Fused imide derivatives

Abstract

This application belongs to the field of medicinal chemistry and relates to fused imide derivatives of Formula I, their preparation methods, pharmaceutical compositions containing the compound, and their use in treating related diseases (e.g., cancer).

Description

[0001] This application is a divisional application of the following application: application date November 18, 2022; application number 202280074055.X; invention title: "Fused Imide Derivatives".

[0002] Cross-reference to related applications

[0003] This application is an international application filed on November 18, 2021, December 31, 2021, July 13, 2022, October 14, 2022, November 4, 2022, and November 11, 2022, respectively, and claims priority and benefits from the aforementioned Chinese patent applications. The disclosure of the aforementioned applications is incorporated herein by reference in its entirety. Technical Field

[0004] This application relates to fused imide derivatives and protein degrading agents, methods for their preparation, pharmaceutical compositions containing the compounds, and their use in treating related diseases (e.g., cancer). Background Technology

[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 high structural homology. Recent studies on B cells, particularly B-cell non-Hodgkin's lymphoma and rheumatoid arthritis, have revealed aberrant BTK expression. Due to its primary expression in B cells and myeloid cells, BTK is a target with good targeting potential and safety.

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

[0008] On the one hand, this application relates to compounds of formula I, their stereoisomers, or pharmaceutically acceptable salts thereof.

[0009]

[0010] in,

[0011] Ring A does not exist, or it is selected from C. 5-10 Cycloalkenyl, 5-10 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl;

[0012] Alternatively, ring A does not exist, or it is selected from C. 5-6 Cycloalkenyl, 5-10 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl;

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

[0014] The ring C is selected from isoxazolyl or furanyl;

[0015] Each R 1 Independently selected from halogens, -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 key, C 3-12 Cycloalkyl or 4-12 membered heterocycloalkyl, wherein the C 3-12 Cycloalkyl or 4-12 membered heterocyclic alkyl groups optionally surrounded by one or more R a replace;

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

[0019] Cy 2 Does not exist, or is selected from C 3-12 Cycloalkyl or 4-12-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally surrounded by one or more R b replace;

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

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

[0022] In some embodiments, this application relates to compounds of formula I, their stereoisomers, or pharmaceutically acceptable salts thereof.

[0023]

[0024] in,

[0025] Ring A does not exist, or it is selected from C. 5-6 Cycloalkenyl, 5-10 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl;

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

[0027] The ring C is selected from isoxazolyl or furanyl;

[0028] Each R 1 Independently selected from halogens, -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 key, C 3-12 Cycloalkyl or 4-12 membered heterocycloalkyl, wherein the C 3-12 Cycloalkyl or 4-12 membered heterocyclic alkyl groups optionally surrounded by one or more R a replace;

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

[0032] Cy 2 Does not exist, or is selected from C 3-12 Cycloalkyl or 4-12-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally surrounded by one or more R b replace;

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

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

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

[0036]

[0037] In other implementations, Cy 1 Selected from one or more R a Substituted 4-12 membered heterocyclic alkyl groups.

[0038] In some embodiments of this application, when ring A is present, Cy 2 or LNK(Cy 2 If it does not exist, it can be directly covalently connected to ring B; similarly, It can also be directly covalently connected to ring B.

[0039] In some embodiments, the PTM described in this application is selected from drugs or derivatives thereof that act on AR, ER, kinases, phosphatases, MDM2, proteins of the human BET bromo domain, Hsp90, HDAC, human lysine methyltransferase, RAF receptor, FKBP, vascular endothelial growth factor, immunosuppression-related receptors or proteins, aryl hydrocarbon receptors, thyroid hormone receptors, 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 in this application 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 in this application is selected from drugs or derivatives thereof that act on ALK, BRD4, CDK4 / 6, PARP, EGFR, γ-secretase, CBFβ-SMMHC, WEE1, MEK, BCR-ABL, MET, KRAS, EGFR, BTK, AR, ER, PDEδ, JAK, MDM2, or RAF.

[0042] In some embodiments, the PTM described in this application is selected from drugs or derivatives thereof that act on BTK or WEE1.

[0043] In some embodiments, the PTM described in this application is selected from drugs that act on BTK or their derivatives.

[0044] On the other hand, this application relates to compounds of formula II-1, their stereoisomers, or pharmaceutically acceptable salts thereof.

[0045]

[0046] in,

[0047] T is selected from CH or N;

[0048] R is selected from hydrogen or a 5-6 membered heterocyclic alkyl group, wherein the heterocyclic alkyl group is optionally marked with =O or C. 1-6 Alkyl substitution;

[0049] The ring E is selected from phenyl, benzocycloalkenyl (e.g., benzo4- to 12-membered cycloalkenyl, or benzo4- to 10-membered cycloalkenyl, or benzo4- to 8-membered cycloalkenyl) or benzoheterocycloalkenyl (e.g., benzo4- to 12-membered heterocycloalkenyl or benzo5- 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 The definitions of n are as described in this application.

[0053] On the other hand, this application relates to compounds of formula II, their stereoisomers, or pharmaceutically acceptable salts thereof.

[0054]

[0055] in,

[0056] T is selected from CH or N;

[0057] R is selected from hydrogen or a 5-6 membered heterocyclic alkyl group, wherein the heterocyclic alkyl group is optionally marked with =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 1The definitions of n are as described in this application.

[0062] In some implementations, 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 in this application. In some embodiments, L is selected from -Cy 1 -LNK-Cy 2 -, where Cy 1 LNK, Cy 2 As stated in this application.

[0063] On the other hand, this application relates to compounds of formula I'a, their stereoisomers, or pharmaceutically acceptable salts thereof.

[0064]

[0065] in,

[0066] T is selected from CH or N;

[0067] R is selected from hydrogen or a 5-6 membered heterocyclic alkyl group, wherein the heterocyclic alkyl group is optionally marked with =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 is as stated in this application.

[0071] In some implementation schemes, X 2 Selected from CH; in some implementations, X 2 Selected from N.

[0072] In some embodiments, the ring E is selected from phenyl, benzo[C], etc. 5-12 Cycloalkenyl or benzo5-12-membered heterocyclic alkenyl.

[0073] In some embodiments, the ring E is selected from phenyl, benzo[C], etc. 5-6 Cycloalkenyl or benzo5-11 heterocyclic alkenyl.

[0074] In some embodiments, the ring E is selected from phenyl, benzo5-membered heterocyclic alkenyl, benzo6-membered heterocyclic alkenyl, benzo10-membered heterocyclic alkenyl, or benzo11-membered heterocyclic alkenyl.

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

[0076] On the other hand, the compounds of formula I, their stereoisomers, or pharmaceutically acceptable salts thereof described in this application are selected from compounds of formula I', their stereoisomers, or pharmaceutically acceptable salts thereof.

[0077]

[0078] in,

[0079] T is selected from CH or N;

[0080] R is selected from hydrogen or a 5-6 membered heterocyclic alkyl group, wherein the heterocyclic alkyl group is optionally marked with =O or C. 1-6 Alkyl substitution.

[0081] In some implementations, ring A is absent, or is selected from C. 5-10 Cycloalkenyl, 5-10 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl.

[0082] In some implementations, ring A is absent, or is selected from C. 5-8 Cycloalkenyl, 5-10 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl.

[0083] In some implementations, ring A is absent, or is selected from C. 5-7 Cycloalkenyl, 5-10 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl.

[0084] In some implementations, ring A is absent, or is selected from C. 5-6 Cycloalkenyl, 5-10 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl.

[0085] In some implementations, ring A is absent, or is selected from C. 5-6 Cycloalkenyl, 5-9 membered heterocyclic alkenyl, phenyl or 5 membered heteroaryl.

[0086] In some implementations, ring A is absent, or is selected from C. 5-6 Cycloalkenyl, 5-9 membered heterocyclic alkenyl, phenyl, pyrroleyl, pyrazolyl, furanyl, 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 heterocyclic alkenyl, phenyl, pyrroleyl, pyrazolyl, furanyl or oxazolyl.

[0088] In some embodiments, ring A is absent, or is selected from cyclopentenyl, dicyclohexenyl, dihydropyrroleyl, tetrahydropyridyl, and tetrahydroazapyridine. The group can be phenyl, dihydrooxazinyl, azirospirooctenyl, azirospirononenyl, phenyl, pyrroleyl, pyrazolyl, furanyl, or oxazolyl.

[0089] In some specific implementation schemes, ring A is selected from C. 5-10 Cycloalkenyl or 5-10 membered heterocyclic alkenyl. In some specific embodiments, ring A is selected from C. 5-8 Cycloalkenyl or 5-9 membered heterocyclic alkenyl. In some specific embodiments, ring A is selected from C. 5-7 Cycloalkenyl or 5-9 membered heterocyclic alkenyl. In some specific embodiments, ring A is selected from C. 5-6 Cycloalkenyl or 5-9 membered heterocyclic alkenyl. In some embodiments, ring A is selected from 5-9 membered heterocyclic alkenyl. In some embodiments, ring A is selected from 5-8 membered heterocyclic alkenyl. In some embodiments, ring A is selected from 5 membered heterocyclic alkenyl. In some embodiments, ring A is selected from 6 membered heterocyclic alkenyl. In some embodiments, ring A is selected from 7 membered heterocyclic alkenyl. In some embodiments, ring A is selected from 8 membered heterocyclic alkenyl. In some embodiments, ring A is selected from 9 membered heterocyclic alkenyl. In some embodiments, ring A is absent, or is selected from C. 5-6 Cycloalkenyl, 5-9 membered heterocyclic alkenyl (preferably 5-8 membered heterocyclic alkenyl, or 5-7 membered heterocyclic alkenyl), or phenyl. In some preferred embodiments, ring A is absent, or is selected from C. 5-6 Cycloalkenyl, or a 5-7 membered heterocyclic alkenyl or phenyl group containing 1-2 heteroatoms selected from N, O, or S (preferably 1-2, for example, 1 N atom). In some specific embodiments, ring A is absent, or is selected from cyclopentenyl, dihydropyrrolyl, tetrahydropyridyl, tetrahydroazapyrrolyl, etc. Benzyl or phenyl.

[0090] In some specific embodiments, ring A is selected from cyclopentenyl, dicyclohexenyl, dihydropyrroleyl, tetrahydropyridyl, and tetrahydroazapyridine. It can be alkyl, dihydrooxazinyl, azirospirooctenyl, or azirospirononenyl.

[0091] In some specific embodiments, ring A is selected from cyclopentenyl or dicyclohexenyl. In some specific embodiments, ring A is selected from dihydropyrroleyl, dihydrooxazinyl, tetrahydropyridyl, tetrahydroazayl. It can be alkyl, azirspirocyclooctenyl or azirspirocyclononenyl.

[0092] In some specific embodiments, ring A is selected from phenyl, pyrrole, pyrazolyl, furanyl, or oxazolyl.

[0093] In some implementations, ring A is absent, or is selected from C. 5-7 Cycloalkenyl, 5-8 membered heterocyclic alkenyl, phenyl or pyrroleyl.

[0094] In other implementations, ring A is absent, or is selected from C. 5-6 Cycloalkenyl, 5-8 membered heterocyclic alkenyl, phenyl or pyrroleyl.

[0095] In other embodiments, ring A is absent, or is selected from C5 cycloalkenyl, 5-membered, 6-membered, 7-membered or 8-membered heterocyclic alkenyl, phenyl or pyrroleyl.

[0096] In other embodiments, ring A is absent, or is selected from cyclopentenyl, dihydropyrroleyl, tetrahydropyridyl, and tetrahydroazapyridine. It can be alkyl, azirrocyclooctene, phenyl or pyrroleyl.

[0097] In some other implementations, ring A does not exist.

[0098] In other implementations, ring A is selected from C. 5-6 Cycloalkenyl or 5-8 membered heterocyclic alkenyl.

[0099] In other embodiments, ring A is selected from cyclopentenyl, dihydropyrroleyl, tetrahydropyridyl, and tetrahydroazapyridine. The ring is selected from cyclopentenyl or aziridine. In other embodiments, ring A is selected from dihydropyrroleyl, tetrahydropyridyl, or tetrahydroaziridine. Benzyl or azirrospirocyclooctene.

[0100] In some other embodiments, ring A is selected from phenyl or pyrrole.

[0101] In some implementation schemes, the structural part (moiety) Selected from In some implementation schemes, the structural part Selected from Among them, the key connected to ring A The asterisk (*) indicates that the bond is connected to an atom on ring A; the bond connected to ring C is... The asterisk (*) indicates that the bond is connected to an atom on the ring C (the asterisk in similar positions below indicates the same or similar meaning).

[0102] In some implementation schemes, the structural portion Selected from In some implementation schemes, the structural portion Selected from (For example ), (example The definition of * is the same as or similar to that above.

[0103] In some specific implementation schemes, the structural part Selected from In some specific implementation schemes, the structural part Selected from In some specific implementation schemes, the structural part Selected from

[0104] In some implementation schemes, the structural portion Selected from

[0105] In some specific implementation schemes, the structural part Selected from In some specific implementation schemes, the structural part Selected from In some specific implementation schemes, the structural part Selected from

[0106] In some implementation schemes, the structural portion Selected from

[0107] In some specific implementation schemes, the structural part Selected from

[0108] In some specific implementation schemes, the structural part Selected from

[0109] In some implementation schemes, the structural portion Selected from

[0110] In some specific implementation schemes, the structural part Selected from

[0111] In some specific implementation schemes, the structural part Selected from

[0112] In some implementation schemes, the structural portion Selected from

[0113] In some specific implementation schemes, the structural part Selected from

[0114] In some specific implementation schemes, the structural part Selected from

[0115] In other implementations, the structural portion Selected from In other implementations, the structural portion Selected from

[0116] In other implementations, the structural portion Selected from In some implementation schemes, the structural portion Selected from

[0117] In some implementations, each R 1 Independently selected from halogens, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 alkoxy or halogenated C 1-3 alkyl.

[0118] In some implementations, each R 1 Independently selected from fluorine, chlorine, bromine, -OH, -NH2, or -CN. In some embodiments, each R 1 It is independently selected from fluorine, chlorine, or bromine.

[0119] In some implementations, each R 1 It is independently selected from fluorine.

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

[0121] In some implementation schemes, the structural portion Selected from

[0122] In some specific implementation schemes, the structural part Selected from

[0123] In some specific implementation schemes, the structural part Selected from

[0124] In some specific implementation schemes, the structural part Selected from

[0125] In some specific implementation schemes, the structural part Selected from

[0126] In some specific implementation schemes, the structural part Selected from

[0127] In other implementations, the structural portion Selected from In some implementation schemes, the structural portion Selected from

[0128] In some implementations, PTM is in,

[0129] T is selected from CH or N;

[0130] R is selected from hydrogen or a 5-6 membered heterocyclic alkyl group, wherein the heterocyclic alkyl group is optionally marked with =O or C. 1-6 Alkyl substitution;

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

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

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

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

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

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

[0137] In some implementations, the structural part -Cy 1 -LNK-Cy 2 -Selected from-Cy 1 -、-Cy 1 -LNK-、-Cy 1 -Cy 2 -、-Cy 1 -LNK-Cy 2 -、-Cy 2 -、-LNK-Cy 2 -. In some implementations, the structural part -Cy 1 -LNK-Cy 2 -Selected from-Cy 1 -、-Cy 1 -Cy 2 -or-Cy 2 -. In some specific implementations, the structural part -Cy 1 -LNK-Cy 2 -Selected from-Cy 1 -LNK-、-Cy 1 -LNK-Cy 2 -or-LNK-Cy 2 -. In some specific implementations, the structural part -Cy 1 -LNK-Cy 2 -Selected from-Cy 1 -LNK-. In some specific implementations, the structural part -Cy 1 -LNK-Cy 2-Selected from-Cy 1 -LNK-Cy 2 -. In some specific implementations, the structural part -Cy 1 -LNK-Cy 2 -Selected from -LNK-Cy 2 -

[0138] In some other implementations, the structural portion -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 implementations, Cy 1 Selected from a key, or optionally by one or more R a The following groups are substituted: C 4-11 Cycloalkyl or 4-11 membered heterocyclic alkyl.

[0140] In some implementations, Cy 1 Selected from a key, or optionally by one or more R a The following groups are substituted: C 6-9 Cycloalkyl or 4-11 membered heterocyclic alkyl groups. In some embodiments, Cy 1 Selected from a key, or optionally by one or more R a The following groups are substituted: C 6-9 Cycloalkyl (e.g., C6 cycloalkyl, C9 cycloalkyl), 5-11 member heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S (e.g., 1-3 or 1-2 heteroatoms selected from N or O).

[0141] In some implementations, Cy 1 Selected from a key, or optionally by one or more R a The following groups can be substituted: C6 cycloalkyl, C9 cycloalkyl, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered or 11-membered heterocyclic alkyl.

[0142] In some implementations, Cy 1 Selected from a key, or optionally by one or more R a The following groups can be substituted: C6 cycloalkyl, C9 cycloalkyl, 4-membered, 6-membered, or 8-11-membered heterocyclic alkyl.

[0143] In some specific implementation schemes, Cy 1 Selected from key. In some specific implementations, Cy1 Selected from C6 cycloalkyl or C9 cycloalkyl, wherein the cycloalkyl group is optionally surrounded by one or more R a Replacement. In some specific implementations, Cy 1 Selected from 4-membered, 6-membered, or 8-11-membered heterocyclic alkyl groups, wherein the heterocyclic alkyl group is optionally surrounded by one or more R groups. a Replacement. In some specific implementations, Cy 1 Selected from 4- or 6-membered heterocyclic alkyl groups, wherein the heterocyclic alkyl group is optionally surrounded by one or more R groups. a Replacement. In some specific implementations, Cy 1 Selected from 8-11 membered heterocyclic alkyl groups, wherein the heterocyclic alkyl group is optionally surrounded by one or more R groups. a Replacement. In some specific implementations, Cy 1 Selected from 8-, 9-, 10-, or 11-membered heterocyclic alkyl groups, wherein the heterocyclic alkyl group is optionally surrounded by one or more R groups. a replace.

[0144] In some implementations, Cy 1 Selected from a key, or optionally by one or more R a The following groups may be substituted: cyclohexyl, spirononyl, azircyclobutyl, octahydrocyclopentylpyrrolidinyl, piperidinyl, monoazirspirononyl, diazirspirononyl, azirbicyclononyl (e.g., monoazirbicyclononyl), monoazirspiroundecyl or diazirspiroundecyl.

[0145] In some specific implementation schemes, Cy 1 Selected from cyclohexyl or spirononyl. In some specific embodiments, Cy 1 Selected from nitrogen-containing heterocyclic butyl or piperidinyl. In some specific embodiments, Cy 1 It is selected from octahydrocyclopentylpyrrolidinyl, monoazaspirononyl, diazaspirononyl, azabicyclononyl, monoazaspironundecyl, or diazaspironundecyl. In some specific embodiments, Cy 1 It is selected from the following groups: cyclohexyl, spirononyl, azepononyl, octahydrocyclopentylpyrrole, azepononyl, oxa-azepononyl or azebicyclononyl.

[0146] In some implementations, Cy 1 Selected from the key, or optionally by one or more R a The following groups are substituted:

[0147] In some implementations, Cy 1 Selected from the key, or optionally by one or more R a The following groups are substituted:

[0148] In some specific implementation schemes, Cy 1 Selected from In some specific implementation schemes, Cy 1 Selected from In some specific implementation schemes, Cy 1 Selected from In some specific implementation schemes, Cy 1 Selected from key,

[0149] In other implementations, Cy 1 Selected from one or more R a Substituted 4-11 membered heterocyclic alkyl groups.

[0150] In other implementations, Cy 1 Selected from one or more R a Substituted 5-, 6-, 7-, 8-, 9-, 10-, or 11-membered heterocyclic alkyl groups.

[0151] In other implementations, Cy 1 Selected from one or more R a Substituted 6-membered or 9-11-membered heterocyclic alkyl groups.

[0152] In other implementations, Cy 1 Selected from one or more R a Substituted 6-, 9-, or 11-membered heterocyclic alkyl groups.

[0153] In other implementations, Cy 1 Selected from one or more R a Substituted piperidinyl, monoazaspirononane, diazaspirononane, or diazaspironundecane.

[0154] In other implementations, Cy 1 Selected from one or more R a Replacement

[0155] In some implementations, LNK is selected from key, C 1-6 Alkylene or C 1-6 Heteroalkylene.

[0156] In some implementations, LNK is selected from key or C 1-4 Alkylene.

[0157] In some implementations, LNK is selected from key or C 1-3 Alkylene.

[0158] In some implementations, LNK is selected from key or -CH2-. In some specific implementations, LNK is selected from key. In some specific implementations, LNK is selected from -CH2-.

[0159] In some implementations, Cy 2 Does not exist, or is selected from C 4-11 Cycloalkyl or 4-11 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally surrounded by one or more R b Replacement. In some specific implementations, Cy 2 It does not exist. In some specific implementations, Cy 2 Selected from C 4-11 Cycloalkyl or 4-11 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally surrounded by one or more R b replace.

[0160] In some implementations, Cy 2 Does not exist, or is selected from C 4-6 Cycloalkyl or 4-6-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally surrounded by one or more R b Replacement. In some specific implementations, Cy 2 Selected from C 4-6 Cycloalkyl or 4-6-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally surrounded by one or more R b Replacement. In some implementations, Cy 2 Does not exist, or is selected from C 4-6 Cycloalkyl or 4-6-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally surrounded by one or more R b The substitution, wherein the heterocyclic alkyl group contains 1-3 (e.g., 1-2) heteroatoms selected from N, O or S (e.g., N or O).

[0161] In some implementations, Cy 2 It does not exist, or is selected from cyclobutyl, cyclopentyl, cyclohexyl, aziridine, pyrrolidinyl, or piperidinyl, wherein the cyclobutyl, cyclopentyl, aziridine, or piperidinyl is optionally surrounded by one or more R b replace.

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

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

[0164] In other implementations, Cy 2 It does not exist, or is selected from cyclobutyl, cyclopentyl, aziridine, pyrrolidinyl, or piperidinyl, wherein the cyclobutyl, cyclopentyl, aziridine, pyrrolidinyl, or piperidinyl is optionally surrounded by one or more R b replace.

[0165] In other implementations, Cy 2 Selected from

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

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

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

[0169] In some implementations, the structural part -Cy 1 -LNK- is selected from key, -CH2-,

[0170] In some specific implementations, the structural part -Cy 1 -LNK- Selected from In some specific implementation schemes, the structural part -Cy 1 -LNK- Selected from In some specific implementations, the structural part -Cy 1 -LNK- Selected from In some specific implementations, the structural part -Cy 1 -LNK- Selected from

[0171] In some other implementations, the structural portion -Cy 1 -LNK- Selected from

[0172] In some implementations, the structural part -LNK-Cy 2 -Selected from the bond, -CH2-,

[0173] In some other implementations, the structural part -LNK-Cy 2 -Selected from the bond, -CH2-,

[0174] In some implementations, the structural part -Cy 1 -Cy 2 -Selected from

[0175] In some other implementations, the structural portion -Cy 1 -Cy 2 -Selected from

[0176] In some implementations, the structural part -Cy 1 -LNK-Cy 2 -Selected from the bond, -CH2-,

[0177] In some specific implementations, the structural part -Cy 1 -LNK-Cy 2 -Selected from In some specific implementations, the structural part -Cy 1 -LNK-Cy 2 -Selected from

[0178] In some other implementations, the structural portion -Cy 1 -LNK-Cy 2 -Selected from

[0179] In some implementation schemes, the structural portion Selected from

[0180]

[0181]

[0182]

[0183] In other implementations, the structural portion Selected from

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

[0185] In some embodiments, R is selected from hydrogen or a 5-6 membered heterocyclic alkyl group, wherein the heterocyclic alkyl group is optionally marked with =O or C. 1-3 Alkyl substitution.

[0186] In some embodiments, R is selected from hydrogen or a 5-membered heterocyclic alkyl group, wherein the heterocyclic alkyl group is optionally marked with =O or C. 1-3 Alkyl substitution.

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

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

[0189] In some embodiments, this application relates to compounds of formula I, their stereoisomers, or pharmaceutically acceptable salts thereof, wherein,

[0190] Ring A does not exist, or it is selected from C. 5-8 Cycloalkenyl, 5-9 membered heterocyclic alkenyl (preferably 5-8 membered heterocyclic alkenyl, or 5-7 membered heterocyclic alkenyl) or phenyl; or, ring A is absent, or selected from C. 5-6 Cycloalkenyl, 5-9 membered heterocyclic alkenyl (preferably 5-8 membered heterocyclic alkenyl, or 5-7 membered heterocyclic alkenyl) or phenyl; preferably, ring A is absent, or is selected from C. 5-6 Cycloalkenyl, a 5-7 membered heterocyclic alkenyl or phenyl containing 1-2 heteroatoms selected from N, O or S (preferably containing 1-2, for example, 1 N atom); or preferably, ring A is selected from C. 5-6 Cycloalkenyl groups, 5-7 membered heterocyclic alkenyl groups 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 benzene ring group;

[0192] The ring C is selected from isoxazolyl or furanyl;

[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, PTM is in,

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

[0197] R is selected from hydrogen or a 5-6 membered heterocyclic alkyl group, wherein the heterocyclic alkyl group is optionally marked with =O or C. 1-6 Alkyl substitution; preferably, R is selected from hydrogen, imidazolinone, or C. 1-4 Alkyl-substituted imidazolinone group; more preferably, R is selected from hydrogen, imidazolinone group, 1-methyl-imidazolinone group, 1-ethyl-imidazolinone group or 1-propyl-imidazolinone group;

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

[0199] Cy 1 Selected from a key, or optionally by one or more R a The following groups are substituted: C 6-9 Cycloalkyl, or 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 key or C 1-4 Alkylene; preferably, LNK is selected from C- or C- bonds. 1-3 Alkylene;

[0201] Cy 2 Does not exist, or is selected from C 4-6 Cycloalkyl or 4-6-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally surrounded by one or more R b Replacement; preferably, Cy 2 Does not exist, or is selected from C 4-6 Cycloalkyl or 4-6-membered heterocyclic alkyl, wherein the heterocyclic alkyl contains 1-2 heteroatoms selected from N or O.

[0202] In some specific embodiments, this application relates to compounds of formula I, their stereoisomers, or pharmaceutically acceptable salts thereof, wherein,

[0203] Cycle A is absent, or is selected from cyclopentenyl, dihydropyrroleyl, tetrahydropyridyl, tetrahydroaza. alkyl or phenyl; preferably, ring A is selected from cyclopentenyl, dihydropyrrolyl, tetrahydropyridyl or tetrahydroazapyridine. More preferably, ring A is selected from dihydropyrrole, tetrahydropyridyl, or tetrahydroazapyridine. base;

[0204] Preferably, the structural part Selected from

[0205] PTM is Preferably, PTM is

[0206] Cy 1 Selected from cyclohexyl, spirononyl, azaspirononyl, octahydrocyclopentylpyrrole, azaspironundecyl, oxa-azaspironundecyl, or azabicyclononyl; preferably, Cy 1 Selected from key,

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

[0208] Cy 2 It does not exist, or is selected from cyclobutyl, cyclopentyl, cyclohexyl, aziridine, pyrrolidinyl, or piperidinyl, wherein the cyclobutyl, cyclopentyl, aziridine, or piperidinyl is optionally surrounded by one or more R b Replacement; preferably, Cy 2 Does not exist, or selected from

[0209] In some embodiments, the heterocyclic alkenyl or heterocyclic alkyl group contains heteroatoms selected from N, NH, O, or S. In some embodiments, the heterocyclic alkenyl or heterocyclic alkyl group contains heteroatoms selected from N, O, or S. In some embodiments, the heteroaryl group contains heteroatoms selected from N, O, or S. In some embodiments, the heteroalkylene group contains heteroatoms selected from N, NH, O, S, S(O), or S(O)₂.

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

[0211] This 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, their stereoisomers, 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 The definitions are as described in this application;

[0214] X is selected from CH or N.

[0215] In some implementation schemes, the structural portion Selected from In some implementation schemes, the structural portion Selected from

[0216] In some implementation schemes, the structural portion Selected from

[0217] In some specific implementation schemes, the structural part Selected from In some specific implementation schemes, the structural part Selected from

[0218] In some implementation schemes, the structural portion Selected from

[0219] In some specific implementation schemes, the structural part Selected from In some specific implementation schemes, the structural part Selected from

[0220] In some implementation schemes, the structural portion Selected from

[0221] In some specific implementation schemes, the structural part Selected from In some specific implementation schemes, the structural part Selected from In some specific implementation schemes, the structural part

[0222] In other implementations, the structural portion Selected from

[0223] In other implementations, the structural portion Selected from

[0224] In other implementations, the structural portion Selected from

[0225] In some implementations, the structural part -Cy 1 -LNK-、-LNK-Cy 2 -、-Cy 1 -Cy 2 -or-Cy 1 -LNK-Cy 2 -As stated in this application.

[0226] This 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] On the other hand, this application relates to compounds of formula I”, their stereoisomers, or pharmaceutically acceptable salts thereof.

[0244]

[0245] in,

[0246] Selected from

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

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

[0249] L is selected from a linking group;

[0250] R 1 The definition of n is as described in this application.

[0251] On the other hand, this application relates to compounds of formula I”-1, portions thereof, stereoisomers thereof, derivatives (specifically, Protac molecules) or pharmaceutically acceptable salts thereof.

[0252]

[0253] in,

[0254] Selected from

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

[0256] L is selected from a linking group;

[0257] R 1 The definition of n is as described in this application.

[0258] In some embodiments of this application, the compound, portion, stereoisomer, derivative (specifically, the Protac molecule), or pharmaceutically acceptable salt thereof of Formula I”-1 is selected from the compound, stereoisomer, or pharmaceutically acceptable salt thereof of Formula I”-1.

[0259] In some implementations, ring A is selected from C. 5-8 Cycloalkenyl (or C) 5-7 Cycloalkenyl), 5-9 membered heterocyclic alkenyl, phenyl, pyrroleyl, pyrazolyl, furanyl, or oxazolyl.

[0260] In some implementations, ring A is selected from C. 5-6Cycloalkenyl, 5-9 membered heterocyclic alkenyl, phenyl, pyrroleyl, pyrazolyl, furanyl, 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 heterocyclic alkenyl, phenyl, pyrrolyl, pyrazolyl, furanyl or oxazolyl.

[0262] In some embodiments, ring A is selected from cyclopentenyl, dicyclohexenyl, dihydropyrroleyl, tetrahydropyridyl, and tetrahydroazapyridine. The group can be alkyl, azirospirooctenyl, dihydrooxazinyl, azirospirononenyl, phenyl, pyrroleyl, pyrazolyl, furanyl, or oxazolyl.

[0263] In some specific implementation schemes, ring A is selected from C. 5-8 Cycloalkenyl or 5-9 membered heterocyclic alkenyl. In some specific embodiments, ring A is selected from C. 5-7 Cycloalkenyl or 5-9 membered heterocyclic alkenyl. In some specific embodiments, ring A is selected from C. 5-6 Cycloalkenyl or 5-9 membered heterocyclic alkenyl. In some embodiments, ring A is selected from 5-8 membered heterocyclic alkenyl. In some embodiments, ring A is selected from 6-8 membered heterocyclic alkenyl. In some embodiments, ring A is selected from 5 membered heterocyclic alkenyl. In some embodiments, ring A is selected from 6 membered heterocyclic alkenyl. In some embodiments, ring A is selected from 7 membered heterocyclic alkenyl. In some embodiments, ring A is selected from 8 membered heterocyclic alkenyl. In some embodiments, ring A is selected from 9 membered heterocyclic alkenyl.

[0264] In some specific embodiments, ring A is selected from cyclopentenyl, dicyclohexenyl, dihydropyrroleyl, tetrahydropyridyl, dihydrooxazinyl, and tetrahydroaza. It can be alkyl, azirspirocyclooctenyl or azirspirocyclononenyl.

[0265] In some specific embodiments, ring A is selected from cyclopentenyl or dicyclohexenyl. In some embodiments, ring A is selected from dihydropyrroleyl, dihydrooxazinyl, tetrahydropyridyl, and tetrahydroazapyryl. It can be alkyl, azirspirocyclooctenyl or azirspirocyclononenyl.

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

[0267] In other implementations, ring A is selected from C. 5-7 Cycloalkenyl, 5-8 membered heterocyclic alkenyl, phenyl or pyrroleyl.

[0268] In other implementations, ring A is selected from C. 5-6 Cycloalkenyl, 5-8 membered heterocyclic alkenyl, phenyl or pyrroleyl.

[0269] In other embodiments, ring A is selected from C5 cycloalkenyl, 5-membered, 6-membered, 7-membered or 8-membered heterocyclic alkenyl, phenyl or pyrroleyl.

[0270] In other embodiments, ring A is selected from cyclopentenyl, dihydropyrroleyl, tetrahydropyridyl, and tetrahydroazapyridine. It can be alkyl, azirrocyclooctene, phenyl or pyrroleyl.

[0271] In other implementations, ring A is selected from C. 5-6 Cycloalkenyl or 5-8 membered heterocyclic alkenyl.

[0272] In other embodiments, ring A is selected from cyclopentenyl, dihydropyrroleyl, tetrahydropyridyl, and tetrahydroazapyridine. Benzyl or azirrospirocyclooctene.

[0273] In some other embodiments, ring A is selected from cyclopentenyl. In some embodiments, ring A is selected from dihydropyrroleyl, tetrahydropyridyl, and tetrahydroazapyryl. Benzyl or azirrospirocyclooctene.

[0274] In some other embodiments, ring A is selected from phenyl or pyrrole.

[0275] In some implementation schemes, the structural portion Selected from

[0276] In some implementation schemes, the structural portion Selected from In some implementation schemes, the structural portion Selected from

[0277] In other implementations, the structural portion Selected from

[0278] In some implementation schemes, the structural portion Selected from In some implementation schemes, the structural portion Selected from

[0279] In some implementation schemes, the structural portion Selected from In some implementation schemes, the structural portion Selected from In some implementation schemes, the structural portion Selected from In other implementations, the structural portion Selected from

[0280] In some implementation schemes, the structural portion Selected from In some implementation schemes, the structural portion Selected from In some implementation schemes, the structural portion Selected from In some implementation schemes, the structural portion Selected from In some implementation schemes, the structural portion Selected from

[0281] In other implementations, the structural portion Selected from

[0282] In some implementations, L is selected from -Cy 1 -LNK-Cy 2 -LNK-、-Cy 1 -LNK-Cy 2 -or-Cy 1 -Cy 2 -LNK-; In some implementations, L is selected from -Cy 1 -LNK-Cy 2 -; In some implementations, Cy 1 LNK, Cy 2 -Cy 1 -LNK-、-LNK-Cy 2 -、-Cy 1 -Cy 2 -or-Cy 1 -LNK-Cy 2 -As described in this application; further, in some embodiments, a portion Selected from Or, in part Selected from

[0283]

[0284]

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

[0286] In some implementations, the PTM is as described in this application.

[0287] In some implementations, PTM is selected from R, T, or ring E are as described in this application.

[0288] In some implementations, PTM is selected from Where R or T is as described in this application.

[0289] On the other hand, this application relates to compounds, portions thereof, isomers (such as stereoisomers), derivatives thereof (specifically, Protac molecules), or pharmaceutically acceptable salts thereof represented by Formula III:

[0290]

[0291] Among them, ring A is selected from C. 5-10 Cycloalkenyl or 5-10 membered heterocyclic alkenyl groups

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

[0293] The ring C is selected from isoxazolyl or furanyl;

[0294] The definition of n is as described in this application;

[0295] Each R 1 Independently selected from halogens, -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 Alkyl groups are optionally surrounded by halogens, -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 heterocyclic alkenyl group contains at least one nitrogen atom.

[0298] In some implementations, ring A is selected from C. 5-8 Cycloalkenyl or 5-10 membered heterocyclic alkenyl;

[0299] Alternatively, ring A can be selected from C. 5-7 Cycloalkenyl or 5-10 membered heterocyclic alkenyl;

[0300] Alternatively, ring A can be selected from C. 5-6 Cycloalkenyl or 5-10 membered heterocyclic alkenyl; or, ring A is selected from C 5-6 Cycloalkenyl or 5-9 membered heterocyclic alkenyl.

[0301] In some implementation schemes, the structural portion Selected from

[0302] In some implementation schemes, the structural portion Selected from

[0303] In some implementation schemes, the structural portion Selected from In some schemes, the structural part Selected from In some schemes, the structural part Selected from

[0304] In some implementation schemes, the structural portion Selected from

[0305] In some specific implementation schemes, the structural part Selected from In some specific implementation schemes, the structural part Selected from In some specific implementation schemes, the structural part Selected from

[0306] In some implementation schemes, the structural portion Selected from

[0307] On the other hand, this application relates to compounds, portions thereof, isomers (such as stereoisomers), derivatives thereof (specifically, Protac molecules), or pharmaceutically acceptable salts thereof represented by Formula III-1:

[0308]

[0309] Among them, R 3 Selected from oxo, hydroxyl, and -(CH2) groups. m -CHO, hydroxyl 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 The definitions of n are as described in this application.

[0310] On the other hand, this application relates to compounds, portions, isomers (such as stereoisomers), derivatives (specifically, Protac molecules), or pharmaceutically acceptable salts thereof represented by formula I”'-1a or I”'-2a:

[0311]

[0312] in,

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

[0314] The definition of n is as described in this application;

[0315] Each R 1 Independently selected from halogens, -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 Alkyl groups are optionally surrounded by halogens, -OH, -NH2, or C. 1-4 Alkyl-OH substitution; or, each R 1 Independently selected from halogens, -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 1-4Alkyl groups are optionally surrounded by halogens, -OH, -NH2, or C. 1-4 Alkyl-OH substitution;

[0316] X 2 Selected from CH or N.

[0317] In some implementations, each R 1 Independently selected from halogens, -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 Alkyl groups are optionally surrounded by halogens, -OH, -NH2, or C. 1-3 Alkyl-OH substitution.

[0318] In some implementations, each R 1 The halogen is independently selected from halogen, -OH, -NH2, -CN, =O, methoxy, -CHO, cyclobutyl or methyl, wherein the cyclobutyl or methyl is optionally substituted by halogen, -OH, -NH2 or CH2OH.

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

[0320] In some specific implementation schemes, each R 1 Independently selected from halogens, -OH, -NH2, -CN, =O, methoxy, -CHO, or C 1-3 Alkyl, the C 1-3 Alkyl groups may optionally be substituted with halogens, -OH, or -NH2.

[0321] In some specific implementation schemes, each R 1 The substance is independently selected from halogen, -OH, -NH2, -CN, =O, methoxy, -CHO or methyl, wherein the methyl group is optionally substituted with -OH or -NH2.

[0322] In some specific implementation schemes, each R 1 It is independently selected from F, -OH, -NH2, -CH2OH, =O, -CHO or -CH2NH2.

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

[0324] On the other hand, this application relates to compounds, portions, isomers (such as stereoisomers), derivatives (specifically, Protac molecules), or pharmaceutically acceptable salts thereof represented by formula I”’-1 or I”’-2:

[0325]

[0326] in,

[0327] Ring A is selected from C 5-10 Cycloalkenyl or 5-10 membered heterocyclic alkenyl; or, ring A is selected from C 5-8 Cycloalkenyl or 5-10 membered heterocyclic alkenyl; or, ring A is selected from C 5-7 Cycloalkenyl or 5-10 membered heterocyclic alkenyl; or, ring A is selected from C 5-6 Cycloalkenyl or 5-10 membered heterocyclic alkenyl; R 1 The definitions of n are as described in this application.

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

[0329] In some embodiments, ring A is selected from cyclopentenyl, dicyclohexenyl, dihydropyrroleyl, tetrahydropyridyl, and tetrahydroazapyridine. It can be alkyl, dihydrooxazinyl, azirospirooctenyl, or azirospirononenyl.

[0330] In some embodiments, ring A is selected from cyclopentenyl or dicyclohexenyl. In some embodiments, ring A is selected from dihydropyrroleyl, tetrahydropyridyl, or tetrahydroazapyryl. It can be alkyl, dihydrooxazinyl, azirospirooctenyl, or azirospirononenyl.

[0331] In some implementations, ring A is selected from... In some implementations, ring A is selected from...

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

[0333] In other embodiments, ring A is selected from cyclopentenyl, dihydropyrroleyl, tetrahydropyridyl, and tetrahydroazapyridine. Benzyl or azirrospirocyclooctene.

[0334] In some other embodiments, ring A is selected from cyclopentenyl. In some embodiments, ring A is selected from dihydropyrroleyl, tetrahydropyridyl, and tetrahydroazapyryl. Benzyl or azirrospirocyclooctene.

[0335] In other embodiments, ring A is selected from...

[0336] This application relates to the following compounds, portions thereof, stereoisomers thereof, derivatives thereof (specifically, such as the Protac molecule), or pharmaceutically acceptable salts thereof:

[0337]

[0338] On the other hand, this application relates to compounds, portions thereof, stereoisomers thereof, derivatives thereof (specifically, Protac molecules) or pharmaceutically acceptable salts thereof represented by the following formulas: I”'-1c or I”'-2d

[0339]

[0340] in,

[0341] Rings A, n and R 1 The definition is as described 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 heterocyclic alkyl;

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

[0348] In some implementations, ring A is selected from C. 5-7 Cycloalkenyl, 5-9 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl.

[0349] In some implementations, ring A is selected from C.5-6 Cycloalkenyl, 5-9 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl.

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

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

[0352] In some implementations, the portion Selected from

[0353] In some implementations, L 1 Selected from the key or -CH2-.

[0354] In some implementations, Cy 3 Selected from C 3-6 Cycloalkyl or 4-6 membered heterocyclic alkyl.

[0355] In some implementations, Cy 3 Selected from C 4-6 Cycloalkyl, 4-membered heterocyclic alkyl or 6-membered heterocyclic alkyl.

[0356] In some implementations, Cy 3 It is selected from cyclobutyl, cyclopentyl, cyclohexyl, aziridine, or piperidinyl.

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

[0358] In some implementation schemes, R 2 Selected from -CHO, OH, or a methyl group substituted with one or more OH groups.

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

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

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

[0362] In some implementations, p is selected from 0 or 1. In some implementations, p is selected from 0. In some implementations, p is selected from 1.

[0363] In some implementation schemes, the structural portion Selected from

[0364] This application relates to the following compounds, portions thereof, stereoisomers thereof, derivatives thereof (specifically, such as the Protac molecule), or pharmaceutically acceptable salts thereof.

[0365]

[0366] This application relates to the following compounds, portions thereof, stereoisomers thereof, derivatives thereof (specifically, such as the Protac molecule), or pharmaceutically acceptable salts thereof.

[0367] On the other hand, this application relates to the use of the aforementioned compounds (e.g., formula III, III-1, I”'-1a, I”'-2a, I”'-1, I”'-2, I”'-1c, I”'-2d, or specific compounds), portions thereof, isomers thereof (e.g., stereoisomers), and derivatives thereof in the Protac molecule. Furthermore, this application relates to the use of the aforementioned compounds (e.g., formula III, III-1, I”'-1a, I”'-2a, I”'-1, I”'-2, I”'-1c, I”'-2d, or specific compounds), portions thereof, isomers thereof (e.g., stereoisomers), and derivatives thereof in constituting a part of the Protac molecule. On the other hand, this application relates to the use of the aforementioned compounds (e.g., formula III, III-1, I”'-1a, I”'-2a, I”'-1, I”'-2, I”'-1c, I”'-2d, or specific compounds), portions thereof, isomers thereof (e.g., stereoisomers), and derivatives thereof in the form of Protac molecules. Furthermore, this application relates to the use of the aforementioned compounds (e.g., formula III, III-1, I”'-1a, I”'-2a, I”'-1, I”'-2, I”'-1c, I”'-2d, or specific compounds), portions thereof, isomers thereof (e.g., stereoisomers), and derivatives thereof for the degradation of proteins, such as the degradation of the proteins by the aforementioned compounds (e.g., formula III, III-1, I”'-1a, I”'-2a, I”'-1, I”'-2, I”'-1c, I”'-2d, or specific compounds), portions thereof, isomers thereof (e.g., stereoisomers), and derivatives thereof in the form of Protac molecules. On the other hand, this application relates to the use of the aforementioned compounds (e.g., formula III, III-1, I”'-1a, I”'-2a, I”'-1, I”'-2, I”'-1c, I”'-2d, or specific compounds), portions thereof, isomers thereof (e.g., stereoisomers), and derivatives thereof in the form of Protac molecules for protein degradation. This application relates to the use of the aforementioned compounds (e.g., formula III, III-1, I”'-1a, I”'-2a, I”'-1, I”'-2, I”'-1c, I”'-2d, or specific compounds), portions thereof, isomers thereof (e.g., stereoisomers), and derivatives thereof (e.g., as preparation intermediates) in the preparation of Protac molecules. This application relates to the use of the aforementioned compounds (e.g., formulas III, III-1, I”'-1a, I”'-2a, I”'-1, I”'-2, I”'-1c, I”'-2d, or specific compounds), portions thereof, isomers thereof (e.g., stereoisomers), and derivatives thereof (e.g., as preparation intermediates) in the preparation of protein degrading agents. Optionally, the Protac molecule may not include Protac molecules involving AR.

[0368] Specifically, for example, in some embodiments, this application relates to the use of the following compounds, portions thereof, stereoisomers thereof, or pharmaceutically acceptable salts thereof in the preparation of Protac molecules:

[0369]

[0370] in,

[0371] Ring A is selected from C 5-10 Cycloalkenyl or 5-10 membered heterocyclic alkenyl; or, ring A is selected from C 5-8 Cycloalkenyl or 5-10 membered heterocyclic alkenyl; or, ring A is selected from C 5-7 Cycloalkenyl or 5-10 membered heterocyclic alkenyl; or, ring A is selected from C 5-6 Cycloalkenyl or 5-10 membered heterocyclic alkenyl, preferably, ring A is selected from cyclopentenyl, dihydropyrroleyl, tetrahydropyridyl or tetrahydroaza 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 halogens, -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 Alkyl groups are optionally surrounded by halogens, -OH, -NH2, or C. 1-4 Alkyl-OH substitution; 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] Part of the compound may be Preferably, the portion is selected from...

[0376] In some embodiments, this application relates to a method for preparing Protac molecules, comprising:

[0377] The Protac molecule was prepared by reacting the following compounds, their portions, their stereoisomers, or pharmaceutically acceptable salts thereof:

[0378]

[0379] in,

[0380] Ring A is selected from C5-10 Cycloalkenyl or 5-10 membered heterocyclic alkenyl; or, ring A is selected from C 5-8 Cycloalkenyl or 5-10 membered heterocyclic alkenyl; or, ring A is selected from C 5-7 Cycloalkenyl or 5-10 membered heterocyclic alkenyl; or, ring A is selected from C 5-6 Cycloalkenyl or 5-10 membered heterocyclic alkenyl, preferably, ring A is selected from cyclopentenyl, dihydropyrroleyl, tetrahydropyridyl or tetrahydroaza 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 halogens, -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 Alkyl groups are optionally surrounded by halogens, -OH, -NH2, or C. 1-4 Alkyl-OH substitution; 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] Part of the compound may be Preferably, the portion is selected from...

[0385] This application relates to the use of the aforementioned compounds (e.g., formulas III, III-1, I”'-1a, I”'-2a, I”'-1, I”'-2, I”'-1c, I”'-2d, or specific compounds), portions thereof, isomers thereof (e.g., stereoisomers), and derivatives thereof for the degradation of BTK proteins, for example, the degradation of BTK proteins by the aforementioned compounds, portions thereof, isomers thereof (e.g., stereoisomers), and derivatives thereof in the form of Protac molecules. On the other hand, this application relates to the use of the aforementioned compounds (e.g., formulas III, III-1, I”'-1a, I”'-2a, I”'-1, I”'-2, I”'-1c, I”'-2d, or specific compounds), portions thereof, isomers thereof (e.g., stereoisomers), and derivatives thereof in the form of Protac molecules for the degradation of BTK proteins.

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

[0387] On the other hand, this application relates to a pharmaceutical composition containing the compounds, portions thereof, stereoisomers thereof, derivatives thereof, or pharmaceutically acceptable salts thereof described above in this application, and the pharmaceutical composition of this application further includes pharmaceutically acceptable excipients.

[0388] On the other hand, this application relates to the use of the aforementioned compounds, portions thereof, stereoisomers thereof, derivatives thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of medicaments for the prevention or treatment of diseases by degrading target proteins bound to target ligands.

[0389] On the other hand, this application relates to the use of the aforementioned compounds, portions thereof, stereoisomers thereof, derivatives thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of medicaments for the prevention or treatment of conditions by binding to cerebellar proteins in vivo.

[0390] On the other hand, this application relates to the use of the above-mentioned compounds, portions thereof, stereoisomers thereof, derivatives thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of medicaments for the prevention or treatment of BTK-related diseases.

[0391] This application relates to a method for treating or preventing diseases in mammals by degrading target proteins that bind to target ligands, including administering a therapeutically effective amount of the aforementioned compound of this application, its stereoisomers, its derivatives, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, to mammals, preferably humans, in the treatment of such mammals.

[0392] This application relates to methods for treating or preventing conditions by binding to cerebellar proteins in vivo, including administering a therapeutically effective amount of the aforementioned compound of this application, its stereoisomers, its derivatives, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, to mammals, preferably humans, who require such treatment.

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

[0394] On the other hand, this application relates to the aforementioned compounds, portions, stereoisomers, derivatives, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for the prevention or treatment of conditions by means of degradation of target proteins that bind to target ligands.

[0395] On the other hand, this application relates to the aforementioned compounds, portions, stereoisomers, derivatives, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for the prevention or treatment of conditions that are treated by binding to cerebellar proteins in the body.

[0396] On the other hand, this application relates to the aforementioned compounds, portions thereof, stereoisomers thereof, derivatives thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for the prevention or treatment of BTK-related diseases.

[0397] On the other hand, this application relates to the use of the aforementioned compounds, portions thereof, stereoisomers thereof, derivatives thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the prevention or treatment of conditions treated by degrading target proteins bound to target ligands.

[0398] On the other hand, this application relates to the use of the aforementioned compounds, portions thereof, stereoisomers thereof, derivatives thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the prevention or treatment of conditions that are treated by binding to cerebellar proteins in vivo.

[0399] On the other hand, this application relates to the use of the aforementioned compounds, portions, stereoisomers, derivatives, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the prevention or treatment of BTK-related diseases. In some embodiments, the aforementioned BTK-related diseases are selected from conditions treated by degrading proteins that bind to BTK target protein ligands; in some embodiments, the aforementioned BTK-related diseases are selected from conditions treated by binding to cerebellar proteins in vivo; in some embodiments, the aforementioned diseases or conditions are selected from autoimmune diseases, inflammatory diseases, or cancer.

[0400] In some specific implementations, the conditions treated by binding to cerebellar proteins in vivo and / or the conditions treated by binding to cerebellar proteins in vivo are selected from BTK-related diseases; in some specific implementations, the BTK-related diseases are selected from autoimmune diseases, inflammatory diseases, or cancer.

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

[0402] In some implementations, this application includes the variables defined above, their implementations, and any combination thereof.

[0403] Technical effect

[0404] The compound of this application exhibits a degradation effect on BTK in OCI-LY10 cells; in vitro, it can inhibit the degradation of BTK in cells (OCI-LY10 cells, TMD8-BTK). C481S Cells or OCI-LY10-BTK C481S Cell proliferation; compared to EGFR and TEC kinases, targeting BTK and / or BTKC481S The kinase is selective; it is metabolically stable in vitro and has good in vivo pharmacokinetic properties; it has an inhibitory effect on mouse TMD-8 xenografts in vivo; it has CRBN protein binding activity and can exhibit the desired IKZF1, IKZF3, and GSPT1 protein degradation activities.

[0405] The compound provided in this application can interact with CRL4. CRBN E3 ubiquitin ligases bind to cereblon receptors, thereby creating new binding sites for novel substrates of proteins that act as mediators of human diseases, leading to the degradation of these novel substrates. The novel morphological surfaces produced by these compounds can directly interact with target proteins or target protein complexes, thereby directly or indirectly reducing protein levels. In various embodiments, the compounds described in this application can reduce the level of novel substrate target proteins through direct ubiquitination of the target protein; or ubiquitinate novel substrate target protein cofactors or target protein complexes or other proteins responsible for controlling target protein homeostasis. These compounds may lead to the degradation of novel substrate target proteins that directly bind to ligands in the brain; degradation of novel substrates that bind to ligands in the brain as cofactors; degradation of ligand-bound brain proteins at the interface between the cofactor and the target protein; degradation of novel substrate target protein complexes that bind to ligands in CRBNs; or reduction of target protein levels by degrading proteins not in the complex or cofactors of novel substrate proteins.

[0406] definition

[0407] Unless otherwise stated, the following terms as used in this application shall have the following meanings. A particular term should not be considered uncertain or unclear unless specifically defined, but should be understood in accordance with its ordinary meaning in the art. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0408] The term "substituted" refers to the substitution of one or more hydrogen atoms on a specific atom by a substituent, provided that the valence state of the specific atom is normal and the resulting compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are substituted; oxo substitution does not occur on aromatic groups.

[0409] The terms “optional” or “optionally” mean that the event or condition subsequently described may or may not occur, including both the occurrence and non-occurrence of said event or condition. The phrase “optionally substituted” indicates that the group is substituted or unsubstituted. For example, the ethyl group being “optionally” substituted with a halogen means that the ethyl group can be unsubstituted (CH2CH3), monosubstituted (e.g., CH2CH2F), polysubstituted (e.g., CHFCH2F, CH2CHF2, etc.), or fully substituted (CF2CF3). Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern that is spatially impossible and / or synthetically undesirable is introduced.

[0410] C in this article m-n This part has an integer number of carbon atoms within 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 (such as R) appears more than once in the composition or structure of a compound, its definition is independent in each case. For example, if a group contains two Rs, then each R has an independent option.

[0412] When a bond cross-bonds two atoms in a ring (including monocyclic, fused, or spirocyclic rings), this bond can bond with any atom in the ring (including monocyclic, fused, or spirocyclic rings). For example, structural units. This indicates that the bonds on both sides can be connected to any two different atoms in ring A, ring B, or ring C; for example... This indicates that the bonds on both sides can be connected to any two different atoms on ring A, the middle benzene ring, or ring C; further for example... This indicates that the bonds on both sides can be connected to any two different atoms in the four rings of the system.

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

[0414] The term "hydroxyl group" refers to the -OH group.

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

[0416] The term "alkyl" refers to a compound with the general formula C10. n H 2n+1 The alkyl group. This alkyl group can be straight-chain or branched. For example, the term "C 1-6"Alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl portion (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio groups has the same definition as above.

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

[0418] The term "heteroalkylene" refers to an alkylene group in which one or more carbon atoms are replaced by heteroatoms, and at least one carbon atom is present. 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 A heteroalkylene group indicates that the heteroalkylene group contains 1 to 12 carbon atoms and one or more heteroatoms (e.g., 1-6, 1-3, 1, 2, or 3 heteroatoms). For example, C 1-6 A heteroalkylene group indicates that the heteroalkylene group contains 1 to 6 carbon atoms and one or more heteroatoms.

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

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

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

[0422] Non-limiting examples of “benzocycloalkenyl” include benzo4- to 12-membered cycloalkenyl, benzo4- to 10-membered cycloalkenyl, or benzo4- to 8-membered (e.g., 4-, 5-, 6-, 7-, or 8-membered) cycloalkenyl.

[0423] The term "cycloalkyl" refers to a fully saturated carbon ring that may exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the carbon 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 "heterocyclic alkyl" refers to a fully saturated cyclic group that may exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 3- to 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 independently selected from sulfur, oxygen, and / or nitrogen (preferably 1 or 2 heteroatoms). Examples of 3-membered heterocyclic alkyl groups include, but are not limited to, ethylene oxide, cyclothioethylene, and cycloazoethylene; non-limiting examples of 4-membered heterocyclic alkyl groups include, but are not limited to, acridine, oxadiazolyl, and thiobutyl; examples of 5-membered heterocyclic alkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, imidazolyl, and tetrahydropyrazolyl; examples of 6-membered heterocyclic alkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, morpholinyl, piperazine, 1,4-thiaoxane, 1,4-dioxane, thiomorpholinyl, 1,3-dithiaalkyl, and 1,4-dithiaalkyl; and examples of 7-membered heterocyclic alkyl groups include, but are not limited to, azirheptanyl, oxeheptanyl, and thioheptanyl. Monocyclic heterocyclic alkyl groups having 5 or 6 ring atoms are preferred.

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

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

[0427] Unless otherwise indicated, the carbon 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, and cycloheptadienyl.

[0428] The term "heteroaryl" refers to a monocyclic or fused polycyclic system containing at least one ring atom selected from N, O, and S, with the remaining ring atoms being C, and having at least one aromatic ring. Preferred heteroaryls have a single 4- to 8-membered ring, particularly a 5- to 8-membered ring, or multiple fused rings containing 6 to 14, particularly 6 to 10, ring atoms. Non-limiting examples of heteroaryls include, but are not limited to, pyrroleyl, furanyl, thiopheneyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothiopheneyl, indoleyl, isoindoleyl, etc.

[0429] In this application, wavy lines are used. One of the absolute configurations representing the center of a solid (e.g.) one, specific express ) or one of the relative configurations (e.g. express When the compounds described herein contain an alkene double bond or other geometrically asymmetric centers, they include E and Z geometric isomers, unless otherwise specified. Similarly, all tautomer forms are included within the scope of this application.

[0430] Groups or structural motifs 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, which can optionally be read from left to right, corresponding to the group or part of the left and right groups in the general formula, respectively, for example, when Cy 1 Selected from Following the reading order from left to right, Cy 1 The left side and the part corresponding to the left side in the general formula Connection, right side and right side part The connection forms the part that is Optionally, the groups or structural moiety in this application, such as LNK, Cy, etc. 1 Cy 2 -Cy 1 -LNK-Cy 2 -、-Cy 1 -LNK- or -LNK-Cy 2 - and its specific options, can be read from right to left, corresponding to the group or part of the left and right groups in the general formula, for example, when Cy 1 Selected from Following the reading order from right to left, Cy 1 The right side corresponds to the left side of the general formula. Connect the left side to the corresponding right side of the general formula. The part formed by the connection is The 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 the target protein and the E3 ubiquitin ligase. These compounds can induce the target protein to be recognized by the cell's proteasome, causing the protein to degrade and effectively reducing the content of the target protein in the cell.

[0432] The term "derivative" refers to a new compound or group of new compounds resulting from the substitution or replacement of one or more hydrogen atoms in the basic structure of a parent compound with other groups or structural parts. In this application, "derivative" refers to a derived compound that retains the parent compound's structure. For example, a parent compound may be 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 target polypeptide; linker is the linking group; and ULM refers to the portion that binds to ubiquitin ligases.

[0433] The term "drug or derivative thereof targeting a protein" or PTM is used to describe small molecules that bind to a target protein or other proteins or peptides of interest; and that the location / presence of said protein or peptide is close to that of a ubiquitin ligase so that degradation of the protein or peptide by the ubiquitin ligase can occur. Non-limiting examples of small molecule target protein binding moieties include drugs or derivatives thereof targeting AR, ER, kinases, phosphatases, MDM2, proteins containing the human BET bromo domain, Hsp90, HDAC, human lysine methyltransferase, RAF receptor, FKBP, angiogenesis factor, immunosuppression-related receptors or proteins, aryl hydrocarbon receptors, thyroid hormone receptors, HIV proteases, HIV integrase, HCV proteases, HBV proteases, or acyl protein thioesterases 1 and / or 2, as well as many others; or including drugs or derivatives targeting ALK, BET, CDK, PARP, EGFR, γ-secretase, CBFβ-SMMHC, WEE1, MEK, B... Drugs or their derivatives targeting CR-ABL, MET, RAS, BTK, VEGFR, JAK, HER2, HDAC, Akt, PI3K, mTOR, AR, ER, PDEδ, SRC, MDM2, RAF, IRAK4, STAT3, and c-Myc, as well as many others; or, drugs or their derivatives targeting ALK, BRD4, CDK4 / 6, PARP, EGFR, γ-secretase, CBFβ-SMMHC, WEE1, MEK, BCR-ABL, MET, KRAS, EGFR, BTK, AR, ER, PDEδ, JAK, MDM2, or RAF, as well as many others.

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

[0435] "Target protein" is used below to describe a protein or polypeptide that binds to a compound according to this 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, as well as other small molecules capable of targeting the protein of interest. These binding moieties are connected via a linker group L to a group. connect.

[0436] Unless otherwise specified, Hydrogen atoms at any position within the brackets [] can be replaced by groups connected by "—".

[0437] The term "treatment" means administering the compound or preparation described in this application to improve or eliminate a disease or one or more symptoms related to said disease, and includes:

[0438] (i) Suppress the disease or disease state, that is, curb its development;

[0439] (ii) Relieve the disease or disease state, even if the disease or disease state subsides.

[0440] The term “prevention” means administering the compound or formulation described in this application to prevent a disease or one or more symptoms associated with the disease, including: preventing the occurrence of a disease or disease state in mammals, particularly when such mammals are susceptible to the disease state but have not yet been diagnosed with the disease state.

[0441] The term "therapeutic effective amount" means the amount of the compound of this application used to treat or prevent a particular disease, condition, or disorder; (ii) to reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder; or (iii) to prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the compound of this application constituting a "therapeutic effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by a person skilled in the art based on their own knowledge and the present disclosure.

[0442] The term "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0443] As pharmaceutically acceptable salts, examples include metal salts, ammonium salts, salts formed with organic bases, salts formed with inorganic acids, salts formed with organic acids, and salts formed with basic or acidic amino acids.

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

[0445] The term "pharmaceuticalally acceptable excipient" refers to excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0446] The word “comprise” or “include” and its English variants such as comprises or comprising should be understood in an open, non-exclusive sense, meaning “including but not limited to”.

[0447] The compounds and intermediates of this application may also exist in different tautomer forms, and all such forms are included within the scope of this application. The terms "tautomer" or "tautomer form" refer to structural isomers of different energies that can interconvert via low energy barriers. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerization. A specific example of a proton tautomer is the imidazole moiety, where a proton can migrate between two ring nitrogens. Valence tautomers include interconversions via the recombination of some bonding electrons.

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

[0449] Unless otherwise stated, in this document, parameter values ​​representing the amount of an ingredient, its physicochemical properties, or reaction conditions, etc., should be understood to be modified by the term "about" in all cases. When the term "about" is used to describe this application, the term "about" indicates an existing error value, such as a variation within ±5%, for example ±1%, or ±0.1% of a particular value.

[0450] This application also includes compounds of this application that are identical to those described herein, but with one or more atoms replaced by isotopes whose atomic weights or mass numbers differ from those commonly found in nature. Examples of isotopes that can be incorporated into compounds of this application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as... 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 31 P,32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.

[0451] Certain isotope-labeled compounds of this application (e.g., using...) 3 H and 14 Those labeled with C can be used in the analysis of compound and / or substrate tissue distribution. Tritiumization (i.e. 3 H) and carbon-14 (i.e. 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability. Positron-emitting isotopes, such as... 15 O、 13 N、 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. The isotopically labeled compounds of this application can typically be prepared by replacing the unlabeled reagent with an isotopically labeled reagent using a procedure similar to those disclosed in the schemes and / or examples below.

[0452] In addition, heavier isotopes (such as deuterium) are used. 2 H)) substitution can provide certain therapeutic advantages resulting from higher metabolic stability (e.g., increased in vivo half-life or reduced dose requirement), and may therefore be preferred in certain situations, where deuterium substitution can be partial or complete, with partial deuterium substitution referring to at least one hydrogen being replaced by at least one deuterium.

[0453] The compounds of this application may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers include enantiomers and diastereomers. The compounds containing asymmetric carbon atoms of this application can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from a racemic mixture or synthesized using chiral starting materials or chiral reagents.

[0454] The pharmaceutical compositions of this application can be prepared by combining the compounds of this application with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalers, gels, microspheres and aerosols.

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

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

[0457] In some embodiments, the pharmaceutical composition is in an oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of this application to be formulated into tablets, pills, lozenges, sugar-coated tablets, capsules, liquids, gels, pastes, suspensions, etc., for oral administration to patients.

[0458] Solid oral compositions can be prepared using conventional mixing, filling, or tableting methods. For example, they can be obtained by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain the core of a tablet or sugar-coated formulation. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents.

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

[0460] In all methods of administration of the compounds of general formula I described herein, the daily dose is 0.01 to 200 mg / kg body weight, administered in single or separate doses.

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

[0462] The chemical reactions in the specific embodiments of this application are carried out in a suitable solvent, which must be suitable for the chemical changes and the reagents and materials required in this application. In order to obtain the compounds of this application, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction process based on existing embodiments.

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

[0464] In some embodiments, the compounds of formula I of this application can be prepared by those skilled in the art of organic synthesis via the following route:

[0465]

[0466] Where X 1 Selected from halogens.

[0467] The compound of general formula (I-1) is coupled to give the compound of general formula (I-2), the compound of general formula (I-2) is hydrolyzed to give the compound of general formula (I-3), and then the compound of general formula (I-4) is obtained by removing the protecting group.

[0468] Compounds of general formula (I-5) are obtained by substituting Cy with hydroxyl groups. 2 The coupling reaction yields compound of general formula (I-6), which, through addition and transesterification with acrylamide, yields compound of general formula (I-7). Compound of general formula (I-7) is then oxidized to yield compound of general formula (I-8). Compounds of general formula (I-4) and general formula (I-8) are then reductively aminationd to yield compound of general formula I.

[0469] Compounds of general formula (I-5) are obtained by substituted Cy with hydroxymethyl groups. 2 The coupling reaction yields compound of general formula (I-9), which, through addition and transesterification with acrylamide, yields compound of general formula (I-10). Compound of general formula (I-10) is then oxidized to yield compound of general formula (I-11). Compounds of general formula (I-4) and general formula (I-11) are then reductively aminationd to yield compound of general 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(dibenzylacetone)dipalladium; THF represents tetrahydrofuran; MeOH represents methanol; PE represents petroleum ether; IBX represents 2-iodobenzoic acid; DIPEA represents N,N'-diisopropylethylamine; DIBAL-H represents di... Isobutylaluminum hydride; NIS represents N-iodosuccinimide; NBS represents N-bromosuccinimide; Tf represents -OSO2CF3; H2O2 represents hydrogen peroxide; Pd(OAc)2 represents target acetic acid; DMA represents N,N-dimethylacetamide; TBSCl represents tert-butyldimethylchlorosilane; TFA represents trifluoroacetic acid; PdCl2(dppf) represents [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride; Ruphos represents 2-bicyclohexylphosphine-2',6'-diisopropoxybiphenyl.

[0472] For 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 publication predates the filing date of this application. All statements regarding the dates of these documents or representations of their contents are based on information available to the applicant and do not constitute any acknowledgment of the accuracy of the dates or contents of these documents. Furthermore, in any country, any reference to these publications herein does not constitute an endorsement that such publication is part of the general knowledge in the art.

[0473] For clarity, this application is further illustrated with examples, but these examples are not intended to limit the scope of this application. All reagents used in this application are commercially available and can be used without further purification. Detailed Implementation

[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 then slowly added dropwise over 20 minutes. The reaction was allowed to proceed 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 filtrate was distilled under reduced pressure to remove the solvent. The crude product was separated by silica gel column chromatography (eluent: EA) to obtain 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] At 0°C, sodium hydride (10.31 g) was slowly added to a mixture of intermediate 1b (40 g) and tetrahydrofuran (300 mL) with stirring. After the addition was complete, the mixture was allowed to react overnight at room temperature. After the reaction was complete, 75 mL of water was added to quench the reaction mixture, and the mixture was stirred vigorously for 10 minutes before separation. 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 then separated. Rotary evaporation of the acetonitrile phase yielded 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 mixture of intermediate 1c (20 g) and tetrahydrofuran (200 mL) with stirring. After stirring for 5 min, the ice bath was removed, and the mixture was stirred at room temperature for 1 h. Then, an ice bath was added, and iodomethane (15.21 g, 6.70 mL) was slowly added dropwise to the reaction system. After the addition was complete, the reaction was allowed to proceed overnight at room temperature. At the end of the reaction, 75 mL of water was added to quench the reaction mixture, and after vigorous stirring for 10 min, the mixture was 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 then separated. The acetonitrile phase was rotary evaporated to give intermediate 1d (22.5 g).

[0484] Step 4: Preparation of intermediate 1e

[0485] Intermediate 1d (20 g) and 4M dioxane hydrochloride solution (25.7 g, 176 mL, 705 mmol) were added sequentially to a single-necked flask, and the reaction was carried out at room temperature. After the reaction was completed, the solvent was removed by vacuum distillation to obtain intermediate 1e (15.5 g).

[0486] Step 5: Preparation of intermediate 1f

[0487] At 0°C, 11.82 g of 3,5-dichloropyrazine-2-onitrile was added to a mixture of intermediate 1e (15 g) and N,N-diisopropylethylamine (35.1 g, 47.5 mL) in 300 mL of DMF with stirring. After 15 minutes, the ice bath was removed, and the mixture was stirred overnight at room temperature. 300 mL of ethyl acetate and 300 mL of water were added to the reaction mixture. The organic phase was separated by extraction twice with 100 mL of ethyl acetate, followed by washing with 200 mL of saturated brine, drying with anhydrous sodium sulfate, and filtering. The solvent was removed by vacuum distillation, and the crude product was separated by silica gel column chromatography (eluent: dichloromethane / methanol = 100:1, v / v) 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 1g of intermediate

[0491] To a single-necked flask, intermediate 1f (13 g), 4-(4-aminophenyl)piperidine-1-carboxylic acid tert-butyl ester (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 N2 protection, the mixture was heated to 100 °C for reaction. After the reaction was complete, the reaction solution was cooled to room temperature, filtered, and the filter cake was washed with 150 mL of dichloromethane. The filtrate was purified by vacuum distillation to remove the solvent, and the crude product was separated by silica gel column chromatography (eluent: dichloromethane / methanol = 100:1, volume ratio) to obtain 1 g (14.2 g) of the target intermediate.

[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 for 1 hour

[0495] To a single-necked flask, 1 g (8 g) of the intermediate, 25 mL of DMSO, and 4.08 g of cesium carbonate were added sequentially. Under ice bath conditions, hydrogen peroxide (21.32 g, 19.21 mL) was added, and the mixture was stirred for 5 min. The ice bath was then removed, and the reaction was allowed to proceed at room temperature. After the reaction was complete, 300 mL of saturated sodium sulfite solution was added to the residue to quench the reaction. The residue showed no color change when tested with starch-potassium iodide reagent. Then, 300 mL of ethyl acetate was added for extraction. The residue was extracted three times with 100 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The solvent was removed under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: dichloromethane / methanol = 100:1, v / v) to obtain the target intermediate 1h (7.22 g).

[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 (3g), dichloromethane (30mL), and trifluoroacetic acid (17.06g, 11.53mL) were added sequentially, and the reaction was carried out at room temperature. After the reaction was completed, the solvent was removed by vacuum distillation to obtain the trifluoroacetate product. 50mL of dichloromethane was added to dissolve the crude product, and saturated sodium bicarbonate aqueous solution was slowly added to adjust the system to a weakly alkaline state. The mixture was then separated. The organic phase was further separated by vacuum distillation to obtain intermediate 1i (2.4g).

[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 toluene (100 mL) solution of intermediate 1j (30 g) was slowly added dropwise to a toluene (50 mL) solution of sodium hydride (27.9 g). After the addition was complete, the mixture was stirred at 0°C for 15 min. Dimethyl carbonate (126 g) was added dropwise to the reaction solution. After the addition was complete, the mixture was stirred at 0°C for 15 min, and then heated to 100°C for 2 hours. The reaction solution was washed once with water (500 mL). The organic layer was discarded, and the pH of the aqueous layer was adjusted to 2-3 with dilute hydrochloric acid (3 mol / L) at low temperature, resulting in the precipitation of a large amount of solid. The solid was filtered and dried 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 1L

[0507] To a reaction flask, intermediate 1k (29.5g), hydroxylamine hydrochloride (15.85g), sodium ethoxide (15.52g), and ethanol (150ml) were added sequentially. The mixture was heated to 85°C for 2 hours under N2 protection. The reaction solution was evaporated to dryness. The residue was extracted with 500mL of saturated sodium carbonate solution using DCM (300mL*2), and the organic layer was discarded. The aqueous layer was adjusted to pH < 3 with dilute hydrochloric acid (3mol / L), resulting in the precipitation of a large amount of solid. The solid was filtered, and the resulting filter cake was washed with water and dried under normal pressure to obtain 26.53g 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, 1 L (26.5 g) of intermediate, 530 mL of ethanol, and 49.9 g, 27.1 mL, 508 mmol of concentrated sulfuric acid were added dropwise. The mixture was heated to 85 °C and reacted 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 mixture 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 give 24.87 g of intermediate 1 M.

[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 the reaction flask, intermediate 1m (2 g), (S)-pyrrolidine-3-methanol (2.087 g), Pd2(dba)3 (1.260 g), potassium phosphate (5.84 g), and finally toluene (60 mL) were added sequentially. The mixture was heated at 80 °C for 4 hours under N2 protection. The reaction solution was washed twice with 100 mL of water. The organic layer was dried over anhydrous sodium sulfate, and the filtrate was concentrated and purified by silica gel column chromatography to obtain 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, first add intermediate 1n (360 mg) and THF (30 mL), then add acrylamide (101 mg) and potassium tert-butoxide (199 mg) at 0 °C. Under N2 protection, slowly heat the mixture to 10 °C and stir. After the reaction is complete, add 100 mL of saturated ammonium chloride solution to the reaction solution at low temperature. Extract twice with EA (50 mL). After drying the organic layer with anhydrous sodium sulfate, evaporate the filtered filtrate to dryness and purify 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), DCM (30 mL), and Desmartin reagent (1.224 g) were added sequentially with stirring. The mixture was reacted at room temperature under N2 protection. After the reaction was complete, the reaction solution was quenched at low temperature with Na2S2O3 aqueous solution (30 mL), and then extracted with NaHCO3 aqueous solution (30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain 290 mg of intermediate 1p, which was directly added to the next reaction step.

[0522] Step 15: Preparation of Compound 1

[0523] To a reaction flask, intermediate 1i (150 mg), intermediate 1p (103 mg), DCM (10 mL), and glacial acetic acid (31.4 mg, 0.030 mL) were added sequentially. After stirring at room temperature for 20 min, sodium cyanoborohydride (59.1 mg) was added, and stirring continued at room temperature. After the reaction was complete, 20 mL of saturated NaHCO3 solution was added to the reaction solution, and the mixture was extracted twice with 20 mL of DCM-MeOH (10:1). The extracts were combined, dried over anhydrous sodium sulfate, filtered, and the resulting filtrate was evaporated to dryness and filtered through a C10 filter. 18 Purification was performed by reversed-phase column chromatography (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 sequentially, followed by Pd2(dba)3 (1.289 g) and 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 under rotary evaporation. The filtrate was purified by silica gel column chromatography (PE-EA = 95:5, v / v, 1500 mL) and then further purified using C2O4. 18 480 mg of intermediate 2b was purified by reverse-phase column chromatography (10 nM ammonium acetate aqueous solution - acetonitrile = 50%:50%, volume ratio).

[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, first add intermediate 2b (450 mg) and THF (40 mL), then add acrylamide (126 mg) and potassium tert-butoxide (249 mg) at 0 °C. Under N2 protection, slowly heat the mixture to 10 °C and stir. After the reaction is complete, add 100 mL of saturated ammonium chloride solution to the reaction solution at low temperature. Extract twice with EA (50 mL). After drying the organic layer with anhydrous sodium sulfate, evaporate the filtrate to dryness by rotary evaporation and purify by silica gel column chromatography (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 a reaction flask, intermediate 2c (440 mg), DCM (30 mL), and Desmartin reagent (1.7 g) were added sequentially with stirring. The mixture was reacted at room temperature under N2 protection. After the reaction was complete, the reaction was quenched at low temperature with Na2S2O3 aqueous solution (30 mL). The extracted organic layer was washed with NaHCO3 aqueous solution (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness to obtain 342 mg of intermediate 2d, which was directly added to the next reaction step.

[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 sequentially. After stirring at room temperature for 20 min, sodium cyanoborohydride (197 mg) was added, and stirring continued at room temperature. After the reaction was complete, 20 mL of saturated NaHCO3 solution was added to the reaction solution, and the mixture was extracted twice with 20 mL of DCM-MeOH (10:1). The extracts were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness and filtered through a C10 filter. 18 Reversed-phase column chromatography (10 nM ammonium acetate aqueous solution - acetonitrile = 50%:50%, volume ratio) yielded 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). At 0 °C, triethylamine (15.89 g, 21.89 mL) was added, followed by the slow dropwise addition of acetyl chloride (12.33 g). After the addition was complete, the mixture was allowed to react at room temperature for 1 h. After the reaction was complete, 300 mL of dichloromethane was added to dilute the system, and then 3M hydrochloric acid was added to adjust the pH to weakly acidic. The mixture was extracted and separated, and the organic phase was collected. The organic phase was then adjusted to weakly alkaline pH with saturated sodium bicarbonate solution, extracted, and separated, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain intermediate 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] Intermediate 3b (8.61 g) and aluminum trichloride (8.92 g) were added sequentially to a single-necked flask, and the mixture was heated to 170 °C and reacted for 2 h. The reaction solution was cooled to room temperature, and 50 mL of dichloromethane was added, followed by approximately 500 mL of 3M hydrochloric acid. The mixture 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 removed by vacuum evaporation 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 in portions. The mixture was first heated to 90°C, then heated to 120°C and reacted 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 removed by vacuum evaporation 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 reacted overnight. The reaction solution was cooled to room temperature, and the pH was adjusted to 5 with 3N hydrochloric acid. The solvent was removed by vacuum evaporation, 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 min 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. The mixture was heated to 90 °C and reacted for 2 h. The reaction solution was cooled to room temperature, and the solvent was removed by vacuum distillation. The residue was diluted with 100 mL of ethyl acetate and 100 mL of water. The pH was adjusted to 7 with saturated sodium bicarbonate solution, and the organic phase was separated. 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 removed by vacuum distillation to obtain 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 3g of intermediate

[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 N2 protection, the mixture was heated to 100 °C and reacted overnight. The reaction solution was cooled to room temperature, and the solvent was removed by vacuum distillation. The crude product was separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1:1, v / v) to obtain 3 g (0.5 g) of the target intermediate.

[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 over 3 hours

[0568] To a three-necked flask, 3 g (500 mg) of intermediate, 98 mg of acrylamide, and 5 mL of anhydrous tetrahydrofuran were added sequentially. Potassium tert-butoxide (233 mg) was slowly added at -15 °C, and the reaction was carried out for 2 h at -15 °C. The reaction was quenched by adding saturated ammonium chloride aqueous solution dropwise, 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 removed under reduced pressure to obtain intermediate 3 h (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, add intermediate 3h (80 mg), acetonitrile (5 mL), and IBX (129 mg) sequentially. Heat the mixture to 85°C and react for 1 hour. Cool the reaction solution to room temperature, filter the reaction solution, collect the filtrate, and use the resulting solution (containing intermediate 3i) directly for the next reaction step.

[0573] Step 9: Preparation of Compound 3

[0574] To a single-necked flask, intermediate 3i (a 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, and the mixture was stirred at room temperature for 1 hour. Then, sodium cyanoborohydride (23.63 mg) was added, and the reaction was continued at room temperature for 2 hours. The solvent was removed by vacuum evaporation, and the mixture was purified by preparative liquid chromatography. Compound 3 (25 mg) was obtained.

[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] Add 25 g of 4a, 68.7 g of diethyl carbonate, and 200 mL of toluene to a reaction flask in sequence. Cool the reaction mixture to 0°C, then add sodium hydride (23.25 g) in portions. Heat the mixture to 120°C and react for 5 h. Stop the reaction, cool the reaction mixture to room temperature, and slowly pour it into 1.5 L of stirred ice water. Extract with 400 mL of ethyl acetate. Adjust the pH of the aqueous phase to 3 with 3N hydrochloric acid, and extract three times with 400 mL of ethyl acetate. Combine the organic phases. Dry over anhydrous sodium sulfate, filter, and remove the solvent 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] 4b (13 g), hydroxylamine hydrochloride (7.50 g), sodium methoxide (5.83 g), and ethanol (100 mL) were added sequentially to a reaction flask. Under N2 protection, the reaction solution was heated to 85 °C and reacted for 15.5 h. The reaction solution was cooled to room temperature, and the solvent was removed by vacuum distillation. 200 mL of water was added to the residue, followed by 3 M hydrochloric acid. The mixture was filtered, and the filter cake was purified by silica gel column chromatography using DCM:CH3OH = 9:1 (v / v) to give 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] Add 5.5 g of 4c, 50 mL of ethanol, and 6.87 mL of concentrated sulfuric acid sequentially to a reaction flask. Heat the mixture to 90 °C and react for 15 h. Cool the reaction solution to room temperature, remove the solvent under reduced pressure, and add 250 mL of ethyl acetate and 250 mL of water to the residue. Adjust the pH to 7 with saturated sodium bicarbonate solution, separate the organic phase, extract the aqueous phase twice with 280 mL of ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure to obtain 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] (S)-pyrrolidine-3-methanol (3.52 g) and intermediate 4d (3.3 g) were added to a reaction flask, followed by Pd2(dba)3 (2.127 g) and potassium phosphate (9.86 g), and finally toluene (100 mL). The mixture was heated to 80 °C for 3.5 h under N2 protection. 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, v / v) 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. Acrylamide (185 mg) and potassium tert-butoxide (292 mg) were then added sequentially at 0 °C. The mixture was reacted in an ice-water bath for 3 h under N2 protection. The reaction solution was added dropwise to an ammonium chloride aqueous solution for neutralization. After extraction with 100 mL of ethyl acetate, 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 give 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] Intermediate 4f (200 mg), DCM (2 mL), and Desmond-Martin oxidant (515 mg) were added to the reaction flask at 0 °C. The reaction was carried out at room temperature for 1 h. The reaction solution was filtered, and after removing part of the solvent by vacuum evaporation, methanol (5 mL), sodium cyanoborohydride (76 mg), and intermediate 1i (291 mg) were added directly. The reaction was carried out at room temperature for 2 h. The reaction solution was purified by silica gel column chromatography (DCM:CH3OH = 10:1, v / v), and then purified by C18 reversed-phase column chromatography (H2O (1 vol% ammonium acetate):CH3CN = 40%:60%, v / v) to obtain 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 a reaction flask, 1-(2-bromo-6-hydroxyphenyl)ethane-1-one (9.5 g), diethyl carbonate (26.1 g), and toluene (200 mL) were added sequentially. The reaction solution was cooled to 0 °C, and sodium hydroxide (8.83 g, 60%, 221 mmol) was added in portions. The mixture was heated to 120 °C and reacted overnight. After cooling to room temperature, the reaction 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 removed by vacuum evaporation 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] Intermediate 5b (11.2 g), MeOH (200 mL), hydroxylamine hydrochloride (9.49 g), and sodium acetate (11.20 g) were added sequentially to a reaction flask. The mixture was heated to 80 °C and reacted for 3 h. The reaction solution was cooled to room temperature, and the pH was adjusted to 5 with 3N hydrochloric acid. The solvent was removed by vacuum evaporation, and 1 L of water was added. The reaction flask was placed in an ice-water bath for cooling, while the pH was adjusted to 3 with 3N hydrochloric acid. The mixture was stirred for 30 min and filtered. The filter cake was collected, dried, and intermediate 5c (8.0 g) was obtained.

[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. The mixture was heated to 90°C and reacted overnight. The reaction solution was cooled to room temperature, and the solvent was removed by vacuum distillation. The residue was diluted with 250 mL of ethyl acetate and 250 mL of water. The pH was adjusted to 7 with saturated sodium bicarbonate solution. The organic phase was separated, and the aqueous phase was extracted twice with 250 mL of ethyl acetate to obtain intermediate 5d (8.64 g).

[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)-pyrrolidine-3-ylmethanol (267 mg), palladium acid (39.5 mg), and potassium phosphate (747 mg) were added sequentially, along with 1,4-dioxane (30 mL) as solvent. Under nitrogen protection, the mixture was heated to 100 °C and reacted overnight. This reaction was repeated four times. After the reaction was complete, the mixtures were cooled to room temperature, combined, filtered, concentrated, and subjected to 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 was lowered to -10°C, potassium tert-butoxide solution (88 mg, 0.784 mL, 0.784 mmol) was slowly added, and the reaction was continued at -10°C. After the reaction was complete, 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 purified by silica gel column chromatography to obtain intermediate 5f (46 mg).

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

[0625] Step 6: Preparation of Compound 5

[0626] To a reaction flask, intermediate 5f (57 mg), acetonitrile (5 mL), and IBX (145 mg) were added sequentially, and the reaction was carried out at 85 °C for 1 hour. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filtrate was used directly for the next reaction (the filtrate contained 5 g of intermediate). MeOH (5 mL) was added to the filtrate, followed by intermediate 1i (68.7 mg) and acetic acid (4.31 mg). The mixture was stirred at room temperature for 20 min, and then sodium cyanoborohydride (27.1 mg) was added. The reaction was continued at room temperature for 3 h. After the reaction was complete, 5 mL of saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with DCM, washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and purified sequentially by normal-phase silica gel column chromatography and C18 reversed-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] Intermediate 6a (3.0 g), DIPEA (5.73 g), and DCM (30 mL) were added to a reaction flask. Trifluoromethanesulfonic anhydride (11.31 g) was slowly added under ice bath conditions, and the mixture was then slowly brought to room temperature for 2 hours. 100 mL of water and 100 mL of DCM were added to the reaction mixture. The organic phase was separated, washed with 100 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain 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] Intermediate 6b (2.6 g), pinacol diborate (2.89 g), potassium acetate (0.694 g), and 1,4-dioxane (30 mL) were added sequentially to the reaction flask. Then, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (0.265 g) was added. The mixture was substituted with N2 three times, and then heated to 85 °C for 2 h. Heating was then stopped. 200 mL of water was added to the reaction mixture, and the mixture was extracted twice with 100 mL of EA solution. 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 obtain intermediate 6c (2.1 g).

[0635] Step 3: Preparation of intermediate 6d

[0636] 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 to the reaction flask. Then, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (0.355 g) was added. The mixture was substituted with N2 three times, and then heated to 70 °C for 2 h. Heating was then stopped. 200 mL of water was added to the reaction solution, and the mixture was 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 obtain intermediate 6d (0.328 g).

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

[0638] Step 4: Preparation of intermediate 6e

[0639] Intermediate 6d (0.32 g), palladium on carbon catalyst (0.032 g), and MeOH (10 mL) were added sequentially to a reaction flask. Under H2 protection, the mixture was reacted at room temperature for 16 h. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to obtain 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 prepared and separated by SFC to obtain intermediate 6f-1 (0.17 g) in the S configuration and intermediate 6f-2 (0.1 g) in the R configuration.

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

[0644] Step 6: Preparation of 6g of intermediate

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

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

[0647] Step 7: Preparation of intermediates over 6 hours

[0648] Add 6 g (0.09 g) of intermediate and 5 mL of dichloromethane to a reaction flask, along with 0.233 g of Desmartin oxidant, and react at room temperature for 1 hour. After the reaction is complete, add 50 mL of dichloromethane and 50 mL of water to the system. Separate the organic phases, extract the aqueous phase twice with 50 mL of dichloromethane, combine the organic phases, dry them with anhydrous sodium sulfate, filter, and concentrate to obtain 6 h (0.08 g) of intermediate.

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

[0650] Step 8: Preparation of Compound 6

[0651] Intermediate 6h (0.09 g), intermediate 1i (0.12 g), and methanol (5 mL) were added to a reaction flask, followed by 1 drop of acetic acid and sodium cyanoborohydride (0.032 g). The reaction was carried out at room temperature for 2 hours. After the reaction was complete, 50 mL of dichloromethane and 50 mL of water were added to the system. 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 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 operation steps from step one to step eight in Example 6, but intermediate 7a was used instead of intermediate 6a as the raw 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 acetonitrile (700 mL) were added sequentially. The mixture was heated to 80 °C and reacted for 5 h. After removing the solvent from the reaction solution under reduced pressure, the crude product was separated by silica gel column chromatography (eluent EA) to obtain 2.06 g of the target 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. The reaction mixture was incubated at 80 °C for 16 h under N2 protection. After cooling the reaction solution to room temperature, the solvent was removed by vacuum distillation. The crude product was purified by silica gel column chromatography (eluting PE:EA = 1:1, v / v) 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] Intermediate 8d (4.00 g), palladium on carbon (2.0 g), and methanol (300 mL) were added sequentially to a single-necked flask. After multiple H2 displacements, the mixture was reacted at room temperature for 16 h. The mixture was filtered, and the solvent was removed from the filtrate 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 the reaction was carried out at 85 °C for 22 h. The reaction solution was cooled to room temperature, and the solvent was removed by vacuum distillation. Dichloromethane and a saturated sodium carbonate aqueous solution were added to the crude product, and the layers were extracted and separated. The organic phase was discarded, and the pH of the aqueous phase was adjusted to 6 with 6 M HCl. The mixture was extracted multiple times with dichloromethane, and the organic phases were combined. After washing with saturated brine and drying with anhydrous sodium sulfate, the mixture was filtered. The solvent was removed from the filtrate by vacuum distillation 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 8g of intermediate

[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 the reaction was carried out at 85 °C for 5 h. The reaction solution was cooled to room temperature, and dichloromethane and a 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 removed from the filtrate under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 1:4, v / v) to obtain 1.01 g of intermediate 8 g.

[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 intermediates over 8 hours

[0683] Under N2 protection at 0°C, acrylamide (48.7 mg) was slowly added dropwise to 8 g (200 mg) of intermediate in 50 mL of THF solution with stirring. The addition was completed after 1 minute. Then, 0.935 mL of potassium tert-butoxide THF solution (1 M) was added dropwise, which was completed in about 1 minute. The mixture was stirred at 0°C for 3 hours. The reaction solution was poured into an ammonium chloride aqueous solution and stirred vigorously for 1 minute. EA was added for extraction, and the mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed 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 after 8 hours.

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

[0685] Step 7: Preparation of intermediate 8i

[0686] Add intermediate 8h (45 mg), IBX oxidant (108 mg), and acetonitrile (10 mL) sequentially to a single-necked flask, and react at 85°C for 0.5 h. Cool the reaction solution to room temperature, filter, and use the filtrate (containing intermediate 8i) directly for the next reaction step.

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

[0688] Step 8: Preparation of Compound 8

[0689] Add intermediate 8i reaction solution (the solution of intermediate 8i obtained in the previous step) and MeOH (10.00 mL) to a single-necked flask. While stirring at room temperature, add intermediate 1i (68.7 mg) and acetic acid (3.85 mg) sequentially. After stirring at room temperature for 30 min, add sodium cyanoborohydride (16.11 mg) and react at room temperature for 21 h. Pour the reaction solution into a mixed solution of dichloromethane and water, and adjust the pH to 8 with saturated sodium bicarbonate. Separate the organic phases; extract the aqueous phase multiple times with dichloromethane, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, remove the solvent from the filtrate under reduced pressure, dissolve the crude product in DMSO, and then use C244 to dissolve the crude product. 18 Reversed-phase column purification: 27.6 mg of compound 8 was obtained by low-pressure column chromatography in Biotage (1 mM ammonium acetate aqueous solution: acetonitrile = 1:1, volume ratio).

[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), acridine-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 N2 protection, the mixture was heated to 100 °C and reacted for 4 h. After the reaction was stopped, the reaction solution was cooled to room temperature and extracted three times with organic solvent DCM (200 mL) and water (500 mL). The organic phases were separated, washed with 500 mL of water, then washed with 500 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography. The eluent was EA, yielding 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] Intermediate 9d (200 mg) and THF (10 mL) were added sequentially to the reaction flask. The temperature was lowered to approximately 0°C, and then acrylamide (53.9 mg) and potassium tert-butoxide (116 mg) were added. Under N2 protection, the mixture was reacted at 0°C for 3.5 h. After the reaction was stopped, the reaction solution was added dropwise to a saturated ammonium chloride aqueous solution, and extracted with 50 mL of ethyl acetate. The organic phases were separated, washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and 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] Intermediate 9e (200 mg), acetonitrile (10.00 mL), and IBX oxidant (533 mg) were added sequentially to the reaction flask, and the reaction was carried out at 80 °C for 1 h. The reaction solution was filtered, and after evaporating to remove a small amount of solvent (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 the reaction was carried out at room temperature for 3 h. The solution was purified by silica gel column chromatography (DCM:CH3OH = 10:1, v / v). The solution was then purified by passing through a 120 g C... 18 Reversed-phase column purification (10 mM ammonium acetate aqueous solution: CH3CN = 40%: 60%) yielded 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] In a single-necked flask, intermediate 10a (100g), triethylamine (92g), and DCM (1L) were added sequentially. Acetyl chloride (39.2g) was added at 0°C, and the reaction was carried out at room temperature for 2.5h. The system was concentrated to remove DCM. Petroleum ether (300ml x 3) was added to the system, followed by extraction with 1000ml of saturated brine. The organic phase was separated and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated to obtain 123g 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 trichloride (94 g) were added sequentially. The mixture was heated to 170°C and reacted for 3 h. The reaction solution was cooled to room temperature, and approximately 500 mL of 6M hydrochloric acid was slowly added to quench the reaction. The solids that appeared were crushed, and the mixture was extracted with DCM and filtered. 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 removed under reduced pressure to obtain 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, add intermediate 10c (107g), diethyl carbonate (174g), and toluene (1000ml) sequentially. After dissolving, cool to approximately 0°C. Add sodium hydride (58.8g) in portions, raise the temperature to 100°C, and once the system stabilizes, raise the temperature to 120°C and react for approximately 1.5 hours. Cool the reaction solution to room temperature and slowly pour it into 2L of stirred ice water. Extract with 500mL of ethyl acetate and discard the organic phase. Adjust the pH of the aqueous phase to 1-2 with 3N hydrochloric acid, filter, and obtain 90g of intermediate 10d.

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

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

[0719] In 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 in portions. Under N2 protection, the mixture was heated to 90°C and reacted for 4.5 h. The reaction solution was cooled to room temperature, and the pH was adjusted to 1-3 with 3N hydrochloric acid. The solvent was removed by vacuum evaporation. 500 mL of water was added to the residue, and the mixture was stirred at room temperature for 30 min. After filtration, the filter cake was washed with 200 mL of water and then transferred to a vacuum oven for drying to obtain 91.6 g of intermediate 10e.

[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 over approximately 3 minutes (system temperature around 50°C). Under N2 protection, the mixture was heated to 85°C and reacted for 3.5 hours. The reaction mixture was cooled to room temperature with stirring. The solvent was removed from the reaction mixture, and the residue was treated with 1500 mL of ice water and 1000 mL of ethyl acetate. A 10% NaOH aqueous solution was added dropwise in an ice-water bath to adjust the pH to approximately 9 (internal temperature < 5°C). The mixture was extracted three times using a separatory funnel. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain 102.6 g of intermediate 10f.

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

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

[0726] To a single-necked flask, intermediate 10f (30 g), azirmonobutane-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 N2 protection, the mixture was heated to 100 °C and reacted for 2.5 h. The reaction solution was cooled to room temperature, and extracted three times with 200 mL of ethyl acetate (3 times) and 1000 mL of water. After separation and combination of the organic phases, each phase was washed with 500 mL of water, then washed with 500 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 12 g of intermediate (10 g).

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

[0728] Step 7: Preparation of intermediate over 10 hours:

[0729] Add 10g of intermediate and 200ml of anhydrous tetrahydrofuran to a three-necked flask. After dissolving, add acrylamide (1.976g). Under N2 protection, cool to about -15℃ and add potassium tert-butoxide (3.894g). Maintain the reaction at -15℃ for about 1.5h. Quench the reaction solution by adding it dropwise to a saturated ammonium chloride solution. Extract with 100mL of ethyl acetate three times. Separate the organic phases and wash with 100mL of saturated brine. Dry with anhydrous sodium sulfate and remove the solvent under reduced pressure. Analyze with silica gel column chromatography to obtain 6.3g of intermediate for 10h.

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

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

[0732] At room temperature, 2-iodobenzoic acid (IBX, 9.32 g) was added to anhydrous acetonitrile (50 ml) of intermediate 10 h and stirred. The mixture was reacted at 90 °C for about 3.5 h. After filtration, the filter cake was washed twice with acetonitrile. The filtrates were combined, the solvent was removed by vacuum distillation, and silica gel column chromatography was performed to obtain 4.6 g of intermediate 10 i.

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

[0734] Step 9: Preparation of Compound 10

[0735] In 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 first. After stirring at room temperature for 30 min, sodium cyanoborohydride (70.3 mg) was added, and the mixture was stirred overnight at room temperature. After the reaction was complete, 20 mL of saturated NaHCO3 aqueous solution was added to the reaction solution, and the mixture was extracted twice with 20 mL of DCM-MeOH (10:1). The extracts were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness and filtered through a C10 filter. 18 Reversed-phase column chromatography (10 nM ammonium acetate aqueous solution - acetonitrile = 50%:50%, volume ratio) yielded 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℃, bis(trimethylsilylaminolithium) (9.44 g) was slowly added dropwise to a THF (150 mL) solution of intermediate 11a (9 g) with stirring. The addition was completed after 5 minutes, and the mixture was stirred and reacted at -78℃ for 0.5 h. A THF (150 mL) solution of N-phenylbis(trifluoromethanesulfonyl)imide (17.47 g) was slowly added to the reaction solution, with the temperature controlled below -60℃. After the addition was complete, the reaction was carried out at -78℃ for 3.5 h. After the reaction was completed, the reaction solution was poured into a saturated ammonium chloride solution on crushed ice, 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, v / v) to obtain 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, 10.06 g of 4-nitrophenylboronic acid pinacol ester, 10 g of intermediate 11b, 11.16 g of potassium carbonate, 4.40 g of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex, 300 mL of 1,4-dioxane, and 50 mL of water were added sequentially. After several N2 purgings, the mixture was heated to 90 °C and reacted for 5 h. After the reaction was complete, the reaction solution 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 phases were separated, washed with 500 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography (PE:EA = 4:1, v / v). 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 MeOH (50 mL) solution of intermediate 11c (1 g). The reaction solution was purged with nitrogen 2-3 times, then with hydrogen 2-3 times, and the mixture was stirred at room temperature for 90 minutes. After the reaction was complete, the mixture was filtered, and the filter cake was washed with 50 mL of DCM solvent. The solvent was removed from the filtrate under reduced pressure to obtain 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, intermediates 1f (1.1 g), 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 N₂ protection, the mixture was heated to 100 °C and reacted for 1.5 h. The reaction was stopped, the reaction solution was cooled to room temperature, filtered, and the filter cake was washed with 150 mL of dichloromethane. The solvent was removed from the filtrate under reduced pressure, and the filtrate 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. Under ice bath conditions, H₂O₂ (0.926 g) was added, and the mixture was stirred for 5 min. The ice bath was then removed, and the reaction was allowed to proceed at room temperature for 1.5 h. After the reaction was stopped, 100 mL of saturated sodium sulfite solution was added to quench the reaction. The reaction was tested with starch-potassium iodide reagent and no color change was observed. Then, 100 mL of ethyl acetate was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain 1.2 g of intermediate 11f.

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

[0759] Step 6: Preparation of 11g of intermediate

[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 the reaction was carried out at room temperature for 3 h. The solvent was removed by vacuum distillation to obtain the trifluoroacetate product. Saturated sodium bicarbonate aqueous solution was slowly added to adjust the system to a weakly alkaline state, and the mixture was stirred for 1 h. The mixture was filtered, the filter cake was rinsed with a small amount of water, and then dried in a vacuum drying oven to obtain 0.8 g of intermediate 11f.

[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 11 g (82 mg), MeOH (5 mL), and acetic acid (4.76 mg) were added sequentially. After stirring at room temperature for 30 min, sodium cyanoborohydride (19.93 mg) was added, and the mixture was stirred at room temperature for 3.5 h. The reaction solution was purified by silica gel column chromatography (DCM:CH3OH = 10:1) to obtain 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] Add 11g (200mg) of intermediate, 30mL of DCM, 10i (115mg) of intermediate, and 3 drops of acetic acid to a single-necked flask in sequence. React at room temperature for 1h, cool in an ice bath, add NaBH4 (36.5mg), and react at room temperature for 20h. Pour the reaction solution into a mixed solvent of DCM / MeOH = 10 / 1 solution and water, and adjust the pH to 8 with saturated sodium bicarbonate aqueous solution. Separate the organic phases. Extract the aqueous phase multiple times with DCM / MeOH = 10 / 1. Combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, remove the solvent from the filtrate under reduced pressure, and purify the crude product by silica gel column chromatography (dichloromethane:methanol = 20:1, v / v). Dissolve the purified product in DMSO and select (120g) commercial C 18 Reversed-phase column purification was performed, followed by low-pressure column chromatography at Biotage (1M ammonium acetate aqueous 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] Under N2 protection at -78°C, DIBAL-H (0.311 g) was slowly added dropwise to a 10 mL solution of DCM containing intermediate 7c (0.5 g) and stirred over 3 minutes. The mixture was then stirred at -78°C for 1 hour. The reaction was quenched by slowly adding 2 mL of methanol at -78°C. The reaction solution was then brought to room temperature, diluted with 20 mL of petroleum ether, stirred for 5 minutes, filtered, and the filtrate was concentrated to obtain intermediate 13b (0.4 g).

[0779] Step 2: Preparation of intermediate 13c

[0780] Intermediate 13b (0.4 g), trimethyl orthoformate (0.261 g), p-toluenesulfonic acid (0.028 g), and methanol (10 mL) were added sequentially to a reaction flask, and the mixture was reacted overnight at room temperature. Approximately 100 mL of saturated sodium bicarbonate aqueous solution was added to the system, and the mixture was extracted three times with 50 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to obtain intermediate 13c (0.32 g).

[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] Intermediate 1m (57g) and sulfuric acid (200mL) were added sequentially to the reaction flask. A mixed solution of nitric acid (25.28g, 401.25mmol) and sulfuric acid (20mL) was slowly added dropwise under ice bath conditions. After the addition was complete, the mixture was slowly brought to room temperature and reacted for 1 hour. The reaction solution was slowly poured into 2L of ice water, and 500mL of ethyl acetate was added for extraction. The organic phase was collected, and the aqueous phase was extracted twice with 500mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to obtain intermediate 13d (53.3g).

[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] Intermediate 13d (40 g), ethanol (400 mL), and stannous chloride dihydrate (115 g) were added sequentially to a reaction flask, 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 ice bath conditions to adjust the pH to 9-10. The mixture was filtered, the organic phase of the filtrate was separated, dried over anhydrous sodium sulfate, filtered again, concentrated, and the concentrate was 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, 3 H).

[0791] Step 5: Preparation of intermediate 13f

[0792] Silver sulfate (29.46 g), elemental iodine (23.98 g), and acetonitrile (300 mL) were added sequentially to a reaction flask, 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, concentrated, and the concentrate was purified by silica gel column chromatography to obtain 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 13g of intermediate

[0796] Intermediate 13f (26.8 g), (E)-1-ethoxyvinyl-2-boronic acid pinacol ester (14.99 g), [1,1'-bis(diphenylphosphine)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 to a reaction flask. Under N2 protection, the mixture was heated to 70 °C and reacted for 6 h. The reaction solution 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, concentrated, and the concentrate was purified by silica gel column chromatography to obtain intermediate 13 g (17 g).

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

[0798] Step 7: Preparation of intermediates over 13 hours

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

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

[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] Intermediate 13i (0.2 g), intermediate 13c (0.185 g), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (0.042 g), potassium carbonate (0.183 g), 1,4-dioxane (10 mL), and water (2.00 mL) were added sequentially to a reaction flask. Under N2 protection, the mixture was heated to 120 °C and reacted for 3 h. The reaction solution 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, concentrated, and the concentrate was purified by silica gel column chromatography to obtain intermediate 13j (0.205 g).

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

[0809] Step 10: Preparation of intermediate 13k

[0810] Intermediate 13j (0.39 g), palladium on carbon catalyst (0.039 g), and MeOH (20 mL) were added sequentially to a reaction flask. The mixture was reacted overnight at room temperature under H2 protection. The reaction solution 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 13l

[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 sodium bicarbonate aqueous solution and 50 mL of DCM were added to the system, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate 13l (0.085 g).

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

[0816] Step 12: Preparation of Compound 13

[0817] Intermediate 13l (0.08 g), intermediate 1i (0.104 g), and dichloroethane (5 mL) were added to a reaction flask, followed by 1 drop of acetic acid and sodium cyanoborohydride (0.026 g). The reaction was carried out at room temperature for 2 hours. After the reaction was complete, dichloromethane (50 mL) and water (50 mL) were added to the system. The organic phase was separated, and the aqueous phase was extracted twice with dichloromethane (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the concentrate was 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] Add 14a (50g), diethyl carbonate (137g), and toluene (200mL) sequentially to a single-necked flask. Cool the reaction mixture to 0°C, then add sodium hydride (46.5g) in portions. First, raise the temperature to 80°C and react for approximately 10 minutes. Heat the mixture to 120°C and react for 5 hours. Cool the reaction mixture to room temperature and slowly pour it into 2L of stirred ice water. Extract with 1L of ethyl acetate and discard the organic phase. Adjust the pH of the aqueous phase to 3 with 3N hydrochloric acid and extract three times with 500mL of ethyl acetate. Combine the organic phases. Dry over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure to obtain intermediate 14b (52g).

[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 reacted overnight. The reaction solution was cooled to room temperature, and the pH was adjusted to 5 with 3N hydrochloric acid. The solvent was removed by vacuum evaporation, and 2 L of water was added. The reaction flask was placed in an ice-water bath for cooling, while the pH was adjusted 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 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. The mixture was heated to 90 °C and reacted for 2 h. The reaction solution was cooled to room temperature, and the solvent was removed by vacuum distillation. The residue was diluted with 1 L of ethyl acetate and 1 L of water. The pH was adjusted to 7 with saturated sodium bicarbonate solution, and the organic phase was separated. 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 removed by vacuum distillation to obtain 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] In a single-necked flask, under ice bath conditions, intermediate 14d (51 g), sulfuric acid (176 g, 96 mL, 1795 mmol), and potassium nitrate (27.2 g) were added sequentially. After the addition was complete, the mixture was reacted at room temperature for 1 h. The reaction solution was slowly poured into 2 L of ice water, and 500 mL of ethyl acetate was added for extraction. 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 removed by vacuum distillation. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1, v / v) 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 removed by vacuum distillation, 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 ice bath conditions to adjust the pH to weakly alkaline. The mixture was filtered, and the filter cake was washed twice with 500 mL of dichloromethane. The filtrate was collected. The organic phase was collected after separation, 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 removed by vacuum distillation. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1, v / v) to obtain the target intermediate 14f (23 g).

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

[0840] Step 6: Preparation of 14g of intermediate

[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. Then, 100 mL of ethyl acetate and 200 mL of water were added to the system. The organic phase was separated, and the aqueous phase was extracted twice with 50 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1, v / v) to obtain the target intermediate 14 g (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 intermediates over 14 hours

[0845] To a single-necked flask, 14 g (4 g) of intermediate, (E)-1-ethoxyvinyl-2-boronic acid pinacol ester (2.237 g), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (1.377 g), potassium carbonate (3.90 g), 1,4-dioxane (40 mL), and water (10.00 mL) were added sequentially. Under N2 protection, the mixture was heated to 80 °C and reacted overnight. The reaction solution was cooled to room temperature, and ethyl acetate (100 mL) and water (100 mL) were added to the system. The organic phases were separated, 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 the solvent was removed by vacuum distillation. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1, v / v) to obtain the target intermediate 14h (2.4 g).

[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 reacted overnight at room temperature. Dichloromethane (100 mL) and water (100 mL) were then 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 the solvent was removed by vacuum distillation. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1, v / v) 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 reaction was carried out at 0 °C for 2 h. The reaction mixture was quenched dropwise with saturated ammonium chloride aqueous solution, and then extracted with 50 mL of ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 3:2, v / v) 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 N2 protection, the mixture was heated to 85 °C and reacted for 2 h. The reaction solution was cooled to room temperature, and ethyl acetate (50 mL) and water (100 mL) were added to the system for extraction. The organic phase was separated, and the mixture was extracted three times with ethyl acetate (50 mL). The extract was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The crude product was separated by silica gel column chromatography (dichloromethane / methanol = 60:1, v / v) 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 14l

[0860] To a single-necked flask, intermediate 14k (50 mg), methanol (3 mL), and Pd / C (10 mg) were added sequentially. The mixture was purged with hydrogen three times and reacted at room temperature for 3 hours. The reaction solution was filtered to remove palladium on carbon, and the filter cake was washed with 5 mL each of dichloromethane, methanol, and ethyl acetate. The filtrate was then distilled under reduced pressure to remove the solvent, yielding intermediate 14k (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), palladium dichloride diacetonitrile (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 more times with ethyl acetate (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain intermediate 14l (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 then added, and the mixture was allowed to react at room temperature. Dichloromethane (20 mL) and water (50 mL) were added to the system for extraction. The organic phases were separated and extracted three times with DCM / MeOH at a ratio of 10:1 (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The mixture was then purified by silica gel column chromatography to give 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] Add 15a (50g), diethyl carbonate (216.9g), and toluene (500mL) sequentially to the reaction flask. Cool the reaction mixture to 0°C, then add sodium hydride (44.06g) in portions. First, raise the temperature to 70°C and react for approximately 10 minutes. Heat the mixture to 120°C and react for 5 hours. Cool the reaction mixture to room temperature and slowly pour it into 2L of stirred ice water. Extract with 1L of ethyl acetate and discard the organic phase. Adjust the pH of the aqueous phase to 3 with 3N hydrochloric acid and extract three times with 500mL of ethyl acetate. Combine the organic phases. Dry the mixture with anhydrous sodium sulfate, filter, and concentrate to obtain intermediate 15b (55g).

[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] Intermediate 15b (55 g), methanol (500 mL), hydroxylamine hydrochloride (63.5 g), and sodium ethoxide (80.8 g) were added sequentially to a reaction flask. The mixture was heated to 80°C and reacted overnight. The reaction solution was cooled to room temperature, and the pH was adjusted to 5 with 3N hydrochloric acid. The solution was concentrated, and 2 L of water was added. The reaction flask was placed in an ice-water bath for cooling, while the pH was adjusted 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 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] Intermediate 15c (54 g), ethanol (400 mL), and sulfuric acid (106 g) were added sequentially to a reaction flask, and the mixture was heated to 90 °C for 2 h. The reaction solution was cooled to room temperature, and the solvent was removed 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 a saturated sodium bicarbonate solution, and the organic phase was separated. 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 obtain intermediate 15d (62 g).

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

[0881] Step 4: Preparation of intermediate 15e

[0882] Intermediate 15d (30 g) and sulfuric acid (200 mL) were added sequentially to the reaction flask. A mixed solution of nitric acid (11.05 g) and sulfuric acid (4 mL) was slowly added under ice bath conditions. After the addition was complete, the mixture was slowly brought to room temperature and reacted for 1 h. The reaction solution was slowly poured into 2 L of ice water, and 300 mL of ethyl acetate was added for extraction. 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 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] Intermediate 15e (29 g), ethanol (300 mL), and stannous chloride dihydrate (130.76 g) were added sequentially to a reaction flask, 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 ice bath conditions to adjust the pH to 9-10. The mixture was filtered, the organic phase of the filtrate was separated, dried over anhydrous sodium sulfate, filtered again, concentrated, and the concentrate was purified by silica gel column chromatography to obtain intermediate 15f (24.3 g).

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

[0887] Step 6: Preparation of 15g of intermediate

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

[0892] Intermediate 7a (5 g), trimethyl orthoformate (11.2 g), p-toluenesulfonic acid (0.606 g), and ethanol (50 mL) were added sequentially to a reaction flask, and the mixture was reacted overnight at room temperature. Approximately 100 mL of saturated sodium bicarbonate aqueous 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 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] Intermediate 15h (4.5 g) and THF (50 mL) were added to the reaction flask. Lithium aluminum hydride (0.998 g) was slowly added under ice bath conditions, and the mixture was then slowly brought to room temperature for 1 h. After the reaction was complete, a small amount of ice water was added to the reaction solution under ice bath conditions to quench the reaction. Then, 200 mL of DCM and 200 mL of water were added. The mixture was filtered, and the organic phase of the filtrate was separated. The filtrate was washed with 200 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 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] Intermediate 15 g (2.2 g), intermediate 15i (1.3 g), triethylsilane (1.71 g), and acetonitrile (20 mL) were added to a reaction flask, followed by the addition of elemental iodine (1.87 g). The mixture was heated to 90 °C and reacted overnight. The reaction solution was cooled to room temperature, concentrated, and then 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 obtain intermediate 15j (1.9 g).

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

[0900] Step 10: Preparation of intermediate 15k

[0901] Intermediate 15j (1.9 g) and DCM (30 mL) were added sequentially to the reaction flask, followed by NBS (1.06 g). The mixture was reacted at room temperature for 1 h. 100 mL of DCM and 100 mL of water were added to the reaction solution to separate the organic phase. The mixture was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain 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] Intermediate 15k (0.7 g), (E)-1-ethoxyvinyl-2-boronic acid pinacol ester (0.419 g), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (0.129 g), potassium carbonate (0.731 g), 1,4-dioxane (10 mL), and water (2 mL) were added sequentially to a microwave tube. The mixture was bubbled with N2 and microwaved at 120 °C for 2 h. The reaction solution 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 obtain intermediate 15k (0.51 g).

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

[0907] Step 12: Preparation of intermediate 15m

[0908] Intermediate 15L (0.5 g), DCM (20 mL), and hydrochloric acid (0.644 mL, 4 mol / L, 2.57 mmol) were added sequentially to the reaction flask, and the mixture was reacted at room temperature for 5 h. Then, 100 mL of DCM and 100 mL of saturated sodium bicarbonate solution were added to the system. The organic phase was separated, and the aqueous phase was extracted twice more with DCM (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to obtain intermediate 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 the reaction was allowed to proceed for 1 h. The reaction solution was quenched by adding 50 mL of saturated ammonium chloride aqueous solution, followed by extraction with 50 mL of DCM. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to obtain intermediate 15n (0.095 g).

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

[0913] Step 14: Preparation of intermediate 15o

[0914] Intermediate 15n (0.09 g) and dichloromethane (5 mL) were added to a reaction flask, followed by Dysmartin oxidant (0.233 g). The reaction was carried out at room temperature for 1 hour. After the reaction was complete, dichloromethane (50 mL) and water (50 mL) were added to the system. The organic phase was separated, and the aqueous phase was extracted twice with dichloromethane (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate 15o (0.08 g).

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

[0916] Step 15: Preparation of Compound 15

[0917] Intermediate 15o (0.08 g), intermediate 1i (0.104 g), and dichloroethane (5 mL) were added to a reaction flask, followed by 1 drop of acetic acid and sodium cyanoborohydride (0.026 g). The reaction was carried out at room temperature for 2 hours. After the reaction was complete, dichloromethane (50 mL) and water (50 mL) were added to the system. The organic phases were separated, and the aqueous phase was extracted twice with dichloromethane (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, 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] At 10°C, 16a (81g), 2,4-dimethoxybenzylamine (83g), and acetic acid (500mL) were added sequentially to a reaction flask, and the temperature was raised to 80°C for reaction. After TLC confirmed that the reaction was complete, water was added to the reaction solution, the solid precipitated, filtered, the filter cake was washed with water, and dried to obtain intermediate 16b (95.78g).

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

[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. The reaction was carried out at 25 °C under hydrogen protection. After the reaction was confirmed to be complete by TLC, the reaction solution was filtered, the filtrate was concentrated, extracted with water and 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 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] 16e (35.00 g), methanol (250 mL), and 4M dioxane hydrochloride solution (123 mL) were added sequentially to a reaction flask, and the reaction was carried out at 25 °C. After TLC confirmed the reaction was complete, the reaction solution was concentrated, and pyridine (200 mL) and trifluoroacetic anhydride (25.20 g) were added. The reaction was stirred at 25 °C. After TLC confirmed the reaction was complete, the reaction solution was poured into a 3M hydrochloric acid aqueous solution, stirred vigorously, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated the filtrate, and dried 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 sequentially to a reaction flask, and the reaction was carried out at 25 °C. After confirming the completeness of the reaction by TLC, the reaction solution was poured into water, stirred vigorously, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated the filtrate, and 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 16g ​​of intermediate

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

[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 intermediates over 16 hours

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

[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] 16h (14.10 g), diethyl carbonate (27.00 g), and toluene (200 mL) were added sequentially to the reaction flask. The mixture was cooled to 0 °C, and 60 wt% sodium hydride (9.16 g) was added. The mixture was then heated to 120 °C and stirred. After confirming the reaction was complete by TLC, the reaction solution was poured into a 3 M hydrochloric acid aqueous solution and stirred vigorously. Ethyl acetate was added for extraction, and the mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography to obtain intermediate 16i (14.96 g).

[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% hydroxylamine aqueous solution (6.36 g), and ethanol (150 mL) were added sequentially to the reaction flask, and the mixture was stirred at 85 °C. After the reaction was confirmed to be complete by TLC, the reaction solution was concentrated, and water and ethyl acetate were added. The mixture was extracted and separated into layers. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to obtain crude intermediate 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] 16kJ (10.13 g), potassium carbonate (12.55 g), N,N-dimethylacetamide (150 mL), and iodoethane (7.08 g) were added sequentially to the reaction flask, and the mixture was stirred at 80 °C. After confirming the completeness of the reaction by TLC, the reaction solution was poured into water, stirred vigorously, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated the filtrate, and 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] Under N2 protection at 0°C, acrylamide (1.32 g) was slowly added to 50 mL of 16 K (10.72 g) tetrahydrofuran solution with stirring. Then, 18.63 mL of 1 M potassium tert-butoxide tetrahydrofuran solution was added dropwise. The mixture was stirred at 0°C. After confirming the reaction was complete by TLC, the reaction solution was poured into an aqueous ammonium chloride solution and stirred vigorously. Ethyl acetate was added for extraction, followed by washing with saturated brine, drying with anhydrous sodium sulfate, filtration, concentration of the filtrate, and purification by silica gel column chromatography to obtain 7.52 g of intermediate 16 L.

[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] 16 L (1.00 g), 4 M dioxane hydrochloride solution (10 mL), and ethyl acetate (50 mL) were added sequentially to the reaction flask. The reaction was carried out at 25 °C. After TLC confirmed that the reaction was complete, the reaction solution was directly filtered. 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] 17a (18 g), AIBN (0.738 g), carbon tetrachloride (500 mL), and NBS (47.8 g) were added sequentially to the reaction flask, and the temperature was raised to 60 °C. After confirming the complete reaction by TLC, the reaction solution was cooled to room temperature, the solvent was removed by vacuum distillation, and dichloromethane was added to the residue. The residue was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation of the filtrate. The residue was purified by silica gel column chromatography to obtain intermediate 17b (18.7 g).

[0972] Step 2: Preparation of intermediate 17c

[0973] 17b (18.7 g), benzylamine (1.78 mL), N,N-diisopropylethylamine (7.13 mL), and toluene (50 mL) were added sequentially to the reaction flask, and the temperature was raised to 50 °C. After confirming the completeness of the reaction by TLC, the reaction solution was cooled to room temperature, the reaction was stopped, and stirring was stopped. The reaction was carried out at room temperature for a total of 2 hours. Ethyl acetate and 1M HCl ice-water solution were added to the reaction solution for extraction, the aqueous phase was collected, the pH was adjusted to about 9 with sodium bicarbonate solid, ethyl acetate was added for extraction, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum evaporation to obtain intermediate 17c (9.6 g).

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

[0975] Step 3: Preparation of intermediate 17d

[0976] 9.6 g of 17C, 200 mL of methanol, 5 g of 10% palladium on carbon, and 50 mL of toluene were added sequentially to a reaction flask. The mixture was purged with hydrogen three times and reacted at room temperature under a hydrogen atmosphere. After confirming the reaction was complete by TLC, the palladium on carbon was filtered, the filter cake was washed twice with methanol, the filtrate was collected, and the solvent was removed by vacuum evaporation to obtain 4.5 g of 17D.

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

[0978] Step 4: Preparation of intermediate 17e

[0979] 17d (4 g), tetrahydrofuran (50 mL), and trifluoroacetic anhydride (5.63 g) were added sequentially to the reaction flask and reacted at room temperature. After the reaction was confirmed to be complete by TLC, an aqueous solution was added to quench the reaction, followed by extraction with ethyl acetate. The organic phase was separated, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain 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 the reaction was carried out at room temperature. After the reaction was confirmed to be complete by TLC, water was added to the reaction solution under ice bath to quench the reaction, the organic phase was separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum evaporation to obtain 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 17g of intermediate

[0985] 17f (6.5 g), dichloromethane (60 mL), triethylamine (7.8 mL), and acetic anhydride (2.94 mL) were added sequentially to the reaction flask, and the reaction was carried out at room temperature. After the reaction was confirmed to be complete by TLC, dichloromethane and water were added to the reaction solution. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation to obtain 17 g (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 intermediates over 17 hours

[0988] 17 g (6 g) and aluminum trichloride (4.39 g) were added sequentially to the reaction flask, and the mixture was gradually heated from room temperature to 150 °C. After the reaction was confirmed to be complete by TLC, the reaction solution was cooled to room temperature, and water and 3M hydrochloric acid aqueous solution were added to the residue. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography after solvent removal under reduced pressure to obtain 17 h (3.78 g).

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

[0990] Step 7: Preparation of intermediate 17j

[0991] In a reaction flask, 550 mg of 17 h, 5.00 mL of MeOH, and 5.00 mL of an aqueous solution of 242 mg of sodium hydroxide were added sequentially, and the reaction was carried out at room temperature. After TLC confirmed the completeness of the reaction, the reaction solution was concentrated to remove methanol, retaining the aqueous phase. 17i was obtained. 5 mL of 1,4-dioxane and 0.462 mL of Boc anhydride (439 mg) were added to the system, and the reaction was carried out at room temperature. After TLC confirmed the completeness of the reaction, 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 200 mg of 17j.

[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] 17kJ (3.5 g) and THF (300 mL) were added sequentially to the reaction flask. 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 in portions, and the reaction mixture was heated to 85 °C. After confirming complete reaction by TLC, 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 3 M hydrochloric acid, then extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum evaporation to obtain 17kJ (7.0 g).

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

[0996] Step 9: Preparation of intermediate 17l

[0997] 17kJ (4.4 g), hydroxylamine aqueous solution (4.16 g, 63.0 mmol), and ethanol (50 mL) were added sequentially to the reaction flask, and the reaction was carried out at 85 °C. After the reaction was confirmed to be complete by TLC, the reaction solution was cooled to room temperature, and the residue was extracted with ethyl acetate and saturated sodium carbonate aqueous solution. The organic phase was discarded. The aqueous phase was adjusted to pH 2-3 with 1 M HCl aqueous solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum evaporation to obtain 17kJ (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] 17 L (3.14 g), potassium carbonate (1.500 g), DMA (5 mL), and iodoethane (2.308 g, 1.183 mL) were added sequentially to a reaction flask. The mixture was heated to 80 °C. After confirming the reaction was complete by TLC, 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 removed from the filtrate under reduced pressure to obtain 17 L (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), THF (75 mL), and acrylamide (0.215 g) were added sequentially to the reaction flask. The mixture was cooled to approximately -15°C, and 2.60 mL of 1 M potassium tert-butoxide tetrahydrofuran solution was added. The system was then heated to 0°C for further reaction. After confirming the completeness of the reaction by TLC, the reaction was quenched dropwise in ammonium chloride solution, extracted with ethyl acetate, and the organic phase was separated. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain 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] 17n (0.428 g) and dichloromethane (10.00 mL) were added sequentially to the reaction flask, followed by trifluoroacetic acid (3.29 g, 2.211 mL). The reaction was allowed to proceed at room temperature. After TLC confirmed the reaction was complete, water was added to the reaction solution, the pH was adjusted to 7-8 with saturated sodium bicarbonate, and then dichloromethane was added for extraction. The solution was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain 17n (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 then added to a high-pressure reactor. The hydrogen pressure was set to 3 MPa and the temperature to 110 °C. After the reaction was confirmed to be complete by TLC, the solvent was removed from the reaction solution under reduced pressure. A dioxane hydrochloride solution (4 mol / L, 100 mL, 400 mmol) was added to the residue, and the solvent was removed under reduced pressure. The residue was then slurried with ethyl acetate, filtered, and the filter cake was collected to obtain the target 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 bath conditions, and the mixture was reacted at room temperature. After TLC confirmed the reaction was complete, the reaction solution was extracted with ethyl acetate and water to separate the organic phases. The aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The filter cake was collected to obtain the target intermediate 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 sequentially to a reaction flask. Acetic anhydride (10.38 g, 9.68 mL) was added under ice bath conditions, and the mixture was allowed to return to room temperature for further reaction. After TLC confirmed the reaction was complete, the solvent was removed from the reaction solution under reduced pressure. Ethyl acetate and water were added to the residue for extraction, and the organic phases were separated. The residue was washed with saturated ammonium chloride solution and saturated brine solution, respectively, and dried over anhydrous sodium sulfate. After filtration, the solvent was removed from the filtrate under reduced pressure to obtain 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 trichloride (14.62 g) were added sequentially to a reaction flask. Under N2 protection, the mixture was heated to 170 °C for reaction. After TLC confirmed the reaction was complete, the reaction solution was cooled to room temperature, water was added to quench the reaction, and then dichloromethane was added for extraction. 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 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 the reaction flask. A solution of sodium hydroxide (4.24 g) in water (100 mL) was added dropwise under ice bath conditions, and the mixture was allowed to return to room temperature. After TLC confirmed the reaction was complete, methanol was removed from the reaction solution under reduced pressure. 1,4-Dioxane (100 mL) and di-tert-butyl dicarbonate (8.49 g, 9.03 mL) were added, and the mixture was allowed to return to room temperature. 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, filtered, and the solvent was removed from the filtrate under reduced pressure to obtain 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 18g of intermediate

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

[1032] Step 7: Preparation of intermediates over 18 hours

[1033] 18 g (9.54 g) of intermediate, 100 mL of EtOH, and 9.93 g, 9.21 mL, and 150 mmol of hydroxylamine aqueous solution were added sequentially to a reaction flask. The mixture was heated to 85 °C. After TLC confirmed the reaction was complete, the pH of the reaction solution was adjusted to 8 with saturated sodium carbonate solution, and ethyl acetate was added for extraction. The organic phases were separated, extracted twice with water, and then combined. The pH was then adjusted to 3 with 1 M hydrochloric acid, and extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure to obtain the target intermediate 18 h (9.01 g).

[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 sequentially to a reaction flask. Under N2 protection, the mixture was heated to 80 °C. After confirming the reaction was complete by TLC, the reaction solution was cooled to room temperature, extracted with ethyl acetate and water, and the organic phase was separated. The solution was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and 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 the reaction flask. The mixture was cooled to -15 °C under N2 protection, and potassium tert-butoxide tetrahydrofuran solution (1 mol / L, 11.14 mL, 11.14 mmol) was added dropwise. After the addition was complete, the temperature was raised to 0 °C. After confirming the reaction was complete by TLC, the system was added to a saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was separated. The solution was 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 sequentially to a reaction flask, followed by dioxane hydrochloride solution (4 mol / L, 3.89 mL, 15.58 mmol). The mixture was reacted at room temperature. After TLC confirmed the reaction was complete, the reaction solution was concentrated to give 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 then added to a high-pressure reactor. The hydrogen pressure was set at 3 MPa and the temperature at 110 °C. After the reaction was confirmed to be complete by TLC, the solvent was removed by vacuum distillation of the reaction solution. A dioxane hydrochloride solution (4 mol / L, 200 mL, 798 mmol) was added to the residue, and the solvent was removed by vacuum distillation. The residue was then slurried with ethyl acetate, filtered, and the filter cake was collected to obtain the target 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 sequentially to the reaction flask. Trifluoroacetic anhydride (61.9 g, 41.0 mL, 295 mmol) was added under ice bath conditions, and the mixture was brought back to room temperature for reaction. After confirming the completeness of the reaction by TLC, 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, filtered, and the solvent was removed from the filtrate under reduced pressure 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 added sequentially to the reaction flask. Acetic anhydride (29.9 g, 27.9 mL, 293 mmol) was added under ice bath conditions, and the mixture was brought back to room temperature for reaction. After TLC confirmed the reaction was complete, the solvent was removed from the reaction solution under reduced pressure. Ethyl acetate and water were added to the residue for extraction, and the organic phases were separated. The residue was washed with saturated ammonium chloride solution and saturated brine solution, respectively, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure 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 trichloride (21.40 g) were added sequentially to the reaction flask. Under N2 protection, the mixture was heated to 170 °C and reacted. After TLC confirmed the reaction was complete, the reaction solution was cooled to room temperature, quenched with water, and then extracted with dichloromethane. The organic phases were separated, and the aqueous phase was extracted twice with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography to obtain 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 the reaction flask. A solution of sodium hydroxide (6.56 g) in water (160 mL) was added dropwise under ice bath conditions, and the mixture was allowed to return to room temperature for further reaction. After TLC confirmed the reaction was complete, methanol was removed from the reaction solution under reduced pressure. 1,4-Dioxane (160 mL) and di-tert-butyl dicarbonate (13.12 g, 13.96 mL) were added, and the mixture was allowed to react at room temperature. After TLC confirmed the reaction was complete, ethyl acetate and water were added to the reaction solution for extraction. The organic phases were separated, and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure to obtain 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 19g of intermediate

[1068] Intermediate 19f (15.92 g, 54.6 mmol), diethyl carbonate (32.3 g, 33.1 mL), and toluene (200 mL) were added sequentially to the reaction flask. 60 wt% sodium hydride (10.93 g, 273 mmol) was added in portions under ice bath conditions. The mixture was heated to 120 °C. After TLC confirmed the reaction was complete, the reaction solution was cooled to room temperature and quenched in ice water. The pH was adjusted to 1-2 with 1 M hydrochloric acid solution, and the solution was extracted with ethyl acetate. The organic phase was separated, and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The residue was slurried with petroleum ether, filtered, and the filter cake was yielded to obtain the target intermediate 19f (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 intermediates over 19 hours

[1071] 19 g (12 g) of intermediate, 120 mL of EtOH, and 12.49 g, 11.59 mL, and 189 mmol of hydroxylamine aqueous solution were added sequentially to the reaction flask. The mixture was heated to 85 °C. After TLC confirmed the reaction was complete, the pH of the reaction solution was adjusted to 8 with saturated sodium bicarbonate solution, and extracted with ethyl acetate. The organic phase was separated, and the aqueous phase was adjusted to pH 3 with 1 M hydrochloric acid and extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure to obtain the target intermediate 19 h (10.44 g).

[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 sequentially to the reaction flask. Under N2 protection, the mixture was heated to 80 °C. After confirming the reaction was complete by TLC, the reaction solution was cooled to room temperature, extracted with ethyl acetate and water, and the organic phase was separated. The solution was washed with 800 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and 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 sequentially to a reaction flask. The mixture was cooled to -15 °C under N2 protection, and potassium tert-butoxide tetrahydrofuran solution (1 mol / L, 9.92 mL, 9.92 mmol) was added dropwise. After the addition was complete, the temperature was raised to 0 °C for the reaction. After confirming the reaction was complete by TLC, the system was added to a saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was separated. The solution was 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 sequentially to a reaction flask, followed by dioxane hydrochloride solution (4 mol / L, 11.03 mL, 44.1 mmol). The mixture was reacted at room temperature. After TLC confirmed the reaction was complete, the reaction solution was concentrated to give 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] At 15°C, liquid bromine (55.5 g) was added dropwise to a solution of 20a (50 g) in acetic acid (180 mL). After the addition was complete, the mixture was allowed to stand at room temperature. After confirming the completeness of the reaction by TLC, methyl tert-butyl ether was added dropwise to the reaction mixture, stirred, and filtered. The filter cake was collected and dried to obtain intermediate 20b (95 g).

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

[1090] Step 2: Preparation of intermediate 20c

[1091] 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 to a reaction flask, and the mixture was reacted overnight at room temperature. The reaction solution was cooled to -15 °C, and sodium borohydride (14.6 g) was added in portions. After the addition was complete, the mixture was allowed to return to room temperature. After confirming the completeness of the reaction by TLC, approximately half of the methanol was removed by concentration. Dichloromethane and water were then added to the reaction solution. The organic phase was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and 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 protection, 20c (47g) was added dropwise to trifluoroacetic anhydride (148g), and the reaction was allowed to proceed to room temperature for 1 hour after the addition was complete. Trifluoroacetic acid (87g) was then added dropwise, and the temperature was raised to 40°C for another 1 hour. Triethylsilane (68g) was then added dropwise, and the temperature was raised to 60°C for the next reaction. After confirming the reaction was complete by TLC, 400mL of ethyl acetate and 600mL of water were added to the reaction mixture. The organic phase was separated, washed three times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and 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 protection, a boron tribromide dichloromethane solution (146 mL, 1 M) was slowly added dropwise to 20d (20.5 g) of dichloroethane (200 mL) with stirring. After the addition was complete, the mixture was moved to room temperature for reaction. After confirming the completeness of the reaction by TLC, the reaction solution was slowly poured into ice water, stirred for 10 min, filtered, and the filter cake was collected and dried to obtain 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] At 0°C, under nitrogen protection, acetic anhydride (5.65 g) was slowly added dropwise to a mixture of 20e (17.0 g) and triethylamine (7.63 g) in 200 mL of dichloroethane with stirring. After the addition was complete, the mixture was moved to room temperature. After confirming the completeness of the reaction by TLC, the reaction solution was slowly poured into water to separate the organic phase. The mixture was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 20f (19.8 g).

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

[1103] Step 6: Preparation of 20g of intermediate

[1104] 20f (19.5g), aluminum trichloride (18.7g), and o-dichlorobenzene (80mL) were added sequentially to the reaction flask, and the mixture was heated to 150℃. After confirming the completeness of the reaction by TLC, the reaction solution was cooled to room temperature, and 250mL of 3N dilute hydrochloric acid was added. The mixture was then extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the concentrate was purified by silica gel column chromatography to obtain 20g (11.2g) of the intermediate.

[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 intermediates over 20 hours

[1108] 20 g (9.5 g), methanol (100 mL), water (20 mL), and sodium hydroxide (1.9 g) were added sequentially to the reaction flask, and the reaction was carried out at room temperature for 1 h. Then, di-tert-butyl dicarbonate (8.2 g) was added, and the reaction was carried out at room temperature. After confirming the reaction was complete by TLC, 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 purified by silica gel column chromatography to obtain intermediate 20 h (8.5 g).

[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] 20 h (8.5 g), diethyl carbonate (16.4 g), and toluene (100 mL) were added sequentially to the reaction flask. 60 wt% sodium hydride (5.57 g) was added in portions, and the reaction solution was heated to 115 °C. After confirming the reaction was complete by TLC, the reaction solution 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 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 solution was heated to 80 °C. After confirming the complete reaction by TLC, the reaction solution was cooled to room temperature, and 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 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] 20kJ (8.5g), potassium carbonate (3.3g), iodoethane (5.1g), and DMA (70mL) were added sequentially to the reaction flask, and the reaction solution was heated to 80℃. After confirming the reaction was complete by TLC, the reaction solution 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 (6.5g).

[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 20l

[1122] At -10℃, under nitrogen protection, 14 mL of sodium tert-butoxide tetrahydrofuran solution (1M) was slowly added dropwise to 70 mL of 20 kJ (5.6 g) tetrahydrofuran solution with stirring. After the addition was complete, the reaction was maintained at this temperature for 30 min. Acrylamide (0.71 g) was weighed and dissolved in 5 mL of tetrahydrofuran, then added dropwise to the reaction solution. After confirming the reaction was complete by TLC, the reaction solution was slowly poured into saturated ammonium chloride solution, ethyl acetate was added, the organic phase was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the concentrate was purified by silica gel column chromatography to obtain intermediate 20 L (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] 20 L (2.5 g), ethyl acetate (30 mL), and dioxane hydrochloride (15 mL, 4 M) were added sequentially to the reaction flask, and the reaction was carried out at room temperature. After confirming the completion of the reaction by TLC, the mixture was filtered, the filter cake was collected, and dried to give 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] In an ice bath, 21a (33.3 g), MeOH (500 mL), iodophenyl diacetic acid (82 g, 246 mmol), and potassium hydroxide (127 g) were added sequentially to a reaction flask, and the mixture was reacted at room temperature. After the reaction was confirmed to be complete by TLC, the solvent was removed by vacuum distillation of the reaction solution. Ethyl acetate and sodium bicarbonate solution were added to the residue for extraction, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The residue was dissolved in THF (500 mL), and then hydrochloric acid (6 M, 68.4 mL) was added. The mixture was reacted at room temperature for 0.5 hours, and then the pH of the reaction solution was adjusted to 8 with saturated sodium bicarbonate solution. Then, 200 mL of ethyl acetate was added for extraction, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain 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 sequentially to the reaction flask. After dissolving, sodium borohydride (17.83 g, 471 mmol) was added, and the reaction was carried out at room temperature. After confirming the completeness of the reaction by TLC, saturated ammonium chloride solution was added dropwise to quench the reaction solution, followed by extraction with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum evaporation 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] 21c (35g), toluene (300mL), and p-toluenesulfonic acid (66.9g) were added sequentially to a reaction flask, and the mixture was heated to 120°C. After the reaction was confirmed to be complete by TLC, the reaction solution was cooled to room temperature, and the reaction was quenched with the organic solvent ethyl acetate and water. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum evaporation to obtain 21d (35.5g).

[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 reacted at room temperature. After TLC confirmed the reaction was complete, saturated ammonium chloride solution was added dropwise to quench the reaction mixture, followed by extraction with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum evaporation to obtain 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 the reaction flask, and the reaction was carried out at room temperature. After the reaction was confirmed to be complete by TLC, the reaction solution was washed with saturated ammonium chloride solution and saturated brine solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 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 21g of compound

[1147] Under ice bath conditions, boron trichloride (19.22 g, 164 mL) was slowly added dropwise to 21 g (17 g) of dichloromethane (500 mL) with stirring. After the addition was complete, the mixture was allowed to rise naturally to room temperature. After confirming the completeness of the reaction by TLC, 160 mL of 1 M HCl and 200 mL of aqueous solution were added to the reaction solution to quench the reaction. Then, dichloromethane was added for extraction, the organic phase was separated, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum evaporation to obtain 21 g (15 g).

[1148] MS(ESI,[MH] - m / z: 190.9.

[1149] Step 7: Preparation of compound 21h

[1150] 21 g (16 g), dichloromethane (200 mL), triethylamine (9.50 g, 13.01 mL), and acetic anhydride (5.27 g, 4.91 mL) were added sequentially to the reaction flask, and the reaction was carried out at room temperature. After the reaction was confirmed to be complete by TLC, the reaction solution was washed with saturated ammonium chloride solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 21 h (14.8 g).

[1151] MS(ESI,[MH] - m / z: 233.01.

[1152] Step 8: Preparation of compound 21i

[1153] 21h (11.6 g), dichloromethane (300 mL), and zirconium tetrachloride (46.2 g, 198 mmol) were added sequentially to the reaction flask, and the reaction was carried out at 50 °C. After the reaction was confirmed to be complete by TLC, the reaction solution was cooled to room temperature, and 3M hydrochloric acid aqueous solution, water, and dichloromethane were added to the residue. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum evaporation to obtain 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 sodium hydroxide (2.63 g) aqueous solution (10.00 mL) were added sequentially to the reaction flask, and the reaction was carried out at room temperature. After TLC confirmed the reaction was complete, the pH of the reaction solution was adjusted to 2-3 with 2M HCl aqueous solution, followed by extraction with ethyl acetate and water. The mixture was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the crude intermediate 21j. Dichloroethane (200 mL), imidazole (17.90 g), and TBSCl (39.6 g) were added, and the mixture was refluxed overnight. The reaction solution was cooled to room temperature, and 100 mL of dichloromethane and 300 mL of water were added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed 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 21l

[1159] 21kJ (8.4 g) and THF (300 mL) were added sequentially to the reaction flask. Diethyl carbonate (16.19 g, 16.52 mL) was added, and the temperature was lowered to approximately 0 °C. 60 wt% sodium hydroxide (5.48 g, 137 mmol) was added in portions, and the reaction mixture was heated to 85 °C. After confirming complete reaction by TLC, the reaction solution was cooled to room temperature and slowly poured into ice water. Extraction was performed with ethyl acetate, and the organic phase was discarded. The aqueous phase was adjusted to pH 1-2 with 3 M hydrochloric acid, then extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain 21kJ (10 g).

[1160] MS(ESI,[MH]-)m / z: 331.2.

[1161] Step 11: Preparation of intermediate 21m

[1162] 21 L (10 g), hydroxylamine aqueous solution (9.93 g, 9.93 mL, 150 mmol), and ethanol (100 mL) were added sequentially to the reaction flask, and the reaction was carried out at 85 °C. After the reaction was confirmed to be complete by TLC, the reaction solution was cooled to room temperature, and the residue was extracted with ethyl acetate and saturated sodium carbonate aqueous solution. The organic phase was discarded. The aqueous phase was adjusted to pH 2-3 with 1 M HCl aqueous solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum evaporation to obtain 21 M (11 g).

[1163] MS(ESI,[MH]-)m / z: 346.2.

[1164] Step 12: Preparation of intermediate 21n

[1165] 21m (10 g), ethanol (150 mL), and sulfuric acid (14.40 g, 7.83 mL, 144 mmol) were added sequentially to the reaction flask, and the reaction was carried out at 85 °C. After TLC confirmed the reaction was complete, the reaction solution was cooled to room temperature, and dichloromethane and saturated sodium bicarbonate water were added to adjust the pH to 7. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum evaporation to obtain 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 Desmartin oxidant (974 mg) were added sequentially to a reaction flask. The mixture was stirred at room temperature. After TLC confirmed the reaction was complete, the reaction solution was quenched in a saturated sodium sulfite solution, extracted with ethyl acetate, and the organic phase was separated. The mixture was washed with 200 mL of saturated sodium bicarbonate solution and 200 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure to obtain compound 21n (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] Synthesis of compounds 22 and 23 in Examples 22 and 23

[1173]

[1174] Step 1: Preparation of intermediate 22b

[1175] In 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 the reaction was confirmed to be complete by TLC, the reaction solution was filtered, the solvent was removed from the filtrate by vacuum distillation, petroleum ether was added and the mixture was stirred, filtered, and the filter cake was collected to obtain intermediate 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] In a reaction flask, 60wt% NaH (187g) and THF (2000mL) were added sequentially. Diethyl malonate (300g, 284mL) was added under ice bath conditions. After stirring at room temperature for 30min, 22b (606g) was added, and the reaction was stirred at room temperature. After confirming the completeness of the reaction by TLC, the reaction solution was quenched by slowly adding a saturated ammonium chloride solution. The solution was extracted with 2000mL petroleum ether and 2000mL water. The aqueous phase was extracted twice with 1000mL petroleum ether. The organic phases were combined, washed twice with 500mL saturated ammonium chloride solution, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by vacuum distillation to remove the solvent. 262g of intermediate 22c was obtained by silica gel column chromatography.

[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] 130 g of 22 c, 1000 mL of DMSO, 300 mL of H2O, and 42.6 g of lithium chloride were added to a reaction flask and stirred at 180 °C. After confirming the reaction was complete by TLC, the reaction solution was quenched in 1000 mL of ice water, the pH was adjusted to 2-3 with 1 M hydrochloric acid, extracted three times with 1 L of ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation of the filtrate to obtain 191 g of intermediate 22 d.

[1183] MS(ESI,[M+H]+)m / z: 193.05

[1184] Step 4: Preparation of intermediate 22e

[1185] In a reaction flask, 22d (85g), ethanol (1000mL), and concentrated sulfuric acid (44g) were added sequentially. The mixture was heated to 70°C. After confirming the reaction was complete by TLC, the reaction solution was cooled to room temperature, the solvent was removed by vacuum distillation, and the residue was poured into ice water. A saturated sodium bicarbonate aqueous solution was added for neutralization. After neutralization, 1000mL of petroleum ether was added for extraction three times, the organic phases were separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation of the filtrate to obtain 99g 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 N2 protection, boron tribromide (415 g, 1657 mL) was added dropwise to 150 g of 22e in 750 mL of dichloromethane with stirring, and the temperature was controlled not to exceed 0 °C. MeOH (500 mL) was added at 0 °C and the reaction was carried out for 30 min. The mixture was then gradually brought to room temperature and stirred for 2 h. After the reaction was complete, the reaction solution was poured into a mixture of 1000 mL of ice water and 1000 mL of dichloromethane and stirred. The mixture was separated using a separatory funnel, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure to obtain 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 22g of intermediate

[1192] In a reaction flask, under N2 protection at 0°C, 130 g of 22f solution and 2000 mL of tetrahydrofuran were added sequentially, followed by the slow addition of a 1 M, 438 mL solution of lithium aluminum hydride tetrahydrofuran. The mixture was reacted in an ice-water bath. After TLC confirmed the reaction was complete, 3 L of water was slowly added to quench the reaction. The pH was adjusted to 1-2 with concentrated hydrochloric acid, and the mixture was extracted three times with 2 L of ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure to obtain 22 g of intermediate (129 g).

[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 intermediates over 22 hours

[1195] In a 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 reaction was allowed to proceed at room temperature after the addition was complete. After confirming the completeness of the reaction by TLC, the reaction solution was poured into a mixed solvent of dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography to obtain 127 g of the intermediate after 22 h.

[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] In a reaction flask, 91 g of 22 h, 2000 mL of dichloromethane, and 342 g of zirconium tetrachloride were added sequentially. The mixture was stirred overnight at 50 °C under N2 protection. After the reaction was complete, the reaction solution was cooled to room temperature and poured into a mixture of 1000 mL of ice water and 1000 mL of dichloromethane. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography to obtain 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 (95g) and ethanol (900mL) were added sequentially to the reaction flask. A solution of sodium hydroxide (77g) in H2O (800mL) was added dropwise under ice bath conditions. The mixture was reacted at room temperature under N2 protection. After TLC confirmed the reaction was complete, the reaction solution was diluted with 2L ethyl acetate and 1L water. 3M hydrochloric acid was slowly added to adjust the pH to 3. The mixture was 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 solvent was removed from the filtrate under reduced pressure to obtain 86g 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] In a reaction flask, 22kJ (37g), 1,2-dichloroethane (700mL), imidazole (36.6g), and tert-butyldimethylchlorosilane (29.7g) were added sequentially, and the reaction was carried out at 75°C. After confirming the completeness of the reaction by TLC, 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 removed from the filtrate under reduced pressure to obtain 60g 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 22l

[1210] In a reaction flask, 22kJ (55g), diethyl carbonate (101g, 103mL), and toluene (1000mL) were added sequentially. The reaction solution was cooled to 0°C, and 60wt% sodium hydride (34.3g, 858mmol) was added in portions. After the addition was complete, the mixture was slowly heated to 120°C. After confirming the completeness of the reaction by TLC, the reaction solution 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. The solution was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation to obtain 53.6g 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] In a reaction flask, 22 L (51 g), hydroxylamine hydrochloride (61.4 g), sodium ethoxide (61.1 g), and ethanol (2000 mL) were added sequentially. The mixture was heated to 85 °C under N2 protection. After TLC confirmed the reaction was complete, the solvent was removed from the reaction solution 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. The pH of the aqueous phase was adjusted to 6-7 with 1 M hydrochloric acid, and then extracted with ethyl acetate again. The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure to obtain 47 g of intermediate 22 M.

[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] Preparation of intermediate 22n in step 13

[1218] In a reaction flask, 47 g of 22m, 1500 mL of ethanol, and 35.4 mL of concentrated sulfuric acid were added sequentially. Under N2 protection, the mixture was heated to 85 °C. After TLC confirmed the reaction was complete, the reaction solution was cooled to room temperature, the solvent was removed by rotary evaporation, dichloromethane was added, and the mixture was neutralized by dropwise addition of saturated sodium bicarbonate aqueous solution. After washing with saturated brine and drying with anhydrous sodium sulfate, the solution was filtered, and the solvent was removed by vacuum evaporation of the filtrate 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] Preparation of intermediates 22o-1, 22o-2 in step 14

[1222] Preparative separation was performed by dissolving 43 g of intermediate 22n in 430 mL of dichloromethane-ethanol solution to a concentration of approximately 100.0 mg / mL. The solution was filtered through a 0.45 μm organic filter membrane, and the filtrate was collected. Instrumentation: YMC high-performance preparative chromatograph; column: CHIRALPAKIG (30*250 mm, S-10 μm); mobile phase A: ethanol; B: n-hexane. The initial peak yielded 9.057 g of intermediate 22o-1, and the subsequent 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] In a reaction flask, under N2 protection, 11.93 g of 22°C, 200 mL of THF, and 3.39 g of acrylamide were added sequentially. After cooling to 0°C, potassium tert-butoxide (3.89 g, 34.7 mL) was added, and the mixture was reacted at 0°C. After confirming the completeness of the reaction by TLC, the reaction solution was added dropwise to an ice-cold saturated ammonium chloride aqueous solution. Ethyl acetate was added for extraction, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to remove the solvent. After filtration, the filter cake was collected to give 6.77 g of compound 22.

[1227] 1 ¹H NMR (500MHz, 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 Example 23 Preparation of Compound

[1228] In a reaction flask, 12.83 g of 22°C-2, 200 mL of THF, and 3.64 g of acrylamide 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 confirming the completeness of the reaction by TLC, the reaction solution was added dropwise to an ice-cold saturated ammonium chloride aqueous solution. Ethyl acetate was added for extraction, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to remove the solvent. After filtration, the filter cake was collected to obtain 7.454 g of the compound from Example 23.

[1229] 1¹H NMR (500MHz, DMSO-d⁶) δ 11.08 (s, 1H), 7.60 (d, J = 8.2Hz, 1H), 7.25 (d, J = 8.1Hz, 1H), 4.74 (td, J = 5.3, 2.2Hz, 1H), 4.56 (dd, J = 11.8, 5.0Hz, 1H), 3.43 (dd, J = 6.8, 5.2Hz, 2H), 3.21–3.09 (m, 2H), 2.94–2.83 (m, 2H), 2.80–2.71 (m, 2H), 2.60 (dt, J = 17.3, 4.2Hz, 1H), 2.46 (dd, J = 12.1, 4.5Hz, 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. After confirming the reaction was complete by TLC, the reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was stirred for 10 min. The mixture was filtered, 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] Intermediate 24b (13.5 g), 10% palladium on carbon (2.70 g), and methanol (200 mL) were added sequentially to the reaction flask. The mixture was purged with hydrogen three times and reacted overnight. The palladium on carbon was removed by filtration, and the mixture was concentrated to obtain 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] 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 to a reaction flask. The mixture was purged with nitrogen three times and heated to 100 °C. After confirming complete reaction by TLC, 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, concentrated, and purified by silica gel column chromatography to obtain 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] Intermediate 24d (6.9 g), cesium carbonate (4.58 g), water (20 mL), DMSO (20 mL), and methanol (70 mL) were added sequentially to the reaction flask. The reaction solution was cooled to 0 °C, and 30 wt% hydrogen peroxide (4.78 g) was added dropwise. After the addition was complete, the mixture was allowed to return to room temperature for further reaction. After confirming the completeness of the reaction by TLC, water and a saturated sodium sulfite aqueous solution were added to the reaction solution, and the mixture was stirred for 10 min. The mixture was then filtered, the filter cake was collected, and dried to obtain 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] Intermediate 24e (2.0 g), dichloromethane (30 mL), and N,N-diisopropylethylamine (1.36 g) were added sequentially to the reaction flask, and the temperature was lowered to 0 °C. Sulfur trioxide pyridine (1.88 g) was dissolved in DMSO (6 mL) and added dropwise to the reaction solution. After the addition was complete, the mixture was allowed to stand at room temperature. After confirming the reaction was complete by TLC, ethyl acetate and water were added to the reaction solution to separate the organic phase. The mixture was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the concentrate was purified by silica gel column chromatography to obtain intermediate 24f (1.1 g).

[1248] MS(ESI,[M+H) + m / z: 507.4.

[1249] Step 6: Preparation of Compound 24

[1250] Intermediate 24f (165 mg), 16 (100 mg), sodium acetate (26.7 mg), and dichloroethane / isopropanol (5:1, 20 mL) were added sequentially to a reaction flask. After stirring at room temperature for 30 min, sodium cyanoborohydride (40.8 mg) was added, and the reaction was allowed to proceed at room temperature. After confirming the completeness of the reaction by TLC, dichloromethane and water were added to the reaction solution to separate the organic phase. The mixture was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain 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 the reaction flask, and the reaction was carried out at room temperature. After the reaction was confirmed to be complete by TLC, the reaction was quenched with water, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was removed by vacuum evaporation to obtain 25b (6.6 g).

[1257] MS(ESI,[M+H]+)m / z: 223.23.

[1258] Step 2: Preparation of intermediate 25c

[1259] 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) were added sequentially to a reaction flask. The mixture was purged with nitrogen three times and heated to 100 °C. After confirming the reaction was complete by TLC, 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, concentrated, and purified by silica gel column chromatography to obtain intermediate 25c (2.3 g).

[1260] MS(ESI,[M+H) + m / z: 393.4.

[1261] Step 3: Preparation of intermediate 25d

[1262] Intermediate 25c (2.1 g), cesium carbonate (1.74 g), water (10 mL), DMSO (15 mL), and methanol (30 mL) were added sequentially to the reaction flask. The reaction solution was cooled to 0 °C, and 30 wt% hydrogen peroxide (1.82 g) was added dropwise. After the addition was complete, the mixture was allowed to return to room temperature for further reaction. After confirming the completeness of the reaction by TLC, water and a saturated sodium sulfite aqueous solution were added to the reaction solution, and the mixture was stirred for 10 min. The mixture was then filtered, the filter cake was collected, and dried to obtain intermediate 25d (2.1 g).

[1263] MS(ESI,[M+H) + m / z: 411.3.

[1264] Step 4: Preparation of intermediate 25e

[1265] Intermediate 25d (0.75 g), dichloromethane (20 mL), and N,N-diisopropylethylamine (0.63 g) were added sequentially to the reaction flask, and the temperature was lowered to 0 °C. Sulfur trioxide pyridine (0.87 g) was dissolved in DMSO (2 mL) and added dropwise to the reaction solution. After the addition was complete, the mixture was allowed to stand at room temperature. After confirming the reaction was complete by TLC, ethyl acetate and water were added to the reaction solution to separate the organic phase. The mixture was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the concentrate was purified by silica gel column chromatography to obtain intermediate 25e (0.45 g).

[1266] MS(ESI,[M+H) + m / z: 409.3.

[1267] Step 5: Preparation of Compound 25

[1268] Intermediate 25e (80 mg), 16 (50 mg), sodium acetate (13.3 mg), and dichloroethane / isopropanol (5:1, 20 mL) were added sequentially to a reaction flask. After stirring at room temperature for 30 min, sodium cyanoborohydride (20.4 mg) was added, and the reaction was allowed to proceed at room temperature. After confirming the reaction was complete by TLC, dichloromethane and water were added to the reaction solution to separate the organic phase. The mixture was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain 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] In a reaction flask, 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 sequentially. The mixture was stirred at room temperature for 0.5 h, and then sodium cyanoborohydride (39.6 mg) was added. The mixture was stirred at room temperature. After TLC confirmed the reaction was complete, the reaction solution was neutralized with acetic acid by adding saturated sodium bicarbonate solution, followed by extraction with 50 mL of dichloromethane and 100 mL of water. The organic phases were separated, and the aqueous phase was extracted twice with 20 mL of dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography to give compound 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] Intermediate 24f (113 mg), 20 (75 mg), sodium acetate (18.3 mg), and dichloroethane / isopropanol (5:1, 20 mL) were added sequentially to a reaction flask. After stirring at room temperature for 30 min, sodium cyanoborohydride (28.1 mg) was added, and the reaction was allowed to proceed at room temperature for 1 h. 50 mL of dichloromethane and 100 mL of water were added to the reaction mixture, the organic phase was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the concentrate was purified by silica gel column chromatography to obtain 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] In a reaction flask, 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 sequentially. The mixture was stirred at room temperature for 0.5 h, and then sodium cyanoborohydride (39.6 mg) was added, followed by stirring at room temperature for 1 h. After the reaction was complete, the acetic acid was neutralized with 2 mL of saturated sodium bicarbonate solution, and then extracted with 50 mL of dichloromethane and 100 mL of water. The organic phase was separated, and the aqueous phase was extracted twice with 20 mL of dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography (DCM:MeOH = 10:1, v / v) to give 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] Intermediate 24f (118 mg), 17 (100 mg), sodium acetate (21.2 mg), and dichloroethane / isopropanol (5:1, 20 mL) were added sequentially to a reaction flask. After stirring at room temperature for 30 min, sodium cyanoborohydride (32.6 mg) was added, and the reaction was allowed to proceed for 1 h at room temperature. 50 mL of dichloromethane and 100 mL of water were added to the reaction mixture, the organic phase was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the concentrate was purified by silica gel column chromatography to obtain 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), piperidine-4-ol (5.13 g, 50.7 mmol), and N,N-diisopropylethylamine (17.86 g, 138 mmol) were added sequentially to a reaction flask, and the mixture was heated to 100 °C. The reaction solution was poured into an ice-water solution, filtered, and the fi...

Claims

1. The following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or .

2. The compound of claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, selected from the following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or .

3. The compound of claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, selected from the following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof: , , , , , , , , , , , , , , , , , , , , ,or .

4. The compound of claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, selected from the following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof: , , , , , , , , , ,or .

5. The compound of claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, selected from the following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof: , , , , , , , , , ,or .

6. The compound of claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, selected from the following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof: ,or .

7. The compound of claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, selected from the following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof: , , , , , , , , , , , , , , , , , , , , , , , , ,or .

8. The compound of claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, selected from the following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof: , , ,or .

9. The compound of claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, selected from the following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , ,or .

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