Condensed imide derivatives

Abstract

Provided are fused imide derivatives of formula I, methods for their preparation, pharmaceutical compositions containing the compounds, and their use in the treatment of related diseases (eg, cancer). [Formula 1] TIFF2024542178000453.tif28143

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is an international application of Chinese Patent Applications Nos. 202111371514.4, 202111667477.1, 202210824373.5, 202211261799.0, 202211378992.2, and 202211413934.9, filed on November 18, 2021, December 31, 2021, July 13, 2022, October 14, 2022, November 4, 2022, and November 11, 2022, respectively, and claims the priority and rights of the Chinese patent applications, the contents of which are hereby incorporated by reference in their entireties. [Technical Field]

[0002] The present application relates to fused imide derivatives and proteolytic agents, methods for their preparation, pharmaceutical compositions containing the compounds, and their use in the treatment of related diseases (e.g., cancer). [Background technology]

[0003] Bruton's tyrosine kinase (BTK) is primarily expressed in B cells and distributed throughout the lymphoid, hematopoietic, and hematopoietic systems. It is a member of the Tec family of non-receptor tyrosine kinases. Other members of this family include Tec, ITK / TSK / EMT, TXK, and BMX, which share high structural homology. Recent studies of B cells, particularly B-cell non-Hodgkin's lymphoma and rheumatoid arthritis, have revealed that BTK is frequently abnormally expressed. Because BTK is primarily expressed in B cells and myeloid cells, it offers excellent targetability and safety.

[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, thereby effectively reducing the amount of target proteins in cells. By introducing ligands that can bind to different target proteins into Protac molecules, technology using Protac molecules can be used to treat various diseases, and this technology has attracted considerable attention in recent years. Summary of the Invention

[0005] 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; Or, ring A is absent, or C 5~6 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 benzene ring 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; Cy 1 is a bond, C 3~12 cycloalkyl group or 4- to 12-membered heterocycloalkyl group, 3~12The cycloalkyl group or 4- to 12-membered heterocycloalkyl group may optionally be one or more R a is replaced by LNK is a binding 1~12 Alkylene group or C 1~12 heteroalkylene groups, Cy 2 does not exist, or C 3~12 cycloalkyl groups or 4- to 12-membered heterocycloalkyl groups, and the cycloalkyl groups or heterocycloalkyl groups may optionally be one or more R b is replaced by 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; The PTM is selected from a drug or a derivative thereof that binds to a target protein.

[0006] In some embodiments, 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 5~6 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 benzene ring 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; Cy1 is a bond, C 3~12 cycloalkyl group or 4- to 12-membered heterocycloalkyl group, 3~12 The cycloalkyl group or 4- to 12-membered heterocycloalkyl group may optionally be one or more R a is replaced by LNK is a binding 1~12 Alkylene group or C 1~12 heteroalkylene groups, Cy 2 does not exist, or C 3~12 cycloalkyl groups or 4- to 12-membered heterocycloalkyl groups, and the cycloalkyl groups or heterocycloalkyl groups may optionally be one or more R b is replaced by 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; The PTM is selected from a drug or a derivative thereof that binds to a target protein.

[0007] In some embodiments, in the compound of Formula I, its stereoisomer, or pharmaceutically acceptable salt thereof, the structural moiety [ka] teeth, [ka] and the PTM is selected from the following structural moiety: [ka] Not selected from.

[0008] In some embodiments, Cy 1 optionally one or more Ra is selected from 4- to 12-membered heterocycloalkyl groups substituted by

[0009] In some embodiments of the present application, when ring A is present, Cy 2 or LNK(Cy 2 is absent), may be directly covalently bonded to ring B, and similarly, [ka] may be covalently attached directly to ring B.

[0010] In some embodiments, the PTM described herein is selected from a drug or derivative thereof that acts on AR, ER, a kinase, a phosphatase, MDM2, human BET bromodomain protein, Hsp90, HDAC, human lysine methyltransferase, a RAF receptor, FKBP, vascular endothelial growth factor, a receptor or protein associated with immunosuppression, an aryl hydrocarbon receptor, a thyroid hormone receptor, HIV protease, HIV integrase, HCV protease, HBV protease, or acylprotein thioesterase 1 and / or acylprotein thioesterase 2.

[0011] In some embodiments, the PTM described herein is selected from drugs or derivatives thereof that act on ALK, BET, CDK, PARP, EGFR, γ-secretase, CBFβ-SMMHC, WEE1, MEK, BCR-ABL, MET, RAS, BTK, VEGFR, JAK, HER2, HDAC, Akt, PI3K, mTOR, AR, ER, PDEδ, SRC, MDM2, RAF, IRAK4, STAT3, and c-Myc.

[0012] In some embodiments, the PTM described herein is selected from a drug or derivative thereof that acts on ALK, BRD4, CDK4 / 6, PARP, EGFR, γ-secretase, CBFβ-SMMHC, WEEl, MEK, BCR-ABL, MET, KRAS, EGFR, BTK, AR, ER, PDEδ, JAK, MDM2, or RAF.

[0013] In some embodiments, the PTMs described herein are selected from drugs or derivatives thereof that act on BTK or WEE1.

[0014] In some embodiments, the PTMs described herein are selected from drugs or derivatives thereof that act on BTK.

[0015] In another aspect, the present application relates to a compound of formula II-1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, T is selected from CH or N; R is selected from hydrogen or a 5- to 6-membered heterocycloalkyl group, said heterocycloalkyl group optionally being ═O or C 1~6 substituted by alkyl groups, Ring E is selected from a phenyl group, a benzocycloalkenyl group (e.g., a 4- to 12-membered benzocycloalkenyl group, a 4- to 10-membered benzocycloalkenyl group, or a 4- to 8-membered benzocycloalkenyl group), or a benzoheterocycloalkenyl group (e.g., a 4- to 12-membered benzo heterocycloalkenyl group or a 5- to 11-membered benzo heterocycloalkenyl group), X 2 is selected from CH or N, L is selected from connecting groups, Ring A, Ring B, Ring C, R 1 and n are as defined herein.

[0016] In another aspect, the present application relates to a compound of formula II, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, T is selected from CH or N; R is selected from hydrogen or a 5- to 6-membered heterocycloalkyl group, said heterocycloalkyl group optionally being ═O or C 1~6 substituted by alkyl groups, Ring E is selected from a phenyl group, a benzocycloalkenyl group, or a benzoheterocycloalkenyl group; X 2 is selected from CH or N, L is selected from connecting groups, Ring A, Ring B, Ring C, R 1 and n are as defined herein.

[0017] In some embodiments, L is -Cy 1 -LNK-Cy 2 -LNK-, -Cy 1 -LNK-Cy 2 -or-Cy 1 -Cy 2 -LNK-, but Cy 1 , LNK, Cy 2 is as described herein. In some embodiments, L is -Cy 1 -LNK-Cy 2 -, but Cy 1 , LNK, Cy 2 is as described herein.

[0018] In another aspect, the present application relates to a compound of formula I'a, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, T is selected from CH or N; R is selected from hydrogen or a 5- to 6-membered heterocycloalkyl group, said heterocycloalkyl group optionally being ═O or C 1~6 substituted by alkyl groups, Ring E is selected from a phenyl group, a benzocycloalkenyl group, or a benzoheterocycloalkenyl group; X 2 is selected from CH or N, Ring A, Ring B, Ring C, R 1 ,n,Cy 1 , LNK and Cy 2 are defined as described herein.

[0019] In some embodiments, X 2 is selected from CH, and in some embodiments, X 2 is selected from N.

[0020] In some embodiments, the ring E is a phenyl group, a benzo C 5~12 It is selected from a cycloalkenyl group and a 5- to 12-membered benzoheterocycloalkenyl group.

[0021] In some embodiments, the ring E is a phenyl group, a benzo C 5~6 It is selected from a cycloalkenyl group and a 5- to 11-membered benzoheterocycloalkenyl group.

[0022] In some embodiments, Ring E is selected from a phenyl group, a 5-membered benzo heterocycloalkenyl group, a 6-membered benzo heterocycloalkenyl group, a 10-membered benzo heterocycloalkenyl group, or an 11-membered benzo heterocycloalkenyl group.

[0023] In some embodiments, the ring E is a phenyl group, [ka] In some specific embodiments, the ring E is selected from a phenyl group. In some specific embodiments, the ring E is selected from [ka] Selected from.

[0024] In another embodiment, the compound of formula I, its stereoisomer or pharmaceutically acceptable salt thereof described herein is selected from the compound of formula I′, its stereoisomer or pharmaceutically acceptable salt thereof, [ka] During the ceremony, T is selected from CH or N; R is selected from hydrogen or a 5- to 6-membered heterocycloalkyl group, said heterocycloalkyl group optionally being ═O or C 1~6 It is substituted by an alkyl group.

[0025] 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.

[0026] In some embodiments, ring A is absent or C 5~8 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.

[0027] In some embodiments, ring A is absent or C 5~7 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.

[0028] 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.

[0029] 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.

[0030] In some embodiments, ring A is absent or C5~6 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.

[0031] 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.

[0032] In some embodiments, ring A is absent or is selected from a cyclopentenyl group, a dicyclohexenyl group, a dihydropyrrolyl group, a tetrahydropyridinyl group, a tetrahydroazepinyl group, a dihydrooxazinyl group, an azaspirooctenyl group, an azaspirononenyl group, a phenyl group, a pyrrolyl group, a pyrazolyl group, a furyl group, or an oxazolyl group.

[0033] In some specific embodiments, ring A is C 5~10 In some specific embodiments, ring A is selected from a cycloalkenyl group or a 5- to 10-membered heterocycloalkenyl group. 5~8 In some specific embodiments, ring A is selected from a cycloalkenyl group or a 5- to 9-membered heterocycloalkenyl group. 5~7 In some specific embodiments, ring A is selected from a cycloalkenyl group or a 5- to 9-membered heterocycloalkenyl group. 5~6In some specific embodiments, ring A is selected from a 5- to 9-membered heterocycloalkenyl group. In some specific embodiments, ring A is selected from a 5- to 8-membered heterocycloalkenyl group. In some specific embodiments, ring A is selected from a 5-membered heterocycloalkenyl group. In some specific embodiments, ring A is selected from a 6-membered heterocycloalkenyl group. In some specific embodiments, ring A is selected from a 7-membered heterocycloalkenyl group. In some specific embodiments, ring A is selected from an 8-membered heterocycloalkenyl group. In some specific embodiments, ring A is selected from a 9-membered heterocycloalkenyl group. In some specific embodiments, ring A is absent or C 5~6 Shik In some preferred embodiments, ring A is selected from the group consisting of C alkyl, C aryl, C methyl ... 5~6 A cycloalkenyl group is selected from a 5- to 7-membered heterocycloalkenyl group containing 1 to 2 heteroatoms selected from N, O, or S (preferably 1 to 2, e.g., 1 N atom), or a phenyl group. In some specific embodiments, ring A is absent or selected from a cyclopentenyl group, a dihydropyrrolyl group, a tetrahydropyridinyl group, a tetrahydroazepinyl group, or a phenyl group.

[0034] In some specific embodiments, ring A is selected from a cyclopentenyl group, a dicyclohexenyl group, a dihydropyrrolyl group, a tetrahydropyridinyl group, a tetrahydroazepinyl group, a dihydrooxazinyl group, an azaspirooctenyl group, or an azaspirononenyl group.

[0035] In some specific embodiments, ring A is selected from a cyclopentenyl group or a dicyclohexenyl group. In some specific embodiments, ring A is selected from a dihydropyrrolyl group, a dihydrooxazinyl group, a tetrahydropyridinyl group, a tetrahydroazepinyl group, an azaspirooctenyl group, or an azaspirononenyl group.

[0036] In some specific embodiments, ring A is selected from a phenyl group, a pyrrolyl group, a pyrazolyl group, a furyl group, or an oxazolyl group.

[0037] In some embodiments, ring A is absent or C 5~7 It is selected from a cycloalkenyl group, a 5- to 8-membered heterocycloalkenyl group, a phenyl group, or a pyrrolyl group.

[0038] Also in some embodiments, ring A is absent or C 5~6 It is selected from a cycloalkenyl group, a 5- to 8-membered heterocycloalkenyl group, a phenyl group, or a pyrrolyl group.

[0039] Also in some embodiments, ring A is absent or is selected from a C5 cycloalkenyl group, a 5-, 6-, 7-, or 8-membered heterocycloalkenyl group, a phenyl group, or a pyrrolyl group.

[0040] Also in some embodiments, ring A is absent or is selected from a cyclopentenyl group, a dihydropyrrolyl group, a tetrahydropyridinyl group, a tetrahydroazepinyl group, an azaspirooctene group, a phenyl group, or a pyrrolyl group.

[0041] Also in some embodiments, ring A is absent.

[0042] Also in some embodiments, ring A is C 5~6 It is selected from a cycloalkenyl group and a 5- to 8-membered heterocycloalkenyl group.

[0043] In some embodiments, ring A is selected from a cyclopentenyl group, a dihydropyrrolyl group, a tetrahydropyridinyl group, a tetrahydroazepinyl group, or an azaspiroctene. In some embodiments, ring A is selected from a cyclopentenyl group. In some embodiments, ring A is selected from a dihydropyrrolyl group, a tetrahydropyridinyl group, a tetrahydroazepinyl group, or an azaspiroctene.

[0044] Also in some embodiments, ring A is selected from a phenyl group or a pyrrolyl group.

[0045] In some embodiments, the structural moiety [ka] teeth, [ka] Or, in some embodiments, the structural moiety is selected from [ka] teeth, [ka] and the bond connected to ring A is selected from [ka] The * in the above indicates that the bond is connected to an atom of ring A, and the bond connected to ring C [ka] The * in the above indicates that the bond is connected to an atom of ring C (hereinafter, * in similar positions have the same or similar meaning).

[0046] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety is selected from [ka] teeth, [ka] (for example, [ka] ), [ka] (for example, [ka] ), [ka] where * has the same or similar definition as above.

[0047] In some specific embodiments, the structural moiety [ka] teeth, [ka] In some specific embodiments, the structural moiety is selected from [ka] teeth, [ka] In some specific embodiments, the structural moiety is selected from [ka] teeth, [ka] Selected from.

[0048] In some embodiments, the structural moiety [ka] teeth, [ka] Selected from.

[0049] In some specific embodiments, the structural moiety [ka] teeth, [ka] In some specific embodiments, the structural moiety is selected from [ka] teeth, [ka] In some specific embodiments, the structural moiety is selected from [ka] teeth, [ka] Selected from.

[0050] In some embodiments, the structural moiety [ka] teeth, [ka] Selected from.

[0051] In some specific embodiments, the structural moiety [ka] teeth, [ka] Selected from.

[0052] In some specific embodiments, the structural moiety [ka] teeth, [ka] Selected from.

[0053] In some embodiments, the structural moiety [ka] teeth, [ka] Selected from.

[0054] In some specific embodiments, the structural moiety [ka] teeth, [ka] Selected from.

[0055] In some specific embodiments, the structural moiety [ka] teeth, [ka] Selected from.

[0056] In some embodiments, the structural moiety [ka] teeth, [ka] Selected from.

[0057] In some specific embodiments, the structural moiety [ka] teeth, [ka] Selected from.

[0058] In some specific embodiments, the structural moiety [ka] teeth, [ka] Selected from.

[0059] Also in some embodiments, the structural moiety [ka] teeth, [ka] Selected from.

[0060] Also in some embodiments, the structural moiety [ka] teeth, [ka] Selected from.

[0061] Also in some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety is selected from [ka] teeth, [ka] Selected from.

[0062] 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 independently selected from alkyl groups .

[0063] In some embodiments, each R 1 is independently selected from fluorine, chlorine, bromine, —OH, —NH, or —CN. In some embodiments, each R 1 are independently selected from fluorine, chlorine, or bromine.

[0064] In some embodiments, each R 1 are independently selected from fluorine.

[0065] In some embodiments, n is selected from 0, 1, or 2. In some embodiments, n is selected from 0 or 1.

[0066] In some embodiments, the structural moiety [ka] teeth, [ka] Selected from.

[0067] In some specific embodiments, the structural moiety [ka] teeth, [ka] Selected from.

[0068] In some specific embodiments, the structural moiety [ka] teeth, [ka] Selected from.

[0069] In some specific embodiments, the structural moiety [ka] teeth, [ka] Selected from.

[0070] In some specific embodiments, the structural moiety [ka] teeth, [ka] Selected from.

[0071] In some specific embodiments, the structural moiety [ka] teeth, [ka] Selected from.

[0072] Also in some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety is selected from [ka] teeth, [ka] Selected from.

[0073] In some embodiments, the PTM is [ka] wherein: T is selected from CH or N; R is selected from hydrogen or a 5- to 6-membered heterocycloalkyl group, The alkyl group is optionally ═O or C 1~6 substituted by alkyl groups, Ring E is selected from a phenyl group, a benzocycloalkenyl group, or a benzoheterocycloalkenyl group.

[0074] In some specific embodiments, T is selected from CH.

[0075] In some specific embodiments, R is hydrogen, an imidazolidinonyl group, or C 1~4Preferably, R is selected from hydrogen, an imidazolidinonyl group, a 1-methyl-imidazolidinonyl group, a 1-ethyl-imidazolidinonyl group, or a 1-propyl-imidazolidinonyl group.

[0076] In some specific embodiments, Ring E is selected from a phenyl group, a benzopiperidinyl group, a benzodihydropyrrolyl group, a spiro[benzopyran-piperidine], or a benzodihydrooxazinopiperazine group. In some specific embodiments, Ring E is selected from a phenyl group.

[0077] In some specific embodiments, ring E is selected from a phenyl group and L is -Cy 1 -LNK-Cy 2 - is selected from X 2 is selected from CH, with the exception of Cy 1 , LNK, Cy 2 is as described herein.

[0078] In some embodiments, the PTM is [ka] and ring E is as defined above. Preferably, the PTM is [ka] More preferably, the PTM is [ka] is.

[0079] In some embodiments, the structural moiety -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, the structural moiety -Cy is selected from 1 -LNK-Cy 2 -is -Cy 1 -, -Cy 1 -Cy 2 -or-Cy 2 In some specific embodiments, the structural moiety -Cy 1 -LNK-Cy 2 -is -Cy 1 -LNK-, -Cy 1 -LNK-Cy 2 -or-LNK-Cy 2 In some specific embodiments, the structural moiety -Cy 1 -LNK-Cy 2 -is -Cy 1 In some specific embodiments, the structural moiety -Cy 1 -LNK-Cy 2 -is -Cy 1 -LNK-Cy 2 In some specific embodiments, the structural moiety -Cy 1 -LNK-Cy 2 -LNK-Cy 2 -Selected from.

[0080] Also in some embodiments, the structural moiety -Cy 1 -LNK-Cy 2 -is -Cy 1 -, -Cy 1 -LNK, -Cy 1 -Cy 2 -or-Cy 1 -LNK-Cy 2 -Selected from.

[0081] In some embodiments, Cy 1 is a bond or, optionally, one or more R a The following groups are substituted by C 4~11 It is selected from a cycloalkyl group or a 4- to 11-membered heterocycloalkyl group.

[0082] In some embodiments, Cy 1 is a bond or, optionally, one or more R a The following groups are substituted by C 6~9 In some embodiments, Cy is selected from a cycloalkyl group or a 4- to 11-membered heterocycloalkyl group. 1 is a bond or, optionally, one or more R a The following groups are substituted by C 6~9 It is selected from a cycloalkyl group (e.g., a C6 cycloalkyl group, a C9 cycloalkyl group), and a 5- to 11-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O, or S (e.g., 1 to 3, or 1 to 2 heteroatoms selected from N or O).

[0083] In some embodiments, Cy 1 is a bond or, optionally, one or more R a and is selected from the following atomic groups: a C6 cycloalkyl group, a C9 cycloalkyl group, a 4-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-membered heterocycloalkyl group, substituted by:

[0084] In some embodiments, Cy 1 is a bond or, optionally, one or more R a is selected from the following atomic groups: a C6 cycloalkyl group, a C9 cycloalkyl group, a 4-, 6-, or 8- to 11-membered heterocycloalkyl group, substituted by:

[0085] In some specific embodiments, Cy 1 is selected from a bond. In some specific embodiments, Cy 1 is selected from a C6 cycloalkyl group or a C9 cycloalkyl group, and the cycloalkyl group is optionally selected from one or more R a In some specific embodiments, Cy is substituted by 1 is selected from 4-, 6-, or 8- to 11-membered heterocycloalkyl groups, said heterocycloalkyl groups optionally containing one or more Ra In some specific embodiments, Cy is substituted by 1 is selected from 4- or 6-membered heterocycloalkyl groups, said heterocycloalkyl groups optionally being selected from one or more R a In some specific embodiments, Cy is substituted by 1 is selected from 8- to 11-membered heterocycloalkyl groups, said heterocycloalkyl groups optionally containing one or more R a In some specific embodiments, Cy is substituted by 1 is selected from 8-, 9-, 10-, or 11-membered heterocycloalkyl groups, said heterocycloalkyl groups optionally containing one or more R a is replaced by

[0086] In some embodiments, Cy 1 is a bond or, optionally, one or more R a By and is selected from the group consisting of a cyclohexyl group, a spirononyl group, an azetidinyl group, an octahydrocyclopentapyrrolyl group, a piperidinyl group, a monoazaspirononyl group, a diazaspirononyl group, an azabicyclononyl group (e.g., a monoazabicyclononyl group), a monoazaspironoundecyl group, and a diazaspironoundecyl group.

[0087] In some specific embodiments, Cy 1 is selected from a cyclohexyl group or a spirononyl group. 1 is selected from an azetidinyl group or a piperidinyl group. 1 is selected from an octahydrocyclopentapyrrolyl group, a monoazaspirononyl group, a diazaspirononyl group, an azabicyclononyl group, a monoazaspiroundecyl group, or a diazaspiroundecyl group. 1is selected from a bond, a piperidinyl group, a cyclohexyl group, a spirononyl group, a monoazaspirononyl group, an octahydrocyclopentapyrrolyl group, a monoazaspironoundecyl group, a monooxamonoazaspironoundecyl group, or an azabicyclononyl group.

[0088] In some embodiments, Cy 1 is a bond or, optionally, one or more R a The following groups substituted by: [ka] Selected from.

[0089] In some embodiments, Cy 1 is a bond or, optionally, one or more R a The following groups substituted by: [ka] Selected from.

[0090] In some specific embodiments, Cy 1 teeth, [ka] In some specific embodiments, Cy 1 teeth, [ka] In some specific embodiments, Cy 1 teeth, [ka] In some specific embodiments, Cy 1 is a bond, [ka] Selected from.

[0091] In some embodiments, Cy 1 optionally one or more R a is selected from 4- to 11-membered heterocycloalkyl groups substituted by

[0092] In some embodiments, Cy 1 optionally one or more R a and the heterocycloalkyl group is selected from 5-, 6-, 7-, 8-, 9-, 10-, or 11-membered heterocycloalkyl groups substituted by:

[0093] In some embodiments, Cy 1 optionally one or more R a and the heterocycloalkyl group is selected from a 6-membered, or 9- to 11-membered heterocycloalkyl group substituted by:

[0094] In some embodiments, Cy 1 optionally one or more R a and wherein the heterocycloalkyl group is selected from 6-, 9-, or 11-membered heterocycloalkyl groups substituted by:

[0095] In some embodiments, Cy 1 optionally one or more R a The compound is selected from a piperidinyl group, monoazaspirononane, diazaspirononane or diazaspirondecane, each substituted by:

[0096] In some embodiments, Cy 1 optionally one or more R a replaced by [ka] Selected from.

[0097] In some embodiments, LNK is a binding, C 1~6 Alkylene group or C 1~6 Hetero It is selected from alkylene groups.

[0098] In some embodiments, LNK is a binding or C 1~4 It is selected from alkylene groups.

[0099] In some embodiments, LNK is a binding or C 1~3 It is selected from alkylene groups.

[0100] In some embodiments, LNK is selected from a bond or -CH2-. In some specific embodiments, LNK is selected from a bond. In some specific embodiments, LNK is selected from -CH2-.

[0101] In some embodiments, Cy 2 does not exist, or C 4~11 cycloalkyl groups or 4- to 11-membered heterocycloalkyl groups, and the cycloalkyl groups or heterocycloalkyl groups may optionally be one or more R b In some specific embodiments, Cy is substituted by 2 In some specific embodiments, Cy 2 is C 4~11 cycloalkyl groups or 4- to 11-membered heterocycloalkyl groups, and the cycloalkyl groups or heterocycloalkyl groups may optionally be one or more R b is replaced by

[0102] In some embodiments, Cy 2 does not exist, or C 4~6 cycloalkyl groups or 4- to 6-membered heterocycloalkyl groups, and the cycloalkyl groups or heterocycloalkyl groups may optionally be one or more R b In some specific embodiments, Cy is substituted by 2 is C 4~6 cycloalkyl groups or 4- to 6-membered heterocycloalkyl groups, and the cycloalkyl groups or heterocycloalkyl groups may optionally be one or more R b In some embodiments, Cy is substituted by 2 does not exist, or C 4~6cycloalkyl groups or 4- to 6-membered heterocycloalkyl groups, and the cycloalkyl groups or heterocycloalkyl groups may optionally be one or more R b wherein said heterocycloalkyl group contains 1 to 3 (eg, 1 to 2) heteroatoms selected from N, O, or S (eg, N or O).

[0103] In some embodiments, Cy 2 is absent or is selected from a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, an azetidinyl group, a pyrrolidinyl group, or a piperidinyl group, and the cyclobutyl group, the cyclopentyl group, the azetidinyl group, the pyrrolidinyl group, or the piperidinyl group is optionally selected from one or more R b is replaced by

[0104] In some embodiments, Cy 2 does not exist, or [ka] Selected from.

[0105] In some embodiments, Cy 2 does not exist, or [ka] Selected from.

[0106] In some embodiments, Cy 2 is absent or is selected from a cyclobutyl group, a cyclopentyl group, an azetidinyl group, a pyrrolidinyl group, or a piperidinyl group, The cyclobutyl, cyclopentyl, azetidinyl, pyrrolidinyl or piperidinyl group may optionally be substituted with one or more R b is replaced by

[0107] In some embodiments, Cy 2 teeth, [ka] Selected from.

[0108] 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.

[0109] In some embodiments, R a , R b are halogen, -OH, -NH2, -CN or C 1~3 alkyl groups.

[0110] In some embodiments, R a , R b are each independently selected from halogen, —OH, —NH 2 , or —CN.

[0111] In some embodiments, the structural moiety -Cy 1 -LNK- is a bond, -CH2-, [ka] Selected from.

[0112] In some specific embodiments, the structural moiety -Cy 1 -LNK- is [ka] In some specific embodiments, the structural moiety -Cy is selected from 1 -LNK- is [ka] In some specific embodiments, the structural moiety -Cy is selected from 1 -LNK- is [ka] In some specific embodiments, the structural moiety -Cy is selected from 1 -LNK- is [ka] Selected from.

[0113] Also in some embodiments, the structural moiety -Cy 1 -LNK- is [ka] Selected from.

[0114] In some embodiments, the structural moiety -LNK-Cy 2 - is a bond, -CH2-, [ka] Selected from.

[0115] In some embodiments, the structural moiety -LNK-Cy 2 - is a bond, -CH2-, [ka] Selected from.

[0116] In some embodiments, the structural moiety -Cy 1 -Cy 2 -teeth, [ka] Selected from.

[0117] Also in some embodiments, the structural moiety -Cy 1 -Cy 2 -teeth, [ka] Selected from.

[0118] In some embodiments, the structural moiety -Cy 1 -LNK-Cy 2 - is a bond, -CH2-, [ka] Selected from.

[0119] In some specific embodiments, the structural moiety -Cy 1 -LNK-Cy 2 -teeth, [ka] In some specific embodiments, the structural moiety -Cy is selected from 1 -LNK-Cy 2 -teeth, [ka] Selected from.

[0120] Also in some embodiments, the structural moiety -Cy 1 -LNK-Cy 2 -teeth, [ka] Selected from.

[0121] In some embodiments, the structural moiety [ka] teeth, [ka] Selected from TIFF2024542178000114.tif227169TIFF2024542178000115.tif239169TIFF2024542178000116.tif119168.

[0122] Also in some embodiments, the structural moiety [ka] teeth, [ka] Selected from TIFF2024542178000119.tif222168.

[0123] In some embodiments, T is selected from CH. In some embodiments, T is selected from N.

[0124] In some embodiments, R is selected from hydrogen or a 5- to 6-membered heterocycloalkyl group, and the heterocycloalkyl group is optionally ═O or C 1~3 It is substituted by an alkyl group.

[0125] In some embodiments, R is selected from hydrogen or a 5-membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally ═O or C 1~3 It is substituted by an alkyl group.

[0126] In some embodiments, R is selected from hydrogen or an imidazolinyl group, wherein the imidazolinyl group is optionally substituted with ═O or a methyl group.

[0127] In some embodiments, R is hydrogen or [ka] Selected from.

[0128] In some embodiments, the present application relates to a compound of Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, provided that: Ring A is absent or C 5~8a cycloalkenyl group, a 5- to 9-membered heterocycloalkenyl group (preferably a 5- to 8-membered heterocycloalkenyl group or a 5- to 7-membered heterocycloalkenyl group), or a phenyl group, or ring A is absent or selected from C 5~6 A cycloalkenyl group, a 5- to 9-membered heterocycloalkenyl group (preferably a 5- to 8-membered heterocycloalkenyl group or a 5- to 7-membered heterocycloalkenyl group), or a phenyl group, and preferably, ring A is absent or selected from C 5~6 a cycloalkenyl group, a 5- to 7-membered heterocycloalkenyl group containing 1 to 2 heteroatoms selected from N, O or S (preferably containing 1 to 2, for example, 1 N atom), or a phenyl group; or preferably, ring A is selected from C 5~6 a 5- to 7-membered heterocycloalkenyl group containing 1 to 2 heteroatoms selected from N, O, or S (preferably containing 1 to 2, for example, 1 N atom); Ring B is selected from benzene ring groups; Ring C is selected from an isoxazolyl group or a furyl group; Each R 1 are independently selected from fluorine, chlorine or bromine, and n is selected from 0, 1 or 2, preferably 0 or 1; Preferably, [ka] teeth, [ka] Selected from PTM is [ka] and preferably the PTM is [ka] where: T is selected from CH or N, preferably CH; R is selected from hydrogen or a 5- to 6-membered heterocycloalkyl group, said heterocycloalkyl group optionally being ═O or C 1~6 Preferably, R is hydrogen, an imidazolidinonyl group, or C 1~4 alkyl-substituted imidazolidinonyl groups, more preferably R is selected from hydrogen, an imidazolidinonyl group, a 1-methyl-imidazolidinonyl group, a 1-ethyl-imidazolidinonyl group, or a 1-propyl-imidazolidinonyl group; Ring E is selected from a phenyl group, a benzocycloalkenyl group, or a benzoheterocycloalkenyl group, and preferably, Ring E is a phenyl group, a benzopiperidinyl group, a benzodihydropyrrolyl group, a spiro[benzopyran-piperidine] group, or a benzodihydrooxazinopipera group. Selected from Gin, Cy 1 is a bond or, optionally, one or more R a The following groups are substituted by C 6~9 a cycloalkyl group or a 5- to 11-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, O, or S (for example, 1 to 3, or 1 to 2 heteroatoms selected from N or O); LNK is a bond or C 1~4 alkylene groups, preferably LNK is a bond or C 1~3 alkylene groups, Cy 2 does not exist, or C 4~6 cycloalkyl groups or 4- to 6-membered heterocycloalkyl groups, and the cycloalkyl groups or heterocycloalkyl groups may optionally be one or more R b and preferably Cy 2 does not exist, or C 4~6 It is selected from a cycloalkyl group or a 4- to 6-membered heterocycloalkyl group, provided that the heterocycloalkyl group contains 1 to 2 heteroatoms selected from N or O.

[0129] In some specific embodiments, the present application relates to a compound of Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, provided that: Ring A is absent or selected from a cyclopentenyl group, a dihydropyrrolyl group, a tetrahydropyridinyl group, a tetrahydroazepinyl group, or a phenyl group, preferably, Ring A is selected from a cyclopentenyl group, a dihydropyrrolyl group, a tetrahydropyridinyl group, or a tetrahydroazepinyl group, more preferably, Ring A is selected from a dihydropyrrolyl group, a tetrahydropyridinyl group, or a tetrahydroazepinyl group; Preferably, the structural moiety [ka] teeth, [ka] Selected from PTM is [ka] and preferably the PTM is [ka] and Cy 1 is selected from a bond, a piperidinyl group, a cyclohexyl group, a spirononyl group, a monoazaspirononyl group, an octahydrocyclopentapyrrolyl group, a monoazaspiroundecyl group, a monooxamonoazaspiroundecyl group, or an azabicyclononyl group, and is preferably selected from Cy 1 is a bond, [ka] Selected from LNK is a bond or C 1~3 alkylene groups, preferably LNK is selected from a bond or -CH2-; Cy 2is absent or is selected from a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, an azetidinyl group, a pyrrolidinyl group, or a piperidinyl group, and the cyclobutyl group, the cyclopentyl group, the azetidinyl group, the pyrrolidinyl group, or the piperidinyl group is optionally selected from one or more R b and preferably Cy 2 does not exist, or [ka] Selected from.

[0130] In some embodiments, in the heterocycloalkenyl or heterocycloalkyl group, heteroatoms are selected from N, NH, O, or S. In some embodiments, in the heterocycloalkenyl or heterocycloalkyl group, heteroatoms are selected from N, O, or S. In some embodiments, in the heteroaryl group, heteroatoms are selected from N, O, or S. In some embodiments, in the heteroalkylene group, heteroatoms are selected from N, NH, O, S, S(O), or S(O).

[0131] In some embodiments, the number of heteroatoms in the heterocycloalkenyl group, heterocycloalkyl group, heteroalkylene group, or heteroaryl group is selected from 1, 2, 3, 4, 5, or 6. In some embodiments, the number of heteroatoms in the heterocycloalkenyl group, heterocycloalkyl group, heteroalkylene group, or heteroaryl group is selected from 1, 2, 3, or 4. In some embodiments, the number of heteroatoms in the heterocycloalkenyl group, heterocycloalkyl group, heteroalkylene group, or heteroaryl group is selected from 1, 2, or 3.

[0132] The present application also relates to compounds of formula I'-1A, I'-2A, I'-1A-1, I'-2A-1, I'-3A-1, I'-3A-2, I'-4A-1, I'-4A-2, their stereoisomers or pharmaceutically acceptable salts thereof, [ka] In the formula, ring A, ring C, Cy 1 , Cy 2 , LNK, R 1 , n, T and X 2 The definitions are as described herein. X is selected from CH or N.

[0133] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety is selected from [ka] teeth, [ka] Selected from.

[0134] In some embodiments, the structural moiety [ka] teeth, [ka] Selected from.

[0135] In some specific embodiments, the structural moiety [ka] teeth, [ka] In some specific embodiments, the structural moiety is selected from [ka] teeth, [ka] Selected from.

[0136] In some embodiments, the structural moiety [ka] teeth, [ka] Selected from.

[0137] In some specific embodiments, the structural moiety [ka] teeth, [ka] In some specific embodiments, the structural moiety is selected from [ka] teeth, [ka] Selected from.

[0138] In some embodiments, the structural moiety [ka] teeth, [ka] Selected from.

[0139] In some specific embodiments, the structural moiety [ka] teeth, [ka] In some specific embodiments, the structural moiety is selected from [ka] teeth, [ka] In some specific embodiments, the structural moiety is selected from [ka] teeth, [ka] Selected from.

[0140] Also in some embodiments, the structural moiety [ka] teeth, [ka] Selected from.

[0141] Also in some embodiments, the structural moiety [ka] teeth, [ka] Selected from.

[0142] Also in some embodiments, the structural moiety [ka] teeth, [ka] Selected from.

[0143] In some embodiments, the structural moiety -Cy 1 -LNK-, -LNK-Cy 2 -, -Cy 1 -Cy 2 -or-Cy 1 -LNK-Cy 2 - is as described herein.

[0144] The present application also relates to the following compounds, their stereoisomers or pharmaceutically acceptable salts thereof: [ka] TIFF2024542178000163.tif242153TIFF2024542178000164.tif202157TIFF2024542178000165.tif222147TIFF20245421780 00166.tif217158TIFF2024542178000167.tif239163TIFF2024542178000168.tif238153TIFF2024542178000169.tif238157 TIFF2024542178000170.tif241167TIFF2024542178000171.tif238156TIFF2024542178000172.tif229161TIFF20245421780 00173.tif194155TIFF2024542178000174.tif220157TIFF2024542178000175.tif227160TIFF2024542178000176.tif188163

[0145] In another aspect, the present application relates to a compound of formula I″, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, [ka] During the ceremony, [ka] teeth, [ka] Selected from Ring A is C 5~10 a cycloalkenyl group, a 5- to 10-membered heterocycloalkenyl group, a phenyl group, or a 5- to 6-membered heteroaryl group, or ring A is selected from C 5~8 a cycloalkenyl group, a 5- to 10-membered heterocycloalkenyl group, a phenyl group, or a 5- to 6-membered heteroaryl group, or ring A is selected from C 5~7 a cycloalkenyl group, a 5- to 10-membered heterocycloalkenyl group, a phenyl group, or a 5- to 6-membered heteroaryl group, or ring A is selected from C 5~6 a cycloalkenyl group, a 5- to 10-membered heterocycloalkenyl group, a phenyl group, or a 5- to 6-membered heteroaryl group, or ring A is selected from C 5~10 or ring A is selected from C 5~8 or ring A is selected from C 5~6 selected from a cycloalkenyl group or a 5- to 9-membered heterocycloalkenyl group, the PTM is selected from a drug or a derivative thereof that binds to a target protein; L is selected from connecting groups, R 1 and n are defined as described herein.

[0146] In another aspect, the present application relates to a compound, moiety, stereoisomer, derivative thereof (specifically, for example, a Protac molecule) or a pharmaceutically acceptable salt thereof of Formula I''-1, [ka] During the ceremony, [ka] teeth, [ka] Selected from Ring A is C 5~10 a cycloalkenyl group, a 5- to 10-membered heterocycloalkenyl group, a phenyl group, or a 5- to 6-membered heteroaryl group, or ring A is selected from C 5~8 A cycloalkenyl group, a 5- to 10-membered heterocycloalkenyl group, a phenyl group, or a 5- to 6-membered hetero aryl groups, or ring A is selected from C 5~7 a cycloalkenyl group, a 5- to 10-membered heterocycloalkenyl group, a phenyl group, or a 5- to 6-membered heteroaryl group, or ring A is selected from C 5~6 a cycloalkenyl group, a 5- to 10-membered heterocycloalkenyl group, a phenyl group, or a 5- to 6-membered heteroaryl group, or ring A is selected from C 5~10 or ring A is selected from C 5~8 or ring A is selected from C 5~6 selected from a cycloalkenyl group or a 5- to 9-membered heterocycloalkenyl group, L is selected from connecting groups, R 1 and n are defined as described herein.

[0147] In some embodiments of the present application, the Formula I"-1 compound, moiety, stereoisomer thereof, derivative (e.g., Protac molecule), or pharmaceutically acceptable salt thereof is selected from the Formula I" compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof.

[0148] In some embodiments, ring A is C 5~8 Cycloalkenyl group (or C 5~7 a 5- to 9-membered heterocycloalkenyl group, a phenyl group, a pyrrolyl group, a pyrazolyl group, a furyl group, or an oxazolyl group.

[0149] In some embodiments, ring A is C 5~6It 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.

[0150] In some embodiments, ring A 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.

[0151] In some embodiments, ring A is chosen from a cyclopentenyl group, a dicyclohexenyl group, a dihydropyrrolyl group, a tetrahydropyridinyl group, a tetrahydroazepinyl group, an azaspirooctenyl group, a dihydrooxazinyl group, an azaspirononenyl group, a phenyl group, a pyrrolyl group, a pyrazolyl group, a furyl group, or an oxazolyl group.

[0152] In some specific embodiments, ring A is C 5~8 In some specific embodiments, ring A is selected from a cycloalkenyl group or a 5- to 9-membered heterocycloalkenyl group. 5~7 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. In some specific embodiments, ring A is selected from a 5- to 8-membered heterocycloalkenyl group. In some specific embodiments, ring A is selected from a 6- to 8-membered heterocycloalkenyl group. In some specific embodiments, ring A is selected from a 5-membered heterocycloalkenyl group. In some specific embodiments, ring A is selected from a 6-membered heterocycloalkenyl group. In some specific embodiments, ring A is selected from a 7-membered heterocycloalkenyl group. In some specific embodiments, ring A is selected from an 8-membered heterocycloalkenyl group. In some specific embodiments, ring A is selected from a 9-membered heterocycloalkenyl group.

[0153] In some specific embodiments, ring A is selected from a cyclopentenyl group, a dicyclohexenyl group, a dihydropyrrolyl group, a tetrahydropyridinyl group, a dihydrooxazinyl group, a tetrahydroazepinyl group, an azaspirooctenyl group, or an azaspirononenyl group.

[0154] In some specific embodiments, ring A is a cyclopentenyl group or a dicyclohexenyl group. In some embodiments, ring A is selected from a dihydropyrrolyl group, a dihydrooxazinyl group, a tetrahydropyridinyl group, a tetrahydroazepinyl group, an azaspirooctenyl group, or an azaspirononenyl group.

[0155] In some embodiments, ring A is selected from a phenyl group, a pyrrolyl group, a pyrazolyl group, a furyl group, or an oxazolyl group.

[0156] Also in some embodiments, ring A is C 5~7 It is selected from a cycloalkenyl group, a 5- to 8-membered heterocycloalkenyl group, a phenyl group, and a pyrrolyl group.

[0157] Also in some embodiments, ring A is C 5~6 It is selected from a cycloalkenyl group, a 5- to 8-membered heterocycloalkenyl group, a phenyl group, and a pyrrolyl group.

[0158] Also in some embodiments, Ring A is selected from a C5 cycloalkenyl group, a 5-, 6-, 7-, or 8-membered heterocycloalkenyl group, a phenyl group, or a pyrrolyl group.

[0159] Also in some embodiments, ring A is selected from a cyclopentenyl group, a dihydropyrrolyl group, a tetrahydropyridinyl group, a tetrahydroazepinyl group, an azaspirooctene group, a phenyl group, or a pyrrolyl group.

[0160] Also in some embodiments, ring A is C 5~6 It is selected from a cycloalkenyl group and a 5- to 8-membered heterocycloalkenyl group.

[0161] Also in some embodiments, ring A is selected from a cyclopentenyl group, a dihydropyrrolyl group, a tetrahydropyridinyl group, a tetrahydroazepinyl group, or an azaspirooctene.

[0162] In some embodiments, ring A is selected from a cyclopentenyl group, hi some embodiments, ring A is selected from a dihydropyrrolyl group, a tetrahydropyridinyl group, a tetrahydroazepinyl group, or an azaspirooctene group.

[0163] Also in some embodiments, ring A is selected from a phenyl group or a pyrrolyl group.

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

[0165] In some embodiments, the structural moiety [ka] teeth, [ka] and in some embodiments, the structural moiety is selected from [ka] teeth, [ka] Selected from.

[0166] Also in some embodiments, the structural moiety [ka] teeth, [ka] Selected from.

[0167] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety is selected from [ka] teeth, [ka] Selected from.

[0168] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety is selected from [ka] teeth, [ka] In some embodiments, the structural moiety is selected from [ka] teeth, [ka] In some embodiments, the structural moiety is selected from [ka] teeth, [ka] Selected from.

[0169] In some embodiments, the structural moiety [ka] teeth, [ka] and in some embodiments, the structural moiety is selected from [ka] teeth, [ka] In some embodiments, the structural moiety is selected from [ka] teeth, [ka] In some embodiments, the structural moiety is selected from [ka] teeth, [ka] In some embodiments, the structural moiety is selected from [ka] teeth, [ka] Selected from.

[0170] Also in some embodiments, the structural moiety [ka] teeth, [ka] Selected from.

[0171] In some embodiments, L is -Cy 1 -LNK-Cy 2 -LNK-, -Cy 1 -LNK-Cy 2 -or-Cy 1 -Cy 2 -LNK-, and in some embodiments, L is selected from -Cy 1 -LNK-Cy 2 -, and in some embodiments, Cy 1 , LNK, Cy 2 , -Cy 1 -LNK-, -LNK-Cy 2 -, -Cy 1 -Cy 2 -or-Cy 1 -LNK-Cy 2 is as described herein, and in some embodiments, the moiety [ka] teeth, [ka] Selected from TIFF2024542178000217.tif35170. Or part [ka] teeth, [ka] Selected from TIFF2024542178000220.tif171161.

[0172] Additionally, in some embodiments, the moiety [ka] teeth, [ka] Selected from or part of [ka] teeth, [ka] Selected from.

[0173] In some embodiments, the PTM is as described herein.

[0174] In some embodiments, the PTM is [ka] wherein R, T, or ring E is as defined herein.

[0175] In some embodiments, the PTM is [ka] wherein R or T is as defined herein.

[0176] In another aspect, the present application relates to a compound, moiety, isomer (e.g., stereoisomer) thereof, derivative (e.g., Protac molecule) or pharmaceutically acceptable salt thereof, represented by Formula III: [ka] In the formula, ring A is C 5~10selected from a cycloalkenyl group or a 5- to 10-membered heterocycloalkenyl group, Ring B is selected from benzene ring groups; Ring C is selected from an isoxazolyl group or a furyl group; n is as defined herein; Each R 1 are halogens, -OH, -NH2, -CN, =O, C 1~4 Alkoxy group, -CHO, C 3~6 cycloalkyl group, 3- to 10-membered heterocycloalkyl group or C 1~4 alkyl groups, 3~6 cycloalkyl group, 3- to 10-membered heterocycloalkyl group or C 1~4 The alkyl group may optionally be a halogen, -OH, -NH2 or C 1~4 It is substituted by alkyl-OH.

[0177] In some embodiments, the compound of Formula III is the following compound: [ka] Not selected from.

[0178] In some embodiments, the heterocycloalkenyl group contains at least one N atom.

[0179] In some embodiments, the ring A is C 5~8 selected from a cycloalkenyl group or a 5- to 10-membered heterocycloalkenyl group, Or, ring A is C 5~7 selected from a cycloalkenyl group or a 5- to 10-membered heterocycloalkenyl group, Or, ring A is C 5~6 Cycloalkenyl group or 5- to 10-membered heterocycloalkenyl group or ring A is selected from C 5~6 It is selected from a cycloalkenyl group and a 5- to 9-membered heterocycloalkenyl group.

[0180] In some embodiments, the structural moiety [ka] teeth, [ka] Selected from.

[0181] In some embodiments, the structural moiety [ka] teeth, [ka] Selected from.

[0182] In some embodiments, the structural moiety [ka] teeth, [ka] In some embodiments, the structural moiety is selected from [ka] teeth, [ka] In some embodiments, the structural moiety is selected from [ka] teeth, [ka] Selected from.

[0183] In some embodiments, the structural moiety [ka] teeth, [ka] Selected from.

[0184] In some specific embodiments, the structural moiety [ka] teeth, [ka] In some specific embodiments, the structural moiety is selected from [ka] teeth, [ka] In some specific embodiments, the structural moiety is selected from [ka] teeth, [ka] Selected from.

[0185] In some embodiments, the structural moiety [ka] teeth, [ka] Selected from.

[0186] In another aspect, the present application relates to a compound, moiety, isomer (e.g., stereoisomer) thereof, derivative thereof (specifically, e.g., Protac molecule), or pharmaceutically acceptable salt thereof, represented by the following formula III-1: [ka] In the formula, R3 is an oxo, hydroxy group, -(CH2) m -CHO, hydroxy C 1~5 alkylene groups, m is 0, 1, 2, 3, 4 or 5, preferably 0; Cy 2 , ring A, ring B, ring C, R 1 and n are as defined herein.

[0187] In another aspect, the present application relates to a compound, moiety, isomer (e.g., stereoisomer), derivative (e.g., Protac molecule), or pharmaceutically acceptable salt thereof, represented by the following formula I'''-1a or I'''-2a: [ka] During the ceremony, Ring A is C 5~10 or ring A is selected from C 5~8 or ring A is selected from C 5~7 or ring A is selected from C 5~6 selected from a cycloalkenyl group or a 5- to 10-membered heterocycloalkenyl group, n is as defined herein; Each R 1 are halogens, -OH, -NH2, -CN, =O, C 1~4 Alkoxy group, -CHO, C 3~6 Cycloalkyl group, 3 to 10 heterocycloalkyl group or C 1~4 alkyl groups, 3~6 Cycloalkyl group, 3 to 10 heterocycloalkyl group or C 1~4 The alkyl group may optionally be a halogen, —OH, —NH or C 1~4 or each R is substituted by alkyl-OH; 1 are halogens, -OH, -NH2, -CN, =O, C 1~4 Alkoxy group, -CHO, C 3~6Cycloalkyl group or C 1~4 alkyl groups, 3~6 Cycloalkyl group or C 1~4 The alkyl group may optionally be a halogen, —OH, —NH or C 1~4 substituted by alkyl-OH, X 2 is selected from CH or N.

[0188] In some embodiments, each R 1 are halogens, -OH, -NH2, -CN, =O, C 1~3 Alkoxy group, -CHO, C 3~4 Cycloalkyl group or C 1~3 alkyl groups, 3~4 Cycloalkyl group or C 1~3 The alkyl group may optionally be a halogen, -OH, -NH2 or C 1~3 It is substituted by alkyl-OH.

[0189] In some embodiments, each R 1 are independently selected from halogen, —OH, —NH2, —CN, ═O, a methoxy group, —CHO, a cyclobutyl group, or a methyl group, and said cyclobutyl group or methyl group is optionally substituted with a halogen, —OH, —NH2, or CH2OH. can be.

[0190] In some embodiments, each R 1 is F, -OH, -NH2, -CH2OH, =O, -CHO, -CH2NH2 or [ka] are independently selected from

[0191] In some specific embodiments, each R 1 is a halogen, -OH, -NH2, -CN, =O, a methoxy group, -CHO or C 1~3 alkyl groups, 1~3 The alkyl group is optionally substituted with a halogen, -OH, or -NH2.

[0192] In some specific embodiments, each R 1 are independently selected from halogen, -OH, -NH2, -CN, =O, a methoxy group, -CHO or a methyl group, said methyl group being optionally substituted by -OH or -NH2.

[0193] In some specific embodiments, each R 1 are independently selected from F, —OH, —NH2, —CH2OH, ═O, —CHO, or —CH2NH2.

[0194] In some embodiments, the moiety [ka] teeth, [ka] and preferably, said moiety is selected from [ka] Selected from.

[0195] In another aspect, the present application relates to a compound, moiety, isomer (e.g., stereoisomer), derivative (e.g., Protac molecule), or pharmaceutically acceptable salt thereof, represented by formula I'''-1 or I'''-2: [ka] During the ceremony, Ring A is C 5~10 or ring A is selected from C 5~8 or ring A is selected from C 5~7 or ring A is selected from C 5~6 a cycloalkenyl group or a 5- to 10-membered heterocycloalkenyl group, R1 and n are as defined herein.

[0196] In some embodiments, ring A is C 5~6 In some embodiments, Ring A is selected from a C5 cycloalkenyl group, a C6 cycloalkenyl group, or a 5-, 6-, 7-, 8-, or 9-membered heterocycloalkenyl group.

[0197] In some embodiments, ring A is chosen from a cyclopentenyl group, a dicyclohexenyl group, a dihydropyrrolyl group, a tetrahydropyridinyl group, a tetrahydroazepinyl group, a dihydrooxazinyl group, an azaspirooctenyl group, or an azaspirononenyl group.

[0198] In some embodiments, ring A is selected from a cyclopentenyl group or a dicyclohexenyl group. In some embodiments, ring A is selected from a dihydropyrrolyl group, a tetrahydropyridinyl group, a tetrahydroazepinyl group, a dihydrooxazinyl group, an azaspirooctenyl group, or an azaspirononenyl group.

[0199] In some embodiments, ring A is [ka] In some embodiments, ring A is selected from: [ka] Selected from.

[0200] Also in some embodiments, ring A is C 5~8 In some embodiments, ring A is selected from a cycloalkenyl group and a 5- to 8-membered heterocycloalkenyl group. 5~6 In some embodiments, Ring A is selected from a C5 cycloalkenyl group, a 5-, 6-, 7-, or 8-membered heterocycloalkenyl group.

[0201] Also in some embodiments, ring A is selected from a cyclopentenyl group, a dihydropyrrolyl group, a tetrahydropyridinyl group, a tetrahydroazepinyl group, or an azaspirooctene.

[0202] In some embodiments, ring A is selected from a cyclopentenyl group, hi some embodiments, ring A is selected from a dihydropyrrolyl group, a tetrahydropyridinyl group, a tetrahydroazepinyl group, or an azaspirooctene group.

[0203] Also in some embodiments, ring A is [ka] Selected from.

[0204] This application relates to the following compounds, moieties, stereoisomers thereof, derivatives thereof (specifically, for example, Protac molecules), or pharmaceutically acceptable salts thereof: [ka] TIFF2024542178000260.tif152132

[0205] In another aspect, the present application relates to a compound, moiety, stereoisomer thereof, derivative thereof (specifically, for example, a Protac molecule), or pharmaceutically acceptable salt thereof, represented by formula I'''-1c or I'''-2d: [ka] During the ceremony, Rings A, n and R 1 are defined as described herein, X 2 is selected from CH or N, L 1 is C 0~3 alkylene groups, Cy 3 is C 3~8selected from a cycloalkyl group or a 3- to 8-membered heterocycloalkyl group, R 2 is -CHO, OH, SH, NH2, COOH, or C substituted by one or more SH, OH, or NH2 1~6 selected from alkyl groups, p is selected from 0, 1, 2 or 3.

[0206] In some embodiments, the 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- or 6-membered heteroaryl group.

[0207] In some embodiments, the ring A is C 5~7 It is selected from a cycloalkenyl group, a 5- to 9-membered heterocycloalkenyl group, a phenyl group, or a 5- or 6-membered heteroaryl group.

[0208] In some embodiments, the 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- or 6-membered heteroaryl group.

[0209] In some embodiments, the ring A is selected from a 5- to 6-membered heterocycloalkenyl group, a phenyl group, or a 5-membered heteroaryl group.

[0210] In some embodiments, ring A is selected from a dihydropyrrolyl group, a tetrahydropyridinyl group, a dihydrooxazinyl group, a phenyl group, a pyrrolyl group, a pyrazolyl group, or a furyl group.

[0211] In some embodiments, the moiety [ka] teeth, [ka] Selected from.

[0212] In some embodiments, L 1 is selected from a bond or -CH2-.

[0213] In some embodiments, Cy 3 is C 3~6 It is selected from a cycloalkyl group or a 4- to 6-membered heterocycloalkyl group.

[0214] In some embodiments, Cy 3 is C 4~6 It is selected from a cycloalkyl group, a 4-membered heterocycloalkyl group, or a 6-membered heterocycloalkyl group.

[0215] In some embodiments, Cy 3 is a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, It is selected from a sil group, an azetidinyl group, or a piperidinyl group.

[0216] In some embodiments, R 2 is -CHO, OH or C substituted by one or more OH or NH 1~3 It is selected from alkyl groups.

[0217] In some embodiments, R 2 is selected from -CHO, OH or a methyl group substituted by one or more OH.

[0218] In some embodiments, R 2 is selected from —CHO, OH, or —CH2OH.

[0219] In some embodiments, X 2 is selected from CH.

[0220] In some embodiments, p is selected from 0, 1, or 2.

[0221] In some embodiments, p is selected from 0 or 1. In some embodiments, p is selected from 0. In some embodiments, p is selected from 1.

[0222] In some embodiments, the structural moiety [ka] teeth, [ka] Selected from.

[0223] This application relates to the following compounds, moieties, stereoisomers thereof, derivatives thereof (specifically, for example, Protac molecules), or pharmaceutically acceptable salts thereof: [ka]

[0224] This application relates to the following compounds, moieties, stereoisomers thereof, derivatives thereof (specifically, for example, Protac molecules), or pharmaceutically acceptable salts thereof: [ka]

[0225] In another aspect, this application relates to the use of the compounds (e.g., of Formula III, Formula III-1, Formula I'''-1a, Formula I'''-2a, Formula I'''-1, Formula I'''-2, Formula I'''-1c, Formula I'''-2d, or specific compounds), moieties, isomers (e.g., stereoisomers), or derivatives thereof in Protac molecules. In another aspect, this application relates to the use of the compounds (e.g., of Formula III, Formula III-1, Formula I'''-1a, Formula I'''-2a, Formula I'''-1, Formula I'''-2, Formula I'''-1c, Formula I'''-2d, or specific compounds), moieties, isomers (e.g., stereoisomers), or derivatives thereof to constitute parts of Protac molecules. In another aspect, this application relates to the compounds (e.g., Formula III, Formula III-1, Formula I'''-1a, Formula I'''-2a, Formula I'''-1, Formula I'''-2, Formula I'''-1c, Formula I'''-2d, 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 compounds (e.g., of Formula III, Formula III-1, Formula I'''-1a, Formula I'''-2a, Formula I'''-1, Formula I'''-2, Formula I'''-1c, Formula I'''-2d, or specific compounds), portions, isomers (e.g., stereoisomers), or derivatives thereof for degrading proteins, e.g., the compounds (e.g., of Formula III, Formula III-1, Formula I'''-1a, Formula I'''-2a, Formula I'''-1, Formula I'''-2, Formula I'''-1c, Formula I'''-2d, or specific compounds), portions, isomers (e.g., stereoisomers), or derivatives thereof degrade the proteins in the form of Protac molecules. In another aspect, the present application relates to the use of the compounds (e.g., of Formula III, Formula III-1, Formula I'''-1a, Formula I'''-2a, Formula I'''-1, Formula I'''-2, Formula I'''-1c, Formula I'''-2d, or specific compounds, moieties, isomers (e.g., stereoisomers), and derivatives thereof, in the form of Protac molecules, for the degradation of proteins.The present application relates to the use of the compounds (e.g., Formula III, Formula III-1, Formula I'''-1a, Formula I'''-2a, Formula I'''-1, Formula I'''-2, Formula I'''-1c, Formula I'''-2d, or specific compounds), moieties, isomers (e.g., stereoisomers), and derivatives (e.g., as production intermediates) in the manufacture of Protac molecules. The present application relates to the use of the compounds (e.g., Formula III, Formula III-1, Formula I'''-1a, Formula I'''-2a, Formula I'''-1, Formula I'''-2, Formula I'''-1c, Formula I'''-2d, or specific compounds), moieties, isomers (e.g., stereoisomers), and derivatives (e.g., as production intermediates) in the manufacture of proteolytic agents. Optionally, the Protac molecules do not include Protac molecules associated with AR.

[0226] Specifically, for example, in some embodiments, the present application relates to the use of the following compounds, portions thereof, stereoisomers thereof, or pharmaceutically acceptable salts thereof in the manufacture of Protac molecules: [ka] During the ceremony, Ring A is C 5~10 or ring A is selected from C 5~8 or ring A is selected from C 5~7 or ring A is selected from C 5~6 a cycloalkenyl group or a 5- to 10-membered heterocycloalkenyl group, preferably, ring A is selected from a cyclopentenyl group, a dihydropyrrolyl group, a tetrahydropyridinyl group, or a tetrahydroazepinyl group; n is selected from 0, 1, 2 or 3, preferably n is selected from 0, 1 or 2; Each R 1 are halogens, -OH, -NH2, -CN, =O, C 1~4 Alkoxy group, -CHO, C 3~6 Cycloalkyl group or C 1~4alkyl groups, 3~6 Cycloalkyl group or C 1~4 The alkyl group may optionally be a halogen, -OH, -NH2 or C 1~4 substituted by alkyl-OH, preferably each R 1 are independently selected from fluorine, chlorine, or bromine; X 2 is selected from CH or N, preferably X 2 is CH, The portion of the compound is [ka] and preferably, the moiety is [ka] Selected from.

[0227] In some embodiments, the present application provides: A method for producing a Protac molecule, comprising reacting the following compound, a portion thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to produce the Protac molecule: [ka] During the ceremony, Ring A is C 5~10 or ring A is selected from C 5~8 or ring A is selected from C 5~7 or ring A is selected from C 5~6 a cycloalkenyl group or a 5- to 10-membered heterocycloalkenyl group, preferably, ring A is selected from a cyclopentenyl group, a dihydropyrrolyl group, a tetrahydropyridinyl group, or a tetrahydroazepinyl group; n is selected from 0, 1, 2 or 3, preferably n is selected from 0, 1 or 2; Each R1 are halogens, -OH, -NH2, -CN, =O, C 1~4 Alkoxy group, -CHO, C 3~6 Cycloalkyl group or C 1~4 alkyl groups, 3~6 -membered alkyl group or C 1~4 The alkyl group may optionally be a halogen, -OH, -NH2 or C 1~4 substituted by alkyl-OH, preferably each R 1 are independently selected from fluorine, chlorine, or bromine; X 2 is selected from CH or N, preferably X 2 is CH, The portion of the compound is [ka] and preferably, the moiety is [ka] Selected from.

[0228] The present application relates to the use of the compounds (e.g., compounds of Formula III, Formula III-1, Formula I'''-1a, Formula I'''-2a, Formula I'''-1, Formula I'''-2, Formula I'''-1c, Formula I'''-2d, or specific compounds), moieties, isomers thereof (e.g., stereoisomers), and derivatives thereof for degrading BTK proteins, for example, the use of the compounds, moieties, isomers thereof (e.g., stereoisomers), and derivatives thereof for degrading BTK proteins. In another aspect, the present application relates to the use of the compounds (e.g., compounds of Formula III, Formula III-1, Formula I'''-1a, Formula I'''-2a, Formula I'''-1, Formula I'''-2, Formula I'''-1c, Formula I'''-2d, or specific compounds), moieties, isomers (e.g., stereoisomers), or derivatives thereof for degrading the BTK protein in the form of a Protac molecule.

[0229] In some embodiments, the Protac molecule or proteolytic agent is selected from a BTK proteolytic agent / molecule.

[0230] In another aspect, the present application relates to a pharmaceutical composition comprising the compound, moiety, stereoisomer, derivative, or pharmaceutically acceptable salt thereof of the present application, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

[0231] In another aspect, this application relates to the use of the above-mentioned compounds, moieties, stereoisomers thereof, derivatives thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the manufacture of a medicament for preventing or treating a condition that is treated by degrading a target protein that is bound to a targeting ligand.

[0232] In another aspect, this application relates to the use of the above-mentioned compounds, moieties, stereoisomers thereof, derivatives thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions 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.

[0233] In another aspect, the present application relates to the use of the above-mentioned compound, moiety, stereoisomer, derivative, or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof in the manufacture of a medicament for preventing or treating a disease associated with BTK.

[0234] The present application relates to a method for treating or preventing a disease state in a mammal by degrading a target protein 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, its derivative or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0235] 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, its derivative or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0236] In another aspect, the present application relates to a method for treating a mammalian disease associated with BTK, 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, its derivative, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0237] In another aspect, the present application relates to the above-mentioned compounds, moieties, stereoisomers thereof, derivatives thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for preventing or treating a condition that is treated by degrading a target protein that binds to a targeting ligand.

[0238] In another aspect, the present application relates to the above compounds, moieties, stereoisomers thereof, derivatives thereof or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for preventing or treating a condition that is treated by binding to a cerebellar protein in the body.

[0239] In another aspect, the present application relates to the above-mentioned compounds, moieties, stereoisomers thereof, derivatives thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for preventing or treating diseases associated with BTK.

[0240] In another aspect, this application relates to the use of the above-mentioned compounds, moieties, stereoisomers thereof, derivatives thereof 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 that is bound to a targeting ligand.

[0241] In another aspect, the present application relates to the use of the above compounds, moieties, stereoisomers thereof, derivatives thereof 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.

[0242] In another aspect, this application relates to the use of the above-described compounds, moieties, stereoisomers thereof, derivatives thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the prevention or treatment of a BTK-associated disease. In some specific embodiments, the BTK-associated disease is selected from conditions that are treated by degrading proteins that bind to BTK target protein ligands. In some specific embodiments, the BTK-associated disease is selected from conditions that are treated by binding to cerebellar proteins in vivo. In some embodiments, the disease or condition is selected from an autoimmune disease, an inflammatory disease, or cancer.

[0243] In some specific embodiments, the condition treated by in vivo binding to a cerebellar protein and / or the condition treated by in vivo binding to a cerebellar protein is selected from a BTK-associated disease, which in some specific embodiments is selected from an autoimmune disease, an inflammatory disease, or a cancer.

[0244] 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.

[0245] In some embodiments, the present application includes the variables and embodiments thereof defined above, and combinations thereof. [Effects of the Invention]

[0246] The compounds of the present application have a degrading effect on BTK in OCI-LY10 cells. C481S Cells or OCI-LY10-BTK C481S Compared to EGFR and TEC kinase, BTK and / or BTK C481S It has kinase selectivity, is stably metabolized in vitro, and has favorable in vivo pharmacokinetic properties, and exhibits inhibitory effects on TMD-8 xenograft tumors in mice in vivo. It has binding activity to CRBN protein and exhibits the desired IKZF1, IKZF3, and GSPT1 proteolytic activity.

[0247] The compounds provided herein are CRL4 CRBN The compounds can bind to the cereblon receptor, an E3 ubiquitin ligase, thereby generating new binding sites for novel substrates, which are proteins that are mediators of human disease, thereby causing degradation of the novel substrate proteins. The novel morphology of the surface generated by these compounds can directly interact with the target protein or target protein complex, thereby directly or indirectly reducing protein levels. In different embodiments, the compounds described herein can reduce the levels of novel substrate target proteins by direct ubiquitination of the target protein, or by direct ubiquitination of the novel substrate target protein. The compounds can ubiquitinate protein cofactors or target protein complexes or other proteins that control the homeostasis of the target protein. These compounds can decrease target protein levels by causing degradation of target proteins that are new substrates for CRBN to which the direct binding ligand binds, degradation of new substrates that bind to cofactors in CRBN as binding ligands, degradation of CRBN that bind to the complex cofactor and target protein interface binding ligand, degradation of target protein complexes that are new substrates for CRBN to which the binding ligand binds, or degradation of cofactors of proteins that are not in the complex or are new substrates for CRBN.

[0248] (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.

[0249] 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 oxygen (=O), two hydrogen atoms are replaced. Oxygen substitution does not occur in aryl groups.

[0250] The terms "optional" or "optionally" refer to the subsequently described event or circumstance, which may or may not occur, and include both cases where the event or circumstance occurs and cases where the event or circumstance does not occur. The term "optionally substituted" for a group of atoms refers to the group of atoms being substituted or unsubstituted. For example, when an ethyl group is "optionally" substituted with a halogen, the ethyl group may be unsubstituted (CHCH), monosubstituted (e.g., CHCHF), polysubstituted (e.g., CHFCHF, CHCHF, etc.), or fully substituted (CFCF). As will be appreciated by those skilled in the art, spatially incompatible and / or synthetically incompatible substitutions or methods of substitution are not permitted for any group of atoms containing one or more substituents.

[0251] Herein, C m~n means that the moiety has an integer number of carbon atoms within a predetermined range, m to n. 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.

[0252] 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.

[0253] When a bond connects two atoms of a ring (including a monocyclic, fused, or spiro ring), such bond may be attached to any atom of the ring (including a monocyclic, fused, or spiro ring). For example, the structural unit [ka] indicates that both bonds may connect to two different atoms in ring A, ring B or ring C, and for example, [ka] indicates that both bonds may connect to two different atoms in ring A, the middle benzene ring, or ring C, and further, for example, [ka] indicates that the bonds on either side may connect to two different atoms in the four rings of the system.

[0254] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0255] The term "hydroxy" refers to an -OH radical.

[0256] The term "amino group" refers to an -NH2 atom group.

[0257] 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.

[0258] The term "alkylene group" refers to an alkyl group that has lost a hydrogen.

[0259] The term "heteroalkylene group" refers to an alkylene group in which one or more C atoms are replaced by heteroatoms and which contains at least one C atom. The heteroatom may be specifically selected from N, NH, O, S, S(O) or S(O)2. The number of heteroatoms is selected from 1, 2, 3, 4, 5 or 6. For example, C 1~12 A heteroalkylene group refers to a group containing 1 to 12 carbon atoms and one or more heteroatoms (e.g., 1 to 6, 1 to 3, 1, 2, or 3 heteroatoms). 1~6 A heteroalkylene group denotes that the heteroalkylene group contains 1 to 6 C atoms and one or more heteroatoms.

[0260] The term "alkoxy" refers to an --O-alkyl group.

[0261] 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.

[0262] The term "cycloalkenyl group" refers to a non-aromatic carbocyclic ring that is not fully saturated and can exist as a monocyclic ring, a bridged ring (e.g., bicyclic ring), or a spirocyclic ring. Unless otherwise specified, such carbocyclic rings are typically 4-12 membered, 4-10 membered, or 4-8 membered rings. Non-limiting examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, and the like.

[0263] Non-limiting examples of "benzocycloalkenyl group" include a 4- to 12-membered benzocycloalkenyl group, a 4- to 10-membered benzocycloalkenyl group, or a 4- to 8-membered (e.g., 4-, 5-, 6-, 7-, or 8-membered) benzocycloalkenyl group.

[0264] 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 is typically 3- to 10-membered (e.g., 5- to 8-membered) ring. 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.

[0265] 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 12-, 3- to 10-, 3- to 8-, 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.

[0266] The term "heterocycloalkenyl group" includes cycloalkenyl groups in which one or more carbon atoms have been 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, have been each independently replaced by O, S(O), NH, 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 12-membered ring (e.g., a 5- to 8-membered ring). Examples of heterocycloalkenyl groups include, but are not limited to, dihydropyrrolyl, tetrahydropyridinyl, tetrahydroazepinyl, and azaspirooctene.

[0267] Non-limiting examples of "benzoheterocycloalkenyl group" include a 4-12 membered benzo heterocycloalkenyl group (e.g., 5-, 6-, 10-, or 11-membered), a 5-11 membered benzo heterocycloalkenyl group, or a 5-8 membered benzo heterocycloalkenyl group (e.g., 4-, 5-, 6-, 7-, or 8-membered). [ka] is.

[0268] Unless otherwise specified, the carbocyclic ring generally has 4 to 8 members. Non-limiting examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, and the like.

[0269] The term "heteroaryl group" refers to a monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, or S, with the remaining ring atoms being C, and at least one aromatic ring. Preferably, the heteroaryl group has one 4-8 membered ring, particularly a 5-8 membered ring, or multiple fused rings containing 6-14, particularly 6-10 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.

[0270] In this application, the wavy line ( [ka] ) represents either the absolute configuration of the stereocenter (e.g., [ka] or [ka] Specifically, [ka] but, [ka] ) or relative positioning (e.g., [ka] but, [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.

[0271] In this application, LNK, Cy 1 , Cy 2 , -Cy 1 -LNK-Cy 2 -, -Cy 1 -LNK- or -LNK-Cy 2 Atomic groups or structural moieties such as - and specific options thereof may optionally be connected to the left and right atomic groups of the group or moiety in the general formula, respectively, by reading from the left, e.g., Cy 1 but [ka] If you choose from the list, read from left to right: Cy 1 The left side of corresponds to the left side of the general formula [ka] The part connected to the right corresponds to the right side. [ka] The part thus formed is connected to [ka] and optionally, in the present application, LNK, Cy 1 , Cy 2 , -Cy 1 -LNK-Cy 2 -, -Cy 1 -LNK- or -LNK-Cy 2 Atomic groups or structural moieties such as - and specific options thereof may be read from the right and correspondingly connected to the left and right atomic groups of the atomic group or moiety in the general formula, e.g., Cy 1 but [ka] If you choose from the list, read from right to left: Cy 1 The right side of the formula corresponds to the left side of the formula [ka] The left side corresponds to the right side of the general formula. [ka] The part thus formed is connected to [ka] The other atomic groups are as described above.

[0272] The term "Protac (proteolysis targeting chimera) molecules" refers to a series of bifunctional compounds that can simultaneously bind to target proteins and E3 ubiquitin ligases, and these compounds induce target proteins to be recognized by the cellular proteasome, leading to the degradation of the target proteins. By inducing the dissolution, the content of the target protein in the cell can be effectively reduced.

[0273] The term "derivative" refers to a new compound or series of compounds produced by replacing one or more hydrogen atoms in the basic structure of a parent compound with other atomic groups or structural moieties. In this application, derivatives refer to compounds derived from the parent compound that retain the parent structure. Specifically, the parent compound is transformed into a Protac molecule, which refers to a PTM-linker-ULM molecule, where PTM is a protein targeting moiety that binds to a target protein or target polypeptide, linker is a connecting atomic group, and ULM is a moiety that binds to a ubiquitin ligase.

[0274] The term "protein targeted drug or derivative thereof" or PTM refers to a small molecule that binds to a target protein or other protein or polypeptide of interest and positions or positions the protein or polypeptide in proximity to a ubiquitin ligase for degradation by the ubiquitin ligase. Non-limiting examples of small molecule target protein binding moieties include drugs or derivatives thereof that target AR, ER, kinases, phosphatases, MDM2, human BET bromodomain protein, Hsp90, HDAC, human lysine methyltransferase, RAF receptor, FKBP, vascular endothelial growth factor, receptors or proteins associated with immunosuppression, aryl hydrocarbon receptor, thyroid hormone receptor, HIV protease, HIV integrase, HCV protease, HBV protease, or acyl protein thioesterase 1 and / or 2, and many others, or target ALK, BET, CDK, PARP, EGFR, γ-secretase (γ-secretase), or other target proteins. ), CBFβ-SMMHC, WEE1, MEK, BCR-ABL, MET, RAS, BTK, VEGFR, JAK, HER2, HDAC, Akt, PI3K, mTOR, AR, ER, PDEδ, SRC, MDM2, RAF, IRAK4, STAT3, and c-Myc or their derivatives, and many others, or drugs targeting ALK, BRD4, CDK4 / 6, PARP, EGFR, γ-secretase, CBFβ-SMMHC, WEE1, MEK, BCR-ABL, MET, KRAS, EGFR, BTK, AR, ER, PDEδ, JAK, MDM2, or RAF or their derivatives, and many others.

[0275] The term "PTM moiety" refers to a drug or derivative thereof that binds to a target protein. Targets for PTM moieties are numerous and are selected from proteins expressed in cells, at least a portion of which sequences are found in cells, and which can bind to the PTM moiety. The term "protein" includes oligopeptide and polypeptide sequences of sufficient length to bind to the PTM moieties described herein. Any protein in a eukaryotic or microbial system (including viruses, bacteria, or fungi) described elsewhere herein is a target for ubiquitination mediated by the compounds described herein. The target protein is preferably a eukaryotic protein.

[0276] "Target protein" hereinafter refers to a protein or polypeptide that binds to the compounds of the present application and is targeted for degradation by ubiquitin ligase. Such small molecule target protein binding moieties further include pharmaceutically acceptable salts, enantiomers, solvates and polymorphs of these compositions, as well as other small molecules capable of targeting the protein of interest. These binding moieties are linked to the moiety by the linker moiety L. [ka] is connected to.

[0277] Unless otherwise specified, [ka] teeth, [ka] This indicates that a hydrogen atom at any position in the atomic group may be replaced by the atomic group connected with "-".

[0278] 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.

[0279] 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.

[0280] 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.

[0281] 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.

[0282] 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.

[0283] 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.

[0284] 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.

[0285] 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."

[0286] 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 be transferred between two ring nitrogen atoms. Valence tautomers include interconversions via recombination of some bonding electrons.

[0287] As used herein, singular terms cover plural referents and vice versa unless the context clearly dictates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly dictates otherwise.

[0288] Unless otherwise specified, in this specification, the values ​​of parameters expressing the amounts of ingredients, physicochemical properties, reaction conditions, etc. are considered to be modified in all cases by the term "about." When the term "about" is used in this application, it indicates the existence of an error value, for example, a change within a range of ±5%, for example, ±1%, or ±0.1% of a specific value.

[0289] 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 normal 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.

[0290] 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 can be isotopically labeled by procedures similar to the embodiments and / or examples disclosed below. Labeling reagents may be used to replace non-isotopically labeled reagents.

[0291] Also, isotopes with larger mass numbers (e.g., deuterium, i.e. 2Substitution 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.

[0292] 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.

[0293] 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.

[0294] 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.

[0295] 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.

[0296] 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.

[0297] 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 pulverized. 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.

[0298] The pharmaceutical compositions are also suitable for parenteral administration, for example as appropriate unit dose sterile solutions, suspensions or lyophilized products.

[0299] 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.

[0300] 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.

[0301] The chemical reactions of specific embodiments of the present application are carried out in a suitable solvent, which may be any of the solvents of the present application. The chemical transformations and the reagents and materials used must be compatible. In order to obtain the compounds of the present application, it may be necessary for those skilled in the art to make modifications or selections of synthetic steps or reaction processes based on conventional practice.

[0302] 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.

[0303] 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] In the formula, X 1 is selected from halogens.

[0304] A compound of general formula (I-2) is obtained from a compound of general formula (I-1) by a coupling reaction, a compound of general formula (I-3) is obtained from the compound of general formula (I-2) by a hydrolysis reaction, and then a compound of general formula (I-4) is obtained by removing the protecting group.

[0305] From the compound of general formula (I-5), hydroxy group-substituted Cy 2 The compound of general formula (I-6) is obtained by a coupling reaction with acrylamide, and the compound of general formula (I-6) is then subjected to addition with acrylamide and aminolysis reaction to obtain the compound of general formula (I-7). The compound of general formula (I-7) is then subjected to an oxidation reaction to obtain the compound of general formula (I-8). The compound of general formula I is obtained by a reductive amination reaction from the compound of general formula (I-4) and the compound of general formula (I-8).

[0306] Hydroxymethyl group-substituted Cy from the compound of general formula (I-5) 2 The compound of general formula (I-9) is obtained by a coupling reaction with acrylamide, and the compound of general formula (I-9) is then subjected to addition with acrylamide and aminolysis reaction to obtain the compound of general formula (I-10). The compound of general formula (I-10) is then subjected to an oxidation reaction to obtain the compound of general formula (I-11). The compound of general formula (I-4) and the compound of general formula (I-11) are then subjected to a reductive amination reaction to obtain the compound of general formula I.

[0307] 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, MeOH represents methanol, PE represents petroleum ether, IBX represents 2-iodoxybenzoic acid, DIPEA represents N,N-diisopropylethylamine, DIBAL-H represents diisobutylaluminum hydride, NIS represents N-iodosuccinimide, NBS represents N-bromosuccinimide, Tf represents -OSO2CF3, H2O2 represents hydrogen peroxide, Pd(OAc)2 represents palladium(II) acetate, DMA represents N,N-dimethylacetamide, TBSCl represents tert-butyldimethylchlorosilane, TFA represents trifluoroacetic acid, PdCl2(dppf) represents [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), and Ruphos represents 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl.

[0308] All patents, patent applications, and other established publications are expressly incorporated herein by reference for purposes of description and disclosure. These publications are provided because they were published prior to the filing date of this application. Any statement as to the disclosure date of such a document or representation of its contents is based on the information known to applicant and does not constitute an admission that the disclosure date of such a document or its contents is correct. Furthermore, the inclusion of such publications in this specification does not constitute an admission that such publications constitute common general knowledge in the art in any country.

[0309] The present invention will now be further described with reference to examples for clarity, but the scope of the present invention is not limited to these examples. All reagents used in the present invention are commercially available products and can be used without purification. DETAILED DESCRIPTION OF THE INVENTION

[0310] Example 1: Synthesis of Compound 1 [ka]

[0311] Step 1: Preparation of intermediate 1b To a reaction flask, intermediate 1a (25 g), triethylamine (25.3 g, 34.8 mL), and dichloromethane (250 mL) were added, in that order. 1-Chloro-2-isocyanate (15.81 g) was slowly added dropwise, completing the reaction in 20 minutes. The reaction was then allowed to proceed at room temperature for 4 hours. 500 mL of water was added to the reaction mixture, and the organic phase was separated. The aqueous phase was extracted twice with 200 mL of dichloromethane. The combined organic phases were dried over sodium sulfate and filtered. The solvent was removed from the filtrate by distillation under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent EA) to obtain the desired intermediate 1b (40.8 g). 1 H NMR(500MHz,DMSO-d6)δ 6.11(q,J=7.1,6.5Hz,2H),3.56(s,1H),3.43(dq,J=8.6,4.5Hz,1H),3.33-3.27(m,2H),3.14-2.84 (m,1H),1.80-1.71(m,1H),1.60(ddq,J=12.2,6.0,3.5,3.0Hz,1H),1.38(s,9H),1.37-1.24(m,2H).

[0312] Step 2: Preparation of intermediate 1c At 0°C, sodium hydride (10.31 g) was slowly added to a stirred solution of Intermediate 1b (40 g) in tetrahydrofuran (300 mL). Upon completion, the reaction was allowed to proceed at room temperature overnight. Upon completion, the reaction was quenched by adding 75 mL of water to the reaction mixture, vigorously stirred for 10 minutes, and then the layers were separated. The aqueous phase was extracted three times with 200 mL of dichloromethane, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation. The concentrate was then diluted with 300 mL of acetonitrile and 300 mL of ethanol. L of petroleum ether was added for extraction, and the layers were separated. The acetonitrile phase was rotary evaporated to give Intermediate 1c (32.2 g).

[0313] Step 3: Preparation of intermediate 1d At 0°C, sodium hydride (5.71 g) was slowly added to a stirred solution of Intermediate 1c (20 g) in tetrahydrofuran (200 mL). After stirring for 5 minutes, the ice bath was removed and the mixture was stirred at room temperature for 1 hour. After that, the ice bath was replaced and iodomethane (15.21 g, 6.70 mL) was slowly added dropwise to the reaction mixture. Upon completion, the mixture was allowed to react at room temperature overnight. Upon completion, the reaction mixture was quenched by adding 75 mL of water. The mixture was stirred vigorously for 10 minutes and then separated. The aqueous phase was extracted three times with 200 mL of dichloromethane, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation. The concentrate was extracted with 300 mL of acetonitrile and 300 mL of petroleum ether, and the mixture was separated. The acetonitrile phase was rotary evaporated to give Intermediate 1d (22.5 g).

[0314] Step 4: Preparation of intermediate 1e Intermediate 1d (20 g) and 4 M hydrochloric acid in dioxane (25.7 g, 176 mL, 705 mmol) were added to a single-neck flask in this order, and the reaction was allowed to proceed at room temperature. Upon completion of the reaction, the solvent was removed by distillation under reduced pressure to obtain intermediate 1e (15.5 g).

[0315] Step 5: Preparation of intermediate 1f At 0 °C, 3,5-dichloropyrazine-2-carbonitrile (11.82 g) was added to a stirred solution of intermediate 1e (15 g) and N,N-diisopropylethylamine (35.1 g, 47.5 mL) in DMF (300 mL). After 15 min, the ice bath was removed and the mixture was stirred at room temperature overnight. 300 mL of ethyl acetate and 300 mL of water were added to the reaction mixture. The organic phase was separated, extracted twice with 100 mL of ethyl acetate, washed with 200 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was removed by distillation under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: dichloromethane:methanol = 100:1, volume ratio) to obtain the desired intermediate 1f (14.5 g). MS (ESI, [M+H] + ) m / z: 321.2. 1 H NMR(500MHz,DMSO-d6)δ 7.94(s,1H),3.30(dtd,J=14.7,7.5,6.8,4.9Hz,2H),3.25-3.22(m,1H),2. 89(s,4H),2.73(s,3H),2.65(s,2H),1.92-1.69(m,3H),1.62-1.48(m,1H).

[0316] Step 6: Preparation of intermediate 1g Intermediate 1f (13 g), tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (9.61 g), cesium carbonate (34.0 g), BINAP (2.166 g), palladium(II) acetate (0.781 g), and 1,4-dioxane (200 mL) were added to a single-neck flask in this order. The mixture was heated to 100 °C under N2 protection. Upon completion of the reaction and cooling to room temperature, the reaction mixture was filtered and the cake was rinsed with 150 mL of dichloromethane. The solvent was removed from the filtrate by vacuum distillation, and the crude product was isolated by silica gel column chromatography (eluent: dichloromethane:methanol = 100:1, volume ratio) to obtain the desired intermediate 1g (14.2 g). MS (ESI, [M+H] + ) m / z: 561.5. 1 H NMR(500MHz,DMSO-d6)δ 8.97(s,1H),7.82(s,1H),7.48-7.43(m,2H),7.16-7.10(m,2H),4.37-4.19(m,2H),4.07(d,J=13.1Hz,2H),3.64-3.59(m,2H),3 .42(dq,J=11.6,3.0Hz,3H),3.34-3.29(m,1H),3.26-3.23(m,2H),2.94(d,J=12.9Hz,1H),2.71(s,3H),2.62(ddt,J=15.5,12.0, 3.3Hz, 1H), 1.82-1.71(m, 5H), 1.58-1.43(m, 3H), 1.42(s, 9H).

[0317] Step 7: Preparation of intermediate 1h Intermediate 1g (8 g), DMSO (25 mL), and cesium carbonate (4.08 g) were added to a single-neck flask in this order. Hydrogen peroxide (21.32 g, 19.21 mL) was added under ice bath conditions. After stirring for 5 minutes, the ice bath was removed and the reaction was allowed to proceed at room temperature. Upon completion of the reaction, the residue was quenched with 300 mL of saturated sodium sulfite solution. No color change was detected by potassium iodide-starch TS. An additional 300 mL of ethyl acetate was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The solvent was removed by vacuum distillation, and the crude product was separated by silica gel column chromatography (eluent: dichloromethane:methanol = 100:1, volume ratio) to obtain the desired intermediate 1h (7.22 g). MS (ESI, [M+H] + ) m / z: 579.51. 1 H NMR(500MHz,DMSO-d6)δ 11.19(s,1H),7.75(d,J=2.8Hz,1H),7.66(s,1H),7.55-7.46(m,2H),7.32(d,J=2.8Hz,1H),7.15(d,J=8.6 Hz,2H),4.36(d,J=12.4Hz,1H),4.27(d,J=13.4Hz,1H),4.06(d,J=12.8Hz,2H),3.61(tt,J=11.0,4.0Hz,1 H),3.25(dd,J=9.5,7.2Hz,2H),3.06-2.91(m,2H),2.70(s,3H),2.62(tt,J=12.1,3.6Hz,1H),2.54(s,4H) ,1.82(dt,J=14.8,3.5Hz,2H),1.79-1.70(m,3H),1.54(s,1H),1.45(dq,J=12.9,4.2Hz,2H),1.42(s,9H).

[0318] Step 8: Preparation of intermediate 1i Intermediate 1h (3 g), dichloromethane (30 mL), and trifluoroacetic acid (17.06 g, 11.53 mL) were added to a single-neck flask in this order and reacted at room temperature. Upon completion of the reaction, the solvent was removed by vacuum distillation to obtain the trifluoroacetate salt product. 50 mL of dichloromethane was added to dissolve the crude product, and saturated aqueous sodium bicarbonate solution was slowly added to adjust the system to a weak alkaline state, after which the liquids were separated. The solvent was removed from the organic phase by vacuum distillation to obtain Intermediate 1i (2.4 g). MS (ESI, [M+H] + ) m / z: 479.44. 1 H NMR(500MHz,DMSO-d6)δ 11.25(s,1H),7.77(d,J=2.8Hz,1H),7.67(s,1H),7.54(d,J=8.3Hz,2H),7.34(d,J=2.8Hz, 1H),7.19-7.12(m,2H),4.32(dd,J=33.8,12.7Hz,2H),3.62(tt,J=11.0,4.0Hz,2H),3.39- 3.31(m,3H),3.30-3.23(m,3H),3.05(t,J=11.7Hz,1H),3.00-2.88(m,3H),2.72(s,3H),1. 95-1.86(m,2H),1.85-1.79(m,2H),1.79-1.64(m,3H),1.57(dtd,J=16.9,8.4,3.7Hz,1H).

[0319] Step 9: Preparation of intermediate 1k At 0°C, a solution of intermediate 1j (30 g) in toluene (100 mL) was slowly added dropwise to a solution of sodium hydride (27.9 g) in toluene (50 mL). After completion, the mixture was stirred for 15 minutes while maintaining the temperature at 0°C. Dimethyl carbonate (126 g) was added dropwise to the reaction mixture. After completion, the mixture was stirred for 15 minutes while maintaining the temperature at 0°C, and then heated to 100°C and reacted for 2 hours. The reaction mixture was washed once with water (500 mL). The organic layer was discarded, and the pH of the aqueous layer was adjusted to 2-3 with dilute hydrochloric acid (3 mol / L) at low temperature, resulting in the precipitation of a large amount of solid. The mixture was suction filtered and dried to give a 3% solid. 0.63 g of intermediate 1k was obtained. MS(ESI,[MH] - ) m / z: 239.0. 1 H NMR(500MHz,DMSO-d6)δ 12.74(s,1H),7.77-7.65(m,2H),7.54(dd,J=8.4,1.9Hz,1H),5.63(s,1H).

[0320] Step 10: Preparation of intermediate 1l Intermediate 1k (29.5 g), hydroxylamine hydrochloride (15.85 g), sodium ethoxide (15.52 g), and ethanol (150 mL) were added to a reaction flask in this order, and the mixture was heated to 85°C under N2 protection and maintained for 2 hours. The reaction mixture was rotary evaporated to dryness, and 500 mL of saturated sodium carbonate solution was added to the residue. Extraction was performed with DCM (300 mL x 2). The organic layer was discarded, and the pH of the aqueous layer was adjusted to less than 3 with dilute hydrochloric acid (3 mol / L). A large amount of solid precipitated, which was suction filtered to obtain a cake, which was washed with water, and dried under atmospheric pressure to obtain 26.53 g of Intermediate 1l. MS(ESI,[MH] - ) m / z: 254.0. 1 H NMR(500MHz,DMSO-d6)δ 12.95(s,1H),8.12(d,J=1.5Hz,1H),7.82(d,J=8.4Hz,1H),7.59(dd,J=8.4,1.6Hz,1H),4.12(s,2H).

[0321] Step 11: Preparation of intermediate 1m Intermediate 1L (26.5 g) and ethanol (530 mL) were added to a reaction flask in this order, and concentrated sulfuric acid (49.9 g, 27.1 mL, 508 mmol) was slowly added dropwise. The mixture was then heated to 85°C and reacted for 4 hours. The reaction solution was rotary evaporated to dryness, and ice water was added to the residue. NaOH solution was added dropwise at low temperature to adjust the pH to approximately 9. The mixture was then extracted twice with 300 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and then suction filtered. The filtrate was rotary evaporated to dryness to obtain 24.87 g of Intermediate 1m. MS(ESI,[MH] - ) m / z: 282.0. 1H NMR(500MHz,DMSO-d6)δ 8.13(d,J=1.5Hz,1H),7.82(d,J=8.4Hz,1H),7.60(dd,J=8.4,1.5Hz,1H),4.23(s,2H),4.15(q,J=7.1Hz,2H),1.19(t,J=7.1Hz,3H).

[0322] Step 12: Preparation of Intermediate 1n To a reaction flask, intermediate 1m (2 g) and (S)-pyrrolidine-3-methanol (2.087 g) were added in this order, followed by Pd(dba) (1.260 g) and potassium phosphate (5.84 g). Finally, toluene (60 mL) was added, and the mixture was heated to 80°C under N2 protection and maintained for 4 hours. The reaction mixture was washed twice with 100 mL of water, and the organic layer was dried over anhydrous sodium sulfate and then suction filtered. The filtrate was concentrated and purified by silica gel column chromatography to obtain intermediate 1n (0.35 g). MS (ESI, [M+H] + ) m / z: 305.20.

[0323] Step 13: Preparation of Intermediate 1o A reaction flask was charged with intermediate 1n (360 mg) and THF (30 mL), and then acrylamide (101 mg) and potassium tert-butoxide (199 mg) were added at 0°C. Under N2 protection, the mixture was slowly heated to 10°C and stirred. After the reaction was complete, 100 mL of saturated ammonium chloride solution was added to the reaction mixture at low temperature, and the mixture was extracted twice with EA (50 mL). The organic layer was dried over anhydrous sodium sulfate and then filtered. The filtrate was rotary evaporated to dryness and purified by silica gel column chromatography (eluent: DCM:MeOH = 95:5, volume ratio) to obtain 245 mg of intermediate 1o. MS (ESI, [M+H] + ) m / z: 330.1.

[0324] Step 14: Preparation of intermediate 1p Intermediate 1o (330 mg) and DCM (30 mL) were added to a reaction flask in that order, and Dess-Martin reagent (1.224 g) was added with stirring. The mixture was reacted at room temperature under N2 protection. After the reaction was complete, the reaction mixture was quenched by adding aqueous Na2SO3 (30 mL) at low temperature, followed by extraction with aqueous NaHCO3 (30 mL). The organic layer was dried over anhydrous sodium sulfate, suction filtered, and the filtrate was evaporated to dryness by rotary evaporation to give 290 mg of intermediate 1p, which was directly used in the next step.

[0325] Step 15: Preparation of Compound 1 To a reaction flask, intermediate 1i (150 mg), intermediate 1p (103 mg), DCM (10 mL), and glacial acetic acid (31.4 mg, 0.030 mL) were added in this order and stirred at room temperature for 20 minutes. After that, sodium cyanoborohydride (59.1 mg) was added and continued stirring at room temperature. After the reaction was completed, 20 mL of saturated NaHCO3 solution was added to the reaction mixture, which was then extracted twice with 20 mL of DCM / MeOH (10:1). The extracts were combined, dried over anhydrous sodium sulfate, and suction filtered. The filtrate was evaporated to dryness by rotary evaporation to give C. 18 Purification by reverse phase column (10 nM aqueous ammonium acetate solution:acetonitrile=50%:50%, volume ratio) gave 55 mg of Compound 1. Q-TOF (ESI, [M+H] + ) m / z: 790.4146. 1H NMR(500MHz,DMSO-d6)δ 11.18(s,1H),11.02(s,1H),7.75(d,J=2.8Hz,1H),7.66(s,1H),7.52(dd,J=13.9,8.4Hz,3H),7.35-7.30(m,1H),7.17( d,J=8.1Hz,2H),6.66(dd,J=8.9,1.8Hz,1H),6.58(d,J=1.8Hz,1H),4.45-4.34(m,2H),4.28(d,J=13.3Hz,1H),3.62(dt, J=11.1,7.0Hz,1H),3.48(t,J=8.5Hz,1H),3.41(d,J=4.7Hz,1H),3.26(dd,J=10.3,7.0Hz,3H),3.12-2.92(m,5H),2.73( s,4H),2.60(ddd,J=21.9,12.8,5.5Hz,2H),2.41(ddd,J=25.0,11.8,4.7Hz,4H),2.20-2.10(m,2H),1.87-1.51(m,10H).

[0326] Example 2: Synthesis of Compound 2 [ka]

[0327] Step 1: Preparation of intermediate 2b To a reaction flask, intermediate 14d (2 g) and (S)-pyrrolidine-3-methanol (1.424 g) were added in this order, followed by Pd2(dba)3 (1.289 g) and potassium phosphate (5.98 g), and finally toluene (50 mL). The reaction was carried out under N2 protection at 80 °C. After the reaction was complete, the reaction solution was washed twice with 50 mL of water, the organic layer was dried over anhydrous sodium sulfate, and then suction filtered. The filtrate was rotary evaporated to dryness and purified on a silica gel column (PE:EA = 95:5, volume ratio, 1500 mL). 18 Purification using a reverse phase column (10 nM aqueous ammonium acetate solution:acetonitrile=50%:50%, volume ratio) gave 480 mg of intermediate 2b. MS (ESI, [M+H] + ) m / z: 305.1. 1H NMR (500 MHz, DMSO-d6) δ 7.17(t,J=7.8Hz,1H),6.96(dd,J=7.9,0.8Hz,1H),6.58(dd,J=7.8,0.9Hz,1 H),4.73(t,J=5.2Hz,1H),4.17-4.09(m,4H),3.67(dd,J=9.7,7.5Hz,1H),3. 60(ddd,J=9.5,8.1,5.0Hz,1H),3.56-3.35(m,4H),2.45(dq,J=14.0,7.0Hz, 1H),2.10-2.01(m,1H),1.76(dq,J=12.2,7.5Hz,1H),1.18(t,J=7.1Hz,3H).

[0328] Step 2: Preparation of intermediate 2c A reaction flask was charged with intermediate 2b (450 mg) and THF (40 mL), and then acrylamide (126 mg) and potassium tert-butoxide (249 mg) were added at 0°C. Under N2 protection, the mixture was slowly heated to 10°C and stirred. After the reaction was complete, 100 mL of saturated ammonium chloride solution was added to the reaction mixture at low temperature, and the mixture was extracted twice with EA (50 mL). The organic layer was dried over anhydrous sodium sulfate and then suction filtered. The filtrate was rotary evaporated to dryness and purified using a silica gel column (DCM:MeOH = 95:5, volume ratio) to obtain 450 mg of intermediate 2c. MS (ESI, [M+H] + ) m / z: 330.1.

[0329] Step 3: Preparation of intermediate 2d Intermediate 2c (440 mg) and DCM (30 mL) were added to a reaction flask in that order, and Dess-Martin reagent (1.7 g) was added with stirring. The mixture was reacted at room temperature under N2 protection. After the reaction was complete, the reaction mixture was quenched by adding aqueous Na2S2O3 (30 mL) at low temperature. The organic layer was extracted and washed with aqueous NaHCO3 (30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered under suction, and evaporated to dryness to give 342 mg of intermediate 2d, which was directly used in the next step.

[0330] Step 4: Preparation of Compound 2 To a reaction flask, intermediate 1i (250 mg), intermediate 2d (171 mg), DCM (10 mL), and glacial acetic acid (31.4 mg, 0.030 mL) were added in this order and stirred at room temperature for 20 minutes. Then, sodium cyanoborohydride (197 mg) was added and the mixture was stirred at room temperature. After the reaction was completed, 20 mL of saturated NaHCO3 solution was added to the reaction mixture, which was then extracted twice with 20 mL of DCM-MeOH (10:1). The extracts were combined, dried over anhydrous sodium sulfate, and suction filtered to obtain the filtrate, which was then rotary evaporated to dryness to give C. 18 The mixture was passed through a reverse phase column (10 nM aqueous ammonium acetate solution:acetonitrile=50%:50%, volume ratio) to obtain 60 mg of Compound 2. Q-TOF (ESI, [M+H] + ) m / z: 790.4157. 1 H NMR(500MHz,DMSO-d6)δ 11.17(s,1H),11.07(s,1H),7.74(d,J=2.8Hz,1H),7.65(s,1H),7.52-7.47(m,2H),7.32(d,J=2.8Hz,1H),7.20-7.12(m,3H),6.9 7(d,J=7.9Hz,1H),6.59(d,J=7.7Hz,1H),4.53(dd,J=11.6,5.0Hz,1H),4.37(d,J=12.6Hz,1H),4.28(d,J=13.3Hz,1H),3.74(ddd, J=9.9,7.2,2.6Hz,1H),3.67-3.59(m,2H),3.55(qd,J=7.4,3.7Hz,1H),3.40-3.32(m,3H),3.30-3.23(m,3H),3.07(d,J=10.9Hz, 1H),3.04-2.90(m,3H),2.77(td,J=11.8,6.0Hz,1H),2.67-2.55(m,2H),2.48-2.34(m,4H),2.21-1.97(m,4H),1.85-1.52(m,9H). 13C NMR (126 MHz, DMSO) δ 173.58, 171.99, 169.70, 160.77, 157.13, 154.01, 153.30, 150.98, 140.44, 137.77, 134.30, 127.46, 125.70, 122.03, 120.33, 118.64, 114.69, 111.16, 108.46, 62.25, 55.11, 54.25, 54.10, 49.11, 48.88, 47.20, 45.46, 44.86, 41.79, 36.13, 33.90, 31.55, 31.41, 29.70, 28.25, 24.50, 23.23.

[0331] Example 3: Synthesis of Compound 3 [ka]

[0332] Step 1: Preparation of intermediate 3b In a single-neck flask, intermediate 3a (20 g) was dissolved in dichloromethane (200 mL). At 0°C, triethylamine (15.89 g, 21.89 mL) was added, and acetyl chloride (12.33 g) was slowly added dropwise. Upon completion, the mixture was allowed to react at room temperature for 1 hour. Upon completion of the reaction, the system was diluted with 300 mL of dichloromethane. The pH of the system was adjusted to a weak acidic state by adding 3M aqueous hydrochloric acid. The organic phase was extracted and separated, and the organic phase was collected. The pH of the organic phase was further adjusted to a weak alkaline state by adding saturated aqueous sodium bicarbonate. The organic phase was extracted and separated, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation to obtain intermediate 3b (28.5 g). 1 H NMR(500MHz,DMSO-d6)δ 7.60(dd,J=5.9,2.7Hz,1H),7.44(t,J=8.7Hz,1H),7.23(ddd,J=8.9,4.1,2.8Hz,1H),2.26(s,3H).

[0333] Step 2: Preparation of intermediate 3c Intermediate 3b (8.61 g) and aluminum(III) chloride (8.92 g) were added to a single-neck flask in this order, and the mixture was heated to 170 °C and reacted for 2 hours. After the reaction mixture cooled to room temperature, 50 mL of dichloromethane was added, followed by the slow addition of approximately 500 mL of 3 M hydrochloric acid. The organic phase was separated, and the aqueous phase was collected. The organic phases were then extracted twice with 250 mL of dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure to obtain Intermediate 3c (11.8 g). MS(ESI,[MH] + ) m / z: 231.0. 1 H NMR(500MHz,DMSO-d6)δ 11.64(s,1H),7.79(d,J=9.3Hz,1H),7.33(d,J=5.8Hz,1H),2.62(s,3H).

[0334] Step 3: Preparation of intermediate 3d In a single-neck flask, intermediate 3c (10 g), diethyl carbonate (25.3 g), and toluene (100 mL) were added in this order, and the reaction mixture was cooled to 0°C. Sodium hydride (8.58 g) was added in several portions, and the mixture was first heated to 90°C, then heated to 120°C, and reacted for 5 hours. After the reaction was completed and the reaction mixture was cooled to room temperature, the reaction mixture was slowly poured into a 1 L stirring flask. The mixture was poured into ice water, extracted with 500 mL of ethyl acetate, and the organic phase was discarded. The pH of the aqueous phase was adjusted to 3 with 3N hydrochloric acid, extracted three times with 300 mL of ethyl acetate, and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure to give Intermediate 3d (9.8 g). MS(ESI,[MH] + ) m / z: 256.95. 1 H NMR(500MHz,DMSO-d6)δ 12.86(s,1H),7.88(d,J=5.6Hz,1H),7.67(d,J=8.5Hz,1H),5.65(s,1H).

[0335] Step 4: Preparation of intermediate 3e Intermediate 3d (9 g), hydroxylamine hydrochloride (7.95 g), sodium ethoxide (2.224 g), and ethanol (50 mL) were added to a single-neck flask in this order, and the mixture was heated to 85 °C and reacted overnight. After the reaction mixture cooled to room temperature, 3N hydrochloric acid was added to adjust the pH to 5. The solvent was removed by distillation under reduced pressure, and 100 L of water was added. While cooling, the pH was adjusted to 3 with 3N hydrochloric acid. The mixture was stirred for 30 minutes and filtered. The cake was collected and dried to obtain Intermediate 3e (8.1 g). MS (ESI, [M+H] + ) m / z: 273.86. 1 H NMR(500MHz,DMSO-d6)δ 12.97(s,1H),8.30(d,J=5.3Hz,1H),7.93(d,J=7.9Hz,1H),4.12(s,2H).

[0336] Step 5: Preparation of intermediate 3f Intermediate 3e (6 g), ethanol (40 mL), and sulfuric acid (9.27 g, 5.04 mL) were added to a single-neck flask in this order, and the mixture was heated to 90 °C and reacted for 2 hours. After the reaction mixture cooled to room temperature, the solvent was removed by distillation under reduced pressure, and the residue was diluted with 100 mL of ethyl acetate and 100 mL of water. The pH was adjusted to 7 with saturated aqueous sodium bicarbonate solution, and the organic phase was separated. The aqueous phase was extracted twice with 100 mL of ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure to obtain Intermediate 3f (5.4 g). MS (ESI, [M+H] + ) m / z: 302.21. 1 H NMR(500MHz,DMSO-d6)δ 8.32(d,J=5.3Hz,1H),7.94(d,J=8.0Hz,1H),4.22(s,2H),4.16(q,J=7.1Hz,2H),1.21(t,J=7.1Hz,3H).

[0337] Step 6: Preparation of intermediate 3g Intermediate 3f (4 g), (S)-pyrrolidine-3-methanol (2.68 g), palladium(II) acetate (0.595 g), potassium phosphate (8.43 g), and 1,4-dioxane (20 mL) were added to a single-neck flask in this order, and the mixture was heated to 100 °C under N2 protection and reacted overnight. After the reaction mixture cooled to room temperature, the solvent was removed by vacuum distillation, and the crude product was separated by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 1:1, volume ratio) to obtain the target intermediate 3f (0.5 g). MS (ESI, [M+H] + ) m / z: 323.11. 1 H NMR(500MHz,DMSO-d6)δ 7.45(d,J=13.3Hz,1H),6.81(d,J=7.0Hz,1H),4.73(t,J=5.2Hz,1H),4.13(q,J=7 .2Hz,2H),4.03(s,2H),3.52(ddd,J=10.5,7.4,3.2Hz,1H),3.49-3.38(m,4H),3. 27(ddd,J=10.0,6.7,3.1Hz,1H),2.41(td,J=14.9,14.1,7.9Hz,1H),2.01(dtd,J =12.2,7.9,7.5,5.3Hz,1H),1.72(dq,J=12.2,7.7Hz,1H),1.19(t,J=7.1Hz,3H).

[0338] Step 7: Preparation of intermediate 3h Intermediate 3g (500 mg), acrylamide (98 mg), and anhydrous tetrahydrofuran (5 mL) were added to a three-neck flask in this order, and potassium tert-butoxide (233 mg) was slowly added at −15° C. The reaction was allowed to proceed for 2 hours at −15° C. Saturated aqueous ammonium chloride solution was added dropwise to the reaction mixture to quench the reaction, followed by extraction with 50 mL of ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with 50 mL of ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure to obtain intermediate 3h (120 mg). MS(ESI,[MH] + ) m / z: 345.9. 1H NMR(500MHz,DMSO-d6)δ 11.03(s,1H),7.52(d,J=13.3Hz,1H),6.82(d,J=6.9Hz,1H),4.72(t,J=5.3Hz,1H ),4.41(dd,J=11.6,5.0Hz,1H),3.45(td,J=11.7,6.2Hz,5H),2.72(ddd,J=17.8,1 2.3,5.7Hz,1H),2.57(dt,J=17.3,4.1Hz,1H),2.39(tq,J=13.0,7.7,6.9Hz,2H),2 .14(dt,J=13.5,4.6Hz,1H),2.00(tq,J=13.4,8.3,7.1Hz,2H),1.77-1.67(m,1H).

[0339] Step 8: Preparation of intermediate 3i To a single-neck flask, intermediate 3h (80 mg), acetonitrile (5 mL), and IBX (129 mg) were added in this order, and the mixture was heated to 85° C. for 1 h. After the reaction mixture cooled to room temperature, it was filtered, and the filtrate was collected to obtain a solution (containing intermediate 3i) that was directly used in the next step.

[0340] Step 9: Preparation of Compound 3 Intermediate 3i (a solution of intermediate 3i obtained in the previous step), intermediate 1i (60 mg), and methanol (1 mL) were added to a single-neck flask in this order, and one drop of acetic acid was added. The mixture was stirred at room temperature for 1 hour, followed by sodium cyanoborohydride (23.63 mg) and the mixture was allowed to react at room temperature for 2 hours. The solvent was removed by distillation under reduced pressure, and the mixture was purified by preparative liquid chromatography to obtain compound 3 (25 mg). MS (ESI, [M+H] + ) m / z: 808.6. 1H NMR(500MHz,DMSO-d6)δ 11.18(s,1H),11.03(s,1H),7.75(s,1H),7.66(s,1H),7.51(dd,J=18.1,10.6Hz,3H),7.33(s,1H), 7.17(d,J=8.1Hz,2H),6.84(d,J=7.0Hz,1H),4.51-4.33(m,2H),4.28(d,J=13.3Hz,1H),3.60(dd,J =25.9,10.7Hz,2H),3.47(d,J=9.5Hz,2H),3.26(t,J=8.1Hz,3H),2.98(dt,J=32.9,12.0Hz,4H),2. 73(s,4H),2.57(dt,J=17.3,4.1Hz,2H),2.42-2.30(m,2H),2.21-1.96(m,4H),1.91-1.45(m,10H). 13 C NMR(126MHz,DMSO-d6)δ 173.59,172.00,169.71,161.59,160.79,156.67,154.02,152.29,150.98,1 48.61,127.45,120.32,118.68,114.69,109.76,109.50,106.13,93.49,54. 85,54.21,49.77,49.10,47.19,45.46,44.85,39.00,35.05,34.96,33.69,31.76,31.62,31.55,31.45,30.86,30.30,29.71,29.46,28.24,24.50,23.01.

[0341] Example 4: Synthesis of Compound 4

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[0342] ステップ1: Modulation of intermediate 4b 4a (25 g), diethyl carbonate (68.7 g), and toluene (200 mL) were added to a reaction flask in this order. The reaction mixture was cooled to 0°C, and sodium hydride (23.25 g) was added in several portions. The mixture was heated to 120°C and reacted for 5 hours. After the reaction was stopped and the reaction mixture was cooled to room temperature, the reaction mixture was slowly poured into 1.5 L of stirred ice water and extracted with 400 mL of ethyl acetate. The pH of the aqueous phase was adjusted to 3 with 3N hydrochloric acid, and extracted three times with 400 mL of ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the solvent was removed by distillation under reduced pressure to obtain 25 g of intermediate 4b. MS(ESI,[MH] + ) m / z: 239.0. 1 H NMR(500MHz,DMSO-d6)δ 12.78(s,1H),7.90(d,J=2.4Hz,1H),7.80(dd,J=8.8,2.5Hz,1H),7.36(d,J=8.8Hz,1H),5.62(s,1H).

[0343] Step 2: Preparation of intermediate 4c A reaction flask was charged with 4b (13 g), hydroxylamine hydrochloride (7.50 g), sodium methoxide (5.83 g), and ethanol (100 mL), in that order. The reaction mixture was heated to 85 °C under N2 protection and reacted for 15.5 hours. After the reaction mixture cooled to room temperature, the solvent was removed by distillation under reduced pressure. 200 mL of water was added to the residue, followed by the addition of 3 M hydrochloric acid. After filtration, the cake was purified by silica gel column chromatography (eluent: DCM:CH3OH = 9:1, volume ratio) to obtain 5.5 g of intermediate 4c. MS(ESI,[MH] + ) m / z: 254.1. 1 H NMR(500MHz,DMSO-d6)δ 12.96(s,1H),8.14(d,J=2.0Hz,1H),7.81(dd,J=8.9,2.0Hz,1H),7.75(d,J=8.8Hz,1H),4.13(s,2H).

[0344] Step 3: Preparation of intermediate 4d 4c (5.5 g), ethanol (50 mL), and concentrated sulfuric acid (12.64 g, 6.87 mL) were added to a reaction flask in this order, and the mixture was heated to 90 °C and reacted for 15 hours. After the reaction mixture was cooled to room temperature, the solvent was removed by distillation under reduced pressure, and 250 mL of ethyl acetate and 250 mL of water were added to the residue. A saturated aqueous solution of sodium bicarbonate was added to adjust the pH to 7, and the organic layer was The phases were separated, the aqueous phase was extracted twice with 280 mL of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent removed by distillation under reduced pressure to give 5.65 g of intermediate 4d. MS (ESI, [M+H] + ) m / z: 282.0. 1 H NMR(500MHz,DMSO-d6)δ 8.16(dd,J=2.0,0.6Hz,1H),7.82(dd,J=8.9,1.9Hz,1H),7.76(dd,J=8.9,0.6Hz,1H),4.23(s,2H),4.15(q,J=7.1Hz,2H),1.21(t,J=7.1Hz,3H).

[0345] Step 4: Preparation of intermediate 4e A reaction flask was charged with (S)-pyrrolidine-3-methanol (3.52 g), intermediate 4d (3.3 g), Pd(dba) (2.127 g), potassium phosphate (9.86 g), and finally toluene (100 mL). Under N protection, the mixture was heated to 80 °C and maintained for 3.5 h. The reaction mixture was stirred, cooled to room temperature, filtered, and the filtrate was purified by silica gel column chromatography (PE:EA = 3:2, volume ratio) to give 0.8 g of intermediate 4e. MS (ESI, [M+H] + ) m / z: 305.2. 1H NMR(500MHz,DMSO-d6)δ 7.54(d,J=9.0Hz,1H),6.98(dd,J=9.0,2.4Hz,1H),6.70(d,J=2.3Hz,1H) ,4.72(t,J=5.2Hz,1H),4.14(q,J=7.1Hz,2H),3.51-3.37(m,2H),3.31-3. 21(m,2H),3.06(dd,J=9.3,6.2Hz,1H),2.48-2.40(m,1H),2.06(dtd,J=1 2.3,7.3,4.9Hz,1H),1.76(dq,J=12.3,7.5Hz,1H),1.20(t,J=7.1Hz,3H).

[0346] Step 5: Preparation of intermediate 4f Intermediate 4e (800 mg) and THF (20 mL) were added to a reaction flask, and then acrylamide (185 mg) and potassium tert-butoxide (292 mg) were added in that order at 0°C. The mixture was reacted in an ice-water bath for 3 hours under N2 protection. The reaction solution was added dropwise to an aqueous ammonium chloride solution to neutralize the reaction, and 100 mL of ethyl acetate was added, followed by extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was purified by silica gel column chromatography (eluent EA) to obtain 0.4 g of intermediate 4f. MS (ESI, [M+H] + ) m / z: 330.2. 1H NMR(500MHz,DMSO-d6)δ 11.10-10.97(m,1H),7.55(d,J=9.0Hz,1H),6.98(dd,J=9.1,2.3Hz,1H),6.68(t,J=2.5Hz,1H),4.72 (td,J=5.2,1.6Hz,1H),4.52(ddd,J=11.4,5.0,1.2Hz,1H),3.51-3.39(m,2H),3.31-3.18(m,2H),3.0 5(ddd,J=17.5,9.5,6.2Hz,1H),2.75(ddd,J=16.9,11.5,5.4Hz,1H),2.62-2.51(m,2H),2.45(dt,J=1 3.9,7.0Hz,1H),2.19-2.01(m,2H),1.76(ddt,J=12.0,7.6,3.4Hz,1H),1.19(dt,J=11.6,7.1Hz,1H).

[0347] Step 6: Synthesis of Compound 4 Intermediate 4f (200 mg) and DCM (2 mL) were added to a reaction flask, and Dess-Martin oxidant (515 mg) was added at 0°C. The reaction mixture was then reacted at room temperature for 1 hour. The reaction mixture was filtered, and after removing part of the solvent from the filtrate by evaporation under reduced pressure, methanol (5 mL), sodium cyanoborohydride (76 mg), and intermediate 1i (291 mg) were added directly and reacted at room temperature for 2 hours. The reaction mixture was purified by silica gel column chromatography (DCM:CH3OH = 10:1, HCl). volume ratio) and further refined by C 18 Purification by reverse phase column (H2O (1 vol% ammonium acetate):CH3CN = 40%:60%, volume ratio) gave 0.44 g of compound 4. MS (ESI, [M+H] + ) m / z: 790.46. 1H NMR(500MHz,DMSO-d6)δ 11.20(s,1H),11.05(s,1H),7.76(d,J=2.9Hz,1H),7.66(s,1H),7.56(d,J=9.0Hz,1H),7.50(d,J=8.1Hz,2H),7.33(d,J=2.8H z,1H),7.17(d,J=8.1Hz,2H),6.98(dd,J=9.2,2.3Hz,1H),6.70(d,J=2.4Hz,1H),4.54(dd,J=11.5,5.0Hz,1H),4.32(dd,J=36 .1,11.7Hz,2H),3.62(tt,J=11.3,4.0Hz,1H),3.44-3.35(m,2H),3.26(ddd,J=16.0,13.1,7.5Hz,4H),3.09-2.90(m,5H),2.8 0-2.74(m,1H),2.72(s,3H),2.67-2.51(m,3H),2.47-2.28(m,3H),2.23-2.09(m,2H),2.07-1.92(m,2H),1.87-1.46(m,10H). 13 C NMR (126 MHz, DMSO-d6) δ 173.67,172.08,169.70,160.78,156.52,156.26,154.02,150.97,145.56,137.82,127.44,122.01,121.98,120.28,118.66,117.61,114.70,110.26,100.53,62.34,55.38,54.42,53.24,49.11,48.14,47.21,45.45,44.85,39.01,36.21,33.75,31.57,31.47,29.98,28.22,24.47,22.96.

[0348] Example 5: Synthesis of Compound 5

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[0349] ステップ1: Modulation of intermediate 5b 1-(2-Bromo-6-hydroxyphenyl)ethan-1-one (9.5 g), diethyl carbonate (26.1 g), and toluene (200 mL) were added to a reaction flask in this order. The reaction mixture was cooled to 0°C, and sodium hydride (8.83 g, 60%, 221 mmol) was added in portions. The mixture was heated to 120°C and reacted overnight. After cooling to room temperature, the reaction mixture was slowly poured into 1.5 L of stirred ice water, extracted with 400 mL of ethyl acetate, and washed with 3 N hydrochloric acid. The pH of the aqueous phase was adjusted to 3 and extracted three times with 400 mL of ethyl acetate. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure to obtain Intermediate 5b (12.4 g). MS(ESI,[MH] - ) m / z: 285.0. 1 H NMR(500MHz,DMSO-d6)δ 10.60(s,1H),7.19(t,J=8.2Hz,1H),7.09(dd,J=7.9,0.9Hz,1H),6.91(dd ,J=8.2,0.9Hz,1H),4.09(q,J=7.1Hz,2H),3.87(s,2H),1.20-1.14(m,3H).

[0350] Step 2: Preparation of intermediate 5c Intermediate 5b (11.2 g), MeOH (200 mL), hydroxylamine hydrochloride (9.49 g), and sodium acetate (11.20 g) were added to a reaction flask in this order, and the mixture was heated to 80 °C and reacted for 3 hours. After the reaction mixture cooled to room temperature, 3N hydrochloric acid was added to adjust the pH to 5. The solvent was removed by distillation under reduced pressure, 1 L of water was added, and the reaction flask was cooled in an ice-water bath while simultaneously adjusting the pH to 3 with 3N hydrochloric acid. The mixture was stirred for 30 minutes and filtered. The cake was collected and dried to obtain Intermediate 5c (8.0 g). 1 H NMR(500MHz,DMSO-d6)δ 12.99(s,1H),7.81(dd,J=8.2,0.8Hz,1H),7.66-7.55(m,2H),4.15(s,2H).

[0351] Step 3: Preparation of intermediate 5d To a reaction flask, intermediate 5c (8 g), ethanol (100 mL), and concentrated sulfuric acid (6.13 g, 3.33 mL) were added in this order, and the mixture was heated to 90°C and reacted overnight. After the reaction mixture cooled to room temperature, the solvent was removed by distillation under reduced pressure, and the residue was diluted with 250 mL of ethyl acetate and 250 mL of water. The pH was adjusted to 7 with saturated aqueous sodium bicarbonate solution, the organic phase was separated, and the aqueous phase was extracted twice with 250 mL of ethyl acetate to obtain intermediate 5d (8.64 g). 1 H NMR(500MHz,DMSO-d6)δ 7.83(dd,J=8.1,0.9Hz,1H),7.69-7.56(m,2H),4.25(s,2H),4.16(q,J=7.1Hz,2H),1.20(t,J=7.1Hz,3H).

[0352] Step 4: Preparation of intermediate 5e Intermediate 5d (500 mg), (S)-pyrrolidin-3-ylmethanol (267 mg), palladium(II) acetate (39.5 mg), and potassium phosphate (747 mg) were added to a reaction flask in this order, and 1,4-dioxane (30 mL) was added. Under nitrogen protection, the mixture was heated to 100°C and reacted overnight. This procedure was repeated four times. After the reaction was completed, the mixture was cooled to room temperature, combined, suction filtered, concentrated, and subjected to silica gel column chromatography to obtain intermediate 5e (240 mg). MS (ESI, [M+H] + ) m / z: 305.0. 1 H NMR(500MHz,DMSO-d6)δ 7.44(t,J=8.0Hz,1H),7.15(d,J=8.2Hz,1H),6.73(d,J=7.8Hz,1H),4.68(t,J=5.2Hz,1H),4.18(s,2H),4.10(q,J=7.1Hz,2H),3.46 -3.37(m,2H),3.30-3.20(m,3H),3.08-3.01(m,1H),2.45-2.33(m,1H),2.04-1.94(m,1H),1.69-1.58(m,1H),1.16(t,J=7.1Hz,3H).

[0353] Step 5: Preparation of intermediate 5f To a reaction flask, intermediate 5e (120 mg), acrylamide (32.2 mg), and THF (5 mL) were added in this order. After the internal temperature was lowered to -10°C, potassium tert-butyl ether was slowly added. A solution of t-butoxide (88 mg, 0.784 mL, 0.784 mmol) was added and the reaction was carried out at −10° C. After completion of the reaction, the reaction was quenched with saturated ammonium chloride, extracted with 20 mL of EA, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to silica gel column chromatography to obtain intermediate 5f (46 mg). MS (ESI, [M+H] + ) m / z: 330.0.

[0354] Step 6: Preparation of Compound 5 Intermediate 5f (57 mg), acetonitrile (5 mL), and IBX (145 mg) were added to a reaction flask in this order and reacted at 85°C for 1 hour. After completion of the reaction, the mixture was cooled to room temperature and filtered under suction. The filtrate was directly used in the next step (the filtrate contained 5 g of the intermediate). MeOH (5 mL) was added to the filtrate, followed by intermediate 1i (68.7 mg) and acetic acid (4.31 mg), in that order. After stirring at room temperature for 20 minutes, sodium cyanoborohydride (27.1 mg) was added and the reaction continued at room temperature for 3 hours. Upon completion of the reaction, 5 mL of saturated sodium bicarbonate solution was added to the reaction mixture, which was then extracted with DCM, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by normal phase silica gel column chromatography, followed by C 18 Purification by reverse phase column chromatography gave compound 5 (28 mg). MS (ESI, [M+H] + ) m / z: 790.6. 1H NMR(500MHz,DMSO-d6)δ 11.19(s,1H),11.08(d,J=17.4Hz,1H),7.83-7.73(m,1H),7.66(s,1H),7.58-7.47(m, 3H),7.39-7.27(m,2H),7.19-7.13(m,2H),7.04(s,1H),4.63-4.56(m,1H),4.42-4.25( m,2H),3.65-3.56(m,1H),3.31-3.14(m,6H),3.12-2.88(m,5H),2.81-2.73(m,1H),2. 69(s,3H),2.63-2.54(m,1H),2.48-2.22(m,5H),2.16-1.90(m,3H),1.89-1.43(m,9H).

[0355] Example 6: Synthesis of Compound 6 [ka]

[0356] Step 1: Preparation of intermediate 6b Intermediate 6a (3.0 g), DIPEA (5.73 g), and DCM (30 mL) were added to a reaction flask, and trifluoromethanesulfonic anhydride (11.31 g) was slowly added in an ice bath. The temperature was then slowly raised to room temperature and the reaction was allowed to proceed for 2 hours. 100 mL of water and 100 mL of DCM were added to the reaction mixture. The organic phase was separated, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to obtain intermediate 6b (5.2 g). 1 H NMR (500 MHz, chloroform-d) δ 5.59 (p, J = 2.3 Hz, 1H), 3.73 (s, 3H), 3.29 (ddt, J = 10.1, 8.6, 7.0 Hz, 1H), 2.98 (ddq, J = 16.3, 6.7, 2.7 Hz, 1H), 2.76-2.70 (m, 2H), 2.37-2.26 (m, 1H).

[0357] Step 2: Preparation of intermediate 6c Intermediate 6b (2.6 g), bis(pinacolato)diboron (2.89 g), potassium acetate (0.694 g), and 1,4-dioxane (30 mL) were added to a reaction flask in this order. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.265 g) was then added. The mixture was then flushed with N2 three times, heated to 85 °C, and reacted for 2 hours. The heating was then stopped. 200 mL of water was added to the reaction mixture, which was then extracted twice with 100 mL of EA. The combined organic layer was washed twice with 100 mL of saturated brine. After washing, the mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to obtain intermediate 6c (2.1 g).

[0358] Step 3: Preparation of intermediate 6d A reaction flask was charged with Intermediate 6c (1.22 g), Intermediate 1m (1.0 g), potassium carbonate (1.34 g), H2O (3 mL), and 1,4-dioxane (15 mL) in this order, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II The dichloromethane adduct (0.355 g) was added, and the mixture was exchanged with N2 three times. The mixture was then heated to 70 °C and reacted for 2 hours, after which the heating was stopped. 200 mL of water was added to the reaction mixture, and the mixture was further extracted twice with 100 mL of DCM. The combined organic layer was washed twice with 100 mL of saturated brine. After washing, it was dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to obtain intermediate compound 6d (0.328 g). MS(ESI,[MH] - ) m / z: 353.2.

[0359] Step 4: Preparation of intermediate 6e To a reaction flask, intermediate 6d (0.32 g), palladium-carbon catalyst (0.032 g), and MeOH (10 mL) were added in this order, and the mixture was reacted at room temperature for 16 hours under H2 protection. Upon completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated to give intermediate 6e (0.17 g). MS(ESI,[MH] - ) m / z: 355.2.

[0360] Step 5: Preparation of intermediates 6f-1 and 6f-2 Intermediate 6e (0.9 g) was separated by preparative SFC to give intermediate 6f-1 (0.17 g) of S configuration and intermediate 6f-2 (0.1 g) of R configuration. MS(ESI,[MH] - ) m / z: 355.2.

[0361] Step 6: Preparation of intermediate 6g Intermediate 6f-1 (0.17 g) and THF (10 mL) were added to a reaction flask, and lithium aluminum hydride (0.02 g) was slowly added in an ice bath. The mixture was then slowly warmed to room temperature and reacted for 1 hour. After completion of the reaction, a small amount of ice water was added to the reaction mixture in an ice bath to quench the reaction. 100 mL of DCM and 100 mL of water were then added. The mixture was filtered, and the organic phase was separated from the filtrate, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to obtain intermediate 6g (0.093 g). MS(ESI,[MH] - ) m / z: 327.1.

[0362] Step 7: Preparation of intermediate 6h A reaction flask was charged with Intermediate 6g (0.09 g), dichloromethane (5 mL), and Dess-Martin oxidant (0.233 g). The mixture was then reacted at room temperature for 1 hour. After the reaction was complete, 50 mL of dichloromethane and 50 mL of water were added. The organic phase was separated, and the aqueous phase was extracted twice with 50 mL of dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give Intermediate 6h (0.08 g). MS(ESI,[MH] - ) m / z: 325.1.

[0363] Step 8: Preparation of Compound 6 A reaction flask was charged with intermediate 6h (0.09 g), intermediate 1i (0.12 g), and methanol (5 mL). One drop of acetic acid was added, followed by sodium cyanoborohydride (0.032 g). The mixture was then reacted at room temperature for 2 hours. After the reaction was complete, 50 mL of dichloromethane and 50 mL of water were added. The organic phase was separated, and the aqueous phase was extracted twice with 50 mL of dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to give compound 6 (0.08 g). MS (ESI, [M+H] + ) m / z: 789.5. 1 H NMR(500MHz,DMSO-d6)δ 11.18(s,1H),11.09(s,1H),7.75(d,J=8.6Hz,2H),7.64(d,J=17.9Hz,2H),7.49 (d,J=8.0Hz,2H),7.32(d,J=8.2Hz,2H),7.16(d,J=8.1Hz,2H),4.56(dd,J=11.9, 5.0Hz,1H),4.39-4.33(m,1H),4.31-4.24(m,1H),3.64-3.58(m,1H),3.27-3. 22(m,4H),3.05-2.91(m,4H),2.78(td,J=11.9,6.1Hz,1H),2.70(s,3H),2.64- 2.59(m,1H),2.46(s,2H),2.39-2.31(m,2H),2.21(ddt,J=13.7,9.5,5.7Hz,3 H),2.12-2.01(m,3H),1.90(s,3H),1.84-1.74(m,8H),1.55(d,J=12.6Hz,2H).

[0364] Example 7: Synthesis of Compound 7 [ka]

[0365] Step 1: Preparation of Compound 7 Example 7 was synthesized by following the procedure steps 1 to 8 of Example 6, except that Intermediate 7a was used as the starting material instead of Intermediate 6a. MS (ESI, [M+H] + ) m / z: 789.5. 1 H NMR(500MHz,DMSO-d6)δ 11.20(s,1H),11.09(s,1H),7.78-7.72(m,2H),7.64(d,J=16.6Hz,2H),7.50(d,J=8.1Hz,2H),7.36-7.29(m,2H),7.16(d,J=8.1Hz,2H),4 .57(dd,J=11.9,5.0Hz,1H),4.36(d,J=12.2Hz,1H),4.28(d,J=13.1Hz,1H),3.60(ddt,J=12.0,5.3,2.9Hz,1H),3.30(s,2H),3.27-3.19(m ,3H),2.99(dt,J=37.1,11.7Hz,4H),2.78(ddd,J=17.2,12.0,5.3Hz,1H),2.70(d,J=2.4Hz,3H),2.61(dt,J=17.3,4.3Hz,1H),2.49-2.44( m,1H),2.19(dq,J=13.8,5.0Hz,2H),2.08(d,J=8.6Hz,2H),2.00(d,J=7.5Hz,1H),1.91(s,1H),1.86-1.62(m,8H),1.56(d,J=13.2Hz,2H).

[0366] Example 8: Synthesis of Compound 8 [ka]

[0367] Step 1: Preparation of intermediate 8c To a single-neck flask were added intermediate 8b (27 g), benzyl bromide (36.8 g), potassium carbonate (29.8 g), and acetonitrile (700 mL) in this order, and the mixture was heated to 80°C and reacted for 5 hours. After removing the solvent from the reaction solution by distillation under reduced pressure, the crude product was separated by silica gel column chromatography (eluent EA) to obtain 2.06 g of intermediate 8c as the target product. MS (ESI, [M+H] + ) m / z: 331.03. 1H NMR(500MHz,DMSO-d6)δ 7.76-7.70(m,2H),7.54(dt,J=7.8,1.8Hz,3H),7.49-7.43(m,2H),7.43-7.38(m,1H),6.09(s,1H),5.35(s,2H).

[0368] Step 2: Preparation of intermediate 8d Intermediate 8c (4 g), 4-hydroxymethylpiperidine (2.77 g), cesium carbonate (7.82 g), palladium(II) chloride (0.213 g), and 1,4-dioxane (150 mL) were added to a single-neck flask in this order, and the mixture was reacted at 80°C for 16 hours under N2 protection. After the reaction mixture cooled to room temperature, the solvent was removed by distillation under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent PE:EA = 1:1, volume ratio) to obtain 4.82 g of intermediate 8d. MS (ESI, [M+H] + ) m / z: 366. 1 H NMR (500 MHz, DMSO-d6) δ 7.55(d,J=9.0Hz,1H),7.53-7.47(m,3H),7.46-7.42(m,2H),7.40(dd,J=3.8 ,2.0Hz,1H),6.93(dd,J=9.1,2.5Hz,1H),5.70(s,1H),5.30(s,2H),4.49(t, J=5.3Hz,1H),3.93(dt,J=13.3,3.5Hz,2H),3.27(t,J=5.8Hz,2H),2.84(td, J=12.7,2.7Hz,2H),1.76-1.69(m,2H),1.65-1.58(m,1H),1.21-1.15(m,2H).

[0369] Step 3: Preparation of intermediate 8e Intermediate 8d (4.00 g), palladium carbon (2.0 g), and methanol (300 mL) were added to a single-neck flask in this order, and the mixture was exchanged with H2 several times. After that, the mixture was reacted at room temperature for 16 hours. The mixture was filtered under suction, the solvent was removed from the filtrate by distillation under reduced pressure, and the crude product was separated by silica gel column chromatography (PE:EA=2:1, volume ratio) to obtain 1.70 g of intermediate 8e. MS (ESI, [M+H] + ) m / z: 276.1. 1 H NMR(500MHz,DMSO-d6)δ 12.01(s,1H),7.56(d,J=8.9Hz,1H),6.92(dd,J=9.0,2.4Hz,1H),6.73(d,J=2.4Hz,1H),5.31(s,1H),4.46(s,1H),3.93(dt,J=13.2, 3.2Hz,2H),3.27(d,J=6.2Hz,2H),2.84(td,J=12.7,2.7Hz,2H),1.76-1.69(m,2H),1.66-1.57(m,1H),1.18(qd,J=12.4,4.1Hz,2H).

[0370] Step 4: Preparation of intermediate 8f Intermediate 8e (1.9 g), hydroxylamine hydrochloride (1.555 g), sodium ethoxide (1.523 g), and ethanol (150 mL) were added to a single-neck flask in this order and reacted at 85° C. for 22 hours. When the reaction mixture cooled to room temperature, the solvent was removed by distillation under reduced pressure. Dichloromethane and saturated aqueous sodium carbonate solution were added to the crude product, followed by extraction and layer separation. The organic phase was discarded, and the pH of the aqueous phase was adjusted to 6 with 6 M HCl. The mixture was extracted several times with dichloromethane. The combined organic phases were 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 1.32 g of Intermediate 8f. MS (ESI, [M+H] - ) m / z: 289.1. 1 H NMR(500MHz,DMSO-d6)δ 12.74(s,1H),7.53(d,J=8.9Hz,1H),7.07(dd,J=8.9,2.1Hz,1H),7.01(d,J=2.0Hz,1H),4.49(t,J=5.4Hz,1H),3.94-3.8 7(m,4H),3.34(s,2H),2.80(td,J=12.5,2.6Hz,2H),1.77-1.71(m,2H),1.63-1.57(m,1H),1.22(dd,J=12.4,3.7Hz,2H).

[0371] Step 5: Preparation of intermediate 8g Intermediate 8f (1.3 g), ethanol (100 mL), and sulfuric acid (1.471 g, 15.00 mmol) were added to a single-neck flask in this order, and the mixture was allowed to react at 85°C for 5 hours. When the reaction mixture cooled to room temperature, dichloromethane and saturated aqueous sodium bicarbonate solution were added to the reaction mixture to adjust the pH to 8. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine, then dried over anhydrous sodium sulfate and filtered. The solvent was removed from the filtrate by distillation under reduced pressure, and the crude product was purified by silica gel column chromatography (PE:EA = 1:4, volume ratio) to obtain 1.01 g of Intermediate 8g. MS (ESI, [M+H] + ) m / z: 319.16. 1 H NMR(500MHz,DMSO-d6)δ 7.53(d,J=9.0Hz,1H),7.08(dd,J=9.0,2.1Hz,1H),7.02(d,J=2.1Hz,1H),4.49(t,J=5.3Hz,1H),4.13(q,J=7.1Hz,2H),4.04(s,2H),3.89(dt,J =12.2,3.4Hz,2H),3.28(t,J=5.8Hz,2H),3.17(d,J=5.2Hz,1H),2.81(td,J=12.6,2.7Hz,2H),1.74(dd,J=13.7,3.7Hz,2H),1.26-1.17(m,5H).

[0372] Step 6: Preparation of intermediate 8h At 0°C, under N2 protection, acrylamide (48.7 mg) was slowly added dropwise to a stirred solution of intermediate 8g (200 mg) in THF (50 mL), and the reaction was completed in 1 minute. Further, a THF solution (1 M) (0.935 mL) of potassium tert-butoxide was added dropwise, and the reaction was completed in about 1 minute. The mixture was stirred at 0°C and reacted for 3 hours. The reaction solution was poured into an aqueous ammonium chloride solution. After vigorously stirring for 1 minute, EA was added for extraction, 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 crude product was separated by silica gel column chromatography (PE:EA = 1:4, volume ratio) to obtain 0.06 g of intermediate 8h. MS (ESI, [M+H] + ) m / z: 344.20.

[0373] Step 7: Preparation of intermediate 8i Intermediate 8h (45 mg), oxidant IBX (108 mg), and acetonitrile (10 mL) were added to a single-neck flask in this order and reacted for 30 minutes at 85° C. After the reaction mixture cooled to room temperature, it was filtered, and the filtrate (containing intermediate 8i) was used directly in the next step. MS (ESI, [M+H] + ) m / z: 342.16.

[0374] Step 8: Preparation of Compound 8 The reaction solution of intermediate 8i (the solution of intermediate 8i obtained in the reaction of the previous step) and MeOH (10.00 mL) were added to a single-neck flask, and while stirring at room temperature, intermediate 1i (68.7 mg) and acetic acid (3.85 mg) were added in that order. After stirring at room temperature for 30 minutes, sodium cyanoborohydride (16.11 mg) was added and the reaction was allowed to proceed at room temperature for 21 hours. The reaction solution was poured into a mixture of dichloromethane and water, and the pH was adjusted to 8 with saturated sodium bicarbonate. The organic phase was separated, and the aqueous phase was extracted several times with dichloromethane. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate by distillation under reduced pressure. The crude product was dissolved in DMSO and C 18 The mixture was purified using a reverse phase column and then with a Biotage medium-low pressure chromatography system (1 mM aqueous ammonium acetate solution:acetonitrile=1:1, volume ratio) to obtain 27.6 mg of Compound 8. HR-MS (ESI, [M+H] + ) m / z:804.43146. 1H NMR(500MHz,DMSO-d6)δ 11.21(s,1H),11.05(s,1H),7.79-7.73(m,1H),7.66(s,1H),7.53(dd,J=22.1,8.4Hz,3H),7.36-7.32(m,1H),7.17(d ,J=8.1Hz,2H),7.09-7.04(m,2H),4.45(dd,J=11.4,5.0Hz,1H),4.39-4.32(m,1H),4.29(d,J=13.1Hz,1H),3.90(d,J =12.3Hz,2H),3.62(dq,J=11.2,6.6,5.5Hz,1H),3.26(dd,J=11.5,5.1Hz,4H),3.06-2.81(m,6H),2.61-2.56(m,1H), 2.54-2.36(m,5H),2.18(dt,J=13.2,5.0Hz,2H),1.99-1.68(m,11H),1.64-1.51(m,2H),1.24(q,J=11.4,9.3Hz,4H).

[0375] Example 9: Synthesis of Compound 9 [ka]

[0376] Step 1: Preparation of intermediate 9d Intermediate 10f (10 g), azetidin-3-ylmethanol (3.51 g), L-proline (1.547 g), copper iodide (1.280 g), DMF (100 mL), and sodium carbonate (8.55 g) were added to a reaction flask in this order. The mixture was heated to 100 °C under N2 protection and reacted for 4 h. After the reaction was stopped and the reaction mixture was cooled to room temperature, it was extracted three times with organic solvents, DCM (200 mL) and water (500 mL). The organic phase was separated and washed with 500 mL of water each time, followed by 500 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography (eluent EA) to give 2.16 g of intermediate 9d. MS (ESI, [M+H] + ) m / z: 291.2. 1H NMR(500MHz,DMSO-d6)δ 7.45-7.38(m,1H),7.36(ddt,J=6.6,4.9,2.6Hz,1H),6.37(d,J=7.9Hz,1H),4.73(t,J=5.3Hz,1H),4.02(q,J=7.1Hz,2H),3.91(s,1H) ,3.83(t,J=7.9Hz,1H),3.55(dd,J=7.8,5.4Hz,2H),3.52-3.46(m,2H),2.71(ttd,J=12.4,8.6,7.2,4.3Hz,1H),1.08(t,J=7.1Hz,3H).

[0377] Step 2: Preparation of intermediate 9e Intermediate 9d (200 mg) and THF (10 mL) were added to a reaction flask in this order, and the temperature was lowered to about 0°C. Acrylamide (53.9 mg) and potassium tert-butoxide (116 mg) were added, and the mixture was reacted at 0°C for 3.5 hours under N2 protection. After the reaction was stopped, the reaction solution was added dropwise to a saturated aqueous ammonium chloride solution and extracted with 50 mL of ethyl acetate. The organic phase was separated and washed with 50 mL of saturated brine, then dried over anhydrous sodium sulfate and filtered. The filtrate was purified by silica gel column chromatography (eluent EA) to obtain 0.035 g of intermediate 9e. MS (ESI, [M+H] + ) m / z: 316.1. 1 H NMR(500MHz,DMSO-d6)δ 11.03(s,1H),7.53(d,J=8.6Hz,1H),6.49(d,J=1.8Hz,1H),6.46(dd,J=8.6,1.9Hz,1H),4.80(t, J=5.2Hz,1H),4.42(dd,J=11.3,5.0Hz,1H),3.94(t,J=7.8Hz,2H),3.65(dd,J=7.7,5.4Hz,2H),3 .59(t,J=5.8Hz,2H),2.82(tdd,J=8.2,6.8,6.0,3.6Hz,1H),2.73(ddd,J=17.0,11.5,5.3Hz,1H) ,2.58(dt,J=17.2,4.4Hz,1H),2.41(dtd,J=13.1,11.4,4.6Hz,1H),2.16(dq,J=13.3,5.0Hz,1H).

[0378] Step 3: Preparation of Compound 9 Intermediate 9e (200 mg), acetonitrile (10.00 mL), and oxidant IBX (533 mg) were added to a reaction flask in this order, and the mixture was allowed to react at 80°C for 1 hour. The reaction mixture was filtered, and a small amount of solvent (containing intermediate 9f) was removed by evaporation. Then, MeOH (10 mL), intermediate 1i (304 mg), and glacial acetic acid (19.04 mg) were added, and the mixture was stirred at room temperature for 30 minutes. After that, sodium cyanoborohydride (80 mg) was added, and the mixture was allowed to react at room temperature for 3 hours. The product was purified by silica gel column chromatography (DCM:CH3OH = 10:1, volume ratio). Another 120 g of C 18 Purification by reverse phase column (10 mM ammonium acetate aqueous solution: CH3CN = 40%:60%) gave 0.09 g of compound 9. MS (ESI, [M+H] + ) m / z: 776.5. 1 H NMR(500MHz,DMSO-d6)δ 11.20(s,1H),11.04(s,1H),7.76(d,J=2.9Hz,1H),7.66(s,1H),7.52(dd,J=22.5,8.4Hz,3H),7.33(d,J=2.9Hz,1 H),7.16(d,J=8.2Hz,2H),6.53-6.45(m,2H),4.43(dd,J=11.4,5.0Hz,1H),4.35(d,J=12.2Hz,1H),4. 29(d,J=13.4Hz,1H),4.04(t,J=7.7Hz,2H),3.60(ddd,J=13.0,8.6,5.4Hz,3H),3.32-3.23(m,4H),3. 04(d,J=11.8Hz,1H),3.01-2.91(m,4H),2.72(s,4H),2.64-2.52(m,3H),2.48-2.36(m,2H),2.17(dq, J=13.2,5.0Hz,1H),2.05(t,J=11.6Hz,2H),1.87-1.80(m,2H),1.80-1.70(m,3H),1.67-1.52(m,3H). 13C NMR (126 MHz, DMSO-d6) δ 173.60, 172.48, 172.09, 169.70, 165.08, 160.79, 156.41, 154.04, 154.02, 150.98, 140.26, 137.83, 127.44, 122.90, 120.26, 118.66, 114.71, 111.21, 110.23, 89.41, 56.68, 55.38, 54.31, 49.12, 47.24, 45.46, 44.85, 41.51, 39.03, 33.59, 31.56, 31.40, 28.21, 27.80, 24.45, 23.29, 21.54.

[0379] Example 10: Synthesis of Compound 10 [ka]

[0380] Step 1: Preparation of intermediate 10b Intermediate 10a (100 g), triethylamine (92 g), and DCM (1 L) were added to a single-neck flask in this order, and acetyl chloride (39.2 g) was added at 0°C. The mixture was allowed to react at room temperature for 2.5 hours. The mixture was then concentrated to remove DCM, and 300 mL x 3 of petroleum ether was added to the mixture. 1000 mL of saturated saline was then added for extraction, and the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 123 g of Intermediate 10b. MS (ESI, [M+H] + ) m / z: 263.0.

[0381] Step 2: Preparation of intermediate 10c Intermediate 10b (123 g) and anhydrous aluminum(III) chloride (94 g) were added to a single-neck flask in this order, and the mixture was heated to 170°C and reacted for 3 hours. When the reaction mixture cooled to room temperature, approximately 500 mL of 6 M hydrochloric acid was slowly added to quench the reaction. The solid that appeared was crushed, and then extracted with DCM and filtered. The organic phase was separated, and the aqueous phase was collected. The organic phase was extracted twice with 250 mL of dichloromethane. The combined organic phase was added to anhydrous sodium sulfate. The mixture was dried at rt, filtered, and the solvent removed by distillation under reduced pressure to give 112 g of intermediate 10c. MS (ESI, [M+H] + ) m / z: 263.1.

[0382] Step 3: Preparation of intermediate 10d Intermediate 10c (107 g), diethyl carbonate (174 g), and toluene (1000 mL) were added to a three-neck flask in this order. After dissolving, the temperature was lowered to approximately 0°C. Sodium hydride (58.8 g) was added in several portions. The temperature was then raised to 100°C. Once the system stabilized, the temperature was then raised to 120°C and the reaction was continued for approximately 1.5 hours. Once the reaction solution had cooled to room temperature, it was slowly poured into 2 L of stirred ice water, extracted with 500 mL of ethyl acetate, and the organic phase was discarded. The pH of the aqueous phase was adjusted to 1-2 with 3N hydrochloric acid, and the mixture was filtered to obtain 90 g of Intermediate 10d. MS (ESI, [M+H] + ) m / z: 289.1.

[0383] Step 4: Preparation of intermediate 10e To a single-neck flask, at 0°C, intermediate 10d (90 g), hydroxylamine hydrochloride (43.4 g), and absolute ethanol (1000 mL) were added in this order. After dissolution, sodium ethoxide (42.5 g) was added in several portions, and the mixture was heated to 90°C under N2 protection and reacted for 4.5 hours. When the reaction solution cooled to room temperature, 3N hydrochloric acid was added to adjust the pH to 1-3, and the solvent was removed by distillation under reduced pressure. 500 mL of water was added to the residue, stirred at room temperature for 30 minutes, filtered, and the cake was washed with 200 mL of water and then transferred to a vacuum oven for drying to obtain 91.6 g of intermediate 10e. MS (ESI, [M+H] + ) m / z: 304.1. 1 H NMR(500MHz,DMSO-d6)δ 8.22(d,J=1.2Hz,1H),7.71(dd,J=8.3,1.3Hz,1H),7.64(d,J=8.3Hz,1H),4.00(s,2H).

[0384] Step 5: Preparation of intermediate 10f Intermediate 10e (91.6 g) and absolute ethanol (1000 mL) were added to a single-neck flask in this order. Concentrated sulfuric acid (148 g, 1511 mmol) was added dropwise at 0°C. The reaction was completed in approximately 3 minutes (the system reached approximately 50°C). Under N2 protection, the mixture was heated to 85°C and reacted for 3.5 hours. The reaction mixture was stirred and cooled to room temperature. The solvent was removed from the reaction mixture, and 1500 mL of ice water and 1000 mL of ethyl acetate were added to the residue. 10% aqueous NaOH solution was added dropwise in an ice-water bath to adjust the pH to approximately 9 (internal temperature <5°C). The mixture was extracted three times in a separatory funnel, the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain 102.6 g of intermediate 10f. MS (ESI, [M+H] + ) m / z: 332.0.

[0385] Step 6: Preparation of Intermediate 10g Intermediate 10f (30 g), azetidin-3-ol (7.29 g), L-proline (5.22 g), copper iodide (4.31 g), anhydrous sodium carbonate (28.8 g), and DMF (300 mL) were added to a single-neck flask in this order. The mixture was heated to 100 °C under N2 protection and reacted for 2.5 hours. After the reaction mixture cooled to room temperature, it was extracted with organic solvents (200 mL x 3 of ethyl acetate and 1000 mL x 3 of water). The organic phases were separated and combined, washed with 500 mL of water each, then washed with 500 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate by vacuum distillation to obtain a crude product. This crude product was purified by silica gel column chromatography to yield 12 g of Intermediate 10g. MS(ESI,[MH] - ) m / z: 275.1.

[0386] Step 7: Preparation of intermediate 10h In a three-neck flask, 10 g of the intermediate (10 g) and anhydrous tetrahydrofuran (200 mL) were added in this order and dissolved. After that, acrylamide (1.976 g) was added and the mixture was stirred under N2 protection. The temperature was lowered to about 5°C, potassium tert-butoxide (3.894 g) was added dropwise, and the system was maintained at -15°C and reacted for about 1.5 hours. The reaction solution was quenched by adding dropwise saturated ammonium chloride solution, and extracted with 100 mL of ethyl acetate three times. The organic phase was separated and washed with 100 mL of saturated brine each time, then dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and 6.3 g of intermediate 10h was obtained through silica gel column chromatography. MS (ESI, [M+H] + ) m / z: 302.1.

[0387] Step 8: Preparation of intermediate 10i At room temperature, 2-iodoxybenzoic acid (IBX, 9.32 g) was added to a stirred solution of intermediate 10h in anhydrous acetonitrile (50 mL), and the mixture was allowed to react at 90°C for approximately 3.5 hours. The mixture was then filtered, and the cake was washed twice with acetonitrile. The filtrates were combined, and the solvent was removed by distillation under reduced pressure. After silica gel column chromatography, 4.6 g of intermediate 10i was obtained. MS (ESI, [M+H] + ) m / z: 300.1.

[0388] Step 9: Preparation of Compound 10 First, intermediate 1i (150 mg), intermediate 10i (133 mg), dichloromethane (10 mL), and glacial acetic acid (50.4 mg, 0.048 mL) were added to a reaction flask and stirred at room temperature for 30 minutes. After that, sodium cyanoborohydride (70.3 mg) was added and stirred at room temperature overnight. After the reaction was completed, 20 mL of saturated aqueous NaHCO3 was added to the reaction mixture, which was then extracted twice with 20 mL of DCM / MeOH (10:1). The extracts were combined, dried over anhydrous sodium sulfate, and suction filtered to obtain the filtrate, which was then rotary evaporated to dryness to give C. 18 After passing through a reverse phase column (10 nM aqueous ammonium acetate solution:acetonitrile=50%:50%, volume ratio), 59 mg of Compound 10 was obtained. Q-TOF (ESI, [M+H] + ) m / z: 762.3847. 1H NMR(500MHz,DMSO-d6)δ 11.20(s,1H),11.04(s,1H),7.76(d,J=2.5Hz,1H),7.65(s,1H),7.56(d,J=8.6Hz,1H),7.49(d,J=8.3Hz,2H),7.33(d,J=2.8Hz,1H),7.16(d, J=8.2Hz,2H),6.56-6.47(m,2H),4.44(dd,J=11.4,5.0Hz,1H),4.34(d,J=12.6Hz,1H),4.28(d,J=13.2Hz,1H),4.04(t,J=7.3Hz,2H),3.72(dd ,J=8.0,5.3Hz,2H),3.61(td,J=11.8,10.6,5.1Hz,1H),3.32-3.20(m, 4H),3.03(t,J=11.8Hz,1H),2.99-2.90(m,3H),2.70(s,4H),2.59(dt,J =17.4,4.5Hz,1H),2.49-2.37(m,2H),2.17(dq,J=14.1,4.9Hz,1H),1.96(t,J=11.2Hz,2H),1.85-1.69(m,5H),1.59(dq,J=15.5,12.0Hz,3H). 13 C NMR(126MHz,DMSO-d6)δ 173.61,172.09,169.70,165.06,160.78,156.44,154.04,153.82,150.97,140.19,137.84,127.43,122.97,120.26,118.67,114 .71,111.34,110.33,89.58,56.40,54.97,50.51,49.13,47.25,45.44,44.85,41.48,33.25,31.55,31.41,28.19,24.44,23.29.

[0389] Example 11: Synthesis of Compound 11

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[0390] ステップ1: Modulation of intermediate 11b Under N2 protection at -78 °C, lithium hexamethyldisilazide (9.44 g) was slowly added dropwise to a stirred solution of Intermediate 11a (9 g) in THF (150 mL). The reaction was completed within 5 minutes, and the mixture was stirred at -78 °C for 30 minutes. A solution of N-phenylbis(trifluoromethanesulfonimide) (17.47 g) in THF (150 mL) was slowly added to the reaction mixture, limiting the temperature to below -60 °C. Upon completion, the reaction was continued at -78 °C for 3.5 hours. Upon completion, the reaction mixture was poured into a saturated ammonium chloride-crushed ice solution and extracted twice with 200 mL of EA. The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (PE:EA = 3:2, volume ratio) to give 13 g of Intermediate 11b. 1 H NMR(500MHz,DMSO-d6)δ 5.87-5.77(m,1H),3.57(d,J=51.4Hz,4H),2.40(d,J=4.3Hz,4H),1.90(t,J=6.3Hz,2H),1.38(s,9H).

[0391] Step 2: Preparation of intermediate 11c A single-neck flask was charged with 4-nitrophenylboronic acid pinacol ester (10.06 g), Intermediate 11b (10 g), potassium carbonate (11.16 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (4.40 g), 1,4-dioxane (300 mL), and water (50 mL), in that order. After several exchanges with N2, the mixture was heated to 90 °C and reacted for 5 h. After completion of the reaction, the reaction mixture was filtered, the cake was washed several times with EA, and then 500 mL of EA and 200 mL of water were added to the filtrate. The organic phase was separated, washed with 500 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography (PE:EA = 4:1, volume ratio). 5.58 g of Intermediate 11c was obtained. MS (ESI, [M+H] + ) m / z: 345.05. 1H NMR(500MHz,DMSO-d6)δ 8.26-8.15(m,2H),7.75-7.61(m,2H),6.43-6.33(m,1H),3.60(d,J=49.0Hz,4H),2. 52(d,J=3.8Hz,2H),2.46(dt,J=4.5,2.4Hz,2H),1.89(t,J=6.2Hz,2H),1.38(s,9H).

[0392] Step 3: Preparation of intermediate 11d Pd / C (10%, 0.015 g) was added to a solution of intermediate 11c (1 g) in MeOH (50 mL), and the reaction mixture was first purged with nitrogen 2-3 times and then with hydrogen 2-3 times. The mixture was stirred at room temperature for 90 minutes. After the reaction was completed, the mixture was filtered and the cake was eluted with 50 mL of DCM. The solvent was removed from the filtrate by distillation under reduced pressure to obtain 1.013 g of intermediate 11d. MS (ESI, [M+H] + ) m / z: 317.2. 1 H NMR(500MHz,DMSO-d6)δ 6.87-6.79(m,2H),6.51-6.42(m,2H),4.79(s,2H),3.58(d,J=13.2Hz,2H),3.47(s,2H),2.24(tt,J=11.9,3.4Hz,1 H),1.87(dd,J=12.9,3.8Hz,2H),1.66-1.57(m,2H),1.48(td,J=13.0,3.5Hz,2H),1.38(s,9H),1.35-1.27(m,2H).

[0393] Step 4: Preparation of intermediate 11e Intermediate 1f (1.1 g), Intermediate 11d (1.053 g), BINAP (0.207 g), Cs2CO3 (3.25 g), Pd(OAc)2 (0.075 g), and 1,4-dioxane (50 mL) were added to a single-neck flask in this order. The mixture was heated to 100 °C under N2 protection and reacted for 1.5 hours. After the reaction was stopped and the reaction mixture was cooled to room temperature, it was filtered and the cake was washed with 150 mL of dichloromethane. The solvent was removed from the filtrate by distillation under reduced pressure, and the mixture was purified by silica gel column chromatography (DCM:CH3OH = 10:1). 1.2 g of Intermediate 11e was obtained. MS (ESI, [M+H] + ) m / z: 601.6. 1 H NMR(500MHz,DMSO-d6)δ 8.93(s,1H),7.81(s,1H),7.47-7.41(m,2H),7.10(d,J=8.6Hz,2H),4.24(d,J=13.1Hz,1H),3.66-3.43(m,6H),3.25(s,4H),3.00-2.86(m ,2H),2.71(d,J=2.2Hz,3H),2.37(d,J=12.2Hz,1H),1.91(d,J=12.7Hz,2H),1.82-1.65(m,6H),1.53(td,J=12.9,3.5Hz,4H),1.38(s,9H).

[0394] Step 5: Preparation of intermediate 11f Intermediate 11e (1.2 g), DMSO (100 mL), MeOH (50 mL), and CsCO (0.532 g) were added to a single-neck flask in this order. H2O2 (0.926 g) was added under ice bath conditions and stirred for 5 minutes. The ice bath was removed and the mixture was allowed to react at room temperature for 1.5 hours. When the reaction was complete, 100 mL of saturated sodium sulfite solution was added to quench the reaction. No color change was detected using potassium iodide-starch TS. An additional 100 mL of ethyl acetate was added for extraction. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation to yield 1.2 g of Intermediate 11f. MS (ESI, [M+H] + ) m / z: 619.41.

[0395] Step 6: Preparation of intermediate 11g Intermediate 11f (1 g), DCM (20 mL), and trifluoroacetic acid (5.53 g, 3.74 mL) were added to a reaction flask in this order and reacted at room temperature for 3 hours. The solvent was removed by distillation under reduced pressure to obtain the trifluoroacetate salt product. Saturated aqueous sodium bicarbonate solution was slowly added to adjust the system to a weak alkaline state, and the mixture was stirred for 1 hour. After filtration, the cake was washed with a small amount of water and dried in a vacuum oven to obtain 0.8 g of Intermediate 11g. MS (ESI, [M+H] + ) m / z: 519.4. 1 H NMR(500MHz,DMSO-d6)δ 11.22(s,1H),7.76(d,J=2.7Hz,1H),7.66(s,1H),7.52-7.46(m,2H),7.33(d,J= 2.8Hz,1H),7.15-7.10(m,2H),4.41-4.26(m,2H),3.77(s,2H),3.65(s,2H),3.60 (dt,J=10.9,4.0Hz,1H),3.40-3.33(m,2H),3.30-3.23(m,2H),3.05(t,J=11.8Hz,1H),2.95(t,J=12.2Hz,1H),2.71(s,3H),2.3 9(tt,J=11.8,3.0Hz,1H),2.08(d,J=12.8Hz,2H),1.86-1.69(m,5H),1.54(td,J=13.3,3.6Hz,3H),1.38(qd,J=13.1,3.1Hz,2H).

[0396] Step 11: Preparation of Compound 11 To a reaction flask, intermediate 9f (50 mg), intermediate 11g (82 mg), MeOH (5 mL), and acetic acid (4.76 mg) were added in this order and stirred at room temperature for 30 minutes. Then, sodium cyanoborohydride (19.93 mg) was added and stirred at room temperature for 3.5 hours. The reaction mixture was purified by silica gel column chromatography (DCM:CHOH=10:1) to give 0.07 g of compound 11. MS (ESI, [M+H] + ) m / z: 816.7. 1 H NMR (500 MHz, DMSO-d6) δ 11.20(s,1H),11.04(s,1H),7.75(d,J=2.9Hz,1H),7.65(s,1H),7.54(d,J= 8.6Hz,1H),7.49(d,J=8.2Hz,2H),7.33(d,J=2.9Hz,1H),7.12(d,J=8.2Hz,2 H),6.52-6.43(m,2H),4.43(dd,J=11.4,5.0Hz,1H),4.37(d,J=12.2Hz,1H), 4.28(d,J=12.7Hz,1H),3.99(t,J=7.5Hz,2H),3.67-3.55(m,3H),3.36-3.30 (m,6H),3.26(dd,J=9.2,7.2Hz,2H),2.98(dt,J=35.3,11.6Hz,4H),2.75(d d,J=11.8,5.5Hz,2H),2.72(s,3H),2.58(dt,J=17.2,4.4Hz,1H),2.45-2.33 (m,2H),2.16(dq,J=13.0,5.0Hz,1H),1.96(d,J=11.0Hz,2H),1.85-1.73(m, 3H),1.69(d,J=12.4Hz,2H),1.59-1.45(m,3H),1.37(q,J=11.1,9.5Hz,2H). 13 C NMR(126MHz,DMSO-d6)δ 173.60,172.08,169.70,165.05,160.78,156.42,154.03,154.01,150.97,140.88,137.73,127.40,122.90,120.14,118.61,114.69,11 1.25,110.24,89.45,65.83,56.17,55.39,49.12,47.19,45.45,44.85,42.69,39.02,35.91,31.54,31.40,30.98,28.22,24.47,23.29.

[0397] Example 12: Synthesis of Compound 12

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[0398] ステップ1: Preparation of compound 12 Intermediate 11g (200 mg), DCM (30 mL), Intermediate 10i (115 mg), and three drops of acetic acid were added to a single-neck flask in this order and allowed to react at room temperature for 1 hour. The temperature was then lowered in an ice bath, and NaBH4 (36.5 mg) was added. The reaction mixture was then allowed to react at room temperature for 20 hours. The reaction mixture was poured into a mixture of DCM:MeOH (10:1) and water, and the pH was adjusted to 8 with saturated aqueous sodium bicarbonate. The organic phase was separated, and the aqueous phase was extracted several times with DCM:MeOH (10:1). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate by vacuum distillation. The crude product was purified by silica gel column chromatography (dichloromethane:methanol (20:1, volume ratio)). The purified product was dissolved in DMSO and eluted with 120 g of C. 18 A commercially available reverse phase column was selected and purified using a Biotage medium-low pressure chromatography system (1 M aqueous ammonium acetate:acetonitrile=1:1, volume ratio) to obtain 61 mg of compound 12. HRMS (ESI, [M+H] + ) m / z:802.41917. 1H NMR (500 MHz, DMSO-d6) δ 11.20(s,1H),11.04(s,1H),7.75(d,J=2.9Hz,1H),7.65(s,1H),7.55(d,J=8.6H z,1H),7.48(d,J=8.3Hz,2H),7.33(d,J=2.9Hz,1H),7.11(d,J=8.3Hz,2H),6.52 (d,J=1.8Hz,1H),6.48(dd,J=8.6,1.9Hz,1H),4.43(dd,J=11.4,5.0Hz,1H),4.3 6(d,J=12.5Hz,1H),4.28(d,J=13.3Hz,1H),3.94(t,J=7.6Hz,2H),3.77-3.68(m ,2H),3.61(ddt,J=15.4,11.2,4.6Hz,2H),3.32-3.20(m,4H),3.08-2.92(m,5H) ,2.74(td,J=11.5,5.7Hz,1H),2.69(s,3H),2.58(dt,J=17.3,4.5Hz,1H),2.41( dddt,J=20.9,14.7,9.7,3.9Hz,2H),2.17(dq,J=13.3,5.0Hz,1H),1.97(d,J=12 .3Hz,2H),1.84-1.66(m,5H),1.59-1.47(m,3H),1.42-1.33(m,2H),1.23(s,1H). 13 C NMR(126MHz,DMSO-d6)δ 173.62,172.10,169.71,165.08,160.78,156.44,154.04,153.66,150.98,140.92,137.72,127.42,122.93,120.16,118.62,11 4.69,111.25,110.34,89.52,61.21,59.19,55.12,53.85,49.11,47.18,45.44,44.85,42.71,39.01,36.60,35.11,31.51,31.4 0,31.01,28.22,24.47,23.29.

[0399] Example 13: Synthesis of Compound 13

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[0400] Step 1: Preparation of intermediate 13b At −78° C., under N2 protection, DIBAL-H (0.311 g) was slowly added dropwise to a stirred solution of Intermediate 7c (0.5 g) in DCM (10 mL), and the reaction was completed in 3 minutes. The mixture was stirred at −78° C. for 1 hour. At −78° C., 2 mL of methanol was slowly added to the reaction solution to quench the reaction. The reaction solution was allowed to stand at room temperature, diluted with 20 mL of petroleum ether, stirred for 5 minutes, filtered, and the filtrate was concentrated to give Intermediate 13b (0.4 g).

[0401] Step 2: Preparation of intermediate 13c Intermediate 13b (0.4 g), trimethyl orthoformate (0.261 g), p-toluenesulfonic acid (0.028 g), and methanol (10 mL) were added to a reaction flask in this order, and the mixture was allowed to react overnight at room temperature. Approximately 100 mL of saturated aqueous sodium bicarbonate solution was added to the system, and the mixture was extracted three times with 50 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to obtain intermediate 13c (0.32 g). 1 H NMR(500MHz,DMSO-d6)δ 6.33-6.28(m,1H),4.13(d,J=7.6Hz,1H),3.23(d,J=1.3Hz,6H),2.50-2.47(m,1 H),2.40(dddt,J=18.3,15.5,8.8,2.4Hz,2H),2.27-2.14(m,2H),1.19(s,12H).

[0402] Step 3: Preparation of intermediate 13d Add intermediate 1m (57 g) and sulfuric acid (200 mL) in this order to a reaction flask, and slowly add a mixture of nitric acid (25.28 g, 401.25 mmol) and sulfuric acid (20 mL) in an ice bath. After completion, the mixture was slowly warmed to room temperature and allowed to react for 1 hour. The reaction mixture was slowly poured into 2 L of ice water, extracted with 500 mL of ethyl acetate, the organic phase was collected, the aqueous phase was extracted twice with 500 mL of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to obtain intermediate 13d (53.3 g). MS(ESI,[MH] - ) m / z: 326.9. 1 H NMR(500MHz,DMSO-d6)δ 8.75(s,1H),8.51(s,1H),4.29(s,2H),4.15(q,J=7.1Hz,2H),1.20(t,J=7.1Hz,3H).

[0403] Step 4: Preparation of intermediate 13e Intermediate 13d (40 g), ethanol (400 mL), and stannous chloride dihydrate (115 g) were added to a reaction flask in this order, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated, and 2 L of dichloromethane and 2 L of water were added to the residue. Saturated aqueous sodium bicarbonate solution was added slowly in an ice bath to adjust the pH to 9-10. After filtration, the organic phase was separated from the filtrate, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to obtain intermediate 13e (35.1 g). MS (ESI, [M+H] + ) m / z: 299.0. 1 H NMR(500MHz,DMSO-d6)δ 7.93(s,1H),7.04(s,1H),5.35(s,2H),4.14(q,J=7.1Hz,2H),4.09(s,2H),1.20(t,J=7.1Hz,3H).

[0404] Step 5: Preparation of intermediate 13f Silver sulfate (29.46 g), iodine (23.98 g), and acetonitrile (300 mL) were added to a reaction flask in this order, followed by the addition of Intermediate 13e (35 g). The mixture was allowed to react at room temperature for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated. 500 mL of ethyl acetate and 500 mL of water were then added. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to obtain Intermediate 13f (27.1 g). MS (ESI, [M+H] + ) m / z: 423.0. 1 H NMR(500MHz,DMSO-d6)δ 8.10(s,1H),5.27(s,2H),4.15(d,J=6.6Hz,4H),1.22(t,J=7.1Hz,3H).

[0405] Step 6: Preparation of intermediate 13g Intermediate 13f (26.8 g), (E)-1-ethoxyethene-2-boronic acid pinacol ester (14.99 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (4.61 g), potassium carbonate (26.14 g), 1,4-dioxane (200 mL), and water (30.00 mL) were added to a reaction flask in this order. The mixture was heated to 70 °C under N2 protection and reacted for 6 hours. After the reaction mixture cooled to room temperature, 500 mL of ethyl acetate and 500 mL of water were added. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to give Intermediate 13f (17 g). MS (ESI, [M+H] + ) m / z: 369.1.

[0406] Step 7: Preparation of intermediate 13h The reaction flask was charged with 13g (17g) of the intermediate, 200mL of DCM, and 57.55mL of hydrochloric acid (4mol / L, 230.22mmol) in this order, and the mixture was reacted at room temperature for 5 hours. 200mL of DCM and 200mL of saturated sodium bicarbonate solution were added to the system. The organic phase was separated, and the aqueous phase was extracted twice with 50mL of dichloromethane. The organic phases were combined. The extract was dried over anhydrous sodium sulfate, filtered, and concentrated, and the concentrate was purified by silica gel column chromatography to obtain intermediate 13h (7.1 g). MS (ESI, [M+H] + ) m / z: 323.0. 1 H NMR(500MHz,DMSO-d6)δ 11.89(s,1H),7.84(d,J=1.7Hz,1H),7.63(t,J=2.8Hz,1H),6.77(dd,J=2.9,1.6Hz,1H),4.29(s,2H),4.13(q,J=7.1Hz,2H),1.19-1.16(m,3H).

[0407] Step 8: Preparation of intermediate 13i Intermediate 13h (3 g), acrylamide (0.792 g), and anhydrous tetrahydrofuran (50 mL) were added to a reaction flask in this order, and potassium tert-butoxide (1.56 g) was slowly added at 0° C. and the mixture was allowed to react for 2 hours. The reaction mixture was quenched by adding 200 mL of saturated aqueous ammonium chloride solution, and the mixture was extracted with 200 mL of DCM. The organic phase was separated, and the aqueous phase was extracted twice with 50 mL of DCM. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to obtain Intermediate 13i (1.34 g). MS(ESI,[MH] - ) m / z: 345.9. 1H NMR(500MHz,DMSO-d6)δ 11.91(s,1H),11.19(s,1H),7.86(s,1H),7.63(t,J=2.9Hz,1H),6.71(dd,J=3.0,1.8Hz,1H),4.72(dd,J=12.0,5.1Hz,1H) ,2.85(ddd,J=17.5,12.2,5.4Hz,1H),2.64(dt,J=17.3,4.1Hz,1H),2.48-2.36(m,1H),2.24(dtd,J=13.7,5.2,3.6Hz,1H).

[0408] Step 9: Preparation of intermediate 13j A reaction flask was charged with Intermediate 13i (0.2 g), Intermediate 13c (0.185 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.042 g), potassium carbonate (0.183 g), 1,4-dioxane (10 mL), and water (2.00 mL), in that order. The mixture was heated to 120 °C under N2 protection and reacted for 3 hours. After the reaction mixture cooled to room temperature, 500 mL of ethyl acetate and 500 mL of water were added. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to obtain Intermediate 13j (0.205 g). MS(ESI,[MH] - ) m / z: 408.2.

[0409] Step 10: Preparation of intermediate 13k To a reaction flask were added intermediate 13j (0.39 g), palladium-carbon catalyst (0.039 g), and MeOH (20 mL), in that order, and the mixture was reacted overnight at room temperature under H2 protection. The reaction solution was filtered, and the filtrate was concentrated to give intermediate 13k (0.36 g). MS(ESI,[MH] - ) m / z: 410.2. 1H NMR(500MHz,DMSO-d6)δ 11.61(s,1H),11.17(s,1H),7.52(t,J=2.8Hz,1H),7.33(d,J=9.7Hz,1H),6.57-6.52(m,1H),4.64( dd,J=11.8,5.1Hz,1H),4.29(d,J=7.6Hz,1H),3.61(ddd,J=24.3,10.6,5.4Hz,1H),3.28(dd,J=7.6, 5.4Hz,6H),2.84(ddd,J=17.2,12.0,5.4Hz,1H),2.62(dt,J=17.3,4.2Hz,1H),2.43(tt,J=12.1,7.0 Hz,2H),2.22(dq,J=13.8,7.7,5.9Hz,2H),2.16-2.09(m,1H),1.87-1.67(m,3H),1.60-1.51(m,1H).

[0410] Step 11: Preparation of intermediate 13l Intermediate 13k (0.1 g), acetone (5 mL), and p-toluenesulfonic acid (0.021 g) were added to a reaction flask in this order, and the mixture was reacted at room temperature for 2 hours. 50 mL of saturated aqueous sodium bicarbonate and 50 mL of DCM were added to the system, and the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate 13l (0.085 g). MS(ESI,[MH] - ) m / z: 364.2.

[0411] Step 12: Preparation of Compound 13 A reaction flask was charged with intermediate 13l (0.08 g), intermediate 1i (0.104 g), and dichloroethane (5 mL). One drop of acetic acid was added, and sodium cyanoborohydride (0.026 g) was then added. The mixture was then reacted at room temperature for 2 hours. After the reaction was complete, dichloromethane (50 mL) and water (50 mL) were added to the mixture. The organic phase was separated, and the aqueous phase was extracted twice with dichloromethane (50 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to give compound 13 (0.042 g). MS (ESI, [M+H] + ) m / z: 828.4. 1 H NMR(500MHz,DMSO-d6)δ 11.73(d,J=27.7Hz,1H),11.28(s,1H),11.17(s,1H),7.78(s,1H),7.67(s,1H),7.56(d,J=7.5Hz,3H),7.40(s,1 H),7.35(s,1H),7.18(d,J=8.0Hz,2H),6.56(s,1H),4.66(dd,J=11.7,5.2Hz,1H),4.39-4.27(m,2H),3.71(s,1H) ),3.62(s,3H),3.26(s,3H),3.07(d,J=11.6Hz,2H),2.97(t,J=12.5Hz,1H),2.84(d,J=14.6Hz,1H),2.71(s,3H) ,2.63(d,J=16.9Hz,2H),2.43(s,1H),2.23(s,2H),2.00(s,3H),1.82(d,J=12.9Hz,4H),1.62(d,J=45.5Hz,4H).

[0412] Example 14: Synthesis of Compound 14 [ka]

[0413] Step 1: Preparation of intermediate 14b To a single-neck flask, 14a (50 g), diethyl carbonate (137 g), and toluene (200 mL) were added in this order. The reaction mixture was cooled to 0 °C, and sodium hydride (46.5 g) was added in several portions. The temperature was first raised to 80 °C and the reaction was continued for approximately 10 minutes. The mixture was then heated to 120 °C and allowed to react for 5 hours. After the reaction mixture cooled to room temperature, it was slowly poured into 2 L of stirred ice water and extracted with 1 L of ethyl acetate. The organic phase was discarded. The pH of the aqueous phase was adjusted to 3 with 3 N hydrochloric acid, and the mixture was extracted three times with 500 mL of ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the solvent was removed by distillation under reduced pressure to obtain intermediate 14b (52 g). MS(ESI,[MH] + ) m / z: 239.0. 1H NMR(500MHz,DMSO-d6)δ 12.77(s,1H),7.94(dd,J=7.8,1.5Hz,1H),7.83(dd,J=7.9,1.5Hz,1H),7.29(t,J=7.9Hz,1H),5.64(s,1H).

[0414] Step 2: Preparation of intermediate 14c Intermediate 14b (52 g), methanol (300 mL), hydroxylamine hydrochloride (52.5 g), and sodium ethoxide (61.9 g) were added to a single-neck flask in this order, and the mixture was heated to 80 °C and reacted overnight. After the reaction mixture cooled to room temperature, 3N hydrochloric acid was added to adjust the pH to 5. The solvent was removed by distillation under reduced pressure, and 2 L of water was added. The reaction flask was cooled in an ice-water bath and simultaneously adjusted to pH 3 with 3N hydrochloric acid. The mixture was stirred for 30 minutes and filtered. The cake was collected and dried to obtain Intermediate 14c (46 g). MS(ESI,[MH] + ) m / z: 254.0.

[0415] Step 3: Preparation of intermediate 14d In a single-neck flask, intermediate 14c (46 g), ethanol (400 mL), and sulfuric acid (106 g, 57.5 mL, 1078 mmol) were added in this order, and the mixture was heated to 90 °C and reacted for 2 hours. After the reaction mixture cooled to room temperature, the solvent was removed by distillation under reduced pressure, and the residue was added to 1 L of The mixture was diluted with ethyl acetate and 1 L of water, and the pH was adjusted to 7 with saturated aqueous sodium bicarbonate solution. The organic phase was separated, and the aqueous phase was extracted twice with 500 mL of ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure to obtain Intermediate 14d (51 g). MS (ESI, [M+H] + ) m / z: 283.0. 1H NMR(500MHz,DMSO-d6)δ 7.93(dd,J=7.6,0.9Hz,1H),7.89(dd,J=7.9,0.9Hz,1H),7.38(t,J=7.8Hz,1H),4.26(s,2H),4.15(q,J=7.1Hz,2H),1.20(t,J=7.1Hz,3H).

[0416] Step 4: Preparation of intermediate 14e To a single-neck flask, in an ice bath, were added intermediate 14d (51 g), sulfuric acid (176 g, 96 mL, 1795 mmol), and potassium nitrate (27.2 g), in that order. Upon completion, the mixture was allowed to react at room temperature for 1 hour. The reaction mixture was slowly poured into 2 L of ice water and extracted with 500 mL of ethyl acetate. The organic phase was collected and the aqueous phase was extracted twice with 500 mL of ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The crude product was isolated by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1, volume ratio) to give intermediate 14e (40 g). 1 H NMR(500MHz,DMSO-d6)δ 8.98(d,J=2.1Hz,1H),8.75(d,J=2.1Hz,1H),4.38(s,2H),4.17(q,J=7.1Hz,2H),1.22(t,J=7.1Hz,3H).

[0417] Step 5: Preparation of intermediate 14f Intermediate 14e (40 g), ethanol (400 mL), and stannous chloride dihydrate (115 g) were added to a single-neck flask in this order, and the mixture was stirred at room temperature for 4 hours. The solvent was removed by distillation under reduced pressure, and 2 L of dichloromethane and 2 L of water were added to the residue. The pH was adjusted to slightly alkaline by slowly adding saturated aqueous sodium bicarbonate solution in an ice bath. The mixture was filtered, and the cake was washed twice with 500 mL of dichloromethane. The filtrate was collected. After separation, the organic phase was collected, and the aqueous phase was further extracted twice with 500 mL of dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1, volume ratio) to obtain the desired intermediate 14f (23 g). MS (ESI, [M+H] + ) m / z: 299.0.

[0418] Step 6: Preparation of intermediate 14g Intermediate 14f (6 g), DMF (50 mL), and NIS (4.51 g) were added to a single-neck flask in this order, and the mixture was allowed to react at room temperature for 1 hour. 100 mL of ethyl acetate and 200 mL of water were added to the system. The organic phase was separated, and the aqueous phase was further extracted twice with 50 mL of ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1, volume ratio) to obtain the target intermediate 14f (8 g). MS(ESI,[MH] + ) m / z: 423.0. 1 H NMR(500MHz,DMSO-d6)δ 7.36(s,1H),5.54(s,2H),4.21-4.10(m,4H),1.22(t,J=7.1Hz,3H).

[0419] Step 7: Preparation of intermediate 14h In a single-neck flask, intermediate 14g (4g), (E)-1-ethoxyethene-2-boronic acid pinacol ester (2.237g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (1.377g), and potassium carbonate were added. Ammonia (3.90 g), 1,4-dioxane (40 mL), and water (10.00 mL) were added in this order, and the mixture was heated to 80 °C under N2 protection and reacted overnight. After the reaction mixture cooled to room temperature, ethyl acetate (100 mL) and water (100 mL) were added to the system. The organic phase was separated and extracted three times with 50 mL of ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1, volume ratio) to obtain the desired intermediate 14h (2.4 g). MS (ESI, [M+H] + ) m / z: 369.1.

[0420] Step 8: Preparation of intermediate 14i Intermediate 14h (1 g), dichloromethane (10 mL), and trifluoroacetic acid (1.544 g, 1.043 mL) were added to a single-neck flask in this order, and the mixture was allowed to react at room temperature overnight. Dichloromethane (100 mL) and water (100 mL) were then added to the system. The organic phase was separated, and the aqueous phase was further extracted twice with dichloromethane (50 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1, volume ratio) to obtain the desired intermediate 14i (0.5 g). MS (ESI, [M+H] + ) m / z: 323.0. 1 H NMR(500MHz,DMSO-d6)δ 11.78(s,1H),7.96(s,1H),7.61(t,J=2.9Hz,1H),6.66(t,J=2.3Hz,1H),4.31(s,2H),4.14(q,J=7.1Hz,2H),1.16(t,J=7.1Hz,3H).

[0421] Step 9: Preparation of intermediate 14j Intermediate 14i (300 mg), acrylamide (66 mg), and anhydrous tetrahydrofuran (5 mL) were added to a three-neck flask in this order, and potassium tert-butoxide (208 mg) was slowly added at 0° C. The mixture was allowed to react for 2 hours at 0° C. The reaction mixture was quenched by dropwise addition of saturated aqueous ammonium chloride solution, and the mixture was extracted with 50 mL of ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate (50 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 3:2, volume ratio) to obtain the target intermediate 14j (0.18 g). MS(ESI,[MH] + ) m / z: 345.9. 1 H NMR(500MHz,DMSO-d6)δ 11.80(s,1H),11.20(s,1H),7.97(d,J=0.8Hz,1H),7.61(t,J=2.8Hz,1H),6.60(t,J=2.3Hz,1H),4.73(dd,J=12.2,5.1Hz,1H),2. 86(ddd,J=17.5,12.3,5.4Hz,1H),2.65(dt,J=17.3,4.0Hz,1H),2.45(qd,J=12.5,4.4Hz,1H),2.25(dtd,J=13.6,5.2,3.4Hz,1H).

[0422] Step 10: Preparation of intermediate 14k Intermediate 14j (480 mg), intermediate 13c (370 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (202 mg), potassium carbonate (572 mg), 1,4-dioxane (5 mL), and water (0.5 mL) were added to a single-neck flask in this order, and the mixture was heated to 85 °C under N2 protection and reacted for 2 hours. After the reaction mixture cooled to room temperature, ethyl acetate (50 mL) and water (100 mL) were added to the system for extraction. The organic phase was separated and further extracted three times with ethyl acetate (50 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 60:1, volume ratio). Separation gave the mixture intermediate 14k (0.35 g). MS(ESI,[MH] + ) m / z: 408.19. 1 H NMR (500 MHz, DMSO-d6) δ 11.63(d,J=30.9Hz,1H),11.18(s,1H),7.57(dt,J=9.7,3.5Hz,2H),6.64(d,J =6.3Hz,1H),6.62-6.48(m,1H),4.71(dt,J=11.4,5.0Hz,1H),4.38-4.21(m,1H ),3.33-3.25(m,6H),3.00-2.79(m,2H),2.79-2.58(m,3H),2.44(tt,J=12.2,6 .3Hz,1H),2.25(dp,J=13.1,5.2Hz,1H),2.16-1.96(m,1H),1.88-1.72(m,1H).

[0423] Step 11: Preparation of intermediate 14l Intermediate 14k (50 mg), methanol (3 mL), and Pd / C (10 mg) were added to a single-neck flask in this order, and the mixture was reacted at room temperature for 3 hours after hydrogen exchange three times. The reaction mixture was filtered to remove palladium carbon, and the cake was washed with 5 mL each of dichloromethane, methanol, and ethyl acetate. The solvent was removed from the filtrate by vacuum distillation to obtain intermediate 14l (40 mg). MS(ESI,[MH] + ) m / z: 410.21. 1 H NMR(500MHz,DMSO-d6)δ 11.52(d,J=2.3Hz,1H),11.18(s,1H),7.54(s,1H),7.47(t,J=2.8Hz,1H),6.49(q,J=2 .3Hz,1H),4.68(ddd,J=11.9,9.1,5.2Hz,1H),4.28(d,J=7.5Hz,1H),3.55-3.41(m,1H) ,3.29(dd,J=7.2,2.3Hz,6H),2.86(ddd,J=17.3,12.1,5.4Hz,1H),2.64(dt,J=17.3,4 .2Hz,1H),2.49-2.38(m,2H),2.29-2.09(m,3H),1.89-1.75(m,2H),1.74-1.61(m,2H).

[0424] Step 12: Preparation of intermediate 14m Intermediate 14l (100 mg), bis(acetonitrile)palladium(II) dichloride (31.5 mg), and acetone (10 mL) were added to a single-neck flask in this order, and the mixture was allowed to react at room temperature for 1 hour. Ethyl acetate (30 mL) and water (50 mL) were added to the system for extraction. The organic phase was separated, and the aqueous phase was further extracted three times with ethyl acetate (30 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure to obtain intermediate 14m (70 mg). MS(ESI,[MH] + ) m / z: 364.11.

[0425] Step 13: Preparation of Compound 14 Intermediate 1i (90 mg), intermediate 14m (68.7 mg), and 1,2-dichloroethane (2 mL) were added to a single-neck flask in this order, and one drop of acetic acid was added. The mixture was stirred at room temperature for 20 minutes, and sodium cyanoborohydride (35.5 mg) was added, and the mixture was allowed to react at room temperature. Dichloromethane (20 mL) and water (50 mL) were added to the system for extraction. The organic phase was separated and further extracted three times with DCM:MeOH = 10:1 (30 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure. The mixture was purified by silica gel column chromatography to obtain compound 14 (20 mg). MS (ESI, [M+H] + ) m / z: 828.52. 1 H NMR(500MHz,DMSO-d6)δ 11.62(d,J=27.7Hz,1H),11.28(s,1H),11.19(s,1H),7.89(s,1H),7.68(s,1H),7.56(d,J=7.5Hz,3H),7 .49(s,1H),7.35(s,1H),7.18(d,J=8.0Hz,2H),6.51(s,1H),4.68(dd,J=11.7,5.2Hz,1H),4.35-4.25(m, 2H),3.76(s,1H),3.61(s,3H),3.31(s,3H),3.13(d,J=11.6Hz,2H),2.91(t,J=12.5Hz,1H),2.79(d,J=14.6Hz,1H),2.7 9(s,3H),2.59(d,J=16.9Hz,2H),2.49(s,1H),2.26(s,2H),2.05(s,3H),1.83(d,J=12.9Hz,4H),1.66(d,J=45.5Hz,4H).

[0426] Example 15: Synthesis of Compound 15 [ka]

[0427] Step 1: Preparation of intermediate 15b 15a (50 g), diethyl carbonate (216.9 g), and toluene (500 mL) were added to a reaction flask in this order. The reaction mixture was cooled to 0 °C, and sodium hydride (44.06 g) was added in several portions. The temperature was first raised to 70 °C and the reaction was continued for approximately 10 minutes. The mixture was heated to 120 °C and the reaction was continued for 5 hours. After the reaction mixture cooled to room temperature, the reaction mixture was slowly poured into 2 L of stirred ice water and extracted with 1 L of ethyl acetate. The organic phase was discarded. The pH of the aqueous phase was adjusted to 3 with 3 N hydrochloric acid, and the mixture was extracted three times with 500 mL of ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate 15b (55 g). 1H NMR(500MHz,DMSO-d6)δ 12.52(s,1H),7.83(dd,J=7.8,1.7Hz,1H),7.65(ddd,J=8.6,7.2,1.7Hz,1H),7.43-7.32(m,2H),5.61(s,1H).

[0428] Step 2: Preparation of intermediate 15c To a reaction flask, intermediate 15b (55 g), methanol (500 mL), hydroxylamine hydrochloride (63.5 g), and sodium ethoxide (80.8 g) were added in this order, and the mixture was heated to 80°C and reacted overnight. After the reaction mixture cooled to room temperature, 3N hydrochloric acid was added to adjust the pH to 5, and the mixture was concentrated. 2 L of water was added, and the reaction flask was placed in an ice-water bath to cool. The pH was adjusted to 3 with 3N hydrochloric acid. The mixture was stirred for 30 minutes and filtered. The cake was collected and dried to give Intermediate 15c (54.5 g). 1 H NMR(500MHz,DMSO-d6)δ 12.90(s,1H),7.86(dt,J=7.9,1.0Hz,1H),7.74(d,J=8.4Hz,1H),7.66(d dd,J=8.3,7.0,1.2Hz,1H),7.40(td,J=7.4,7.0,0.9Hz,1H),4.11(s,2H).

[0429] Step 3: Preparation of intermediate 15d Intermediate 15c (54 g), ethanol (400 mL), and sulfuric acid (106 g) were added to a reaction flask in this order, and the mixture was heated to 90 °C and reacted for 2 hours. After the reaction mixture cooled to room temperature, the solvent was removed by distillation under reduced pressure, and the residue was diluted with 1 L of ethyl acetate and 1 L of water. The pH was adjusted to 7 with saturated aqueous sodium bicarbonate solution, and the organic phase was separated. The aqueous phase was extracted twice with 500 mL of ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give Intermediate 15d (62 g). MS (ESI, [M+H] + ) m / z: 206.1.

[0430] Step 4: Preparation of intermediate 15e Intermediate 15d (30 g) and sulfuric acid (200 mL) were added to a reaction flask in this order, and a mixture of nitric acid (11.05 g) and sulfuric acid (4 mL) was slowly added in an ice bath. After completion of the reaction, the mixture was slowly warmed to room temperature and reacted for 1 hour. The reaction mixture was slowly poured into 2 L of ice water, extracted with 300 mL of ethyl acetate, and the organic phase was collected. The aqueous phase was extracted twice with 100 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to obtain Intermediate 15e (29.3 g). MS (ESI, [M+H] + ) m / z: 251.1.

[0431] Step 5: Preparation of intermediate 15f Intermediate 15e (29 g), ethanol (300 mL), and stannous chloride dihydrate (130.76 g) were added to a reaction flask in this order, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated, and 1 L of dichloromethane and 0.5 L of water were added to the residue. Saturated aqueous sodium bicarbonate solution was added slowly in an ice bath to adjust the pH to 9-10. After filtration, the organic phase was separated from the filtrate, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to obtain Intermediate 15f (24.3 g). MS(ESI,[MH] - ) m / z: 219.1.

[0432] Step 6: Preparation of Intermediate 15g Intermediate 15f (24 g) and DCM (200 mL) were added to a reaction flask in this order, and NBS (21.34 g) was added at 0° C. The mixture was reacted at room temperature for 1 hour. 500 mL of DCM and 500 mL of water were added to the reaction mixture, and the organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to obtain Intermediate 15g (22.4 g). MS (ESI, [M+H] + ) m / z: 299.2. 1H NMR(500MHz,DMSO-d6)δ 7.52(d,J=8.9Hz,1H),7.17(d,J=8.9Hz,1H),4.87(s,2H),4.19-4.11(m,4H),1.20(t,J=7.1Hz,3H).

[0433] Step 7: Preparation of intermediate 15h To a reaction flask were added Intermediate 7a (5 g), trimethyl orthoformate (11.2 g), p-toluenesulfonic acid (0.606 g), and ethanol (50 mL) in this order, and the mixture was allowed to react at room temperature overnight. Approximately 100 mL of saturated aqueous sodium bicarbonate solution was added to the system, and the resulting mixture was stirred for 100 minutes. The mixture was extracted with 3 mL of ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to obtain intermediate 15h (4.5 g). 1 H NMR(500MHz,chloroform-d)δ 4.14(q,J=7.1Hz,2H),3.21(d,J=10.6Hz,6H),2.92-2.81(m,1H),2.14-2 .03(m,2H),2.01-1.91(m,2H),1.91-1.78(m,2H),1.25(t,J=7.1Hz,3H).

[0434] Step 8: Preparation of Intermediate 15i A reaction flask was charged with intermediate 15h (4.5 g) and THF (50 mL), and lithium aluminum hydride (0.998 g) was slowly added in an ice bath. The mixture was then slowly warmed to room temperature and reacted for 1 hour. After completion of the reaction, a small amount of ice water was added to the reaction mixture in an ice bath to quench the reaction. 200 mL of DCM and 200 mL of water were then added. The mixture was filtered, and the organic phase was separated from the filtrate, washed with 200 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate 15i (3.9 g). 1H NMR(500MHz,chloroform-d)δ 3.55(dhept,J=15.8,5.4,4.9Hz,2H),3.21(d,J=3.0Hz,6H),2.28(dddd,J=15.1,8.8,7.6,3.9Hz,1H),2.05-1.96(m,1H),1.90( dddd,J=10.2,8.8,3.7,1.5Hz,2H),1.85-1.81(m,1H),1.80-1.73(m,1H),1.58(ddd,J=13.4,7.3,1.3Hz,1H),1.51-1.40(m,1H).

[0435] Step 9: Preparation of intermediate 15j A reaction flask was charged with Intermediate 15g (2.2 g), Intermediate 15i (1.3 g), triethylsilane (1.71 g), and acetonitrile (20 mL). Iodine (1.87 g) was then added, and the temperature was raised to 90 °C and the reaction was carried out overnight. The reaction mixture was cooled to room temperature and concentrated, followed by the addition of 200 mL of DCM and 200 mL of water. The organic phase was separated, washed with 200 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to obtain Intermediate 15j (1.9 g). MS (ESI, [M+H] + ) m / z: 319.2.

[0436] Step 10: Preparation of intermediate 15k Intermediate 15j (1.9 g) and DCM (30 mL) were added to a reaction flask in this order, followed by NBS (1.06 g), and the mixture was allowed to react at room temperature for 1 hour. 100 mL of DCM and 100 mL of water were added to the reaction mixture, and the organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to obtain intermediate 15k (0.75 g). MS (ESI, [M+H] + ) m / z: 397.2. 1H NMR(500MHz,DMSO-d6)δ 7.63(dd,J=9.0,7.4Hz,1H),7.18(dd,J=9.2,3.4Hz,1H),4.96(d,J=7.6Hz,1H),4.70 -4.63(m,1H),4.19-4.12(m,4H),3.92(hept,J=6.3Hz,1H),3.40-3.36(m,1H),2.18(d dd,J=12.4,8.4,6.6Hz,1H),2.14-2.02(m,1H),1.94-1.76(m,1H),1.75-1.61(m,1H), 1.51(dddd,J=20.0,15.4,10.7,6.6Hz,2H),1.35-1.23(m,1H),1.20(t,J=7.1Hz,3H).

[0437] Step 11: Preparation of intermediate 15l In a waveguide, intermediate 15k (0.7 g), (E)-1-ethoxyethene-2-boronic acid pina Cholesterol (0.419 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.129 g), potassium carbonate (0.731 g), 1,4-dioxane (10 mL), and water (2 mL) were added in this order, followed by bubbling with N2 and reacting at 120 °C for 2 hours under microwave irradiation. When the reaction mixture cooled to room temperature, 100 mL of ethyl acetate and 100 mL of water were added. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to yield intermediate 15l (0.51 g). MS (ESI, [M+H] + ) m / z: 389.2.

[0438] Step 12: Preparation of intermediate 15m Intermediate 15l (0.5 g), DCM (20 mL), and hydrochloric acid (0.644 mL, 4 mol / L, 2.57 mmol) were added to a reaction flask in this order, and the mixture was allowed to react at room temperature for 5 hours. 100 mL of DCM and 100 mL of saturated sodium bicarbonate solution were added to the system. The organic phase was separated, and the aqueous phase was extracted twice with DCM (50 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to obtain intermediate 15m (0.24 g). MS (ESI, [M+H] + ) m / z: 343.1.

[0439] Step 13: Preparation of intermediate 15n Intermediate 15m (0.18 g), acrylamide (0.041 g), and anhydrous tetrahydrofuran (10 mL) were added to a reaction flask in this order, and potassium tert-butoxide (0.071 g) was slowly added at 0° C. and the mixture was allowed to react for 1 hour. The reaction mixture was quenched by adding 50 mL of saturated aqueous ammonium chloride solution, and the mixture was extracted with 50 mL of DCM. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to obtain intermediate 15n (0.095 g). MS (ESI, [M+H] + ) m / z: 368.2.

[0440] Step 14: Preparation of Intermediate 15o Intermediate 15n (0.09 g), dichloromethane (5 mL), and Dess-Martin oxidant (0.233 g) were added to a reaction flask and allowed to react at room temperature for 1 hour. After the reaction was complete, dichloromethane (50 mL) and water (50 mL) were added to the system. The organic phase was separated, and the aqueous phase was extracted twice with dichloromethane (50 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give Intermediate 15o (0.08 g). MS(ESI,[MH] - ) m / z: 364.1.

[0441] Step 15: Preparation of Compound 15 A reaction flask was charged with intermediate 15o (0.08 g), intermediate 1i (0.104 g), dichloroethane (5 mL), one drop of acetic acid, and sodium cyanoborohydride (0.026 g) and the mixture was allowed to react at room temperature for 2 hours. After the reaction was complete, dichloromethane (50 mL) and water (50 mL) were added to the mixture. The organic phase was separated, and the aqueous phase was extracted twice with dichloromethane (50 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to give compound 15 (0.042 g). MS (ESI, [M+H] + ) m / z: 828.4. 1 H NMR(500MHz,DMSO-d6)δ 11.18(s,2H),7.91(dd,J=9.2,2.0Hz,1H),7.80-7.69(m,2H),7.66(s,1H),7.56-7.42(m,3H),7.37-7.29(m,1H),7.15(d,J=8.1 Hz,2H),6.58(dd,J=7.9,3.0Hz,1H),5.09(d,J=38.6Hz,1H),4.69(dd,J=11.9,5.1Hz,1H),4.31(dd,J=38.9,12.7Hz,2H),3.60(d q,J=10.9,5.8,4.5Hz,1H),3.30(d,J=7.9Hz,2H),3.23(d,J=8.1Hz,2H),3.05-2.92(m,3H),2.85(ddd,J=17.4,12.1,5.5Hz,1H),2.6 8(s,3H),2.63(dt,J=17.2,4.2Hz,1H),2.47-2.33(m,4H),2.28-2.19(m,2H),1.99(s,4H),1.85-1.70(m,5H),1.58(d,J=36.0Hz,3H).

[0442] Example 16: Synthesis of Compound 16 [ka]

[0443] Step 1: Preparation of intermediate 16b At 10°C, 16a (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. After confirming that the reaction was complete by TLC, water was added to the reaction solution, and a solid precipitated. The solid was filtered under suction, and the cake was washed with water and dried to obtain 95.78 g of intermediate 16b. MS (ESI, [M+H] - ) 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).

[0444] Step 2: Preparation of intermediate 16c At 10° C., a 2.5 M solution of lithium aluminum hydride in tetrahydrofuran (227 mL) was slowly added dropwise to a solution of 16b (96.00 g) in tetrahydrofuran (1000 mL), and the mixture was allowed to react at 80° C. After confirming complete reaction by TLC, a 15 wt % aqueous solution of sodium hydroxide and water were added to the reaction mixture, which was then suction filtered. The cake was washed with a dichloromethane:MeOH=1:1 solution, and the filtrate was concentrated. The crude product was separated and purified by silica gel column chromatography to obtain 55.87 g of intermediate 16c. 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).

[0445] Step 3: Preparation of intermediate 16d A reaction flask was charged with 16c (48.00 g), methanol (350 mL), and palladium hydroxide. Carbon dioxide (4.8 g) and di-tert-butyl dicarbonate (41.4 g) were added in this order, and the mixture was reacted under hydrogen protection at 25° C. After confirming the complete reaction by TLC, the reaction mixture was suction filtered, and the filtrate was concentrated and extracted with water and ethyl acetate. After washing with saturated brine, the mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was separated and purified by silica gel column chromatography to obtain 34.43 g of intermediate 16d. 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).

[0446] Step 4: Preparation of intermediate 16e 16d (35.00 g), methanol (250 mL), and 4 M hydrochloric acid in dioxane (123 mL) were added to a reaction flask in this order and reacted at 25 °C. After complete reaction was confirmed by TLC, the reaction mixture was concentrated, and pyridine (200 mL) and trifluoroacetic anhydride (25.20 g) were added and stirred at 25 °C. After complete reaction was confirmed by TLC, the reaction mixture was poured into 3 M aqueous hydrochloric acid and stirred vigorously. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and dried to give 32.48 g of intermediate 16e. MS (ESI, [M+H] - ) 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).

[0447] Step 5: Preparation of intermediate 16f To a reaction flask were added 16e (32.48 g), dichloromethane (300 mL), triethylamine (28.40 g), 4-dimethylaminopyridine (1.72 g), and acetic anhydride (15.78 g) in this order, and the reaction was carried out at 25° C. After confirming the complete reaction by TLC, the reaction solution was poured into water, vigorously stirred, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was separated and purified by silica gel column chromatography to obtain 33.82 g of intermediate 16f. 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).

[0448] Step 6: Preparation of intermediate 16g 16f (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. After confirming the complete reaction by TLC, 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 and purified by silica gel column chromatography to obtain 18.19 g of intermediate 16g. 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).

[0449] Step 7: Preparation of intermediate 16h In a reaction flask, add 16g (18.19g), sodium hydroxide (7.56g), and methanol. Methanol (150 mL) and water (150 mL) were added in this order and reacted at 25° C. for 2.5 hours. The reaction mixture was concentrated to remove 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. for 2 hours. The reaction mixture 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 and purified by silica gel column chromatography to obtain 14.10 g of intermediate 16h. MS (ESI, [M+H] - ) 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).

[0450] Step 8: Preparation of intermediate 16i A reaction flask was charged with 16h (14.10 g), diethyl carbonate (27.00 g), and toluene (200 mL) in this order. The temperature was lowered to 0°C, and 60 wt% sodium hydride (9.16 g) was added. The temperature was then raised to 120°C and the mixture was stirred. After confirming complete reaction by TLC, the reaction mixture was poured into 3M aqueous hydrochloric acid, 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 and purified by silica gel column chromatography to obtain 14.96 g of intermediate 16i. MS (ESI, [M+H] + ) m / z: 250.20. 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).

[0451] Step 9: Preparation of intermediate 16j To a reaction flask were added 16i (14.96 g), 50% aqueous hydroxylamine solution (6.36 g), and ethanol (150 mL) in this order, followed by stirring at 85° C. After confirming the complete reaction by TLC, the reaction solution was concentrated, followed by the addition of water and ethyl acetate, followed by extraction and layer separation. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain a crude product of intermediate 16j (10.13 g). MS (ESI, [M+H] - ) 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).

[0452] Step 10: Preparation of intermediate 16k To a reaction flask were added 16j (10.13 g), potassium carbonate (12.55 g), N,N-dimethylacetamide (150 mL), and ethyl iodide (7.08 g) in this order, and the mixture was stirred at 80° C. After confirming complete reaction by TLC, the reaction mixture was poured into water and vigorously stirred. Ethyl acetate was added for extraction, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was separated and purified by silica gel column chromatography to obtain 11.22 g of intermediate 16k. MS (ESI, [M+H] + ) m / z: 247.16. 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,2H),4.22(d,J=4.3Hz,2H),4.13(p,J=7.2Hz,2H),1.48(d,J=2.1Hz,9H),1.21-1.17(m,3H).

[0453] Step 11: Preparation of intermediate 16l At 0°C, under N2 protection, acrylamide (1.32 g) was slowly added to a stirred solution of 16k (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, and the mixture was stirred at 0°C to react. After confirming complete reaction by TLC, the reaction solution was poured into an aqueous ammonium chloride solution and vigorously stirred. Ethyl acetate was added for extraction, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was separated and purified by silica gel column chromatography to obtain 7.52 g of intermediate 16l. MS (ESI, [M+H] + ) m / z: 272.02. 1H 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).

[0454] Step 12: Preparation of Compound 16 To a reaction flask, 16L (1.00 g), 4 M hydrochloric acid in dioxane (10 mL), and ethyl acetate (50 mL) were added in that order, and the reaction was carried out at 25°C. After confirming the complete reaction by TLC, the reaction solution was directly filtered, and the cake was washed with ethyl acetate and dried to obtain 0.83 g of compound 16. 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).

[0455] Example 17: Synthesis of Compound 17 [ka]

[0456] Step 1: Preparation of intermediate 17b 17a (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 for reaction. After confirming complete reaction by TLC, the reaction mixture was cooled to room temperature, and the solvent was removed by distillation under reduced pressure. 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 17b (18.7 g).

[0457] Step 2: Preparation of intermediate 17c 17b (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 confirming complete reaction by TLC, the reaction was completed when the reaction mixture cooled to room temperature. Stirring was stopped and the mixture was allowed to react at room temperature for a total of 2 h. The reaction mixture was extracted with ethyl acetate and 1 M HCl in ice water. The aqueous phase was collected, and the pH was adjusted to approximately 9 with solid sodium bicarbonate. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation to give intermediate 17c (9.6 g). MS (ESI, [M+H] + ) m / z: 240.1.

[0458] Step 3: Preparation of intermediate 17d A reaction flask was charged with 17c (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. After confirming the complete reaction by TLC, the palladium on carbon was filtered, and the cake was washed twice with methanol. The filtrate was collected and the solvent was removed by distillation under reduced pressure to give 17d (4.5 g). MS (ESI, [M+H] + ) m / z: 149.9.

[0459] Step 4: Preparation of intermediate 17e 17d (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. After confirming the complete reaction by TLC, the reaction mixture was quenched by adding aqueous solution, followed by extraction with ethyl acetate. The organic phase was separated, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to give 17e (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).

[0460] Step 5: Preparation of intermediate 17f 17e (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. After confirming the complete reaction by TLC, the reaction was quenched by adding water to the reaction mixture in an ice bath. The organic phase was separated, extracted with dichloromethane, and the combined organic phase was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure to give 17f (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).

[0461] Step 6: Preparation of intermediate 17g 17f (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 reacted at room temperature. After confirming complete reaction by TLC, dichloromethane and water were added to the reaction solution. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure to obtain 17f (7 g). 1H 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).

[0462] Step 7: Preparation of intermediate 17h To a reaction flask were added 17g (6g) and aluminum(III) chloride (4.39g), in that order, and the mixture was gradually heated from room temperature to 150°C. After complete reaction was confirmed by TLC, the reaction mixture was cooled to room temperature, and water and 3M aqueous hydrochloric acid were added to the residue. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was removed from the filtrate under reduced pressure, and the filtrate was purified by silica gel column chromatography to give 17h (3.78g). MS(ESI,[MH] - ) m / z: 271.9.

[0463] Step 7: Preparation of intermediate 17j 17h (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. After confirming complete reaction by TLC, the reaction mixture was concentrated to remove methanol and the aqueous phase was retained. 17i was obtained. 1,4-Dioxane (5 mL) and Boc anhydride (439 mg, 0.462 mL) were added to the mixture and reacted at room temperature. After confirming complete reaction by TLC, the reaction mixture was extracted with ethyl acetate and saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 17j (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).

[0464] Step 8: Preparation of intermediate 17k Add 17j (3.5 g) and THF (300 mL) in this order to a reaction flask, and Chilled water (14.91 g, 15.29 mL) was added and the mixture was cooled to approximately 0°C. 60 wt% sodium hydride (5.05 g, 126 mmol) was added in several portions, and the reaction system was heated to 85°C. After confirming complete reaction by TLC, the reaction mixture was cooled to room temperature and slowly poured into ice water, extracted with ethyl acetate, and the organic phase was discarded. The pH of the aqueous phase was adjusted to 1-2 with 3M hydrochloric acid, and then extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure to obtain 17k (7.0 g). MS(ESI,[MH] - ) m / z: 348.3.

[0465] Step 9: Preparation of intermediate 17l 17k (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. After confirming complete reaction by TLC, the reaction mixture was cooled to room temperature, and the residue was extracted with ethyl acetate and saturated aqueous sodium carbonate. The organic phase was discarded. The pH of the aqueous phase was adjusted to 2-3 with 1M aqueous HCl, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation to obtain 17k (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).

[0466] Step 10: Preparation of intermediate 17m To a reaction flask were added 17m (3.14 g), potassium carbonate (1.500 g), DMA (5 mL), and ethyl iodide (2.308 g, 1.183 mL), in that order, and the mixture was heated to 80°C. After complete reaction was confirmed by TLC, the reaction mixture was cooled to room temperature and poured into a mixture of ethyl acetate and 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 17m (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).

[0467] Step 11: Preparation of intermediate 17n A reaction flask was charged with 17m (1.5 g) and THF (75 mL), in that order, followed by the addition of acrylamide (0.215 g). The temperature was then lowered to approximately -15°C, and 1 M potassium tert-butoxide in tetrahydrofuran (2.60 mL) was added. The temperature was then raised to 0°C and the reaction was allowed to proceed. After confirming the reaction was complete by TLC, the mixture was quenched by adding ammonium chloride solution dropwise, 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 17n (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).

[0468] Step 12: Preparation of Compound 17 17n (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. After confirming the complete reaction by TLC, water was added to the reaction mixture, the pH was adjusted to 7-8 with saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to give 17 (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).

[0469] Example 18: Synthesis of Compound 18 [ka]

[0470] Step 1: Preparation of intermediate 18b Intermediate 18a (25 g) was purified with methanol (1000 mL) and acetic acid (103 g, 99 mL) and then added to a high-pressure reactor, which was set to a hydrogen pressure of 3 MPa and a temperature of 110 °C. After confirming complete reaction by TLC, the solvent was removed from the reaction mixture by vacuum distillation. To the residue was added a solution of hydrochloric acid in dioxane (4 mol / L, 100 mL, 400 mmol), and the solvent was removed by vacuum distillation. The residue was slurried with ethyl acetate, filtered, and the cake was collected to give the desired intermediate 18b (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).

[0471] Step 2: Preparation of intermediate 18c Intermediate 18b (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. After confirming the complete reaction by TLC, the reaction mixture was extracted with ethyl acetate and water. The organic phase was separated and the aqueous phase was extracted twice 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 filtered cake was collected to obtain the target intermediate 18c (22.67 g). MS (ESI, [M+H] - ) 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).

[0472] Step 3: Preparation of intermediate 18d Intermediate 18c (22.67 g), dichloromethane (200 mL), triethylamine (28.1 g, 38.6 mL), and DMAP (0.282 g, 2.311 mmol) 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. After confirming complete reaction by TLC, the solvent was removed from the reaction solution by vacuum distillation. The residue was extracted with ethyl acetate and water. The organic phase was separated, washed with saturated ammonium chloride solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate by vacuum distillation to obtain intermediate 18d (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).

[0473] Step 4: Preparation of intermediate 18e Intermediate 18d (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. After confirming the complete reaction by TLC, the reaction mixture was cooled to room temperature and quenched by adding water. Dichloromethane was then added for extraction, and the organic phase was separated and washed with 500 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was purified by silica gel column chromatography to obtain the target intermediate 18e (10.16 g). MS (ESI, [M+H] - ) m / z: 286.0. 1H 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).

[0474] Step 5: Preparation of intermediate 18f Intermediate 18e (10.16 g) and MeOH (100 mL) were added to a reaction flask in this order. A solution of sodium hydroxide (4.24 g) in water (100 mL) was added dropwise in an ice bath, and the mixture was allowed to warm to room temperature. After confirming complete reaction by TLC, the methanol was removed from the reaction solution by vacuum distillation. 1,4-dioxane (100 mL) and di-tert-butyl dicarbonate (8.49 g, 9.03 mL) were added, and the mixture was allowed to warm to room temperature. After confirming complete reaction by TLC, the reaction solution was extracted with ethyl acetate and water. The organic phase was separated, washed with 1000 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was removed from the filtrate by vacuum distillation to obtain the desired intermediate 18f (8.96 g). MS (ESI, [M+H] + ) m / z: 192.0. 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).

[0475] Step 6: Preparation of intermediate 18g Intermediate 18f (8.76 g), diethyl carbonate (17.76 g, 18.21 mL), and toluene (90 mL) were added to a reaction flask in this order, and 60 wt% sodium hydride (6.01 g, 150 mmol) was added in portions in an ice bath. The mixture was heated to 120 °C and reacted. After confirming the complete reaction by TLC, the reaction mixture was cooled to room temperature and poured into ice water to quench the reaction. 1 M hydrochloric acid solution was added to adjust the pH to 1-2, and ethyl acetate was added. The organic phase was separated, washed with 600 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was removed from the filtrate by distillation under reduced pressure. Petroleum ether was added to the residue to form a slurry, which was then filtered. The cake was collected to give 18g (12.03g) of the target intermediate.

[0476] Step 7: Preparation of intermediate 18h Intermediate 18g (9.54 g), EtOH (100 mL), and aqueous hydroxylamine (9.93 g, 9.21 mL, 150 mmol) were added to a reaction flask in this order, and the mixture was heated to 85 °C. After confirming complete reaction by TLC, the reaction mixture was adjusted to pH 8 with saturated sodium carbonate solution, extracted with ethyl acetate, and the organic phase was separated. The organic phase was extracted twice with water and combined, then adjusted to pH 3 with 1 M hydrochloric acid and extracted three times with ethyl acetate. The combined organic phase 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 give the desired intermediate 18h (9.01 g). MS (ESI, [M+H] - ) m / z: 331.0.

[0477] Step 8: Preparation of intermediate 18i Intermediate 18h (9.01 g), potassium carbonate (11.24 g), DMA (90 mL), and ethyl iodide (5.07 g, 2.63 mL, 32.5 mmol) were added to a reaction flask in this order, and the mixture was heated to 80 °C under N2 protection. After confirming complete reaction by TLC, the reaction mixture was cooled to room temperature and extracted with ethyl acetate and water. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was purified by silica gel column chromatography to obtain the desired intermediate 18i (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).

[0478] Step 9: Preparation of intermediate 18j Intermediate 18i (7.3 g), tetrahydrofuran (80 mL), and acrylamide (0.864 g, 12.15 mmol) were added to a reaction flask in this order. Under N2 protection, the temperature was lowered to -15 °C, and potassium tert-butoxide in tetrahydrofuran (1 mol / L, 11.14 mL, 11.14 mmol) was added dropwise. Upon completion of the reaction, the temperature was raised to 0 °C. After confirming the complete reaction by TLC, the system was added to saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was purified by silica gel column chromatography to give the desired intermediate 18j (4.54 g). MS (ESI, [M+H] - ) m / z: 384.3. 1H 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).

[0479] Step 10: Preparation of Compound 18 Intermediate 18j (300 mg) and ethyl acetate (5 mL) were added to a reaction flask in this order, followed by a solution of hydrochloric acid in dioxane (4 mol / L, 3.89 mL, 15.58 mmol). The mixture was allowed to react at room temperature. After complete reaction was confirmed by TLC, the reaction mixture was concentrated to give compound 18 (235 mg). MS (ESI, [M+H] + ) m / z: 286.10. 1 H 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).

[0480] Example 19: Synthesis of Compound 19 [ka]

[0481] Step 1: Preparation of intermediate 19b Intermediate 19a was purified with methanol (1680 mL) and acetic acid (166 mL) and then added to a high-pressure reactor, which was set to a hydrogen pressure of 3 MPa and a temperature of 110°C. After confirming the complete reaction by TLC, the solvent was removed from the reaction mixture by distillation under reduced pressure. To the residue was added a solution of hydrochloric acid in dioxane (4 mol / L, 200 mL, 798 mmol), and the solvent was removed by distillation under reduced pressure. Ethyl acetate was added to the residue to form a slurry, which was then filtered. The cake was collected to give the desired intermediate 19b (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).

[0482] Step 2: Preparation of intermediate 19c Intermediate 19b (40 g) and tetrahydrofuran (400 mL) were added to a reaction flask in this order, and trifluoroacetic anhydride (61.9 g, 41.0 mL, 295 mmol) was added in an ice bath. The mixture was then allowed to warm to room temperature and react. After confirming complete reaction by TLC, the reaction mixture was extracted with ethyl acetate and water. The organic phase was separated, washed with 1000 mL of 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 19c (81 g). MS (ESI, [M+H] - ) m / z: 244.04.

[0483] Step 3: Preparation of intermediate 19d A reaction flask was charged with intermediate 19c (65.3 g), dichloromethane (650 mL), triethylamine (81 g, 111 mL, 799 mmol), and DMAP (0.813 g). Acetic anhydride (29.9 g, 27.9 mL, 293 mmol) was added in an ice bath, and the mixture was allowed to warm to room temperature and react. After confirming the complete reaction by TLC, the solvent was removed from the reaction solution by distillation under reduced pressure. The residue was extracted with ethyl acetate and water, and the organic phase was separated and 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 the target intermediate 19d (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).

[0484] Step 4: Preparation of intermediate 19e Intermediate 19d (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. After confirming the complete reaction by TLC, the reaction mixture was cooled to room temperature and quenched by adding water. Dichloromethane was then added for extraction. The organic phase was separated and the aqueous phase was extracted twice with dichloromethane. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was purified by silica gel column chromatography to obtain the target intermediate 19e (16.21 g). MS (ESI, [M+H] - ) 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).

[0485] Step 5: Preparation of intermediate 19f Intermediate 19e (15.7 g) and MeOH (160 mL) were added to a reaction flask in this order. A solution of sodium hydroxide (6.56 g) in water (160 mL) was added dropwise in an ice bath, and the mixture was allowed to warm to room temperature and react. After complete reaction was confirmed by TLC, the methanol was removed from the reaction mixture by vacuum distillation. 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. After complete reaction was confirmed by TLC, the reaction mixture was extracted with ethyl acetate and water. The organic phase was separated, and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was removed from the filtrate by vacuum distillation to yield the desired intermediate 19f (19.83 g). MS (ESI, [M+H] + ) m / z: 192.0. 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).

[0486] Step 6: Preparation of intermediate 19g Intermediate 19f (15.92 g, 54.6 mmol), 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, 273 mmol) was added in portions in an ice bath, and the mixture was heated to 120 °C for reaction. After confirming the complete reaction by TLC and the reaction mixture had cooled 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 ethyl acetate was added for extraction. The organic phase was separated, and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was then removed from the filtrate by distillation under reduced pressure, and the residue was slurried with petroleum ether, filtered, and the cake was collected to give 19 g (12 g) of the target intermediate. 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).

[0487] Step 7: Preparation of intermediate 19h Intermediate 19g (12 g), EtOH (120 mL), and aqueous hydroxylamine (12.49 g, 11.59 mL, 189 mmol) were added to a reaction flask in this order, and the mixture was heated to 85 °C. After confirming complete reaction by TLC, the reaction mixture was adjusted to pH 8 with saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was separated. The pH of the aqueous phase was adjusted to 3 with 1 M hydrochloric acid and extracted three times 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 desired intermediate 19h (10.44 g). MS (ESI, [M+H] - ) m / z: 331.0. 1 H 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).

[0488] Step 8: Preparation of intermediate 19i Intermediate 19h (10.44 g), potassium carbonate (13.02 g), DMA (110 mL), and ethyl iodide (5.88 g, 3.05 mL, 37.7 mmol) were added to a reaction flask in this order, and the mixture was heated to 80 °C under N2 protection. After confirming complete reaction by TLC, the reaction mixture was cooled to room temperature and extracted with ethyl acetate and water. The organic phase was separated, washed with 800 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was purified by silica gel column chromatography to obtain the desired intermediate 19i (8.31 g). MS (ESI, [M+H] + ) m / z: 361.2.

[0489] Step 9: Preparation of intermediate 19j Intermediate 19i (5.5 g), tetrahydrofuran (50 mL), and acrylamide (0.759 g, 10.68 mmol) were added to a reaction flask in this order. Under N2 protection, the temperature was lowered to -15 °C, and potassium tert-butoxide in tetrahydrofuran (1 mol / L, 9.92 mL, 9.92 mmol) was added dropwise. Upon completion of the reaction, the temperature was raised to 0 °C. After confirming the complete reaction by TLC, the system was added to saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was purified by silica gel column chromatography to give the desired intermediate 19j (2.81 g). MS (ESI, [M+H] - ) m / z: 384.34. 1 H 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).

[0490] Step 10: Preparation of Compound 19 Intermediate 19j (850 mg) and ethyl acetate (20 mL) were added to a reaction flask in this order, followed by a solution of hydrochloric acid in dioxane (4 mol / L, 11.03 mL, 44.1 mmol). The mixture was allowed to react at room temperature. After confirming the complete reaction by TLC, the reaction mixture was concentrated to give compound 19 (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).

[0491] Example 20: Synthesis of Compound 20 [ka]

[0492] Step 1: Preparation of intermediate 20b Bromine (55.5 g) was added dropwise to a solution of 20a (50 g) in acetic acid (180 mL) at 15° C., and upon completion, the reaction was allowed to warm to room temperature. After complete reaction was confirmed by TLC, tert-butyl methyl ether was added dropwise to the reaction solution, which was then stirred and filtered. The cake was collected and dried to give intermediate 20b (95 g). MS (ESI, [M+H] + ) m / z: 231.9.

[0493] Step 2: Preparation of intermediate 20c 20b (80 g), 2,2-dimethoxyethanal (66.9 g), triethylamine (27.3 g), anhydrous sodium sulfate (80 g), and methanol (600 mL) were added to a reaction flask in this order and allowed to react overnight at room temperature. The reaction mixture was cooled to -15 °C, and sodium borohydride (14.6 g) was added in several portions. Upon completion, the mixture was cooled to room temperature and allowed to react. After confirming complete reaction by TLC, the mixture was concentrated to remove approximately half of the methanol, and dichloromethane and water were added to the reaction mixture. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to obtain intermediate 20c (60 g). MS (ESI, [M+H] + ) m / z: 319.9.

[0494] Step 3: Preparation of intermediate 20d At 0°C, under nitrogen protection, 20c (47 g) was added dropwise to trifluoroacetic anhydride (148 g). Upon completion, the mixture was cooled to room temperature and allowed to react for 1 hour. Trifluoroacetic acid (87 g) was added dropwise, and the temperature was raised to 40°C and allowed to react for 1 hour. Triethylsilane (68 g) was added dropwise, and the temperature was raised to 60°C and allowed to react. After confirming complete reaction by TLC, 400 mL of ethyl acetate and 600 mL of water were added to the reaction solution. The organic phase was separated, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to obtain intermediate 20d (20.5 g). 1 H 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).

[0495] Step 4: Preparation of intermediate 20e 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 20d (20.5 g) in dichloroethane (200 mL), and upon completion, the reaction was allowed to warm to room temperature. After complete reaction was confirmed by TLC, the reaction solution was slowly poured into ice water, stirred for 10 min, filtered, and the cake was collected and dried to give 20e (18.5 g). MS(ESI,[MH] + ) m / z: 337.9. 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).

[0496] Step 5: Preparation of intermediate 20f At 0°C, under nitrogen protection, acetic anhydride (5.65 g) was slowly added dropwise to a stirred solution of 20e (17.0 g) and triethylamine (7.63 g) in dichloroethane (200 mL). Upon completion, the mixture was allowed to warm to room temperature. After confirming the complete reaction by TLC, the reaction mixture was slowly poured into water, and the organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 20f (19.8 g). MS (ESI, [M+H] + ) m / z: 381.7.

[0497] Step 6: Preparation of Intermediate 20g 20f (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 for reaction. After complete reaction was confirmed by TLC, the reaction mixture was cooled to room temperature, and 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 20g (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).

[0498] Step 7: Preparation of intermediate 20h 20g (9.5g), methanol (100mL), water (20mL), and sodium hydroxide (1.9g) were added to a reaction flask in this order and allowed to react at room temperature for 1 hour. Di-tert-butyl dicarbonate (8.2g) was added and allowed to react at room temperature. After confirming complete reaction by TLC, ethyl acetate and water were added to the reaction solution. The organic phase was separated and washed with saturated saline. After that, it was dried over anhydrous sodium sulfate, filtered, and the concentrate was purified by silica gel column chromatography to obtain intermediate 20h (8.5 g). 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).

[0499] Step 8: Preparation of intermediate 20i 20h (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 reaction mixture was heated to 115 °C and reacted. After confirming complete reaction by TLC, the reaction mixture was cooled to room temperature, and ethyl acetate and 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 20i (9.0 g). MS(ESI,[MH]+ ) m / z: 330.1.

[0500] Step 9: Preparation of intermediate 20j 20i (9.0 g), aqueous hydroxylamine solution (8.7 g), and ethanol (100 mL) were added to a reaction flask in this order, and the reaction mixture was heated to 80 °C. After confirming complete reaction by TLC, the reaction mixture was cooled to room temperature, and then ethyl acetate and 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 20j (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).

[0501] Step 10: Preparation of intermediate 20k 20j (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 reaction mixture was heated to 80 °C. After confirming complete reaction by TLC, the reaction mixture was cooled to room temperature, and ethyl acetate and 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 20k (6.5 g). MS(ESI,[MH] + ) m / z: 373.1. 1H 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).

[0502] Step 11: Preparation of intermediate 20l Under nitrogen protection, sodium tert-butoxide in tetrahydrofuran (14 mL, 1 M) was slowly added dropwise to a stirred solution of 20k (5.6 g) in tetrahydrofuran (70 mL) at -10 °C. Upon completion, the mixture was allowed to react for 30 minutes while maintaining the temperature. Acrylamide (0.71 g) was weighed and dissolved in 5 mL of tetrahydrofuran, and the mixture was added dropwise to the reaction mixture. After confirming the complete reaction by TLC, the reaction mixture was slowly poured into saturated ammonium chloride solution, ethyl acetate was added, the organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the concentrate was purified by silica gel column chromatography to obtain intermediate 20l (2.5 g). MS(ESI,[MH] + ) m / z: 397.9. 1 H 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).

[0503] Step 12: Preparation of Compound 20 A reaction flask was charged with 20L (2.5 g), ethyl acetate (30 mL), and hydrochloric acid-dioxane (15 mL, 4 M) in that order, and the mixture was allowed to react at room temperature. After confirming the complete reaction by TLC, the mixture was filtered, and the cake was collected and dried to give compound 20 (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).

[0504] Example 21: Synthesis of Compound 21 [ka]

[0505] Step 1: Preparation of compound 21b In an ice bath, 21a (33.3 g), MeOH (500 mL), iodobenzene diacetate (82 g, 246 mmol), and potassium hydroxide (127 g) were added to a reaction flask in this order, and the mixture was allowed to react at room temperature. After confirming the complete reaction by TLC, the solvent was removed from the reaction solution by distillation under reduced pressure. The residue was extracted with ethyl acetate and 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). Hydrochloric acid (6 M, 68.4 mL) was added and the reaction was allowed to proceed at room temperature for 30 minutes. The pH of the reaction solution was then adjusted with saturated sodium bicarbonate solution. The mixture was adjusted to 8, and then extracted with 200 mL of ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain 21b (16 g). MS (ESI, [M+H] + ) m / z: 178.9.

[0506] Step 2: Preparation of compound 21c 21b (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. After confirming the complete reaction by TLC, the reaction mixture was quenched by adding saturated ammonium chloride solution dropwise, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. After filtration, the solvent was removed by distillation under reduced pressure to give 21c (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).

[0507] Step 3: Preparation of compound 21d 21c (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 confirming the complete reaction by TLC, the reaction mixture was cooled to room temperature, and then organic solvents, ethyl acetate and water, were added to quench the reaction. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure to obtain 21d (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).

[0508] Step 4: Preparation of compound 21e 21d (35 g), MeOH (400 mL), and sodium borohydride (5.83 g) were added to a reaction flask in this order and reacted at room temperature. After confirming the complete reaction by TLC, the reaction mixture was quenched by adding saturated ammonium chloride solution dropwise, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. After filtration, the solvent was removed by distillation under reduced pressure to give 21e (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).

[0509] Step 5: Preparation of compound 21f 21e (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. After confirming the complete reaction by TLC, the reaction mixture was washed with saturated ammonium chloride solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 21f (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),3.32-3.20(m,1H),3.18-3.09(m,1H),2.85(dd,J=34.6,17.1Hz,2H),1.97( d, J = 15.3 Hz, 3H).

[0510] Step 6: Preparation of Compound 21g In an ice bath, boron trichloride (19.22 g, 164 mL) was slowly added dropwise to a stirred solution of 21f (17 g) in dichloromethane (500 mL). Upon completion, the mixture was allowed to warm to room temperature and react. After confirming the complete reaction by TLC, 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 and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure to give 21f (15 g). MS(ESI,[MH] - ) m / z: 190.9.

[0511] Step 7: Preparation of compound 21h 21g (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. After confirming complete reaction by TLC, the reaction solution was washed with saturated ammonium chloride solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 21h (14.8g). MS(ESI,[MH] - ) m / z: 233.01.

[0512] Step 8: Preparation of Compound 21i 21h (11.6 g), dichloromethane (300 mL), and zirconium(IV) tetrachloride (46.2 g, 198 mmol) were added to a reaction flask in this order and reacted at 50 °C. After confirming complete reaction by TLC, the reaction mixture was cooled to room temperature, and 3 M aqueous hydrochloric acid, water, and dichloromethane were added to the residue. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure to obtain 21i (11.4 g). 1H 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).

[0513] Step 9: Preparation of Compound 21k A reaction flask was charged with 21i (15.4 g), ethanol (200 mL), and an aqueous solution (10.00 mL) of sodium hydroxide (2.63 g), in that order, and the mixture was allowed to react at room temperature. After confirming complete reaction by TLC, the reaction mixture was adjusted to pH 2-3 with 2M aqueous HCl. The mixture was then extracted with ethyl acetate and water, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure to obtain crude intermediate product 21j. Dichloroethane (200 mL), imidazole (17.90 g), and TBSCl (39.6 g) were added, and the mixture was refluxed overnight. After the reaction mixture 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 21k (15.4 g). 1 H 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).

[0514] Step 10: Preparation of Compound 21l 21k (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 approximately 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 confirming complete reaction by TLC, the reaction solution was cooled to room temperature. The reaction solution was slowly poured into ice water, extracted with ethyl acetate, and the organic phase was discarded. The pH of the aqueous phase was adjusted to 1-2 with 3M hydrochloric acid, and then extracted with ethyl acetate. The solution was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation to obtain 21k (10 g). MS(ESI,[MH] - ) m / z: 331.2.

[0515] Step 11: Preparation of intermediate 21m 21L (10 g), aqueous hydroxylamine (9.93 g, 9.93 mL, 150 mmol), and ethanol (100 mL) were added to a reaction flask in this order and reacted at 85°C. After confirming complete reaction by TLC, the reaction mixture was cooled to room temperature. The residue was extracted with ethyl acetate and saturated aqueous sodium carbonate, and the organic phase was discarded. The pH of the aqueous phase was adjusted to 2-3 with 1M aqueous HCl, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation to obtain 21m (11 g). MS(ESI,[MH] - ) m / z: 346.2.

[0516] Step 12: Preparation of intermediate 21n 21m (10 g), ethanol (150 mL), and sulfuric acid (14.40 g, 7.83 mL, 144 mmol) were added to a reaction flask in this order, and the reaction was carried out at 85°C. After confirming the complete reaction by TLC, the reaction mixture was cooled to room temperature, and then 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, filtered, and the solvent was removed by distillation under reduced pressure to obtain 21n (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).

[0517] Step 13: Preparation of Intermediate 21 Compound 21n (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. After confirming complete reaction by TLC, the reaction mixture was quenched by pouring into saturated sodium sulfite solution and extracting with ethyl acetate. The organic phase was separated, washed with 200 mL of saturated sodium bicarbonate solution and 200 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate by distillation under reduced pressure to give compound 21 (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).

[0518] Examples 22 and 23: Synthesis of Compounds 22 and 23 [ka]

[0519] Step 1: Preparation of intermediate 22b To a reaction flask, CCl4 (6750 mL), 22a (450 g), 2,2'-azobis(isobutyronitrile) (18.45 g), and N-bromosuccinimide (1194 g) were added in this order. The mixture was heated to 80 °C and refluxed. After complete reaction was confirmed by TLC, 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 obtain intermediate 22b (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).

[0520] Step 2: Preparation of intermediate 22c 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. 22b (606 g) was then added and the mixture was stirred at room temperature. After confirming the complete reaction by TLC, the reaction mixture was quenched by slowly adding saturated ammonium chloride solution dropwise. 2000 mL of petroleum ether and 2000 mL of water were added for extraction. The aqueous phase was extracted twice with 1000 mL of petroleum ether. The combined organic phases were washed twice with 500 mL of saturated ammonium chloride solution, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate by vacuum distillation. 262 g of intermediate 22c was obtained by purification using silica gel column chromatography. MS(ESI,[MH] + ) m / z: 293.2. 1 H 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).

[0521] Step 3: Preparation of intermediate 22d A reaction flask was charged with 22c (130 g), DMSO (1000 mL), HO (300 mL), and lithium chloride (42.6 g), and the mixture was stirred at 180 °C. After confirming the complete reaction by TLC, the reaction mixture was poured into 1000 mL of ice water to quench the reaction. 1 M hydrochloric acid was added to adjust the pH to 2-3, and the mixture was extracted three times with 1 L of ethyl acetate. The mixture 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 191 g of intermediate 22d. MS (ESI, [M+H] + ) m / z: 193.05.

[0522] Step 4: Preparation of intermediate 22e To a reaction flask, 22d (85 g), ethanol (1000 mL), and concentrated sulfuric acid (44 g) were added, in that order, and the mixture was heated to 70 °C. After confirming complete reaction by TLC, the reaction was completed. Once the reaction mixture had cooled 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. After neutralization, the mixture was extracted three times with 1000 mL of petroleum ether. 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 99 g of intermediate 22e. 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).

[0523] Step 5: Preparation of intermediate 22f Under N2 protection, boron tribromide (415 g, 1657 mL) was added dropwise to a stirred solution of 22e (150 g) in dichloromethane (750 mL) in a reaction flask, and the reaction was carried out at a temperature of 0°C or below. MeOH (500 mL) was added at 0°C and the reaction was carried out for 30 minutes, then the temperature was gradually returned to room temperature and stirred for 2 hours. Upon completion of the reaction, the reaction solution 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 122 g of intermediate 22f. 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).

[0524] Step 6: Synthesis of intermediate 22g To a reaction flask, 22f (130 g) and tetrahydrofuran (2000 mL) were added 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 allowed to react in an ice-water bath. After confirming the complete reaction by TLC, the reaction was quenched by slowly adding 3 L of water dropwise. The pH was adjusted to 1-2 with concentrated hydrochloric acid, and the mixture was extracted three times with 2 L of ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was removed from the filtrate under reduced pressure to give 129 g of intermediate 22g. 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).

[0525] Step 7: Preparation of intermediate 22h In a reaction flask, 22g (120g), 4-dimethylaminopyridine (7.14g), dichloromethane (2000mL), and triethylamine (177g, 244mL) were added in this order, and acetyl chloride (101g, 91mL) was slowly added dropwise at 0°C. Upon completion, the reaction was allowed to proceed at room temperature. After confirming the complete reaction by TLC, the reaction solution was diluted with dichloromethane. The mixture was poured into a mixed solvent of methane and water, the organic phase was separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography to obtain 127 g of intermediate 22h. 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).

[0526] Step 8: Preparation of intermediate 22i A reaction flask was charged with 22h (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 yield 90 g of intermediate 22i. MS(ESI,[MH] + ) m / z: 247.2. 1H NMR(500MHz,DMSO-d6)δ 12.34(s,1H),7.73(d,J=8.0Hz,1H),6.83(d,J=8.0Hz,1H),4.68(t,J=5.3Hz,1H),3.36(ddd, J=7.1,5.3,2.0Hz,2H),3.03-2.94(m,1H),2.92-2.82(m,1H),2.76-2.68(m,1H),2.61(s,3H).

[0527] Step 9: Preparation of intermediate 22j A reaction flask was charged with 22i (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. After confirming complete reaction by TLC, the reaction mixture 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 three times with ethyl acetate. The organic layers 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 to obtain 86 g of intermediate 22j. 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).

[0528] Step 10: Preparation of intermediate 22k To a reaction flask, 22j (37 g), 1,2-dichloroethane (700 mL), imidazole (36.6 g), and tert-butyldimethylchlorosilane (29.7 g) were added in this order, and the reaction was carried out at 75 °C. After confirming complete reaction by TLC, the reaction mixture was cooled to room temperature, and dichloromethane and 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, yielding 60 g of intermediate 22k. 1 H 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).

[0529] Step 11: Preparation of Intermediate 22l To a reaction flask, 22k (55 g), diethyl carbonate (101 g, 103 mL), and toluene (1000 mL) were added in this order. The reaction mixture was cooled to 0°C, and 60 wt% sodium hydride (34.3 g, 858 mmol) was added in several portions. Upon completion, the mixture was slowly heated to 120°C. After confirming complete reaction by TLC, the reaction mixture was slowly poured into ice water and extracted with ethyl acetate. The pH of the aqueous phase was adjusted to 3 with 3N hydrochloric acid, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the solvent was removed by distillation under reduced pressure to obtain 53.6 g of intermediate 22l. MS(ESI,[MH] + ) m / z: 345.1. 1H 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).

[0530] Step 12: Preparation of intermediate 22m A reaction flask was charged with 22L (51 g), hydroxylamine hydrochloride (61.4 g), sodium ethoxide (61.1 g), and ethanol (2000 mL) in this order, and the mixture was heated to 85°C under N2 protection. After confirming complete reaction by TLC, the reaction mixture was evaporated 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 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 for extraction. 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 47 g of intermediate 22m. 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).

[0531] Step 13: Preparation of Intermediate 22n A reaction flask was charged with 22m (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 confirming the complete reaction by TLC, the reaction mixture was cooled to room temperature, and the solvent was removed by rotary evaporation. Dichloromethane was added, and saturated aqueous sodium bicarbonate was added dropwise to neutralize. 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 43 g of intermediate 22n. MS(ESI,[MH] + ) m / z: 276.1. 1 H 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).

[0532] Step 14: Preparation of intermediates 22o-1 and 22o-2 A preparative separation was performed. 43 g of intermediate 22n was dissolved in 430 mL of dichloromethane-ethanol solution to a concentration of approximately 100.0 mg / mL. The solution was filtered through a 0.45 μm organic filter. The equipment used was a YMC high-pressure preparative chromatograph. The chromatography column was a CHIRALPAK IG (30 x 250 mm, S-10 μm) with a mobile phase of A: ethanol, B: n-hexane. The first peak yielded 9.057 g of intermediate 22o-1, and the second peak yielded 8.833 g of intermediate 22o-2. 22o-1:MS(ESI,[MH] + ) m / z: 276.1. 22o-2: MS(ESI, [MH] + ) m / z: 276.1.

[0533] Step 15: Preparation of Compound 22 Under N2 protection, 22o-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. Potassium tert-butoxide (3.89 g, 34.7 mL) was added, and the mixture was reacted at 0 °C. After confirming complete reaction by TLC, 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 twice with ethyl acetate, and the combined organic phases were 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 and filtered to obtain 6.77 g of compound 22. 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).

[0534] Step 16: Preparation of Compound 23 A reaction flask was charged with 22o-2 (12.83 g), THF (200 mL), and acrylamide (3.64 g) in this order. The temperature was then lowered to 0°C. Potassium tert-butoxide (4.18 g, 37.3 mL) was added, and the mixture was reacted at 0°C under N2 protection. After confirming the complete reaction by TLC, 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 twice with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was removed from the filtrate by distillation under reduced pressure. The cake was collected and filtered to give 7.454 g of compound 23. 1H 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).

[0535] Example 24: Synthesis of Compound 24 [ka]

[0536] Step 1: Preparation of intermediate 24b To a reaction flask were added 24a (7.00 g), 4-piperidinemethanol (6.86 g), N,N-diisopropylethylamine (9.62 g), and dimethyl sulfoxide (70 mL) in this order, and the mixture was heated to 100° C. After confirming the complete reaction by TLC, the reaction mixture was cooled to room temperature, and water was added to the reaction mixture, which was stirred for 10 minutes and filtered. The cake was collected and dried to obtain intermediate 24b (13.7 g). MS (ESI, [M+H] + ) m / z: 237.1.

[0537] Step 2: Preparation of intermediate 24c Intermediate 24b (13.5 g), 10% palladium on carbon (2.70 g), and methanol (200 mL) were added to a reaction flask in this order, and the mixture was exchanged with hydrogen three times and reacted overnight. The palladium on carbon was removed by suction filtration, and the mixture was concentrated to give Intermediate 24c (9.0 g). MS (ESI, [M+H] + ) m / z: 207.3. 1H NMR(500MHz,DMSO-d6)δ 6.68(d,J=8.2Hz,2H),6.47(d,J=8.2Hz,2H),4.59(s,2H),4.45(t,J=5.3Hz,1H),3.34(s,2H),3.28(dd,J=6.5,3.1Hz, 2H),2.44(t,J=11.7Hz,2H),1.71(d,J=12.5Hz,2H),1.40(ddt,J=11.5,8.6,4.1Hz,1H),1.23(qd,J=12.2,4.0Hz,2H).

[0538] Step 3: Preparation of intermediate 24d Intermediate 1f (6.0 g), 24c (3.86 g), BINAP (1.16 g), cesium carbonate (18.28 g), palladium(II) acetate (0.42 g), and 1,4-dioxane (80 mL) were added to a reaction flask in this order. The mixture was purged with nitrogen three times and heated to 100 °C. After confirming complete reaction by TLC, the reaction mixture was cooled to room temperature, and ethyl acetate and water were added to the residue. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to give intermediate 24d (7.1 g). MS (ESI, [M+H] + ) m / z: 491.5. 1 H NMR(500MHz,DMSO-d6)δ 8.79(s,1H),7.75(s,1H),7.42-7.31(m,2H),6.92-6.79(m,2H),4.47(t,J=5.3Hz,1H),4.39-4.17(m,2H) ),3.66-3.52(m,3H),3.31-3.21(m,5H),2.99-2.86(m,2H),2.70(s,3H),2.61-2.53(m,2H),1.81-1.69(m ,5H),1.57-1.43(m,2H),1.29-1.16(m,3H).

[0539] Step 4: Preparation of intermediate 24e Intermediate 24d (6.9 g), cesium carbonate (4.58 g), water (20 mL), DMSO (20 mL), and methanol (70 mL) were added to a reaction flask in this order. The reaction mixture was cooled to 0°C, and 30 wt% hydrogen peroxide (4.78 g) was added dropwise. Upon completion of the reaction, the mixture was cooled to room temperature and allowed to react. After TLC showed complete reaction, water and saturated aqueous sodium sulfite solution were added to the reaction mixture, which was stirred for 10 minutes and filtered. The cake was collected and dried to obtain Intermediate 24e (6.0 g). MS (ESI, [M+H] + ) m / z: 509.5. 1 H NMR(500MHz,DMSO-d6)δ 10.97(s,1H),7.70(d,J=2.8Hz,1H),7.60(s,1H),7.44-7.36(m,2H),7.27(d,J=2. 8Hz,1H),6.91-6.83(m,2H),4.47(t,J=5.3Hz,1H),4.31(dd,J=49.3,12.9Hz,2H),3 .66-3.54(m,3H),3.32-3.21(m,6H),3.03-2.88(m,2H),2.70(s,3H),2.57(td,J=12 .1,2.6Hz,2H),1.84-1.72(m,5H),1.59-1.44(m,2H),1.25(tt,J=12.1,2.7Hz,2H).

[0540] Step 5: Preparation of intermediate 24f Intermediate 24e (2.0 g), dichloromethane (30 mL), and N,N-diisopropylethylamine (1.36 g) were added to a reaction flask in this order, and the temperature was lowered to 0 °C. Sulfur trioxide-pyridine (1.88 g) was dissolved in DMSO (6 mL) and added dropwise to the reaction mixture. Upon completion, the mixture was allowed to cool to room temperature. After TLC confirmed the reaction was complete, ethyl acetate and water were added to the reaction mixture. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to give Intermediate 24f (1.1 g). MS (ESI, [M+H] + ) m / z: 507.4.

[0541] Step 6: Preparation of Compound 24 Intermediate 24f (165 mg), 16 (100 mg), sodium acetate (26.7 mg), and dichloroethane / isopropanol (5:1, 20 mL) were added to a reaction flask in this order and stirred at room temperature for 30 minutes. After stirring, sodium cyanoborohydride (40.8 mg) was added and the mixture was allowed to react at room temperature. After confirming the complete reaction by TLC, dichloromethane and water were added to the reaction mixture. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to give compound 24 (100 mg). MS (ESI, [M+H] + ) m / z: 761.6. 1 H NMR(500MHz,DMSO-d6)δ 11.10(s,1H),10.98(s,1H),7.72(d,J=7.9Hz,2H),7.60(s,1H),7.47-7.37(m,2H),7.35-7.21(m,2H),6.93-6.85(m,2H) ,4.60(dd,J=11.9,5.0Hz,1H),4.32(dd,J=50.6,12.8Hz,2H),4.15(s,2H),4.04(t,J=2.4Hz,2H),3.69-3.55(m,3H),3.35 (dd,J=8.6,6.2Hz,1H),3.32-3.19(m,3H),2.96(dt,J=28.7,11.7Hz,2H),2.77(ddd,J=17.2,12.0,5.3Hz,1H),2.70(s,3H) ),2.68-2.54(m,5H),2.53(s,1H),2.20(dq,J=13.5,4.3Hz,1H),1.96-1.64(m,6H),1.61-1.48(m,1H),1.36-1.27(m,2H).

[0542] Example 25: Synthesis of Compound 25 [ka]

[0543] Step 1: Preparation of intermediate 25b 25a (5.0 g), tetrahydropyridine (3.49 g), DMF (40 mL), and N,N-diisopropylethylamine (18.57 g, 25.10 mL) were added to a reaction flask in this order and reacted at room temperature. After confirming the complete reaction by TLC, the reaction was quenched by adding water, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure to give 25b (6.6 g). MS (ESI, [M+H] + ) m / z: 223.23.

[0544] Step 2: Preparation of intermediate 25c A reaction flask was charged with 25b (2.00 g), 24c (6.86 g), BINAP (0.51 g), cesium carbonate (8.12 g), palladium(II) acetate (0.18 g), and 1,4-dioxane (50 mL), in that order. The mixture was purged with nitrogen three times and heated to 100 °C. After confirming complete reaction by TLC, the reaction mixture was cooled to room temperature, and ethyl acetate and water were added to the residue. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to give intermediate 25c (2.3 g). MS (ESI, [M+H] + ) m / z: 393.4.

[0545] Step 3: Preparation of intermediate 25d Intermediate 25c (2.1 g), cesium carbonate (1.74 g), water (10 mL), DMSO (15 mL), and methanol (30 mL) were added to a reaction flask in this order. The reaction mixture was cooled to 0°C, and 30 wt% hydrogen peroxide (1.82 g) was added dropwise. Upon completion of the reaction, the mixture was cooled to room temperature and allowed to react. After TLC showed complete reaction, water and saturated aqueous sodium sulfite solution were added to the reaction mixture, which was stirred for 10 minutes and filtered. The cake was collected and dried to obtain Intermediate 25d (2.1 g). MS (ESI, [M+H] + ) m / z: 411.3.

[0546] Step 4: Preparation of intermediate 25e Intermediate 25d (0.75 g), dichloromethane (20 mL), and N,N-diisopropylethylamine (0.63 g) were added to a reaction flask in this order, and the temperature was lowered to 0°C. Sulfur trioxide-pyridine (0.87 g) was dissolved in DMSO (2 mL) and added dropwise to the reaction mixture. Upon completion, the mixture was allowed to cool to room temperature and react. After confirming the complete reaction by TLC, ethyl acetate and water were added to the reaction mixture. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was then purified by silica gel column chromatography. Purification by separation gave intermediate 25e (0.45 g). MS (ESI, [M+H] + ) m / z: 409.3.

[0547] Step 5: Preparation of Compound 25 Intermediate 25e (80 mg), 16 (50 mg), sodium acetate (13.3 mg), and dichloroethane / isopropanol (5:1, 20 mL) were added to a reaction flask in this order and stirred at room temperature for 30 minutes. After that, sodium cyanoborohydride (20.4 mg) was added and the mixture was allowed to react at room temperature. After confirming the complete reaction by TLC, dichloromethane and water were added to the reaction mixture. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to give compound 25 (25 mg). MS (ESI, [M+H] + ) m / z: 644.4. 1H NMR(500MHz,DMSO-d6)δ 11.10(s,1H),11.06(s,1H),7.75-7.66(m,2H),7.60(s,1H),7.43(d,J=8.6Hz,2H),7.31(d,J=8.1Hz,1H),7.26( d,J=2.9Hz,1H),6.92(d,J=8.6Hz,2H),4.60(dd,J=11.9,5.0Hz,1H),4.16(s,2H),4.05(s,2H),3.73-3.55(m,6H) ),2.77(ddd,J=17.3,12.0,5.4Hz,1H),2.63(ddd,J=24.4,12.5,5.4Hz,5H),2.55(d,J=4.9Hz,1H),2.21(dt,J=1 3.3,4.6Hz,1H),1.93-1.85(m,2H),1.74-1.62(m,3H),1.57(p,J=5.5,5.1Hz,4H),1.31(td,J=11.7,3.3Hz,2H).

[0548] Example 26: Synthesis of Compound 26 [ka]

[0549] Compound 18 (107 mg), intermediate 24f (60 mg), acetic acid (6.31 mg, 6.02 μL), 1,2-dichloroethane (5 mL), and isopropanol (2 mL) were added to a reaction flask in this order. The mixture was stirred at room temperature for 30 minutes, followed by the addition of sodium cyanoborohydride (39.6 mg). The mixture was stirred at room temperature. After confirming complete reaction by TLC, 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 extracted twice with 20 mL of dichloromethane. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was purified by silica gel column chromatography to give compound 26 (124 m...

Claims

1. A compound of formula II-1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 During the ceremony, Ring A is absent or selected from a C 5-10 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 benzene ring groups; Ring C is selected from an isoxazolyl group or a furyl group; each R 1 is independently selected from halogen, —OH, —NH 2 , —CN, a C 1-4 alkyl group, a C 1-4 alkoxy group, or a haloC 1-4 alkyl group; n is selected from 0, 1, 2 or 3; T is selected from CH or N; R is selected from hydrogen or a 5- to 6-membered heterocycloalkyl group, said heterocycloalkyl group optionally being ═O or C １～６ substituted by alkyl groups, Ring E is selected from a phenyl group, a benzo C 4-12 cycloalkenyl group, or a benzo 4-12 membered heterocycloalkenyl group; X ２ is selected from CH or N, L is -Cy 1 -LNK-Cy 2 -LNK-, -Cy 1 -LNK-Cy 2 - or -Cy 1 -Cy 2 -LNK-, wherein Cy 1 is selected from a single bond, a C 3-12 cycloalkyl group or a 4-12 membered heterocycloalkyl group, said C 3-12 cycloalkyl group or 4-12 membered heterocycloalkyl group optionally substituted by one or more R a ; each LNK is independently selected from a single bond, a C 1-12 alkylene group, or a C 1-12 heteroalkylene group; Cy 2 is absent or selected from a C 3-12 cycloalkyl group or a 4-12 membered heterocycloalkyl group, said C 3-12 cycloalkyl group or 4-12 membered heterocycloalkyl group optionally substituted by one or more R b ; A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein each R a and R b is independently selected from a halogen, —OH, —NH 2 , —CN, a C 1-4 alkyl group, a C 1-4 alkoxy group, a haloC 1-4 alkyl group, a C 1-4 alkylamino group, or a diC 1-4 alkylamino group.

2. Ring A is selected from a C 5-8 cycloalkenyl group, a 5- to 10-membered heterocycloalkenyl group, a phenyl group, or a 5- to 6-membered heteroaryl group; or Ring A is selected from a C 5-7 cycloalkenyl group, a 5- to 10-membered heterocycloalkenyl group, a phenyl group, or a 5- to 6-membered heteroaryl group; or Ring A is selected from a C 5-6 cycloalkenyl group, a 5- to 10-membered heterocycloalkenyl group, a phenyl group, or a 5- to 6-membered heteroaryl group; or Ring A is selected from a C 5-6 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; or Ring A is selected from a C 5 cycloalkenyl group, a C 6 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; or Ring A is selected from a cyclopentenyl group, a dicyclohexenyl group, a dihydropyrrolyl group, a tetrahydropyridinyl group, a tetrahydroazepinyl group, a dihydrooxazinyl group, an azaspirooctenyl group, an azaspirononenyl group, a phenyl group, a pyrrolyl group, a pyrazolyl group, a furyl group, or an oxazolyl group, Ring A is selected from a C 5-6 cycloalkenyl group or a 5- to 9-membered heterocycloalkenyl group, or Ring A is selected from a cyclopentenyl group, a dicyclohexenyl group, a dihydropyrrolyl group, a tetrahydropyridinyl group, a tetrahydroazepinyl group, a dihydrooxazinyl group, an azaspirooctenyl group, or an azaspirononenyl group, or Ring A is absent or is selected from a C 5-8 cycloalkenyl group, a 5- to 10-membered heterocycloalkenyl group, a phenyl group or a 5-membered heteroaryl group; or Ring A is absent or is selected from a C 5-7 cycloalkenyl group, a 5- to 9-membered heterocycloalkenyl group, a phenyl group or a 5-membered heteroaryl group; or The compound, its stereoisomer, or pharmaceutically acceptable salt thereof according to claim 1, wherein ring A is absent or selected from a C 5-6 cycloalkenyl group, a 5- to 9-membered heterocycloalkenyl group, a phenyl group, or a 5-membered heteroaryl group.

3. selected from the group consisting of compounds of formula I'a, stereoisomers thereof, and pharmaceutically acceptable salts thereof; 【Chemistry 2】 During the ceremony, Ring A, Ring B, Ring C, Ring E, T, R, Cy 1 , Cy 2 , LNK, R １ 2. The compound according to claim 1, its stereoisomer or pharmaceutically acceptable salt thereof, wherein the definition of X 2 or n is as defined in claim 1.

4. A compound of formula I', a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, 【Transformation 3】 During the ceremony, The compound according to claim 1, its stereoisomer or pharmaceutically acceptable salt thereof, wherein the definitions of Ring A, Ring B, Ring C, T, R, Cy 1 , Cy 2 , LNK, R 1 or n are as defined in claim 1.

5. Ring E is a phenyl group, a benzo C ５～１２ a cycloalkenyl group or a 5- to 12-membered benzoheterocycloalkenyl group; Or, ring E is a phenyl group, a benzo C ５～６ a cycloalkenyl group or a 5- to 11-membered benzoheterocycloalkenyl group; or the compound according to claim 1, its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein ring E is selected from a phenyl group, a 5-membered benzo heterocycloalkenyl group, a 6-membered benzo heterocycloalkenyl group, a 10-membered benzo heterocycloalkenyl group, or an 11-membered benzo heterocycloalkenyl group.

6. structural part 【Chemistry 4】 teeth, 【Transformation 5】 Selected from Or structural part 【Transformation 6】 teeth, 【Transformation 7】 2. The compound of claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, selected from:

7. structural part 【Transformation 8】 teeth, 【Chemistry 9】 Selected from Or structural part 【Chemistry 10】 teeth, 【Chemistry 11】 2. The compound of claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, selected from:

8. Each R １ is a 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 is fluorine, chlorine, bromine, -OH, -NH ２ or -CN; Or, each R １ are independently selected from fluorine, chlorine, or bromine; Or, each R １ is independently selected from fluorine, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to claim 1 .

9. 2. The compound according to claim 1, wherein n is selected from 0, 1 or 2, or n is selected from 0 or 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

10. structural part 【Chemistry 12】 teeth, 【Chemistry 13】 2. The compound of claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, selected from:

11. Structural part-Cy １ -LNK-Cy ２ - is -Cy １ -, -Cy １ -LNK, -Cy １ -Cy ２ -, -Cy １ -LNK-Cy ２ -, -Cy ２ -or-LNK-Cy ２ Selected from - or the structural moiety -Cy １ -LNK-Cy ２ - is -Cy １ -, -Cy １ -Cy ２ - or - Cy ２ Selected from - Or the structural moiety -Cy 1 -LNK-Cy 2 - is a single bond, -CH 2 -, 【Chemistry 14】 2. The compound of claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, selected from:

12. Cy １ is a single bond or, optionally, one or more R ａ the following groups substituted by: ４～１１ selected from a cycloalkyl group or a 4- to 11-membered heterocycloalkyl group; Or Cy １ is a single bond or, optionally, one or more R ａ the following groups substituted by: ６～９ selected from a cycloalkyl group or a 4- to 11-membered heterocycloalkyl group; Or Cy １ is a single bond or, optionally, one or more R ａ the following groups substituted by: ６ Cycloalkyl group, C ９ cycloalkyl groups, and 4-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-membered heterocycloalkyl groups; Or Cy １ is a single bond or, optionally, one or more R ａ the following groups substituted by: ６ Cycloalkyl group, C ９ selected from cycloalkyl groups, 4-, 6-, or 8- to 11-membered heterocycloalkyl groups; Or Cy １ is selected from a single bond, Or Cy １ optionally one or more R ａ C, substituted by ６ Cycloalkyl group or C ９ cycloalkyl groups, Or Cy １ optionally one or more R ａ a 4-, 6-, or 8- to 11-membered heterocycloalkyl group substituted by Or Cy １ optionally one or more R ａ and selected from 8-, 9-, 10-, or 11-membered heterocycloalkyl groups substituted by Or Cy １ is a single bond or, optionally, one or more R ａ a cyclohexyl group, a spirononyl group, an azetidinyl group, an octahydrocyclopentapyrrolyl group, a piperidinyl group, a monoazaspirononyl group, a diazaspirononyl group, an azabicyclononyl group, a monoazaspiroundecyl group, or a diazaspiroundecyl group, each of which is substituted by 2. The compound of claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof.

13. LNK is a single bond, C １～６ Alkylene group or C １～６ heteroalkylene groups, Or, LNK is a single bond or C １～４ alkylene groups, Or, LNK is a single bond or C １～３ alkylene groups, Or, LNK is a single bond or —CH ２ 2. The compound of claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, selected from:

14. Cy ２ does not exist, or C ４～１１ cycloalkyl groups or 4- to 11-membered heterocycloalkyl groups, wherein the cycloalkyl groups or heterocycloalkyl groups are optionally selected from one or more R ｂ is replaced by Or Cy ２ does not exist, or C ４～６ cycloalkyl groups or 4- to 6-membered heterocycloalkyl groups, and the cycloalkyl groups or heterocycloalkyl groups may optionally be one or more R ｂ is replaced by Or Cy ２ is absent or is selected from a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, an azetidinyl group, a pyrrolidinyl group, or a piperidinyl group, and the cyclobutyl group, the cyclopentyl group, the azetidinyl group, the pyrrolidinyl group, or the piperidinyl group may optionally be selected from one or more R ｂ is replaced by Or Cy ２ teeth, 【Chemistry 15】 2. The compound of claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, selected from:

15. R ａ , R ｂ are halogen, —OH, and —NH ２ , -CN,C １～３ Alkyl group, C １～３ Alkoxy group, halo C １～３ Alkyl group, C １～３ Alkylamino group or diC １～３ alkylamino groups; Or, R ａ , R ｂ are halogen, —OH, and —NH ２ , -CN or C １～３ independently selected from alkyl groups, Or, R ａ , R ｂ are halogen, —OH, and —NH ２ 2. The compound of claim 1, its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein each of the compound and the stereoisomer is independently selected from -CN or -CN.

16. wherein R is selected from hydrogen or a 5- to 6-membered heterocycloalkyl group, and the heterocycloalkyl group is optionally ═O or C １～３ substituted by alkyl groups, or wherein R is selected from hydrogen or a 5-membered heterocycloalkyl group, and the heterocycloalkyl group is optionally selected from ═O or C １～３ substituted by alkyl groups, or wherein R is selected from hydrogen or an imidazolinyl group, the imidazolinyl group being optionally substituted by ═O or a methyl group; Or, the R is hydrogen or 【Chemistry 16】 2. The compound of claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, selected from:

17. The compound of claim 1, wherein the compound is a compound of formula I'-1A, formula I'-2A, formula I'-3A-1, or formula I'-3A -2 compounds, 【Chemistry 17】 X is selected from CH or N; The compound of claim 1, its stereoisomer or pharmaceutically acceptable salt thereof, wherein the definitions of ring A, ring C, T, Cy 1 , Cy 2 , LNK, R 1 , X 2 or n are as defined in claim 1.

18. The compound of claim 1, wherein the compound is selected from the group consisting of compounds of formula I'-1A-1, formula I'-2A-1, formula I'-4A-1, and formula I'-4A-2; [Chemistry 18] X is selected from CH or N; 2. The compound of claim 1, its stereoisomer or pharmaceutically acceptable salt thereof, wherein the definitions of ring A, T, Cy 1 , Cy 2 , LNK, R 1 , X 2 or n are as defined in claim 1.

19. The following compound, its stereoisomer or pharmaceutically acceptable salt thereof: 【Chemistry 19】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】

20. A compound of Formula I'''-1a or Formula I'''-2a, a moiety, a stereoisomer thereof, a derivative thereof, or a pharmaceutically acceptable salt thereof, 【Chemistry 20】 During the ceremony, Ring A is C ５～１０ from a cycloalkenyl group or a 5- to 10-membered heterocycloalkenyl group Chosen, n is selected from 0, 1, 2, or 3; Each R １ is a halogen, —OH, —NH ２ , -CN, =O, C １～４ Alkoxy group, —CHO, C ３～６ a cycloalkyl group, a 3- to 10-membered heterocycloalkyl group, or a C １～４ alkyl groups, ３～６ a cycloalkyl group, a 3- to 10-membered heterocycloalkyl group, or a C １～４ The alkyl group may optionally be a halogen, —OH, —NH ２ Or C １～４ substituted by alkyl-OH, X ２ is selected from CH or N, a compound, moiety, stereoisomer thereof, derivative thereof, or a pharmaceutically acceptable salt thereof.

21. Each R 1 is independently selected from halogen, —OH, —NH 2 , —CN, ═O, a C 1-4 alkoxy group, —CHO, a C 3-6 cycloalkyl group, or a C 1-4 alkyl group, wherein the C 3-6 cycloalkyl group or the C 1-4 alkyl group is optionally substituted with halogen, —OH, —NH 2 , or a C 1-4 alkyl-OH; Or, each R １ is a halogen, —OH, —NH ２ , -CN, =O, C １～３ Alkoxy group, —CHO, C ３～４ Cycloalkyl group or C １～３ alkyl groups, ３～４ Cycloalkyl group or C １～３ The alkyl group may optionally be a halogen, —OH, —NH ２ Or C １～３ substituted by alkyl-OH, Or, each R １ is a halogen, —OH, —NH ２ , —CN, ═O, a methoxy group, —CHO, a cyclobutyl group or a methyl group, wherein the cyclobutyl group or the methyl group is optionally selected from halogen, —OH, —NH ２ or CH ２ is substituted by OH, Or, each R １ is F, -OH, -NH ２ , -CH ２ OH, =O, -CHO, -CH ２ NH ２ or 【Chemistry 21】 21. The compound, moiety, stereoisomer thereof, derivative thereof, or pharmaceutically acceptable salt thereof of claim 20, independently selected from:

22. The compound is selected from compounds represented by formula I'''-1 or I'''-2, respectively: 【Chemistry 22】 During the ceremony, Ring A, R １ or n is defined as in claim 20, the compound, moiety, stereoisomer, derivative or pharmaceutically acceptable salt thereof of claim 20.

23. Ring A is C ５～８ or ring A is selected from C ５～７ or ring A is selected from C ５～６ or ring A is selected from C ５～６ a cycloalkenyl group or a 5- to 9-membered heterocycloalkenyl group; Or, ring A is C ５ Cycloalkenyl group, C ６ Cycloalkenyl group, 5-membered, 6-membered, 7-membered , 8- or 9-membered heterocycloalkenyl groups; or ring A is selected from a cyclopentenyl group, a dicyclohexenyl group, a dihydropyrrolyl group, a tetrahydropyridinyl group, a tetrahydroazepinyl group, a dihydrooxazinyl group, an azaspirooctenyl group, or an azaspirononenyl group; Or, ring A is 【Chemistry 23】 Selected from Or, ring A is 【Chemistry 24】 21. The compound, moiety, stereoisomer, derivative or pharmaceutically acceptable salt thereof of claim 20 selected from:

24. The following compounds, moieties, stereoisomers thereof, derivatives thereof, or pharmaceutically acceptable salts thereof: 【Chemistry 25】 【change】

25. A compound, moiety, stereoisomer, derivative, or pharmaceutically acceptable salt thereof of formula I'''-1c or I'''-2d, 【Chemistry 26】 During the ceremony, Ring A is absent or selected from a C 5-10 cycloalkenyl group, a 5- to 10-membered heterocycloalkenyl group, a phenyl group, or a 5- to 6-membered heteroaryl group; n is selected from 0, 1, 2 or 3; each R 1 is independently selected from halogen, —OH, —NH 2 , —CN, a C 1-4 alkyl group, a C 1-4 alkoxy group, or a haloC 1-4 alkyl group; X ２ is selected from CH or N, L １ is C ０～３ alkylene groups, Cy ３ is C ３～８ selected from a cycloalkyl group or a 3- to 8-membered heterocycloalkyl group; R ２ is -CHO, OH, SH, NH ２ , COOH, one or more SH, OH or NH ２ C replaced by １～６ selected from alkyl groups, p is selected from 0, 1, 2, or 3; a compound, moiety, stereoisomer thereof, derivative thereof, or pharmaceutically acceptable salt thereof;

26. Ring A is C ５～９ selected from a cycloalkenyl group, a 5- to 9-membered heterocycloalkenyl group, a phenyl group, or a 5- or 6-membered heteroaryl group; Or, ring A is C ５～７ selected from a cycloalkenyl group, a 5- to 9-membered heterocycloalkenyl group, a phenyl group, or a 5- or 6-membered heteroaryl group; Or, ring A is selected from a 5- to 9-membered heterocycloalkenyl group, a phenyl group, or a 5- to 6-membered heteroaryl group; Or, ring A is selected from a 5- to 6-membered heterocycloalkenyl group, a phenyl group, or a 5-membered heteroaryl group; Or, ring A is selected from a dihydropyrrolyl group, a tetrahydropyridinyl group, a dihydrooxazinyl group, a phenyl group, a pyrrolyl group, a pyrazolyl group, or a furyl group; Or the part 【Chemistry 27】 teeth, 【Chemistry 28】 26. The compound, moiety, stereoisomer, derivative or pharmaceutically acceptable salt thereof of claim 25, selected from:

27. L １ is a single bond or -CH ２ and / or Cy ３ is C ３～６ selected from a cycloalkyl group or a 4- to 6-membered heterocycloalkyl group; Or Cy ３ is C ４～６ selected from a cycloalkyl group, a 4-membered heterocycloalkyl group, or a 6-membered heterocycloalkyl group; Or Cy ３ is selected from cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl or piperidinyl, and / or R ２ is —CHO, OH, or one or more OH or NH ２ C replaced by １～３ selected from alkyl groups, Or, R ２ is selected from —CHO, OH, or a methyl group substituted by one or more OH; Or, R ２ is —CHO, OH or —CH ２ OH, and / or p is selected from 0, 1 or 2; or p is selected from 0 or 1; or p is selected from 0, or p is selected from 1, and / or structural part 【Chemistry 29】 teeth, 【Transformation 30】 26. The compound, moiety, stereoisomer, derivative or pharmaceutically acceptable salt thereof of claim 25, selected from:

28. The following compounds, moieties, stereoisomers thereof, derivatives thereof, or pharmaceutically acceptable salts thereof: 【Chemistry 31】

29. Use of a compound, moiety, stereoisomer, derivative or pharmaceutically acceptable salt thereof according to any one of claims 20 to 28 in a Protac molecule. Optionally, the use of said compound, moiety, stereoisomer, derivative or pharmaceutically acceptable salt thereof to constitute part of a Protac molecule; Optionally, use of said compound, moiety, stereoisomer, derivative or pharmaceutically acceptable salt thereof to degrade proteins; Optionally, the use of said compound, moiety, stereoisomer, derivative or pharmaceutically acceptable salt thereof for degrading proteins in the form of Protac molecules, or the use of said compound, moiety, stereoisomer, derivative or pharmaceutically acceptable salt thereof in the manufacture of a proteolytic agent; Or the use of said compound, moiety, stereoisomer, derivative or pharmaceutically acceptable salt thereof in the manufacture of a Protac molecule.

30. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a compound, moiety, stereoisomer thereof, derivative thereof or a pharmaceutically acceptable salt thereof according to any one of claims 20 to 28.

31. A Protac molecule comprising the compound, moiety, stereoisomer thereof, derivative thereof or pharmaceutically acceptable salt thereof according to any one of claims 20 to 28.

32. The compound according to any one of claims 1 to 19, its stereoisomer, or a pharmaceutically acceptable salt thereof, or A compound, moiety, stereoisomer, derivative or pharmaceutically acceptable salt thereof according to any one of claims 20 to 28, or A pharmaceutical composition comprising a compound according to any one of claims 1 to 19, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a compound, moiety, stereoisomer thereof, derivative thereof or a pharmaceutically acceptable salt thereof according to any one of claims 20 to 28. a drug for preventing or treating a condition that is treated by degrading a target protein that binds to a target ligand, for preventing or treating a condition that is treated by binding to a protein in the cerebellum in the body, or for preventing or treating a disease associated with BTK, comprising

33. the BTK-associated disease is selected from conditions that are treated by degrading proteins that bind to BTK target protein ligands; Alternatively, the BTK-related disease is selected from an autoimmune disease, an inflammatory disease, or a cancer.

33. The drug of claim 32.

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