Fused imide derivative

Abstract

The invention belongs to the field of medicinal chemistry, and relates to a fused imide derivative as shown in a formula I, a preparation method thereof, a pharmaceutical composition containing the compound, and application of the fused imide derivative in treatment of related diseases (such as cancer). # imgabs0 #

Description

[0001] This application is a divisional application of the following application: Application date November 18, 2022; Application number 202280074055.X; Invention name: "Condensed imide derivatives".

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application is an international application based on and claims the benefit of priority to, Chinese patent application numbers 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. The disclosures of the aforementioned applications are hereby incorporated by reference in their entirety. Technical Field

[0004] The present application relates to fused imide derivatives and protein degraders, preparation methods thereof, pharmaceutical compositions containing the compounds, and uses thereof in treating related diseases (such as cancer). Background Art

[0005] Bruton's tyrosine kinase (BTK) is primarily expressed in B cells and distributed throughout the lymphatic, hematopoietic, and blood systems. It is a member of the Tec family of non-receptor tyrosine kinases, which also includes TEC, ITK / TSK / EMT, TXK, and BMX, sharing a high degree of structural homology. Recent studies on B cells, particularly in B cell non-Hodgkin's lymphoma and rheumatoid arthritis, have revealed that BTK is often abnormally expressed. Because it is primarily expressed in B cells and myeloid cells, BTK is a well-targeted and safe target.

[0006] Protac (proteolysis targeting chimera) molecules are a class of bifunctional compounds that can simultaneously bind to target proteins and E3 ubiquitin ligases. These compounds can induce target proteins to be recognized by the cell's proteasome, causing degradation of the target protein and effectively reducing the target protein's content in the cell. By introducing ligands that can bind to different target proteins into Protac molecules, Protac technology has become possible for the treatment of various diseases and has garnered widespread attention in recent years. Detailed Description of the Invention

[0008] In one aspect, the present application relates to a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0009]

[0010] in,

[0011] Ring A is absent or selected from C 5-10 Cycloalkenyl, 5-10 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl;

[0012] Alternatively, Ring A is absent or is selected from C 5-6 Cycloalkenyl, 5-10 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl;

[0013] Ring B is selected from a benzene ring group;

[0014] Ring C is selected from isoxazolyl or furyl;

[0015] Each R 1 independently selected from halogen, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy or halogenated C 1-4 alkyl;

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

[0017] Cy 1 Selected from bond, C 3-12 Cycloalkyl or 4-12 membered heterocycloalkyl, the C 3-12 Cycloalkyl or 4-12 membered heterocycloalkyl is optionally substituted with one or more R a replace;

[0018] LNK is selected from the key, C 1-12 Alkylene or C 1-12 heteroalkylene;

[0019] Cy 2 Not present, or selected from C 3-12 Cycloalkyl or 4-12 membered heterocycloalkyl, the cycloalkyl or heterocycloalkyl being optionally substituted by one or more R b replace;

[0020] Each R a and R b Each independently selected from halogen, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 1-4 Alkylamino, or di-C 1-4 Alkylamino;

[0021] The PTM is selected from drugs or their derivatives that bind to the target protein.

[0022] In some embodiments, the present application relates to a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0023]

[0024] in,

[0025] Ring A is absent or selected from C 5-6 Cycloalkenyl, 5-10 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl;

[0026] Ring B is selected from a benzene ring group;

[0027] Ring C is selected from isoxazolyl or furyl;

[0028] Each R 1 independently selected from halogen, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy or halogenated C 1-4 alkyl;

[0029] n is selected from 0, 1, 2 or 3;

[0030] Cy 1 Selected from bond, C 3-12 Cycloalkyl or 4-12 membered heterocycloalkyl, the C 3-12 Cycloalkyl or 4-12 membered heterocycloalkyl is optionally substituted with one or more R a replace;

[0031] LNK is selected from the key, C 1-12 Alkylene or C 1-12 heteroalkylene;

[0032] Cy 2 Not present, or selected from C 3-12 Cycloalkyl or 4-12 membered heterocycloalkyl, the cycloalkyl or heterocycloalkyl being optionally substituted by one or more R b replace;

[0033] Each R a and R b Each independently selected from halogen, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 1-4 Alkylamino, or di-C 1-4 Alkylamino;

[0034] The PTM is selected from drugs or their derivatives that bind to the target protein.

[0035] In some embodiments, in the compound of formula I, its stereoisomers or pharmaceutically acceptable salts thereof, the structural moiety Selected from And the PTM is not selected from the following structural parts:

[0036]

[0037] In other embodiments, Cy 1 Selected from optionally one or more R a Substituted 4-12 membered heterocycloalkyl.

[0038] In some embodiments of the present application, when Ring A is present, Cy 2 or LNK(Cy 2 When absent) can be directly covalently linked to ring B; similarly, Direct covalent attachment to ring B is also possible.

[0039] In some embodiments, the PTM described herein is selected from drugs or derivatives thereof that act on AR, ER, kinase, phosphatase, MDM2, human BET bromodomain proteins, Hsp90, HDAC, human lysine methyltransferase, RAF receptor, FKBP, vascular growth factor, immunosuppression-related receptors or proteins, aryl hydrocarbon receptor, thyroid hormone receptor, HIV protease, HIV integrase, HCV protease, HBV protease or acyl protein thioesterase 1 and / or acyl protein thioesterase 2.

[0040] 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.

[0041] In some embodiments, the PTM described herein is selected from drugs or derivatives thereof that act 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.

[0042] In some embodiments, the PTM described herein is selected from drugs acting on BTK or WEE1 or derivatives thereof.

[0043] In some embodiments, the PTM described herein is selected from drugs that act on BTK or derivatives thereof.

[0044] On the other hand, the present application relates to a compound of formula II-1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof,

[0045]

[0046] in,

[0047] T is selected from CH or N;

[0048] R is selected from hydrogen, or 5-6 membered heterocycloalkyl, the heterocycloalkyl being optionally substituted by ═O or C 1-6 Alkyl substitution;

[0049] Ring E is selected from phenyl, benzocycloalkenyl (e.g., benzo 4 to 12-membered cycloalkenyl, or benzo 4 to 10-membered cycloalkenyl, or benzo 4 to 8-membered cycloalkenyl), or benzoheterocycloalkenyl (e.g., benzo 4 to 12-membered heterocycloalkenyl, or benzo 5 to 11-membered heterocycloalkenyl);

[0050] X 2 selected from CH or N;

[0051] L is selected from a linking group;

[0052] Ring A, Ring B, Ring C, R 1 and n are as defined in this application.

[0053] In another aspect, the present application relates to a compound of formula II, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0054]

[0055] in,

[0056] T is selected from CH or N;

[0057] R is selected from hydrogen, or 5-6 membered heterocycloalkyl, the heterocycloalkyl being optionally substituted by ═O or C 1-6 Alkyl substitution;

[0058] Ring E is selected from phenyl, benzocycloalkenyl or benzoheterocycloalkenyl;

[0059] X 2 selected from CH or N;

[0060] L is selected from a linking group;

[0061] Ring A, Ring B, Ring C, R 1and n are as defined in this application.

[0062] In some embodiments, L is selected from -Cy 1 -LNK-Cy 2 -LNK-, -Cy 1 -LNK-Cy 2 -or-Cy 1 -Cy 2 -LNK-, where Cy 1 、LNK、Cy 2 As described herein. In some embodiments, L is selected from -Cy 1 -LNK-Cy 2 -, where Cy 1 、LNK、Cy 2 As described in this application.

[0063] In another aspect, the present application relates to a compound of formula I'a, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0064]

[0065] in,

[0066] T is selected from CH or N;

[0067] R is selected from hydrogen, or 5-6 membered heterocycloalkyl, the heterocycloalkyl being optionally substituted by ═O or C 1-6 Alkyl substitution;

[0068] Ring E is selected from phenyl, benzocycloalkenyl or benzoheterocycloalkenyl;

[0069] X 2 selected from CH or N;

[0070] Ring A, Ring B, Ring C, R 1 、n、Cy 1 , LNK and Cy 2 The definition of is as described in this application.

[0071] In some embodiments, X 2 is selected from CH; in some embodiments, X 2 Selected from N.

[0072] In some embodiments, the ring E is selected from phenyl, benzo 5-12 Cycloalkenyl or benzo 5-12 membered heterocycloalkenyl.

[0073] In some embodiments, the ring E is selected from phenyl, benzo 5-6 Cycloalkenyl or benzo 5-11 membered heterocycloalkenyl.

[0074] In some embodiments, the ring E is selected from phenyl, benzo 5-membered heterocycloalkenyl, benzo 6-membered heterocycloalkenyl, benzo 10-membered heterocycloalkenyl, or benzo 11-membered heterocycloalkenyl.

[0075] In some embodiments, the ring E is selected from phenyl, In some embodiments, the ring E is selected from phenyl. In some embodiments, the ring E is selected from

[0076] On the other hand, the compound of formula I, its stereoisomers or pharmaceutically acceptable salts thereof described in the present application is selected from the compound of formula I', its stereoisomers or pharmaceutically acceptable salts thereof,

[0077]

[0078] in,

[0079] T is selected from CH or N;

[0080] R is selected from hydrogen, or 5-6 membered heterocycloalkyl, the heterocycloalkyl being optionally substituted by ═O or C 1-6 Alkyl substitution.

[0081] In some embodiments, Ring A is absent or is selected from C 5-10 cycloalkenyl, 5-10 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl.

[0082] In some embodiments, Ring A is absent or is selected from C 5-8 cycloalkenyl, 5-10 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl.

[0083] In some embodiments, Ring A is absent or is selected from C 5-7 cycloalkenyl, 5-10 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl.

[0084] In some embodiments, Ring A is absent or is selected from C 5-6 cycloalkenyl, 5-10 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl.

[0085] In some embodiments, Ring A is absent or is selected from C 5-6 cycloalkenyl, 5-9 membered heterocycloalkenyl, phenyl or 5 membered heteroaryl.

[0086] In some embodiments, Ring A is absent or is selected from C 5-6 cycloalkenyl, 5-9 membered heterocycloalkenyl, phenyl, pyrrolyl, pyrazolyl, furyl, or oxazolyl.

[0087] In some embodiments, Ring A is absent or is selected from C5 cycloalkenyl, C6 cycloalkenyl, 5-membered, 6-membered, 7-membered, 8-membered, or 9-membered heterocycloalkenyl, phenyl, pyrrolyl, pyrazolyl, furanyl, or oxazolyl.

[0088] In some embodiments, Ring A is absent or is selected from cyclopentenyl, bicyclohexenyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydroazepine 1-Hydroxy-1,1-dihydro-1,1-doxy ...

[0089] In some embodiments, Ring A is selected from C 5-10 In some embodiments, ring A is selected from C 5-8 In some embodiments, ring A is selected from C 5-7 In some embodiments, ring A is selected from C 5-6 In some embodiments, ring A is selected from 5-9 membered heterocycloalkenyl. In some embodiments, ring A is selected from 5-8 membered heterocycloalkenyl. In some embodiments, ring A is selected from 5 membered heterocycloalkenyl. In some embodiments, ring A is selected from 6 membered heterocycloalkenyl. In some embodiments, ring A is selected from 7 membered heterocycloalkenyl. In some embodiments, ring A is selected from 8 membered heterocycloalkenyl. In some embodiments, ring A is selected from 9 membered heterocycloalkenyl. In some embodiments, ring A is absent or selected from C 5-6 In some preferred embodiments, ring A is absent or is selected from C 5-6 cycloalkenyl, 5-7 membered heterocycloalkenyl containing 1-2 heteroatoms selected from N, O or S (preferably containing 1-2, for example 1 N atom) or phenyl. In some specific embodiments, ring A is absent or is selected from cyclopentenyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydroazepine phenyl or phenyl.

[0090] In some embodiments, ring A is selected from cyclopentenyl, bicyclohexenyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydroazepine 1-Hydroxy-1,1-dihydro ...

[0091] In some embodiments, ring A is selected from cyclopentenyl or bicyclohexenyl. In some embodiments, ring A is selected from dihydropyrrolyl, dihydrooxazinyl, tetrahydropyridinyl, tetrahydroazepine, azaspirocyclooctenyl or azaspirocyclononenyl.

[0092] In some embodiments, Ring A is selected from phenyl, pyrrolyl, pyrazolyl, furanyl, or oxazolyl.

[0093] In some embodiments, Ring A is absent or is selected from C 5-7 cycloalkenyl, 5-8 membered heterocycloalkenyl, phenyl or pyrrolyl.

[0094] In other embodiments, Ring A is absent or is selected from C 5-6 cycloalkenyl, 5-8 membered heterocycloalkenyl, phenyl or pyrrolyl.

[0095] In other embodiments, Ring A is absent or is selected from C5 cycloalkenyl, 5-membered, 6-membered, 7-membered, or 8-membered heterocycloalkenyl, phenyl, or pyrrolyl.

[0096] In other embodiments, Ring A is absent or is selected from cyclopentenyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydroazepine yl, azaspirocyclooctene, phenyl or pyrrolyl.

[0097] In other embodiments, Ring A is absent.

[0098] In other embodiments, Ring A is selected from C 5-6 cycloalkenyl or 5-8 membered heterocycloalkenyl.

[0099] In other embodiments, Ring A is selected from cyclopentenyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydroazepine In other embodiments, ring A is selected from cyclopentenyl. In other embodiments, ring A is selected from dihydropyrrolyl, tetrahydropyridinyl, tetrahydroaza Base or azaspirocyclooctene.

[0100] In other embodiments, Ring A is selected from phenyl or pyrrolyl.

[0101] In some embodiments, the moiety Selected from In some embodiments, the moiety Selected from Among them, the bond to ring A The * in the table indicates that the bond is connected to an atom on ring A; the bond to ring C The * in the ' represents that the bond is connected to an atom on the ring C (hereinafter, * in similar positions represents the same or similar meaning).

[0102] In some embodiments, the moiety Selected from In some embodiments, the moiety Selected from (For example ), (example Wherein, * is defined the same or similarly to the above.

[0103] In some embodiments, the moiety Selected from In some embodiments, the moiety Selected from In some embodiments, the moiety Selected from

[0104] In some embodiments, the moiety Selected from

[0105] In some embodiments, the moiety Selected from In some embodiments, the moiety Selected from In some embodiments, the moiety Selected from

[0106] In some embodiments, the moiety Selected from

[0107] In some embodiments, the moiety Selected from

[0108] In some embodiments, the moiety Selected from

[0109] In some embodiments, the moiety Selected from

[0110] In some embodiments, the moiety Selected from

[0111] In some embodiments, the moiety Selected from

[0112] In some embodiments, the moiety Selected from

[0113] In some embodiments, the moiety Selected from

[0114] In some embodiments, the moiety Selected from

[0115] In other embodiments, the moiety Selected from In other embodiments, the moiety Selected from

[0116] In other embodiments, the moiety Selected from In some embodiments, the moiety Selected from

[0117] In some embodiments, each R 1 independently selected from halogen, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy or halogenated C 1-3 alkyl.

[0118] In some embodiments, each R 1 In some embodiments, each R 1 are independently selected from fluorine, chlorine or bromine.

[0119] In some embodiments, each R 1 are independently selected from fluorine.

[0120] In some embodiments, n is selected from 0, 1, or 2. In some embodiments, n is selected from 0 or 1.

[0121] In some embodiments, the moiety Selected from

[0122] In some embodiments, the moiety Selected from

[0123] In some embodiments, the moiety Selected from

[0124] In some embodiments, the moiety Selected from

[0125] In some embodiments, the moiety Selected from

[0126] In some embodiments, the moiety Selected from

[0127] In other embodiments, the moiety Selected from In some embodiments, the moiety Selected from

[0128] In some embodiments, the PTM is in,

[0129] T is selected from CH or N;

[0130] R is selected from hydrogen, or 5-6 membered heterocycloalkyl, the heterocycloalkyl being optionally substituted by ═O or C 1-6 Alkyl substitution;

[0131] Ring E is selected from phenyl, benzocycloalkenyl or benzoheterocycloalkenyl.

[0132] In some specific embodiments, T is selected from CH.

[0133] In some specific embodiments, R is selected from hydrogen, imidazolidinone or C 1-4 Alkyl-substituted imidazolidinone; preferably, R is selected from hydrogen, imidazolidinone, 1-methyl-imidazolidinone, 1-ethyl-imidazolidinone or 1-propyl-imidazolidinone.

[0134] In some specific embodiments, ring E is selected from phenyl, benzopiperidinyl, chromanyl, spiro[benzopyran-piperidine] or benzodihydrooxazinopiperazine. In some specific embodiments, ring E is selected from phenyl.

[0135] In some embodiments, ring E is selected from phenyl, L is selected from -Cy 1 -LNK-Cy 2 -, X 2 Selected from CH, where Cy 1 、LNK、Cy 2 As described in this application.

[0136] In some embodiments, the PTM is Ring E is as defined above. Preferably, PTM is More preferably, the PTM is

[0137] In some embodiments, the moiety -Cy 1 -LNK-Cy 2 -Selected from-Cy 1 -、-Cy 1 -LNK-, -Cy 1 -Cy 2 -、-Cy 1 -LNK-Cy 2 -、-Cy 2 -、-LNK-Cy 2 -. In some embodiments, the moiety -Cy 1 -LNK-Cy 2 -Selected from-Cy 1 -、-Cy 1 -Cy 2 -or-Cy 2 -. In some embodiments, the moiety -Cy 1 -LNK-Cy 2 -Selected from-Cy 1 -LNK-, -Cy 1 -LNK-Cy 2 -or-LNK-Cy 2 -. In some embodiments, the moiety -Cy 1 -LNK-Cy 2 -Selected from-Cy 1 -LNK-. In some embodiments, the moiety -Cy 1 -LNK-Cy 2-Selected from-Cy 1 -LNK-Cy 2 -. In some embodiments, the moiety -Cy 1 -LNK-Cy 2 -Selected from-LNK-Cy 2 -.

[0138] In other embodiments, the moiety -Cy 1 -LNK-Cy 2 -Selected from-Cy 1 -、-Cy 1 -LNK, -Cy 1 -Cy 2 -or-Cy 1 -LNK-Cy 2 -.

[0139] In some embodiments, Cy 1 is selected from a bond, or optionally replaced by one or more R a Substituted with the following groups: C 4-11 cycloalkyl or 4-11 membered heterocycloalkyl.

[0140] In some embodiments, Cy 1 is selected from a bond, or optionally replaced by one or more R a Substituted with the following groups: C 6-9 In some embodiments, Cy 1 is selected from a bond, or optionally replaced by one or more R a Substituted with the following groups: C 6-9 Cycloalkyl (eg, C6 cycloalkyl, C9 cycloalkyl), 5-11 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S (eg, 1-3, or 1-2 heteroatoms selected from N or O).

[0141] In some embodiments, Cy 1 is selected from a bond, or optionally replaced by one or more R a Substituted: C6 cycloalkyl, C9 cycloalkyl, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered or 11-membered heterocycloalkyl.

[0142] In some embodiments, Cy 1 is selected from a bond, or optionally replaced by one or more R a Substituted: C6 cycloalkyl, C9 cycloalkyl, 4-membered, 6-membered, or 8-11-membered heterocycloalkyl.

[0143] In some embodiments, Cy 1 In some embodiments, Cy1 Selected from C6 cycloalkyl or C9 cycloalkyl, the cycloalkyl is optionally substituted by one or more R a In some embodiments, Cy 1 is selected from 4-membered, 6-membered, or 8-11-membered heterocycloalkyl, the heterocycloalkyl being optionally substituted by one or more R a In some embodiments, Cy 1 is selected from 4-membered or 6-membered heterocycloalkyl, the heterocycloalkyl being optionally substituted by one or more R a In some embodiments, Cy 1 is selected from 8-11 membered heterocycloalkyl, the heterocycloalkyl being optionally substituted by one or more R a In some embodiments, Cy 1 is selected from 8-membered, 9-membered, 10-membered or 11-membered heterocycloalkyl, the heterocycloalkyl being optionally substituted by one or more R a replace.

[0144] In some embodiments, Cy 1 is selected from a bond, or optionally replaced by one or more R a Substituted cyclohexyl, spironanyl, azetidinyl, octahydrocyclopentapyrrolyl, piperidinyl, monoazaspironanyl, diazaspironanyl, azabicyclononanyl (e.g., monoazabicyclononanyl), monoazaspiroundecyl, or diazaspiroundecyl.

[0145] In some embodiments, Cy 1 is selected from cyclohexyl or spirononyl. In some embodiments, Cy 1 In some embodiments, Cy 1 is selected from octahydrocyclopentylpyrrolyl, monoazaspironanyl, diazaspironanyl, azabicyclononanyl, monoazaspiroundecyl or diazaspiroundecyl. In some embodiments, Cy 1 is selected from a bond, piperidinyl, cyclohexyl, spironanyl, monoazaspironanyl, octahydrocyclopentapyrrolyl, monoazaspiroundecyl, monooxa-azaspiroundecyl or azabicyclononanyl.

[0146] In some embodiments, Cy 1 is selected from a bond, or optionally replaced by one or more R a Substituted with the following groups:

[0147] In some embodiments, Cy 1 is selected from a bond, or optionally replaced by one or more R a Substituted with the following groups:

[0148] In some embodiments, Cy 1 Selected from In some embodiments, Cy 1 Selected from In some embodiments, Cy 1 Selected from In some embodiments, Cy 1 Select from key,

[0149] In other embodiments, Cy 1 Selected from optionally one or more R a Substituted 4- to 11-membered heterocycloalkyl.

[0150] In other embodiments, Cy 1 Selected from optionally one or more R a substituted 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered or 11-membered heterocycloalkyl.

[0151] In other embodiments, Cy 1 Selected from optionally one or more R a substituted 6-membered, or 9-11-membered heterocycloalkyl.

[0152] In other embodiments, Cy 1 Selected from optionally one or more R a substituted 6-membered, 9-membered or 11-membered heterocycloalkyl.

[0153] In other embodiments, Cy 1 Selected from optionally one or more R a substituted piperidinyl, monoazaspironane, diazaspironane or diazaspiroundecane.

[0154] In other embodiments, Cy 1 Selected from optionally one or more R a Replaced

[0155] In some embodiments, LNK is selected from a bond, C 1-6 Alkylene or C 1-6 Heteroalkylene.

[0156] In some embodiments, LNK is selected from a bond or C 1-4 Alkylene.

[0157] In some embodiments, LNK is selected from a bond or C 1-3 Alkylene.

[0158] In some embodiments, LNK is selected from a bond or -CH2-. In some embodiments, LNK is selected from a bond. In some embodiments, LNK is selected from -CH2-.

[0159] In some embodiments, Cy 2 Not present, or selected from C 4-11 Cycloalkyl or 4-11 membered heterocycloalkyl, the cycloalkyl or heterocycloalkyl being optionally substituted by one or more R b In some embodiments, Cy 2 In some embodiments, Cy 2 Selected from C 4-11 Cycloalkyl or 4-11 membered heterocycloalkyl, the cycloalkyl or heterocycloalkyl being optionally substituted by one or more R b replace.

[0160] In some embodiments, Cy 2 Not present, or selected from C 4-6 Cycloalkyl or 4-6 membered heterocycloalkyl, the cycloalkyl or heterocycloalkyl is optionally substituted by one or more R b In some embodiments, Cy 2 Selected from C 4-6 Cycloalkyl or 4-6 membered heterocycloalkyl, the cycloalkyl or heterocycloalkyl is optionally substituted by one or more R b In some embodiments, Cy 2 Not present, or selected from C 4-6 Cycloalkyl or 4-6 membered heterocycloalkyl, the cycloalkyl or heterocycloalkyl is optionally substituted by one or more R b Substituted, wherein the heterocycloalkyl group contains 1-3 (eg 1-2) heteroatoms selected from N, O or S (eg N or O).

[0161] In some embodiments, Cy 2 is absent or is selected from cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl or piperidinyl, wherein the cyclobutyl, cyclopentyl, azetidinyl, pyrrolidinyl or piperidinyl is optionally replaced by one or more R b replace.

[0162] In some embodiments, Cy 2 Does not exist, or is selected from

[0163] In some embodiments, Cy 2 Does not exist, or is selected from

[0164] In other embodiments, Cy 2 is absent or is selected from cyclobutyl, cyclopentyl, azetidinyl, pyrrolidinyl or piperidinyl, wherein the cyclobutyl, cyclopentyl, azetidinyl, pyrrolidinyl or piperidinyl is optionally replaced by one or more R b replace.

[0165] In other embodiments, Cy 2 Selected from

[0166] In some embodiments, R a and R b Each independently selected from halogen, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, C 1-3 Alkylamino, or di-C 1-3 Alkylamino.

[0167] In some embodiments, R a and R b Each independently selected from halogen, -OH, -NH2, -CN or C 1-3 alkyl.

[0168] In some embodiments, R a and R b Each is independently selected from halogen, -OH, -NH2 or -CN.

[0169] In some embodiments, the moiety -Cy 1 -LNK- is selected from a bond, -CH2-,

[0170] In some embodiments, the moiety -Cy 1 -LNK-Selected In some embodiments, the moiety -Cy 1 -LNK-Selected In some embodiments, the moiety -Cy 1 -LNK-Selected In some embodiments, the moiety -Cy 1 -LNK-Selected

[0171] In other embodiments, the moiety -Cy 1 -LNK-Selected

[0172] In some embodiments, the moiety -LNK-Cy 2 - is selected from a bond, -CH2-,

[0173] In other embodiments, the moiety -LNK-Cy 2 - is selected from a bond, -CH2-,

[0174] In some embodiments, the moiety -Cy 1 -Cy 2 -Selected

[0175] In other embodiments, the moiety -Cy 1 -Cy 2 -Selected

[0176] In some embodiments, the moiety -Cy 1 -LNK-Cy 2 - is selected from a bond, -CH2-,

[0177] In some embodiments, the moiety -Cy 1 -LNK-Cy 2 -Selected In some embodiments, the moiety -Cy 1 -LNK-Cy 2 -Selected

[0178] In other embodiments, the moiety -Cy 1 -LNK-Cy 2 -Selected

[0179] In some embodiments, the moiety Selected from

[0180]

[0181]

[0182]

[0183] In other embodiments, the moiety Selected from

[0184] In some embodiments, T is selected from CH. In some embodiments, T is selected from N.

[0185] In some embodiments, R is selected from hydrogen, or 5-6 membered heterocycloalkyl, which is optionally substituted by ═O or C 1-3 Alkyl substitution.

[0186] In some embodiments, R is selected from hydrogen or 5-membered heterocycloalkyl, which is optionally substituted by ═O or C 1-3 Alkyl substitution.

[0187] In some embodiments, the R is selected from hydrogen or imidazolinyl, the imidazolinyl optionally substituted with =0 or methyl.

[0188] In some embodiments, R is selected from hydrogen or

[0189] In some embodiments, the present application relates to a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0190] Ring A is absent or selected from C 5-8 cycloalkenyl, 5-9 membered heterocycloalkenyl (preferably 5-8 membered heterocycloalkenyl, or 5-7 membered heterocycloalkenyl) or phenyl; or, ring A is absent or selected from C 5-6 cycloalkenyl, 5-9 membered heterocycloalkenyl (preferably 5-8 membered heterocycloalkenyl, or 5-7 membered heterocycloalkenyl) or phenyl; preferably, ring A is absent or selected from C 5-6 Cycloalkenyl, 5-7 membered heterocycloalkenyl containing 1-2 heteroatoms selected from N, O or S (preferably containing 1-2, for example 1 N atom) or phenyl; or preferably, ring A is selected from C 5-6 Cycloalkenyl, 5-7 membered heterocycloalkenyl containing 1-2 heteroatoms selected from N, O or S (preferably containing 1-2, for example 1 N atom);

[0191] Ring B is selected from a benzene ring group;

[0192] Ring C is selected from isoxazolyl or furyl;

[0193] Each R 1 Independently selected from fluorine, chlorine or bromine; n is selected from 0, 1 or 2, preferably 0 or 1;

[0194] Preferably, Selected from

[0195] PTM is Preferably, the PTM is in,

[0196] T is selected from CH or N, preferably selected from CH;

[0197] R is selected from hydrogen, or 5-6 membered heterocycloalkyl, the heterocycloalkyl being optionally substituted by ═O or C 1-6 Alkyl substituted; preferably, R is selected from hydrogen, imidazolinone or C 1-4 Alkyl-substituted imidazolidinone; more preferably, R is selected from hydrogen, imidazolidinone, 1-methyl-imidazolidinone, 1-ethyl-imidazolidinone or 1-propyl-imidazolidinone;

[0198] Ring E is selected from phenyl, benzocycloalkenyl or benzoheterocycloalkenyl; preferably, ring E is selected from phenyl, benzopiperidinyl, chromanyl, spiro[benzopyran-piperidine] or benzodihydrooxazinopiperazine;

[0199] Cy 1 is selected from a bond, or optionally replaced by one or more R a Substituted with the following groups: C 6-9 Cycloalkyl, or a 5-11 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S (e.g., 1-3, or 1-2 heteroatoms selected from N or O);

[0200] LNK is selected from the key or C 1-4 Alkylene; preferably, LNK is selected from a bond or C 1-3 alkylene;

[0201] Cy 2 Not present, or selected from C 4-6 Cycloalkyl or 4-6 membered heterocycloalkyl, the cycloalkyl or heterocycloalkyl is optionally substituted by one or more R b Substituted; preferably, Cy 2 Not present, or selected from C 4-6 Cycloalkyl or 4-6 membered heterocycloalkyl wherein the heterocycloalkyl contains 1-2 heteroatoms selected from N or O.

[0202] In some specific embodiments, the present application relates to a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0203] Ring A is absent or is selected from cyclopentenyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydroazepine Preferably, ring A is selected from cyclopentenyl, dihydropyrrolyl, tetrahydropyridinyl or tetrahydroazepine More preferably, ring A is selected from dihydropyrrolyl, tetrahydropyridinyl or tetrahydroazepine base;

[0204] Preferably, the structural part Selected from

[0205] PTM is Preferably, the PTM is

[0206] Cy 1 is selected from a bond, piperidinyl, cyclohexyl, spironanyl, monoazaspironanyl, octahydrocyclopentylpyrrolyl, monoazaspiroundecyl, monooxa-azaspiroundecyl or azabicyclononanyl; preferably, Cy 1 Select from key,

[0207] LNK is selected from the key or C 1-3 Alkylene; preferably, LNK is selected from a bond or -CH2-;

[0208] Cy 2 is absent or is selected from cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl or piperidinyl, wherein the cyclobutyl, cyclopentyl, azetidinyl, pyrrolidinyl or piperidinyl is optionally replaced by one or more R b Substituted; preferably, Cy 2 Does not exist, or is selected from

[0209] In some embodiments, the heterocycloalkenyl or heterocycloalkyl group, wherein the heteroatom is selected from N, NH, O, or S. In some embodiments, the heterocycloalkenyl or heterocycloalkyl group, wherein the heteroatom is selected from N, O, or S. In some embodiments, the heteroaryl group, wherein the heteroatom is selected from N, O, or S. In some embodiments, the heteroalkylene group, wherein the heteroatom is selected from N, NH, O, S, S(O), or S(O)2.

[0210] In some embodiments, the heterocycloalkenyl, heterocycloalkyl, heteroalkylene or heteroaryl, wherein the number of heteroatoms is selected from 1, 2, 3, 4, 5 or 6. In some embodiments, the heterocycloalkenyl, heterocycloalkyl, heteroalkylene or heteroaryl, wherein the number of heteroatoms is selected from 1, 2, 3 or 4. In some embodiments, the heterocycloalkenyl, heterocycloalkyl, heteroalkylene or heteroaryl, wherein the number of heteroatoms is selected from 1, 2 or 3.

[0211] The present application also relates to compounds of formula I'-1A, formula I'-2A, formula I'-1A-1, formula I'-2A-1, formula I'-3A-1, formula I'-3A-2, formula I'-4A-1, formula I'-4A-2, stereoisomers thereof, or pharmaceutically acceptable salts thereof,

[0212]

[0213] Among them, ring A, ring C, Cy 1 、Cy 2 、LNK、R 1 , n, T and X 2 Definitions as described in this application;

[0214] X is selected from CH or N.

[0215] In some embodiments, the moiety Selected from In some embodiments, the moiety Selected from

[0216] In some embodiments, the moiety Selected from

[0217] In some embodiments, the moiety Selected from In some embodiments, the moiety Selected from

[0218] In some embodiments, the moiety Selected from

[0219] In some embodiments, the moiety Selected from In some embodiments, the moiety Selected from

[0220] In some embodiments, the moiety Selected from

[0221] In some embodiments, the moiety Selected from In some embodiments, the moiety Selected from In some embodiments, the moiety

[0222] In other embodiments, the moiety Selected from

[0223] In other embodiments, the moiety Selected from

[0224] In other embodiments, the moiety Selected from

[0225] In some embodiments, the moiety -Cy 1 -LNK-, -LNK-Cy 2 -、-Cy 1 -Cy 2 -or-Cy 1 -LNK-Cy 2 - as described in this application.

[0226] The present application also relates to the following compounds, their stereoisomers or pharmaceutically acceptable salts thereof:

[0227]

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243] In another aspect, the present application relates to a compound of formula I", a stereoisomer thereof or a pharmaceutically acceptable salt thereof,

[0244]

[0245] in,

[0246] Selected from

[0247] Ring A is selected from C 5-10 Cycloalkenyl, 5-10 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl; or, Ring A is selected from C 5-8 Cycloalkenyl, 5-10 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl; or, Ring A is selected from C 5-7 Cycloalkenyl, 5-10 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl; or, Ring A is selected from C 5-6 Cycloalkenyl, 5-10 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl; or, Ring A is selected from C 5-10 Cycloalkenyl or 5-10 membered heterocycloalkenyl; or, Ring A is selected from C 5-8 Cycloalkenyl or 5-10 membered heterocycloalkenyl; or, Ring A is selected from C 5-6 Cycloalkenyl or 5-9 membered heterocycloalkenyl;

[0248] The PTM is selected from drugs or their derivatives that bind to the target protein;

[0249] L is selected from a linking group;

[0250] R 1 and n are as defined in this application.

[0251] In another aspect, the present application relates to a compound of formula I"-1, a moiety, a stereoisomer, a derivative thereof (particularly a Protac molecule) or a pharmaceutically acceptable salt thereof,

[0252]

[0253] in,

[0254] Selected from

[0255] Ring A is selected from C 5-10 Cycloalkenyl, 5-10 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl; or, Ring A is selected from C 5-8 Cycloalkenyl, 5-10 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl; or, Ring A is selected from C 5-7 Cycloalkenyl, 5-10 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl; or, Ring A is selected from C 5-6 Cycloalkenyl, 5-10 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl; or, Ring A is selected from C 5-10 Cycloalkenyl or 5-10 membered heterocycloalkenyl; or, Ring A is selected from C 5-8 Cycloalkenyl or 5-10 membered heterocycloalkenyl; or, Ring A is selected from C 5-6 Cycloalkenyl or 5-9 membered heterocycloalkenyl;

[0256] L is selected from a linking group;

[0257] R 1 and n are as defined in this application.

[0258] In some embodiments of the present application, the compound of formula I"-1, part, stereoisomer thereof, derivative (specifically such as Protac molecule) or pharmaceutically acceptable salt thereof is selected from the compound of formula I", stereoisomer thereof or pharmaceutically acceptable salt thereof.

[0259] In some embodiments, Ring A is selected from C 5-8 Cycloalkenyl (or C 5-7 cycloalkenyl), 5-9 membered heterocycloalkenyl, phenyl, pyrrolyl, pyrazolyl, furyl, or oxazolyl.

[0260] In some embodiments, Ring A is selected from C 5-6 cycloalkenyl, 5-9 membered heterocycloalkenyl, phenyl, pyrrolyl, pyrazolyl, furyl, or oxazolyl.

[0261] In some embodiments, Ring A is selected from C5 cycloalkenyl, C6 cycloalkenyl, 5-membered, 6-membered, 7-membered, 8-membered, or 9-membered heterocycloalkenyl, phenyl, pyrrolyl, pyrazolyl, furanyl, or oxazolyl.

[0262] In some embodiments, Ring A is selected from cyclopentenyl, bicyclohexenyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydroazepine 1-Hydroxy, ...

[0263] In some embodiments, Ring A is selected from C 5-8 In some embodiments, ring A is selected from C 5-7 In some embodiments, ring A is selected from C 5-6 In some embodiments, ring A is selected from a 5- to 8-membered heterocycloalkenyl group. In some embodiments, ring A is selected from a 6- to 8-membered heterocycloalkenyl group. In some embodiments, ring A is selected from a 5-membered heterocycloalkenyl group. In some embodiments, ring A is selected from a 6-membered heterocycloalkenyl group. In some embodiments, ring A is selected from a 7-membered heterocycloalkenyl group. In some embodiments, ring A is selected from an 8-membered heterocycloalkenyl group. In some embodiments, ring A is selected from a 9-membered heterocycloalkenyl group.

[0264] In some embodiments, ring A is selected from cyclopentenyl, bicyclohexenyl, dihydropyrrolyl, tetrahydropyridinyl, dihydrooxazinyl, tetrahydroazepine azaspirocyclooctenyl or azaspirocyclononenyl.

[0265] In some embodiments, wherein ring A is selected from cyclopentenyl or bicyclohexenyl. In some embodiments, wherein ring A is selected from dihydropyrrolyl, dihydrooxazinyl, tetrahydropyridinyl, tetrahydroazepine azaspirocyclooctenyl or azaspirocyclononenyl.

[0266] In some embodiments, Ring A is selected from phenyl, pyrrolyl, pyrazolyl, furanyl, or oxazolyl.

[0267] In other embodiments, Ring A is selected from C 5-7 cycloalkenyl, 5-8 membered heterocycloalkenyl, phenyl or pyrrolyl.

[0268] In other embodiments, Ring A is selected from C 5-6 cycloalkenyl, 5-8 membered heterocycloalkenyl, phenyl or pyrrolyl.

[0269] In other embodiments, Ring A is selected from C5 cycloalkenyl, 5-membered, 6-membered, 7-membered, or 8-membered heterocycloalkenyl, phenyl, or pyrrolyl.

[0270] In other embodiments, Ring A is selected from cyclopentenyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydroazepine yl, azaspirocyclooctene, phenyl or pyrrolyl.

[0271] In other embodiments, Ring A is selected from C 5-6 cycloalkenyl or 5-8 membered heterocycloalkenyl.

[0272] In other embodiments, Ring A is selected from cyclopentenyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydroazepine Base or azaspirocyclooctene.

[0273] In other embodiments, wherein ring A is selected from cyclopentenyl. In some embodiments, wherein ring A is selected from dihydropyrrolyl, tetrahydropyridinyl, tetrahydroazepine Base or azaspirocyclooctene.

[0274] In other embodiments, Ring A is selected from phenyl or pyrrolyl.

[0275] In some embodiments, the moiety Selected from

[0276] In some embodiments, the moiety Selected from In some embodiments, the moiety Selected from

[0277] In other embodiments, the moiety Selected from

[0278] In some embodiments, the moiety Selected from In some embodiments, the moiety Selected from

[0279] In some embodiments, the moiety Selected from In some embodiments, the moiety Selected from In some embodiments, the moiety Selected from In other embodiments, the moiety Selected from

[0280] In some embodiments, the moiety Selected from In some embodiments, the moiety Selected from In some embodiments, the moiety Selected from In some embodiments, the moiety Selected from In some embodiments, the moiety Selected from

[0281] In other embodiments, the moiety Selected from

[0282] In some embodiments, L is selected from -Cy 1 -LNK-Cy 2 -LNK-, -Cy 1 -LNK-Cy 2 -or-Cy 1 -Cy 2 -LNK-; in some embodiments, L is selected from -Cy 1 -LNK-Cy 2 -; In some embodiments, wherein Cy 1 、LNK、Cy 2 、-Cy 1 -LNK-, -LNK-Cy 2 -、-Cy 1 -Cy 2 -or-Cy 1 -LNK-Cy 2 - as described herein; further, in some embodiments, part Selected from Or, part Selected from

[0283]

[0284]

[0285] Furthermore, in some other embodiments, part Selected from or part Selected from

[0286] In some embodiments, the PTM is as described herein.

[0287] In some embodiments, the PTM is selected from wherein R, T or ring E is as described in the present application.

[0288] In some embodiments, the PTM is selected from wherein R or T is as described in this application.

[0289] In another aspect, the present application relates to a compound, a moiety, an isomer thereof (such as a stereoisomer), a derivative thereof (specifically a Protac molecule) or a pharmaceutically acceptable salt thereof represented by the following formula III:

[0290]

[0291] wherein ring A is selected from C 5-10 Cycloalkenyl or 5-10 membered heterocycloalkenyl,

[0292] Ring B is selected from a benzene ring group;

[0293] Ring C is selected from isoxazolyl or furyl;

[0294] n is defined as described in this application;

[0295] Each R 1 independently selected from halogen, -OH, -NH2, -CN, =O, C 1-4 Alkoxy, -CHO, C 3-6 Cycloalkyl, 3-10 membered heterocycloalkyl or C 1-4 Alkyl, the C 3-6 Cycloalkyl, 3-10 membered heterocycloalkyl or C 1-4 The alkyl group is optionally substituted with halogen, -OH, -NH2 or C 1-4 Alkyl-OH substitution.

[0296] In some embodiments, the compound represented by Formula III is not selected from the following compounds:

[0297] In some embodiments, the heterocycloalkenyl group contains at least one nitrogen atom.

[0298] In some embodiments, the ring A is selected from C 5-8 Cycloalkenyl or 5-10 membered heterocycloalkenyl;

[0299] Alternatively, Ring A is selected from C 5-7 Cycloalkenyl or 5-10 membered heterocycloalkenyl;

[0300] Alternatively, Ring A is selected from C 5-6 Cycloalkenyl or 5-10 membered heterocycloalkenyl; or, Ring A is selected from C 5-6 cycloalkenyl or 5-9 membered heterocycloalkenyl.

[0301] In some embodiments, the moiety Selected from

[0302] In some embodiments, the moiety Selected from

[0303] In some embodiments, the moiety Selected from In some embodiments, the structural part Selected from In some embodiments, the structural part Selected from

[0304] In some embodiments, the moiety Selected from

[0305] In some embodiments, the moiety Selected from In some embodiments, the moiety Selected from In some embodiments, the moiety Selected from

[0306] In some embodiments, the moiety Selected from

[0307] In another aspect, the present application relates to a compound, a moiety, an isomer thereof (such as a stereoisomer), a derivative thereof (specifically a Protac molecule) or a pharmaceutically acceptable salt thereof represented by the following formula III-1:

[0308]

[0309] Among them, R 3 Selected from oxo, hydroxy, -(CH2) m -CHO, hydroxy C 1-5 Alkylene, 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 in this application.

[0310] In another aspect, the present application relates to a compound, moiety, isomer (such as stereoisomer), derivative (specifically Protac molecule) or pharmaceutically acceptable salt thereof represented by the following formula I"'-1a or I"'-2a:

[0311]

[0312] in,

[0313] Ring A is selected from C 5-10 Cycloalkenyl or 5-10 membered heterocycloalkenyl; or, Ring A is selected from C 5-8 Cycloalkenyl or 5-10 membered heterocycloalkenyl; or, Ring A is selected from C 5-7 Cycloalkenyl or 5-10 membered heterocycloalkenyl; or, Ring A is selected from C 5-6 Cycloalkenyl or 5-10 membered heterocycloalkenyl;

[0314] n is defined as described in this application;

[0315] Each R 1 independently selected from halogen, -OH, -NH2, -CN, =O, C 1-4 Alkoxy, -CHO, C 3-6 Cycloalkyl, 3-10 heterocycloalkyl or C 1-4 Alkyl, the C 3-6 Cycloalkyl, 3-10 heterocycloalkyl or C 1-4 The alkyl group is optionally substituted with halogen, -OH, -NH2 or C 1-4 Alkyl-OH substituted; or, each R 1 independently selected from halogen, -OH, -NH2, -CN, =O, C 1-4 Alkoxy, -CHO, C 3-6 Cycloalkyl or C 1-4 Alkyl, the C 3-6 Cycloalkyl or C 1-4 The alkyl group is optionally substituted with halogen, -OH, -NH2 or C 1-4 Alkyl-OH substitution;

[0316] X 2 is selected from CH or N.

[0317] In some embodiments, each R 1 independently selected from halogen, -OH, -NH2, -CN, =O, C 1-3 Alkoxy, -CHO, C 3-4 Cycloalkyl or C 1-3 Alkyl, the C 3-4 Cycloalkyl or C 1-3 The alkyl group is optionally substituted with halogen, -OH, -NH2 or C 1-3 Alkyl-OH substitution.

[0318] In some embodiments, each R 1 Independently selected from halogen, -OH, -NH2, -CN, =O, methoxy, -CHO, cyclobutane or methyl, said cyclobutane or methyl being optionally substituted with halogen, -OH, -NH2 or CH2OH.

[0319] In some embodiments, each R 1 Independently selected from F, -OH, -NH2, -CH2OH, =O, -CHO, -CH2NH2 or

[0320] In some embodiments, each R 1 are independently selected from halogen, -OH, -NH2, -CN, =O, methoxy, -CHO or C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with halogen, -OH or -NH2.

[0321] In some embodiments, each R 1 independently selected from halogen, -OH, -NH2, -CN, =O, methoxy, -CHO or methyl, said methyl being optionally substituted with -OH or -NH2.

[0322] In some embodiments, each R 1 Independently selected from F, -OH, -NH2, -CH2OH, =O, -CHO or -CH2NH2.

[0323] In some embodiments, the portion Selected from Preferably, the portion is selected from

[0324] In another aspect, the present application relates to a compound, moiety, isomer (such as stereoisomer), derivative (specifically Protac molecule) or pharmaceutically acceptable salt thereof represented by the following formula I"'-1 or I"'-2:

[0325]

[0326] in,

[0327] Ring A is selected from C 5-10 Cycloalkenyl or 5-10 membered heterocycloalkenyl; or, Ring A is selected from C 5-8 Cycloalkenyl or 5-10 membered heterocycloalkenyl; or, Ring A is selected from C 5-7 Cycloalkenyl or 5-10 membered heterocycloalkenyl; or, Ring A is selected from C 5-6 Cycloalkenyl or 5-10 membered heterocycloalkenyl; R 1 and n are as defined in this application.

[0328] In some embodiments, Ring A is selected from C 5-6 In some embodiments, ring A is selected from C5 cycloalkenyl, C6 cycloalkenyl, 5-membered, 6-membered, 7-membered, 8-membered, or 9-membered heterocycloalkenyl.

[0329] In some embodiments, Ring A is selected from cyclopentenyl, bicyclohexenyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydroazepine 1-Hydroxy-1,1-dihydro ...

[0330] In some embodiments, wherein ring A is selected from cyclopentenyl or bicyclohexenyl. In some embodiments, wherein ring A is selected from dihydropyrrolyl, tetrahydropyridinyl, tetrahydroazepine 1-Hydroxy-1,1-dihydro ...

[0331] In some embodiments, wherein Ring A is selected from In some embodiments, wherein Ring A is selected from

[0332] In other embodiments, Ring A is selected from C 5-8 In some other embodiments, ring A is selected from C 5-6 In some embodiments, ring A is selected from C5 cycloalkenyl, 5-membered, 6-membered, 7-membered, or 8-membered heterocycloalkenyl.

[0333] In other embodiments, Ring A is selected from cyclopentenyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydroazepine Base or azaspirocyclooctene.

[0334] In other embodiments, Ring A is selected from cyclopentenyl. In some embodiments, Ring A is selected from dihydropyrrolyl, tetrahydropyridinyl, tetrahydroazepine Base or azaspirocyclooctene.

[0335] In other embodiments, Ring A is selected from

[0336] The present application relates to the following compounds, moieties, stereoisomers thereof, derivatives thereof (particularly such as Protac molecules) or pharmaceutically acceptable salts thereof:

[0337]

[0338] In another aspect, the present application relates to a compound, moiety, stereoisomer, derivative thereof (specifically, Protac molecule), or pharmaceutically acceptable salt thereof represented by the following formula I"'-1c or I"'-2d:

[0339]

[0340] in,

[0341] Ring A, n and R 1 is as defined in this application;

[0342] X 2 selected from CH or N;

[0343] L 1 Selected from C 0-3 alkylene;

[0344] Cy 3 Selected from C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl;

[0345] R 2 Selected from -CHO, OH, SH, NH2, COOH, or C substituted by one or more SH, OH or NH2 1-6 alkyl;

[0346] p is selected from 0, 1, 2 or 3.

[0347] In some embodiments, the ring A is selected from C 5-9 cycloalkenyl, 5-9 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl.

[0348] In some embodiments, the ring A is selected from C 5-7 cycloalkenyl, 5-9 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl.

[0349] In some embodiments, the ring A is selected from C 5-6 cycloalkenyl, 5-9 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl.

[0350] In some embodiments, the ring A is selected from 5-6 membered heterocycloalkenyl, phenyl, or 5 membered heteroaryl.

[0351] In some embodiments, the ring A is selected from dihydropyrrolyl, tetrahydropyridinyl, dihydrooxazinyl, phenyl, pyrrolyl, pyrazolyl, or furanyl.

[0352] In some embodiments, the portion Selected from

[0353] In some embodiments, L 1 is selected from a bond or -CH2-.

[0354] In some embodiments, Cy 3 Selected from C 3-6 Cycloalkyl or 4-6 membered heterocycloalkyl.

[0355] In some embodiments, Cy 3 Selected from C 4-6 cycloalkyl, 4-membered heterocycloalkyl or 6-membered heterocycloalkyl.

[0356] In some embodiments, Cy 3 is selected from cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl or piperidinyl.

[0357] In some embodiments, R 2 Selected from -CHO, OH or C substituted by one or more OH or NH2 1-3 alkyl.

[0358] In some embodiments, R 2 is selected from -CHO, OH or methyl substituted by one or more OH.

[0359] In some embodiments, R 2 Selected from -CHO, OH or -CH2OH.

[0360] In some embodiments, X 2 Selected from CH.

[0361] In some embodiments, p is selected from 0, 1 or 2.

[0362] 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.

[0363] In some embodiments, the moiety Selected from

[0364] The present application relates to the following compounds, moieties, stereoisomers thereof, derivatives thereof (particularly such as Protac molecules) or pharmaceutically acceptable salts thereof,

[0365]

[0366] The present application relates to the following compounds, moieties, stereoisomers thereof, derivatives thereof (particularly such as Protac molecules) or pharmaceutically acceptable salts thereof,

[0367] On the other hand, the present application relates to the use of the compound (e.g., Formula III, III-1, I"'-1a, I"'-2a, I"'-1, I"'-2, I"'-1c, I"'-2d or a specific compound), a portion, an isomer thereof (such as a stereoisomer), or a derivative thereof in a Protac molecule. On the other hand, the present application relates to the use of the compound (e.g., Formula III, III-1, I"'-1a, I"'-2a, I"'-1, I"'-2, I"'-1c, I"'-2d or a specific compound), a portion, an isomer thereof (such as a stereoisomer), or a derivative thereof for constituting a portion of a Protac molecule. On the other hand, the present application relates to the compound (e.g., Formula III, III-1, I"'-1a, I"'-2a, I"'-1, I"'-2, I"'-1c, I"'-2d or a specific compound), a portion, an isomer thereof (such as a stereoisomer), or a derivative thereof in the form of a Protac molecule. On the other hand, the present application relates to the use of the compound (e.g., Formula III, III-1, I"'-1a, I"'-2a, I"'-1, I"'-2, I"'-1c, I"'-2d or a specific compound), a portion, an isomer thereof (such as a stereoisomer), or a derivative thereof for degrading proteins, for example, the compound (e.g., Formula III, III-1, I"'-1a, I"'-2a, I"'-1, I"'-2, I"'-1c, I"'-2d or a specific compound), a portion, an isomer thereof (such as a stereoisomer), or a derivative thereof in the form of a Protac molecule to degrade the protein. On the other hand, the present application relates to the use of the compound (e.g., Formula III, III-1, I"'-1a, I"'-2a, I"'-1, I"'-2, I"'-1c, I"'-2d or a specific compound), a portion, an isomer thereof (such as a stereoisomer), or a derivative thereof in the form of a Protac molecule for degrading proteins. The present application relates to the use of the compound (e.g., Formula III, III-1, I"'-1a, I"'-2a, I"'-1, I"'-2, I"'-1c, I"'-2d or a specific compound), a portion, an isomer thereof (such as a stereoisomer), or a derivative thereof (e.g., as a preparation intermediate) in the preparation of a Protac molecule. The present application relates to the use of the compound (e.g., Formula III, III-1, I"'-1a, I"'-2a, I"'-1, I"'-2, I"'-1c, I"'-2d or a specific compound), a portion thereof, an isomer thereof (such as a stereoisomer), or a derivative thereof (e.g., as a preparation intermediate) in the preparation of a protein degrader. Optionally, the Protac molecule may not include a Protac molecule related to AR.

[0368] For example, in some embodiments, the present application relates to the use of the following compounds, their portions, their stereoisomers, or their pharmaceutically acceptable salts in the preparation of Protac molecules:

[0369]

[0370] in,

[0371] Ring A is selected from C 5-10 Cycloalkenyl or 5-10 membered heterocycloalkenyl; or, Ring A is selected from C 5-8 Cycloalkenyl or 5-10 membered heterocycloalkenyl; or, Ring A is selected from C 5-7 Cycloalkenyl or 5-10 membered heterocycloalkenyl; or, Ring A is selected from C 5-6 Cycloalkenyl or 5-10 membered heterocycloalkenyl, preferably, ring A is selected from cyclopentenyl, dihydropyrrolyl, tetrahydropyridinyl or tetrahydroazepine base;

[0372] n is selected from 0, 1, 2 or 3, preferably, n is selected from 0, 1 or 2;

[0373] Each R 1 independently selected from halogen, -OH, -NH2, -CN, =O, C 1-4 Alkoxy, -CHO, C 3-6 Cycloalkyl or C 1-4 Alkyl, the C 3-6 Cycloalkyl or C 1-4 The alkyl group is optionally substituted with halogen, -OH, -NH2 or C 1-4 Alkyl-OH substituted; preferably, each R 1 independently selected from fluorine, chlorine or bromine;

[0374] X 2 Selected from CH or N, preferably, X 2 for CH;

[0375] The compound may be part of Preferably, the portion is selected from

[0376] In some embodiments, the present application relates to a method for preparing a Protac molecule, comprising:

[0377] The Protac molecule is prepared by reacting the following compound, a moiety thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0378]

[0379] in,

[0380] Ring A is selected from C5-10 Cycloalkenyl or 5-10 membered heterocycloalkenyl; or, Ring A is selected from C 5-8 Cycloalkenyl or 5-10 membered heterocycloalkenyl; or, Ring A is selected from C 5-7 Cycloalkenyl or 5-10 membered heterocycloalkenyl; or, Ring A is selected from C 5-6 Cycloalkenyl or 5-10 membered heterocycloalkenyl, preferably, ring A is selected from cyclopentenyl, dihydropyrrolyl, tetrahydropyridinyl or tetrahydroazepine base;

[0381] n is selected from 0, 1, 2 or 3, preferably, n is selected from 0, 1 or 2;

[0382] Each R 1 independently selected from halogen, -OH, -NH2, -CN, =O, C 1-4 Alkoxy, -CHO, C 3-6 Cycloalkyl or C 1-4 Alkyl, the C 3-6 membered cycloalkyl or C 1-4 The alkyl group is optionally substituted with halogen, -OH, -NH2 or C 1-4 Alkyl-OH substituted; preferably, each R 1 independently selected from fluorine, chlorine or bromine;

[0383] X 2 Selected from CH or N, preferably, X 2 for CH;

[0384] The compound may be part of Preferably, the portion is selected from

[0385] The present application relates to the use of the compound (e.g., Formula III, III-1, I"'-1a, I"'-2a, I"'-1, I"'-2, I"'-1c, I"'-2d or a specific compound), a portion, an isomer thereof (such as a stereoisomer), or a derivative thereof for degrading BTK protein, for example, the compound, a portion, an isomer thereof (such as a stereoisomer), or a derivative thereof for degrading the BTK protein in the form of a Protac molecule. On the other hand, the present application relates to the use of the compound (e.g., Formula III, III-1, I"'-1a, I"'-2a, I"'-1, I"'-2, I"'-1c, I"'-2d or a specific compound), a portion, an isomer thereof (such as a stereoisomer), or a derivative thereof for degrading BTK protein in the form of a Protac molecule.

[0386] In some embodiments, the Protac molecule or protein degrader is selected from BTK protein degraders / molecules.

[0387] On the other hand, the present application relates to a pharmaceutical composition, which contains the above-mentioned compound, part, stereoisomer, derivative or pharmaceutically acceptable salt thereof, and the pharmaceutical composition of the present application also includes a pharmaceutically acceptable excipient.

[0388] On the other hand, the present application relates to the use of the above-mentioned compounds, parts, stereoisomers, derivatives or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of drugs for preventing or treating diseases treated by degrading target proteins bound to targeting ligands.

[0389] On the other hand, the present application relates to the use of the above-mentioned compounds, parts, stereoisomers, derivatives or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of drugs for preventing or treating diseases that are treated by binding to cerebellar proteins in vivo.

[0390] On the other hand, the present application relates to the use of the above-mentioned compound, part, stereoisomer, derivative or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof in the preparation of a drug for preventing or treating BTK-related diseases.

[0391] The present application relates to a method for treating or preventing a disease in a mammal by degrading a target protein bound to a targeting ligand, comprising administering a therapeutically effective amount of the above-mentioned compound of the present application, its stereoisomers, its derivatives or pharmaceutically acceptable salts, or pharmaceutical compositions thereof to a mammal, preferably a human, in need of such treatment.

[0392] The present application relates to a method for treating or preventing a disease that is treated by binding to a cerebellar protein in vivo, comprising administering a therapeutically effective amount of the above-mentioned compound of the present application, its stereoisomers, its derivatives or pharmaceutically acceptable salts, or pharmaceutical compositions thereof to a mammal, preferably a human, in need of such treatment.

[0393] On the other hand, the present application relates to a method for treating BTK-related diseases in mammals, comprising administering a therapeutically effective amount of the above-mentioned compound of the present application, its stereoisomers, its derivatives or pharmaceutically acceptable salts, or pharmaceutical compositions thereof to a mammal, preferably a human, in need of such treatment.

[0394] On the other hand, the present application relates to the above-mentioned compound, part, stereoisomer, derivative or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof for preventing or treating a disease treated by degrading a target protein bound to a targeting ligand.

[0395] In another aspect, the present application relates to the above-mentioned compound, moiety, stereoisomer, derivative or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof for preventing or treating a disease that is treated by binding to a cerebellar protein in vivo.

[0396] On the other hand, the present application relates to the above-mentioned compound, portion, stereoisomer, derivative or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof for preventing or treating BTK-related diseases.

[0397] On the other hand, the present application relates to the use of the above-mentioned compounds, parts, stereoisomers, derivatives or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in preventing or treating diseases that are treated by degrading target proteins bound to targeting ligands.

[0398] In another aspect, the present application relates to the use of the above-mentioned compounds, moieties, stereoisomers, derivatives thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in preventing or treating diseases that are treated by binding to cerebellar proteins in vivo.

[0399] In another aspect, the present application relates to the use of the above-mentioned compounds, moieties, stereoisomers, derivatives thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for preventing or treating BTK-related diseases. In some embodiments, the BTK-related diseases are selected from conditions treated by degrading proteins that bind to BTK target protein ligands; in some embodiments, the BTK-related diseases are selected from conditions treated by binding to cerebellum proteins in vivo; and in some embodiments, the diseases or conditions are selected from autoimmune diseases, inflammatory diseases, or cancer.

[0400] In some embodiments, the above-mentioned conditions treated by binding to cerebellum protein in vivo and / or the conditions treated by binding to cerebellum protein in vivo are selected from BTK-related diseases; in some embodiments, the above-mentioned BTK-related diseases are selected from autoimmune diseases, inflammatory diseases or cancer.

[0401] In some embodiments, the "one or more" is selected from one, two, three, four, five, or six. In some embodiments, the "one or more" is selected from one, two, or three. In some embodiments, the "one or more" is selected from one, or two.

[0402] In some embodiments, the present application encompasses the above-defined variables and embodiments thereof, and any combination thereof.

[0403] Technical Effects

[0404] The compounds of the present application have a degradation effect on OCI-LY10 cell BTK; they can inhibit cells (OCI-LY10 cells, TMD8-BTK C481S cells or OCI-LY10-BTK C481S Compared with EGFR and TEC kinase, targeting BTK and / or BTKC481S The kinase is selective; it is metabolically stable in vitro and has good pharmacokinetic properties in vivo; it has an inhibitory effect on TMD-8 transplanted tumors in mice in vivo; it has CRBN protein binding activity and can exhibit the desired IKZF1, IKZF3, and GSPT1 protein degradation activity.

[0405] The compounds provided in this application can be combined with CRL4 CRBN The compounds described herein can bind to the cereblon receptor of an E3 ubiquitin ligase, thereby creating new binding sites for protein neosubstrates that are mediators of human disease, thereby leading to degradation of the neosubstrate protein. The neomorphic surface created by these compounds can directly interact with the target protein or target protein complex, thereby directly or indirectly reducing protein levels. In various embodiments, the compounds described herein can result in a reduction in the levels of the neosubstrate target protein by direct ubiquitination of the target protein; or ubiquitination of a neosubstrate target protein cofactor or target protein complex or other protein responsible for controlling target protein homeostasis. These compounds can result in degradation of the neosubstrate target protein that is directly bound to ligand-bound brain; degradation of the neosubstrate that is a cofactor bound to ligand-bound brain; degradation of the complex cofactor and target protein interface bound to ligand-bound brain; degradation of the neosubstrate target protein complex bound to ligand-bound CRBN; or reduction of target protein levels by degradation of proteins that are not in the complex or cofactors of the neosubstrate protein.

[0406] definition

[0407] Unless otherwise indicated, the following terms used in this application have the following meanings. A particular term should not be construed as undefined or unclear unless specifically defined, but rather should be understood according to its ordinary meaning in the art. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0408] The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is an oxo (i.e., =O), it means that two hydrogen atoms are replaced. Oxo does not occur on aromatic groups.

[0409] The term "optionally" or "optionally" means that the event or circumstance described subsequently may or may not occur, and the description includes both the occurrence of the event or circumstance and the non-occurrence of the event or circumstance. A group "optionally substituted" means that the group is substituted or unsubstituted. For example, an ethyl group is "optionally" substituted with a halogen, meaning that the ethyl group may be unsubstituted (CH2CH3), monosubstituted (such as CH2CH2F), polysubstituted (such as CHFCH2F, CH2CHF2, etc.), or fully substituted (CF2CF3). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that would be sterically impossible and / or incomposable to synthesize will be introduced.

[0410] In this article, C m-n The moiety has an integer number of carbon atoms in a given range (mn). For example, "C 1-6 ” means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

[0411] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. For example, if a group contains two R's, each R has an independent option.

[0412] When a bond cross-links two atoms in a ring (including a monocyclic, fused, or spirocyclic ring), the bond can be bonded to any atom in the ring (including a monocyclic, fused, or spirocyclic ring). Indicates that the bonds on both sides can be connected to any two different atoms on ring A, ring B or ring C; for example Indicates that the bonds on both sides can be connected to any two different atoms on ring A, the middle benzene ring or ring C; further, for example It means that the bonds on both sides can be connected to any two different atoms in the four rings in the system.

[0413] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0414] The term "hydroxy" refers to an -OH group.

[0415] The term "amino" refers to a -NH2 group.

[0416] The term "alkyl" refers to a group of the formula C n H 2n+1 The alkyl group may be straight chain or branched. For example, the term "C 1-6The term "alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl portion (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio has the same definition as above.

[0417] The term "alkylene" is an alkyl group that has lost one hydrogen.

[0418] The term "heteroalkylene" refers to an alkylene group in which one or more carbon atoms are replaced by heteroatoms and contains at least one carbon atom. Specific heteroatoms can be 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 Heteroalkylene means that the heteroalkylene contains 1 to 12 C atoms and one or more heteroatoms (e.g., 1-6, 1-3, 1, 2, or 3 heteroatoms). 1-6 Heteroalkylene means that the heteroalkylene contains 1 to 6 C atoms and one or more heteroatoms.

[0419] The term "alkoxy" refers to an -O-alkyl group.

[0420] The term "alkenyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond. Non-limiting examples of alkenyl include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.

[0421] The term "cycloalkenyl" refers to a non-aromatic carbocyclic ring that is not fully saturated and can exist as a monocycle, a bridged ring (e.g., a bicyclic ring) or a spirocycle. Unless otherwise indicated, the carbocyclic ring is typically a 4 to 12-membered ring, a 4 to 10-membered ring, or a 4 to 8-membered ring. Non-limiting examples of cycloalkenyl include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, etc.

[0422] Non-limiting examples of "benzocycloalkenyl" include benzo 4- to 12-membered cycloalkenyl, benzo 4- to 10-membered cycloalkenyl, or benzo 4- to 8-membered (eg, 4-, 5-, 6-, 7-, or 8-membered) cycloalkenyl.

[0423] The term "cycloalkyl" refers to a fully saturated carbocyclic ring that can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 3- to 10-membered ring (e.g., a 5- to 8-membered ring). Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, etc.

[0424] The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 3 to 12-membered ring, a 3 to 10-membered ring, a 3 to 8-membered ring, a 3 to 7-membered ring, a 3 to 6-membered ring or a 3 to 5-membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and / or nitrogen. Examples of 3-membered heterocycloalkyl groups include, but are not limited to, oxirane, thioethane, and aziridine groups; non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, and thietanyl groups; examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, and tetrahydropyrazolyl groups; examples of 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, and 1,4-dithianyl groups; examples of 7-membered heterocycloalkyl groups include, but are not limited to, azepanyl, oxetanyl, and thiepanyl groups. Preferably, the heterocycloalkyl group is a monocyclic group having 5 or 6 ring atoms.

[0425] The term "heterocycloalkenyl" includes cycloalkenyl groups in which one or more carbon atoms are replaced by heteroatoms, for example, cycloalkenyl groups in which up to three carbon atoms, in one embodiment up to two carbon atoms, in another embodiment one carbon atom are independently replaced by O, S(O), NH or N, provided that at least one cycloalkenyl carbon-carbon double bond is retained. Cyclic groups that may exist as monocyclic, bridged or spirocyclic rings may be 3 to 12 membered rings (e.g., 5 to 8 membered rings). Examples of heterocycloalkenyl groups include, but are not limited to, dihydropyrrolyl, tetrahydropyridyl, tetrahydroazapyridine, pyrrol ... Base or azaspirocyclooctene.

[0426] Non-limiting examples of "benzoheterocycloalkenyl" include benzo 4 to 12-membered heterocycloalkenyl (e.g., 5-membered, 6-membered, 10-membered, or 11-membered), benzo 5 to 11-membered heterocycloalkenyl, or benzo 5 to 8-membered (e.g., 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered) heterocycloalkenyl. Specific examples include

[0427] Unless otherwise indicated, the carbocyclic ring is typically a 4- to 8-membered ring. Non-limiting examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, and the like.

[0428] The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, S, with the remaining ring atoms being C, and having at least one aromatic ring. Preferred heteroaryl groups have single 4 to 8-membered rings, especially 5 to 8-membered rings, or multiple fused rings containing 6 to 14, especially 6 to 10, ring atoms. Non-limiting examples of heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, etc.

[0429] In this application, wavy lines are used represents one of the absolute configurations of a stereocenter (e.g. one, specific express ) or one of the relative configurations (e.g. express When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, they are intended to include both E and Z geometric isomers. Likewise, all tautomeric forms are encompassed within the scope of this application.

[0430] The groups or structural parts in this application such as LNK, Cy 1 、Cy 2 、-Cy 1 -LNK-Cy 2 -、-Cy 1 -LNK- or -LNK-Cy 2 - and its specific options, optionally can be read in order from left to right, correspondingly connected to the group or part of the left side group and the right side group in the general formula, for example, when Cy 1 Selected from Reading from left to right, Cy 1 The left side corresponds to the left side of the general formula Connection, right to right section Connect, forming part Optionally, the groups or structural parts in this application such as LNK, Cy 1 、Cy 2 、-Cy 1 -LNK-Cy 2 -、-Cy 1 -LNK- or -LNK-Cy 2 - and its specific options can be read from right to left, and are respectively connected to the group or part of the left group and the right group in the general formula. For example, when Cy 1 Selected from According to the reading order from right to left, Cy 1 The right side corresponds to the left side of the general formula Connect the left side with the corresponding right side of the general formula The connected part is Other groups are the same as described above.

[0431] The term "Protac (proteolysis targeting chimera) molecule" refers to a class of bifunctional compounds that can simultaneously bind to target proteins and E3 ubiquitin ligases. Such compounds can induce the target protein to be recognized by the cell's proteasome, causing protein degradation, and can effectively reduce the content of the target protein in the cell.

[0432] The term "derivative" refers to a new compound or a group of new compounds produced by replacing or replacing one or more hydrogen atoms in the basic structure of a parent compound with other groups or structural moieties. Derivatives in this application refer to derivative compounds that retain the parent structure. For example, a parent compound is derived into a Protac molecule, specifically a PTM-linker-ULM molecule, where PTM is the protein target portion that binds to the target protein or peptide; linker is the connecting group; and ULM refers to the portion that binds to the ubiquitin ligase.

[0433] The term "protein-targeted drug or derivative thereof" or PTM is used to describe a small molecule that binds to a target protein or other protein or polypeptide of interest and positions the protein or polypeptide in proximity to a ubiquitin ligase so that degradation of the protein or polypeptide by the ubiquitin ligase can occur. Non-limiting examples of small molecule target protein binding moieties include drugs or derivatives targeting AR, ER, kinases, phosphatases, MDM2, human BET bromodomain proteins, Hsp90, HDAC, human lysine methyltransferases, RAF receptors, FKBP, angiogenic factors, receptors or proteins associated with immunosuppression, aryl hydrocarbon receptors, thyroid hormone receptors, HIV protease, HIV integrase, HCV protease, HBV protease, or acyl protein thioesterase 1 and / or 2, and many others; or drugs or derivatives targeting ALK, BET, CDK, PARP, EGFR, γ-secretase, CBFβ-SMMHC, WEE1, MEK, B CR-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, as well as many others; or, including drugs targeting 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 or their derivatives, as well as many others.

[0434] The term "PTM group" is a drug or a derivative thereof that binds to a target protein. The targets of the PTM group are numerous and are selected from proteins expressed in cells so that at least a portion of the sequence is found in the cell, and the protein can bind to the PTM group. The term "protein" includes oligopeptides and polypeptide sequences of sufficient length that can bind to the PTM group according to the present application. Any protein in a eukaryotic system or microbial system (including viruses, bacteria or fungi) as described elsewhere herein is a target for ubiquitination mediated by the compounds according to the present application. The target protein is preferably a eukaryotic protein.

[0435] "Targeting protein" is used below to describe a protein or polypeptide that is bound to the compound according to the present application and is degraded by a ubiquitin ligase. Such small molecule target protein binding moieties also include pharmaceutically acceptable salts, enantiomers, solvates and polymorphs of these compositions and other small molecules that can target the protein of interest. These binding moieties are connected to the group via a linker group L. connect.

[0436] Unless otherwise specified, It is used to indicate that the hydrogen atom at any position of the group in [] can be replaced by a group connected by “—”.

[0437] The term "treatment" means administering the compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0438] (i) inhibiting a disease or disease state, i.e., arresting its development;

[0439] (ii) ameliorating the disease or condition, i.e., causing regression of the disease or condition.

[0440] The term "prevention" means administering a compound or formulation described herein to prevent a disease or one or more symptoms associated with the disease, including preventing the occurrence of a disease or disease state in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.

[0441] The term "therapeutically effective amount" means an amount of a compound of the present invention that (i) treats or prevents a specific disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The amount of a compound of the present invention that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and this disclosure.

[0442] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0443] As the pharmaceutically acceptable salt, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids and the like can be mentioned.

[0444] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or their salts and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.

[0445] The term "pharmaceutically acceptable excipient" refers to an excipient that is non-irritating to organisms and does not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0446] The word "comprise" or "comprises" and its English variations such as comprises or comprising should be understood as having an open and non-exclusive meaning, ie, "including but not limited to".

[0447] The compounds and intermediates of the present application can also exist in different tautomeric forms, and all such forms are included in the scope of the present application. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also referred to as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. The specific example of a proton tautomer is the imidazole moiety, in which a proton can migrate between two ring nitrogens. Valence tautomers include interconversions by reorganization of some bonding electrons.

[0448] In this document, unless the context clearly indicates otherwise, singular terms include plural referents and vice versa. Similarly, the word "or" is intended to include "and" unless the context clearly indicates otherwise.

[0449] Unless otherwise indicated, herein, the parameter values ​​representing the amount of ingredients or physicochemical properties or reaction conditions, etc. should be understood as being modified by the term "about" in all cases. When the term "about" is used to describe the present application, the term "about" indicates that there is an error value, for example, it indicates a change within the range of ±5%, such as ±1% or ±0.1% of a particular value.

[0450] The present application also includes isotopically labeled compounds of the present application that are identical to those described herein, but in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P.32 P. 35 S. 18 F. 123 I. 125 I and 36 Cl et al.

[0451] Certain isotope-labeled compounds of the present application (e.g. 3 H and 14 C-labeled) can be used in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emitting isotopes such as 15 O. 13 N. 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present application can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0452] In addition, the use of heavier isotopes such as deuterium (i.e. 2 H)) substitution may offer certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and may therefore be preferred in certain circumstances, wherein deuterium substitution may be partial or complete, partial deuterium substitution meaning that at least one hydrogen is replaced by at least one deuterium.

[0453] The compounds of the present invention may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers include, for example, enantiomers and diastereomers. The compounds of the present invention containing asymmetric carbon atoms can be isolated in optically pure forms or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0454] The pharmaceutical compositions of the present application can be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, and can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.

[0455] Typical routes of administration of the compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0456] The pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.

[0457] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, and the like for oral administration to a patient.

[0458] Solid oral compositions can be prepared by conventional mixing, filling, or tableting methods. For example, they can be prepared by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then granulating the mixture to obtain a tablet or dragee core. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents.

[0459] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

[0460] In all methods of administration described herein, the compounds of formula I are administered at a dosage of 0.01 to 200 mg / kg body weight per day, in single or divided doses.

[0461] The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent replacement methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.

[0462] The chemical reactions described in the specific embodiments of the present application are carried out in a suitable solvent that is compatible with the chemical transformations described herein and the reagents and materials required. To obtain the compounds described herein, it may sometimes be necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.

[0463] An important consideration in synthetic route planning in this field is the selection of appropriate protecting groups for reactive functional groups (such as amino groups in this application). For example, reference can be made to Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc.

[0464] In some embodiments, the compound of formula I of the present application can be prepared by a person skilled in the art of organic synthesis through the following route:

[0465]

[0466] where X 1 Selected from halogen.

[0467] The compound of general formula (I-1) is subjected to coupling reaction to obtain the compound of general formula (I-2), the compound of general formula (I-2) is subjected to hydrolysis reaction to obtain the compound of general formula (I-3), and then the protecting group is removed to obtain the compound of general formula (I-4).

[0468] The compound of general formula (I-5) is represented by Cy substituted with hydroxyl group. 2 The coupling reaction yields a compound of formula (I-6), which undergoes addition reaction with acrylamide and amine transesterification reaction to yield a compound of formula (I-7). The compound of formula (I-7) undergoes oxidation reaction to yield a compound of formula (I-8). The compound of formula (I-4) and the compound of formula (I-8) undergo reductive amination reaction to yield a compound of formula I.

[0469] The compound of general formula (I-5) is represented by Cy substituted with hydroxymethyl 2 The coupling reaction yields a compound of formula (I-9), which undergoes addition reaction with acrylamide and amine transesterification to yield a compound of formula (I-10). The compound of formula (I-10) undergoes oxidation reaction to yield a compound of formula (I-11). The compound of formula (I-4) and the compound of formula (I-11) undergo reductive amination reaction to yield a compound of formula I.

[0470] This application uses the following abbreviations:

[0471] Boc represents tert-butyloxycarbonyl; Et represents ethyl; EA represents ethyl acetate; DMSO represents dimethyl sulfoxide; DMF represents N,N-dimethylformamide; BINAP represents 1,1'-binaphthyl-2,2'-bis(diphenylphosphine); DCM represents dichloromethane; Pd2(dba)3 represents tris(dibenzylideneacetone)dipalladium; THF represents tetrahydrofuran; MeOH represents methanol; PE represents petroleum ether; IBX represents 2-iodoacylbenzoic acid; DIPEA represents N,N'-diisopropylethylamine; DIBAL-H represents diisopropylamine Isobutylaluminum hydride; NIS represents N-iodosuccinimide; NBS represents N-bromosuccinimide; Tf represents -OSO2CF3; H2O2 represents hydrogen peroxide; Pd(OAc)2 represents acetic acid; DMA represents N,N-dimethylacetamide; TBSCl represents tert-butyldimethylchlorosilane; TFA represents trifluoroacetic acid; PdCl2(dppf) represents [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride; Ruphos represents 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl.

[0472] For the purposes of description and disclosure, all patents, patent applications, and other identified publications are expressly incorporated herein by reference. These publications are provided solely because their disclosure predates the filing date of the present application. All statements regarding the dates of these documents or the representations of their contents are based on information available to the applicant and do not constitute any admission as to the correctness of the dates of these documents or the contents of these documents. Furthermore, any citation of these publications herein does not constitute an admission that such publications constitute part of the common general knowledge in the art in any country.

[0473] For the sake of clarity, the present application is further illustrated with examples, but the examples do not limit the scope of the present application. All reagents used in the present application are commercially available and can be used without further purification. DETAILED DESCRIPTION

[0474] Example 1 Synthesis of Compound 1

[0475]

[0476]

[0477] Step 1: Preparation of intermediate 1b

[0478] To a reaction flask, intermediate 1a (25 g), triethylamine (25.3 g, 34.8 mL), and dichloromethane (250 mL) were added sequentially. 1-chloro-2-isocyanate (15.81 g) was slowly added dropwise over 20 minutes. The mixture was allowed to react at room temperature for 4 hours. 500 mL of water was added to the reaction system, 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 separated by silica gel column chromatography (eluent: EA) to obtain the target intermediate 1b (40.8 g).

[0479] 1 H NMR(500MHz,DMSO-d6)δ6.11(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).

[0480] Step 2: Preparation of intermediate 1c

[0481] Sodium hydride (10.31 g) was slowly added to a solution of intermediate 1b (40 g) in tetrahydrofuran (300 mL) at 0°C. The mixture was allowed to react overnight at room temperature. After completion of the reaction, 75 mL of water was added to the reaction solution to quench the reaction. After vigorous stirring for 10 minutes, 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 extracted with 300 mL of acetonitrile and 300 mL of petroleum ether, and the layers were separated. The acetonitrile phase was rotary evaporated to yield intermediate 1c (32.2 g).

[0482] Step 3: Preparation of intermediate 1d

[0483] At 0°C, sodium hydride (5.71 g) was slowly added to a solution of intermediate 1c (20 g) in tetrahydrofuran (200 mL). Stir for 5 minutes, then remove the ice bath. Stir at room temperature for 1 hour, then return to an ice bath. Iodomethane (15.21 g, 6.70 mL) was slowly added dropwise to the reaction system. The reaction mixture was allowed to react overnight at room temperature. Upon completion of the reaction, 75 mL of water was added to quench the reaction mixture. After vigorous stirring for 10 minutes, 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 extracted with 300 mL of acetonitrile and 300 mL of petroleum ether, and the layers were separated. The acetonitrile phase was rotary evaporated to yield intermediate 1d (22.5 g).

[0484] Step 4: Preparation of intermediate 1e

[0485] To a single-necked flask, intermediate 1d (20 g) and 4M dioxane hydrochloride solution (25.7 g, 176 mL, 705 mmol) were added sequentially and reacted at room temperature. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain intermediate 1e (15.5 g).

[0486] Step 5: Preparation of Intermediate 1f

[0487] 3,5-Dichloropyrazine-2-carbonitrile (11.82 g) was added to a mixture of intermediate 1e (15 g) and N,N-diisopropylethylamine (35.1 g, 47.5 mL) in DMF (300 mL) at 0°C. After 15 minutes, the ice bath was removed and the mixture was stirred at room temperature overnight. Ethyl acetate (300 mL) and water (300 mL) were added to the reaction mixture. The organic phase was separated and 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 evaporated under reduced pressure, and the crude product was separated by silica gel column chromatography (eluent: dichloromethane / methanol = 100:1, volume ratio) to obtain the target intermediate 1f (14.5 g).

[0488] MS (ESI, [M+H] + )m / z:321.2.

[0489] 1 H NMR(500MHz,DMSO-d6)δ7.94(s,1H),3.30(dtd,J=14.7,7.5,6.8,4.9Hz,2H),3.25–3.2 2(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).

[0490] Step 6: Preparation of Intermediate 1g

[0491] To a single-necked flask, 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 acetate (0.781 g), and 1,4-dioxane (200 mL) were added sequentially. Under nitrogen protection, the mixture was heated to 100°C for reaction. After the reaction was completed, the reaction solution was cooled to room temperature and filtered. The filter cake was rinsed with 150 mL of dichloromethane. The solvent was evaporated from the filtrate under reduced pressure, and the crude product was separated by silica gel column chromatography (eluent: dichloromethane / methanol = 100:1, volume ratio) to obtain the target intermediate 1g (14.2 g).

[0492] MS (ESI, [M+H] + )m / z:561.5

[0493] 1 H NMR(500MHz,DMSO-d6)δ8.97(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=11.6,3.0 Hz,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).

[0494] Step 7: Preparation of Intermediate 1h

[0495] To a single-necked flask, add intermediate 1g (8g), DMSO (25mL), and cesium carbonate (4.08g) in sequence. Add hydrogen peroxide (21.32g, 19.21mL) under ice. Stir for 5 minutes, remove the ice bath, and allow the mixture to react at room temperature. Upon completion, quench the reaction by adding 300mL of saturated sodium sulfite solution to the residue. Detection with starch potassium iodide reagent should not cause color change. Extraction should then be performed with 300mL of ethyl acetate. Extraction should be repeated three times with 100mL of ethyl acetate. The combined organic phases should be dried over anhydrous sodium sulfate and filtered. The solvent should be evaporated under reduced pressure, and the crude product should be separated by silica gel column chromatography (eluent: dichloromethane / methanol = 100:1, volume ratio) to yield the target intermediate 1h (7.22g).

[0496] MS (ESI, [M+H] + )m / z:579.51.

[0497] 1H NMR (500MHz, DMSO-d6) δ11.19(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,1 H),7.15(d,J=8.6Hz,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,1H),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).

[0498] Step 8: Preparation of intermediate 1i

[0499] To a single-necked flask, intermediate 1h (3 g), dichloromethane (30 mL), and trifluoroacetic acid (17.06 g, 11.53 mL) were added sequentially and reacted at room temperature. Upon completion of the reaction, the solvent was evaporated under reduced pressure to obtain the trifluoroacetate salt. The crude product was dissolved in 50 mL of dichloromethane, and saturated aqueous sodium bicarbonate was slowly added to adjust the system to a weak alkaline state. The phases were then separated. The organic phase was evaporated under reduced pressure to remove the solvent, yielding intermediate 1i (2.4 g).

[0500] MS (ESI, [M+H] + )m / z:479.44

[0501] 1H NMR(500MHz,DMSO-d6)δ11.25(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,3 H),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).

[0502] Step 9: Preparation of intermediate 1k

[0503] At 0°C, a solution of intermediate 1j (30 g) in toluene (100 mL) was slowly added dropwise to a solution of sodium hydroxide (27.9 g) in toluene (50 mL). After completion of the addition, the mixture was stirred at 0°C for 15 minutes. Dimethyl carbonate (126 g) was added dropwise to the reaction solution. After completion of the addition, the mixture was stirred at 0°C for 15 minutes. The mixture was then heated to 100°C and reacted for 2 hours. The reaction solution was washed once with water (500 mL). The organic layer was discarded, and the aqueous layer was adjusted to pH 2-3 with dilute hydrochloric acid (3 mol / L) at low temperature. A large amount of solid precipitated. Filter and dry with suction to obtain 30.63 g of intermediate 1k.

[0504] MS (ESI, [MH] - )m / z:239.0

[0505] 1 H NMR (500MHz, DMSO-d6) δ12.74 (s, 1H), 7.77–7.65 (m, 2H), 7.54 (dd, J = 8.4, 1.9Hz, 1H), 5.63 (s, 1H).

[0506] Step 10: Preparation of Intermediate 11

[0507] To a reaction flask, intermediate 1k (29.5 g), hydroxylamine hydrochloride (15.85 g), sodium ethoxide (15.52 g), and ethanol (150 ml) were added sequentially. Under N2 protection, the mixture was heated to 85°C for 2 hours. The reaction solution was evaporated to dryness, and the residue was added with 500 mL of saturated sodium carbonate solution and extracted with DCM (300 mL x 2). The organic layer was discarded, and the aqueous layer was adjusted to pH <3 with dilute hydrochloric acid (3 mol / L). A large amount of solid precipitated, which was filtered and the resulting filter cake was washed with water and dried under atmospheric pressure to yield 26.53 g of intermediate 1l.

[0508] MS (ESI, [MH] - )m / z:254.0.

[0509] 1 H NMR (500MHz, DMSO-d6) δ12.95(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).

[0510] Step 11: Preparation of intermediate 1m

[0511] To a reaction flask, intermediate 1l (26.5 g) and ethanol (530 ml) were added sequentially, followed by the slow dropwise addition of concentrated sulfuric acid (49.9 g, 27.1 ml, 508 mmol). The mixture was heated to 85°C for 4 hours. The reaction solution was evaporated to dryness, and the residue was added to ice water. NaOH solution was added dropwise at low temperature to adjust the pH to ≈ 9. The product was then extracted twice with 300 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness to obtain 24.87 g of intermediate 1m.

[0512] MS (ESI, [MH] - )m / z:282.0

[0513] 1 H NMR(500MHz,DMSO-d6)δ8.13(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).

[0514] Step 12: Preparation of Intermediate 1n

[0515] To a reaction flask, intermediate 1m (2 g) and (S)-pyrrolidine-3-methanol (2.087 g) were added sequentially, followed by Pd(dba) (1.260 g) and potassium phosphate (5.84 g). Finally, toluene (60 mL) was added. Under nitrogen, the mixture was heated at 80°C for 4 hours. The reaction solution was washed twice with 100 mL of water. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to afford intermediate 1n (0.35 g).

[0516] MS (ESI, [M+H] + )m / z:305.20.

[0517] Step 13: Preparation of Intermediate 1o

[0518] To the reaction flask, the intermediate 1n (360 mg) and THF (30 mL) were first added, and 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 with stirring. After the reaction was complete, 100 mL of saturated ammonium chloride solution was added to the reaction solution at low temperature, and the mixture was extracted twice with EA (50 mL). The organic layer was dried over anhydrous sodium sulfate, and the filtered filtrate was evaporated to dryness and purified by silica gel column chromatography (eluent: DCM:MeOH = 95:5, volume ratio) to obtain 245 mg of intermediate 1o.

[0519] MS (ESI, [M+H] + )m / z:330.1

[0520] Step 14: Preparation of intermediate 1p

[0521] To a reaction flask, intermediate 1o (330 mg) and DCM (30 mL) were added sequentially, followed by Dess-Martin reagent (1.224 g) 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 and extracted with aqueous NaHCO3 (30 mL). The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was evaporated to dryness to obtain 290 mg of intermediate 1p, which was directly used in the next reaction.

[0522] Step 15: Preparation of Compound 1

[0523] To the 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 sequence. After stirring at room temperature for 20 min, sodium cyanoborohydride (59.1 mg) was added and continued to stir at room temperature. After the reaction was completed, 20 mL of saturated NaHCO3 solution was added to the reaction solution, and the solution was extracted twice with 20 mL of DCM-MeOH (10:1). The extracts were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness and filtered through C 18 The mixture was purified by reverse phase column (10 nM ammonium acetate aqueous solution-acetonitrile = 50%:50%, volume ratio) to obtain 55 mg of compound 1.

[0524] Q-TOF(ESI,[M+H] + )m / z:790.4146

[0525] 1 H NMR (500MHz, DMSO-d6) δ11.18(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).

[0526] Example 2 Synthesis of Compound 2

[0527]

[0528] Step 1: Preparation of intermediate 2b

[0529] To the reaction flask, intermediate 14d (2 g) and (S)-pyrrolidine-3-methanol (1.424 g) were added in sequence, followed by Pd2(dba)3 (1.289 g), potassium phosphate (5.98 g), and finally toluene (50 mL). The reaction was carried out at 80°C under N2 protection. 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 the filtrate was evaporated to dryness and purified on a silica gel column (PE-EA = 95:5, volume ratio, 1500 mL). The product was further purified by C 18 The intermediate 2b was purified by reverse phase column (10 nM aqueous ammonium acetate solution-acetonitrile = 50%:50%, volume ratio) to give 480 mg.

[0530] MS (ESI, [M+H] + )m / z:305.1.

[0531] 1 H NMR(500MHz,DMSO-d6)δ7.17(t,J=7.8Hz,1H),6.96(dd,J=7.9,0.8Hz,1H),6.58(d d,J=7.8,0.9Hz,1H),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).

[0532] Step 2: Preparation of intermediate 2c

[0533] To the reaction flask, intermediate 2b (450 mg) and THF (40 mL) were first added, and 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 with stirring. After the reaction was complete, 100 mL of saturated ammonium chloride solution was added to the reaction solution at low temperature, and the mixture was extracted twice with EA (50 mL). The organic layer was dried over anhydrous sodium sulfate, and the filtrate was evaporated to dryness and purified on a silica gel column (DCM:MeOH=95:5, volume ratio) to obtain 450 mg of intermediate 2c.

[0534] MS (ESI, [M+H] + )m / z:330.1.

[0535] Step 3: Preparation of intermediate 2d

[0536] To the reaction flask, intermediate 2c (440 mg) and DCM (30 mL) were added in sequence, followed by Dess-Martin reagent (1.7 g) with stirring. The mixture was reacted at room temperature under N2 protection. After the reaction was complete, Na2S2O3 aqueous solution (30 mL) was added to quench the reaction at low temperature. The organic layer was extracted and washed with NaHCO3 aqueous solution (30 mL), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate, which was evaporated to dryness to obtain 342 mg of intermediate 2d, which was directly used in the next reaction.

[0537] Step 4: Preparation of compound 2

[0538] To the 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 sequence. After stirring at room temperature for 20 min, sodium cyanoborohydride (197 mg) was added and continued to stir at room temperature. After the reaction was completed, 20 mL of saturated NaHCO3 solution was added to the reaction solution, and the solution was extracted twice with 20 mL of DCM-MeOH (10:1). The extracts were combined, dried over anhydrous sodium sulfate, and the filtrate was evaporated to dryness by suction. 18 Reverse phase column (10 nM ammonium acetate aqueous solution-acetonitrile = 50%:50%, volume ratio) to obtain 60 mg of compound 2.

[0539] Q-TOF(ESI,[M+H] + )m / z:790.4157.

[0540] 1H NMR (500MHz, DMSO-d6) δ11.17(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),6.97(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).

[0541] 13 C NMR (126MHz, DMSO) δ173.58,171.99,169.70,160.77,157.13,154.01,153.3 0,150.98,140.44,137.77,134.30,127.46,125.70,122.03,120.33,118.64, 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.

[0542] Example 3 Synthesis of Compound 3

[0543]

[0544] Step 1: Preparation of intermediate 3b

[0545] In a single-necked flask, intermediate 3a (20 g) was dissolved in dichloromethane (200 mL). Triethylamine (15.89 g, 21.89 mL) was added at 0°C, followed by the slow dropwise addition of acetyl chloride (12.33 g). The mixture was allowed to react at room temperature for 1 h. After the reaction, 300 mL of dichloromethane was added to dilute the mixture, and the pH was adjusted to a weakly acidic state by adding 3M aqueous hydrochloric acid. The organic phase was separated by extraction and collected. The pH of the organic phase was then adjusted to a weakly alkaline state by using saturated aqueous sodium bicarbonate. The organic phase was separated by extraction and collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to yield intermediate 3b (28.5 g).

[0546] 1 H NMR (500MHz, DMSO-d6) δ7.60(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).

[0547] Step 2: Preparation of intermediate 3c

[0548] To a single-necked flask, intermediate 3b (8.61 g) and aluminum chloride (8.92 g) were added sequentially, and the mixture was heated to 170°C for 2 h. The reaction mixture was cooled to room temperature, 50 mL of dichloromethane was added, and approximately 500 mL of 3M hydrochloric acid was slowly added. The liquid was separated, and the organic phase was collected. The aqueous phase was extracted twice with 250 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain intermediate 3c (11.8 g).

[0549] MS (ESI, [MH] + )m / z:231.0

[0550] 1 H NMR (500MHz, DMSO-d6) δ11.64(s,1H),7.79(d,J=9.3Hz,1H),7.33(d,J=5.8Hz,1H),2.62(s,3H).

[0551] Step 3: Preparation of intermediate 3d

[0552] To a single-necked flask, intermediate 3c (10 g), diethyl carbonate (25.3 g), and toluene (100 mL) were added sequentially. The reaction mixture was cooled to 0°C and sodium hydride (8.58 g) was added portionwise. The mixture was heated to 90°C and then to 120°C for 5 h. After the reaction was complete, the reaction mixture was cooled to room temperature and slowly poured into 1 L of stirred ice water. The mixture was extracted with 500 mL of ethyl acetate and the organic phase was discarded. The aqueous phase was adjusted to pH 3 with 3N hydrochloric acid and extracted three times with 300 mL of ethyl acetate. The organic phases were combined. The mixture was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain intermediate 3d (9.8 g).

[0553] MS (ESI, [MH] + )m / z:256.95.

[0554] 1 H NMR (500MHz, DMSO-d6) δ12.86(s,1H),7.88(d,J=5.6Hz,1H),7.67(d,J=8.5Hz,1H),5.65(s,1H).

[0555] Step 4: Preparation of intermediate 3e

[0556] To a single-necked flask, intermediate 3d (9 g), hydroxylamine hydrochloride (7.95 g), sodium ethoxide (2.224 g), and ethanol (50 mL) were added sequentially. The mixture was heated to 85°C and allowed to react overnight. The reaction solution was cooled to room temperature, and 3N hydrochloric acid was added to adjust the pH to 5. The solvent was evaporated under reduced pressure, and 100 L of water was added. The mixture was cooled and the pH was adjusted to 3 with 3N hydrochloric acid. The mixture was stirred for 30 minutes and filtered. The filter cake was collected and dried to obtain intermediate 3e (8.1 g).

[0557] MS (ESI, [M+H] + )m / z:273.86.

[0558] 1 H NMR (500MHz, DMSO-d6) δ12.97(s,1H),8.30(d,J=5.3Hz,1H),7.93(d,J=7.9Hz,1H),4.12(s,2H).

[0559] Step 5: Preparation of intermediate 3f

[0560] To a single-necked flask, intermediate 3e (6 g), ethanol (40 mL), and sulfuric acid (9.27 g, 5.04 mL) were added sequentially, and the mixture was heated to 90°C for 2 h. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. 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. The organic phase was separated, and the aqueous phase was extracted twice with 100 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to provide intermediate 3f (5.4 g).

[0561] MS (ESI, [M+H] + )m / z:302.21.

[0562] 1 H NMR (500MHz, DMSO-d6) δ8.32(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).

[0563] Step 6: Preparation of Intermediate 3g

[0564] To a single-necked flask, intermediate 3f (4 g), (S)-pyrrolidine-3-methanol (2.68 g), palladium acetate (0.595 g), potassium phosphate (8.43 g), and 1,4-dioxane (20 mL) were added sequentially. Under nitrogen, the mixture was heated to 100°C overnight. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1:1, volume ratio) to obtain the target intermediate 3g (0.5 g).

[0565] MS (ESI, [M+H] + )m / z:323.11.

[0566] 1H NMR(500MHz,DMSO-d6)δ7.45(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),3.49–3.3 8(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).

[0567] Step 7: Preparation of Intermediate 3h

[0568] To a three-necked flask, intermediate 3g (500 mg), acrylamide (98 mg), and anhydrous tetrahydrofuran (5 mL) were added sequentially. Potassium tert-butoxide (233 mg) was slowly added at -15°C, and the mixture was allowed to react for 2 h at -15°C. Saturated aqueous ammonium chloride was added dropwise to the reaction solution 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 organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain intermediate 3h (120 mg).

[0569] MS (ESI, [MH] + )m / z:345.9.

[0570] 1 H NMR (500MHz, DMSO-d6) δ11.03(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(dd d,J=17.8,12.3,5.7Hz,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).

[0571] Step 8: Preparation of intermediate 3i

[0572] To a single-necked flask, intermediate 3h (80 mg), acetonitrile (5 mL), and IBX (129 mg) were added sequentially, and the mixture was heated to 85°C for 1 h. The reaction solution was cooled to room temperature, filtered, and the filtrate was collected. The resulting solution (containing intermediate 3i) was used directly in the next reaction.

[0573] Step 9: Preparation of compound 3

[0574] To a single-necked flask, intermediate 3i (the solution of intermediate 3i obtained in the previous step), intermediate 1i (60 mg), and methanol (1 mL) were added sequentially. One drop of acetic acid was added dropwise. After stirring at room temperature for 1 hour, sodium cyanoborohydride (23.63 mg) was added and the mixture was allowed to react at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and the product was purified by preparative liquid chromatography to obtain compound 3 (25 mg).

[0575] MS (ESI, [M+H] + )m / z:808.6.

[0576] 1 H NMR(500MHz,DMSO-d6)δ11.18(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,4 H),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).

[0577] 13C NMR(126MHz,DMSO-d6)δ173.59,172.00,169.71,161.59,160.79,156.67,154.02, 152.29,150.98,148.61,127.45,120.32,118.68,114.69,109.76,109.50,106.13 ,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.

[0578] Example 4 Synthesis of Compound 4

[0579]

[0580]

[0581] Step 1: Preparation of intermediate 4b

[0582] To a reaction flask, 4a (25 g), diethyl carbonate (68.7 g), and toluene (200 mL) were added sequentially. The reaction mixture was cooled to 0°C, and sodium hydride (23.25 g) was added portionwise. The mixture was heated to 120°C and allowed to react for 5 h. The reaction was terminated, the reaction mixture was cooled to room temperature, and the reaction mixture was slowly poured into 1.5 L of stirred ice water and extracted with 400 mL of ethyl acetate. The aqueous phase was adjusted to pH 3 with 3N hydrochloric acid and extracted three times with 400 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain 25 g of intermediate 4b.

[0583] MS (ESI, [MH] + )m / z:239.0

[0584] 1 H NMR (500MHz, DMSO-d6) δ12.78(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).

[0585] Step 2: Preparation of intermediate 4c

[0586] To a reaction flask were added 4b (13 g), hydroxylamine hydrochloride (7.50 g), sodium methoxide (5.83 g), and ethanol (100 mL) in sequence. Under N₂ protection, the reaction mixture was heated to 85°C for 15.5 h. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. 200 mL of water was added to the residue, followed by 3 M hydrochloric acid. The residue was filtered, and the filter cake was purified by silica gel column chromatography using a solvent (DCM:CH₃OH = 9:1, volume ratio) to afford 5.5 g of intermediate 4c.

[0587] MS (ESI, [MH] + )m / z:254.1.

[0588] 1 H NMR (500MHz, DMSO-d6) δ12.96(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).

[0589] Step 3: Preparation of intermediate 4d

[0590] To a reaction flask were added 4c (5.5 g), ethanol (50 mL), and concentrated sulfuric acid (12.64 g, 6.87 mL) in sequence. The mixture was heated to 90°C for 15 h. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. To the residue were added 250 mL of ethyl acetate and 250 mL of water. A saturated aqueous sodium bicarbonate solution was added to adjust the pH to 7. The organic phase was separated, and the aqueous phase was extracted twice with 280 mL of ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to yield 5.65 g of intermediate 4d.

[0591] MS (ESI, [M+H] + )m / z:282.0

[0592] 1 H NMR(500MHz,DMSO-d6)δ8.16(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).

[0593] Step 4: Preparation of intermediate 4e

[0594] To a reaction flask, (S)-pyrrolidine-3-methanol (3.52 g) and intermediate 4d (3.3 g) were added, followed by Pd(dba) (2.127 g) and potassium phosphate (9.86 g). Finally, toluene (100 mL) was added. Under N2 protection, the mixture was heated to 80°C for 3.5 h. The reaction solution was cooled to room temperature with stirring, filtered, and the filtrate was purified by silica gel column chromatography (PE:EA = 3:2, volume ratio) to obtain 0.8 g of intermediate 4e.

[0595] MS (ESI, [M+H] + )m / z:305.2.

[0596] 1 H NMR(500MHz,DMSO-d6)δ7.54(d,J=9.0Hz,1H),6.98(dd,J=9.0,2.4Hz,1H),6.7 0(d,J=2.3Hz,1H),4.72(t,J=5.2Hz,1H),4.14(q,J=7.1Hz,2H),3.51–3.37(m,2 H),3.31–3.21(m,2H),3.06(dd,J=9.3,6.2Hz,1H),2.48–2.40(m,1H),2.06(dt d,J=12.3,7.3,4.9Hz,1H),1.76(dq,J=12.3,7.5Hz,1H),1.20(t,J=7.1Hz,3H).

[0597] Step 5: Preparation of intermediate 4f

[0598] Intermediate 4e (800 mg) and THF (20 mL) were added to a reaction flask, followed by acrylamide (185 mg) and potassium tert-butoxide (292 mg) at 0°C. Under N2 protection, the mixture was reacted in an ice-water bath for 3 h. The reaction solution was added dropwise to an aqueous ammonium chloride solution for neutralization. 100 mL of ethyl acetate was added and the mixture was extracted. 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.

[0599] MS (ESI, [M+H] + )m / z:330.2.

[0600] 1H NMR (500MHz, DMSO-d6) δ11.10–10.97(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),3.05(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(d t,J=13.9,7.0Hz,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).

[0601] Step 6: Synthesis of compound 4

[0602] To a reaction flask, intermediate 4f (200 mg) and DCM (2 mL) were added, followed by Dess-Martin periodinane (515 mg) at 0°C and allowed to react at room temperature for 1 h. The reaction mixture was filtered, and the filtrate was partially evaporated under reduced pressure to remove the solvent. Methanol (5 mL), sodium cyanoborohydride (76 mg), and intermediate 1i (291 mg) were then added and allowed to react at room temperature for 2 h. The reaction mixture was purified by silica gel column chromatography (DCM:CH3OH = 10:1, v / v) and then by C18 reverse-phase column chromatography (H2O (1 vol% ammonium acetate):CH3CN = 40%:60%, v / v) to yield 0.44 g of compound 4.

[0603] MS (ESI, [M+H] + )m / z:790.46.

[0604] 1H NMR (500MHz, DMSO-d6) δ11.20(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=2.8Hz,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) ),2.80–2.74(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).

[0605] 13 C NMR(126MHz,DMSO-d6)δ173.67,172.08,169.70,160.78,156.52,156.26,154 .02,150.97,145.56,137.82,127.44,122.01,121.98,120.28,118.66,117.6 1,114.70,110.26,100.53,62.34,55.38,54.42,53.24,49.11,48.14,47.21,45.45,44.85,39.01,36.21,33.75,31.57,31.47,29.98,28.22,24.47,22.96.

[0606] Example 5 Synthesis of Compound 5

[0607]

[0608] Step 1: Preparation of intermediate 5b

[0609] To the reaction flask, 1-(2-bromo-6-hydroxyphenyl)ethane-1-one (9.5 g), diethyl carbonate (26.1 g) and toluene (200 mL) were added in sequence. The reaction solution was cooled to 0°C, and sodium hydroxide (8.83 g, 60%, 221 mmol) was added portionwise. The mixture was heated to 120°C and reacted overnight. The mixture was cooled to room temperature and the reaction solution was slowly poured into 1.5 L of stirred ice water and extracted with 400 mL of ethyl acetate. The aqueous phase was adjusted to pH 3 with 3N hydrochloric acid 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 evaporated under reduced pressure to obtain intermediate 5b (12.4 g).

[0610] MS (ESI, [MH] - )m / z:285.0.

[0611] 1 H NMR(500MHz,DMSO-d6)δ10.60(s,1H),7.19(t,J=8.2Hz,1H),7.09(dd,J=7.9,0.9Hz,1 H),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).

[0612] Step 2: Preparation of intermediate 5c

[0613] To a reaction flask, intermediate 5b (11.2 g), MeOH (200 mL), hydroxylamine hydrochloride (9.49 g), and sodium acetate (11.20 g) were added sequentially. The mixture was heated to 80°C for 3 h. The reaction solution was cooled to room temperature, and 3N hydrochloric acid was added to adjust the pH to 5. The solvent was evaporated under reduced pressure, and 1 L of water was added. The reaction flask was cooled in an ice-water bath while adjusting the pH to 3 with 3N hydrochloric acid. The mixture was stirred for 30 min and filtered. The filter cake was collected and dried to obtain intermediate 5c (8.0 g).

[0614] 1 H NMR (500MHz, DMSO-d6) δ12.99 (s, 1H), 7.81 (dd, J = 8.2, 0.8Hz, 1H), 7.66–7.55 (m, 2H), 4.15 (s, 2H).

[0615] Step 3: Preparation of intermediate 5d

[0616] To a reaction flask, intermediate 5c (8 g), ethanol (100 mL), and concentrated sulfuric acid (6.13 g, 3.33 mL) were added sequentially, and the mixture was heated to 90°C and allowed to react overnight. The reaction solution was cooled to room temperature, and the solvent was evaporated under reduced pressure. 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. 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).

[0617] 1 H NMR (500MHz, DMSO-d6) δ7.83(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).

[0618] Step 4: Preparation of intermediate 5e

[0619] To a reaction flask, intermediate 5d (500 mg), (S)-pyrrolidin-3-ylmethanol (267 mg), palladium chloride (39.5 mg), and potassium phosphate (747 mg) were added sequentially. 1,4-dioxane (30 mL) was added as the solvent. Under nitrogen, the mixture was heated to 100°C and reacted overnight. The above reaction procedure was repeated four times. After completion of the reaction, the mixture was cooled to room temperature, combined, filtered, concentrated, and purified by silica gel column chromatography to obtain intermediate 5e (240 mg).

[0620] MS (ESI, [M+H] + )m / z:305.0.

[0621] 1 H NMR (500MHz, DMSO-d6) δ7.44(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=7.1H z,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).

[0622] Step 5: Preparation of intermediate 5f

[0623] To a reaction flask, intermediate 5e (120 mg), acrylamide (32.2 mg), and THF (5 mL) were added sequentially. After the internal temperature dropped to -10°C, potassium tert-butoxide solution (88 mg, 0.784 mL, 0.784 mmol) was slowly added and allowed to react at -10°C. After completion, 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 afford intermediate 5f (46 mg).

[0624] MS (ESI, [M+H] + )m / z:330.0.

[0625] Step 6: Preparation of compound 5

[0626] To the reaction flask, intermediate 5f (57 mg), acetonitrile (5 mL), and IBX (145 mg) were added in sequence and reacted at 85 ° C for 1 hour. After the reaction was completed, it was cooled to room temperature, filtered, and the filtrate was used directly in the next reaction (the filtrate contained intermediate 5g). MeOH (5 mL) was added to the filtrate, followed by intermediate 1i (68.7 mg) and acetic acid (4.31 mg). After stirring at room temperature for 20 minutes, sodium cyanoborohydride (27.1 mg) was added and the reaction was continued at room temperature for 3 hours. After the reaction was completed, 5 mL of saturated sodium bicarbonate solution was added to the reaction solution, extracted with DCM, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by normal phase silica gel column chromatography and C18 reverse phase column chromatography to obtain compound 5 (28 mg).

[0627] MS (ESI, [M+H] + )m / z:790.6.

[0628] 1 H NMR(500MHz,DMSO-d6)δ11.19(s,1H),11.08(d,J=17.4Hz,1H),7.83–7.73(m,1H),7.66(s,1 H),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,1 H),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).

[0629] Example 6 Preparation of Compound 6

[0630]

[0631] Step 1: Preparation of intermediate 6b

[0632] To a reaction flask, intermediate 6a (3.0 g), DIPEA (5.73 g), and DCM (30 mL) were added. Trifluoromethanesulfonic anhydride (11.31 g) was slowly added under an ice bath, and the mixture was slowly warmed to room temperature for 2 h. 100 mL of water and 100 mL of DCM were added to the reaction solution. The organic phase was separated, washed with 100 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was separated and purified by silica gel column chromatography to yield the mixture intermediate 6b (5.2 g). 1 H NMR(500MHz,Chloroform-d)δ5.59(p,J=2.3Hz,1H),3.73(s,3H),3.29(ddt,J=10.1,8. 6,7.0Hz,1H),2.98(ddq,J=16.3,6.7,2.7Hz,1H),2.76–2.70(m,2H),2.37–2.26(m,1H).

[0633] Step 2: Preparation of intermediate 6c

[0634] To a reaction flask, intermediate 6b (2.6 g), pinacol diboron (2.89 g), potassium acetate (0.694 g), and 1,4-dioxane (30 mL) were added sequentially. [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.265 g) was added. The atmosphere was purged with nitrogen three times. The mixture was then heated to 85°C for 2 h, after which heating was stopped. 200 mL of water was added to the reaction solution, which was then extracted twice with 100 mL of EA. The combined organic layers were washed twice with 100 mL of saturated sodium chloride solution. After washing, the mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to afford intermediate 6c (2.1 g).

[0635] Step 3: Preparation of intermediate 6d

[0636] To a reaction flask, intermediate 6c (1.22 g), intermediate 1m (1.0 g), potassium carbonate (1.34 g), H₂O (3 mL), and 1,4-dioxane (15 mL) were added sequentially. [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.355 g) was added. The atmosphere was purged with nitrogen three times. The mixture was then heated to 70°C for 2 h, after which heating was stopped. 200 mL of water was added to the reaction solution, which was then extracted twice with 100 mL of DCM. The combined organic layers were washed twice with 100 mL of saturated sodium chloride solution. After washing, the mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to yield intermediate 6d (0.328 g).

[0637] MS (ESI, [MH] - )m / z:353.2.

[0638] Step 4: Preparation of intermediate 6e

[0639] To the reaction flask, intermediate 6d (0.32 g), palladium-carbon catalyst (0.032 g), and MeOH (10 mL) were added sequentially. Under H₂ protection, the mixture was reacted at room temperature for 16 h. Upon completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated to afford intermediate 6e (0.17 g).

[0640] MS (ESI, [MH] - )m / z:355.2.

[0641] Step 5: Preparation of intermediates 6f-1 and 6f-2

[0642] Intermediate 6e (0.9 g) was separated by SFC to obtain intermediate 6f-1 (0.17 g) with S configuration and intermediate 6f-2 (0.1 g) with R configuration.

[0643] MS (ESI, [MH] - )m / z:355.2.

[0644] Step 6: Preparation of Intermediate 6g

[0645] Intermediate 6f-1 (0.17 g) and THF (10 mL) were added to the reaction flask. Lithium aluminum tetrahydride (0.02 g) was slowly added under an ice bath, and the mixture was slowly warmed to room temperature for 1 h. After completion of the reaction, a small amount of ice water was added to the reaction solution under an ice bath to quench the reaction. 100 mL of DCM and 100 mL of water were then added, and the mixture was filtered. The organic phase of the filtrate was separated, washed with 100 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was separated and purified by silica gel column chromatography to obtain Intermediate 6g (0.093 g).

[0646] MS (ESI, [MH]- )m / z:327.1.

[0647] Step 7: Preparation of Intermediate 6h

[0648] To a reaction flask, add intermediate 6g (0.09g) and dichloromethane (5mL), add Dess-Martin periodinane (0.233g), and react at room temperature for 1 hour. After the reaction is complete, add dichloromethane (50)mL and water (50)mL to the system. The organic phase is separated, and the aqueous phase is extracted twice with 50mL of dichloromethane. The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate 6h (0.08g).

[0649] MS (ESI, [MH] - )m / z:325.1.

[0650] Step 8: Preparation of compound 6

[0651] To a reaction flask, intermediate 6h (0.09 g), intermediate 1i (0.12 g), and methanol (5 mL) were added, followed by 1 drop of acetic acid and sodium cyanoborohydride (0.032 g). The mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, 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 organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was separated and purified by silica gel column chromatography to obtain compound 6 (0.08 g).

[0652] MS (ESI, [M+H] + )m / z:789.5.

[0653] 1H NMR (500MHz, DMSO-d6) δ11.18(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,3H),2.12–2.01(m,3H),1.90(s,3H),1.84–1.74(m,8H),1.55(d,J=12.6Hz,2H).

[0654] Example 7 Preparation of Compound 7

[0655]

[0656] Step 1: Preparation of compound 7

[0657] Example 7 was synthesized by referring to the operating procedures of the first to eighth steps in Example 6, except that Intermediate 7a was used instead of Intermediate 6a as the starting material.

[0658] MS (ESI, [M+H] + )m / z:789.5.

[0659] 1H NMR (500MHz, DMSO-d6) δ11.20(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).

[0660] Example 8: Preparation of Compound 8

[0661]

[0662] Step 1: Preparation of intermediate 8c

[0663] To a single-necked flask, intermediate 8b (27 g), benzyl bromide (36.8 g), potassium carbonate (29.8 g), and 700 mL of acetonitrile were added sequentially. The mixture was heated to 80°C for 5 h. The solvent was evaporated under reduced pressure, and the crude product was separated by silica gel column chromatography (eluent EA) to obtain 2.06 g of the desired product, intermediate 8c.

[0664] MS (ESI, [M+H] + )m / z:331.03.

[0665] 1 H NMR (500MHz, DMSO-d6) δ7.76–7.70(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).

[0666] Step 2: Preparation of intermediate 8d

[0667] To a single-necked flask, intermediate 8c (4 g), 4-hydroxymethylpiperidine (2.77 g), cesium carbonate (7.82 g), palladium chloride (0.213 g), and 1,4-dioxane (150 mL) were added sequentially. Under nitrogen protection, the reaction was carried out at 80°C for 16 h. The reaction solution was cooled to room temperature, and the solvent was evaporated under reduced pressure. 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.

[0668] MS (ESI, [M+H] + )m / z:366.

[0669] 1 H NMR(500MHz,DMSO-d6)δ7.55(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,2 H),4.49(t,J=5.3Hz,1H),3.93(dt,J=13.3,3.5Hz,2H),3.27(t,J=5.8Hz,2H),2.8 4(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).

[0670] Step 3: Preparation of intermediate 8e

[0671] To a single-necked flask, intermediate 8d (4.00 g), palladium on carbon (2.0 g), and methanol (300 mL) were added sequentially. After multiple H2 substitutions, the reaction was allowed to proceed at room temperature for 16 h. The filtrate was filtered, and the solvent was evaporated under reduced pressure. The crude product was separated by silica gel column chromatography (PE:EA = 2:1, volume ratio) to obtain 1.70 g of intermediate 8e.

[0672] MS (ESI, [M+H] + )m / z:276.1

[0673] 1H NMR (500MHz, DMSO-d6) δ12.01(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).

[0674] Step 4: Preparation of intermediate 8f

[0675] To a single-necked flask, intermediate 8e (1.9 g), hydroxylamine hydrochloride (1.555 g), sodium ethoxide (1.523 g), and ethanol (150 mL) were added sequentially and reacted at 85°C for 22 h. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. Dichloromethane and saturated aqueous sodium carbonate were added to the crude product, and the layers were separated by extraction. The organic phase was discarded, and the aqueous phase was adjusted to pH 6 with 6M HCl. The mixture was extracted with dichloromethane several times. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated from the filtrate under reduced pressure to obtain 1.32 g of intermediate 8f.

[0676] MS (ESI, [M+H] - )m / z:289.1.

[0677] 1 H NMR (500MHz, DMSO-d6) δ12.74(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 ),3.94–3.87(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).

[0678] Step 5: Preparation of Intermediate 8g

[0679] To a single-necked flask, intermediate 8f (1.3 g), ethanol (100 mL), and sulfuric acid (1.471 g, 15.00 mmol) were added sequentially and reacted at 85°C for 5 h. The reaction solution was cooled to room temperature, and dichloromethane and saturated sodium bicarbonate aqueous solution were added 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, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated from the filtrate under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 1:4, volume ratio) to obtain 1.01 g of intermediate 8g.

[0680] MS (ESI, [M+H] + )m / z:319.16.

[0681] 1 H NMR(500MHz,DMSO-d6)δ7.53(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).

[0682] Step 6: Preparation of intermediate 8h

[0683] 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). The addition was complete after 1 minute. A 1M solution of potassium tert-butoxide in THF (0.935 ml) was then added dropwise over approximately 1 minute. The mixture was stirred at 0°C for 3 hours. The reaction solution was poured into an aqueous ammonium chloride solution and stirred vigorously for 1 minute. Extraction was then performed with EA, followed by washing with saturated brine and drying over anhydrous sodium sulfate. The solution was filtered, and the solvent was evaporated from the filtrate under reduced pressure. The crude product was separated by silica gel column chromatography (PE:EA = 1:4, volume ratio) to obtain 0.06 g of intermediate 8h.

[0684] MS (ESI, [M+H] + )m / z:344.20.

[0685] Step 7: Preparation of intermediate 8i

[0686] To a single-necked flask, intermediate 8h (45 mg), IBX oxidant (108 mg), and acetonitrile (10 mL) were added sequentially and reacted at 85°C for 0.5 h. The reaction solution was cooled to room temperature and filtered, and the filtrate (containing intermediate 8i) was used directly in the next reaction.

[0687] MS (ESI, [M+H] + )m / z:342.16.

[0688] Step 8: Preparation of Compound 8

[0689] The reaction solution of intermediate 8i (the solution of intermediate 8i obtained in the previous step) and MeOH (10.00 mL) were added to a single-necked flask. Under stirring at room temperature, intermediate 1i (68.7 mg) and acetic acid (3.85 mg) were added in sequence. 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 mixed solution 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 with dichloromethane several times. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to remove the solvent under reduced pressure. The crude product was dissolved with DMSO and C 18 The mixture was purified by reverse phase column and Biotage medium-low pressure chromatography (1 mM aqueous ammonium acetate solution: acetonitrile = 1:1, volume ratio) to give 27.6 mg of compound 8.

[0690] HR-MS (ESI, [M+H] + )m / z:804.43146.

[0691] 1H NMR (500MHz, DMSO-d6) δ11.21(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).

[0692] Example 9 Synthesis of Compound 9

[0693]

[0694] Step 1: Preparation of intermediate 9d

[0695] To a reaction flask, intermediate 10f (10 g), azetidine-3-ylmethanol (3.51 g), L-proline (1.547 g), cuprous iodide (1.280 g), DMF (100 mL), and sodium carbonate (8.55 g) were added sequentially. Under nitrogen protection, the mixture was heated to 100°C for 4 h. After the reaction was terminated, the reaction solution was cooled to room temperature and extracted three times with DCM (200 mL) and water (500 mL). The organic phase was separated, washed with 500 mL of water, then with 500 mL of water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography with EA as the eluent to obtain 2.16 g of intermediate 9d.

[0696] MS (ESI, [M+H] + )m / z:291.2.

[0697] 1H NMR (500MHz, DMSO-d6) δ7.45–7.38(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).

[0698] Step 2: Preparation of intermediate 9e

[0699] To a reaction flask, intermediate 9d (200 mg) and THF (10 mL) were added sequentially. The temperature was lowered to approximately 0°C, followed by the addition of acrylamide (53.9 mg) and potassium tert-butoxide (116 mg). Under N2 protection, the mixture was reacted at 0°C for 3.5 h. After the reaction ceased, the reaction solution was added dropwise to saturated aqueous ammonium chloride solution and extracted with 50 mL of ethyl acetate. The organic phase was separated, washed with 50 mL of saturated brine, 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.

[0700] MS (ESI, [M+H] + )m / z:316.1.

[0701] 1 H NMR (500MHz, DMSO-d6) δ11.03(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=17.0,11.5,5.3H z,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).

[0702] Step 3: Preparation of Example 9

[0703] To the reaction flask, intermediate 9e (200 mg), acetonitrile (10.00 mL), and IBX oxidant (533 mg) were added sequentially and reacted at 80°C for 1 h. The reaction solution was filtered and a small amount of solvent was evaporated to remove (containing intermediate 9f). MeOH (10 mL), intermediate 1i (304 mg), and glacial acetic acid (19.04 mg) were added. After stirring at room temperature for 30 min, sodium cyanoborohydride (80 mg) was added and reacted at room temperature for 3 h. Purification was performed by silica gel column chromatography (DCM:CH3OH = 10:1, volume ratio). The product was then passed through 120 g C 18 Purification by reverse phase column (10 mM aqueous ammonium acetate solution: CH 3 CN=40%:60%) afforded 0.09 g of compound 9.

[0704] MS (ESI, [M+H] + )m / z:776.5.

[0705] 1 H NMR (500MHz, DMSO-d6) δ11.20(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 ,1H),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).

[0706] 13C NMR(126MHz,DMSO-d6)δ173.60,172.48,172.09,169.70,165.08,160.79,156 .41,154.04,154.02,150.98,140.26,137.83,127.44,122.90,120.26,118.6 6,114.71,111.21,110.23,89.41,56.68,55.38,54.31,49.12,47.24,45.46,44.85,41.51,39.03,33.59,31.56,31.40,28.21,27.80,24.45,23.29,21.54.

[0707] Example 10 Synthesis of Compound 10

[0708]

[0709] Step 1: Preparation of intermediate 10b:

[0710] To a single-necked flask, intermediate 10a (100 g), triethylamine (92 g) and DCM (1 L) were added in sequence. Acetyl chloride (39.2 g) was added at 0°C and reacted at room temperature for 2.5 h. The system was concentrated to remove DCM. 300 ml*3 of petroleum ether was added to the system, followed by extraction with 1000 ml of saturated brine. The organic phase was separated and dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 123 g of intermediate 10b.

[0711] MS (ESI, [M+H] + )m / z:263.0.

[0712] Step 2: Preparation of intermediate 10c:

[0713] To a single-necked flask, intermediate 10b (123 g) and anhydrous aluminum chloride (94 g) were added sequentially, and the mixture was heated to 170°C for 3 h. The reaction mixture was cooled to room temperature, and the reaction was quenched by slowly adding approximately 500 mL of 6 M hydrochloric acid. The resulting solid was crushed, extracted with DCM, and filtered. The organic phase was separated, collected, and the aqueous phase was extracted twice with 250 mL of dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to yield 112 g of intermediate 10c.

[0714] MS (ESI, [M+H] + )m / z:263.1.

[0715] Step 3: Preparation of intermediate 10d:

[0716] To a three-necked flask, intermediate 10c (107 g), diethyl carbonate (174 g), and toluene (1000 ml) were added sequentially. After dissolution, the temperature was lowered to approximately 0°C. Sodium hydride (58.8 g) was added portionwise. The temperature was raised to 100°C. Once the system stabilized, the temperature was then raised to 120°C for approximately 1.5 hours. The reaction solution was cooled to room temperature and slowly poured into 2 L of stirred ice water. Extraction was performed with 500 mL of ethyl acetate, and the organic phase was discarded. The aqueous phase was adjusted to pH 1-2 with 3N hydrochloric acid and filtered to yield 90 g of intermediate 10d.

[0717] MS (ESI, [M+H] + )m / z:289.1.

[0718] Step 4: Preparation of intermediate 10e:

[0719] To a single-necked flask at 0°C, intermediate 10d (90 g), hydroxylamine hydrochloride (43.4 g), and anhydrous ethanol (1000 ml) were added sequentially. After dissolution, sodium ethoxide (42.5 g) was added portionwise. Under nitrogen, the mixture was heated to 90°C for 4.5 h. The reaction mixture was cooled to room temperature, and 3N hydrochloric acid was added to adjust the pH to 1-3. The solvent was evaporated under reduced pressure, and 500 mL of water was added to the residue. The mixture was stirred at room temperature for 30 min and filtered. The filter cake was washed with 200 mL of water and dried in a vacuum oven to obtain 91.6 g of intermediate 10e.

[0720] MS (ESI, [M+H] + )m / z:304.1.

[0721] 1 H NMR (500MHz, DMSO-d6) δ8.22(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).

[0722] Step 5: Preparation of intermediate 10f:

[0723] To a single-necked flask, intermediate 10e (91.6 g) and anhydrous ethanol (1000 ml) were added sequentially. Concentrated sulfuric acid (148 g, 1511 mmol) was added dropwise at 0°C for approximately 3 minutes (the system temperature was approximately 50°C). Under nitrogen, the mixture was heated to 85°C for 3.5 hours. The reaction solution was cooled to room temperature with stirring. The solvent was removed from the reaction solution, and the residue was added with 1500 mL of ice water and 1000 mL of ethyl acetate. 10% aqueous NaOH was added dropwise in an ice-water bath to adjust the pH to approximately 9 (internal temperature <5°C). The solution was extracted three times using a separatory funnel. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation to obtain 102.6 g of intermediate 10f.

[0724] MS (ESI, [M+H] + )m / z:332.0.

[0725] Step 6: Preparation of intermediate 10g:

[0726] To a single-necked flask, intermediate 10f (30 g), azetidin-3-ol (7.29 g), L-proline (5.22 g), cuprous iodide (4.31 g), anhydrous sodium carbonate (28.8 g), and DMF (300 ml) were added sequentially. Under nitrogen protection, the mixture was heated to 100°C for 2.5 h. The reaction solution was cooled to room temperature and extracted three times with ethyl acetate (200 mL*3) and water (1000 mL). The organic phases were separated and combined, washed with 500 mL of water each, then with 500 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to remove the solvent to obtain the crude product, which was purified by silica gel column chromatography to yield 12 g of intermediate 10g.

[0727] MS (ESI, [MH] - )m / z:275.1.

[0728] Step 7: Preparation of intermediate 10h:

[0729] To a three-necked flask, add intermediate 10g (10g) and anhydrous tetrahydrofuran (200ml) in sequence, add acrylamide (1.976g) after dissolution, and under N2 protection, reduce the temperature to about -15°C, add potassium tert-butoxide (3.894g) dropwise, keep the system at -15°C and react for about 1.5h, add the reaction solution dropwise to saturated ammonium chloride solution to quench, add 100mL*3 of ethyl acetate for extraction, separate the organic phase, wash with 100mL of saturated brine respectively, and dry over anhydrous sodium sulfate. Evaporate the solvent under reduced pressure and obtain 6.3g of intermediate 10h by silica gel column chromatography.

[0730] MS (ESI, [M+H] + )m / z:302.1.

[0731] Step 8: Preparation of intermediate 10i:

[0732] 2-Iodoacylbenzoic acid (IBX, 9.32 g) was added to a stirred solution of intermediate 10h in anhydrous acetonitrile (50 ml) at room temperature, and the mixture was reacted at 90°C for about 3.5 h. The mixture was filtered, and the filter cake was washed twice with acetonitrile. The filtrates were combined, the solvent was evaporated under reduced pressure, and the mixture was purified by silica gel column chromatography to give 4.6 g of intermediate 10i.

[0733] MS (ESI, [M+H] + )m / z:300.1.

[0734] Step 9: Preparation of compound 10

[0735] To a reaction flask, intermediate 1i (150 mg), intermediate 10i (133 mg), dichloromethane (10 mL), and glacial acetic acid (50.4 mg, 0.048 mL) were added, stirred at room temperature for 30 min, and then sodium cyanoborohydride (70.3 mg) was added and stirred at room temperature overnight. After the reaction, 20 mL of saturated aqueous NaHCO3 solution was added to the reaction solution, and the solution was extracted twice with 20 mL of DCM-MeOH (10:1). The extracts were combined, dried over anhydrous sodium sulfate, and filtered to obtain a filtrate that was evaporated to dryness. The mixture was then purified by C 18 Reverse phase column (10 nM ammonium acetate aqueous solution-acetonitrile = 50%:50%, volume ratio) to obtain 59 mg of compound 10.

[0736] Q-TOF(ESI,[M+H] + )m / z:762.3847.

[0737] 1 H NMR (500MHz, DMSO-d6) δ11.20(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=11.4,5.0H z,1H),4.34(d,J=12.6Hz,1H),4.28(d,J=13.2Hz,1H),4.04(t,J=7.3Hz,2 H),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).

[0738] 13C NMR (126MHz, DMSO-d6) δ173.61,172.09,169.70,165.06,160.78,156.44,154.04,153.82,150.97,140.19,137.84,127.43,122.97,120.26, 118.67,114.71,111.34,110.33,89.58,56.40,54.97,50.51,49.13,4 7.25,45.44,44.85,41.48,33.25,31.55,31.41,28.19,24.44,23.29.

[0739] Example 11 Synthesis of Compound 11

[0740]

[0741] Step 1: Preparation of intermediate 11b

[0742] Under N₂ protection at -78°C, lithium bis(trimethylsilylamide) (9.44 g) was slowly added dropwise to a stirred solution of intermediate 11a (9 g) in THF (150 mL). The addition was complete after 5 minutes, and the mixture was stirred at -78°C for 0.5 h. A solution of N-phenylbis(trifluoromethanesulfonyl)imide (17.47 g) in THF (150 mL) was slowly added to the reaction solution, maintaining the temperature below -60°C. After addition, the reaction was continued at -78°C for 3.5 h. Upon completion of the reaction, the reaction solution was poured into a saturated ammonium chloride solution on crushed ice and extracted twice with 200 mL of EA. The organic phases were combined, 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 yield 13 g of intermediate 11b.

[0743] 1 H NMR (500MHz, DMSO-d6) δ5.87–5.77(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).

[0744] Step 2: Preparation of intermediate 11c

[0745] To a single-necked flask, 4-nitrophenylboronic acid pinacol ester (10.06 g), intermediate 11b (10 g), potassium carbonate (11.16 g), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (4.40 g), 1,4-dioxane (300 mL), and water (50 mL) were added sequentially. After repeated nitrogen displacement, the mixture was heated to 90°C for 5 h. After the reaction, the reaction mixture was filtered, and the filter cake was washed several times with EA. 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.

[0746] MS (ESI, [M+H] + )m / z:345.05

[0747] 1 H NMR (500MHz, DMSO-d6) δ8.26–8.15(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).

[0748] Step 3: Preparation of intermediate 11d

[0749] Pd / C (10%, 0.015 g) was added to a solution of intermediate 11c (1 g) in MeOH (50 mL). The reaction mixture was purged with nitrogen 2-3 times, then with hydrogen 2-3 times, and stirred at room temperature for 90 minutes. After the reaction, the mixture was filtered, and the filter cake was rinsed with 50 mL of DCM. The solvent was evaporated from the filtrate under reduced pressure to yield 1.013 g of intermediate 11d.

[0750] MS (ESI, [M+H] + )m / z:317.2.

[0751] 1H NMR (500MHz, DMSO-d6) δ6.87–6.79(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,1H),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).

[0752] Step 4: Preparation of intermediate 11e

[0753] To a single-necked flask, 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 sequentially. Under nitrogen, the mixture was heated to 100°C for 1.5 h. After the reaction was terminated, the reaction mixture was cooled to room temperature and filtered. The filter cake was rinsed with 150 mL of dichloromethane. The solvent was evaporated from the filtrate under reduced pressure, and the product was purified by silica gel column chromatography (DCM:CH3OH = 10:1). 1.2 g of intermediate 11e was obtained.

[0754] MS (ESI, [M+H] + )m / z:601.6.

[0755] 1 H NMR(500MHz,DMSO-d6)δ8.93(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).

[0756] Step 5: Preparation of intermediate 11f

[0757] To a single-necked flask, intermediate 11e (1.2 g), DMSO (100 mL), MeOH (50 mL), and Cs2CO3 (0.532 g) were added sequentially. H2O2 (0.926 g) was added under ice-cooling. After stirring for 5 minutes, the ice-cooling bath was removed and the mixture was allowed to react at room temperature for 1.5 hours. The reaction was terminated and quenched by adding 100 mL of saturated sodium sulfite solution. The starch potassium iodide reagent was used to detect the color change. Extraction was then performed with 100 mL of ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to yield 1.2 g of intermediate 11f.

[0758] MS (ESI, [M+H] + )m / z:619.41.

[0759] Step 6: Preparation of Intermediate 11g

[0760] To a reaction flask, intermediate 11f (1 g), DCM (20 mL), and trifluoroacetic acid (5.53 g, 3.74 mL) were added sequentially and allowed to react at room temperature for 3 h. The solvent was evaporated under reduced pressure to obtain the trifluoroacetate salt. Saturated aqueous sodium bicarbonate was slowly added to adjust the system to a weak alkaline state, and the mixture was stirred for 1 h. Filter the mixture, rinse the filter cake with a small amount of water, and dry it in a vacuum oven to obtain 0.8 g of intermediate 11g.

[0761] MS (ESI, [M+H] + )m / z:519.4.

[0762] 1 H NMR (500MHz, DMSO-d6) δ11.22(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),2.39(tt,J=11.8,3.0 Hz,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).

[0763] Step 11: Preparation of compound 11

[0764] To a reaction flask, intermediate 9f (50 mg), intermediate 11g (82 mg), MeOH (5 mL), and acetic acid (4.76 mg) were added sequentially. The mixture was stirred at room temperature for 30 min, followed by sodium cyanoborohydride (19.93 mg). The mixture was stirred at room temperature for 3.5 h. The reaction mixture was purified by silica gel column chromatography (DCM:CH3OH = 10:1) to yield 0.07 g of Example 11.

[0765] MS (ESI, [M+H] + )m / z:816.7.

[0766] 1 H NMR(500MHz,DMSO-d6)δ11.20(s,1H),11.04(s,1H),7.75(d,J=2.9Hz,1H),7.6 5(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,2H),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(dd,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).

[0767] 13C NMR(126MHz,DMSO-d6)δ173.60,172.08,169.70,165.05,160.78,156.42, 154.03,154.01,150.97,140.88,137.73,127.40,122.90,120.14,118.61 ,114.69,111.25,110.24,89.45,65.83,56.17,55.39,49.12,47.19,45.4 5,44.85,42.69,39.02,35.91,31.54,31.40,30.98,28.22,24.47,23.29.

[0768] Example 12: Synthesis of Compound 12

[0769]

[0770] Step 1: Preparation of compound 12

[0771] To a single-necked flask, intermediate 11g (200 mg), DCM (30 mL), intermediate 10i (115 mg), and 3 drops of acetic acid were added in sequence. The mixture was allowed to react at room temperature for 1 h. The mixture was cooled in an ice bath, and NaBH4 (36.5 mg) was added. The reaction mixture was allowed to react at room temperature for 20 h. The reaction solution was poured into a mixture of DCM / MeOH = 10 / 1 solution and water, and the pH was adjusted to 8 with saturated sodium bicarbonate aqueous solution. The organic phase was separated, and the aqueous phase was extracted multiple 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 evaporated from the filtrate under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1, volume ratio). The purified product was dissolved in DMSO, and commercial product C (120 g) was selected. 18 The mixture was purified by reverse phase column and passed through Biotage medium-low pressure chromatography (1 M aqueous ammonium acetate solution: acetonitrile = 1:1, volume ratio) to obtain 61 mg of compound 12.

[0772] HRMS (ESI) m / z [M+H] + :802.41917.

[0773] 1H NMR(500MHz,DMSO-d6)δ11.20(s,1H),11.04(s,1H),7.75(d,J=2.9Hz,1H),7.65(s ,1H),7.55(d,J=8.6Hz,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),4.36(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).

[0774] 13 C NMR(126MHz,DMSO-d6)δ173.62,172.10,169.71,165.08,160.78,156.44,154 .04,153.66,150.98,140.92,137.72,127.42,122.93,120.16,118.62,114.6 9,111.25,110.34,89.52,61.21,59.19,55.12,53.85,49.11,47.18,45.44,44.85,42.71,39.01,36.60,35.11,31.51,31.40,31.01,28.22,24.47,23.29.

[0775] Example 13 Preparation of Compound 13

[0776]

[0777] Step 1: Preparation of intermediate 13b

[0778] At -78°C under N2 protection, DIBAL-H (0.311 g) was slowly added dropwise to a solution of intermediate 7c (0.5 g) in DCM (10 mL). The addition was complete after 3 minutes, and the mixture was stirred at -78°C for 1 hour. The reaction mixture was quenched by the slow addition of 2 mL of methanol at -78°C. The reaction mixture was allowed to cool to room temperature and diluted with 20 mL of petroleum ether. The mixture was stirred for 5 minutes, filtered, and the filtrate was concentrated to obtain the mixture intermediate 13b (0.4 g).

[0779] Step 2: Preparation of intermediate 13c

[0780] To a reaction flask, intermediate 13b (0.4 g), trimethyl orthoformate (0.261 g), p-toluenesulfonic acid (0.028 g), and methanol (10 mL) were added sequentially, and the mixture was allowed to react at room temperature overnight. Approximately 100 mL of saturated aqueous sodium bicarbonate solution was added, 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 afford the mixture intermediate 13c (0.32 g).

[0781] 1 H NMR(500MHz,DMSO-d6)δ6.33–6.28(m,1H),4.13(d,J=7.6Hz,1H),3.23(d,J=1.3Hz,6H),2.5 0–2.47(m,1H),2.40(dddt,J=18.3,15.5,8.8,2.4Hz,2H),2.27–2.14(m,2H),1.19(s,12H).

[0782] Step 3: Preparation of intermediate 13d

[0783] To the reaction flask, intermediate 1m (57 g) and sulfuric acid (200 mL) were added sequentially. A mixed solution of nitric acid (25.28 g, 401.25 mmol) and sulfuric acid (20 mL) was slowly added dropwise under an ice bath. After completion of the addition, the mixture was slowly warmed to room temperature and reacted for 1 h. The reaction solution 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 organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was separated and purified by silica gel column chromatography to obtain intermediate 13d (53.3 g).

[0784] MS (ESI, [MH] - )m / z:326.9.

[0785] 1H NMR (500MHz, DMSO-d6) δ8.75(s,1H),8.51(s,1H),4.29(s,2H),4.15(q,J=7.1Hz,2H),1.20(t,J=7.1Hz,3H).

[0786] Step 4: Preparation of intermediate 13e

[0787] To a reaction flask, intermediate 13d (40 g), ethanol (400 mL), and stannous chloride dihydrate (115 g) were added sequentially, and the mixture was stirred at room temperature for 4 h. The reaction solution was concentrated, and 2 L of dichloromethane and 2 L of water were added to the residue. A saturated aqueous solution of sodium bicarbonate was slowly added under an ice bath to adjust the pH to 9-10. The filtrate was filtered, and the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was separated and purified by silica gel column chromatography to obtain intermediate 13e (35.1 g).

[0788] MS (ESI, [M+H] + )m / z:299.0.

[0789] 1 H NMR (500MHz, DMSO-d6) δ7.93 (s, 1H), 7.04 (s, 1H), 5.35 (s, 2H), 4.14 (q, J = 7.1Hz, 2H), 4.09 (s, 2H),

[0790] 1.20 (t, J = 7.1 Hz, 3H).

[0791] Step 5: Preparation of intermediate 13f

[0792] To a reaction flask, silver sulfate (29.46 g), iodine (23.98 g), and acetonitrile (300 mL) were added sequentially, followed by Intermediate 13e (35 g). The mixture was reacted at room temperature for 1 h. The reaction solution was filtered, and the filtrate was concentrated. 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 afford Intermediate 13f (27.1 g).

[0793] MS (ESI, [M+H] + )m / z:423.0.

[0794] 1 H NMR (500MHz, DMSO-d6) δ8.10 (s, 1H), 5.27 (s, 2H), 4.15 (d, J = 6.6Hz, 4H), 1.22 (t, J = 7.1Hz, 3H).

[0795] Step 6: Preparation of Intermediate 13g

[0796] To a reaction flask, intermediate 13f (26.8 g), (E)-1-ethoxyvinyl-2-boronic acid pinacol ester (14.99 g), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (4.61 g), potassium carbonate (26.14 g), 1,4-dioxane (200 mL), and water (30.00 mL) were added sequentially. Under nitrogen, the mixture was heated to 70°C for 6 h. The reaction mixture was cooled to room temperature, and 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 13g (17 g).

[0797] MS (ESI, [M+H] + )m / z:369.1.

[0798] Step 7: Preparation of Intermediate 13h

[0799] To a reaction flask, intermediate 13g (17g), DCM (200mL), and hydrochloric acid (57.55mL, 4mol / L, 230.22mmol) were added sequentially, and the mixture was reacted at room temperature for 5h. DCM (200mL) and saturated sodium bicarbonate solution (200mL) 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, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was separated and purified by silica gel column chromatography to obtain intermediate 13h (7.1g).

[0800] MS (ESI, [M+H] + )m / z:323.0.

[0801] 1 H NMR(500MHz,DMSO-d6)δ11.89(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).

[0802] Step 8: Preparation of intermediate 13i

[0803] Intermediate 13h (3 g), acrylamide (0.792 g), and anhydrous tetrahydrofuran (50 mL) were added sequentially to a reaction flask. Potassium tert-butoxide (1.56 g) was slowly added at 0°C and allowed to react for 2 h. The reaction solution was quenched by adding 200 mL of saturated aqueous ammonium chloride and extracted with 200 mL of DCM. The organic phase was separated, and the aqueous phase was extracted twice with 50 mL of DCM. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was separated and purified by silica gel column chromatography to obtain intermediate 13i (1.34 g).

[0804] MS (ESI, [MH] - )m / z:345.9.

[0805] 1 H NMR (500MHz, DMSO-d6) δ11.91(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).

[0806] Step 9: Preparation of intermediate 13j

[0807] To a reaction flask were added Intermediate 13i (0.2 g), Intermediate 13c (0.185 g), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.042 g), potassium carbonate (0.183 g), 1,4-dioxane (10 mL), and water (2.00 mL). Under nitrogen, the mixture was heated to 120°C for 3 h. The reaction mixture was cooled to room temperature, and 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 afford the mixture Intermediate 13j (0.205 g).

[0808] MS (ESI, [MH] - )m / z:408.2.

[0809] Step 10: Preparation of intermediate 13k

[0810] To the reaction flask were added intermediate 13j (0.39 g), palladium-carbon catalyst (0.039 g), and MeOH (20 mL) in sequence. The mixture was reacted at room temperature overnight under H2 protection. The reaction mixture was filtered, and the filtrate was concentrated to obtain intermediate 13k (0.36 g).

[0811] MS (ESI, [MH] - )m / z:410.2.

[0812] 1 H NMR (500MHz, DMSO-d6) δ11.61(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. 1,7.0Hz,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).

[0813] Step 11: Preparation of Intermediate 131

[0814] Intermediate 13k (0.1 g), acetone (5 mL), and p-toluenesulfonic acid (0.021 g) were added sequentially to a reaction flask, and the mixture was reacted at room temperature for 2 h. 50 mL of saturated aqueous sodium bicarbonate and 50 mL of DCM were added to the system. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to afford Intermediate 13l (0.085 g).

[0815] MS (ESI, [MH] - )m / z:364.2.

[0816] Step 12: Preparation of compound 13

[0817] To a reaction flask, intermediate 13l (0.08 g), intermediate 1i (0.104 g), and dichloroethane (5 mL) were added, followed by 1 drop of acetic acid and sodium cyanoborohydride (0.026 g). The mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, dichloromethane (50 mL) and water (50 mL) were added. The organic phase was separated, and the aqueous phase was extracted twice with dichloromethane (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was separated and purified by silica gel column chromatography to obtain compound 13 (0.042 g).

[0818] MS (ESI, [M+H] + )m / z:828.4.

[0819] 1 H NMR (500MHz, DMSO-d6) δ11.73(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=7.5 Hz,3H),7.40(s,1H),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).

[0820] Example 14 Synthesis of Compound 14

[0821]

[0822]

[0823] Step 1: Preparation of intermediate 14b

[0824] To a single-necked flask, 14a (50 g), diethyl carbonate (137 g), and toluene (200 mL) were added in sequence. The reaction mixture was cooled to 0°C and sodium hydride (46.5 g) was added in batches. The temperature was first raised to 80°C and the reaction was allowed to proceed for about 10 minutes. The mixture was heated to 120°C and allowed to react for 5 hours. The reaction mixture was cooled to room temperature and slowly poured into 2 L of stirred ice water. The mixture was extracted with 1 L of ethyl acetate and the organic phase was discarded. The aqueous phase was adjusted to pH 3 with 3N hydrochloric acid and extracted three times with 500 mL of ethyl acetate. The organic phases were combined. The mixture was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain intermediate 14b (52 g).

[0825] MS (ESI, [MH] + )m / z:239.0.

[0826] 1 H NMR (500MHz, DMSO-d6) δ12.77(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).

[0827] Step 2: Preparation of intermediate 14c

[0828] To a single-necked flask, intermediate 14b (52 g), methanol (300 mL), hydroxylamine hydrochloride (52.5 g), and sodium ethoxide (61.9 g) were added sequentially. The mixture was heated to 80°C and allowed to react overnight. The reaction solution was cooled to room temperature, and 3N hydrochloric acid was added to adjust the pH to 5. The solvent was evaporated under reduced pressure, and 2 L of water was added. The reaction flask was cooled in an ice-water bath while adjusting the pH to 3 with 3N hydrochloric acid. The mixture was stirred for 30 minutes and filtered. The filter cake was collected and dried to yield intermediate 14c (46 g).

[0829] MS (ESI, [MH] + )m / z:254.0.

[0830] Step 3: Preparation of intermediate 14d

[0831] To a single-necked flask, intermediate 14c (46 g), ethanol (400 mL), and sulfuric acid (106 g, 57.5 mL, 1078 mmol) were added sequentially, and the mixture was heated to 90°C for 2 h. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was diluted with 1 L of ethyl acetate and 1 L of water. The pH was adjusted to 7 with saturated aqueous sodium bicarbonate. The organic phase was separated, and the aqueous phase was extracted twice with 500 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to provide intermediate 14d (51 g).

[0832] MS (ESI, [M+H]+ )m / z:283.0.

[0833] 1 H NMR(500MHz,DMSO-d6)δ7.93(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).

[0834] Step 4: Preparation of intermediate 14e

[0835] To a single-necked flask, under an ice bath, were added intermediate 14d (51 g), sulfuric acid (176 g, 96 mL, 1795 mmol), and potassium nitrate (27.2 g) in sequence. After addition was complete, the mixture was allowed to react at room temperature for 1 h. The reaction solution 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 organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1, volume ratio) to obtain the target intermediate 14e (40 g).

[0836] 1 H NMR (500MHz, DMSO-d6) δ8.98(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).

[0837] Step 5: Preparation of intermediate 14f

[0838] To a single-necked flask, intermediate 14e (40 g), ethanol (400 mL), and stannous chloride dihydrate (115 g) were added sequentially, and the mixture was stirred at room temperature for 4 h. The solvent was evaporated under reduced pressure, and 2 L of dichloromethane and 2 L of water were added to the residue. Saturated aqueous sodium bicarbonate was slowly added under an ice bath to adjust the pH to a weak base. The mixture was filtered, the filter cake rinsed twice with 500 mL of dichloromethane, and the filtrate collected. After separation, the organic phase was collected, and the aqueous phase was extracted twice with 500 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1, volume ratio) to obtain the target intermediate 14f (23 g).

[0839] MS (ESI, [M+H] + )m / z:299.0.

[0840] Step 6: Preparation of Intermediate 14g

[0841] To a single-necked flask, intermediate 14f (6 g), DMF (50 mL), and NIS (4.51 g) were added sequentially, and the mixture was reacted at room temperature for 1 h. Ethyl acetate (100 mL) and water (200 mL) were added. The organic phase was separated, and the aqueous phase was extracted twice with 50 mL of ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated 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 14g (8 g).

[0842] MS (ESI, [MH] + )m / z:423.0.

[0843] 1 H NMR (500MHz, DMSO-d6) δ7.36 (s, 1H), 5.54 (s, 2H), 4.21–4.10 (m, 4H), 1.22 (t, J = 7.1Hz, 3H).

[0844] Step 7: Preparation of Intermediate 14h

[0845] To a single-necked flask, intermediate 14g (4g), (E)-1-ethoxyvinyl-2-boronic acid pinacol ester (2.237g), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (1.377g), potassium carbonate (3.90g), 1,4-dioxane (40mL), and water (10.00mL) were added sequentially. Under nitrogen protection, the mixture was heated to 80°C overnight. The reaction mixture was cooled to room temperature, and ethyl acetate (100mL) and water (100mL) were added. The organic phase was separated and extracted three times with 50mL of ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated 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 14h (2.4g).

[0846] MS (ESI, [M+H] + )m / z:369.1.

[0847] Step 8: Preparation of intermediate 14i

[0848] To a single-necked flask, intermediate 14h (1 g), dichloromethane (10 mL), and trifluoroacetic acid (1.544 g, 1.043 mL) were added sequentially, and the mixture was allowed to react at room temperature overnight. Dichloromethane (100 mL) and water (100 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 the solvent was evaporated 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 14i (0.5 g).

[0849] MS (ESI, [M+H] + )m / z:323.0.

[0850] 1 H NMR(500MHz,DMSO-d6)δ11.78(s,1H),7.96(s,1H),7.61(t,J=2.9Hz,1H),6.6 6(t,J=2.3Hz,1H),4.31(s,2H),4.14(q,J=7.1Hz,2H),1.16(t,J=7.1Hz,3H).

[0851] Step 9: Preparation of Intermediate 14j

[0852] To a three-necked flask, intermediate 14i (300 mg), acrylamide (66 mg), and anhydrous tetrahydrofuran (5 mL) were added sequentially. Potassium tert-butoxide (208 mg) was slowly added at 0°C, and the mixture was allowed to react for 2 h at 0°C. The reaction solution was dropwise added to saturated aqueous ammonium chloride 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 ethyl acetate (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated 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).

[0853] MS (ESI, [MH] + )m / z:345.9.

[0854] 1H NMR (500MHz, DMSO-d6) δ11.80(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).

[0855] Step 10: Preparation of Intermediate 14k

[0856] To a single-necked flask, intermediate 14j (480 mg), intermediate 13c (370 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (202 mg), potassium carbonate (572 mg), 1,4-dioxane (5 mL), and water (0.5 mL) were added sequentially. Under nitrogen, the mixture was heated to 85°C for 2 h. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (50 mL) and water (100 mL). The organic phase was separated and extracted three times with ethyl acetate (50 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The crude product was separated by silica gel column chromatography (dichloromethane / methanol = 60:1, volume ratio) to obtain intermediate 14k (0.35 g).

[0857] MS (ESI, [MH] + )m / z:408.19.

[0858] 1 H NMR(500MHz,DMSO-d6)δ11.63(d,J=30.9Hz,1H),11.18(s,1H),7.57(dt,J=9.7,3.5 Hz,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=1 2.2, 6.3Hz, 1H), 2.25 (dp, J=13.1, 5.2Hz, 1H), 2.16–1.96 (m, 1H), 1.88–1.72 (m, 1H).

[0859] Step 11: Preparation of Intermediate 141

[0860] To a single-necked flask, intermediate 14k (50 mg), methanol (3 mL), and Pd / C (10 mg) were added sequentially. The atmosphere was replaced with hydrogen three times, and the mixture was reacted at room temperature for 3 h. The reaction solution was filtered to remove the palladium on carbon, and the filter cake was rinsed with 5 mL each of dichloromethane, methanol, and ethyl acetate. The filtrate was then distilled under reduced pressure to remove the solvent, yielding intermediate 14l (40 mg).

[0861] MS (ESI, [MH] + )m / z:410.21.

[0862] 1 H NMR (500MHz, DMSO-d6) δ11.52(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=1 7.3,4.2Hz,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).

[0863] Step 12: Preparation of Intermediate 14m

[0864] To a single-necked flask, intermediate 14l (100 mg), bis(acetonitrile) palladium chloride (31.5 mg), and acetone (10 mL) were added sequentially, and the mixture was reacted at room temperature for 1 h. 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 extracted three times with ethyl acetate (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to provide intermediate 14m (70 mg).

[0865] MS (ESI, [MH] + )m / z:364.11

[0866] Step 13: Preparation of compound 14

[0867] To a single-necked flask, intermediate 1i (90 mg), intermediate 14m (68.7 mg), and 1,2-dichloroethane (2 mL) were added sequentially. One drop of acetic acid was added dropwise, and the mixture was stirred at room temperature for 20 minutes. Sodium cyanoborohydride (35.5 mg) was added, and the mixture was reacted at room temperature. Dichloromethane (20 mL) and water (50 mL) were added to the system for extraction. The organic phase was separated and extracted three times with DCM / MeOH = 10:1 (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The product was purified by silica gel column chromatography to obtain compound 14 (20 mg).

[0868] MS (ESI, [M+H] + )m / z:828.52.

[0869] 1 H NMR (500MHz, DMSO-d6) δ11.62(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=7.5 Hz,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),2.79( 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).

[0870] Example 15 Preparation of Compound 15

[0871]

[0872] Step 1: Preparation of intermediate 15b

[0873] To the reaction flask, 15a (50 g), diethyl carbonate (216.9 g), and toluene (500 mL) were added sequentially. The reaction mixture was cooled to 0°C and sodium hydride (44.06 g) was added portionwise. The temperature was first raised to 70°C and the reaction was allowed to proceed for about 10 minutes. The mixture was heated to 120°C and allowed to react for 5 hours. The reaction mixture was cooled to room temperature and slowly poured into 2 L of stirred ice water. The mixture was extracted with 1 L of ethyl acetate and the organic phase was discarded. The aqueous phase was adjusted to pH 3 with 3N hydrochloric acid and extracted three times with 500 mL of ethyl acetate. The organic phases were combined. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to afford intermediate 15b (55 g).

[0874] 1 H NMR (500MHz, DMSO-d6) δ12.52(s,1H),7.83(dd,J=7.8,1.7Hz,1H),7.65(ddd,J=8.6,7.2,1.7Hz,1H),7.43–7.32(m,2H),5.61(s,1H).

[0875] Step 2: Preparation of intermediate 15c

[0876] To a reaction flask were added intermediate 15b (55 g), methanol (500 mL), hydroxylamine hydrochloride (63.5 g), and sodium ethoxide (80.8 g), and the mixture was heated to 80°C overnight. The reaction solution was cooled to room temperature, adjusted to pH 5 with 3N hydrochloric acid, and concentrated. 2 L of water was added, and the reaction flask was cooled in an ice-water bath while adjusting the pH to 3 with 3N hydrochloric acid. The mixture was stirred for 30 minutes and filtered. The filter cake was collected and dried to yield intermediate 15c (54.5 g).

[0877] 1 H NMR(500MHz,DMSO-d6)δ12.90(s,1H),7.86(dt,J=7.9,1.0Hz,1H),7.74(d,J=8.4Hz, 1H), 7.66 (ddd, J=8.3, 7.0, 1.2Hz, 1H), 7.40 (td, J=7.4, 7.0, 0.9Hz, 1H), 4.11 (s, 2H).

[0878] Step 3: Preparation of intermediate 15d

[0879] To a reaction flask, intermediate 15c (54 g), ethanol (400 mL), and sulfuric acid (106 g) were added sequentially, and the mixture was heated to 90°C for 2 h. The reaction solution was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was diluted with 1 L of ethyl acetate and 1 L of water. The pH was adjusted to 7 with saturated aqueous sodium bicarbonate. The organic phase was separated, and 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 to afford intermediate 15d (62 g).

[0880] MS (ESI, [M+H] + )m / z:206.1.

[0881] Step 4: Preparation of intermediate 15e

[0882] To the reaction flask, intermediate 15d (30 g) and sulfuric acid (200 mL) were added sequentially. A mixed solution of nitric acid (11.05 g) and sulfuric acid (4 mL) was slowly added under an ice bath. After the addition was complete, the temperature was slowly warmed to room temperature and the reaction was allowed to react for 1 h. The reaction solution was slowly poured into 2 L of ice water and extracted with 300 mL of ethyl acetate. The organic phase was collected and 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 separated and purified by silica gel column chromatography to obtain intermediate 15e (29.3 g).

[0883] MS (ESI, [M+H] + )m / z:251.1.

[0884] Step 5: Preparation of intermediate 15f

[0885] To a reaction flask were added intermediate 15e (29 g), ethanol (300 mL), and stannous chloride dihydrate (130.76 g), and the mixture was stirred at room temperature for 4 h. The reaction solution was concentrated, and 1 L of dichloromethane and 0.5 L of water were added to the residue. A saturated aqueous solution of sodium bicarbonate was slowly added under an ice bath to adjust the pH to 9-10. The organic phase of the filtrate was separated, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was separated and purified by silica gel column chromatography to afford intermediate 15f (24.3 g).

[0886] MS (ESI, [MH] - )m / z:219.1.

[0887] Step 6: Preparation of Intermediate 15g

[0888] Intermediate 15f (24 g) and DCM (200 mL) were added sequentially to a reaction flask. NBS (21.34 g) was added at 0°C, and the mixture was reacted at room temperature for 1 h. The reaction solution was added with 500 mL of DCM and 500 mL of water. The organic phase was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to afford Intermediate 15g (22.4 g).

[0889] MS (ESI, [M+H] + )m / z:299.2.

[0890] 1H NMR (500MHz, DMSO-d6) δ7.52(d,J=8.9Hz,1H),7.17(d,J=8.9Hz,1H),4.87(s,2H),4.19–4.11(m,4H),1.20(t,J=7.1Hz,3H).

[0891] Step 7: Preparation of Intermediate 15h

[0892] To a reaction flask, intermediate 7a (5 g), trimethyl orthoformate (11.2 g), p-toluenesulfonic acid (0.606 g), and ethanol (50 mL) were added sequentially, and the mixture was reacted at room temperature overnight. Approximately 100 mL of saturated aqueous sodium bicarbonate solution was added to the system, and the mixture was extracted three times with 100 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was separated and purified by silica gel column chromatography to obtain intermediate 15h (4.5 g).

[0893] 1 H NMR(500MHz,Chloroform-d)δ4.14(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).

[0894] Step 8: Preparation of intermediate 15i

[0895] To a reaction flask, intermediate 15h (4.5 g) and THF (50 mL) were added. Lithium aluminum tetrahydride (0.998 g) was slowly added under an ice bath, and the mixture was slowly warmed to room temperature for 1 h. After completion of the reaction, a small amount of ice water was added to the reaction solution under an ice bath to quench the reaction. Then, 200 mL of DCM and 200 mL of water were added, and the mixture was filtered. The organic phase of the filtrate was separated, washed with 200 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to afford intermediate 15i (3.9 g).

[0896] 1H NMR(500MHz,Chloroform-d)δ3.55(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(dddd,J=13.4,7.3,1.3Hz,1H),1.51–1.40(m,1H).

[0897] Step 9: Preparation of Intermediate 15j

[0898] To a reaction flask were added Intermediate 15g (2.2 g), Intermediate 15i (1.3 g), triethylsilane (1.71 g), and acetonitrile (20 mL), followed by elemental iodine (1.87 g). The temperature was raised to 90°C and the reaction mixture was allowed to react overnight. The reaction solution was cooled to room temperature, concentrated, and 200 mL of DCM and 200 mL of water were added. The organic phase was separated, washed with 200 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to afford Intermediate 15j (1.9 g).

[0899] MS (ESI, [M+H] + )m / z:319.2.

[0900] Step 10: Preparation of Intermediate 15k

[0901] To a reaction flask, intermediate 15j (1.9 g) and DCM (30 mL) were added, followed by NBS (1.06 g). The mixture was reacted at room temperature for 1 h. The reaction solution was added with 100 mL of DCM and 100 mL of water. The organic phase was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to afford intermediate 15k (0.75 g).

[0902] MS (ESI, [M+H] + )m / z:397.2.

[0903] 1H NMR(500MHz,DMSO-d6)δ7.63(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(ddd,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).

[0904] Step 11: Preparation of Intermediate 15l

[0905] To a microwave tube were added Intermediate 15k (0.7 g), (E)-1-ethoxyvinyl-2-boronic acid pinacol ester (0.419 g), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.129 g), potassium carbonate (0.731 g), 1,4-dioxane (10 mL), and water (2 mL) in sequence. N2 was bubbled through the solution and microwaved at 120°C for 2 h. The reaction mixture was cooled to room temperature, and 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 afford Intermediate 15l (0.51 g).

[0906] MS (ESI, [M+H] + )m / z:389.2.

[0907] Step 12: Preparation of Intermediate 15m

[0908] To a reaction flask, intermediate 15l (0.5 g), DCM (20 mL), and hydrochloric acid (0.644 mL, 4 mol / L, 2.57 mmol) were added sequentially, and the mixture was reacted at room temperature for 5 h. DCM (100 mL) and saturated sodium bicarbonate solution (100 mL) were added. 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 afford intermediate 15m (0.24 g).

[0909] MS (ESI, [M+H] + )m / z:343.1

[0910] Step 13: Preparation of intermediate 15n

[0911] Intermediate 15m (0.18 g), acrylamide (0.041 g), and anhydrous tetrahydrofuran (10 mL) were added sequentially to a reaction flask. Potassium tert-butoxide (0.071 g) was slowly added at 0°C and allowed to react for 1 h. The reaction solution was quenched by adding 50 mL of saturated aqueous ammonium chloride and 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 afford Intermediate 15n (0.095 g).

[0912] MS (ESI, [M+H] + )m / z:368.2.

[0913] Step 14: Preparation of Intermediate 15o

[0914] To a reaction flask, intermediate 15n (0.09 g) and dichloromethane (5 mL) were added, followed by Dess-Martin periodinane (0.233 g) and the reaction was allowed to react at room temperature for 1 hour. After completion of the reaction, dichloromethane (50 mL) and water (50 mL) were added. 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 afford intermediate 15o (0.08 g).

[0915] MS (ESI, [MH] - )m / z:364.1.

[0916] Step 15: Preparation of Compound 15

[0917] To a reaction flask, intermediate 15o (0.08 g), intermediate 1i (0.104 g), and dichloroethane (5 mL) were added, followed by 1 drop of acetic acid and sodium cyanoborohydride (0.026 g). The mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, 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 organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was separated and purified by silica gel column chromatography to obtain compound 15 (0.042 g).

[0918] MS (ESI, [M+H] + )m / z:828.4.

[0919] 1H NMR(500MHz,DMSO-d6)δ11.18(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=8.1Hz,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(dq,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), 2.68(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).

[0920] Example 16 Synthesis of Compound 16

[0921]

[0922] Step 1: Preparation of intermediate 16b

[0923] To a reaction flask at 10°C, 16a (81 g), 2,4-dimethoxybenzylamine (83 g), and acetic acid (500 mL) were added sequentially and the temperature was raised to 80°C. After TLC confirmed the completion of the reaction, water was added to the reaction solution to precipitate a solid, which was filtered, washed with water, and dried to obtain intermediate 16b (95.78 g).

[0924] MS (ESI, [M+H] - )m / z:312.02

[0925] 1H NMR (500MHz, DMSO-d6) δ11.03(s,1H),7.62(dd,J=8.4,7.1Hz,1H),7.29(d,J=7.1Hz,1H),7.22(d,J=8.4Hz,1H), 6.90(d,J=8.4Hz,1H),6.56(d,J=2.4Hz,1H),6.43(dd,J=8.4,2.4Hz,1H),4.60(s,2H),3.80(s,3H),3.73(s,3H).

[0926] Step 2: Preparation of intermediate 16c

[0927] A 2.5M solution of lithium aluminum tetrahydride in tetrahydrofuran (227 mL) was slowly added dropwise to a solution of 16b (96.00 g) in tetrahydrofuran (1000 mL) at 10°C, and the reaction was allowed to proceed at 80°C. After TLC confirmed the completion of the reaction, a 15 wt% aqueous sodium hydroxide solution and water were added to the reaction solution, which was then filtered. The filter cake was washed with a 1:1 solution of dichloromethane:MeOH, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography to obtain 55.87 g of intermediate 16c.

[0928] MS (ESI, [M+H] + )m / z:286.01

[0929] 1 H NMR(500MHz,DMSO-d6)δ9.28(s,1H),7.24(d,J=8.3Hz,1H),6.97(t,J=7.7Hz,1H),6.64(d,J=7.4Hz ,1H),6.59(d,J=8.0Hz,1H),6.55(d,J=2.4Hz,1H),6.51(dd,J=8.3,2.4Hz,1H),3.81–3.71(m,12H).

[0930] Step 3: Preparation of intermediate 16d

[0931] 16c (48.00 g), methanol (350 mL), palladium hydroxide (4.8 g), and di-tert-butyl dicarbonate (41.4 g) were added sequentially to a reaction flask and reacted at 25°C under a hydrogen atmosphere. After TLC confirmed the reaction was complete, the reaction solution was filtered, the filtrate was concentrated, and extraction was added with water and ethyl acetate. The product was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography to obtain 34.43 g of intermediate 16d.

[0932] 1H NMR (500MHz, DMSO-d6) δ7.07(t,J=7.7Hz,1H),6.68(ddd,J=18.9,7.8,2.7Hz,2H),4.56–4.50(m,2H),4.48–4.42(m,2H),1.45(s,9H).

[0933] Step 4: Preparation of intermediate 16e

[0934] 16d (35.00 g), methanol (250 mL), and 4 M hydrochloric acid in dioxane (123 mL) were added to the reaction flask in sequence and reacted at 25°C. After TLC confirmed the reaction was complete, the reaction solution was concentrated, pyridine (200 mL) and trifluoroacetic anhydride (25.20 g) were added, and the reaction was stirred at 25°C. After TLC confirmed the reaction was complete, the reaction solution was poured into 3 M aqueous hydrochloric acid and stirred vigorously. Extraction was added with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 32.48 g of intermediate 16e.

[0935] MS (ESI, [M+H] - )m / z:229.99

[0936] 1 H NMR(500MHz,DMSO-d6)δ9.82(d,J=24.4Hz,1H),7.16(td,J=7.7,3.7Hz,1H),6.81(dd,J=11 .5,7.5Hz,1H),6.74(d,J=8.0Hz,1H),4.99(s,1H),4.89(s,1H),4.80(s,1H),4.70(s,1H).

[0937] Step 5: Preparation of intermediate 16f

[0938] 16e (32.48 g), dichloromethane (300 mL), triethylamine (28.40 g), 4-dimethylaminopyridine (1.72 g), and acetic anhydride (15.78 g) were added to the reaction flask in sequence and reacted at 25°C. After TLC confirmed the completion of the reaction, the reaction solution was poured into water and vigorously stirred. Extraction was added 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.

[0939] 1H NMR (500MHz, DMSO-d6) δ7.41(td,J=7.8,2.3Hz,1H),7.30(t,J=8.5Hz,1H),7.12(dd,J=7 .9,2.9Hz,1H),5.09(s,1H),4.90(d,J=12.3Hz,2H),4.72(s,1H),2.31(d,J=3.4Hz,3H).

[0940] Step 6: Preparation of Intermediate 16g

[0941] 16f (30.00 g), aluminum chloride (29.30 g), and o-dichlorobenzene (200 mL) were added to the reaction flask in sequence and reacted at 150°C. After TLC confirmed the completion of the reaction, the reaction solution was poured into aqueous citric acid solution and stirred vigorously. Ethyl acetate was added for extraction, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was separated by silica gel column chromatography to obtain (18.19 g) of intermediate 16g.

[0942] 1 H NMR (500MHz, DMSO-d6) δ12.38(s,1H),7.94(dd,J=8.2,4.7Hz,1H),7.01(dd,J=12.7,8.1Hz ,1H),5.07(s,1H),4.94(s,1H),4.86(s,1H),4.74(d,J=1.6Hz,1H),2.66(d,J=1.0Hz,3H).

[0943] Step 7: Preparation of Intermediate 16h

[0944] 16g (18.19g), sodium hydroxide (7.56g), methanol (150mL), and water (150mL) were added to the reaction flask in sequence and reacted at 25°C for 2.5h. The reaction solution was concentrated to remove methanol, and 1,4-dioxane (150mL) and di-tert-butyl dicarbonate (15.14g) were added to the residue and stirred at 25°C for 2h. The reaction solution was poured into water and stirred vigorously. Ethyl acetate was added for extraction, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography to obtain (14.10g) of intermediate 16h.

[0945] MS (ESI, [M+H] - )m / z:276.07

[0946] 1H NMR(500MHz,DMSO-d6)δ12.36(s,1H),7.89(dd,J=8.1,2.9Hz,1H),6.95(t,J=8.0Hz,1H ),4.62(dt,J=13.4,2.2Hz,2H),4.51(dt,J=13.9,2.3Hz,2H),2.65(s,3H),1.46(s,9H).

[0947] Step 8: Preparation of intermediate 16i

[0948] To the reaction flask were added 16h (14.10 g), diethyl carbonate (27.00 g), and toluene (200 mL) in sequence. The temperature was lowered to 0°C, and 60 wt% sodium hydride (9.16 g) was added. The temperature was then raised to 120°C with stirring. After TLC confirmed the completion of the reaction, the reaction solution was poured into 3M aqueous hydrochloric acid and vigorously stirred. Extraction was then added with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography to obtain 14.96 g of intermediate 16i.

[0949] MS (ESI, [M+H] + )m / z:250.20

[0950] 1 H NMR (500MHz, DMSO-d6) δ11.72(d,J=9.6Hz,1H),7.82(dd,J=8.2,4.7Hz,1H),6.97(t,J=8.4Hz,1H),4.63(dt,J=12.4,2.1Hz, 2H), 4.53 (dt, J = 13.7, 2.1Hz, 2H), 4.22 (d, J = 2.5Hz, 2H), 4.13 (q, J = 7.1Hz, 2H), 1.46 (d, J = 1.9Hz, 9H), 1.19 (t, J = 7.1Hz, 3H).

[0951] Step 9: Preparation of Intermediate 16j

[0952] 16i (14.96 g), 50% aqueous hydroxylamine solution (6.36 g), and ethanol (150 mL) were added sequentially to the reaction flask and stirred at 85°C. After TLC confirmed the completion of the reaction, the reaction solution was concentrated, and water and ethyl acetate were added. The layers were extracted and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude intermediate 16j (10.13 g).

[0953] MS (ESI, [M+H] - )m / z:317.20

[0954] 1H NMR (500MHz, DMSO-d6) δ12.59(s,1H),7.78(d,J=8.2Hz,1H),7.38(t,J=7.6Hz,1H),4.85( dt,J=13.5,2.5Hz,2H),4.75(dt,J=12.2,2.4Hz,2H),4.11(s,2H),1.49(d,J=2.1Hz,9H).

[0955] Step 10: Preparation of Intermediate 16k

[0956] 16j (10.13 g), potassium carbonate (12.55 g), N,N-dimethylacetamide (150 mL), and iodoethane (7.08 g) were added to the reaction flask in sequence and stirred at 80°C. After TLC confirmed the reaction was complete, the reaction solution was poured into water and vigorously stirred. Ethyl acetate was added for extraction, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography to obtain 11.22 g of intermediate 16k.

[0957] MS (ESI, [M+H] + )m / z:247.16

[0958] 1 H NMR(500MHz,DMSO-d6)δ7.78(d,J=8.0Hz,1H),7.39(t,J=7.5Hz,1H),4.89–4.82(m,2H),4.75(dd,J=11 .8,2.8Hz,2H),4.22(d,J=4.3Hz,2H),4.13(p,J=7.2Hz,2H),1.48(d,J=2.1Hz,9H),1.21–1.17(m,3H).

[0959] Step 11: Preparation of Intermediate 16l

[0960] 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), followed by dropwise addition of a 1 M solution of potassium tert-butoxide in tetrahydrofuran (18.63 mL). The mixture was stirred at 0°C. After TLC confirmed the completion of the reaction, the reaction solution was poured into an aqueous ammonium chloride solution and vigorously stirred. Ethyl acetate was added for extraction, the mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography to obtain 7.52 g of intermediate 16l.

[0961] MS (ESI, [M+H] + )m / z:272.02

[0962] 1H NMR (500MHz, DMSO-d6) δ11.11(s,1H),7.80(dd,J=8.1,2.7Hz,1H),7.37(t,J=7.9Hz,1H),4.85(dd,J=12.2,2.6Hz,2H),4.75(dt,J=12.0,2.3Hz ,2H),4.63(dd,J=12.1,4.9Hz,1H),2.78(ddd,J=17.3,12.1,5.3Hz,1H),2.67–2.51(m,2H),2.20(dq,J=13.5,4.7Hz,1H),1.49(d,J=2.6Hz,9H).

[0963] Step 12: Preparation of compound 16

[0964] 16l (1.00 g), 4 M hydrochloric acid dioxane solution (10 mL), and ethyl acetate (50 mL) were added to the reaction flask in sequence and reacted at 25°C. After TLC confirmed the completion of the reaction, the reaction solution was directly filtered, and the filter cake was washed with ethyl acetate and dried to obtain 0.83 g of compound 16.

[0965] MS (ESI, [M+H] + )m / z:272.11

[0966] 1 H NMR (500MHz, DMSO-d6) δ11.13(s,1H),10.36(s,2H),7.90(d,J=8.1Hz,1H),7.45(d,J=8.2Hz,1H),4.81(s,2H),4.70–4.63(m, 3H), 2.79(ddd,J=17.4,12.2,5.3Hz,1H),2.62(dt,J=17.3,4.0Hz,1H),2.59–2.52(m,1H),2.21(ddt,J=13.2,5.1,2.5Hz,1H).

[0967] Example 17 Preparation of Compound 17

[0968]

[0969]

[0970] Step 1: Preparation of intermediate 17b

[0971] To the reaction flask were added 17a (18 g), AIBN (0.738 g), carbon tetrachloride (500 mL), and NBS (47.8 g) in sequence, and the temperature was raised to 60°C for reaction. After TLC confirmed the completion of the reaction, the reaction solution was cooled to room temperature, the solvent was evaporated under reduced pressure, and dichloromethane was added to the residue. The product was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure from the filtrate. The product was purified by silica gel column chromatography to afford intermediate 17b (18.7 g).

[0972] Step 2: Preparation of intermediate 17c

[0973] To the reaction flask, 17b (18.7 g), benzylamine (1.78 mL), N,N-diisopropylethylamine (7.13 mL), and toluene (50 mL) were added sequentially and the temperature was raised to 50°C. After TLC confirmed the completion of the reaction, the reaction solution was cooled to room temperature, and stirring was stopped. The reaction was continued at room temperature for a total of 2 h. Ethyl acetate and 1M HCl in ice water were added to the reaction solution for extraction. The aqueous phase was collected, and the pH was adjusted to approximately 9 with solid sodium bicarbonate. Ethyl acetate was added for extraction, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to provide intermediate 17c (9.6 g).

[0974] MS (ESI, [M+H] + )m / z:240.1.

[0975] Step 3: Preparation of Intermediate 17d

[0976] To a reaction flask were added 17c (9.6 g), methanol (200 mL), 10% palladium on carbon (5 g), and toluene (50 mL) in sequence. The atmosphere was replaced with hydrogen three times, and the mixture was reacted at room temperature under a hydrogen atmosphere. After TLC confirmed the completion of the reaction, the palladium on carbon was filtered, the filter cake was rinsed twice with methanol, the filtrate was collected, and the solvent was evaporated under reduced pressure to afford 17d (4.5 g).

[0977] MS (ESI, [M+H] + )m / z:149.9.

[0978] Step 4: Preparation of intermediate 17e

[0979] To the reaction flask were added 17d (4 g), tetrahydrofuran (50 mL), and trifluoroacetic anhydride (5.63 g) in sequence and allowed to react at room temperature. After TLC confirmed the completion of the reaction, aqueous solution was added to quench the reaction 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 afford 17e (4.58 g).

[0980] 1H NMR(500MHz,DMSO-d6)δ7.29(t,J=9.3Hz,1H),6.98(d,J=8.6Hz,1H),6.93–6.86(m,1 H), 4.97 (d, J = 21.7Hz, 2H), 4.77 (dd, J = 21.4, 5.2Hz, 2H), 3.76 (dd, J = 3.6, 1.6Hz, 3H).

[0981] Step 5: Preparation of intermediate 17f

[0982] 17e (4.6 g), dichloromethane (200 mL), and boron tribromide (1 M, 18.76 mL) were added sequentially to the reaction flask and allowed to react at room temperature. After TLC confirmed the reaction was complete, water was added to the reaction solution under ice-cooling to quench the reaction. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 17f (4.2 g).

[0983] 1 H NMR (500MHz, DMSO-d6) δ7.16(t,J=8.8Hz,1H),6.87–6.59(m,2H),4.92(d,J=20.8Hz,2H),4.72(d,J=19.9Hz,2H).

[0984] Step 6: Preparation of Intermediate 17g

[0985] To a reaction flask were added 17f (6.5 g), dichloromethane (60 mL), triethylamine (7.8 mL), and acetic anhydride (2.94 mL) in sequence and allowed to react at room temperature. After TLC confirmed the reaction was complete, 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 evaporated under reduced pressure to yield 17g (7 g).

[0986] 1 H NMR(500MHz,DMSO-d6)δ7.42(dd,J=10.0,8.3Hz,1H),7.17(dd,J=14.0,2.1Hz,1H) ,7.09(d,J=8.2Hz,1H),5.03(d,J=6.6Hz,2H),4.83(d,J=6.9Hz,2H),2.27(s,3H).

[0987] Step 7: Preparation of Intermediate 17h

[0988] To the reaction flask were added 17g (6g) and aluminum chloride (4.39g), and the mixture was gradually heated from room temperature to 150°C. After TLC confirmed the completion of the reaction, the reaction solution 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, filtered, and the filtrate was stripped of solvent under reduced pressure. The product was purified by silica gel column chromatography to afford 17h (3.78g).

[0989] MS (ESI, [MH] - )m / z:271.9.

[0990] Step 7: Preparation of Intermediate 17j

[0991] To the reaction flask were added 17h (550 mg), MeOH (5.00 mL), and an aqueous solution of sodium hydroxide (242 mg) (5.00 mL) in sequence, and the mixture was allowed to react at room temperature. After TLC confirmed the reaction was complete, the reaction solution was concentrated, the methanol was removed, 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 system and allowed to react at room temperature. After TLC confirmed the reaction was complete, the reaction solution 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).

[0992] 1 H NMR (500MHz, DMSO-d6) δ12.11(d,J=19.3Hz,1H),7.88(d,J=9.5Hz,1H),6.74–6.56(m,1H),4.60–4.50(m,4H),2.63(d,J=6.5Hz,3H),1.45(s,9H).

[0993] Step 8: Preparation of intermediate 17k

[0994] To a reaction flask, 17j (3.5 g) and THF (300 mL) were added sequentially. Diethyl carbonate (14.91 g, 15.29 mL) was added and the temperature was lowered to approximately 0°C. 60 wt% sodium hydroxide (5.05 g, 126 mmol) was added portionwise and the reaction was heated to 85°C. After TLC confirmed the reaction was complete, the reaction solution was cooled to room temperature and slowly poured into ice water. The solution was extracted with ethyl acetate, and the organic phase was discarded. The aqueous phase was adjusted to pH 1-2 with 3M hydrochloric acid, then extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to yield 17k (7.0 g).

[0995] MS (ESI, [MH] - )m / z:348.3.

[0996] Step 9: Preparation of Intermediate 17l

[0997] To the reaction flask were added 17k (4.4 g), aqueous hydroxylamine solution (4.16 g, 63.0 mmol), and ethanol (50 mL) in sequence, and the mixture was allowed to react at 85°C. After TLC confirmed the reaction was complete, the reaction solution was cooled to room temperature, and the residue was extracted with ethyl acetate and saturated aqueous sodium carbonate. The organic phase was discarded. The aqueous phase was adjusted to pH 2-3 with 1M aqueous HCl, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to yield 17l (3.25 g).

[0998] 1 H NMR(500MHz,DMSO-d6)δ12.83(s,1H),7.74(d,J=13.0Hz,1H),7.68(d,J=3.5Hz ,1H),4.71(d,J=13.6Hz,2H),4.66(d,J=11.4Hz,2H),4.07(s,2H),1.47(s,9H).

[0999] Step 10: Preparation of Intermediate 17m

[1000] To a reaction flask, 17l (3.14 g), potassium carbonate (1.500 g), DMA (5 mL), and iodoethane (2.308 g, 1.183 mL) were added sequentially. The mixture was heated to 80°C for reaction. After TLC confirmed the reaction was complete, the reaction solution 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, filtered, and the solvent was evaporated from the filtrate under reduced pressure to yield 17m (2.47 g).

[1001] 1 H NMR(500MHz,DMSO-d6)δ7.73(d,J=15.9Hz,1H),7.69(d,J=3.5Hz,1H),4.69(d d,J=23.8,12.4Hz,4H),4.19–4.11(m,4H),1.47(s,9H),1.20(t,J=7.1Hz,3H).

[1002] Step 11: Preparation of intermediate 17n

[1003] 17m (1.5 g) and THF (75 mL) were added to the reaction flask in sequence, followed by acrylamide (0.215 g). The temperature was lowered to approximately -15°C, and 1 M potassium tert-butoxide solution in tetrahydrofuran (2.60 mL) was added. The system was then heated to 0°C for reaction. After TLC confirmed the reaction was complete, the mixture was added dropwise to ammonium chloride solution for quenching, and extracted with ethyl acetate. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to afford 17n (0.88 g).

[1004] 1 H NMR (500MHz, DMSO-d6) δ11.11(d,J=3.4Hz,1H),7.78(d,J=12.4Hz,1H),7.70(s,1H),4.68(dd,J=29.4,13.3Hz,4H),4.58(dd,J=12.0,4. 9Hz,1H),2.79(ddd,J=17.3,12.1,5.3Hz,1H),2.62(dt,J=17.3,4.1Hz,1H),2.56–2.50(m,1H),2.31–2.14(m,1H),1.47(d,J=1.5Hz,9H).

[1005] Step 12: Preparation of compound 17

[1006] To the reaction flask, 17n (0.428 g) and dichloromethane (10.00 mL) were added, followed by trifluoroacetic acid (3.29 g, 2.211 mL) and allowed to react at room temperature. After TLC confirmed the reaction was complete, water was added to the reaction solution, and the pH was adjusted to 7-8 with saturated sodium bicarbonate. The solution was then extracted with dichloromethane, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to yield 17 (0.439 g).

[1007] MS (ESI, [M+H] + )m / z:272.24.

[1008] 1 H NMR (500MHz, DMSO-d6) δ7.81–7.77(m,1H),7.74(s,1H),4.59(dd,J=12.1,5.0Hz,1H),4.49(s,2H),4.43(s,2H),2.79(ddd ,J=17.4,12.2,5.3Hz,1H),2.62(dt,J=17.3,4.0Hz,1H),2.47(dd,J=12.4,4.4Hz,1H),2.20(ddt,J=13.3,5.2,2.6Hz,1H).

[1009] Example 18 Synthesis of Compound 18

[1010]

[1011] Step 1: Preparation of intermediate 18b

[1012] Intermediate 18a (25 g) was dissolved in methanol (1000 mL) and acetic acid (103 g, 99 mL) and added to an autoclave set at a hydrogen pressure of 3 MPa and a temperature of 110°C. After TLC confirmed the completion of the reaction, the solvent was evaporated under reduced pressure. To the residue was added a dioxane hydrochloride solution (4 mol / L, 100 mL, 400 mmol), and the solvent was evaporated under reduced pressure. The residue was slurried in ethyl acetate and filtered to obtain the filter cake, yielding the desired intermediate 18b (28.97 g).

[1013] MS (ESI, [M+H] + )m / z:150.0.

[1014] 1H NMR(500MHz,DMSO-d6)δ10.01(s,1H),7.06(t,J=7.8Hz,1H),6.76(d,J=8.0Hz,1H),6 .64(d,J=7.6Hz,1H),4.01(t,J=4.9Hz,2H),3.33–3.25(m,2H),2.94(t,J=6.2Hz,2H).

[1015] Step 2: Preparation of Intermediate 18c

[1016] Intermediate 18b (28.97 g) and tetrahydrofuran (300 mL) were added sequentially to a reaction flask. Trifluoroacetic anhydride (27.0 mL) was added under ice-cooling conditions, and the mixture was allowed to react at room temperature. After TLC confirmed the completion of the reaction, the reaction solution 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 evaporated under reduced pressure, and the filter cake was collected by filtration to obtain the target intermediate 18c (22.67 g).

[1017] MS (ESI, [M+H] - )m / z:244.0.

[1018] 1 H NMR(500MHz,DMSO-d6)δ7.03(q,J=7.9Hz,1H),6.74–6.68(m,1H),6.64(t,J=6.9Hz,1 H), 4.61 (d, J = 23.5Hz, 2H), 3.78 (td, J = 6.0, 3.7Hz, 2H), 2.84 (dt, J = 16.8, 5.9Hz, 2H).

[1019] Step 3: Preparation of Intermediate 18d

[1020] 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 the reaction flask in the order described. Acetic anhydride (10.38 g, 9.68 mL) was added under ice-cooling, and the mixture was allowed to return to room temperature for reaction. After TLC confirmed the completion of the reaction, the solvent was evaporated under reduced pressure, and 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, and filtered. The filtrate was evaporated under reduced pressure to remove the solvent, yielding the target intermediate 18d (21.94 g).

[1021] 1 H NMR(500MHz,DMSO-d6)δ7.30(dt,J=11.1,7.8Hz,1H),7.18–7.11(m,1H),7.05(dt,J=8.0,2.2H z,1H),4.59(s,2H),3.81(q,J=6.1Hz,2H),2.95(dt,J=10.1,6.0Hz,2H),2.33(d,J=9.5Hz,3H).

[1022] Step 4: Preparation of intermediate 18e

[1023] Intermediate 18d (21 g) and aluminum chloride (14.62 g) were added sequentially to the reaction flask. Under N protection, the mixture was heated to 170°C for reaction. After TLC confirmed the completion of the reaction, the reaction solution was cooled to room temperature and quenched with water. The reaction solution was then extracted with dichloromethane. The organic phase was separated, 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).

[1024] MS (ESI, [M+H] - )m / z:286.0.

[1025] 1 H NMR (500MHz, DMSO-d6) δ12.76(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).

[1026] Step 5: Preparation of Intermediate 18f

[1027] Intermediate 18e (10.16 g) and MeOH (100 mL) were added sequentially to a reaction flask. A solution of sodium hydroxide (4.24 g) in water (100 mL) was added dropwise in an ice bath, and the mixture was allowed to warm to room temperature. After TLC confirmed the completion of the reaction, the methanol was evaporated under reduced pressure, and 1,4-dioxane (100 mL) and di-tert-butyl dicarbonate (8.49 g, 9.03 mL) were added. The mixture was allowed to warm to room temperature. After TLC confirmed the completion of the reaction, 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, filtered, and the solvent was evaporated from the filtrate under reduced pressure to yield the target intermediate 18f (8.96 g).

[1028] MS (ESI, [M+H] + )m / z:192.0.

[1029] 1 H NMR(500MHz,DMSO-d6)δ12.72(s,1H),7.76(d,J=8.2Hz,1H),6.80(d,J=8.2Hz,1H), 4.41(s,2H),3.55(t,J=5.8Hz,2H),2.80(t,J=5.8Hz,2H),2.63(s,3H),1.43(s,9H).

[1030] Step 6: Preparation of Intermediate 18g

[1031] Intermediate 18f (8.76 g), diethyl carbonate (17.76 g, 18.21 mL), and toluene (90 mL) were added to a reaction flask in sequence. 60 wt% sodium hydroxide (6.01 g, 150 mmol) was added portionwise in an ice bath, and the mixture was heated to 120°C. After TLC confirmed the reaction was complete, the reaction solution was cooled to room temperature and quenched by pouring into ice water. 1 M hydrochloric acid was added to adjust the pH to 1-2, and ethyl acetate was added for extraction. The organic phase was separated, washed with 600 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to remove the solvent under reduced pressure, and the residue was slurried with petroleum ether and filtered to obtain the filter cake of target intermediate 18g (12.03 g).

[1032] Step 7: Preparation of Intermediate 18h

[1033] Intermediate 18g (9.54g), EtOH (100mL), and aqueous hydroxylamine solution (9.93g, 9.21mL, 150mmol) were added to the reaction flask in sequence, and the mixture was heated to 85°C for reaction. After TLC confirmed the completion of the reaction, the reaction solution was adjusted to pH 8 by adding saturated sodium carbonate solution, and extracted with ethyl acetate. The organic phase was separated, extracted twice with water, and then combined. The organic phases were then adjusted to pH 3 with 1M 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 evaporated from the filtrate under reduced pressure to obtain the target intermediate 18h (9.01g).

[1034] MS (ESI, [M+H] - )m / z:331.0.

[1035] Step 8: Preparation of intermediate 18i

[1036] Intermediate 18h (9.01 g), potassium carbonate (11.24 g), DMA (90 mL), and iodoethane (5.07 g, 2.63 mL, 32.5 mmol) were added to the reaction flask in this order. Under nitrogen, the mixture was heated to 80°C for reaction. After TLC confirmed the reaction was complete, the reaction solution 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 target intermediate 18i (7.33 g).

[1037] MS (ESI, [M+H] + )m / z:361.0.

[1038] 1 H NMR(500MHz,DMSO-d6)δ7.63(d,J=8.1Hz,1H),7.21(d,J=8.2Hz,1H),4.76(s,2H),4.18(s,2H),4.1 3(q,J=7.1Hz,2H),3.66(t,J=5.8Hz,2H),2.93(t,J=5.8Hz,2H),1.45(s,9H),1.19(t,J=7.1Hz,3H).

[1039] Step 9: Preparation of Intermediate 18j

[1040] Intermediate 18i (7.3 g), tetrahydrofuran (80 mL), and acrylamide (0.864 g, 12.15 mmol) were added sequentially to a reaction flask under N2 protection. The mixture was cooled to -15°C and potassium tert-butoxide solution in tetrahydrofuran (1 mol / L, 11.14 mL, 11.14 mmol) was added dropwise. After completion of the addition, the temperature was raised to 0°C for reaction. After TLC confirmed the reaction was complete, the system was added to saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography to obtain the target intermediate 18j (4.54 g).

[1041] MS (ESI, [M+H] - )m / z:384.3

[1042] 1 H NMR(500MHz,DMSO-d6)δ11.09(s,1H),7.65(d,J=8.1Hz,1H),7.20(d,J=8.2Hz ,1H),4.76(s,2H),4.58(dd,J=12.0,5.0Hz,1H),3.66(t,J=5.8Hz,2H),2.93( t,J=5.8Hz,2H),2.77(ddd,J=17.3,12.1,5.3Hz,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).

[1043] Step 10: Preparation of compound 18

[1044] Intermediate 18j (300 mg) and ethyl acetate (5 mL) were added to a reaction flask, followed by a dioxane hydrochloride solution (4 mol / L, 3.89 mL, 15.58 mmol). The mixture was allowed to react at room temperature. After TLC confirmed the reaction was complete, the reaction solution was concentrated to yield compound 18 (235 mg).

[1045] MS (ESI, [M+H] + )m / z:286.10.

[1046] 1H NMR (500MHz, DMSO-d6) δ11.08(s,1H),7.55(d,J=8.1Hz,1H),7.10(d,J=8.2Hz,1H),4.55(dd,J=11.9,5.0Hz,1H),4.07(s,2H),3.00(t,J=5. 7Hz,2H),2.81(t,J=5.7Hz,2H),2.78–2.71(m,1H),2.60(dt,J=17.3,4.2Hz,1H),2.46(dd,J=12.2,4.5Hz,1H),2.18(dq,J=13.6,4.9Hz,1H).

[1047] Example 19 Synthesis of Compound 19

[1048]

[1049] Step 1: Preparation of intermediate 19b

[1050] Intermediate 19a was dissolved in methanol (1680 mL) and acetic acid (166 mL) and added to an autoclave at a hydrogen pressure of 3 MPa and a temperature of 110°C. After TLC confirmed the completion of the reaction, the solvent was evaporated under reduced pressure. To the residue was added a dioxane hydrochloride solution (4 mol / L, 200 mL, 798 mmol), and the solvent was evaporated under reduced pressure. The residue was slurried in ethyl acetate and filtered to obtain the filter cake, yielding the desired intermediate 19b (46.96 g).

[1051] MS (ESI, [M+H] + )m / z:150.0.

[1052] 1 H NMR (500MHz, DMSO-d6) δ9.81(s,1H),7.03(t,J=7.7Hz,1H),6.78(d,J=7.8Hz,1H),6.62(d,J=7.6Hz,1H),4.15(s,2H),3.35(s,2H),2.79(s,2H).

[1053] Step 2: Preparation of Intermediate 19c

[1054] Intermediate 19b (40 g) and tetrahydrofuran (400 mL) were added to the reaction flask in sequence. Trifluoroacetic anhydride (61.9 g, 41.0 mL, 295 mmol) was added in an ice bath, and the mixture was allowed to return to room temperature for reaction. After TLC confirmed the reaction was complete, ethyl acetate and water were added to the reaction solution for extraction. The organic phase was separated, washed with 1000 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure to remove the solvent to obtain the target intermediate 19c (81 g).

[1055] MS (ESI, [M+H] - )m / z:244.04.

[1056] Step 3: Preparation of Intermediate 19d

[1057] Intermediate 19c (65.3 g), dichloromethane (650 mL), triethylamine (81 g, 111 mL, 799 mmol), and DMAP (0.813 g) were sequentially added to the reaction flask. Acetic anhydride (29.9 g, 27.9 mL, 293 mmol) was added under ice-cooling, and the mixture was allowed to return to room temperature for reaction. After TLC confirmed the reaction was complete, the solvent was evaporated under reduced pressure, and 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, and filtered. The filtrate was evaporated under reduced pressure to remove the solvent to obtain the target intermediate 19d (55.6 g).

[1058] 1 H NMR(500MHz,Chloroform-d)δ7.28(d,J=7.9Hz,1H),7.10–7.02(m,1H),7.02–6.95(m,1 H),4.79(d,J=27.0Hz,2H),3.92–3.78(m,2H),2.82–2.72(m,2H),2.33(d,J=2.0Hz,3H).

[1059] Step 4: Preparation of intermediate 19e

[1060] Intermediate 19d (30.73 g) and aluminum chloride (21.40 g) were added sequentially to the reaction flask. Under N protection, the mixture was heated to 170°C for reaction. After TLC confirmed the completion of the reaction, the reaction solution was cooled to room temperature and quenched with water. Dichloromethane was then added for extraction. The organic phase was separated, and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were 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).

[1061] MS (ESI, [M+H] - )m / z:286.0.

[1062] 1H NMR (500MHz, DMSO-d6) δ12.74(d,J=11.3Hz,1H),7.82(d,J=8.3Hz,1H),6.91(dd,J=14.9,8.3Hz,1 H), 4.80 (d, J = 9.9Hz, 2H), 3.86 (dt, J = 8.2, 5.9Hz, 2H), 2.77 (dt, J = 17.7, 6.1Hz, 2H), 2.64 (s, 3H).

[1063] Step 5: Preparation of intermediate 19f

[1064] Intermediate 19e (15.7 g) and MeOH (160 mL) were added sequentially to a reaction flask. A solution of sodium hydroxide (6.56 g) in water (160 mL) was added dropwise under an ice bath, and the mixture was allowed to return to room temperature for reaction. After TLC confirmed the reaction was complete, the methanol was evaporated under reduced pressure, and 1,4-dioxane (160 mL) and di-tert-butyl dicarbonate (13.12 g, 13.96 mL) were added. The mixture was allowed to react at room temperature. After TLC confirmed the reaction was complete, the reaction solution 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 evaporated from the filtrate under reduced pressure to yield the target intermediate 19f (19.83 g).

[1065] MS (ESI, [M+H] + )m / z:192.0.

[1066] 1 H NMR(500MHz,DMSO-d6)δ12.76(s,1H),7.76(d,J=8.3Hz,1H),6.80(d,J=8.3Hz ,1H),4.52(s,2H),3.57(d,J=1.8Hz,2H),2.64(d,J=6.1Hz,5H),1.43(s,9H).

[1067] Step 6: Preparation of Intermediate 19g

[1068] Intermediate 19f (15.92 g, 54.6 mmol), diethyl carbonate (32.3 g, 33.1 mL), and toluene (200 mL) were added to the reaction flask in sequence. 60 wt% sodium hydroxide (10.93 g, 273 mmol) was added portionwise in an ice bath, and the mixture was heated to 120°C for reaction. After TLC confirmed the reaction was complete, the reaction solution was cooled to room temperature and quenched by pouring into ice water. 1 M hydrochloric acid 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 filtrate was evaporated to remove the solvent under reduced pressure, and the residue was slurried with petroleum ether and filtered to obtain the filter cake of target intermediate 19g (12 g).

[1069] 1 H NMR(500MHz,DMSO-d6)δ12.46(s,1H),7.64(d,J=8.1Hz,1H),7.17(d,J=8.2Hz,1H), 5.56(s,1H),4.60(s,2H),3.62(t,J=6.0Hz,2H),2.83(t,J=5.8Hz,2H),1.44(s,9H).

[1070] Step 7: Preparation of Intermediate 19h

[1071] Intermediate 19g (12g), EtOH (120mL), and aqueous hydroxylamine solution (12.49g, 11.59mL, 189mmol) were added to the reaction flask in sequence, and the mixture was heated to 85°C for reaction. After TLC confirmed the completion of the reaction, the reaction solution was adjusted to pH 8 by adding saturated sodium bicarbonate solution, and extracted with ethyl acetate. The organic phase was separated, and the aqueous phase was adjusted to pH 3 with 1M 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 evaporated from the filtrate under reduced pressure to obtain the target intermediate 19h (10.44g).

[1072] MS (ESI, [M+H] - )m / z:331.0.

[1073] 1 H NMR(500MHz,DMSO-d6)δ12.85(s,1H),7.63(d,J=8.1Hz,1H),7.21(d,J=8.2Hz,1H), 4.67(s,2H),4.07(s,2H),3.69(t,J=5.9Hz,2H),2.98(t,J=5.9Hz,2H),1.44(s,9H).

[1074] Step 8: Preparation of intermediate 19i

[1075] Intermediate 19h (10.44 g), potassium carbonate (13.02 g), DMA (110 mL), and iodoethane (5.88 g, 3.05 mL, 37.7 mmol) were added to the reaction flask in sequence. Under nitrogen, the mixture was heated to 80°C for reaction. After TLC confirmed the reaction was complete, the reaction solution 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 target intermediate 19i (8.31 g).

[1076] MS (ESI, [M+H] + )m / z:361.2.

[1077] Step 9: Preparation of Intermediate 19j

[1078] Intermediate 19i (5.5 g), tetrahydrofuran (50 mL), and acrylamide (0.759 g, 10.68 mmol) were added to the reaction flask in sequence. The mixture was cooled to -15°C under N2 protection and potassium tert-butoxide solution in tetrahydrofuran (1 mol / L, 9.92 mL, 9.92 mmol) was added dropwise. After completion of the addition, the temperature was raised to 0°C for reaction. After TLC confirmed the reaction was complete, the system was added to saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography to obtain the target intermediate 19j (2.81 g).

[1079] MS (ESI, [M+H] - )m / z:384.34.

[1080] 1 H NMR(500MHz,DMSO-d6)δ11.09(s,1H),7.64(d,J=8.2Hz,1H),7.20(d,J=8.3Hz ,1H),4.67(s,2H),4.57(dd,J=12.0,5.0Hz,1H),3.69(t,J=5.9Hz,2H),2.98( t,J=5.9Hz,2H),2.77(ddd,J=17.3,12.1,5.3Hz,1H),2.61(dt,J=17.3,4.1Hz ,1H),2.54(d,J=4.5Hz,1H),2.18(dtd,J=13.5,5.2,3.7Hz,1H),1.44(s,9H).

[1081] Step 10: Preparation of compound 19

[1082] Intermediate 19j (850 mg) and ethyl acetate (20 mL) were added to a reaction flask, followed by a dioxane hydrochloride solution (4 mol / L, 11.03 mL, 44.1 mmol). The mixture was allowed to react at room temperature. After TLC confirmed the reaction was complete, the reaction solution was concentrated to yield compound 19 (760 mg).

[1083] MS (ESI, [M+H] + )m / z:286.12.

[1084] 1 H NMR (500MHz, DMSO-d6) δ11.08(s,1H),7.54(d,J=8.1Hz,1H),7.05(d,J=8.2Hz,1H),4.54(dd,J=11.8,5.0Hz,1H),3.97(s,2H),3.03(t,J=5.8Hz,2 H),2.86(t,J=5.8Hz,2H),2.76(td,J=12.0,5.9Hz,1H),2.60(dt,J=17.3,4.2Hz,1H),2.46(dd,J=12.2,4.4Hz,1H),2.18(dq,J=13.5,4.8Hz,1H).

[1085] Example 20 Synthesis of Compound 20

[1086]

[1087] Step 1: Preparation of intermediate 20b

[1088] Liquid bromine (55.5 g) was added dropwise to a solution of 20a (50 g) in acetic acid (180 mL) at 15°C. After the addition was complete, the mixture was allowed to react at room temperature. After TLC confirmed the reaction was complete, methyl tert-butyl ether was added dropwise to the reaction mixture, stirred, and filtered. The filter cake was collected and dried to yield intermediate 20b (95 g).

[1089] MS (ESI, [M+H] + )m / z:231.9.

[1090] Step 2: Preparation of intermediate 20c

[1091] To a reaction flask, 20b (80 g), glyoxal dimethyl acetal (66.9 g), triethylamine (27.3 g), anhydrous sodium sulfate (80 g), and methanol (600 mL) were added sequentially and allowed to react at room temperature overnight. The reaction solution was cooled to -15°C, and sodium borohydride (14.6 g) was added portionwise. After completion of addition, the mixture was allowed to react at room temperature. After TLC confirmed the completion of the reaction, approximately half of the methanol was removed by concentration, and dichloromethane and water were added to the reaction solution. The organic phase was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to obtain intermediate 20c (60 g).

[1092] MS (ESI, [M+H] + )m / z:319.9.

[1093] Step 3: Preparation of intermediate 20d

[1094] At 0°C under nitrogen, 20c (47g) was added dropwise to trifluoroacetic anhydride (148g). After the addition was complete, the mixture was allowed to react at room temperature for 1h. Trifluoroacetic acid (87g) was added dropwise, and the temperature was raised to 40°C for 1h. Triethylsilane (68g) was added dropwise, and the temperature was raised to 60°C for 1h. After TLC confirmed the reaction was complete, 400mL of ethyl acetate and 600mL of water were added to the reaction solution. The organic phase was separated, washed three times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to obtain intermediate 20d (20.5g).

[1095] 1H NMR(500MHz,DMSO-d6)δ7.46(dd,J=8.9,1.7Hz,1H),6.87(d,J=8.9Hz,1H),3.77(d,J=2.8Hz,3 H),3.67(ddt,J=14.4,5.7,3.4Hz,4H),3.22(ddd,J=11.9,6.4,4.6Hz,2H),3.16–3.06(m,2H).

[1096] Step 4: Preparation of intermediate 20e

[1097] At 0°C, under nitrogen, 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). After the addition was complete, the mixture was allowed to react at room temperature. After TLC confirmed the reaction was complete, the reaction solution was slowly poured into ice water, stirred for 10 min, filtered, and the filter cake was collected and dried to yield 20e (18.5 g).

[1098] MS (ESI, [MH] + )m / z:337.9.

[1099] 1H NMR (500MHz, DMSO-d6) δ9.74(s,1H),7.26(dd,J=8.7,1.3Hz,1H),6.68(dd,J=8.7,3.1Hz,1H),3.73–3.61(m,4H),3.23–3.13(m,2H),3.12–3.02(m,2H).

[1100] Step 5: Preparation of intermediate 20f

[1101] Acetic anhydride (5.65 g) was slowly added dropwise to a stirred solution of 20e (17.0 g) and triethylamine (7.63 g) in 200 mL of dichloroethane at 0°C under nitrogen. After the addition was complete, the mixture was allowed to react at room temperature. After TLC confirmed the reaction was complete, the reaction solution was slowly poured into water. The organic phase was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 20f (19.8 g).

[1102] MS (ESI, [M+H] + )m / z:381.7.

[1103] Step 6: Preparation of intermediate 20g

[1104] To the reaction flask, 20f (19.5 g), aluminum chloride (18.7 g), and o-dichlorobenzene (80 mL) were added sequentially and the temperature was raised to 150°C. After TLC confirmed the reaction was complete, the reaction solution was cooled to room temperature, 250 mL of 3N dilute hydrochloric acid was added, and extraction was performed with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the concentrate was separated and purified by silica gel column chromatography to obtain the intermediate 20 g (11.2 g).

[1105] MS (ESI, [MH] + )m / z:300.0.

[1106] 1H NMR(500MHz,DMSO-d6)δ12.83(d,J=4.8Hz,1H),7.78(dd,J=8.1,3.5Hz,1H),6.83(t ,J=8.3Hz,1H),3.69(ddd,J=12.9,9.6,5.9Hz,4H),3.11–3.00(m,4H),2.64(s,3H).

[1107] Step 7: Preparation of Intermediate 20h

[1108] To the reaction flask, 20g (9.5g), methanol (100mL), water (20mL), and sodium hydroxide (1.9g) were added in sequence and allowed to react at room temperature for 1h. Di-tert-butyl dicarbonate (8.2g) was added and allowed to react at room temperature. After TLC confirmed the reaction was complete, ethyl acetate 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 concentrate was separated and purified by silica gel column chromatography to obtain intermediate 20h (8.5g).

[1109] 1 H NMR(500MHz,DMSO-d6)δ12.80(s,1H),7.74(d,J=8.1Hz,1H),6.79(d,J=8.2Hz,1H ),3.45(dt,J=11.6,5.0Hz,4H),2.92(q,J=5.0Hz,4H),2.63(s,3H),1.38(s,9H).

[1110] Step 8: Preparation of intermediate 20i

[1111] To the reaction flask were added 20h (8.5 g), diethyl carbonate (16.4 g), and toluene (100 mL) in sequence. 60 wt% sodium hydroxide (5.57 g) was added portionwise, and the reaction mixture was heated to 115°C. After TLC confirmed the reaction was complete, the reaction mixture was cooled to room temperature, and ethyl acetate and water were added. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the concentrate was purified by silica gel column chromatography to yield intermediate 20i (9.0 g).

[1112] MS (ESI, [MH] + )m / z:330.1.

[1113] Step 9: Preparation of Intermediate 20j

[1114] 20i (9.0 g), hydroxylamine aqueous solution (8.7 g), and ethanol (100 mL) were added sequentially to the reaction flask, and the reaction mixture was heated to 80°C. After TLC confirmed the reaction was complete, 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 separated and purified by silica gel column chromatography to obtain intermediate 20j (8.5 g).

[1115] MS (ESI, [MH] + )m / z:345.4.

[1116] 1H NMR (500MHz, DMSO-d6) δ7.53(d,J=8.0Hz,1H),7.12(d,J=8.0Hz,1H),3.73(q,J=13.9,11.5Hz,2 H),3.59–3.54(m,2H),3.52–3.47(m,2H),3.13(t,J=5.2Hz,2H),3.07–2.98(m,2H),1.40(s,9H).

[1117] Step 10: Preparation of intermediate 20k

[1118] 20j (8.5 g), potassium carbonate (3.3 g), iodoethane (5.1 g), and DMA (70 mL) were added sequentially to the reaction flask, and the reaction mixture was heated to 80°C. After TLC confirmed the reaction was complete, the reaction mixture was cooled to room temperature, and ethyl acetate and water were added. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the concentrate was purified by silica gel column chromatography to obtain intermediate 20k (6.5 g).

[1119] MS (ESI, [MH] + )m / z:373.1.

[1120] 1 H NMR (500MHz, DMSO-d6) δ7.56(d,J=8.0Hz,1H),7.22(d,J=8.0Hz,1H),4.13(dd,J=13.7,6.6Hz,4H),3.55(dt ,J=28.2,5.0Hz,4H),3.17(s,2H),3.05(t,J=5.2Hz,2H),1.38(dd,J=9.3,4.4Hz,9H),1.19(t,J=6.5Hz,3H).

[1121] Step 11: Preparation of Intermediate 201

[1122] At -10°C, under nitrogen, a 1M solution of sodium tert-butoxide in tetrahydrofuran (14 mL) was slowly added dropwise to a stirred solution of 20k (5.6 g) in tetrahydrofuran (70 mL). The mixture was then incubated for 30 min. Acrylamide (0.71 g) was dissolved in 5 mL of tetrahydrofuran and added dropwise to the reaction mixture. After TLC confirmed the reaction was complete, the reaction mixture was slowly poured into saturated ammonium chloride. Ethyl acetate was added, and the organic phase was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The concentrate was purified by silica gel column chromatography to yield Intermediate 20l (2.5 g).

[1123] MS (ESI, [MH] + )m / z:397.9.

[1124] 1 H NMR (500MHz, DMSO-d6) δ11.08(s,1H),7.58(d,J=8.0Hz,1H),7.21(d,J=8.1Hz,1H),4.55(dd,J=12.0,4.9Hz,1H),3.55(dt,J=31.4,5.0Hz,4H),3.22–3 .00(m,4H),2.77(ddd,J=17.3,12.0,5.3Hz,1H),2.60(dt,J=17.3,4.1Hz,1 H),2.46(dd,J=12.2,4.4Hz,1H),2.20–2.12(m,1H),1.38(d,J=6.3Hz,9H).

[1125] Step 12: Preparation of compound 20

[1126] 20l (2.5 g), ethyl acetate (30 mL), and dioxane hydrochloride (15 mL, 4 M) were added to the reaction flask in sequence and reacted at room temperature. After TLC confirmed the reaction was complete, the mixture was filtered, the filter cake was collected, and dried to obtain compound 20 (18.5 g).

[1127] MS (ESI, [M+H] + )m / z:300.2.

[1128] 1H NMR (500MHz, DMSO-d6) δ11.10(s,1H),9.53(s,2H),7.65(d,J=8.1Hz,1H),7.27(d,J=8.1Hz,1H),4.59(dd,J=12.1,4.9Hz,1H),3.43(dd,J= 7.0,3.3Hz,2H),3.37–3.19(m,6H),2.78(ddd,J=17.3,12.1,5.3Hz,1H),2.61(dt,J=17.3,4.1Hz,1H),2.17(dtd,J=13.4,5.2,3.6Hz,1H).

[1129] Example 21 Synthesis of Compound 21

[1130]

[1131] Step 1: Preparation of compound 21b

[1132] 21a (33.3 g), MeOH (500 mL), iodophenyldiacetic acid (82 g, 246 mmol), and potassium hydroxide (127 g) were sequentially added to a reaction flask under an ice bath, and the mixture was allowed to react at room temperature. After TLC confirmed the completion of the reaction, the reaction solution was evaporated under reduced pressure to remove the solvent. 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 evaporated under reduced pressure. The residue was dissolved in THF (500 mL), followed by the addition of hydrochloric acid (6 M, 68.4 mL). The reaction was allowed to react at room temperature for 0.5 h. The reaction solution was then adjusted to pH 8 with saturated sodium bicarbonate solution, extracted with 200 mL of ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to afford 21b (16 g).

[1133] MS (ESI, [M+H] + )m / z:178.9.

[1134] Step 2: Preparation of compound 21c

[1135] 21b (80 g) and MeOH (1000 mL) were added to a reaction flask in sequence. Sodium borohydride (17.83 g, 471 mmol) was added after the solution was dissolved and allowed to react at room temperature. After TLC confirmed the reaction was complete, saturated ammonium chloride solution was added dropwise to quench the reaction solution. Ethyl acetate was added for extraction, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain 21c (82 g).

[1136] 1 H NMR (500MHz, DMSO-d6) δ7.17(t,J=7.8Hz,1H),6.87(d,J=7.4Hz,1H),6.80(d,J=8.1Hz,1H),5.34(d,J=6.3Hz,1H),5.13(d,J=5.0Hz,1 H), 4.67 (t, J = 5.8Hz, 1H), 4.06 (ddd, J = 12.0, 6.8, 5.1Hz, 1H), 3.75 (s, 3H), 3.03 (dd, J = 15.8, 7.1Hz, 1H), 2.43 (dd, J = 15.8, 6.5Hz, 1H).

[1137] Step 3: Preparation of compound 21d

[1138] To the reaction flask were added 21c (35 g), toluene (300 mL), and p-toluenesulfonic acid (66.9 g) in sequence, and the mixture was heated to 120°C for reaction. After TLC confirmed the completion of the reaction, the reaction solution was cooled to room temperature and quenched by the addition of ethyl acetate and water. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to yield 21d (35.5 g).

[1139] 1 H NMR (500MHz, DMSO-d6) δ7.26–7.22(m,1H),6.93–6.87(m,2H),3.79(s,3H),3.53(s,2H),3.37(s,2H).

[1140] Step 4: Preparation of compound 21e

[1141] 21d (35 g), MeOH (400 mL), and sodium borohydride (5.83 g) were added sequentially to a reaction flask and allowed to react at room temperature. After TLC confirmed the reaction was complete, the reaction solution was quenched by dropwise addition of saturated ammonium chloride solution. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to yield 21e (18 g).

[1142] 1 H NMR (500MHz, DMSO-d6) δ7.13–7.07(m,1H),6.83–6.78(m,1H),6.74(d,J=8.1Hz,1H),4.81(d,J=3.8Hz,1H),4.49( tq,J=6.5,3.4Hz,1H),3.75(s,3H),3.04(dd,J=16.1,6.1Hz,1H),2.94(dd,J=16.3,6.2Hz,1H),2.79–2.61(m,2H).

[1143] Step 5: Preparation of compound 21f

[1144] 21e (60 g), dichloromethane (500 mL), triethylamine (111 g, 152 mL), and acetic anhydride (41.0 g, 38.2 mL) were added sequentially to a reaction flask and allowed to react at room temperature. After TLC confirmed the reaction was complete, 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 yield 21f (37.2 g).

[1145] 1 H NMR(500MHz,DMSO-d6)δ7.22–7.06(m,1H),6.82(dd,J=27.3,8.3Hz,2H),5.41(s,1H),3.78(d,J=13.2 Hz,3H),3.32–3.20(m,1H),3.18–3.09(m,1H),2.85(dd,J=34.6,17.1Hz,2H),1.97(d,J=15.3Hz,3H).

[1146] Step 6: Preparation of compound 21g

[1147] Boron trichloride (19.22 g, 164 mL) was slowly added dropwise to a stirred solution of 21f (17 g) in dichloromethane (500 mL) under an ice bath. After the addition was complete, the mixture was allowed to warm to room temperature. After TLC confirmed the reaction was complete, the reaction solution was quenched by adding 160 mL of 1M HCl and 200 mL of aqueous solution. The mixture was then extracted with dichloromethane. The organic phase was separated, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to yield 21g (15 g).

[1148] MS (ESI, [MH] - )m / z:190.9.

[1149] Step 7: Preparation of compound 21h

[1150] To the reaction flask were added 21g (16g), dichloromethane (200mL), triethylamine (9.50g, 13.01mL), and acetic anhydride (5.27g, 4.91mL) in sequence and allowed to react at room temperature. After TLC confirmed the completion of the reaction, 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 yield 21h (14.8g).

[1151] MS (ESI, [MH] - )m / z:233.01.

[1152] Step 8: Preparation of compound 21i

[1153] To the reaction flask, 21h (11.6 g), dichloromethane (300 mL), and zirconium tetrachloride (46.2 g, 198 mmol) were added sequentially and reacted at 50°C. After TLC confirmed the reaction was complete, the reaction solution was cooled to room temperature, and 3M 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 evaporated under reduced pressure to yield 21i (11.4 g).

[1154] 1 H NMR (500MHz, DMSO-d6) δ12.34(s,1H),7.80(d,J=8.0Hz,1H),6.91(d,J=8.0Hz,1H),5.45(tt,J=6.3,2.2Hz,1H),3.37–3.33 (m,1H),3.19(dd,J=17.3,6.3Hz,1H),2.95(dd,J=17.9,2.2Hz,1H),2.86(dd,J=17.3,2.1Hz,1H),2.63(s,3H),1.97(s,3H).

[1155] Step 9: Preparation of compound 21k

[1156] 21i (15.4 g), ethanol (200 mL), and an aqueous solution of sodium hydroxide (2.63 g) (10.00 mL) were added to the reaction flask in sequence and reacted at room temperature. After TLC confirmed the completion of the reaction, the reaction solution was adjusted to pH 2-3 by adding 2M HCl aqueous solution, then extracted with ethyl acetate and water, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude intermediate 21j. Dichloroethane (200 mL), imidazole (17.90 g), and TBSCl (39.6 g) were added and refluxed overnight. The reaction solution was cooled to room temperature, extracted with 100 mL of dichloromethane and 300 mL of water. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain 21k (15.4 g).

[1157] 1 H NMR (500MHz, DMSO-d6) δ12.25(s,1H),7.69(d,J=8.0Hz,1H),6.79(d,J=8.0Hz,1H),4.64(dq,J=6.2,3.2Hz,1H),3.05(ddd,J =56.3,16.6,6.2Hz,2H),2.71(dd,J=17.0,3.6Hz,1H),2.61(dd,J=16.3,3.5Hz,1H),2.51(s,3H),0.78(s,9H),0.00(s,6H).

[1158] Step 10: Preparation of compound 211

[1159] 21k (8.4 g) and THF (300 mL) were added to the reaction flask in sequence. Diethyl carbonate (16.19 g, 16.52 mL) was added and the temperature was cooled to approximately 0°C. 60 wt% sodium hydroxide (5.48 g, 137 mmol) was added portionwise and the reaction was heated to 85°C. After TLC confirmed the reaction was complete, the reaction solution was cooled to room temperature and slowly poured into ice water. The solution was extracted with ethyl acetate and the organic phase was discarded. The aqueous phase was adjusted to pH 1-2 with 3M hydrochloric acid and then extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to yield 21l (10 g).

[1160] MS (ESI, [MH]-) m / z: 331.2.

[1161] Step 11: Preparation of Intermediate 21m

[1162] To the reaction flask, 21l (10 g), aqueous hydroxylamine solution (9.93 g, 9.93 mL, 150 mmol), and ethanol (100 mL) were added sequentially and reacted at 85°C. After TLC confirmed the reaction was complete, the reaction solution was cooled to room temperature, and the residue was extracted with ethyl acetate and saturated aqueous sodium carbonate. The organic phase was discarded. The aqueous phase was adjusted to pH 2-3 with 1 M aqueous HCl, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to yield 21m (11 g).

[1163] MS (ESI, [MH]-) m / z: 346.2.

[1164] Step 12: Preparation of intermediate 21n

[1165] To a reaction flask, 21m (10 g), ethanol (150 mL), and sulfuric acid (14.40 g, 7.83 mL, 144 mmol) were added sequentially and reacted at 85°C. After TLC confirmed the reaction was complete, the reaction solution was cooled to room temperature and adjusted to pH 7 by adding dichloromethane and saturated sodium bicarbonate solution. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to yield 21n (5.8 g).

[1166] MS (ESI, [M+H]+) m / z: 261.97.

[1167] 1 H NMR (500MHz, DMSO-d6) δ7.65(d,J=8.0Hz,1H),7.33(d,J=8.0Hz,1H),5.09(d,J=4.0Hz,1H),4.71(dt,J=6.4,3.1Hz,1H ),4.26–4.12(m,4H),3.30(ddd,J=31.0,16.5,6.0Hz,2H),2.98(ddd,J=31.6,16.5,3.0Hz,2H),1.22(t,J=7.1Hz,3H).

[1168] Step 13: Preparation of Intermediate 21

[1169] Compound 21n (300 mg), dichloromethane (10 mL), and Dess-Martin periodinane (974 mg) were added sequentially to a reaction flask, and the mixture was stirred at room temperature. After TLC confirmed the reaction was complete, the reaction solution was poured into saturated sodium sulfite solution to quench the mixture, followed by extraction 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 filtrate was evaporated under reduced pressure to remove the solvent to yield compound 21 (320 mg).

[1170] MS (ESI, [M+H] +)m / z:260.0.

[1171] 1 H NMR(500MHz,DMSO-d6)δ7.74(d,J=8.1Hz,1H),7.38(d,J=8.1Hz,1H),4.21(s ,2H),4.14(q,J=7.1Hz,2H),3.79(s,2H),3.72(s,2H),1.19(t,J=7.1Hz,3H).

[1172] Example 22, 23 Synthesis of Compounds 22, 23

[1173]

[1174] Step 1: Preparation of intermediate 22b

[1175] To a reaction flask, CCl₄ (6750 mL), 22a (450 g), 2,2-azobisisobutyronitrile (18.45 g), and N-bromosuccinimide (1194 g) were added sequentially. The mixture was heated to 80°C and refluxed. After TLC confirmed the reaction was complete, the reaction solution was filtered, the solvent was evaporated under reduced pressure, and the filtrate was slurried with petroleum ether. The mixture was filtered and the filter cake was collected to obtain intermediate 22b (833 g).

[1176] 1 H NMR (500MHz, DMSO-d6) δ7.34(d,J=8.1Hz,1H),7.06(ddd,J=17.8,8.1,1.1Hz,2H),4.77(d,J=9.5Hz,4H),3.87(s,3H).

[1177] Step 2: Preparation of intermediate 22c

[1178] To a reaction flask, 60 wt% NaH (187 g) and THF (2000 mL) were added sequentially. Diethyl malonate (300 g, 284 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 30 min before the addition of 22b (606 g). The reaction was allowed to stir at room temperature. After TLC confirmed the reaction was complete, the reaction solution was slowly added dropwise to a saturated ammonium chloride solution to quench the reaction. 2000 mL of petroleum ether and 2000 mL of water were added, and 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 and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure to remove the solvent, and purified by silica gel column chromatography to yield 262 g of intermediate 22c.

[1179] MS (ESI, [MH]+) m / z: 293.2

[1180] 1H NMR(500MHz,DMSO-d6)δ7.16(t,J=7.8Hz,1H),6.80(dd,J=15.3,7.8Hz,2H),4.1 4(q,J=7.1Hz,4H),3.77(s,3H),3.48(s,2H),3.38(s,2H),1.17(t,J=7.0Hz,6H).

[1181] Step 3: Preparation of intermediate 22d

[1182] To a reaction flask, 22c (130 g), DMSO (1000 mL), H₂O (300 mL), and lithium chloride (42.6 g) were added and stirred at 180°C. After TLC confirmed the reaction was complete, the reaction solution was poured into 1000 mL of ice water to quench, and the pH was adjusted to 2-3 with 1 M hydrochloric acid. The solution was extracted three times with 1 L of ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure to remove the solvent to yield 191 g of intermediate 22d.

[1183] MS (ESI, [M+H]+) m / z: 193.05

[1184] Step 4: Preparation of intermediate 22e

[1185] To the reaction flask, 22d (85 g), ethanol (1000 mL), and concentrated sulfuric acid (44 g) were added sequentially, and the mixture was heated to 70°C for reaction. After TLC confirmed the reaction was complete, the reaction solution was cooled to room temperature, the solvent was evaporated under reduced pressure, and the residue was poured into ice water and neutralized with saturated aqueous sodium bicarbonate. After neutralization, 1000 mL of petroleum ether was added and extracted three times. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to remove the solvent to obtain 99 g of intermediate 22e.

[1186] MS (ESI, [M+H]+) m / z: 221.1

[1187] 1 H NMR (500MHz, DMSO-d6) δ7.13(t,J=7.8Hz,1H),6.81(d,J=7.5Hz,1H),6.76(d,J=8.2Hz,1H),4.09(q,J=7 .1Hz,2H),3.76(s,3H),3.36–3.31(m,1H),3.20–3.10(m,2H),3.10–2.96(m,2H),1.20(t,J=7.1Hz,3H).

[1188] Step 5: Preparation of intermediate 22f

[1189] In a reaction flask, under nitrogen protection, boron tribromide (415 g, 1657 mL) was added dropwise to a stirred solution of 22e (150 g) in dichloromethane (750 mL), with the reaction temperature controlled to be below 0°C. MeOH (500 mL) was added and the reaction was allowed to proceed at 0°C for 30 minutes. The mixture was then 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, stirred, and separated using a separatory funnel. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent in the filtrate was removed under reduced pressure to yield 122 g of intermediate 22f.

[1190] 1 H NMR(500MHz,DMSO-d6)δ9.24(s,1H),6.95(t,J=7.7Hz,1H),6.70–6.60(m,1H),6.62–6.52(m,1H),4.10(q ,J=7.1Hz,2H),3.33–3.27(m,1H),3.13–3.01(m,3H),2.96(dd,J=16.1,7.1Hz,1H),1.20(t,J=7.1Hz,3H).

[1191] Step 6: Synthesis of Intermediate 22g

[1192] To a reaction flask at 0°C under N2 protection, 22f (130g) and tetrahydrofuran (2000mL) were added sequentially, followed by the slow dropwise addition of a 1M solution of lithium aluminum tetrahydride in tetrahydrofuran (438mL). The mixture was then reacted in an ice-water bath. After TLC confirmed the reaction was complete, 3L of water was slowly added dropwise to quench the reaction. The pH was adjusted to 1-2 with concentrated hydrochloric acid, and the reaction was extracted three times with 2L of ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was then freed from the solvent under reduced pressure to yield 129g of intermediate 22g.

[1193] 1 H NMR (500MHz, DMSO-d6) δ6.88(t,J=7.7Hz,1H),6.58(d,J=7.3Hz,1H),6.52(d,J=7.9Hz,1H),3.38–3. 32(m,2H),2.84(ddd,J=33.5,16.2,8.3Hz,2H),2.60(dq,J=13.9,8.1,6.6Hz,1H),2.55–2.49(m,3H).

[1194] Step 7: Preparation of Intermediate 22h

[1195] To the reaction flask, 22 g (120 g), 4-dimethylaminopyridine (7.14 g), dichloromethane (2000 mL), and triethylamine (177 g, 244 mL) were added sequentially. Acetyl chloride (101 g, 91 mL) was slowly added dropwise at 0°C, and the mixture was allowed to react at room temperature. After TLC confirmed the reaction was complete, the reaction solution was poured into a mixture of dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography to obtain 127 g of intermediate 22h.

[1196] MS (ESI, [M+H]+) m / z: 249.3

[1197] 1 H NMR (500MHz, DMSO-d6) δ7.18(t,J=7.7Hz,1H),7.11(d,J=7.4Hz,1H),6.88(d,J=7.9Hz,1H),4.07–3.96(m,2H),3 .11–3.00(m,1H),2.87(dd,J=15.9,7.8Hz,1H),2.81–2.69(m,2H),2.56–2.50(m,1H),2.27(s,3H),2.02(s,3H).

[1198] Step 8: Preparation of intermediate 22i

[1199] To the reaction flask, 22h (91 g), dichloromethane (2000 mL), and zirconium tetrachloride (342 g) were added sequentially. The reaction was stirred at 50°C overnight under N2 protection. After completion of the reaction, the reaction solution was cooled to room temperature and poured into a mixed solvent of 1000 mL of ice water and 1000 mL of dichloromethane. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was purified by silica gel column chromatography to yield 90 g of intermediate 22i.

[1200] MS (ESI, [MH]+) m / z: 247.2

[1201] 1 H NMR (500MHz, DMSO-d6) δ12.34(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).

[1202] Step 9: Preparation of intermediate 22j

[1203] 22i (95 g) and ethanol (900 mL) were added sequentially to a reaction flask. A solution of sodium hydroxide (77 g) in H₂O (800 mL) was added dropwise under an ice bath. The mixture was reacted at room temperature under N₂ protection. After TLC confirmed the reaction was complete, the reaction solution was diluted with 2 L of ethyl acetate and 1 L of water. 3 M hydrochloric acid was slowly added to adjust the pH to 3. The layers were separated, and the aqueous layer was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to remove the solvent under reduced pressure to obtain 86 g of intermediate 22j.

[1204] MS (ESI, [MH]+) m / z: 205.1

[1205] 1 H NMR (500MHz, DMSO-d6) δ12.34(s,1H),7.73(d,J=8.0Hz,1H),6.84(d,J=8.0Hz,1H),4.68(t,J=5.3Hz,1H),3.36(ddd,J=7.0,5 .2,2.0Hz,2H),2.98(dd,J=17.0,8.2Hz,1H),2.92–2.82(m,1H),2.72(dd,J=16.9,5.6Hz,1H),2.61(s,3H),2.61–2.53(m,2H).

[1206] Step 10: Preparation of Intermediate 22k

[1207] To a reaction flask, 22j (37 g), 1,2-dichloroethane (700 mL), imidazole (36.6 g), and tert-butyldimethylsilyl chloride (29.7 g) were added sequentially and reacted at 75°C. After TLC confirmed the reaction was complete, the reaction solution 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, filtered, and the solvent was evaporated from the filtrate under reduced pressure to obtain 60 g of intermediate 22k.

[1208] 1 H NMR (500MHz, DMSO-d6) δ12.31(s,1H),7.71(d,J=8.0Hz,1H),6.82(d,J=8.0Hz,1H),3.52(d,J=6.4Hz,2H),2.97(dd,J=16.9,8.0Hz,1H),2. 85(dd,J=15.4,7.5Hz,1H),2.69(dd,J=16.9,5.6Hz,1H),2.64–2.59(m,1H),2.58(s,3H),2.55(d,J=5.6Hz,1H),0.82(s,9H),0.00(s,6H).

[1209] Step 11: Preparation of Intermediate 221

[1210] To a reaction flask, 22k (55 g), diethyl carbonate (101 g, 103 mL), and toluene (1000 mL) were added sequentially. The reaction mixture was cooled to 0°C, and 60 wt% sodium hydride (34.3 g, 858 mmol) was added portionwise. After completion of the addition, the mixture was slowly heated to 120°C for reaction. After TLC confirmed the reaction was complete, the reaction mixture was slowly poured into ice water and extracted with ethyl acetate. The aqueous phase was adjusted to pH 3 with 3N hydrochloric acid and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by evaporation under reduced pressure to yield 53.6 g of intermediate 22l.

[1211] MS (ESI, [MH]+) m / z: 345.1.

[1212] 1 H NMR (500MHz, DMSO-d6) δ12.31(s,1H),7.57(d,J=7.9Hz,1H),7.16(d,J=7.9Hz,1H),5.49(s,1H),3.56(d,J=6.4Hz,2H) ,3.04(ddd,J=16.0,13.3,8.1Hz,2H),2.75(td,J=14.8,13.3,4.4Hz,2H),2.71–2.63(m,1H),0.81(s,9H),0.00(s,6H).

[1213] Step 12: Preparation of Intermediate 22m

[1214] 22l (51 g), hydroxylamine hydrochloride (61.4 g), sodium ethoxide (61.1 g) and ethanol (2000 mL) were added to the reaction flask in sequence and heated to 85°C under N2 protection. After TLC confirmed the completion of the reaction, the reaction solution was solvent-free under reduced pressure, 2 L of water was added, and the pH was adjusted to 8-9 with saturated sodium carbonate solution. Ethyl acetate was added for extraction, and the aqueous phase was collected. 1 M hydrochloric acid was added to the aqueous phase to adjust the pH to 6-7, and ethyl acetate was added for extraction. The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was solvent-free under reduced pressure to obtain 47 g of intermediate 22m.

[1215] MS (ESI, [MH]+) m / z: 360.2.

[1216] 1H NMR(500MHz,DMSO-d6)δ7.55(d,J=8.0Hz,1H),7.22(d,J=8.0Hz,1H),3.97(s,2H),3. 57(d,J=6.6Hz,2H),3.16–3.07(m,2H),2.88–2.72(m,3H),0.81(s,9H),0.00(s,6H).

[1217] Step 13 Preparation of Intermediate 22n

[1218] To a reaction flask, 22m (47 g), ethanol (1500 mL), and concentrated sulfuric acid (65.1 g, 35.4 mL) were added sequentially. Under N2 protection, the mixture was heated to 85°C for reaction. After TLC confirmed the reaction was complete, the reaction solution was cooled to room temperature, the solvent was removed by rotary evaporation, and dichloromethane was added. Saturated aqueous sodium bicarbonate was added dropwise to neutralize the reaction. The reaction mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was then evaporated under reduced pressure to remove the solvent to obtain 43 g of intermediate 22n.

[1219] MS (ESI, [MH]+) m / z: 276.1

[1220] 1 H NMR (500MHz, DMSO-d6) δ7.58(d,J=8.0Hz,1H),7.27(d,J=8.0Hz,1H),4.74(q,J=4.9Hz,1H),4.16(s,2H),4.12(t,J=7.1Hz,2H) ,3.43(dd,J=6.8,5.3Hz,2H),3.15(ddd,J=29.7,16.4,8.3Hz,2H),2.93–2.81(m,2H),2.79–2.70(m,1H),1.19(t,J=7.1Hz,3H).

[1221] Step 14 Preparation of intermediates 22o-1, 22o-2 and

[1222] For preparative resolution, 43 g of intermediate 22n was dissolved in 430 mL of dichloromethane-ethanol solution to a concentration of approximately 100.0 mg / mL. The filtrate was filtered through a 0.45 μm organic filter membrane. The instrument was a YMC high-pressure preparative chromatograph, using a CHIRALPAKIG column (30 x 250 mm, S-10 μm). Mobile phases A: ethanol and B: n-hexane. The leading peak yielded 9.057 g of intermediate 22o-1, and the trailing peak yielded 8.833 g of intermediate 22o-2.

[1223] 22o-1:MS(ESI,[MH]+)m / z: 276.1.

[1224] 22o-2:MS(ESI,[MH]+)m / z: 276.1.

[1225] Step 15 Preparation of Compound 22

[1226] To the reaction flask, 22o-1 (11.93 g), THF (200 mL), and acrylamide (3.39 g) were added sequentially under N2 protection. After cooling to 0°C, potassium tert-butoxide (3.89 g, 34.7 mL) was added, and the mixture was allowed to react at 0°C. After TLC confirmed the completion of the reaction, the reaction solution was added dropwise to an ice-cold saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure to remove the solvent, filtered, and the filter cake was collected to obtain 6.77 g of compound 22.

[1227] 1 H NMR (500 MHz, DMSO-d6) δ 11.08 (s, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 8.1 Hz, 1H), 4.74 (td, J = 5.3, 2.2 Hz, 1H), 4.56 (dd, J = 11.8, 5.0 Hz, 1H), 3.43 (dd, J = 6.8, 5.3 Hz, 2H), 3.22–3.09 (m, 2H), 2.94–2.83 (m, 2H), 2.76 (dq, J = 16.9, 6.3 Hz, 2H), 2.60 (dt, J = 17.3, 4.2 Hz, 1H), 2.50–2.44 (m, 1H), 2.23–2.13 (m, 1H). Step 16 Preparation of the compound of Example 23

[1228] To a reaction flask, 22o-2 (12.83 g), THF (200 mL), and acrylamide (3.64 g) were added sequentially. After cooling to 0°C, potassium tert-butoxide (4.18 g, 37.3 mL) was added. The mixture was reacted at 0°C under N2 protection. After TLC confirmed the reaction was complete, the reaction solution was added dropwise to an ice-cold 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 filtrate was evaporated under reduced pressure to remove the solvent, filtered, and the filter cake collected to yield 7.454 g of Example 23.

[1229] 1H NMR (500 MHz, DMSO-d6) δ 11.08 (s, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.25 (d, J = 8.1 Hz, 1H), 4.74 (td, J = 5.3, 2.2 Hz, 1H), 4.56 (dd, J = 11.8, 5.0 Hz, 1H), 3.43 (dd, J = 6.8, 5.2 Hz, 2H), 3.21–3.09 (m, 2H), 2.94–2.83 (m, 2H), 2.80–2.71 (m, 2H), 2.60 (dt, J = 17.3, 4.2 Hz, 1H), 2.46 (dd, J = 12.1, 4.5 Hz, 1H), 2.23–2.15 (m, 1H). Example 24 Synthesis of Compound 24

[1230]

[1231] Step 1: Preparation of intermediate 24b

[1232] 24a (7.00 g), 4-piperidinemethanol (6.86 g), N,N-diisopropylethylamine (9.62 g), and dimethyl sulfoxide (70 mL) were added sequentially to a reaction flask, and the mixture was heated to 100°C for reaction. After TLC confirmed the completion of the reaction, the reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was stirred for 10 minutes. The mixture was filtered, and the filter cake was collected and dried to obtain intermediate 24b (13.7 g).

[1233] MS (ESI, [M+H] + )m / z:237.1.

[1234] Step 2: Preparation of intermediate 24c

[1235] To the reaction flask were added intermediate 24b (13.5 g), 10% palladium on carbon (2.70 g), and methanol (200 mL) in sequence, and the atmosphere was replaced with hydrogen three times, and the reaction was allowed to proceed overnight. The palladium on carbon was removed by filtration, and the mixture was concentrated to give intermediate 24c (9.0 g).

[1236] MS (ESI, [M+H] + )m / z:207.3.

[1237] 1H NMR (500MHz, DMSO-d6) δ6.68(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).

[1238] Step 3: Preparation of intermediate 24d

[1239] To a reaction flask, intermediate 1f (6.0 g), 24c (3.86 g), BINAP (1.16 g), cesium carbonate (18.28 g), palladium acetate (0.42 g), and 1,4-dioxane (80 mL) were added sequentially. The atmosphere was purged with nitrogen three times, and the mixture was heated to 100°C for reaction. After TLC confirmed the reaction was complete, the reaction solution was cooled to room temperature, and ethyl acetate and water were added to the residue. The organic phase was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to afford intermediate 24d (7.1 g).

[1240] MS (ESI, [M+H] + )m / z:491.5.

[1241] 1 H NMR (500MHz, DMSO-d6) δ8.79(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).

[1242] Step 4: Preparation of intermediate 24e

[1243] To a reaction flask were added intermediate 24d (6.9 g), cesium carbonate (4.58 g), water (20 mL), DMSO (20 mL), and methanol (70 mL) in that order. The reaction mixture was cooled to 0°C and 30 wt% hydrogen peroxide (4.78 g) was added dropwise. After completion of the addition, the mixture was allowed to react at room temperature. After TLC confirmed the completion of the reaction, water and saturated aqueous sodium sulfite were added to the reaction mixture, stirred for 10 min, filtered, and the filter cake collected and dried to afford intermediate 24e (6.0 g).

[1244] MS (ESI, [M+H] + )m / z:509.5.

[1245] 1 H NMR(500MHz,DMSO-d6)δ10.97(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).

[1246] Step 5: Preparation of intermediate 24f

[1247] To a reaction flask, intermediate 24e (2.0 g), dichloromethane (30 mL), and N,N-diisopropylethylamine (1.36 g) were added sequentially, and the temperature was lowered to 0°C. Sulfur trioxide (1.88 g) was dissolved in DMSO (6 mL) and added dropwise to the reaction mixture. After complete addition, the mixture was brought 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 sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to afford intermediate 24f (1.1 g).

[1248] MS (ESI, [M+H] + )m / z:507.4.

[1249] Step 6: Preparation of compound 24

[1250] To a reaction flask were added intermediate 24f (165 mg), 16 (100 mg), sodium acetate (26.7 mg), and dichloroethane / isopropanol (5:1, 20 mL). The mixture was stirred at room temperature for 30 min, followed by the addition of sodium cyanoborohydride (40.8 mg) and the reaction was allowed to react at room temperature. After TLC confirmed the completion of the reaction, dichloromethane and water were added to the reaction solution. The organic phase was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was separated and purified by silica gel column chromatography to afford compound 24 (100 mg).

[1251] MS (ESI, [M+H] + )m / z:761.6.

[1252] 1H NMR(500MHz,DMSO-d6)δ11.10(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).

[1253] Example 25 Synthesis of Compound 25

[1254]

[1255] Step 1: Preparation of intermediate 25b

[1256] 25a (5.0 g), tetrahydropyridine (3.49 g), DMF (40 mL), and N,N-diisopropylethylamine (18.57 g, 25.10 mL) were added sequentially to a reaction flask and allowed to react at room temperature. TLC confirmed the reaction was complete, and the reaction was quenched with water. Ethyl acetate was added for extraction, and the organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to yield 25b (6.6 g).

[1257] MS (ESI, [M+H]+) m / z: 223.23.

[1258] Step 2: Preparation of intermediate 25c

[1259] To a reaction flask were added 25b (2.00 g), 24c (6.86 g), BINAP (0.51 g), cesium carbonate (8.12 g), palladium acetate (0.18 g), and 1,4-dioxane (50 mL) in sequence. The atmosphere was purged with nitrogen three times, and the mixture was heated to 100°C for reaction. After TLC confirmed the reaction was complete, the reaction solution was cooled to room temperature, and ethyl acetate and water were added to the residue. The organic phase was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to afford intermediate 25c (2.3 g).

[1260] MS (ESI, [M+H] + )m / z:393.4.

[1261] Step 3: Preparation of intermediate 25d

[1262] To a reaction flask were added intermediate 25c (2.1 g), cesium carbonate (1.74 g), water (10 mL), DMSO (15 mL), and methanol (30 mL) in sequence. The reaction solution was cooled to 0°C and 30 wt% hydrogen peroxide (1.82 g) was added dropwise. After completion of the addition, the mixture was allowed to react at room temperature. After TLC confirmed the completion of the reaction, water and saturated aqueous sodium sulfite were added to the reaction solution. The mixture was stirred for 10 min, filtered, and the filter cake was collected and dried to afford intermediate 25d (2.1 g).

[1263] MS (ESI, [M+H] + )m / z:411.3.

[1264] Step 4: Preparation of intermediate 25e

[1265] To a reaction flask, intermediate 25d (0.75 g), dichloromethane (20 mL), and N,N-diisopropylethylamine (0.63 g) were added sequentially, and the temperature was lowered to 0°C. Sulfur trioxide (0.87 g) was dissolved in DMSO (2 mL) and added dropwise to the reaction mixture. After complete addition, the mixture was allowed to react at 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 sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to afford intermediate 25e (0.45 g).

[1266] MS (ESI, [M+H] + )m / z:409.3.

[1267] Step 5: Preparation of compound 25

[1268] To a reaction flask were added intermediate 25e (80 mg), 16 (50 mg), sodium acetate (13.3 mg), and dichloroethane / isopropanol (5:1, 20 mL). The mixture was stirred at room temperature for 30 min, followed by the addition of sodium cyanoborohydride (20.4 mg) and the reaction was allowed to proceed at room temperature. After TLC confirmed the completion of the reaction, dichloromethane and water were added to the reaction solution. The organic phase was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to afford compound 25 (25 mg).

[1269] MS (ESI, [M+H] + )m / z:644.4.

[1270] 1H NMR (500MHz, DMSO-d6) δ11.10(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(d t,J=13.3,4.6Hz,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).

[1271] Example 26 Synthesis of Compound 26

[1272]

[1273]

[1274] 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 0.5 h, followed by the addition of sodium cyanoborohydride (39.6 mg). The mixture was stirred at room temperature. After TLC confirmed the completion of the reaction, the reaction solution was neutralized with saturated sodium bicarbonate solution to remove the acetic acid, and then extracted with 50 mL of dichloromethane and 100 mL of water. The organic phase was separated, and the aqueous phase was extracted twice with 20 mL of dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography to yield compound 26 (124 mg).

[1275] MS (ESI, [M+H] + )m / z:776.58.

[1276] 1 H NMR (500MHz, DMSO-d6) δ11.09(s,1H),10.97(s,1H),7.71(d,J=2.9Hz,1H),7.63–7.56(m,2H),7.41(d,J=8.6Hz,2H),7.28(d,J=2.9Hz,1H) ,7.15(d,J=8.2Hz,1H),6.87(d,J=8.6Hz,2H),4.56(dd,J=11.9,5.0Hz,1H),4.36(d,J=12.6Hz,1H),4.26(d,J=13.2Hz,1H),3.81(s,2H),3. 64–3.56(m,3H),3.27(ddd,J=29.3,13.9,6.4Hz,4H),3.02–2.89(m,4H),2.81–2.72(m,3H),2.70(s,3H),2.62(ddd,J=21.5,10.8,7.6Hz,3H ),2.53(d,J=4.9Hz,1H),2.45(d,J=6.5Hz,2H),2.18(dq,J=13.6,4.8Hz,1H),1.90–1.69(m,6H),1.59–1.49(m,1H),1.27(d,J=12.3Hz,2H).

[1277] Example 27 Synthesis of Compound 27

[1278]

[1279] Step 1: Preparation of compound 27

[1280] To the reaction flask were added intermediate 24f (113 mg), 20 (75 mg), sodium acetate (18.3 mg), and dichloroethane / isopropanol (5:1, 20 mL). After stirring at room temperature for 30 min, sodium cyanoborohydride (28.1 mg) was added and the mixture was allowed to react at room temperature for 1 h. The reaction solution was added with 50 mL of dichloromethane and 100 mL of water. The organic phase was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was separated and purified by silica gel column chromatography to give compound 27 (90 mg).

[1281] MS (ESI, [M+H] + )m / z:790.6.

[1282] 1 H NMR (500MHz, DMSO-d6) δ11.09(s,1H),10.98(s,1H),7.71(d,J=3.0Hz,1H),7.60(s,1H),7.54(d,J=8.0Hz,1H),7.45–7.39(m,2H),7.28(d,J=2.9Hz, 1H),7.18(d,J=8.2Hz,1H),6.88(d,J=9.0Hz,2H),4.55(dd,J=11.9,5.0Hz ,1H),4.32(dd,J=47.1,12.9Hz,2H),3.61(dd,J=9.7,5.8Hz,3H),3.35(dd, J=7.4,2.1Hz,1H),3.31–3.22(m,3H),3.16(dd,J=6.9,2.9Hz,2H),3.05(d d,J=6.5,3.3Hz,2H),2.97(dt,J=32.0,12.3Hz,2H),2.71(s,4H),2.70–2. 55(m,7H),2.47(dd,J=12.2,4.4Hz,1H),2.36(d,J=7.1Hz,2H),2.18(dt,J =9.1,3.1Hz,1H),1.88–1.63(m,6H),1.61–1.50(m,1H),1.32–1.24(m,2H).

[1283] Example 28 Synthesis of Compound 28

[1284]

[1285] Compound 19 (107 mg), intermediate 24f (60 mg), acetic acid (6.31 mg, 6.02 μL, 0.105 mmol), 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 0.5 h, followed by the addition of sodium cyanoborohydride (39.6 mg) and the reaction was stirred at room temperature for 1 h. After completion of the reaction, the acetic acid was neutralized with 2 mL of saturated sodium bicarbonate solution, and the mixture was extracted with 50 mL of dichloromethane and 100 mL of water. The organic phase was separated, and the aqueous phase was extracted twice with 20 mL of dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was purified by silica gel column chromatography (DCM:MeOH = 10:1, volume ratio) to obtain compound 28 (96 mg).

[1286] MS (ESI, [M+H] + )m / z:776.40.

[1287] 1 H NMR (500MHz, DMSO-d6) δ11.09(s,1H),10.98(s,1H),7.71(d,J=3.0Hz,1H),7.58(d,J=14.0Hz,2H),7.41(d,J=8.5Hz,2H),7.28(d,J=2.9 Hz,1H),7.11(d,J=8.2Hz,1H),6.87(d,J=8.5Hz,2H),4.56(dd,J=11.9,5.0Hz,1H),4.36(d,J=12.5Hz,1H),4.26(d,J=13.3Hz,1H),3.70( s,2H),3.65–3.55(m,3H),3.27(ddd,J=28.5,15.0,7.7Hz,4H),3.05–2.88(m,4H),2.77(p,J=6.4Hz,3H),2.69(s,3H),2.66–2.57(m,3H), 2.49–2.44(m,1H),2.40(d,J=6.8Hz,2H),2.19(dt,J=13.2,4.7Hz,1H),1.88–1.69(m,6H),1.61–1.49(m,1H),1.27(q,J=8.8,5.1Hz,2H).

[1288] Example 29 Synthesis of Compound 29

[1289]

[1290] Step 1: Preparation of compound 29

[1291] To a reaction flask were added intermediate 24f (118 mg), 17 (100 mg), sodium acetate (21.2 mg), and dichloroethane / isopropanol (5:1, 20 mL). The mixture was stirred at room temperature for 30 min, followed by the addition of sodium cyanoborohydride (32.6 mg). The mixture was allowed to react at room temperature for 1 h. The reaction mixture was added with 50 mL of dichloromethane and 100 mL of water. The organic phase was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to afford compound 29 (60 mg).

[1292] MS (ESI, [M+H] + )m / z:762.5.

[1293] 1H NMR (500MHz, DMSO-d6) δ11.09(s,1H),10.98(s,1H),7.71(d,J=2.9Hz,1H),7.65(s,1H),7.60(d,J=2.9Hz,2H),7.45–7.38(m, 2H),7.28(d,J=2.9Hz,1H),6.94–6.83(m,2H),4.55(dd,J=11.9,5.0Hz,1H),4.45–4.20(m,2H),3.91(d,J=25.4Hz,4H),3.60( dd,J=9.9,5.9Hz,3H),3.32–3.21(m,4H),2.96(dt,J=28.1,11.7Hz,2H),2.77(ddd,J=17.3,12.0,5.4Hz,1H),2.70(s,3H),2. 67–2.56(m,5H),2.53(d,J=4.6Hz,1H),2.19(dq,J=13.6,4.9Hz,1H),1.93–1.71(m,5H),1.70–1.49(m,2H),1.35–1.26(m,2H).

[1294] Example 30 Synthesis of Compound 30

[1295]

[1296] Step 1: Preparation of intermediate 30b

[1297] 30a (6.5 g), DMSO (50 mL), piperidin-4-ol (5.13 g, 50.7 mmol), and N,N-diisopropylethylamine (17.86 g, 138 mmol) were added to a reaction flask in sequence, and the mixture was heated to 100°C for reaction. The reaction solution was poured into an ice-water solution and filtered. The filter cake was dried to obtain 30b (10.13 g).

[1298] MS (ESI, [M+H]+) m / z: 223.2.

[1299] Step 2: Preparation of intermediate 30c

[1300] To the reaction flask were added 30b (10 g), 10% palladium on carbon (0.3 g, 0.282 mmol), and methanol (100 mL). The atmosphere was replaced with hydrogen three times and the reaction was allowed to proceed at room temperature under a hydrogen atmosphere. After TLC confirmed the reaction was complete, the palladium on carbon was removed by filtration, and the filtrate was concentrated to afford 30c (8.45 g).

[1301] 1 H NMR (500MHz, DMSO-d6) δ6.70–6.62(m,2H),6.53–6.37(m,2H),4.59(d,J=4.2Hz,1H),4.51(s,2H),3.52(tq,J=8.5,4.1Hz,1H), 3.20(ddd,J=12.4,6.4,2.7Hz,2H),2.58(ddd,J=12.6,10.4,2.9Hz,2H),1.84–1.70(m,2H),1.47(dtd,J=13.0,9.7,3.8Hz,2H).

[1302] Step 3: Preparation of intermediate 30d

[1303] To a single-necked flask, intermediate 1f (5 g), 30c (3.00 g), cesium carbonate (15.24 g), BINAP (0.971 g), palladium acetate (0.350 g), and 1,4-dioxane (100 mL) were added sequentially. Under nitrogen, the mixture was heated to 100°C for reaction. After the reaction, the reaction solution was cooled to room temperature and purified by silica gel column chromatography to obtain 30d (6.6 g).

[1304] 1 H NMR(500MHz,DMSO-d6)δ8.78(s,1H),7.75(s,1H),7.40–7.29(m,2H),7.00–6.78 (m,2H),4.66(d,J=4.2Hz,1H),4.41–4.13(m,2H),3.71–3.49(m,2H),3.44(dt,J= 12.3,4.3Hz,2H),3.31–3.19(m,4H),3.00–2.83(m,2H),2.77(ddd,J=12.6,10.1 ,2.9Hz,2H),2.70(s,3H),1.84–1.68(m,5H),1.48(tdd,J=12.8,9.3,5.9Hz,3H).

[1305] Step 4: Preparation of intermediate 30e

[1306] To a single-necked flask, intermediate 30d (6.6 g), DMSO (25 mL), and cesium carbonate (4.08 g) were added sequentially. Under an ice bath, 30 wt% hydrogen peroxide (4.24 mL) was added. After stirring for 5 min, the ice bath was removed and the mixture was allowed to react at room temperature. Upon completion of the reaction, 300 mL of saturated sodium sulfite solution was added to the residue to quench the reaction. The residue was tested for color change using a starch potassium iodide reagent and then extracted with 300 mL of ethyl acetate. The mixture was then extracted three times with 100 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced pressure, and the crude product was separated by silica gel column chromatography to yield the target intermediate 30e (6.4 g).

[1307] MS (ESI, [M+H]+) m / z: 495.19

[1308] Step 5: Preparation of intermediate 30f

[1309] N,N-Diisopropylethylamine (8.49 g, 65.7 mmol) was added to a solution of 30e (6.5 g) in dichloromethane (60 mL) under ice-cooling. A solution of pyridine sulfur trioxide (6.27 g) in DMSO (5 mL) was then added and allowed to react at room temperature. After completion of the reaction, 300 mL of saturated sodium sulfite solution was added to quench the reaction mixture. The mixture was then extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to yield 30f (5.9 g).

[1310] MS (ESI, [M+H]+) m / z: 492.47.

[1311] Step 6: Preparation of compound 30

[1312] To the reaction flask were added 30f (0.15 g), isopropanol (1 mL), 1,2-dichloroethane (5.00 mL), 16 (0.141 g), and sodium cyanoborohydride (0.057 g) in sequence. The mixture was reacted at room temperature. After completion of the reaction, the compound was purified by silica gel column chromatography to obtain 30 (15 mg).

[1313] MS (ESI, [M+H]+) m / z: 748.35.

[1314] 1H NMR (500MHz, DMSO-d6) δ11.10(s,1H),10.98(s,1H),7.72(d,J=8.3Hz,2H),7.60(s,1H),7.43(d,J=8.4Hz,2H),7.32(d,J=8.2Hz,1H), 7.29–7.22(m,1H),6.91(d,J=8.6Hz,2H),4.60(dd,J=11.9,5.0Hz,1H),4.36(d,J=12.4Hz,1H),4.27(d,J=13.5Hz,1H),4.22(s,2H),4 .11(s,2H),3.58(d,J=12.1Hz,3H),3.27(dq,J=15.0,8.1,7.2Hz,3H),2.97(dt,J=32.4,12.1Hz,2H),2.77(t,J=11.8Hz,3H),2.71(m, 4H),2.61(dt,J=17.3,4.5Hz,2H),2.57–2.52(m,1H),2.25–2.14(m,1H),2.04(d,J=12.3Hz,2H),1.86–1.71(m,3H),1.70–1.50(m,3H).

[1315] Example 31 Synthesis of Compound 31

[1316]

[1317] Step 1: Preparation of intermediate 31a

[1318] To a single-necked flask, intermediate 25b (1 g), 30c (0.859 g), cesium carbonate (4.39 g), BINAP (0.280 g), palladium acetate (0.101 g), and 1,4-dioxane (10 mL) were added sequentially. Under nitrogen, the mixture was heated to 100°C for reaction. After the reaction, the reaction solution was cooled to room temperature and purified by silica gel column chromatography to afford 31a (0.85 g).

[1319] MS (ESI, [M+H]+) m / z: 378.43.

[1320] Step 2: Preparation of intermediate 31b

[1321] To a single-necked flask, intermediate 31a (2.8 g), DMSO (10 mL), and cesium carbonate (2.4 g) were added sequentially. Under an ice bath, 30 wt% hydrogen peroxide (2.52 mL) was added. After stirring for 5 min, the ice bath was removed and the mixture was allowed to react at room temperature. Upon completion of the reaction, 300 mL of saturated sodium sulfite solution was added to the residue to quench the reaction. The residue was tested for color change using a starch potassium iodide reagent and then extracted with 300 mL of ethyl acetate. The mixture was then extracted three times with 100 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced pressure, and the crude product was separated by silica gel column chromatography to obtain the target intermediate 31b (2.85 g).

[1322] MS (ESI, [M+H]+) m / z: 396.37.

[1323] Step 3: Preparation of intermediate 31c

[1324] N,N-Diisopropylethylamine (2.54 g) was added to a solution of 31b (2.6 g) in dichloromethane (30 mL) under ice-cooling, followed by a solution of pyridine sulfur trioxide (1.56 g) in DMSO (5 mL) and allowed to react at room temperature. After completion of the reaction, 300 mL of saturated sodium sulfite solution was added to the reaction solution to quench the reaction, followed by extraction with 200 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to yield 31c (1.85 g).

[1325] 1 H NMR (500MHz, DMSO-d6) δ11.11(s,1H),7.70(d,J=2.9Hz,1H),7.61(s,1H),7.52–7.43(m,2H),7.27(d,J=3.0Hz,1H), 7.06–6.96(m,2H),3.66(t,J=5.4Hz,4H),3.53(t,J=6.0Hz,4H),2.42(t,J=6.0Hz,4H),1.62(dq,J=34.2,5.9Hz,6H).

[1326] Step 4: Preparation of compound 31

[1327] To the reaction flask were added 31c (0.1 g), isopropa...

Claims

1. A compound of formula II-1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, in, T is selected from CH or N; R is selected from hydrogen, or 5-6 membered heterocycloalkyl, the heterocycloalkyl being optionally substituted with =O or C 1-6 Alkyl substitution; Ring E is selected from phenyl, benzocycloalkenyl or benzoheterocycloalkenyl; X 2 is selected from CH or N; L is selected from a linking group, Ring A is absent or selected from C 5-10 Cycloalkenyl, 5-10 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl; Ring B is selected from a benzene ring group; Ring C is selected from isoxazolyl or furanyl; Each R 1 independently selected from halogen, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy or halogenated C 1-4 alkyl; n is selected from 0, 1, 2 or 3.

2. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Ring E is selected from phenyl, benzo 5-12 Cycloalkenyl or benzo 5-12 membered heterocycloalkenyl; Alternatively, ring E is selected from phenyl, benzo 5-6 Cycloalkenyl or benzo 5-11 membered heterocycloalkenyl; Alternatively, ring E is selected from phenyl, benzo 5-membered heterocycloalkenyl, benzo 6-membered heterocycloalkenyl, benzo 10-membered heterocycloalkenyl or benzo 11-membered heterocycloalkenyl.

3. The compound according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein Ring A is absent or is selected from C 5-8 cycloalkenyl, 5-10 membered heterocycloalkenyl, phenyl or 5 membered heteroaryl; Ring A is absent or selected from C 5-7 cycloalkenyl, 5-9 membered heterocycloalkenyl, phenyl or 5 membered heteroaryl; Ring A is absent or selected from C 5-6 Cycloalkenyl, 5-9 membered heterocycloalkenyl, phenyl or 5 membered heteroaryl; Alternatively, ring A is absent or is selected from C 5-6 Cycloalkenyl, 5-9 membered heterocycloalkenyl, phenyl, pyrrolyl, pyrazolyl, furanyl, or oxazolyl; Alternatively, Ring A is absent or is selected from C5 cycloalkenyl, C6 cycloalkenyl, 5-membered, 6-membered, 7-membered, 8-membered or 9-membered heterocycloalkenyl, phenyl, pyrrolyl, pyrazolyl, furanyl or oxazolyl; Alternatively, ring A is absent or is selected from cyclopentenyl, bicyclohexenyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydroazepine 1-amino-1-nitro-2-nitro-1-oxazinyl, ... Alternatively, ring A is selected from C 5-6 Cycloalkenyl or 5-9 membered heterocycloalkenyl; Alternatively, ring A is selected from cyclopentenyl, bicyclohexenyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydroazepine yl, dihydrooxazinyl, azaspirocyclooctenyl or azaspirocyclononenyl.

4. The compound according to any one of claims 1 to 3, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the structural part Selected from Or, the structural part Selected from Or, the structural part Selected from Or, the structural part Selected from 5. The compound according to any one of claims 1 to 4, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein each R 1 independently selected from halogen, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy or halogenated C 1-3 alkyl; Or, each R 1 independently selected from fluorine, chlorine, bromine, -OH, -NH2 or -CN; Or, each R 1 independently selected from fluorine, chlorine or bromine; Or, each R 1 are independently selected from fluorine.

6. The compound according to any one of claims 1 to 5, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the structural part Selected from 7. The compound according to any one of claims 1 to 6, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is selected from -Cy 1 -LNK-Cy 2 -LNK-, -Cy 1 -LNK-Cy 2 -or-Cy 1 -Cy 2 -LNK-, in, Cy 1 is selected from a bond, or optionally one or more R a Substituted with the following groups: C 4-11 Cycloalkyl or 4-11 membered heterocycloalkyl; Or, Cy 1 is selected from a bond, or optionally one or more R a Substituted with the following groups: C 6-9 Cycloalkyl or 4-11 membered heterocycloalkyl; Or, Cy 1 is selected from a bond, or optionally one or more R a Substituted from the following groups: C6 cycloalkyl, C9 cycloalkyl, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered or 11-membered heterocycloalkyl; Or, Cy 1 is selected from a bond, or optionally one or more R a Substituted with the following groups: C6 cycloalkyl, C9 cycloalkyl, 4-membered, 6-membered, or 8-11-membered heterocycloalkyl; Or, Cy 1 Select from keys; Or, Cy 1 Selected from one or more R a Substituted C6 cycloalkyl or C9 cycloalkyl; Or, Cy 1 Selected from one or more R a Substituted 4-membered, 6-membered, or 8-11-membered heterocycloalkyl; Or, Cy 1 Selected from one or more R a substituted 8-membered, 9-membered, 10-membered or 11-membered heterocycloalkyl; Or, Cy 1 is selected from a bond, or optionally one or more R a substituted cyclohexyl, spironanyl, azetidinyl, octahydrocyclopentylpyrrolyl, piperidinyl, monoazaspironanyl, diazaspironanyl, azabicyclononanyl, monoazaspiroundecyl or diazaspiroundecyl; Wherein, LNK is selected from a bond, C 1-6 Alkylene or C 1-6 heteroalkylene; Alternatively, LNK is selected from a key or C 1-4 Alkylene; Alternatively, LNK is selected from a key or C 1-3 Alkylene; Alternatively, LNK is selected from a bond or -CH2-; Among them, Cy 2 Not present, or selected from C 4-11 Cycloalkyl or 4-11 membered heterocycloalkyl, the cycloalkyl or heterocycloalkyl is optionally substituted by one or more R b replace; Or, Cy 2 Not present, or selected from C 4-6 Cycloalkyl or 4-6 membered heterocycloalkyl, the cycloalkyl or heterocycloalkyl is optionally substituted by one or more R b replace; Or, Cy 2 is absent or is selected from cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl or piperidinyl, wherein the cyclobutyl, cyclopentyl, azetidinyl, pyrrolidinyl or piperidinyl is optionally replaced by one or more R b replace; Or, Cy 2 Selected from Where R a and R b Each is independently selected from halogen, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, C 1-3 Alkylamino, or di-C 1-3 Alkylamino; Or, R a and R b Each is independently selected from halogen, -OH, -NH2, -CN or C 1-3 alkyl; Or, R a and R b Each is independently selected from halogen, -OH, -NH2 or -CN.

8. The compound according to any one of claims 1 to 7, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R is selected from hydrogen, or a 5-6 membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted by =O or C 1-3 Alkyl substitution; Alternatively, R is selected from hydrogen or a 5-membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted by =O or C 1-3 Alkyl substitution; Alternatively, said R is selected from hydrogen or imidazolinyl, said imidazolinyl being optionally substituted by =O or methyl; Alternatively, R is selected from hydrogen or 9. The compound according to any one of claims 1 to 8, its stereoisomer or pharmaceutically acceptable salt thereof, wherein the compound of formula II-1 is selected from the group consisting of compounds of formula I'a, formula I', formula I'-1A, formula I'-2A, formula I'-1A-1, formula I'-2A-1, formula I'-3A-1, formula I'-3A-2, formula I'-4A-1, and formula I'-4A-2, in, X is selected from CH or N.

10. The following compound, its stereoisomer or its pharmaceutically acceptable salt:

11. A pharmaceutical composition comprising the compound according to any one of claims 1 to 10, its stereoisomer or a pharmaceutically acceptable salt thereof.

12. Use of the compound according to any one of claims 1 to 10, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 11 in the preparation of a medicament for preventing or treating autoimmune diseases, inflammatory diseases or cancer.

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