STAT6 degrader

Abstract

Disclosed in the present invention are an STAT6 small-molecule degrader represented by general formula 1 and a derivative, stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, which can be used for treating and preventing related diseases mediated by STAT6 signaling pathway.

Description

A class of STAT6 degrading agents

[0001] Related applications

[0002] This application claims priority to the following invention patents filed with the China National Intellectual Property Administration, the entire contents of which are incorporated herein by reference:

[0003] 1. Invention title: A type of STAT6 degrading agent; Application number: 202510375510.5; Application date: March 27, 2025;

[0004] 2. Invention title: A type of STAT6 degrading agent; Application number: 202510531498.2; Application date: April 25, 2025;

[0005] 3. Invention title: A type of STAT6 degrading agent; Application number: 202510626862.3; Application date: May 15, 2025;

[0006] 4. Invention title: A type of STAT6 degrading agent; Application number: 202510877766.6; Application date: June 27, 2025;

[0007] 5. Invention title: A type of STAT6 degrading agent, application number: 202510994449.2, application date: July 18, 2025;

[0008] 6. Invention title: A type of STAT6 degrading agent, application number: 202511529651.4, application date: October 24, 2025;

[0009] 7. Invention title: A type of STAT6 degrading agent, application number: 202511809807.4, application date: December 3, 2025.

[0010] 8. Invention title: A type of STAT6 degrading agent, application number: 202511909656.X, application date: December 17, 2025. Technical Field

[0011] This invention belongs to the field of medicine, specifically relating to a class of STAT6 small molecule degraders that can be used to treat and prevent diseases mediated by the STAT6 signaling pathway. Background Technology

[0012] STAT6 (Signal Transducer and Activator of Transcription 6) is a key transcription factor in the JAK-STAT signaling pathway, widely involved in the regulation of the immune system, especially playing an important role in Th2 immune responses (Science 2003, 300(5625), 1527-1528). STAT6 is mainly activated by the cytokines interleukin-4 (IL-4) and IL-13. These cytokines bind to their specific receptors, the IL-4 receptor complex or the IL-13 receptor complex, activating JAK kinase, which in turn phosphorylates STAT6, promoting its dimerization and translocation to the cell nucleus (Cytokine 2015, 75(1), 38-50). In the cell nucleus, the STAT6 dimer binds to specific DNA sequences (GAS elements), regulating the transcription of downstream immune-related genes, thereby regulating the differentiation, proliferation, and secretion of inflammatory factors of immune cells.

[0013] STAT6 is a transcription factor essential for the development of allergic inflammation. Mice lacking STAT6 expression exhibit significantly reduced inflammation in various models, such as allergic respiratory disease, food allergy, eosinophilic esophagitis, and atopic dermatitis (J. Immunol. 2009, 182, 7501-7508; Journal of Experimental Medicine 1998, 187(9), 1537-1542.). Furthermore, mice expressing constitutively activated STAT6 are prone to allergic diseases. Therefore, STAT6 plays an important role in the pathophysiology of Th2 inflammation, atopic dermatitis, or asthma (Pathol. Res. Pract. 2021, 223, 153477.). STAT6 also plays a role in regulating the tumor microenvironment (TME), and STAT6 activating mutations have been found in patient follicular lymphoma samples (Blood, The Journal of the American Society of Hematology 2015, 125(4), 668-679.). Therefore, the STAT6 signaling pathway is a potential therapeutic target for a variety of human diseases and conditions.

[0014] Current treatment strategies largely focus on indirectly reducing STAT6 activation by inhibiting IL-4, IL-13, and their receptors, or by interfering with the JAK-STAT signaling pathway. For example, anti-IL-4R and anti-IL-13 antibodies have demonstrated efficacy in alleviating allergic and autoimmune diseases in preclinical and clinical studies. However, these antibody therapies have certain limitations, including inconvenient administration, significant side effects, and drug resistance. In recent years, targeted protein degradation (TPD) induced by proteolysis-targeting chimeras (PROTAC) technology has become a powerful method for discovering chemical biology tool compounds and developing novel therapies (Drug Discov. Today Technol. 2019, 31, 15-27). Developing small-molecule STAT6 degraders to precisely modulate the activity of the STAT6 signaling pathway is an effective strategy to overcome these limitations and improve treatment efficacy. Summary of the Invention

[0015] According to one aspect of the invention, an object of the invention is to provide a compound represented by general formula 1 and its derivatives, stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts:

[0016] Among them, X3 and X4 are each independently selected from C or N atoms.

[0017] Preferably, X3 and X4 are not both N atoms;

[0018] L 01 C 1-6 Alkylene, C 3-8 Cycloalkylene groups, saturated four- to eight-membered heterocyclic groups containing one to three heteroatoms selected from N, O, and S;

[0019] Preferably, L 01 C 1-4 Alkylene, C 3-6 Cycloalkylene groups, saturated four- to six-membered heterocyclic groups containing one to three heteroatoms selected from N, O, and S;

[0020] Preferably, L 01 C 2-3 Alkylene, C 5-6 Cycloalkylene groups, saturated four- to six-membered heterocyclic groups containing one or two heteroatoms selected from N, O, and S;

[0021] More preferably, L 01 The derivatives are ethylene, propylene, cyclopentylene, and cyclohexylene.

[0022] L02 C 2-6 imidene group, C 2-6 Alynyl group, saturated seven- to fourteen-membered heterocyclic group containing one to three heteroatoms selected from N or O, bicyclic group or spirocyclic group;

[0023] Preferably, L 02 C 2-4 imidene group, C 2-4 Alynyl group, saturated seven- to ten-membered heterocyclic group containing one or two heteroatoms selected from N or O, bicyclic group or spirocyclic group;

[0024] Preferably, L 02 C 2-4 imidene group, C 2-4 Ethyne group, X1 and X2 are each independently selected from C or N atoms;

[0025] More preferably, L 02 Vinylidene, ethynylene, X1 and X2 are each independently selected from C or N atoms;

[0026] R1, R3, and R4 are each independently selected from H, halogen atoms, cyano groups, carbonyl groups, amino groups, hydroxyl groups, amide groups (-C(=O)NH2), substituted or unsubstituted C atoms. 1-6 Alkyl, substituted or unsubstituted halogenated C 1-6 Alkyl, substituted or unsubstituted C 1-6 alkoxy groups, wherein "substitution" means that the substituent can be substituted by 1 to 3 R groups. a Instead, each time R appears, a Each is independently selected from hydrogen, deuterium, halogen atoms, and carbon. 1-3 Alkyl, C 1-3 Alkyl, cyano, carbonyl, amino, hydroxyl, amide (-C(=O)NH2);

[0027] Alternatively, R3 and R4 are connected to form a ring structure, the ring structure being selected from substituted or unsubstituted C. 4-10 cycloalkyl, substituted or unsubstituted C 6-14 Aryl, four- to eight-membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, substituted or unsubstituted five- to eight-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S, wherein "substituted" means that the substituent can be substituted by 1 to 3 R atoms. b Instead, each time R appears, b Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl, C 1-3 Alkoxy, cyano, carbonyl, halogen atom, amino, hydroxyl

[0028] Alternatively, R2 and R3 can be connected to form a ring structure, the ring structure being selected from substituted or unsubstituted C. 4-10 cycloalkyl, substituted or unsubstituted C 6-14 Aryl, four- to eight-membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, substituted or unsubstituted five- to eight-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S, wherein "substituted" means that the substituent can be substituted by 1 to 3 R atoms. c Instead, each time R appears, c Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl, C 1-3 Alkoxy, cyano, carbonyl, halogen atom, amino, hydroxyl

[0029] Preferably, R1, R3, and R4 are each independently selected from H, halogen atoms, cyano groups, carbonyl groups, amino groups, hydroxyl groups, and substituted or unsubstituted C atoms. 1-3 Alkyl, substituted or unsubstituted halogenated C 1-3 Alkyl, substituted or unsubstituted C 1-3 alkoxy groups, wherein "substitution" means that the substituent can be substituted by 1 to 3 R groups. a Instead, each time R appears, a Each is independently selected from hydrogen, deuterium, halogen atoms, and carbon. 1-3 Alkyl, C 1-3 Alkyl, cyano, amino, hydroxyl;

[0030] Preferably, R1, R3, and R4 are each independently selected from H, halogen atoms, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, difluoropropyl, trifluoropropyl, tetrafluoropropyl, pentafluoropropyl, hexafluoropropyl, perfluoropropyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, difluoroethoxy, trifluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, difluoropropoxy, trifluoropropoxy, tetrafluoropropoxy, pentafluoropropoxy, hexafluoropropoxy, and perfluoropropoxy.

[0031] Preferably, R3 and R4 are connected to form a ring structure, the ring structure being selected from substituted or unsubstituted C. 4-8 cycloalkyl, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted four- to eight-membered heterocyclic groups containing one or two heteroatoms selected from N and O, and substituted or unsubstituted five- to eight-membered heteroaryl groups containing one or two heteroatoms selected from N and O, wherein "substituted" means that the substituent can be substituted by one to three R atoms.b Instead, each time R appears, b Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl, C 1-3 Alkoxy, cyano, carbonyl, halogen atom, amino, hydroxyl

[0032] Preferably, R3 and R4 are connected to form a ring structure, the ring structure being selected from substituted or unsubstituted C. 6-10 Aryl, substituted or unsubstituted five- to six-membered heterocyclic groups containing one or two heteroatoms selected from N and O, substituted or unsubstituted five- to six-membered heteroaryl groups containing one or two heteroatoms selected from N and O, wherein "substituted" means that the substituent can be substituted by one to three R atoms. b Instead, each time R appears, b Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl, carbonyl, halogen atom

[0033] Preferably, R2 and R3 are connected to form a ring structure, the ring structure being selected from substituted or unsubstituted C. 4-8 cycloalkyl, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted four- to eight-membered heterocyclic groups containing one or two heteroatoms selected from N and O, and substituted or unsubstituted five- to eight-membered heteroaryl groups containing one or two heteroatoms selected from N and O, wherein "substituted" means that the substituent can be substituted by one to three R atoms. c Instead, each time R appears, c Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl, C 1-3 Alkoxy, cyano, carbonyl, halogen atom, amino, hydroxyl

[0034] Preferably, R3 and R4 are connected to form a ring structure, the ring structure being selected from substituted or unsubstituted C. 6-10 Aryl, substituted or unsubstituted five- to six-membered heterocyclic groups containing one or two heteroatoms selected from N and O, substituted or unsubstituted five- to six-membered heteroaryl groups containing one or two heteroatoms selected from N and O, wherein "substituted" means that the substituent can be substituted by one to three R atoms. c Instead, each time R appears, c Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl, carbonyl, halogen atom

[0035] R2 is selected from H, halogen atoms, substituted or unsubstituted C atoms. 1-6 Alkyl, substituted or unsubstituted C 1-6Alkoxy, substituted or unsubstituted amino, substituted or unsubstituted C 4-10 cycloalkyl, substituted or unsubstituted C 6-14 Aryl, four- to eight-membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, substituted or unsubstituted five- to eight-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S, wherein "substituted" means that the substituent can be substituted by 1 to 3 R atoms. d Instead, each time R appears, d Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl, C 1-3 Alkoxy, cyano, carbonyl, halogen atom, amino, hydroxyl

[0036] Preferably, R2 is selected from H, halogen atoms, substituted or unsubstituted amino groups, and substituted or unsubstituted C atoms. 4-6 cycloalkyl, substituted or unsubstituted C 6-10 Aryl, tetra- to hexacyclic heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, and penta- to octacyclic heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, wherein "substitution" means that the substituent can be substituted by 1 to 3 R atoms. d Instead, each time R appears, d Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl, C 1-3 Alkoxy, cyano, carbonyl, halogen atom, amino, hydroxyl

[0037] Preferably, R2 is selected from H, substituted or unsubstituted amino groups, and substituted or unsubstituted C groups. 4-6 cycloalkyl, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted tetra- to hexacyclic heterocyclic groups containing one or two heteroatoms selected from N and O, and substituted or unsubstituted five- to six-membered heteroaryl groups containing one or two heteroatoms selected from N and O, wherein "substituted" means that the substituent can be substituted by one to three R atoms. d Instead, each time R appears, d Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl, C 1-3 Alkoxy, carbonyl,

[0038] Preferably, R2 is selected from H,

[0039] Each occurrence of R5 is independently selected from H, halogen atoms, and substituted or unsubstituted C atoms. 1-6 Alkyl, substituted or unsubstituted halogenated C 1-6Alkyl, substituted or unsubstituted C 1-6 alkoxy groups, wherein "substitution" means that the substituent can be substituted by 1 to 3 R groups. e Instead, each time R appears, e Each is independently selected from hydrogen, deuterium, halogen atoms, and carbon. 1-3 Alkyl, C 1-3 Alkoxy, cyano, carbonyl, amino, hydroxy, amide;

[0040] Preferably, each occurrence of R5 is independently selected from H, halogen atoms, substituted or unsubstituted C atoms. 1-4 Alkyl, Halogenated C 1-4 Alkyl, substituted or unsubstituted C 1-4 alkoxy groups, wherein "substitution" means that the substituent can be substituted by 1 to 3 R groups. e Instead, each time R appears, e Each is independently selected from hydrogen, deuterium, halogen atoms, and carbon. 1-3 Alkyl, C 1-3 Alkoxy;

[0041] Preferably, each occurrence of R5 is independently selected from H, halogen atoms, and -OCF3;

[0042] n5 is an integer of 0, 1, 2 or 3;

[0043] R6 and R7 are each independently selected from H, halogen atom, cyano group, carbonyl group, amino group, hydroxyl group, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, wherein "substitution" means that the substituent can be substituted by 1 to 3 R groups. f Instead, each time R appears, f Each is independently selected from hydrogen, deuterium, halogen atoms, and carbon. 1-3 Alkyl, C 1-3 Alkoxy, cyano, carbonyl, amino, hydroxyl, -C(=O)NR e1 R e2 , where R e1 and R e2 Each is independently selected from hydrogen and C. 1-3 alkyl;

[0044] Alternatively, R6 and R7 are connected to form a ring structure, the ring structure being selected from substituted or unsubstituted saturated or unsaturated C. 4-10 cycloalkyl, substituted or unsubstituted C 6-14Aryl groups, four- to eleven-membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, and five- to fourteen-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S, wherein "substitution" means that the substituent can be substituted by 1 to 3 R atoms. g Instead, each time R appears, g Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl, C 1-3 Alkyl, cyano, carbonyl, halogen atom, amino, hydroxyl;

[0045] Preferably, R6 and R7 are each independently selected from H, halogen atom, cyano group, carbonyl group, amino group, hydroxyl group, substituted or unsubstituted C. 1-4 Alkyl, substituted or unsubstituted C 2-4 alkenyl, substituted or unsubstituted C 2-4 Alkyne group, wherein "substitution" means that the substituent can be substituted by one or two R groups. f Instead, each time R appears, f Each is independently selected from hydrogen, deuterium, halogen atoms, and carbon. 1-3 Alkyl, C 1-3 Alkoxy, carbonyl, amino, -C(=O)NR e1 R e2 , where R e1 and R e2 Each is independently selected from hydrogen and C. 1-3 Alkyl, or two R e1 and R e2 It forms four- to seven-membered rings with the attached nitrogen atom;

[0046] Preferably, R6 and R7 are each independently selected from H, substituted or unsubstituted C. 2-4 alkenyl, substituted or unsubstituted C 2-4 Alkyne group, wherein "substitution" means that the substituent can be substituted by one or two R groups. f Instead, each time R appears, f Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl, -C(=O)NR e1 R e2 , where R e1 and R e2 Each is independently selected from hydrogen and C. 1-3 Alkyl, or two R e1 and R e2 It forms four- to seven-membered rings with the attached nitrogen atom;

[0047] Preferably, R6 and R7 are each independently selected from H,

[0048] Preferably, R6 and R7 are connected to form a ring structure, the ring structure being selected from substituted or unsubstituted saturated or unsaturated C. 4-10 Cycloalkyl groups, substituted or unsubstituted four- to eleven-membered heterocyclic groups containing one to three heteroatoms selected from N and O, and substituted or unsubstituted five- to fourteen-membered heteroaryl groups containing one to three heteroatoms selected from N and O, wherein "substituted" means that the substituent can be substituted by one to three R atoms. g Instead, each time R appears, g Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl, C 1-3 Alkoxy, cyano, carbonyl, halogen atom, amino, hydroxyl, oxo, thio;

[0049] Preferably, R6 and R7 are connected to form a parallel ring structure consisting of a 5-membered ring and a 6-membered ring, or a 5-membered ring and a 7-membered ring, wherein the ring structure is selected from...

[0050] R8 is selected from H, halogen atoms, substituted or unsubstituted C atoms. 1-6 Alkyl, substituted or unsubstituted halogenated C 1-6 Alkyl, substituted or unsubstituted C 1-6 alkoxy groups, wherein "substitution" means that the substituent can be substituted by 1 to 3 R groups. h Instead, each time R appears, h Each is independently selected from hydrogen, deuterium, halogen atoms, and carbon. 1-3 Alkyl, C 1-3 Alkoxy, cyano, carbonyl, amino, hydroxy, amide;

[0051] Preferably, R8 is selected from H, halogen atoms, substituted or unsubstituted C atoms. 1-3 Alkyl, substituted or unsubstituted halogenated C 1-3 Alkyl, substituted or unsubstituted C 1-3 alkoxy groups, wherein "substitution" means that the substituent can be substituted by 1 to 3 R groups. h Instead, each time R appears, h Each is independently selected from hydrogen, deuterium, halogen atoms, and carbon. 1-3 Alkyl, C 1-3 Alkoxy, cyano, carbonyl, amino, hydroxyl;

[0052] Preferably, R8 is selected from H, halogen atoms, and C. 1-3 Alkyl, C 1-3 Alkoxy;

[0053] Preferably, R8 is a halogen atom;

[0054] Preferably, the compound represented by general formula 1 according to the present invention and its derivatives, stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts can be represented by general formulas 2-1, 2-2, 2-3, 2-4 and 2-5 as follows:

[0055] Among them, L 01 L 02 The definitions of X3, X4, R1, R2, R3, R4, R5, R6, R7, R8, and n5 are the same as in general formula 1;

[0056] X5 is selected from C or N atoms;

[0057] X6 is selected from NH, O atoms, or sulfur atoms;

[0058] L1 is selected from chemical bonds, formamide groups (-C(=O)NH-), imino groups (-NH-), and oxygen groups (-O-);

[0059] Ring A is selected from substituted or unsubstituted saturated or unsaturated C. 4-10 cycloalkyl, substituted or unsubstituted C 6-14 Aryl groups, four- to ten-membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, and five- to fourteen-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S, wherein "substitution" means that the substituent can be substituted by 1 to 3 R atoms. i Instead, each time R appears, i Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl, C 1-3 Alkyl, cyano, carbonyl, halogen atom, amino, hydroxyl, thio;

[0060] Preferably, ring A is selected from substituted or unsubstituted saturated or unsaturated C. 4-10 Cycloalkyl groups, substituted or unsubstituted four- to ten-membered heterocyclic groups containing 1 to 3 heteroatoms selected from N and O, and substituted or unsubstituted five- to fourteen-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N and O, wherein "substituted" means that the substituent can be substituted by 1 to 3 R atoms. i Instead, each time R appears, i Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl, C 1-3 Alkoxy, cyano, carbonyl, halogen atom, amino, hydroxyl, oxo, thio;

[0061] Preferably, ring A is selected from

[0062] R9 and R 10Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl groups; or forming four- to eight-membered saturated or unsaturated heterocyclic groups or four- to eight-membered heteroaryl groups with the nitrogen atoms attached to them;

[0063] Preferably, R9 and R 10 Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl groups; or forming four- to seven-membered saturated or unsaturated heterocyclic groups or four- to seven-membered heteroaryl groups with the nitrogen atoms attached to them;

[0064] Ring B is selected from substituted or unsubstituted saturated or unsaturated C. 4-10 cycloalkyl, substituted or unsubstituted C 6-14 Aryl groups, four- to ten-membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, and five- to fourteen-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S, wherein "substitution" means that the substituent can be substituted by 1 to 3 R atoms. j Instead, each time R appears, j Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl, C 1-3 Alkyl, cyano, carbonyl, halogen atom, amino, hydroxyl;

[0065] Preferably, ring B is selected from substituted or unsubstituted saturated or unsaturated C. 4-10 cycloalkyl, substituted or unsubstituted C 6-14 Aryl, substituted or unsubstituted four- to six-membered heterocyclic groups containing one or two heteroatoms selected from N and O, and substituted or unsubstituted five- to six-membered heteroaryl groups containing one or two heteroatoms selected from N and O, wherein "substituted" means that the substituent can be substituted by one or two R atoms. j Instead, each time R appears, j Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl, C 1-3 Alkyl group, cyano group, carbonyl group, halogen atom, amino group, hydroxyl group;

[0066] Preferably, ring B is

[0067] Preferably, the compound represented by general formula 1 according to the present invention and its derivatives, stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts can be represented by general formulas 3-1, 3-2, 3-3, 3-4, 3-5 and 3-6 as follows:

[0068] Among them, L 01The definitions of X1, X2, X3, X4, R1, R2, R3, R4, R5, R6, R7, R8, and n5 are the same as in general formula 1;

[0069] X5 is selected from C or N atoms;

[0070] X6 is selected from NH, oxygen atom, or sulfur atom;

[0071] L1 is selected from chemical bonds, formamide groups (-C(=O)NH-), imino groups (-NH-), and oxygen groups (-O-);

[0072] Ring A is selected from substituted or unsubstituted saturated or unsaturated C. 4-10 cycloalkyl, substituted or unsubstituted C 6-14 Aryl groups, four- to ten-membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, and five- to fourteen-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S, wherein "substitution" means that the substituent can be substituted by 1 to 3 R atoms. i Instead, each time R appears, i Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl, C 1-3 Alkyl, cyano, carbonyl, halogen atom, amino, hydroxyl, thio;

[0073] Preferably, ring A is selected from substituted or unsubstituted saturated or unsaturated C. 4-10 Cycloalkyl groups, substituted or unsubstituted four- to ten-membered heterocyclic groups containing 1 to 3 heteroatoms selected from N and O, and substituted or unsubstituted five- to fourteen-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N and O, wherein "substituted" means that the substituent can be substituted by 1 to 3 R atoms. i Instead, each time R appears, i Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl, C 1-3 Alkoxy, cyano, carbonyl, halogen atom, amino, hydroxyl, oxo, thio;

[0074] Preferably, ring A is selected from

[0075] R9 and R 10 Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl groups; or forming four- to eight-membered saturated or unsaturated heterocyclic groups or four- to eight-membered heteroaryl groups with the nitrogen atoms attached to them;

[0076] Preferably, R9 and R 10 Each is independently selected from hydrogen, deuterium, and C. 1-3Alkyl groups; or forming four- to seven-membered saturated or unsaturated heterocyclic groups or four- to seven-membered heteroaryl groups with the nitrogen atoms attached to them;

[0077] Ring B is selected from substituted or unsubstituted saturated or unsaturated C. 4-10 cycloalkyl, substituted or unsubstituted C 6-14 Aryl groups, four- to ten-membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, and five- to fourteen-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S, wherein "substitution" means that the substituent can be substituted by 1 to 3 R atoms. j Instead, each time R appears, j Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl, C 1-3 Alkyl group, cyano group, carbonyl group, halogen atom, amino group, hydroxyl group;

[0078] Preferably, ring B is selected from substituted or unsubstituted saturated or unsaturated C. 4-10 cycloalkyl, substituted or unsubstituted C 6-14 Aryl, substituted or unsubstituted four- to six-membered heterocyclic groups containing one or two heteroatoms selected from N and O, and substituted or unsubstituted five- to six-membered heteroaryl groups containing one or two heteroatoms selected from N and O, wherein "substituted" means that the substituent can be substituted by one or two R atoms. j Instead, each time R appears, j Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl, C 1-3 Alkyl group, cyano group, carbonyl group, halogen atom, amino group, hydroxyl group;

[0079] Preferably, ring B is

[0080] Preferably, the compounds, derivatives, stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts represented by general formulas 1, 2-1, 2-2, 2-3, 2-4, 3-1, 3-2, 3-3, and 3-4 according to the present invention are selected from the following compounds:

[0081] According to another aspect of the invention, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of the active ingredient of the compound of general formula 1, general formula 2-1, general formula 2-2, general formula 2-3, general formula 2-4 and general formula 2-5, general formula 3-1, general formula 3-2, general formula 3-3, general formula 3-4, general formula 3-5 and general formula 3-6 and specific compounds 1-119, and their derivatives, stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts, and pharmaceutically acceptable excipients.

[0082] According to another aspect of the invention, the invention provides the use of compounds of general formulas 1, 2-1, 2-2, 2-3, 2-4 and 2-5, 3-1, 3-2, 3-3, 3-4, 3-5 and 3-6, and specific compounds 1-119, and their derivatives, stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts, or pharmaceutical compositions thereof, in the preparation for the treatment and prevention of diseases mediated by the STAT6 signaling pathway.

[0083] Preferably, the diseases mediated by the STAT6 signaling pathway include atopic dermatitis, asthma, chronic obstructive pulmonary disease (COPD), nodular prurigo, urticaria, neurodermatitis, sinusitis, allergic rhinitis, eosinophilic esophagitis, eosinophilic gastritis, colitis, bronchiectasis, etc.

[0084] According to another aspect of the invention, the invention provides a method for treating diseases mediated by the STAT6 signaling pathway, the method comprising providing a subject with a therapeutically effective amount of the compound of the invention, comprising the compounds of general formulas 1, 2-1, 2-2, 2-3, 2-4 and 2-5, 3-1, 3-2, 3-3, 3-4, 3-5 and 3-6, and the compounds shown in specific compounds 1-119, and their derivatives, stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts or the pharmaceutical composition thereof.

[0085] According to another aspect of the invention, another object of the invention is to provide a method for preparing compounds, stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the compounds represented by general formulas 1, 2-1, 2-2, 2-3, 2-4, 2-5, 3-1, 3-2, 3-3, 3-4, 3-5, and 3-6, thereof, in a manner known to those skilled in the art, for example, referring to the synthetic steps disclosed in prior art WO2025049820. More specifically, the synthesis can be carried out according to method a below, wherein the reaction conditions used in each step of these methods, such as reaction time, reaction pressure, and reaction temperature, can be appropriately selected according to the reactants and conventional reaction mechanisms, and the reactants can be appropriately selected according to the structure of the final product.

[0086] Synthesis method a:

[0087] or

[0088] or

[0089] Step 1: Using the method described in Tetrahedron, 1991, 47(9), 1737-1744 or similar, aniline 3-1-1 was converted into indole analog 3-1-2 by Fisher's indole ring closure method.

[0090] Alternatively, intermediate 3-1-2 can also be prepared by referring to the method reported in Chemistry of Heterocyclic Compounds, 2014, vol.50, #2, pp.211-216, where the substituted aniline is first converted into phenylhydrazine hydrochloride, and then reacted with 1-methyl-2-piperidinone in the presence of phosphorus oxychloride and DMF.

[0091] The second step involves reacting indole analog 3-1-2 with boron ester intermediate A1 via a Suzuki coupling reaction to obtain intermediate 3-1-3. The synthesis of intermediate A1 can be referenced to the analog in patent WO2025049820.

[0092] In the third step, intermediate 3-1-3 is coupled with boronic ester intermediates B-1, B-3, and B-5 via a Suzuki coupling reaction to obtain compound of general formula 3-1. B-1, B-3, and B-5 can be prepared using the synthetic method described in patent WO2025049820.

[0093] Alternatively, intermediate 3-1-2 can also be synthesized using the following method:

[0094] The first step is to start from the existing compound 3a and add a formaldehyde group via the Mannich reaction to obtain intermediate 4-1-1;

[0095] The second step involves condensing intermediate 4-1-1 with alkylamine or hydroxylamine and then reducing it with NaBH3CN or zinc powder to amine intermediate 4-1-2.

[0096] In the third step, intermediate 4-1-2 is heated under acidic or alkaline conditions to close the lactam ring, yielding intermediate 3-1-2. Detailed Implementation

[0097] The present invention will now be described in detail. Before proceeding with the description, it should be understood that the terminology used in this specification and the appended claims should not be construed as limited to its general or dictionary meaning, but rather should be interpreted according to the meaning and concept corresponding to the technical aspects of the invention, based on the principle that the inventors are allowed to appropriately define the terms for the best interpretation. Therefore, the description presented herein is merely a preferred example for illustrative purposes and is not intended to limit the scope of the invention. It should be understood that other equivalents or modifications can be obtained from it without departing from the spirit and scope of the invention.

[0098] In this document, the terms “comprising,” “including,” “having,” “containing,” or any similar terms are open-ended transitional phrases intended to encompass non-exclusive inclusions. For example, a composition or article containing a plural element is not limited to the elements listed herein, but may also include other elements not explicitly listed but typically inherent to the composition or article. Furthermore, unless explicitly stated otherwise, the term “or” is inclusive, not exclusive. For example, the condition “A or B” is satisfied in any of the following cases: A is true (or exists) and B is false (or does not exist); A is false (or does not exist) and B is true (or exists); A and B are both true (or exist). Moreover, in this document, the terms “comprising,” “including,” “having,” and “containing” should be interpreted as specifically disclosed and simultaneously encompassing closed or semi-closed transitional phrases such as “composed of” and “substantially composed of.”

[0099] In this document, all features or conditions defined in the form of numerical ranges or percentage ranges are for the sake of brevity and convenience only. Accordingly, descriptions of numerical ranges or percentage ranges should be considered as covering and specifically disclosing all possible secondary ranges and individual values ​​within those ranges, particularly integer values. For example, a range description of "1 to 8" should be considered as specifically disclosing all secondary ranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, etc., particularly secondary ranges defined by all integer values, and should be considered as specifically disclosing individual values ​​within those ranges such as 1, 2, 3, 4, 5, 6, 7, 8, etc. Unless otherwise specified, the foregoing interpretation applies to all content throughout this invention, regardless of its scope.

[0100] If a quantity or other numerical value or parameter is expressed as a range, a preferred range, or a series of upper and lower limits, it should be understood that this document has specifically disclosed all ranges consisting of any upper or preferred value of that range and the lower or preferred value of that range, regardless of whether such ranges are separately disclosed. Furthermore, when a range of numerical values ​​is mentioned herein, unless otherwise stated, the range shall include its endpoints and all integers and fractions within the range.

[0101] In this document, numerical values ​​are to be understood as having a precision with significant digits, provided that the purpose of the invention can be achieved. For example, the number 40.0 should be understood to cover a range from 39.50 to 40.49.

[0102] In this document, when Markush groups or alternative terms are used to describe features or examples of the invention, those skilled in the art should understand that subgroups of all elements within a Markush group or option list, or any individual element, can also be used to describe the invention. For example, if X is described as "selected from the group consisting of X1, X2, and X3," it also indicates that the claim that X is X1 and the claim that X is X1 and / or X2 have been fully described. Furthermore, when Markush groups or alternative terms are used to describe features or examples of the invention, those skilled in the art should understand that any combination of subgroups of all elements within a Markush group or option list, or any combination of individual elements, can also be used to describe the invention. Accordingly, for example, if X is described as "selected from the group consisting of X1, X2, and X3," and Y is described as "selected from the group consisting of Y1, Y2, and Y3," it indicates that the claim that X is X1 or X2 or X3 and Y is Y1 or Y2 or Y3 has been fully described.

[0103] definition

[0104] The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are determined according to the periodic table on the inner cover of the CAS edition of the *Handbook of Chemistry and Physics*, 75th edition, and specific functional groups are generally defined as described therein. This invention is not intended to be limited in any way by the exemplary list of substituents described herein.

[0105] The compounds described herein may contain one or more asymmetric centers and therefore may exist in a variety of isomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures rich in one or more stereoisomers. Isomers can be separated from mixtures by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferably, isomers can be prepared by asymmetric synthesis. This disclosure further covers the compounds described herein as individual isomers substantially free of other isomers, or as mixtures of various isomers.

[0106] When listing a series of values, the intention is to cover every value within that range and every subrange. For example, "C 1-6 "Aims to cover C1, C2, C3, C4, C5, C6, C 1-6 C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-5 C 2-4 C 2-3 C 3-6 C 3-5 C 3-4 C 4-6 C 4-5 and C 5-6 .

[0107] The term "alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms ("C..."). 1-6 Alkyl group (“C”). In some embodiments, the alkyl group has 1 to 6 carbon atoms (“C”). 1-6 Alkyl group). In some embodiments, the alkyl group has 1 to 5 carbon atoms (“C1”). 1-5 Alkyl group). In some embodiments, the alkyl group has 1 to 4 carbon atoms (“C1”). 1-4 Alkyl group). In some embodiments, the alkyl group has 1 to 3 carbon atoms (“C1”). 1-3 Alkyl group (“alkyl”). In some embodiments, the alkyl group has 1 to 2 carbon atoms (“C”). 1-2Alkyl group (“C1 alkyl”). In some embodiments, the alkyl group has 1 carbon atom (“C1 alkyl”). In some embodiments, the alkyl group has 2 to 6 carbon atoms (“C1 alkyl”). 2-6 Alkyl group). C 1-6 Examples of alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentyl, neopentyl, 3-methyl-2-butyl, tert-pentyl), and hexyl (C6) (e.g., n-hexyl). Unless otherwise stated, each example of an alkyl group is independently unsubstituted or substituted with one or more substituents (e.g., halogens, such as F). In some embodiments, the alkyl group is an unsubstituted C1. 1-6 Alkyl groups, such as -CH3. In some embodiments, the alkyl group is a substituted C- group. 1-6 Alkyl groups, such as -CF3.

[0108] "Alkoxy" or "oxyalkyl" means monovalent -O-alkyl, wherein the alkyl moiety has a specified number of carbon atoms. Alkoxy groups in this disclosure typically contain 1-6 carbon atoms ("C1-6 alkoxy groups"), and include, for example, methoxy, ethoxy, isopropoxy, tert-butyloxy, etc. Unless otherwise stated, each instance of an alkoxy group may independently be optionally substituted, i.e., unsubstituted ("unsubstituted alkoxy group") or substituted with one or more substituents ("substituted alkoxy group"), said substituents being, for example, halogen atoms, nitro groups, amino groups, hydroxyl groups, cyano groups, amide groups, etc. In some embodiments, the alkoxy group is an unsubstituted C1-6 alkoxy group. 1-6 Alkyl group. In some embodiments, the alkoxy group is a substituted C- group. 1-6 Alkyl group.

[0109] "Cycloalkyl" refers to a non-aromatic ring system having 3 to 6 ring carbon atoms ("C"). 3-6 A group consisting of a cycloalkyl group and a non-aromatic cycloalkyl group with zero heteroatoms. An example C 3-6 Cycloalkyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), etc. As shown in the foregoing examples, in some embodiments, the cycloalkyl group is a monocyclic (“monocyclic cycloalkyl”) or contains a fused ring, bridged ring, or spirocyclic system, such as a bicyclic system (“bicyclic cycloalkyl”), and may be saturated or may be partially unsaturated. “Cycloalkyl” also includes ring systems in which the cycloalkyl group as defined above is fused with one or more aryl or heteroaryl groups at the junction point on the carbon ring, and in this case, the carbon number continues to refer to the number of carbons in the carbon ring system. Unless otherwise stated, each instance of a cycloalkyl group is optionally substituted independently, i.e., unsubstituted or substituted by one or more substituents.

[0110] "Heterocyclic alkyl" or "heterocyclic group" refers to a four- to eight-membered non-aromatic ring system having a ring carbon atom and one to three ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("four- to eight-membered heterocyclic group"). In heterocyclic groups containing one or more nitrogen atoms, the linkage can be a carbon atom or a nitrogen atom, provided the valence allows. Heterocyclic alkyl can be monocyclic ("monocyclic heterocyclic alkyl group") or fused, bridged, or spirocyclic, such as bicyclic ("bicyclic heterocyclic alkyl group"), and can be saturated or partially unsaturated. Heterocyclic bicyclic systems can contain one or more heteroatoms in one or both rings. "Heterocyclic alkyl" also includes ring systems in which the linkage of a heterocycle as defined above with one or more carbocyclic groups is on the carbocyclic group or the heterocycle, or ring systems in which the linkage of a heterocycle as defined above with one or more aryl or heteroaryl groups is on the heterocycle, and in this case, the number of ring members continues to refer to the number of ring members in the heterocyclic system. Unless otherwise stated, each instance of a heterocyclic group is independently and optionally substituted, i.e., unsubstituted or substituted by one or more substituents.

[0111] A "bridged ring group" refers to a polycyclic structure in which at least two rings share two carbon atoms in the molecule. The number of carbon atoms preceding the "bridged ring group" is, for example, C. 7-10 A bridged ring group refers to the total number of carbon atoms in the multiple rings of the group. Unless otherwise stated, each instance of a bridged ring group may be independently and optionally substituted, i.e., unsubstituted or substituted by one or more substituents, where chemical valence permits.

[0112] "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the ring array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C"). 6-14 Aryl group (“C6 aryl”). In some embodiments, the aryl group has 6 ring carbon atoms (“C6 aryl”; for example, phenyl). In some embodiments, the aryl group has 10 ring carbon atoms (“C6 aryl”). 10 Aryl; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms (“C”). 14"Aryl"; for example, anthracene. "Aryl" also includes ring systems in which the aryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein the groups or linkages are on the aromatic ring, and in this case, the number of carbon atoms continues to refer to the number of carbon atoms in the aromatic ring system. Unless otherwise stated, each instance of an aryl group is optionally independently substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted by one or more substituents ("substituted aryl"), which may be, for example, halogen atoms, nitro, amino, hydroxyl, cyano, amide, etc. In some embodiments, the aryl group is an unsubstituted C 6-14 Aryl. In some embodiments, the aryl group is a substituted C. 6-14 Aryl.

[0113] "Heteroaryl" refers to a group having a five- to eight-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 π electrons shared in a cyclic array) having a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("five- to eight-membered heteroaryl"). In heteroaryls containing one or more nitrogen atoms, the linkage can be a carbon atom or a nitrogen atom, provided the valence allows. Heteroaryl bicyclic systems may contain one or more heteroatoms in one or both rings. "Heteroaryl" includes a ring system in which the heteroaryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein the linkage is on the heteroaryl ring, and in this case, the number of ring members continues to refer to the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes a ring system in which a heteroaryl ring as defined above is fused with one or more aryl groups, wherein the connection point is on the aryl or heteroaryl ring, and in this case, the number of ring members refers to the number of ring members in the fused (aryl / heteroaryl) ring system.

[0114] "Alkenyl" refers to a straight-chain or branched hydrocarbon group having 2 to 6 carbon atoms, one or more carbon-carbon double bonds, and no triple bonds. 2-6 The alkenyl group ("alkenyl") can be located at the end of the carbon chain or at any position permitted by the chemical structure therein. In some embodiments, the alkenyl group has 2 to 6 carbon atoms ("C"). 2-6 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 5 carbon atoms (“C”). 2-5 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 4 carbon atoms (“C”). 2-4 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 3 carbon atoms (“C”). 2-3 The alkenyl group (“C2-alkenyl”) has two carbon atoms in some embodiments. The one or more carbon-carbon double bonds can be internal (e.g., in a 2-butenyl group) or terminal (e.g., in a 1-butenyl group). 2-4Examples of alkenyl groups include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), etc. 2-6 Examples of alkenyl groups include the aforementioned C... 2-4 Alkenyl groups, including pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. Unless otherwise stated, each instance of an alkenyl group is optionally substituted independently, i.e., unsubstituted (“unsubstituted alkenyl”) or substituted by one or more substituents (“substituted alkenyl”). In some embodiments, the alkenyl group is an unsubstituted C5 group. 2-6 Alkenyl. In some embodiments, the alkenyl group is a substituted C. 2-6 Alkenyl. In alkenyl groups, the stereochemical C=C double bond is not specified (e.g., -CH=CHCH3 or...). It can be an (E)- or (Z)- double bond.

[0115] "Alkyne" refers to a straight-chain or branched hydrocarbon group having 2 to 6 carbon atoms, one or more carbon-carbon triple bonds, and optionally one or more double bonds. 2-6 The alkynyl group (“C6”) can be located at the end of a long carbon chain or at any position permitted by the chemical structure therein. In some embodiments, the alkynyl group has 2 to 6 carbon atoms (“C6”). 2-6 The alkynyl group (“H”) has 2 to 5 carbon atoms in some embodiments. 2-5 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 4 carbon atoms (“C”). 2-4 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 3 carbon atoms (“C”). 2-3 The alkynyl group (“C2-alkynyl”) is present in some embodiments. The one or more carbon-carbon triple bonds can be internal (e.g., in the 2-butynyl group) or terminal (e.g., in the 1-butynyl group). 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), and 2-butynyl (C4). 2-6 Examples of alkenyl groups include the C group mentioned above. 2-4 The alkynyl group includes pentynyl (C5), hexynyl (C6), etc. Unless otherwise stated, each instance of the alkynyl group is optionally substituted independently, i.e., unsubstituted (“unsubstituted alkynyl”) or substituted by one or more substituents (“substituted alkynyl”). In some embodiments, the alkynyl group is an unsubstituted C5 group. 2-6 Alkyne group. In some embodiments, the alkynyl group is a substituted C- group. 2-6 Alkyne group.

[0116] Unless otherwise expressly provided, atoms, portions or groups described herein may be unsubstituted or substituted, provided that valence permits.

[0117] "Halogen" or "halogen" refers to fluorine (fluorinated, -F), chlorine (chlorinated, -Cl), bromine (brominated, -Br), or iodine (iodinated, -I).

[0118] The term "pharmaceutically acceptable salt" refers to those salts that, within reasonable medical judgment, are suitable for contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are amino salts formed with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with organic acids (acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid) or by using other methods known in the art (such as ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentylpropionate, diglucuronate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucohepanoate, glyceryl phosphate, glucuronate, hemisulfate, heptahydrate, hydrogen iodide, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, dodecyl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and nitrogen. + (C 1-4 Alkyl)4 - Salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Where appropriate, other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using balancing ions such as halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0119] The term "tautomer" or "tautomerizing" refers to a compound in which two or more interconvertions result from at least one formal migration of a hydrogen atom and at least one change in valence (e.g., a single bond becomes a double bond, a triple bond becomes a single bond, or vice versa). The exact proportions of tautomers depend on several factors, including temperature, solvent, and pH. Tautomerization reactions (i.e., reactions that provide tautomer pairs) can be catalyzed by acids or bases. Exemplary tautomerization reactions include keto-enol, amide-imide, lactam-lactamimide, enamine-imide, and enamine-(different enamines) tautomerization reactions.

[0120] It should also be understood that compounds with the same molecular formula but different properties, different atomic bonding sequences, or different spatial arrangements of atoms are called "isomers". Isomers with different atomic spatial arrangements are called "stereoisomers".

[0121] Stereoisomers that are not mirror images of each other are called "diastereomers," while stereoisomers that are not mirror images of each other are called "enantiomers." When a compound has an asymmetry center, for example, if it is bonded to four different groups, a pair of enantiomers may exist. Enantiomers can be characterized by the absolute configuration of their asymmetry center and are described by the R- and S-sequence rules of Cahn and Prelog or by rotating the molecular plane of polarization, and are represented as dextrorotatory or levorotatory (i.e., (+) or (-)- isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0122] The term “inhibition” or “inhibitor” refers to the ability of a compound to reduce, slow down, block, or prevent the activity of a particular biological process (such as the activity of Nav1.8 in tissues).

[0123] The term "subject" to be administered refers to a person (i.e., a male or female of any age group, such as a pediatric subject (e.g., an infant, child, or adolescent) or an adult subject (e.g., a young adult, middle-aged, or elderly person)). "Patient" refers to a human subject who requires treatment for a disease.

[0124] The term "biological sample" refers to any sample that includes tissue samples (e.g., tissue sections and needle biopsies); cell samples (e.g., cytological smears such as Pap smears or blood smears or cell samples obtained by microdissection); samples of whole organisms (e.g., yeast or bacterial samples); or any sample containing cellular parts, fragments, or organelles (e.g., obtained by lysing cells and separating their components by centrifugation or other methods). Other examples of biological samples include blood, serum, urine, semen, feces, cerebrospinal fluid, interstitial fluid, mucus, tears, sweat, pus, biopsy tissue (e.g., obtained by surgical or needle biopsy), nipple aspirate, milk, vaginal fluid, saliva, swabs (e.g., oral swabs), or any material containing biomolecules derived from the first biological sample.

[0125] The term “administration” means the implantation, absorption, ingestion, injection, inhalation or other introduction of the compound or a combination thereof described herein into or onto a subject.

[0126] The term "treatment" refers to reversing, alleviating, delaying the onset of the disease described herein, or inhibiting its development. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to susceptible subjects before the onset of symptoms (e.g., based on a history of symptoms and / or based on exposure to a pathogen) to delay or prevent the occurrence of the disease. Treatment may also continue after symptoms have subsided, for example, to delay or prevent recurrence.

[0127] The "therapeuticly effective amount" of a compound described herein is an amount sufficient to provide therapeutic benefit in treating a condition or to delay or minimize one or more symptoms associated with said condition. Therapeuticly effective amount of a compound refers to the amount of a therapeutic agent, alone or in combination with other therapies, that provides therapeutic benefit in treating the condition. The term "therapeuticly effective amount" may include amounts that improve overall treatment, reduce or avoid symptoms, signs, or causes, and / or enhance the therapeutic efficacy of another therapeutic agent.

[0128] The pharmaceutical compositions described herein can be prepared by any method known in the field of pharmacology. Generally, such preparation methods involve conjugating the compound described herein (i.e., the “active ingredient”) with a carrier or excipient, and / or one or more other adjuvants, and then, if necessary and / or required, shaping and / or packaging the product into the desired single- or multi-dose units.

[0129] Pharmaceutical compositions may be prepared, packaged, and / or sold in batches, as single-unit doses, and / or in multiple single-unit doses. The relative amounts of the active ingredient, pharmaceutically acceptable excipients, and / or any additional ingredients in the pharmaceutical compositions described herein will vary depending on the individual, size, and / or condition of the subject to be treated, and also on the route of administration of the composition. The compositions may contain from 0.1% to 100% (w / w) of the active ingredient.

[0130] Pharmaceutically acceptable excipients used in the preparation of the provided pharmaceutical compositions include inert diluents, dispersants and / or granulators, surfactants and / or emulsifiers, disintegrants, binders, preservatives, buffers, lubricants and / or oils. Excipients such as cocoa butter and suppository waxes, colorants, coating agents, sweeteners, flavorings and spices may also be present in the compositions.

[0131] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (e.g., cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofurfuryl alcohol, fatty acid esters of propylene glycol and sorbitol, and mixtures thereof. In addition to inert diluents, oral compositions may include adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavorings, and fragrances. In some embodiments for parenteral administration, the combinations described herein are mixed with solubilizers such as alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.

[0132] Injectable formulations, such as sterile injectable aqueous or oily suspensions, can be formulated using suitable dispersants or wetting agents and suspending agents according to known techniques. Sterile injectable formulations can be sterile injectable solutions, suspensions, or emulsions in non-toxic, non-enteric-acceptable diluents or solvents, such as solutions of 1,3-butanediol. Acceptable carriers and solvents that can be used are water, Ringer's solution, USP, and physiological saline solutions. Furthermore, sterile, fixed oils are commonly used as solvents or suspension media. For this purpose, any mild fixed oil that can be used includes synthetic monoglycerides or diglycerides. In addition, fatty acids (such as oleic acid) are used in the preparation of injectable formulations.

[0133] To prolong the effect of a drug, it is generally desirable to reduce absorption from subcutaneous or intramuscular injections. This can be achieved by using liquid suspensions of crystals or amorphous materials with poor water solubility. The absorption rate of the drug depends on the dissolution rate, which in turn depends on crystal size and crystal form. Alternatively, delayed absorption of parenteral drug forms can be achieved by dissolving or suspending the drug in an oily carrier.

[0134] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In this solid dosage form, the active ingredient is mixed with at least one inert, pharmaceutically acceptable mixture of the following: excipients or carriers, such as sodium citrate or dicalcium phosphate and / or (a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as, for example, carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato or cassava starch, alginic acid, certain silicates, and sodium carbonate; (e) solution inhibitors, such as petrolatum; (f) absorption enhancers, such as quaternary ammonium compounds; (g) wetting agents, such as, for example, cetyl alcohol and glyceryl monostearate; (h) absorbents, such as kaolin and bentonite; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, and mixtures thereof. In the case of capsules, tablets, or pills, the dosage form may contain a buffer.

[0135] The active ingredient can be in the form of microcapsules having one or more of the excipients described above. Tablets, sugar-coated pills, capsules, pellets, and granules in solid dosage forms can be prepared using coatings and shells (such as enteric coatings, release-controlling agent coatings, and other coatings known in the pharmaceutical formulation field). In such solid dosage forms, the active ingredient can be mixed with at least one inert diluent (e.g., sucrose, lactose, or starch). Conventionally, such dosage forms can contain substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, or pellets, the dosage form can contain a buffer. They may optionally contain a light-blocking agent and can be compositions having the property that they release the active ingredient only, or preferably, in a delayed manner, in certain portions of the intestine. Examples of encapsulants that can be used include polymers and waxes.

[0136] Although the description of the pharmaceutical compositions provided herein is primarily directed toward pharmaceutical compositions suitable for administration to humans, such compositions are generally suitable for administration to all types of animals. Modification of pharmaceutical compositions suitable for human administration to make the compositions suitable for administration to a variety of animals is readily understood, and such modifications can be designed and / or carried out by those skilled in the art using conventional experimental methods.

[0137] The compounds described herein are typically formulated in dosing units for ease of administration and uniformity of dosage. However, it is understood that the full routine use of the compositions described herein should be determined by a physician using reasonable medical judgment. The specific therapeutically effective dose level for any particular subject or organism depends on a range of factors including: the severity of the disease and condition being treated; the activity of the specific active ingredient used; the specific composition used; the subject's age, weight, health status, sex, and diet; the timing, route of administration, and excretion rate of the specific active ingredient; the duration of treatment; the combination with or consistency with the specific active ingredient used; and other factors known in the medical field.

[0138] The compounds and compositions provided herein can be administered via conventional routes, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intracapsular, subcutaneous, intraventricular, transdermal, subcutaneous, rectal, vaginal, intraperitoneal, and topical (e.g., via powder, ointment, cream, and / or droplets). Particularly anticipated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), topical administration via blood and / or lymphatic supply, and / or direct administration to the intended site. Generally, the most suitable route of administration will depend on a range of factors, including the nature of the agent (e.g., stability in the gastrointestinal environment) and / or the condition of the subject (e.g., whether oral administration is permissible).

[0139] The exact amount of compound required to achieve an effective dose will vary depending on the subject, taking into account factors such as the subject's race, age, and general condition, the severity of side effects or illness, confirmation of the specific compound, and the mode of administration. An effective dose may be included in a single dose (e.g., a single oral dose) or multiple doses (e.g., multiple oral doses). In some embodiments, when multiple doses are administered to a subject or applied to a biological sample, tissue, or cell, any two doses of the multiple doses contain different or substantially the same compound described herein. In some embodiments, when multiple doses are administered to a subject or applied to a biological sample, tissue, or cell, the frequency of administration of multiple doses to the subject or to the tissue or cell may be three doses per day, two doses per day, one dose per day, one dose every two days, one dose every three days, or one dose per week. In some embodiments, the frequency of administration of multiple doses to a subject or to the tissue or cell is one dose per day. In some embodiments, the frequency of administration of multiple doses to a subject or to the tissue or cell is two doses per day. In some embodiments, when multiple doses are administered to a subject or applied to a biological sample, tissue, or cell, the duration between the first and last doses of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifespan of the subject, biological sample, tissue, or cell. In some embodiments, the duration between the first and last doses of the multiple doses is three months, six months, or one year. In some embodiments, the duration between the first and last doses of the multiple doses is the lifespan of the subject, biological sample, tissue, or cell. In some embodiments, the doses described herein (e.g., any single or multiple doses) independently comprise 1 mg to 3 mg, 3 mg to 10 mg, 10 mg to 30 mg, 30 mg to 100 mg, 100 mg to 300 mg, 300 mg to 1,000 mg, or 1 g to 10 g of the compound described herein. In some embodiments, the doses described herein independently comprise 3 mg to 10 mg of the compound described herein. In some embodiments, the dosage described herein independently comprises 10 mg to 30 mg of the compound described herein. In some embodiments, the dosage described herein independently comprises 30 mg to 100 mg of the compound described herein. In some embodiments, the dosage described herein independently comprises 100 mg to 300 mg of the compound described herein. In some embodiments, the dosage described herein independently comprises 300 mg to 1000 mg of the compound described herein.

[0140] The following embodiments are merely examples illustrating implementations of the present invention and do not constitute any limitation on the present invention. Those skilled in the art will understand that modifications made without departing from the spirit and concept of the present invention fall within the protection scope of the present invention. Unless otherwise specified, the reagents and instruments used in the following embodiments are commercially available products.

[0141] 1 The 1H NMR spectra were obtained using a Bruker instrument (400 MHz), and chemical shifts are expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. 1 H NMR representation: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of doublet, dt = doublet of triplet. If the coupling constant is provided, the unit is Hz.

[0142] Mass spectrometry is performed using an LC / MS instrument, and the ionization method can be ESI or APCI.

[0143] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) are 0.15mm to 0.2mm in diameter, and the silica gel plates used for thin-layer chromatography separation and purification are 0.4mm to 0.5mm in diameter.

[0144] Column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0145] In the following examples, all temperatures are in Celsius unless otherwise specified. Unless otherwise specified, all starting materials and reagents are commercially available or synthesized according to known methods. Commercially available materials and reagents are used directly without further purification. Unless otherwise specified, they are purchased from manufacturers including but not limited to Aldrich Chemical Company, ABCR GmbH & Co. KG, Acros Organics, Shanghai Bid Pharmaceutical Technology Co., Ltd., and Shanghai Titan Technology Co., Ltd.

[0146] The following embodiments are merely examples illustrating implementations of the present invention and do not constitute any limitation on the present invention. Those skilled in the art will understand that modifications made without departing from the spirit and concept of the present invention fall within the protection scope of the present invention. Unless otherwise specified, the reagents and instruments used in the following embodiments are commercially available products.

[0147] Synthesis of intermediate 3-((5-fluoro-2-methoxy-4-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (C):

[0148] Under a nitrogen atmosphere, a mixture of 3-((4-(4-(4-chlorobenzin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione (100 mg, 0.224 mmol, according to the preparation method of intermediate AQ in patent WO2025049820), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxoboropentan) (86 mg, 0.336 mmol), XPhos-Pd-G3 (5 mg, 0.05 mmol), potassium acetate (77 mg, 0.772 mmol), and dioxane (5 mL) was heated to 90 °C and stirred for 2 h. After cooling, the solvent was removed by concentration under reduced pressure, and the residue was purified by normal-phase silica gel column chromatography to give a gray solid intermediate C (80 mg, yield 66%).

[0149] MS(ESI): m / z 539.3 [M+H] + RT = 1.77 min.

[0150] Synthesis of intermediate 3-((4-(4-(2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)piperazin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione (D):

[0151] Under a nitrogen atmosphere, a mixture of 3-((4-(4-(4-bromo-2,3-difluorophenyl)piperazin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione (350 mg, 0.67 mmol, according to the preparation method of intermediate FK in patent WO2025049820), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxoboronane) (237 mg, 0.86 mmol), XPhos-Pd-G3 (50 mg, 0.06 mmol), potassium acetate (131 mg, 1.34 mmol), and dioxane (10 mL) was heated to 90 °C and stirred for 2 h. After cooling, the solvent was removed by concentration under reduced pressure, and the residue was purified by normal-phase silica gel column chromatography to give a gray solid intermediate D (200 mg, yield 52%).

[0152] MS(ESI): m / z 575.4 [M+H] + RT = 1.99 min.

[0153] Synthesis Example:

[0154] Example 1: Synthesis of 3-(4-(4-(4-(7-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-8-fluoro-1-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-5-yl)phenyl)piperidin-1-yl)-3-fluorophenyl)piperidin-2,6-dione (1):

[0155] Step 1: Synthesis of 3-(2-(3-bromo-5-chloro-2-fluorophenyl)hydrazone)piperidin-2-one (1c):

[0156] At -10°C, an aqueous solution (5 mL) of sodium nitrite (0.75 g, 11 mmol) was slowly added dropwise to a solution of 3-bromo-5-chloro-2-fluoroaniline 1a (1000.0 mg, 5.0 mmol) and concentrated hydrochloric acid (3.3 mL, 40 mmol) in 10 mL of water. After the addition was complete, the mixture was stirred at -10°C for 1 hour. Then, solid 2-oxypiperidine-3-carboxylic acid 1b (700 mg, 5.0 mmol) was added to the reaction system. The mixture was allowed to heat naturally and stirred overnight. The reaction system was then concentrated with an aqueous solution of sodium hydroxide (NaOH, 2N) and purified by normal-phase silica gel column chromatography to obtain a yellow solid crude product 1c (100 mg, 24.3% yield). MS (ESI): m / z 334.0 [M+H] + .

[0157] Step 2: Synthesis of 7-bromo-5-chloro-8-fluoro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-one (1d):

[0158] A solution of 3-(2-(3-bromo-5-chloro-2-fluorophenyl)hydrazone)piperidin-2-one (1c) (400 mg, 1.30 mmol) and formic acid (10 mL) was placed in a sealed tube and heated to 80 °C with stirring for 10 hours. After cooling and concentration, the solution was purified by normal-phase silica gel column chromatography (EA:PE = 60%–90%) to give a white solid 1d (100 mg, 24.3% yield). MS (ESI): m / z 316.9 [M+H] + .

[0159] Step 3: Synthesis of 7-(1-(3-(1-hydropyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-chloro-8-fluoro-2,3,4,9-tetrahydro-1-hydropyrido[3,4-b]indol-1-one (1e):

[0160] In an argon atmosphere, a mixture of 7-bromo-5-chloro-8-fluoro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-one 1d (80 mg, 0.27 mmol), 3-(1H-pyrazol-1-yl)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronylcyclo-2-yl)-3,6-dihydropyridin-1(2H)-yl)propane-1-one A (108 mg, 0.32 mmol, refer to the preparation of intermediate N in WO2025049820A1), Pd(dppf)Cl2 (28 mg, 0.04 mmol), K2CO3 (70 mg, 0.50 mmol), and dioxane / water (6 mL, 5:1) was heated to 90 °C and stirred for 2 hours. After concentration under reduced pressure, the product was purified by reverse-phase column chromatography to give a brown solid 1e (60 mg, 50% yield). MS (ESI): m / z 442.2 [M+H] + .

[0161] Step 4: Synthesis of 3-(4-(4-(7-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-8-fluoro-1-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-5-yl)phenyl)piperidin-1-yl)-3-fluorophenyl)piperidin-2,6-dione (1):

[0162] 7-(1-(3-(1-hydropyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-chloro-8-fluoro-2,3,4,9-tetrahydro-1-hydropyrido[3,4-b]indol-1-one (1e, 60 mg, 0.13 mmol), 3-(3-fluoro-4-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)phenyl)piperidin-1-yl)phenyl)piperidin-2,6-dione B (87 mg, 0.17 mmol, see WO2025049820) Preparation of intermediate OP (A1): A mixture of XPhos-Pd-G3 (11 mg, 0.013 mmol), CsF (60 mg, 0.40 mmol), and dioxane / water (8 mL, 3:1) was degassed three times with nitrogen and heated to 80 °C with stirring for 2 hours under a nitrogen atmosphere. The solvent was removed by concentration, and the mixture was first purified by normal-phase silica gel column chromatography (0-15% MeOH:DCM = 0-15%), followed by purification by reversed-phase HPLC (FA conditions, acetonitrile:water = 0-95%) to obtain a white solid. Example 1 compound (1, 40 mg, 38.1% yield) MS (ESI): m / z 772.5 [M+H] + .

[0163] 1H NMR(400MHz,DMSO)δ12.33(s,1H),10.84(s,1H),7.79-7.64(m,2H),7.50-7.35( m,5H),7.03(dt,J=23.2,7.6Hz,3H),6.87(dd,J=25.0,6.3Hz,1H),6.25-6.11(m, 2H),4.46-4.25(m,4H),3.82(dd,J=11.8,4.8Hz,1H),3.67-3.43(m,4H),3.30(s, 2H),3.03-2.93(m,2H),2.90-2.60(m,5H),2.38-2.15(m,4H),2.12-1.75(m,6H).

[0164] Example 2: Synthesis of 3-(4-(4-(4-(7-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-8-fluoro-2-methyl-1-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-5-yl)phenyl)piperidin-1-yl)-3-fluorophenyl)piperidin-2,6-dione (2):

[0165] Step 1: Synthesis of 7-bromo-5-chloro-8-fluoro-2-methyl-9-((2-(trimethylsilyl)ethoxy)methyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-one (2a):

[0166] At -10°C, 20 mg (0.5 mmol) of NaH (in 60% kerosene) was added to a 2 mL solution of dry DMF containing 130 mg (0.41 mmol) of 7-bromo-5-chloro-8-fluoro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-one 1d. After stirring for 15 minutes, 0.5 mL of DMF containing 83 mg (0.41 mmol) of SEM-Cl was added dropwise to the reaction system. The reaction mixture was stirred at -10°C for 1 hour. While maintaining at -10°C, 1.0 mmol (40 mg) of NaH (in 60% kerosene) was added to the reaction system and stirred for 15 minutes. Then, 0.5 mL of DMF containing 142 mg (1.0 mmol) of CH3I was added dropwise to the reaction mixture, and the mixture was heated to room temperature and stirred for 1 hour. 5 mL of water was added dropwise to the reaction system, and the mixture was extracted with ethyl acetate (3 x 10 mL).

[0167] The combined organic phases were washed once with a saturated sodium chloride aqueous solution, dried, and the solvent was concentrated under reduced pressure. The residue was purified by normal-phase silica gel column chromatography to give a yellow oily compound 2a (60 mg, 58% yield).

[0168] MS(ESI): m / z 343.0 [M+H] + ;

[0169] 1 H NMR (400MHz, DMSO) δ7.51(d,J=4.8Hz,1H),6.11(s,2H),3.67(t,J=7.2Hz,2H),3.44(t, J=8.0Hz,2H),3.28(d,J=7.2Hz,2H),3.02(s,3H),0.76(t,J=8.0Hz,2H),-0.14(s,9H).

[0170] Step 2: Synthesis of 7-bromo-5-chloro-8-fluoro-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-one (2b):

[0171] 7-Bromo-5-chloro-8-fluoro-2-methyl-9-((2-(trimethylsilyl)ethoxy)methyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-one (60 mg, 0.13 mmol) was dissolved in 1 M TBAF / THF (3 mL) and stirred at 60 °C for 16 h. The solvent was concentrated, and ethyl acetate (15 mL) was added to the residue. The residue was washed with water (5 x 6 mL) and dried over anhydrous sodium sulfate. The solvent was concentrated and purified by normal-phase silica gel column chromatography (EA:EA = 0-60%) to give a yellow oily compound 2b (39 mg, 90% yield). MS (ESI): m / z 331.2 [M+H] + .

[0172] Step 3: Synthesis of 7-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-chloro-8-fluoro-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-one (2c):

[0173] In an argon atmosphere, a mixture of 7-bromo-5-chloro-8-fluoro-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-one 2b (66 mg, 0.2 mmol), 3-(1H-pyrazol-1-yl)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-3,6-dihydropyridin-1(2H)-yl)propane-1-one A (90 mg, 0.3 mmol, refer to the preparation of intermediate N in WO2025049820A1), Pd(dppf)Cl2 (28 mg, 0.04 mmol), K2CO3 (83 mg, 0.6 mmol), and dioxane / water (6 mL, 5:1) was heated to 90 °C and stirred for 2 hours. The mixture was directly concentrated in solvent and purified first by normal-phase silica gel column chromatography (methanol:dichloromethane = 0-30%), followed by reverse-phase preparative column chromatography to give a brown solid compound 2c (30 mg, 34% yield). MS (ESI): m / z 456.1 [M+H] + .

[0174] Step 4: Synthesis of 3-(4-(4-(7-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-8-fluoro-2-methyl-1-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-5-yl)phenyl)piperidin-1-yl)-3-fluorophenyl)piperidin-2,6-dione (2):

[0175] 7-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-chloro-8-fluoro-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-one 2c (30 mg, 0.066 mmol), 3-(3-fluoro-4-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)piperidin-1-yl)phenyl)piperidin-2,6-dione B (44 mg, 0.09 mmol, reference WO2025049820) Preparation of intermediate OP (A1): A mixture of XPhos-Pd-G3 (11 mg, 0.013 mmol), CsF (30 mg, 0.2 mmol), and dioxane / water (4 mL / 1 mL) was degassed with nitrogen and heated to 80 °C with stirring for 2 hours under a nitrogen atmosphere. After solvent concentration under reduced pressure, the mixture was purified by normal-phase silica gel column chromatography (methanol:dichloromethane = 0-15%), followed by purification by reversed-phase preparative HPLC (FA conditions, acetonitrile:water = 0-95%) to give compound 2 (20 mg, 38.6% yield) as a white solid. MS (ESI): m / z 786.5 [M+H] + .

[0176] 1 H NMR (400MHz, DMSO) δ12.31 (d, J = 8.3Hz, 1H), 10.83 (s, 1H), 7.76-7.66 (m, 1H), 7.47-7.26 (m, 5H),7.10-7.01(m,2H),6.98(d,J=8.7Hz,1H),6.87(dd,J=24.6,6.3Hz,1H),6.23-6.09(m,2H ),4.41-4.22(m,4H),3.82(dd,J=11.7,4.8Hz,1H),3.66-3.53(m,2H),3.55-3.42(m,4H),3. 04-2.91(m,5H),2.87-2.62(m,4H),2.61-2.55(m,2H),2.37-2.15(m,4H),2.07-1.76(m,5H).

[0177] Example 3: Synthesis of 3-(4-(4-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-8-yl)phenyl)piperidin-1-yl)-3-fluorophenyl)piperidin-2,6-dione (3):

[0178] Step 1: Synthesis of methyl 6-bromo-4-chloro-7-fluoro-3-carboxaldehyde-1H-indole-2-carboxylate (3b):

[0179] To a solution of methyl 6-bromo-4-chloro-7-fluoro-1H-indole-2-carboxylate 3a (122 mg, 0.4 mmol, see the synthesis of intermediate P in WO2025049820) in acetonitrile (10 mL), CuCl2 (27 mg, 0.2 mmol), tetramethylethylenediamine (TMEDA) (69.7 mg, 0.6 mmol), and K2CO3 (111 mg, 0.8 mmol) were added. The reaction mixture was stirred at 100 °C for 35 min. The reaction mixture was then cooled and diluted with water (30 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by normal-phase silica gel column chromatography (EA:PE = 0–20%) to give a yellow solid 3b (25 mg, 19% yield).

[0180] MS(ESI): m / z 333.9 [M+H] + .

[0181] Step 2: Synthesis of methyl(E)-6-bromo-4-chloro-7-fluoro-3-((hydroxyimino)methyl)-1H-indole-2-carboxylic acid methyl ester (3c):

[0182] To a methanol (50 mL) solution of methyl 6-bromo-4-chloro-7-fluoro-3-carboxaldehyde-1H-indole-2-carboxylate (420 mg, 1.25 mmol), hydroxylamine hydrochloride (260 mg, 3.7 mmol) and sodium carbonate (370 mg, 3.5 mmol) were added. The resulting mixture was heated to 50 °C and stirred for 1 h. The solvent was removed by concentration under reduced pressure, and water (10 mL) was added to the residue and filtered. The filtrate was extracted with dichloromethane (20 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated under reduced pressure to obtain a crude solid product, which was used directly in the next reaction.

[0183] MS(ESI): m / z 348.9[M+H]+.

[0184] Step 3: Synthesis of methyl 3-(aminomethyl)-6-bromo-4-chloro-7-fluoro-1H-indole-2-carboxylic acid ester (3d):

[0185] Zinc powder (260 mg, 4 mmol) was added to a mixture of acetic acid (50 mL) containing 3c (360 mg, 1 mmol) and sodium acetate (328 mg, 4 mmol), and the mixture was stirred at room temperature for 30 min. Methanol (50 mL) was added to the reaction mixture, and the mixture was filtered. The solvent in the filtrate was removed by vacuum concentration to obtain 400 mg of crude product. The crude product was purified by reversed-phase preparative HPLC (Xtimate Prep C18 10 μm 21.2 × 250 mm) using a water (0.2% FA) / acetonitrile mobile phase to obtain intermediate 3d (88 mg).

[0186] MS(ESI): m / z 335.0[M+H]+.

[0187] Step 4: Synthesis of 3-(aminomethyl)-6-bromo-4-chloro-7-fluoro-1H-indole-2-carboxylic acid (3e):

[0188] To a methanol (30 mL) solution containing 3d (60 mg, 0.18 mmol), add a water (5 mL) solution containing NaOH (21 mg, 0.53 mmol), and stir at 50 °C for 5 h. Then, concentrate under reduced pressure to remove the solvent. Add water and hydrochloric acid to the residue, and freeze-dry directly to obtain crude product 3e (90 mg), which is used directly in the next reaction.

[0189] MS(ESI): m / z 320.0[M+H]+.

[0190] Step 5: Synthesis of 6-bromo-8-chloro-5-fluoro-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (3f):

[0191] EDCI (92 mg, 0.48 mmol) was added to an anhydrous 4-methylmorpholine solution containing 3e (80 mg, 0.16 mmol) and DMAP (44 mg, 0.36 mmol). The mixture was stirred at room temperature for 24 h under a nitrogen atmosphere, and the solvent was removed by concentration under reduced pressure. The residue was purified by reversed-phase preparative HPLC (Xtimate Prep C18 10 μm 21.2 × 250 mm) using water (0.2% FA) / acetonitrile as the mobile phase to obtain 3f (11 mg).

[0192] MS(ESI): m / z 303.0[M+H]+.

[0193] Step Six: Synthesis of 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-8-chloro-5-fluoro-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (3g):

[0194] Under nitrogen protection, a mixture of 3f (5.5 mg, 0.018 mmol), 3-(1H-pyrazol-1-yl)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-3,6-dihydropyridin-1(2H)-yl)propane-1-one (18 mg, 0.054 mmol) (intermediate A), Pd(dppf)Cl2 (4 mg, 0.0005 mmol), and K2CO3 (10 mg, 0.072 mmol) in dioxane / water (20 mL, 5:1) was stirred at 90 °C for 2 h. After cooling, the solvent was removed by concentration under reduced pressure, and the residue was purified by normal-phase silica gel column chromatography (methanol / dichloromethane = 0–10%) to give 3 g (6 mg, 78% yield) of intermediate.

[0195] MS(ESI): m / z 428.1 [M+H] + .

[0196] Step 7: Synthesis of 3-(4-(4-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-8-yl)phenyl)piperidin-1-yl)-3-fluorophenyl)piperidin-2,6-dione (3):

[0197] Under nitrogen protection, a mixture of intermediate 3 g (6 mg, 0.014 mmol), 3-(3-fluoro-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)piperidin-1-yl)phenyl)piperidin-2,6-dione (14 mg, 0.028 mmol) (intermediate B), XPhos-Pd-G3 (4 mg, 0.005 mmol), cesium fluoride (6.4 mg, 0.042 mmol), dioxane (15 mL), and water (2 mL) was stirred at 80 °C for 2 h. The solvent was removed by vacuum concentration. The residue was first preliminarily purified by normal-phase silica gel column chromatography (methanol / dichloromethane = 0-10%), and then purified by reverse-phase preparative HPLC (Xtimate Prep C18 10μm 21.2×250mm) with water (0.2% FA) / acetonitrile as the mobile phase to obtain a white solid final product 3 (3.6 mg).

[0198] MS(ESI): m / z 758.3 [M+H] + .

[0199] 1 H NMR(400MHz,DMSO)δ12.17(s,1H),10.83(s,1H),8.35(s,1H),7.78-7.68(m,1H),7.6 6-7.56(m,2H),7.50-7.34(m,3H),7.14-6.95(m,4H),6.87(s,1H),6.23-6.12(m,2H), 4.46-4.28(m,4H),3.86-3.76(m,1H),3.68-3.62(m,1H),3.60-3.55(m,1H),3.53-3.4 2(m,2H),3.25-2.91(m,5H),2.87-2.60(m,5H),2.37-2.13(m,3H),2.06-1.81(m,5H).

[0200] Example 4: Synthesis of 3-(4-(4-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2-methyl-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-8-yl)phenyl)piperidin-1-yl)-3-fluorophenyl)piperidin-2,6-dione (4):

[0201] Step 1: Synthesis of methyl 6-bromo-4-chloro-7-fluoro-3-carboxaldehyde-1H-indole-2-carboxylate (3b):

[0202] To a solution of methyl 6-bromo-4-chloro-7-fluoro-1H-indole-2-carboxylate 3a (122 mg, 0.4 mmol, see the synthesis of intermediate P in WO2025049820) in acetonitrile (10 mL), CuCl2 (27 mg, 0.2 mmol), tetramethylethylenediamine (TMEDA) (69.7 mg, 0.6 mmol), and K2CO3 (111 mg, 0.8 mmol) were added. The reaction mixture was stirred at 100 °C for 35 min. The reaction mixture was then cooled and diluted with water (30 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by normal-phase silica gel column chromatography (EA:PE = 0–20%) to give a yellow solid 3b (25 mg, 19% yield).

[0203] MS(ESI): m / z 333.9 [M+H] + .

[0204] Step 2: Synthesis of methyl 6-bromo-4-chloro-7-fluoro-3-((methylamine)methyl)-1H-indole-2-carboxylic acid (4a):

[0205] To a methanol (5 mL) solution of methyl 6-bromo-4-chloro-7-fluoro-3-carboxymethyl-1H-indole-2-carboxylate 3b (200 mg, 0.6 mmol) and methylamine hydrochloride (81 mg, 1.2 mmol), triethylamine TEA (182 mg, 1.8 mmol) and NaBH3CN (76 mg, 1.2 mmol) were added. The resulting reaction mixture was stirred at room temperature for 16 h, then diluted with dichloromethane (50 mL). After washing with saturated brine (20 mL x 3), the solvent was concentrated under reduced pressure. The residue was purified by normal-phase silica gel column chromatography (MeOH:DCM = 0–10%) to give a brown oily substance 4a (70 mg, 33% yield).

[0206] MS(ESI): m / z 348.9 [M+H] + .

[0207] Step 3: Synthesis of 6-bromo-8-chloro-5-fluoro-2-methyl-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (4b):

[0208] K₂CO₃ (28 mg, 0.2 mmol) was added to a methanol (2 mL) solution of methyl 6-bromo-4-chloro-7-fluoro-3-((methylamine)methyl)-1H-indole-2-carboxylate 4a (70 mg, 0.2 mmol). The resulting mixture was stirred at 60 °C for 16 hours, cooled, and the solvent was concentrated under reduced pressure to give a yellow solid compound 4b (90 mg, crude product), which was used directly in the next reaction.

[0209] MS(ESI): m / z 317.3 [M+H] + .

[0210] Step 4: Synthesis of 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-8-chloro-5-fluoro-2-methyl-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one 4c:

[0211] In a nitrogen atmosphere, a mixture of 6-bromo-8-chloro-5-fluoro-2-methyl-1,4-dihydropyrrolo[3,4-b]indol-3(2H)-one 4b (90 mg crude, 0.2 mmol), 3-(1H-pyrrolo-1-yl)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-3,6-dihydropyridin-1(2H)-yl)propane-1-one A (104 mg, 0.31 mmol), Pd(dppf)Cl2 (24 mg, 0.033 mmol), K2CO3 (83 mg, 0.6 mmol), and dioxane / water (3 mL, 5:1) was stirred at 90 °C for 2 h. After cooling, the solvent in the reaction mixture was concentrated under reduced pressure, and the residue was purified by normal-phase silica gel column chromatography (MeOH:DCM = 0-10%) to give 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-8-chloro-5-fluoro-2-methyl-1,4-dihydropyrrolo[3,4-b]indol-3(2H)-one 4c (40 mg, 45% yield).

[0212] MS(ESI): m / z 442.1 [M+H] + .

[0213] Step 5: Synthesis of 3-(4-(4-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2-methyl-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-8-yl)phenyl)piperidin-1-yl)-3-fluorophenyl)piperidin-2,6-dione (4):

[0214] In a nitrogen atmosphere, a mixture of 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-8-chloro-5-fluoro-2-methyl-1,4-dihydropyrrolo[3,4-b]indol-3(2H)-one 4c (40 mg, 0.09 mmol), 3-(3-fluoro-4-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)phenyl)piperidin-1-yl)phenyl)piperidin-2,6-dione B (64 mg, 0.13 mmol), XPhos-Pd-G3 (13 mg, 0.02 mmol), CsF (41 mg, 0.27 mmol) and dioxane / water (3 mL / 0.5 mL) was stirred at 80 °C for 2 h. After cooling, the solvent was concentrated under reduced pressure. The residue was first purified by normal-phase silica gel column chromatography (methanol:dichloromethane = 0-10%), and then by reverse-phase preparative HPLC (Xtimate Prep C18 10μm 21.2×250mm, A: acetonitrile, B: 0.2% FA / water, A:B = 40-70%) to obtain a white solid 3-(4-(4-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2-methyl-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-8-yl)phenyl)piperidin-1-yl)-3-fluorophenyl)piperidin-2,6-dione 4 (30 mg).

[0215] MS(ESI): m / z 772.3 [M+H] + .

[0216] 1 H NMR(400MHz,DMSO)δ12.55(s,1H),10.84(s,1H),7.73-7.70(m,1H),7.59-7.57(m, 2H),7.45-7.37(m,3H),7.14-6.97(m,4H),6.21-6.17(m,2H),4.39-4.31(m,6H),3 .84-3.80(m,1H),3.66-3.63(m,1H),3.60-3.56(m,1H),3.51-3.48(m,2H),3.05(s ,3H),3.00-2.95(m,2H),2.85-2.62(m,5H),2.33-2.19(m,3H),2.04-1.87(m,5H).

[0217] Example 5: Synthesis of (E)-3-(5-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4'-(1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidin-4-yl)-4-fluoro-[1,1'-biphenyl]-3-yl)-N,N-dimethylacrylamide (5):

[0218] Step 1: Synthesis of (E)-3-(3-bromo-5-chloro-2-fluorophenyl)-N,N-dimethylpropionamide (5b):

[0219] Diethyl (2-(dimethylamino)-2-oxoethyl)phosphonate (1.42 g, 6.36 mmol) and DBU (967 mg, 6.36 mmol) were added sequentially to a suspension of dried MeCN (10 mL) containing LiCl (267 mg, 6.36 mmol). The mixture was stirred at room temperature for 10 minutes. A solution of 3-bromo-5-chloro-2-fluorobenzaldehyde (1 g, 4.24 mmol) in acetonitrile (10 mL) was added dropwise to the reaction system. After stirring at room temperature for 12 hours, the reaction was quenched with saturated ammonium chloride aqueous solution, water (30 mL) was added, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by normal-phase silica gel column chromatography (EA: PE = 0%–40%) to give a white solid 5b (860 mg, 66.5% yield). MS (ESI): m / z 306.0 [M+H] + .

[0220] Step 2: Synthesis of (E)-3-(3-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-chloro-2-fluorophenyl)-N,N-dimethylacrylamide (5c):

[0221] Under nitrogen protection, (E)-3-(3-bromo-5-chloro-2-fluorophenyl)-N,N-dimethylpropionamide 5b (200 mg, 0.66 mmol), 3-(1H-pyrazol-1-yl)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-3,6-dihydropyridin-1(2H)-yl)propane-1-one A (260 mg, 0.79 mmol, refer to the preparation of intermediate N in WO2025049820A1), Pd(dppf)Cl2 (24 mg, 0.033 mmol), K2CO3 (273 mg, 1.98 mmol), and a mixture of dioxane / water (6 mL, 5:1) were stirred at 90 °C for 2 h and the reaction was monitored by LCMS. The system was directly concentrated after cooling, and the residue was purified by reversed-phase HPLC (0.1% ammonium bicarbonate, acetonitrile:water = 0-95%) to give a brown solid 5c (130 mg, 46% yield). MS (ESI): m / z 430.9 [M+H] + .

[0222] Step 3: Synthesis of (E)-3-(5-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-4'-(1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidin-4-yl)-4-fluoro-[1,1'-biphenyl]-3-yl)-N,N-dimethylacrylamide (5):

[0223] (E)-3-(3-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-chloro-2-fluorophenyl)-N,N-dimethylacrylamide 5c (110 mg, 0.256 mmol), 3-(3-fluoro-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)piperidin-1-yl)phenyl)piperidin-2,6-dione B (148 mg, 0.3 mmol, see WO2025049820) Preparation of intermediate OP (A1): A mixture of XPhos-Pd-G3 (27 mg, 0.03 mmol), CsF (117 mg, 0.768 mmol), and dioxane (6 mL) / water (2 mL) was degassed and heated and stirred at 80 °C for 2 h under a nitrogen atmosphere. The reaction system was concentrated, and the residue was initially purified by normal-phase silica gel column chromatography (methanol:dichloromethane = 0-30%), followed by purification by reversed-phase HPLC (0.1% trifluoroacetic acid, acetonitrile:water = 0-95%) to give a white solid 5 (50.0 mg, 25.7% yield). MS (ESI): m / z 761.5 [M+H] + .

[0224] 1 H NMR (400MHz, DMSO) δ10.84 (s, 1H), 8.10 (d, J = 6.2Hz, 1H), 7.75-7.53 (m, 5H ),7.48-7.35(m,4H),7.11-6.93(m,3H),6.22-6.13(m,2H),4.40-4.23(m,4 H),3.86-3.77(m,1H),3.66-3.43(m,4H),3.19(s,3H),3.02-2.92(m,5H),2 .84-2.60(m,5H),2.34-2.17(m,3H),2.05-1.97(m,1H),1.96-1.81(m,4H).

[0225] Example 7: Synthesis of 3-(4-(4-(4-(8-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-9-fluoro-2-methyl-1-oxo-1,2,3,4,5,10-hexahydroacrophenin[3,4-b]indol-6-yl)phenyl)piperidin-1-yl)-3-fluorophenyl)piperidin-2,6-dione (7):

[0226] Step 1: Synthesis of (3-bromo-5-chloro-2-fluorophenyl)hydrazine (7a):

[0227] Under ice bath conditions, 10 mL of an aqueous solution of NaNO2 (690 mg, 10.0 mmol) was added to a hydrochloric acid (2N, 150 mL) solution containing 2.44 g, 10.0 mmol of 3-bromo-5-chloro-2-fluoroaniline. After the addition was complete, the mixture was kept in an ice bath and stirred for 2 h. Then, a hydrochloric acid (2N, 20 mL) solution containing 5.67 g, 3 eq of SnCl2 was slowly added dropwise to the reaction system. After the addition was complete, the mixture was kept in an ice bath and stirred for another 2 h. The mixture was filtered, and the filtrate was directly purified by reversed-phase preparative HPLC (acetonitrile / water = 15-50%) to obtain a white solid intermediate 7a (1.1 g, yield: 42%).

[0228] MS(ESI): m / z 239,241 [M+H] + RT = 1.624 min

[0229] Step 2: Synthesis of 8-bromo-6-chloro-9-fluoro-2-methyl-3,4,5,10-tetrahydroacepine[3,4-b]indole-1(2H)-one (7b):

[0230] Under aquatic cooling conditions, a solution of 1-methyl-2-piperidinone (113 mg, 1 mmol) and anhydrous DMF (153 mg, 2.1 mmol) in anhydrous toluene (2 mL) was slowly added dropwise to a stirred solution of POCl3 (765 mg, 5 mmol) in anhydrous toluene (2 mL). After the addition was complete, the system was heated to 110 °C and stirred under reflux for 5.5 h, excluding water vapor. After cooling, the solvent and residual phosphorus oxychloride were removed by vacuum concentration. Ice water (5 mL) was added to the residue, and the mixture was stirred for 1.5 h. A solution of (3-bromo-5-chloro-2-fluorophenyl)hydrazine 7a (239 mg, 1 mmol) in ethanol (5 mL) was added to the system, and the mixture was heated under reflux for 2 h. The ethanol solvent was removed by vacuum concentration, and a saturated sodium bicarbonate aqueous solution was added dropwise to the residue to adjust the pH to 8. Extracted with dichloromethane (20 mL * 2), the organic phases were combined, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the organic solvent. The residue was purified by reversed-phase preparative HPLC (Xtimate Prep C18 10 μm 21.2 × 250 mm) using water (0.2% FA) / acetonitrile as the mobile phase to give a white solid intermediate 7b (15 mg, yield 4.3%).

[0231] MS(ESI): m / z 347.3 [M+H] + RT = 1.81 min.

[0232] 1 H NMR (400MHz, DMSO-d6) δ12.17(s,1H),7.30(s,1H),3.51-3.49(m,2H),3.31-3.29(m,2H),3.10(s,3H),2.08-2.06(m,2H).

[0233] Step 3: Synthesis of 8-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-6-chloro-9-fluoro-2-methyl-3,4,5,10-tetrahydroacrophenin[3,4-b]indole-1(2H)-one (7c):

[0234] In a nitrogen atmosphere, a mixture of 8-bromo-6-chloro-9-fluoro-2-methyl-3,4,5,10-tetrahydroacoxane[3,4-b]indol-1(2H)-one 7b (15 mg, 0.043 mmol), 3-(1H-pyrrolo-1-yl)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-3,6-dihydropyridin-1(2H)-yl)propane-1-one A (36 mg, 0.108 mmol), Pd(dppf)Cl2 (8 mg, 0.001 mmol), potassium carbonate (20 mg, 0.14 mmol), and dioxane / water (20 mL, 5:1) was heated to 90 °C and stirred for 2 h. The solvent was removed by vacuum concentration, and the residue was purified by normal-phase silica gel column chromatography (methanol / dichloromethane = 0-10%) to obtain a relatively pure crude intermediate 7c (20 mg crude product), which was directly used in the next reaction.

[0235] MS(ESI): m / z 470.1 [M+H] + RT = 1.80 min.

[0236] Step 4: Synthesis of 3-(4-(4-(4-(8-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-9-fluoro-2-methyl-1-oxo-1,2,3,4,5,10-hexahydroacrophenin[3,4-b]indol-6-yl)phenyl)piperidin-1-yl)-3-fluorophenyl)piperidin-2,6-dione (7):

[0237] Under a nitrogen atmosphere, 8-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-6-chloro-9-fluoro-2-methyl-3,4,5,10-tetrahydroacoxane[3,4-b]indol-1(2H)-one 7c (20 mg, 0.042 mmol), 3-(3-fluoro-4-(4-(4-(4,4,5,5-tetramethyl) A mixture of 28 mg (0.056 mmol) of 1,3,2-dioxoboronyl-2-yl)phenyl)piperidin-1-yl)phenyl)piperidin-2,6-dione B, XPos-Pd-G3 (8 mg, 0.01 mmol), CsF (12.8 mg, 0.084 mmol), and dioxane (5 mL) / water (1 mL) was heated to 80 °C and stirred for 2 h. The solvent was removed by vacuum concentration, followed by crude purification using a normal-phase silica gel column (methanol / dichloromethane = 0-10%), and then purified by reversed-phase preparative HPLC (Xtimate Prep C18 10 μm 21.2 × 250 mm) with water (0.2% FA) / acetonitrile as the mobile phase to obtain a white solid 7 (10 mg).

[0238] MS(ESI): m / z 800.1 [M+H] + RT = 1.85 min.

[0239] 1 H NMR(400MHz,DMSO)δ11.73(s,1H),10.83(s,1H),7.72-7.70(m,1H),7.42-7.3 2(m,5H),7.08-6.97(m,3H),6.78-6.69(m,1H),6.20-6.16(m,2H),4.46-4.20 (m,4H),3.62-3.46(m,1H),3.42-3.26(m,6H),3.07(s,3H),2.98–2.93(m,3H) ,2.86-2.78(m,3H),2.67-2.61(m,1H),2.43-2.20(m,5H),2.00-1.89(m,6H).

[0240] Example 82: Synthesis of 3-(4-(4-(4-(8-(1-(3-(1H-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-9-fluoro-2-methyl-1-oxo-1,2,3,4,5,10-hexahydroacrophenin[3,4-b]indol-6-yl)phenyl)piperidin-1-yl)-3-fluorophenyl)piperidin-2,6-dione (82):

[0241] Step 1: Synthesis of 8-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-6-chloro-9-fluoro-2-methyl-3,4,5,10-tetrahydroacrophenin[3,4-b]indole-1(2H)-one (82a):

[0242] In a nitrogen atmosphere, intermediates 7b (15 mg, 0.043 mmol) of 8-bromo-6-chloro-9-fluoro-2-methyl-3,4,5,10-tetrahydroacoxane[3,4-b]indol-1(2H)-one and intermediate A-1 (36 mg, 0.108 mmol, WO2025049820) were prepared. Preparation of intermediate AJ): Pd(dppf)Cl2 (8 mg, 0.001 mmol), potassium carbonate (20 mg, 0.14 mmol), and dioxane / water (6 mL, 5:1) were heated to 90 °C and stirred for 2 h. After cooling, the organic solvent in the reaction system was removed under reduced pressure, and the residue was purified by normal-phase silica gel column chromatography (MeOH / DCM: 0–10%) to give the target intermediate 82a (10 mg, 38% yield).

[0243] MS(ESI): m / z 471.1 [M+H] + RT = 1.33 min.

[0244] Step 2: Synthesis of 3-(4-(4-(4-(8-(1-(3-(1H-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-9-fluoro-2-methyl-1-oxo-1,2,3,4,5,10-hexahydroacrophenin[3,4-b]indol-6-yl)phenyl)piperidin-1-yl)-3-fluorophenyl)piperidin-2,6-dione (82):

[0245] In a nitrogen atmosphere, 8-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-6-chloro-9-fluoro-2-methyl-3,4,5,10-tetrahydroacoxane[3,4-b]indole-1(2H)-one intermediate 82a (20 mg, 0.043 mmol), 3-(3-fluoro-4-(4-(4-(4,4,5) 5-Tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)phenyl)piperidin-1-yl)phenyl)piperidin-2,6-dione (42 mg, 0.085 mmol), XPhos-Pd-G3 (8 mg, 0.01 mmol), and cesium fluoride (13 mg, 0.085 mmol) were heated to 80 °C and stirred for 2 h in a mixture of dioxane (4 mL) and water (1 mL). After cooling, the organic solvent in the reaction system was removed under reduced pressure, and the crude product was purified by normal-phase silica gel column chromatography (0-30% MeOH / DCM) to give crude product. Then, the crude product was obtained by reverse-phase preparative HPLC (0.2% formic acid, 0-95% acetonitrile / water) to give white solid final product 82 (18 mg, 53% yield).

[0246] MS (ESI): m / z 801.3[M+H]+, RT=1.75min.

[0247] 1H NMR (400MHz, DMSO) δ11.75(d,J=9.7Hz,1H),10.84(s,1H),8.11(d,J=10.1Hz,1H),7.68(d, J=10.8Hz,1H),7.35(q,J=8.4Hz,4H),7.14-6.88(m,3H),6.80-6.70(m,1H),6.15(d,J=10. 1Hz,1H),4.71-4.49(m,2H),4.36-4.30(m,2H),3.83-3.79(m,1H),3.62-3.57(m,2H),3.47 -3.40(m,4H),3.15-2.99(m,5H),2.89-2.59(m,4H),2.39-2.10(m,6H),2.02-1.79(m,7H).

[0248] Examples 148 and 149: (S)-3-(4-(4-(8-(1-(3-(1H-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-9-fluoro-2-methyl-1-oxo-1,2,3,4,5,10-hexahydroacrophenin[3,4-b]indol-6-yl)phenyl)piperidin-1-yl)-3-fluorophenyl)piperidin-2,6-dione (148) and (R)-3-(4-(4-(8-(1-(3-(1H-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-9-fluoro-2-methyl-1-oxo-1,2,3,4,5,10-hexahydroacromene[3,4-b]indol-6-yl)phenyl)piperidin-1-yl)-3-fluorophenyl)piperidin-2,6-dione (149):

[0249] 3-(4-(4-(4-(8-(1-(3-(1H-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-9-fluoro-2-methyl-1-oxo-1,2,3,4,5,10-hexahydroacrophenin[3,4-b]indol-6-yl)phenyl)piperidin-1-yl)-3-fluorophenyl)piperidin-2,6-dione (15 mg, 82 g) was resolved to two isomers by chiral SFC conditions (instrument: SFC-150 / Waters; chiral column: AS25*250mm, 10 μm / Daicel; mobile phase: CO2 / (MEOH / ACN)=45 / 55). The first received isomer was 148 g (5.1 mg, yield 34%), MS (ESI): m / z 802.2 [M+H]. + RT = 1.78 min; 1 H NMR (400MHz, DMSO) δ11.74(d,J=9.5Hz,1H),10.83(s,1H),8.11(d,J=10.1Hz,1H),7.68( d,J=10.8Hz,1H),7.38–7.35(m,4H),7.06–6.99(m,3H),6.72–6.70(m,1H),6.17–6.10(m ,1H),4.64–4.60(m,2H),4.36–4.28(m,2H),3.84–3.78(m,1H),3.63–3.56(m,2H),3.51– 3.41(m,4H),3.11–3.07(m,5H),2.84–2.62(m,4H),2.35–2.14(m,6H),2.00–1.82(m,7H).

[0250] The second received isomer, 149 (4.2 mg, yield 28%), MS (ESI): m / z 802.1 [M+H] + RT = 1.78 min 1 H NMR (400MHz, DMSO) δ11.74(d,J=9.5Hz,1H),10.83(s,1H),8.11(d,J=10.1Hz,1H),7.68( d,J=10.8Hz,1H),7.38–7.30(m,4H),7.06–6.95(m,3H),6.80–6.69(m,1H),6.17–6.10(m ,1H),4.65–4.57(m,2H),4.36–4.30(m,2H),3.84–3.78(m,1H),3.66–3.56(m,2H),3.51– 3.41(m,4H),3.11–3.04(m,5H),2.84–2.66(m,4H),2.38–2.14(m,6H),2.00–1.82(m,7H).

[0251] Given that the stereostructures of these two chiral isomers cannot be accurately characterized, their absolute configurations are provisionally given in this paper for the sake of convenience.

[0252] Example 120: Synthesis of 3-((4-(4-(4-(8-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-9-fluoro-2-methyl-1-oxo-1,2,3,4,5,10-hexahydroacromene[3,4-b]indol-6-yl)phenyl)piperidin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidin-2,6-dione (120):

[0253] Under a nitrogen atmosphere, 8-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-6-chloro-9-fluoro-2-methyl-3,4,5,10-tetrahydroacetaminophen[3,4-b]indol-1(2H)-one 7c (9 mg, 0.02 mmol), 3-((5-fluoro-2-methoxy-4-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)piperazin-1-yl)phenyl)amino)piperidin-2,6-dione C (16 mg, 0.03 mmol), XPhos-Pd-G3 (4 mg, 0.005 mmol), CsF (6 mg, 0.04 mmol), dioxane (4 mL), and water (1 mL) were added to the mixture. The mixture (mL) was heated to 80°C and stirred for 2 hours. After cooling, the solvent was removed by concentration under reduced pressure. The residue was first preliminarily purified by normal-phase silica gel column chromatography (mobile phase: methanol / dichloromethane = 0-30%), and then purified by reverse-phase preparative HPLC (formic acid conditions, acetonitrile / water = 0-95%) to give a white solid compound 120 (3 mg, yield 19%).

[0254] MS (ESI): m / z 846.2[M+H]+, RT=1.75 min.

[0255] 1 H NMR (400 MHz, DMSO-d6) δ11.69(d,J=11.0 Hz,1H),10.87(s,1H),7.71(dd,J=10.3,2.0 Hz,1H),7.47-7.39(m,1H),7.26(d,J=8.5 Hz,2H),7.04(d,J=8.5 Hz,2H),6.71-6.54(m,3H),6.22-6.08(m,2H),5.14(d,J=6.4 Hz,1H),4.40-4.19(m,5H),3.82(s,3H),3.65-3.55(m,2H),3.49-3.42(m,4H),3.08(s,8H),2.97(t,J=7.8 Hz,2H),2.86-2.77(m,1H),2.60-2.58(m,1H),2.45-2.39(m,2H),2.34-2.21(m,3H),2.18-2.11(m,1H),2.03-1.82(m,3H).

[0256] Example 121: Synthesis of 3-((4-(4-(4-(8-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-9-fluoro-2-methyl-1-oxo-1,2,3,4,5,10-hexahydroacromene[3,4-b]indol-6-yl)-2,3-difluorophenyl)piperidin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidin-2,6-dione (121):

[0257] Under a nitrogen atmosphere, 8-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-6-chloro-9-fluoro-2-methyl-3,4,5,10-tetrahydroacoxane[3,4-b]indol-1(2H)-one 7c (40 mg, 0.085 mmol), 3-((4-(4-(2,3-difluoro-4-(4,4,5,5-tetramethyl-1, A mixture of 3,2-dioxoboronyl-2-yl)phenyl)piperazin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione (98 mg, 0.17 mmol), XPhos-Pd-G3 (17 mg, 0.02 mmol), CsF (26 mg, 0.17 mmol), dioxane (5 mL), and water (1 mL) was heated to 80 °C and stirred for 2 hours. After cooling, the solvent was removed by concentration under reduced pressure. The residue was initially purified by normal-phase silica gel column chromatography (mobile phase: methanol / dichloromethane = 0-30%), followed by reverse-phase preparative HPLC (formic acid conditions, acetonitrile / water = 0-95%) to give compound 121 (20 mg, yield 27%) as a white solid.

[0258] MS(ESI): m / z 882.5[M+H]+, RT=1.78min.

[0259] 1H NMR (400MHz, DMSO-d6) δ11.81(d,J=11.3Hz,1H),10.86(s,1H),7.80-7.64(m,1H),7.40(d,J=22.7Hz,1H),7.21-7 .08(m,1H),6.97(t,J=8.2Hz,1H),6.89-6.65(m,2H),6.59(d,J=14.3Hz,1H),6.24-6.07(m,2H),5.14(d,J=6.5Hz ,1H),4.46-4.17(m,5H),3.82(s,3H),3.59(dt,J=25.4,5.5Hz,2H),3.42(s,2H),3.30-3.20(m,4H),3.16-3.06(m ,7H),3.03-2.92(m,2H),2.89-2.74(m,1H),2.57(s,1H),2.42-2.21(m,4H),2.22-2.07(m,1H),2.01-1.74(m,3H).

[0260] Example 129: Synthesis of 3-(4-(4-(4-(8-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-4-methyl-5-oxo-3,4,5,6-tetrahydro-2H-[1,4]oxaconitine[6,7-b]indol-10-yl)phenyl)piperidin-1-yl)-3-fluorophenyl)piperidin-2,6-dione (129):

[0261] Step 1: Synthesis of methyl 6-bromo-4-chloro-3-diazo-7-fluoro-3H-indole-2-carboxylate (129a):

[0262] Sodium nitrite (2 g, 29 mmol) and acetic acid (3 mL) were added separately to a DMF / DCM (10 mL, 1:1) solution of methyl 6-bromo-4-chloro-7-fluoro-1H-indole-2-carboxylate 3a (200 mg, 0.653 mmol) at room temperature. The mixture was stirred at room temperature for 96 hours. The reaction mixture was concentrated under reduced pressure to remove dichloromethane, and the residue was then poured into ice water (50 g). The mixture was filtered, and the resulting solid was dried under vacuum to give a white solid, methyl 6-bromo-4-chloro-3-diazo-7-fluoro-3H-indole-2-carboxylate 129a (120 mg, yield 55.4%). MS (ESI): m / z 332.0, 334.0 [M+H] + Rt = 1.91 min.

[0263] Step 2: Synthesis of methyl 6-bromo-3-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-4-chloro-7-fluoro-1H-indole-2-carboxylate (129b):

[0264] Rhodium dimer acetate (40 mg) was added to a DCE (2 mL) solution of N-tert-butoxycarbonyl-N-methyl-2-aminoethanol (84 mg, 0.482 mmol) and methyl 6-bromo-4-chloro-3-diazo-7-fluoro-3H-indole-2-carboxylate 129a (80 mg, 0.241 mmol). The resulting mixture was heated to 85 °C under a nitrogen atmosphere and stirred for 48 hours. After cooling, the solvent in the reaction system was removed by concentration under reduced pressure. The residue was purified by normal-phase silica gel column chromatography (ethyl acetate: petroleum ether = 0% to 33%) to give a white solid methyl 6-bromo-3-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-4-chloro-7-fluoro-1H-indole-2-carboxylate 129b (53.2 mg, yield 46%).

[0265] MS(ESI): m / z 479.2, 481.2 [M+H] + Rt = 2.14 min

[0266] Step 3: Synthesis of methyl 6-bromo-4-chloro-7-fluoro-3-(2-(methylamino)ethoxy)-1H-indole-2-carboxylate (129c):

[0267] At room temperature, 1 mL of 4 M dioxane hydrochloride solution was added to 1 mL of dichloromethane solution of methyl 6-bromo-3-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-4-chloro-7-fluoro-1H-indole-2-carboxylate 129b (53.2 mg, 0.111 mmol). The resulting mixture was stirred at room temperature for 30 minutes. The solvent in the reaction system was removed by concentration under reduced pressure to give 46.1 mg (100% yield) of white solid methyl 6-bromo-4-chloro-7-fluoro-3-(2-(methylamino)ethoxy)-1H-indole-2-carboxylate hydrochloride 129c.

[0268] MS(ESI): m / z 379.0, 381.0 [M+H] + Rt = 1.78 min

[0269] Step 4: Synthesis of 8-bromo-10-chloro-7-fluoro-4-methyl-3,4-dihydro-2H-[1,4]oxaprotinin[6,7-b]indole-5(6H)-one (129d):

[0270] K₂CO₃ (45.9 mg, 0.333 mol) was added to a methanol (4 mL) solution of methyl 6-bromo-4-chloro-7-fluoro-3-(2-(methylamino)ethoxy)-1H-indole-2-carboxylate hydrochloride (46.1 mg, 0.111 mmol). The resulting mixture was stirred at 70 °C for 18 hours. After cooling, the methanol was removed by concentration under reduced pressure. The residue was dissolved in dichloromethane (10 mL), washed with water (2 mL), and the organic phase was dried over anhydrous sodium sulfate. After filtration, the solvent was removed by concentration under reduced pressure to give a white solid 8-bromo-10-chloro-7-fluoro-4-methyl-3,4-dihydro-2H-[1,4]oxaconitine[6,7-b]indole-5(6H)-one 129d (32 mg, yield 82.9%).

[0271] MS(ESI): m / z 347.0, 349.0 [M+H] + Rt = 1.84 min

[0272] Step 5: Synthesis of 8-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-10-chloro-7-fluoro-4-methyl-3,4-dihydro-2H-[1,4]oxacloheptaphylline[6,7-b]indole-5(6H)-one (129e):

[0273] In a nitrogen atmosphere, a mixture of 8-bromo-10-chloro-7-fluoro-4-methyl-3,4-dihydro-2H-[1,4]oxaprotinin[6,7-b]indol-5(6H)-one (30 mg, 0.086 mmol), 3-(1H-pyrazol-1-yl)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-3,6-dihydropyridin-1(2H)-yl)propane-1-one A (43 mg, 0.129 mmol), Pd(dppf)Cl2 (15 mg, 0.02 mmol), K2CO3 (40 mg, 0.28 mmol), and dioxane / water (6 mL, 5:1) was heated to 90 °C and stirred for 2 hours. After cooling, the solvent in the reaction system was removed by concentration under reduced pressure. The residue was purified by normal-phase silica gel column chromatography (MeOH:DCM = 0-10%) to obtain a yellow oily substance 8-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-10-chloro-7-fluoro-4-methyl-3,4-dihydro-2H-[1,4]oxaconitine[6,7-b]indole-5(6H)-one 129e (30 mg, yield 73%).

[0274] MS(ESI): m / z 472.1 [M+H] + Rt = 1.66 min.

[0275] Step Six: Synthesis of 3-(4-(4-(4-(8-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-4-methyl-5-oxo-3,4,5,6-tetrahydro-2H-[1,4]oxazobenzene[6,7-b]indol-10-yl)phenyl)piperidin-1-yl)-3-fluorophenyl)piperidin-2,6-dione (129):

[0276] In a nitrogen atmosphere, 8-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-10-chloro-7-fluoro-4-methyl-3,4-dihydro-2H-[1,4]oxaconitine[6,7-b]indole-5(6H)-one (9 mg, 0.02 mmol), 3-(3-fluoro-4-(4-(4-(4,4,5,5-) A mixture of tetramethyl-1,3,2-dioxoboron-2-yl)phenyl)piperidin-1-yl)phenyl)piperidin-2,6-dione B (15 mg, 0.03 mmol), XPhos-Pd-G3 (4 mg, 0.005 mmol), CsF (6 mg, 0.04 mmol), dioxane (4 mL), and water (1 mL) was heated to 80 °C and stirred for 2 hours. The solvent in the reaction system was removed by vacuum concentration. The residue was purified by reverse-phase HPLC using acetonitrile:water (containing 0.06% NH4HCO3) = 0-95% as the mobile phase to give compound 129 (6 mg, 38% yield) as a yellow solid.

[0277] MS(ESI): m / z 802.3 [M+H] + Rt = 1.38 min.

[0278] 1H NMR (400MHz, DMSO) δ11.30(s,1H),10.83(s,1H),7.76-7.68(m,1H),7.53-7.41(m,3H),7.38-7.32(m,2H),7.06( t,J=9.7Hz,2H),6.98(d,J=7.6Hz,1H),6.83-6.69(m,1H),6.24-6.08(m,2H),4.43-4.30(m,3H),4.31-4.16(m,3H ),3.89-3.76(m,1H),3.72-3.65(m,3H),3.59-3.53(m,1H),3.50-3.48(m,2H),3.07(s,3H),3.01-2.90(m,2H),2 .90-2.77(m,2H),2.72-2.61(m,2H),2.36-2.29(m,2H),2.27-2.18(m,2H),2.05-1.98(m,1H),1.98-1.79(m,4H).

[0279] Example 135: Synthesis of 3-((4-(4-(8-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-4-methyl-5-oxo-3,4,5,6-tetrahydro-2H-[1,4]oxaconitine[6,7-b]indol-10-yl)phenyl)piperazin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione (135):

[0280] In a nitrogen atmosphere, 8-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-10-chloro-7-fluoro-4-methyl-3,4-dihydro-2H-[1,4]oxaconitine[6,7-b]indole-5(6H)-one 129e (9 mg, 0.02 mmol), 3-((5-fluoro-2-methoxy-4-(4-(4-(4,4, A mixture of 5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione C (16 mg, 0.03 mmol), XPhos-Pd-G3 (4 mg, 0.005 mmol), CsF (6 mg, 0.04 mmol), dioxane (4 mL), and water (1 mL) was heated to 80 °C and stirred for 2 hours. The organic solvent in the reaction system was removed by vacuum concentration. The residue was purified by reverse-phase HPLC using acetonitrile:water (containing 0.06% NH4HCO3) = 0-95% as the mobile phase to give compound 135 (9 mg, 56% yield), a yellow solid.

[0281] MS(ESI): m / z 848.4 [M+H] + Rt = 1.33 min.

[0282] 1 H NMR (400MHz, DMSO) δ11.20(s,1H),11.04-10.53(m,1H),7.74-7.72(m,1H),7.47-7.33(m,3H),7.01(d ,J=8.8Hz,2H),6.78-6.63(m,2H),6.61-6.57(m,1H),65.21-6.1(m,2H),5.15(d,J=6.7Hz,1H),4.43-4 .31(m,3H),4.26(s,4H),3.82(s,3H),3.73-3.65(m,2H),3.59-3.57(m,2H),3.08(s,7H),3.02-2.90( m,2H),2.87-2.73(m,2H),2.61-2.52(m,5H),2.38-2.21(m,2H),2.19-2.05(m,1H),1.98-1.80(m,1H).

[0283] Example 136: Synthesis of 3-((4-(4-(8-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-4-methyl-5-oxo-3,4,5,6-tetrahydro-2H-[1,4]oxacloheptaphylline[6,7-b]indol-10-yl)-2,3-difluorophenyl)piperazin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione (136):

[0284] In a nitrogen atmosphere, 8-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-10-chloro-7-fluoro-4-methyl-3,4-dihydro-2H-[1,4]oxaconitine[6,7-b]indole-5(6H)-one 129e (9 mg, 0.02 mmol), 3-((4-(4-(2,3-difluoro-4-(4,4,5,5-) Tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)piperazin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidin-2,6-dione D (17 mg, 0.03 mmol), XPhos-Pd-G3 (4 mg, 0.005 mmol), CsF (6 mg, 0.04 mmol), dioxane (4 mL), and water (1 mL) were heated to 80 °C and stirred for 2 hours. The organic solvent in the reaction system was removed by vacuum concentration. The residue was purified by reverse-phase HPLC using acetonitrile:water (containing 0.06% NH4HCO3) = 0-95% as the mobile phase to give compound 136 (6 mg, 36% yield) as a yellow solid.

[0285] MS(ESI): m / z 884.4 [M+H] + Rt = 1.83 min.

[0286] 1 H NMR (400MHz, DMSO) δ11.37(d,J=12.5Hz,1H),10.87(s,1H),7.72-7.70(m,1H),7.45-7.34(m,1H),7.16(t,J=8.0 Hz,1H),6.93(t,J=8.3Hz,1H),6.83-6.73(m,1H),6.71(d,J=8.1Hz,1H),6.01-6.57(m,1H),6.23-6.08(m,2H),5. 15(d,J=6.6Hz,1H),4.38-4.19(m,7H),3.82(s,3H),3.70-3.53(m,4H),3.25(s,4H),3.11(s,4H),3.07(s,3H),2 .99-2.93(m,2H),2.84-2.76(m,2H),2.57-2.55(m,1H),2.30-2.27(m,3H),2.16-2.10(m,1H),1.95-1.90(m,1H).

[0287] Example 145: Synthesis of 3-(4-(4-(8-(1-(3-(1H-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-9-fluoro-2-(methyl-d3)-1-oxo-1,2,3,4,5,10-hexahydroacrophenin[3,4-b]indol-6-yl)phenyl)piperidin-1-yl)-3-fluorophenyl)piperidin-2,6-dione (145):

[0288] Step 1: Synthesis of 1-(methyl-d3)piperidin-2-one (145a):

[0289] Under ice bath conditions, NaH (1.25 g, 28 mmol, in 60% kerosene) was added to a solution of piperidin-2-one (2500 mg, 25.0 mmol) and 18-crown-6 (100 mg, 0.4 mmol) in anhydrous tetrahydrofuran (20 mL). After the addition was complete, the system was kept in an ice bath and stirred for 20 minutes. Then, a solution of CD3I (5800 mg, 40.0 mmol) in anhydrous tetrahydrofuran (10 mL) was added to the reaction system. The mixture was allowed to warm naturally to room temperature and stirred for 16 hours. The reaction was quenched with water (30 mL), and the organic solvent in the reaction system was removed under reduced pressure. Add NaOH aqueous solution (1N, 30 mL) to the residue, and extract with dichloromethane containing 10% methanol (3 x 40 mL). Dry the organic phase with anhydrous magnesium sulfate, filter, and remove the organic solvent under reduced pressure to give the oily target intermediate 145a (1800 mg, 62% yield). MS (ESI): m / z 117.4 [M+H] + RT = 0.83 min.

[0290] Step 2: Synthesis of 8-bromo-6-chloro-9-fluoro-2-(methyl-d3)-3,4,5,10-tetrahydrooxacapheptan[3,4-b]indole-1(2H)-one (145b):

[0291] Under water bath conditions, a solution of 1-(methyl-d3)piperidin-2-one (117 mg, 1 mmol) and anhydrous DMF (153 mg, 2.1 mmol) in anhydrous toluene (2 mL) was slowly added dropwise to a solution of POCl3 (765 mg, 5 mmol) in anhydrous toluene (2 mL). The system turned into a yellow two-phase mixture. After the addition was complete, the system was heated to 110 °C and refluxed for 5.5 h in the absence of water vapor. After cooling, the solvent in the reaction system was removed under reduced pressure. Water (5 mL) was added to the residue and stirring was continued for 1.5 h. An ethanol solution (5 mL) of (3-bromo-5-chloro-2-fluorophenyl)hydrazine 7a (239 mg, 1 mmol) was added to the system, and the system was refluxed for 2 h after the addition was complete. After cooling, the organic solvent in the reaction system was removed under reduced pressure. A saturated sodium bicarbonate aqueous solution was added to adjust the pH of the system to 8. The system was then extracted with dichloromethane (20 mL * 2), the organic phases were combined, and dried over anhydrous sodium sulfate. The organic solvent was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (Xtimate Prep C18 10μm 21.2×250mm, phase B: water (0.2% formic acid), phase A: acetonitrile) to give a white solid target intermediate 145b (15mg, yield: 4.3%).

[0292] MS(ESI): m / z 347.9 [M+H] + RT = 1.99 min.

[0293] Step 3: Synthesis of 8-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-6-chloro-9-fluoro-2-(methyl-d3)-3,4,5,10-tetrahydrooxaprotinin[3,4-b]indole-1(2H)-one (145c):

[0294] In a nitrogen atmosphere, intermediates 145b (15 mg, 0.043 mmol) of 8-bromo-6-chloro-9-fluoro-2-(methyl-d3)-3,4,5,10-tetrahydrooxacapramene[3,4-b]indol-1(2H)-one and intermediate A-1 (36 mg, 0.108 mmol, WO2025049820) were prepared. Preparation of intermediate A1 AJ): A mixture of Pd(dppf)Cl2 (8 mg, 0.001 mmol) and potassium carbonate (20 mg, 0.14 mmol) in dioxane / water (6 mL, 5:1) was heated to 90 °C and stirred for 2 h. After cooling, the organic solvent in the reaction system was removed under reduced pressure. The residue was purified by normal phase column chromatography (mobile phase MeOH:DCM = 0–10%) to obtain the target intermediate 145c (10 mg, yield 38%). MS (ESI): m / z 474.0 [M+H] + RT = 1.33 min.

[0295] Step 4: Synthesis of 3-(4-(4-(8-(1-(3-(1H-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-9-fluoro-2-(methyl-d3)-1-oxo-1,2,3,4,5,10-hexahydroacrophenin[3,4-b]indol-6-yl)phenyl)piperidin-1-yl)-3-fluorophenyl)piperidin-2,6-dione (145):

[0296] In a nitrogen atmosphere, 8-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-6-chloro-9-fluoro-2-(methyl-d3)-3,4,5,10-tetrahydrooxaconitine[3,4-b]indole-1(2H)-one intermediate 145c (20 mg, 0.043 mmol), 3-(3-fluoro-4-(4-(4-(4,4)-) A mixture of intermediate B (42 mg, 0.085 mmol), XPhos-Pd-G3 (8 mg, 0.01 mmol), and cesium fluoride (13 mg, 0.085 mmol) in dioxane (4 mL) and water (1 mL) was heated to 80 °C and stirred for 2 h. After cooling, the organic solvent in the reaction system was removed under reduced pressure. The residue was initially purified by normal-phase silica gel column chromatography (mobile phase: 0-30% MeOH / DCM), and then purified by reversed-phase preparative HPLC (acetonitrile / water containing 0.2% formic acid = 0-95%) to give a white solid final product 145 (12 mg, yield = 53%).

[0297] MS (ESI): m / z 804.5[M+H]+, RT=1.75min.

[0298] 1H NMR (400MHz, DMSO) δ11.75(d,J=9.7Hz,1H),10.84(s,1H),8.11(d,J=10.1Hz,1H),7.68(d,J= 10.8Hz,1H),7.35(q,J=8.4Hz,4H),7.14-6.88(m,3H),6.75(dd,J=31.4,6.4Hz,1H),6.15(d, J=10.1Hz,1H),4.71-4.49(m,2H),4.33-4.30(m,2H),3.82-3.79(m,1H),3.63-3.56(m,2H),3 .47-3.40(m,4H),3.15-2.99(m,5H),2.89-2.59(m,4H),2.39-2.10(m,6H),2.02-1.79(m,7H).

[0299] Example 146: Synthesis of 3-(4-((4-(8-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-9-fluoro-2-methyl-1-oxo-1,2,3,4,5,10-hexahydroacromene[3,4-b]indol-6-yl)phenyl)ethynyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (146):

[0300] Step 1: Synthesis of 3-(4-((4-chlorophenyl)ethynyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (146b):

[0301] To a DMSO (6 mL) solution of 1-chloro-4-ethynylbenzene 146a (300 mg, 2.2 mmol) and 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (745 mg, 2.2 mmol), Pd(PPh3)2Cl2 (154 mg, 2.2 mmol), CuI (43 mg, 2.2 mmol), and triethylamine (666.6 mg, 6.6 mmol) were added. After the addition was complete, the reaction system was heated to 100 °C under a nitrogen atmosphere and stirred for 3 hours. After cooling, the mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by reversed-phase preparative HPLC (acetonitrile: water with 0.1% formic acid = 0-60%) to obtain a white solid intermediate 146b (90 mg, yield = 10%). MS(ESI) m / z 394.0 [M+H] + .

[0302] Step 2: Synthesis of 3-(3-methyl-2-oxo-4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)ethynyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (146c):

[0303] In a nitrogen atmosphere, 3-(4-((4-chlorophenyl)ethynyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione intermediate 146b (90 mg, 0.229 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxoboronalcyclopentane) (116 mg, 0.458 mmol), Pd-Xphos were added. A mixture of G3 (38.7 mg, 0.0458 mmol) and methyl acetate (67.3 mg, 0.687 mmol) in dioxane (2 mL) was heated to 100 °C and stirred for 2 h. After cooling, the solvent in the reaction system was removed under reduced pressure, and the residue was purified by normal-phase silica gel column chromatography (EA:PE = 0-100%) to give a gray solid target intermediate 146c (100 mg, yield = 90%).

[0304] MS(ESI) m / z 486.5 [M+H] + .

[0305] Step 3: Synthesis of 3-(4-((4-(8-(1-(3-(1H-pyrazol-1-yl)propionamide)-1,2,5,6-tetrahydropyridin-3-yl)-9-fluoro-2-methyl-1-oxo-1,2,3,4,5,10-hexahydroacrophenin[3,4-b]indol-6-yl)phenyl)ethynyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (146):

[0306] In a nitrogen atmosphere, 146c (18 mg, 0.038 mmol) of 8-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-6-chloro-9-fluoro-2-methyl-3,4,5,10-tetrahydrooxacontin[3,4-b]indol-1(2H)-one, 3-(3-methyl-2-oxo-4-((4-(4,4,5,5-tetramethyl-1,3,2-oxo-4-yl)-((4,4,5,5-tetramethyl-1,3,2 ... -dioxoboronyl(2-yl)phenyl(ethynyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (18.4 mg, 0.038 mmol), XPhos-Pd-G3 (6.4 mg, 0.0076 mmol), and cesium fluoride (12 mg, 0.076 mmol) were heated to 90 °C and stirred for 2 h in a mixture of dioxane / water (3 mL, 2:1). After cooling, the organic solvent in the reaction system was removed under reduced pressure. The mixture was first purified by normal-phase silica gel column chromatography (methanol:dichloromethane = 0-30%), and then purified by reverse-phase preparative HPLC with acetonitrile:water (containing 0.06% NH4HCO3) = 0-95% as the mobile phase to obtain the target final product 146 (12 mg, yield = 39.9%) as a yellow solid.

[0307] MS(ESI) m / z 793.0 [M+H] + . 1H NMR(400MHz,d6-DMSO)δ11.84(s,1H),11.15(s,1H),7.70(s,1H),7.66(d,J=8.2Hz,2H),7.57-7.52(m,1H), 7.49(d,J=7.8Hz,2H),7.42-7.36(m,1H),7.26(d,J=7.7Hz,1H),7.22(d,J=7.6Hz,1H),7.11-7.08(m,1H),6. 78-6.63(m,1H),6.20-6.13(m,2H),5.46-5.38(m,1H),4.38-4.26(m,4H),3.78(s,3H),3.63(s,1H),3.57(s, 2H),3.43(s,2H),3.08(s,3H),3.08-2.95(m,2H),2.67(s,3H),2.38-2.32(m,4H),2.06(s,1H),1.88(s,2H).

[0308] Example 147: Synthesis of 3-((4-(4-(8-(1-(3-(1H-bpyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-9-fluoro-2-methyl-1-oxo-1,2,3,4,5,10-hexahydroacromene[3,4-b]indol-6-yl)phenyl)piperidin-1-yl)-3-fluorophenyl)amino)piperidin-2,6-dione (147):

[0309] In a nitrogen atmosphere, 8-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-6-chloro-9-fluoro-2-methyl-3,4,5,10-tetrahydrooxaheptaquinone[3,4-b]indol-1(2H)-one 7c (9 mg, 0.02 mmol), 3-((3-fluoro-4-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)piperidin-1-yl)phenyl)amino)piperidin-2,6-dione D-1 (16 mg, 0.03 mmol, reference WO2025049820) was prepared. Preparation of intermediate A1 GE), XPhos-Pd-G3 (4 mg, 0.005 mmol), and cesium fluoride (6 mg, 0.04 mmol) were heated to 80 °C and stirred for 2 h in a mixture of dioxane (4 mL) and water. After cooling, the organic solvent in the reaction system was removed under reduced pressure. The mixture was first preliminarily purified by normal-phase silica gel column chromatography (methanol / dichloromethane = 0-30%), and then purified by reverse-phase preparative HPLC (acetonitrile / water containing 0.2% formic acid = 0-95%) to obtain a white solid final product 147 (13 mg, yield = 37%).

[0310] MS (ESI): m / z 815.1[M+H]+, RT=1.57min.

[0311] 1H NMR (400MHz, DMSO) δ11.93-11.52(m,1H),10.78(s,1H),7.78-7.66(m,1H),7.47-7.23(m,5H) ,6.90(t,J=9.4Hz,1H),6.74(dd,J=26.6,6.4Hz,1H),6.60-6.38(m,2H),6.27-6.09(m,2H),5 .82(d,J=7.6Hz,1H),4.50-4.10(m,5H),3.79-3.37(m,4H),3.29-3.20(m,2H),3.07(s,3H),2 .98-2.95(m,2H),2.83-2.61(m,5H),2.36-2.31(m,4H),2.16-2.06(m,1H),1.97-1.69(m,7H).

[0312] Example 162: Synthesis of 3-(4-((4-(8-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-9-fluoro-2-methyl-1-oxo-1,2,3,4,5,10-hexahydroacrophenin[3,4-b]indol-6-yl)phenyl)ethynyl)-3-fluorophenyl)piperidine-2,6-dione (162):

[0313] Step 1, Synthesis of 3-(4-bromo-3-fluorophenyl)piperidine-2,6-dione (162-b):

[0314] Under ice bath conditions, t-BuOK (2.00 g, 17.8 mmol) was added to a THF (40 mL) solution of methyl 2-(4-bromo-3-fluorophenyl)acetate 162-a (4 g, 16.1 mmol, CAS 942282-41-9) and acrylamide (1.15 g, 16.2 mmol, 1.12 mL, CAS 79-06-1). After the addition was complete, the reaction system was heated to 50 °C under a nitrogen atmosphere and stirred for 2 hours. After cooling, the reaction solvent was removed under reduced pressure, and the crude product was purified by normal phase column chromatography (PE:EA = 10 / 1 to 1 / 1) to give a white solid intermediate 162-b (2.2 g, yield: 48%).

[0315] MS(ESI): m / z 286.1 [M+H] + RT = 1.58 min.

[0316] Step 2: Synthesis of 3-(4-((4-chlorophenyl)ethynyl)-3-fluorophenyl)piperidine-2,6-dione (162-c):

[0317] To a DMSO (3 mL) solution of 1-chloro-4-ethynylbenzene (68 mg, 0.5 mmol) and 3-(4-bromo-3-fluorophenyl)piperidin-2,6-dione (143 mg, 0.5 mmol), Pd(PPh3)2Cl2 (35.1 mg, 0.05 mmol), CuI (9.5 mg, 0.05 mmol), and triethylamine (152 mg, 1.5 mmol) were added. The reaction mixture was heated to 100 °C and stirred for 16 hours under a nitrogen atmosphere. After cooling, the mixture was filtered, and the solvent in the filtrate was removed under reduced pressure. The residue was purified by reverse-phase preparative HPLC (acetonitrile / water containing 0.1% formic acid = 0-60%) to give a white solid 162-c (20 mg, yield: 11.7%).

[0318] MS(ESI): m / z 340.0 [MH] + RT = 2.13 min.

[0319] Step 3: Preparation of 3-(3-fluoro-4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)ethynyl)phenyl)piperidine-2,6-dione (162-c).

[0320] Under a nitrogen atmosphere, a mixture of 3-(4-((4-chlorophenyl)ethynyl)-3-fluorophenyl)piperidin-2,6-dione 162-c (340 mg, 1.0 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxoboronylcyclopentane) (380 mg, 1.5 mmol), XPhos-Pd-G3 (170 mg, 0.2 mmol), KOAc (294 mg, 3.0 mmol), and dioxane (15 mL) was heated to 100 °C and stirred for 2 hours. After cooling, the reaction solvent was removed under reduced pressure, and the residue was purified by normal-phase silica gel column chromatography (EA / PE = 0-100%) to give a gray solid 162-c (100 mg, yield: 23%).

[0321] MS(ESI): m / z 434.2 [M+H] + RT = 2.02 min.

[0322] Step 4: Synthesis of 3-(4-((4-(8-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-9-fluoro-2-methyl-1-oxo-1,2,3,4,5,10-hexahydroacrophenin[3,4-b]indol-6-yl)phenyl)ethynyl)-3-fluorophenyl)piperidine-2,6-dione (162):

[0323] In a nitrogen atmosphere, 8-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-6-chloro-9-fluoro-2-methyl-3,4,5,10-tetrahydrooxaconitine[3,4-b]indol-1(2H)-one 7c (18 mg, 0.04 mmol), 3-(3-fluoro-4-((4-(4,4,5,5-tetramethyl) The mixture of 1,3,2-dioxoborhexacyclopentan-2-yl)phenyl)ethynyl)phenyl)piperidin-2,6-dione 162-c (70 mg, 0.16 mmol), XPhos-Pd-G3 (9 mg, 0.01 mmol), and CsF (18 mg, 0.12 mmol) in a dioxane (4 mL) / water (1 mL) solution was degassed, heated to 80 °C, and stirred for 2 hours. After cooling, the solvent in the reaction system was removed under reduced pressure. The residue was initially purified by normal-phase silica gel column chromatography (methanol / dichloromethane = 0-30%), and then purified by reversed-phase preparative HPLC (acetonitrile / water containing 0.1% formic acid = 0-95%) to give a white solid compound 162 (7.2 mg, yield: 24%).

[0324] MS(ESI): m / z 740.9 [M+H] + RT = 1.81 min.

[0325] 1H NMR(400MHz,DMSO)δ11.84(d,J=10.4Hz,1H),10.93(s,1H),8.47(s,1H),7.75–7.58( m,4H),7.53–7.35(m,3H),7.34–7.10(m,2H),6.86–6.70(m,1H),6.34–5.94(m,1H),4 .48–4.24(m,3H),4.11–3.93(m,1H),3.68–3.55(m,2H),3.46–3.42(m,2H),3.13–2.9 1(m,4H),2.76–2.65(m,2H),2.59–2.56(m,2H),2.42–2.16(m,5H),2.11–1.81(m,3H).

[0326] Example 173: Synthesis of 3-((4-(4-(8-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-4-methyl-5-oxo-2,3,4,5-tetrahydro-1H-benzofurano[3,2-e][1,4]diazaphen-10-yl)-2,3-difluorophenyl)piperazin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione (173):

[0327] Step 1, Preparation of 4-bromo-6-chloro-3-fluoro-2-hydroxybenzaldehyde (173b):

[0328] A mixture of 3-bromo-5-chloro-2-fluorophenol (2.24 g, 10 mmol), sodium hydroxide solid (4 g, 100 mmol), water (10 mL), and chloroform (10 mL) was heated to 100 °C and stirred for 12 h. After cooling, the reaction mixture was poured into ice water (40 mL), and the pH was adjusted to 6-7 with 3N hydrochloric acid aqueous solution. The mixture was then extracted with dichloromethane (3 x 50 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the organic solvent, and the residue was purified by normal-phase silica gel column chromatography (SGC) (EA:PE = 0-50%) to give the target compound 173b (200 mg, 8% yield) as a yellow solid.

[0329] MS(ESI): m / z 250.2 [MH] - RT = 1.31 min.

[0330] 1 H NMR (400MHz, DMSO) δ11.86 (s, 1H), 10.26 (s, 1H), 7.49 (s, J = 5.6Hz, 1H).

[0331] Step 2, Preparation of tert-butyl-(2-((4-bromo-6-chloro-3-fluoro-2-hydroxybenzyl)amino)ethyl)(methyl)carbonate (173c):

[0332] A methanol (6 mL) solution of 4-bromo-6-chloro-3-fluoro-2-hydroxybenzaldehyde (100 mg, 0.4 mmol) and tert-butyl(2-aminoethyl)(methyl)carbonate intermediate 173b (70 mg, 0.4 mmol) was heated to 70 °C and stirred for 2 h. The solution was cooled, concentrated under reduced pressure to remove the solvent, and dried under vacuum to give a yellow oily target compound 173c (160 mg, crude product), which was used directly in the next reaction.

[0333] Step 3, Preparation of methyl 6-bromo-3-((2-((tert-butoxycarbonyl)(methyl)amino)ethyl)amino)-4-chloro-7-fluorobenzofuran-2-carboxylic acid ester (173d):

[0334] Methyl 2,2-dichloroacetate (71 mg, 0.5 mmol) was added to a dry DMF mixture of tert-butyl-(2-((4-bromo-6-chloro-3-fluoro-2-hydroxybenzylmethyl)amino)ethyl)(methyl)carbonate intermediate 173c (160 mg, 0.4 mmol) and potassium carbonate solid (166 mg, 1.2 mmol). After the addition was complete, the reaction mixture was stirred at room temperature for 16 h. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (2 x 15 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure to remove the solvent, and the residue was purified by normal-phase silica gel column chromatography (EA:PE = 0-50%) to give a yellow oily target compound 173d (110 mg, yield 58%).

[0335] MS(ESI): m / z 479.0 [M+H] + RT = 2.11 min.

[0336] Step four, preparation of methyl 6-bromo-4-chloro-7-fluoro-3-((2-(methylamino)ethyl)amino)benzofuran-2-carboxylic acid ester (173e):

[0337] A solution of ethyl acetate (4 M, 2.3 mL, 9.6 mmol) of hydrogen chloride was added to a dry dichloromethane (1 mL) solution of methyl 6-bromo-3-((2-((tert-butyloxycarbonyl)(methyl)amino)ethyl)amino)-4-chloro-7-fluorobenzofuran-2-carboxylic acid intermediate 173d (110 mg, 0.23 mmol). After the addition was complete, the reaction mixture was stirred at room temperature for 2 h. The solvent was removed by concentration under reduced pressure and dried under vacuum to obtain a yellow solid, target compound 173e (87 mg, crude product), which was used directly in the next step of the reaction.

[0338] MS(ESI): m / z 379.0 [M+H] + RT = 1.35 min

[0339] Step 5, Preparation of 8-bromo-10-chloro-7-fluoro-4-methyl-1,2,3,4-tetrahydro-5H-benzofurano[3,2-e][1,4]diazapheno-5-one (173f):

[0340] Potassium carbonate solid (95 mg, 0.69 mmol) was added to a methanol (6 mL) solution of methyl 6-bromo-4-chloro-7-fluoro-3-((2-(methylamino)ethyl)amino)benzofuran-2-carboxylic acid ester hydrochloride intermediate 173e (87 mg, 0.23 mmol). After the addition was complete, the reaction system was heated to 70 °C and stirred for 16 h. After cooling, water (10 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (2 x 15 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure to remove the solvent, and the residue was purified by normal-phase silica gel column chromatography (SGC) (EA:PE = 0-80%) to give a yellow solid target compound 173f (52 mg, yield 65%).

[0341] MS(ESI): m / z 347.0[M+H]+, RT=1.71min.

[0342] Step 6, Preparation of 8-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-10-chloro-7-fluoro-4-methyl-1,2,3,4-tetrahydro-5H-benzofurano[3,2-e][1,4]diazaphen-5-one (173 g):

[0343] In a nitrogen atmosphere, a mixture of 8-bromo-10-chloro-7-fluoro-4-methyl-1,2,3,4-tetrahydro-5H-benzofurano[3,2-e][1,4]diazaphen-5-one intermediate 173f (35 mg, 0.1 mmol), 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-3,6-dihydropyridin-1(2H)-yl)-3-(1H-1,2,3-triazol-1-yl)propane-1-one intermediate A-1 (50 mg, 0.15 mmol), Pd(dppf)Cl2 (15 mg, 0.02 mmol), and potassium carbonate solid (28 mg, 0.2 mmol) in dioxane / water (5 mL, 4:1) was heated to 90 °C and stirred for 2 h. The solvent was removed by cooling and concentration under reduced pressure. The residue was purified by reversed-phase preparative HPLC (using acetonitrile: water containing 0.06% NH4HCO3 = 0-95%) as the mobile phase to give 173 g (24 mg, 50% yield) of the target compound as a white solid. MS (ESI): m / z 473.3 [M+H] + RT = 1.09 min.

[0344] Step 7, Preparation of 3-((4-(4-(8-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-4-methyl-5-oxo-2,3,4,5-tetrahydro-1H-benzofurano[3,2-e][1,4]diazaphen-10-yl)-2,3-difluorophenyl)piperazin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione (173):

[0345] 173 g (12 mg, 0.025 mmol) of 8-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-10-chloro-7-fluoro-4-methyl-1,2,3,4-tetrahydro-5H-benzofurano[3,2-e][1,4]diazaphen-5-one intermediate, 3-((4-(4-(2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3-) The intermediate D (44 mg, 0.075 mmol), XPhos-Pd-G3 (6 mg, 0.007 mmol), and cesium fluoride solid (8 mg, 0.05 mmol) were degassed in a mixture of dioxane (4 mL) and water (1 mL), and then heated to 90 °C and stirred for 2 h under a nitrogen atmosphere. After cooling, most of the solvent was removed by concentration under reduced pressure. The residue was directly purified by reversed-phase preparative HPLC (formic acid conditions, acetonitrile:water = 0-95%) to give the target compound 173 (4 mg, 18% yield) as a white solid.

[0346] MS(ESI): m / z 886.4 [M+H] + RT = 1.66 min.

[0347] 1H NMR (400MHz, DMSO) δ10.88(s,1H),8.44(s,1H),8.13(s,1H),7.70(s,1H),7.15(t,J=8.3Hz,1H),7.08–6.89(m ,2H),6.70(d,J=8.2Hz,1H),6.59(d,J=14.3Hz,1H),6.15(d,J=10.8Hz,1H),5.15(d,J=7.0Hz,1H),5.01(s,1H) ,4.62(t,J=6.8Hz,2H),4.39–4.25(m,1H),4.16-4.13(m,2H),3.82(s,3H),3.68-3.61(m,2H),3.47(s,2H),3.4 2–3.32(m,6H),3.17–3.02(m,8H),2.85–2.75(m,1H),2.63–2.56(m,2H),2.20–2.08(m,1H),2.02–1.90(m,1H).

[0348] Example 180: Synthesis of 3-(4-(4-(4-(8-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-4-methyl-5-oxo-2,3,4,5-tetrahydro-1H-benzofurano[3,2-e][1,4]diazaphen-10-yl)phenyl)piperidin-1-yl)-3-fluorophenyl)piperidin-2,6-dione (180):

[0349] 173 g (12 mg, 0.025 mmol) of 8-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-10-chloro-7-fluoro-4-methyl-1,2,3,4-tetrahydro-5H-benzofurano[3,2-e][1,4]diazepine-5-one intermediate, 3-(3-fluoro-4-(4-(4,4,5,5-tetramethyl- A mixture of 1,3,2-dioxoboronyl-2-yl)phenyl)piperidin-1-yl)phenyl)piperidin-2,6-dione intermediate B (38 mg, 0.075 mmol), XPhos-Pd-G3 (6 mg, 0.007 mmol), and cesium fluoride solid (8 mg, 0.05 mmol) in dioxane (4 mL) and water (1 mL) was first degassed, then heated to 90 °C under a nitrogen atmosphere and stirred for 2 h. After cooling, most of the solvent in the reaction system was removed by concentration under reduced pressure. The residue was purified by reverse-phase preparative Prep-HPLC (formic acid conditions, acetonitrile:water = 0-95%) to give the target compound 180 (4 mg, 18% yield) as a white solid.

[0350] MS(ESI): m / z 825.3 [M+Na] + RT = 1.51 min.

[0351] 1H NMR (400MHz, DMSO) δ10.96–10.73(m,1H),8.42(s,1H),8.13(s,1H),7.70(s,1H),7.45- 7.42(m,4H),7.15–6.89(m,4H),6.16(d,J=11.7Hz,1H),4.63(t,J=6.7Hz,3H),4.17-4.1 4(m,2H),3.87–3.77(m,1H),3.72–3.60(m,2H),3.58–3.46(m,5H),3.16–3.04(m,2H),3 .00(s,3H),2.91–2.75(m,3H),2.69–2.57(m,3H),2.25–2.16(m,1H),2.07–1.82(m,6H).

[0352] The synthesis of the specific compounds and intermediates listed in Table 1 below can be carried out with reference to existing technologies and the synthesis steps in patent WO2025049820.

[0353] Table 1

[0354] Test Example 1: STAT6 Degradation Test

[0355] A549 cells were seeded in 96-well plates containing 100 μL of culture medium at a density of 1.5 × 10⁶ cells / well. 4 Up to 5×10 5Cells / well. The compound was then added at a 1:3 dilution to the assay plate, resulting in nine concentrations up to 10 μM at 3-fold dilutions. The assay plates were incubated at 37°C for 4 to 24 hours with 5% CO2. The assay plates were centrifuged for 5 minutes, and the cell pellet was treated with 100 μl / well of RIPA lysis buffer (Boston Bioproducts, BP-115D) and protease and phosphatase inhibitors. The MSD assay plate (MSD, L15×A) was coated with capture antibody (Abnova, H00006777) in PBS at a concentration of 40 μl / well. The plate was then incubated overnight at 4°C, washed once with 150 μl / well of TBST buffer (Cell Signaling Technology, #9997S), and blocked with 150 μl / well of blocking buffer (MSD, R93BA-4). Cell lysates were added to the MSD assay plate and incubated at room temperature for 1 hour. The plates were then washed three times with 150 μl / well TBST buffer (Cell Signaling Technology, #5397S), and 25 μl / well primary antibody was added. The plates were then incubated at room temperature for 1 hour, washed three times with 150 μl / well TBST buffer, and 25 μl / well secondary antibody SULFO-TAG anti-rabbit antibody (MSD, R32AB-1) was added. The plates were then incubated at room temperature for 1 hour, washed three times with 150 μl / well TBST buffer, and 150 μl / well MSD reading buffer (MSD, R92TC-2) was added. The plates were then read using an MSD plate reader. Data were analyzed using GraphPad Prism, and a four-parameter inhibition vs. response nonlinear regression was used to fit dose-dependent STAT6 degradation activity. The compound degradation effects are shown in Table 2.

[0356] Table 2: STAT6 degradation effect

[0357] Test Example 2: STAT6 Degradation Assay: STAT6 protein levels in A549 cell line were detected using the MSD method.

[0358] 1) A549 cells (purchased from ATCC, CRM-CCL-185) were cultured in complete medium (F-12K + 10% fetal bovine serum + 1X penicillin-streptomycin solution, purchased from ATCC, Corning, and Solarbio, respectively) at 37°C and 5% CO2. On the day of the experiment, after digesting the cells with trypsin, the cells were counted, diluted to the specified concentration (2*10^4 cells / 80μL / well), and seeded into Corning 96-well plates, and incubated overnight at 37°C.

[0359] 2) The test compound was dissolved in DMSO to prepare a 10 mM stock solution. The stock solution was diluted to 1 mM with DMSO, and 30 μL was added to a 384-well plate. The solution was then diluted 3-fold by adding 10 μL of the solution to 20 μL of DMSO, resulting in a total of 11 concentration points.

[0360] 3) Take another 96-well plate, add 200 nl of serially diluted compound solution, and then add 100 μL of culture medium.

[0361] 4) Add 80 μL of the compound solution to each well into A549 cells, gently shake the cell culture plate to mix, and incubate at 37°C for 24 hours.

[0362] 5) Discard the culture medium, add 70 μL of cell lysis buffer to each well (composed of 50 mL of RIPA buffer, purchased from Boston BioProducts, 5 PhosSTOP phosphatase inhibitor mixed tablets and 1 protease inhibitor mixed tablet, purchased from Roche), seal the plate, and shake at 600 rpm at 4°C for 30 minutes.

[0363] 6) Coat MSD plates with STAT6 capture antibody (purchased from Abnova), diluted 1:500 with PBS, 40 μL / well. Incubate overnight at 4°C with shaking at 600 rpm.

[0364] 7) Wash the plate three times with 150 μL of 1X TBST. Then add 150 μL of blocking buffer (TBST containing 3% BSA) and shake at 600 rpm for 1 hour at room temperature. Then wash the plate once with 150 μL of 1X TBST.

[0365] 8) Add 50 μL of cell lysis buffer to an MSD plate and shake at 600 rpm for 1 hour.

[0366] 9) Wash the plate three times with 150 μL of 1X TBST, add 25 μL of rabbit anti-SATAT6 primary antibody diluted 1:500 (purchased from CST), and shake at 600 rpm for 1 hour at room temperature.

[0367] 10) Wash the plate three times with 150 μL of 1X TBST, add 25 μL of 1 μg / ml SULFO-TAG goat anti-rabbit secondary antibody, and shake at 600 rpm for 1 hour at room temperature.

[0368] 11) Wash the plate three times with 150 μL of 1X TBST, add 150 μL of 2X MSD reading buffer, and read the value on a MESO SECTOR S 600.

[0369] 12) The MSD signal was plotted using XLfit, and DC was calculated using a 4-parameter logic model. 50And Dmax value. The degradation effect of the compound is shown in Table 3.

[0370] Table 3: STAT6 degradation effect

[0371] Test Example 3: STAT6 Degradation Assay: STAT6 protein levels in the A549 cell line were detected using the MSD method.

[0372] 1) A549 cells (purchased from ATCC, CRM-CCL-185) were cultured in complete medium (F-12K + 10% fetal bovine serum + 1X penicillin-streptomycin solution, purchased from ATCC, Corning, and Solarbio, respectively) at 37°C and 5% CO2. On the day of the experiment, after digesting the cells with trypsin, the cells were counted, diluted to the specified concentration (2*10^4 cells / 80μL / well), and seeded into Corning 96-well plates, and incubated overnight at 37°C.

[0373] 2) The test compound was dissolved in DMSO to prepare a 10 mM stock solution. The stock solution was diluted to 0.03 mM with DMSO, and 30 μL was added to a 384-well plate. The solution was then diluted 3-fold by adding 10 μL of the solution to 20 μL of DMSO, resulting in a total of 10 concentration points.

[0374] 3) Take another 96-well plate, add 200 nl of serially diluted compound solution, and then add 100 μL of culture medium.

[0375] 4) Add 80 μL of the compound solution to each well into A549 cells, gently shake the cell culture plate to mix, and incubate at 37°C for 24 hours.

[0376] 5) Discard the culture medium, add 70 μL of cell lysis buffer to each well (composed of 50 mL of RIPA buffer, purchased from Boston BioProducts, 5 PhosSTOP phosphatase inhibitor mixed tablets and 1 protease inhibitor mixed tablet, purchased from Roche), seal the plate, and shake at 600 rpm at 4°C for 30 minutes.

[0377] 6) Coat MSD plates with STAT6 capture antibody (purchased from Abnova), diluted 1:500 with PBS, 40 μL / well. Incubate overnight at 4°C with shaking at 600 rpm.

[0378] 7) Wash the plate three times with 150 μL of 1X TBST. Then add 150 μL of blocking buffer (TBST containing 3% BSA) and shake at 600 rpm for 1 hour at room temperature. Then wash the plate once with 150 μL of 1X TBST.

[0379] 8) Add 50 μL of cell lysis buffer to an MSD plate and shake at 600 rpm for 1 hour.

[0380] 9) Wash the plate three times with 150 μL of 1X TBST, add 25 μL of rabbit anti-SATAT6 primary antibody diluted 1:500 (purchased from CST), and shake at 600 rpm for 1 hour at room temperature.

[0381] 10) Wash the plate three times with 150 μL of 1X TBST, add 25 μL of 1 μg / ml SULFO-TAG goat anti-rabbit secondary antibody, and shake at 600 rpm for 1 hour at room temperature.

[0382] 11) Wash the plate three times with 150 μL of 1X TBST, add 150 μL of 2X MSD reading buffer, and read the value on a MESO SECTOR S 600.

[0383] 12) The MSD signal was plotted using XLfit, and DC was calculated using a 4-parameter logic model. 50 And Dmax value. The degradation effect of the compound is shown in Table 4.

[0384] Table 4: STAT6 degradation effect

[0385] Test Example 4: STAT6 Degradation Assay: Detection of STAT6 protein levels in human PBMCs using the MSD method.

[0386] 4.1 Preparation of working solution:

[0387] 1) Preparation of lysis buffer: 50ml RIPA buffer (Boston BioProducts BP-115D), 5 PhosSTOP phosphatase inhibitor mixed tablets (Roche, 4906837001), 1 EDTA-free complete protease inhibitor tablet (Roche, 4693116001).

[0388] 2) Preparation of 1X washing buffer: 100 mL of Tris buffered saline solution (TBST-10X) containing Tween 20 (CST, 9997S), 900 mL of Milli-Q grade water;

[0389] 3) Preparation of 3% blocking solution: 3 g bovine serum albumin reagent grade powder, 100 mL 1X washing buffer;

[0390] 4) Preparation of capture antibody solution: 18 mL PBS buffer (Solarbio, P1020-500), 36 μL STAT6 antibody (Abnova H00006778);

[0391] 5) Preparation of antibody solution: 10.8 mL of 1% blocking solution, 21.6 μL of STAT6 antibody (CST 5397s);

[0392] 6) Preparation of secondary antibody solution: 21.6 μL of anti-rabbit antibody (goat), sulfonated label (MSD, R32AB-1), 10.8 mL of 1% blocking solution;

[0393] 7) Preparation of 2X read buffer: 100 mL of read buffer T(4X) (MSD, R92TC-1), 100mL of grade A water.

[0394] 4.2 Preparation of lysis buffer samples:

[0395] 1) Dissolve the test compound in DMSO to prepare a 10 mM stock solution. Dilute the compound to a concentration of 0.01 mM with DMSO, and add 40 μL / well to a 384-well plate (purchased from LABCYTE). Perform a 4-fold serial dilution by adding 10 μL of the compound to 30 μL of DMSO, resulting in 10 concentration points. Add DMSO only to one well.

[0396] 2) On the day of the experiment, use an Echo 655 to dispense 100 nl of serially diluted DMSO solution into each well of a 96-well plate (Corning 3894).

[0397] 3) Gently thaw human peripheral blood mononuclear cells (from TPCS) in a 37°C water bath. The thawing process should be rapid (approximately 2 minutes). Once the contents of the sample vial have thawed, immediately remove it from the water bath and sterilize it by immersion or spraying with 70% ethanol. All subsequent operations should be performed under strict aseptic conditions.

[0398] 4) Transfer the cells to preheated complete growth medium, let the cells stand at 37°C and 5% CO2 for 2 hours, and then centrifuge at 225Xg for 10 minutes.

[0399] 5) Discard the supernatant, resuspend the cell pellet in an appropriate amount of preheated complete culture medium, and then take one sample for use. An automatic cell counter performs the counting.

[0400] 6) Dilute the cells to the designed concentration (0.5*10^6 cells / 100ul / well) according to the cell density, and seed the cells into Corning 3894 cell culture plates. Shake the cell culture plates at 720 rpm for 5 minutes. Incubate at 37°C for 24 hours.

[0401] 7) Stir at 4000 rpm for 10 minutes, then discard the culture medium at 4°C. Add 60 μL of lysis buffer to each well. Seal the plate and shake at 600 rpm four times. Incubate at 4°C for approximately 30 minutes.

[0402] 4.3 MSD detection and plate reading:

[0403] 1) After coating the MSD plate with 40 μL / well of mouse anti-STAT6 capture antibody (Abnova H00006778) diluted 1:500, shake overnight at 600 rpm and 4°C.

[0404] 2) Clean the bare MSD-coated board three times with 1x TBST (CST#9997S) at 150ul / well.

[0405] 3) Block the MSD plate with 150 μl of blocking buffer per well. Shake at 600 rpm for 1 hour at room temperature. The blocking buffer is a TBST solution of 3% bovine serum albumin.

[0406] 4) Wash the MSD plate once with 150 μL / well of 1x TBST. Add 40 μL of sample lysis buffer to each well of the Apricot MSD plate. Shake at 600 rpm for 1 hour at room temperature.

[0407] 5) Wash the MSD plate three times with 150 μl / well of 1×TBST. Add 25 μl / well of primary antibody (rabbit CST 5397, lot number 5, dilution ratio 1:500). Shake at 600 rpm for 1 hour at room temperature.

[0408] 6) Wash the MSD plate three times with 150 μl / well of 1×TBST. Add the secondary antibody detection antibody, SULFO-TAG anti-rabbit antibody (R32AB-1, batch number W0021059S). Final concentration: 1 μg / ml. 25 μl / well. Incubate at room temperature, shaking at 600 rpm for 1 hour.

[0409] 7) Wash the MSD plate three times with 150 μL / well of 1x TBST. Add 2X MSD read buffer (diluted with water to 4X solution), 150 μL / well. Read the values ​​on a MESO SECTOR S 600.

[0410] 4.4 Data Processing and Analysis:

[0411] The MSD signal was plotted using XLfit, and the IC was calculated by fitting a curve using Equation 201 using the XLfit (v5.3.1.3) function. 50 And the maximum percentage of degradation. Table 5 shows the effect of the compound on the degradation of STAT6 in PBMCs.

[0412] Table 5. Effects of compounds on the degradation of STAT6 in PBMCs:

[0413] Test Example 5: IL-4-induced TARC ELISA assay in PBMC:

[0414] Human CCL17 / TARC ELISA kit (purchased from Bioss, bsk11053)

[0415] 5.1 Preparation of test compound solution: Prepare a 100 μM (or other concentration of interest) solution of the test compound with DMSO, and then perform 4-fold serial dilutions on a 384 plate using TECAN EVO200, for a total of 9 concentration points.

[0416] 5.2 ELISA Experiment:

[0417] 1) After thawing, peripheral blood mononuclear cells (PBMCs) (purchased from SCHBIO, P122110605C) were suspended in RPMI 1640 complete medium (purchased from Gibco, 11875119) containing 10% FBS and incubated at 37°C and 5% CO2 for 2 hours.

[0418] 2) Dispense 110 nL of the compound solution into 96-well cell plates using an Echo 655 (purchased from Labcyte).

[0419] 3) Adjust the cell culture medium to 500k cells / well / 100μL, add it to a 96-well V-type plate (purchased from Corning), and incubate for 1 hour.

[0420] 4) After 1 hour, add 10 μL of human recombinant IL-4 (purchased from R&D, 204-IL-010) to a final concentration of 1 ng / ml, and incubate at 37°C and 5% CO2 for 24 hours.

[0421] 5) Add the prepared standard, standard zero point and test sample to the ELISA plate at a concentration of 100 μL / well and incubate in the dark for 90 min.

[0422] 6) Wash 5 times with 350 μL / well of washing buffer.

[0423] 7) Add 100 μL of biotinylated antibody to the ELISA plate at each well and incubate for 60 minutes.

[0424] 8) Wash 5 times with 350 μL / well of washing buffer.

[0425] 9) Add 100 μL of the enzyme-coupled application solution to the ELISA plate at each well and incubate for 30 minutes.

[0426] 10) Wash 5 times with 350 μL / well of washing buffer.

[0427] 11) Add 100 μL / well of substrate and develop in the dark for 10-20 minutes.

[0428] 12) Add 100 μL of stop solution to each well of the ELISA plate and measure the OD value using Ensight at a wavelength of 450 nm.

[0429] 5.3 Data Analysis:

[0430] 1) Calculate the inhibition percentage using the following formula:

[0431] % Inhibition = (HC reading - Sample reading) / (HC reading - LC reading) * 100

[0432] LC: DMSO / cells / test medium;

[0433] HC:DMSO / cells / stimulant

[0434] 2) Use Xlfit (v5.3.1.3) to fit the curve and calculate IC. 50 Formula 201, calculate the IC50 of each compound.

[0435] The inhibitory effects of the compounds in the examples on IL-4-induced TARC expression are shown in Table 6.

[0436] Table 6: TARC inhibition effect:

[0437] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. A compound represented by general formula 1 and its derivatives, stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts: in, X3 and X4 are each independently selected from C or N atoms. L 01 C 1-6 Alkylene, C 3-8 Cycloalkylene groups, saturated four- to eight-membered heterocyclic groups containing one to three heteroatoms selected from N, O, and S; L 02 C 2-6 imidene group, C 2-6 Alynyl group, saturated seven- to fourteen-membered heterocyclic group containing one to three heteroatoms selected from N or O, bicyclic group or spirocyclic group; R1, R3, and R4 are each independently selected from H, halogen atoms, cyano groups, carbonyl groups, amino groups, hydroxyl groups, amide groups (-C(=O)NH2), substituted or unsubstituted C atoms. 1-6 Alkyl, substituted or unsubstituted halogenated C 1-6 Alkyl, substituted or unsubstituted C 1-6 alkoxy groups, wherein "substitution" means that the substituent can be substituted by 1 to 3 R groups. a Instead, each time R appears, a Each is independently selected from hydrogen, deuterium, halogen atoms, and carbon. 1-3 Alkyl, C 1-3 Alkyl, cyano, carbonyl, amino, hydroxyl, amide (-C(=O)NH2); Alternatively, R3 and R4 are connected to form a ring structure, the ring structure being selected from substituted or unsubstituted C. 4-10 cycloalkyl, substituted or unsubstituted C 6-14 Aryl, four- to eight-membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, and five- to eight-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S, wherein "substitution" means that the substituent can be substituted by 1 to 3 R atoms. b Instead, each time R appears, b Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl, C 1-3 Alkoxy, cyano, carbonyl, halogen atom, amino, hydroxyl Alternatively, R2 and R3 can be connected to form a ring structure, the ring structure being selected from substituted or unsubstituted C. 4-10 cycloalkyl, substituted or unsubstituted C 6-14 Aryl, four- to eight-membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, and five- to eight-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S, wherein "substitution" means that the substituent can be substituted by 1 to 3 R atoms. c Instead, each time R appears, c Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl, C 1-3 Alkoxy, cyano, carbonyl, halogen atom, amino, hydroxyl R2 is selected from H, halogen atoms, substituted or unsubstituted C atoms. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted amino, substituted or unsubstituted C 4-10 cycloalkyl, substituted or unsubstituted C 6-14 Aryl, four- to eight-membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, and five- to eight-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S, wherein "substitution" means that the substituent can be substituted by 1 to 3 R atoms. d Instead, each time R appears, d Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl, C 1-3 Alkoxy, cyano, carbonyl, halogen atom, amino, hydroxyl Each occurrence of R5 is independently selected from H, halogen atoms, and substituted or unsubstituted C atoms. 1-6 Alkyl, substituted or unsubstituted halogenated C 1-6 Alkyl, substituted or unsubstituted C 1-6 alkoxy groups, wherein "substitution" means that the substituent can be substituted by 1 to 3 R groups. e Instead, each time R appears, e Each is independently selected from hydrogen, deuterium, halogen atoms, and carbon. 1-3 Alkyl, C 1-3 Alkoxy, cyano, carbonyl, amino, hydroxy, amide; Preferably, each occurrence of R5 is independently selected from H, halogen atoms, substituted or unsubstituted C atoms. 1-4 Alkyl, Halogenated C 1-4 Alkyl, substituted or unsubstituted C 1-4 alkoxy groups, wherein "substitution" means that the substituent can be substituted by 1 to 3 R groups. e Instead, each time R appears, e Each is independently selected from hydrogen, deuterium, halogen atoms, and carbon. 1-3 Alkyl, C 1-3 Alkoxy; n5 is an integer of 0, 1, 2 or 3; R6 and R7 are each independently selected from H, halogen atom, cyano group, carbonyl group, amino group, hydroxyl group, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, wherein "substitution" means that the substituent can be substituted by 1 to 3 R groups. f Instead, each time R appears, f Each is independently selected from hydrogen, deuterium, halogen atoms, and carbon. 1-3 Alkyl, C 1-3 Alkoxy, cyano, carbonyl, amino, hydroxyl, -C(=O)NR e1 R e2 , where R e1 and R e2 Each is independently selected from hydrogen and C. 1-3 alkyl; Alternatively, R6 and R7 are connected to form a ring structure, the ring structure being selected from substituted or unsubstituted saturated or unsaturated C. 4-10 cycloalkyl, substituted or unsubstituted C 6-14 Aryl groups, four- to eleven-membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, and five- to fourteen-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S, wherein "substitution" means that the substituent can be substituted by 1 to 3 R atoms. g Instead, each time R appears, g Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl, C 1-3 Alkyl, cyano, carbonyl, halogen atom, amino, hydroxyl; R8 is selected from H, halogen atoms, substituted or unsubstituted C atoms. 1-6 Alkyl, substituted or unsubstituted halogenated C 1-6 Alkyl, substituted or unsubstituted C 1-6 alkoxy groups, wherein "substitution" means that the substituent can be substituted by 1 to 3 R groups. h Instead, each time R appears, h Each is independently selected from hydrogen, deuterium, halogen atoms, and carbon. 1-3 Alkyl, C 1-3 Alkoxy, cyano, carbonyl, amino, hydroxy, amide.

2. The compound represented by general formula 1 and its derivatives, stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts according to claim 1, characterized in that, Preferably, X3 and X4 are not both N atoms; Preferably, L 01 C 1-4 Alkylene, C 3-6 Cycloalkylene groups, saturated four- to six-membered heterocyclic groups containing one to three heteroatoms selected from N, O, and S; Preferably, L 01 C 2-3 Alkylene, C 5-6 Cycloalkylene groups, saturated four- to six-membered heterocyclic groups containing one or two heteroatoms selected from N, O, and S; More preferably, L 01 The derivatives are ethylene, propylene, cyclopentylene, and cyclohexylene. Preferably, L 02 C 2-4 imidene group, C 2-4 Alynyl group, saturated seven- to ten-membered heterocyclic group containing one or two heteroatoms selected from N or O, bicyclic group, or spirocyclic group; Preferably, L 02 C 2-4 imidene group, C 2-4 Ethyne-1, X1 and X2 are each independently selected from C or N atoms; More preferably, L 02 Vinylidene, ethynylene, X1 and X2 are each independently selected from C or N atoms; Preferably, R1, R3, and R4 are each independently selected from H, halogen atoms, cyano groups, carbonyl groups, amino groups, hydroxyl groups, and substituted or unsubstituted C atoms. 1-3 Alkyl, substituted or unsubstituted halogenated C 1-3 Alkyl, substituted or unsubstituted C 1-3 alkoxy groups, wherein "substitution" means that the substituent can be substituted by 1 to 3 R groups. a Instead, each time R appears, a Each is independently selected from hydrogen, deuterium, halogen atoms, and carbon. 1-3 Alkyl, C 1-3 Alkyl, cyano, amino, hydroxyl; Preferably, R1, R3, and R4 are each independently selected from H, halogen atoms, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, difluoropropyl, trifluoropropyl, tetrafluoropropyl, pentafluoropropyl, hexafluoropropyl, perfluoropropyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, difluoroethoxy, trifluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, difluoropropoxy, trifluoropropoxy, tetrafluoropropoxy, pentafluoropropoxy, hexafluoropropoxy, and perfluoropropoxy. Preferably, R3 and R4 are connected to form a ring structure, the ring structure being selected from substituted or unsubstituted C. 4-8 cycloalkyl, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted four- to eight-membered heterocyclic groups containing one or two heteroatoms selected from N and O, and substituted or unsubstituted five- to eight-membered heteroaryl groups containing one or two heteroatoms selected from N and O, wherein "substituted" means that the substituent can be substituted by one to three R atoms. b Instead, each time R appears, b Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl, C 1-3 Alkoxy, cyano, carbonyl, halogen atom, amino, hydroxyl Preferably, R3 and R4 are connected to form a ring structure, the ring structure being selected from substituted or unsubstituted C. 6-10 Aryl, substituted or unsubstituted five- to six-membered heterocyclic groups containing one or two heteroatoms selected from N and O, substituted or unsubstituted five- to six-membered heteroaryl groups containing one or two heteroatoms selected from N and O, wherein "substituted" means that the substituent can be substituted by one to three R atoms. b Instead, each time R appears, b Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl, carbonyl, halogen atom Preferably, R2 and R3 are connected to form a ring structure, the ring structure being selected from substituted or unsubstituted C. 4-8 cycloalkyl, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted four- to eight-membered heterocyclic groups containing one or two heteroatoms selected from N and O, and substituted or unsubstituted five- to eight-membered heteroaryl groups containing one or two heteroatoms selected from N and O, wherein "substituted" means that the substituent can be substituted by one to three R atoms. c Instead, each time R appears, c Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl, C 1-3 Alkoxy, cyano, carbonyl, halogen atom, amino, hydroxyl Preferably, R3 and R4 are connected to form a ring structure, the ring structure being selected from substituted or unsubstituted C. 6-10 Aryl, substituted or unsubstituted five- to six-membered heterocyclic groups containing one or two heteroatoms selected from N and O, substituted or unsubstituted five- to six-membered heteroaryl groups containing one or two heteroatoms selected from N and O, wherein "substituted" means that the substituent can be substituted by one to three R atoms. c Instead, each time R appears, c Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl, carbonyl, halogen atom Preferably, R2 is selected from H, halogen atoms, substituted or unsubstituted amino groups, and substituted or unsubstituted C atoms. 4-6 cycloalkyl, substituted or unsubstituted C 6-10 Aryl, tetra- to hexacyclic heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, and penta- to octacyclic heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, wherein "substitution" means that the substituent can be substituted by 1 to 3 R atoms. d Instead, each time R appears, d Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl, C 1-3 Alkoxy, cyano, carbonyl, halogen atom, amino, hydroxyl Preferably, R2 is selected from H, substituted or unsubstituted amino groups, and substituted or unsubstituted C groups. 4-6 cycloalkyl, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted tetra- to hexacyclic heterocyclic groups containing one or two heteroatoms selected from N and O, and substituted or unsubstituted five- to six-membered heteroaryl groups containing one or two heteroatoms selected from N and O, wherein "substituted" means that the substituent can be substituted by one to three R atoms. d Instead, each time R appears, d Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl, C 1-3 Alkoxy, carbonyl, Preferably, R2 is selected from H, Preferably, each occurrence of R5 is independently selected from H, halogen atoms, substituted or unsubstituted C atoms. 1-4 Alkyl, Halogenated C 1-4 Alkyl, substituted or unsubstituted C 1-4 alkoxy groups, wherein "substitution" means that the substituent can be substituted by 1 to 3 R groups. e Instead, each time R appears, e Each is independently selected from hydrogen, deuterium, halogen atoms, and carbon. 1-3 Alkyl, C 1-3 Alkoxy; Preferably, each occurrence of R5 is independently selected from H, halogen atoms, and -OCF3; Preferably, R6 and R7 are each independently selected from H, halogen atom, cyano group, carbonyl group, amino group, hydroxyl group, substituted or unsubstituted C. 1-4 Alkyl, substituted or unsubstituted C 2-4 alkenyl, substituted or unsubstituted C 2-4 Alkyne group, wherein "substitution" means that the substituent can be substituted by one or two R groups. f Instead, each time R appears, f Each is independently selected from hydrogen, deuterium, halogen atoms, and carbon. 1-3 Alkyl, C 1-3 Alkoxy, carbonyl, amino, -C(=O)NR e1 R e2 , where R e1 and R e2 Each is independently selected from hydrogen and C. 1-3 Alkyl, or two R e1 and R e2 It forms four- to seven-membered rings with the attached nitrogen atom; Preferably, R6 and R7 are each independently selected from H, substituted or unsubstituted C. 2-4 alkenyl, substituted or unsubstituted C 2-4 Alkyne group, wherein "substitution" means that the substituent can be substituted by one or two R groups. f Instead, each time R appears, f Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl, -C(=O)NR e1 R e2 , where R e1 and R e2 Each is independently selected from hydrogen and C. 1-3 Alkyl, or two R e1 and R e2 It forms four- to seven-membered rings with the attached nitrogen atom; Preferably, R6 and R7 are each independently selected from H, Preferably, R6 and R7 are connected to form a ring structure, the ring structure being selected from substituted or unsubstituted saturated or unsaturated C. 4-10 Cycloalkyl groups, substituted or unsubstituted four- to eleven-membered heterocyclic groups containing one to three heteroatoms selected from N and O, and substituted or unsubstituted five- to fourteen-membered heteroaryl groups containing one to three heteroatoms selected from N and O, wherein "substituted" means that the substituent can be substituted by one to three R atoms. g Instead, each time R appears, g Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl, C 1-3 Alkoxy, cyano, carbonyl, halogen atom, amino, hydroxyl, oxo, thio; Preferably, R6 and R7 are connected to form a parallel ring structure consisting of a 5-membered ring and a 6-membered ring, or a 5-membered ring and a 7-membered ring, wherein the ring structure is selected from... Preferably, R8 is selected from H, halogen atoms, substituted or unsubstituted C atoms. 1-3 Alkyl, substituted or unsubstituted halogenated C 1-3 Alkyl, substituted or unsubstituted C 1-3 alkoxy groups, wherein "substitution" means that the substituent can be substituted by 1 to 3 R groups. h Instead, each time R appears, h Each is independently selected from hydrogen, deuterium, halogen atoms, and carbon. 1-3 Alkyl, C 1-3 Alkoxy, cyano, carbonyl, amino, hydroxyl; Preferably, R8 is selected from H, halogen atoms, and C. 1-3 Alkyl, C 1-3 Alkoxy; Preferably, R8 is a halogen atom.

3. The compounds and their derivatives, stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts represented by general formula 1 according to claim 1 are represented by the following general formulas 2-1, 2-2, 2-3, 2-4 and 2-5: in, L 01 L 02 The definitions of X3, X4, R1, R2, R3, R4, R5, R6, R7, R8, and n5 are the same as those in general formula 1 in claim 1 or 2; X5 is selected from C or N atoms; X6 is selected from NH, O atoms, or sulfur atoms; L1 is selected from chemical bonds, formamide groups (-C(=O)NH-), imino groups (-NH-), and oxygen groups (-O-); Ring A is selected from substituted or unsubstituted saturated or unsaturated C. 4-10 cycloalkyl, substituted or unsubstituted C 6-14 Aryl groups, four- to ten-membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, and five- to fourteen-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S, wherein "substitution" means that the substituent can be substituted by 1 to 3 R atoms. i Instead, each time R appears, i Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl, C 1-3 Alkyl, cyano, carbonyl, halogen atom, amino, hydroxyl, thio; R9 and R 10 Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl groups; or forming four- to eight-membered saturated or unsaturated heterocyclic groups or four- to eight-membered heteroaryl groups with the nitrogen atoms attached to them; Ring B is selected from substituted or unsubstituted saturated or unsaturated C. 4-10 cycloalkyl, substituted or unsubstituted C 6-14 Aryl groups, four- to ten-membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, and five- to fourteen-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S, wherein "substitution" means that the substituent can be substituted by 1 to 3 R atoms. j Instead, each time R appears, j Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl, C 1-3 Alkoxy, cyano, carbonyl, halogen atom, amino, hydroxyl.

4. The compound represented by general formula 1 and its derivatives, stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts according to claim 3, characterized in that, Preferably, ring A is selected from substituted or unsubstituted saturated or unsaturated C. 4-10 Cycloalkyl groups, substituted or unsubstituted four- to ten-membered heterocyclic groups containing 1 to 3 heteroatoms selected from N and O, and substituted or unsubstituted five- to fourteen-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N and O, wherein "substituted" means that the substituent can be substituted by 1 to 3 R atoms. i Instead, each time R appears, i Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl, C 1-3 Alkoxy, cyano, carbonyl, halogen atom, amino, hydroxyl, oxo, thio; Preferably, ring A is selected from Preferably, R9 and R 10 Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl groups; or forming four- to seven-membered saturated or unsaturated heterocyclic groups or four- to seven-membered heteroaryl groups with the nitrogen atoms attached to them; Preferably, ring B is selected from substituted or unsubstituted saturated or unsaturated C. 4-10 cycloalkyl, substituted or unsubstituted C 6-14 Aryl, substituted or unsubstituted four- to six-membered heterocyclic groups containing one or two heteroatoms selected from N and O, and substituted or unsubstituted five- to six-membered heteroaryl groups containing one or two heteroatoms selected from N and O, wherein "substituted" means that the substituent can be substituted by one or two R atoms. j Instead, each time R appears, j Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl, C 1-3 Alkyl, cyano, carbonyl, halogen atom, amino, hydroxyl; 5. The compound represented by general formula 1 according to claim 1 and its derivatives, stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts are represented by the following general formulas 3-1, 3-2, 3-3, 3-4, 3-5 and 3-6: in, L 01 L 02 The definitions of X3, X4, R1, R2, R3, R4, R5, R6, R7, R8, and n5 are the same as those in general formula 1 of claim 1 or 2; X5 is selected from C or N atoms; X6 is selected from NH, oxygen atom, or sulfur atom; L1 is selected from chemical bonds, formamide groups (-C(=O)NH-), imino groups (-NH-), and oxygen groups (-O-); Ring A is selected from substituted or unsubstituted saturated or unsaturated C. 4-10 cycloalkyl, substituted or unsubstituted C 6-14 Aryl groups, four- to ten-membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, and five- to fourteen-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S, wherein "substitution" means that the substituent can be substituted by 1 to 3 R atoms. i Instead, each time R appears, i Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl, C 1-3 Alkyl, cyano, carbonyl, halogen atom, amino, hydroxyl, thio; R9 and R 10 Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl groups; or forming four- to eight-membered saturated or unsaturated heterocyclic groups or four- to eight-membered heteroaryl groups with the nitrogen atoms attached to them; Ring B is selected from substituted or unsubstituted saturated or unsaturated C. 4-10 cycloalkyl, substituted or unsubstituted C 6-14 Aryl groups, four- to ten-membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S, and five- to fourteen-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S, wherein "substitution" means that the substituent can be substituted by 1 to 3 R atoms. j Instead, each time R appears, j Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl, C 1-3 Alkoxy, cyano, carbonyl, halogen atom, amino, hydroxyl.

6. The compound represented by general formula 1 and its derivatives, stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts according to claim 5, characterized in that, Preferably, ring A is selected from substituted or unsubstituted saturated or unsaturated C. 4-10 Cycloalkyl groups, substituted or unsubstituted four- to ten-membered heterocyclic groups containing 1 to 3 heteroatoms selected from N and O, and substituted or unsubstituted five- to fourteen-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N and O, wherein "substituted" means that the substituent can be substituted by 1 to 3 R atoms. i Instead, each time R appears, i Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl, C 1-3 Alkoxy, cyano, carbonyl, halogen atom, amino, hydroxyl, oxo, thio; Preferably, ring A is selected from Preferably, R9 and R 10 Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl groups; or forming four- to seven-membered saturated or unsaturated heterocyclic groups or four- to seven-membered heteroaryl groups with the nitrogen atoms attached to them; Preferably, ring B is selected from substituted or unsubstituted saturated or unsaturated C. 4-10 cycloalkyl, substituted or unsubstituted C 6-14 Aryl, substituted or unsubstituted four- to six-membered heterocyclic groups containing one or two heteroatoms selected from N and O, and substituted or unsubstituted five- to six-membered heteroaryl groups containing one or two heteroatoms selected from N and O, wherein "substituted" means that the substituent can be substituted by one or two R atoms. j Instead, each time R appears, j Each is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl, C 1-3 Alkyl, cyano, carbonyl, halogen atom, amino, hydroxyl; Preferably, ring B is 7. The compound represented by general formula 1 according to claim 1 and its derivatives, stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts, selected from the following compounds:

8. A pharmaceutical composition comprising a therapeutically effective amount of the active ingredient as a compound of any one of claims 1 to 7, comprising a compound of general formula 1, general formula 2-1, general formula 2-2, general formula 2-3, general formula 2-4 and general formula 2-5, general formula 3-1, general formula 3-2, general formula 3-3, general formula 3-4, general formula 3-5 and general formula 3-6, and specific compounds 1-119, and their derivatives, stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts, and pharmaceutically acceptable excipients.

9. The use of the compounds of any one of claims 1 to 7, comprising general formulas 1, 2-1, 2-2, 2-3, 2-4 and 2-5, 3-1, 3-2, 3-3, 3-4, 3-5 and 3-6, and the compounds represented by specific compounds 1 to 119, and their derivatives, stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts, or the pharmaceutical compositions according to claim 8, in the preparation of a treatment for and prevention of diseases mediated by the STAT6 signaling pathway; Preferably, the diseases mediated by the STAT6 signaling pathway include atopic dermatitis, asthma, chronic obstructive pulmonary disease (COPD), nodular prurigo, urticaria, neurodermatitis, sinusitis, allergic rhinitis, eosinophilic esophagitis, eosinophilic gastritis, colitis, and bronchiectasis.

10. A method of treating a disease mediated by the STAT6 signaling pathway, the method comprising providing a subject with a therapeutically effective amount of compounds of formula 1, 2-1, 2-2, 2-3, 2-4 and 2-5, 3-1, 3-2, 3-3, 3-4, 3-5 and 3-6, and compounds represented by specific compounds 1-119, and their derivatives, stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts, or pharmaceutical compositions according to claim 8.

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