Bifunctional degrader and use thereof

Abstract

The present invention relates to a bifunctional degrader and a use thereof, and in particular to a compound containing a structure represented by formula (IV) and a pharmaceutical composition comprising the compound, and uses of the compound and the composition in the preparation of drugs for treating and / or preventing diseases.

Description

A bifunctional degrading agent and its uses

[0001] This application is based on and claims priority to the following applications: CN application number 202510365019.4, filed on March 26, 2025; CN application number 202510560950.8, filed on April 29, 2025; CN application number 202510661986.5, filed on May 21, 2025; CN application number 202511156613.9, filed on August 18, 2025; and CN application number 202511400008.1, filed on September 28, 2025. The disclosures of the aforementioned applications are incorporated herein by reference in their entirety. Technical Field

[0002] This invention discloses compounds and methods for effectively regulating signal transduction and transcription activator factor 6 (“STAT6”) through ubiquitination and / or degradation. This invention also provides pharmaceutical compositions comprising the compounds of this invention, and methods for treating various diseases using said compositions. Background Technology

[0003] STAT6, a member of the STAT protein family, may be involved in IL-4 / IL-13-mediated allergic responses and mediates the differentiation of T helper 2 cells (Th2) (Hebenstreit et al., Cytokine & growth factor reviews 17(3):173-188 (2006); Chapoval et al., Journal of leukocyte biology 87(6):1011-1018 (2010)). STAT6 is mainly activated by interleukin-4 (IL-4) and interleukin-13 (IL-13). Its C-terminal tyrosine residues are phosphorylated by Janus kinase or other kinases, subsequently dimerizing and being transported from the cytoplasm to the nucleus, activating the JAK-STAT6 signaling pathway and regulating the transcription of downstream genes. STAT6 plays an important role in immune regulation, inflammatory responses, cell proliferation, and differentiation. Studies have shown that abnormal activation of STAT6 is closely associated with a variety of diseases, including allergic diseases (such as asthma), autoimmune diseases, cancers (such as lymphoma and solid tumors), and fibrotic diseases. Therefore, STAT6 is considered an important target for the treatment of these diseases. Among them, the thymus and activating regulatory chemokine (TARC) are important downstream target genes of STAT6. Their upregulation can mediate the recruitment of Th2 cells to sites of inflammation, exacerbating allergic inflammatory responses. Studies have shown that inhibiting STAT6 activity can effectively reduce the release of TARC, thereby alleviating the pathological process of allergic diseases (such as atopic dermatitis) (Hebenstreit et al., 2006, Cytokine & Growth Factor Reviews 17 (2006) 173–188). In addition, CD23 (FcεRII), as another key molecule regulated by STAT6, is mainly expressed on the surface of immune cells such as B cells and macrophages, and participates in IgE-mediated immune responses. Activation of the STAT6 signaling pathway can induce upregulation of CD23 expression, thereby promoting the conversion of B cells to the IgE class and aggravating allergic reactions. Therefore, inhibiting STAT6 can downregulate CD23 expression, which helps to block the allergic cascade. Periostin is an extracellular matrix protein secreted by airway epithelial cells, fibroblasts, etc., under the regulation of the IL-13 / STAT6 signaling pathway. It participates in tissue remodeling and fibrosis, playing an important role, especially in the chronic inflammatory stage of allergic diseases such as asthma. By inhibiting STAT6-mediated periodin release, airway remodeling and fibrosis can be effectively intervened, improving disease prognosis.However, currently reported small molecule inhibitors of STAT6 generally lack high affinity and selectivity, or lack a clear cellular mode of action (Mandal, et al., J. Med. Chem. 58(22): 8970-8984 (2015); Nagashima, et al., Bioorganic & Medicinal Chemistry, 15(2), 1044-1055 (2007)).

[0004] The ubiquitin-proteasome pathway (UPP) is the primary protein degradation system in eukaryotic cells, responsible for regulating intracellular protein homeostasis. The UPP plays a crucial role in physiological processes such as cell cycle regulation, signal transduction, DNA repair, and immune responses. Bifunctional small molecules designed based on the UPP, comprising target protein ligands, E3 ubiquitin ligase ligands, and a linker strand, recruit selected proteins to the E3 ubiquitin ligase, promoting the ubiquitination of the target proteins and their degradation by the proteasome. These molecules can selectively degrade specific target proteins, remove pathogenic or carcinogenic proteins, and are recyclable, achieving efficient degradation at low doses.

[0005] Therefore, bifunctional small molecule compounds that utilize E3 ligase-mediated protein degradation to target disease-related proteins such as STAT6 hold promise as therapeutic agents. There is room for further improvement in these therapeutic agents. Summary of the Invention

[0006] A first aspect of the present invention provides a compound, or a stereoisomer thereof, or a tautomer thereof, or a solvate thereof, or an isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is shown in formula (IV).

[0007] in,

[0008] LBM is the ligand portion of the E3 ubiquitin ligase.

[0009] L is a linking group;

[0010] L 1 Selected from key, C 1-6 Alkylene, C 2-6 imidene group, C 2-6 The C- group and any combination thereof, wherein the C- group 1-6 Alkylene and C 2-6 The alkenyl group may be selected independently by one or more of H, halogens, -CN, -OH, -COOH, -NH2, C 1- 6-alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6Alkyl)2, C 3-8 Substitution of cycloalkyl and 4-10 membered heterocyclic groups; or the C 1-6 Alkylene and C 2-6 The carbon atoms in the alkenyl backbone are optionally selected by one or more independently chosen from -C (=O), -NH-, -N (=C). 1-6 alkyl)-, C 3-8 Substitution of cycloalkyl and 4-10 membered heterocyclic groups;

[0011] L 2 Selected from bonds, O, S, N (R) L ), C(=O), C(=O)N(R) L ), N(R L C(=O) and any combination thereof, R L Selected from H and C 1-4 alkyl;

[0012] R 1 Selected from H, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl and 5-10 membered heterocyclic, wherein C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 heteroaryl, and 5-10 heterocyclic groups are optionally selected by one or more elements chosen from H, halogen, -CN, -OH, -COOH, -NH2, C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl and -N-(C 1-6 Substitution of alkyl groups;

[0013] Ring W is selected from C 3-15 Cycloalkyl and 4-15 membered heterocyclic groups, wherein the C 3-15 Cycloalkyl and 4-15 membered heterocyclic groups include spirocyclic, monocyclic, fused, or bridged rings;

[0014] w is 0, 1, 2, 3, 4, 5, or 6;

[0015] Each R W Each is independently selected from H, halogens, -CN, -OH, -COOH, -NH2, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl and -N-(C 1-6 Alkyl)2;

[0016] R 2 Selected from H, halogens, -CN, -OH, -COOH, -NH2, C1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl and -N-(C 1-6 Alkyl)2; or,

[0017] R 2 And one of the R W Forming C with the attached atoms 5-10 Cycloalkenyl, 5-10 membered heterocyclic and 5-10 membered heteroaryl;

[0018] Ring V is a 5-6 membered heteroaryl group;

[0019] v is 0, 1, or 2;

[0020] R V Selected from H, halogens, -CN, -OH, -COOH, -NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1- 6-alkyl, -NH-C 1-6 Alkyl and -N-(C 1-6 Alkyl)2;

[0021] L 3 Selected from bonds, O, S, N (R) L ), C(=O), C(=O)N(R) L ) and N(R L C(=O), R L Selected from H and C 1-4 alkyl;

[0022] R 3 Selected from C 1-6 Alkyl, C 3-10 Cycloalkyl and 4-10 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-10 The cycloalkyl group and the 4-10 membered heterocyclic group are optionally surrounded by one or more groups selected from H, halogen, -CN, -OH, -COOH, -NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl and -N-(C 1-6 Substitution of alkyl groups; or,

[0023] R 3 And one of the R V Forming C with the attached atoms 5-10 Cycloalkenyl and 5-10 membered heterocyclic groups;

[0024] R 4Selected from H and halogens;

[0025] The condition is that,

[0026] When ring W is azacyclohexene, piperidinyl, or homopiperidinyl:

[0027] 1) L contains or,

[0028] 2)R 2 And one of the R W To form a ring with the atoms connected to it; or,

[0029] 3)R 3 And one of the R V It forms a ring with the atoms connected to it;

[0030] in,

[0031] Rings E and F are each independently selected from C. 6-10 Aryl, C 3-10 Cycloalkyl, 5-12-membered heteroaryl and 4-12-membered heterocyclic groups;

[0032] e and f are each independently 1, 2, 3, 4, 5 or 6;

[0033] Each R E and each R F Each is independently selected from H, halogens, -CN, -OH, -COOH, -NH2, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl and -N-(C 1-6 Alkyl)2;

[0034] Ring I is C 6-10 Aryl, C 4-10 cycloalkyl, C 4-10 Cycloalkenyl, 5-12-membered heteroaryl and 4-12-membered heterocyclic groups.

[0035] In some embodiments, when ring W is azacyclohexene, L contains Ring E, Ring F, Ring I, R E R F e, f are as defined in any embodiment of the present invention.

[0036] In some implementations, L is

[0037] L 4 L 5 L 6 Each is independently selected from key, C 1-6 Alkylene, C2-6 imidene group, C 2-6 alkyne group, O, S, N(R) L ), C(=O), C(=O)N(RL), N(RL)C(=O) and any combination thereof, R L Selected from H and C 1-4 alkyl;

[0038] Rings E and F are each independently selected from C. 6-10 Aryl, C 3-10 Cycloalkyl, 5-12-membered heteroaryl and 4-12-membered heterocyclic groups;

[0039] e and f are each independently 0, 1, 2, 3, 4, 5 or 6;

[0040] Each R E and each R F Each is independently selected from H, halogens, -CN, -OH, -COOH, -NH2, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl and -N-(C 1-6 Alkyl)2; or,

[0041] One of the R E And an R F The atoms connected to each other form rings, making the structural unit for e and f are each independently 1, 2, 3, 4, 5, or 6, and ring I is C. 6-10 Aryl, C 4- 10 cycloalkyl, C 4-10 Cycloalkenyl, 5-12 membered heteroaryl and 4-12 membered heterocyclic;

[0042] L 6 Connected to LBM.

[0043] In some implementations, when ring W is azircyclohexene, the structural unit for Ring E, Ring F, Ring I, R E R F e, f are as defined in any embodiment of the present invention. In some embodiments, the compound contains the structure shown in formula (I).

[0044] in,

[0045] L 1 Selected from key, C 1-6 Alkylene, C 2-6 imidene group, C2-6 The C- group and any combination thereof, wherein the C- group 1-6 Alkylene and C 2-6 The alkenyl group may be selected independently by one or more of H, halogens, -CN, -OH, -COOH, -NH2, C 1- 6-alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 Alkyl)2, C 3-8 Substitution of cycloalkyl and 4-10 membered heterocyclic groups; or the C 1-6 Alkylene and C 2-6 The carbon atoms in the alkenyl backbone are optionally selected by one or more independently chosen from -C(=O)-, -NH-, -N(C 1-6 alkyl)-, C 3-8 Substitution of cycloalkyl and 4-10 membered heterocyclic groups;

[0046] L 2 Selected from bonds, O, S, N (R) L ), C(=O), C(=O)N(R) L ), N(R L C(=O) and any combination thereof, R L Selected from H and C 1-4 alkyl;

[0047] R 1 Selected from H, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl and 5-10 membered heterocyclic, wherein C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 heteroaryl, and 5-10 heterocyclic groups are optionally selected by one or more elements chosen from H, halogen, -CN, -OH, -COOH, -NH2, C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl and -N-(C 1-6 Substitution of alkyl groups;

[0048] Ring W is selected from C 3-15 Cycloalkyl and 4-15 membered heterocyclic groups, wherein the C 3-15 Cycloalkyl and 4-15 membered heterocyclic groups include monocyclic, spirocyclic, fused, or bridged rings;

[0049] w is 0, 1, 2, 3, 4, 5, or 6;

[0050] Each R WEach is independently selected from H, halogens, -CN, -OH, -COOH, -NH2, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl and -N-(C 1-6 Alkyl)2;

[0051] R 2 Selected from H, halogens, -CN, -OH, -COOH, -NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl and -N-(C 1-6 Alkyl)2; or,

[0052] R 2 And one of the R W Forming C with the attached atoms 5-10 Cycloalkenyl, 5-10 membered heterocyclic and 5-10 membered heteroaryl;

[0053] Ring V is a 5-6 membered heteroaryl group;

[0054] v is 0, 1, or 2;

[0055] R V Selected from H, halogens, -CN, -OH, -COOH, -NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1- 6-alkyl, -NH-C 1-6 Alkyl and -N-(C 1-6 Alkyl)2;

[0056] L 3 Selected from bonds, O, S, N (R) L ), C(=O), C(=O)N(R) L ) and N(R L C(=O), R L Selected from H and C 1-4 alkyl;

[0057] R 3 Selected from C 1-6 Alkyl, C 3-10 Cycloalkyl and 4-10 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-10 The cycloalkyl group and the 4-10 membered heterocyclic group are optionally surrounded by one or more groups selected from H, halogen, -CN, -OH, -COOH, -NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC1-6 Alkyl, -NH-C 1-6 Alkyl and -N-(C 1-6 Substitution of alkyl groups; or,

[0058] R 3 And one of the R V Forming C with the attached atoms 5-10 Cycloalkenyl and 5-10 membered heterocyclic groups;

[0059] R 4 Selected from H and halogens;

[0060] L 4 L 5 and L 6 Each is independently selected from key, C 1-6 Alkylene, C 2-6 imidene group, C 2-6 alkyne group, O, S, N(R) L ), C(=O), C(=O)N(R) L ), N(R L C(=O) and any combination thereof, R L Selected from H and C 1-4 alkyl;

[0061] Rings E and F are each independently selected from C. 6-10 Aryl, C 3-10 Cycloalkyl, 5-12-membered heteroaryl and 4-12-membered heterocyclic groups;

[0062] e and f are each independently 0, 1, 2, 3, 4, 5 or 6;

[0063] Each R E and each R F Each is independently selected from H, halogens, -CN, -OH, -COOH, -NH2, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl and -N-(C 1-6 Alkyl)2; or,

[0064] One of the R E And an R F Forming C with the attached atoms 5-10 cycloalkyl, C 5-10 Cycloalkenyl and 5-10 membered heterocyclic groups;

[0065] The condition is that,

[0066] When ring W is azacyclohexene, piperidinyl, or homopiperidinyl, R 2 And one of the RW It forms a ring with the adjacent atoms, or, R 3 And one of the R V It forms a ring with the connected atoms, or an R E And an R F It forms a ring with the atoms connected to it.

[0067] In some implementations, in formula (I), Indicates the connection site with LBM.

[0068] In some embodiments, the compound contains the structure shown in formula (I).

[0069] in,

[0070] L 1 Selected from key, C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Alynyl groups and any combination thereof;

[0071] L 2 Selected from bonds, O, S, N (R) L ), C(=O), C(=O)N(R) L ), N(R L C(=O) and any combination thereof, R L Selected from H and C 1-4 alkyl;

[0072] R 1 Selected from H, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl and 5-10 membered heterocyclic, wherein C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 heteroaryl, and 5-10 heterocyclic groups are optionally selected by one or more elements chosen from H, halogen, -CN, -OH, -COOH, -NH2, C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl and -N-(C 1-6 Substitution of alkyl groups;

[0073] Ring W is selected from C 3-15 Cycloalkyl and 4-15 membered heterocyclic groups;

[0074] w is 0, 1, 2, 3, 4, 5, or 6;

[0075] Each R W Each is independently selected from H, halogens, -CN, -OH, -COOH, -NH2, and C. 1-6 Alkyl, C1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl and -N-(C 1-6 Alkyl)2;

[0076] R 2 Selected from H, halogens, -CN, -OH, -COOH, -NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl and -N-(C 1-6 Alkyl)2; or,

[0077] R 2 And one of the R W Forming C with the attached atoms 5-10 Cycloalkenyl, 5-10 membered heterocyclic and 5-10 membered heteroaryl;

[0078] Ring V is a 5-6 membered heteroaryl group;

[0079] v is 0, 1, or 2;

[0080] R V Selected from H, halogens, -CN, -OH, -COOH, -NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1- 6-alkyl, -NH-C 1-6 Alkyl and -N-(C 1-6 Alkyl)2;

[0081] L 3 Selected from bonds, O, S, N (R) L ), C(=O), C(=O)N(R) L ) and N(R L C(=O), R L Selected from H and C 1-4 alkyl;

[0082] R 3 Selected from C 1-6 Alkyl, C 3-10 Cycloalkyl and 4-10 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-10 The cycloalkyl group and the 4-10 membered heterocyclic group are optionally surrounded by one or more groups selected from H, halogen, -CN, -OH, -COOH, -NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl and -N-(C 1-6Substitution of alkyl groups; or,

[0083] R 3 And one of the R V Forming C with the attached atoms 5-10 Cycloalkenyl and 5-10 membered heterocyclic groups;

[0084] R 4 Selected from H and halogens;

[0085] L 4 L 5 and L 6 Each is independently selected from key, C 1-6 Alkylene, C 2-6 imidene group, C 2-6 alkyne group, O, S, N(R) L ), C(=O), C(=O)N(R) L ), N(R L C(=O) and any combination thereof, R L Selected from H and C 1-4 alkyl;

[0086] Rings E and F are each independently selected from C. 6-10 Aryl, C 3-10 Cycloalkyl, 5-12-membered heteroaryl and 4-12-membered heterocyclic groups;

[0087] e and f are each independently 0, 1, 2, 3, 4, 5 or 6;

[0088] Each R E and each R F Each is independently selected from H, halogens, -CN, -OH, -COOH, -NH2, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl and -N-(C 1-6 Alkyl)2; or,

[0089] One of the R E And an R F Forming C with the attached atoms 5-10 cycloalkyl, C 5-10 Cycloalkenyl and 5-10 membered heterocyclic groups;

[0090] The condition is that,

[0091] When ring W is a 6-membered monocyclic heterocyclic group, R 2 And one of the R W It forms a ring with the adjacent atoms, or, R 3 And one of the R VIt forms a ring with the connected atoms, or an R E And an R F It forms a ring with the atoms connected to it.

[0092] In some implementations, when ring W is a 6-membered monocyclic heterocyclic group, R 2 And one of the R W It forms a ring with the adjacent atoms, or, R 3 And one of the R V It forms a ring with the connected atoms, or an R E And an R F It forms a ring with the atoms connected to it.

[0093] In some embodiments, the ring W is not piperidinyl or homopiperidinyl.

[0094] In some implementations, L 1 Selected from key, C 1-6 Alkylene, C 2-6 imidene group, C 2-6 The C- group and any combination thereof, wherein the C- group 1-6 Alkylene and C 2-6 The carbon atoms in the alkenyl backbone are optionally selected from one or more independently from C. 3- Substitution of 8-cyclic alkyl groups and 4-10-membered heterocyclic groups.

[0095] In some implementations, L 1 Selected from key, C 1-4 Alkylene, C 2-4 imide and Among them, ring U is selected from C 3-8 cycloalkyl (e.g., C10) 3-6 Cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl), z1 and z2 are each independently 0, 1, 2, or 3, and z1 + z2 ≤ 3, with *terminus connected to L. 2 Connected.

[0096] In some implementations, L 1 Selected from key, C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Alynyl groups and any combination thereof.

[0097] In some implementations, L 1 Selected from key, C 1-4 Alkylene and C 2-4 Alkenyl group.

[0098] In some implementations, L 1Selected from -CH2-, -CH2CH2-, -CH(CH3)-, -CH2CH(CH3)-, -CH(CH3)CH2-, *End and L 2 Connected.

[0099] In some implementations, L 1 Selected from -CH2-, -CH2CH2-, -CH(CH3)-, -CH2CH(CH3)- and -CH(CH3)CH2-.

[0100] In some implementations, L 1 Selected from -CH2CH2-.

[0101] In some implementations, L 2 Selected from bonds, O, S, N (R) L ) and C(=O), R L Selected from H and methyl.

[0102] In some implementations, L 2 Selected from the bond and -C(=O)-.

[0103] In some implementations, -L 1 -L 2 -* is selected from -CH2CH2-* and -CH2CH2C(=O)-*.

[0104] In some implementations, R 1 Selected from H, C 3-8 Cycloalkyl, 5-6 membered heteroaryl and 5-6 membered heterocyclic, wherein C 3-8 Cycloalkyl, 5-6-membered heteroaryl, and 5-6-membered heterocyclic groups are optionally separated by one or more elements selected from H, halogen, -CN, -OH, -COOH, -NH2, and C. 1-4 Alkyl groups are substituted.

[0105] In some implementations, R 1 It is a 5-6-membered heteroaryl group, wherein the 5-6-membered heteroaryl group is optionally substituted by 1, 2, or 3 groups selected from H, halogen, -CN, -OH, -COOH, -NH2, and methyl.

[0106] In some implementations, R 1 It is selected from pyrrole, pyrazolyl, imidazolyl, triazolyl, thiophenyl, thiazolyl and pyridyl.

[0107] In some implementations, R 1 Selected from

[0108] In some embodiments, ring W is a 5-15 member heterocyclic group, which includes monocyclic, spirocyclic, fused, or bridged rings.

[0109] In some embodiments, ring W is selected from 5-7 nucleotide monocyclic heterocyclic groups, 7-15 nucleotide spirocyclic heterocyclic groups, and 7-15 nucleotide fused heterocyclic groups.

[0110] In some embodiments, ring W is selected from 5-7 nucleotide monocyclic heterocyclic groups and 7-15 nucleotide spirocyclic heterocyclic groups.

[0111] In some implementations, ring W is a 7-15 member spirocyclic heterocyclic group.

[0112] In some implementations, ring W is selected from 5-7 member monocyclic heterocyclic groups, Where W1 is a 5-8 membered heterocyclic group, and W2 is a C group. 3-6 Cycloalkyl, W3 is a 5-7 membered heterocyclic group, and W4 is a 5-6 membered heteroaryl group.

[0113] In some embodiments, ring W is selected from 5-7 member monocyclic heterocyclic groups and Where W1 is a 5-8 membered heterocyclic group, and W2 is a C group. 3-6 Cycloalkyl.

[0114] In some implementations, ring W is Where W1 is a 5-8 membered heterocyclic group, and W2 is a C group. 3-6 Cycloalkyl.

[0115] In some embodiments, ring W is selected from 5-7 membered monocyclic azircyclic alkenyl groups, 5-7 membered monocyclic azircyclic alkyl groups, etc. W1 is selected from 5-8-membered nitrogen-containing heterocyclic alkyl and 5-8-membered nitrogen-containing heterocyclic alkenyl groups; W2 is selected from cyclopropyl, cyclobutyl, and cyclopentyl groups; W3 is selected from 5-7-membered nitrogen-containing heterocyclic alkyl and 5-7-membered nitrogen-containing heterocyclic alkenyl groups; W4 is selected from pyrrole, pyrazol, and imidazolyl groups; *terminus is associated with L. 2 Connected.

[0116] In some embodiments, ring W is selected from 5-7 membered monocyclic azircyclic alkenyl groups, 5-7 membered monocyclic azircyclic alkyl groups, etc. W1 is selected from 5-8-membered nitrogen-containing heterocyclic alkyl and 5-8-membered nitrogen-containing heterocyclic alkenyl groups; W2 is selected from cyclopropyl, cyclobutyl, and cyclopentyl groups; W3 is selected from 5-7-membered nitrogen-containing heterocyclic alkyl and 5-7-membered nitrogen-containing heterocyclic alkenyl groups; W4 is selected from pyrrole, pyrazol, and imidazolyl groups; *terminus is associated with L. 2 Connected.

[0117] In some embodiments, ring W is selected from azicyclohexenyl, azicycloheptenyl, ... Azacyclohexenylpyrazolyl and azacyclohexenylimidazolyl, wherein p1, p2, and p3 are each independently 0, 1, or 2, and p1 + p2 ≤ 2; p4, p5, and p6 are each independently 0, 1, or 2, and p4 + p5 ≤ 2; the * terminus is associated with L. 2 Connected.

[0118] In some embodiments, cycloW is selected from azircyclohexenyl, Azacyclohexenylpyrazolyl and azacyclohexenylimidazolyl, wherein p1, p2, and p3 are each independently 0, 1, or 2, and p1 + p2 ≤ 2, and the * terminus is related to L. 2 Connected.

[0119] In some implementations, ring W is selected from Azacyclohexenylpyrazolyl and azacyclohexenylimidazolyl, wherein p1, p2, and p3 are each independently 0, 1, or 2, and p1 + p2 ≤ 2; p4, p5, and p6 are each independently 0, 1, or 2, and p4 + p5 ≤ 2; the * terminus is associated with L. 2 Connected.

[0120] In some implementations, ring W is selected from Where p1, p2, and p3 are each independently 0, 1, or 2, and p1 + p2 ≤ 2, * and L 2 Connected. In some implementations, p1, p2, and p3 are each independently 0 or 1.

[0121] In some implementations, ring W is Where p1, p2, and p3 are each independently 0, 1, or 2, and p1 + p2 ≤ 2, * and L 2 Connected. In some implementations, p1, p2, and p3 are each independently 0 or 1.

[0122] In some implementations, w is 0, 1, 2, or 3.

[0123] In some implementations, each R W Each is independently selected from H, halogens, -CN, -OH, -COOH, -NH2, and C. 1-4 Alkyl, C 1-4 Halogenated alkyl groups and -OC 1-4 alkyl.

[0124] In some implementations, each R W Each is independently selected from H, halogen, -CN, -OH, -COOH, -NH2, -CH3 and -CH2CH3.

[0125] In some implementations, each R W Each is independently selected from H, -F, and -CH3.

[0126] In some implementations, structural units Selected from Among them, * end and L 2 Connected.

[0127] In some implementations, structural units Selected from Among them, * end and L 2 Connected.

[0128] In some implementations, structural units Selected from Among them, * end and L 2 Connected. In some implementations, structural units Selected from Among them, * end and L 2 Connected.

[0129] In some implementations, structural units for Among them, * end and L 2 Connected.

[0130] In some implementations, R 4 Selected from H and F.

[0131] In some implementations, R 4 It is F.

[0132] In some implementations, R 2 Selected from H, halogens, -CN, -OH, -COOH, -NH2, C 1-4 Alkyl, C 1- 4-Halogenated Alkyl Groups and -OC 1-4 alkyl.

[0133] In some implementations, R 2 Selected from H, halogens, -CN, -OH, -COOH, -NH2, -CH3 and -CH2CH3.

[0134] In some implementations, R 2 For H.

[0135] In some implementations, R 2 And one of the R W The atoms connected to each other form rings, making the structural unit for Where ring J is C 5-8 Cycloalkenyl, 5-8 membered heterocyclic and 5-6 membered heteroaryl, cycloW, R W and R 4 As defined in any embodiment of the present invention, w is 1, 2, 3, 4, 5 or 6.

[0136] In some implementations, structural units for Among them, rings W and R W and R 4 As defined in any embodiment of the present invention, X 1 Selected from CH2, O, S and NH, where q is 0, 1 or 2.

[0137] In some implementations, structural units Selected from

[0138] In some implementations, ring V is a 5-membered heteroaryl group.

[0139] In some embodiments, ring V is selected from pyrrole, pyrazolyl, imidazolyl, furanyl, and thiophene.

[0140] In some implementations, ring V is a pyrrole group.

[0141] R V Selected from H, halogens, -CN, -OH, -COOH, -NH2, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups and -OC 1- 4-alkyl group.

[0142] In some implementations, R V Selected from H, halogens, -CN, -OH, -COOH, -NH2, -CH3 and -CH2CH3.

[0143] In some implementations, R V For H.

[0144] In some implementations, structural units for

[0145] In some implementations, L 3 Selected from C(=O) and C(=O)N(R) L ), R L Selected from H and C 1-4 alkyl.

[0146] In some implementations, L 3The expression is -C(=O)N(CH3)-*, where the * terminus is connected to R. 3 Connected.

[0147] In some implementations, R 3 Selected from C 1-6 Alkyl, C 3-8 Cycloalkyl and 4-8 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-8 The cycloalkyl group and the 4-8 membered heterocyclic group are optionally surrounded by one or more groups selected from H, halogen, -CN, -OH, -NH2 and C. 1-6 Alkyl groups are substituted.

[0148] In some implementations, R 3 Selected from C 1-4 Alkyl, C 3-6 Cycloalkyl and 4-6 membered heterocyclic groups, wherein the C 1-4 Alkyl, C 3-6 The cycloalkyl and 4-6 membered heterocyclic groups may be optionally substituted with 1, 2, 3, 4 or 5 groups selected from H, halogens and methyl.

[0149] In some implementations, R 3 It is selected from methyl, ethyl, propyl, halomethyl, haloethyl, cyclopropyl, aziridine, pyrrolyl, piperidinyl, piperazine, and morpholinyl.

[0150] In some implementations, R 3 It is -CH3.

[0151] In some implementations, -L 3 -R 3 It is -C(=O)N(CH3)2.

[0152] In some implementations, R 3 And one of the R V The atoms connected to each other form rings, making the structural unit for Among them, ring K is a 5-8 member heterocyclic group, and rings V and R are... V L 3 and R 4 As defined in any embodiment of the present invention, v is 1 or 2.

[0153] In some implementations, structural units for Among them, ring R V R L and R 4 As defined in any embodiment of the present invention, s is 0, 1, or 2.

[0154] In some implementations, structural units for

[0155] In some implementations, L 4 L 5 and L 6 Each is independently selected from key, C 1-6 Alkylene, C 2-6 alkyne group, O, N(R) L ), C(=O), C(=O)N(R) L ), N(R L C(=O) and any combination thereof, R L Selected from H and C 1-4 alkyl.

[0156] In some implementations, L 4 L 5 and L 6 Each is independently selected from key, C 1-4 Alkylene and C (=O).

[0157] In some implementations, L 4 For key.

[0158] In some implementations, L 5 Selected from the bond and C (=O).

[0159] In some implementations, L 5 For key.

[0160] In some implementations, L 6 Selected from the bond, -CH2CH2- and -CH2CH2CH2-.

[0161] In some implementations, L 6 Selected from the bond and -CH2CH2-.

[0162] In some implementations, L 6 For key.

[0163] In some embodiments, ring E and ring F are each independently selected from phenyl, C 3-10 Cycloalkyl and 4-12 membered heterocyclic groups.

[0164] In some embodiments, ring E and ring F are each independently selected from phenyl, C 3-7 Cycloalkyl and 4-10 membered heterocyclic groups.

[0165] In some embodiments, ring E and ring F are each independently selected from phenyl, cyclobutyl, cyclopentyl, aziridine, pyrrolidinyl, piperidinyl, piperazine, etc.

[0166] In some embodiments, ring E is selected from phenyl.

[0167] In some embodiments, cyclic F is selected from piperidinyl, piperazine, and...

[0168] In some embodiments, ring F is selected from piperidinyl and piperazineyl.

[0169] In some implementations, e and f are each independently 0, 1, 2, 3 or 4.

[0170] In some implementations, e and f are each independently 1, 2, 3, or 4.

[0171] In some implementations, each R E and each R F Each is independently selected from H, halogen, -OH, -NH2, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, -OC 1-4 Alkyl and -OC 1-4 Halogenated alkyl groups.

[0172] In some implementations, each R E and each R F Each is independently selected from H, halogen, -OH, -NH2, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups and -OC 1-4 alkyl.

[0173] In some implementations, each R E and each R F Each is independently selected from H, -F, -Cl, -CH3, -CH2CH3, -CF3, -OCH3 and -OCF3.

[0174] In some implementations, each R E and each R F Each is independently selected from H, -F, -Cl, -CH3, -CH2CH3, -CF3 and -OCH3.

[0175] In some implementations, each R E Each is independently selected from H, F, -Cl, -CH3, -CF3 and -OCF3.

[0176] In some implementations, each R E Each is independently selected from H, F, -Cl, -CH3 and -OCF3.

[0177] In some implementations, each R E Each is independently selected from H and halogens.

[0178] In some implementations, each R E Each is independently selected from H, F and -Cl.

[0179] In some implementations, each R E Each is independently selected from H and F.

[0180] In some implementations, each R F Each is independently represented by H.

[0181] In some implementations, structural units Selected from Among them, * end and L 5 Connected.

[0182] In some implementations, structural units Selected from Among them, * end and L 5 Connected.

[0183] In some implementations, structural units Selected from Among them, * end and L 5 Connected.

[0184] In some implementations, structural units Selected from Among them, * end and L 5 Connected.

[0185] In some implementations, structural units Selected from Among them, * end and L 5 Connected.

[0186] In some implementations, structural units Selected from Among them, * end and L 6 Connected.

[0187] In some implementations, structural units Selected from Among them, * end and L 6 Connected.

[0188] In some implementations, ring I is selected from C 5-10 cycloalkyl, C 5-10 Cycloalkenyl and 5-10 membered heterocyclic groups.

[0189] In some embodiments, ring I is a 5-8 membered heterocyclic alkenyl group containing 1, 2 or 3 heteroatoms selected from N or O.

[0190] In some implementations, an R E And an R F The atoms connected to each other form rings, making the structural unit for Among them, ring I is a 5-8 membered heterocyclic group, and rings E, F, and R are also present. E and R F As defined in any embodiment of the present invention, e and f are each independently 1, 2, 3, 4, 5 or 6.

[0191] In some implementations, structural units for Among them, rings E, F, and R E and R F As defined in any embodiment of the present invention, e and f are each independently 1, 2, 3, 4, 5, or 6, X 2 X 3 and X 4 Each is independently selected from chemical bonds, CH2, O, S, and NH, and X 2 X 3 and X 4 It is not always 0, and t is 0, 1, or 2.

[0192] In some implementations, structural units for Among them, rings E, F, and R E and R F As defined in any embodiment of the present invention, e and f are each independently 1, 2, 3, 4, 5, or 6, X 2 X 3 and X 4 Each is independently selected from CH2, O, S, and NH, and X 2 X 3 and X 4 It is not always 0, and t is 0, 1, or 2.

[0193] In some implementations, structural units for Among them, rings E, F, and R E and R F As defined in any embodiment of the present invention, e and f are each independently 1, 2, 3, 4, 5, or 6, X 2 and X 3 Each is independently selected from CH2, O, S and NH, with t being 0, 1 or 2.

[0194] In some implementations, structural units Selected from Among them, R E and R F As defined in any embodiment of the present invention, e and f are each independently 1, 2, 3 or 4, t1 and t3 are each independently 1, 2 or 3, and t2, t4 and t5 are each independently 0, 1 or 2.

[0195] In some implementations, structural units Selected from Among them, R E and R F As defined in any embodiment of the present invention, e and f are each independently 1, 2, 3 or 4, t3 is 1 or 2, and t4 is 0, 1 or 2.

[0196] In some implementations, structural units Selected from Among them, R E and R F As defined in any embodiment of the present invention, e and f are each independently 1, 2, 3 or 4, t3 is 1 or 2, and t4 is 0, 1 or 2.

[0197] In some implementations, structural units Selected from Among them, R E As defined in any embodiment of the present invention.

[0198] In some implementations, structural units Selected from Among them, R E As defined in any embodiment of the present invention.

[0199] In some implementations, structural units Selected from Among them, R E As defined in any embodiment of the present invention.

[0200] In some implementations, structural units for Among them, R E As defined in any embodiment of the present invention.

[0201] In some implementations, structural units Selected from

[0202] In some implementations, structural units Selected from

[0203] In some implementations, structural units Selected from

[0204] In some implementations, structural units Selected from

[0205] In some implementations, Selected from Among them, R E R F e, f and L 6 As defined in any embodiment of the present invention.

[0206] In some implementations, Selected from Among them, R E R F e, f and L 6 As defined in any embodiment of the present invention.

[0207] In some implementations, Selected from

[0208] In some implementations, Selected from

[0209] In some embodiments, the compound is as shown in formula (II).

[0210] LBM is the ligand portion of the E3 ubiquitin ligase.

[0211] Ring W, Ring V, Ring E, Ring F, w, v, e, f, R W R V R E R F L 1 L 2 L 3 L 4 L 5 L 6 R 1 R 2 R 3 and R 4 As defined in any embodiment of the present invention.

[0212] In some embodiments, the compound is as shown in formula (III).

[0213] in,

[0214] Ring W, Ring V, Ring E, Ring F, w, v, e, f, R W R V R E R F L 1 L 2 L 3 L 4 L 5 L 6 R 1 R 2 R 3 and R 4 As defined in any embodiment of the present invention,

[0215] Ring G is selected from C 6-10 Aryl, C 3-10 Cycloalkyl, 5-12-membered heteroaryl and 4-12-membered heterocyclic groups;

[0216] g can be 0, 1, 2, 3, 4, 5, or 6;

[0217] Each R G Each is independently selected from H, halogens, -CN, -OH, -COOH, -NH2, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl and -N-(C 1-6 Alkyl)2;

[0218] L 7 Selected from bonds, O, S, N (R) L ), C(=O), C(=O)N(R) L ) and N(RL C(=O), R L Selected from H and C 1-4 alkyl;

[0219] R 5 Selected from H, halogens, -CN, -OH, -COOH, -NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl and -N-(C 1-6 Alkyl)2;

[0220] L 8 Selected from bonds, CH2, C(=O), C(=S), S(=O) and

[0221] m is 0 or 1.

[0222] In some embodiments, when ring W is azircyclohexene, an R E And an R F The atoms connected to each other form rings, making the structural unit for Ring E, Ring F, Ring I, e, f, R E R F As defined in any embodiment of the present invention.

[0223] In some embodiments, ring G is selected from phenyl, naphthyl, 5-10 membered heteroaryl, and 9-10 membered heterocyclic group.

[0224] In some embodiments, ring G is selected from phenyl, naphthyl, 5-6 membered heteroaryl, 9-10 membered heteroaryl and 9-10 membered heterocyclic group.

[0225] In some embodiments, ring G is selected from phenyl, naphthyl, pyrazolyl, benzopyrazolyl, pyridopyrazolyl, pyridoimidazolyl, quinolinyl, isoquinolinyl, etc.

[0226] In some embodiments, ring G is selected from phenyl, naphthyl, pyrazolyl, benzopyrazolyl, pyridopyrazolyl, pyridoimidazolyl, quinolinyl, isoquinolinyl, etc.

[0227] In some embodiments, ring G is phenyl.

[0228] In some implementations, ring G is selected from: Among them, * end and L 7 Connected.

[0229] In some embodiments, cyclic G is selected from phenyl and 9-10 heteroaryl groups.

[0230] In some implementations, ring G is selected from: Among them, * end and L 7 Connected.

[0231] In some implementations, g is 0, 1, 2, 3, or 4.

[0232] In some implementations, each R G Each is independently selected from H, halogen, -OH, -NH2, C 1-4 Alkyl, C 1- 4-Halogenated Alkyl Groups and -OC 1-4 alkyl.

[0233] In some implementations, each R G Each is independently selected from H, -F, -Cl, -CH3, -CH2CH3, -CF3 and -OCH3.

[0234] In some implementations, each R G Each is independently selected from H, -F, -CH3, and -OCH3.

[0235] In some implementations, each R G Each is independently selected from H, -F, and -OCH3.

[0236] In some implementations, structural units Selected from Among them, * end and L 7 Connected.

[0237] In some implementations, structural units Selected from Among them, * end and L 7 Connected. In some implementations, structural units Selected from Among them, * end and L 7 Connected.

[0238] In some implementations, structural units for Among them, * end and L 7 Connected.

[0239] In some implementations, L 7 Selected from bonds, O, N (R) L ) and C(=O)N(R L), R L Selected from H and C 1-4 alkyl.

[0240] In some implementations, L 7 Selected from bonds and N(R) L ), R L Selected from H, -CH3 and -CH2CH3.

[0241] In some implementations, L 7 Selected from bonds and NH.

[0242] In some implementations, R 5 Selected from H, halogens, -CN, -OH, -COOH, -NH2, C 1-4 Alkyl, C 1- 4-Halogenated Alkyl Groups and -OC 1-4 alkyl.

[0243] In some implementations, R 5 Selected from H, halogens, -CN, -OH, -COOH, C 1-4 Alkyl groups and -NH2.

[0244] In some implementations, R 5 Selected from H, halogens, -CN, -OH, -COOH and -NH2.

[0245] In some implementations, R 5 Selected from H, F and -CH3.

[0246] In some implementations, R 5 For H.

[0247] In some implementations, L 8 Selected from bonds, CH2 and C (=O).

[0248] In some implementations, L 8 It is C (=O).

[0249] In some implementations, m is 1.

[0250] In some implementations, structural units Selected from Among them, R G And g is as defined in any embodiment of the present invention.

[0251] In some implementations, structural units Selected from Among them, R GAnd g is as defined in any embodiment of the present invention.

[0252] In some implementations, structural units Selected from Among them, R G And g is as defined in any embodiment of the present invention.

[0253] In some embodiments, the compound is selected from the structure shown in formula (III-1).

[0254] Among them, rings W1, W2, V, E, F, G, w, v, e, f, g, m, and R W R V R E R F R G L 1 L 2 L 3 L 4 L 5 L 6 L 7 L 8 R 1 R 2 R 3 R 4 R 5 As defined in any embodiment of the present invention.

[0255] In some implementations, structural units for Where p1, p2, and p3 are each independently 0, 1, or 2, and p1 + p2 ≤ 2, * and L 2 Connected.

[0256] In some implementations, structural units for Selected from *End and L 2 Connected.

[0257] In some implementations, structural units for Selected from *End and L 2 Connected.

[0258] In some implementations, structural units for Preferred More preferably *End and L 2 Connected.

[0259] In some embodiments, the compound is selected from the structure shown in formula (III-1A);

[0260] Among them, rings V, E, F, G, v, e, f, g, m, and R V R E R F R G L 1 L 2 L 3 L 4 L 5 L 6 L 7 L 8 R 1 R 2 R 3 R 4 R 5 p1, p2, and p3 are as defined in any embodiment of the present invention.

[0261] In some implementations, structural units Selected from Preferred More preferably Among them, * end and L 2 Connected.

[0262] In some embodiments, the compound is selected from the structure shown in formula (III-2).

[0263] Among them, rings W3, W4, V, E, F, G, w, v, e, f, g, m, and R W R V R E R F R G L 1 L 2 L 3 L 4 L 5 L 6 L 7 L 8 R 1 R 2 R 3 R 4 R 5As defined in any embodiment of the present invention.

[0264] In some implementations, structural units Selected from *End and L 2 Connected.

[0265] In some embodiments, the compound is selected from the structure shown in formula (III-3).

[0266] Among them, rings J, W, V, E, F, G, w, v, e, f, g, m, and R W R V R E R F R G L 1 L 2 L 3 L 4 L 5 L 6 L 7 L 8 R 1 R 3 R 4 R 5 As defined in any embodiment of the present invention.

[0267] In some embodiments, the compound is selected from the structure shown in formula (III-4).

[0268] Among them, rings K, W, V, E, F, G, w, v, e, f, g, m, and R W R V R E R F R G L 1 L 2 L 3 L 4 L 5 L 6 L 7 L 8 R 1 R 2 R 4 R 5 As defined in any embodiment of the present invention.

[0269] In some embodiments, the compound is selected from the structure shown in formula (III-5).

[0270] Among them, ring I, ring W, ring V, ring E, ring F, ring G, w, v, e, f, g, m, R W R V R E R F R G L 1 L 2 L 3 L 4 L 6 L 7 L 8 R 1 R 2 R 3 R 4 R 5 As defined in any embodiment of the present invention.

[0271] In some embodiments, the compound is selected from the structures shown in formula (III-5A), formula (III-5B), and formula (III-5C).

[0272] Among them, rings V, E, F, I, G, v, e, f, g, m, and R V R E R F R G L 1 L 2 L 3 L 4 L 5 L 6 L 7 L 8 R 1 R 2 R 3 R 4 R 5 t 3 and t 4 As defined in any embodiment of the present invention.

[0273] In some implementations, structural units Selected from Preferred More preferably Among them, * end and L 2 Connected.

[0274] In some embodiments, the compound is selected from the structure shown in formula (III-6).

[0275] Among them, rings W1, W2, V, E, F, G, w, v, e, f, g, m, and R W R V R E R F R G L 1 L 2 L 3 L 4 L 5 L 6 L 7 L 8 R 1 R 2 R 3 R 4 R 5 As defined in any embodiment of the present invention.

[0276] In some implementations, structural units for Among them, p4, p5, and p6 are each independently 0, 1, or 2, and p4 + p5 ≤ 2, * and L 2 Connected.

[0277] In some implementations, structural units Selected from *End and L 2 Connected.

[0278] In some embodiments, the compound is as shown in formula (V).

[0279] in,

[0280] Ring W, Ring V, Ring G, w, v, g, m, R W R V R G L, L 1 L 2 L 3 L 7 L 8 R 1 R 2 R 3 R 4 R 5 As defined in any embodiment of the present invention;

[0281] The condition is that when ring W is azircyclohexene, piperidinyl, or homopiperidinyl,

[0282] 1) L contains Wherein, the * end is connected to ring G; or,

[0283] 2)R 2 And one of the R W To form a ring with the atoms connected to it; or,

[0284] 3)R 3 And one of the R V It forms a ring with the atoms connected to it;

[0285] The rings E, F, I, and R E R F e, f are as defined in any embodiment of the present invention.

[0286] In some embodiments, when ring W is azacyclohexene, L contains The rings E, F, I, and R E R F e, f are as defined in any embodiment of the present invention.

[0287] In some embodiments, ring W is a 7-15 member spirocyclic heterocyclic group, preferably Where p1, p2, and p3 are each independently 0, 1, or 2, and p1 + p2 ≤ 2, * and L 2 Connected.

[0288] In some embodiments, the compound has the structure shown in formula (V-1).

[0289] Among them, rings V, G, v, g, m, and R V R G L, L 1 L 2 L 3 L 7 L 8 R 1 R 2 R 3 R 4 R 5 p1, p2 and p3 are as defined in any embodiment of the present invention.

[0290] In some implementations, Selected from Preferred More preferably *End and L 2 Connected.

[0291] In some embodiments, the compound is selected from the compounds shown in Table A:

[0292] Table A

[0293] In some embodiments, the compound is selected from the compounds shown in Table B:

[0294] Table B

[0295] A second aspect of the present invention provides a compound, or a stereoisomer thereof, or a tautomer thereof, or a solvate thereof, or an isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof, wherein the compound comprises the structure shown in formula (M1).

[0296] in,

[0297] Ring W, Ring V, w, v, R W R V L 1 L 2 L 3 R 1 R 2 R 3 and R 4 As defined in any embodiment of the present invention;

[0298] The condition is that when ring W is azircyclohexene, piperidinyl, or homopiperidinyl, R 2 And one of the R W It forms a ring with the adjacent atoms, or, R 3 And one of the R V It forms a ring with the atoms connected to it.

[0299] In some implementations, when ring W is a 6-membered monocyclic heterocyclic group, R 2 And one of the R W It forms a ring with the adjacent atoms, or, R 3 And one of the R V It forms a ring with the atoms connected to it.

[0300] In some embodiments, the compound is as shown in formula (M2).

[0301] in,

[0302] Ring W, Ring V, w, v, R W R V L 1 L 2 L 3 R 1 R 2 R 3 and R 4 As defined in any embodiment of the present invention,

[0303] R M Selected from H, halogens, and reactive boric acid groups.

[0304] In some implementations, R M Selected from H, F, Cl and

[0305] In some implementations, R M For Cl and

[0306] In some embodiments, the compound is selected from the compounds shown in Table C:

[0307] Table C

[0308] The third aspect of the invention provides the use of the compounds described in the second aspect of the invention, or their stereoisomers, tautomers, solvates, isotopically labeled compounds, or pharmaceutically acceptable salts thereof, in the preparation of the compounds described in the first aspect of the invention, or their stereoisomers, tautomers, solvates, isotopically labeled compounds, or pharmaceutically acceptable salts thereof.

[0309] A fourth aspect of the invention provides a pharmaceutical composition comprising the compound described in the first aspect of the invention, or a stereoisomer thereof, or a tautomer thereof, or a solvate thereof, or an isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers and / or excipients.

[0310] The fifth aspect of the invention provides the use of the compounds described in the first aspect of the invention, or their stereoisomers, tautomers, or solvates, or their isotopically labeled compounds, or their pharmaceutically acceptable salts, or the pharmaceutical compositions described in the fourth aspect of the invention, in the preparation of medicaments for treating and / or preventing diseases.

[0311] The fifth aspect of the invention also provides the compounds described in the first aspect of the invention, or their stereoisomers, tautomers, or solvates, or their isotopically labeled compounds, or their pharmaceutically acceptable salts, or the pharmaceutical compositions described in the fourth aspect of the invention, for the treatment and / or prevention of diseases.

[0312] The fifth aspect of the invention also provides a method for treating and / or preventing disease, comprising administering to an individual in need an effective amount of the compound of the first aspect of the invention, or a stereoisomer thereof, or a tautomer thereof, or a solvate thereof, or an isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the fourth aspect of the invention.

[0313] In some implementations, the disease is a STAT6-mediated disease.

[0314] In some embodiments, the disease is selected from allergic diseases (e.g., asthma, dermatitis, rhinitis, eczema), autoimmune diseases (e.g., multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus), cancers (e.g., lymphoma and solid tumors), fibrotic diseases, and any combination thereof.

[0315] A sixth aspect of the present invention provides a method for preparing the compound described in the first aspect of the present invention, or its stereoisomer, tautomer, solvate, isotopically labeled compound, or pharmaceutically acceptable salt thereof, comprising:

[0316] Among them, rings W, V, w, v, and R W R V L, L 1 L 2 L 3 R 1 R 3 R 4 LBM is as defined in any embodiment of the present invention;

[0317] or

[0318] Among them, rings W, V, E, F, G, w, v, e, f, g, m, and R W R V R E R F R G L 1 L 2 L 3 L 4 L 5 L 6 L 7 L 8 R 1 R 2 R 3 R 4 R 5 As defined in any embodiment of the present invention;

[0319] or,

[0320] Among them, rings V, E, F, G, v, e, f, g, m, and R V R E R F R G L 1 L 2 L 3 L 4 L 5 L 6 L 7 L 8 R 1 R 2 R 3 R 4 R 5p1, p2, and p3 are as defined in any embodiment of the present invention;

[0321] or,

[0322] III-5A-e was prepared using either method one or method two.

[0323] Method 1:

[0324] Method 2:

[0325] L 6a Selected from -C(=O)C 1-6 alkylene-;

[0326] Ring V, Ring E, Ring F, Ring G, Ring I, v, e, f, g, m, R V R E R F R G L 1 L 2 L 3 L 4 L 5 L 6 L 7 L 8 R 1 R 2 R 3 R 4 R 5 p1, p2, and p3 are as defined in any embodiment of the present invention.

[0327] In some implementations, III-a is obtained by the following method:

[0328] Among them, L 6a Selected from -C(=O)C 1-6 alkylene-;

[0329] Rings E, F, G, e, f, g, m, R E R F R G L 4 L 5 L 6 L 7 L 8 R 5 As defined in any embodiment of the present invention.

[0330] In some implementations, III-5A-a2 is obtained by the following method:

[0331] Among them, ring I contains O atoms, and rings E, F, I, e, f, and R... E R F L 4 As defined in any embodiment of the present invention.

[0332] Terminology Definition

[0333] In this application, unless otherwise stated, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. Furthermore, to better understand this application, definitions and explanations of relevant terms are provided below.

[0334] When the terms “for example,” “such as,” or variations thereof are used in this document, these terms will not be considered restrictive terms but will be interpreted as meaning “including but not limited to” or “not limited to.”

[0335] When this document uses the terms “including,” “contains,” or variations thereof, it also provides the meanings of the terms “consisting of” and “substantially composed of.”

[0336] Unless otherwise specified herein or clearly contradicted by the context, the terms “an” and “a kind” as well as “the” and similar designations shall be interpreted to cover both the singular and the plural in the context of describing the invention (especially in the context of the following claims).

[0337] As used in this application, the term "and / or" should be considered as a specific disclosure of each of two or more specified features or elements, and any combination of two or more features or elements. Therefore, the term "and / or" as used in phrases, such as "A and / or B" herein, is intended to include "A and B", "A or B", "A" (alone), and "B" (alone).

[0338] As used in this application, the term "stereoisomer" refers to an isomer formed by at least one asymmetric center. In compounds having one or more (e.g., 1, 2, 3, or 4) asymmetric centers, racemic mixtures, single enantiomers, diastereomer mixtures, and individual diastereomers can be produced. Specific individual molecules may also exist as geometric isomers (cis / trans).

[0339] Similarly, the compounds of this application may exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that the scope of this application covers all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0340] Unless otherwise stated, the compounds of this application may exist as stereoisomers (including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, trans-blocking isomers, and mixtures thereof). The compounds of this application may exhibit more than one type of isomerism and may consist of mixtures thereof (e.g., racemic mixtures and diastereomer pairs).

[0341] The compounds of this invention may exist as solvates (such as hydrates), wherein the compounds of this application contain a solvent, such as water, methanol, or ethanol, as a structural element of the compound's crystal lattice. The amount of the solvent may be stoichiometric or non-stoichiometric.

[0342] As used herein, the term "isotope-labeled compound" refers to a compound in which one or more atoms are replaced by atoms of the same number but with a different atomic mass or mass number than the dominant atomic mass or mass number found in nature. Examples of isotopes suitable for inclusion in compounds of this application include, but are not limited to, hydrogen isotopes such as... 2 H, 3 H; carbon isotopes, for example 11 C, 13 C and 14 C; Chlorine isotopes, for example 36 Cl; fluorine isotopes, for example 18 F; Iodine isotopes, for example 123 I and 125 I; nitrogen isotopes, for example 13 N and 15 N; oxygen isotopes, for example 15 O, 17 O and 18 O; and sulfur isotopes such as 35 S.

[0343] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of the compounds of the present invention that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. Such salts include salts that have undergone acid addition reactions with inorganic or organic acids, or salts containing acidic protons present on the parent compound but surrounded by metal ions, or salts that have formed coordination reactions with organic bases. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed by amino groups with inorganic or organic acids, or salts formed using other methods used in the art (e.g., ion exchange). Salts derived from suitable bases include alkali metals, alkaline earth metals, and ammonium salts. Where appropriate, other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using, for example, relative ions of an acid radical. Pharmaceutically acceptable salts are also intended to encompass half-salts, wherein the compound:acid ratio is 2:1.

[0344] As used in this application, “selected from bond” means that the groups on both sides of the variable are directly connected, for example, ALB, where ALB is AB when L is a bond.

[0345] As used in this application, the term "optionally substituted with" means that the group may be unsubstituted or substituted with a substituent, for example, "C..." 1-6 "Alkyl optional halogen substitution" indicates C 1-6 Alkyl groups can be unsubstituted or substituted with halogens to yield haloalkyl groups. It should be understood that when stating "R is selected from C...", the expression "R is selected from C..." is considered appropriate. 1-6 Alkyl, -OC 1-6 Alkyl and -NH-C 1-6 Alkyl, the C 1-6 When "alkyl groups are optionally substituted with halogens", it indicates that C 1-6 Alkyl, -OC 1-6 Alkyl and -NH-C 1-6 C in alkyl 1-6 Alkyl groups are optionally substituted with halogens. It should be understood that -N-(C 1-6 Alkyl)2 indicates that two carbon atoms are attached to the nitrogen atom. 1-6 Alkyl groups, which can be the same or different.

[0346] As used in this application, the term "substitution" means that the group itself is replaced by the corresponding group, for example, in A-CH2-B, -CH2- is replaced by -NH-, thus obtaining A-NH-B.

[0347] As used herein, unless otherwise expressly indicated, the descriptive phrase “...each independently selected” used throughout may mean either that the specific options expressed by the same or different symbols in different groups do not affect each other, or that the specific options expressed by the same or different symbols in the same group do not affect each other.

[0348] As used in this application, the term "alkyl" refers to a straight-chain or branched monovalent saturated hydrocarbon group, such as C10. 1-6 Alkyl groups refer to those having 1 to 6 carbon atoms, such as 1, 2, 3, 4, 5, or 6 carbon atoms. The C... 1-6 Alkyl groups include C 1-5 Alkyl, C 1-4 Alkyl groups, etc. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, etc., wherein the propyl group includes n-propyl and isopropyl, and the butyl group includes n-butyl, isobutyl, and neobutyl.

[0349] As used in this application, the term "alkenyl" refers to a straight-chain or branched unsaturated hydrocarbon group containing at least one double bond. 2-6 Alkenyl groups refer to those having 2 to 6 (e.g., 2, 3, 4, 5, or 6) carbon atoms, including C. 2-5 alkenyl, C 2-4 alkenyl, C 2-3 Alkenes, etc., and non-limiting examples include, but are not limited to, -CH=CH2, -CH=CH-CH=CH2 or -CH=C(CH)3-CH3.

[0350] As used in this application, the term "alkynyl" refers to a straight-chain or branched unsaturated hydrocarbon group containing at least one triple bond, such as C 2-6 Alkynyl groups refer to groups having 2 to 6 (e.g., 2, 3, 4, 5, or 6) carbon atoms, including C. 2-5 alkynyl group, C 2-4 alkynyl group, C 2-3 Alkyne groups, etc. Non-limiting examples of alkynyl groups include ethynyl or propynyl, etc.

[0351] As used in this application, the term "alkylene" refers to a divalent group formed by the loss of a hydrogen atom from an "alkyl" group, as defined above; the term "alkenylene" refers to a divalent group formed by the loss of a hydrogen atom from an "alken" group, as defined above; and the term "alkynylene" refers to a divalent group formed by the loss of a hydrogen atom from an "alkyn" group, as defined above.

[0352] As used in this application, the term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0353] As used in this application, the term "halogenated" refers to a modified group being substituted with one or more halogens, for example, substituted with 1, 2, 3, 4, 5, or 6 halogens. For example, "C 1-6"Halogenated alkyl" refers to C as defined above. 1-6 The alkyl group is substituted with one or more halogens, including but not limited to CF3, CHF2, or CF2CF3.

[0354] As used herein, the term "cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of carbon atoms. For example, C 3-10 The cycloalkyl group has 3 to 10 carbon atoms, such as 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, wherein the C 3-10 Cycloalkyl groups include C 3-8 cycloalkyl, C 3-6 cycloalkyl, C 6-8 Cycloalkyl groups, etc. The cycloalkyl groups include monocyclic, bicyclic, or polycyclic rings, including spirocyclic, fused, or bridged rings, and including monovalent, divalent, or polyvalent groups. Non-limiting examples of cycloalkyl groups include cyclohexyl, cycloheptyl, adamantyl, etc.

[0355] As used herein, the term "cycloalkenyl" refers to a partially unsaturated cyclic hydrocarbon group consisting of carbon atoms. For example, C 5-12 The cycloalkenyl group has 5 to 12 carbon atoms, such as 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, wherein the C 5-12 Cycloalkenyl groups include C 5-8 Cycloalkenyl, C 6-12 Cycloalkenyl, C 6-10 Cycloalkenyl, C 6-8 Cycloalkenyl groups, etc. The cycloalkenyl groups include monocyclic, bicyclic, or polycyclic rings, including spirocyclic, fused, or bridged rings, and including monovalent, divalent, or polyvalent groups. Examples include, but are not limited to, cyclohexenyl and hexahydronaphthyl.

[0356] As used herein, the term "heterocyclic group" refers to a saturated or partially unsaturated cyclic group composed of ring atoms, wherein 1, 2, 3, or 4 ring atoms are heteroatoms, and the remainder are carbon atoms; preferably, the heteroatoms are selected from N, O, or S, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized. For example, a 5-12 membered heterocyclic group refers to a group composed of 5-12 ring atoms, including 5-10 membered heterocyclic groups, 5-7 membered heterocyclic groups, 4-8 membered heterocyclic groups, 4-6 membered heterocyclic groups, etc. The heterocyclic group includes monocyclic, bicyclic, or polycyclic rings, including spirocyclic, fused, or bridged rings, including heterocyclic alkyl and heterocyclic alkenyl groups, including monovalent, divalent, or polyvalent groups. The term "heterocyclic alkyl" refers to a saturated cyclic group composed of ring atoms, wherein 1, 2, 3, or 4 ring atoms are heteroatoms, and the remainder are carbon atoms. The term "heterocyclic alkenyl" refers to a partially unsaturated cyclic group composed of ring atoms, wherein one, two, three, or four ring atoms are heteroatoms, and the remainder are carbon atoms. Examples include, but are not limited to, oxocyclic butyl, azircyclic butyl, pyrrolidinyl, piperidinyl, piperazine, morpholinyl, and azircyclic hexenyl. The term "azircyclic alkenyl" means that at least one heteroatom in the heterocyclic group is a nitrogen atom, and examples include, but are not limited to, […].

[0357] As used in this application, the term "partially unsaturated" refers to a ring system that is neither saturated (i.e., does not contain double bonds) nor completely unsaturated (i.e., contains the maximum possible number of double bonds). In other words, a partially unsaturated ring system contains at least one double bond, but not the maximum possible number of double bonds.

[0358] As used in this application, the term "aryl" refers to an unsaturated carbocyclic group having a conjugated π-electron system, such as C6- 10 The aryl group consists of 6 to 10 (e.g., 6, 7, 8, 9, or 10) carbon atoms. The aryl group includes monocyclic, bicyclic, or polycyclic rings, and includes monovalent, divalent, or polyvalent groups. Non-limiting examples include, but are not limited to, phenyl.

[0359] As used herein, the term "heteroaryl" refers to an unsaturated group consisting of ring atoms with a conjugated π-electron system, wherein 1, 2, 3, or 4 ring atoms are heteroatoms, and the remainder are carbon atoms; preferably, the heteroatoms are selected from N, O, or S, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized. For example, 5-10-membered heteroaryls consist of 5 to 10 (e.g., 5, 6, 7, 8, 9, or 10) ring atoms, including 5-9-membered, 9-10-membered, and 5-6-membered heteroaryls, etc. The heteroaryls include monocyclic, bicyclic, and polycyclic forms, such as aryl-heteroaryls and heteroaryl-heteroaryls, including monovalent, divalent, or polyvalent groups. Examples include, but are not limited to, imidazolyl, pyridinyl, quinolinyl, or isoquinolinyl groups, etc.

[0360] In this application, unless otherwise defined, the cyclic structure (e.g., aryl, cycloalkyl, heteroaryl, heterocyclic) includes monocyclic and non-monocyclic structures (e.g., bicyclic or polycyclic), and the non-monocyclic structure includes spirocyclic, fused ring, and bridged ring.

[0361] As used herein, the term "reactive boric acid group" refers to a boron-containing group through which a group (e.g., an aryl group) can be coupled to a halogenated group, such as...

[0362] In this application, unless otherwise stated, when a group has one or more connectable sites, any one or more sites of that group can be linked to other groups by chemical bonds. When the chemical bond connection is non-directional, it means that the chemical bond can be linked to any connectable site. For example, R represents W It can be connected only to ring W1, only to ring W2, or simultaneously to both ring W1 and ring W2; for example... R represents W It can be connected only to ring W3, only to ring W4, or both ring W3 and ring W4.

[0363] In this application, straight lines and wavy lines are used. The asterisk (*) and the definite article symbol (*) indicate connection points. The asterisks * and * have the same meaning and are interchangeable. Unless otherwise specified, the direction of connection between variables can be determined based on the general formula to which the variable belongs. Furthermore, for the same variables and their superordinate or subordinate ranges, the same connection symbol indicates the same connection point. For example, the structural unit can be determined based on the general formula. The wavy line at the end indicates the relationship with L. 4 Connected, the asterisk indicates that it is connected to L. 6 Connected, the lower-level range of this structural unit, for example The same connection symbol used for this structural unit indicates the same connection point, that is, the wavy line end indicates the connection with L. 4 Connected, the asterisk indicates that it is connected to L. 6 Connected; for example, based on the general formula, -L can be determined. 1 -L 2 The * end of -* indicates that it is connected to ring W. For its lower range -CH2CH2-, the * end also indicates that it is connected to ring W.

[0364] In this application, unless otherwise stated, when one or more variables are defined as defined in one or more embodiments, combinations of those one or more variables may also be covered as defined in this or these embodiments. For example, for equation (II), rings W, V, E, F, w, v, e, f, and R are defined.W R V R E R F L 1 L 2 L 3 L 4 L 5 L 6 R 1 R 2 R 3 and R 4 As defined in any embodiment of the present invention, these variables represent themselves and the structural units obtained by combining these variables, for example... It can also be defined as in any embodiment of the present invention.

[0365] As used herein, the term "pharmaceutically acceptable carrier and / or excipient" means a carrier and / or excipient that is pharmacologically and / or physiologically compatible with the subject and the active ingredient, and is well known in the art (see, for example, Remington's Pharmaceutical Sciences. Edited by Gennaro AR, 19th ed. Pennsylvania: Mack Publishing Company, 1995). Pharmaceutical carriers and / or excipients include, but are not limited to: pH adjusters, surfactants, ionic strength enhancers, diluents, agents for maintaining osmotic pressure, agents for delaying absorption, preservatives, and stabilizers.

[0366] As used in this application, the term "effective amount" refers to the amount of a compound that, when administered, will alleviate one or more symptoms of the treated condition to a certain extent.

[0367] As used herein, the term "treatment" aims to alleviate, reduce, improve, or eliminate a targeted disease state or symptom. A subject is successfully "treated" if, in accordance with the methods described herein, a therapeutic amount of the compound, its stereoisomer, its tautomer, its solvate, its isotopically labeled compound, its pharmaceutically acceptable salt, or the pharmaceutical composition thereof, and the subject exhibits an observable and / or detectable reduction or improvement in one or more indications and symptoms. It should also be understood that treatment of the disease state or symptom includes not only complete treatment but also the achievement of some biological or medically relevant outcome without achieving complete treatment.

[0368] As used in this application, the term "prevention" aims to avoid, reduce, prevent, or delay the onset of a disease or disease-related symptoms that have not yet appeared before the administration of the relevant drug. "Prevention" does not necessarily require the complete prevention of the onset of a disease or disease-related symptoms. For example, reducing the risk of a subject developing a specific disease or disease-related symptoms after the administration of the relevant drug, or lessening the severity of subsequently occurring related symptoms, can be considered as "prevention" of the onset or development of the disease. Beneficial effects

[0369] The compounds of this application can effectively degrade STAT6 and regulate the transcription of downstream genes, playing an important role in STAT6-mediated diseases such as immune regulation, inflammatory responses, cell proliferation, and differentiation. Exemplarily, the compounds of this application can effectively inhibit IL-13-induced TARC release, IL-13-induced CD23 expression, and IL-13-induced Periodin release, blocking IL-13-mediated downstream signaling pathways. Furthermore, the compounds of this application exhibit excellent pharmacokinetic properties, such as high in vivo exposure and good drug-likeness. In addition, the compounds of this application also have excellent safety performance, for example, no significant inhibitory effect on the CYP450 enzyme 2C9 isoform. Detailed Implementation

[0370] The embodiments of the present invention will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be considered as limiting the scope of the invention. Unless otherwise specified in the examples, conventional conditions or conditions recommended by the manufacturer are followed. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products.

[0371] I. Compound Examples

[0372] The structure of the compound was determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). Chemical shift δ is expressed in terms of 10⁻⁶. -6 The measurements are given in ppm. NMR measurements were performed using a Bruker NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0373] LCMS measurements were performed using an Agilent 1260 Infinity II (ESI) mass spectrometer, a Waters UPLC H Class plus (ESI) or a Shimadzu LCMS-2020 (ESI).

[0374] High-performance liquid chromatography (HPLC) analysis was performed using an Agilent 1260 or a Shimadzu LC-20AD.

[0375] Preparative high-performance liquid chromatography (pre-HPLC) uses a GILSON GX-281 or an Agilent 1260 Infinity II preparative liquid chromatograph.

[0376] Chiral preparations were performed using supercritical fluid chromatography (SFC) with a Shimadzu LC-30Adsf or Shimadzu LC-20AD instrument.

[0377] The silica gel plates used for thin-layer chromatography are GF254 acrylic adhesive silica gel plates from Anhui Liangchen Silicon Source Materials Co., Ltd. The silica gel plates used in thin-layer chromatography (TLC) are 0.2 mm in diameter, while the silica gel plates used for thin-layer chromatography separation and purification are 0.5 mm in diameter.

[0378] Column chromatography typically uses 200-300 mesh silica gel from Anhui Liangchen Silicon Source Materials Co., Ltd. as a carrier.

[0379] DC 50 (HiBiT technology) and ICs 50 The values ​​were measured using a SpectraMax i3X microplate reader (MD, Inc., USA).

[0380] DC 50 The determination (MSD technique) was performed using an ultrasensitive multifactor electrochemiluminescence analyzer (Quick Plex SQ120 MM, MSD).

[0381] The known starting materials disclosed herein can be synthesized using or in accordance with methods known in the art, or can be purchased from companies such as Bid Pharmaceuticals, Leyan, Shaoyuan Chemical Technology, and Anaiji Chemicals.

[0382] Unless otherwise specified, all reactions in the following examples were carried out under an argon or nitrogen atmosphere.

[0383] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0384] A hydrogen atmosphere refers to a reaction vessel connected to a hydrogen balloon with a volume of approximately 1L.

[0385] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0386] An oxygen atmosphere refers to a reaction flask connected to an oxygen balloon with a volume of approximately 1L.

[0387] Unless otherwise specified in the following examples, the solution refers to an aqueous solution, and the reaction temperature is room temperature, which is 20℃-30℃.

[0388] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system used for column chromatography to purify the compounds, and the developing solvent system for TLC included: A: dichloromethane / methanol system, B: petroleum ether / ethyl acetate system. The volume ratio of the solvent was adjusted according to the polarity of the compounds, and small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0389] Example 1-1: Preparation of Compound 1

[0390] Step 1

[0391] At -10°C, a solution of 1-1 (1.97 g, 10.00 mmol, synthetic method referred to ACS Omega (2019), 4(4), 7498-7515) in N,N-dimethylformamide (5 mL) was added dropwise to a suspension of sodium hydride (600 mg, 60%, 15.00 mmol) in tetrahydrofuran (30 mL). The resulting mixture was stirred at 0°C for 30 minutes, and then propargyl bromide (1.78 g, 15.00 mmol) was added dropwise. After the addition was complete, the mixture was heated to 25°C and stirred for 16 hours. The reaction solution was slowly poured into ice water (50 mL), extracted with ethyl acetate (40 mL * 3), and the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by vacuum distillation. The residue was purified by silica gel column chromatography to give product 1-2 (1.29 g, yield: 55%).

[0392] MS m / z(ESI):236.2[M+1].

[0393] Step Two

[0394] Dissolve 1-2 (1.25 g, 5.31 mmol) in dry toluene (13 mL). Under an argon atmosphere, cuprous chloride (53 mg, 0.53 mmol), pinacol diborate (1.48 g, 5.83 mmol), tri-tert-butylphosphine tetrafluoroborate (184 mg, 0.64 mmol), and sodium tert-butoxide (51 mg, 0.53 mmol) are added sequentially. Then, methanol (425 μL, 10.49 mmol) is slowly added dropwise to the stirred reaction mixture. The resulting mixture is stirred at 25 °C for 2 hours. The reaction mixture is filtered, and the filtrate is concentrated by vacuum distillation. The residue is purified by silica gel column chromatography to give product 1-3 (945 mg, yield: 49%).

[0395] MS m / z(ESI): 364.3 [M+1].

[0396] Step 3

[0397] Dissolve 1-3 (940 mg, 2.59 mmol) in dry dichloromethane (30 mL) and reflux under nitrogen atmosphere for 1 hour. Cool the reaction solution to 25 °C, then add Grubbs second-generation catalyst (398 mg, 0.47 mmol). Stir the resulting mixture at 25 °C for 16 hours. Filter the reaction solution, concentrate the filtrate by vacuum distillation, and purify the residue by silica gel column chromatography to give product 1-4 (469 mg, yield: 54%).

[0398] MS m / z(ESI): 336.3 [M+1].

[0399] Step Four

[0400] Product 1-4 (460 mg, 1.37 mmol) was added to an ethyl acetate hydrochloride solution (4 mol / L, 6 mL), and the resulting mixture was stirred at 25 °C for 1 hour. The reaction solution was then concentrated under reduced pressure to give product 1-5 (385 mg).

[0401] MS m / z(ESI):236.2[M+1].

[0402] Step 5

[0403] Dissolve 1-6 (168 mg, 1.20 mmol) in dry pyridine (2 mL), and add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (277 mg, 1.44 mmol) and 1-5 (359 mg, 1.32 mmol) sequentially under a nitrogen atmosphere. The resulting mixture is stirred at 25 °C for 5 hours. The reaction solution is directly concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give product 1-7 (321 mg, yield: 75%).

[0404] MS m / z(ESI): 358.4 [M+1].

[0405] Step Six

[0406] 1-7 (320 mg, 0.89 mmol), 1-8 (286 mg, 0.89 mmol, synthetic method referred to WO2025049820A1), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (130 mg, 0.18 mmol), and potassium carbonate (368 mg, 2.67 mmol) were added sequentially to a mixed solution of 1,4-dioxane (4 mL) and water (1 mL). The resulting mixture was heated to 80 °C and stirred for 12 hours under a nitrogen atmosphere. After the reaction solution was cooled to room temperature, water (15 mL) was added, and the mixture was extracted with ethyl acetate (15 mL * 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by vacuum distillation. The residue was purified by high performance liquid chromatography to obtain product 1-9 (159 mg, yield: 39%).

[0407] MS m / z(ESI): 470.2 [M+1].

[0408] Step Seven

[0409] Dissolve 1-9 (155 mg, 0.33 mmol) in dimethyl sulfoxide (3 mL), then add pinacol diboronate (167 mg, 0.66 mmol), potassium acetate (97 mg, 0.99 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (56 mg, 66 μmol) sequentially. The resulting mixture is heated to 80 °C and stirred for 12 hours under a nitrogen atmosphere. The reaction solution is then directly concentrated under reduced pressure, and the residue is analyzed by high-performance liquid chromatography to obtain product 1-10 (39 mg, yield: 21%).

[0410] MS m / z(ESI): 562.3 [M+1].

[0411] Step 8

[0412] 1-10 (39 mg, 69 μmol), 1-11 (37 mg, 69 μmol, synthetic method referred to WO2025049820 A1), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (10 mg, 14 μmol), and potassium carbonate (29 mg, 0.21 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 80 °C and stirred for 12 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high performance liquid chromatography to obtain product 1 (4.2 mg, yield: 7%).

[0413] MS m / z(ESI): 882.4 [M+1].

[0414] 1 H NMR(400MHz,DMSO-d6)δ12.20(s,1H),10.84(s,1H),7.68–7.65(m,1H),7.64–7.60(m,2H ),7.47–7.42(m,2H),7.10–7.02(m,2H),7.02–6.95(m,2H),6.91–6.85(m,1H),6.23–6.1 6(m,1H),6.14–6.06(m,1H),4.44–4.27(m,2H),3.91–3.74(m,1H),3.61–3.41(m,2H),3. 33(s,6H),3.28–2.99(m,10H),2.88–2.62(m,6H),2.34–2.13(m,1H),2.09–1.81(m,5H).

[0415] Examples 1-2: Preparation of Compound 2

[0416] Step 1

[0417] At -10°C, a solution of 2-1 (10 g, 47.32 mmol, synthetic method referred to Chemical Science (2020), 11(31), 8167-8175) in N,N-dimethylformamide (25 mL) was added dropwise to a suspension of sodium hydride (2.84 g, 60%, 70.98 mmol) in tetrahydrofuran (150 mL). The resulting mixture was stirred at 0°C for 30 minutes, and then propargyl bromide (8.42 g, 70.98 mmol) was added dropwise. After the addition was complete, the mixture was heated to 25°C and stirred for 16 hours. The reaction solution was slowly poured into ice water (300 mL), extracted with ethyl acetate (300 mL * 3), and the combined organic phases were washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by vacuum distillation. The residue was purified by silica gel column chromatography to obtain product 2-2 (5.66 g, yield: 48%).

[0418] MS m / z(ESI):250.2[M+1].

[0419] Step Two

[0420] Dissolve 2-2 (5.60 g, 22.45 mmol) in dry toluene (60 mL). Under an argon atmosphere, cuprous chloride (224 mg, 2.24 mmol), pinacol diborate (6.26 g, 24.64 mmol), tri-tert-butylphosphine tetrafluoroborate (778 mg, 2.70 mmol), and sodium tert-butoxide (215 mg, 2.24 mmol) are added sequentially. Then, methanol (1.82 mL, 44.90 mmol) is slowly added dropwise to the stirred reaction mixture. The resulting mixture is stirred at 25 °C for 2 hours. The reaction mixture is filtered, and the filtrate is concentrated by vacuum distillation. The residue is purified by silica gel column chromatography to give product 2-3 (3.47 g, yield: 41%).

[0421] MS m / z(ESI): 378.3 [M+1].

[0422] Step 3

[0423] Dissolve 2-3 (3.45 g, 9.14 mmol) in dry dichloromethane (100 mL) and reflux under nitrogen atmosphere for 1 hour. Cool the reaction solution to 25 °C, then add Grubbs second-generation catalyst (1.41 g, 1.66 mmol). Stir the resulting mixture at 25 °C for 16 hours. Filter the reaction solution, concentrate the filtrate by vacuum distillation, and purify the residue by silica gel column chromatography to give product 2-4 (1.53 g, yield: 48%).

[0424] MS m / z(ESI): 350.3 [M+1].

[0425] Step Four

[0426] Product 2-4 (1.50 g, 4.28 mmol) was added to an ethyl acetate hydrochloride solution (4 mol / L, 20 mL), and the resulting mixture was stirred at 25 °C for 1 hour. The reaction solution was then concentrated under reduced pressure to give product 2-5 (1.26 g).

[0427] MS m / z(ESI):250.2[M+1].

[0428] Step 5

[0429] Dissolve 1-6 (550 mg, 3.92 mmol) in dry pyridine (10 mL), and add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (903 mg, 4.71 mmol) and 2-5 (1.23 g, 4.31 mmol) sequentially under a nitrogen atmosphere. The resulting mixture is stirred at 25 °C for 5 hours. The reaction solution is directly concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give product 2-6 (917 mg, yield: 63%).

[0430] MS m / z(ESI): 372.3 [M+1].

[0431] Step Six

[0432] 2-6 (910 mg, 2.45 mmol), 1-8 (783 mg, 2.45 mmol, synthetic method referred to WO2025049820A1), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (358 mg, 0.49 mmol), and potassium carbonate (1.01 g, 7.35 mmol) were added sequentially to a mixed solution of 1,4-dioxane (8 mL) and water (2 mL). The resulting mixture was heated to 80 °C and stirred for 12 hours under a nitrogen atmosphere. After the reaction solution was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL * 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by vacuum distillation. The residue was purified by high performance liquid chromatography to obtain product 2-7 (415 mg, yield: 35%).

[0433] MS m / z(ESI):484.2[M+1].

[0434] Step Seven

[0435] 2-7 (410 mg, 0.84 mmol) was dissolved in dimethyl sulfoxide (5 mL), followed by the sequential addition of pinacol diborate (429 mg, 1.69 mmol), potassium acetate (247 mg, 2.52 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (142 mg, 168 μmol). The resulting mixture was heated to 80 °C and stirred for 12 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was subjected to high-performance liquid chromatography (HPLC) to prepare product 2-8 (121 mg, yield: 25%).

[0436] MS m / z(ESI): 576.4 [M+1].

[0437] Step 8

[0438] 2-8 (50 mg, 86 μmol), 1-11 (46 mg, 86 μmol, synthetic method referred to WO2025049820 A1), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (13 mg, 18 μmol), and potassium carbonate (35 mg, 0.26 mmol) were added sequentially to a mixed solution of 1,4-dioxane (4 mL) and water (1 mL). The resulting mixture was heated to 80 °C and stirred for 12 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high performance liquid chromatography to obtain product 2 (5.5 mg, yield: 7%).

[0439] MS m / z(ESI): 896.4 [M+1].

[0440] Examples 1-3: Preparation of Compound 3

[0441] Step 1

[0442] At -10°C, a solution of 3-1 (10 g, 47.32 mmol, synthetic method referred to WO2021113506 A1) in N,N-dimethylformamide (25 mL) was added dropwise to a suspension of sodium hydride (2.84 g, 60%, 70.98 mmol) in tetrahydrofuran (150 mL). The resulting mixture was stirred at 0°C for 30 minutes, and then propargyl bromide (8.42 g, 70.98 mmol) was added dropwise. After the addition was complete, the mixture was heated to 25°C and stirred for 16 hours. The reaction solution was slowly poured into ice water (300 mL), extracted with ethyl acetate (300 mL * 3), and the combined organic phases were washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by vacuum distillation. The residue was purified by silica gel column chromatography to give product 3-2 (6.83 g, yield: 58%).

[0443] MS m / z(ESI):250.2[M+1].

[0444] Step Two

[0445] Dissolve 3-2 (6.80 g, 27.27 mmol) in dry toluene (70 mL). Under an argon atmosphere, cuprous chloride (270 mg, 2.73 mmol), pinacol diborate (7.62 g, 30.00 mmol), tri-tert-butylphosphine tetrafluoroborate (943 mg, 3.27 mmol), and sodium tert-butoxide (262 mg, 2.73 mmol) are added sequentially. Then, methanol (2.21 mL, 54.54 mmol) is slowly added dropwise to the stirred reaction mixture. The resulting mixture is stirred at 25 °C for 2 hours. The reaction mixture is filtered, and the filtrate is concentrated by vacuum distillation. The residue is purified by silica gel column chromatography to give product 3-3 (4.53 g, yield: 44%).

[0446] MS m / z(ESI): 378.3 [M+1].

[0447] Step 3

[0448] Dissolve 3-3 (4.50 g, 11.92 mmol) in dry dichloromethane (120 mL) and reflux under nitrogen atmosphere for 1 hour. Cool the reaction solution to 25 °C, then add Grubbs second-generation catalyst (1.84 g, 2.16 mmol). Stir the resulting mixture at 25 °C for 16 hours. Filter the reaction solution, concentrate the filtrate by vacuum distillation, and purify the residue by silica gel column chromatography to give product 3-4 (2.12 g, yield: 51%).

[0449] MS m / z(ESI): 350.3 [M+1].

[0450] Step Four

[0451] Add 3-4 (2.10 g, 6.01 mmol) to an ethyl acetate hydrochloride solution (4 mol / L, 30 mL), and stir the resulting mixture at 25 °C for 1 hour. The reaction solution was then concentrated under reduced pressure to give product 3-5 (1.78 g).

[0452] MS m / z(ESI):250.2[M+1].

[0453] Step 5

[0454] Dissolve 1-6 (650 mg, 4.63 mmol) in dry pyridine (10 mL), and add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.07 g, 5.57 mmol) and 3-5 (1.46 g, 5.09 mmol) sequentially under a nitrogen atmosphere. The resulting mixture is stirred at 25 °C for 5 hours. The reaction solution is directly concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give product 3-6 (1.15 g, yield: 67%).

[0455] MS m / z(ESI): 372.3 [M+1].

[0456] Step Six

[0457] 3-6 (1.10 g, 2.96 mmol), 1-8 (946 mg, 2.96 mmol, synthetic method referred to WO2025049820A1), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (432 mg, 0.59 mmol), and potassium carbonate (1.22 g, 8.88 mmol) were added sequentially to a mixed solution of 1,4-dioxane (12 mL) and water (3 mL). The resulting mixture was heated to 80 °C and stirred for 12 hours under a nitrogen atmosphere. After the reaction solution was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL * 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by vacuum distillation. The residue was purified by high performance liquid chromatography to obtain product 3-7 (473 mg, yield: 33%).

[0458] MS m / z(ESI):484.2[M+1].

[0459] Step Seven

[0460] Dissolve 3-7 (470 mg, 0.97 mmol) in dimethyl sulfoxide (5 mL), then add pinacol diboronate (493 mg, 1.94 mmol), potassium acetate (285 mg, 2.91 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (164 mg, 194 μmol) sequentially. The resulting mixture is heated to 80 °C and stirred for 12 hours under a nitrogen atmosphere. The reaction solution is then directly concentrated under reduced pressure, and the residue is analyzed by high-performance liquid chromatography (HPLC) to obtain product 3-8 (162 mg, yield: 29%).

[0461] MS m / z(ESI): 576.4 [M+1].

[0462] Step 8

[0463] 3-8 (50 mg, 86 μmol), 1-11 (46 mg, 86 μmol, synthetic method referred to WO2025049820 A1), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (13 mg, 18 μmol), and potassium carbonate (35 mg, 0.26 mmol) were added sequentially to a mixed solution of 1,4-dioxane (4 mL) and water (1 mL). The resulting mixture was heated to 80 °C and stirred for 12 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high performance liquid chromatography to obtain product 3 (6.8 mg, yield: 9%).

[0464] MS m / z(ESI): 896.4 [M+1].

[0465] 1 H NMR (400MHz, DMSO-d6) δ12.30–12.01(m,1H),10.86(s,1H),7.71–7.49(m,1H),7.43–7.25(m,2H),7.22–6.89(m, 2H),6.73(d,J=8.0Hz,1H),6.69–6.64(m,1H),6.60(d,J=14.2Hz,1H),6.21–6.05(m,1H),5.91–5.78(m,1H),4.5 5–4.37(m,2H),4.37–4.16(m,4H),3.83(s,3H),3.48(d,J=30.1Hz,2H),3.37–3.27(m,5H),3.25–2.99(m,8H),2. 99–2.90(m,1H),2.90–2.70(m,2H),2.68–2.54(m,1H),2.36–2.07(m,3H),2.03–1.88(m,1H),0.66–0.43(m,4H).

[0466] Examples 1-4: Preparation of Compound 4

[0467] Step 1

[0468] At -10°C, a solution of 4-1 (10 g, 47.32 mmol, synthetic method referred to WO2023275199 A1) in N,N-dimethylformamide (25 mL) was added dropwise to a suspension of sodium hydride (2.84 g, 60%, 70.98 mmol) in tetrahydrofuran (150 mL). The resulting mixture was stirred at 0°C for 30 minutes, and then propargyl bromide (8.42 g, 70.98 mmol) was added dropwise. After the addition was complete, the mixture was heated to 25°C and stirred for 16 hours. The reaction solution was slowly poured into ice water (300 mL), extracted with ethyl acetate (300 mL * 3), and the combined organic phases were washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by vacuum distillation. The residue was purified by silica gel column chromatography to give product 4-2 (6.12 g, yield: 52%).

[0469] MS m / z(ESI):250.2[M+1].

[0470] Step Two

[0471] Dissolve 4-2 (6.10 g, 24.46 mmol) in dry toluene (70 mL). Under an argon atmosphere, cuprous chloride (242 mg, 2.44 mmol), pinacol diborate (7.45 g, 29.35 mmol), tri-tert-butylphosphine tetrafluoroborate (846 mg, 2.93 mmol), and sodium tert-butoxide (235 mg, 2.45 mmol) are added sequentially. Then, methanol (1.98 mL, 48.92 mmol) is slowly added dropwise to the stirred reaction mixture. The resulting mixture is stirred at 25 °C for 2 hours. The reaction mixture is filtered, and the filtrate is concentrated by vacuum distillation. The residue is purified by silica gel column chromatography to give product 4-3 (4.52 g, yield: 49%).

[0472] MS m / z(ESI): 378.3 [M+1].

[0473] Step 3

[0474] 4-3 (4.50 g, 11.92 mmol) was dissolved in dry dichloromethane (120 mL), and the mixture was heated to reflux under a nitrogen atmosphere for 1 hour. The reaction solution was cooled to 25 °C, and then Grubbs second-generation catalyst (1.84 g, 2.16 mmol) was added. The resulting mixture was stirred at 25 °C for 16 hours. The reaction solution was filtered, and the filtrate was concentrated by vacuum distillation. The residue was purified by silica gel column chromatography to give product 4-4 (1.87 g, yield: 45%).

[0475] MS m / z(ESI): 350.3 [M+1].

[0476] Step Four

[0477] 4-4 (1.80 g, 4.77 mmol) was added to an ethyl acetate hydrochloride solution (4 mol / L, 25 mL), and the resulting mixture was stirred at 25 °C for 1 hour. The reaction solution was then directly concentrated under reduced pressure to give product 4-5 (1.41 g).

[0478] MS m / z(ESI):250.2[M+1].

[0479] Step 5

[0480] Dissolve 1-6 (600 mg, 4.28 mmol) in dry pyridine (10 mL), and add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (987 mg, 5.14 mmol) and 4-5 (1.35 g, 4.71 mmol) sequentially under a nitrogen atmosphere. The resulting mixture is stirred at 25 °C for 5 hours. The reaction solution is directly concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give product 4-6 (1.17 g, yield: 74%).

[0481] MS m / z(ESI): 372.3 [M+1].

[0482] Step Six

[0483] 4-6 (1.10 g, 2.96 mmol), 1-8 (946 mg, 2.96 mmol, synthetic method referred to WO2025049820A1), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (432 mg, 0.59 mmol), and potassium carbonate (1.22 g, 8.88 mmol) were added sequentially to a mixed solution of 1,4-dioxane (12 mL) and water (3 mL). The resulting mixture was heated to 80 °C and stirred for 12 hours under a nitrogen atmosphere. After the reaction solution was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL * 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by vacuum distillation. The residue was purified by high performance liquid chromatography to obtain product 4-7 (501 mg, yield: 35%).

[0484] MS m / z(ESI):484.2[M+1].

[0485] Step Seven

[0486] 4-7 (500 mg, 1.03 mmol) was dissolved in dimethyl sulfoxide (6 mL), followed by the sequential addition of pinacol diborate (524 mg, 2.06 mmol), potassium acetate (303 mg, 3.09 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (174 mg, 206 μmol). The resulting mixture was heated to 80 °C and stirred for 12 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was subjected to high-performance liquid chromatography (HPLC) to prepare product 4-8 (130 mg, yield: 22%).

[0487] MS m / z(ESI): 576.4 [M+1].

[0488] Step 8

[0489] 4-8 (50 mg, 86 μmol), 1-11 (46 mg, 86 μmol, synthetic method referred to WO2025049820 A1), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (13 mg, 18 μmol), and potassium carbonate (35 mg, 0.26 mmol) were added sequentially to a mixed solution of 1,4-dioxane (4 mL) and water (1 mL). The resulting mixture was heated to 80 °C and stirred for 12 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high performance liquid chromatography to obtain product 4 (7.6 mg, yield: 10%).

[0490] MS m / z(ESI): 896.4 [M+1].

[0491] Examples 1-5: Preparation of Compound 5

[0492] Step 1

[0493] 5-1 (500 mg, 3.54 mmol) was dissolved in dry pyridine (7 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (815 mg, 4.25 mmol) and 4-5 (1.11 g, 3.89 mmol) were added sequentially under a nitrogen atmosphere. The resulting mixture was stirred at 25 °C for 5 hours. The reaction solution was directly concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give product 5-2 (761 mg, yield: 58%).

[0494] MS m / z(ESI): 373.3 [M+1].

[0495] Step Two

[0496] 5-2 (750 mg, 2.01 mmol), 1-8 (645 mg, 2.01 mmol, synthetic method referred to WO2025049820A1), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (295 mg, 0.40 mmol), and potassium carbonate (832 mg, 6.03 mmol) were added sequentially to a mixed solution of 1,4-dioxane (8 mL) and water (2 mL). The resulting mixture was heated to 80 °C and stirred for 12 hours under a nitrogen atmosphere. After the reaction solution was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL * 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by vacuum distillation. The residue was purified by high performance liquid chromatography to obtain product 5-3 (251 mg, yield: 35%).

[0497] MS m / z(ESI): 485.2 [M+1].

[0498] Step 3

[0499] 5-3 (250 mg, 0.51 mmol) was dissolved in dimethyl sulfoxide (4 mL), followed by the sequential addition of pinacol diborate (262 mg, 1.02 mmol), potassium acetate (150 mg, 1.53 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (87 mg, 103 μmol). The resulting mixture was heated to 80 °C and stirred for 12 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was subjected to high-performance liquid chromatography (HPLC) to prepare product 5-4 (65 mg, yield: 22%).

[0500] MS m / z(ESI): 577.4 [M+1].

[0501] Step Four

[0502] 5-4 (50 mg, 86 μmol), 1-11 (46 mg, 86 μmol, synthetic method referred to WO2025049820 A1), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (13 mg, 18 μmol), and potassium carbonate (35 mg, 0.26 mmol) were added sequentially to a mixed solution of 1,4-dioxane (4 mL) and water (1 mL). The resulting mixture was heated to 80 °C and stirred for 12 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high performance liquid chromatography to obtain product 5 (5.6 mg, yield: 7%).

[0503] MS m / z(ESI): 897.4 [M+1].

[0504] Examples 1-6: Preparation of Compound 6

[0505] Step 1

[0506] 5-1 (500 mg, 3.54 mmol) was dissolved in dry pyridine (7 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (815 mg, 4.25 mmol) and 2-5 (1.11 g, 3.89 mmol) were added sequentially under a nitrogen atmosphere. The resulting mixture was stirred at 25 °C for 5 hours. The reaction solution was directly concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give product 6-1 (485 mg, yield: 37%).

[0507] MS m / z(ESI): 373.3 [M+1].

[0508] Step Two

[0509] 6-1 (480 mg, 1.29 mmol), 1-8 (412 mg, 1.29 mmol, synthetic method referred to WO2025049820A1), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (190 mg, 0.26 mmol), and potassium carbonate (534 mg, 3.87 mmol) were added sequentially to a mixed solution of 1,4-dioxane (8 mL) and water (2 mL). The resulting mixture was heated to 80 °C and stirred for 12 hours under a nitrogen atmosphere. After the reaction solution was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL * 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by vacuum distillation. The residue was purified by high performance liquid chromatography to obtain product 6-2 (153 mg, yield: 24%).

[0510] MS m / z(ESI): 485.2 [M+1].

[0511] Step 3

[0512] 6-2 (150 mg, 0.31 mmol) was dissolved in dimethyl sulfoxide (3 mL), followed by the sequential addition of pinacol diboronate (157 mg, 0.62 mmol), potassium acetate (91 mg, 0.93 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (52 mg, 62 μmol). The resulting mixture was heated to 80 °C and stirred for 12 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high performance liquid chromatography to yield product 6-3 (42 mg, yield: 23%).

[0513] MS m / z(ESI): 577.4 [M+1].

[0514] Step Four

[0515] 6-3 (42 mg, 73 μmol), 1-11 (39 mg, 73 μmol, synthetic method referred to WO2025049820 A1), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (11 mg, 15 μmol), and potassium carbonate (30 mg, 0.22 mmol) were added sequentially to a mixed solution of 1,4-dioxane (4 mL) and water (1 mL). The resulting mixture was heated to 80 °C and stirred for 12 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high performance liquid chromatography to obtain product 6 (3.3 mg, yield: 5%).

[0516] MS m / z(ESI): 897.4 [M+1].

[0517] Examples 1-7: Preparation of Compound 7

[0518] Step 1

[0519] 5-1 (500 mg, 3.54 mmol) was dissolved in dry pyridine (7 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (815 mg, 4.25 mmol) and 3-5 (1.11 g, 3.89 mmol) were added sequentially under a nitrogen atmosphere. The resulting mixture was stirred at 25 °C for 5 hours. The reaction solution was directly concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give product 7-1 (552 mg, yield: 41%).

[0520] MS m / z(ESI): 373.3 [M+1].

[0521] Step Two

[0522] 7-1 (550 mg, 1.47 mmol), 1-8 (472 mg, 1.47 mmol, synthetic method referred to WO2025049820A1), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (217 mg, 0.30 mmol), and potassium carbonate (610 mg, 4.42 mmol) were added sequentially to a mixed solution of 1,4-dioxane (8 mL) and water (2 mL). The resulting mixture was heated to 80 °C and stirred for 12 hours under a nitrogen atmosphere. After the reaction solution was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL * 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by vacuum distillation. The residue was purified by high performance liquid chromatography to obtain product 7-2 (195 mg, yield: 40%).

[0523] MS m / z(ESI): 485.2 [M+1].

[0524] Step 3

[0525] 7-2 (195 mg, 0.40 mmol) was dissolved in dimethyl sulfoxide (4 mL), followed by the sequential addition of pinacol diboronate (206 mg, 0.80 mmol), potassium acetate (118 mg, 1.20 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (67 mg, 80 μmol). The resulting mixture was heated to 80 °C and stirred for 12 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high performance liquid chromatography to yield product 7-3 (36 mg, yield: 15%).

[0526] MS m / z(ESI): 577.4 [M+1].

[0527] Step Four

[0528] 7-3 (36 mg, 62 μmol), 1-11 (33 mg, 62 μmol, synthesis method referred to WO2025049820 A1), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (9 mg, 13 μmol), and potassium carbonate (26 mg, 0.19 mmol) were added sequentially to a mixed solution of 1,4-dioxane (4 mL) and water (1 mL). The resulting mixture was heated to 80 °C and stirred for 12 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high performance liquid chromatography to obtain product 7 (2.8 mg, yield: 5%).

[0529] MS m / z(ESI): 897.4 [M+1].

[0530] Examples 1-8: Preparation of Compound 8

[0531] Step 1

[0532] Methyltriphenylphosphine bromide (13.44 g, 37.63 mmol) was added to dry tetrahydrofuran (150 mL). Under nitrogen protection, the mixture was cooled to 0 °C, and then a tetrahydrofuran solution of bis(trimethylsilyl)aminopotassium (37.63 mL, 1 mol / L) was slowly added dropwise. The resulting mixture was heated to 25 °C and stirred for 1 hour. Then, the mixture was cooled to -70 °C, and a tetrahydrofuran solution of 8-1 (5.00 g, 25.09 mmol, dissolved in 50 mL of tetrahydrofuran) was slowly added dropwise. After the addition was complete, the mixture was heated to 25 °C and stirred for another 12 hours. A saturated ammonium chloride solution (300 mL) was slowly added to the reaction mixture, followed by extraction with ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give product 8-2 (2.63 g, yield: 53%).

[0533] MS m / z(ESI):198.2[M+1].

[0534] Step Two

[0535] At -10°C, a solution of 8-2 (2.60 g, 13.18 mmol) in N,N-dimethylformamide (5 mL) was added dropwise to a suspension of sodium hydride (791 mg, 60%, 19.77 mmol) in tetrahydrofuran (30 mL). The resulting mixture was stirred at 0°C for 30 minutes, followed by the dropwise addition of propargyl bromide (2.35 g, 19.77 mmol). After the addition was complete, the mixture was heated to 25°C and stirred for 16 hours. The reaction mixture was slowly poured into ice water (50 mL), extracted with ethyl acetate (40 mL x 3), and the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by vacuum distillation. The residue was purified by silica gel column chromatography to give product 8-3 (1.58 g, yield: 50%).

[0536] MS m / z(ESI):236.2[M+1].

[0537] Step 3

[0538] Dissolve 8-3 (1.50 g, 6.37 mmol) in dry toluene (20 mL). Under an argon atmosphere, cuprous chloride (63 mg, 0.64 mmol), pinacol diborate (1.78 g, 7.01 mmol), tri-tert-butylphosphine tetrafluoroborate (219 mg, 0.76 mmol), and sodium tert-butoxide (62 mg, 0.64 mmol) are added sequentially. Then, methanol (516 μL, 12.74 mmol) is slowly added dropwise to the stirred reaction mixture. The resulting mixture is stirred at 25 °C for 2 hours. The reaction mixture is filtered, and the filtrate is concentrated by vacuum distillation. The residue is purified by silica gel column chromatography to give product 8-4 (904 mg, yield: 39%).

[0539] MS m / z(ESI): 364.3 [M+1].

[0540] Step Four

[0541] 8-4 (900 mg, 2.47 mmol) was dissolved in dry dichloromethane (30 mL), and the mixture was refluxed under a nitrogen atmosphere for 1 hour. The reaction solution was cooled to 25 °C, and then Grubbs second-generation catalyst (378 mg, 0.45 mmol) was added. The resulting mixture was stirred at 25 °C for 16 hours. The reaction solution was filtered, and the filtrate was concentrated by vacuum distillation. The residue was purified by silica gel column chromatography to give product 8-5 (422 mg, yield: 50%).

[0542] MS m / z(ESI): 336.3 [M+1].

[0543] Step 5

[0544] 8-5 (420 mg, 1.25 mmol) was added to an ethyl acetate hydrochloride solution (4 mol / L, 6 mL), and the resulting mixture was stirred at 25 °C for 1 hour. The reaction solution was then directly concentrated under reduced pressure to give product 8-6 (358 mg).

[0545] MS m / z(ESI):236.2[M+1].

[0546] Step Six

[0547] Dissolve 1-6 (150 mg, 1.07 mmol) in dry pyridine (2 mL), and add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (246 mg, 1.28 mmol) and 8-6 (320 mg, 1.18 mmol) sequentially under a nitrogen atmosphere. The resulting mixture is stirred at 25 °C for 5 hours. The reaction solution is directly concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give product 8-7 (284 mg, yield: 74%).

[0548] MS m / z(ESI): 358.4 [M+1].

[0549] Step Seven

[0550] 8-7 (280 mg, 0.78 mmol), 1-8 (252 mg, 0.78 mmol, synthetic method referred to WO2025049820A1), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (115 mg, 0.16 mmol), and potassium carbonate (323 mg, 2.34 mmol) were added sequentially to a mixed solution of 1,4-dioxane (4 mL) and water (1 mL). The resulting mixture was heated to 80 °C and stirred for 12 hours under a nitrogen atmosphere. After the reaction solution was cooled to room temperature, water (15 mL) was added, and the mixture was extracted with ethyl acetate (15 mL * 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by vacuum distillation. The residue was purified by high performance liquid chromatography to obtain product 8-8 (145 mg, yield: 39%).

[0551] MS m / z(ESI): 470.2 [M+1].

[0552] Step 8

[0553] Dissolve 8-8 (145 mg, 0.30 mmol) in dimethyl sulfoxide (3 mL), then add pinacol diboronate (156 mg, 0.60 mmol), potassium acetate (88 mg, 0.90 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (51 mg, 60 μmol) sequentially. The resulting mixture is heated to 80 °C and stirred for 12 hours under a nitrogen atmosphere. The reaction solution is then directly concentrated under reduced pressure, and the residue is analyzed by high-performance liquid chromatography to obtain product 8-9 (31 mg, yield: 18%).

[0554] MS m / z(ESI): 562.3 [M+1].

[0555] Step Nine

[0556] 8-9 (31 mg, 55 μmol), 1-11 (29 mg, 55 μmol, synthetic method referred to WO2025049820 A1), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (8 mg, 11 μmol), and potassium carbonate (23 mg, 0.17 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 80 °C and stirred for 12 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high performance liquid chromatography to obtain product 8 (2.5 mg, yield: 5%).

[0557] MS m / z(ESI): 882.4 [M+1].

[0558] 1H NMR (400MHz, DMSO-d6) δ12.22(s,1H),10.87(s,1H),7.77–7.67(m,1H),7.46–7.36(m,1H),7.35–7.26(m,1H),7.13–6.9 5(m,2H),6.79–6.68(m,1H),6.68–6.63(m,1H),6.62–6.55(m,1H),6.24–6.14(m,1H),5.70–5.59(m,1H),5.21–5.08(m,1 H),4.52–4.42(m,1H),4.42–4.24(m,4H),3.82(s,3H),3.54–3.46(m,2H),3.33(s,6H),3.30–3.22(m,4H),3.17–3.06(m ,5H),3.04–2.90(m,2H),2.87–2.74(m,1H),2.21–2.07(m,1H),2.02–1.88(m,1H),0.92–0.83(m,1H),0.83–0.69(m,3H).

[0559] Examples 1-9: Preparation of Compound 9

[0560] Step 1

[0561] Dissolve 9-1 (100 mg, 0.26 mmol, synthesis method referred to WO2024015340) in dichloromethane (3 mL), then add trifluoroacetic acid (1.2 mL). After the addition is complete, stir the mixture at 25 °C for 0.5 hours. Concentrate the reaction solution directly under reduced pressure to obtain product 9-2 (90 mg, crude product).

[0562] MS m / z(ESI):287.1[M+1].

[0563] Step Two

[0564] 9-2 (90 mg, crude) was dissolved in dry acetonitrile (5 mL). Under a nitrogen atmosphere, 9-3 (49 mg, 0.26 mmol), N,N-diisopropylethylamine (167 mg, 1.29 mmol), and potassium carbonate (107 mg, 0.77 mmol) were added. The resulting mixture was stirred at 80 °C for 12 hours. The reaction solution was cooled to below 25 °C and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give product 9-4 (81 mg, yield: 69%).

[0565] MS m / z(ESI):456.1[M+1].

[0566] Step 3

[0567] Dissolve 9-4 (81 mg, 0.17 mmol) in ethanol (2 mL) and water (2 mL), then add iron powder (49 mg, 0.89 mmol) and ammonium chloride (76 mg, 1.42 mmol). After the addition is complete, stir the mixture at 80 °C for 12 hours. Cool the reaction solution to below 25 °C, filter, extract the filtrate, dry the organic phase, filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to give product 9-5 (60 mg, yield: 79%).

[0568] MS m / z(ESI):426.2[M+1].

[0569] Step Four

[0570] Dissolve 9-5 (60 mg, 0.14 mmol) and 9-6 (67 mg, 0.35 mmol) in dry N,N-dimethylformamide (3 mL), add sodium bicarbonate (24 mg, 0.28 mmol), and stir the mixture at 80 °C for 12 hours. Cool the reaction mixture to below 25 °C, add saturated ammonium chloride solution, extract, dry the organic phase, filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to give product 9-7 (32 mg, yield: 42%).

[0571] MS m / z(ESI): 537.2 [M+1].

[0572] Step 5

[0573] Dissolve 9-7 (32 mg, 59 μmol) and 9-8 (35 mg, 65 μmol, synthetic method referred to WO2025049820 A1) in 1,4-dioxane (4 mL) and water (1 mL), then add [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (5 mg, 59 μmol) and potassium carbonate (25 mg, 0.18 mmol). After the addition is complete, purge with nitrogen three times. The resulting mixture is stirred at 80 °C for 12 hours under a nitrogen atmosphere. The reaction solution temperature is lowered to below 25 °C, water is added, extraction is performed, the organic phase is dried, filtered, concentrated under reduced pressure, and the residue is purified by high performance liquid chromatography to obtain product 9 (6.5 mg, yield: 12%).

[0574] MS m / z(ESI): 866.6 [M+1].

[0575] 1H NMR (400MHz, DMSO-d6) δ12.20–12.08(m,1H),10.86(s,1H),7.78–7.67(m,1H),7.47–7.34(m,1H),7.00–6 .89(m,2H),6.87(d,J=7.4Hz,1H),6.68(d,J=8.0Hz,1H),6.64–6.56(m,2H),6.23–6.09(m,2H),5.33–5.31 (m,1H),4.43–4.25(m,6H),4.05–3.95(m,1H),3.94–3.87(m,1H),3.81(s,3H),3.71–3.52(m,2H),3.38–3. 25(m,2H),3.21–3.02(m,8H),3.00–2.75(m,4H),2.65–2.55(m,1H),2.40–2.09(m,4H),2.05–1.87(m,1H).

[0576] Examples 1-10: Preparation of Compound 10

[0577] Step 1

[0578] 10⁻¹ (96 mg, 0.25 mmol, synthesis method referred to WO2024240268) was dissolved in dichloromethane (3 mL), and then trifluoroacetic acid (1 mL) was added. After the addition was complete, the resulting mixture was stirred at 25 °C for 0.5 hours. The reaction solution was then concentrated directly under reduced pressure to obtain product 10⁻² (80 mg, crude product).

[0579] MS m / z(ESI):287.1[M+1].

[0580] Step Two

[0581] 10⁻² (80 mg, crude) was dissolved in dry acetonitrile (5 mL). Under a nitrogen atmosphere, 9⁻³ (47 mg, 0.25 mmol), N,N-diisopropylethylamine (160 mg, 1.24 mmol), and potassium carbonate (103 mg, 0.74 mmol) were added. After the addition was complete, the mixture was stirred at 80 °C for 12 hours. The reaction solution was cooled to below 25 °C and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give product 10⁻³ (74 mg, yield: 65%).

[0582] MS m / z(ESI):456.1[M+1].

[0583] Step 3

[0584] 10⁻³ (74 mg, 0.16 mmol) was dissolved in ethanol (2 mL) and water (2 mL), and iron powder (45 mg, 0.81 mmol) and ammonium chloride (69 mg, 1.30 mmol) were added. After the addition was complete, the mixture was stirred at 80 °C for 12 hours. The reaction solution was cooled to below 25 °C, filtered, and the filtrate was extracted. The organic phase was dried, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give product 10⁻⁴ (55 mg, yield: 80%).

[0585] MS m / z(ESI):426.2[M+1].

[0586] Step Four

[0587] 10⁻⁴ (55 mg, 0.13 mmol) and 9⁻⁶ (62 mg, 0.32 mmol) were dissolved in dry N,N-dimethylformamide (3 mL), and sodium bicarbonate (21.7 mg, 0.258 mmol) was added. After the addition was complete, the mixture was stirred at 80 °C for 12 hours. The reaction solution was cooled to below 25 °C, and a saturated ammonium chloride solution was added for extraction. The organic phase was dried, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give product 10⁻⁵ (30 mg, yield: 42%).

[0588] MS m / z(ESI): 537.2 [M+1].

[0589] Step 5

[0590] 10⁻⁵ (30 mg, 56 μmol) and 9⁻⁸ (33 mg, 61.4 μmol) were dissolved in 1,4-dioxane (2 mL) and water (0.5 mL). [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (5 mg, 6 μmol) and potassium carbonate (23 mg, 167 μmol) were added. After the addition was complete, nitrogen was purged three times. The resulting mixture was stirred at 80 °C for 1 hour under a nitrogen atmosphere. The reaction mixture was cooled to below 25 °C, water was added, and extraction was performed. The organic phase was dried, filtered, and concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography to obtain product 10 (8.0 mg, yield: 17%).

[0591] MS m / z(ESI): 866.6 [M+1].

[0592] 1H NMR (400MHz, DMSO-d6) δ12.22–12.03(m,1H),10.86(s,1H),7.76–7.68(m,1H),7.47–7.36(m,1H),7.01–6 .90(m,2H),6.87(d,J=7.3Hz,1H),6.67(d,J=8.0Hz,1H),6.64–6.55(m,2H),6.24–6.09(m,2H),5.33–5.31 (m,1H),4.46–4.26(m,6H),4.04–3.93(m,2H),3.81(s,3H),3.68–3.53(m,2H),3.39–3.21(m,2H),3.20–3. 00(m,8H),2.97–2.74(m,4H),2.65–2.54(m,1H),2.38–2.22(m,2H),2.21–2.08(m,1H),2.07–1.88(m,2H).

[0593] Examples 1-11: Preparation of Compound 11

[0594] Step 1

[0595] 11-1 (130 mg, 0.33 mmol, synthesis method referred to WO2024240268) was dissolved in dichloromethane (3 mL), and then trifluoroacetic acid (1 mL) was added. After the addition was complete, the resulting mixture was stirred at 25 °C for 0.5 hours. The reaction solution was then concentrated under reduced pressure to obtain product 11-2 (116 mg, crude product).

[0596] MS m / z(ESI):287.1[M+1].

[0597] Step Two

[0598] 11-2 (116 mg, crude product) was dissolved in dry acetonitrile (5 mL). Under a nitrogen atmosphere, 9-3 (64 mg, 0.34 mmol), N,N-diisopropylethylamine (217 mg, 1.68 mmol), and potassium carbonate (139 mg, 1.01 mmol) were added. After the addition was complete, the mixture was stirred at 80 °C for 12 hours. The reaction solution was cooled to below 25 °C and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give product 11-3 (102 mg, yield: 67%).

[0599] MS m / z(ESI):456.1[M+1].

[0600] Step 3

[0601] 11-3 (102 mg, 0.18 mmol) was dissolved in ethanol (2 mL) and water (2 mL), and iron powder (63 mg, 1.12 mmol) and ammonium chloride (96 mg, 1.79 mmol) were added. After the addition was complete, the mixture was stirred at 80 °C for 12 hours. The reaction solution was cooled to below 25 °C, filtered, and the filtrate was extracted. The organic phase was dried, filtered, concentrated under reduced pressure, and the residue was purified by normal-phase silica gel column chromatography to give product 11-4 (71 mg, yield: 75%).

[0602] MS m / z(ESI):426.2[M+1].

[0603] Step Four

[0604] Dissolve 11-4 (71 mg, 0.17 mmol) and 9-6 (80 mg, 0.42 mmol) in dry N,N-dimethylformamide (3 mL), add sodium bicarbonate (28 mg, 0.33 mmol), and stir the mixture at 80 °C for 12 hours. Cool the reaction mixture to below 25 °C, add saturated ammonium chloride solution, extract, dry the organic phase, filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain product 11-5 (35 mg, yield: 39%).

[0605] MS m / z(ESI): 537.2 [M+1].

[0606] Step 5

[0607] Dissolve 11-5 (35 mg, 65 μmol) and 9-8 (39 mg, 72 μmol) in 1,4-dioxane (4 mL) and water (1 mL), then add [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (6 mg, 7 μmol) and potassium carbonate (27 mg, 195 μmol). After the addition is complete, purge with nitrogen three times. The resulting mixture is stirred at 80 °C for 1 hour under a nitrogen atmosphere. The reaction solution temperature is lowered to below 25 °C, water is added, extraction is performed, the organic phase is dried, filtered, and concentrated under reduced pressure. The residue is purified by high-performance liquid chromatography to obtain product 11 (10 mg, yield: 18%).

[0608] MS m / z(ESI): 866.6 [M+1].

[0609] 1H NMR(400MHz,DMSO-d6)δ12.20–12.10(m,1H),10.86(s,1H),7.77–7.67(m,1H),7.47–7.35 (m,1H),7.03–6.84(m,3H),6.72–6.65(m,1H),6.65–6.55(m,2H),6.25–6.08(m,2H),4.50– 4.43(m,1H),4.41–4.26(m,5H),4.13–4.02(m,1H),3.97–3.87(m,1H),3.81(s,3H),3.69– 3.55(m,2H),3.43–2.74(m,14H),2.68–2.55(m,2H),2.39–2.06(m,3H),2.02–1.88(m,1H).

[0610] Examples 1-12: Preparation of Compound 12

[0611] Step 1

[0612] 12-1 (120 mg, 0.31 mmol, synthesis method referred to WO2025026455) was dissolved in dichloromethane (3 mL), and then trifluoroacetic acid (1 mL) was added. After the addition was complete, the resulting mixture was stirred at 25 °C for 0.5 hours. The reaction solution was then concentrated under reduced pressure to obtain product 12-2 (102 mg, crude product).

[0613] MS m / z(ESI):285.1[M+1].

[0614] Step Two

[0615] 12-2 (102 mg, crude product) was dissolved in dry acetonitrile (5 mL). Under a nitrogen atmosphere, 9-3 (59 mg, 0.31 mmol), N,N-diisopropylethylamine (201 mg, 1.56 mmol), and potassium carbonate (129 mg, 0.93 mmol) were added. After the addition was complete, the mixture was stirred at 80 °C for 12 hours. The reaction solution was cooled to below 25 °C and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give product 12-3 (84 mg, yield: 59%).

[0616] MS m / z(ESI):454.2[M+1].

[0617] Step 3

[0618] 12-3 (84 mg, 0.185 mmol) was dissolved in ethanol (2 mL) and water (2 mL), and iron powder (52 mg, 0.92 mmol) and ammonium chloride (79 mg, 1.48 mmol) were added. After the addition was complete, the mixture was stirred at 80 °C for 12 hours. The reaction solution was cooled to below 25 °C, filtered, and the filtrate was extracted. The organic phase was dried, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give product 12-4 (56 mg, yield: 71%).

[0619] MS m / z(ESI):424.2[M+1].

[0620] Step Four

[0621] Dissolve 12-4 (56 mg, 0.13 mmol) and 9-6 (63 mg, 0.33 mmol) in dry N,N-dimethylformamide (3 mL), add sodium bicarbonate (22 mg, 0.26 mmol), and stir the mixture at 80 °C for 12 hours. Cool the reaction mixture to below 25 °C, add saturated ammonium chloride solution, extract, dry the organic phase, filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain product 12-5 (28 mg, yield: 40%).

[0622] MS m / z(ESI): 535.3 [M+1].

[0623] Step 5

[0624] Dissolve 12-5 (28 mg, 52 μmol) and 9-8 (31 mg, 57 μmol) in 1,4-dioxane (2 mL) and water (0.5 mL), then add [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (4 mg, 5 μmol) and potassium carbonate (22 mg, 157 μmol). After the addition is complete, purge with nitrogen three times. The resulting mixture is stirred at 80 °C for 1 hour under a nitrogen atmosphere. The reaction solution temperature is lowered to below 25 °C, water is added, extraction is performed, the organic phase is dried, filtered, concentrated under reduced pressure, and the residue is purified by high performance liquid chromatography to obtain product 12 (9 mg, yield: 20%).

[0625] MS m / z(ESI): 864.4 [M+1].

[0626] Examples 1-13: Preparation of Compound 13

[0627] Step 1

[0628] 13-1 (145 mg, 0.37 mmol, synthesis method referred to CN119219669) was dissolved in dichloromethane (3 mL), and then trifluoroacetic acid (1 mL) was added. After the addition was complete, the resulting mixture was stirred at 25 °C for 0.5 hours. The reaction solution was then concentrated under reduced pressure to obtain product 13-2 (124 mg, crude product).

[0629] MS m / z(ESI):285.1[M+1].

[0630] Step Two

[0631] 13-2 (124 mg, crude) was dissolved in dry acetonitrile (5 mL). Under a nitrogen atmosphere, 9-3 (59 mg, 0.38 mmol), N,N-diisopropylethylamine (243 mg, 1.88 mmol), and potassium carbonate (156 mg, 1.13 mmol) were added. After the addition was complete, the mixture was stirred at 80 °C for 12 hours. The reaction solution was cooled to below 25 °C and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give product 13-3 (110 mg, yield: 64%).

[0632] MS m / z(ESI):454.2[M+1].

[0633] Step 3

[0634] 13-3 (110 mg, 0.24 mmol) was dissolved in ethanol (2 mL) and water (2 mL), and iron powder (68 mg, 1.21 mmol) and ammonium chloride (103 mg, 1.94 mmol) were added. After the addition was complete, the mixture was stirred at 80 °C for 12 hours. The reaction solution was cooled to below 25 °C, filtered, and the filtrate was extracted. The organic phase was dried, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give product 13-4 (64 mg, yield: 62%).

[0635] MS m / z(ESI):424.2[M+1].

[0636] Step Four

[0637] Dissolve 13-4 (64 mg, 0.15 mmol) and 9-6 (73 mg, 0.38 mmol) in dry N,N-dimethylformamide (3 mL), add sodium bicarbonate (25 mg, 0.30 mmol), and stir the mixture at 80 °C for 12 hours. Cool the reaction mixture to below 25 °C, add saturated ammonium chloride solution, extract, dry the organic phase, filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain product 13-5 (38 mg, yield: 47%).

[0638] MS m / z(ESI): 535.3 [M+1].

[0639] Step 5

[0640] Dissolve 13-5 (38 mg, 71 μmol) and 9-8 (42 mg, 78 μmol) in 1,4-dioxane (2 mL) and water (0.5 mL), then add [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (6 mg, 7 μmol) and potassium carbonate (29 mg, 213 μmol). After the addition is complete, purge with nitrogen three times. The resulting mixture is stirred at 80 °C for 1 hour under a nitrogen atmosphere. The reaction solution temperature is lowered to below 25 °C, water is added, extraction is performed, the organic phase is dried, filtered, and concentrated under reduced pressure. The residue is purified by high-performance liquid chromatography to obtain product 13 (7.5 mg, yield: 12%).

[0641] MS m / z(ESI): 864.4 [M+1].

[0642] Examples 1-14: Preparation of Compound 14

[0643] Step 1

[0644] 1-10 (40 mg, 71 μmol), 14-1 (29 mg, 71 μmol, synthetic method referred to WO2025049820 A1), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (10 mg, 14 μmol), and potassium carbonate (29 mg, 0.21 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 80 °C and stirred for 12 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high performance liquid chromatography to obtain product 14 (5.3 mg, yield: 9%).

[0645] MS m / z(ESI):800.4[M+1].

[0646] 1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.87(s,1H),7.71–7.60(m,1H),7.48–7.37(m,1H),7.37 –7.28(m,1H),7.14–6.93(m,2H),6.81–6.52(m,3H),6.26–6.03(m,2H),5.20–5.08(m,1H),4.50– 4.41(m,1H),4.41–4.26(m,4H),3.82(s,3H),3.53–3.46(m,2H),3.33(s,6H),3.31–3.24(m,4H) ,3.16–3.07(m,5H),3.04–2.92(m,2H),2.87–2.74(m,1H),2.34–2.13(m,1H),2.09–1.81(m,5H).

[0647] Examples 1-15: Preparation of Compound 15

[0648] Step 1

[0649] 2-8 (40 mg, 69 μmol), 14-1 (28 mg, 69 μmol, synthetic method referred to WO2025049820 A1), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (10 mg, 14 μmol), and potassium carbonate (29 mg, 0.21 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 80 °C and stirred for 12 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high performance liquid chromatography to obtain product 15 (3.9 mg, yield: 7%).

[0650] MS m / z(ESI): 814.4 [M+1].

[0651] Examples 1-16: Preparation of Compound 16

[0652] Step 1

[0653] 8-9 (40 mg, 71 μmol), 14-1 (29 mg, 71 μmol, synthetic method referred to WO2025049820 A1), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (10 mg, 14 μmol), and potassium carbonate (29 mg, 0.21 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 80 °C and stirred for 12 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high performance liquid chromatography to obtain product 16 (8.6 mg, yield: 15%).

[0654] MS m / z(ESI):800.4[M+1].

[0655] 1 H NMR(400MHz,DMSO-d6)δ12.18(s,1H),10.84(s,1H),7.76–7.68(m,1H),7.64–7.60(m,2H),7.46–7.41(m,2H),7 .40–7.33(m,1H),7.09–6.96(m,3H),6.88–6.84(m,1H),6.25–6.14(m,1H),5.70–5.63(m,1H),4.54–4.42(m,1H) ,4.43–4.31(m,3H),3.85–3.78(m,1H),3.58–3.43(m,2H),3.32(s,6H),3.31–3.20(m,5H),3.16–3.04(m,5H),3. 04–2.91(m,3H),2.85–2.72(m,1H),2.20–2.07(m,1H),2.03–1.86(m,1H),0.91–0.83(m,1H),0.83–0.67(m,3H).

[0656] Examples 1-17: Preparation of Compound 17

[0657] Step 1

[0658] 3-8 (40 mg, 69 μmol), 14-1 (28 mg, 69 μmol, synthetic method referred to WO2025049820 A1), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (10 mg, 14 μmol), and potassium carbonate (29 mg, 0.21 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 80 °C and stirred for 12 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high performance liquid chromatography to obtain product 17 (5.1 mg, yield: 9%).

[0659] MS m / z(ESI): 814.4 [M+1].

[0660] Examples 1-18: Preparation of Compound 18

[0661] Step 1

[0662] 4-8 (40 mg, 69 μmol), 14-1 (28 mg, 69 μmol, synthetic method referred to WO2025049820 A1), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (10 mg, 14 μmol), and potassium carbonate (29 mg, 0.21 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 80 °C and stirred for 12 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high performance liquid chromatography to obtain product 18 (3.6 mg, yield: 6%).

[0663] MS m / z(ESI): 814.4 [M+1].

[0664] Examples 1-19: Preparation of Compound 19

[0665] It was prepared by a similar synthesis method as in Example 1-1.

[0666] MS m / z(ESI): 883.4 [M+1].

[0667] Examples 1-20: Preparation of Compound 20

[0668] Step 1

[0669] 20-1 (530 mg, 2.46 mmol) was dissolved in dichloromethane (20 mL), followed by the addition of dimethyl sulfoxide (1.75 mL, 24.6 mmol), triethylamine (1.71 mL, 12.3 mmol), and pyridine sulfur trioxide (1.18 g, 7.39 mmol). After the addition was complete, the mixture was reacted at 25 °C for 1 hour. Water (20 mL) was added to the reaction mixture, followed by extraction with dichloromethane (30 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give product 20-2 (377 mg, yield: 72%).

[0670] MS m / z(ESI):158.1[M+1-56].

[0671] Step Two

[0672] Methyltriphenylphosphine bromide (947 mg, 2.65 mmol) was added to dry tetrahydrofuran (15 mL). Under nitrogen protection, the mixture was cooled to 0 °C. Then, a tetrahydrofuran solution of bis(trimethylsilyl)aminopotassium (3.5 mL, 1 mol / L) was slowly added dropwise. After stirring at 0 °C for 1 hour, a tetrahydrofuran solution of 20-3 (377 mg, 1.77 mmol, dissolved in 5 mL of tetrahydrofuran) was slowly added dropwise. After the addition was complete, the mixture was stirred at 0 °C for another 1 hour. A saturated ammonium chloride solution (20 mL) was slowly added to the reaction mixture, followed by extraction with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give product 20-3 (310 mg, yield: 83%).

[0673] MS m / z(ESI):156.1[M+1-56].

[0674] Step 3

[0675] At -10°C, a solution of 20-3 (150 mg, 0.71 mmol) in N,N-dimethylformamide (2 mL) was added dropwise to a suspension of sodium hydride (56.8 mg, 60%, 1.42 mmol) in tetrahydrofuran (3 mL). The resulting mixture was stirred at 0°C for 30 minutes, followed by the dropwise addition of propargyl bromide (169 mg, 1.42 mmol). After the addition was complete, the mixture was heated to 25°C and stirred for 16 hours. The reaction mixture was slowly poured into ice water (30 mL), extracted with ethyl acetate (30 mL x 3), and the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by vacuum distillation. The residue was purified by silica gel column chromatography to give product 20-4 (129 mg, yield: 73%).

[0676] MS m / z(ESI):194.2[M+1-56].

[0677] Step Four

[0678] 20-4 (129 mg, 0.52 mmol) was dissolved in dry toluene (8 mL). Cuprous chloride (5.12 mg, 0.052 mmol), pinacol diborate (144.5 mg, 0.57 mmol), tri-tert-butylphosphine tetrafluoroborate (18.01 mg, 0.062 mmol), and sodium tert-butoxide (14.9 mg, 0.16 mmol) were added sequentially under an argon atmosphere. Methanol (0.042 mL, 1.03 mmol) was then slowly added dropwise to the stirred reaction mixture. The resulting mixture was stirred at 25 °C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated by vacuum distillation. The residue was purified by silica gel column chromatography to give product 20-5 (154 mg, yield: 79%).

[0679] MS m / z(ESI):322.3[M+1-56].

[0680] Step 5

[0681] 20-5 (104 mg, 0.28 mmol) was dissolved in dry dichloromethane (5 mL), and the mixture was refluxed under a nitrogen atmosphere for 1 hour. The reaction solution was cooled to 25 °C, and then Grubbs second-generation catalyst (93.6 mg, 0.11 mmol) was added. The resulting mixture was stirred at 25 °C for 16 hours. The reaction solution was filtered, and the filtrate was concentrated by vacuum distillation. The residue was purified by silica gel column chromatography to give product 20-6 (70 mg, yield: 73%).

[0682] MS m / z(ESI):294.3[M+1-56].

[0683] Step Six

[0684] 20-6 (70 mg, 0.20 mmol) was added to an ethyl acetate hydrochloride solution (4 mol / L, 2 mL), and the resulting mixture was stirred at 25 °C for 1 hour. The reaction solution was then directly concentrated under reduced pressure to give product 20-7 (60 mg).

[0685] MS m / z(ESI):250.3[M+1].

[0686] Step Seven

[0687] Dissolve 1-6 (42.1 mg, 0.30 mmol) in dry pyridine (3 mL), and add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (57.6 mg, 0.30 mmol) and 20-7 (60 mg, 0.20 mmol) sequentially under a nitrogen atmosphere. The resulting mixture is stirred at 25 °C for 5 hours. The reaction solution is directly concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give product 20-8 (70 mg, yield: 94%).

[0688] MS m / z(ESI): 372.4 [M+1].

[0689] Step 8

[0690] 20-8 (78 mg, 0.21 mmol), 1-8 (67.1 mg, 0.21 mmol, synthetic method referred to WO2025049820A1), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (30.7 mg, 0.042 mmol), and potassium carbonate (87.1 mg, 0.63 mmol) were added sequentially to a mixed solution of 1,4-dioxane (4 mL) and water (1 mL). The resulting mixture was heated to 80 °C and stirred for 12 hours under a nitrogen atmosphere. After the reaction solution was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL * 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by vacuum distillation. The residue was purified by high performance liquid chromatography to obtain product 20-9 (65 mg, yield: 64%).

[0691] MS m / z(ESI):484.4[M+1].

[0692] Step Nine

[0693] 20-9 (65 mg, 0.13 mmol) was dissolved in dimethyl sulfoxide (4 mL), followed by the sequential addition of pinacol diboronate (68.2 mg, 0.27 mmol), potassium acetate (39.5 mg, 0.40 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (22.7 mg, 26 μmol). The resulting mixture was heated to 80 °C and stirred for 12 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was subjected to high-performance liquid chromatography (HPLC) to prepare product 20-10 (65 mg, yield: 84%).

[0694] MS m / z(ESI): 576.6 [M+1].

[0695] Step 10

[0696] 20-10 (22 mg, 38 μmol), 1-11 (21.2 mg, 40 μmol, synthetic method referred to WO2025049820A1), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (6.5 mg, 7.6 μmol), and cesium fluoride (17.4 mg, 0.11 mmol) were added sequentially to a mixed solution of 1,4-dioxane (4 mL) and water (1 mL). The resulting mixture was heated to 80 °C and stirred for 12 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high performance liquid chromatography to obtain product 20 (2.6 mg, yield: 8%).

[0697] MS m / z(ESI): 896.5 [M+1].

[0698] 1 H NMR (400MHz, DMSO-d6) δ12.22–12.08(m,1H),10.86(s,1H),7.72–7.47(m,1H),7.44–7.24(m,2 H),7.22–6.85(m,2H),6.77–6.70(m,1H),6.68–6.56(m,2H),6.20–6.08(m,1H),5.45–5.23(m,1 H),4.55–4.15(m,6H),3.83(s,3H),3.72–3.56(m,2H),3.36–2.89(m,10H),2.87–2.65(m,2H), 2.61–2.52(m,1H),2.20–2.09(m,1H),2.06–1.83(m,4H),1.37–1.15(m,4H),0.79–0.55(m,4H).

[0699] Examples 1-22: Preparation of Compound 22

[0700] Prepared using a synthesis method similar to that used in Examples 1-12.

[0701] MS m / z(ESI): 865.6 [M+1].

[0702] Examples 1-23: Preparation of Compound 23

[0703] Prepared using a synthesis method similar to that used in Examples 1-8.

[0704] MS m / z(ESI): 883.4 [M+1].

[0705] Examples 1-24: Preparation of Compound 24

[0706] Prepared using a synthesis method similar to that used in Examples 1-13.

[0707] MS m / z(ESI): 865.4 [M+1].

[0708] Examples 1-25: Preparation of Compound 25

[0709] Prepared using a synthesis method similar to that used in Examples 1-11.

[0710] MS m / z(ESI): 867.5 [M+1].

[0711] Examples 1-26: Preparation of Compound 26

[0712] Prepared using a synthesis method similar to that used in Examples 1-10.

[0713] MS m / z(ESI): 867.6 [M+1].

[0714] Examples 1-27: Preparation of Compound 27

[0715] Prepared using a synthesis method similar to that used in Examples 1-9.

[0716] MS m / z(ESI): 867.5 [M+1].

[0717] Examples 1-31: Preparation of compound 31

[0718] MS m / z(ESI): 865.5 [M+1].

[0719] Examples 1-46: Preparation of Compound 46

[0720] It was prepared by a similar synthesis method as in Example 1-1.

[0721] MS m / z(ESI): 815.5 [M+1].

[0722] Examples 1-47: Preparation of Compound 47

[0723] Prepared using a synthesis method similar to that used in Examples 1-8.

[0724] MS m / z(ESI): 815.4 [M+1].

[0725] Examples 1-48: Preparation of Compound 48

[0726] The sample was prepared using a similar synthesis method as in Examples 1-2.

[0727] MS m / z(ESI): 829.5 [M+1].

[0728] Examples 1-62: Preparation of Compound 62

[0729] It was prepared by a similar synthesis method as in Example 1-1.

[0730] MS m / z(ESI): 846.5 [M+1].

[0731] Examples 1-63: Preparation of Compound 63

[0732] Prepared using a synthesis method similar to that used in Examples 1-8.

[0733] MS m / z(ESI): 846.4 [M+1].

[0734] Examples 1-78: Preparation of Compound 78

[0735] It was prepared by a similar synthesis method as in Example 1-1.

[0736] MS m / z(ESI): 917.4 [M+1].

[0737] Examples 1-79: Preparation of Compound 79

[0738] Step 1

[0739] 79-1 (213 mg, 0.75 mmol, synthetic method referred to WO2025049820 A1) and 79-2 (146 mg, 0.50 mmol, synthetic method referred to WO2025049820 A1) were dissolved in a dry tetrahydrofuran and dimethyl sulfoxide mixture (5.2 mL, 10:3). A mixture of potassium acetate (147 mg, 1.49 mmol) and acetic acid (149 mg, 2.49 mmol) was added, and the mixture was stirred under a nitrogen atmosphere for 30 minutes. Then, sodium cyanoborohydride (94 mg, 1.49 mmol) was added. After the addition was complete, the mixture was stirred at 25 °C for 1 hour. The reaction solution was directly purified by reversed-phase C18 column chromatography to obtain product 79-3 (220 mg, yield: 77%).

[0740] MS m / z(ESI): 562.2 [M+1].

[0741] Step Two

[0742] 8-9 (60 mg, 110 μmol), 79-3 (60 mg, 110 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (18 mg, 22 μmol), and cesium fluoride (49 mg, 0.32 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 80 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 79 (30 mg, yield: 31%).

[0743] MS m / z(ESI): 917.4 [M+1].

[0744] 1 H NMR (400MHz, DMSO-d6) δ12.26–12.13(m,1H),11.07(s,1H),7.85–7.62(m,1H),7.43–7. 39(m,1H),7.35–7.25(m,2H),7.23–7.14(m,1H),7.02–6.89(m,2H),6.56–6.45(m,1H), 6.23–6.13(m,1H),5.78–5.68(m,1H),5.68–5.59(m,1H),4.53–4.25(m,4H),3.59–3.44 (m,2H),3.30–2.79(m,12H),2.77–2.59(m,14H),2.41–2.10(m,2H),0.92–0.66(m,4H).

[0745] Examples 1-80: Preparation of Compound 80

[0746] The sample was prepared using a similar synthesis method as in Examples 1-2.

[0747] MS m / z(ESI): 930.5 [M+1].

[0748] Examples 1-81: Preparation of Compound 81

[0749] Step 1

[0750] 430-9 (60 mg, 104 μmol), 79-3 (58.9 mg, 104 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (17.7 mg, 21 μmol), and cesium fluoride (47.5 mg, 0.31 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 80 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 81 (25 mg, yield: 26%).

[0751] MS m / z(ESI): 931.4 [M+1].

[0752] Example 1-111: Preparation of compound 111

[0753] Prepared using a synthesis method similar to that used in Examples 1-3.

[0754] MS m / z(ESI): 834.5 [M+1].

[0755] Examples 1-115: Preparation of Compound 115

[0756] Prepared using a synthesis method similar to that used in Examples 1-3.

[0757] MS m / z(ESI): 870.4 [M+1].

[0758] Examples 1-116: Preparation of Compound 116

[0759] Prepared using a synthesis method similar to that used in Examples 1-3.

[0760] MS m / z(ESI): 788.5 [M+1].

[0761] Examples 1-118: Preparation of Compound 118

[0762] Step 1

[0763] 131-3 (40 mg, 71 μmol), 14-1 (29 mg, 71 μmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (10 mg, 14 μmol), and potassium carbonate (29 mg, 0.21 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 85 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 118 (15 mg, yield: 26%).

[0764] MS m / z(ESI):801.4[M+1].

[0765] 1 H NMR (400MHz, DMSO-d6) δ12.23–12.13(m,1H),10.83(s,1H),8.16–8.05(m,1H),7.74–7.64(m,1H) ),7.64–7.56(m,2H),7.50–7.39(m,2H),7.14–6.90(m,4H),6.91–6.83(m,1H),5.76–5.61(m,1H) ,4.68–4.56(m,2H),4.53–4.40(m,2H),3.87–3.77(m,1H),3.58–3.43(m,4H),3.29–2.94(m,4H) ,2.88–2.60(m,4H),2.55–2.32(m,4H),2.30–2.15(m,1H),2.07–1.80(m,6H),0.94–0.71(m,4H).

[0766] Examples 1-120: Preparation of Compound 120

[0767] Prepared using a synthesis method similar to that used in Examples 1-6.

[0768] MS m / z(ESI): 815.5 [M+1].

[0769] Examples 1-121: Preparation of Compound 121

[0770] Step 1

[0771] 5-1 (150 mg, 1.06 mmol) was dissolved in dry pyridine (2 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (246 mg, 1.28 mmol) and 430-6 (337 mg, 1.18 mmol) were added sequentially under a nitrogen atmosphere. The resulting mixture was stirred at 25 °C for 5 hours. The reaction solution was directly concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give product 121-1 (210 mg, yield: 53%).

[0772] MS m / z(ESI): 373.3 [M+1].

[0773] Step Two

[0774] 121-1 (210 mg, 0.56 mmol), 1-8 (183 mg, 0.56 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (81 mg, 0.12 mmol), and potassium carbonate (232 mg, 1.68 mmol) were added sequentially to a mixed solution of 1,4-dioxane (4 mL) and water (1 mL). The resulting mixture was heated to 80 °C and stirred for 12 hours under a nitrogen atmosphere. After cooling the reaction solution to room temperature, water (15 mL) was added, and the mixture was extracted with ethyl acetate (15 mL * 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by vacuum distillation. The residue was purified by silica gel column chromatography to obtain product 121-2 (146 mg, yield: 53%).

[0775] MS m / z(ESI): 485.2 [M+1].

[0776] Step 3

[0777] 121-2 (140 mg, 0.29 mmol) was dissolved in 1,4-dioxane (5 mL), followed by the sequential addition of pinacol diboronate (151 mg, 0.58 mmol), potassium acetate (85 mg, 0.87 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (49 mg, 58 μmol). The resulting mixture was heated to 95 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain product 121-3 (88 mg, yield: 52%).

[0778] MS m / z(ESI): 577.3 [M+1].

[0779] Step Four

[0780] 121-3 (40 mg, 69 μmol), 14-1 (36 mg, 69 μmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (10 mg, 14 μmol), and potassium carbonate (28 mg, 0.21 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 85 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 121 (13 mg, yield: 23%).

[0781] MS m / z(ESI): 815.4 [M+1].

[0782] 1 H NMR(400MHz,DMSO-d6)δ12.49–11.92(m,1H),10.83(s,1H),8.20–8.05(m,1H) ),7.72–7.59(m,3H),7.48–7.39(m,2H),7.12–6.95(m,4H),6.90–6.83(m,1H) ,6.31–6.22(m,1H),4.72–4.59(m,2H),4.40–4.23(m,2H),4.03–3.42(m,5H), 3.38–2.95(m,6H),2.92–2.52(m,6H),2.38–2.17(m,1H),2.10–1.81(m,12H).

[0783] Examples 1-122: Preparation of Compound 122

[0784] Prepared using a synthesis method similar to that used in Examples 1-5.

[0785] MS m / z(ESI): 815.4 [M+1].

[0786] Examples 1-123: Preparation of Compound 123

[0787] Prepared using a synthesis method similar to that used in Examples 1-7.

[0788] MS m / z(ESI): 815.5 [M+1].

[0789] Examples 1-124: Preparation of Compound 124

[0790] Prepared using a synthesis method similar to that used in Examples 1-20.

[0791] MS m / z(ESI): 815.5 [M+1].

[0792] Examples 1-127: Preparation of Compound 127

[0793] Prepared using a synthesis method similar to that used in Examples 1-4.

[0794] MS m / z(ESI): 789.4 [M+1].

[0795] Examples 1-130: Preparation of Compound 130

[0796] Step 1

[0797] 79-1 (149 mg, 0.52 mmol, synthetic method referred to WO2025049820 A1) and 9-2 (100 mg, 0.35 mmol) were dissolved in a dry tetrahydrofuran and dimethyl sulfoxide mixture (5.2 mL, 10:3). A mixture of potassium acetate (103 mg, 1.04 mmol) and acetic acid (105 mg, 1.74 mmol) was added, and the mixture was stirred under a nitrogen atmosphere for 30 minutes. Then, sodium cyanoborohydride (66 mg, 1.04 mmol) was added. After the addition was complete, the mixture was stirred at 25 °C for 1 hour. The reaction solution was directly purified by reversed-phase C18 column chromatography to give product 130-1 (142 mg, yield: 72%).

[0798] MS m / z(ESI): 556.2 [M+1].

[0799] Step Two

[0800] 8-9 (60 mg, 110 μmol), 130-1 (60 mg, 110 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (18 mg, 22 μmol), and cesium fluoride (49 mg, 0.32 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 80 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 130 (28 mg, yield: 29%).

[0801] MS m / z(ESI): 911.5 [M+1].

[0802] 1H NMR (400MHz, DMSO-d6) δ12.27–11.98(m,1H),11.07(s,1H),7.77–7.67(m,1H),7.46–7.38(m,1H),7.32–7. 24(m,1H),7.00–6.87(m,3H),6.87–6.82(m,1H),6.61–6.55(m,1H),6.24–6.15(m,1H),5.78–5.67(m,1H), 5.67–5.58(m,1H),4.52–4.42(m,1H),4.41–4.25(m,4H),4.02–3.89(m,1H),3.89–3.76(m,1H),3.57–3.44 (m,2H),3.31–2.90(m,13H),2.90–2.52(m,10H),2.38–2.15(m,2H),1.95–1.81(m,1H),0.92–0.70(m,4H).

[0803] Example 1-131: Preparation of compound 131

[0804] Step 1

[0805] 5-1 (150 mg, 1.06 mmol) was dissolved in dry pyridine (2 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (246 mg, 1.28 mmol) and 8-6 (320 mg, 1.18 mmol) were added sequentially under a nitrogen atmosphere. The resulting mixture was stirred at 25 °C for 2 hours. The reaction solution was directly concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give product 131-1 (205 mg, yield: 54%).

[0806] MS m / z(ESI): 359.3 [M+1].

[0807] Step Two

[0808] 131-1 (200 mg, 0.56 mmol), 1-8 (252 mg, 0.56 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (81 mg, 0.12 mmol), and potassium carbonate (232 mg, 1.68 mmol) were added sequentially to a mixed solution of 1,4-dioxane (4 mL) and water (1 mL). The resulting mixture was heated to 80 °C and stirred for 16 hours under a nitrogen atmosphere. After the reaction solution was cooled to room temperature, water (15 mL) was added, and the mixture was extracted with ethyl acetate (15 mL * 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by vacuum distillation. The residue was purified by high-performance liquid chromatography to obtain product 131-2 (156 mg, yield: 59%).

[0809] MS m / z(ESI):471.2[M+1].

[0810] Step 3

[0811] 131-2 (150 mg, 0.32 mmol) was dissolved in dimethyl sulfoxide (3 mL), followed by the sequential addition of pinacol diborate (166 mg, 0.64 mmol), potassium acetate (94 mg, 0.90 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (54 mg, 60 μmol). The resulting mixture was heated to 95 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was subjected to high-performance liquid chromatography (HPLC) to prepare product 131-3 (102 mg, yield: 56%).

[0812] MS m / z(ESI): 563.3 [M+1].

[0813] Step Four

[0814] 131-3 (50 mg, 89 μmol), 130-1 (41 mg, 74 μmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (11 mg, 15 μmol), and potassium carbonate (30 mg, 0.22 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 85 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 131 (16 mg, yield: 19%).

[0815] MS m / z(ESI): 912.5 [M+1].

[0816] Examples 1-144: Preparation of Compound 144

[0817] Step 1

[0818] 79-1 (149 mg, 0.52 mmol, synthetic method referred to WO2025049820 A1) and 10-2 (100 mg, 0.35 mmol) were dissolved in a dry mixture of tetrahydrofuran and dimethyl sulfoxide (5.2 mL, 10:3). A mixture of potassium acetate (103 mg, 1.04 mmol) and acetic acid (105 mg, 1.74 mmol) was added, and the mixture was stirred under a nitrogen atmosphere for 30 minutes. Then, sodium cyanoborohydride (66 mg, 1.04 mmol) was added, and the mixture was stirred at 25 °C for 1 hour. The reaction solution was directly purified by reversed-phase C18 column chromatography to give product 144-1 (130 mg, yield: 66%).

[0819] MS m / z(ESI): 556.3 [M+1].

[0820] Step Two

[0821] 8-9 (60 mg, 110 μmol), 144-1 (60 mg, 110 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (18 mg, 22 μmol), and cesium fluoride (49 mg, 0.32 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 80 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 144 (31 mg, yield: 32%).

[0822] MS m / z(ESI): 911.6 [M+1].

[0823] 1H NMR (400MHz, DMSO-d6) δ12.43–11.94(m,1H),11.08(s,1H),7.77–7.67(m,1H),7.55–7. 31(m,3H),7.14–7.05(m,1H),7.03–6.87(m,2H),6.61–6.52(m,1H),6.25–6.14(m,1H), 5.79–5.72(m,1H),5.67–5.59(m,1H),4.51–4.18(m,5H),4.16–3.73(m,2H),3.67–3.23 (m,10H),3.23–2.79(m,10H),2.79–2.52(m,6H),2.39–2.14(m,2H),0.94–0.66(m,4H).

[0824] Examples 1-145: Preparation of Compound 145

[0825] Step 1

[0826] 131-3 (50 mg, 89 μmol), 144-1 (41 mg, 74 μmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (11 mg, 15 μmol), and potassium carbonate (30 mg, 0.22 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 85 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 145 (19 mg, yield: 23%).

[0827] MS m / z(ESI): 912.4 [M+1].

[0828] Examples 1-148: Preparation of Compound 148

[0829] Step 1

[0830] 430-9 (60 mg, 104 μmol), 144-1 (58 mg, 104 μmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (17.7 mg, 21 μmol), and potassium carbonate (47.5 mg, 0.31 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 85 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 148 (22 mg, yield: 23%).

[0831] MS m / z(ESI): 925.5 [M+1].

[0832] Example 1-160: Preparation of Compound 160

[0833] Step 1

[0834] 9-8 (60 mg, 112 μmol), 130-1 (63 mg, 112 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (19 mg, 22 μmol), and cesium fluoride (51 mg, 0.34 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 80 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to give product 160 (27 mg, yield: 27%).

[0835] MS m / z(ESI): 885.5 [M+1].

[0836] 1 H NMR (400MHz, DMSO-d6) δ12.23–12.13(m,1H),11.08(s,1H),7.78–7.67(m,1H),7. 53–7.33(m,3H),7.17–6.89(m,3H),6.64–6.57(m,1H),6.24–6.09(m,2H),5.81–5. 71(m,1H),4.43–4.24(m,6H),4.15–4.03(m,1H),3.98–3.72(m,1H),3.67–3.39(m ,2H),3.27–2.91(m,9H),2.91–2.63(m,8H),2.55–2.43(m,5H),2.39–2.15(m,5H).

[0837] Example 1-161: Preparation of Compound 161

[0838] Step 1

[0839] 161-1 (50 mg, 93 μmol, synthetic method referred to WO2025049820 A1), 130-1 (43 mg, 77 μmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (12 mg, 16 μmol), and potassium carbonate (32 mg, 0.23 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 85 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high performance liquid chromatography to obtain product 161 (12 mg, yield: 17%).

[0840] MS m / z(ESI): 886.4 [M+1].

[0841] Example 1-162: Preparation of Compound 162

[0842] Step 1

[0843] 9-8 (60 mg, 112 μmol), 144-1 (63 mg, 112 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (19 mg, 22 μmol), and cesium fluoride (51 mg, 0.34 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 80 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 162 (30 mg, yield: 30%).

[0844] MS m / z(ESI): 885.6 [M+1].

[0845] 1H NMR(400MHz,DMSO-d6)δ12.21–12.07(m,1H),11.07(s,1H),7.76–7.68(m,1H),7.46–7.35(m,2H) ,7.34–7.24(m,1H),6.96(d,J=7.0Hz,1H),6.93–6.88(m,1H),6.87–6.82(m,1H),6.64–6.55(m,1 H),6.23–6.09(m,2H),5.78–5.68(m,1H),4.51–4.18(m,6H),4.00–3.91(m,1H),3.87–3.77(m,1H ),3.67–3.53(m,2H),3.41–2.92(m,9H),2.90–2.61(m,8H),2.58–2.43(m,5H),2.38–2.18(m,5H).

[0846] Example 1-163: Preparation of Compound 163

[0847] Step 1

[0848] 161-1 (50 mg, 93 μmol), 144-1 (43 mg, 77 μmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (12 mg, 16 μmol), and potassium carbonate (32 mg, 0.23 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 85 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 163 (18 mg, yield: 26%).

[0849] MS m / z(ESI): 886.4 [M+1].

[0850] Examples 1-315: Preparation of Compound 315

[0851] Step 1

[0852] 9-7 (40 mg, 74 μmol), 8-9 (42 mg, 74 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (13 mg, 15 μmol), and cesium fluoride (33 mg, 0.22 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 85 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 315 (21 mg, yield: 31%).

[0853] MS m / z(ESI): 892.4 [M+1].

[0854] 1 H NMR (400MHz, DMSO-d6) δ12.20–12.03(m,1H),10.86(s,1H),7.76–7.67(m,1H),7.46–7.35(m,1H),7.01– 6.90(m,2H),6.90–6.82(m,1H),6.72–6.63(m,1H),6.63–6.56(m,2H),6.24–6.14(m,1H),5.68–5.58(m,1 H),5.22–5.12(m,1H),4.52–4.24(m,6H),4.04–3.95(m,1H),3.94–3.86(m,1H),3.81(s,3H),3.57–3.44 (m,2H),3.32–2.74(m,14H),2.69–2.54(m,2H),2.20–2.08(m,1H),2.03–1.85(m,1H),0.93–0.65(m,4H).

[0855] Example 1-365: Preparation of Compound 365

[0856] Step 1

[0857] 365-1 (1 g, 3.14 mmol) was dissolved in isopropanol (15 mL). 389-2 (814 mg, 3.76 mmol), ethylene glycol (389 mg, 6.27 mmol), cuprous iodide (149 mg, 0.78 mmol), and potassium phosphate (1.33 g, 6.27 mmol) were added to the reaction system. The reaction mixture was heated to 100 °C, protected under nitrogen, and reacted at this temperature for 24 hours. The reaction was quenched with water (50 mL), extracted with dichloromethane (100 mL x 3), and the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by vacuum distillation. The residue was purified by silica gel column chromatography to obtain product 365-2 (510 mg, yield: 38%).

[0858] MS m / z(ESI):367.1[M+1-56].

[0859] Step Two

[0860] 365-2 (510 mg, 1.20 mmol) was dissolved in ultradry N,N-dimethylacetamide (10 mL), and sodium hydride (144 mg, 3.61 mmol, 60%) was added at 0 °C. The mixture was stirred at room temperature for 2 hours. The solution was quenched with saturated ammonium chloride aqueous solution (50 mL), extracted with ethyl acetate (100 mL * 2), and the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by vacuum distillation. The residue was purified by silica gel column chromatography to obtain product 365-3 (450 mg, yield: 93%).

[0861] MS m / z(ESI):347.1[M+1-56].

[0862] Step 3

[0863] 365-3 (150 mg, 0.37 mmol) was dissolved in dichloromethane (3 mL), and then an ethyl acetate solution of hydrogen chloride (3 mL) was added. After the addition was complete, the mixture was stirred at 25 °C for 1 hour. The reaction solution was then concentrated under reduced pressure to obtain product 365-4 (135 mg, crude product).

[0864] MS m / z(ESI): 303.1 [M+1].

[0865] Step Four

[0866] 79-1 (158 mg, 0.56 mmol, synthetic method referred to WO2025049820 A1) and 365-4 (135 mg, crude product) were dissolved in a dry tetrahydrofuran and dimethyl sulfoxide mixture (5.2 mL, 10:3). A mixture of potassium acetate (109 mg, 1.11 mmol) and acetic acid (111 mg, 1.85 mmol) was added, and the mixture was stirred under a nitrogen atmosphere for 30 minutes. Then, sodium cyanoborohydride (70 mg, 1.11 mmol) was added. After the addition was complete, the mixture was stirred at 25 °C for 1 hour. The reaction solution was directly purified by reversed-phase C18 column chromatography to obtain product 365-5 (132 mg, yield: 61%).

[0867] MS m / z(ESI): 572.1 [M+1].

[0868] Step 5

[0869] 9-8 (60 mg, 112 μmol), 365-5 (64 mg, 112 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (19 mg, 22 μmol), and cesium fluoride (51 mg, 0.34 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 80 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 365 (20 mg, yield: 20%).

[0870] MS m / z(ESI): 901.4 [M+1].

[0871] 1 H NMR (400MHz, DMSO-d6) δ12.21–12.01(m,1H),11.07(s,1H),7.80–7.65(m,1H),7.49–7. 34(m,2H),7.34–7.24(m,1H),7.02–6.79(m,3H),6.50–6.41(m,1H),6.25–6.06(m,2H), 5.79–5.67(m,1H),4.52–4.20(m,5H),4.11–3.98(m,1H),3.89–3.76(m,1H),3.68–3.50 (m,2H),3.30–2.89(m,13H),2.89–2.52(m,10H),2.42–2.13(m,4H),2.00–1.81(m,1H).

[0872] Example 1-366: Preparation of Compound 366

[0873] Step 1

[0874] 365-1 (1 g, 3.14 mmol) was dissolved in isopropanol (15 mL). 366-1 (814 mg, 3.76 mmol), ethylene glycol (389 mg, 6.27 mmol), cuprous iodide (149 mg, 0.78 mmol), and potassium phosphate (1.33 g, 6.27 mmol) were added to the reaction system. The reaction mixture was heated to 100 °C, protected under nitrogen, and reacted at this temperature for 24 hours. The reaction was quenched with water (50 mL), extracted with dichloromethane (100 mL x 3), and the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by vacuum distillation. The residue was purified by silica gel column chromatography to obtain product 366-2 (550 mg, yield: 41%).

[0875] MS m / z(ESI):367.2[M+1-56].

[0876] Step Two

[0877] 366-2 (550 mg, 1.30 mmol) was dissolved in ultradry N,N-dimethylacetamide (10 mL), and sodium hydride (156 mg, 3.89 mmol, 60%) was added at 0 °C. The mixture was stirred at room temperature for 2 hours. The solution was quenched with saturated ammonium chloride aqueous solution (50 mL), extracted with ethyl acetate (100 mL * 2), and the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by vacuum distillation. The residue was purified by silica gel column chromatography to obtain product 366-3 (455 mg, yield: 87%).

[0878] MS m / z(ESI):347.1[M+1-56].

[0879] Step 3

[0880] 366-3 (150 mg, 0.37 mmol) was dissolved in dichloromethane (3 mL), and then an ethyl acetate solution of hydrogen chloride (3 mL) was added. After the addition was complete, the mixture was stirred at 25 °C for 1 hour. The reaction solution was then concentrated under reduced pressure to give product 366-4 (126 mg, crude product).

[0881] MS m / z(ESI): 303.1 [M+1].

[0882] Step Four

[0883] 79-1 (158 mg, 0.56 mmol, synthetic method referred to WO2025049820 A1) and 366-4 (126 mg, crude product) were dissolved in a dry tetrahydrofuran and dimethyl sulfoxide mixture (5.2 mL, 10:3). A mixture of potassium acetate (109 mg, 1.11 mmol) and acetic acid (111 mg, 1.85 mmol) was added, and the mixture was stirred under a nitrogen atmosphere for 30 minutes. Then, sodium cyanoborohydride (70 mg, 1.11 mmol) was added. After the addition was complete, the mixture was stirred at 25 °C for 1 hour. The reaction solution was directly purified by reversed-phase C18 column chromatography to obtain product 366-5 (140 mg, yield: 65%).

[0884] MS m / z(ESI): 572.3 [M+1].

[0885] Step 5

[0886] 9-8 (60 mg, 112 μmol), 366-5 (64 mg, 112 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (19 mg, 22 μmol), and cesium fluoride (51 mg, 0.34 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 80 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 366 (21 mg, yield: 21%).

[0887] MS m / z(ESI): 901.5 [M+1].

[0888] 1 H NMR (400MHz, DMSO-d6) δ12.21–11.87(m,1H),11.07(s,1H),7.78–7.67(m,1H),7.46–7.35(m, 2H),7.32–7.25(m,1H),7.05(s,1H),7.01–6.82(m,2H),6.79(s,1H),6.53–6.42(m,1H),6.25– 6.16(m,1H),5.79–5.66(m,1H),4.41–4.25(m,5H),4.02–3.91(m,1H),3.90–3.79(m,1H),3.7 0–3.53(m,2H),3.32–2.91(m,13H),2.91–2.52(m,10H),2.41–2.10(m,3H),2.07–1.82(m,2H).

[0889] Example 1-367: Preparation of Compound 367

[0890] Step 1

[0891] 8-9 (60 mg, 107 μmol), 365-5 (61 mg, 107 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (18 mg, 21 μmol), and cesium fluoride (49 mg, 0.32 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 80 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 367 (24 mg, yield: 24%).

[0892] MS m / z(ESI): 927.4 [M+1].

[0893] 1 H NMR (400MHz, DMSO-d6) δ12.28–12.05(m,1H),11.08(s,1H),10.48–10.01(m,1H),7.76–7.68(m,1 H),7.54–7.45(m,1H),7.40–7.35(m,1H),7.05–6.95(m,1H),6.94–6.81(m,2H),6.49–6.41(m,1H ),6.24–6.13(m,1H),5.84–5.70(m,1H),5.68–5.57(m,1H),4.50–4.22(m,6H),4.19–4.03(m,1H) ,3.99–3.36(m,9H),3.32–2.79(m,12H),2.79–2.63(m,5H),2.36–2.16(m,2H),0.99–0.55(m,4H).

[0894] Example 1-368: Preparation of Compound 368

[0895] Step 1

[0896] 8-9 (60 mg, 107 μmol), 366-5 (61 mg, 107 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (18 mg, 21 μmol), and cesium fluoride (49 mg, 0.32 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 80 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 368 (26 mg, yield: 26%).

[0897] MS m / z(ESI): 927.5 [M+1].

[0898] 1 H NMR (400MHz, DMSO-d6) δ12.28–12.05(m,1H),11.08(s,1H),10.48–10.01(m,1H),7.76–7.68(m,1 H),7.54–7.45(m,1H),7.40–7.35(m,1H),7.05–6.95(m,1H),6.94–6.81(m,2H),6.49–6.41(m,1H ),6.24–6.13(m,1H),5.84–5.70(m,1H),5.68–5.57(m,1H),4.57–4.22(m,6H),4.15–3.56(m,7H) ,3.56–3.35(m,5H),3.35–2.90(m,9H),2.90–2.62(m,6H),2.44–2.12(m,2H),0.96–0.56(m,4H).

[0899] Example 1-377: Preparation of Compound 377

[0900] Step 1

[0901] 377-1 (2 g, 6.27 mmol) was dissolved in isopropanol (25 mL). 389-2 (1.63 g, 7.53 mmol), ethylene glycol (0.70 mL, 12.5 mmol), cuprous iodide (299 mg, 1.57 mmol), and potassium phosphate (2.66 g, 12.5 mmol) were added to the reaction mixture. The reaction solution was heated to 100 °C, protected under nitrogen, and reacted at this temperature for 24 hours. The reaction mixture was quenched with water (50 mL), extracted with dichloromethane (100 mL x 3), and the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by vacuum distillation. The residue was purified by silica gel column chromatography to obtain product 377-2 (1.08 g, yield: 42%).

[0902] MS m / z(ESI):351.1[M+1-56].

[0903] Step Two

[0904] 377-2 (1.00 g, 2.45 mmol) was dissolved in ultradry N,N-dimethylacetamide (20 mL), and sodium hydride (393 mg, 9.82 mmol, 60%) was added at 0 °C. The mixture was stirred at 25 °C for 2 hours under a nitrogen atmosphere. The mixture was quenched with saturated ammonium chloride aqueous solution (50 mL), extracted with ethyl acetate (100 mL * 2), and the combined organic phases were washed with saturated brine (50 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by vacuum distillation. The residue was purified by silica gel column chromatography to obtain product 377-3 (853 mg, yield: 89%).

[0905] MS m / z(ESI):331.1[M+1-56].

[0906] Step 3

[0907] 377-3 (200 mg, 0.52 mmol) was dissolved in dichloromethane (2 mL), and then an ethyl acetate solution of hydrogen chloride (2 mL) was added. After the addition was complete, the resulting mixture was stirred at 25 °C for 1 hour. The reaction solution was then concentrated directly under reduced pressure to give product 377-4 (170 mg, crude product).

[0908] MS m / z(ESI):287.1[M+1].

[0909] Step Four

[0910] Dissolve 79-1 (222 mg, 0.78 mmol) and 377-4 (170 mg, crude product) in a dry mixture of tetrahydrofuran and dimethyl sulfoxide (6.5 mL, 10:3). Add potassium acetate (153 mg, 1.56 mmol) and acetic acid (156 mg, 2.60 mmol). Stir the mixture under a nitrogen atmosphere for 30 minutes. Then add sodium cyanoborohydride (98 mg, 1.56 mmol). After the addition is complete, stir the mixture at 25 °C for 1 hour. Purify the reaction solution directly using a reversed-phase C18 column to obtain product 377-5 (133 mg, yield: 30%).

[0911] MS m / z(ESI): 556.3 [M+1].

[0912] Step 5

[0913] 9-8 (40 mg, 74 μmol), 377-5 (42 mg, 74 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (13 mg, 15 μmol), and cesium fluoride (34 mg, 0.22 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 85 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 377 (14 mg, yield: 21%).

[0914] MS m / z(ESI): 885.4 [M+1].

[0915] Example 1-378: Preparation of compound 378

[0916] Step 1

[0917] 377-1 (2 g, 6.27 mmol) was dissolved in isopropanol (25 mL). 366-1 (1.63 g, 7.53 mmol), ethylene glycol (0.70 mL, 12.5 mmol), cuprous iodide (299 mg, 1.57 mmol), and potassium phosphate (2.66 g, 12.5 mmol) were added to the reaction mixture. The reaction solution was heated to 100 °C, protected under nitrogen, and reacted at this temperature for 24 hours. The reaction mixture was quenched with water (50 mL), extracted with dichloromethane (100 mL x 3), and the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by vacuum distillation. The residue was purified by silica gel column chromatography to obtain product 378-1 (1.15 g, yield: 45%).

[0918] MS m / z(ESI):351.1[M+1-56].

[0919] Step Two

[0920] 378-1 (1.10 g, 2.70 mmol) was dissolved in ultradry N,N-dimethylacetamide (20 mL), and sodium hydride (432 mg, 10.80 mmol, 60%) was added at 0 °C. The mixture was stirred at 25 °C for 2 hours under a nitrogen atmosphere. The mixture was quenched with saturated ammonium chloride aqueous solution (50 mL), extracted with ethyl acetate (100 mL * 2), and the combined organic phases were washed with saturated brine (50 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by vacuum distillation. The residue was purified by silica gel column chromatography to obtain product 378-2 (906 mg, yield: 86%).

[0921] MS m / z(ESI):331.1[M+1-56].

[0922] Step 3

[0923] 378-2 (200 mg, 0.52 mmol) was dissolved in dichloromethane (2 mL), and then an ethyl acetate solution of hydrogen chloride (2 mL) was added. After the addition was complete, the resulting mixture was stirred at 25 °C for 1 hour. The reaction solution was then concentrated under reduced pressure to obtain product 378-3 (175 mg, crude product).

[0924] MS m / z(ESI):287.1[M+1].

[0925] Step Four

[0926] Dissolve 79-1 (222 mg, 0.78 mmol) and 378-3 (175 mg, crude product) in a dry mixture of tetrahydrofuran and dimethyl sulfoxide (6.5 mL, 10:3). Add potassium acetate (153 mg, 1.56 mmol) and acetic acid (156 mg, 2.6 mmol). Stir the mixture under a nitrogen atmosphere for 30 minutes, then add sodium cyanoborohydride (98 mg, 1.56 mmol). After the addition is complete, stir the mixture at 25 °C for 1 hour. Purify the reaction solution directly using a reversed-phase C18 column to obtain product 378-4 (126 mg, yield: 29%).

[0927] MS m / z(ESI): 556.3 [M+1].

[0928] Step 5

[0929] 9-8 (40 mg, 74 μmol), 378-4 (42 mg, 74 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (13 mg, 15 μmol), and cesium fluoride (34 mg, 0.22 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 85 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 378 (19 mg, yield: 29%).

[0930] MS m / z(ESI): 885.4 [M+1].

[0931] Example 1-379: Preparation of compound 379

[0932] Step 1

[0933] 377-5 (30 mg, 54 μmol), 8-9 (36 mg, 65 μmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (8 mg, 11 μmol), and potassium carbonate (22 mg, 0.16 mmol) were sequentially added to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 85 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 379 (17 mg, yield: 34%).

[0934] MS m / z(ESI): 911.5 [M+1].

[0935] 1 H NMR(400MHz,DMSO-d6)δ12.29–12.15(m,1H),11.08(s,1H),7.77–7.64(m,1H),7.5 1–7.46(m,1H),7.45–7.31(m,2H),7.19–7.10(m,1H),7.06–6.95(m,3H),6.89–6.8 2(m,1H),6.23–6.15(m,1H),5.82–5.71(m,1H),4.60–4.07(m,6H),4.04–3.30(m,1 4H),3.27–2.63(m,13H),2.27–2.16(m,1H),2.07–1.94(m,1H),0.92–0.59(m,4H).

[0936] Example 1-380: Preparation of Compound 380

[0937] Step 1

[0938] 378-4 (30 mg, 54 μmol), 8-9 (36 mg, 65 μmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (8 mg, 11 μmol), and potassium carbonate (22 mg, 0.16 mmol) were sequentially added to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 85 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 380 (14 mg, yield: 28%).

[0939] MS m / z(ESI): 911.5 [M+1].

[0940] 1 H NMR(400MHz,DMSO-d6)δ12.38–11.96(m,1H),11.07(s,1H),7.77–7.66(m,1H),7.46–7.36(m ,2H),7.32–7.25(m,1H),7.15–7.09(m,1H),7.03–6.90(m,4H),6.86–6.81(m,1H),6.27–6.1 5(m,1H),5.79–5.70(m,1H),4.46–4.26(m,5H),4.03–3.93(m,1H),3.88–3.76(m,1H),3.69– 3.54(m,2H),3.32–2.93(m,12H),2.91–2.52(m,10H),2.39–2.15(m,5H),1.95–1.84(m,1H).

[0941] Example 1-389: Preparation of compound 389

[0942] Step 1

[0943] 389-1 (2 g, 6.27 mmol) was dissolved in isopropanol (25 mL). 389-2 (1.63 g, 7.53 mmol), ethylene glycol (0.70 mL, 12.5 mmol), cuprous iodide (299 mg, 1.57 mmol), and potassium phosphate (2.66 g, 12.5 mmol) were added to the reaction mixture. The reaction solution was heated to 100 °C, protected under nitrogen, and reacted at this temperature for 24 hours. The reaction was quenched with water (50 mL), extracted with dichloromethane (100 mL x 3), and the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by vacuum distillation. The residue was purified by silica gel column chromatography to obtain product 389-3 (1.21 g, yield: 47%).

[0944] MS m / z(ESI):351.1[M+1-56].

[0945] Step Two

[0946] 389-3 (1.35 g, 3.31 mmol) was dissolved in ultradry N,N-dimethylacetamide (25 mL), and sodium hydride (398 mg, 9.94 mmol) was added at 0 °C. The mixture was stirred at room temperature for 2 hours. The solution was quenched with saturated ammonium chloride aqueous solution (50 mL), extracted with ethyl acetate (100 mL * 2), and the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by vacuum distillation. The residue was purified by silica gel column chromatography to give product 389-4 (1.20 g, yield: 93%). MS m / z (ESI): 331.1 [M+1-56].

[0947] Step 3

[0948] Dissolve 389-4 (200 mg, 0.52 mmol) in dichloromethane (2 mL), then add 2 mL of ethyl acetate solution of hydrogen chloride. After the addition is complete, stir the mixture at 25 °C for 1 hour. Concentrate the reaction solution directly under reduced pressure to obtain product 389-5 (170 mg, crude product).

[0949] MS m / z(ESI):287.1[M+1].

[0950] Step Four

[0951] 79-1 (222 mg, 0.78 mmol, synthetic method referred to WO2025049820 A1) and 389-5 (170 mg, crude product) were dissolved in a dry tetrahydrofuran and dimethyl sulfoxide mixture (6.5 mL, 10:3). A mixture of potassium acetate (153 mg, 1.56 mmol) and acetic acid (156 mg, 2.6 mmol) was added, and the mixture was stirred under a nitrogen atmosphere for 30 minutes. Then, sodium cyanoborohydride (98 mg, 1.56 mmol) was added. After the addition was complete, the mixture was stirred at 25 °C for 1 hour. The reaction solution was directly purified by reversed-phase C18 column chromatography to obtain product 389-6 (160 mg, yield: 54%).

[0952] MS m / z(ESI): 556.3 [M+1].

[0953] Step 5

[0954] 9-8 (60 mg, 112 μmol), 389-6 (62 mg, 112 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (19 mg, 22 μmol), and cesium fluoride (51 mg, 0.34 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 80 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 389 (20 mg, yield: 20%).

[0955] MS m / z(ESI): 885.6 [M+1].

[0956] Example 1-390: Preparation of compound 390

[0957] Step 1

[0958] Dissolve 79-1 (100 mg, 0.35 mmol, synthetic method referred to WO2025049820 A1) and 11-2 (149 mg, 0.52 mmol) in a dry mixture of tetrahydrofuran and dimethyl sulfoxide (5.2 mL, 10:3). Add potassium acetate (102.5 mg, 1.04 mmol) and acetic acid (104.6 mg, 1.74 mmol). Stir the mixture under nitrogen atmosphere for 30 minutes. Then add sodium cyanoborohydride (65.7 mg, 1.04 mmol). After the addition is complete, stir the mixture at 25 °C for 1 hour. Purify the reaction solution directly by reversed-phase C18 column to obtain product 390-1 (125 mg, yield: 63%).

[0959] MS m / z(ESI): 556.4 [M+1].

[0960] Step Two

[0961] 9-8 (60 mg, 112 μmol), 390-1 (62.25 mg, 112 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (18.97 mg, 22 μmol), and cesium fluoride (51.07 mg, 0.34 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 80 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 390 (22 mg, yield: 22%).

[0962] MS m / z(ESI): 885.5 [M+1].

[0963] Example 1-391: Preparation of compound 391

[0964] Step 1

[0965] 389-6 (30 mg, 54 μmol), 8-9 (36 mg, 65 μmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (8 mg, 11 μmol), and potassium carbonate (22 mg, 0.16 mmol) were sequentially added to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 85 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 391 (16 mg, yield: 28%).

[0966] MS m / z(ESI): 892.4 [M+1].

[0967] Example 1-392: Preparation of compound 392

[0968] Step 1

[0969] 390-1 (30 mg, 54 μmol), 8-9 (36 mg, 65 μmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (8 mg, 11 μmol), and potassium carbonate (22 mg, 0.16 mmol) were sequentially added to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 85 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high performance liquid chromatography to obtain product 392 (21 mg, yield: 43%).

[0970] MS m / z(ESI): 892.4 [M+1].

[0971] Example 1-393: Preparation of compound 393

[0972] Step 1

[0973] 389-6 (30 mg, 54 μmol), 161-1 (35 mg, 65 μmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (8 mg, 11 μmol), and potassium carbonate (22 mg, 0.16 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 85 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 393 (11 mg, yield: 23%).

[0974] MS m / z(ESI): 867.4 [M+1].

[0975] Example 1-394: Preparation of Compound 394

[0976] Step 1

[0977] 390-1 (30 mg, 54 μmol), 161-1 (35 mg, 65 μmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (8 mg, 11 μmol), and potassium carbonate (22 mg, 0.16 mmol) were sequentially added to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 85 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 394 (13 mg, yield: 27%).

[0978] MS m / z(ESI): 867.4 [M+1].

[0979] Example 1-395: Preparation of Compound 395

[0980] Step 1

[0981] 389-6 (30 mg, 54 μmol), 131-3 (35 mg, 65 μmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (8 mg, 11 μmol), and potassium carbonate (22 mg, 0.16 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 85 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 395 (9 mg, yield: 18%).

[0982] MS m / z(ESI): 893.4 [M+1].

[0983] Example 1-396: Preparation of Compound 396

[0984] Step 1

[0985] 390-1 (30 mg, 54 μmol), 131-3 (35 mg, 65 μmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (8 mg, 11 μmol), and potassium carbonate (22 mg, 0.16 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 85 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 396 (12 mg, yield: 24%).

[0986] MS m / z(ESI): 893.4 [M+1].

[0987] Example 1-397: Preparation of compound 397

[0988] Step 1

[0989] 365-5 (30 mg, 52 μmol), 161-1 (35 mg, 65 μmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (8 mg, 11 μmol), and potassium carbonate (22 mg, 0.16 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 85 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to yield product 397 (11 mg, yield: 23%).

[0990] MS m / z(ESI): 902.3 [M+1].

[0991] Example 1-398: Preparation of Compound 398

[0992] Step 1

[0993] 366-5 (30 mg, 52 μmol), 161-1 (35 mg, 65 μmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (8 mg, 11 μmol), and potassium carbonate (22 mg, 0.16 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 85 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 398 (18 mg, yield: 37%).

[0994] MS m / z(ESI): 902.3 [M+1].

[0995] Example 1-399: Preparation of compound 399

[0996] Step 1

[0997] 365-5 (30 mg, 52 μmol), 131-3 (37 mg, 65 μmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (8 mg, 11 μmol), and potassium carbonate (22 mg, 0.16 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 85 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to yield product 399 (14 mg, yield: 27%).

[0998] MS m / z(ESI): 928.3 [M+1].

[0999] Example 1-400: Preparation of Compound 400

[1000] Step 1

[1001] 366-5 (30 mg, 52 μmol), 131-3 (37 mg, 65 μmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (8 mg, 11 μmol), and potassium carbonate (22 mg, 0.16 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 85 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to yield product 400 (15 mg, yield: 28%).

[1002] MS m / z(ESI): 928.3 [M+1].

[1003] Example 1-409: Preparation of compound 409

[1004] Step 1

[1005] 377-5 (30 mg, 54 μmol), 161-1 (35 mg, 65 μmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (8 mg, 11 μmol), and potassium carbonate (22 mg, 0.16 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 85 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to yield product 409 (12 mg, yield: 23%).

[1006] MS m / z(ESI): 886.4 [M+1].

[1007] Examples 1-410: Preparation of compound 410

[1008] Step 1

[1009] 378-4 (30 mg, 54 μmol), 161-1 (35 mg, 65 μmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (8 mg, 11 μmol), and potassium carbonate (22 mg, 0.16 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 85 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to yield product 410 (15 mg, yield: 29%).

[1010] MS m / z(ESI): 886.4 [M+1].

[1011] Examples 1-411: Preparation of compound 411

[1012] Step 1

[1013] 377-5 (30 mg, 54 μmol), 131-3 (36 mg, 65 μmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (8 mg, 11 μmol), and potassium carbonate (22 mg, 0.16 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 85 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 411 (11 mg, yield: 22%).

[1014] MS m / z(ESI): 912.4 [M+1].

[1015] Examples 1-412: Preparation of compound 412

[1016] Step 1

[1017] 378-4 (30 mg, 54 μmol), 131-3 (36 mg, 65 μmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (8 mg, 11 μmol), and potassium carbonate (22 mg, 0.16 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 85 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 412 (13 mg, yield: 25%).

[1018] MS m / z(ESI): 912.4 [M+1].

[1019] Examples 1-421: Preparation of compound 421

[1020] Step 1

[1021] 79-3 (30 mg, 53 μmol), 131-3 (36 mg, 64 μmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (8 mg, 11 μmol), and potassium carbonate (22 mg, 0.16 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 85 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 421 (14 mg, yield: 28%).

[1022] MS m / z(ESI): 918.4 [M+1].

[1023] Examples 1-422: Preparation of compound 422

[1024] Step 1

[1025] 422-1 (1 g, 3.32 mmol) was dissolved in isopropanol (15 mL). 389-2 (862 mg, 3.99 mmol), ethylene glycol (413 mg, 6.65 mmol), cuprous iodide (158 mg, 0.83 mmol), and potassium phosphate (1.41 g, 6.65 mmol) were added to the reaction system. The reaction mixture was heated to 100 °C, protected under nitrogen, and reacted at this temperature for 24 hours. The reaction was quenched with water (50 mL), extracted with dichloromethane (100 mL x 3), and the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by vacuum distillation. The residue was purified by silica gel column chromatography to obtain product 422-2 (435 mg, yield: 34%).

[1026] MS m / z(ESI):333.1[M+1-56].

[1027] Step Two

[1028] 422-2 (435 mg, 1.20 mmol) was dissolved in ultradry N,N-dimethylacetamide (10 mL), and sodium hydride (134 mg, 3.35 mmol, 60%) was added at 0 °C. The mixture was stirred at room temperature for 2 hours. The solution was quenched with saturated ammonium chloride aqueous solution (50 mL), extracted with ethyl acetate (100 mL * 2), and the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by vacuum distillation. The residue was purified by silica gel column chromatography to obtain product 422-3 (350 mg, yield: 85%).

[1029] MS m / z(ESI):313.1[M+1-56].

[1030] Step 3

[1031] 422-3 (150 mg, 0.41 mmol) was dissolved in dichloromethane (3 mL), and then an ethyl acetate solution of hydrogen chloride (3 mL) was added. After the addition was complete, the resulting mixture was stirred at 25 °C for 1 hour. The reaction solution was then concentrated under reduced pressure to obtain product 422-4 (125 mg, crude product).

[1032] MS m / z(ESI):269.1[M+1].

[1033] Step Four

[1034] 79-1 (175 mg, 0.62 mmol, synthetic method referred to WO2025049820 A1) and 422-4 (125 mg, crude product) were dissolved in a dry tetrahydrofuran and dimethyl sulfoxide mixture (5.2 mL, 10:3). A mixture of potassium acetate (121 mg, 1.23 mmol) and acetic acid (123 mg, 2.05 mmol) was added, and the mixture was stirred under a nitrogen atmosphere for 30 minutes. Then, sodium cyanoborohydride (77 mg, 1.23 mmol) was added. After the addition was complete, the mixture was stirred at 25 °C for 1 hour. The reaction solution was directly purified by reversed-phase C18 column chromatography to obtain product 422-5 (135 mg, yield: 60%).

[1035] MS m / z(ESI): 538.1 [M+1].

[1036] Step 5

[1037] 9-8 (60 mg, 112 μmol), 422-5 (60 mg, 112 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (19 mg, 22 μmol), and cesium fluoride (51 mg, 0.34 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 80 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 422 (30 mg, yield: 31%).

[1038] MS m / z(ESI): 867.4 [M+1].

[1039] 1 H NMR(400MHz,DMSO-d6)δ12.27–12.11(m,1H),11.08(s,1H),7.77–7.66(m,1H),7.5 3–7.31(m,3H),7.25–7.11(m,2H),7.11–7.04(m,1H),7.04–6.90(m,2H),6.86–6.7 9(m,1H),6.22–6.16(m,1H),5.82–5.71(m,1H),4.45–4.19(m,6H),4.15–4.04(m,1 H),3.93–3.77(m,2H),3.69–3.02(m,14H),3.02–2.52(m,10H),2.40–2.15(m,4H).

[1040] Example 1-423: Preparation of compound 423

[1041] Step 1

[1042] 422-1 (1 g, 3.32 mmol) was dissolved in isopropanol (15 mL). 366-1 (862 mg, 3.99 mmol), ethylene glycol (413 mg, 6.65 mmol), cuprous iodide (158 mg, 0.83 mmol), and potassium phosphate (1.41 g, 6.65 mmol) were added to the reaction system. The reaction mixture was heated to 100 °C, protected under nitrogen, and reacted at this temperature for 24 hours. The reaction was quenched with water (50 mL), extracted with dichloromethane (100 mL x 3), and the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by vacuum distillation. The residue was purified by silica gel column chromatography to obtain product 423-1 (480 mg, yield: 37%).

[1043] MS m / z(ESI):333.2[M+1-56].

[1044] Step Two

[1045] 423-1 (480 mg, 1.23 mmol) was dissolved in ultradry N,N-dimethylacetamide (10 mL), and sodium hydride (148 mg, 3.70 mmol, 60%) was added at 0 °C. The mixture was stirred at room temperature for 2 hours. The solution was quenched with saturated ammonium chloride aqueous solution (50 mL), extracted with ethyl acetate (100 mL * 2), and the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by vacuum distillation. The residue was purified by silica gel column chromatography to obtain product 423-2 (360 mg, yield: 79%).

[1046] MS m / z(ESI):313.2[M+1-56].

[1047] Step 3

[1048] 423-2 (150 mg, 0.41 mmol) was dissolved in dichloromethane (3 mL), and then an ethyl acetate solution of hydrogen chloride (3 mL) was added. After the addition was complete, the resulting mixture was stirred at 25 °C for 1 hour. The reaction solution was then concentrated under reduced pressure to obtain product 423-3 (120 mg, crude product).

[1049] MS m / z(ESI):269.1[M+1].

[1050] Step Four

[1051] 79-1 (175 mg, 0.62 mmol, synthetic method referred to WO2025049820 A1) and 423-3 (125 mg, crude product) were dissolved in a dry tetrahydrofuran and dimethyl sulfoxide mixture (5.2 mL, 10:3). A mixture of potassium acetate (121 mg, 1.23 mmol) and acetic acid (123 mg, 2.05 mmol) was added, and the mixture was stirred under a nitrogen atmosphere for 30 minutes. Then, sodium cyanoborohydride (77 mg, 1.23 mmol) was added. After the addition was complete, the mixture was stirred at 25 °C for 1 hour. The reaction solution was directly purified by reversed-phase C18 column chromatography to obtain product 423-4 (140 mg, yield: 62%).

[1052] MS m / z(ESI): 538.2 [M+1].

[1053] Step 5

[1054] 9-8 (60 mg, 112 μmol), 423-4 (60 mg, 112 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (19 mg, 22 μmol), and cesium fluoride (51 mg, 0.34 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 80 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 423 (28 mg, yield: 29%).

[1055] MS m / z(ESI): 867.4 [M+1].

[1056] 1 H NMR(400MHz,DMSO-d6)δ12.49–11.96(m,1H),11.07(s,1H),7.76–7.67(m,1H),7.45– 7.38(m,1H),7.33–7.24(m,1H),7.08–6.91(m,4H),6.84(s,1H),6.23–6.15(m,1H),5. 76–5.63(m,2H),4.52–4.24(m,5H),4.15–4.04(m,1H),3.87–3.74(m,1H),3.57–3.44( m,2H),3.32–2.91(m,13H),2.91–2.53(m,11H),2.44–2.16(m,2H),0.93–0.69(m,4H).

[1057] Examples 1-424: Preparation of Compound 424

[1058] Step 1

[1059] 8-9 (60 mg, 107 μmol), 422-5 (58 mg, 107 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (18 mg, 21 μmol), and cesium fluoride (49 mg, 0.32 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 80 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 424 (20 mg, yield: 21%).

[1060] MS m / z(ESI): 893.6 [M+1].

[1061] 1 H NMR (400MHz, DMSO-d6) δ12.27–12.02(m,1H),10.91(s,1H),7.75–7.62(m,2H),7.45–7.35(m,2 H),7.30–7.23(m,1H),7.16–7.09(m,1H),6.89–6.72(m,2H),6.38–6.32(m,1H),6.22–6.15(m,1 H),5.62–5.55(m,1H),4.51–4.32(m,6H),4.29(s,3H),4.20–4.06(m,1H),3.94–3.77(m,1H),3 .73–3.35(m,11H),3.21–2.86(m,9H),2.79–2.51(m,2H),2.43–2.07(m,2H),0.92–0.67(m,4H).

[1062] Examples 1-425: Preparation of Compound 425

[1063] Step 1

[1064] 8-9 (60 mg, 107 μmol), 423-4 (58 mg, 107 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (18 mg, 21 μmol), and cesium fluoride (49 mg, 0.32 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 80 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 425 (25 mg, yield: 26%).

[1065] MS m / z(ESI): 893.5 [M+1].

[1066] 1 H NMR (400MHz, DMSO-d6) δ12.36–11.77(m,1H),11.09(s,1H),7.75–7.68(m,1H),7.52–7.42(m,1 H),7.39–7.33(m,1H),7.25–7.06(m,3H),7.03–6.91(m,2H),6.82(s,1H),6.23–6.16(m,1H),5. 81–5.72(m,1H),5.68–5.62(m,1H),4.52–4.21(m,6H),4.15–4.05(m,1H),3.93–3.78(m,1H),3 .67–3.44(m,8H),3.33–2.92(m,10H),2.92–2.52(m,7H),2.44–2.10(m,2H),0.93–0.68(m,4H).

[1067] Examples 1-426: Preparation of Compound 426

[1068] Step 1

[1069] 422-5 (30 mg, 54 μmol), 161-1 (35 mg, 65 μmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (8 mg, 11 μmol), and potassium carbonate (22 mg, 0.16 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 85 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 426 (15 mg, yield: 32%).

[1070] MS m / z(ESI): 868.5 [M+1].

[1071] Examples 1-427: Preparation of Compound 427

[1072] Step 1

[1073] 423-4 (30 mg, 54 μmol), 161-1 (35 mg, 65 μmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (8 mg, 11 μmol), and potassium carbonate (22 mg, 0.16 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 85 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 427 (12 mg, yield: 25%).

[1074] MS m / z(ESI): 868.5 [M+1].

[1075] Examples 1-428: Preparation of Compound 428

[1076] Step 1

[1077] 422-5 (30 mg, 55 μmol), 131-3 (36 mg, 65 μmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (8 mg, 11 μmol), and potassium carbonate (22 mg, 0.16 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 85 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 428 (10 mg, yield: 20%).

[1078] MS m / z(ESI): 894.4 [M+1].

[1079] Examples 1-429: Preparation of compound 429

[1080] Step 1

[1081] 423-4 (30 mg, 55 μmol), 131-3 (36 mg, 65 μmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (8 mg, 11 μmol), and potassium carbonate (22 mg, 0.16 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 85 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 429 (15 mg, yield: 30%).

[1082] MS m / z(ESI): 894.4 [M+1].

[1083] Examples 1-430: Preparation of Compound 430

[1084] Step 1

[1085] Methyltriphenylphosphine bromide (13.44 g, 37.63 mmol) was added to dry tetrahydrofuran (150 mL). Under nitrogen protection, the mixture was cooled to 0 °C, and then a tetrahydrofuran solution of bis(trimethylsilyl)aminopotassium (37.63 mL, 1 mol / L) was slowly added dropwise. The resulting mixture was heated to 25 °C and stirred for 1 hour. Then, the mixture was cooled to -70 °C, and a tetrahydrofuran solution of 430-1 (5.00 g, 25.09 mmol, dissolved in 50 mL of tetrahydrofuran) was slowly added dropwise. After the addition was complete, the mixture was heated to 25 °C and stirred for another 12 hours. A saturated ammonium chloride solution (300 mL) was slowly added to the reaction mixture, followed by extraction with ethyl acetate (200 mL * 3). The organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give product 430-2 (2.13 g, yield: 40%).

[1086] MS m / z(ESI):212.2[M+1].

[1087] Step Two

[1088] At -10°C, a solution of 430-2 (2.10 g, 9.93 mmol) in N,N-dimethylformamide (5 mL) was added dropwise to a suspension of sodium hydride (586 mg, 14.89 mmol, 60%) in tetrahydrofuran (30 mL). The resulting mixture was stirred at 0°C for 30 minutes, followed by the dropwise addition of propargyl bromide (1.77 g, 14.89 mmol). After the addition was complete, the mixture was heated to 25°C and stirred for 16 hours. The reaction mixture was slowly poured into ice water (50 mL), extracted with ethyl acetate (40 mL x 3), and the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by vacuum distillation. The residue was purified by silica gel column chromatography to give product 430-3 (1.26 g, yield: 50%).

[1089] MS m / z(ESI):250.2[M+1].

[1090] Step 3

[1091] 430-3 (1.25 g, 5.01 mmol) was dissolved in dry toluene (20 mL). Cuprous chloride (49 mg, 0.50 mmol), pinacol diborate (1.40 g, 5.51 mmol), tri-tert-butylphosphine tetrafluoroborate (173 mg, 0.60 mmol), and sodium tert-butoxide (48 mg, 0.50 mmol) were added sequentially under an argon atmosphere. Methanol (406 μL, 10.02 mmol) was then slowly added dropwise to the stirred reaction mixture. The resulting mixture was stirred at 25 °C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated by vacuum distillation. The residue was purified by silica gel column chromatography to give product 430-4 (912 mg, yield: 48%).

[1092] MS m / z(ESI): 378.3 [M+1].

[1093] Step Four

[1094] 430-4 (900 mg, 2.38 mmol) was dissolved in dry dichloromethane (30 mL), and the mixture was refluxed under a nitrogen atmosphere for 1 hour. The reaction solution was cooled to 25 °C, and then Grubbs second-generation catalyst (360 mg, 0.43 mmol) was added. The resulting mixture was stirred at 25 °C for 16 hours. The reaction solution was filtered, and the filtrate was concentrated by vacuum distillation. The residue was purified by silica gel column chromatography to give product 430-5 (386 mg, yield: 46%).

[1095] MS m / z(ESI): 350.3 [M+1].

[1096] Step 5

[1097] 430-5 (380 mg, 1.08 mmol) was added to an ethyl acetate hydrochloride solution (4 mol / L, 6 mL), and the resulting mixture was stirred at 25 °C for 1 hour. The reaction solution was then directly concentrated under reduced pressure to give product 430-6 (337 mg).

[1098] MS m / z(ESI):250.2[M+1].

[1099] Step Six

[1100] Dissolve 1-6 (150 mg, 1.07 mmol) in dry pyridine (2 mL), and add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (246 mg, 1.28 mmol) and 430-6 (337 mg, 1.18 mmol) sequentially under a nitrogen atmosphere. The resulting mixture is stirred at 25 °C for 5 hours. The reaction solution is directly concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give product 430-7 (211 mg, yield: 53%).

[1101] MS m / z(ESI): 372.4 [M+1].

[1102] Step Seven

[1103] 430-7 (210 mg, 0.56 mmol), 1-8 (183 mg, 0.56 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (81 mg, 0.12 mmol), and potassium carbonate (232 mg, 1.68 mmol) were added sequentially to a mixed solution of 1,4-dioxane (4 mL) and water (1 mL). The resulting mixture was heated to 80 °C and stirred for 12 hours under a nitrogen atmosphere. After cooling the reaction solution to room temperature, water (15 mL) was added, and the mixture was extracted with ethyl acetate (15 mL * 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by vacuum distillation. The residue was purified by high-performance liquid chromatography to obtain product 430-8 (141 mg, yield: 52%).

[1104] MS m / z(ESI):484.2[M+1].

[1105] Step 8

[1106] 430-8 (140 mg, 0.29 mmol) was dissolved in dimethyl sulfoxide (3 mL), followed by the sequential addition of pinacol diborate (151 mg, 0.58 mmol), potassium acetate (85 mg, 0.87 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (49 mg, 58 μmol). The resulting mixture was heated to 95 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high performance liquid chromatography to yield product 430-9 (95 mg, yield: 57%).

[1107] MS m / z(ESI): 576.3 [M+1].

[1108] Step Nine

[1109] 430-9 (40 mg, 69 μmol), 1-11 (36 mg, 69 μmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (10 mg, 14 μmol), and potassium carbonate (28 mg, 0.21 mmol) were sequentially added to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 85 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 430 (19 mg, yield: 30%).

[1110] MS m / z(ESI): 896.4 [M+1].

[1111] 1 H NMR (400MHz, DMSO-d6) δ12.25–12.14(m,1H),10.84(s,1H),7.77–7.67(m,1H),7.47–7.28(m,2 H),7.11–6.96(m,2H),6.75–6.69(m,1H),6.69–6.63(m,1H),6.63–6.55(m,1H),6.28–6.15(m,2 H),5.19–5.09(m,1H),4.46–4.19(m,5H),3.82(s,3H),3.78–3.58(m,2H),3.31–2.91(m,13H), 2.91–2.74(m,1H),2.70–2.55(m,1H),2.20–2.08(m,1H),2.08–1.80(m,9H),1.50–1.27(m,1H).

[1112] Examples 1-431: Preparation of compounds 431 and 432

[1113] Compound 1 (57 mg, 64 μmol) was separated by chirality using SFC (column: OX column, 250 × 20 mm, 10 μm; mobile phase: A-n-heptane, B-isopropanol / acetonitrile (0.1% ammonia), isocratic elution, B%: 80%), yielding single-configuration compound 431 (shorter retention time) and single-configuration compound 432 (longer retention time).

[1114] Compound 431, a single configuration, is a white solid, 18 mg, with a yield of 31%.

[1115] MS m / z(ESI): 882.3 [M+1].

[1116] 1 H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.86(s,1H),7.69–7.62(m,1H),7.48–7.38(m,1H) ),7.38–7.29(m,1H),7.08–6.92(m,2H),6.77–6.64(m,2H),6.64–6.54(m,1H),6.25–6.0 2(m,2H),5.23–5.10(m,1H),4.44–4.23(m,3H),3.82(s,3H),3.32–2.95(m,18H),2.94–2 .71(m,3H),2.71–2.52(m,1H),2.43–2.06(m,2H),2.03–1.84(m,1H),1.45–0.46(m,3H).

[1117] Compound 432, a single configuration, is a white solid, 24 mg, with a yield of 42%.

[1118] MS m / z(ESI): 882.3 [M+1].

[1119] 1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),10.86(s,1H),7.69–7.62(m,1H),7.48–7.38(m,1H) ),7.38–7.29(m,1H),7.08–6.92(m,2H),6.77–6.64(m,2H),6.64–6.54(m,1H),6.25–6.0 2(m,2H),5.23–5.10(m,1H),4.44–4.23(m,3H),3.82(s,3H),3.32–2.95(m,18H),2.94–2 .71(m,3H),2.71–2.52(m,1H),2.43–2.06(m,2H),2.03–1.84(m,1H),1.45–0.46(m,3H).

[1120] Examples 1-432: Preparation of compounds 433 and 434

[1121] Compound 8 (35 mg, 45 μmol) was separated by chirality using SFC (column: OX column, 250 × 20 mm, 10 μm; mobile phase: A-n-heptane, B-ethanol / acetonitrile (0.1% ammonia), isocratic elution, B%: 80%), yielding single-configuration compound 433 (shorter retention time) and single-configuration compound 434 (longer retention time).

[1122] Compound 433, a single configuration, is a white solid, 13 mg, with a yield of 32%.

[1123] MS m / z(ESI): 882.3 [M+1].

[1124] 1 H NMR(400MHz,DMSO-d6)δ12.29–12.13(m,1H),10.86(s,1H),7.77–7.65(m,1H),7.48–7.23(m,2H),7 .13–6.94(m,2H),6.76–6.54(m,3H),6.27–6.10(m,1H),5.72–5.58(m,1H),5.21–5.11(m,1H),4.51– 4.43(m,1H),4.41–4.33(m,3H),4.33–4.24(m,1H),3.82(s,3H),3.57–3.45(m,2H),3.41–2.91(m,1 5H),2.88–2.75(m,1H),2.69–2.53(m,1H),2.34–2.12(m,2H),2.01–1.86(m,1H),0.89–0.70(m,4H).

[1125] The single-configuration compound 434 is a white solid, 13 mg, with a yield of 32%.

[1126] MS m / z(ESI): 882.3 [M+1].

[1127] 1 H NMR(400MHz,DMSO-d6)δ12.29–12.13(m,1H),10.86(s,1H),7.77–7.65(m,1H),7.48–7.23(m,2H),7 .13–6.94(m,2H),6.76–6.54(m,3H),6.27–6.10(m,1H),5.72–5.58(m,1H),5.21–5.11(m,1H),4.51– 4.43(m,1H),4.41–4.33(m,3H),4.33–4.24(m,1H),3.82(s,3H),3.57–3.45(m,2H),3.41–2.91(m,1 5H),2.88–2.75(m,1H),2.69–2.53(m,1H),2.34–2.12(m,2H),2.01–1.86(m,1H),0.89–0.70(m,4H).

[1128] Examples 1-433: Preparation of compounds 435 and 436

[1129] Compound 9 (17 mg, 19 μmol) was separated by chirality using SFC (column: OX column, 250 × 20 mm, 10 μm; mobile phase: A-n-heptane, B-ethanol / acetonitrile (0.1% ammonia), isocratic elution, B%: 100%), yielding single-configuration compound 435 (shorter retention time) and single-configuration compound 436 (longer retention time).

[1130] Compound 435, a single configuration, is a white solid, 7 mg, with a yield of 41%.

[1131] MS m / z(ESI): 866.4 [M+1].

[1132] 1H NMR(400MHz,DMSO-d6)δ12.24–11.99(m,1H),10.86(s,1H),7.83–7.51(m,1H),7.58– 7.31(m,1H),7.11–6.78(m,3H),6.72–6.65(m,1H),6.65–6.56(m,2H),6.25–6.09(m,2 H),4.45–4.23(m,6H),4.09–3.87(m,2H),3.81(s,3H),3.69–3.53(m,2H),3.42–2.73 (m,14H),2.69–2.54(m,2H),2.40–2.21(m,2H),2.20–2.08(m,1H),2.04–1.87(m,1H).

[1133] Compound 436, a single configuration, is a white solid, 7 mg, with a yield of 41%.

[1134] MS m / z(ESI): 866.4 [M+1].

[1135] 1 H NMR(400MHz,DMSO-d6)δ12.24–11.99(m,1H),10.86(s,1H),7.83–7.51(m,1H),7 .58–7.31(m,1H),7.01–6.90(m,2H),6.90–6.85(m,1H),6.72–6.65(m,1H),6.65– 6.56(m,2H),6.25–6.09(m,2H),4.45–4.23(m,6H),4.09–3.87(m,2H),3.81(s,3 H),3.69–3.53(m,2H),3.42–2.73(m,14H),2.69–2.54(m,2H),2.41–1.86(m,4H).

[1136] Examples 1-434: Preparation of compounds 437 and 438

[1137] Compound 16 (50 mg, 43 μmol) was separated by chirality using SFC (column: WHELK column, 250 × 20 mm, 10 μm; mobile phase: A-carbon dioxide, B-ethanol / acetonitrile (0.1% ammonia), isocratic elution, B%: 60%), yielding single-configuration compound 437 (shorter retention time) and single-configuration compound 438 (longer retention time).

[1138] The single-configuration compound 437 is a white solid, 17 mg, with a yield of 34%.

[1139] MS m / z(ESI): 800.3 [M+1].

[1140] 1 H NMR (400MHz, DMSO-d6) δ12.31–12.08(m,1H),10.83(s,1H),7.76–7.68(m,1H),7.66–7 .58(m,2H),7.48–7.36(m,3H),7.12–6.95(m,4H),6.91–6.80(m,1H),6.24–6.13(m,1H) ,5.70–5.61(m,1H),4.53–4.32(m,4H),3.88–3.76(m,1H),3.56–3.41(m,4H),3.31–2. 89(m,9H),2.89–2.59(m,3H),2.44–2.17(m,2H),2.11–1.80(m,5H),0.93–0.69(m,4H).

[1141] Compound 438, a single configuration, is a white solid, 18 mg, with a yield of 36%.

[1142] MS m / z(ESI): 800.3 [M+1].

[1143] 1 H NMR (400MHz, DMSO-d6) δ12.31–12.08(m,1H),10.83(s,1H),7.76–7.68(m,1H),7.66–7 .58(m,2H),7.48–7.36(m,3H),7.12–6.95(m,4H),6.91–6.80(m,1H),6.24–6.13(m,1H) ,5.70–5.61(m,1H),4.53–4.32(m,4H),3.88–3.76(m,1H),3.56–3.41(m,4H),3.31–2. 89(m,9H),2.89–2.59(m,3H),2.44–2.17(m,2H),2.11–1.80(m,5H),0.93–0.69(m,4H).

[1144] Examples 1-435: Preparation of compounds 439 and 440

[1145] Compound 79 (38 mg, 41 μmol) was separated by chirality using SFC (column: WHELK column, 250 × 20 mm, 10 μm; mobile phase: A-carbon dioxide, B-ethanol / acetonitrile (0.1% ammonia), isocratic elution, B%: 70%), yielding single-configuration compound 439 (shorter retention time) and single-configuration compound 440 (longer retention time).

[1146] Compound 439, a single configuration, is a white solid, yielding 13 mg in 34% yield.

[1147] MS m / z(ESI): 917.3 [M+1].

[1148] 1 H NMR (400MHz, DMSO-d6) δ12.26–12.13(m,1H),11.07(s,1H),7.85–7.62(m,1H),7.43–7. 39(m,1H),7.35–7.25(m,2H),7.23–7.14(m,1H),7.02–6.89(m,2H),6.56–6.45(m,1H), 6.23–6.13(m,1H),5.78–5.68(m,1H),5.68–5.59(m,1H),4.53–4.25(m,4H),3.59–3.44 (m,2H),3.30–2.79(m,12H),2.77–2.59(m,14H),2.41–2.10(m,2H),0.92–0.66(m,4H).

[1149] Compound 440, a single configuration, is a white solid, 16 mg, with a yield of 42%.

[1150] MS m / z(ESI): 917.3 [M+1].

[1151] 1H NMR (400MHz, DMSO-d6) δ12.26–12.13(m,1H),11.07(s,1H),7.85–7.62(m,1H),7.43–7. 39(m,1H),7.35–7.25(m,2H),7.23–7.14(m,1H),7.02–6.89(m,2H),6.56–6.45(m,1H), 6.23–6.13(m,1H),5.78–5.68(m,1H),5.68–5.59(m,1H),4.53–4.25(m,4H),3.59–3.44 (m,2H),3.30–2.79(m,12H),2.77–2.59(m,14H),2.41–2.10(m,2H),0.92–0.66(m,4H).

[1152] Examples 1-436: Preparation of compounds 441 and 442

[1153] Compound 118 (45 mg, 56 μmol) was separated by chirality using SFC (column: WHELK column, 250 × 20 mm, 10 μm; mobile phase: A-carbon dioxide, B-ethanol / acetonitrile (0.1% ammonia)) to obtain single-configuration compound 441 (shorter retention time) and single-configuration compound 442 (longer retention time).

[1154] Compound 441, a single configuration, is a white solid, 18 mg, with a yield of 40%.

[1155] MS m / z(ESI):801.4[M+1].

[1156] 1 H NMR (400MHz, DMSO-d6) δ12.23–12.13(m,1H),10.83(s,1H),8.16–8.05(m,1H),7.74–7.64(m,1H) ),7.64–7.56(m,2H),7.50–7.39(m,2H),7.14–6.90(m,4H),6.91–6.83(m,1H),5.76–5.61(m,1H) ,4.68–4.56(m,2H),4.53–4.40(m,2H),3.87–3.77(m,1H),3.58–3.43(m,4H),3.29–2.94(m,4H) ,2.88–2.60(m,4H),2.55–2.32(m,4H),2.30–2.15(m,1H),2.07–1.80(m,6H),0.94–0.71(m,4H).

[1157] Compound 442, a single configuration, is a white solid, 16 mg, with a yield of 35%.

[1158] MS m / z(ESI):801.4[M+1].

[1159] 1 H NMR (400MHz, DMSO-d6) δ12.23–12.13(m,1H),10.83(s,1H),8.16–8.05(m,1H),7.74–7.64(m,1H) ),7.64–7.56(m,2H),7.50–7.39(m,2H),7.14–6.90(m,4H),6.91–6.83(m,1H),5.76–5.61(m,1H) ,4.68–4.56(m,2H),4.53–4.40(m,2H),3.87–3.77(m,1H),3.58–3.43(m,4H),3.29–2.94(m,4H) ,2.88–2.60(m,4H),2.55–2.32(m,4H),2.30–2.15(m,1H),2.07–1.80(m,6H),0.94–0.71(m,4H).

[1160] Examples 1-437: Preparation of compounds 443 and 444

[1161] Compound 130 (40 mg, 44 μmol) was chirally separated by SFC to obtain single-configuration compound 443 (shorter retention time) and single-configuration compound 444 (longer retention time).

[1162] Compound 443, a single configuration, is a white solid, 15 mg, with a yield of 37%.

[1163] MS m / z(ESI): 911.4 [M+1].

[1164] The single-configuration compound 444 is a white solid, 14 mg, with a yield of 35%.

[1165] MS m / z(ESI): 911.4 [M+1].

[1166] Examples 1-438: Preparation of compounds 445 and 446

[1167] Compound 131 (25 mg, 27 μmol) was chirally separated by SFC to obtain single-configuration compound 445 (shorter retention time) and single-configuration compound 446 (longer retention time).

[1168] Compound 445, a single configuration, is a white solid, yielding 8 mg in 32% yield.

[1169] MS m / z(ESI): 912.2 [M+1].

[1170] Compound 446, a single configuration, is a white solid, 10 mg, yield: 40%.

[1171] MS m / z(ESI): 912.2 [M+1].

[1172] Examples 1-439: Preparation of compounds 447 and 448

[1173] Compound 144 (50 mg, 55 μmol) was chirally separated by SFC to obtain single-configuration compound 447 (shorter retention time) and single-configuration compound 448 (longer retention time).

[1174] Compound 447, a single configuration, is a white solid, 19 mg, with a yield of 38%.

[1175] MS m / z(ESI): 911.3 [M+1].

[1176] Compound 448, a single configuration, is a white solid, yielding 23 mg in 46% yield.

[1177] MS m / z(ESI): 911.3 [M+1].

[1178] Examples 1-440: Preparation of compounds 449 and 450

[1179] Compound 145 (19 mg, 21 μmol) was chirally separated by SFC to obtain single-configuration compound 449 (shorter retention time) and single-configuration compound 450 (longer retention time).

[1180] Compound 449, a single configuration, is a white solid, yielding 8 mg in 42% yield.

[1181] MS m / z(ESI): 912.3 [M+1].

[1182] Compound 450, a single configuration, is a white solid, yielding 7 mg in 36% yield.

[1183] MS m / z(ESI): 912.3 [M+1].

[1184] Examples 1-441: Preparation of compounds 451 and 452

[1185] Compound 160 (61 mg, 69 μmol) was separated by chirality using SFC (column: WHELK column, 250 × 20 mm, 10 μm; mobile phase: A-n-heptane, B-ethanol / acetonitrile (0.1% ammonia), isocratic elution, B%: 70%), yielding single-configuration compound 451 (shorter retention time) and single-configuration compound 452 (longer retention time).

[1186] Compound 451, a single configuration, is a white solid, yielding 22 mg in 36% yield.

[1187] MS m / z(ESI): 885.2 [M+1].

[1188] 1 H NMR (400MHz, DMSO-d6) δ12.32–11.94(m,1H),11.07(s,1H),7.77–7.68(m,1H),7.46–7.36(m ,2H),7.33–7.24(m,1H),6.99–6.87(m,3H),6.87–6.81(m,1H),6.63–6.55(m,1H),6.23–6.1 6(m,1H),5.77–5.68(m,1H),4.43–4.23(m,5H),4.00–3.90(m,1H),3.88–3.78(m,1H),3.67– 3.54(m,2H),3.29–2.91(m,11H),2.91–2.59(m,11H),2.36–2.17(m,5H),1.94–1.84(m,1H).

[1189] Compound 452, a single configuration, is a white solid, 27 mg, with a yield of 44%.

[1190] MS m / z(ESI): 885.2 [M+1].

[1191] 1H NMR(400MHz,DMSO-d6)δ12.29–12.02(m,1H),11.07(s,1H),7.79–7.63(m,1H),7.47– 7.34(m,2H),7.32–7.24(m,1H),7.00–6.87(m,3H),6.87–6.80(m,1H),6.60(s,1H),6. 25–6.16(m,1H),5.78–5.68(m,1H),4.40–4.26(m,5H),3.99–3.77(m,2H),3.69–3.53( m,2H),3.30–2.90(m,11H),2.90–2.55(m,11H),2.40–2.17(m,5H),1.96–1.84(m,1H).

[1192] Examples 1-442: Preparation of compounds 453 and 454

[1193] Compound 161 (22 mg, 25 μmol) was chirally separated by SFC to obtain single-configuration compound 453 (shorter retention time) and single-configuration compound 454 (longer retention time).

[1194] Compound 453, a single configuration, is a white solid, 9 mg, with a yield of 40%.

[1195] MS m / z(ESI): 886.4 [M+1].

[1196] The single-configuration compound 454 is a white solid, 8 mg, with a yield of 36%.

[1197] MS m / z(ESI): 886.4 [M+1].

[1198] Examples 1-443: Preparation of compounds 455 and 456

[1199] Compound 162 (44 mg, 50 μmol) was separated by chirality using SFC (column: WHELK column, 250 × 20 mm, 10 μm; mobile phase: A-n-heptane, B-ethanol / acetonitrile (0.1% ammonia), isocratic elution, B%: 70%), yielding single-configuration compound 455 (shorter retention time) and single-configuration compound 456 (longer retention time).

[1200] Compound 455, a single configuration, is a white solid, 16 mg, with a yield of 36%.

[1201] MS m / z(ESI): 885.4 [M+1].

[1202] 1 H NMR (400MHz, DMSO-d6) δ12.29–11.94(m,1H),11.07(s,1H),7.76–7.67(m,1H),7.48–7.39(m,1 H),7.38–7.36(m,1H),7.33–7.25(m,1H),6.99–6.87(m,3H),6.87–6.79(m,1H),6.60(s,1H),6. 23–6.15(m,1H),5.78–5.66(m,1H),4.46–4.23(m,5H),4.02–3.87(m,1H),3.87–3.77(m,1H),3. 70–3.54(m,2H),3.31–2.92(m,12H),2.92–2.53(m,10H),2.37–2.16(m,5H),1.93–1.84(m,1H).

[1203] Compound 456, a single configuration, is a white solid, 18 mg, with a yield of 40%.

[1204] MS m / z(ESI): 885.4 [M+1].

[1205] 1 H NMR (400MHz, DMSO-d6) δ12.26–11.94(m,1H),11.07(s,1H),7.77–7.68(m,1H),7.46–7. 35(m,2H),7.33–7.25(m,1H),7.00–6.82(m,4H),6.63–6.58(m,1H),6.23–6.15(m,1H), 5.79–5.68(m,1H),4.41–4.24(m,5H),4.00–3.90(m,1H),3.87–3.77(m,1H),3.69–3.54 (m,2H),3.31–2.90(m,11H),2.89–2.54(m,11H),2.36–2.18(m,5H),1.95–1.83(m,1H).

[1206] Examples 1-444: Preparation of compounds 457 and 458

[1207] Compound 163 (37 mg, 42 μmol) was chirally separated by SFC to obtain single-configuration compound 457 (shorter retention time) and single-configuration compound 458 (longer retention time).

[1208] The single-configuration compound 457 is a white solid, 13 mg, with a yield of 35%.

[1209] MS m / z(ESI): 886.3 [M+1].

[1210] Compound 458, a single configuration, is a white solid, yielding 17 mg in 45% yield.

[1211] MS m / z(ESI): 886.3 [M+1].

[1212] Examples 1-445: Preparation of compounds 459 and 460

[1213] Compound 365 (20 mg, 22 μmol) was separated by chirality using SFC (column: WHELK column, 250 × 20 mm, 10 μm; mobile phase: A-n-heptane, B-ethanol, isocratic elution, B%: 80%) to obtain single-configuration compound 459 (shorter retention time) and single-configuration compound 460 (longer retention time).

[1214] Compound 459, a single configuration, is a white solid, yielding 8 mg in 40% yield.

[1215] MS m / z(ESI): 901.3 [M+1].

[1216] 1 H NMR (400MHz, DMSO-d6) δ12.25–12.00(m,1H),11.07(s,1H),7.75–7.68(m,1H),7.45–7.35(m, 2H),7.33–7.24(m,1H),7.05(s,1H),7.00–6.83(m,2H),6.79(s,1H),6.50–6.44(m,1H),6.24– 6.16(m,1H),5.77–5.67(m,1H),4.42–4.23(m,5H),4.01–3.91(m,1H),3.89–3.79(m,1H),3.6 9–3.52(m,2H),3.27–2.91(m,11H),2.91–2.52(m,12H),2.46–2.13(m,4H),1.94–1.82(m,1H).

[1217] Compound 460, a single configuration, is a white solid, yielding 7 mg in 35% yield.

[1218] MS m / z(ESI): 901.3 [M+1].

[1219] 1H NMR (400MHz, DMSO-d6) δ12.25–11.98(m,1H),11.07(s,1H),7.77–7.66(m,1H),7.46–7.35(m, 2H),7.33–7.23(m,1H),7.05(s,1H),7.01–6.83(m,2H),6.79(s,1H),6.52–6.43(m,1H),6.23– 6.15(m,1H),5.78–5.67(m,1H),4.44–4.23(m,5H),4.03–3.92(m,1H),3.89–3.79(m,1H),3.6 9–3.53(m,2H),3.28–2.90(m,11H),2.90–2.53(m,12H),2.38–2.16(m,4H),1.94–1.81(m,1H).

[1220] Examples 1-446: Preparation of compounds 461 and 462

[1221] Compound 366 (30 mg, 33 μmol) was separated by chirality using SFC (column: WHELK column, 250 × 20 mm, 10 μm; mobile phase: A-n-heptane, B-ethanol / acetonitrile, isocratic elution, B%: 70%) to obtain single-configuration compound 461 (shorter retention time) and single-configuration compound 462 (longer retention time).

[1222] Compound 461, a single configuration, is a white solid, 12 mg, with a yield of 40%.

[1223] MS m / z(ESI): 901.3 [M+1].

[1224] 1 H NMR (400MHz, DMSO-d6) δ12.21–12.05(m,1H),11.07(s,1H),7.78–7.64(m,1H),7.48–7.3 4(m,2H),7.34–7.22(m,1H),7.05(s,1H),7.01–6.83(m,2H),6.79(s,1H),6.51–6.43(m,1 H),6.23–6.16(m,1H),5.79–5.66(m,1H),4.45–4.23(m,5H),4.02–3.78(m,2H),3.70–3. 53(m,2H),3.32–2.91(m,10H),2.91–2.52(m,13H),2.41–2.10(m,4H),1.95–1.79(m,1H).

[1225] Compound 462, a single configuration, is a white solid, 13 mg, with a yield of 43%.

[1226] MS m / z(ESI): 901.3 [M+1].

[1227] 1 H NMR(400MHz,DMSO-d6)δ12.21–12.00(m,1H),11.06(s,1H),7.77–7.66(m,1H),7.46–7.3 6(m,2H),7.33–7.24(m,1H),7.05(s,1H),7.01–6.82(m,2H),6.79(s,1H),6.51–6.44(m,1 H),6.23–6.15(m,1H),5.77–5.69(m,1H),4.44–4.24(m,5H),4.03–3.77(m,2H),3.70–3. 50(m,2H),3.31–2.91(m,10H),2.92–2.52(m,13H),2.38–2.14(m,4H),1.94–1.82(m,1H).

[1228] Examples 1-447: Preparation of compounds 463 and 464

[1229] Compound 367 (30 mg, 32 μmol) was separated by chirality using SFC (column: WHELK column, 250 × 20 mm, 10 μm; mobile phase: A-n-heptane, B-ethanol / acetonitrile, isocratic elution, B%: 70%) to obtain single-configuration compound 463 (shorter retention time) and single-configuration compound 464 (longer retention time).

[1230] The single-configuration compound 463 was a white solid, 11 mg, with a yield of 36%.

[1231] MS m / z(ESI): 927.3 [M+1].

[1232] 1H NMR (400MHz, DMSO-d6) δ12.24–12.05(m,1H),11.07(s,1H),7.76–7.69(m,1H),7.50–7.34(m,1 H),7.34–7.25(m,1H),7.15–6.76(m,4H),6.51–6.42(m,1H),6.24–6.15(m,1H),5.81–5.68(m,1 (H), 5.68–5.59 (m, 1H), 4.66–4.20 (m, 5H), 4.06–3.78 (m, 2H), 3.57–3.44 (m, 2H), 3.27–2.89 (m, 15H), 2.89–2.61 (m, 6H), 2.48–1.80 (m, 5H), 0.93–0.70 (m, 4H). Monomorphic compound 464, white solid, 10 mg, yield: 33%.

[1233] MS m / z(ESI): 927.3 [M+1].

[1234] 1 H NMR (400MHz, DMSO-d6) δ12.20–12.05(m,1H),11.07(s,1H),7.75–7.68(m,1H),7.47–7.36( m,1H),7.36–7.24(m,1H),7.15–6.78(m,4H),6.51–6.43(m,1H),6.23–6.15(m,1H),5.80–5. 69(m,1H),5.67–5.58(m,1H),4.53–4.25(m,5H),4.06–3.77(m,2H),3.59–3.44(m,2H),3.27 –2.90(m,15H),2.88–2.56(m,6H),2.54–2.11(m,4H),2.00–1.81(m,1H),0.89–0.67(m,4H).

[1235] Examples 1-448: Preparation of compounds 465 and 466

[1236] Compound 368 (26 mg, 28 μmol) was separated by chirality using SFC (column: WHELK column, 250 × 20 mm, 10 μm; mobile phase: A-n-heptane, B-ethanol / acetonitrile (0.1% ammonia), isocratic elution, B%: 80%), yielding single-configuration compound 465 (shorter retention time) and single-configuration compound 466 (longer retention time).

[1237] Compound 465, a single configuration, is a white solid, 10 mg, with a yield of 38%.

[1238] MS m / z(ESI): 927.3 [M+1].

[1239] 1 H NMR (400MHz, DMSO-d6) δ12.19–12.04(m,1H),11.07(s,1H),7.76–7.67(m,1H),7.45–7.38(m,1H),7.33 –7.25(m,1H),7.05(s,1H),7.00–6.83(m,2H),6.78(s,1H),6.50–6.43(m,1H),6.23–6.14(m,1H),5.79– 5.68(m,1H),5.67–5.58(m,1H),4.52–4.42(m,1H),4.42–4.27(m,4H),4.03–3.79(m,2H),3.57–3.45(m ,2H),3.32–2.89(m,13H),2.89–2.52(m,10H),2.36–2.16(m,2H),1.95–1.82(m,1H),0.90–0.66(m,4H).

[1240] The single-configuration compound 466 is a white solid, 9 mg, with a yield of 34%.

[1241] MS m / z(ESI): 927.3 [M+1].

[1242] 1 H NMR (400MHz, DMSO-d6) δ12.16–12.06(m,1H),11.07(s,1H),7.75–7.66(m,1H),7.43–7.38(m,1H),7.32 –7.24(m,1H),7.05(s,1H),6.99–6.83(m,2H),6.78(s,1H),6.50–6.43(m,1H),6.23–6.16(m,1H),5.78 –5.69(m,1H),5.68–5.58(m,1H),4.53–4.26(m,5H),4.02–3.92(m,1H),3.92–3.77(m,1H),3.57–3.46( m,2H),3.33–2.92(m,14H),2.91–2.51(m,9H),2.37–2.15(m,2H),1.94–1.81(m,1H),0.91–0.67(m,4H).

[1243] Examples 1-449: Preparation of compounds 467 and 468

[1244] Compound 377 (55 mg, 62 μmol) was chirally separated by SFC to obtain single-configuration compound 467 (shorter retention time) and single-configuration compound 468 (longer retention time).

[1245] Compound 467, a single configuration, is a white solid, 18 mg, with a yield of 32%.

[1246] MS m / z(ESI): 885.4 [M+1].

[1247] Compound 468, a single configuration, is a white solid, 22 mg, with a yield of 40%.

[1248] MS m / z(ESI): 885.4 [M+1].

[1249] Examples 1-450: Preparation of compounds 469 and 470

[1250] Compound 378 (40 mg, 45 μmol) was chirally separated by SFC to obtain single-configuration compound 469 (shorter retention time) and single-configuration compound 470 (longer retention time).

[1251] Compound 469, a single configuration, is a white solid, yielding 15 mg in 37% yield.

[1252] MS m / z(ESI): 885.4 [M+1].

[1253] Compound 470, a single configuration, is a white solid, yielding 14 mg in 35% yield.

[1254] MS m / z(ESI): 885.4 [M+1].

[1255] Examples 1-451: Preparation of compounds 471 and 472

[1256] Compound 379 (40 mg, 44 μmol) was separated by chirality using SFC (column: WHELK column, 250 × 20 mm, 10 μm; mobile phase: A-n-heptane, B-ethanol / acetonitrile, isocratic elution, B%: 70%) to obtain single-configuration compound 471 (shorter retention time) and single-configuration compound 472 (longer retention time).

[1257] Compound 471, a single configuration, is a white solid, yielding 13 mg in 32% yield.

[1258] MS m / z(ESI): 911.2 [M+1].

[1259] 1 H NMR (400MHz, DMSO-d6) δ12.29–12.11(m,1H),11.07(s,1H),7.75–7.69(m,1H),7. 44–7.37(m,2H),7.33–7.26(m,1H),7.04–6.93(m,3H),6.89–6.80(m,1H),6.24–6. 14(m,1H),5.78–5.69(m,1H),5.69–5.64(m,1H),4.51–4.26(m,5H),4.16–4.03(m, 1H),3.63–3.05(m,17H),3.05–2.59(m,8H),2.50–2.16(m,4H),0.92–0.70(m,4H).

[1260] Compound 472, a single configuration, is a white solid, 14 mg, with a yield of 35%.

[1261] MS m / z(ESI): 911.2 [M+1].

[1262] 1 H NMR (400MHz, DMSO-d6) δ12.34–12.08(m,1H),11.07(s,1H),7.78–7.63(m,1H),7.59–7.22(m,3H),7.22–6.76(m,4H),6.28–6.14(m,1H),5.86–5. 56(m,2H),4.59–4.00(m,5H),3.92–3.66(m,1H),3.58–3.44(m,2H),3.26 –2.79(m,18H),2.79–2.58(m,5H),2.54–2.10(m,4H),0.94–0.67(m,4H).

[1263] Examples 1-452: Preparation of compounds 473 and 474

[1264] Compound 380 (50 mg, 54 μmol) was chirally separated by SFC to obtain single-configuration compound 473 (shorter retention time) and single-configuration compound 474 (longer retention time).

[1265] Compound 473, a single configuration, is a white solid, 21 mg, with a yield of 42%.

[1266] MS m / z(ESI): 911.2 [M+1].

[1267] Compound 474, a single configuration, is a white solid, yielding 18 mg in 36% yield.

[1268] MS m / z(ESI): 911.2 [M+1].

[1269] Examples 1-453: Preparation of compounds 475 and 476

[1270] Compound 389 (45 mg, 51 μmol) was chirally separated by SFC to obtain single-configuration compound 475 (shorter retention time) and single-configuration compound 476 (longer retention time).

[1271] Compound 475, a single configuration, is a white solid, 20 mg, with a yield of 44%.

[1272] MS m / z(ESI): 885.4 [M+1].

[1273] Compound 476, a single configuration, is a white solid, 18 mg, with a yield of 40%.

[1274] MS m / z(ESI): 885.4 [M+1].

[1275] Examples 1-454: Preparation of compounds 477 and 478

[1276] Compound 390 (30 mg, 34 μmol) was chirally separated by SFC to obtain single-configuration compound 477 (shorter retention time) and single-configuration compound 478 (longer retention time).

[1277] Compound 477, a single configuration, is a white solid, 11 mg, with a yield of 36%.

[1278] MS m / z(ESI): 885.4 [M+1].

[1279] Compound 478, a single configuration, is a white solid, 12 mg, with a yield of 40%.

[1280] MS m / z(ESI): 885.4 [M+1].

[1281] Examples 1-455: Preparation of compounds 479 and 480

[1282] Compound 391 (30 mg, 33 μmol) was chirally separated by SFC to obtain single-configuration compound 479 (shorter retention time) and single-configuration compound 480 (longer retention time).

[1283] Compound 479, a single configuration, is a white solid, 13 mg, with a yield of 43%.

[1284] MS m / z(ESI): 911.4 [M+1].

[1285] Compound 480, a single configuration, is a white solid, 9 mg, with a yield of 30%.

[1286] MS m / z(ESI): 911.4 [M+1].

[1287] Examples 1-456: Preparation of compounds 481 and 482

[1288] Compound 392 (30 mg, 33 μmol) was chirally separated by SFC to obtain single-configuration compound 481 (shorter retention time) and single-configuration compound 482 (longer retention time).

[1289] Compound 481, a single configuration, is a white solid, yielding 11 mg in 36% yield.

[1290] MS m / z(ESI): 911.4 [M+1].

[1291] Compound 482, a single configuration, is a white solid, yielding 11 mg in 36% yield.

[1292] MS m / z(ESI): 911.4 [M+1].

[1293] Examples 1-457: Preparation of compounds 483 and 484

[1294] Compound 393 (40 mg, 45 μmol) was chirally separated by SFC to obtain single-configuration compound 483 (shorter retention time) and single-configuration compound 484 (longer retention time).

[1295] Compound 483, a single configuration, is a white solid, 15 mg, with a yield of 37%.

[1296] MS m / z(ESI): 886.4 [M+1].

[1297] Compound 484, a single configuration, is a white solid, 16 mg, with a yield of 40%.

[1298] MS m / z(ESI): 886.4 [M+1].

[1299] Examples 1-458: Preparation of compounds 485 and 486

[1300] Compound 394 (40 mg, 45 μmol) was chirally separated by SFC to obtain single-configuration compound 485 (shorter retention time) and single-configuration compound 486 (longer retention time).

[1301] Compound 485, a single configuration, is a white solid, yielding 14 mg in 35% yield.

[1302] MS m / z(ESI): 886.4 [M+1].

[1303] Compound 486, a single configuration, is a white solid, 16 mg, with a yield of 40%.

[1304] MS m / z(ESI): 886.4 [M+1].

[1305] Examples 1-459: Preparation of compounds 487 and 488

[1306] Compound 395 (25 mg, 27 μmol) was chirally separated by SFC to obtain single-configuration compound 487 (shorter retention time) and single-configuration compound 488 (longer retention time).

[1307] Compound 487, a single configuration, is a white solid, 9 mg, with a yield of 36%.

[1308] MS m / z(ESI): 912.3 [M+1].

[1309] Compound 488, a single configuration, is a white solid, 9 mg, with a yield of 36%.

[1310] MS m / z(ESI): 912.3 [M+1].

[1311] Examples 1-460: Preparation of compounds 489 and 490

[1312] Compound 396 (40 mg, 44 μmol) was chirally separated by SFC to obtain single-configuration compound 489 (shorter retention time) and single-configuration compound 490 (longer retention time).

[1313] Compound 489, a single configuration, is a white solid, yielding 14 mg in 35% yield.

[1314] MS m / z(ESI): 912.3 [M+1].

[1315] Compound 490, a single configuration, is a white solid, yielding 15 mg in 37% yield.

[1316] MS m / z(ESI): 912.3 [M+1].

[1317] Examples 1-461: Preparation of compounds 491 and 492

[1318] Compound 397 (30 mg, 33 μmol) was chirally separated by SFC to obtain single-configuration compound 491 (shorter retention time) and single-configuration compound 492 (longer retention time).

[1319] Compound 491, a single configuration, is a white solid, 11 mg, with a yield of 36%.

[1320] MS m / z(ESI): 902.3 [M+1].

[1321] Compound 492, a single configuration, is a white solid, yielding 13 mg in 43% yield.

[1322] MS m / z(ESI): 902.3 [M+1].

[1323] Examples 1-462: Preparation of compounds 493 and 494

[1324] Compound 398 (30 mg, 33 μmol) was chirally separated by SFC to obtain single-configuration compound 493 (shorter retention time) and single-configuration compound 494 (longer retention time).

[1325] Compound 493, a single configuration, is a white solid, 10 mg, yield: 33%.

[1326] MS m / z(ESI): 902.3 [M+1].

[1327] Compound 494, a single configuration, is a white solid, 13 mg, with a yield of 43%.

[1328] MS m / z(ESI): 902.3 [M+1].

[1329] Examples 1-463: Preparation of compounds 495 and 496

[1330] Compound 399 (35 mg, 38 μmol) was chirally separated by SFC to obtain single-configuration compound 495 (shorter retention time) and single-configuration compound 496 (longer retention time).

[1331] Compound 495, a single configuration, is a white solid, 15 mg, with a yield of 42%.

[1332] MS m / z(ESI): 928.3 [M+1].

[1333] Compound 496, a single configuration, is a white solid, yielding 13 mg in 37% yield.

[1334] MS m / z(ESI): 928.3 [M+1].

[1335] Examples 1-464: Preparation of compounds 497 and 498

[1336] Compound 400 (30 mg, 32 μmol) was chirally separated by SFC to obtain single-configuration compound 497 (shorter retention time) and single-configuration compound 498 (longer retention time).

[1337] Compound 497, a single configuration, is a white solid, 11 mg, with a yield of 36%.

[1338] MS m / z(ESI): 928.3 [M+1].

[1339] Compound 498, a single configuration, is a white solid, 12 mg, with a yield of 40%.

[1340] MS m / z(ESI): 928.3 [M+1].

[1341] Examples 1-465: Preparation of compounds 499 and 500

[1342] Compound 409 (30 mg, 34 μmol) was chirally separated by SFC to obtain single-configuration compound 499 (shorter retention time) and single-configuration compound 500 (longer retention time).

[1343] Compound 499, a single configuration, is a white solid, 9 mg, with a yield of 30%.

[1344] MS m / z(ESI): 886.3 [M+1].

[1345] Compound 500, a single configuration, is a white solid, 12 mg, with a yield of 40%.

[1346] MS m / z(ESI): 886.3 [M+1].

[1347] Examples 1-466: Preparation of compounds 501 and 502

[1348] Compound 410 (30 mg, 34 μmol) was chirally separated by SFC to obtain single-configuration compound 501 (shorter retention time) and single-configuration compound 502 (longer retention time).

[1349] Compound 501, a single configuration, is a white solid, 10 mg, with a yield of 33%.

[1350] MS m / z(ESI): 886.3 [M+1].

[1351] The single-configuration compound 502 is a white solid, 12 mg, with a yield of 40%.

[1352] MS m / z(ESI): 886.3 [M+1].

[1353] Examples 1-467: Preparation of compounds 503 and 504

[1354] Compound 411 (28 mg, 31 μmol) was chirally separated by SFC to obtain single-configuration compound 503 (shorter retention time) and single-configuration compound 504 (longer retention time).

[1355] The single-configuration compound 503 was a white solid, 9 mg, with a yield of 32%.

[1356] MS m / z(ESI): 912.4 [M+1].

[1357] Compound 504, a single configuration, is a white solid, 9 mg, with a yield of 32%.

[1358] MS m / z(ESI): 912.4 [M+1].

[1359] Examples 1-468: Preparation of compounds 505 and 506

[1360] Compound 412 (35 mg, 38 μmol) was chirally separated by SFC to obtain single-configuration compound 505 (shorter retention time) and single-configuration compound 506 (longer retention time).

[1361] Compound 505, a single configuration, is a white solid, 13 mg, with a yield of 37%.

[1362] MS m / z(ESI): 912.4 [M+1].

[1363] The single-configuration compound 506 is a white solid, 11 mg, yield: 31%.

[1364] MS m / z(ESI): 912.4 [M+1].

[1365] Examples 1-469: Preparation of compounds 507 and 508

[1366] Compound 421 (30 mg, 33 μmol) was chirally separated by SFC to obtain single-configuration compound 507 (shorter retention time) and single-configuration compound 508 (longer retention time).

[1367] Compound 507, a single configuration, is a white solid, 10 mg, yield: 33%.

[1368] MS m / z(ESI): 918.4 [M+1].

[1369] The single-configuration compound 508 was a white solid, 11 mg, with a yield of 36%.

[1370] MS m / z(ESI): 918.4 [M+1].

[1371] Examples 1-470: Preparation of compounds 509 and 510

[1372] Compound 422 (30 mg, 35 μmol) was separated by chirality using SFC (column: WHELK column, 250 × 20 mm, 10 μm; mobile phase: A-n-heptane, B-ethanol, isocratic elution, B%: 80%) to obtain single-configuration compound 509 (shorter retention time) and single-configuration compound 510 (longer retention time).

[1373] Compound 509, a single configuration, is a white solid, 10 mg, with a yield of 33%.

[1374] MS m / z(ESI): 867.2 [M+1].

[1375] 1H NMR(400MHz,DMSO-d6)δ12.23–12.00(m,1H),11.07(s,1H),7.75–7.68(m,1H),7.45–7.36 (m,2H),7.32–7.24(m,1H),7.16–7.09(m,1H),7.05–6.89(m,4H),6.84(s,1H),6.23–6.15( m,1H),5.78–5.69(m,1H),4.43–4.23(m,5H),4.04–3.93(m,1H),3.87–3.77(m,1H),3.69– 3.55(m,2H),3.30–2.92(m,13H),2.92–2.52(m,9H),2.39–2.15(m,5H),1.97–1.83(m,1H).

[1376] Compound 510, a single configuration, is a white solid, 9 mg, with a yield of 30%.

[1377] MS m / z(ESI): 867.2 [M+1].

[1378] 1 H NMR(400MHz,DMSO-d6)δ12.25–11.90(m,1H),11.06(s,1H),7.76–7.69(m,1H),7.46–7.35 (m,2H),7.32–7.24(m,1H),7.15–7.08(m,1H),7.04–6.89(m,4H),6.84(s,1H),6.22–6.15( m,1H),5.76–5.68(m,1H),4.42–4.24(m,5H),4.04–3.93(m,1H),3.87–3.74(m,1H),3.69– 3.55(m,2H),3.28–2.92(m,14H),2.92–2.52(m,8H),2.36–2.18(m,5H),1.96–1.84(m,1H).

[1379] Examples 1-471: Preparation of compounds 511 and 512

[1380] Compound 423 (30 mg, 35 μmol) was chirally separated by SFC to obtain single-configuration compound 511 (shorter retention time) and single-configuration compound 512 (longer retention time).

[1381] Compound 511, a single configuration, is a white solid, 10 mg, yield: 33%.

[1382] MS m / z(ESI): 867.2 [M+1].

[1383] Compound 512, a single configuration, is a white solid, 10 mg, yield: 33%.

[1384] MS m / z(ESI): 867.2 [M+1].

[1385] Examples 1-472: Preparation of compounds 513 and 514

[1386] Compound 424 (40 mg, 45 μmol) was chirally separated by SFC to obtain single-configuration compound 513 (shorter retention time) and single-configuration compound 514 (longer retention time).

[1387] Compound 513, a single configuration, is a white solid, 15 mg, with a yield of 37%.

[1388] MS m / z(ESI): 893.4 [M+1].

[1389] The single-configuration compound 514 is a white solid, 16 mg, with a yield of 40%.

[1390] MS m / z(ESI): 893.4 [M+1].

[1391] Examples 1-473: Preparation of compounds 515 and 516

[1392] Compound 425 (40 mg, 45 μmol) was chirally separated by SFC to obtain single-configuration compound 515 (shorter retention time) and single-configuration compound 516 (longer retention time).

[1393] Compound 515, a single configuration, is a white solid, 14 mg, with a yield of 35%.

[1394] MS m / z(ESI): 893.4 [M+1].

[1395] Compound 516, a single configuration, is a white solid, yielding 17 mg in 42% yield.

[1396] MS m / z(ESI): 893.4 [M+1].

[1397] Examples 1-474: Preparation of compounds 517 and 518

[1398] Compound 426 (40 mg, 46 μmol) was chirally separated by SFC to obtain single-configuration compound 517 (shorter retention time) and single-configuration compound 518 (longer retention time).

[1399] Compound 517, a single configuration, is a white solid, 16 mg, with a yield of 40%.

[1400] MS m / z(ESI): 868.4 [M+1].

[1401] Compound 518, a single configuration, is a white solid, 15 mg, with a yield of 37%.

[1402] MS m / z(ESI): 868.4 [M+1].

[1403] Examples 1-475: Preparation of compounds 519 and 520

[1404] Compound 427 (30 mg, 35 μmol) was chirally separated by SFC to obtain single-configuration compound 519 (shorter retention time) and single-configuration compound 520 (longer retention time).

[1405] Compound 519, a single configuration, is a white solid, 11 mg, with a yield of 36%.

[1406] MS m / z(ESI): 868.4 [M+1].

[1407] Compound 520, a single configuration, is a white solid, 11 mg, with a yield of 36%.

[1408] MS m / z(ESI): 868.4 [M+1].

[1409] Examples 1-476: Preparation of compounds 521 and 522

[1410] Compound 428 (30 mg, 33 μmol) was chirally separated by SFC to obtain single-configuration compound 521 (shorter retention time) and single-configuration compound 522 (longer retention time).

[1411] Compound 521, a single configuration, is a white solid, 11 mg, with a yield of 36%.

[1412] MS m / z(ESI): 894.4 [M+1].

[1413] Compound 522, a single configuration, is a white solid, 9 mg, with a yield of 30%.

[1414] MS m / z(ESI): 894.4 [M+1].

[1415] Examples 1-477: Preparation of compounds 523 and 524

[1416] Compound 429 (30 mg, 33 μmol) was chirally separated by SFC to obtain single-configuration compound 523 (shorter retention time) and single-configuration compound 524 (longer retention time).

[1417] Compound 523, a single configuration, is a white solid, 10 mg, yield: 33%.

[1418] MS m / z(ESI): 894.4 [M+1].

[1419] Compound 524, a single configuration, is a white solid, 10 mg, yield: 33%.

[1420] MS m / z(ESI): 894.4 [M+1].

[1421] Examples 1-478: Preparation of compounds 525 and 526

[1422] Compound 430 (40 mg, 45 μmol) was separated by chirality using SFC (column: OX column, 250 × 20 mm, 10 μm; mobile phase: A-n-heptane, B-ethanol / acetonitrile (0.1% ammonia), isocratic elution, B%: 80%), yielding single-configuration compound 525 (shorter retention time) and single-configuration compound 526 (longer retention time).

[1423] Compound 525, a single configuration, is a white solid, 15 mg, with a yield of 37%.

[1424] MS m / z(ESI): 896.4 [M+1].

[1425] 1H NMR (400MHz, DMSO-d6) δ12.25–12.14(m,1H),10.84(s,1H),7.77–7.67(m,1H),7.47–7.28(m,2 H),7.11–6.96(m,2H),6.75–6.69(m,1H),6.69–6.63(m,1H),6.63–6.55(m,1H),6.28–6.15(m,2 H),5.19–5.09(m,1H),4.46–4.19(m,5H),3.82(s,3H),3.78–3.58(m,2H),3.31–2.91(m,13H), 2.91–2.74(m,1H),2.70–2.55(m,1H),2.20–2.08(m,1H),2.08–1.80(m,9H),1.50–1.27(m,1H).

[1426] Compound 526, a single configuration, is a white solid, 16 mg, with a yield of 40%.

[1427] MS m / z(ESI): 896.4 [M+1].

[1428] 1 H NMR (400MHz, DMSO-d6) δ12.25–12.14(m,1H),10.84(s,1H),7.77–7.67(m,1H),7.47–7.28(m,2 H),7.11–6.96(m,2H),6.75–6.69(m,1H),6.69–6.63(m,1H),6.63–6.55(m,1H),6.28–6.15(m,2 H),5.19–5.09(m,1H),4.46–4.19(m,5H),3.82(s,3H),3.78–3.58(m,2H),3.31–2.91(m,13H), 2.91–2.74(m,1H),2.70–2.55(m,1H),2.20–2.08(m,1H),2.08–1.80(m,9H),1.50–1.27(m,1H).

[1429] Examples 1-479: Preparation of Compound 527

[1430] Step 1

[1431] 389-5 (200 mg, 0.69 mmol) was dissolved in dry N,N-dimethylformamide (8 mL). Under a nitrogen atmosphere, 9-3 (131 mg, 0.69 mmol) and potassium carbonate (286 mg, 2.07 mmol) were added. After the addition was complete, the mixture was stirred at 80 °C for 12 hours. The reaction solution was cooled to below 25 °C and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give product 527-1 (211 mg, yield: 67%).

[1432] MS m / z(ESI):456.1[M+1].

[1433] Step Two

[1434] 527-1 (200 mg, 0.43 mmol) was added to trifluoroacetic acid (5 mL), followed by zinc powder (140 mg, 2.15 mmol). After the addition was complete, the mixture was stirred at 25 °C for 0.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by reversed-phase silica gel chromatography to give product 527-2 (112 mg, yield: 61%).

[1435] MS m / z(ESI):426.2[M+1].

[1436] Step 3

[1437] 527-2 (110 mg, 0.25 mmol) and 9-6 (123 mg, 0.64 mmol) were dissolved in dry N,N-dimethylformamide (4 mL), and sodium bicarbonate (42 mg, 0.50 mmol) was added. After the addition was complete, the mixture was stirred at 80 °C for 12 hours. The reaction solution was cooled to below 25 °C, and a saturated ammonium chloride solution was added for extraction. The organic phase was dried, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give product 527-3 (48 mg, yield: 395%).

[1438] MS m / z(ESI): 537.2 [M+1].

[1439] Step Four

[1440] 527-3 (40 mg, 74 μmol) and 9-8 (40 mg, 74 μmol) were dissolved in 1,4-dioxane (4 mL) and water (1 mL). [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (6 mg, 7 μmol) and potassium carbonate (31 mg, 222 μmol) were added. After the addition was complete, nitrogen was purged three times. The resulting mixture was stirred at 80 °C for 1 hour under a nitrogen atmosphere. The reaction mixture was cooled to below 25 °C, water was added, and extraction was performed. The organic phase was dried, filtered, and concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography to obtain product 527 (22 mg, yield: 34%).

[1441] MS m / z(ESI): 866.6 [M+1].

[1442] 1 H NMR (400MHz, DMSO-d6) δ12.20–12.11(m,1H),10.86(s,1H),7.76–7.68(m,1H),7.45– 7.36(m,1H),7.02–6.82(m,3H),6.75–6.65(m,1H),6.65–6.55(m,2H),6.25–6.06(m,2 H),4.53–4.42(m,1H),4.42–4.24(m,5H),4.11–4.02(m,1H),3.98–3.88(m,1H),3.81 (s,3H),3.68–3.55(m,2H),3.50–2.72(m,14H),2.70–2.55(m,2H),2.37–1.89(m,4H).

[1443] Example 1-480: Preparation of Compound 528

[1444] Step 1

[1445] 528-1 (1 g, 2.98 mmol) was dissolved in isopropanol (25 mL). 389-2 (774 mg, 3.58 mmol), ethylene glycol (0.332 mL, 5.96 mmol), cuprous iodide (142 mg, 0.75 mmol), and potassium phosphate (1.27 g, 5.96 mmol) were added to the reaction mixture. The reaction solution was heated to 100 °C, protected under nitrogen, and reacted at this temperature for 24 hours. The reaction was quenched with water (50 mL), extracted with dichloromethane (100 mL x 3), and the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by vacuum distillation. The residue was purified by silica gel column chromatography to obtain product 528-3 (470 mg, yield: 37%).

[1446] MS m / z(ESI):367.1[M+1-56].

[1447] Step Two

[1448] 528-3 (470 mg, 1.11 mmol) was dissolved in ultradry N,N-dimethylacetamide (10 mL), and sodium hydride (133 mg, 3.33 mmol) was added at 0 °C. The mixture was stirred at room temperature for 2 hours. The solution was quenched with saturated ammonium chloride aqueous solution (50 mL), extracted with ethyl acetate (100 mL * 2), and the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by vacuum distillation. The residue was purified by silica gel column chromatography to obtain product 528-4 (340 mg, yield: 76%).

[1449] MS m / z(ESI):347.2[M+1-56].

[1450] Step 3

[1451] 528-4 (150 mg, 0.37 mmol) was dissolved in dichloromethane (4 mL), and then an ethyl acetate solution of hydrogen chloride (4 mL) was added. After the addition was complete, the resulting mixture was stirred at 25 °C for 1 hour. The reaction solution was then concentrated under reduced pressure to give product 528-5 (126 mg, crude product).

[1452] MS m / z(ESI): 303.2 [M+1].

[1453] Step Four

[1454] 79-1 (158 mg, 0.56 mmol, synthetic method referred to WO2025049820 A1) and 528-5 (126 mg, crude product) were dissolved in a dry tetrahydrofuran and dimethyl sulfoxide mixture (5.2 mL, 10:3). A mixture of potassium acetate (109 mg, 1.11 mmol) and acetic acid (111 mg, 1.85 mmol) was added, and the mixture was stirred under a nitrogen atmosphere for 30 minutes. Then, sodium cyanoborohydride (70 mg, 1.11 mmol) was added. After the addition was complete, the mixture was stirred at 25 °C for 1 hour. The reaction solution was directly purified by reversed-phase C18 column chromatography to obtain product 528-6 (112 mg, yield: 52%).

[1455] MS m / z(ESI): 572.3 [M+1].

[1456] Step 5

[1457] 9-8 (60 mg, 112 μmol), 528-6 (64.2 mg, 112 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (19 mg, 22 μmol), and cesium fluoride (51 mg, 0.34 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 80 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 528 (22 mg, yield: 22%).

[1458] MS m / z(ESI): 901.4 [M+1].

[1459] 1 H NMR (400MHz, DMSO-d6) δ12.19–12.03(m,1H),11.07(s,1H),7.79–7.65(m,1H),7.49–7.34( m,2H),7.34–7.24(m,1H),7.01–6.94(m,2H),6.94–6.83(m,2H),6.48–6.42(m,1H),6.23–6. 07(m,1H),5.78–5.68(m,1H),4.52–4.25(m,5H),4.10–3.99(m,1H),3.90–3.79(m,1H),3.68 –3.52(m,2H),3.31–2.91(m,13H),2.90–2.53(m,9H),2.38–2.14(m,5H),1.97–1.85(m,1H).

[1460] Example 1-481: Preparation of Compound 529

[1461] Step 1

[1462] 528-1 (1 g, 2.98 mmol) was dissolved in isopropanol (25 mL). 366-1 (774 mg, 3.58 mmol), ethylene glycol (0.332 mL, 5.96 mmol), cuprous iodide (142 mg, 0.75 mmol), and potassium phosphate (1.27 g, 5.96 mmol) were added to the reaction mixture. The reaction solution was heated to 100 °C, protected under nitrogen, and reacted at this temperature for 24 hours. The reaction was quenched with water (50 mL), extracted with dichloromethane (100 mL x 3), and the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by vacuum distillation. The residue was purified by silica gel column chromatography to obtain product 529-1 (452 ​​mg, yield: 36%).

[1463] MS m / z(ESI):367.3[M+1-56].

[1464] Step Two

[1465] 529-1 (452 ​​mg, 1.07 mmol) was dissolved in ultradry N,N-dimethylacetamide (10 mL), and sodium hydride (128 mg, 3.20 mmol) was added at 0 °C. The mixture was stirred at room temperature for 2 hours. The mixture was quenched with saturated ammonium chloride aqueous solution (50 mL), extracted with ethyl acetate (100 mL * 2), and the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by vacuum distillation. The residue was purified by silica gel column chromatography to obtain product 529-2 (333 mg, yield: 77%).

[1466] MS m / z(ESI):347.1[M+1-56].

[1467] Step 3

[1468] 529-2 (150 mg, 0.37 mmol) was dissolved in dichloromethane (4 mL), and then an ethyl acetate solution of hydrogen chloride (4 mL) was added. After the addition was complete, the resulting mixture was stirred at 25 °C for 1 hour. The reaction solution was then concentrated under reduced pressure to obtain product 529-3 (130 mg, crude product).

[1469] MS m / z(ESI): 303.1 [M+1].

[1470] Step Four

[1471] 79-1 (158 mg, 0.56 mmol, synthetic method referred to WO2025049820 A1) and 529-3 (130 mg, crude product) were dissolved in a dry tetrahydrofuran and dimethyl sulfoxide mixture (5.2 mL, 10:3). A mixture of potassium acetate (109 mg, 1.11 mmol) and acetic acid (111 mg, 1.85 mmol) was added, and the mixture was stirred under a nitrogen atmosphere for 30 minutes. Then, sodium cyanoborohydride (70 mg, 1.11 mmol) was added. After the addition was complete, the mixture was stirred at 25 °C for 1 hour. The reaction solution was directly purified by reversed-phase C18 column chromatography to obtain product 529-4 (120 mg, yield: 55%).

[1472] MS m / z(ESI): 572.2 [M+1].

[1473] Step 5

[1474] 9-8 (60 mg, 112 μmol), 529-4 (64.2 mg, 112 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (19 mg, 22 μmol), and cesium fluoride (51 mg, 0.34 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 80 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 529 (24 mg, yield: 24%).

[1475] MS m / z(ESI): 901.5 [M+1].

[1476] 1 H NMR(400MHz,Chloroform-d)δ9.59–9.44(m,1H),8.24–8.12(m,1H),7.62–7.48 (m,2H),7.38–7.30(m,1H),7.25–7.22(m,1H),7.02–6.78(m,4H),6.65–6.58(m, 1H),6.28–6.21(m,1H),5.31–5.21(m,1H),4.63–4.53(m,2H),4.53–4.41(m,3H ),4.34–3.99(m,4H),3.88–3.51(m,7H),3.50–2.67(m,16H),2.53–2.29(m,5H).

[1477] Example 1-482: Preparation of Compound 530

[1478] Step 1

[1479] 8-9 (60 mg, 107 μmol), 528-6 (61.2 mg, 107 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (18 mg, 21 μmol), and cesium fluoride (48.7 mg, 0.32 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 80 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 530 (25 mg, yield: 25%).

[1480] MS m / z(ESI): 927.5 [M+1].

[1481] 1 H NMR (400MHz, DMSO-d6) δ12.38–11.92(m,1H),11.08(s,1H),7.74–7.66(m,1H),7.53–7.45(m ,1H),7.40–7.33(m,1H),7.14–7.07(m,1H),7.04–6.96(m,2H),6.93–6.82(m,1H),6.50–6.3 9(m,1H),6.23–6.14(m,1H),5.81–5.71(m,1H),5.64–5.56(m,1H),4.57–4.13(m,6H),3.94– 3.29(m,10H),3.26–2.81(m,11H),2.81–2.52(m,6H),2.39–2.14(m,2H),0.93–0.66(m,4H).

[1482] Example 1-483: Preparation of Compound 531

[1483] Step 1

[1484] 8-9 (60 mg, 107 μmol), 529-4 (61.2 mg, 107 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (18 mg, 21 μmol), and cesium fluoride (48.7 mg, 0.32 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 80 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 531 (20 mg, yield: 20%).

[1485] MS m / z(ESI): 927.6 [M+1].

[1486] Example 1-484: Preparation of Compound 532

[1487] Step 1

[1488] 8-9 (50 mg, 89 μmol), 527-3 (48 mg, 89 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (16 mg, 18 μmol), and cesium fluoride (41 mg, 0.27 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 85 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 532 (26 mg, yield: 33%).

[1489] MS m / z(ESI): 892.4 [M+1].

[1490] Example 1-485: Preparation of Compound 533

[1491] Step 1

[1492] 8-9 (50 mg, 89 μmol), 11-5 (48 mg, 89 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (16 mg, 18 μmol), and cesium fluoride (41 mg, 0.27 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 85 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 533 (29 mg, yield: 36%).

[1493] MS m / z(ESI): 892.4 [M+1].

[1494] 1 H NMR (400MHz, DMSO-d6) δ12.24–12.08(m,1H),10.94–10.82(m,1H),7.78–7.65(m,1H),7.48– 7.33(m,1H),7.05–6.80(m,3H),6.73–6.65(m,1H),6.65–6.53(m,2H),6.27–6.12(m,1H),5. 69–5.52(m,1H),4.52–4.26(m,6H),4.11–4.02(m,1H),3.97–3.89(m,1H),3.81(s,3H),3.55 –3.46(m,2H),3.39–2.74(m,12H),2.70–2.55(m,3H),2.37–1.84(m,3H),0.90–0.64(m,4H).

[1495] Examples 1-486: Preparation of compounds 534 and 535

[1496] Compound 11 (40 mg, 45 μmol) was separated by chirality using SFC (column: OX column, 250 × 20 mm, 10 μm; mobile phase: A-n-heptane, B-ethanol / acetonitrile (0.1% ammonia), isocratic elution, B%: 80%), yielding single-configuration compound 534 (shorter retention time) and single-configuration compound 535 (longer retention time).

[1497] Compound 534, a single configuration, is a white solid, 12 mg, with a yield of 30%.

[1498] MS m / z(ESI): 866.4 [M+1].

[1499] 1H NMR(400MHz,DMSO-d6)δ12.22–12.09(m,1H),10.86(s,1H),7.79–7.67(m,1H),7.47–7.34 (m,1H),7.07–6.83(m,3H),6.75–6.52(m,3H),6.28–6.06(m,2H),5.24–5.09(m,1H),4.51– 4.43(m,1H),4.42–4.24(m,5H),4.13–4.03(m,1H),3.96–3.87(m,1H),3.81(s,3H),3.68– 3.53(m,2H),3.42–3.01(m,10H),3.01–2.75(m,4H),2.70–2.55(m,2H),2.38–1.89(m,4H).

[1500] Compound 535, a single configuration, is a white solid, 14 mg, with a yield of 35%.

[1501] MS m / z(ESI): 866.4 [M+1].

[1502] 1 H NMR (400MHz, DMSO-d6) δ12.27–12.04(m,1H),10.86(s,1H),7.81–7.65(m,1H),7.49–7.33(m,1H),7.02–6.90(m,2 H),6.90–6.84(m,1H),6.71–6.64(m,1H),6.64–6.54(m,2H),6.24–6.16(m,1H),6.15–6.10(m,1H),5.23–5.12(m,1 H),4.52–4.41(m,1H),4.42–4.23(m,5H),4.14–4.01(m,1H),3.96–3.87(m,1H),3.81(s,3H),3.69–3.53(m,2H),3 .42–3.23(m,2H),3.23–2.75(m,12H),2.70–2.55(m,2H),2.36–2.23(m,2H),2.21–2.07(m,1H),2.01–1.85(m,1H).

[1503] Examples 1-487: Preparation of compounds 536 and 537

[1504] Compound 533 (30 mg, 45 μmol) was separated by chirality using SFC (column: OX column, 250 × 20 mm, 10 μm; mobile phase: A-n-heptane, B-ethanol / acetonitrile (0.1% ammonia), isocratic elution, B%: 80%), yielding single-configuration compound 536 (shorter retention time) and single-configuration compound 537 (longer retention time).

[1505] Compound 536, a single configuration, is a white solid, 12 mg, with a yield of 40%.

[1506] MS m / z(ESI): 892.4 [M+1].

[1507] 1 H NMR(400MHz,DMSO-d6)δ12.24–12.06(m,1H),10.86(s,1H),7.77–7.65(m,1H),7.50–7.31 (m,1H),7.01–6.83(m,3H),6.75–6.55(m,3H),6.26–6.14(m,1H),5.70–5.57(m,1H),5.22– 5.09(m,1H),4.54–4.24(m,6H),4.13–4.03(m,1H),3.99–3.87(m,1H),3.81(s,3H),3.58– 3.46(m,2H),3.32–2.75(m,14H),2.71–2.52(m,2H),2.22–1.87(m,2H),0.93–0.67(m,4H).

[1508] Compound 537, a single configuration, is a white solid, 10 mg, yield: 33%.

[1509] MS m / z(ESI): 892.4 [M+1].

[1510] 1H NMR (400MHz, DMSO-d6) δ12.21–12.06(m,1H),10.86(s,1H),7.79–7.66(m,1H),7.49–7.32(m,1 H),7.05–6.82(m,3H),6.75–6.53(m,3H),6.27–6.10(m,1H),5.71–5.55(m,1H),5.25–5.08(m,1 H),4.52–4.42(m,2H),4.42–4.24(m,4H),4.13–4.01(m,1H),3.96–3.88(m,1H),3.81(s,3H),3 .57–3.44(m,2H),3.32–2.74(m,14H),2.71–2.52(m,2H),2.21–1.86(m,2H),0.92–0.67(m,4H).

[1511] Examples 1-488: Preparation of compounds 538 and 539

[1512] Compound 527 (40 mg, 45 μmol) was separated by chirality using SFC (column: OX column, 250 × 20 mm, 10 μm; mobile phase: A-n-heptane, B-ethanol / acetonitrile (0.1% ammonia), isocratic elution, B%: 80%), yielding single-configuration compound 538 (shorter retention time) and single-configuration compound 539 (longer retention time).

[1513] Compound 538, a single configuration, is a white solid, yielding 13 mg in 32% yield.

[1514] MS m / z(ESI): 866.4 [M+1].

[1515] 1H NMR(400MHz,DMSO-d6)δ12.27–12.06(m,1H),10.86(s,1H),7.81–7.64(m,1H),7.49–7.30(m,1H),7.02– 6.83(m,3H),6.75–6.64(m,1H),6.64–6.54(m,2H),6.27–6.05(m,2H),5.28–5.09(m,1H),4.52–4.42(m,1 H),4.42–4.24(m,5H),4.14–4.01(m,1H),3.97–3.86(m,1H),3.81(s,3H),3.71–3.53(m,2H),3.43–3.01 (m,12H),3.00–2.72(m,2H),2.70–2.54(m,2H),2.37–2.21(m,2H),2.22–2.08(m,1H),2.01–1.86(m,1H).

[1516] Compound 539, a single configuration, is a white solid, 16 mg, with a yield of 40%.

[1517] MS m / z(ESI): 866.4 [M+1].

[1518] 1 H NMR (400MHz, DMSO-d6) δ12.24–12.07(m,1H),10.86(s,1H),7.77–7.65(m,1H),7.45–7.33(m,1H),7. 06–6.81(m,3H),6.72–6.55(m,3H),6.27–6.06(m,2H),5.22–5.12(m,1H),4.51–4.42(m,1H),4.42–4. 23(m,5H),4.13–4.03(m,1H),3.97–3.88(m,1H),3.85–3.75(m,3H),3.70–3.54(m,2H),3.42–3.21(m, 2H),3.21–2.72(m,12H),2.70–2.54(m,2H),2.38–2.21(m,2H),2.20–2.07(m,1H),2.04–1.86(m,1H).

[1519] Examples 1-489: Preparation of compounds 540 and 541

[1520] Compound 315 (35 mg, 39 μmol) was separated by chirality using SFC (column: OX column, 250 × 20 mm, 10 μm; mobile phase: A-n-heptane, B-ethanol / acetonitrile (0.1% ammonia), isocratic elution, B%: 80%), yielding single-configuration compound 540 (shorter retention time) and single-configuration compound 541 (longer retention time).

[1521] Compound 540, a single configuration, is a white solid, 10 mg, with a yield of 28%.

[1522] MS m / z(ESI): 892.4 [M+1].

[1523] 1 H NMR(400MHz,DMSO-d6)δ12.20–12.08(m,1H),10.86(s,1H),7.75–7.69(m,1H),7.45–7.37(m,1H),6 .97–6.89(m,2H),6.89–6.84(m,1H),6.71–6.63(m,1H),6.63–6.56(m,2H),6.22–6.16(m,1H),5.67– 5.59(m,1H),5.25–5.09(m,1H),4.48–4.28(m,6H),4.05–3.87(m,2H),3.81(s,3H),3.55–3.46(m,2 H),3.45–2.73(m,14H),2.70–2.53(m,1H),2.23–2.09(m,1H),2.05–1.88(m,2H),0.90–0.68(m,4H).

[1524] Compound 541, a single configuration, is a white solid, 10 mg, with a yield of 28%.

[1525] MS m / z(ESI): 892.4 [M+1].

[1526] 1H NMR (400MHz, DMSO-d6) δ12.19–12.05(m,1H),10.86(s,1H),7.75–7.69(m,1H),7.45–7.35 (m,1H),6.99–6.84(m,3H),6.71–6.64(m,1H),6.64–6.56(m,2H),6.22–6.15(m,1H),5.69– 5.60(m,1H),5.20–5.12(m,1H),4.49–4.25(m,6H),4.05–3.86(m,2H),3.81(s,3H),3.55– 3.46(m,2H),3.31–2.75(m,14H),2.70–2.52(m,2H),2.38–1.88(m,2H),0.91–0.69(m,4H).

[1527] Examples 1-490: Preparation of Compound 542

[1528] Step 1

[1529] Dissolve 542-1 (1.50 g, 5.56 mmol) and 542-2 (1.02 g, 4.45 mmol) in toluene (30 mL). Under a nitrogen atmosphere, add 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (346 mg, 0.56 mmol), tris(dibenzylacetone)palladium (509 mg, 0.56 mmol), and sodium tert-butoxide (2.13 g, 22.23 mmol) to the reaction system. Then, heat the reaction mixture to 95 °C and stir for 4 hours. Allow the reaction solution to cool naturally to room temperature, then filter and concentrate under reduced pressure using a filter. Purify the residue by silica gel column chromatography to obtain product 542-3 (350 mg, yield: 15%).

[1530] MS m / z(ESI):401.1[M+1].

[1531] Step Two

[1532] 542-3 (350 mg, 0.87 mmol) was added to an ethyl acetate hydrochloride solution (4 mol / L, 10 mL), and the resulting mixture was stirred at 25 °C for 1 hour. The reaction solution was then concentrated under reduced pressure to give product 542-4 (301 mg).

[1533] MS m / z(ESI):301.1[M+1].

[1534] Step 3

[1535] 542-4 (200 mg, 0.59 mmol) was dissolved in dry N,N-dimethylformamide (5 mL). Under a nitrogen atmosphere, 9-3 (112 mg, 0.59 mmol) and triethylamine (179 mg, 1.78 mmol) were added. After the addition was complete, the mixture was heated to 80 °C and stirred for 12 hours. The reaction solution was allowed to cool naturally to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain product 542-5 (220 mg, yield: 79%).

[1536] MS m / z(ESI): 470.2 [M+1].

[1537] Step Four

[1538] 542-5 (220 mg, 0.47 mmol) was dissolved in trifluoroacetic acid (20 mL), and then zinc powder (122 mg, 1.87 mmol) was added. After the addition was complete, the mixture was stirred at 25 °C for 0.5 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain product 542-6 (151 mg, yield: 72%).

[1539] MS m / z(ESI): 440.2 [M+1].

[1540] Step 5

[1541] 542-6 (150 mg, 0.34 mmol) and 9-6 (62 mg, 0.32 mmol) were dissolved in dry N,N-dimethylformamide (3 mL), and sodium bicarbonate (57 mg, 0.68 mmol) was added. After the addition was complete, the mixture was stirred at 80 °C for 12 hours. The reaction solution was cooled to below 25 °C, and a saturated ammonium chloride solution was added for extraction. The organic phase was dried, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give product 542-7 (101 mg, yield: 53%).

[1542] MS m / z(ESI): 551.2 [M+1].

[1543] Step Six

[1544] Dissolve 542-7 (30 mg, 54 μmol) and 8-9 (34 mg, 60 μmol) in 1,4-dioxane (2 mL) and water (0.5 mL), then add [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (5 mg, 6 μmol) and potassium carbonate (28 mg, 180 μmol). After the addition is complete, purge with nitrogen three times. The resulting mixture is stirred at 80 °C for 1 hour under a nitrogen atmosphere. The reaction solution temperature is lowered to below 25 °C, water is added, extraction is performed, the organic phase is dried, filtered, concentrated under reduced pressure, and the residue is purified by high performance liquid chromatography to obtain product 542 (27 mg, yield: 54%).

[1545] MS m / z(ESI): 906.6 [M+1].

[1546] 1 H NMR(400MHz,DMSO-d6)δ12.23–12.04(m,1H),10.86(s,1H),7.79–7.64(m,1H),7.49– 7.31(m,1H),7.16–6.88(m,3H),6.77–6.66(m,1H),6.63–6.52(m,2H),6.24–6.13(m,1 H),5.68–5.58(m,1H),5.18–5.10(m,1H),4.58–4.21(m,6H),3.82(s,3H),3.57–3.35 (m,3H),3.26–2.75(m,12H),2.71–2.53(m,4H),2.38–1.86(m,5H),0.92–0.69(m,4H).

[1547] Example 1-491: Preparation of Compound 543

[1548] Step 1

[1549] 79-1 (100 mg, 0.35 mmol, synthetic method referred to WO2025049820 A1) and 542-4 (118 mg, 0.35 mmol) were dissolved in a dry mixture of tetrahydrofuran and dimethyl sulfoxide (5 mL, 1:1). Potassium acetate (69 mg, 0.70 mmol) and acetic acid (105 mg, 1.75 mmol) were added. The mixture was stirred under a nitrogen atmosphere for 30 minutes, followed by the addition of sodium cyanoborohydride (45 mg, 0.70 mmol). After the addition was complete, the mixture was stirred at 25 °C for 1 hour. The reaction solution was directly purified by reversed-phase C18 column chromatography to obtain product 543-1 (116 mg, yield: 58%).

[1550] MS m / z(ESI): 570.2 [M+1].

[1551] Step Two

[1552] 9-8 (60 mg, 112 μmol), 543-1 (64 mg, 112 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (19 mg, 22 μmol), and cesium fluoride (51 mg, 0.34 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 80 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 543 (31 mg, yield: 31%).

[1553] MS m / z(ESI): 899.4 [M+1].

[1554] 1 H NMR (400MHz, DMSO-d6) δ12.27–12.07(m,1H),11.08(s,1H),7.79–7.65(m,1H),7.56–7.30(m,1H),7.27–6.85(m,5H),6.66–6.54(m,1H),6.26–6. 08(m,2H),5.83–5.66(m,1H),4.41–4.23(m,6H),3.70–3.42(m,8H),3.27 –2.92(m,10H),2.92–2.53(m,9H),2.40–2.16(m,5H),2.03–1.88(m,1H).

[1555] Examples 1-492: Preparation of Compound 544

[1556] Step 1

[1557] 544-1 (149 mg, 0.52 mmol, synthetic method referred to WO2025049820 A1) and 9-2 (150 mg, 0.52 mmol) were dissolved in a dry mixture of tetrahydrofuran and dimethyl sulfoxide (5 mL, 1:1). Potassium acetate (103 mg, 1.04 mmol) and acetic acid (105 mg, 1.74 mmol) were added. The mixture was stirred under a nitrogen atmosphere for 30 minutes, followed by the addition of sodium cyanoborohydride (66 mg, 1.04 mmol). After the addition was complete, the mixture was stirred at 25 °C for 1 hour. The reaction solution was directly purified by reversed-phase C18 chromatography to obtain product 544-2 (121 mg, yield: 41%).

[1558] MS m / z(ESI): 558.2 [M+1].

[1559] Step Two

[1560] 9-8 (60 mg, 112 μmol), 544-2 (62 mg, 112 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (18 mg, 22 μmol), and cesium fluoride (49 mg, 0.32 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 80 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 544 (33 mg, yield: 33%).

[1561] MS m / z(ESI): 885.5 [M+1].

[1562] 1 H NMR(400MHz,DMSO-d6)δ12.27–11.98(m,1H),10.90(s,1H),7.76–7.69(m,1H),7.59–7.54(m,1H),7 .45–7.35(m,1H),7.25–7.19(m,1H),7.07–7.01(m,1H),6.97–6.87(m,2H),6.87–6.82(m,1H),6.63 –6.56(m,1H),6.23–6.08(m,2H),4.44–4.26(m,6H),4.24(s,3H),3.99–3.90(m,1H),3.87–3.77(m, 1H),3.68–3.52(m,2H),3.31–2.91(m,9H),2.91–2.51(m,9H),2.41–2.11(m,5H),1.94–1.83(m,1H).

[1563] Examples 1-493: Preparation of Compound 545

[1564] Step 1

[1565] 544-1 (149 mg, 0.52 mmol, synthetic method referred to WO2025049820 A1) and 10-2 (150 mg, 0.52 mmol) were dissolved in a dry mixture of tetrahydrofuran and dimethyl sulfoxide (5 mL, 1:1). Potassium acetate (103 mg, 1.04 mmol) and acetic acid (105 mg, 1.74 mmol) were added. The mixture was stirred under a nitrogen atmosphere for 30 minutes, followed by the addition of sodium cyanoborohydride (66 mg, 1.04 mmol). After the addition was complete, the mixture was stirred at 25 °C for 1 hour. The reaction solution was directly purified by reversed-phase C18 chromatography to obtain product 545-1 (135 mg, yield: 46%).

[1566] MS m / z(ESI): 558.2 [M+1].

[1567] Step Two

[1568] 9-8 (60 mg, 112 μmol), 545-1 (62 mg, 112 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (18 mg, 22 μmol), and cesium fluoride (49 mg, 0.32 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 80 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 545 (38 mg, yield: 38%).

[1569] MS m / z(ESI): 885.5 [M+1].

[1570] Example 1-494: Preparation of Compound 546

[1571] Step 1

[1572] 8-9 (60 mg, 107 μmol), 544-2 (62 mg, 107 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (18 mg, 21 μmol), and cesium fluoride (48.7 mg, 0.32 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 80 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 546 (28 mg, yield: 28%).

[1573] MS m / z(ESI): 911.4 [M+1].

[1574] 1 H NMR(400MHz,DMSO-d6)δ12.24–12.13(m,1H),10.91(s,1H),7.73–7.69(m,1H),7.69–7.64(m,1H),7 .46–7.34(m,2H),7.30–7.22(m,1H),7.16–7.07(m,1H),6.89–6.74(m,2H),6.39–6.31(m,1H),6.24– 6.14(m,1H),5.64–5.52(m,1H),4.50–4.31(m,7H),4.28(s,3H),4.21–4.05(m,1H),3.96–3.77(m,1 H),3.69–3.34(m,10H),3.25–2.88(m,9H),2.78–2.55(m,2H),2.42–2.10(m,2H),0.92–0.66(m,4H).

[1575] Examples 1-495: Preparation of Compound 547

[1576] Step 1

[1577] 8-9 (60 mg, 107 μmol), 545-1 (62 mg, 107 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (18 mg, 21 μmol), and cesium fluoride (48.7 mg, 0.32 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 80 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 547 (36 mg, yield: 36%).

[1578] MS m / z(ESI): 911.4 [M+1].

[1579] 1H NMR(400MHz,DMSO-d6)δ12.28–12.00(m,1H),10.91(s,1H),7.75–7.69(m,1H),7.69–7.62(m,1 H),7.45–7.35(m,1H),7.29–7.21(m,1H),7.15–7.06(m,2H),6.99–6.87(m,2H),6.62–6.53(m,1 H),6.23–6.16(m,1H),5.67–5.58(m,1H),4.51–4.33(m,5H),4.28(s,3H),4.14–3.73(m,2H),3 .66–3.22(m,11H),3.22–2.83(m,8H),2.83–2.52(m,4H),2.43–2.08(m,2H),0.93–0.68(m,4H).

[1580] Examples 1-496: Preparation of Compound 548

[1581] Step 1

[1582] 544-1 (149 mg, 0.52 mmol, synthetic method referred to WO2025049820 A1) and 389-5 (150 mg, 0.52 mmol) were dissolved in a dry mixture of tetrahydrofuran and dimethyl sulfoxide (5 mL, 1:1). Potassium acetate (103 mg, 1.04 mmol) and acetic acid (105 mg, 1.74 mmol) were added. The mixture was stirred under a nitrogen atmosphere for 30 minutes, followed by the addition of sodium cyanoborohydride (66 mg, 1.04 mmol). After the addition was complete, the mixture was stirred at 25 °C for 1 hour. The reaction solution was directly purified by reversed-phase C18 chromatography to obtain product 548-1 (108 mg, yield: 37%).

[1583] MS m / z(ESI): 558.2 [M+1].

[1584] Step Two

[1585] 9-8 (60 mg, 112 μmol), 548-1 (62 mg, 112 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (18 mg, 22 μmol), and cesium fluoride (49 mg, 0.32 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 80 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 548 (27 mg, yield: 27%).

[1586] MS m / z(ESI): 885.5 [M+1].

[1587] Examples 1-497: Preparation of Compound 549

[1588] Step 1

[1589] 544-1 (149 mg, 0.52 mmol, synthetic method referred to WO2025049820 A1) and 11-2 (150 mg, 0.52 mmol) were dissolved in a dry mixture of tetrahydrofuran and dimethyl sulfoxide (5 mL, 1:1). Potassium acetate (103 mg, 1.04 mmol) and acetic acid (105 mg, 1.74 mmol) were added. The mixture was stirred under a nitrogen atmosphere for 30 minutes, followed by the addition of sodium cyanoborohydride (66 mg, 1.04 mmol). After the addition was complete, the mixture was stirred at 25 °C for 1 hour. The reaction solution was directly purified by reversed-phase C18 chromatography to obtain product 549-1 (133 mg, yield: 45%).

[1590] MS m / z(ESI): 558.2 [M+1].

[1591] Step Two

[1592] 9-8 (60 mg, 112 μmol), 549-1 (62 mg, 112 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (18 mg, 22 μmol), and cesium fluoride (49 mg, 0.32 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 80 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 549 (22 mg, yield: 22%).

[1593] MS m / z(ESI): 885.5 [M+1].

[1594] Examples 1-498: Preparation of Compound 550

[1595] Step 1

[1596] 8-9 (60 mg, 107 μmol), 548-1 (62 mg, 107 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (18 mg, 21 μmol), and cesium fluoride (48.7 mg, 0.32 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 80 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 550 (39 mg, yield: 37%).

[1597] MS m / z(ESI): 911.4 [M+1].

[1598] Examples 1-499: Preparation of Compound 551

[1599] Step 1

[1600] 8-9 (60 mg, 107 μmol), 549-1 (62 mg, 107 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (18 mg, 21 μmol), and cesium fluoride (48.7 mg, 0.32 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 80 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 551 (31 mg, yield: 30%).

[1601] MS m / z(ESI): 911.4 [M+1].

[1602] Examples 1-500: Preparation of Compound 552

[1603] Step 1

[1604] 544-1 (149 mg, 0.52 mmol, synthetic method referred to WO2025049820 A1) and 377-4 (150 mg, 0.52 mmol) were dissolved in a dry mixture of tetrahydrofuran and dimethyl sulfoxide (5 mL, 1:1). Potassium acetate (103 mg, 1.04 mmol) and acetic acid (105 mg, 1.74 mmol) were added. The mixture was stirred under a nitrogen atmosphere for 30 minutes, followed by the addition of sodium cyanoborohydride (66 mg, 1.04 mmol). After the addition was complete, the mixture was stirred at 25 °C for 1 hour. The reaction solution was directly purified by reversed-phase C18 column chromatography to obtain product 552-1 (115 mg, yield: 39%).

[1605] MS m / z(ESI): 558.2 [M+1].

[1606] Step Two

[1607] 9-8 (60 mg, 112 μmol), 552-1 (62 mg, 112 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (18 mg, 22 μmol), and cesium fluoride (49 mg, 0.32 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 80 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 552 (36 mg, yield: 36%).

[1608] MS m / z(ESI): 885.5 [M+1].

[1609] Example 1-501: Preparation of Compound 553

[1610] Step 1

[1611] 544-1 (149 mg, 0.52 mmol, synthetic method referred to WO2025049820 A1) and 378-3 (150 mg, 0.52 mmol) were dissolved in a dry mixture of tetrahydrofuran and dimethyl sulfoxide (5 mL, 1:1). Potassium acetate (103 mg, 1.04 mmol) and acetic acid (105 mg, 1.74 mmol) were added. The mixture was stirred under a nitrogen atmosphere for 30 minutes, followed by the addition of sodium cyanoborohydride (66 mg, 1.04 mmol). After the addition was complete, the mixture was stirred at 25 °C for 1 hour. The reaction solution was directly purified by reversed-phase C18 column chromatography to obtain product 553-1 (95 mg, yield: 20%).

[1612] MS m / z(ESI): 558.2 [M+1].

[1613] Step Two

[1614] 9-8 (60 mg, 112 μmol), 553-1 (62 mg, 112 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (18 mg, 22 μmol), and cesium fluoride (49 mg, 0.32 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 80 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 553 (16 mg, yield: 16%).

[1615] MS m / z(ESI): 885.5 [M+1].

[1616] Example 1-502: Preparation of Compound 554

[1617] Step 1

[1618] 8-9 (60 mg, 107 μmol), 552-1 (62 mg, 107 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (18 mg, 21 μmol), and cesium fluoride (48.7 mg, 0.32 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 80 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 554 (20 mg, yield: 20%).

[1619] MS m / z(ESI): 911.4 [M+1].

[1620] Example 1-503: Preparation of Compound 555

[1621] Step 1

[1622] 8-9 (60 mg, 107 μmol), 553-1 (62 mg, 107 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (18 mg, 21 μmol), and cesium fluoride (48.7 mg, 0.32 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 80 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 555 (34 mg, yield: 34%).

[1623] MS m / z(ESI): 911.4 [M+1].

[1624] 1 H NMR(400MHz,DMSO-d6)δ12.40–12.04(m,1H),10.92(s,1H),7.76–7.69(m,1H),7.69–7.62 (m,1H),7.47–7.36(m,1H),7.30–7.21(m,1H),7.18–6.94(m,4H),6.88–6.80(m,1H),6.23– 6.15(m,1H),5.66(s,1H),4.54–4.23(m,10H),4.19–4.09(m,1H),3.90–3.80(m,3H),3.79– 3.51(m,3H),3.41–2.89(m,14H),2.77–2.57(m,2H),2.41–2.09(m,2H),0.92–0.69(m,4H).

[1625] Example 1-504: Preparation of Compound 556

[1626] Step 1

[1627] 544-1 (149 mg, 0.52 mmol, synthetic method referred to WO2025049820 A1) and 422-4 (140 mg, 0.52 mmol) were dissolved in a dry mixture of tetrahydrofuran and dimethyl sulfoxide (5 mL, 1:1). Potassium acetate (103 mg, 1.04 mmol) and acetic acid (105 mg, 1.74 mmol) were added. The mixture was stirred under a nitrogen atmosphere for 30 minutes, followed by the addition of sodium cyanoborohydride (66 mg, 1.04 mmol). After the addition was complete, the mixture was stirred at 25 °C for 1 hour. The reaction solution was directly purified by reversed-phase C18 column chromatography to obtain product 556-1 (88 mg, yield: 31%).

[1628] MS m / z(ESI): 540.2 [M+1].

[1629] Step Two

[1630] 9-8 (60 mg, 112 μmol), 556-1 (62 mg, 112 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (18 mg, 22 μmol), and cesium fluoride (49 mg, 0.32 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 80 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 556 (17 mg, yield: 17%).

[1631] MS m / z(ESI): 867.4 [M+1].

[1632] Example 1-505: Preparation of Compound 557

[1633] Step 1

[1634] 544-1 (149 mg, 0.52 mmol, synthetic method referred to WO2025049820 A1) and 423-3 (140 mg, 0.52 mmol) were dissolved in a dry mixture of tetrahydrofuran and dimethyl sulfoxide (5 mL, 1:1). Potassium acetate (103 mg, 1.04 mmol) and acetic acid (105 mg, 1.74 mmol) were added. The mixture was stirred under a nitrogen atmosphere for 30 minutes, followed by the addition of sodium cyanoborohydride (66 mg, 1.04 mmol). After the addition was complete, the mixture was stirred at 25 °C for 1 hour. The reaction solution was directly purified by reversed-phase C18 column chromatography to obtain product 557-1 (103 mg, yield: 36%).

[1635] MS m / z(ESI): 540.2 [M+1].

[1636] Step Two

[1637] 9-8 (60 mg, 112 μmol), 557-1 (62 mg, 112 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (18 mg, 22 μmol), and cesium fluoride (49 mg, 0.32 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 80 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 557 (37 mg, yield: 38%).

[1638] MS m / z(ESI): 867.4 [M+1].

[1639] Example 1-506: Preparation of Compound 558

[1640] Step 1

[1641] 8-9 (60 mg, 107 μmol), 556-1 (57 mg, 107 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (18 mg, 21 μmol), and cesium fluoride (48.7 mg, 0.32 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 80 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 558 (28 mg, yield: 29%).

[1642] MS m / z(ESI): 893.4 [M+1].

[1643] 1H NMR (400MHz, DMSO-d6) δ12.22–12.10(m,1H),10.91(s,1H),7.74–7.69(m,1H),7.69–7.63(m,1 H),7.45–7.37(m,1H),7.28–7.17(m,2H),7.17–7.05(m,3H),7.01–6.91(m,1H),6.87–6.76(m,1 H),6.26–6.14(m,1H),5.69–5.57(m,1H),4.50–4.33(m,5H),4.28(s,3H),4.16–3.70(m,2H),3. 65–3.21(m,10H),3.21–2.83(m,11H),2.78–2.52(m,2H),2.45–2.12(m,2H),0.93–0.69(m,4H).

[1644] Example 1-507: Preparation of compound 559

[1645] Step 1

[1646] 8-9 (60 mg, 107 μmol), 557-1 (57 mg, 107 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (18 mg, 21 μmol), and cesium fluoride (48.7 mg, 0.32 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 80 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 559 (31 mg, yield: 32%).

[1647] MS m / z(ESI): 893.4 [M+1].

[1648] 1H NMR(400MHz,DMSO-d6)δ12.38–11.90(m,1H),10.92(s,1H),7.74–7.69(m,1H),7.69–7.63 (m,1H),7.46–7.37(m,1H),7.28–7.05(m,5H),7.01–6.91(m,1H),6.82(s,1H),6.22–6.16( m,1H),5.67–5.61(m,1H),4.54–4.20(m,10H),4.17–4.04(m,1H),3.88–3.77(m,2H),3.66– 3.46(m,4H),3.32–2.91(m,12H),2.76–2.52(m,4H),2.44–2.08(m,2H),0.89–0.71(m,4H).

[1649] Example 1-508: Preparation of Compound 560

[1650] Step 1

[1651] 544-1 (149 mg, 0.52 mmol, synthetic method referred to WO2025049820 A1) and 365-4 (158 mg, 0.52 mmol) were dissolved in a dry mixture of tetrahydrofuran and dimethyl sulfoxide (5 mL, 1:1). Potassium acetate (103 mg, 1.04 mmol) and acetic acid (105 mg, 1.74 mmol) were added. The mixture was stirred under a nitrogen atmosphere for 30 minutes, followed by the addition of sodium cyanoborohydride (66 mg, 1.04 mmol). After the addition was complete, the mixture was stirred at 25 °C for 1 hour. The reaction solution was directly purified by reversed-phase C18 column chromatography to obtain product 560-1 (112 mg, yield: 37%).

[1652] MS m / z(ESI): 574.2 [M+1].

[1653] Step Two

[1654] 9-8 (60 mg, 112 μmol), 560-1 (64 mg, 112 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (18 mg, 22 μmol), and cesium fluoride (49 mg, 0.32 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 80 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 560 (31 mg, yield: 30%).

[1655] MS m / z(ESI): 901.4 [M+1].

[1656] Example 1-509: Preparation of Compound 561

[1657] Step 1

[1658] 544-1 (149 mg, 0.52 mmol, synthetic method referred to WO2025049820 A1) and 366-4 (158 mg, 0.52 mmol) were dissolved in a dry mixture of tetrahydrofuran and dimethyl sulfoxide (5 mL, 1:1). A mixture of potassium acetate (103 mg, 1.04 mmol) and acetic acid (105 mg, 1.74 mmol) was added, and the mixture was stirred under a nitrogen atmosphere for 30 minutes. Then, sodium cyanoborohydride (66 mg, 1.04 mmol) was added, and the mixture was stirred at 25 °C for 1 hour. The reaction solution was directly purified by reversed-phase C18 column chromatography to obtain product 561-1 (123 mg, yield: 41%).

[1659] MS m / z(ESI): 574.2 [M+1].

[1660] Step Two

[1661] 9-8 (60 mg, 112 μmol), 561-1 (64 mg, 112 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (18 mg, 22 μmol), and cesium fluoride (49 mg, 0.32 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 80 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 561 (25 mg, yield: 24%).

[1662] MS m / z(ESI): 901.4 [M+1].

[1663] Examples 1-510: Preparation of Compound 562

[1664] Step 1

[1665] 8-9 (60 mg, 107 μmol), 560-1 (62 mg, 107 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (18 mg, 21 μmol), and cesium fluoride (48.7 mg, 0.32 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 80 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 562 (22 mg, yield: 22%).

[1666] MS m / z(ESI): 927.4 [M+1].

[1667] 1 H NMR(400MHz,DMSO-d6)δ12.32–11.85(m,1H),10.91(s,1H),7.76–7.64(m,2H),7.46– 7.23(m,3H),7.16–7.08(m,1H),6.93–6.83(m,2H),6.50–6.43(m,1H),6.22–6.16(m,1 H),5.66–5.59(m,1H),4.51–4.32(m,5H),4.28(s,3H),4.15–3.72(m,2H),3.65–3.21 (m,8H),3.21–2.87(m,11H),2.85–2.52(m,2H),2.40–2.10(m,4H),0.99–0.61(m,4H).

[1668] Examples 1-511: Preparation of Compound 563

[1669] Step 1

[1670] 8-9 (60 mg, 107 μmol), 561-1 (62 mg, 107 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (18 mg, 21 μmol), and cesium fluoride (48.7 mg, 0.32 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 80 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 563 (27 mg, yield: 27%).

[1671] MS m / z(ESI): 927.4 [M+1].

[1672] Examples 1-512: Preparation of Compound 564

[1673] Step 1

[1674] 544-1 (149 mg, 0.52 mmol, synthetic method referred to WO2025049820 A1) and 528-5 (158 mg, 0.52 mmol) were dissolved in a dry mixture of tetrahydrofuran and dimethyl sulfoxide (5 mL, 1:1). Potassium acetate (103 mg, 1.04 mmol) and acetic acid (105 mg, 1.74 mmol) were added. The mixture was stirred under a nitrogen atmosphere for 30 minutes, followed by the addition of sodium cyanoborohydride (66 mg, 1.04 mmol). After the addition was complete, the mixture was stirred at 25 °C for 1 hour. The reaction solution was directly purified by reversed-phase C18 column chromatography to obtain product 564-1 (82 mg, yield: 27%).

[1675] MS m / z(ESI): 574.2 [M+1].

[1676] Step Two

[1677] 9-8 (60 mg, 112 μmol), 564-1 (64 mg, 112 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (18 mg, 22 μmol), and cesium fluoride (49 mg, 0.32 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The resulting mixture was heated to 80 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction solution was directly concentrated under reduced pressure, and the residue was prepared by high-performance liquid chromatography to obtain product 564 (15 mg, yield: 14%).

[1678] MS m / z(ESI): 901.4 [M+1].

[1679] Examples 1-513: Preparation of Compound 565

[1680] Step 1

[1681] 544-1 (149 mg, 0.52 mmol, synthetic method referred to WO2025049820 A1) and 529-3 (158 mg, 0.52 mmol) were d...

Claims

A compound, or a stereoisomer thereof, or a tautomer thereof, or a solvate thereof, or an isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof, wherein the compound comprises the structure shown in formula (IV), in, LBM is the ligand portion of the E3 ubiquitin ligase. L is a linking group; L 1 Selected from key, C 1-6 Alkylene, C 2-6 imidene group, C 2-6 The C- group and any combination thereof, wherein the C- group 1-6 Alkylene and C 2-6 The alkenyl group may be selected independently by one or more of H, halogens, -CN, -OH, -COOH, -NH2, C 1- 6-alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 Alkyl)2, C 3-8 Substitution of cycloalkyl and 4-10 membered heterocyclic groups; or the C 1-6 Alkylene and C 2-6 The carbon atoms in the alkenyl backbone are optionally selected by one or more independently chosen from -C (=O), -NH-, -N (=C). 1-6 alkyl)-, C 3-8 Substitution of cycloalkyl and 4-10 membered heterocyclic groups; L 2 Selected from bonds, O, S, N (R) L ), C(=O), C(=O)N(R) L ), N(R L C(=O) and any combination thereof, R L Selected from H and C 1-4 alkyl; R 1 Selected from H, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl and 5-10 membered heterocyclic, wherein C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 heteroaryl, and 5-10 heterocyclic groups are optionally selected by one or more elements chosen from H, halogen, -CN, -OH, -COOH, -NH2, C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl and -N-(C 1-6 Substitution of alkyl groups; Ring W is selected from C 3-15 Cycloalkyl and 4-15 membered heterocyclic groups, wherein the C 3-15 Cycloalkyl and 4-15 membered heterocyclic groups include spirocyclic, monocyclic, fused, or bridged rings; w is 0, 1, 2, 3, 4, 5, or 6; Each R W Each is independently selected from H, halogens, -CN, -OH, -COOH, -NH2, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl and -N-(C 1-6 Alkyl)2; R 2 Selected from H, halogens, -CN, -OH, -COOH, -NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl and -N-(C 1-6 Alkyl)2; or, R 2 And one of the R W Forming C with the attached atoms 5-10 Cycloalkenyl, 5-10 membered heterocyclic and 5-10 membered heteroaryl; Ring V is a 5-6 membered heteroaryl group; v is 0, 1, or 2; R V Selected from H, halogens, -CN, -OH, -COOH, -NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1- 6-alkyl, -NH-C 1-6 Alkyl and -N-(C 1-6 Alkyl)2; L 3 Selected from bonds, O, S, N (R) L ), C(=O), C(=O)N(R) L ) and N(R L C(=O), R L Selected from H and C 1-4 alkyl; R 3 Selected from C 1-6 Alkyl, C 3-10 Cycloalkyl and 4-10 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-10 The cycloalkyl group and the 4-10 membered heterocyclic group are optionally surrounded by one or more groups selected from H, halogen, -CN, -OH, -COOH, -NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl and -N-(C 1-6 Substitution of alkyl groups; or, R 3 And one of the R V Forming C with the attached atoms 5-10 Cycloalkenyl and 5-10 membered heterocyclic groups; R 4 Selected from H and halogens; The condition is that, When ring W is azacyclohexene, piperidinyl, or homopiperidinyl: 1) L contains Wherein, the * terminal is connected to the LBM; or, 2)R 2 And one of the R W To form a ring with the atoms connected to it; or, 3)R 3 And one of the R V It forms a ring with the atoms connected to it; in, Rings E and F are each independently selected from C. 6-10 Aryl, C 3-10 Cycloalkyl, 5-12-membered heteroaryl and 4-12-membered heterocyclic groups; e and f are each independently 1, 2, 3, 4, 5 or 6; Each R E and each R F Each is independently selected from H, halogens, -CN, -OH, -COOH, -NH2, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl and -N-(C 1-6 Alkyl)2; Ring I is C 6-10 Aryl, C 4-10 cycloalkyl, C 4-10 Cycloalkenyl, 5-12-membered heteroaryl and 4-12-membered heterocyclic groups. The compound of claim 1, or its stereoisomer, its tautomer, its solvate, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, L is L 4 L 5 L 6 Each is independently selected from key, C 1-6 Alkylene, C 2-6 imidene group, C 2-6 alkyne group, O, S, N(R) L ), C(=O), C(=O)N(R) L ), N(R L C(=O) and any combination thereof, R L Selected from H and C 1-4 alkyl; Rings E and F are each independently selected from C. 6-10 Aryl, C 3-10 Cycloalkyl, 5-12-membered heteroaryl and 4-12-membered heterocyclic groups; e and f are each independently 0, 1, 2, 3, 4, 5 or 6; Each R E and each R F Each is independently selected from H, halogens, -CN, -OH, -COOH, -NH2, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl and -N-(C 1-6 Alkyl)2; or, One of the R E And an R F The atoms connected to each other form rings, making the structural unit for e and f are each independently 1, 2, 3, 4, 5, or 6, and ring I is C. 6-10 Aryl, C 4- 10 cycloalkyl, C 4-10 Cycloalkenyl, 5-12 membered heteroaryl and 4-12 membered heterocyclic; L 6 Connected to LBM. The compound of claim 1 or 2, or its stereoisomer, its tautomer, its solvate, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein the compound contains the structure shown in formula (I), in, L 1 Selected from key, C 1-6 Alkylene, C 2-6 imidene group, C 2-6 The C- group and any combination thereof, wherein the C- group 1-6 Alkylene and C 2-6 The alkenyl group may be selected independently by one or more of H, halogens, -CN, -OH, -COOH, -NH2, C 1- 6-alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 Alkyl)2, C 3-8 Substitution of cycloalkyl and 4-10 membered heterocyclic groups; or the C 1-6 Alkylene and C 2-6 The carbon atoms in the alkenyl backbone are optionally selected by one or more independently chosen from -C (=O), -NH-, -N (=C). 1-6 alkyl)-, C 3-8 Substitution of cycloalkyl and 4-10 membered heterocyclic groups; L 2 Selected from bonds, O, S, N (R) L ), C(=O), C(=O)N(R) L ), N(R L C(=O) and any combination thereof, R L Selected from H and C 1-4 alkyl; R 1 Selected from H, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl and 5-10 membered heterocyclic, wherein C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 heteroaryl, and 5-10 heterocyclic groups are optionally selected by one or more elements chosen from H, halogen, -CN, -OH, -COOH, -NH2, C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl and -N-(C 1-6 Substitution of alkyl groups; Ring W is selected from C 3-15 Cycloalkyl and 4-15 membered heterocyclic groups, wherein the C 3-15 Cycloalkyl and 4-15 membered heterocyclic groups include spirocyclic, monocyclic, fused, or bridged rings; w is 0, 1, 2, 3, 4, 5, or 6; Each R W Each is independently selected from H, halogens, -CN, -OH, -COOH, -NH2, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl and -N-(C 1-6 Alkyl)2; R 2 Selected from H, halogens, -CN, -OH, -COOH, -NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl and -N-(C 1-6 Alkyl)2; or, R 2 And one of the R W Forming C with the attached atoms 5-10 Cycloalkenyl, 5-10 membered heterocyclic and 5-10 membered heteroaryl; Ring V is a 5-6 membered heteroaryl group; v is 0, 1, or 2; R V Selected from H, halogens, -CN, -OH, -COOH, -NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1- 6-alkyl, -NH-C 1-6 Alkyl and -N-(C 1-6 Alkyl)2; L 3 Selected from bonds, O, S, N (R) L ), C(=O), C(=O)N(R) L ) and N(R L C(=O), R L Selected from H and C 1-4 alkyl; R 3 Selected from C 1-6 Alkyl, C 3-10 Cycloalkyl and 4-10 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-10 The cycloalkyl group and the 4-10 membered heterocyclic group are optionally surrounded by one or more groups selected from H, halogen, -CN, -OH, -COOH, -NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl and -N-(C 1-6 Substitution of alkyl groups; or, R 3 And one of the R V Forming C with the attached atoms 5-10 Cycloalkenyl and 5-10 membered heterocyclic groups; R 4 Selected from H and halogens; L 4 L 5 and L 6 Each is independently selected from key, C 1-6 Alkylene, C 2-6 imidene group, C 2-6 alkyne group, O, S, N(R) L ), C(=O), C(=O)N(R) L ), N(R L C(=O) and any combination thereof, R L Selected from H and C 1-4 alkyl; Rings E and F are each independently selected from C. 6-10 Aryl, C 3-10 Cycloalkyl, 5-12-membered heteroaryl and 4-12-membered heterocyclic groups; e and f are each independently 0, 1, 2, 3, 4, 5 or 6; Each R E and each R F Each is independently selected from H, halogens, -CN, -OH, -COOH, -NH2, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl and -N-(C 1-6 Alkyl)2; or, One of the R E And an R F Forming C with the attached atoms 5-10 cycloalkyl, C 5-10 Cycloalkenyl and 5-10 membered heterocyclic groups; The condition is that, When ring W is azacyclohexene, piperidinyl, or homopiperidinyl, R 2 And one of the R W It forms a ring with the adjacent atoms, or, R 3 And one of the R V It forms a ring with the connected atoms, or an R E And an R F It forms a ring with the atoms connected to it; Indicates the connection site with LBM. The compound of any one of claims 1-3, or its stereoisomer, its tautomer, its solvate, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, L 1 Selected from key, C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Alynyl groups and any combination thereof; Preferably, L 1 Selected from key, C 1-4 Alkylene and C 2-4 alkenyl; Preferably, L 1 Selected from -CH2-, -CH2CH2-, -CH(CH3)-, -CH2CH(CH3)- and -CH(CH3)CH2-; Preferably, L 1 Selected from -CH2CH2-; L 2 Selected from bonds, O, S, N (R) L ) and C(=O), R L Selected from H and methyl; Preferably, L 2 Selected from the bond and -C (=O)-; Preferably, -L 1 -L 2 -* is selected from -CH2CH2-* and -CH2CH2C(=O)-*. The compound of any one of claims 1-4, or its stereoisomer, its tautomer, its solvate, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, R 1 Selected from H, C 3-8 Cycloalkyl, 5-6 membered heteroaryl and 5-6 membered heterocyclic, wherein C 3-8 Cycloalkyl, 5-6-membered heteroaryl, and 5-6-membered heterocyclic groups are optionally separated by one or more elements selected from H, halogen, -CN, -OH, -COOH, -NH2, and C. 1-4 Alkyl group substitution; Preferably, R 1 It is a 5-6-membered heteroaryl group, wherein the 5-6-membered heteroaryl group is optionally substituted by 1, 2, or 3 groups selected from H, halogen, -CN, -OH, -COOH, -NH2 and methyl; Preferably, R 1 Selected from pyrrole, pyrazolyl, imidazolyl, triazolyl, thiophenyl, thiazolyl, and pyridinyl; Preferably, R 1 Selected from The compound of any one of claims 1-5, or its stereoisomer, its tautomer, its solvate, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, Ring W is a 5-15 member heterocyclic group, which includes spirocyclic, monocyclic, fused ring or bridged ring; Preferably, ring W is selected from 7-15 spirocyclic heterocyclic groups, 5-7 unicyclic heterocyclic groups, and 7-15 fused heterocyclic groups; Preferably, ring W is selected from 5-7 member monocyclic heterocyclic groups and Where W1 is a 5-8 membered heterocyclic group, and W2 is a C group. 3-6 Cycloalkyl, W3 is a 5-7 membered heterocyclic group, and W4 is a 5-6 membered heteroaryl group; Preferably, ring W is selected from 5-7 membered monocyclic nitrogen-containing alkenyl groups, 5-7 membered monocyclic nitrogen-containing alkyl groups and W1 is selected from 5-8-membered nitrogen-containing heterocyclic alkyl and 5-8-membered nitrogen-containing heterocyclic alkenyl groups; W2 is selected from cyclopropyl, cyclobutyl, and cyclopentyl groups; W3 is selected from 5-7-membered nitrogen-containing heterocyclic alkyl and 5-7-membered nitrogen-containing heterocyclic alkenyl groups; W4 is selected from pyrrole, pyrazol, and imidazolyl groups; *terminus is associated with L. 2 Connected; Preferably, ring W is selected from The compounds are azircyclohexenyl, azircycloheptenyl, azircyclohexenylpyrazolyl, and azircyclohexenylimidazolyl, wherein p1, p2, and p3 are each independently 0, 1, or 2, and p1 + p2 ≤ 2; p4, p5, and p6 are each independently 0, 1, or 2, and p4 + p5 ≤ 2; and the *terminus is L. 2 Connected; Preferably, ring W is selected from Azacyclohexenylpyrazolyl and azacyclohexenylimidazolyl, wherein p1, p2, and p3 are each independently 0, 1, or 2, and p1 + p2 ≤ 2; p4, p5, and p6 are each independently 0, 1, or 2, and p4 + p5 ≤ 2; the * terminus is associated with L. 2 Connected; w can be 0, 1, 2, or 3; Each R W Each is independently selected from H, halogens, -CN, -OH, -COOH, -NH2, and C. 1-4 Alkyl, C 1-4 Halogenated alkyl groups and -OC 1-4 alkyl; Preferably, each R W Each is independently selected from H, halogens, -CN, -OH, -COOH, -NH2, -CH3, and -CH2CH3; Preferably, each R W Each is independently selected from H, -F, and -CH3; Preferably, structural unit Selected from Among them, * end and L 2 Connected; Preferably, structural unit Selected from The compound of any one of claims 1-6, or its stereoisomer, its tautomer, its solvate, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, R 4 Selected from H and F; Preferably, R 4 It is F. The compound of any one of claims 1-7, or its stereoisomer, its tautomer, its solvate, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, R 2 Selected from H, halogens, -CN, -OH, -COOH, -NH2, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups and -OC 1-4 alkyl; Preferably, R 2 Selected from H, halogens, -CN, -OH, -COOH, -NH2, -CH3, and -CH2CH3; Preferably, R 2 For H. The compound of any one of claims 1-8, or its stereoisomer, its tautomer, its solvate, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, R 2 And one of the R W The atoms connected to each other form rings, making the structural unit for Where ring J is C 5-8 Cycloalkenyl, 5-8 membered heterocyclic and 5-6 membered heteroaryl, cycloW, R W and R 4 As defined in any one of claims 1-8, w is 1, 2, 3, 4, 5, or 6; Preferably, structural unit for Among them, rings W and R W and R 4 As defined in any one of claims 1-8, X 1 Selected from CH2, O, S and NH, where q is 0, 1 or 2; Preferably, structural unit Selected from The compound of any one of claims 1-9, or its stereoisomer, its tautomer, its solvate, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, Ring V is a 5-membered heteroaryl group; Preferably, ring V is selected from pyrrole, pyrazolyl, imidazolyl, furanyl, and thiopheneyl; Preferably, ring V is a pyrrole group; R V Selected from H, halogens, -CN, -OH, -COOH, -NH2, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups and -OC 1- 4-alkyl; Preferably, R V Selected from H, halogens, -CN, -OH, -COOH, -NH2, -CH3, and -CH2CH3; Preferably, R V For H; Preferably, structural unit for The compound of any one of claims 1-10, or its stereoisomer, its tautomer, its solvate, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, L 3 Selected from C(=O) and C(=O)N(R) L ), R L Selected from H and C 1-4 alkyl; Preferably, L 3 The expression is -C(=O)N(CH3)-*, where the * terminus is connected to R. 3 Connected; R 3 Selected from C 1-6 Alkyl, C 3-8 Cycloalkyl and 4-8 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-8 The cycloalkyl group and the 4-8 membered heterocyclic group are optionally surrounded by one or more groups selected from H, halogen, -CN, -OH, -NH2 and C. 1-6 Alkyl group substitution; Preferably, R 3 Selected from C 1-4 Alkyl, C 3-6 Cycloalkyl and 4-6 membered heterocyclic groups, wherein the C 1-4 Alkyl, C 3-6 The cycloalkyl and 4-6 membered heterocyclic groups may be optionally substituted with 1, 2, 3, 4 or 5 groups selected from H, halogens and methyl groups; Preferably, R 3 Selected from methyl, ethyl, propyl, halomethyl, haloethyl, cyclopropyl, aziridine, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl; Preferably, R 3 -CH3; Preferably, -L 3 -R 3 It is -C(=O)N(CH3)2. The compound of any one of claims 1-11, or its stereoisomer, its tautomer, its solvate, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, R 3 And one of the R V The atoms connected to each other form rings, making the structural unit for Among them, ring K is a 5-8 member heterocyclic group, and rings V and R are... V L 3 and R 4 As defined in any one of claims 1-11, v is 1 or 2; Preferably, structural unit for Among them, ring R V R L and R 4 As defined in any one of claims 1-11, s is 0, 1, or 2; Preferably, structural unit for The compound of any one of claims 1-12, or its stereoisomer, its tautomer, its solvate, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, L 4 L 5 and L 6 Each is independently selected from key, C 1-6 Alkylene, C 2-6 alkyne group, O, N(R) L ), C(=O), C(=O)N(R) L ), N(R L C(=O) and any combination thereof, R L Selected from H and C 1-4 alkyl; Preferably, L 4 L 5 and L 6 Each is independently selected from key, C 1-4 Alkylene and C (=O); Preferably, L 4 For key; Preferably, L 5 Selected from the bond and C (=O); Preferably, L 5 For key; Preferably, L 6 Selected from the bond, -CH2CH2- and -CH2CH2CH2-. The compound of any one of claims 1-13, or its stereoisomer, its tautomer, its solvate, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, Ring E and ring F are each independently selected from phenyl, C 3-10 Cycloalkyl and 4-12 membered heterocyclic groups, Preferably, ring E and ring F are each independently selected from phenyl, C 3-7 Cycloalkyl and 4-10 membered heterocyclic groups, Preferably, ring E and ring F are each independently selected from phenyl, cyclobutyl, cyclopentyl, aziridine, pyrrolidinyl, piperidinyl, piperazine, and so on. Preferably, ring E is selected from phenyl; Preferably, ring F is selected from piperidinyl, piperazine, and... f and g are each independently 0, 1, 2, 3 or 4; Each R E and each R F Each is independently selected from H, halogen, -OH, -NH2, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, -OC 1-4 Alkyl and -OC 1-4 Halogenated alkyl groups; Preferably, each R E and each R F Each is independently selected from H, -F, -Cl, -CH3, -CH2CH3, -CF3, -OCH3, and -OCF3; Preferably, each R E Each is independently selected from H, F, -Cl, -CH3, -CF3, and -OCF3; Preferably, each R F Each is independently represented by H; Preferably, structural unit Selected from Among them, * end and L 5 Connected; Preferably, structural unit Selected from Among them, * end and L 6 Connected. The compound of any one of claims 1-14, or its stereoisomer, its tautomer, its solvate, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, An R E And an R F The atoms connected to each other form rings, making the structural unit for Among them, ring I is a 5-8 membered heterocyclic group, and rings E, F, and R are also present. E and R F As defined in any one of claims 1-14, e and f are each independently 1, 2, 3, 4, 5, or 6; Preferably, structural unit for Among them, rings E, F, and R E and R F As defined in any one of claims 1-14, e and f are each independently 1, 2, 3, 4, 5, or 6, X 2 X 3 and X 4 Each is independently selected from chemical bonds, CH2, O, S, and NH, and X 2 X 3 and X 4 Not both 0, t can be 0, 1 or 2; Preferably, structural unit Selected from Among them, R E and R F As defined in any one of claims 1-14, e and f are each independently 1, 2, 3 or 4, t1 and t3 are each independently 1, 2 or 3, and t2, t4 and t5 are each independently 0, 1 or 2; Preferably, structural unit Selected from Among them, R E As defined in any one of claims 1-14; Preferably, structural unit Selected from The compound of any one of claims 1-15, or its stereoisomer, its tautomer, its solvate, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, The compound is shown in formula (III). in, Ring W, Ring V, Ring E, Ring F, w, v, e, f, R W R V R E R F L 1 L 2 L 3 L 4 L 5 L 6 R 1 R 2 R 3 and R 4 As defined in any one of claims 1-15, Ring G is selected from C 6-10 Aryl, C 3-10 Cycloalkyl, 5-12-membered heteroaryl and 4-12-membered heterocyclic groups; g can be 0, 1, 2, 3, 4, 5, or 6; Each R G Each is independently selected from H, halogens, -CN, -OH, -COOH, -NH2, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl and -N-(C 1-6 Alkyl)2; L 7 Selected from bonds, O, S, N (R) L ), C(=O), C(=O)N(R) L ) and N(R L C(=O), R L Selected from H and C 1-4 alkyl; R 5 Selected from H, halogens, -CN, -OH, -COOH, -NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl and -N-(C 1-6 Alkyl)2; L 8 Selected from bonds, CH2, C(=O), C(=S), S(=O) and m is 0 or 1. The compound of claim 16, or its stereoisomer, its tautomer, its solvate, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, Ring G is selected from phenyl, naphthyl, 5-10 membered heteroaryl, and 9-10 membered heterocyclic groups. Preferably, ring G is selected from phenyl, naphthyl, pyrazolyl, benzopyrazolyl, pyridopyrazolyl, pyridoimidazolyl, quinolinyl, isoquinolinyl, etc. Preferably, ring G is phenyl; Preferably, ring G is selected from: Among them, * end and L 7 Connected; g can be 0, 1, 2, 3, or 4; Each R G Each is independently selected from H, halogen, -OH, -NH2, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups and -OC 1-4 alkyl; Preferably, each R G Each is independently selected from H, -F, -Cl, -CH3, -CH2CH3, -CF3, and -OCH3; Preferably, each R G Each is independently selected from H, -F, -CH3, and -OCH3; Preferably, structural unit Selected from Among them, * end and L 7 Connected. The compound of claim 16 or 17, or its stereoisomer, its tautomer, its solvate, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, L 7 Selected from bonds, O, N (R) L ) and C(=O)N(R L ), R L Selected from H and C 1-4 alkyl; Preferably, L 7 Selected from bonds and N(R) L ), R L Selected from H, -CH3, and -CH2CH3; Preferably, L 7 Selected from bonds and NH. The compound of any one of claims 16-18, or its stereoisomer, its tautomer, its solvate, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, R 5 Selected from H, halogens, -CN, -OH, -COOH, -NH2, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups and -OC 1-4 alkyl; Preferably, R 5 Selected from H, halogens, -CN, -OH, -COOH, C 1-4 Alkyl groups and -NH2; Preferably, R 5 Selected from H, F and -CH3. The compound of any one of claims 16-19, or its stereoisomer, its tautomer, its solvate, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, L 8 Selected from bonds, CH2, and C (=O); Preferably, L 8 It is C (=O). The compound of any one of claims 16-20, or its stereoisomer, its tautomer, its solvate, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, m is 1. The compound of any one of claims 16-21, or its stereoisomer, its tautomer, its solvate, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, Structural unit Selected from Among them, R G and g as defined in any one of claims 1-21. The compound of any one of claims 16-22, or its stereoisomer, its tautomer, its solvate, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, The compound is selected from the structures shown in formula (III-1), (III-2), (III-3), (III-4), (III-5), or (III-6). Among them, rings W1, W2, V, E, F, G, w, v, e, f, g, m, and R W R V R E R F R G L 1 L 2 L 3 L 4 L 5 L 6 L 7 L 8 R 1 R 2 R 3 R 4 R 5 As defined in any one of claims 1-22, Preferably, structural unit for Where p1, p2, and p3 are each independently 0, 1, or 2, and p1 + p2 ≤ 2, * and L 2 Connected; Preferably, structural unit for Selected from *End and L 2 Connected; Among them, rings W3, W4, V, E, F, G, w, v, e, f, g, m, and R W R V R E R F R G L 1 L 2 L 3 L 4 L 5 L 6 L 7 L 8 R 1 R 2 R 3 R 4 R 5 As defined in any one of claims 1-22, Preferably, structural unit Selected from *End and L 2 Connected; Among them, rings J, W, V, E, F, G, w, v, e, f, g, m, and R W R V R E R F R G L 1 L 2 L 3 L 4 L 5 L 6 L 7 L 8 R 1 R 3 R 4 R 5 As defined in any one of claims 1-22; Among them, rings K, W, V, E, F, G, w, v, e, f, g, m, and R W R V R E R F R G L 1 L 2 L 3 L 4 L 5 L 6 L 7 L 8 R 1 R 2 R 4 R 5 As defined in any one of claims 1-22; Among them, ring I, ring W, ring V, ring E, ring F, ring G, w, v, e, f, g, m, R W R V R E R F R G L 1 L 2 L 3 L 4 L 6 L 7 L 8 R 1 R 2 R 3 R 4 R 5 As defined in any one of claims 1-22; Among them, rings W1, W2, V, E, F, G, w, v, e, f, g, m, and R W R V R E R F R G L 1 L 2 L 3 L 4 L 5 L 6 L 7 L 8 R 1 R 2 R 3 R 4 R 5 As defined in any one of claims 1-22, Preferably, structural unit for Among them, p4, p5, and p6 are each independently 0, 1, or 2, and p4 + p5 ≤ 2, * and L 2 Connected; Preferably, structural unit Selected from *End and L 2 Connected; Preferably, the compound is selected from the structures shown in formula (III-1A), formula (III-5A), formula (III-5B), or formula (III-5C). Among them, rings V, E, F, I, G, v, e, f, g, m, and R V R E R F R G L 1 L 2 L 3 L 4 L 5 L 6 L 7 L 8 R 1 R 2 R 3 R 4 R 5 p1, p2, p3, t 3 and t 4 As defined in any one of claims 1-22; Preferably, structural unit Selected from Preferred More preferably Among them, * end and L 2 Connected. The compound of claim 1 or 2, or its stereoisomer, its tautomer, its solvate, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, The compound is shown in formula (V). in, Ring W, Ring V, w, v, R W R V L, L 1 L 2 L 3 R 1 R 2 R 3 R 4 As defined in any one of claims 1-23; Ring G is selected from C 6-10 Aryl, C 3-10 Cycloalkyl, 5-12-membered heteroaryl and 4-12-membered heterocyclic groups; g can be 0, 1, 2, 3, 4, 5, or 6; Each R G Each is independently selected from H, halogens, -CN, -OH, -COOH, -NH2, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl and -N-(C 1-6 Alkyl)2; L 7 Selected from bonds, O, S, N (R) L ), C(=O), C(=O)N(R) L ) and N(R L C(=O), R L Selected from H and C 1-4 alkyl; R 5 Selected from H, halogens, -CN, -OH, -COOH, -NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl and -N-(C 1-6 Alkyl)2; L 8 Selected from bonds, CH2, C(=O), C(=S), S(=O) and m is 0 or 1; The condition is that when ring W is azircyclohexene, piperidinyl, or homopiperidinyl, 1) L contains Wherein, the * end is connected to ring G; or, 2)R 2 And one of the R W To form a ring with the atoms connected to it; or, 3)R 3 And one of the R V It forms a ring with the atoms connected to it; The rings E, F, I, and R E R F e, f are as defined in any one of claims 1-23. Preferably, when ring W is azacyclohexene, L contains The rings E, F, I, and R E R F e, f are as defined in any one of claims 1-23. The compound of claim 24, or its stereoisomer, its tautomer, its solvate, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, Ring W is a 7-15 member spirocyclic heterocyclic group, preferably... Where p1, p2, and p3 are each independently 0, 1, or 2, and p1 + p2 ≤ 2, * and L 2 Connected. The compound of claim 24 or 25, or its stereoisomer, its tautomer, its solvate, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, Ring G is selected from phenyl, naphthyl, 5-10 membered heteroaryl, and 9-10 membered heterocyclic groups. Preferably, ring G is selected from phenyl, naphthyl, pyrazolyl, benzopyrazolyl, pyridopyrazolyl, pyridoimidazolyl, quinolinyl, isoquinolinyl, etc. Preferably, ring G is phenyl; Preferably, ring G is selected from: Among them, * end and L 7 Connected; g can be 0, 1, 2, 3, or 4; Each R G Each is independently selected from H, halogen, -OH, -NH2, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups and -OC 1-4 alkyl; Preferably, each R G Each is independently selected from H, -F, -Cl, -CH3, -CH2CH3, -CF3, and -OCH3; Preferably, each R G Each is independently selected from H, -F, -CH3, and -OCH3; Preferably, structural unit Selected from Among them, * end and L 7 Connected. The compound of claims 24-26, or its stereoisomers, tautomers, solvates, isotopically labeled compounds, or pharmaceutically acceptable salts thereof, wherein, L 7 Selected from bonds, O, N (R) L ) and C(=O)N(R L ), R L Selected from H and C 1-4 alkyl; Preferably, L 7 Selected from bonds and N(R) L ), R L Selected from H, -CH3, and -CH2CH3; Preferably, L 7 Selected from bonds and NH. The compound of any one of claims 24-27, or its stereoisomer, its tautomer, its solvate, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, R 5 Selected from H, halogens, -CN, -OH, -COOH, -NH2, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups and -OC 1-4 alkyl; Preferably, R 5 Selected from H, halogens, -CN, -OH, -COOH, C 1-4 Alkyl groups and -NH2; Preferably, R 5 Selected from H, F and -CH3. The compound of any one of claims 24-28, or its stereoisomer, its tautomer, its solvate, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, L 8 Selected from bonds, CH2, and C (=O); Preferably, L 8 It is C (=O). The compound of any one of claims 24-29, or its stereoisomer, its tautomer, its solvate, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, m is 1. The compound of any one of claims 24-30, or its stereoisomer, its tautomer, its solvate, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, Structural unit Selected from Among them, R G and g as defined in any one of claims 24-30. The compound of any one of claims 24-31, or its stereoisomer, its tautomer, its solvate, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, The compound has the structure shown in formula (V-1). Among them, rings V, G, v, g, m, and R V R G L, L 1 L 2 L 3 L 7 L 8 R 1 R 2 R 3 R 4 R 5 p1, p2 and p3 are as defined in any one of claims 24 to 31; Preferably, Selected from Preferred More preferably *End and L 2 Connected. The compound of any one of claims 1-32, or its stereoisomer, its tautomer, its solvate, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, The compounds are selected from those shown in Table A. The compound of claim 33, or its stereoisomer, its tautomer, its solvate, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, The compounds are selected from those shown in Table B. A compound, or its stereoisomer, or its tautomer, or its solvate, or its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, The compound contains the structure shown in formula (M1). in, Ring W, Ring V, w, v, R W R V L 1 L 2 L 3 R 1 R 2 R 3 and R 4 As defined in any one of claims 1-34; The condition is that when ring W is azircyclohexene, piperidinyl, or homopiperidinyl, R 2 And one of the R W It forms a ring with the adjacent atoms, or, R 3 And one of the R V It forms a ring with the atoms connected to it. The compound of claim 35, or its stereoisomer, its tautomer, its solvate, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, The compound is shown in formula (M2). in, Ring W, Ring V, w, v, R W R V L 1 L 2 L 3 R 1 R 2 R 3 and R 4 As defined in any one of claims 1-34, R M Selected from H, halogens, and reactive boric acid groups. The compound of claim 35 or 36, or its stereoisomer, its tautomer, its solvate, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, R M Selected from H, F, Cl and Preferably, R M For Cl and The compound of any one of claims 35-37, or a stereoisomer thereof, or a tautomer thereof, or a solvate thereof, or an isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the compounds shown in Table C. Use of the compound of any one of claims 35-38, or its stereoisomer, tautomer, solvate, isotopically labeled compound, or pharmaceutically acceptable salt thereof, in the preparation of the compound of any one of claims 1-34, or its stereoisomer, tautomer, solvate, isotopically labeled compound, or pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising the compound of any one of claims 1-34, or a stereoisomer thereof, or a tautomer thereof, or a solvate thereof, or an isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers and / or excipients. The use of the compound of any one of claims 1-34, or its stereoisomer, tautomer, solvate, isotopically labeled compound, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 40, in the preparation of a medicament for treating and / or preventing a disease, preferably, wherein the disease is a STAT6-mediated disease; preferably, the disease is selected from allergic diseases (e.g., asthma, dermatitis, rhinitis, eczema), autoimmune diseases (e.g., multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus), cancers (e.g., lymphoma and solid tumors), fibrotic diseases, and any combination thereof. A method for preparing the compound of any one of claims 1-34, or its stereoisomer, tautomer, solvate, isotopically labeled compound, or pharmaceutically acceptable salt thereof, comprising: Among them, rings W, V, w, v, and R W R V L, L 1 L 2 L 3 R 1 R 3 R 4 LBM as defined in any one of claims 1-34; or, Among them, rings W, V, E, F, G, w, v, e, f, g, m, and R W R V R E R F R G L 1 L 2 L 3 L 4 L 5 L 6 L 7 L 8 R 1 R 2 R 3 R 4 R 5 As defined in any one of claims 1-34; or, Among them, rings V, E, F, G, v, e, f, g, m, and R V R E R F R G L 1 L 2 L 3 L 4 L 5 L 6 L 7 L 8 R 1 R 2 R 3 R 4 R 5 p1, p2, and p3 are as defined in any one of claims 1-34; or, III-5A-e was prepared using either method one or method two. Method 1: Method 2: L 6a Selected from -C(=O)C 1-6 alkylene-; Ring V, Ring E, Ring F, Ring G, Ring I, v, e, f, g, m, R V R E R F R G L 1 L 2 L 3 L 4 L 5 L 6 L 7 L 8 R 1 R 2 R 3 R 4 R 5 p1, p2, and p3 are as defined in any one of claims 1-34.

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