [ka] teeth, [ka] or [ka] or structural fragments thereof [ka] teeth, [ka] or [ka] Selected from.

[0036] In some embodiments, the structural fragment [ka] teeth, [ka] or [ka] Selected from.

[0037] In some embodiments, the structural fragment [ka] teeth, [ka] or [ka] In some embodiments, the structural fragment is selected from [ka] teeth, [ka] or [ka] Selected from.

[0038] In some specific embodiments, the structural fragment [ka] teeth, [ka] or [ka] In some specific embodiments, the structural fragment is selected from: [ka] teeth, [ka] or [ka] In some more specific embodiments, the structural fragment is selected from: [ka] teeth, [ka] or [ka] or structural fragments thereof [ka] teeth, [ka] or [ka] or structural fragments thereof [ka] teeth, [ka] or [ka] or structural fragments thereof [ka] teeth, [ka] or [ka] Selected from.

[0039] In some embodiments, the structural fragment [ka] teeth, [ka] or [ka] Selected from.

[0040] In some embodiments, the structural fragment [ka] teeth, [ka] or [ka] In some embodiments, the structural fragment is selected from [ka] teeth, [ka] or [ka] Selected from.

[0041] In some specific embodiments, the structural fragment [ka] teeth, [ka] or [ka] In some specific embodiments, the structural fragment is selected from: [ka] teeth, [ka] or [ka] Selected from.

[0042] In some more specific embodiments, the structural fragment [ka] teeth, [ka] or structural fragments thereof [ka] teeth, [ka] or [ka] or structural fragments thereof [ka] teeth, [ka] or [ka] or a structural fragment [ka] teeth, [ka] or [ka] Selected from.

[0043] In some embodiments, each R 1 are halogens, -OH, -NH2, -CN, C 1~3 Alkyl group, C 1~3 Alkoxy group or haloC 1~3 In some embodiments, each R 1 is independently selected from fluorine, chlorine, bromine, —OH, —NH, or —CN. In some embodiments, each R 1 is independently selected from fluorine, chlorine, or bromine. In some embodiments, each R 1 are independently selected from fluorine.

[0044] In some embodiments, n is selected from 0, 1, or 2. In some embodiments, n is selected from 0 or 1.

[0045] In some specific embodiments, n is selected from 0.

[0046] In some embodiments, the structural fragment [ka] teeth, [ka] or [ka] Selected from.

[0047] In some specific embodiments, the structural fragment [ka] teeth, [ka] or [ka] In some specific embodiments, the structural fragment is selected from [ka] teeth, [ka] or [ka] In some more specific embodiments, the structural fragment is selected from: [ka] teeth, [ka] or [ka] or structural fragments thereof [ka] teeth, [ka] or [ka] or structural fragments thereof [ka] teeth, [ka] or [ka] or structural fragments thereof [ka] teeth, [ka] or [ka] Selected from.

[0048] In some embodiments, L is C 1~30 Alkylene group, C 2~30 Alkenylene group or C 2~30 alkynylene groups, 1~30 Alkylene group, C 2~30 Alkenylene group or C 2~30 One or more -CH2- in the alkynylene group may optionally be -O-, C 3~12 Cycloalkyl groups, 3- to 12-membered heterocycloalkyl groups, 4- to 12-membered heterocycloalkenyl groups, C6~12 Aryl group, 5- to 12-membered heteroaryl group, -NH-, -N(C 1~6 alkyl)- or -S-, and said C 1~30 Alkylene group, C 2~30 Alkenylene group or C 2~30 Alkynylene groups are optionally substituted with one or more substituents.

[0049] In some embodiments, L is C 1~20 Alkylene group, C 2~20 Alkenylene group or C 2~20 alkynylene groups, 1~20 Alkylene group, C 2~20 Alkenylene group or C 2~20 One or more -CH2- in the alkynylene group may optionally be -O-, C 3~10 Cycloalkyl groups, 3- to 10-membered heterocycloalkyl groups, 4- to 10-membered heterocycloalkenyl groups, C 6~10 Aryl group, 5- to 10-membered heteroaryl group, -NH-, -N(C 1~6 alkyl)- or -S-, and said C 1~20 Alkylene group, C 2~20 Alkenylene group or C 2~20 Alkynylene groups are optionally substituted with one or more substituents.

[0050] In some embodiments, L is C 1~15 Alkylene group, C 2~15 Alkenylene group or C 2~15 alkynylene groups, 1~15 Alkylene group, C 2~15 Alkenylene group or C 2~15 One or more -CH2- in the alkynylene group may optionally be -O-, C 3~8 Cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, 4- to 8-membered heterocycloalkenyl groups, C 6~8 Aryl group, 5- to 8-membered heteroaryl group, -NH-, -N(C 1~4 alkyl)- or -S-, and said C 1~20Alkylene group, C 2~15 Alkenylene group or C 2~15 Alkynylene groups are optionally substituted with one or more substituents.

[0051] In some embodiments, L is C 1~10 Alkylene group, C 2~10 Alkenylene group or C 2~10 alkynylene groups, 1~10 Alkylene group, C 2~10 Alkenylene group or C 2~10 One or more -CH2- in the alkynylene group may optionally be -O-, C 3~6 Cycloalkyl groups, 3- to 6-membered heterocycloalkyl groups, 4- to 6-membered heterocycloalkenyl groups, C6 aryl groups, 5- to 6-membered heteroaryl groups, -NH-, -N(C 1~3 alkyl)- or -S-, and said C 1~10 Alkylene group, C 2~10 Alkenylene group or C 2~10 Alkynylene groups are optionally substituted with one or more substituents.

[0052] In some embodiments, L is C 1~6 Alkylene group, C 2~6 Alkenylene group or C 2~6 alkynylene groups, 1~6 Alkylene group, C 2~6 Alkenylene group or C 2~6 One or more -CH2- in the alkynylene group may optionally be -O-, C 3~6 Cycloalkyl groups, 3- to 6-membered heterocycloalkyl groups, 4- to 6-membered heterocycloalkenyl groups, C6 aryl groups, 5- to 6-membered heteroaryl groups, -NH-, -N(C 1~3 alkyl)- or -S-, and said C 1~6 Alkylene group, C 2~6 Alkenylene group or C 2~6 Alkynylene groups are optionally substituted with one or more substituents.

[0053] In some embodiments, L is C 1~4 Alkylene group, C 2~4 Alkenylene group or C 2~4 alkynylene groups, 1~4 Alkylene group, C 2~4 Alkenylene group or C 2~4 One or more (e.g., one or two, one or three, etc.) -CH2- in the alkynylene group may optionally be replaced by -O-, C 4~6 Cycloalkyl groups, 4- to 6-membered heterocycloalkyl groups, 4- to 6-membered heterocycloalkenyl groups, C6 aryl groups, 5- to 6-membered heteroaryl groups, -NH-, -N(C 1~3 alkyl)- or -S-, and said C 1~4 Alkylene group, C 2~4 Alkenylene group or C 2~4 Alkynylene groups are optionally substituted with one or more substituents.

[0054] In some embodiments, L is C 1~6 alkylene groups, 1~6 One or more -CH2- in the alkylene group may optionally be -O-, C 3~10 Cycloalkyl groups, 4- to 10-membered heterocycloalkyl groups, 4- to 10-membered heterocycloalkenyl groups, -NH-, -N(C 1~3 alkyl)- or -S-, and said C 1~6 Alkylene groups are optionally substituted with one or more substituents.

[0055] In some embodiments, in the definition of L, the substituent is ═O, OH, NH, halogen, CN, C 1~6 Alkyl group or C 1~6 In some embodiments, in the definition of L, the substituent is selected from ═O, OH, NH 2 , halogen, or CN.

[0056] In some embodiments, L is -LNK 1 -Cy 1 -LNK-Cy 2 -LNK2 -Selected from, however, Cy 1 is a bond or, optionally, one or more R a C replaced by 3~12 selected from a cycloalkyl group, a 4- to 12-membered heterocycloalkyl group, or a 4- to 12-membered heterocycloalkenyl group; LNK, LNK 1 , LNK 2 are bonds, C 1~12 Alkylene group or C 1~12 heteroalkylene groups, Cy 2 is a bond or, optionally, one or more R b C replaced by 3~12 selected from a cycloalkyl group, a 4- to 12-membered heterocycloalkyl group, or a 4- to 12-membered heterocycloalkenyl group; Each R a and R b are halogen, -OH, -NH2, -CN, and C, respectively. 1~4 Alkyl group, C 1~4 Alkoxy group, haloC 1~4 Alkyl group, C 1~4 Alkylamino group, diC 1~4 Alkylamino group, C 3~12 It is independently selected from a cycloalkyl group and a 4- to 12-membered heterocycloalkyl group.

[0057] In some embodiments, L is -LNK 1 -Cy 1 -LNK-Cy 2 -LNK 2 -Selected from, however, Cy 1 is a bond or, optionally, one or more R a C replaced by 3~12 selected from a cycloalkyl group or a 4- to 12-membered heterocycloalkyl group, LNK, LNK 1 , LNK 2 are bonds, C 1~12 Alkylene group or C 1~12heteroalkylene groups, Cy 2 is a bond or, optionally, one or more R b C replaced by 3~12 selected from a cycloalkyl group or a 4- to 12-membered heterocycloalkyl group, Each R a and R b are halogen, -OH, -NH2, -CN, and C, respectively. 1~4 Alkyl group, C 1~4 Alkoxy group, haloC 1~4 Alkyl group, C 1~4 Alkylamino group, or diC 1~4 alkylamino groups.

[0058] In some embodiments, L is -LNK 1 -Cy 1 -LNK-Cy 2 -LNK 2 -, where Cy 1 and Cy 2 is not a bond at the same time.

[0059] In some embodiments, L is -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 -Selected from.

[0060] In some embodiments, L is -Cy 1 -LNK-Cy 2 -or-Cy1 -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 2 In some embodiments, L is selected from -Cy 1 -LNK-Cy 2 -LNK 2 -Selected from.

[0061] In some embodiments, L or -Cy 1 -LNK-Cy 2 -is -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 -is -Cy 1 -, -Cy 1 -Cy 2 -or-Cy 2 In some specific embodiments, L or -Cy 1 -LNK-Cy 2 -is -Cy 1 -LNK-, -Cy 1 -LNK-Cy 2 -or-LNK-Cy 2 In some specific embodiments, L or -Cy 1 -LNK-Cy 2 -is -Cy 1 In some specific embodiments, L or -Cy 1 -LNK-Cy 2 -is -Cy 1 -LNK-Cy 2 In some specific embodiments, L or -Cy1 -LNK-Cy 2 -LNK-Cy 2 In some embodiments, Cy 1 optionally one or more R a C replaced by 3~12 Cy is selected from a cycloalkyl group or a 4- to 12-membered heterocycloalkyl group; 2 is a bond or, optionally, one or more R b C replaced by 3~12 It is selected from a cycloalkyl group or a 4- to 12-membered heterocycloalkyl group.

[0062] In some embodiments, LNK, LNK 1 , LNK 2 is selected from the group consisting of: 1 is a bond.

[0063] In some embodiments, LNK is C 1~6 Alkylene group or C 1~6 heteroalkylene groups, LNK 1 , LNK 2 is a bond.

[0064] In some embodiments, the LNK 2 is C 1~6 Alkylene group or C 1~6 heteroalkylene groups, LNK, LNK 1 is a bond.

[0065] In some embodiments, the LNK 1 , LNK 2 is selected from a bond, and LNK is a bond or C 1~6 Alkylene group or C 1~6 heteroalkylene groups, and Cy 2 is a bond and Cy 1 optionally one or more R a C replaced by 4~11 It is selected from a cycloalkyl group or a 4- to 11-membered heterocycloalkyl group.

[0066] In some embodiments, LNK is C 1~6 Alkylene group or C 1~6 heteroalkylene groups, LNK 1 , LNK 2 is a bond, Cy 2 is a bond and Cy 1 optionally one or more R a C replaced by 4~11 It is selected from a cycloalkyl group or a 4- to 11-membered heterocycloalkyl group.

[0067] In some embodiments, LNK is C 1~6 Alkylene group or C 1~6 heteroalkylene groups, LNK 1 , LNK 2 is a bond, Cy 1 is a bond and Cy 2 optionally one or more R b C replaced by 4~11 It is selected from a cycloalkyl group or a 4- to 11-membered heterocycloalkyl group.

[0068] In some embodiments, LNK is C 1~6 Alkylene group or C 1~6 heteroalkylene groups, LNK 1 , LNK 2 is a bond, Cy 1 optionally one or more R a C replaced by 4~11 Cy is selected from a cycloalkyl group or a 4- to 11-membered heterocycloalkyl group; 2 optionally one or more R b C replaced by 4~11 It is selected from a cycloalkyl group or a 4- to 11-membered heterocycloalkyl group.

[0069] In some embodiments, Cy 1is a bond, or optionally one or more R a C replaced by 4~11 It is a cycloalkyl group, a 4- to 11-membered heterocycloalkyl group, or a 4- to 11-membered heterocycloalkenyl group.

[0070] In some embodiments, Cy 1 is a bond. In some embodiments, Cy 1 optionally one or more R a C replaced by 6~9 It is selected from a cycloalkyl group, a 4- to 11-membered heterocycloalkyl group, or a 4- to 9-membered heterocycloalkenyl group (for example, a 5- to 7-membered heterocycloalkenyl group).

[0071] In some embodiments, Cy 1 optionally one or more R a a C6 cycloalkyl group, a C9 cycloalkyl group, a 4-, 5-, 6-, 7-, 8-, 9-, 10- or 11-membered heterocycloalkyl group, or a 6-membered heterocycloalkenyl group substituted by

[0072] In some embodiments, Cy 1 optionally one or more R a In some embodiments, Cy is selected from a C6 cycloalkyl group, a C9 cycloalkyl group, a 4-, 6-, or 8- to 11-membered heterocycloalkyl group, or a 5- to 6-membered heterocycloalkenyl group substituted with 1 optionally one or more R a and a C6 cycloalkyl group, a C9 cycloalkyl group, a 4-, 6-, or 8- to 11-membered heterocycloalkyl group, or a 6-membered heterocycloalkenyl group substituted by

[0073] In some embodiments, Cy 1 is a bond or, optionally, one or more R a C replaced by 4~11 It is selected from a cycloalkyl group or a 4- to 11-membered heterocycloalkyl group.

[0074] In some embodiments, Cy 1 is a bond. In some embodiments, Cy 1 optionally one or more R a C replaced by 6~9 It is selected from a cycloalkyl group or a 4- to 11-membered heterocycloalkyl group.

[0075] In some embodiments, Cy 1 optionally one or more R a and a C6 cycloalkyl group, a C9 cycloalkyl group, a 4-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-membered heterocycloalkyl group substituted by

[0076] In some embodiments, Cy 1 optionally one or more R a In some embodiments, Cy is selected from a C6 cycloalkyl group, a C9 cycloalkyl group, a 4-membered, 6-membered, or 8-11-membered heterocycloalkyl group substituted with 1 optionally one or more R a In some embodiments, Cy is selected from 4- or 5-membered heterocycloalkyl groups substituted with 1 optionally one or more R a In some embodiments, Cy is selected from 6-9 membered heterocycloalkyl groups substituted with 1 optionally one or more R a In some specific embodiments, Cy is selected from 6-, 8-, or 9-membered heterocycloalkyl groups substituted with 1 optionally one or more R a and a 6-membered heterocycloalkyl group or a 9-membered heterocycloalkyl group substituted by:

[0077] In some embodiments, Cy 1 optionally one or more R aand a piperidinyl group, a diazaspirononyl group, a piperazinyl group, a monoazaspirononyl group, a cyclohexyl group, a spirononyl group, an azetidinyl group, a pyrrolidinyl group, an octahydrocyclopentapyrrolyl group, an azabicyclononyl group, a monoazaspironoundecyl group, a diazaspironoundecyl group, or a tetrahydropyridinyl group, each of which is substituted by:

[0078] In some embodiments, Cy 1 optionally one or more R a In some specific embodiments, Cy is selected from piperidinyl, diazaspirononyl, piperazinyl, monoazaspirononyl, cyclohexyl, spirononyl, azetidinyl, octahydrocyclopentapyrrolyl, azabicyclononyl, monoazaspironoundecyl, or diazaspirondecyl groups substituted with 1 optionally one or more R a In some specific embodiments, Cy is selected from a piperidinyl group, a diazaspirononyl group, a piperazinyl group, or a monoazaspirononyl group substituted with 1 optionally one or more R a azetidinyl, pyrrolidinyl or tetrahydropyridinyl substituted by:

[0079] In some embodiments, Cy 1 optionally one or more R a replaced by [ka] or [ka] Selected from.

[0080] In some embodiments, Cy 1 optionally one or more R a replaced by [ka] or [ka] Selected from.

[0081] In some specific embodiments, Cy 1 optionally one or more R a replaced by [ka] or [ka] In some specific embodiments, Cy 1 optionally one or more R a replaced by [ka] or [ka] Selected from.

[0082] In some embodiments, LNK, LNK 1 , LNK 2 are bonds, C 1~6 Alkylene group or C 1~6 heteroalkylene groups.

[0083] In some embodiments, LNK, LNK 1 , LNK 2 are bonds, C 1~3 Alkylene group or C 1~3 heteroalkylene groups.

[0084] In some embodiments, LNK, LNK 1 , LNK 2 are bonds or C 1~4are independently selected from alkylene groups.

[0085] In some embodiments, LNK, LNK 1 , LNK 2 are bonds or C 1~3 are independently selected from alkylene groups.

[0086] In some embodiments, LNK, LNK 1 , LNK 2 are each independently selected from a bond or -CH2-. In some specific embodiments, LNK is a bond. In some specific embodiments, LNK, LNK 1 , LNK 2 are each independently -CH2-.

[0087] In some embodiments, Cy 2 is a bond or, optionally, one or more R b C replaced by 4~11 In some specific embodiments, Cy is selected from a cycloalkyl group or a 4- to 11-membered heterocycloalkyl group. 2 is a bond. In some specific embodiments, Cy 2 optionally one or more R b C replaced by 4~11 It is selected from a cycloalkyl group or a 4- to 11-membered heterocycloalkyl group.

[0088] In some embodiments, Cy 2 is a bond or, optionally, one or more R b C replaced by 4~6 In some embodiments, Cy is selected from a cycloalkyl group or a 4- to 6-membered heterocycloalkyl group. 2 optionally one or more R b C replaced by 4~6 It is selected from a cycloalkyl group or a 4- to 6-membered heterocycloalkyl group.

[0089] In some embodiments, Cy2 is a bond or, optionally, one or more R b In some specific embodiments, Cy is selected from cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, or piperidinyl groups substituted with 2 is a bond or, optionally, one or more R b and the alkyl group is selected from cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl or piperidinyl substituted by:

[0090] In some embodiments, Cy 2 is a bond, [ka] or [ka] In some specific embodiments, Cy 2 is a bond, [ka] or [ka] Selected from.

[0091] In some embodiments, R a , R b are halogen, -OH, -NH2, -CN, and C, respectively. 1~3 Alkyl group, C 1~3 Alkoxy group, haloC 1~3 Alkyl group, C 1~3 Alkylamino group, or diC 1~3 alkylamino groups.

[0092] In some embodiments, R a , R b are halogen, -OH, -NH2, -CN or C 1~3 independently selected from alkyl groups.

[0093] In some embodiments, R a , R b are each independently selected from halogen, —OH, —NH 2 , or —CN.

[0094] In some embodiments, the structural fragment -Cy 1 -LNK- is [ka] or [ka] Selected from.

[0095] In some embodiments, the structural fragment -Cy 1 -LNK- is [ka] or [ka] Selected from.

[0096] In some specific embodiments, the structural fragment -Cy 1 -LNK- is [ka] or [ka] In some specific embodiments, the structural fragment -Cy 1 -LNK- is [ka] or [ka] Selected from.

[0097] In some embodiments, the structural fragment -LNK-Cy 2 - is a bond, -CH2-, [ka] or [ka] Selected from.

[0098] In some specific embodiments, the structural fragment -LNK-Cy 2 - is a bond, -CH2-, [ka] or [ka] Selected from.

[0099] In some embodiments, the structural fragment -Cy 1 -Cy 2 -teeth, [ka] or [ka] Selected from.

[0100] In some embodiments, the structural fragment -Cy 1 -Cy 2 -teeth, [ka] or [ka] Selected from.

[0101] In some specific embodiments, the structural fragment -Cy 1 -Cy2 -teeth, [ka] or [ka] Selected from.

[0102] In some embodiments, the structural fragment -Cy 1 -Cy 2 -LNK 2 -teeth, [ka] or [ka] Selected from.

[0103] In some embodiments, the structural fragment or -Cy 1 -Cy 2 -LNK 2 -teeth, [ka] or [ka] Selected from.

[0104] In some embodiments, the structural fragment -L- or -LNK 1 -Cy 1 -LNK-Cy 2 -LNK 2 -teeth, [ka] or [ka] Selected from.

[0105] Also in some embodiments, the structural fragment -L- or -LNK 1 -Cy 1 -LNK-Cy 2 -LNK 2 -teeth, [ka] or [ka] Selected from.

[0106] In some specific embodiments, the structural fragment -L- or -LNK 1 -Cy 1 -LNK-Cy 2 -LNK 2 -teeth, [ka] or [ka] or [ka] Selected from.

[0107] In some embodiments, the structural fragment [ka] teeth, [ka] [ka] [ka] or [ka] Selected from.

[0108] In some embodiments, the structural fragment [ka] teeth, [ka] [ka] or [ka] In some embodiments, the structural fragment is selected from [ka] teeth, [ka] or [ka] Selected from.

[0109] In some embodiments, X 1 , X 2 , X 3 are each independently selected from N or CH, and X 4 is CH. In some embodiments, X 1 , X 2 are each independently selected from N or CH, and X 3 , X 4 is CH. In some embodiments, X 1 , X 2 are each independently N and X 3 , X 4 is CH. In some embodiments, X 1 , X 2 , X 3 , X 4 is CH. In some embodiments, X 1 , X 4 is CH and X 2 , X3 is N. In some embodiments, X 2 , X 3 are each independently CH, and X 1 , X 4 is N. In some embodiments, X 1 , X 3 are each independently CH, and X 2 , X 4 is N. In some embodiments, X 2 , X 3 are each independently selected from N or CH, and X 1 , X 4 is CH. In some embodiments, X 1 , X 3 are each independently selected from N or CH, and X 2 is N and X 4 is CH.

[0110] In some embodiments, X 5 is CH.

[0111] In some embodiments, X 6 is -O-, -NH- or -N(C 1~3 In some embodiments, X is selected from the group consisting of aryl, ... 6 is selected from —O— or —N(CH3)—.

[0112] In some embodiments, each R 2 are halogens, -OH, -NH2, -CN, C 1~3 Alkyl group, C 1~3 Alkoxy group or haloC 1~3 In some embodiments, each R 2 is a halogen, -OH, -NH2, -CN or C 1~3 In some embodiments, each R 2 is independently selected from fluorine, chlorine, bromine, —OH, —NH, or —CN. In some embodiments, each R 2 is independently selected from fluorine, chlorine, bromine, or —CN. In some embodiments, each R2 are independently selected from chlorine or —CN.

[0113] In some embodiments, each R 4 are halogens, -OH, -NH2, -CN, C 1~3 Alkyl group, C 1~3 Alkoxy group or haloC 1~3 In some embodiments, each R 4 is a halogen, -OH, -NH2, -CN or C 1~3 In some embodiments, each R 4 are independently selected from fluorine, chlorine, bromine, —OH, —NH 2 or —CN.

[0114] 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.

[0115] In some embodiments, the structural fragment [ka] teeth, [ka] is.

[0116] In some embodiments, each R 3 and R 4 are halogen, -OH, -NH2, -CN, and C, respectively. 1~3 Alkyl group, C 1~3 Alkoxy group or haloC 1~3 In some embodiments, each R 3 and R 4 are halogen, -OH, -NH2, -CN or C 1~3In some embodiments, each R 3 and R 4 are each independently selected from fluorine, chlorine, bromine, —OH, —NH 2 , or —CN.

[0117] 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 0.

[0118] In some embodiments, the structural fragment [ka] teeth, [ka] or [ka] In some embodiments, the structural fragment is selected from [ka] teeth, [ka] or [ka] Optionally, in the structural fragment [ka] or [ka] pR 3 where p and R 3 are defined as described herein.

[0119] In some embodiments, the structural fragment [ka] or [ka] teeth, [ka] or [ka] Optionally, in the structural fragment [ka] or [ka] pR 3 where p and R 3 are defined as described herein.

[0120] In some embodiments, the structural fragment [ka] teeth, [ka] or [ka] Optionally, in the structural fragment [ka] or [ka] pR 3 where p and R 3are defined as described herein.

[0121] In some embodiments, the structural fragment [ka] teeth, [ka] or [ka] Optionally, in the structural fragment [ka] or [ka] pR 3 where p and R 3 are defined as described herein.

[0122] In some specific embodiments, the structural fragment [ka] teeth, [ka] Optionally, in the structural fragment [ka] pR 3 where p and R 3 are defined as described herein.

[0123] In some specific embodiments, the structural fragment [ka] teeth, [ka] or [ka] Optionally, in the structural fragment [ka] or [ka] pR 3 where p and R 3 are defined as described herein.

[0124] In some specific embodiments, the structural fragment [ka] teeth, [ka] or [ka] or structural fragments thereof [ka] teeth, [ka] or [ka] or structural fragments thereof [ka] teeth, [ka] Optionally, in the structural fragment [ka] or [ka] pR 3 where p and R 3 are defined as described herein.

[0125] In some embodiments, the heterocycloalkenyl, heteroaryl, heterocycloalkyl, or heteroalkylene groups contain one or more heteroatoms or heteroatom groups independently selected from -O-, -NH-, -N-, -S-, C=O, -C(=O)NH-, -C(=O)O-, -S(=O)-, or -S(=O)-; in some embodiments, the heterocycloalkenyl, heteroaryl, heterocycloalkyl, or heteroalkylene groups contain one or more heteroatoms or heteroatom groups independently selected from -O-, -NH-, -N-, or -S-; in some embodiments, the heterocycloalkenyl, heteroaryl, heterocycloalkyl, or heteroalkylene groups contain one or more heteroatoms or heteroatom groups independently selected from -O-, -NH-, or -N-. In some embodiments, the number of heteroatoms or heteroatom groups is independently selected from 1, 2, 3, 4, 5, or 6, or selected from 1, 2, 3, or 4, or selected from 1, 2, or 3, or selected from 1 or 2.

[0126] In some embodiments, the heteroatoms in the heterocycloalkenyl groups are selected from N, NH, O, or S. In some embodiments, the heteroatoms in the heterocycloalkenyl groups are selected from N, O, or S. In some specific embodiments, the heteroatoms in the heterocycloalkenyl groups are selected from N or O. In some embodiments, the number of heteroatoms in the heterocycloalkenyl groups is selected from 1, 2, 3, 4, 5, or 6. In some embodiments, the number of heteroatoms in the heterocycloalkenyl groups is selected from 1, 2, 3, or 4. In some embodiments, the number of heteroatoms in the heterocycloalkenyl groups is selected from 1, 2, or 3. In some specific embodiments, the number of heteroatoms in the heterocycloalkenyl groups is selected from 1 or 2.

[0127] In some specific embodiments, the heterocycloalkenyl group contains 1 to 3 (e.g., 1 to 2) heteroatoms selected from -O-, -NH-, -N-, or -S-. In some specific embodiments, the heteroaryl group contains 1 to 3 (e.g., 1 to 2) heteroatoms selected from -O-, -NH-, -N-, or -S-. In some specific embodiments, the heterocycloalkyl group contains 1 to 3 (e.g., 1 to 2) heteroatoms selected from -O-, -NH-, -N-, or -S-. In some specific embodiments, the heteroalkylene group contains 1 to 3 (e.g., 1 to 2) heteroatoms selected from -O-, -NH-, -N-, or -S-.

[0128] It should be noted that any of the embodiments of the compounds of the present application described above and the specific X 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 tIt is understood that any specific substituent described for the L substituent can be independently combined with substituents of other embodiments and / or compounds herein to form embodiments of the invention not specifically described above. Also, any particular X in the specific embodiments and / or claims may be combined with any particular X 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 , when a range of substituents is disclosed for an L substituent, it is understood that one or more substituents may be deleted from that range and the remaining range of substituents is also considered an embodiment of the present application.

[0129] The formula I-AA compound, formula I-1 compound or formula I compound, its stereoisomer or pharmaceutically acceptable salt thereof according to the present application is selected from the formula I-A1 compound or formula IA compound, its stereoisomer or pharmaceutically acceptable salt thereof, respectively; [ka] In the formula, 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 herein.

[0130] In some embodiments, the structural fragment [ka] is as described in this application.

[0131] The formula I-AA compound, formula I-1 compound or formula I compound, its stereoisomer or pharmaceutically acceptable salt thereof according to the present application is selected from the group consisting of compounds 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, its stereoisomer or pharmaceutically acceptable salt thereof, [ka] [ka] In the formula, 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 are defined as described herein, X is selected from CH or N.

[0132] The formula I-AA compound, formula I-1 compound, formula I compound, formula IA compound, stereoisomers thereof, or pharmaceutically acceptable salts thereof according to the present application are selected from 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, stereoisomers thereof, or pharmaceutically acceptable salts thereof, [ka] [ka] In the formula, ring A, ring B, ring C, R 1 , R2 , m, n, X 1 , X 2 , X 3 , X 5 , X 6 , Cy 1 , Cy 2 , LNK, LNK 1 , LNK 2 are defined as described herein, X is selected from CH or N.

[0133] In some embodiments, X 1 , X 2 is CH and X 3 is CH. In some embodiments, X 1 , X 2 is N and X 3 is CH. In some embodiments, X 2 , X 3 is N and X 1 is CH.

[0134] In some embodiments, X 1 , X 2 is CH. In some embodiments, X 1 , X 2 is N.

[0135] In some embodiments, the structural fragment [ka] teeth, [ka] or [ka] or a structural fragment [ka] teeth, [ka] or [ka] or a structural fragment [ka] teeth, [ka] or [ka] or a structural fragment [ka] teeth, [ka] or [ka] or a structural fragment [ka] teeth, [ka] or [ka] or a structural fragment [ka] teeth, [ka] or [ka] Selected from.

[0136] In some embodiments, the structural fragment [ka] teeth, [ka] or [ka] Or it is selected from [ka] or [ka] Or it is selected from [ka] or [ka] Selected from.

[0137] In some embodiments, the structural fragment [ka] , -Cy 1 -LNK-, -LNK-Cy 2 -, -Cy 1 -Cy 2 -or-Cy 1 -LNK-Cy 2 - is as described above.

[0138] In some embodiments, optionally, the compound according to the present application is not: [ka]

[0139] In some embodiments, optionally, the compound according to the present application is not: [ka]

[0140] In some embodiments, the structural moiety [ka] or [ka] teeth, [ka] or [ka] Not selected from.

[0141] In some embodiments, the structural moiety [ka] or [ka] teeth, [ka] or [ka] Not selected from.

[0142] In some embodiments, the structural moiety [ka] or [ka] teeth, [ka] or [ka] In some embodiments, the structural moiety is not selected from [ka] or [ka] teeth, [ka] or [ka] Not selected from.

[0143] In some embodiments, the structural fragment [ka] teeth, [ka] or [ka] In some embodiments, the structural fragment is not selected from [ka] teeth, [ka] or [ka] In some embodiments, the structural fragment is not selected from [ka] teeth, [ka] or [ka] Not selected from.

[0144] In another aspect, the present application relates to a compound, moiety, stereoisomer, derivative thereof (e.g., Protac molecule) of Formula I' or Formula I" or a pharmaceutically acceptable salt thereof: [ka] wherein ring A is absent or C 5~10 selected from a cycloalkenyl group, a 5- to 10-membered heterocycloalkenyl group, a phenyl group, or a 5- to 6-membered heteroaryl group; Ring B is selected from phenyl groups; Ring C is selected from an isoxazolyl group or a furyl group; L is selected from a linking group, optionally where L is as defined herein, and optionally R 1 and n are defined as described herein.

[0145] In some embodiments, the structural moiety [ka] is as described in this application.

[0146] In another aspect, the present application relates to a compound, moiety, stereoisomer, derivative thereof (e.g., Protac molecule) of formula I'-a or formula I''-a, or a pharmaceutically acceptable salt thereof: [ka] wherein ring A is absent or C 5~10selected from a cycloalkenyl group, a 5- to 10-membered heterocycloalkenyl group, a phenyl group, or a 5- to 6-membered heteroaryl group; Ring B is selected from phenyl groups; Ring C is selected from an isoxazolyl group or a furyl group; Each R 1a are halogens, -OH, -NH2, -CN, =O, -CHO, C 1~4 Alkyl group, C 1~4 Alkoxy group, C 1~6 Alkyl OC(O)-, C 3~12 cycloalkyl groups or 4- to 12-membered heterocycloalkyl groups, 1~4 Alkyl group, C 1~4 Alkoxy group, C 3~12 The cycloalkyl group or 4- to 12-membered heterocycloalkyl group may optionally contain one or more halogen atoms, ═O, —OH, —NH, —CN, CHO, COOH, —C 1~4 Alkyl-OH, C 1~6 alkylOC(O)-, or optionally C 1~6 substituted by a 4- to 10-membered heterocycloalkyl group substituted by alkylCOC(O)-; n is selected from 0, 1, 2 or 3.

[0147] In some embodiments, ring A is absent or C 5~7 It is selected from a cycloalkenyl group, a 5- to 9-membered heterocycloalkenyl group, a phenyl group, or a 5- to 6-membered heteroaryl group.

[0148] In some embodiments, ring A is absent or C 5~6 It is selected from a cycloalkenyl group, a 5- to 10-membered heterocycloalkenyl group, a phenyl group, or a 5- or 6-membered heteroaryl group.

[0149] In some embodiments, ring A is absent or C 5~6 It is selected from a cycloalkenyl group, a 5- to 9-membered heterocycloalkenyl group, a phenyl group, or a 5- to 6-membered heteroaryl group.

[0150] In some embodiments, ring A is absent or C 5~6 It is selected from a cycloalkenyl group, a 5- to 9-membered heterocycloalkenyl group, a phenyl group, or a 5-membered heteroaryl group.

[0151] In some embodiments, ring A is absent or C 5~6 It is selected from a cycloalkenyl group, a 5- to 9-membered heterocycloalkenyl group, a phenyl group, a pyrrolyl group, a pyrazolyl group, a furyl group, and an oxazolyl group.

[0152] In some embodiments, ring A is absent or is selected from a C5 cycloalkenyl group, a C6 cycloalkenyl group, a 5-, 6-, 7-, 8-, or 9-membered heterocycloalkenyl group, a phenyl group, a pyrrolyl group, a pyrazolyl group, a furyl group, or an oxazolyl group.

[0153] In some embodiments, ring A is absent or is selected from a cyclopentenyl group, a monocyclohexenyl group, a bicyclohexenyl group, a dihydropyrrolyl group, a tetrahydropyridinyl group, a tetrahydroazepinyl group, an azaspirooctenyl group, an azaspirononenyl group, a phenyl group, a pyrrolyl group, a pyrazolyl group, a furyl group, an oxazolyl group, or a dihydrooxazinyl group.

[0154] In some specific embodiments, ring A is C 5~9 It is selected from a cycloalkenyl group, a 5- to 9-membered heterocycloalkenyl group, a phenyl group, or a 5-membered heteroaryl group.

[0155] In some specific embodiments, ring A is C 5~6 It is selected from a cycloalkenyl group, a 5- to 9-membered heterocycloalkenyl group, a phenyl group, or a 5-membered heteroaryl group.

[0156] In some specific embodiments, ring A is C 5~9 In some specific embodiments, ring A is selected from a cycloalkenyl group or a 5- to 9-membered heterocycloalkenyl group. 5~6It is selected from a cycloalkenyl group and a 5- to 9-membered heterocycloalkenyl group.

[0157] In some specific embodiments, ring A is C 5~9 In some specific embodiments, ring A is selected from C 5~6 In some specific embodiments, ring A is selected from 5- to 9-membered heterocycloalkenyl groups.

[0158] In some specific embodiments, ring A is selected from a cyclopentenyl group, a dihydropyrrolyl group, a tetrahydropyridinyl group, a tetrahydroazepinyl group, an azaspirononenyl group, an azaspirooctenyl group, a phenyl group, a pyrrolyl group, or a pyrazolyl group.

[0159] In some specific embodiments, ring A is selected from a cyclopentenyl group, a dihydropyrrolyl group, a tetrahydropyridinyl group, a tetrahydroazepinyl group, an azaspirononenyl group, or an azaspirooctenyl group. In some specific embodiments, ring A is selected from a cyclopentenyl group, a dihydropyrrolyl group, a tetrahydropyridinyl group, a tetrahydroazepinyl group, or an azaspirooctene group.

[0160] In some specific embodiments, ring A is selected from a cyclopentenyl group, hi some specific embodiments, ring A is selected from a dihydropyrrolyl group, a tetrahydropyridinyl group, a tetrahydroazepinyl group, or an azaspirooctene group.

[0161] In some specific embodiments, ring A is selected from a phenyl group, a pyrrolyl group, or a pyrazolyl group.

[0162] In some embodiments, ring A is [ka] or [ka] Selected from.

[0163] In some specific embodiments, Ring C is an isoxazolyl group. In some specific embodiments, Ring C is a furyl group.

[0164] In some embodiments, the structural moiety [ka] teeth, [ka] or [ka] Selected from.

[0165] In some embodiments, the structural fragment [ka] teeth, [ka] or [ka] In some embodiments, the structural fragment is selected from [ka] teeth, [ka] or [ka] or structural fragments thereof [ka] teeth, [ka] or [ka] or structural fragments thereof [ka] teeth, [ka] Selected from.

[0166] In some embodiments, the structural fragment [ka] teeth, [ka] or [ka] In some embodiments, the structural fragment is selected from [ka] teeth, [ka] or [ka] or structural fragments thereof [ka] teeth, [ka] or [ka] or structural fragments thereof [ka] teeth, [ka] Selected from.

[0167] In some embodiments, the structural fragment [ka] teeth, [ka] or [ka] Selected from.

[0168] In some specific embodiments, the structural fragment [ka] teeth, [ka] or [ka] In some more specific embodiments, the structural fragment is selected from: [ka] teeth, [ka] or [ka] or structural fragments thereof [ka] teeth, [ka] or [ka] Selected from.

[0169] In some embodiments, the structural fragment [ka] teeth, [ka] or [ka] Selected from.

[0170] In some specific embodiments, the structural fragment [ka] teeth, [ka] or [ka] In some more specific embodiments, the structural fragment is selected from [ka] teeth, [ka] or [ka] or structural fragments thereof [ka] teeth, [ka] or [ka] Selected from.

[0171] In some embodiments, each R 1a are halogens, -OH, -NH2, -CN, -CHO, C 1~6 Alkyl OC(O)-, C 1~4 Alkyl group, C 1~4 Alkoxy group, C 3~10 a cycloalkyl group or a 4- to 10-membered heterocycloalkyl group, 1~4 Alkyl group, C 1~4 Alkoxy group, C 3~10 The cycloalkyl group or 4- to 10-membered heterocycloalkyl group may optionally contain one or more halogen atoms, ═O, —OH, —NH, —CN, CHO, COOH, —C 1~4 Alkyl-OH, C 1~6 alkylOC(O)-, or optionally C 1~6 It is substituted by a 4-10 membered heterocycloalkyl group which is substituted by alkylCOC(O)-.

[0172] In some embodiments, each R 1a are halogens, -OH, -NH2, -CN, -CHO, C 1~4 Alkyl OC(O)-, C 1~3 Alkyl group, C 1~3 Alkoxy group, C 3~9 cycloalkyl groups or 4- to 9-membered heterocycloalkyl groups, 1~3 Alkyl group, C 1~3 Alkoxy group, C 3~9 The cycloalkyl group or 4- to 9-membered heterocycloalkyl group may optionally contain one or more halogen, —OH, ═O, —NH, —CN, CHO, COOH, or —C 1~4 Alkyl-OH, C 1~4alkylOC(O)-, or optionally C 1~4 It is substituted by a 4-9 membered heterocycloalkyl group substituted by alkylCOC(O)-.

[0173] In some embodiments, each R 1a are halogens, -OH, -NH2, -CN, -CHO, C 1~6 Alkyl OC(O)-, C 1~3 Alkyl group, C 1~3 Alkoxy group, C 3~6 cycloalkyl groups or 4- to 6-membered heterocycloalkyl groups, 1~3 Alkyl group, C 1~3 Alkoxy group, C 4~6 The cycloalkyl group or 4- to 6-membered heterocycloalkyl group may optionally contain one or more halogen atoms, such as -OH, =O, -NH2, -CN, CHO, COOH, -C 1~4 Alkyl-OH, C 1~6 alkylOC(O)-, or optionally C 1~6 It is substituted by a 3- to 6-membered heterocycloalkyl group substituted by alkylCOC(O)-.

[0174] In some embodiments, each R 1a are halogens, -OH, -NH2, -CN, -CHO, C 1~4 Alkyl OC(O)-, C 1~3 alkyl group or 4- to 6-membered heterocycloalkyl group, 1~3 The alkyl group or 4- to 6-membered heterocycloalkyl group may optionally be one or more of -OH, ═O, -NH, -CN, CHO, COOH, C 1~4 alkylOC(O)-, or optionally C 1~4 It is substituted by a 4-6 membered heterocycloalkyl group substituted by alkylOC(O)-.

[0175] In some embodiments, each R 1a are halogens, -OH, -CHO, (CH3)3COC(O)-, C 1~3 alkyl group, cyclobutyl group, or piperidinyl group,1~3 The alkyl, cyclobutyl or piperidinyl group is optionally substituted by one or more -OH, (CH3)3COC(O)-, or cyclobutyl groups optionally substituted by (CH3)3COC(O)-.

[0176] In some embodiments, each R 1a is F, -OH, -CHO, (CH3)3COC(O)-, -CH2OH, [ka] or [ka] are independently selected from

[0177] 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.

[0178] This application relates to the following compounds, moieties, stereoisomers thereof, derivatives (specifically, Protac molecules, etc.), or pharmaceutically acceptable salts thereof: [ka] [ka] [ka] [ka] or [ka]

[0179] In another aspect, the present application relates to the use of the compound (e.g., Formula I' or Formula I" or Formula I'-a or Formula I"-a or specific compounds), moieties, isomers (e.g., stereoisomers), and derivatives thereof in a Protac molecule. In another aspect, the present application relates to the use of the compound (e.g., Formula I' or Formula I" or Formula I'-a or Formula I"-a or specific compounds), moieties, isomers (e.g., stereoisomers), and derivatives thereof to constitute a part of a Protac molecule. In another aspect, the present application relates to the compound (e.g., Formula I' or Formula I" or Formula I'-a or Formula I"-a or specific compounds), moieties, isomers (e.g., stereoisomers), and derivatives thereof present in the form of a Protac molecule. In another aspect, the present application relates to the use of the compound (e.g., Formula I' or Formula I" or Formula I'-a or Formula I"-a or specific compound), portion, isomer (e.g., stereoisomer) or derivative thereof for degrading proteins, for example, the compound (e.g., Formula I' or Formula I" or Formula I'-a or Formula I"-a or specific compound), portion, isomer (e.g., stereoisomer) or derivative thereof degrades the protein in the form of a Protac molecule. In another aspect, the present application relates to the use of the compound (e.g., Formula I' or Formula I" or Formula I'-a or Formula I"-a or specific compound), portion, isomer (e.g., stereoisomer) or derivative thereof for degrading proteins in the form of a Protac molecule. The present application relates to the use of the compounds (e.g., Formula I' or Formula I" or Formula I'-a or Formula I"-a or specific compounds), moieties, isomers (e.g., stereoisomers), and derivatives (e.g., as production intermediates) thereof in the production of Protac molecules. The present application relates to the use of the compounds (e.g., Formula I' or Formula I" or Formula I'-a or Formula I"-a or specific compounds), moieties, isomers (e.g., stereoisomers), and derivatives (e.g., as production intermediates) thereof in the production of proteolytic agents.

[0180] 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, provided that: Ring A is C 5~6a cycloalkenyl group, a 5- to 8-membered heterocycloalkenyl group containing 1 to 3 heteroatoms selected from N, O, or S (for example, 1 to 2 heteroatoms selected from N or O), a phenyl group, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, or S (for example, 1 to 2 heteroatoms selected from N or O); Ring B is a phenyl group, Ring C is selected from an isoxazolyl group or a furyl group; Each R 1 is a halogen, -OH, -NH2, -CN or C 1~3 independently selected from alkyl groups (methyl, ethyl, propyl, etc.), n is selected from 0 or 1; L is for LNK 1 -Cy 1 -LNK-Cy 2 -LNK 2 -Selected from LNK, LNK 1 , LNK 2 are bonds or C 1~3 alkylene groups, and Cy 1 is a bond, C 3~7 a cycloalkyl group, a 4- to 7-membered heterocycloalkyl group, or a 5- to 7-membered heterocycloalkenyl group; Cy 2 is a bond, C 3~7 a cycloalkyl group, a 4- to 7-membered heterocycloalkyl group, or a 5- to 7-membered heterocycloalkenyl group, and Cy 1 and Cy 2 is not a bond at the same time, X 1 , X 2 , X 3 , X 4 are each independently selected from N or CH; X 5 is selected from CH or N, X 6 is -O-, -NH- or -N(C 1~6 alkyl)-, Each R 2 , R 3 and R 4are halogen, -OH, -NH2, -CN or C 1~3 independently selected from alkyl groups (methyl, ethyl, propyl, etc.), m is selected from 1 or 2; p and q are each independently selected from 0 or 1.

[0181] 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, provided that: Ring A is selected from a cyclopentenyl group, a dihydropyrrolyl group, a tetrahydropyridinyl group, a tetrahydroazepinyl group, an azaspirooctenyl group, a phenyl group, a pyrrolyl group, and a pyrazolyl group; Ring B is a phenyl group, Ring C is selected from an isoxazolyl group or a furyl group; n is 0, L is optionally C 1~3 a piperidinyl group, a diazaspirononyl group, a piperazinyl group, or a monoazaspirononyl group linked to an alkylene group; [ka] , an azetidinyl group, or a tetrahydropyridinyl group; X 1 , X 2 , X 3 and X 4 are all CH, or X 1 , X 2 , X 3 and X 4 two of which are N and two of which are CH; X 5 is selected from CH or N, X 6 is -O-, -NH- or -N(C 1~4 alkyl)-, R 2 is selected from halogen or —CN, m is 2, p and q are each independently 0.

[0182] The present application also relates to the following compounds, their stereoisomers or pharmaceutically acceptable salts thereof: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or [ka]

[0183] In some embodiments, the pharmaceutically acceptable salt is selected from a maleate salt.

[0184] The present application further includes embodiments obtained by arbitrarily combining, deleting, or replacing the above-described embodiments.

[0185] In another aspect, the present application relates to a pharmaceutical composition comprising the compound of the present application, its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition of the present application further comprises a pharmaceutically acceptable excipient.

[0186] In another aspect, the present application relates to the use of the above-described compound, its stereoisomer or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof in the manufacture of a medicament for preventing or treating a condition that is treated by degrading a target protein (such as the androgen receptor (AR)) that binds to a targeting ligand.

[0187] In another aspect, the present application relates to the use of the above compound, its stereoisomer or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof in the manufacture of a medicament for preventing or treating a condition that is treated by binding to a cerebellar protein in the body.

[0188] In another aspect, the present application relates to the use of the above-mentioned compound, its stereoisomer or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof in the manufacture of a medicament for preventing or treating an AR-related disease.

[0189] The present application relates to a method for treating or preventing a disease state in a mammal that is treated by degrading a target protein (such as the androgen receptor (AR)) that binds to a targeting ligand, the method comprising administering to a mammal (preferably a human) in need of such treatment a therapeutically effective amount of the compound of the present application, its stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0190] The present application relates to a method for treating or preventing a condition that is treated in vivo by binding to a cerebellar protein, comprising administering to a mammal (preferably a human) in need of such treatment a therapeutically effective amount of the compound of the present application, its stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0191] In another aspect, the present application relates to a method for treating an AR-related disorder in a mammal, comprising administering to a mammal (preferably a human) in need of such treatment a therapeutically effective amount of any of the above-described compounds of the present application, its stereoisomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0192] In another aspect, the present application relates to the above-mentioned compound, its stereoisomer or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof for preventing or treating a condition that is treated by degrading a target protein (such as the androgen receptor (AR)) that binds to a targeting ligand.

[0193] In another aspect, the present application relates to the above compound, its stereoisomer or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof for preventing or treating a condition that is treated by binding to a cerebellar protein in the body.

[0194] In another aspect, the present application relates to the above-mentioned compound, its stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating an AR-related disease.

[0195] In another aspect, the present application relates to the use of the above-mentioned compounds, their stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the prevention or treatment of a condition that is treated by degrading a target protein (such as the androgen receptor (AR)) that binds to a targeting ligand.

[0196] In another aspect, the present application relates to the use of the above compounds, their stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the prevention or treatment of conditions that are treated by binding to cerebellar proteins in the body.

[0197] In another aspect, the present application relates to the use of the above-mentioned compound, its stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the prevention or treatment of AR-related diseases.

[0198] In some specific embodiments, the AR-related disease is selected from conditions that are treated by degrading and / or inhibiting a protein (the androgen receptor (AR)) that binds to an AR target protein ligand; in some specific embodiments, the AR-related disease is selected from conditions that are treated by binding to a cerebellar protein in the body; in some embodiments, the disease or condition is selected from cancer, e.g., prostate cancer.

[0199] In some specific embodiments, the condition treated in vivo by binding to a cerebellar protein and / or by degrading a target protein bound to a targeting ligand is selected from an AR-related disease, and in some specific embodiments, the AR-related disease is selected from cancer, e.g., prostate cancer.

[0200] As used herein, "one or more" refers to an integer between 1 and 10. For example, "one or more" refers to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, and in some embodiments, the "one or more" is selected from 1, 2, 3, 4, 5, or 6. In some embodiments, the "one or more" is selected from 1, 2, or 3. In some embodiments, the "one or more" is selected from 1 or 2.

[0201] In some embodiments, the present application includes the variables and embodiments thereof defined above, and any combination thereof. [Effects of the Invention]

[0202] The compounds of the present application have degradation activity against AR in VCaP cells and AR in LNCaP cells, and antiproliferative activity against VCaP cells and LNCaP cells. In addition, the compounds of the present application have good in vitro stability in liver microsomes and good in vivo pharmacokinetic properties (specifically, parameters such as AUC) in mammals (e.g., mice), and can suppress tumor growth in the body, demonstrating their potential as drugs.

[0203] (definition) Unless otherwise specified, the following terms used in this application have the following meanings: Certain terms, unless otherwise defined, are to be understood in their ordinary sense in the art and not as open or unclear. When trade names are mentioned herein, they refer to the corresponding product or its active ingredient.

[0204] The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom by a substituent, provided that the valence of the atom is normal and the resulting compound is stable. When the substituent is oxo (=O), two hydrogen atoms are replaced. Oxo does not occur in aryl groups.

[0205] The term "optional" or "optionally" refers to the subsequently described event or circumstance, which may or may not occur, and includes both cases where the event or circumstance occurs and cases where the event or circumstance does not occur. "Optionally substituted" includes both unsubstituted and substituted; for example, when an ethyl group is "optionally" substituted with a halogen, the ethyl group may be unsubstituted (CH2CH3), monosubstituted (e.g., CH2CH2F), polysubstituted (e.g., CHFCH2F, CH2CHF2), or fully substituted (CF2CF3). Those skilled in the art will understand that spatially incompatible and / or synthetically incompatible substitutions or methods of substitution are not permitted for any atomic group containing one or more substituents.

[0206] Herein, C m~n means that the moiety has an integer number of carbon atoms within a given range. For example, "C 1~6 " means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

[0207] When a variable (e.g., R) occurs more than once in a compound composition or structure, each occurrence is independently defined. For example, if a group contains two R, each R is an independent option.

[0208] When a bond connects two atoms of a ring (including a monocyclic, fused, or spiro ring), such bond can connect to any atom on the ring (including a monocyclic, fused, or spiro ring). For example, the structural unit [ka] represents that the bonds on both sides may be connected to any two different atoms of ring A, ring B, or ring C, and another example is [ka] represents that the bonds on both sides may be connected to any two different atoms of ring A, the middle benzene ring, or ring C, and another example is [ka] indicates that the bonds on either side may connect to any two different atoms in the four rings of the system.

[0209] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0210] The term "hydroxy" refers to an -OH radical.

[0211] The term "amino group" refers to an -NH2 atom group.

[0212] The term "cyano" refers to the radical --CN.

[0213] The term "alkyl group" refers to a group having the general formula C n H 2n+1 The alkyl group may be straight or branched. For example, the term "C 1~6The term "alkyl group" 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 same definition as above applies to the alkyl group portion (i.e., alkyl group) of an alkoxy group, alkylamino group, dialkylamino group, alkylsulfonyl group, and alkylthio group.

[0214] The term "alkylene group" refers to a divalent group formed by removing one hydrogen from any position of an alkyl group, e.g., the term "C 1~6 "Alkyl group" refers to an alkylene group containing 1 to 6 carbon atoms; 1~4 "Alkyl group" refers to an alkylene group containing from 1 to 4 carbon atoms, including, but not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-.

[0215] The term "alkenylene group" refers to a divalent group formed by removing one hydrogen from any position of an alkenyl group, e.g., the term "C 2~6 An "alkenyl group" refers to an alkenylene group containing 2 to 6 carbon atoms; 2~4 "Alkenyl group" refers to an alkenylene group containing 2 to 4 carbon atoms, including, but not limited to, -CH2CH=CH-, -CH2CH2CH=CH-, or -CH2CH=CHCH2-.

[0216] The term "alkynylene group" refers to a divalent group formed by removing one hydrogen from any position of an alkynyl group, e.g., the term "C 2~6 An "alkynyl group" refers to an alkynylene group containing 2 to 6 carbon atoms; 2~4 "Alkynyl group" refers to an alkynylene group containing 2 to 4 carbon atoms; [ka] or [ka] Including, but not limited to:

[0217] The term "heteroalkyl group" refers to a straight or branched chain alkyl group consisting of a specified number of carbon atoms and at least one heteroatom, preferably 1 to 14 carbons, more preferably 1 to 10 carbons, even more preferably 1 to 6 carbons, and most preferably 1 to 3 carbons in the chain, and preferably 1, 2, or 3 heteroatoms selected from S, O, and N. For example, C m Heteroalkyl groups represent alkyl groups having heteroatoms inserted within a chain of m carbon atoms and at least one heteroatom (e.g., 1 to 3 heteroatoms selected from S, O, and N) located between any two carbon atoms or connected to the terminal carbon atom, provided that the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. The heteroatom or heteroatoms may be located at any position within the heterohydrocarbyl group, including the position at which the hydrocarbon group is attached to the remainder of the molecule; exemplary heteroalkyl groups include alkyl ethers, secondary and tertiary alkylamines, amides, alkyl sulfides, and the like, including alkoxy groups, alkylthio groups, alkylamino groups, and unless otherwise specified, C 1~6 Heteroalkyl groups include C1, C2, C3, C4, C5 and C6 heteroalkyl groups, such as C 1~6 Alkoxy group, C 1~6 Alkylthio group, C 1~6 It is an alkylamino group.

[0218] The term "heteroalkylene group" refers to a divalent radical formed by removing one hydrogen from any position of a heteroalkyl group.

[0219] The term "alkoxy" refers to an --O-alkyl group.

[0220] The term "alkenyl group" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms and having at least one double bond. Non-limiting examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.

[0221] The term "cycloalkenyl group" refers to a non-aromatic carbocyclic ring that is not fully saturated and can exist as a monocyclic, bicyclic bridged ring, or spiro ring. Unless otherwise specified, the carbocyclic ring is typically 4 to 16-membered, 4 to 12-membered, 4 to 10-membered, or 4 to 8-membered. Non-limiting examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, and the like.

[0222] The term "cycloalkyl group" refers to a carbocyclic ring that is fully saturated and can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise specified, the carbocyclic ring typically has 3 to 16 members (e.g., 3 to 10 members, or 5 to 8 members). Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantanyl, and the like.

[0223] The term "heterocycloalkyl group" refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise specified, the heterocyclic ring is generally a 3- to 16-, 3- to 11-, 3- to 10-, 3- to 7-, 3- to 6-, or 3- to 5-membered ring containing 1 to 3 (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, oxiranyl, thiiranyl, and aziridinyl groups; non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, and thietanyl groups; and examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, and tetrahydrofuryl. 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, and examples of 7-membered heterocycloalkyl groups include, but are not limited to, azepanyl, oxepanyl, and thiepanyl groups. Preferred are monocyclic heterocycloalkyl groups having 5 or 6 ring atoms.

[0224] The term "spirocycle" refers to a fully saturated or partially unsaturated polycyclic ring system in which the monocyclic rings share one carbon atom (called a spiroatom), and includes carbocyclic and heterocyclic rings. Unless otherwise specified, the spirocycle has 5 to 20 members, preferably 6 to 14 members, and more preferably 8 to 12 members. When the spirocycle is heterocyclic, one or more ring atoms of the polycyclic ring may be N, O, S(O), or N-C(O). n , P(O) n (where n is 0, 1 or 2) and the remaining ring atoms are carbon atoms.

[0225] The term "spirocycloalkyl group" refers to a fully saturated all-carbon polycyclic ring in which one carbon atom (called a spiro atom) is shared between the monocyclic rings. Unless otherwise specified, the spirocycloalkyl group has 5 to 20 members, preferably 6 to 14 members, and more preferably 8 to 12 members. Depending on the number of spiro atoms shared between the rings, the spirocycloalkyl group can be classified as a monospirocycloalkyl group, a bisspirocycloalkyl group, or a multispirocycloalkyl group. Preferably, the spirocycloalkyl group is a monospirocycloalkyl group or a bisspirocycloalkyl group, and more preferably, the spirocycloalkyl group is a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups are: [ka] and [ka] Includes.

[0226] The term "spiroheterocycloalkyl group" refers to a fully saturated polycyclic ring in which the monocyclic rings share one carbon atom (called a spiroatom) and one or more ring atoms of the polycyclic ring are N, O, S(O), n , P(O) n (where n is 0, 1 or 2) and the remaining ring atoms are carbon atoms. Unless otherwise specified, the spiroheterocycloalkyl group has 5 to 20 members, preferably 6 to 14 members, and more preferably 6 to 10 members. Depending on the number of spiro atoms shared between rings, the spiroheterocycle is classified as a monospiroheterocycle, a bisspiroheterocycle, or a multispiroheterocycle, and is preferably a monospiroheterocycle or a bisspiroheterocycle, and more preferably a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospiroheterocycle. Non-limiting examples of spiroheterocycloalkyl groups are: [ka] or [ka] Includes:

[0227] The term "heterocycloalkenyl group" includes cycloalkenyl groups in which one or more carbon atoms (e.g., 1 to 5, 1 to 4, 1 to 3, or 1 to 2) are replaced by heteroatoms. Specifically, for example, cycloalkenyl groups in which up to three carbon atoms, in one embodiment up to two carbon atoms, and in another embodiment one carbon atom, are each independently replaced by O, S, S(O), or N, provided that at least one cycloalkenyl carbon-carbon double bond is retained. The cyclic group, which may exist as a monocyclic, bridged, or spirocyclic ring, may be a 3- to 16-membered ring (e.g., a 3- to 12-membered, 5- to 8-membered ring, specifically a 5-, 6-, 7-, 8-, 9-, 10-, or 11-membered ring, etc.). Examples of heterocycloalkenyl groups include, but are not limited to, a dihydropyrrolyl group, a tetrahydropyridinyl group, a tetrahydroazepinyl group, or an azaspirooctene.

[0228] The term "aryl group" refers to an all-carbon monocyclic or fused polycyclic aromatic cyclic group having a conjugated π-electron system. For example, an aryl group may have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, 1,2,3,4-tetrahydronaphthalene, and the like.

[0229] The term "heteroaryl group" refers to a monocyclic or fused polycyclic ring system containing at least one (e.g., 1 to 5, 1 to 4, 1 to 3, or 1 to 2) ring atom selected from N, O, or S, the remaining ring atoms being C, and having at least one aromatic ring. Preferably, the heteroaryl group has one 4- to 8-membered ring, particularly a 5- to 8-membered ring (e.g., 5-, 6-, 7-, or 8-membered) or multiple fused rings containing 6 to 14, particularly 6 to 10 (e.g., 6, 7, 8, 9, or 10) ring atoms. Non-limiting examples of heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuryl, benzothienyl, indolyl, isoindolyl, and the like.

[0230] Unless otherwise specified, the term "hetero" refers to a heteroatom or heteroatom group (i.e., a group of atoms containing a heteroatom), and includes atoms other than carbon (C) and hydrogen (H) and groups of atoms containing these heteroatoms, such as oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), silicon (Si), germanium (Ge), aluminum (Al), boron (B), -O Includes -, -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)-.

[0231] The term "derivative" refers to a new compound or series of compounds produced by one or more chemical reactions or structural changes, in which the basic structure of the parent compound is retained, and only the side chains, functional groups or substituents are changed or modified.

[0232] The terms "substituent", "optionally substituted by one or more substituents" or "optionally substituted" include substitution with all substituents or substituents mentioned in the context of this specification, for example, the terms "halogen", "deuterium", " [ka] ","-NH2," "-NH(C 1~4 alkyl)" "-N(C 1~4 Alkyl)2, -OH, -OC 1~4 alkyl group, -CN, C 1~4Some non-limiting examples of the "substituent" include a mercapto group, a nitro group, a nitroso group, a cyano group, an azide atomic group, a sulfoxide atomic group, a sulfone atomic group, a sulfonamide atomic group, a carboxy group, an aldehyde group, an imine atomic group, an alkyl group, a haloalkyl group, a cycloalkyl group, a halocycloalkyl group, an alkenyl group, a haloalkenyl group, a cycloalkenyl group, a halocycloalkenyl group, an alkynyl group, a haloalkynyl group, a cyclo Alkynyl group, halocycloalkynyl group, heteroalkyl group, haloheteroalkyl group, alkoxy group, alkylthio group, aryl group, aryloxy group, arylthio group, arylalkylene group, arylalkoxy group, arylalkylthio group, heteroaryl group, heteroaryloxy group, heteroarylthio group, heteroarylalkylene group, heteroarylalkoxy group, heteroarylalkylthio group, heterocyclyl group, heterocyclyloxy group, heterocyclylthio group, heterocyclylalkylene group, heterocyclylalkoxy group, heterocyclyl The substituents include acylalkylthio groups, acyl groups, acyloxy groups, carbamate atomic groups, amido groups, ureido groups, epoxy atomic groups, ester atomic groups, oxo groups, etc., and the substituents optionally include oxo, hydroxy groups, amino groups, nitro groups, halogens, cyano groups, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkoxy groups, alkylamino groups, dialkylamino groups, haloalkylamino groups, halodialkylamino groups, carboxy groups, -C(O)O-alkyl groups, -OC(O)-alkyl groups, -C(O)NH, -C(O)NH-alkyl groups, -C (O)N(alkyl)2, -NHC(O)-alkyl group, -C(O)-alkyl group, -S(O)-alkyl group, -S(O)2-alkyl group, -S(O)2NH2, -S(O)2NH-alkyl group, -S(O)2N(alkyl)2, cycloalkyl group, cycloalkylalkylene group, cycloalkyloxy, heterocyclyl group, heterocyclylalkylene group, heterocyclyloxy group, heterocycloalkyl group, heterocycloalkylalkylene group, heterocycloalkyloxy, heteroaryl group, heteroarylalkylene group, heteroaryloxy group,It is substituted by one or more substituents selected from an aryl group, an arylalkylene group, or an aryloxy group.

[0233] In some embodiments herein, the substituent is selected from the group consisting of deuterium, tritium, a hydroxy group, a mercapto group, a halogen, an amino group, a nitro group, a nitroso group, a cyano group, an azide group, a sulfoxide group, a sulfone group, a sulfonamide group, a carboxy group, an aldehyde group, an imine group, C 1~12 Alkyl group, halo C 1~12 Alkyl groups, 3- to 12-membered cycloalkyl groups, halo 3- to 12-membered cycloalkyl groups, C 2~12 Alkenyl group, haloC 2~12 Alkenyl group, 3- to 12-membered cycloalkenyl group, halo 3- to 12-membered cycloalkenyl group, C 2~12 Alkynyl group, haloC 2~12 Alkynyl group, 8-12 membered cycloalkynyl group, halo 8-12 membered cycloalkynyl group, C 1~12 Heteroalkyl groups, haloC 1~12 Heteroalkyl groups, C 1~12 Alkoxy group, C 1~12 Alkylthio group, 6- to 10-membered aryl group, 6- to 10-membered aryloxy group, 6- to 10-membered arylthio group, 6- to 10-membered arylC 1~12 Alkylene group, 6-10 membered aryl C 1~12 Alkoxy group, 6-10 membered aryl C 1~12 Alkylthio group, 5- to 10-membered heteroaryl group, 5- to 10-membered heteroaryloxy group, 5- to 10-membered heteroarylthio group, 5- to 10-membered heteroarylalkylene group, 5- to 10-membered heteroarylalkoxy group, 5- to 10-membered heteroarylalkylthio group, 3- to 12-membered heterocyclyl group, 3- to 12-membered heterocyclyloxy group, 3- to 12-membered heterocyclylthio group, 3- to 12-membered heterocyclylC 1~12 Alkylene group, 3-12 membered heterocyclyl C 1~12 Alkoxy group, 3- to 12-membered heterocyclyl C 1~12 Alkylthio group, C 1~12 Acyl group, C 1~12 Acyloxy group, carbamate group, C 1~12Amide group, ureido group, epoxy group, C 2~12 ester groups and oxo, the substituents being optionally selected from oxo, hydroxy, amino, nitro, halogen, cyano, C 1~12 Alkyl group, C 2~12 Alkenyl group, C 2~12 Alkynyl group, C 1~12 Alkoxy group, haloC 1~12 Alkoxy group, C 1~12 Alkylamino group, diC 1~12 Alkylamino group, haloC 1~12 Alkylamino group, HalodiC 1~12 Alkylamino group, carboxy group, -C(O)OC 1~12 Alkyl group, -OC(O)-C 1~12 Alkyl group, -C(O)NH2, -C(O)NH-C 1~12 Alkyl group, -C(O)N(C 1~12 alkyl)2, -NHC(O)-C 1~12 Alkyl group, -C(O)-C 1~12 Alkyl group, -S(O)-C 1~12 Alkyl group, -S(O)2-C 1~12 Alkyl group, -S(O)2NH2, -S(O)2NH-C 1~12 Alkyl group, -S(O)N(C 1~12 Alkyl) 2, 3- to 12-membered cycloalkyl group, 3- to 12-membered cycloalkyl C 1~12 Alkylene group, 3- to 12-membered cycloalkyloxy, 3- to 12-membered heterocyclyl group, 3- to 12-membered heterocyclylC 1~12 Alkylene group, 3- to 12-membered heterocyclyloxy group, 3- to 12-membered heterocycloalkyl group, 3- to 12-membered heterocycloalkylC 1~12 Alkylene group, 3- to 12-membered heterocycloalkyloxy, 5- to 10-membered heteroaryl group, 5- to 10-membered heteroarylC 1~12 Alkylene group, 5- to 10-membered heteroaryloxy group, 6- to 10-membered aryl group, 6- to 10-membered arylC 1~12 It is substituted with one or more substituents selected from an alkylene group or a 6- to 10-membered aryloxy group.

[0234] Unless otherwise specified, the term "hetero" refers to a heteroatom or heteroatom group (i.e., a group of atoms containing a heteroatom), and includes atoms other than carbon (C) and hydrogen (H) and groups of atoms 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), and does not include specific Examples of 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 heteroatom of a heteroatom or heteroatom group (i.e., a group of atoms containing a heteroatom) designated by the term "hetero" is selected from oxygen, nitrogen, or sulfur.

[0235] The term "derivative" refers to a new compound or series of compounds produced by one or more chemical reactions or structural changes, in which the basic structure of the parent compound is retained, and only the side chains, functional groups or substituents are changed or modified.

[0236] In this application, the wavy line ( [ka] ) represents one of the absolute configurations of the stereocenter (e.g., [ka] or [ka] Specifically, [ka] teeth, [ka] or [ka] ) or one of the relative configurations (e.g., [ka] teeth, [ka] or [ka] (Represents the formula:). When the compounds described herein contain an alkene double bond or other center of geometric asymmetry, unless otherwise specified, they include E,Z geometric isomers. Likewise, all tautomeric forms are included within the scope of this application.

[0237] In this application, -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 A group or structural fragment such as -, etc., and specific alternatives thereof may optionally be read from left to right and correspondingly connected to the group to the left and the group to the right of that group or fragment in the general formula, e.g., L is -Cy 1 -LNK-Cy 2 -Chosen from Cy 1 but [ka] When selected from, reading from left to right, Cy 1 The left side of is the corresponding left fragment in the general formula [ka] and the right side is the right fragment. [ka] and the fragment thus formed is [ka] and optionally, in this application, -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 A group or structural fragment such as - and specific alternatives thereof may be read from right to left and correspondingly connected to the group to the left and right of that group or fragment in the general formula, e.g., L is -Cy 1 -LNK-Cy 2 -Chosen from Cy 1 but [ka] When selected from, reading from right to left, Cy 1 The right side of the fragment corresponds to the left side of the general formula [ka] and the left side is the corresponding right side fragment in the general formula [ka] and the fragment thus formed is [ka] The other atomic groups are the same as above.

[0238] The term "treatment" means administering a compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with said disease, and (i) arresting the disease or disease state, i.e., inhibiting its progression; (ii) Alleviating a disease or disease state, i.e., eliminating the disease or disease state.

[0239] The term "prevention" refers to the administration of a compound or formulation described herein to prevent a disease or one or more symptoms associated with said disease, and includes preventing the appearance of a disease or disease state in a mammal, particularly when the mammal is susceptible to such a disease state but has not yet been diagnosed with the disease state.

[0240] The term "therapeutically effective amount" refers to an amount of a compound of the present application used to (i) treat or prevent a particular disease, condition, or disorder, (ii) reduce, ameliorate, or eliminate one or more symptoms of a particular disease, condition, or disorder, or (iii) prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The "therapeutically effective amount" of a compound of the present application will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal being treated, but can be determined by one of skill in the art based on their knowledge and the present disclosure.

[0241] The term "pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms that are medically determined to be suitable for use in contact with the tissues of humans and animals, are not toxic or irritating, and are not likely to cause an allergic reaction or other problem or complication, and the benefit-to-risk ratio is reasonable.

[0242] Pharmaceutically acceptable salts include, for example, metal salts, ammonium salts, salts formed with organic bases, salts formed with inorganic acids, salts formed with organic acids, salts formed with basic or acidic amino acids, and the like.

[0243] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or salts thereof with pharmaceutically acceptable excipients, which facilitates administration of the compounds of the present application to an organism.

[0244] The term "pharmaceutically acceptable additive" refers to an additive that does not cause obvious irritation to living organisms and does not impair the physiological activity and properties of the active compound. For example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc. are well known to those skilled in the art as suitable additives.

[0245] The term "comprise" and similar terms, such as the English expressions "comprises" or "comprising," are to be understood in an open and non-exclusive sense, meaning "including, but not limited to."

[0246] As used herein, singular terms cover plural referents and vice versa unless the context clearly dictates otherwise. Similarly, as used herein, the word "or" is intended to include "and" unless the context clearly dictates otherwise.

[0247] Unless otherwise specified, numbers used herein to express amounts of ingredients, measurements, or reaction conditions are understood to be modified in all circumstances by the term "about." When used in conjunction with percentages, the term "about" can represent, for example, ±1%, preferably ±0.5%, and more preferably ±0.1%.

[0248] The compounds and intermediates of the present application may 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 with different energies that can be interconverted via a low energy barrier. For example, proton tautomers (also called prototropic tautomers) include interconversions via proton transfer, such as ketone-enol isomerization and imine-enamine isomerization. A specific example of a proton tautomer is an imidazole moiety, where a proton can transfer between two ring nitrogen atoms. Specifically, for example, any compound of the present disclosure that is a pyrazole alone or part of a heterocyclyl group may exist in the form of any two tautomers or a mixture of any number of two tautomers, i.e., [ka] , or [ka] The present disclosure includes all possible tautomers of the compounds of the present disclosure, single tautomers, or any mixture of said tautomers in any ratio.

[0249] The present application further includes compounds of the present application that are identical to the compounds described herein, except that one or more atoms have been replaced by an atom whose atomic mass or mass number is different from the usual atomic mass or mass number found in nature, i.e., isotopically labeled. Examples of isotopes that can be associated with the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, for example, 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,36 Cl, etc.

[0250] Some isotopically labeled compounds of the present application (e.g., 3 H, 14 C) can be used for tissue distribution analysis of compounds and / or substrates. 3 H), carbon-14 (i.e. 14 C) is particularly preferred because it is easy to prepare and detect. Positron-emitting isotopes, e.g. 15 O. 13 N, 11 C. 18 F can be used to measure substrate occupancy in positron emission tomography (PET) studies. Generally, isotopically labeled compounds of the present application may be prepared by procedures similar to those disclosed in the embodiments and / or examples below, using an isotopically labeled reagent to replace a non-isotopically labeled reagent.

[0251] Also, isotopes with larger mass numbers (e.g., deuterium, i.e. 2 Substitution with hydrogen (H) may be preferable in some cases because it provides greater metabolic stability and offers therapeutic advantages (e.g., increased in vivo half-life or reduced dose requirements). However, deuterium substitution may be partial or complete, with partial deuterium substitution meaning that at least one hydrogen is replaced with at least one deuterium.

[0252] The compounds of the present application may be asymmetric, e.g., have one or more stereoisomers. Unless otherwise specified, all stereoisomers, such as enantiomers and diastereomers, are included. Compounds of the present application containing asymmetric carbon atoms can be isolated in optically pure or racemic form. Optically pure forms can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0253] The pharmaceutical compositions of the present application may be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable additives, and may be prepared as solid, semi-solid, liquid, or gaseous preparations, such as tablets, pills, capsules, powders, granules, creams, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres, aerosols, etc.

[0254] Typical routes of administration of the compounds of the present application, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous.

[0255] The pharmaceutical compositions of the present application may be manufactured by conventional methods well known in the art, for example, by mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, lyophilizing or the like.

[0256] In some embodiments, the pharmaceutical composition is in a form for oral administration. For oral administration, the pharmaceutical composition may be prepared by mixing the active compound with pharmaceutically acceptable additives well known in the art. These additives may allow the compound of the present application to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, suspensions, etc. for oral administration to patients.

[0257] Oral solid compositions may be prepared by conventional methods such as blending, filling, and tableting. For example, the active compound may be mixed with a solid additive, and the mixture may be optionally milled. If necessary, other suitable additives may be added, and the mixture may then be granulated to form tablets or dragee cores. Suitable additives include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, flavoring agents, etc.

[0258] The pharmaceutical compositions are also suitable for parenteral administration, for example as appropriate unit dose sterile solutions, suspensions or lyophilized products.

[0259] In all the administration methods of the compound of general formula I described herein, the daily dose is 0.01 to 200 mg / kg body weight, and the dose is administered in a single dose or in divided doses.

[0260] The compounds of the present application may be prepared by various synthetic methods familiar to those skilled in the art, including the specific embodiments listed below, embodiments in combination with other chemical synthetic methods, and equivalent alternative forms familiar to those skilled in the art, and preferred embodiments include, but are not limited to, the examples of the present application.

[0261] The chemical reactions of the specific embodiments of the present application are carried out in a suitable solvent, which must be compatible with the chemical transformations of the present application and the reagents and raw materials used. In order to obtain the compounds of the present application, it may be necessary for those skilled in the art to modify or select synthetic steps or reaction processes based on conventional embodiments.

[0262] In the art, one of the important factors to be considered in formulating a synthetic route is the selection of an appropriate protecting group for a reactive functional group (e.g., an amino group in the present application). In this regard, see, for example, "Greene's Protective Groups in Organic Synthesis (4th Ed.)." Hoboken, New Jersey: John Wiley & Sons, Inc.

[0263] In some embodiments, compounds of formula I of the present application may be prepared by one skilled in the art of organic synthesis by the following route. [ka] A compound of general formula I-2 is obtained by a substitution reaction of a compound of general formula I-1, a compound of general formula I-3 is obtained by a deprotection reaction of the compound of general formula I-2, a compound of general formula I-4 is obtained by a condensation reaction, a compound of general formula I-4 is obtained by an oxidation reaction of the compound of general formula I-5, and a hydroxy group-substituted Cy of a chlorinated aromatic carboxylic acid is obtained. 1The compound of general formula I-6 is obtained by a substitution reaction with the compound of general formula I-7, and the compound of general formula I-7 is obtained by a deprotection reaction. Finally, the compound of general formula I-5 is obtained by a reductive amination reaction with the compound of general formula I-7 to obtain the compound of general formula I.

[0264] The compound of general formula I-3 is condensed with the compound of general formula I-10 to obtain the compound of general formula I-8, and the compound of general formula I-8 is deprotected to obtain the compound of general formula I-9. 1 The compound of general formula I-10 is obtained by a substitution reaction with the compound of general formula I-11, and the compound of general formula I-11 is obtained by an oxidation reaction. The compound of general formula I-9 is obtained by a reductive amination reaction of the compound of general formula I-11 with the compound of general formula I-12.

[0265] The following abbreviations are used in this application: Boc represents a tert-butoxycarbonyl group, Et represents an ethyl group, EA represents ethyl acetate, DMSO represents dimethyl sulfoxide, DMF represents N,N-dimethylformamide, BINAP represents 1,1'-binaphthalene-2,2'-bis(diphenylphosphine), DCM represents dichloromethane, Pd2(dba)3 represents tris(dibenzylideneacetone)dipalladium(0), THF represents tetrahydrofuran, PMB represents a p-methoxybenzyl group, MeOH represents methanol, PE represents petroleum ether, IBX represents 2-iodoxybenzoic acid, DIPEA represents N,N-diisopropylethylamine, and 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-bis(diphenylphosphino)-9,9-dimethylxanthene, DCE represents dichloroethane, DMA or DMAC represents N,N-dimethylacetamide, AIBN represents azobisisobutyronitrile, DMAP represents 4-dimethylaminopyridine, CCl4 represents carbon tetrachloride, and Ruphos represents 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl.

[0266] The present invention will now be further described with reference to examples to clarify the present invention, but the scope of the present invention is not limited to these examples. All reagents used in the present application are commercially available products and can be used without purification. DETAILED DESCRIPTION OF THE INVENTION

[0267] Example 1: Synthesis of Intermediate 1 [ka] [ka] Step 1: Preparation of intermediate 1b At 10°C, 1a (81 g), 2,4-dimethoxybenzenemethanamine (83 g), and acetic acid (500 mL) were added to a reaction flask in this order, and the temperature was raised to 80°C to carry out the reaction. Completion of the reaction was confirmed. Water (800 mL) was added to the reaction solution, which was then subjected to suction filtration. The cake was washed with water and dried to obtain intermediate 1b (95.78 g). MS(ESI, [MH] - ) m / z: 312.02 1 H NMR(500MHz,DMSO-d6)δ 11.03(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).

[0268] Step 2: Preparation of intermediate 1c At 10° C., a 2.5 M solution of lithium aluminum hydride in tetrahydrofuran (227 mL) was slowly added dropwise to a solution of 1b (96.00 g) in tetrahydrofuran (1000 mL), and the mixture was allowed to react at 80° C. A 15% aqueous solution of sodium hydroxide (30.5 g) and water (100 mL) were added to the reaction mixture, which was then suction filtered. The cake was washed with a dichloromethane:MeOH=1:1 solution, the filtrate was concentrated, and the crude product was purified by silica gel column chromatography to obtain intermediate 1c (55.87 g). MS (ESI, [M+H] + ) m / z: 286.01 1 H NMR(500MHz,DMSO-d6)δ 9.28(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).

[0269] Step 3: Preparation of intermediate 1d 1c (48.00 g), methanol (350 mL), palladium(II) hydroxide (4.8 g), and di-tert-butyl dicarbonate (41.4 g) were added to a reaction flask in this order, and the mixture was reacted under hydrogen protection at 25° C. The reaction mixture was suction filtered, and the filtrate was concentrated. Water (200 mL) and ethyl acetate were added for extraction, and the mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography to obtain intermediate 1d (34.43 g). 1 H NMR(500MHz,DMSO-d6)δ 7.07(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).

[0270] Step 4: Preparation of intermediate 1e 1d (35.00 g), methanol (250 mL), and 4 M hydrochloric acid in 1,4-dioxane (123 mL) were added to a reaction flask in this order, and the mixture was allowed to react at 25°C for 3 hours. The reaction mixture was concentrated, and pyridine (200 mL) and trifluoroacetic anhydride (25.20 g) were added. The mixture was stirred at 25°C for 40 hours. The reaction mixture was poured into 3 M aqueous hydrochloric acid, stirred vigorously, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give intermediate 1e (32.48 g). MS(ESI, [MH] - ) m / z: 229.99 1 H NMR(500MHz,DMSO-d6)δ 9.82(d,J=24.4Hz,1H),7.16(td,J=7.7,3.7Hz,1H),6.81(dd,J=11.5,7.5Hz,1 H),6.74(d,J=8.0Hz,1H),4.99(s,1H),4.89(s,1H),4.80(s,1H),4.70(s,1H).

[0271] Step 5: Preparation of intermediate 1f 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 a reaction flask in this order, and the mixture was allowed to react at 25° C. After the reaction was completed, the reaction solution was poured into water and vigorously stirred. Dichloromethane was added for extraction, and the mixture was 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). 1 H NMR(500MHz,DMSO-d6)δ 7.41(td,J=7.8,2.3Hz,1H),7.30(t,J=8.5Hz,1H),7.12(dd,J=7.9,2.9Hz,1 H),5.09(s,1H),4.90(d,J=12.3Hz,2H),4.72(s,1H),2.31(d,J=3.4Hz,3H).

[0272] Step 6: Preparation of intermediate 1g 1f (30.00 g), aluminum(III) chloride (29.30 g), and o-dichlorobenzene (200 mL) were added to a reaction flask in this order and reacted at 150°C for 1 hour. The reaction solution was poured into an aqueous citric acid solution, vigorously stirred, extracted with ethyl acetate, 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 1g (18.19 g). 1 H NMR(500MHz,DMSO-d6)δ 12.38(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).

[0273] Step 7: Preparation of intermediate 1h 1g (18.19 g), sodium hydroxide (7.56 g), methanol (150 mL), and water (150 mL) were added to a reaction flask in this order and reacted at 25° C. The reaction solution was concentrated to remove the methanol, and 1,4-dioxane (150 mL) and di-tert-butyl dicarbonate (15.14 g) were added to the residue and stirred at 25° C. Upon completion of the reaction, 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. The crude product was separated by silica gel column chromatography to obtain intermediate 1h (14.10 g). MS(ESI, [MH] - ) m / z: 276.07 1 H NMR(500MHz,DMSO-d6)δ 12.36(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).

[0274] Step 8: Preparation of intermediate 1i 1h (14.10 g), diethyl carbonate (27.00 g), and toluene (200 mL) were added to a reaction flask in this order, and the temperature was lowered to 0°C. 60 wt% sodium hydride (9.16 g) was added, and the temperature was then raised to 120°C and the mixture was stirred. Upon completion of the reaction, the reaction mixture was poured into a 3M aqueous hydrochloric acid solution, vigorously stirred, and extracted with ethyl acetate. The mixture was 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 1i (14.96 g). 1H NMR(500MHz,DMSO-d6)δ 11.72(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(d t,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).

[0275] Step 9: Preparation of intermediate 1j A reaction flask was charged with 1i (14.96 g), 50% aqueous hydroxylamine solution (6.36 g), and ethanol (150 mL) in this order, and the mixture was allowed to react for 3 hours with stirring at 85° C. The reaction mixture was concentrated, and then water and ethyl acetate were added. The mixture was extracted and separated into layers. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give a crude product of intermediate 1j (10.13 g). MS(ESI, [MH] - ) m / z: 317.20 1 H NMR(500MHz,DMSO-d6)δ 12.59(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).

[0276] Step 10: Preparation of intermediate 1k 1j (10.13 g), potassium carbonate (12.55 g), N,N-dimethylacetamide (150 mL), and ethyl iodide (7.08 g) were added to a reaction flask in this order, and the mixture was stirred at 80° C. for 1 hour. The reaction mixture was poured into water, stirred vigorously, extracted with ethyl acetate, 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). MS (ESI, [M+H] + ) m / z: 347.16 1 H NMR(500MHz,DMSO-d6)δ 7.78(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,2 H),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).

[0277] Step 11: Preparation of intermediate 1l 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), and then a 1 M solution of potassium tert-butoxide in tetrahydrofuran (18.63 mL) was added dropwise. The mixture was stirred at 0°C for 3 hours. The reaction mixture was poured into an aqueous ammonium chloride solution and stirred vigorously. 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 1l (7.52 g). MS (ESI, [M+H] + ) m / z: 372.02 1 H NMR(500MHz,DMSO-d6)δ 11.11(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).

[0278] Step 12: Preparation of Intermediate 1 1 L (1.00 g), 4 M hydrochloric acid in 1,4-dioxane (10 mL), and ethyl acetate (50 mL) were added to a reaction flask in this order, and the reaction was carried out at 25°C for 8 hours. The reaction solution was directly filtered, and the cake was washed with ethyl acetate and then dried to obtain intermediate 1 (0.83 g). MS (ESI, [M+H] + ) m / z: 272.11 1 H NMR(500MHz,DMSO-d6)δ 11.13(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(d dd,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).

[0279] Example 2: Synthesis of Intermediate 2 [ka] [ka] Step 1: Preparation of intermediate 2b 2a (18 g), AIBN (0.738 g), carbon tetrachloride (500 mL), and NBS (47.8 g) were added to a reaction flask in this order, and the temperature was raised to 60 °C to allow the reaction to proceed. When the reaction mixture cooled to room temperature, the solvent was removed by distillation under reduced pressure, and 200 mL of dichloromethane was added to the residue. After washing with saturated brine, the mixture was dried over anhydrous sodium sulfate and filtered. The solvent was removed from the filtrate by distillation under reduced pressure, and the mixture was purified by silica gel column chromatography to obtain intermediate 2b (18.7 g).

[0280] Step 2: Preparation of intermediate 2c 2b (18.7 g), benzylamine (1.78 mL), N,N-diisopropylethylamine (7.13 mL), and toluene (50 mL) were added to a reaction flask in this order, and the temperature was raised to 50 °C. After the reaction was completed, 200 mL of ethyl acetate and 200 mL of 1 M HCl-ice water solution were added to the reaction mixture, and the aqueous phase was collected. The pH was adjusted to approximately 8 with solid sodium bicarbonate, and ethyl acetate was added for extraction. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure to obtain intermediate 2c (9.6 g). MS (ESI, [M+H] + ) m / z: 240.1

[0281] Step 3: Preparation of intermediate 2d A reaction flask was charged with 2c (9.6 g), methanol (200 mL), 10% palladium on carbon (5 g), and toluene (50 mL) in this order, and the mixture was reacted under a hydrogen atmosphere at room temperature. The palladium on carbon was filtered, the cake was washed with methanol, and the filtrate was collected and the solvent was removed by distillation under reduced pressure to give 2d (4.5 g). MS (ESI, [M+H] + ) m / z: 149.9

[0282] Step 4: Preparation of intermediate 2e 2d (4 g), tetrahydrofuran (50 mL), and trifluoroacetic anhydride (5.63 g) were added to a reaction flask in this order and reacted at room temperature. 200 mL of aqueous solution was added to the reaction mixture 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 give 2e (4.58 g). 1 H NMR(500MHz,DMSO-d6)δ 7.29(t,J=9.3Hz,1H),6.98(d,J=8.6Hz,1H),6.93-6.86(m,1H),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).

[0283] Step 5: Preparation of intermediate 2f 2e (4.6 g), dichloromethane (200 mL), and boron tribromide (1 M, 18.76 mL) were added to a reaction flask in this order and reacted at room temperature. 200 mL of aqueous solution was added to the reaction mixture in an ice bath to quench the reaction. 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 removed by distillation under reduced pressure to obtain 2f (4.2 g). 1 H NMR(500MHz,DMSO-d6)δ 7.16(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).

[0284] Step 6: Preparation of intermediate 2g 2f (6.5 g), dichloromethane (60 mL), triethylamine (7.8 mL), and acetic anhydride (2.94 mL) were added to a reaction flask in this order and allowed to react at room temperature. 200 mL of organic solvent dichloromethane 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 solvent was removed by distillation under reduced pressure to obtain 2f (7 g). 1 H NMR(500MHz,DMSO-d6)δ 7.42(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).

[0285] Step 7: Preparation of intermediate 2h To the reaction flask, 2g (6g) and aluminum(III) chloride (4.39g) were added in that order, and the mixture was gradually heated from room temperature to 150°C to react. When the reaction mixture cooled to room temperature, 500mL of water and 100mL of 3M aqueous hydrochloric acid were added to the residue. The organic phase was separated, washed with 100mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The filtrate was purified by silica gel column chromatography to give 2h (3.78g). MS(ESI, [MH] - ) m / z: 271.9

[0286] Step 7: Preparation of intermediate 2j 2h (550 mg), MeOH (5.00 mL), and an aqueous solution (5.00 mL) of sodium hydroxide (242 mg) were added to a reaction flask in this order and reacted at room temperature. The reaction mixture was concentrated to remove the methanol, and the aqueous phase was retained to obtain 2i. 1,4-Dioxane (5 mL) and Boc anhydride (439 mg, 0.462 mL) were added to the mixture and reacted at room temperature. The reaction mixture 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 then concentrated to obtain 2j (200 mg). 1 H NMR(500MHz,DMSO-d6)δ 12.11(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).

[0287] Step 8: Preparation of intermediate 2k 2j (3.5 g) and THF (300 mL) were added to a reaction flask in this order, followed by diethyl carbonate (14.91 g, 15.29 mL). The temperature was cooled to around 0 °C, and 60 wt% sodium hydride (5.05 g, 126 mmol) was added in several portions. The reaction system was heated to 85 °C and reacted. After the reaction mixture cooled to room temperature, it was slowly poured into 500 mL of ice water and extracted with ethyl acetate. The organic phase was discarded. The pH of the aqueous phase was adjusted to 1-2 with 3 M hydrochloric acid, followed by extraction with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure to obtain 2k (7.0 g). MS(ESI, [MH] - ) m / z: 348.3

[0288] Step 9: Preparation of intermediate 2l 2k (4.4 g), aqueous hydroxylamine (4.16 g, 63.0 mmol), and ethanol (50 mL) were added to a reaction flask in this order and reacted at 85°C. When the reaction mixture cooled to room temperature, the residue was extracted with 200 mL of ethyl acetate and 100 mL of saturated aqueous sodium carbonate, and the organic phase was discarded. The aqueous phase was adjusted to pH 2-3 with 1 M aqueous HCl, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the solvent removed by vacuum distillation to obtain 2l (3.25 g). 1 H NMR(500MHz,DMSO-d6)δ 12.83(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).

[0289] Step 10: Preparation of intermediate 2m 2L (3.14 g), potassium carbonate (1.500 g), DMA (5 mL), and ethyl iodide (2.308 g, 1.183 mL) were added to a reaction flask in this order, and the mixture was heated to 80 °C to react. After the reaction mixture cooled to room temperature, it was 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 removed from the filtrate by distillation under reduced pressure to give 2m (2.47 g). 1 H NMR(500MHz,DMSO-d6)δ 7.73(d,J=15.9Hz,1H),7.69(d,J=3.5Hz,1H),4.69(dd,J=23.8,12.4Hz,4H),4.19-4.11(m,4H),1.47(s,9H),1.20(t,J=7.1Hz,3H).

[0290] Step 11: Preparation of intermediate 2n 2m (1.5 g) and THF (75 mL) were added to a reaction flask in this order, followed by the addition of acrylamide (0.215 g). The temperature was lowered to around -15°C, and a 1 M solution of potassium tert-butoxide in tetrahydrofuran (2.60 mL) was added. The system temperature was raised to 0°C and the reaction was carried out for 1.5 hours. The mixture was quenched by adding dropwise 200 mL of ammonium chloride solution, 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 give 2n (0.88 g). 1 H NMR(500MHz,DMSO-d6)δ 11.11(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).

[0291] Step 12: Preparation of Intermediate 2 2n (0.428 g) and dichloromethane (10.00 mL) were added to a reaction flask in this order, followed by trifluoroacetic acid (3.29 g, 2.211 mL), and the mixture was allowed to react at room temperature for 1 hour. 80 mL of water was added to the reaction mixture, the pH was adjusted to 7-8 with saturated sodium bicarbonate, and dichloromethane was added for extraction. 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). MS (ESI, [M+H] + ) m / z: 272.24 1 H NMR(500MHz,DMSO-d6)δ 7.81-7.77(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).

[0292] Example 3: Synthesis of Intermediate 3 [ka] [ka] Step 1: Preparation of intermediate 3b Intermediate 3a (25 g) was purified in methanol (1000 mL) and acetic acid (103 g, 99 mL, 1722 mmol) and then loaded into a continuous hydrogenation reactor at a pressure of 3 MPa, a temperature of 110 °C, and a flow rate of 3 mL / min. Upon completion of the reaction, the solvent was removed from the reaction mixture by distillation under reduced pressure. To the residue was added a solution of hydrochloric acid in 1,4-dioxane (4 mol / L, 100 mL). The solvent was then removed by distillation under reduced pressure. The residue was slurried with ethyl acetate, filtered, and the cake was collected to give intermediate 3b (28.97 g). MS (ESI, [M+H] + ) m / z: 150.0 1H NMR(500MHz,DMSO-d6)δ 10.01(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).

[0293] Step 2: Preparation of intermediate 3c Intermediate 3b (28.97 g) and tetrahydrofuran (300 mL) were added to a reaction flask in this order, and trifluoroacetic anhydride (27.0 mL) was added in an ice bath. The mixture was allowed to react at room temperature. Upon completion of the reaction, the reaction mixture 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 removed by distillation under reduced pressure. The cake was collected and filtered to give the target intermediate 3c (22.67 g). MS(ESI, [MH] - ) m / z: 244.0 1 H NMR(500MHz,DMSO-d6)δ 7.03(q,J=7.9Hz,1H),6.74-6.68(m,1H),6.64(t,J=6.9Hz,1H),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).

[0294] Step 3: Preparation of intermediate 3d Intermediate 3c (22.67 g), dichloromethane (200 mL), triethylamine (28.1 g, 38.6 mL), and DMAP (0.282 g) were added to a reaction flask in this order. Acetic anhydride (10.38 g, 9.68 mL) was added in an ice bath, and the mixture was allowed to warm to room temperature. Upon completion of the reaction, the solvent was removed from the reaction mixture by vacuum distillation. 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, respectively, dried over anhydrous sodium sulfate, and filtered. The solvent was removed from the filtrate by vacuum distillation to yield intermediate 3d (21.94 g). 1 H NMR(500MHz,DMSO-d6)δ 7.30(dt,J=11.1,7.8Hz,1H),7.18-7.11(m,1H),7.05(dt,J=8.0,2.2Hz,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).

[0295] Step 4: Preparation of intermediate 3e Intermediate 3d (21 g) and aluminum(III) chloride (14.62 g) were added to a reaction flask in this order, and the mixture was heated to 170 °C under N2 protection. When the reaction was complete and the reaction mixture cooled to room temperature, 300 mL of water was added to quench the reaction, and dichloromethane was added for extraction. The organic phases were combined, washed with 500 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified using a silica gel column to obtain the target intermediate 3e (10.16 g). MS(ESI, [MH] - ) m / z: 286.0 1 H NMR(500MHz,DMSO-d6)δ 12.76(d,J=8.4Hz,1H),7.83(t,J=8.8Hz,1H),6.86(dd,J=8.3,5.7Hz,1H),4.67(d,J =25.1Hz,2H),3.86-3.78(m,2H),2.94(dt,J=13.3,5.9Hz,2H),2.64(d,J=1.2Hz,3H).

[0296] Step 5: Preparation of intermediate 3f Intermediate 3e (10.16 g) and methanol (100 mL) were added to a reaction flask in this order, and a solution of sodium hydroxide (4.24 g) in water (100 mL) was added dropwise in an ice bath. The mixture was allowed to warm to room temperature and react. Upon completion of the reaction, methanol was removed from the reaction mixture by distillation under reduced pressure. 1,4-dioxane (100 mL) and di-tert-butyl dicarbonate (8.49 g, 9.03 mL) were added, and the mixture was allowed to react at room temperature. Upon completion of the reaction, the reaction mixture was extracted with 500 mL of ethyl acetate and 800 mL of water, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate by distillation under reduced pressure to obtain the desired intermediate 3f (8.96 g). MS (ESI, [M+H] + ) m / z: 292.0 1 H NMR(500MHz,DMSO-d6)δ 12.72(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).

[0297] Step 6: Preparation of intermediate 3g Intermediate 3f (8.76 g), diethyl carbonate (17.76 g, 18.21 mL), and toluene (90 mL) were added to a reaction flask in this order. 60 wt% sodium hydride (6.01 g) was added in several portions in an ice bath, and the mixture was heated to 120 °C. Upon completion of the reaction and cooling to room temperature, the reaction mixture was poured into ice water to quench the reaction. 1 M hydrochloric acid solution was added to adjust the pH to 1-2, and 300 mL of ethyl acetate was added for extraction. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate by distillation under reduced pressure to obtain the target intermediate 3f (12.03 g).

[0298] Step 7: Preparation of intermediate 3h Intermediate 3g (9.54 g), EtOH (100 mL), and aqueous hydroxylamine (9.93 g, 9.21 mL) were added to a reaction flask in this order, and the mixture was heated to 85 °C. Upon completion of the reaction, 200 mL of saturated sodium carbonate solution was added to the reaction mixture to adjust the pH to 9-10. Ethyl acetate was added for extraction. The organic phase was separated and extracted twice with water. The aqueous phases were combined, and the pH of the aqueous phase was adjusted to 3 with 1 M hydrochloric acid. 200 mL of ethyl acetate was added for extraction. The mixture was dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate by vacuum distillation to yield the desired intermediate 3h (9.01 g). MS(ESI, [MH] - ) m / z: 331.0

[0299] Step 8: Preparation of intermediate 3i Intermediate 3h (9.01 g), potassium carbonate (11.24 g), DMA (90 mL), and ethyl iodide (5.07 g, 2.63 mL) were added to a reaction flask in this order, and the mixture was heated to 80 °C under N2 protection. Upon completion of the reaction and cooling to room temperature, 200 mL of ethyl acetate and 1000 mL of water were added for extraction. The organic phase was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was purified using a silica gel column to obtain the target intermediate 3i (7.33 g). MS (ESI, [M+H] + ) m / z: 361.0 1 H NMR(500MHz,DMSO-d6)δ 7.63(d,J=8.1Hz,1H),7.21(d,J=8.2Hz,1H),4.76(s,2H),4.18(s,2H),4.13(q,J=7.1H) z,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).

[0300] Step 9: Preparation of intermediate 3j Intermediate 3i (7.3 g), tetrahydrofuran (80 mL), and acrylamide (0.864 g) were added to a reaction flask in this order, and under N2 protection, the temperature was lowered to -15 °C, and a solution of potassium tert-butoxide in tetrahydrofuran (1 mol / L, 11.14 mL) was added dropwise. Upon completion of the reaction, the temperature was raised to 0 °C. Upon completion of the reaction, the resulting reaction mixture was added to 200 mL of saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified using a silica gel column to obtain the target intermediate 3j (4.54 g). MS(ESI, [MH] - ) m / z: 384.3 1 H NMR(500MHz,DMSO-d6)δ 11.09(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=17.3,12.1,5.3Hz,1H),2.61(dt,J=17.3,4.1Hz,1H),2.54(d,J=4.5Hz,1H),2.18(dtd,J=13.5,5.2,3.6Hz,1H),1.45(s,9H).

[0301] Step 10: Preparation of Intermediate 3 Intermediate 3j (300 mg) and ethyl acetate (5 mL) were added to a reaction flask in this order, followed by a solution of hydrochloric acid in 1,4-dioxane (4 mol / L, 3.89 mL), and the mixture was allowed to react at room temperature. Upon completion of the reaction, the reaction mixture was concentrated to give Intermediate 3 (235 mg). MS (ESI, [M+H] + ) m / z: 286.10 1H NMR(500MHz,DMSO-d6)δ 11.08(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).

[0302] Example 4: Synthesis of Intermediate 4 [ka] [ka] Step 1: Preparation of intermediate 4b Intermediate 4a was purified in methanol (1680 mL) and acetic acid (166 mL) and then loaded into a continuous hydrogenation reactor at a pressure of 3 MPa, a temperature of 110 °C, and a flow rate of 3 mL / min. Upon completion of the reaction, the solvent was removed from the reaction mixture by distillation under reduced pressure. To the residue was added a solution of hydrochloric acid in 1,4-dioxane (4 mol / L, 200 mL). The solvent was then removed by distillation under reduced pressure. The residue was slurried in 100 mL of ethyl acetate, filtered, and the cake was collected to give intermediate 4b (46.96 g). MS (ESI, [M+H] + ) m / z: 150.0 1 H NMR(500MHz,DMSO-d6)δ 9.81(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).

[0303] Step 2: Preparation of intermediate 4c Intermediate 4b (40 g) and tetrahydrofuran (400 mL) were added to a reaction flask in this order, and trifluoroacetic anhydride (61.9 g, 41.0 mL) was added in an ice bath and the reaction was allowed to proceed at room temperature. Upon completion of the reaction, the reaction mixture 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 solvent was removed from the filtrate by distillation under reduced pressure to obtain the target intermediate 4c (81 g). MS(ESI, [MH] - ) m / z: 244.04

[0304] Step 3: Preparation of intermediate 4d Intermediate 4c (65.3 g), dichloromethane (650 mL), triethylamine (81 g, 111 mL), and DMAP (0.813 g) were added to a reaction flask in this order, and acetic anhydride (29.9 g, 27.9 mL) was added in an ice bath. The reaction was allowed to proceed at room temperature. Upon completion of the reaction, the solvent was removed from the reaction mixture by distillation 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, respectively, dried over anhydrous sodium sulfate, and filtered. The solvent was removed from the filtrate by distillation under reduced pressure to obtain intermediate 4d (55.6 g). 1 H NMR(500MHz,chloroform-d)δ 7.28(d,J=7.9Hz,1H),7.10-7.02(m,1H),7.02-6.95(m,1H),4.79(d,J=2 7.0Hz,2H),3.92-3.78(m,2H),2.82-2.72(m,2H),2.33(d,J=2.0Hz,3H).

[0305] Step 4: Preparation of intermediate 4e Intermediate 4d (30.73 g) and aluminum(III) chloride (21.40 g) were added to a reaction flask in this order, and the mixture was heated to 170 °C under N2 protection and reacted for 1 hour. After the reaction was completed and the reaction mixture was cooled to room temperature, 300 mL of water was added to quench the reaction, followed by extraction with dichloromethane. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified using a silica gel column to obtain the target intermediate 4e (16.21 g). MS(ESI, [MH] - ) m / z: 286.0 1 H NMR(500MHz,DMSO-d6)δ 12.74(d,J=11.3Hz,1H),7.82(d,J=8.3Hz,1H),6.91(dd,J=14.9,8.3Hz,1H),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).

[0306] Step 5: Preparation of intermediate 4f Intermediate 4e (15.7 g) and methanol (160 mL) were added to a reaction flask in this order, and a solution of sodium hydroxide (6.56 g) in water (160 mL) was added dropwise in an ice bath. The mixture was allowed to warm to room temperature and react. Upon completion of the reaction, methanol was removed from the reaction mixture by distillation under reduced pressure. 1,4-dioxane (160 mL) and di-tert-butyl dicarbonate (13.12 g, 13.96 mL) were added, and the mixture was allowed to react at room temperature for 1 hour. Upon completion of the reaction, the reaction mixture 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 solvent was removed from the filtrate by distillation under reduced pressure to yield the desired intermediate 4f (19.83 g). MS (ESI, [M+H] + ) m / z: 292.5 1 H NMR(500MHz,DMSO-d6)δ 12.76(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).

[0307] Step 6: Preparation of intermediate 4g Intermediate 4f (15.92 g), diethyl carbonate (32.3 g, 33.1 mL), and toluene (200 mL) were added to a reaction flask in this order. 60 wt% sodium hydride (10.93 g) was added in portions in an ice bath, and the mixture was heated to 120 °C. Upon completion of the reaction and cooling to room temperature, the reaction was 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 phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate by vacuum distillation. The residue was slurried in 100 mL of petroleum ether, filtered, and the cake was collected to obtain the target intermediate 4f (12 g). 1 H NMR(500MHz,DMSO-d6)δ 12.46(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).

[0308] Step 7: Preparation of intermediate 4h Intermediate 4g (12 g), ethanol (120 mL), and aqueous hydroxylamine solution (12.49 g, 11.59 mL) were added to a reaction flask in this order, and the mixture was heated to 85 °C to react. Upon completion of the reaction, 200 mL of saturated sodium bicarbonate solution was added to the reaction mixture, followed by extraction with 100 mL of ethyl acetate. The organic phase was separated, and the aqueous phase was adjusted to pH 3 with 1 M hydrochloric acid. 200 mL of ethyl acetate was added. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate by distillation under reduced pressure to obtain the desired intermediate 4h (10.44 g). MS(ESI, [MH] - ) m / z: 331.0 1H NMR(500MHz,DMSO-d6)δ 12.85(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).

[0309] Step 8: Preparation of intermediate 4i Intermediate 4h (10.44 g), potassium carbonate (13.02 g), DMA (110 mL), and ethyl iodide (5.88 g, 3.05 mL) were added to a reaction flask in this order, and the mixture was heated to 80 °C under N2 protection. Upon completion of the reaction and cooling to room temperature, 200 mL of ethyl acetate and 1000 mL of water were added for extraction. The organic phase was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was purified using a silica gel column to obtain the target intermediate 4i (8.31 g). MS (ESI, [M+H] + ) m / z: 361.2

[0310] Step 9: Preparation of intermediate 4j Intermediate 4i (5.5 g), tetrahydrofuran (50 mL), and acrylamide (0.759 g) were added to a reaction flask in this order, and under N2 protection, the temperature was lowered to -15 °C, and a solution of potassium tert-butoxide in tetrahydrofuran (1 mol / L, 9.92 mL) was added dropwise. Upon completion of the reaction, the temperature was raised to 0 °C. Upon completion of the reaction, the resulting reaction mixture was added to 200 mL of saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified using a silica gel column to obtain the target intermediate 4j (2.81 g). MS(ESI, [MH] - ) m / z: 384.34 1H NMR(500MHz,DMSO-d6)δ 11.09(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).

[0311] Step 10: Preparation of Intermediate 4 Intermediate 4j (850 mg) and ethyl acetate (20 mL) were added to a reaction flask in this order, followed by a solution of hydrochloric acid in 1,4-dioxane (4 mol / L, 11.03 mL). The mixture was allowed to react at room temperature. Upon completion of the reaction, the reaction mixture was concentrated to give Intermediate 4 (760 mg). MS (ESI, [M+H] + ) m / z: 286.12 1 H NMR(500MHz,DMSO-d6)δ 11.08(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,2H),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).

[0312] Example 5: Synthesis of Intermediate 5 [ka] [ka] Step 1: Preparation of intermediate 5b Bromine (55.5 g) was added dropwise to a solution of 5a (50 g) in acetic acid (180 mL) at 15° C., and upon completion, the mixture was transferred to room temperature and allowed to react for 1 hour. tert-Butyl methyl ether (800 mL) was added dropwise to the reaction mixture, which was then filtered. The cake was collected and dried to give intermediate 5b (95 g). MS (ESI, [M+H] + ) m / z: 230.1

[0313] Step 2: Preparation of intermediate 5c A reaction flask was charged with 5b (80 g), 2,2-dimethoxyethanal (66.9 g), triethylamine (27.3 g), anhydrous sodium sulfate (80 g), and methanol (600 mL), in that order, and the mixture was allowed to react at room temperature overnight. The temperature of the reaction mixture was lowered to -15 °C, and sodium borohydride (14.6 g) was added in several portions. Upon completion, the mixture was allowed to react at room temperature. The reaction mixture 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 purified by silica gel column chromatography to obtain intermediate 5c (60 g). MS (ESI, [M+H] + ) m / z: 318.1

[0314] Step 3: Preparation of intermediate 5d At 0°C under nitrogen protection, 5c (47 g) was added dropwise to trifluoroacetic anhydride (148 g), and upon completion, the mixture was transferred to room temperature and allowed to react. Trifluoroacetic acid (87 g) was added dropwise, and the temperature was raised to 40°C and the reaction was allowed to proceed. Triethylsilane (68 g) was added dropwise, and the temperature was raised to 60°C and the reaction was allowed to proceed. 400 mL of ethyl acetate and 600 mL 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 (20.5 g). 1H NMR(500MHz,DMSO-d6)δ 7.46(dd,J=8.9,1.7Hz,1H),6.87(d,J=8.9Hz,1H),3.77(d,J=2.8Hz,3H),3.67(dd t,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).

[0315] Step 4: Preparation of intermediate 5e At 0°C under nitrogen protection, a solution of boron tribromide in dichloromethane (146 mL, 1 M) was slowly added dropwise to a stirred solution of 5d (20.5 g) in dichloromethane (200 mL), and the mixture was allowed to warm to room temperature. Upon completion of the reaction, the reaction mixture was slowly poured into 400 mL of ice water, stirred, filtered, and the cake was collected and dried to give 5e (18.5 g). MS(ESI, [MH] - ) m / z: 336.1 1 H NMR(500MHz,DMSO-d6)δ 9.74(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).

[0316] Step 5: Preparation of intermediate 5f Acetic anhydride (5.65 g) was slowly added dropwise to a stirred solution of 5e (17.0 g) and triethylamine (7.63 g) in dichloromethane (200 mL) under nitrogen protection at 0°C, and the mixture was allowed to warm to room temperature. Upon completion of the reaction, the reaction mixture was slowly poured into 200 mL of water, and the organic layer was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give 5f (19.8 g). MS (ESI, [M+H] + ) m / z: 380.1

[0317] Step 6: Preparation of intermediate 5g 5f (19.5 g), aluminum(III) chloride (18.7 g), and o-dichlorobenzene (80 mL) were added to a reaction flask in this order, and the temperature was raised to 150 °C to carry out the reaction. After the reaction was completed and the temperature of the reaction solution had dropped to room temperature, 250 mL of 3N dilute hydrochloric acid and ethyl acetate were added for extraction. 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). MS(ESI, [MH] - ) m / z: 300.0 1 H NMR(500MHz,DMSO-d6)δ 12.83(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).

[0318] Step 7: Preparation of intermediate 5h A reaction flask was charged with 5g (9.5g), methanol (100mL), water (20mL), and sodium hydroxide (1.9g) in this order, and the reaction was allowed to proceed at room temperature. Next, di-tert-butyl dicarbonate (8.2g) was added, and upon completion of the reaction, 200mL of ethyl acetate and 400mL 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 purified by silica gel column chromatography to obtain intermediate 5h (8.5g). 1 H NMR(500MHz,DMSO-d6)δ 12.80(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).

[0319] Step 8: Preparation of intermediate 5i 5h (8.5 g), diethyl carbonate (16.4 g), and toluene (100 mL) were added to a reaction flask in this order, and 60 wt% sodium hydride (5.57 g) was added in several portions. The temperature of the reaction solution was raised to 115 °C and the reaction was continued. Upon completion of the reaction, the reaction solution was cooled to room temperature, and 200 mL of ethyl acetate and 300 mL of water were added to the reaction solution. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the concentrate was purified by silica gel column chromatography to obtain intermediate 5i (9.0 g). MS(ESI, [MH] - ) m / z: 330.1

[0320] Step 9: Preparation of intermediate 5j 5i (9.0 g), aqueous hydroxylamine solution (8.7 g), and ethanol (100 mL) were added to a reaction flask in this order, and the temperature of the reaction solution was raised to 80 °C. Upon completion of the reaction, the reaction solution was cooled to room temperature, and 200 mL of ethyl acetate and 300 mL of water were added to the reaction solution. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the concentrate was purified by silica gel column chromatography to obtain intermediate 5j (8.5 g). MS(ESI, [MH] - ) m / z: 345.4 1 H NMR(500MHz,DMSO-d6)δ 7.53(d,J=8.0Hz,1H),7.12(d,J=8.0Hz,1H),3.73(q,J=13.9,11.5Hz,2H),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).

[0321] Step 10: Preparation of intermediate 5k 5j (8.5 g), potassium carbonate (3.3 g), ethyl iodide (5.1 g), and DMA (70 mL) were added to a reaction flask in this order, and the temperature of the reaction solution was raised to 80 °C to carry out the reaction. The reaction solution was cooled to room temperature, and 200 mL of ethyl acetate and 300 mL of water were added to the reaction solution. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the concentrate was purified by silica gel column chromatography to obtain intermediate 5k (6.5 g). MS(ESI, [MH] - ) m / z: 373.1 1 H NMR(500MHz,DMSO-d6)δ 7.56(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).

[0322] Step 11: Preparation of intermediate 5l At -10°C under nitrogen protection, a solution of sodium tert-butoxide in tetrahydrofuran (14 mL, 1 M) was slowly added dropwise to a stirred solution of 5k (5.6 g) in tetrahydrofuran (70 mL). Upon completion, the mixture was allowed to react for 30 minutes while maintaining the temperature. A weight amount of acrylamide (0.71 g) was dissolved in 5 mL of tetrahydrofuran and added dropwise to the reaction mixture. The mixture was allowed to react for 2 hours while maintaining the temperature. The reaction mixture was slowly poured into 200 mL of saturated ammonium chloride solution, and 200 mL of ethyl acetate was added. The organic layer was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the concentrate was purified by silica gel column chromatography to obtain intermediate 5l (2.5 g). MS(ESI, [MH] - ) m / z: 397.9 1H NMR(500MHz,DMSO-d6)δ 11.08(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,1H),2.46(dd,J=12.2,4.4Hz,1H),2.20-2.12(m,1H),1.38(d,J=6.3Hz,9H).

[0323] Step 12: Preparation of Intermediate 5 5L (2.5 g), ethyl acetate (30 mL), and hydrochloric acid in 1,4-dioxane (15 mL, 4 M) were added to a reaction flask in this order and reacted at room temperature. After the reaction was completed, the mixture was filtered, and the cake was collected and dried to obtain intermediate 5 (18.5 g). MS (ESI, [M+H] + ) m / z: 300.2 1 H NMR(500MHz,DMSO-d6)δ 11.10(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).

[0324] Example 6: Synthesis of Intermediate 6 [ka] [ka] Step 1: Preparation of intermediate 6b Carbon tetrachloride (1500 mL), 6a (100 g), 2,2'-azobis(isobutyronitrile) (4.1 g), and N-bromosuccinimide (265 g) were added to a reaction flask in this order and heated to 80°C for reaction. Upon completion of the reaction, the mixture was filtered under suction, the mother liquor was concentrated to dryness, and the residue was slurried with petroleum ether, filtered under suction, and the cake was collected and dried to obtain intermediate 6b (154 g). 1 H NMR(500MHz,DMSO-d6)δ 7.36-7.33(m,1H),7.09-7.04(m,2H),4.78(s,2H),4.76(s,2H),3.87(s,3H).

[0325] Step 2: Preparation of intermediate 6c Isopropylidene malonate (150 g), DMSO (500 mL), triethylamine (255 mL), and Intermediate 6b (120 g) were added to a reaction flask in this order and reacted at room temperature. Upon completion of the reaction, the reaction mixture was poured into water, extracted with EA, washed with saturated aqueous citric acid, saturated aqueous sodium bicarbonate, and then 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 under suction, and the cake was collected and dried to give Intermediate 6c (45 g). 1 H NMR(500MHz,DMSO-d6)δ 7.21(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).

[0326] Step 3: Preparation of intermediate 6d At 0° C., under nitrogen protection, a solution of lithium aluminum hydride in tetrahydrofuran (1 M, 163 mL) was slowly added dropwise to a stirred solution of intermediate 6c (45 g) in THF (500 mL), limiting the temperature to below 5° C., and the mixture was reacted at 0° C. for 30 minutes, then warmed to room temperature. Upon completion of the reaction, the reaction was quenched by adding saturated ammonium chloride solution (200 mL), extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate 6d (40.5 g). 1 H NMR(500MHz,DMSO-d6)δ 7.07(t,J=7.8Hz,1H),6.74(d,J=7.4Hz,1H),6.70(d,J=8.1Hz,1H),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).

[0327] Step 4: Preparation of intermediate 6e At −20° C. under nitrogen protection, trifluoroacetic anhydride (122 g) was slowly added dropwise to a stirred solution of intermediate 6d (40.5 g) and DIPEA (76 g) in DCM (500 mL), and the mixture was stirred at −5° C. for 30 minutes, then warmed to room temperature, and the reaction was completed. Upon completion of the reaction, the reaction was quenched by adding 100 mL of water, extracted with DCM, washed with 10% aqueous citric acid, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to silica gel column chromatography to give intermediate 6e (64.2 g). 1 H NMR(500MHz,DMSO-d6)δ 7.20-7.16(m,1H),6.84-6.80(m,2H),4.25(s,4H),3.77(s,3H),2.87(s,2H),2.77(s,2H).

[0328] Step 5: Preparation of intermediate 6f Under nitrogen protection, intermediate 6e (63.4 g), benzylamine (11.51 g), DIPEA (41.6 g), and acetonitrile (500 mL) were added to a reaction flask in this order and allowed to react overnight at room temperature. Upon completion of the reaction, intermediate 6f (31.5 g) was obtained by silica gel column chromatography. 1H NMR(500MHz,DMSO-d6)δ 7.33-7.24(m,4H),7.24-7.18(m,1H),7.09(t,J=7.8Hz,1H),6.78(d,J=7.4Hz,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).

[0329] Step 6: Preparation of intermediate 6g At 0 °C, a solution of Intermediate 6f (25.2 g) in DCM (500 mL) was added with 4 M hydrochloric acid in 1,4-dioxane (79 mL). The mixture was allowed to react for 5 minutes, then concentrated to dryness under reduced pressure. DCM (500 mL) was added, the temperature was lowered to -78 °C, and boron tribromide in dichloromethane (1 M, 271 mL) was added dropwise. Upon completion, the mixture was allowed to warm to room temperature and react overnight. Upon completion, the reaction mixture was cooled in an ice bath, quenched with methanol, and the pH was adjusted to neutral with saturated sodium bicarbonate solution. The mixture was extracted with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give Intermediate 6g (29.6 g). MS (ESI, [M+H] + ) m / z: 266.1 1 H NMR(500MHz,DMSO-d6)δ 9.26(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).

[0330] Step 7: Preparation of intermediate 6h Intermediate 6g (29.60 g), palladium carbon (10%, 29.6 g), and MeOH (600 mL) were added to a reaction flask in this order, and the mixture was exchanged with hydrogen. After that, the mixture was reacted overnight at 40°C under hydrogen protection. When the reaction was completed, the mixture was filtered by suction and concentrated to obtain intermediate 6h (23.1 g). MS (ESI, [M+H] + ) m / z: 176.1

[0331] Step 8: Preparation of intermediate 6i At room temperature, intermediate 6h (23.5 g), THF (500 mL), and trifluoroacetic anhydride (28.4 g) were added to a reaction flask in this order and reacted at room temperature. Upon completion of the reaction, 200 mL of saturated sodium bicarbonate was added to quench the reaction, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to silica gel column chromatography to give intermediate 6i (25.92 g). MS(ESI, [MH] - ) m / z: 270.1

[0332] Step 9: Preparation of intermediate 6j Intermediate 6i (23.5 g), DCM (500 mL), triethylamine (17.53 g), DMAP (1.058 g), and acetic anhydride (9.73 g) were added to a reaction flask in this order at room temperature, and the mixture was allowed to react at room temperature. Upon completion of the reaction, the mixture was quenched by adding water, extracted with DCM, and the organic phase was collected, washed with 5% aqueous citric acid, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to give Intermediate 6j (18.58 g). 1 H NMR(500MHz,DMSO-d6)δ 7.20(t,J=7.7Hz,1H),7.16-7.10(m,1H),6.91(dd,J=8.0,0.9Hz,1H),4.4 3-4.31(m,2H),4.10-3.98(m,2H),3.25(s,2H),3.07(s,2H),2.28(s,3H).

[0333] Step 10: Preparation of intermediate 6k Intermediate 6j (18.4 g), aluminum(III) chloride (15.66 g), and o-dichlorobenzene (200 mL) were added to a reaction flask in this order, and the mixture was allowed to react while the temperature was gradually increased from 70°C to 150°C. After the reaction was completed and cooled to room temperature, 1000 mL of EA, 60 mL of 3 M hydrochloric acid, and 200 mL of water were added in this order to dissolve the mixture. The mixture was extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to silica gel column chromatography to obtain Intermediate 6k (15.11 g). MS(ESI, [MH] - ) m / z: 312.1 1 H NMR(500MHz,DMSO-d6)δ 12.35(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).

[0334] Step 11: Preparation of intermediate 6l At 0°C, a solution of intermediate 6k (15.11 g) in MeOH (150 mL) was added to 1M aqueous sodium hydroxide (97 mL) and the mixture was allowed to react at room temperature until completion. The methanol was concentrated to remove the aqueous phase, and dioxane (150 mL) and Boc anhydride (11.58 g) were added to the residue. The mixture was allowed to react at room temperature until completion. The pH was adjusted to 5-6 with 10% citric acid, extracted with EA, washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to silica gel column chromatography to give intermediate 6l (11.40 g). MS(ESI, [MH] - ) m / z: 316.1 1 H NMR(500MHz,DMSO-d6)δ 12.34(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).

[0335] Step 12: Preparation of intermediate 6m At 0°C, sodium hydride (60 wt%, 6.93 g) was added in portions to a mixture of toluene (200 mL) and THF (100 mL) containing intermediate 6l (11 g) and diethyl carbonate (20.47 g), and the temperature was raised to 100°C to complete the reaction. The reaction mixture was cooled to room temperature, quenched by adding water, extracted with EA, and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to silica gel column chromatography to obtain intermediate 6m (12.62 g). MS(ESI, [MH] - ) m / z: 388.2 1 H NMR(500MHz,DMSO-d6)δ 11.74(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).

[0336] Step 13: Preparation of intermediate 6n Intermediate 6m (12.5 g), hydroxylamine (5.30 g), and ethanol (200 mL) were added to a reaction flask in this order and reacted at 85 °C until the reaction was complete. After the reaction mixture cooled to room temperature, the solvent was removed by distillation 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 adjusted to approximately 4 with 1 M dilute hydrochloric acid, and the aqueous phase was extracted with EA. The organic phases were combined, washed with 200 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to yield Intermediate 6n (10.12 g). 1H NMR(500MHz,DMSO-d6)δ 12.86(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).

[0337] Step 14: Preparation of intermediate 6o Intermediate 6n (9.6 g), potassium carbonate (11.11 g), DMA (150 mL), and ethyl iodide (6.27 g) were added to a reaction flask in this order and reacted at 85° C. until the reaction was complete. After the reaction mixture cooled to room temperature, 600 mL of water and EA were added for extraction, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to silica gel column chromatography to obtain intermediate 6o (11.02 g). MS (ESI, [M+H] + ) m / z: 387.2

[0338] Step 15: Preparation of intermediate 6p At −5° C., under nitrogen protection, a solution of potassium tert-butoxide in tetrahydrofuran (1 M, 15.52 mL) was slowly added dropwise to a stirred solution of intermediate 6o (10 g) and acrylamide (1.104 g) in THF (300 mL). After 10 minutes, upon completion of the addition, the mixture was stirred at −5° C. to allow the reaction to proceed. 200 mL of saturated ammonium chloride solution was added to quench the reaction, followed by extraction with DCM twice, each time with 300 mL. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to silica gel column chromatography to give intermediate 6p (4.32 g). MS (ESI, [M+H] + ) m / z: 412.2 1H NMR(500MHz,DMSO-d6)δ 11.08(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),3.3 8(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).

[0339] Step 16: Preparation of Intermediate 6 A reaction flask was charged with 6p (50 mg), DCM (5.00 mL), and EA (5 mL) in this order, and the reaction mixture was clarified. Trifluoroacetic acid (1 mL) was added. The mixture was stirred at 25° C. overnight, and upon completion, the mixture was concentrated to dryness, dissolved in DMSO, purified by reverse phase chromatography, and lyophilized to give intermediate 6 (25 mg). MS (ESI, [M+H] + ) m / z: 312.2 1 H NMR(500MHz,DMSO-d6)δ 7.63(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).

[0340] Example 7: Synthesis of Intermediate 7 [ka] [ka] Step 1: Preparation of compound 7b 7a (33.3 g), MeOH (500 mL), iodobenzene diacetate (82 g, 246 mmol), and potassium hydroxide (127 g) were added to a reaction flask in an ice bath, in that order, and the mixture was allowed to react at room temperature for 3 hours. The solvent was removed from the reaction mixture by distillation 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 removed by distillation under reduced pressure. The residue was dissolved in THF (500 mL), and then hydrochloric acid (6 M, 68.4 mL) was added and the mixture was allowed to react at room temperature. Upon completion of the reaction, the pH of the reaction mixture was adjusted to 8 with saturated sodium bicarbonate solution, followed by extraction with ethyl acetate, drying over anhydrous sodium sulfate, concentration, and purification by silica gel column chromatography to give 7b (16 g). MS (ESI, [M+H] + ) m / z: 178.9

[0341] Step 2: Preparation of compound 7c 7b (80 g) and MeOH (1000 mL) were added to a reaction flask in this order, and after clarification, sodium borohydride (17.83 g, 471 mmol) was added and the reaction was allowed to proceed at room temperature. Upon completion of the reaction, the reaction mixture was quenched by adding 500 mL of saturated ammonium chloride solution dropwise, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and filtered. The solvent was then removed by distillation under reduced pressure to obtain 7c (82 g). 1 H NMR(500MHz,DMSO-d6)δ 7.17(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,1H),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).

[0342] Step 3: Preparation of compound 7d 7c (35 g), toluene (300 mL), and p-toluenesulfonic acid (66.9 g) were added to a reaction flask in this order, and the mixture was heated to 120°C to react. After the reaction was completed and the reaction solution cooled to room temperature, 200 mL of organic solvent ethyl acetate and 500 mL of water were added to quench the reaction, and the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure to obtain 7d (35.5 g). 1 H NMR(500MHz,DMSO-d6)δ 7.26-7.22(m,1H),6.93-6.87(m,2H),3.79(s,3H),3.53(s,2H),3.37(s,2H).

[0343] Step 4: Preparation of Compound 7e 7d (35 g), MeOH (400 mL), and sodium borohydride (5.83 g) were added to a reaction flask in this order and allowed to react at room temperature. Upon completion of the reaction, the reaction mixture was quenched by adding 500 mL of saturated ammonium chloride solution dropwise, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and filtered. The solvent was then removed by distillation under reduced pressure to give 7e (18 g). 1 H NMR(500MHz,DMSO-d6)δ 7.13-7.07(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).

[0344] Step 5: Preparation of compound 7f 7e (60 g), dichloromethane (500 mL), triethylamine (111 g, 152 mL), and acetic anhydride (41.0 g, 38.2 mL) were added to a reaction flask in this order and reacted at room temperature. Upon 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 give 7f (37.2 g). 1 H NMR(500MHz,DMSO-d6)δ 7.22-7.06(m,1H),6.82(dd,J=27.3,8.3Hz,2H),5.41(s,1H),3.78(d,J=13.2Hz,3H),3.3 2-3.20(m,1H),3.18-3.09(m,1H),2.85(dd,J=34.6,17.1Hz,2H),1.97(d,J=15.3Hz,3H).

[0345] Step 6: Preparation of Compound 7g In an ice bath, boron trichloride (19.22 g, 164 mL) was slowly added dropwise to a stirred solution of 7f (17 g) in dichloromethane (500 mL). Upon completion, the mixture was allowed to warm to room temperature and react. Upon completion, the reaction was quenched by adding 160 mL of 1 M HCl and 200 mL of aqueous solution, followed by extraction with dichloromethane. The organic phase was separated, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure to give 7f (15 g). MS(ESI, [MH] - ) m / z: 190.9

[0346] Step 7: Preparation of compound 7h 7g (16g), dichloromethane (200mL), triethylamine (9.50g, 13.01mL), and acetic anhydride (5.27g, 4.91mL) were added to a reaction flask in this order and reacted at room temperature. Upon completion of 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 give 7h (14.8g). MS(ESI, [MH] - ) m / z: 233.01

[0347] Step 8: Preparation of Compound 7i 7h (11.6 g), dichloromethane (300 mL), and zirconium(IV) tetrachloride (46.2 g) were added to a reaction flask in this order and reacted at 50 °C. After the reaction was completed and the reaction mixture cooled to room temperature, 200 mL of 3 M 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 removed by distillation under reduced pressure to obtain 7i (11.4 g). 1 H NMR(500MHz,DMSO-d6)δ 12.34(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),3.1 9(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).

[0348] Step 9: Preparation of compound 7k 7i (15.4 g), ethanol (200 mL), and an aqueous solution (10.00 mL) of sodium hydroxide (2.63 g) were added to a reaction flask in this order and allowed to react at room temperature. Upon completion of the reaction, the pH of the reaction mixture was adjusted to 2-3 with 2M aqueous HCl. The mixture was then extracted with 100 mL of ethyl acetate and 200 mL of water. The mixture was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure to obtain crude intermediate 7j. Dichloroethane (200 mL), imidazole (17.90 g), and TBSCl (39.6 g) were added and the mixture was refluxed overnight. Once the reaction mixture had cooled to room temperature, 100 mL of dichloromethane and 300 mL of water were added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure to obtain 7k (15.4 g). 1H NMR(500MHz,DMSO-d6)δ 12.25(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).

[0349] Step 10: Preparation of Compound 7l 7k (8.4 g) and THF (300 mL) were added to a reaction flask in this order. Diethyl carbonate (16.19 g, 16.52 mL) was added and the temperature was cooled to around 0°C. 60 wt% sodium hydride (5.48 g, 137 mmol) was added in several portions, and the reaction system was heated to 85°C. After the reaction was completed and the reaction solution cooled to room temperature, the reaction solution was slowly poured into 500 mL of ice water and extracted with 200 mL of ethyl acetate. The organic phase was discarded. The pH of the aqueous phase was adjusted to 1-2 with 3 M hydrochloric acid, followed by extraction with ethyl acetate. The solution was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation to obtain 7k (10 g). MS(ESI, [MH] - ) m / z: 331.2

[0350] Step 11: Preparation of intermediate 7m 7L (10 g), aqueous hydroxylamine solution (9.93 g, 9.93 mL), and ethanol (100 mL) were added to a reaction flask in this order and reacted at 85°C. After the reaction was completed and the reaction mixture cooled to room temperature, the residue was extracted with 200 mL of ethyl acetate and 100 mL of saturated aqueous sodium carbonate solution, and the organic phase was discarded. The aqueous phase was adjusted to pH 2-3 with 1 M aqueous HCl, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the solvent removed by vacuum distillation to obtain 7m (11 g). MS(ESI, [MH] - ) m / z: 346.2

[0351] Step 12: Preparation of intermediate 7n 7m (10 g), ethanol (150 mL), and sulfuric acid (14.40 g, 7.83 mL) were added to a reaction flask in this order and reacted at 85°C. After the reaction was completed and the reaction solution cooled to room temperature, 200 mL of dichloromethane and saturated aqueous sodium bicarbonate solution were added to adjust the pH to 7. The organic phase was separated, dried over anhydrous sodium sulfate, and filtered. The solvent was then removed by distillation under reduced pressure to obtain 7n (5.8 g). MS (ESI, [M+H] + ) m / z: 261.97 1 H NMR(500MHz,DMSO-d6)δ 7.65(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),4.26-4.1 2(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).

[0352] Step 13: Preparation of Intermediate 7 Compound 7n (300 mg), dichloromethane (10 mL), and Dess-Martin oxidant (974 mg) were added to a reaction flask in this order, and the mixture was stirred at room temperature. Upon completion of the reaction, the reaction mixture was quenched by pouring it into saturated sodium sulfite solution and then extracted with 100 mL of ethyl acetate. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium bicarbonate solution and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate by distillation under reduced pressure to yield intermediate 7 (320 mg). MS (ESI, [M+H] + ) m / z: 260.0 1 H NMR(500MHz,DMSO-d6)δ 7.74(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).

[0353] Examples 8 and 9: Synthesis of Intermediates 8 and 9 [ka] [ka] Step 1: Preparation of intermediate 8b To a reaction flask were added CCl4 (6750 mL), 8a (450 g), 2,2'-azobis(isobutyronitrile) (18.45 g), and N-bromosuccinimide (1194 g), in that order. The mixture was heated to 80 °C to react. Upon completion of the reaction, the reaction mixture was filtered, and the solvent was removed from the filtrate by vacuum distillation. Petroleum ether was added to form a slurry, and the mixture was filtered. The cake was collected to give intermediate 8b (833 g). 1 H NMR(500MHz,DMSO-d6)δ 7.34(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).

[0354] Step 2: Preparation of intermediate 8c A reaction flask was charged with 60 wt% NaH (187 g) and THF (2000 mL), in that order. Diethyl malonate (300 g, 284 mL) was added in an ice bath, and the mixture was stirred at room temperature for 30 minutes. 8b (606 g) was then added and the mixture was stirred at room temperature for 2 hours. Upon completion of the reaction, the mixture was quenched by slowly adding saturated ammonium chloride solution dropwise. 2000 mL of petroleum ether and 2000 mL of water were added, followed by extraction. The mixture was then dried over anhydrous sodium sulfate and filtered. The solvent was removed from the filtrate by vacuum distillation, and the mixture was purified by silica gel column chromatography to give intermediate 8c (262 g). MS(ESI, [MH] - ) m / z: 291.2 1H NMR(500MHz,DMSO-d6)δ 7.16(t,J=7.8Hz,1H),6.80(dd,J=15.3,7.8Hz,2H),4.14(q,J=7.1Hz,4H),3.77(s,3H),3.48(s,2H),3.38(s,2H),1.17(t,J=7.0Hz,6H).

[0355] Step 3: Preparation of intermediate 8d A reaction flask was charged with 8c (130 g), DMSO (1000 mL), HO (300 mL), and lithium chloride (42.6 g), and the mixture was stirred at 180° C. Upon completion of the reaction, the reaction mixture was quenched by pouring it into 1000 mL of ice water, and the pH was adjusted to 2-3 with 1 M hydrochloric acid. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate by distillation under reduced pressure to give intermediate 8d (191 g). MS (ESI, [M+H] + ) m / z: 193.05

[0356] Step 4: Preparation of intermediate 8e 85 g of 8d, 1000 mL of ethanol, and 44 g of concentrated sulfuric acid were added to a reaction flask in this order, and the mixture was heated to 70 °C to react. Upon completion of the reaction and cooling to room temperature, the solvent was removed by distillation under reduced pressure. The residue was poured into ice water and neutralized with saturated aqueous sodium bicarbonate. 1000 mL of petroleum ether was then added for extraction. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate by distillation under reduced pressure to obtain intermediate 8e (99 g). MS (ESI, [M+H] + ) m / z: 221.1 1 H NMR(500MHz,DMSO-d6)δ 7.13(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).

[0357] Step 5: Preparation of intermediate 8f Under N2 protection, boron tribromide (415 g, 1657 mL) was added dropwise to a stirred solution of 8e (150 g) in dichloromethane (750 mL) in a reaction flask, and the mixture was allowed to react at 0° C. Upon completion of the reaction, MeOH (500 mL) was added, and the mixture was gradually returned to room temperature and stirred. The reaction mixture was poured into a mixed solvent of 1000 mL of ice water and 1000 mL of dichloromethane, and stirred. The mixture was separated using a separatory funnel, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was removed from the filtrate under reduced pressure to obtain intermediate 8f (122 g). 1 H NMR(500MHz,DMSO-d6)δ 9.24(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,2 H),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).

[0358] Step 6: Preparation of intermediate 8g A reaction flask was charged with 8f (130 g) and tetrahydrofuran (2000 mL) in this order under N2 protection at 0°C. A tetrahydrofuran solution of lithium aluminum hydride (1 M, 438 mL) was slowly added dropwise, and the mixture was reacted in an ice-water bath. Upon completion of the reaction, 3 L of water was slowly added dropwise to quench the reaction. The pH was adjusted to 1-2 with concentrated hydrochloric acid, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was removed from the filtrate under reduced pressure to give intermediate 8f (129 g). 1 H NMR(500MHz,DMSO-d6)δ 6.88(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).

[0359] Step 7: Preparation of intermediate 8h A reaction flask was charged with 8g (120g), 4-dimethylaminopyridine (7.14g), dichloromethane (2000mL), and triethylamine (177g, 244mL) in this order, and acetyl chloride (101g, 91mL) was slowly added dropwise at 0°C and the reaction was allowed to proceed at room temperature. Upon completion of the reaction, the reaction solution was poured into a mixture of dichloromethane (1000mL) and water (1000mL), 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 (127g). MS (ESI, [M+H] + ) m / z: 249.3 1 H NMR(500MHz,DMSO-d6)δ 7.18(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).

[0360] Step 8: Preparation of intermediate 8i A reaction flask was charged with 8h (91 g), dichloromethane (2000 mL), and zirconium(IV) tetrachloride (342 g), in that order, and the mixture was stirred overnight at 50 °C under N2 protection. Upon completion of the reaction and cooling to room temperature, the mixture was poured into a mixture 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). MS(ESI, [MH] - ) m / z: 247.2

[0361] Step 9: Preparation of intermediate 8j A reaction flask was charged with 8i (95 g) and ethanol (900 mL) in that order, and a solution of sodium hydroxide (77 g) in HO (800 mL) was added dropwise in an ice bath. The mixture was reacted at room temperature under N2 protection. Upon completion of the reaction, the reaction solution was diluted with 2 L of ethyl acetate and 1 L of water, and the pH was adjusted to 3 by slowly adding 3 M hydrochloric acid. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was removed from the filtrate by distillation under reduced pressure to obtain intermediate 8j (86 g). MS(ESI, [MH] - ) m / z: 205.1 1 H NMR(500MHz,DMSO-d6)δ 12.34(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,2 H),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).

[0362] Step 10: Preparation of intermediate 8k 8j (37 g), 1,2-dichloroethane (700 mL), imidazole (36.6 g), and tert-butyldimethylchlorosilane (29.7 g) were added to a reaction flask in this order and reacted at 75 °C. After the reaction was completed and the reaction solution cooled to room temperature, 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, and filtered. The solvent was removed from the filtrate by distillation under reduced pressure to obtain intermediate 8k (60 g). 1H NMR(500MHz,DMSO-d6)δ 12.31(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).

[0363] Step 11: Preparation of intermediate 8l A reaction flask was charged with 8k (55 g), diethyl carbonate (101 g, 103 mL), and toluene (1000 mL) in this order. The reaction mixture was cooled to 0°C, and 60 wt% sodium hydride (34.3 g, 858 mmol) was added in portions. Upon completion, the mixture was slowly heated to 120°C. Upon completion, 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 vacuum distillation to yield intermediate 8l (53.6 g). MS(ESI, [MH] - ) m / z: 345.1 1 H NMR(500MHz,DMSO-d6)δ 12.31(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).

[0364] Step 12: Preparation of intermediate 8m A reaction flask was charged with 8L (51 g), hydroxylamine hydrochloride (61.4 g), sodium ethoxide (61.1 g), and ethanol (2000 mL) in that order, and the mixture was heated to 85°C under N2 protection. Upon completion of the reaction, the solvent was removed from the reaction mixture 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 to the reaction mixture, and the aqueous phase was collected. 1 M hydrochloric acid was added to the aqueous phase to adjust the pH to 6-7, and further ethyl acetate was added to the reaction mixture. The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was removed from the filtrate under reduced pressure to obtain intermediate 8m (47 g). MS(ESI, [MH] - ) m / z: 360.2 1 H NMR(500MHz,DMSO-d6)δ 7.55(d,J=8.0Hz,1H),7.22(d,J=8.0Hz,1H),3.97(s,2H),3.57(d,J=6.6 Hz,2H),3.16-3.07(m,2H),2.88-2.72(m,3H),0.81(s,9H),0.00(s,6H).

[0365] Step 13: Preparation of intermediate 8n A reaction flask was charged with 8m (47 g), ethanol (1500 mL), and concentrated sulfuric acid (65.1 g, 35.4 mL) in this order, and the mixture was heated to 85°C under N2 protection to react. After the reaction mixture cooled to room temperature, the solvent was removed by rotary evaporation, 1000 mL of dichloromethane was added, and the mixture was neutralized by dropwise addition of saturated aqueous sodium bicarbonate solution. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate by distillation under reduced pressure to obtain intermediate 8n (43 g). MS (ESI, [M+H] + ) m / z: 276.1 1H NMR(500MHz,DMSO-d6)δ 7.58(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).

[0366] Step 14: Preparation of intermediates 8o-1 and 8o-2 Preparative separation was performed as follows: 43 g of intermediate 8n was dissolved in 430 mL of dichloromethane-ethanol solution to a concentration of approximately 100.0 mg / mL, and the solution was filtered through a 0.45 μm organic filter to obtain the filtrate. The apparatus used was a YMC high-pressure preparative chromatograph, the chromatographic column was a CHIRALPAK IG (innovation 036#, 30 × 250 mm, S-10 μm), and the mobile phase was A: ethanol, B: n-hexane. Intermediate 8o-1 (9.057 g) was obtained from the first peak, and intermediate 8o-2 (8.833 g) was obtained from the second peak. 8o-1: MS (ESI, [M+H] + ) m / z: 276.1 8o-2: MS (ESI, [M+H] + ) m / z: 276.1

[0367] Step 15: Preparation of Intermediate 8 Under N2 protection, 8o-1 (11.93 g), THF (200 mL), and acrylamide (3.39 g) were added to a reaction flask in this order, and the temperature was lowered to 0 °C. Then, a solution of potassium tert-butoxide in tetrahydrofuran (1 M, 34.7 mL) was added, and the mixture was reacted at 0 °C. Upon completion of the reaction, the reaction solution was added dropwise to an ice-cooled saturated aqueous ammonium chloride solution, extracted with 1000 mL of ethyl acetate, and the aqueous phase was extracted with 500 mL of ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was removed from the filtrate by distillation under reduced pressure, and the cake was collected by filtration to obtain 6.77 g of intermediate 8. 1 H NMR(500MHz,DMSO-d6)δ 11.08(s,1H),7.60(d,J=8.0Hz,1H),7.25(d,J=8.1Hz,1H),4.74(td,J=5.3,2.2Hz,1H),4.56(dd,J=11.8,5.0Hz,1H),3.43(dd,J=6.8,5.3Hz ,2H),3.22-3.09(m,2H),2.94-2.83(m,2H),2.76(dq,J=16.9,6.3Hz,2 H),2.60(dt,J=17.3,4.2Hz,1H),2.50-2.44(m,1H),2.23-2.13(m,1H).

[0368] Step 16: Preparation of Intermediate 9 A reaction flask was charged with 8o-2 (12.83 g), THF (200 mL), and acrylamide (3.64 g) in this order, and the temperature was lowered to 0°C. A 1 M solution of potassium tert-butoxide in tetrahydrofuran (37.3 mL) was added, and the mixture was reacted at 0°C under N2 protection. Upon completion of the reaction, the reaction mixture was added dropwise to an ice-cooled saturated aqueous ammonium chloride solution and extracted with ethyl acetate. 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 solvent was removed from the filtrate by distillation under reduced pressure, and the cake was collected by filtration to obtain intermediate 9 (7.454 g). 1 H NMR(500MHz,DMSO-d6)δ 11.08(s,1H),7.60(d,J=8.2Hz,1H),7.25(d,J=8.1Hz,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(d t,J=17.3,4.2Hz,1H),2.46(dd,J=12.1,4.5Hz,1H),2.23-2.15(m,1H).

[0369] Example 10: Synthesis of Intermediate 10 [ka] [ka] Step 1: Preparation of intermediate 10b 10a (100 g), 2,4-dimethoxybenzenemethanamine (102 g), and acetic acid (600 mL) were added to a reaction flask in this order, and the reaction was completed at 80°C. Water was added to the reaction solution, and the mixture was suction filtered. The cake was washed with water and dried to obtain intermediate 10b (95.7 g). MS(ESI, [MH] - ) m / z: 312.02 1 H NMR(500MHz,DMSO-d6)δ 11.03(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).

[0370] Step 2: Preparation of intermediate 10c Intermediate 10b (130 g), potassium carbonate (97 g), iodomethane (65 mL), and N,N-dimethylformamide (1 L) were added to a reaction flask in this order, and the reaction was completed at 80° C. After cooling to room temperature, water was added to the reaction solution, which was then suction filtered. The cake was washed with water and dried to obtain Intermediate 10c (126 g). MS (ESI, [M+H] + ) m / z: 327.99 1 H NMR(500MHz,DMSO-d6)δ 7.80(dd,J=8.5,7.2Hz,1H),7.48(d,J=8.4Hz,1H),7.45-7.39(m,1H),6.91(d,J=8.5Hz,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).

[0371] Step 3: Preparation of intermediate 10d A reaction flask was charged with Intermediate 10c (128 g) and tetrahydrofuran (800 mL) in this order, and lithium aluminum hydride (89 g) was slowly added under N2 protection at 0°C. The temperature was raised to 80°C and the reaction was completed. 89 mL of water was slowly added dropwise to the reaction solution in an ice bath, followed by 267 mL of 15% aqueous NaOH solution, and then 89 mL of water. The mixture was stirred for 30 minutes, suction filtered through diatomaceous earth, the cake was washed with ethyl acetate, the filtrate was collected, the organic layer was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain Intermediate 10d (86.4 g). MS (ESI, [M+H] + ) m / z: 300.20 1 H NMR(500MHz,DMSO-d6)δ 7.26(d,J=8.3Hz,1H),7.18(t,J=7.8Hz,1H),6.90-6.77(m,2H),6.57(d,J=2.4Hz,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).

[0372] Step 4: Preparation of Intermediate 10e Intermediate 10d (86 g), 10% palladium on carbon (15 g), methanol (500 mL), and di-tert-butyl dicarbonate (63.3 g) were added to a reaction flask in this order, and the reaction was carried out at room temperature under a hydrogen atmosphere at 0° C. The reaction mixture was filtered, and the filtrate was concentrated to give Intermediate 10e (100 g). 1 H NMR(500MHz,DMSO)δ 7.27(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).

[0373] Step 5: Preparation of intermediate 10f Intermediate 10e (100 g), dichloromethane (1000 mL), and trifluoroacetic acid (457 g) were added to a reaction flask in this order and reacted at room temperature for 2 hours, at which point the reaction was complete. The reaction mixture was directly concentrated, and the concentrate was dissolved in tetrahydrofuran (1000 mL). Trifluoroacetic anhydride (84 g) was added in an ice-water bath, and the reaction was completed at room temperature. The reaction mixture was quenched by slowly adding saturated sodium bicarbonate solution, followed by extraction with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain Intermediate 10f (57.4 g).

[0374] Step 6: Preparation of Intermediate 10g Intermediate 10f (40 g) and acetonitrile (500 mL) were added to a reaction flask in this order, and after dissolution, N-bromosuccinimide (30.5 g) was added and the reaction was carried out at 75°C until completion. The reaction solution was quenched by adding ice water, and then suction filtered. The cake was washed with water and dried to obtain Intermediate 10g (60 g). 1 H NMR(500MHz,DMSO-d6)δ 7.51(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).

[0375] Step 7: Preparation of intermediate 10h 10g (40g) and chloroacetyl chloride (30mL) were added to a reaction flask in this order, and trifluoromethanesulfonic acid (120mL) was slowly added dropwise in an ice-water bath. The reaction was completed at 50°C. The reaction solution was slowly added dropwise to ice-water, extracted twice with dichloromethane, and the organic phases were combined and washed twice with saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and then purified by silica gel column chromatography to obtain the target intermediate 10h (20g). 1H NMR(500MHz,DMSO-d6)δ 7.84(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).

[0376] Step 8: Preparation of intermediate 10i The reaction flask was charged with 10h (20 g) and dichloromethane (300 mL), in that order, and boron trichloride (149 mL) was slowly added dropwise in an ice-water bath. The reaction was completed at room temperature. The reaction mixture was slowly poured into ice water and extracted twice with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the desired intermediate 10i (20 g). MS (ESI, [M+H] + ) m / z: 386.00 1 H NMR(500MHz,DMSO-d6)δ 11.37(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).

[0377] Step 9: Preparation of intermediate 10j 19.5 g of 10i, 12.7 g of sodium bicarbonate, and 900 mL of acetonitrile were added to a reaction flask in this order, and the reaction was completed at 80° C. Water and ethyl acetate were added, and the organic layer was collected and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the target intermediate 10j (24 g). 1 H NMR(500MHz,DMSO-d6)δ 7.87(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).

[0378] Step 10: Preparation of Intermediate 10k A reaction flask was charged with 10j (23.4 g), 10% palladium on carbon (1.4 g), sodium bicarbonate (5.61 g), and ethanol (400 mL), in that order, and the reaction was completed at room temperature in the presence of hydrogen. The reaction mixture was filtered, and the solvent was removed from the filtrate by distillation under reduced pressure. Ethyl acetate and water were added to the residue, and the organic layer was separated and dried over anhydrous sodium sulfate. The organic layer was filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the target intermediate 10k (12 g). MS(ESI, [MH] - ) m / z: 270.00 1 H NMR(500MHz,DMSO-d6)δ 7.65(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).

[0379] Step 11: Preparation of intermediate 10l 10k (11.5 g), ethyl (triphenylphosphoranylidene)acetate (22.2 g), and toluene (30 mL) were added to a reaction flask in this order, and 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, filtered, and the filtrate was concentrated and then purified by silica gel column chromatography to obtain the target intermediate 10l (5.3 g). 1 H NMR(500MHz,DMSO-d6)δ 7.96(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).

[0380] Step 12: Preparation of intermediate 10m 10L (5.3 g), potassium carbonate (6.4 g), and ethanol (50 mL) were added to a reaction flask in this order, and the reaction was completed at room temperature. 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). MS (ESI, [M+H] + ) m / z: 246.10

[0381] Step 13: Preparation of intermediate 10n 10m (4.3 g), triethylamine (3.47 g), and dichloromethane (50 mL) were added to a reaction flask in this order, followed by di-tert-butyl dicarbonate (4.11 g). The reaction was completed at room temperature. Water was added to the reaction mixture, and 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 10n (3.7 g). 1 H NMR(500MHz,DMSO-d6)δ 7.93(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).

[0382] Step 14: Preparation of Intermediate 10o A reaction flask was charged with 10n (3.7 g), acrylamide (0.84 g), and N,N-dimethylformamide (50 mL) in this order. The temperature was lowered to 0°C, and potassium tert-butoxide (8.6 mL, 1 M) was slowly added dropwise. The reaction was completed at 0°C. The reaction mixture was added dropwise to an ice-cooled aqueous ammonium chloride solution and extracted with ethyl acetate. 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 desired intermediate 10o (2.6 g). 1H NMR(500MHz,DMSO-d6)δ 10.90(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).

[0383] Step 15: Preparation of Intermediate 10 The reaction flask was charged with 10o (2.4 g) and dioxane (15 mL), followed by the addition of a 4 M solution of hydrochloric acid in dioxane (15 mL). The reaction was allowed to proceed at room temperature until completion. The reaction mixture was added with tert-butyl methyl ether, filtered under suction, and the cake was washed with tert-butyl methyl ether. The cake was collected and dried to give the desired intermediate 10 (2.0 g). MS (ESI, [M+H] + ) m / z: 271.15 1 H NMR(500MHz,DMSO-d6)δ 10.92(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).

[0384] Example 11: Synthesis of Intermediate 11 [ka] [ka] Step 1: Preparation of intermediate 11b Intermediate 11a and methanol (1500 mL) were added to a reaction flask in that order. Sodium cyanoborohydride (148 g) was added at 0 °C, and the mixture was allowed to react at 0 °C for 10 minutes. Trifluoroborane-ethyl ether (334 g) was added dropwise at 0 °C, and the mixture was heated to 75 °C. Upon completion of the reaction, 50 mL of saturated sodium bicarbonate solution was added to the reaction mixture, and the solvent was removed by distillation under reduced pressure. The mixture was extracted with dichloromethane and water, and the organic phase was separated, dried over anhydrous sodium sulfate, and filtered. The solvent was removed from the filtrate by distillation under reduced pressure to obtain the desired intermediate 11b (102.65 g). MS (ESI, [M+H] + ) m / z: 212.2 1 H NMR(500MHz,DMSO-d6)δ 7.38(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).

[0385] Step 2: Preparation of intermediate 11c Intermediate 11b (100.06 g) and tetrahydrofuran (1000 mL) were added to a reaction flask in this order, and trifluoroacetic anhydride (95 g, 63.2 mL) was added in an ice bath. The mixture was allowed to warm to room temperature and react. Upon completion of the reaction, the reaction mixture 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 solvent was removed from the filtrate by distillation under reduced pressure to obtain the target intermediate 11c (137.6 g). 1 H NMR(500MHz,DMSO-d6)δ 7.54(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).

[0386] Step 3: Preparation of intermediate 11d Intermediate 11c (137.6 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (36.5 g), bis(pinacolato)diboron (136 g), potassium acetate (131 g), and dioxane (1500 mL) were added to a reaction flask in this order, and the mixture was heated to 85 °C under N2 protection. Upon completion of the reaction, the reaction mixture was filtered, the solvent removed from the filtrate by distillation under reduced pressure, petroleum ether was added to form a slurry, and the mixture was filtered. The filtrate was extracted with 2 L of water, the organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent removed from the filtrate by distillation under reduced pressure to obtain intermediate 11d (165.4 g). MS (ESI, [M+H] + ) m / z: 356.2 1 H NMR(500MHz,DMSO-d6)δ 7.59(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).

[0387] Step 4: Preparation of intermediate 11e Intermediate 11d (165.4 g), tetrahydrofuran (1000 mL), and acetic acid (98 g, 93 mL) were added to a reaction flask in this order, and 30% hydrogen peroxide (185 g, 166 mL) was added under ice bath conditions. The mixture was allowed to warm to room temperature and react. Upon completion of the reaction, the reaction mixture was quenched by pouring it into ice-cold saturated sodium thiosulfate solution, the pH was adjusted to 8 with saturated sodium bicarbonate solution, and ethyl acetate was added for extraction. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate by vacuum distillation. The residue was slurried in 200 mL of petroleum ether / tert-butyl methyl ether, filtered, and the cake was collected to give intermediate 11e (85.3 g). MS(ESI, [MH] - ) m / z: 244.2 1H NMR(500MHz,DMSO-d6)δ 9.80(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).

[0388] Step 5: Preparation of intermediate 11f Intermediate 11e (30 g), acetonitrile (300 mL), potassium carbonate (33.8 g), and tert-butyl bromoacetate (26.3 g, 19.89 mL) were added to a reaction flask in this order, and the mixture was heated to 80° C. Upon completion of the reaction, the reaction mixture was extracted with 500 mL of ethyl acetate and 1000 mL of water, and the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure to obtain the desired intermediate 11f (47.4 g). 1 H NMR(500MHz,DMSO-d6)δ 7.18(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).

[0389] Step 6: Preparation of intermediate 11g Intermediate 11f (47.4 g), dichloromethane (500 mL), and trifluoroacetic acid (207 g, 140 mL) were added to a reaction flask in this order, and the mixture was allowed to react at room temperature for 1 hour. Upon completion of the reaction, the solvent was removed from the reaction solution by distillation under reduced pressure, and dichloromethane was added to the residue, followed by distillation under reduced pressure to remove the solvent, yielding the desired intermediate 11g (34.2 g). MS(ESI, [MH] - ) m / z: 302.0 1H NMR(500MHz,DMSO-d6)δ 13.04(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).

[0390] Step 7: Preparation of intermediates 11h and 11i Intermediate 11g (33.7 g), tetrahydrofuran (350 mL), and sulfinyl chloride (39.7 g) were added to a reaction flask in this order, and the mixture was heated to 75 °C. Upon completion of the reaction and cooling to room temperature, the solvent was removed by distillation under reduced pressure to yield the desired intermediate 11h. Dichloromethane (350 mL) and aluminum(III) chloride (39.7 g) were added to intermediate 11h, and the mixture was stirred at room temperature to allow the reaction to proceed. Upon completion of the reaction, the reaction was quenched by pouring into 500 mL of ice water, filtered through diatomaceous earth, and the filtrate was extracted with 100 mL of dichloromethane and 100 mL of water. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure to yield the desired intermediate 11i (32.5 g). 1 H NMR(500MHz,DMSO-d6)δ 7.50(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).

[0391] Step 8: Preparation of intermediate 11j Intermediate 11i (32.5 g), ethyl (triphenylphosphoranylidene)acetate (54.7 g), and toluene (350 mL) were added to a reaction flask in this order, and the mixture was heated to 120°C under N2 protection to react. Upon completion of the reaction, the reaction mixture was extracted with 300 mL of ethyl acetate and 800 mL of water, and the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was purified using a silica gel column to obtain the target intermediate 11j (19.37 g). 1H NMR(500MHz,DMSO-d6)δ 7.92(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).

[0392] Step 9: Preparation of intermediate 11k Intermediate 11j, potassium carbonate (22.60 g, 164 mmol), and ethanol (200 mL) were added to a reaction flask in this order, and the mixture was allowed to react at room temperature. Upon completion of the reaction, 300 mL of ethyl acetate and 500 mL of water were added to the reaction mixture for extraction. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate by distillation under reduced pressure to obtain the target intermediate 11k (13.12 g). MS (ESI, [M+H] + ) m / z: 260.1 1 H NMR(500MHz,DMSO-d6)δ 7.81(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).

[0393] Step 10: Preparation of intermediate 11l Intermediate 11k (13.12 g), dichloromethane (130 mL), triethylamine (10.24 g, 14.10 mL), and di-tert-butyl dicarbonate (12.15 g, 12.92 mL) were added to a reaction flask in this order, and the mixture was allowed to react at room temperature. Upon completion of the reaction, the solvent was removed from the reaction mixture by distillation 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 using a silica gel column to obtain the desired intermediate 11l (16.32 g). MS (ESI, [M+H] + ) m / z: 360.2 1 H NMR(500MHz,DMSO-d6)δ 7.88(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).

[0394] Step 11: Preparation of intermediate 11m Intermediate 11l (16.32 g), N,N-dimethylformamide (160 mL), and acrylamide (3.55 g) were added to a reaction flask in this order, and the temperature was lowered to 0°C under N2 protection. Then, a solution of potassium tert-butoxide in tetrahydrofuran (1 mol / L, 40.9 mL) was added, and the mixture was reacted at 0°C. Upon completion of the reaction, the reaction solution was added dropwise to an ice-cooled saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic phase separated, dried over anhydrous sodium sulfate, filtered, and the solvent removed by distillation under reduced pressure. The residue was slurried in 200 mL of petroleum ether / ethyl acetate, filtered, and the cake was collected to obtain the desired intermediate 11m (14.5 g). MS (ESI, [M+H] + ) m / z: 385.1 1H NMR(500MHz,DMSO-d6)δ 10.89(s,1H),7.88(s,1H),7.39(d,J=8.0Hz,1H),7.05(d,J=8.0Hz,1H),4.73(s,2H),4.12(dd,J=12.0,4.9Hz,1H),3.63(t,J=5.8Hz,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).

[0395] Step 12: Preparation of Intermediate 11 Intermediate 11m (14.5 g), dichloromethane (150 mL), and a solution of hydrochloric acid in 1,4-dioxane (4 mol / L, 141 mL) were added to a reaction flask in this order, and the mixture was reacted at room temperature. The solvent was removed from the reaction mixture by distillation under reduced pressure, and the residue was slurried with tert-butyl methyl ether. The mixture was filtered, and the cake was collected to obtain Intermediate 11 (12.6 g). MS (ESI, [M+H] + ) m / z: 285.1 1 H NMR (500 MHz, DMSO-d6) δ 10.90(s,1H),9.87(s,2H),7.93(s,1H),7.49(d,J=8.0Hz,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).

[0396] Example 12: Synthesis of Intermediate 12 [ka] [ka] Step 1: Preparation of intermediate 12a Intermediate 4c, acetonitrile (130 mL), potassium carbonate (14.09 g), and tert-butyl bromoacetate (10.94 g, 8.29 mL) were added to a reaction flask in this order, and the mixture was heated to 80°C to react. Upon 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 removed by distillation under reduced pressure to obtain the target intermediate 12a (20.33 g). 1 H NMR(500MHz,DMSO-d6)δ 7.17(t,J=8.0Hz,1H),6.87(t,J=7.8Hz,1H),6.76(t,J=8.0Hz,1H),4.75(d,J=4.8Hz,2H),4.7 0(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).

[0397] Step 2: Preparation of intermediate 12b Intermediate 12a (20.33 g), dichloromethane (100 mL), and trifluoroacetic acid (29.0 g, 19.61 mL) were added to a reaction flask in this order, and the mixture was allowed to react at room temperature. Upon completion of the reaction, the solvent was removed from the reaction mixture by vacuum distillation, and dichloromethane was added to the residue, followed by vacuum distillation to remove the solvent, yielding intermediate 12b (16.2 g). MS(ESI, [MH] - ) m / z: 301.9 1 H NMR(500MHz,DMSO-d6)δ 13.00(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).

[0398] Step 3: Preparation of intermediates 12c and 12d Intermediate 12b (16.2 g), tetrahydrofuran (160 mL), and sulfinyl chloride (30.0 g, 18.29 mL) were added to a reaction flask in this order, and the mixture was heated to 75 °C and reacted for 2 hours. Upon completion of the reaction, the solvent was removed by distillation under reduced pressure to yield the desired intermediate 12c. Trifluoromethanesulfonic acid (100 mL) was added dropwise to intermediate 12c in an ice bath, and the mixture was stirred at room temperature to react. Upon completion of the reaction, the reaction solution was poured into 2000 mL of ice-water solution, 500 mL of ethyl acetate was added, the organic phase was separated, and the pH was adjusted to 8 with saturated sodium bicarbonate solution. The organic phase was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was purified using a silica gel column to yield the desired intermediate 12d (3.27 g). 1 H NMR(500MHz,DMSO-d6)δ 7.49(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).

[0399] Step 4: Preparation of intermediate 12e Intermediate 12d (4.59 g), ethyl (triphenylphosphoranylidene)acetate (8.41 g), and toluene (100 mL) were added to a reaction flask in this order, and the mixture was heated to 130 °C under N2 protection. Upon 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 using a silica gel column to obtain the target intermediate 12e (3.93 g). 1H NMR(500MHz,DMSO-d6)δ 7.92(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).

[0400] Step 5: Preparation of intermediate 12f Intermediate 12e (3.93 g), potassium carbonate (4.36 g), and ethanol (50 mL) were added to a reaction flask in this order, and the mixture was allowed to react at room temperature. Upon completion of the reaction, 200 mL of ethyl acetate and 300 mL of water were added for extraction, and 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 solvent was removed by distillation under reduced pressure to obtain the desired intermediate 12f (2.63 g). MS (ESI, [M+H] + ) m / z: 260.1 1 H NMR(500MHz,DMSO-d6)δ 7.83(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).

[0401] Step 6: Preparation of intermediate 12g 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 a reaction flask in this order, and the mixture was allowed to react at room temperature. Upon completion of the reaction, the solvent was removed from the reaction mixture by distillation under reduced pressure. 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 using a silica gel column to obtain the target intermediate 12f (3.53 g). MS (ESI, [M+H] + ) m / z: 360.1 1 H NMR(500MHz,DMSO-d6)δ 7.88(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).

[0402] Step 7: Preparation of intermediate 12h Intermediate 12g (3.71 g), N,N-dimethylformamide (12 mL), and acrylamide (0.807 g) were added to a reaction flask in this order, and the temperature was lowered to 0°C under N2 protection. A solution of potassium tert-butoxide in tetrahydrofuran (1 mol / L, 8.26 mL) was added, and the mixture was reacted at 0°C for 1 hour. Upon completion of the reaction, the reaction solution was added dropwise to ice-cooled saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was purified using a silica gel column to obtain the desired intermediate 12h (2.57 g). MS (ESI, [M+H] + ) m / z: 385.2 1H NMR(500MHz,DMSO-d6)δ 10.89(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).

[0403] Step 8: Preparation of Intermediate 12 Intermediate 12h (2.57 g), dichloromethane (25 mL), and a solution of hydrochloric acid in 1,4-dioxane (4 mol / L, 25.10 mL) were added to a reaction flask in this order, and the mixture was allowed to react at room temperature. Upon completion of the reaction, the solvent was removed from the reaction mixture by distillation under reduced pressure, and the residue was slurried with tert-butyl methyl ether. The mixture was filtered, and the cake was collected to give Intermediate 12 (2.09 g). MS (ESI, [M+H] + ) m / z: 285.1 1 H NMR (500 MHz, DMSO-d6) δ 10.90(s,1H),9.72(s,2H),7.94(s,1H),7.48(d,J=8.1Hz,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).

[0404] Example 13: Synthesis of intermediate 13 [ka] [ka] Step 1: Preparation of intermediate 13a A reaction flask was charged with 5d (32.0 g), 10% palladium on carbon (6.1 g), and methanol (250 mL), in that order, and the mixture was heated under hydrogen for three times and allowed to react overnight. Upon completion of the reaction, diatomaceous earth was added and the mixture was filtered. The filtrate was rotary evaporated, 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 give intermediate 13a (22.7 g). MS (ESI, [M+H] + ) m / z: 274.0

[0405] Step 2: Preparation of intermediate 13b At 0°C under nitrogen protection, boron tribromide dichloromethane solution (125 mL, 1 M) was slowly added dropwise to a solution of 13a (22.7 g) in dichloromethane (200 mL), and the reaction was allowed to warm to room temperature upon completion. Upon completion of the reaction, the reaction solution was slowly poured into 350 mL of ice water and stirred for 10 minutes. The dichloromethane was rotary evaporated, filtered, and the cake was collected and dried to give 13b (21.1 g). MS(ESI, [MH] - ) m / z: 258.1 1 H NMR(500MHz,DMSO-d6)δ 9.39(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).

[0406] Step 3: Preparation of intermediate 13c 13b (20.5 g), tert-butyl bromoacetate (18.5 g), potassium carbonate (27.3 g), and DMF (100 mL) were added to a reaction flask in this order, and the temperature of the reaction solution was raised to 80 °C to react. The reaction solution was cooled to room temperature, and 200 mL of ethyl acetate and 300 mL of water were added to the reaction solution. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 13c (34.5 g). MS(ESI, [MH] - ) m / z: 372.1

[0407] Step 4: Preparation of intermediate 13d 13c (29.5 g), trifluoroacetic acid (90.2 g), and dichloromethane (200 mL) were added to a reaction flask in this order and reacted at room temperature. Upon completion of the reaction, the dichloromethane was evaporated by rotary evaporation, 300 mL of water was added, stirred for 10 minutes, filtered, and the cake was collected and dried to give 13d (23.5 g). MS(ESI, [MH] - ) m / z: 316.0

[0408] Step 5: Preparation of intermediate 13f A reaction flask was charged with 13d (21.2 g), sulfinyl chloride (79.5 g), and tetrahydrofuran (200 mL) in this order, and the temperature of the reaction mixture was raised to 80 °C for reaction. The solvent was removed from the reaction mixture by rotary evaporation to give 13e, and dichloromethane (200 mL) was added. The temperature of the reaction mixture was lowered to 0 °C, and trifluoromethanesulfonic acid (49.7 g) was slowly added dropwise. Upon completion, the mixture was allowed to cool to room temperature for reaction. The reaction mixture was slowly poured into 400 mL of ice water, dichloromethane was added, and the organic phase was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the concentrate was purified by silica gel column chromatography to give intermediate 13f (8.8 g). MS (ESI, [M+H] + ) m / z: 300.1 1H NMR(500MHz,DMSO-d6)δ 7.44(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).

[0409] Step 6: Preparation of intermediate 13g 13f (8.8 g), ethyl (triphenylphosphoranylidene)acetate (14.2 g), and toluene (50 mL) were added to a reaction flask in this order, and the temperature of the reaction solution was raised to 130° C. and reacted overnight. The temperature of the reaction solution was lowered to room temperature, and 50 mL of ethyl acetate and 60 mL of water were added. The organic phase was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the concentrate was purified by silica gel column chromatography to obtain intermediate 13g (6.8 g). MS (ESI, [M+H] + ) m / z: 370.1 1 H NMR(500MHz,DMSO-d6)δ 7.92-7.84(m,1H),7.36(dd,J=7.8,3.1Hz,1H),7.10(t,J=7.9Hz,1H),4.10(q,J=7.1H z,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).

[0410] Step 7: Preparation of intermediate 13h To a reaction flask were added 13g (6.8g), potassium carbonate (7.6g), and ethanol (100mL) in this order, and the temperature of the reaction mixture was raised to 50°C and allowed to react overnight. The temperature of the reaction mixture was lowered 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, filtered, and the concentrate was purified by silica gel column chromatography to obtain intermediate 13h (3.8g). MS (ESI, [M+H] + ) m / z: 274.2

[0411] Step 8: Preparation of intermediate 13i A reaction flask was charged with 13h (3.8 g), triethylamine (2.8 g), and dichloromethane (50 mL) in this order, and Boc anhydride (3.64 g) was added with stirring. The mixture was then reacted 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, filtered, and the concentrate was purified by silica gel column chromatography to obtain intermediate 13i (3.9 g).

[0412] Step 9: Preparation of intermediate 13j At 0 °C under nitrogen protection, 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) and allowed to react until complete. Upon completion, the reaction mixture was slowly poured into 100 mL of saturated ammonium chloride and stirred for 10 min. The mixture was filtered to collect the cake. The cake was slurried in ethyl acetate, filtered, and dried to give 13j (2.1 g). MS(ESI, [MH] - ) m / z: 397.0 1 H NMR (500 MHz, DMSO-d6) δ 10.88(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,2 H),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).

[0413] Step 10: Preparation of Intermediate 13 13j (2.1 g), hydrochloric acid, 1,4-dioxane (10 mL), and dichloromethane (10 mL) were added to a reaction flask in this order and reacted at room temperature. After the reaction was completed, the mixture was filtered, and the cake was eluted with a small amount of tert-butyl methyl ether and dried to obtain intermediate 13 (1.6 g). MS (ESI, [M+H] + ) m / z: 299.1 1 H NMR (500 MHz, DMSO-d6) δ 10.89(s,1H),9.57(s,2H),7.91(s,1H),7.37(d,J=7.8Hz,1H),7.11(d,J=8.0H z,1H),4.12(dd,J=12.1,4.9Hz,1H),3.38(s,2H),3.26(td,J=8.1,7.3,3.8Hz,4 H),3.20(dt,J=8.6,3.9Hz,2H),2.75(ddd,J=17.4,12.3,5.4Hz,1H),2.57(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).

[0414] Example 14: Synthesis of Intermediate 14 [ka] [ka] Step 1: Preparation of intermediate 14a Intermediate 8e (14.95 g) and THF (200 mL) were added to a reaction flask in this order, and the temperature was lowered to 0° C. under N2 protection. Then, a solution of lithium aluminum hydride in tetrahydrofuran (5.67 g, 59.8 mL) was added, and after the dropwise addition was completed, the mixture was reacted at 0° C. for 2 hours. After the reaction was completed, water was slowly added dropwise to the reaction mixture at 0° C. to quench the reaction. Anhydrous sodium sulfate was added, and the mixture was filtered. The solvent was removed from the filtrate by distillation under reduced pressure to obtain the desired intermediate 14a (11.15 g). 1H NMR(500MHz,DMSO-d6)δ 7.08(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).

[0415] Step 2: Preparation of intermediate 14b Intermediate 14a, dichloromethane (100 mL), triethylamine (18.99 g), and 4-dimethylaminopyridine (0.191 g) were added to a reaction flask in this order. Acetic anhydride (7.03 g, 6.55 mL) was added in an ice bath, and the mixture was allowed to react at room temperature for 1 hour. Upon completion of the reaction, the solvent was removed from the reaction mixture by vacuum distillation. 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, respectively, dried over anhydrous sodium sulfate, and filtered. The solvent was removed from the filtrate by vacuum distillation to give intermediate 14b (12.97 g). 1 H NMR(500MHz,DMSO-d6)δ 7.13-7.09(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=15.6,7.9Hz, 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).

[0416] Step 3: Preparation of intermediate 14c Intermediate 14b (10.15 g), N-bromosuccinimide (9.02 g), and acetonitrile (100 mL) were added to a reaction flask in this order, and the mixture was heated to 75° C. and reacted for 1 hour. Upon completion of the reaction, 200 mL of ethyl acetate and 500 mL of water were added for extraction, and 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 solvent was removed by distillation under reduced pressure to obtain the desired intermediate 14c (14.11 g). 1 H NMR(500MHz,DMSO-d6)δ 7.31(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).

[0417] Step 4: Preparation of intermediate 14d Trifluoromethanesulfonic acid (40 mL) was slowly added dropwise to a stirred solution of Intermediate 14c (14.11 g) and chloroacetyl chloride (5.13 g, 3.61 mL) in an ice bath. Upon completion, the mixture was stirred at room temperature and allowed to react for 1 hour. Upon completion, the reaction mixture was poured into 500 mL of ice-water solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the solvent removed by distillation under reduced pressure to give the desired Intermediate 14d (15.23 g). 1 H NMR(500MHz,DMSO-d6)δ 7.67(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).

[0418] Step 5: Preparation of intermediate 14e At −35° C., under N protection, a solution of boron trichloride in dichloromethane (1 mol / L, 73.0 mL) was slowly added dropwise to a stirred solution of intermediate 14d (15.23 g) in dichloromethane (450 mL), and upon completion, the mixture was stirred and reacted at −30° C. Upon completion, the reaction was quenched by adding 100 mL of aqueous hydrochloric acid (1 M) at −30° C., and the mixture was allowed to cool to room temperature. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure to give intermediate 14e (15.24 g). MS (ESI, [M+H] + ) m / z: 361.1 1 H NMR(500MHz,DMSO-d6)δ 11.26(s,1H),7.87(s,1H),5.19(s,2H),4.05(dd,J=7.0,2.5Hz,2H),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).

[0419] Step 6: Preparation of intermediate 14f Intermediate 14e (15.24 g), acetonitrile (150 mL), and sodium carbonate (4.41 g) were added to a reaction flask in this order, and the mixture was heated to 75° C. Upon completion of the reaction, 200 mL of ethyl acetate and 500 mL of water were added for extraction, and 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 solvent was removed by distillation under reduced pressure to obtain the target intermediate 14f (13.97 g). 1 H NMR(500MHz,DMSO-d6)δ 7.64(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).

[0420] Step 7: Preparation of intermediate 14g Intermediate 14f (6.85 g), ethyl (triphenylphosphoranylidene)acetate (11.01 g), and toluene (80 mL) were added to a reaction flask in this order, and the mixture was heated to 130°C under N2 protection to react. Upon completion of the reaction, 200 mL of ethyl acetate and 300 mL of water were added for extraction, the organic phase was separated, the aqueous phase was extracted with ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified using a silica gel column to obtain the target intermediate 14f (4.09 g). 1 H NMR(500MHz,DMSO-d6)δ 7.90(s,1H),7.65(s,1H),4.13-4.08(m,4H),3.77(s,2H),3.16-3.11(m,1H),3.01-2 .91(m,2H),2.76(ddd,J=23.5,16.3,6.3Hz,2H),2.04(s,3H),1.19(t,J=7.1Hz,3H).

[0421] Step 8: Preparation of intermediate 14h Intermediate 14g (1.2 g), 10% palladium on carbon (1.2 g), ethanol (40 mL), and dichloromethane (20 mL) were added to a reaction flask in this order. After the atmosphere was exchanged with H2, the mixture was reacted at room temperature. Upon reaction completion, the mixture was filtered through diatomaceous earth. The pH of the filtrate was adjusted to 8 with saturated sodium bicarbonate solution, and 200 mL of ethyl acetate and 200 mL of water were added for extraction. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with 300 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure to give intermediate 14h (1.01 g).

[0422] Step 9: Preparation of intermediates 14i-1 and 14i-2 Intermediate 14h (0.98 g), potassium carbonate (1.713 g), and ethanol (15 mL) were added to a reaction flask in this order, and the mixture was allowed to react at room temperature for 18 hours. Upon completion of the reaction, 100 mL of ethyl acetate and 100 mL of water were added for extraction. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation to obtain the desired intermediate 14i (0.9 g). Intermediate 14i was then separated by high-performance liquid chromatography to obtain intermediates 14i-1 (0.36 g) and 14i-2 (0.42 g). The composition of the fraction was as follows: The apparatus and preparative column used were a YMC K-prep Lab 100 g high-pressure preparative chromatograph, with the preparative column model being CHIRALART Amylose-SA (5 μm, 30 × 250 mm). The mobile phase system was n-hexane / ethanol, with isocratic elution at a ratio of n-hexane:ethanol = 90:10. The data for 14i-1 were as follows: MS (ESI, [M+H] + ) m / z: 275.2 1 H NMR(500MHz,DMSO-d6)δ 7.81(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),2.7 8(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).

[0423] Step 10: Preparation of Intermediate 14 Intermediate 14i-1 (350 mg), N,N-dimethylformamide (10 mL), and acrylamide (100 mg) were added to a reaction flask in this order, and the temperature was lowered to 0°C under N2 protection. A solution of potassium tert-butoxide in tetrahydrofuran (1 mol / L, 1.025 mL) was added, and the mixture was reacted at 0°C for 1 hour. Upon completion of the reaction, the reaction solution was added dropwise to an ice-cooled saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was purified using a silica gel column to obtain Intermediate 14 (0.204 g). MS (ESI, [M+H] + ) m / z: 300.1 1 H NMR (500 MHz, DMSO-d6) δ 10.87(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,2H),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).

[0424] Example 15: Synthesis of Intermediate 15 [ka] [ka] Intermediate 14i-2 (420 mg), N,N-dimethylformamide (10 mL), and acrylamide (120 mg) were added to a reaction flask in this order, and the temperature was lowered to 0°C under N2 protection. Potassium tert-butoxide (1 mol / L, 1.221 mL) was then added, and the mixture was reacted at 0°C. Upon completion of the reaction, the reaction solution was added dropwise to an ice-cooled saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was purified using a silica gel column to obtain Intermediate 15 (0.237 g). MS (ESI, [M+H] + ) m / z: 300.1 1 H NMR(500MHz,DMSO-d6)δ 10.87(s,1H),7.80(s,1H),7.33(d,J=7.8Hz,1H),7.09(d,J=7.9Hz,1H),4.69(t,J=5.2H) z,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).

[0425] Example 16: Synthesis of Intermediate 16 [ka] [ka] Step 1: Preparation of intermediate 16b A reaction flask was charged with 16a (60 g), potassium carbonate (1.315 g), N,N-dimethylformamide (500 mL), and iodomethane (172 g) in this order, and the mixture was heated to 80°C under N2 protection. Upon completion of the reaction, the mixture was cooled to room temperature, diluted with ethyl acetate, washed with saturated sodium chloride solution, and the organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to give the desired intermediate 16b (64.5 g). MS (ESI, [M+H] + ) m / z: 163.10

[0426] Step 2: Preparation of intermediate 16c Potassium hydroxide (152 g) and methanol (600 mL) were added to a reaction flask in this order and stirred in an ice bath for 20 minutes. Intermediate 16b (40 g) was added and stirred for another 20 minutes. Iodobenzene diacetate (98 g) was added and the mixture was allowed to react at room temperature for 1 hour under N2 protection. The reaction was completed. The solvent was removed from the reaction mixture by vacuum distillation, and 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 removed by vacuum distillation. The concentrate was dissolved in tetrahydrofuran (600 mL), and then hydrochloric acid (82 mL, 6 M) was added and the mixture was allowed to react at room temperature for 30 minutes. The reaction was then completed. The pH of the reaction mixture was adjusted to 8-9 with saturated sodium bicarbonate solution, followed by extraction with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to yield the desired intermediate 16c (35.1 g). 1 H NMR(500MHz,chloroform-d)δ 7.42-7.31(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).

[0427] Step 3: Preparation of intermediate 16d A reaction flask was charged with Intermediate 16c (37 g) and methanol (500 mL) in this order, followed by sodium borohydride (8.25 g). The mixture was reacted at room temperature for 1.5 hours until the reaction was complete. The reaction mixture was quenched by adding saturated ammonium chloride solution dropwise, extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give Intermediate 16d (50 g).

[0428] Step 4: Preparation of intermediate 16e Intermediate 16d (35 g), toluene (300 mL), and p-toluenesulfonic acid (66.9 g) were added to a reaction flask in this order, and the mixture was reacted at 120 °C under N2 protection until the reaction was complete. The reaction solution was cooled to room temperature, and the solvent was removed by distillation 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 organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and then purified by silica gel column chromatography to obtain the target intermediate 16e (35.5 g). 1 H NMR(500MHz,DMSO-d6)δ 7.26-7.22(m,1H),6.93-6.87(m,2H),3.79(s,3H),3.53(s,2H),3.37(s,2H).

[0429] Step 5: Preparation of intermediate 16f At 0°C, intermediate 16e (35 g) and methanol (400 mL) were added to a reaction flask in this order, and sodium borohydride (5.83 g) was added in portions and the reaction was allowed to proceed at room temperature. Upon completion of the reaction, the reaction mixture was quenched by the dropwise addition of saturated ammonium chloride solution, followed by the addition of water and ethyl acetate. 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 16f (18 g). 1H NMR(500MHz,DMSO-d6)δ 7.10(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).

[0430] Step 6: Preparation of intermediate 16g A reaction flask was charged with 15 g of 16f, 150 mL of dichloromethane, 27.8 g of triethylamine, and 0.28 g of 4-dimethylaminopyridine, in that order. Acetic anhydride (10.2 g) was added in an ice bath, and the mixture was allowed to react at room temperature. Upon completion of the reaction, the solvent was removed by distillation 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 organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to give the target intermediate 16f (9.3 g). MS (ESI, [M+H] + ) m / z: 207.10 1 H NMR(500MHz,DMSO-d6)δ 7.22-7.06(m,1H),6.82(dd,J=27.3,8.3Hz,2H),5.41(s,1H),3.78(d,J=13.2Hz,3H),3.3 2-3.20(m,1H),3.18-3.09(m,1H),2.85(dd,J=34.6,17.1Hz,2H),1.97(d,J=15.3Hz,3H).

[0431] Step 7: Preparation of intermediate 16h 16g (5.6g), N-bromosuccinimide (5.32g), and acetonitrile (50mL) were added to a reaction flask in this order and reacted at 70°C. Upon completion of the reaction, the reaction solution was cooled to room temperature, and water and ethyl acetate were added. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and then purified by silica gel column chromatography to obtain the desired intermediate 16h (6.4g). 1 H NMR(500MHz,DMSO-d6)δ 7.36(d,J=8.6Hz,1H),6.81(d,J=8.7Hz,1H),5.41(tt,J=6.4,2.0Hz,1H),3.77(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).

[0432] Step 8: Preparation of intermediate 16i A reaction flask was charged with 16h (6.3 g) and chloroacetyl chloride (7.49 g) in this order, and trifluoromethanesulfonic acid (60 mL) was slowly added dropwise in an ice-water bath. The reaction was allowed to proceed at room temperature. Upon completion of the reaction, the reaction mixture was slowly added dropwise to ice water and extracted with dichloromethane. The combined organic phases were washed with saturated aqueous sodium bicarbonate solution, and 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). 1 H NMR(500MHz,DMSO-d6)δ 7.71(s,1H),5.46(tq,J=7.5,3.4,2.7Hz,1H),5.00(s,2H),3.87(d,J=1.9Hz,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).

[0433] Step 9: Preparation of intermediate 16j A reaction flask was charged with 16i ​​(7.0 g) and dichloromethane (70 mL) in this order, and boron trichloride (58 mL) was slowly added dropwise in an ice-water bath. The reaction was allowed to proceed at room temperature. Upon completion of the reaction, the reaction mixture 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 give the target intermediate 16j (5.0 g). MS(ESI, [MH] - ) m / z: 347.00 1 H NMR(500MHz,DMSO-d6)δ 11.24(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).

[0434] Step 10: Preparation of intermediate 16k To a reaction flask were added 16j (4.9 g), sodium carbonate (2.99 g), and acetonitrile (120 mL) in this order, and the reaction was carried out at 50° C. Upon completion of the reaction, water and ethyl acetate were added, and the organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and then purified by silica gel column chromatography to obtain the target intermediate 16k (3.7 g). 1 H NMR(500MHz,DMSO-d6)δ 7.69(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).

[0435] Step 11: Preparation of intermediate 16l A reaction flask was charged with 16k (3.0 g), 10% palladium on carbon (0.257 g), sodium bicarbonate (0.81 g), and ethanol (90 mL), in that order, and the mixture was reacted at room temperature in the presence of hydrogen. Upon completion of the reaction, the reaction mixture was filtered, and the solvent was removed from the filtrate by distillation under reduced pressure. Ethyl acetate and water were added to the residue, and the organic layer was separated and dried over anhydrous sodium sulfate. The organic layer was then filtered, and the filtrate was concentrated to obtain the target intermediate 16l (2.4 g). 1 H NMR(500MHz,DMSO-d6)δ 7.90(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).

[0436] Step 12: Preparation of intermediate 16m 16l (2.4 g), ethyl (triphenylphosphoranylidene)acetate (5.4 g), and toluene (30 mL) were added to a reaction flask in this order, and the reaction was carried out under N2 protection at 120°C. Upon completion of the reaction, 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 and then purified by silica gel column chromatography to obtain the target intermediate 16m (0.58 g). 1 H NMR(500MHz,DMSO-d6)δ 7.85(s,1H),7.42(d,J=7.9Hz,1H),7.18(d,J=7.9Hz,1H),5.54(tt,J=6.3,2.3Hz,1H),4.10(q,J=7.1Hz,2H),3.77(s,2H),3.46(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).

[0437] Step 13: Preparation of intermediate 16n 16m (2.4 g), potassium carbonate (0.79 g), and ethanol (30 mL) were added to a reaction flask in this order and reacted at room temperature. Upon completion of the reaction, 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 and purified by silica gel column chromatography to obtain the target intermediate 16n (0.42 g). MS (ESI, [M+H] + ) m / z: 261.10 1 H NMR(500MHz,DMSO-d6)δ 7.89(s,1H),7.36(d,J=7.8Hz,1H),7.13(d,J=7.8Hz,1H),4.96(d,J=4.1H z,1H),4.62(td,J=6.2,2.8Hz,1H),4.10(q,J=7.1Hz,2H),3.75(d,J=1.0H z,2H),3.24(dd,J=16.2,6.1Hz,1H),3.18(dd,J=16.0,6.0Hz,1H),2.92(d d,J=16.2,3.3Hz,1H),2.85(dd,J=16.0,3.3Hz,1H),1.18(t,J=7.1Hz,3H).

[0438] Step 14: Preparation of Intermediate 16 16n (90 mg), acrylamide (27 mg), and N,N-dimethylformamide (4 mL) were added to a reaction flask in this order, and the temperature was lowered to 0° C. Potassium tert-butoxide (0.28 mL, 1 M) was slowly added dropwise, and the reaction was carried out at 0° C. Upon completion of the reaction, the reaction solution was added dropwise to an ice-cooled aqueous ammonium chloride solution and extracted with ethyl acetate. 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 desired intermediate 16 (20 mg). 1H NMR(500MHz,DMSO-d6)δ 10.88(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=16.0,6.0 Hz,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).

[0439] Example 17: Synthesis of Compound 17 [ka] [ka] Step 1: Preparation of intermediate 17b At 0 °C under nitrogen protection, sodium hydride (60 wt%, 7.7 g) was added in portions to a solution of 17a (20.0 g) and trans-4-(tert-butoxycarbonylamino)cyclohexanol (27.7 g) in DMF (100 mL), and the reaction was allowed to proceed at room temperature until complete. Upon completion, the reaction mixture was slowly poured into 400 mL of ice water and stirred for 10 min. The cake was collected by filtration and dried to give 17b (39.1 g). MS (ESI, [M+H] + ) m / z: 351.1 1 H NMR(500MHz,DMSO-d6)δ 7.84(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,1H),4.49(dd t,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).

[0440] Step 2: Preparation of intermediate 17c 17b (20.5 g) and HCl (1,4-dioxane) (100 mL) were added to a reaction flask in this order and reacted at room temperature. The solvent was evaporated from the reaction mixture by rotary evaporation, and n-hexane was added to form a slurry at room temperature. The mixture was filtered, and the cake was collected and dried to give 17c (18.3 g). MS (ESI, [M+H] + ) m / z: 251.1

[0441] Step 3: Preparation of intermediate 17e 17d (10.0 g), 4-piperidinemethanol (8.1 g), DIPEA (11.2 g), and DMSO (90 mL) were added to a reaction flask in this order, and the temperature of the reaction mixture was raised to 90 °C. Upon completion of the reaction, 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 give intermediate 17e (12.0 g). MS (ESI, [M+H] + ) m / z: 252.0 1 H NMR(500MHz,DMSO-d6)δ 7.80(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).

[0442] Step 3: Preparation of intermediate 17f 17e (10.1 g), sodium hydroxide (2.4 g), methanol (100 mL), and water (10 mL) were added to a reaction flask in this order and reacted at room temperature for 1 hour. Upon completion of the reaction, the pH of the reaction mixture was adjusted to 3-4 with concentrated hydrochloric acid, and the solvent was evaporated by rotary evaporation. The mixture was slurried with DCM / MEOH, filtered, and the filtrate was concentrated to dryness to give intermediate 17f (1.2 g). MS(ESI, [MH] - ) m / z: 236.2 1H NMR(500MHz,DMSO-d6)δ 7.91(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).

[0443] Step 4: Preparation of intermediate 17g 17f (1.1 g), 17c (1.1 g), HATU (2.2 g), DIPEA (1.5 g), and DMF (20 mL) were added to a reaction flask in this order and reacted at room temperature. Upon completion of the reaction, 70 mL of ethyl acetate and 150 mL of water were added, and the organic phase was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the concentrate was purified by silica gel column chromatography to obtain intermediate 17g (1.2 g). MS (ESI, [M+H] + ) m / z: 470.4 1 H NMR(500MHz,DMSO-d6)δ 8.63-8.50(m,1H),7.88-7.71(m,2H),7.43-7.24(m,2H),7.12(tq,J=7.7,4.7,3.7Hz,1H) ,4.50(dtt,J=20.4,10.3,4.6Hz,4H),3.90-3.76(m,1H),2.97(q,J=13.1Hz,2H),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).

[0444] Step 5: Preparation of intermediate 17h A reaction flask was charged with 17g (0.5 g), Dess-Martin oxidant (1.3 g), and dichloromethane (30 mL) in that order, and the reaction was allowed to proceed at room temperature. Upon completion of the reaction, 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, filtered, and concentrated to give intermediate 17h (0.6 g).

[0445] Step 6: Preparation of Compound 17 To a reaction flask, 17h (90 mg), intermediate 1 (60 mg), sodium acetate (16 mg), and DCE / isopropanol (5:1, 20 mL) were added in this order and allowed to react at room temperature for 30 minutes. Sodium cyanoborohydride (24 mg) was then added and allowed to react at room temperature. Upon completion of the reaction, the solvent was evaporated from the reaction mixture, and the crude product was purified by silica gel column chromatography to give compound 17 (30 mg). MS (ESI, [M+H] + ) m / z: 723.4 1 H NMR(500MHz,DMSO-d6)δ 11.09(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).

[0446] Example 18: Synthesis of Compound 18 [ka] [ka] 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 a reaction flask in this order, and the mixture was allowed to react at room temperature. Upon completion of the reaction, 2 mL of saturated sodium bicarbonate solution was added to the reaction mixture to neutralize the acetic acid, followed by extraction with 50 mL of dichloromethane and 100 mL of water. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified using a silica gel column to give compound 18 (42 mg). MS (ESI, [M+H] + ) m / z: 737.3 1 H NMR(500MHz,DMSO-d6)δ 11.09(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=6.2,5.6Hz,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).

[0447] Example 19: Synthesis of Compound 19 [ka] [ka] 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 a reaction flask in this order, and the mixture was allowed to react at room temperature. Upon completion of the reaction, 2 mL of saturated sodium bicarbonate solution was added to the reaction mixture to neutralize the acetic acid, followed by extraction with 50 mL of dichloromethane and 100 mL of water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was purified using a silica gel column to give compound 19 (48 mg). MS (ESI, [M+H] + ) m / z: 737.3 1 H NMR(500MHz,DMSO-d6)δ 11.09(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=12.6Hz,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=13.3,4.5 Hz,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).

[0448] Example 20: Synthesis of Compound 20 [ka] [ka] Step 1: Preparation of compound 20 A reaction flask was charged with 17h (95 mg), intermediate 5 (60 mg), sodium acetate (18 mg), and DCE / isopropanol (5:1, 20 mL) in this order, and the mixture was allowed to react at room temperature for 30 minutes. Sodium cyanoborohydride (26 mg) was then added, and the mixture was allowed to react at room temperature. The solvent was evaporated from the reaction mixture by rotary evaporation, and the crude product was purified by silica gel column chromatography to give compound 20 (22 mg). MS (ESI, [M+H] + ) m / z: 751.6 1 H NMR(500MHz,DMSO-d6)δ 11.08(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),7.41-7.30(m,2H),7. 23-7.10(m,2H),4.61-4.44(m,4H),3.93-3.80(m,1H),3.20-3.10(m,2H),3.09-2.98(m,4H),2.77(ddd,J=17.2, 12.0,5.3Hz,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).

[0449] Example 21: Synthesis of Compound 21 [ka] [ka] Step 1: Preparation of compound 21 A reaction flask was charged with 17h (85 mg), intermediate 6 (66 mg), sodium acetate (20 mg), and DCE / isopropanol (5:1, 20 mL) in this order, and the mixture was allowed to react at room temperature for 30 minutes. Sodium cyanoborohydride (28 mg) was then added, and the mixture was allowed to react at room temperature. Upon completion of the reaction, the solvent was evaporated from the reaction mixture, and the crude product was purified by silica gel column chromatography to give compound 21 (42 mg). MS (ESI, [M+H] + ) m / z: 763.5 1 H NMR(500MHz,DMSO-d6)δ 11.08(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=13.2Hz,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).

[0450] Example 22: Synthesis of Compound 22 [ka] [ka] Step 1: Preparation of intermediate 22a To a reaction flask were added 17d (10.0 g), 4-hydroxypiperidine (7.1 g), DIPEA (11.2 g), and DMSO (90 mL), and the temperature of the reaction mixture was raised to 90° C. and the mixture was reacted for 2 hours. Upon completion of the reaction, the mixture was poured into 300 mL of water, filtered, and the cake was collected and dried to give intermediate 22a (8.2 g). MS (ESI, [M+H] + ) m / z: 238.1 1 H NMR(500MHz,DMSO-d6)δ 7.80(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,2H),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).

[0451] Step 2: Preparation of intermediate 22b 22a (8.3 g), sodium hydroxide (2.8 g), methanol (70 mL), and water (10 mL) were added to a reaction flask in this order and allowed to react at room temperature. Upon completion of the reaction, the pH of the reaction mixture was adjusted to 3-4 with concentrated hydrochloric acid, and the solvent was evaporated by rotary evaporation. The mixture was slurried with DCM / MeOH, filtered, and the filtrate was concentrated to dryness to give intermediate 22b (1.2 g). MS(ESI, [MH] - ) m / z: 222.1 1 H NMR(500MHz,DMSO-d6)δ 7.80(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),3.77(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).

[0452] Step 3: Preparation of intermediate 22c 22b (1.5 g), 17c (1.3 g), HATU (3.0 g), DIPEA (2.1 g), and DMF (30 mL) were added to a reaction flask in this order and reacted at room temperature. Upon completion of the reaction, 70 mL of ethyl acetate and 150 mL of water were added, and the organic phase was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the concentrate was purified by silica gel column chromatography to obtain intermediate 22c (1.4 g). MS (ESI, [M+H] + ) m / z: 456.3 1 H NMR(500MHz,DMSO-d6)δ 8.58(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=13.1,3.8H z,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).

[0453] Step 4: Preparation of intermediate 22d 22c (0.5 g), Dess-Martin oxidant (1.4 g), and dichloromethane (30 mL) were added to a reaction flask in this order and reacted at room temperature for 1 hour. Upon completion of the reaction, 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, filtered, and concentrated to give intermediate 22d (0.6 g).

[0454] Step 5: Preparation of Compound 22 22d (88 mg), intermediate 1 (69 mg), sodium acetate (25 mg), and DMA (20 mL) were added to a reaction flask in this order and allowed to react at room temperature for 30 minutes. Sodium cyanoborohydride (31 mg) was then added and the reaction was allowed to react at room temperature for 2 hours. The solvent was evaporated from the reaction mixture by rotary evaporation, and the crude product was purified by silica gel column chromatography to give compound 22 (32 mg). MS (ESI, [M+H] + ) m / z: 709.3 1 H NMR(500MHz,DMSO-d6)δ 11.10(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,1 H),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).

[0455] Example 23: Synthesis of Compound 23 [ka] [ka] Step 1: Preparation of compound 23 22d (108 mg), intermediate 5 (79 mg), sodium acetate (28 mg), and DMA (20 mL) were added to a reaction flask in this order and allowed to react at room temperature for 30 minutes. Sodium cyanoborohydride (33 mg) was then added and the reaction was allowed to continue at room temperature. The solvent was evaporated from the reaction mixture by rotary evaporation, and the crude product was purified by silica gel column chromatography to give compound 23 (27 mg). MS (ESI, [M+H] + ) m / z: 737.4 1 H NMR(500MHz,DMSO-d6)δ 11.07(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),7.23-7.1 0(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,1 H),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).

[0456] Examples 24 and 25: Synthesis of Compounds 24 and 25 [ka] [ka] Step 1: Preparation of intermediate 24b To a reaction flask were added 24a (1.443 g), DMSO (10 mL), DIPEA (2.247 g, 3.08 mL), and methyl 6-chloropyridazine-3-carboxylate (1 g) in this order, and the mixture was reacted at 90° C. Upon completion of the reaction, the mixture was poured into ice water, suction filtered, and the cake was dried to give 24b (2.7 g). MS (ESI, [M+H] + ) m / z: 363.16 1 H NMR(500MHz,DMSO-d6)δ 7.81(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).

[0457] Step 2: Preparation of intermediate 24c 24b (2.6 g), MeOH (30 mL), and water (3 mL) were added to a reaction flask in this order, followed by sodium hydroxide (1.43 g) and the mixture was allowed to react at room temperature. Upon completion of the reaction, the pH was adjusted to 4-5 with 6 M hydrochloric acid, and the solvent was concentrated. Approximately 100 mL of MeOH / DCM (v:v = 1:10) was added to the mixture to form a slurry. The solid was removed by suction filtration, and the mother liquor was concentrated to give 24c (1.9 g). MS (ESI, [M+H] + ) m / z: 349.25

[0458] Step 3: Preparation of intermediate 24d A reaction flask was charged with 17c (0.85 g), 24c (1.031 g), DCM (10 mL), HATU (1.68 g), and DIPEA (1.148 g, 1.551 mL) in this order, and the mixture was allowed to react at room temperature. Upon completion of the reaction, the reaction mixture was diluted with 100 mL of ethyl acetate and washed with 100 mL of 10% aqueous citric acid, followed by 100 mL of saturated sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give 24d (1.61 g). MS (ESI, [M+H] + ) m / z: 581.28

[0459] Step 4: Preparation of intermediate 24e A reaction flask was charged with 24d (1.61 g), DCM (20 mL), and trifluoroacetic acid (5 mL) in this order, and the mixture was allowed to react at room temperature. Upon completion of the reaction, the mixture was added to 200 mL of saturated sodium bicarbonate solution, extracted with 200 mL of DCM, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give 24e (1.3 g). MS (ESI, [M+H] + ) m / z: 481.22 1 H NMR(500MHz,DMSO-d6)δ 8.59(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( dtd,J=15.2,7.8,3.9Hz,1H),3.68(t,J=5.7Hz,4H),3.57(s,4H),2.16 -2.05(m,2H),1.94-1.85(m,2H),1.84-1.76(m,3H),1.74-1.44(m,5H).

[0460] Step 5: Preparation of intermediates 24f-1 and 24f-2 A reaction flask was charged with 24e (350 mg), 1,2-dichloroethane (10 mL), isopropanol (3 mL), intermediate 7 (208 mg), and one drop of acetic acid, in that order. Then, sodium cyanoborohydride (137 mg) was added, and the mixture was allowed to react overnight at room temperature. Upon completion of the reaction, 20 mL of saturated sodium bicarbonate solution and 50 mL of water were added to the reaction mixture, 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 the crude product. The crude product was then separated by high-performance liquid chromatography to obtain intermediate 24f-1 (95 mg) in the first peak and intermediate 24f-2 (85 mg) in the second peak, in that order.

[0461] The preparative configuration was as follows: The apparatus and preparative column used were a YMC high-pressure preparative chromatograph, and the preparative column model was CHIRALART Cellulose-SB. The mobile phase system was ethanol-dichloromethane (1:1) / n-hexane, with isocratic elution at ethanol-dichloromethane (1:1) / n-hexane = 50:50. The characteristic data of 24f-1 were as follows: MS (ESI, [M+H] + ) m / z: 724.30 1 H NMR(500MHz,DMSO-d6)δ 8.58(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),7.2 7(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).

[0462] Step 6: Preparation of Compound 24 24f-1 (91 mg), acrylamide (8.93 mg), and THF (10 mL) were added to a reaction flask in this order, and a 1 M solution of potassium tert-butoxide in tetrahydrofuran (0.088 mL) was added in an ice bath, and the mixture was reacted at 0° C. Upon completion of the reaction, the reaction mixture 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 then purified by silica gel column chromatography to give compound 24 (17 mg). MS (ESI, [M+H]+ ) m / z: 749.30 1 H NMR(500MHz,DMSO-d6)δ 11.09(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,2 H),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=11.8H) z,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).

[0463] Step 7: Preparation of Compound 25 24f-2 (80 mg), acrylamide (7.93 mg), and THF (10 mL) were added to a reaction flask in this order, and a 1 M solution of potassium tert-butoxide in tetrahydrofuran (0.078 mL) was added in an ice bath, and the mixture was reacted at 0° C. Upon completion of the reaction, the reaction mixture 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 then purified by silica gel column chromatography to give compound 25 (15 mg). MS (ESI, [M+H] + ) m / z: 749.52 1H NMR(500MHz,DMSO-d6)δ 11.09(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,2 H),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=11.8H) z,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).

[0464] Example 26: Synthesis of Compound 26 [ka] [ka] Step 1: Preparation of intermediate 26b To a reaction flask were added 26a (5.94 g), DMSO (30 mL), DIPEA (1.23 g, 15.39 mL), and methyl 6-chloropyridazine-3-carboxylate (5 g) in this order, and the mixture was reacted at 90° C. Upon completion of the reaction, the mixture was poured into ice water, suction filtered, and the cake was dried to give 26b (11.3 g). MS (ESI, [M+H] + ) m / z: 323.07 1 H NMR(500MHz,DMSO-d6)δ 7.87(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).

[0465] Step 2: Preparation of intermediate 26c A reaction flask was charged with 26b (11.3 g), MeOH (100 mL), and water (30 mL), in that order. NaOH (7.01 g) was then added, and the mixture was allowed to react at room temperature. Upon completion of the reaction, the pH was adjusted to 4-5 with 6 M hydrochloric acid, and the solvent was concentrated. Approximately 100 mL of MeOH / DCM (v:v = 1:10) was then added to form a slurry. The solid was removed by suction filtration, and the mother liquor was concentrated to give 26c (9.8 g). MS (ESI, [M+H] + ) m / z: 308.99

[0466] Step 3: Preparation of intermediate 26d A reaction flask was charged with 17c (2.5 g), 26c (2.68 g), DCM (30 mL), HATU (4.30 g), and DIPEA (5.63 g, 7.60 mL) in this order, and the mixture was allowed to react at room temperature. Upon completion of the reaction, the mixture was diluted with 100 mL of ethyl acetate and washed with 100 mL of 10% aqueous citric acid, followed by saturated sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give 26d (3.2 g). MS (ESI, [M+H] + ) m / z: 541.21

[0467] Step 4: Preparation of intermediate 26e A reaction flask was charged with 26d (3.2 g), DCM (20 mL), and trifluoroacetic acid (5 mL) in this order, and the mixture was allowed to react at room temperature. Upon completion of the reaction, the mixture was added to 200 mL of saturated sodium bicarbonate solution, extracted with DCM, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give 26e (2.56 g). MS (ESI, [M+H] + ) m / z: 441.20 1H NMR (500 MHz, DMSO-d6) δ 8.62(d,J=8.2Hz,1H),7.85(t,J=9.3Hz,2H),7.39(d,J=2.4Hz,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),2.16-2.0 5(m,2H),1.95-1.84(m,2H),1.64(qd,J=13.1,3.1Hz,2H),1.58-1.45(m,2H).

[0468] Step 5: Preparation of intermediate 26f Intermediate 8 (50 mg), Dess-Martin oxidant (141 mg), dichloromethane (5 mL), and DMF (1 mL) were added to a reaction flask in this order, and the mixture was allowed to react at room temperature. Upon completion of the reaction, the reaction mixture was extracted with 50 mL of water and 20 mL of ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate by distillation under reduced pressure to give intermediate 26f (50 mg). MS (ESI, [M+H] + ) m / z: 299.51

[0469] Step 6: Preparation of intermediate 26g 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 a reaction flask in this order, and the mixture was stirred at room temperature. Upon completion of the reaction, 2 mL of saturated sodium bicarbonate solution was added to the reaction mixture to neutralize the acetic acid, followed by extraction with 50 mL of dichloromethane and 100 mL of water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified using a silica gel column to yield compound 26g (30 mg). MS (ESI, [M+H] +) m / z: 723.36

[0470] Step 7: Preparation of Compound 26 26g (30 mg), maleic acid (4.81 mg), and MeOH / DCM (v:v = 1:10, 5 mL) were added to a reaction flask in this order, and the reaction mixture was clarified and concentrated. The reaction mixture was slurried with 10 mL of petroleum ether and then suction filtered to give 26 (32 mg). MS (ESI, [M+H] + ) m / z: 723.43 1 H NMR(500MHz,DMSO-d6)δ 11.09(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,1H),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).

[0471] Example 27: Synthesis of Compound 27 [ka] [ka] Step 1: Preparation of intermediate 27a Intermediate 9 (50 mg), Dess-Martin oxidant (141 mg), dichloromethane (5 mL), and DMF (1 mL) were added to a reaction flask in this order, and the mixture was allowed to react at room temperature. Upon completion of the reaction, the reaction mixture was extracted with 50 mL of water and 20 mL of ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate by distillation under reduced pressure to give intermediate 27a (50 mg). MS (ESI, [M+H] + ) m / z: 299.31

[0472] Step 6: Preparation of intermediate 27b Intermediate 27a (50 mg), 1,2-dichloroethane (6 mL), isopropanol (2 mL), intermediate 26e (88 mg), acetic acid (5.00 mg), and sodium cyanoborohydride (20.93 mg) were added to a reaction flask in this order, and the mixture was stirred at room temperature. Upon completion of the reaction, 2 mL of saturated sodium bicarbonate solution was added to the reaction mixture to neutralize the acetic acid, followed by extraction with 50 mL of dichloromethane and 100 mL of water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified using a silica gel column to give compound 27b (53 mg). MS (ESI, [M+H] + ) m / z: 723.42

[0473] Step 2: Preparation of compound 27 27b (53 mg), maleic acid (8.51 mg), and MeOH / DCM (v:v = 1:10, 5 mL) were added to a reaction flask in this order, and the reaction mixture was clarified and concentrated. The concentrate was slurried in 10 mL of petroleum ether and then suction filtered to give 27 (58 mg). MS (ESI, [M+H] + ) m / z: 723.52 1H NMR(500MHz,DMSO-d6)δ 11.09(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,1H),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).

[0474] Example 28: Synthesis of Compound 28 [ka] [ka] Step 1: Preparation of intermediate 28a Intermediate 14 (50 mg), IBX (94 mg), and dimethyl sulfoxide (5 mL) were added to a reaction flask in this order, and the mixture was allowed to react at room temperature. Upon completion of the reaction, 100 mL of sodium bicarbonate solution was added to the reaction mixture, which was then extracted with 100 mL of ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give the desired intermediate 28a (50 mg). MS (ESI, [M+H] + ) m / z: 298.41

[0475] Step 2: Preparation of compound 28 Intermediate 28a (50 mg), 1,2-dichloroethane (6 mL), isopropanol (2 mL), intermediate 26e (90 mg), acetic acid (5.00 mg), and sodium cyanoborohydride (20 mg) were added to a reaction flask in this order, and the mixture was stirred at room temperature for 1 hour. Upon completion of the reaction, 2 mL of saturated sodium bicarbonate solution was added to the reaction mixture to neutralize the acetic acid, followed by extraction with 50 mL of dichloromethane and 100 mL of water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified using a silica gel column to give compound 28 (72 mg). MS (ESI, [M+H] + ) m / z: 722.43 1 H NMR(500MHz,DMSO-d6)δ 10.87(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,2H),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).

[0476] Example 29: Synthesis of Compound 29 [ka] [ka] Step 1: Preparation of intermediate 29a Intermediate 15 (50 mg), IBX (94 mg), and dimethyl sulfoxide (5 mL) were added to a reaction flask in this order, and the mixture was allowed to react at room temperature. Upon completion of the reaction, 100 mL of sodium bicarbonate solution was added to the reaction mixture, which was then extracted with 100 mL of ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give the desired intermediate 29a (50 mg). MS (ESI, [M+H] + ) m / z: 298.35

[0477] Step 2: Preparation of compound 29 Intermediate 29a (50 mg), 1,2-dichloroethane (6 mL), isopropanol (2 mL), intermediate 26e (90 mg), acetic acid (5.00 mg), and sodium cyanoborohydride (20 mg) were added to a reaction flask in this order, and the mixture was stirred at room temperature for 1 hour. Upon completion of the reaction, 2 mL of saturated sodium bicarbonate solution was added to the reaction mixture to neutralize the acetic acid, followed by extraction with 50 mL of dichloromethane and 100 mL of water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified using a silica gel column to give compound 29 (93 mg). MS (ESI, [M+H] + ) m / z: 722.47 1H NMR(500MHz,DMSO-d6)δ 10.87(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,2H),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).

[0478] Example 30: Synthesis of Compound 30 [ka] [ka] Step 1: Preparation of Intermediate 30b Methyl 6-chloropyridazine-3-carboxylate (10 g), Intermediate 30a (26.9 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (4.73 g), sodium carbonate (18.43 g), dioxane (200 mL), and water (7 mL) were added to a reaction flask in this order, and the mixture was heated to 85 °C under N2 protection. Upon completion of the reaction, 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 using a silica gel column to give the desired Intermediate 30b (8.92 g). MS (ESI, [M+H] + ) m / z: 320.0 1H NMR(500MHz,DMSO-d6)δ 8.17(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).

[0479] Step 2: Preparation of Intermediate 30c A reaction flask was charged with 8.92 g of intermediate 30b, 210 mL of methanol, 30 mL of dichloromethane, and 2.23 g of 10% palladium on carbon, in that order. After the atmosphere was exchanged with H2, the mixture was reacted at room temperature for 5 hours. Upon completion of the reaction, the mixture was filtered, and the solvent was removed from the filtrate by distillation under reduced pressure. 20 mL of dimethyl sulfoxide was added to the residue, filtered, and the cake was collected. The cake was slurried in 50 mL of water, filtered, and the cake was collected to give 2.66 g of the desired intermediate 30c. MS (ESI, [M+H] + ) m / z: 322.1 1 H NMR(500MHz,DMSO-d6)δ 8.15(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).

[0480] Step 3: Preparation of intermediate 30d Intermediate 30c (1.7 g), sodium hydroxide (0.423 g), methanol (20 mL), and water (1 mL) were added to a reaction flask in this order, and the mixture was allowed to react at room temperature. Upon completion of the reaction, saturated citric acid solution was added to adjust the pH to 2-3, and dichloromethane was added to the organic phase, which was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure to give intermediate 30d (1.63 g). MS(ESI, [MH] -) m / z: 306.2 1 H NMR(500MHz,DMSO-d6)δ 13.75(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).

[0481] Step 4: Preparation of intermediate 30e Intermediate 30d (1.637 g), dichloromethane (30 mL), HATU (2.430 g), N,N-diisopropylethylamine (2.75 g, 3.72 mL), and Intermediate 17c (1.335 g) were added to a reaction flask in this order, and the mixture was allowed to react at room temperature. Upon completion of the reaction, 200 mL of ethyl acetate and 300 mL of saturated citric acid solution were added, and the organic phase was separated and washed with saturated sodium bicarbonate solution and saturated brine, respectively, then dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure to give Intermediate 30e (2.52 g). MS (ESI, [M+H] + ) m / z: 540.3

[0482] Step 5: Preparation of intermediate 30f Intermediate 30e (2.52 g), dichloromethane (30 mL), and trifluoroacetic acid (37.0 g, 25 mL) were added to a reaction flask in this order, and the mixture was allowed to react at room temperature. Upon completion of the reaction, the solvent was removed from the reaction mixture by vacuum distillation. 200 mL of dichloromethane / methanol (v:v = 9:1) was added to the residue, and the pH was adjusted to strong basicity with 20% sodium hydroxide solution. The organic phase was separated, and the aqueous phase was extracted with 100 mL of dichloromethane / methanol (v:v = 9:1). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation to give intermediate 30f (1.88 g). MS (ESI, [M+H] + ) m / z: 440.3 1 H NMR(500MHz,DMSO-d6)δ 9.04(d,J=8.1Hz,1H),8.13(d,J=8.7Hz,1H),7.83(dd,J=31.5,8.8Hz,2H),7.40(s,1 H),7.15(d,J=9.0Hz,1H),4.54(d,J=11.6Hz,1H),3.92(q,J=11.0,10.4Hz,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).

[0483] Step 6: Preparation of Compound 30 Intermediate 26f (60 mg), 1,2-dichloroethane (5 mL), isopropanol (1 mL), Intermediate 30f (88 mg), and sodium cyanoborohydride (37.7 mg) were added to a reaction flask in this order, and the mixture was stirred at room temperature. Upon completion of the reaction, 2 mL of saturated sodium bicarbonate solution was added to the reaction mixture to neutralize the acetic acid, followed by extraction with 50 mL of dichloromethane and 100 mL of water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was purified using a silica gel column to give compound 30 (77 mg). MS (ESI, [M+H] + ) m / z: 722.5 1H NMR(500MHz,DMSO-d6)δ 11.09(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=11.8Hz,4H),1.94-1.84(m,6H),1.70(q,J=12.4Hz,2H),1.53(q,J=11.3Hz,2H).

[0484] Example 31: Synthesis of Compound 31 [ka] [ka] Intermediate 27a (60 mg), 1,2-dichloroethane (5 mL), isopropanol (1 mL), intermediate 30f (88 mg), and sodium cyanoborohydride (37.7 mg) were added to a reaction flask in this order, and the mixture was stirred at room temperature. Upon completion of the reaction, 2 mL of saturated sodium bicarbonate solution was added to the reaction mixture to neutralize the acetic acid, followed by extraction with 50 mL of dichloromethane and 100 mL of water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was purified using a silica gel column to yield compound 31 (48 mg). MS (ESI, [M+H] + ) m / z: 722.5 1 H NMR(500MHz,DMSO-d6)δ 11.09(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,1 H),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).

[0485] Example 32: Synthesis of Compound 32

change

change

[0486] Example 33: Synthesis of Compound 33 [ka] [ka] Intermediate 29a (50 mg), 1,2-dichloroethane (5 mL), isopropanol (1 mL), intermediate 30f (73.5 mg), and sodium cyanoborohydride (31.5 mg) were added to a reaction flask in this order, and the mixture was stirred at room temperature. Upon completion of the reaction, 2 mL of saturated sodium bicarbonate solution was added to the reaction mixture to neutralize the acetic acid, followed by extraction with 50 mL of dichloromethane and 100 mL of water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was purified using a silica gel column to give compound 33 (37 mg). MS (ESI, [M+H] + ) m / z: 721.6 1 H NMR(500MHz,DMSO-d6)δ 10.88(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=2.4Hz,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).

[0487] Example 34: Synthesis of Compound 34 [ka] [ka] Step 1: Preparation of intermediate 34b 34a (3 g), DCM (30 mL), and trifluoroacetic acid (5 mL) were added to a reaction flask in this order, and the mixture was allowed to react at room temperature. Upon completion of the reaction, the reaction mixture was concentrated to give 34b (2.67 g).

[0488] Step 2: Preparation of intermediate 34c 34b (2.67 g), DMSO (30 mL), DIPEA (15 mL), and methyl 6-chloropyridazine-3-carboxylate (2 g) were added to a reaction flask in this order, and the mixture was reacted at 120° C. Upon completion of 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 give 34c (3.1 g). MS (ESI, [M+H] + ) m / z: 292.18

[0489] Step 3: Preparation of intermediate 34d A reaction flask was charged with 34c (3 g), MeOH (100 mL), and water (30 mL), followed by sodium hydroxide (2.88 g), and the mixture was allowed to react at room temperature. After the reaction was completed, 6 M hydrochloric acid was added to the mixture to adjust the pH to 4-5, and the solvent was concentrated. MeOH / DCM was added to the mixture to form a slurry, which was then filtered by suction to remove the solids. The mother liquor was concentrated to give 34d (3.1 g). MS (ESI, [M+H] + ) m / z: 278.14

[0490] Step 4: Preparation of intermediate 34e A reaction flask was charged with 17c (1 g), 34d (1.48 g), DCM (10 mL), HATU (1.58 g), and DIPEA (2.43 mL) in this order, and the mixture was allowed to react at room temperature. Upon 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 (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give 34e (1.1 g). MS (ESI, [M+H]+ ) m / z: 510.21 1 H NMR(500MHz,DMSO-d6)δ 8.56(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).

[0491] Step 5: Preparation of intermediate 34f 34e (600 mg), DCM (10 mL), and Dess-Martin oxidant (926 mg) were added to a reaction flask in this order, and the mixture was allowed to react at room temperature. Upon completion of the reaction, the reaction mixture was quenched with saturated sodium thiosulfate and sodium bicarbonate solutions, extracted with dichloromethane, and the organic phase was separated. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give 34f (490 mg). 1H NMR(500MHz,DMSO-d6)δ 9.71(d,J=1.6Hz,1H),8.57(d,J=8.2Hz,1H),7.85(d,J=8.7Hz,1H),7.80(d,J=9.6Hz,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(dtd,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).

[0492] Step 6: Preparation of intermediate 34g 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 a reaction flask in this order, and the mixture was stirred at room temperature. Upon completion of the reaction, 2 mL of saturated sodium bicarbonate solution was added to the reaction mixture to neutralize the acetic acid, followed by extraction with 50 mL of dichloromethane and 100 mL of water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and then purified using a silica gel column to yield compound 34g (40 mg). MS (ESI, [M+H] + ) m / z: 763.18

[0493] Step 7: Preparation of Compound 34 The reaction mixture was concentrated, slurried with petroleum ether, and filtered under vacuum to give compound 34 (43 mg). MS (ESI, [M+H] + ) m / z: 763.58 1 H NMR(500MHz,DMSO-d6)δ 11.12(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),7.41-7.3 1(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=5.3H z,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),2.58-2.5 3(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).

[0494] Example 35: Synthesis of Compound 35 [ka] [ka] Step 1: Preparation of intermediate 35a 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 a reaction flask in this order, and the mixture was stirred at room temperature for 1 hour. Upon completion of the reaction, 2 mL of saturated sodium bicarbonate solution was added to the reaction mixture to neutralize the acetic acid, followed by extraction with 50 mL of dichloromethane and 100 mL of water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified using a silica gel column to give Intermediate 35a (92 mg). MS (ESI, [M+H] +) m / z: 777.5

[0495] Step 2: Preparation of Compound 35 To a reaction flask, intermediate 35a (92 mg), dichloromethane (10 mL), methanol (5 mL), and maleic acid (15.11 mg) were added in this order, and the mixture was allowed to react at room temperature. Upon completion of the reaction, the solvent was removed by distillation under reduced pressure, and the residue was slurried in petroleum ether, filtered, and the cake was collected to give compound 35 (63 mg). MS (ESI, [M+H] + ) m / z: 777.5 1 H NMR(500MHz,DMSO-d6)δ 11.10(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).

[0496] Example 36: Synthesis of Compound 36 [ka] [ka] Step 1: Preparation of intermediate 36a 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 a reaction flask in this order, and the mixture was stirred at room temperature for 1 hour. Upon completion of the reaction, 2 mL of saturated sodium bicarbonate solution was added to the reaction mixture to neutralize the acetic acid. Then, 50 mL of dichloromethane and 100 mL of water were added for extraction. The organic phase was separated, and the aqueous phase was ...

Claims

1. A compound of formula I-AA, its stereoisomers or pharmaceutically acceptable salts thereof. 【Chemical 1】 (In the formula, Ring A is absent or C ５～１５ selected from a cycloalkenyl group, a 5- to 15-membered heterocycloalkenyl group, a phenyl group, or a 5- or 6-membered heteroaryl group; Ring B is selected from a phenyl group or a 5- to 6-membered heteroaryl group; Ring C is selected from 5- to 6-membered heteroaryl groups; Each R １ is a halogen, -OH, -NH ２ , -CN,C １～１０ Alkyl group, C １～１０ Alkoxy group or halo C １～１０ alkyl groups, and the —OH and —NH ２ , C １～１０ Alkyl group, C １～１０ Alkoxy group or halo C １～１０ The alkyl group is optionally substituted by one or more substituents; n is selected from 0, 1, 2 or 3; L is selected from linking groups; X ５ is selected from CH or N; X ６ is —O—, —NH— or —N(C １～６ alkyl)-, and the —NH— or —N(C １～６ alkyl)- is optionally substituted by one or more substituents; Each R ２ , R ３ and R ４ are halogen, —OH, and —NH ２ , -CN,C １～１０ Alkyl group, C １～１０ Alkoxy group or halo C １～１０ alkyl groups, and the —OH and —NH ２ , C １～１０ Alkyl group, C １～１０ Alkoxy group or halo C １～１０ The alkyl group is optionally substituted by one or more substituents; m, p, and q are each independently selected from 0, 1, 2, 3, or 4; Ring G is C ６～１０ selected from an aryl group or a 5- to 10-membered heteroaryl group; Ring E is C ３～１０ selected from a cycloalkyl group or a 3- to 10-membered heterocycloalkyl group; Ring F is C ６～１０ selected from an aryl group or a 5- to 10-membered heteroaryl group; R ｔ is hydrogen, -OH, C １～６ Alkyl group, C ３～１０ cycloalkyl group or 3- to 10-membered heterocycloalkyl group, １～６ Alkyl group, C ３～１０ The cycloalkyl group or 3- to 10-membered heterocycloalkyl group is optionally substituted with one or more substituents.

2. 2. The compound of claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the formula I-AA compound is selected from the formula I-1 compounds: 【Chemistry 2】 (In the formula, Ring A is absent or C ５～１０ selected from a cycloalkenyl group, a 5- to 10-membered heterocycloalkenyl group, a phenyl group, or a 5- or 6-membered heteroaryl group; Ring B is selected from phenyl groups; Ring C is selected from an isoxazolyl group or a furyl group; Each R １ is a halogen, -OH, -NH ２ , -CN,C １～４ Alkyl group, C １～４ Alkoxy group or halo C １～４ independently selected from alkyl groups, n is selected from 0, 1, 2 or 3; L is selected from linking groups; X １ , X ２ , X ３ , X ４ are each independently selected from N or CH; X ５ is selected from CH or N; X ６ is —O—, —NH— or —N(C １～６ alkyl)-, Each R ２ , R ３ and R ４ are halogen, —OH, and —NH ２ , -CN,C １～４ Alkyl group, C １～４ Alkoxy group or halo C １～４ independently selected from alkyl groups, m, p, and q are each independently selected from 0, 1, 2, 3, and 4.

3. Ring A is absent or C ５～７ selected from a cycloalkenyl group, a 5- to 10-membered heterocycloalkenyl group, a phenyl group, or a 5- or 6-membered heteroaryl group; Or, ring A is absent or C ５～６ selected from a cycloalkenyl group, a 5- to 9-membered heterocycloalkenyl group, a phenyl group, or a 5- or 6-membered heteroaryl group; or the compound according to claim 1 or 2, its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein ring A is absent or selected from a cyclopentenyl group, a monocyclohexenyl group, a bicyclohexenyl group, a dihydropyrrolyl group, a tetrahydropyridinyl group, a tetrahydroazepinyl group, an azaspirooctenyl group, an azaspirononenyl group, a phenyl group, a pyrrolyl group, a pyrazolyl group, a furyl group, an oxazolyl group, or a dihydrooxazinyl group.

4. structural fragment 【Chemistry 3】 but, 【Chemistry 4】 or 【Chemistry 5】 Selected from or structural fragments 【Chemistry 6】 but, 【Chemistry 7】 or 【Chemistry 8】 Selected from or structural fragments 【Chemistry 9】 but, 【Chemistry 10】 or 【Chemistry 11】 Selected from or structural fragments 【Chemistry 12】 but, 【Chemistry 13】 or 【Chemistry 14】 The compound according to any one of claims 1 to 3, its stereoisomer or a pharmaceutically acceptable salt thereof, selected from:

5. Each R １ is halogen, -OH, -NH ２ , -CN,C １～３ Alkyl group, C １～３ Alkoxy group or halo C １～３ independently selected from alkyl groups, Or, each R １ fluorine, chlorine, bromine, -OH, -NH ２ 5. The compound according to any one of claims 1 to 4, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein each of the compound and the stereoisomer is independently selected from -CN or -CN.

6. The L is C １～３０ Alkylene group, C ２～３０ Alkenylene group or C ２～３０ alkynylene groups, １～３０ Alkylene group, C ２～３０ Alkenylene group or C ２～３０ One or more —CH ２ - is optionally -O-, C ３～１２ a cycloalkyl group, a 3- to 12-membered heterocycloalkyl group, a 4- to 12-membered heterocycloalkenyl group, C ６～１２ Aryl group, 5- to 12-membered heteroaryl group, —NH—, —N(C １～６ alkyl)- or -S-, and said C １～３０ Alkylene group, C ２～３０ Alkenylene group or C ２～３０ An alkynylene group is optionally substituted by one or more substituents; Or, the L is -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 -Selected from, however, Cy １ is a bond or, optionally, one or more R ａ C replaced by ３～１２ selected from a cycloalkyl group, a 4- to 12-membered heterocycloalkyl group, or a 4- to 12-membered heterocycloalkenyl group; LNK, LNK １ , LNK ２ are bonds, C １～１２ Alkylene group or C １～１２ heteroalkylene groups, Cy ２ is a bond or, optionally, one or more R ｂ C replaced by ３～１２ selected from a cycloalkyl group, a 4- to 12-membered heterocycloalkyl group, or a 4- to 12-membered heterocycloalkenyl group; Each R ａ and R ｂ are halogen, —OH, and —NH ２ , -CN,C １～４ Alkyl group, C １～４ Alkoxy group, halo C １～４ Alkyl group, C １～４ Alkylamino group, diC １～４ Alkylamino group, C ３～１２ The compound according to any one of claims 1 to 5, its stereoisomer or a pharmaceutically acceptable salt thereof, which is independently selected from a cycloalkyl group or a 4- to 12-membered heterocycloalkyl group.

7. Cy １ is a bond or, optionally, one or more R ａ C replaced by ４～１１ selected from a cycloalkyl group, a 4- to 11-membered heterocycloalkyl group, or a 4- to 11-membered heterocycloalkenyl group; Or Cy １ optionally one or more R ａ a piperidinyl group, a diazaspirononyl group, a piperazinyl group, a monoazaspirononyl group, a cyclohexyl group, a spirononyl group, an azetidinyl group, an octahydrocyclopentapyrrolyl group, an azabicyclononyl group, a monoazaspironoundecyl group, a diazaspironoundecyl group, a pyrrolidinyl group, or a tetrahydropyridinyl group, each of which is substituted by Or Cy １ optionally one or more R ａ replaced by 【Chemistry 15】 or 【Chemistry 16】 7. The compound of claim 6, its stereoisomer or a pharmaceutically acceptable salt thereof, selected from:

8. Cy ２ is a bond or, optionally, one or more R ｂ C replaced by ４～１１ selected from a cycloalkyl group or a 4- to 11-membered heterocycloalkyl group; Or Cy ２ is a bond or, optionally, one or more R ｂ cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl or piperidinyl substituted by Or Cy ２ But the bond, 【Chemistry 17】 or 【Chemistry 18】 7. The compound of claim 6, its stereoisomer or a pharmaceutically acceptable salt thereof, selected from:

9. Structural fragment -L- or -LNK １ -Cy １ -LNK-Cy ２ -LNK ２ -but, 【Chemistry 19】 or 【Chemistry 20】 7. The compound of claim 6, its stereoisomer or a pharmaceutically acceptable salt thereof, selected from:

10. structural fragment 【Chemical 21】 but, 【Chemical 22】 【Chemical 23】 【Chemistry 24】 or 【Chemistry 25】 The compound according to any one of claims 1 to 9, its stereoisomer or a pharmaceutically acceptable salt thereof, selected from:

11. structural fragment 【Chemical 26】 or 【Chemical 27】 but, 【Chemical 28】 or 【Chemical formula 29】 3. The compound according to claim 1 or 2, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from:

12. the compound of formula I-AA or formula I-1 is selected from the compounds of formula I, formula I-A1 or formula IA; 【Chemistry 30】 or the formula I-AA compound or formula I-1 compound is selected from compounds 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; 【Chemical 31】 【Chemical Formula 32】 wherein X is selected from CH or N; or the formula I-AA compound or formula I-1 compound is selected from 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; 【Chemical 33】 【Chemical Formula 34】 12. The compound according to any one of claims 1 to 11, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein X is selected from CH or N.

13. Ring A is C ５～６ a cycloalkenyl group, a 5- to 8-membered heterocycloalkenyl group containing 1 to 3 heteroatoms selected from N, O, or S (e.g., 1 to 2 heteroatoms selected from N or O), a phenyl group, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, or S (e.g., 1 to 2 heteroatoms selected from N or O); Ring B is a phenyl group, Ring C is selected from an isoxazolyl group or a furyl group; Each R １ is halogen, -OH, -NH ２ , -CN or C １～３ independently selected from alkyl groups (e.g., methyl, ethyl, and propyl); n is selected from 0 or 1; L is LNK １ -Cy １ -LNK-Cy ２ -LNK ２ - Selected from LNK, LNK １ , LNK ２ are each a bond or C １～３ alkylene groups; Cy １ is a bond, C ３～７ a cycloalkyl group, a 4- to 7-membered heterocycloalkyl group, or a 5- to 7-membered heterocycloalkenyl group; Cy ２ is a bond, C ３～７ a cycloalkyl group, a 4- to 7-membered heterocycloalkyl group, or a 5- to 7-membered heterocycloalkenyl group, and Cy １ and Cy ２ is not simultaneously a bond, X １ , X ２ , X ３ , X ４ are each independently selected from N or CH; X ５ is selected from CH or N; X ６ is —O—, —NH— or —N(C １～６ alkyl)-, Each R ２ , R ３ and R ４ are halogen, -OH, and -NH ２ , -CN or C １～３ independently selected from alkyl groups (e.g., methyl, ethyl, and propyl); m is selected from 1 or 2; 3. The compound according to claim 1 or 2, its stereoisomer or pharmaceutically acceptable salt thereof, wherein 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, which is a compound selected from the following: 【Chemistry 35】 【Chemical 36】 【Chemical 37】 【Chemical Formula 38】 【Chemical Formula 39】 【Chemistry 40】 【Chemistry 41】 【Chemistry 42】 【Chemistry 43】 【Chemical 44】 or 【Chemistry 45】

15. A compound of Formula I' or Formula I'', a moiety, a stereoisomer, a derivative, or a pharmaceutically acceptable salt thereof: 【Chemistry 46】 wherein ring A is absent or C ５～１０ selected from a cycloalkenyl group, a 5- to 10-membered heterocycloalkenyl group, a phenyl group, or a 5- or 6-membered heteroaryl group; Ring B is selected from phenyl groups; Ring C is selected from an isoxazolyl group or a furyl group; L is selected from a linking group.

16. A compound of formula I'-a or formula I''-a, a moiety, a stereoisomer thereof, a derivative, or a pharmaceutically acceptable salt thereof: 【Chemistry 47】 wherein ring A is absent or C ５～１０ selected from a cycloalkenyl group, a 5- to 10-membered heterocycloalkenyl group, a phenyl group, or a 5- or 6-membered heteroaryl group; Ring B is selected from phenyl groups; Ring C is selected from an isoxazolyl group or a furyl group; Each R １ａ is a halogen, -OH, -NH ２ , -CN,=O, -CHO,C １～４ Alkyl group, C １～４ Alkoxy group, C １～６ Alkyl OC(O)-, C ３～１２ cycloalkyl group or 4- to 12-membered heterocycloalkyl group, １～４ Alkyl group, C １～４ Alkoxy group, C ３～１２ The cycloalkyl group or 4- to 12-membered heterocycloalkyl group may optionally contain one or more halogens, ═O, —OH, —NH ２ , -CN, CHO, COOH, -C １～４ Alkyl-OH, C １～６ alkylOC(O)-, or optionally C １～６ substituted by a 4- to 10-membered heterocycloalkyl group substituted by alkylCOC(O)—; n is selected from 0, 1, 2, or 3.

17. 17. The compound, moiety, stereoisomer, derivative or pharmaceutically acceptable salt thereof of claim 15 or 16, which is a compound selected from: 【Chemistry 48】 【Chemistry 49】 【Chemistry 50】 【Chemistry 51】 or 【Chemistry 52】

18. Use of the compound, moiety, isomer, derivative or pharmaceutically acceptable salt thereof according to any one of claims 15 to 17, which exists in the form of a Protac molecule, in a Protac molecule, or for constituting a part of a Protac molecule, or for degrading the androgen receptor (AR).

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a compound, moiety, isomer thereof, derivative or pharmaceutically acceptable salt thereof according to any one of claims 15 to 17.

20. 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, moiety, isomer thereof, derivative or pharmaceutically acceptable salt thereof according to any one of claims 15 to 17, or a pharmaceutical composition according to claim 19, in the manufacture of a medicament for the prevention or treatment of a condition that is treated by degrading a target protein that binds to a targeting ligand.

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