Ternary fused ring compound and application thereof in medicine

Abstract

The invention provides a ternary condensed ring compound with a structure as shown in a formula (I), or pharmaceutically acceptable salt, isotope derivative and solvate thereof, or stereoisomer, geometric isomer and tautomer thereof, or prodrug molecule and metabolite thereof, as well as a medicinal composition and application thereof. The compound provided by the invention can efficiently inhibit STAT6 phosphorylation, can be used for preparing drugs for preventing and treating inflammatory diseases, and can also be used for preparing antitumor drugs.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to ternary fused ring compounds, their preparation methods and their pharmaceutical applications. Specifically, it relates to the compound shown in formula (I) or its pharmaceutically acceptable salts, isotope derivatives, solvates, or its stereoisomers, geometric isomers, tautomers, or its prodrug molecules, metabolites, and their pharmaceutical applications. Background Technology

[0002] Transcription factors play a crucial role in eukaryotic gene expression by binding to specific DNA sites and regulating the transcription of virtually every gene in the cellular genome. It is estimated that there are over 1600 transcription factors in the human genome, and nearly 20% have been associated with different disease phenotypes. Many transcription factors have been identified as being associated with inflammatory and oncological diseases.

[0003] STAT6 is a key component of the Jak-STAT signaling pathway, which connects extracellular signals from various cytokines, hormones, and growth factors with nuclear transcription mechanisms. Four JAK (Janus tyrosine kinase) proteins (JAK1, JAK2, JAK3, TYK2) and seven STAT members (STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, STAT6) have been identified in mammals. STAT proteins regulate the expression of numerous genes, including those involved in cell survival, development, differentiation, migration, apoptosis, and immune responses.

[0004] STAT6, primarily stimulated by IL-4 and IL-13, plays a crucial role in type II inflammation dominated by helper T cells (Th2). Therefore, it is closely related to the pathophysiology of various allergic diseases, such as atopic dermatitis, bullous pemphigoid, nodular prurigo, chronic spontaneous urticaria, eosinophilic esophagitis and food allergies, chronic rhinosinusitis with nasal polyps (CRSwNP), chronic rhinosinusitis without nasal polyps (CRSsNP), NSAID-induced respiratory disease exacerbated by nonsteroidal anti-inflammatory drugs (NSAID-ERD / AERD), allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), eosinophilic granulomatous polyangiitis (EGPA), and allergic bronchopulmonary aspergillosis. The JAK-STAT6 transduction pathway can induce tumor-associated macrophages (TAMs) to polarize towards M2-type TAMs, playing a role in forming an immunosuppressive tumor microenvironment and promoting intratumoral angiogenesis. Furthermore, STAT6 is also involved in the regulation of the tumor microenvironment. In addition, certain forms of lymphoma, particularly Hodgkin's lymphoma, primary mediastinal and primary central nervous system lymphomas, as well as some follicular and T-cell lymphomas, are associated with STAT6 pathway dysregulation. Therefore, STAT6 has broad application prospects in inflammatory and tumor diseases. Because STAT6 is downstream of the JAK-STAT pathway, regulating STAT6 may be safer than using JAK inhibitors.

[0005] Currently, there are no STAT6 inhibitors on the market, but targeting the STAT6 signaling pathway may provide a better treatment strategy for these diseases. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to provide a novel ternary fused-ring compound that can be used as a STAT6 inhibitor to prepare drugs for treating STAT6-mediated diseases or conditions and related diseases or conditions.

[0007] On the one hand, the present invention provides a ternary fused-ring compound of formula (I) or its pharmaceutically acceptable salt, isotope derivative, solvate, or its stereoisomer, geometric isomer, tautomer, or its prodrug molecule or metabolite:

[0008]

[0009] in,

[0010] It can be a single bond or a double bond;

[0011] It is a 9-membered aromatic heterocycle;

[0012] X 1 Selected from CR 5Or N; X 2 Selected from C(R) 5 ) f or N(R) 5 ) g ;X 3 X 4 X 5 Each is independently selected from C or N; X 7 Selected from C(R) 5 ) h or N(R) 5 ) i ;X 6 Selected from CR 11 、N(R 11 ) j , S, O or Se;

[0013] f and h are each independently selected from 1 or 2; g, i, and j are each independently selected from 0 or 1;

[0014] p is selected from 1 or 2; s is selected from 0, 1, 2, 3, 4 or 5;

[0015] n is selected from 0, 1, 2, and 3;

[0016] R 1 R 6 Each is independently selected from R g CR 1a R 2a P(O)OR 1b OR 2b CR 1a R 2a P(O)OR 1b NHR 2b CR 1a R 2a P(O)(OR 1b )(NH(AA)C(O)OR 1c ), CR 1a R 2a P(O)(NHR 2c )(NH(AA)C(O)OR 1c ), CR 1a R 2a P(O)(NH(AA)C(O)OR 1c )(NH(AA)C(O)OR 1c ), P(O)OR 1b OR 2b ,

[0017] P(O)(OR 1b )(NH(AA)C(O)OR 1c ), P(O)(NHR2c )(NH(AA)C(O)OR 1c ) or P(O)(NH(AA)C(O)OR 1c )(NH(AA)C(O)OR 1c );

[0018] R 1a R 2a Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 1-4 Hydroxyalkyl; or, R 1a and R 2a It forms C3-C6 cycloalkyl or 3-6 membered heterocyclic groups with the atoms it is attached to;

[0019] R 1b R 2b Each is independently selected from -R 1aa -R 1aa -OC(O)-R 1ab -R 1aa -C(O)OR 1ab -R 1aa -OC(O)OR 1ab -R 1aa -OR 1ab -R 1aa -SC(O)OR 1ab -R 1aa -SC(O)-R 1ab -R 1aa -SR 1ab -R 1aa -OR 1ab -R 1aa -SR 1ab -SR 1ac -R 1aa -SR 1ab -OR 1ac -R 1aa -OC(O)NH-R 1ab -R 1aa -OC(O)NR 1ab R 1ac -R 1aa -OC(O)-R 1ab -OR 1ac -R 1aa -OC(O)OR 1ab -OR 1ac -R 1aa -SC(O)OR 1ab -OR1ac -R 1aa -SC(O)-R 1ab -OR 1ac or -R 1aa -OC(O)-(NH(AA)C(O)OR 1c );

[0020] R 1aa R 1ab R 1ac Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-20 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, 5-7 membered heterocyclic group, C 6-12 Aryl, 5-12 heteroaryl, -C 1-20 Alkylene C 2-6 alkynyl group, -C 1-20 Alkylene C 3-12 cycloalkyl, -C 1-20 Alkylene C 6-12 Aryl or C 1-20 Alkylene C 2-10 heteroaryl, the C 1-20 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 5-7 membered heterocyclic group, C 6-12 Aryl, 5-12 heteroaryl, C 1-20 Alkylene C 2-6 alkynyl group, C 1-20 Alkylene C 3-12 cycloalkyl, C 1-20 Alkylene C 6-12 Aryl or C 1-20 Alkylene C 2-10 Heteroaryl groups, optionally further reacted with one or more R groups h 、-Si(R h )3 or C(O)OR h replace;

[0021] R 1c R 2c Each C is independently selected from hydrogen, deuterium, or may be optionally substituted with one or more substituent groups. 1-6 Alkyl, 5-7 membered heterocyclic, C 6-12 Aryl, 5-12 heteroaryl, C 1-4 Alkylene C 6-12 Aryl or C 1-4 Alkylene C 2-10 Heteroaryl groups, wherein the substituents are selected from deuterium, halogen, cyano, hydroxyl, amino, C1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups;

[0022] AA is selected from residues of natural or non-natural amino acids, wherein the residues of the natural or non-natural amino acids are in the α or β configuration;

[0023] R 2 Each C group is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, or optionally substituted with one or more substituents. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 The substituent is an alkylamine group or a 4-10 membered heterocyclic group, wherein the substituent is selected from deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl or C 1-4 Halogenated alkoxy groups;

[0024] Or, two Rs 2 And the atoms they are attached to cyclize to form C3-C6 cycloalkyl groups, C 6-12 Aryl or 3-6 membered heterocyclic groups, wherein the C3-C6 cycloalkyl group, C 6-12 The aryl or 3-6 membered heterocyclic group may optionally be further surrounded by one or more groups selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Substituents of haloalkyl groups;

[0025] R 2A R 2B Each C group is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, or optionally substituted with one or more substituents. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 The substituent is an alkylamine group or a 4-10 membered heterocyclic group, wherein the substituent is selected from deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-4 Alkyl, C 1-4Alkoxy, C 1-4 Halogenated alkyl or C 1-4 Halogenated alkoxy groups;

[0026] Or, R 2A and R 2B Together with the atoms they are attached to, they form C7-C. 10 Cycloalkyl or 7-10 membered heterocyclic groups, wherein the C7-C 10 Cycloalkyl or 7-10 membered heterocyclic groups may optionally be selected from one or more R 3 Or R 4 Substitution of groups;

[0027] Or, R 2 With R 2A And the atoms they are attached to cyclize to form C3-C6 cycloalkyl groups, C 6-12 Aryl or 3-6 membered heterocyclic groups, wherein the C3-C6 cycloalkyl group, C 6-12 The aryl or 3-6 membered heterocyclic group may optionally be further surrounded by one or more groups selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Substituents of haloalkyl groups;

[0028] The R 3 R 4 Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, or optionally influenced by one or more R groups. Y Replacement C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-NH(CO)(CO)-, C 1-6 Alkyl (CO)-, C 1-6 Alkyl (CO)(CO)-, C 6-12 Aryl(CO)-, C 6-12 Aryl(CO)(CO)-, C 6-12 aryl-NH(CO)(CO)-, 5-12-membered heteroaryl(CO)-, 5-12-membered heteroaryl(CO)(CO)-, 5-12-membered heteroaryl-NH(CO)(CO)-, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 Alkylamine group, 4-10 membered heterocyclic group, C 6-12 Aryl, 5-12 heteroaryl, -C 1-6 Alkylene C 6-12 Aryl or C 1-6Alkylene-C 2-10 Mixed aromatics;

[0029] Or, R 3 and R 4 The atoms attached to them together form a C3-C6 cycloalkyl or a 3-6 membered heterocyclic group, wherein the C3-C6 cycloalkyl or 3-6 membered heterocyclic group may optionally be bonded by one or more R Y1 Or R Y2 replace;

[0030] R Y1 R Y2 Each is independently selected from deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl or C 1-4 Halogenated alkoxy groups;

[0031] Each R 5 Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl or C 1-6 Halogenated alkyl; or two R 5 The atoms to which they are attached cyclize to form C3-C6 cycloalkyl or 3-6 membered heterocyclic groups, wherein the C3-C6 cycloalkyl or 3-6 membered heterocyclic group may optionally be further cyclically bonded by one or more elements selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Substituents of haloalkyl groups;

[0032] R 7 R 8 Each is independently selected from hydrogen, deuterium, or optionally converted by one or more R. Z Replacement C 1-6 Alkyl, 5-12 membered heterocyclic, 5-12 membered cycloalkyl, C 6-12 Aryl, 5-12 heteroaryl, C 1-4 Alkylene C 6-12 Aryl or C 1-4 Alkylene C 2-10 Mixed aromatics;

[0033] Or, R 7 and R 8 Together with the atoms they are attached to, they form a 4-14 membered heterocyclic group or a 5-12 membered heteroaryl group, wherein the 4-14 membered heterocyclic group or the 5-12 membered heteroaryl group may optionally be further bonded by one or more R groups. Z replace;

[0034] R 11 Selected from hydrogen or deuterium;

[0035] R Y Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, imino, or optionally by one or more R groups. Q Replacement C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 Alkylamine group, 4-10 membered heterocyclic group, C 6-12 Aryl, 5-12 heteroaryl, -NR a R b -OR a -C(O)R a -C(O)OR a -NHC(O)OR a -NR b C(O)OR a -NR b C(O)R a -NR a C(O)NR b R c -C(O)NR a R b -S(O)R c -S(O)2R c -S(O)=NHR c -S(O)NR c R d or -S(O)2NR c R d ;

[0036] R Z Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, imino, or optionally by one or more R groups. Q Replacement C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 Alkylamine group, 4-10 membered heterocyclic group, C 6-12 Aryl, 5-12 heteroaryl, -NR a R b -OR a -C(O)Ra -C(O)OR a -NHC(O)OR a -NR b C(O)OR a -NR b C(O)R a -NR a C(O)NR b R c -C(O)NR a R b -S(O)R c -S(O)2R c -S(O)=NHR c -S(O)NR c R d or -S(O)2NR c R d ;

[0037] R Q Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, imino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 Alkylamine group, 4-10 membered heterocyclic group, C 6-12 Aryl, 5-12 heteroaryl, -NR e R f -OR e -C(O)R e -C(O)OR e -NHC(O)OR e -NHC(O)R e -NR e C(O)OR f -NR e C(O)R f -NR g C(O)NR e R f -C(O)NR e R f -S(O)R e -S(O)2R e -S(O)=NHR e -S(O)NRe R f or -S(O)2NR e R f ;

[0038] R a R b R c R d R e R f R g R h Each C group is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, imino, or optionally substituted with one or more substituents. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 Alkylamine group, 4-10 membered heterocyclic group, C 6-12 Aryl, 5-12 heteroaryl, C 1-4 Alkylene C 6-12 Aryl or C 1-4 Alkylene C 2-10 Heteroaryl groups, wherein the substituents are selected from deuterium, halogen, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy, phenyl, or benzyl;

[0039] The condition is that the compound of formula (I) is not selected from any one or more of the following compounds, or isomers or mixtures of isomers of any one of the following compounds:

[0040]

[0041]

[0042]

[0043] In some embodiments of the present invention, the Selected from

[0044]

[0045] On the one hand, the present invention provides ternary fused-ring compounds of formula (II), (III), (IV), (V) or (VI), or their pharmaceutically acceptable salts, isotope derivatives, solvates, or their stereoisomers, geometric isomers, tautomers, or their prodrug molecules or metabolites:

[0046]

[0047] in,

[0048] p is selected from 1 or 2; s is selected from 0, 1, 2, 3, 4 or 5;

[0049] n is independently selected from 0, 1, 2, and 3;

[0050] m can be independently selected from 0, 1, 2, 3, 4, 5 or 6;

[0051] R 1 R 6 Each is independently selected from R g CR 1a R 2a P(O)OR 1b OR 2b CR 1a R 2a P(O)OR 1b NHR 2b ,

[0052] CR 1a R 2a P(O)(OR 1b )(NH(AA)C(O)OR 1c ), CR 1a R 2a P(O)(NHR 2c )(NH(AA)C(O)OR 1c ), CR 1a R 2a P(O)(NH(AA)C(O)OR 1c )(NH(AA)C(O)OR 1c ), P(O)OR 1b OR 2b ,

[0053] P(O)(OR 1b )(NH(AA)C(O)OR 1c ), P(O)(NHR 2c )(NH(AA)C(O)OR 1c ) or P(O)(NH(AA)C(O)OR 1c )(NH(AA)C(O)OR 1c);

[0054] R 1a R 2a Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 1-4 Hydroxyalkyl; or, R 1a and R 2a It forms C3-C6 cycloalkyl or 3-6 membered heterocyclic groups with the atoms it is attached to;

[0055] R 1b R 2b Each is independently selected from -R 1aa -R 1aa -OC(O)-R 1ab -R 1aa -C(O)OR 1ab -R 1aa -OC(O)OR 1ab -R 1aa -OR 1ab -R 1aa -SC(O)OR 1ab -R 1aa -SC(O)-R 1ab -R 1aa -SR 1ab -R 1aa -OR 1ab -R 1aa -SR 1ab -SR 1ac -R 1aa -SR 1ab -OR 1ac -R 1aa -OC(O)NH-R 1ab -R 1aa -OC(O)NR 1ab R 1ac -R 1aa -OC(O)-R 1ab -OR 1ac -R 1aa -OC(O)OR 1ab -OR 1ac -R 1aa -SC(O)OR 1ab -OR 1ac -R 1aa -SC(O)-R 1ab -OR 1ac or -R 1aa-OC(O)-(NH(AA)C(O)OR 1c );

[0056] R 1aa R 1ab R 1ac Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-20 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, 5-7 membered heterocyclic group, C 6-12 Aryl, 5-12 heteroaryl, -C 1-20 Alkylene C 2-6 alkynyl group, -C 1-20 Alkylene C 3-12 cycloalkyl, -C 1-20 Alkylene C 6-12 Aryl or C 1-20 Alkylene C 2-10 heteroaryl, the C 1-20 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 5-7 membered heterocyclic group, C 6-12 Aryl, 5-12 heteroaryl, C 1-20 Alkylene C 2-6 alkynyl group, C 1-20 Alkylene C 3-12 cycloalkyl, C 1-20 Alkylene C 6-12 Aryl or C 1-20 Alkylene C 2-10 Heteroaryl groups, optionally further reacted with one or more R groups h 、-Si(R h )3 or C(O)OR h replace;

[0057] R 1c R 2c Each C is independently selected from hydrogen, deuterium, or may be optionally substituted with one or more substituent groups. 1-6 Alkyl, 5-7 membered heterocyclic, C 6-12 Aryl, 5-12 heteroaryl, C 1-4 Alkylene C 6-12 Aryl or C 1-4 Alkylene C 2-10 Heteroaryl groups, wherein the substituents are selected from deuterium, halogen, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups;

[0058] AA is selected from residues of natural or non-natural amino acids, wherein the residues of the natural or non-natural amino acids are in the α or β configuration;

[0059] R 2 Each C group is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, or optionally substituted with one or more substituents. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 The substituent is an alkylamine group or a 4-10 membered heterocyclic group, wherein the substituent is selected from deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl or C 1-4 Halogenated alkoxy groups;

[0060] Or, two Rs 2 And the atoms they are attached to cyclize to form C3-C6 cycloalkyl groups, C 6-12 Aryl or 3-6 membered heterocyclic groups, wherein the C3-C6 cycloalkyl group, C 6-12 The aryl or 3-6 membered heterocyclic group may optionally be further surrounded by one or more groups selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Substituents of haloalkyl groups;

[0061] R 2A R 2B Each C group is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, or optionally substituted with one or more substituents. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 The substituent is an alkylamine group or a 4-10 membered heterocyclic group, wherein the substituent is selected from deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl or C 1-4 Halogenated alkoxy groups;

[0062] Or, R2A and R 2B Together with the atoms they are attached to, they form C7-C. 10 Cycloalkyl or 7-10 membered heterocyclic groups, wherein the C7-C 10 Cycloalkyl or 7-10 membered heterocyclic groups may optionally be selected from one or more R 3 Or R 4 Substitution of groups;

[0063] Or, R 2 With R 2A And the atoms they are attached to cyclize to form C3-C6 cycloalkyl groups, C 6-12 Aryl or 3-6 membered heterocyclic groups, wherein the C3-C6 cycloalkyl group, C 6-12 The aryl or 3-6 membered heterocyclic group may optionally be further surrounded by one or more groups selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Substituents of haloalkyl groups;

[0064] The R 3 R 4 Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, or optionally influenced by one or more R groups. Y Replacement C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-NH(CO)(CO)-, C 1-6 Alkyl (CO)-, C 1-6 Alkyl (CO)(CO)-, C 6-12 Aryl(CO)-, C 6-12 Aryl(CO)(CO)-, C 6-12 aryl-NH(CO)(CO)-, 5-12-membered heteroaryl(CO)-, 5-12-membered heteroaryl(CO)(CO)-, 5-12-membered heteroaryl-NH(CO)(CO)-, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 Alkylamine group, 4-10 membered heterocyclic group, C 6-12 Aryl, 5-12 heteroaryl, -C 1-6 Alkylene C 6-12 Aryl or C 1-6 Alkylene-C 2-10 Mixed aromatics;

[0065] Or, R 3 and R 4The atoms attached to them together form a C3-C6 cycloalkyl or a 3-6 membered heterocyclic group, wherein the C3-C6 cycloalkyl or 3-6 membered heterocyclic group may optionally be bonded by one or more R Y1 Or R Y2 replace;

[0066] R Y1 R Y2 Each is independently selected from deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl or C 1-4 Halogenated alkoxy groups;

[0067] R 5 Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl or C 1-6 Halogenated alkyl; or two R 5 The atoms to which they are attached cyclize to form C3-C6 cycloalkyl or 3-6 membered heterocyclic groups, wherein the C3-C6 cycloalkyl or 3-6 membered heterocyclic group may optionally be further cyclically bonded by one or more elements selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Substituents of haloalkyl groups;

[0068] R 7 R 8 Each is independently selected from hydrogen, deuterium, or optionally converted by one or more R. Z Replacement C 1-6 Alkyl, 5-12 membered heterocyclic, 5-12 membered cycloalkyl, C 6-12 Aryl, 5-12 heteroaryl, C 1-4 Alkylene C 6-12 Aryl or C 1-4 Alkylene C 2-10 Mixed aromatics;

[0069] Or, R 7 and R 8 Together with the atoms they are attached to, they form a 4-14 membered heterocyclic group or a 5-12 membered heteroaryl group, wherein the 4-14 membered heterocyclic group or the 5-12 membered heteroaryl group may optionally be further bonded by one or more R groups. Z replace;

[0070] R Y Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, imino, or optionally by one or more R groups. Q Replacement C 1-6 Alkyl, C 1-6 Alkoxy, C2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 Alkylamine group, 4-10 membered heterocyclic group, C 6-12 Aryl, 5-12 heteroaryl, -NR a R b -OR a -C(O)R a -C(O)OR a -NHC(O)OR a -NR b C(O)OR a -NR b C(O)R a -NR a C(O)NR b R c -C(O)NR a R b -S(O)R c -S(O)2R c -S(O)=NHR c -S(O)NR c R d or -S(O)2NR c R d ;

[0071] R Z Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, imino, or optionally by one or more R groups. Q Replacement C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 Alkylamine group, 4-10 membered heterocyclic group, C 6-12 Aryl, 5-12 heteroaryl, -NR a R b -OR a -C(O)R a -C(O)OR a -NHC(O)OR a -NR b C(O)OR a -NR b C(O)R a-NR a C(O)NR b R c -C(O)NR a R b -S(O)R c -S(O)2R c -S(O)=NHR c -S(O)NR c R d or -S(O)2NR c R d ;

[0072] R Q Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, imino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 Alkylamine group, 4-10 membered heterocyclic group, C 6-12 Aryl, 5-12 heteroaryl, -NR e R f -OR e -C(O)R e -C(O)OR e -NHC(O)OR e -NHC(O)R e -NR e C(O)OR f -NR e C(O)R f -NR g C(O)NR e R f -C(O)NR e R f -S(O)R e -S(O)2R e -S(O)=NHR e -S(O)NR e R f or -S(O)2NR e R f ;

[0073] R a R b R c Rd R e R f R g R h Each C group is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, imino, or optionally substituted with one or more substituents. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 Alkylamine group, 4-10 membered heterocyclic group, C 6-12 Aryl, 5-12 heteroaryl, C 1-4 Alkylene C 6-12 Aryl or C 1-4 Alkylene C 2-10 Heteroaryl groups, wherein the substituents are selected from deuterium, halogen, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy, phenyl, or benzyl.

[0074] In some embodiments of the present invention, the compound has a structure as shown in formula (IIA), (IIIA), (IVA), (VA), or (VIA):

[0075]

[0076] in,

[0077] It can be a single bond or a double bond;

[0078] q and t are each independently selected from 0, 1 or 2, and q and t are not both selected from 0 at the same time;

[0079] Z is selected from S, O, -S(=O)-, -S(=O)2-, -S(=O)=NH, CHR 10 CR 9 R 10 or NR 10 ;

[0080] Y is selected from CHR 9 CR 9 R 10 or NR 9 ;

[0081] R 3 R 4Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, or optionally influenced by one or more R groups. Y Replacement C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-NH(CO)(CO)-, C 1-6 Alkyl (CO)-, C 1-6 Alkyl (CO)(CO)-, C 6-12 Aryl(CO)-, C 6-12 Aryl(CO)(CO)-, C 6-12 aryl-NH(CO)(CO)-, 5-12-membered heteroaryl(CO)-, 5-12-membered heteroaryl(CO)(CO)-, 5-12-membered heteroaryl-NH(CO)(CO)-, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 Alkylamine group, 4-10 membered heterocyclic group, C 6-12 Aryl, 5-12 heteroaryl, C 1-6 Alkylene C 6-12 Aryl or C 1-6 Alkylene C 2-10 Mixed aromatics;

[0082] Or, R 3 and R 4 The atoms attached to them together form a C3-C6 cycloalkyl or a 3-6 membered heterocyclic group, wherein the C3-C6 cycloalkyl or 3-6 membered heterocyclic group may optionally be bonded by one or more R Y1 Or R Y2 replace;

[0083] R 9 R 10 Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, or optionally influenced by one or more R groups. Y Replacement C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-NH(CO)(CO)-, C 1-6 Alkyl (CO)-, C 1-6 Alkyl (CO)(CO)-, C 6-12 Aryl(CO)-, C 6-12 Aryl(CO)(CO)-, C 6-12aryl-NH(CO)(CO)-, 5-12-membered heteroaryl(CO)-, 5-12-membered heteroaryl(CO)(CO)-, 5-12-membered heteroaryl-NH(CO)(CO)-, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 Alkylamine group, 4-10 membered heterocyclic group, C 6-12 Aryl, 5-12 heteroaryl, C 1-6 Alkylene C 6-12 Aryl or C 1-6 Alkylene C 2-10 Mixed aromatics;

[0084] Or, R 9 and R 10 The atoms attached to them together form a C3-C6 cycloalkyl or a 3-6 membered heterocyclic group, wherein the C3-C6 cycloalkyl or 3-6 membered heterocyclic group may optionally be bonded by one or more R Y1 Or R Y2 replace;

[0085] R Y1 R Y2 Each is independently selected from deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl or C 1-4 Halogenated alkoxy groups;

[0086] R Y Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, imino, or optionally by one or more R groups. Q Replacement C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 Alkylamine group, 4-10 membered heterocyclic group, C 6-12 Aryl, 5-12 heteroaryl, -NR a R b -OR a -C(O)R a -C(O)OR a -NHC(O)OR a -NR b C(O)ORa -NR b C(O)R a -NR a C(O)NR b R c -C(O)NR a R b -S(O)R c -S(O)2R c -S(O)=NHR c -S(O)NR c R d or -S(O)2NR c R d ;

[0087] Among them, p, s, R 1 R 2 R 5 R 6 R 7 R 8 R a R b R c R d R Q The definition is as described in general formula (II).

[0088] In some embodiments of the present invention, the compound has a structure as shown in formulas (IIA-a), (IIA-b), (IIA-c), (IIA-d), (IIA-e), (IIA-f), (IIIA-a), (IIIA-b), (IIIA-c), (IVA-a), (IVA-b), (IVA-c), (VA-a), (VA-b), (VA-c), (VIA-a), (VIA-b), or (VIA-c):

[0089]

[0090]

[0091] Among them, p, s, R 1 R 2 R 5 R 6 R 7 R 8 Z, Y, R 3 R 4 The definition is as stated in general formula (IIA).

[0092] In a further embodiment of the invention, the compound has the structure shown in the following formulas: (IIA-a1), (IIA-b1), (IIA-c1), (IIA-d1), (IIA-e1), (IIA-f1), (IIA-a2), (IIA-b2), (IIA-c2), (IIA-d2), (IIA-e2), (IIA-f2), (IIIA-a1), (IIIA-b1), (IIIA-c1), (IVA-a1), (IVA-b1), (IVA-c1), (VA-a1), (VA-b1), (VA-c1), (VIA-a1), (VIA-b1), or (VIA-c1):

[0093]

[0094]

[0095] Among them, s, R 1 R 2 R 5 R 6 R 7 R 8 Z, Y, R 3 R 4 The definition is as stated in general formula (IIA).

[0096] In some embodiments of the present invention, the R 3 R 4 Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, or optionally influenced by one or more R groups. Y Replacement C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-NH(CO)(CO)-, C 1-6 Alkyl (CO)-, C 1-6 Alkyl (CO)(CO)-, C 6-12 Aryl(CO)-, C 6-12 Aryl(CO)(CO)-, C 6-12 aryl-NH(CO)(CO)-, 5-12-membered heteroaryl(CO)-, 5-12-membered heteroaryl(CO)(CO)-, 5-12-membered heteroaryl-NH(CO)(CO)-, C 3-6 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-12 Aryl, 5-12 heteroaryl, C 1-6 Alkylene C 6-12 Aryl or C 1-6 Alkylene C 2-10 Heteroaryl, the R YEach is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, imino, or C. 1-6 alkyl.

[0097] In a further embodiment of the present invention, the R 3 R 4 Each element is independently selected from hydrogen, deuterium, hydroxyl, or optionally coated with one or more R atoms. Y Replacement C 1-6 Alkyl-NH(CO)(CO)-, C 1-6 Alkyl (CO)-, C 1-6 Alkyl (CO)(CO)-, C 6-12 Aryl(CO)-, C 6-12 Aryl(CO)(CO)-, C 6-12 Aryl-NH(CO)(CO)-, 5-12-membered heteroaryl(CO)-, 5-12-membered heteroaryl(CO)(CO)-, 5-12-membered heteroaryl-NH(CO)(CO)-, wherein R Y Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, imino, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkyl groups.

[0098] In some embodiments of the present invention, the R 3 and R 4 The atoms to which they are attached together form a C3-C6 cycloalkyl group, wherein the C3-C6 cycloalkyl group may optionally be bonded by one or more R Y1 Or R Y2 Replace; the R Y1 R Y2 Each is independently selected from deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl or C 1-4 Halogenated alkoxy groups.

[0099] In some embodiments of the present invention, the compound has the following formulas: (IIA-1), (IIA-2), (IIA-3), (IIA-4), (IIA-5), (IIA-6), (IIA-7), (IIA-8), (IIA-9), (IIA-10), (IIA-11), (IIA-12), (IIA-13), (IIA-14), (IIA-15), (IIA-16), (IIA-17), (IIA-18), (IIIA-1), (IIIA-2), (IIIA-3), (IIIA-4), (IIIA-5), (IIIA-6), (III ...1), (IIIA-1), (IIIA-2), (IIIA-3), (IIIA-4), (IIIA-5), (IIIA-6), (IIIA-1), (IIIA-1), (IIIA-2), (IIIA-3), (IIIA-4), (IIIA-5), (IIIA-6), (IIIA-1), (IIIA-1), (IIIA-2), (IIIA-3), A-7), (IIIA-8), (IIIA-9), (IVA-1), (IVA-2), (IVA-3), (IVA-4), (IVA-5), (IVA-6), (IVA-7), (IVA-8), (IVA-9), (VA-1), (VA-2), (VA-3), ( Structure shown in VA-4), (VA-5), (VA-6), (VA-7), (VA-8), (VA-9), (VIA-1), (VIA-2), (VIA-3), (VIA-4), (VIA-5), (VIA-6), (VIA-7), (VIA-8) or (VIA-9):

[0100]

[0101]

[0102]

[0103]

[0104] Among them, s, R 1 R 2 R 5 R 6 R 7 R 8 R 9 R 10 R Y1 R Y2 The definition is as defined in general formula (IIA).

[0105] In some embodiments of the present invention, the R 9 and R 10 The atoms attached to them together form a C3-C6 cycloalkyl or a 3-6 membered heterocyclic group, wherein the C3-C6 cycloalkyl or 3-6 membered heterocyclic group may optionally be bonded by one or more R Y1 Or R Y2 Instead, the R Y1 Or RY2 Each is independently selected from deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl or C 1-4 Halogenated alkoxy groups.

[0106] In some embodiments of the present invention, the R 9 R 10 The atoms attached to them together form a cyclopropyl group, which may optionally be converted by one or more R atoms. Y1 Or R Y2 Instead, the R Y1 Or R Y2 Each is independently selected from deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl or C 1-4 Halogenated alkoxy groups.

[0107] In some embodiments of the present invention, the R 9 and R 10 Each is independently selected from hydrogen, deuterium, or optionally converted by one or more R. Y Replacement C 1-6 Alkyl, C 1-6 Alkyl-NH(CO)(CO)-, C 1-6 Alkyl (CO)-, C 1-6 Alkyl (CO)(CO)-, C 6-12 Aryl(CO)-, C 6-12 Aryl(CO)(CO)-, C 6-12 Aryl-NH(CO)(CO)-, 5-12-membered heteroaryl(CO)-, 5-12-membered heteroaryl(CO)(CO)-, 5-12-membered heteroaryl-NH(CO)(CO)-, wherein R Y Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, imino, or C. 1-6 alkyl.

[0108] In some embodiments of the present invention, the compound has a structure as shown in formula (IIB), (IIIB), (IVB), (VB), or (VIB):

[0109]

[0110] R 2 Each C group is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, or optionally substituted with one or more substituents. 1-6Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 The substituent is an alkylamine group or a 4-10 membered heterocyclic group, wherein the substituent is selected from deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl or C 1-4 Halogenated alkoxy groups;

[0111] Or, two Rs 2 And the atoms they are attached to cyclize to form C3-C6 cycloalkyl groups, C 6-12 Aryl or 3-6 membered heterocyclic groups, wherein the C3-C6 cycloalkyl group, C 6-12 The aryl or 3-6 membered heterocyclic group may optionally be further surrounded by one or more groups selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Substituents of haloalkyl groups;

[0112] R 2A R 2B Each C group is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, or optionally substituted with one or more substituents. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 The substituent is an alkylamine group or a 4-10 membered heterocyclic group, wherein the substituent is selected from deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl or C 1-4 Halogenated alkoxy groups;

[0113] Or, R 2 With R 2A And the atoms they are attached to cyclize to form C3-C6 cycloalkyl groups, C 6-12 Aryl or 3-6 membered heterocyclic groups, wherein the C3-C6 cycloalkyl group, C 6-12 The aryl or 3-6 membered heterocyclic group may optionally be further surrounded by one or more groups selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C1-6 Alkoxy or C 1-6 Substituents of haloalkyl groups;

[0114] Wherein, n, p, s, R 1 R 5 R 6 R 7 R 8 The definition is as stated in general formula (II).

[0115] In some embodiments of the present invention, the compound has a structure as shown in formulas (IIB-a), (IIB-b), (IIB-c), (IIB-d), (IIB-e), (IIB-f), (IIIB-a), (IIIB-b), (IIIB-c), (IVB-a), (IVB-b), (IVB-c), (VB-a), (VB-b), (VB-c), (VIB-a), (VIB-b), or (VIB-c):

[0116]

[0117] Among them, s, R 1 R 2 R 2B R 5 R 6 R 7 R 8 The definition is as defined in general formula (II).

[0118] In some embodiments of the present invention, the compound has a structure as shown in formulas (IIB-a1), (IIB-b1), (IIB-c1), (IIB-d1), (IIB-e1), (IIB-f1), (IIIB-a1), (IIIB-b1), (IIIB-c1), (IVB-a1), (IVB-b1), (IVB-c1), (VB-a1), (VB-b1), (VB-c1), (VIB-a1), (VIB-b1), or (VIB-c1):

[0119]

[0120] Among them, s, R 1 R 2 R 5 R 6 R 7 R 8 The definition is as defined in general formula (II).

[0121] In some embodiments of the present invention, the R 2Selected from hydrogen or hydroxyl.

[0122] In some embodiments of the present invention, the R 5 Each is independently selected from hydrogen, halogen, or C. 1-6 Alkyl; or, two Rs 5 The atoms to which they are attached cyclize to form C3-C6 cycloalkyl groups, wherein the C3-C6 cycloalkyl groups may optionally be further cyclically bonded by one or more atoms selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C6, and C6. 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 The alkyl halogroup is substituted by a substituent.

[0123] In some embodiments of the present invention, the R 1 R 6 Each is independently selected from R g CR 1a R 2a P(O)OR 1b OR 2b or CR 1a R 2a P(O)OR 1b NHR 2b ;

[0124] Among them, R 1a R 2a Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 1-4 Hydroxyalkyl;

[0125] R 1b R 2b Each is independently selected from -R 1aa -R 1aa -OC(O)-R 1ab -R 1aa -C(O)OR 1ab -R 1aa -OC(O)OR 1ab -R 1aa -OR 1ab -R 1aa -SC(O)OR 1ab -R 1aa -SC(O)-R 1ab -R 1aa -SR 1ab -R 1aa -OR 1ab -R 1aa -SR 1ab -SR1ac -R 1aa -SR 1ab -OR 1ac -R 1aa -OC(O)NH-R 1ab -R 1aa -OC(O)NR 1ab R 1ac -R 1aa -OC(O)-R 1ab -OR 1ac -R 1aa -OC(O)OR 1ab -OR 1ac -R 1aa -SC(O)OR 1ab -OR 1ac or -R 1aa -SC(O)-R 1ab -OR 1ac ;

[0126] R 1aa R 1ab R 1ac Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-20 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, 5-7 membered heterocyclic group, C 6-12 Aryl, 5-12 heteroaryl, -C 1-20 Alkylene C 2-6 alkynyl group, -C 1-20 Alkylene C 3-12 cycloalkyl, -C 1-20 Alkylene C 6-12 Aryl or C 1-20 Alkylene C 2-10 heteroaryl, the C 1-20 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 5-7 membered heterocyclic group, C 6-12 Aryl, 5-12 heteroaryl, C 1-20 Alkylene C 2-6 alkynyl group, C 1-20 Alkylene C 3-12 cycloalkyl, C 1-20 Alkylene C 6-12 Aryl or C 1-20 Alkylene C 2-10 Heteroaryl groups, optionally further reacted with one or more R groups h 、-Si(R h)3 or C(O)OR h replace;

[0127] R g R h Each C group is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, imino, or optionally substituted with one or more substituents. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, wherein the substituent group is selected from deuterium, halogen, cyano, hydroxyl, amino, or C. 1-4 alkyl.

[0128] In a further embodiment of the present invention, the R 1a Or R 2a Each is independently selected from hydrogen, halogen, or oxo, with the halogen preferably being F or Cl.

[0129] In some embodiments of the present invention, the R 1 Or R 6 Independently selected

[0130]

[0131]

[0132] In some embodiments of the present invention, the R 7 R 8 Each is independently selected from hydrogen, deuterium, or optionally converted by one or more R. Z Replacement C 1-6 Alkyl, C 1-6 Alkyl C(O)NHC 1-6 Alkyl, 5-12 membered heterocyclic, 5-12 membered cycloalkyl, C 6-12 Aryl, 5-12 heteroaryl, C 1-4 Alkylene C 6-12 Aryl or C 1-4 Alkylene C 2-10 Mixed aromatics;

[0133] The R Z Independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, oxo, amino, or optionally influenced by one or more R groups. Q Replacement C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl, wherein R Q Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, imino, C 1-6Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylamine group, 4-10 membered heterocyclic group, C 6-12 Aryl, 5-12 heteroaryl, -NR e R f -C(O)R e -NHC(O)R e or -NR e C(O)R f The R e R f Each element is independently selected from hydrogen, deuterium, or C. 1-6 alkyl.

[0134] In some embodiments of the present invention, the R 7 and R 8 Together with the atoms they are attached to, they form a 4-14 membered heterocyclic group, which may optionally be bonded by one or more R... Z replace;

[0135] The R Z Independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, oxo, or optionally influenced by one or more R groups. Q Replacement C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl, wherein R Q Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, imino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylamine group, 4-10 membered heterocyclic group, C 6-12 Aryl, 5-12 heteroaryl, -NR e R f -C(O)R e -NHC(O)R e or -NR e C(O)R f The R e R f Each element is independently selected from hydrogen, deuterium, or C. 1-6 alkyl.

[0136] In some embodiments of the present invention, the Selected from:

[0137]

[0138] In some embodiments of the present invention, the Selected from:

[0139]

[0140] In some embodiments of the present invention, the compound is selected from the following structural compounds:

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147]

[0148] On the other hand, the present invention provides a pharmaceutical composition comprising a compound as shown in the above general formulas or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule or metabolite thereof.

[0149] In another aspect, the present invention provides the use of compounds represented by the above general formulas or pharmaceutically acceptable salts, isotope derivatives, solvates, or stereoisomers, geometric isomers, tautomers, or prodrug molecules, metabolites, or pharmaceutical compositions thereof in the preparation of medicaments for treating STAT6-mediated diseases or conditions and related diseases or conditions.

[0150] In another aspect, the present invention provides the use of compounds represented by the above general formulas or pharmaceutically acceptable salts, isotope derivatives, solvates, or stereoisomers, geometric isomers, tautomers, or prodrug molecules, metabolites, or pharmaceutical compositions thereof in the treatment of STAT6-mediated diseases or conditions and related diseases or conditions.

[0151] The present invention also provides a method of treatment for a disease or symptom, the method comprising administering to a patient in need a therapeutically effective amount of a compound as shown in the above general formulas or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, or pharmaceutical composition thereof described above.

[0152] In some implementations, the disease being treated and / or prevented is a STAT6-mediated disease, which is a tumor or a type II inflammation-related disease selected from atopic dermatitis, bullous pemphigoid, nodular prurigo, chronic spontaneous urticaria, eosinophilic esophagitis, food allergy, chronic rhinosinusitis with nasal polyps (CRSwNP), chronic rhinosinusitis without nasal polyps (CRSsNP), nonsteroidal anti-inflammatory drug-induced respiratory disease (NSAID-ERD / AERD), allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), eosinophilic granulomatous polyangiitis (EGPA), or allergic bronchopulmonary aspergillosis.

[0153] Furthermore, the tumor is selected from lymphoma, solitary fibrous tumor, colon cancer, esophageal cancer, breast cancer, bile duct cancer, liver cancer, kidney cancer, gastric cancer, head and neck squamous cell carcinoma, prostate cancer, lung cancer, non-small cell lung cancer (NSCLC), acute B-lymphoblastic leukemia, bladder cancer, pancreatic cancer, osteosarcoma, myeloma, glioma, ovarian cancer, or skin cancer.

[0154] The "compounds represented by the above general formulas" in the present invention refer to those selected from formula (I), (II), (III), (IV), (V), (VI), (IIA), (IIIA), (IVA), (VA), (VIA), (IIA-a), (IIA-b), (IIA-c), (IIA-d), (IIA-e), (IIA-f), (IIIA-a), (IIIA-b), (IIIA-c), (IVA-a), (IVA-b), (IVA-c), (VA-a), (VA-b), (VA-c), (VIA-a), (VIA-b), (VIA-c), (IIA-a1), (IIA-b1), (IIA-c1), (IIA-d1), (IIA-e1), (IIA-f1), (IIA-a2), (IIA-b2), (IIA-c2), (IIA-d2), (IIA-e2), (IIA-f2), (IIIA-a1), (IIIA-b1), (IIIA-c1), (IVA-a1), (IVA-b1), (IVA-c1), (VA-a1), (VA-b1), (VA-c1), (VIA-a1), (VIA-b1), (VIA-c1), (IIA-1), (IIA-2), (IIA-3), (IIA-4), (IIA-5), (IIA-6), (IIA-7), (IIA-8), (IIA-9), (IIA-10), (IIA-11), (IIA-12), (IIA-13), (IIA-14), (IIA-15), (IIA-16), (IIA-17), (IIA-18), (IIIA-1), (IIIA-2), (IIIA-3), (IIIA-4), (IIIA-5), (IIIA-6), (IIIA-7), (IIIA-8), (IIIA-9), (IVA-1), (IVA-2), (IVA-3), (IVA-4), (IVA-5), (IVA-6), (IVA-7), (IVA-8), (IVA-9), (VA-1), (VA-2), (VA-3), (VA-4), (VA-5), (VA-6), (VA-7), (VA-8), (VA-9), (VIA-1), (VIA-2), (VIA-3), (VIA-4), (VIA-5), (VIA-6), (VIA-7), (VIA-8), (VIA-9), (IIB), (IIIB), (IVB), (VB), (VIB), (IIB-a), (IIB-b), (IIB-c), (IIB-d), (IIB-e), (IIB-f), (IIIB-a), (IIIB-b), (IIIB-c), (IVB-a),Compounds of any one or more of the following general formulas: (IVB-b), (IVB-c), (VB-a), (VB-b), (VB-c), (VIB-a), (VIB-b), (VIB-c), (IIB-a1), (IIB-b1), (IIB-c1), (IIB-d1), (IIB-e1), (IIB-f1), (IIIB-a1), (IIIB-b1), (IIIB-c1), (IVB-a1), (IVB-b1), (IVB-c1), (VB-a1), (VB-b1), (VB-c1), (VIB-a1), (VIB-b1), or (VIB-c1).

[0155] Unless otherwise stated, the general chemical terms used in the structural formulas have their usual meanings.

[0156] For example, unless otherwise stated, the term "halogen" as used in this invention refers to fluorine, chlorine, bromine, or iodine.

[0157] In this invention, unless otherwise stated, "alkyl" includes straight-chain or branched monovalent saturated hydrocarbon groups. For example, alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc. Similarly, "C 1-6 "alkyl" 1-6 "" refers to a group consisting of 1, 2, 3, 4, 5 or 6 carbon atoms arranged in a straight or branched form.

[0158] The term "alkylene" refers to the group formed by removing one hydrogen atom from the aforementioned "alkyl". Examples include methylene, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH(CH3)-, and -CH2CH(CH3)CH2-.

[0159] The term "alkoxy" refers to the oxygen ether form of the aforementioned straight-chain or branched alkyl group, i.e., -O-alkyl.

[0160] The term "halogenated alkyl" refers to an alkyl group in which one or more H atoms have been replaced by halogen atoms.

[0161] The term "haloalkoxy" refers to a group consisting of -O-haloalkyl groups.

[0162] The term "oxo" or "oxo group" refers to an oxygen atom in the form of a divalent substituent, which forms a carbonyl group when attached to a carbon atom, and a sulfoxide group, sulfone group, or N-oxide group when attached to a heteroatom.

[0163] The term "cycloalkyl" refers to a cyclic system having at least one cycloalkyl group. Preferably, C3-12 Cycloalkyl, more preferably C 3-6 Yuan, of which "C" 3-12 The term "cycloalkyl" refers to the fact that a cycloalkyl group can have 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 cyclic atoms. The cycloalkyl group can include monocyclic and polycyclic rings (e.g., having 2, 3, or 4 fused rings, spirocyclic, bridged rings, etc.). In some embodiments, the cycloalkyl group includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, etc.; the cycloalkyl group can also be fused to an aryl, heterocyclic, or heteroaryl ring, wherein the ring connected to the parent structure is a cycloalkyl group.

[0164] The term "alkenyl" refers to an alkyl group having one or more carbon-carbon double bonds, such as vinyl, propenyl, 1,3-butadiene, cis-butenyl, trans-butenyl, etc.

[0165] The term "alkenyl" refers to the group formed by removing one hydrogen atom from the aforementioned "alkenyl" group, such as -CH=CH-, -CH2CH=CH-, -CH2CH=CHCH2-, etc.

[0166] The term "imino" refers to the divalent group remaining after removing two hydrogen atoms from an ammonia molecule, with the structural formula: HN= (or -NH-). When it is attached to a hydrocarbon group, it forms a secondary amine.

[0167] The term "alkynyl" refers to an alkyl group having one or more carbon-carbon triple bonds, such as ethynyl, propynyl, etc.

[0168] The term "aryl," in this invention, unless otherwise stated, refers to an unsubstituted or substituted monocyclic or fused-ring aromatic group comprising a carbide ring atom. Preferably C 6-12 aryl, more preferably aryl is C 6-10 Aromatic ring groups, either monocyclic or bicyclic. Preferably phenyl or naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl group, wherein the ring attached to the parent structure is an aryl ring; non-limiting examples include, but are not limited to, benzocyclopentyl.

[0169] The term "heteroaryl" in this invention, unless otherwise stated, refers to a monocyclic or polycyclic (e.g., fused bicyclic) aromatic heterocycle having at least one heteroatom selected from N, O, and / or S, wherein the nitrogen or sulfur heteroatom is selectively oxidized, and the nitrogen heteroatom is selectively quaternized. Preferably, it is a 5-14 membered heteroaryl, wherein "5-14" in 5-14 membered heteroaryl refers to a heteroaryl containing 5-14 cyclic atoms of C, N, O, or S. More preferably, it is a 5-10 membered heteroaryl, and even more preferably, it is a 5-6 membered heteroaryl. Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrroloyl, thiazolyl, thiadiazolyl, triazolyl, pyridinyl, pyridazinyl, indolyl, azaindolyl, indolyl, benzimidazolyl, benzofuranyl, benzothiophene, benzoisoxazolyl, benzothiazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyladenine, quinolinyl, or isoquinolinyl. The heteroaryl group may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring.

[0170] The term "heterocyclic group" refers to a ring system having at least one cyclic alkyl or cyclic alkenyl group containing a heterocycle, wherein the heteroatom is selected from N, O, and / or S. The heterocyclic group can include monocyclic or polycyclic groups (e.g., having 2, 3, or 4 fused rings, spirocyclic, bridged rings, etc.). The heterocyclic group can be connected to other parts of the compound via cyclic carbon atoms or cyclic heteroatoms. Preferably, it is a 3-14 membered heterocyclic group, where "3-14" refers to a heterocyclic group consisting of 3-14 cyclic atoms of C, N, O, or S; more preferably, it is a 3-6 membered heterocyclic group, and even more preferably, a 5-6 membered heterocyclic group; wherein the nitrogen or sulfur heteroatom can be selectively oxidized, and the nitrogen heteroatom can be selectively quaternized. Examples of these heterocyclic groups include, but are not limited to, aza-butyl, pyrrolidinyl, piperidinyl, piperazinyl, oxoperazinyl, oxoperridinyl, tetrahydrofuranyl, dioxopentyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, and tetrahydrooxadiazolyl. Spiroheterocycles can be 6- to 12-membered spiroheterocycles, including, but not limited to, 4-azaspiro[2,4]heptane and 4-azaspiro[2,4]heptane. The heterocyclic group can be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group.

[0171] The term "benzyl" refers to the group formed by removing a hydrogen atom from the methyl carbon in a toluene molecule (C6H5CH2-).

[0172] The term "amino acid residue" refers to the unit of amino acids that make up a polypeptide. When these amino acids are linked together, some of their groups participate in the formation of peptide bonds, resulting in the loss of a water molecule. Therefore, the amino acid unit in a polypeptide is called an amino acid residue; that is, the remaining part after the amino acids linked by peptide bonds lose water. For example, the glycine residue is: -NH-CH2-CO-.

[0173] The term "α-amino acid" refers to any natural (encoded) and non-natural α-aminocarboxylic acid, including their D-isomers, which are called α-amino acids when the amino group is attached to a carbon atom (also called the α-carbon atom) directly bonded to the carboxyl carbon.

[0174] The term "β-amino acid" refers to any β-aminocarboxylic acid, that is, when the amino group is attached to a carbon atom (also called the β-carbon atom) that is one carbon atom away from the carboxyl carbon. Examples include β-alanine and isoserine.

[0175] The term "alkylamino" refers to an open-chain alkyl group containing a nitrogen atom, such as C1-C6 alkylamino groups, including but not limited to methylamino, ethylamino, isopropylamino, dimethylamino, methylethylamino, diethylamino, etc.

[0176] The term "alkathioyl" refers to a straight-chain or branched alkyl group linked by sulfur atoms, i.e., -S-alkyl, such as C 1-6 Alkylthio groups include, but are not limited to, methylthio, ethylthio, propylthio (including n-propylthio and isopropylthio), butylthio (including n-butylthio, isobutylthio, sec-butylthio, and tert-butylthio), pentylthio (including n-pentylthio, isopentylthio, and neopentylthio), and hexylthio (n-hexylthio, 2-methylpentylthio, 3-methylpentylthio, 2,3-dimethylbutylthio, and 2,2-dimethylbutylthio).

[0177] The term "alkylsulfonyl" refers to a straight-chain or branched alkyl group linked by a sulfone group, i.e., -SO2-alkyl, such as C 1-6 Alkyl sulfone groups, including but not limited to methyl sulfone, ethyl sulfone, propane sulfone (including n-propane sulfone and isopropane sulfone), butyl sulfone (including n-butyl sulfone, isobutyl sulfone, sec-butyl sulfone, and tert-butyl sulfone), pentyl sulfone (including n-pentyl sulfone, isopentyl sulfone, and neopentyl sulfone), and hexyl sulfone (n-hexyl sulfone, 2-methylpentyl sulfone, 3-methylpentyl sulfone, 2,3-dimethylbutyl sulfone, and 2,2-dimethylbutyl sulfone), etc.

[0178] The term "cyano" refers to the -CN group.

[0179] The term "medicinal salt" refers to salt prepared from a pharmaceutically acceptable, non-toxic alkali or acid.

[0180] The "compound" described in this invention includes, but is not limited to, compounds in the following forms: free base, stereoisomer, geometric isomer, tautomer, isotope, pharmaceutically acceptable salt, solvate, hydrate, prodrug (ester), etc.

[0181] The "compound" described in this invention can be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers include, for example, enantiomers and diastereomers. Compounds containing asymmetric carbon atoms in this invention can be isolated in optically active pure form or in racemic form. Optically active pure form can be obtained by resolution of racemic mixtures, synthesis using chiral starting materials or chiral reagents.

[0182] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of this invention, prepared by reacting a compound having specific substituents discovered in this invention with a relatively non-toxic acid or base. When the compounds of this invention contain relatively acidic functional groups, a base addition salt can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts or similar salts. When the compounds of this invention contain relatively basic functional groups, an acid addition salt can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Certain specific compounds of this invention contain both basic and acidic functional groups, and thus can be converted into either a base or an acid addition salt.

[0183] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof.

[0184] When the compounds provided by this invention are acids, their corresponding salts can be conveniently prepared from pharmaceutically acceptable, non-toxic bases, including inorganic and organic bases. Salts derived from inorganic bases include salts of aluminum, ammonium, calcium, copper (high and low valence), ferric iron, ferrous iron, lithium, magnesium, manganese (high and low valence), potassium, sodium, zinc, etc. Salts of ammonium, calcium, magnesium, potassium, and sodium are particularly preferred. Non-toxic organic bases capable of being derived into pharmaceutically acceptable salts include primary, secondary, and tertiary amines, as well as cyclic amines and amines containing substituents, such as naturally occurring and synthetic amines containing substituents. Other pharmaceutically acceptable non-toxic organic bases that can form salts include ion exchange resins, as well as arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, chloroprocaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.

[0185] When the compound provided by this invention is a base, pharmaceutically acceptable non-toxic acids, including inorganic and organic acids, can be used to conveniently prepare their corresponding salts. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucilage, nitric acid, pyric acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, oxalic acid, propionic acid, glycolic acid, hydroiodic acid, perchloric acid, cyclohexanesulfonic acid, salicylic acid, 2-naphthalenesulfonic acid, saccharinic acid, trifluoroacetic acid, tartaric acid, and p-toluenesulfonic acid. More preferably, citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid. More preferably, formic acid and hydrochloric acid.

[0186] Unless otherwise stated, the term "isomer" is intended to include geometric isomers, cis-trans isomers, stereo isomers, enantiomers, optical isomers, diastereomers and tautomers.

[0187] In addition to the salt form, the compounds provided by this invention also exist in prodrug form. The prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to be converted into the compounds of this invention. Furthermore, the prodrugs can be converted into the compounds of this invention in the in vivo environment via chemical or biochemical methods.

[0188] The compounds of this invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium. 3 H), Iodine-125 125 I) or C-14 14C). For example, deuterium can be used to replace hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds of this invention, regardless of radioactivity, are included within the scope of this invention.

[0189] The drug prodrugs of the compounds of this invention are included within the scope of protection of this invention. Generally, a drug prodrug refers to a functional derivative that is readily converted into the desired compound in vivo. For example, any pharmaceutically acceptable salt, ester, salt of ester, or other derivative of the compounds of this application, which, upon administration to a receptor, can directly or indirectly provide the compound of this application or its pharmaceutically active metabolites or residues.

[0190] The compounds described in this invention may contain one or more asymmetric centers, and may thereby produce diastereomers and optical isomers. This invention includes all possible diastereomers and their racemic mixtures, their substantially pure enantiomers, all possible geometric isomers, and their pharmaceutical salts.

[0191] When the compounds represented by the above general formulas have tautomers, unless otherwise stated, the present invention includes any possible tautomers and their pharmaceutical salts, and mixtures thereof.

[0192] This invention also includes atoms of all isotopes, whether in intermediates or final compounds. Isotopic atoms include those having the same number of atoms but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0193] The term "pharmaceutical composition" refers to a mixture of one or more compounds of this application or their pharmaceutical salts with pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compounds of this application to an organism.

[0194] In this invention, the terms "a," "an," "the," "at least one," and "one or more" are used interchangeably. Thus, for example, a mixture comprising "a" pharmaceutically acceptable excipient can be interpreted as indicating that the pharmaceutical composition includes "one or more" pharmaceutically acceptable excipients.

[0195] The term "pharmaceuticalally acceptable excipient" refers to excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0196] The pharmaceutical compositions of the present invention can be prepared by combining the compounds of this application with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalers, gels, microspheres and aerosols.

[0197] Typical routes of administration for the compounds of the present invention or their pharmaceutical salts or pharmaceutical compositions include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, nasal, ocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0198] The term "treatment" generally refers to achieving the desired pharmacological and / or physiological effect. This effect can be therapeutic, depending on whether it partially or completely stabilizes or cures the disease and / or causes side effects due to the disease. As used herein, "treatment" encompasses any treatment of a patient's disease, including: (a) suppressing the symptoms of the disease, i.e., preventing its progression; or (b) alleviating the symptoms of the disease, i.e., causing the disease or symptoms to regress.

[0199] The term "effective amount" means (i) the amount of the compound of this application used to treat or prevent a particular disease, condition, or disorder; (ii) to reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder; or (iii) to prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the compound of this application constituting a "therapeutic effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by a person skilled in the art based on their own knowledge and the present disclosure.

[0200] The term "STAT6" refers to member 6 of the family of signal transduction and transcription activator factors.

[0201] Based on the target of STAT6 inhibitors, this invention developed a series of novel ternary fused-ring compounds and conducted related biological experiments. The results showed that the series of compounds significantly inhibited STAT6 phosphorylation, and exhibited high inhibitory activity in STAT6 protein fluorescence polarization experiments, demonstrating great promise for clinical application. Detailed Implementation

[0202] To make the above content clearer and more explicit, the technical solution of the present invention will be further illustrated by the following embodiments. The following embodiments are only used to illustrate specific implementation methods of the present invention so that those skilled in the art can understand the present invention, but are not intended to limit the scope of protection of the present invention. In the specific implementation methods of the present invention, the technical means or methods, etc., not specifically described, are conventional technical means or methods in the art.

[0203] Unless otherwise stated, all temperatures in this invention refer to degrees Celsius.

[0204] This invention uses the following abbreviations:

[0205] DCM: Dichloromethane; DMF: N,N-Dimethylformamide; DIPEA / DIEA: N,N-Diisopropylethylamine; EA: Ethyl acetate; LC-MS: Liquid Chromatography-Mass Spectrometry; HATU: 2-(7-azabenzotriazole)-N,N,N',N'-Tetramethylurea hexafluorophosphate; TFA: Trifluoroacetic acid; Cd powder; CuCl: Cuprous chloride; LiOH: Lithium hydroxide; EtOH: Ethanol; MeONa: Sodium methoxide; DMEDA: N,N'-Dimethylethylenediamine; ACN: Acetonitrile; DDQ: 2,3-Dichloro-5,6-dicyanobenzoquinone; THF: Tetrahydrofuran; TMSBr: Trimethylbromosilane; AgNO3: Nitric acid Silver; NaOH: Sodium hydroxide; CH3I: Iodomethane; NaH: Sodium hydride; DMSO: Dimethyl sulfoxide; Ac2O: Acetic anhydride; tBuOK: Potassium tert-butoxide; DMF-DMA: N,N-Dimethylformamide dimethyl acetal; Bop: Benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate; DBU: 1,8-Diazacyclo[5,4,0]undecene-7; EDCI: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; HOBT: 1-Hydroxybenzotriazole; MeCN: Acetonitrile; LC-MS: Liquid chromatography-mass spectrometry; 20mL×3: 3 times, 20mL each time; 30mL×3: 3 times, 30mL each time.

[0206] Preparation Example 1: Synthesis of (3R,4S or 3S,4R)-1-((3S,6S,10aS)-6-amino-5-oxodecahydropyrrolo[1,2-a]azacyclobutane-3-carbonyl)-4-phenylpyrrolidin-3-nitrile (intermediate M1)

[0207]

[0208] Step 1: Synthesis of ((3S,6S,10aS)-3-((3R,4S or 3S,4R)-3-cyano-4-phenylpyrrolidine-1-carbonyl)-5-oxodecahydropyrrolo[1,2-a]azo-6-yl) tert-butyl carbamate (M1-2)

[0209] (3S,6S,10aS)-6-((tert-Butoxycarbonyl)amino)-5-oxodecahydropyrrolo[1,2-a]azo-3-carboxylic acid (M1-1, 326 mg, 1 mmol) and (3R,4S or 3S,4R)-4-phenylpyrrolidine-3-carbamate (206 mg, 1.2 mmol, prepared according to WO2023133336) were added to a flask, along with 5 mL of DMF as solvent. The flask was cooled to 0°C in an ice bath, and then HATU (570 mg, 1.5 mmol) and DIPEA (193 mg, 1.5 mmol) were added while maintaining this temperature. The mixture was then allowed to return to room temperature for further reaction. After 10 min, LC-MS showed that the reaction was complete, and 40 mL of DMF was added. EA was dissolved, washed three times with saturated saline (20 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The product was then passed through a reverse-phase column (methanol / water = 5-95% gradient elution) to obtain the target product ((3S,6S,10aS)-3-((3R,4 or 3S,4R)-3-cyano-4-phenylpyrrolidine-1-carbonyl)-5-oxodecahydropyrrolo[1,2-a]azo-6-yl)carbamate tert-butyl ester, which was lyophilized to give M1-2 (290 mg), with a yield of 60%.

[0210] LC-MS (m / z): 481.1 [M+H] + .

[0211] 1 H NMR(400MHz,Chloroform-d)δ7.28-7.44(m,5H),4.94-5.37(m,1H),4.18-4.72(m,4H),3.97-4.17 (m,2H),3.51-3.82(m,2H),3.09-3.36(m,1H),1.89-2.20(m,6H),1.54-1.76(m,5H),1.43(s,9H).

[0212] Step 2: Synthesis of (3R,4S or 3S,4R)-1-((3S,6S,10aS)-6-amino-5-oxodecahydropyrrolo[1,2-a]azopyren-3-carbonyl)-4-phenylpyrrolidine-3-carbamate (M1)

[0213] ((3S,6S,10aS)-3-((3R,4S or 3S,4R)-3-cyano-4-phenylpyrrolidine-1-carbonyl)-5-oxodecahydropyrrolo[1,2-a]azo-6-yl) tert-butyl carbamate (M1-2, 290 mg, 0.6 mmol) was dissolved in 12 mL of DCM, cooled to 0 °C in an ice bath, and then 3 mL of trifluoroacetic acid was added. After restoring to room temperature for 1 h, LC-MS monitoring showed that the reaction was complete. The target compound M1 was more polar than the starting material. After drying the organic phase, TFA was removed twice with anhydrous toluene. M1 was obtained without purification and could be directly used for the next step of amide condensation reaction.

[0214] LC-MS (m / z): 381.2 [M+H] + .

[0215] Preparation Example 2: Synthesis of (5S,8S,10aR)-5-amino-8-((R)-2-phenylmorpholine-4-carbonyl)-3-propionylheptahydropyrrolo[1,2-a][1,5]diazoazine-6(1H)-one (intermediate M2)

[0216]

[0217] Step 1: Synthesis of compound methyl(5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6-oxodecahydropyrrolo[1,2-a][1,5]diazo-8-carboxylic acid (M2-2)

[0218] Compound M2-1 (0.200 g, 0.580 mmol) was dissolved in THF (5 mL), followed by the sequential addition of triethylamine (0.118 g, 1.17 mmol) and propionyl chloride (65.0 mg, 0.700 mmol) at 0 °C. A white solid precipitated, and the mixture was reacted at 0 °C for 1 hour. After the reaction was confirmed to be complete by LC-MS, water (20 mL) was added, and the aqueous phase was extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane:methanol = 90:10 as eluent) to give compound M2-2 (0.227 g), with a yield of 98.7%.

[0219] LC-MS (m / z): 398.0 [M+H] + .

[0220] Step 2: Synthesis of compound (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6-oxo-3-propionyldecahydropyrrolo[1,2-a][1,5]diazo-8-carboxylic acid (M2-3)

[0221] Compound M2-2 (0.227 g, 0.572 mmol) was dissolved in dioxane (4 mL), and an aqueous solution of lithium hydroxide (48.0 mg, 1.15 mmol) (2 mL) was added. The mixture was reacted at 25 °C for 1 hour. After the reaction was complete as monitored by LC-MS, most of the solvent was removed by concentration under reduced pressure. 1.0 M dilute hydrochloric acid was added to the reaction solution to adjust the pH of the aqueous phase to 5. The aqueous phase was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound M2-3 (0.222 g), with a yield of 99.0%.

[0222] LC-MS (m / z): 384.0 [M+H] + .

[0223] Step 3: Synthesis of compound (5S,8S,10aR)-6-oxo-8-((R)-2-phenylmorpholine-4-carbonyl)-3-propionylhydropyrrolo[1,2-a][1,5]diazoazine-5-yl)tert-butyl carbamate (M2-4)

[0224] Compound M2-3 (0.222 g, 0.579 mmol) and (R)-2-phenylmorpholine (0.112 g, 0.687 mmol) were dissolved in N,N-dimethylformamide (3 mL). Diisopropylethylamine (0.221 g, 1.71 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (0.260 g, 0.684 mmol) were added sequentially, and the mixture was reacted at 25 °C for 1 hour. After the reaction was complete as monitored by LC-MS, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate as eluent) to give compound M2-4 (0.293 g), with a yield of 97.6%.

[0225] LC-MS (m / z): 529.0 [M+H] + .

[0226] Step 4: Synthesis of compound (5S,8S,10aR)-5-amino-8-((R)-2-phenylmorpholine-4-carbonyl)-3-propionylheptahydropyrrolo[1,2-a][1,5]diazoazine-6(1H)-one (M2)

[0227] Compound M2-4 (0.293 g, 0.555 mmol) was dissolved in anhydrous dichloromethane (10 mL). The reaction solution was cooled to 0 °C, and trifluoroacetic acid (2 mL) was added dropwise. The reaction solution was then placed at 25 °C for 1 hour. After the reaction was monitored by TLC (alkalinization) to confirm its completeness, the solution was concentrated under reduced pressure to obtain compound M2 (0.310 g, crude product).

[0228] LC-MS (m / z): 429.0 [M+H] + .

[0229] Preparation Example 3: Synthesis of (3S,6S,10aS)-6-amino-3-((R)-2-phenylmorpholine-4-carbonyl)octahydropyrrolo[1,2-a]zosin-5(1H)-one trifluoroacetate (intermediate M3)

[0230]

[0231] Step 1: Synthesis of tert-butyl ((3S,6S,10aS)-5-oxo-3-((R)-2-phenylmorpholine-4-carbonyl)decahydropyrrolo[1,2-a]zozin-6-yl)carbamate (M3-1)

[0232] Compound M1-1 (326.00 mg, 1.00 mmol) and (R)-2-phenylmorpholine (163.00 mg, 1.00 mmol) were dissolved in N,N-dimethylformamide (5 mL). The reaction solution was cooled to 0 °C, and diisopropylethylamine (322.00 mg, 2.50 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (570.00 mg, 1.50 mmol) were added sequentially. The mixture was then reacted at 25 °C for 30 minutes. After the reaction was monitored by LC-MS to be complete, water (20 mL) was added, and the mixture was extracted with ethyl acetate (3 times, 20 mL each time). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 40:60 as eluent) to give compound M3-1 (470.00 mg), yield 99.8%.

[0233] LC-MS (m / z): 472.0 [M+H] + .

[0234] Step 2: Synthesis of compound (3S,6S,10aS)-6-amino-3-((R)-2-phenylmorpholine-4-carbonyl)octahydropyrrolo[1,2-a]zosin-5(1H)-one trifluoroacetate (M3)

[0235] Compound M3-1 (470.00 mg, 1.00 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (5 mL) was added. The reaction mixture was placed at 25 °C and reacted for 1 hour. After the reaction was confirmed to be complete by LC-MS, the solution was concentrated under reduced pressure to give compound M3 (370.00 mg), with a yield of 99.7%.

[0236] LC-MS (m / z): 372.0 [M+H] + .

[0237] Example 1: Synthesis of (1-(((3S,6S,10aS)-3-(3R,4S or 3S,4R)-3-cyano-4-phenylpyrrolidine-1-carbonyl)-5-oxodecahydropyrrolo[1,2-a]azo-6-yl)amino)-3,4-dihydropyrazine[1,2-a]indol-8-yl)difluoromethyl)phosphonic acid (1)

[0238]

[0239] Step 1: Synthesis of compound ethyl 5-bromo-1-(cyanomethyl)-1H-indole-2-carboxylate (1-1)

[0240] Compound 1-SM (2.00 g, 7.49 mmol) was dissolved in anhydrous N,N-dimethylformamide (20 mL). Sodium hydride (450.0 mg, 11.25 mmol) was added at 0 °C and stirred for 30 minutes while maintaining the temperature. Then, bromoacetonitrile (1.26 g, 10.50 mmol) was added, and the mixture was reacted at 25 °C for 2 hours. After the reaction was complete as monitored by LCMS, water (20 mL) was added to quench the reaction. The aqueous phase was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 80:20 as eluent) to give compound 1-1 (2.30 g), yield 99.9%.

[0241] 1 H NMR (600MHz, DMSO-d6) δ7.99(d,J=1.9Hz,1H),7.80(d,J=8.9Hz,1H),7.59(dd,J=8.9 ,2.0Hz,1H),7.38(s,1H),5.78(s,2H),4.38(q,J=7.1Hz,2H),1.37(t,J=7.1Hz,3H).

[0242] Step 2: Synthesis of compound 8-bromo-3,4-dihydropyrazino[1,2-a]indole-1(2H)-one (1-2)

[0243] Compound 1-1 (2.20 g, 7.19 mmol) and cobalt chloride (1.80 g, 13.8 mmol) were dissolved in a mixed solvent of methanol (30 mL) and tetrahydrofuran (15 mL). Sodium borohydride (1.65 g, 43.4 mmol) was added in portions at 0 °C, and the reaction mixture was incubated at 60 °C for 2 hours. After the reaction was complete as monitored by LC-MS, the mixture was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (using dichloromethane:methanol = 91:9 as eluent) to give compound 1-2 (612.0 mg), with a yield of 32.2%.

[0244] LC-MS (m / z): 265.0 / 267.0 [M+H] + .

[0245] Step 3: Synthesis of compound 8-iodo-3,4-dihydropyrazino[1,2-a]indole-1(2H)-one (1-3)

[0246] Compounds 1-2 (612.0 mg, 2.32 mmol) were dissolved in dioxane (10 mL), and N,N'-dimethylethylenediamine (41.0 mg, 0.47 mmol), cuprous iodide (88.0 mg, 0.46 mmol), and potassium iodide (770.0 mg, 4.64 mmol) were added to a sealed tube. The mixture was purged with nitrogen three times and reacted at 110 °C for 16 hours. After the reaction was complete as monitored by LC-MS, a saturated ammonium chloride aqueous solution (20 mL) was added to quench the reaction. The aqueous phase was extracted with dichloromethane (20 mL × 3), and the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol = 91:9 as eluent) to give compounds 1-3 (936.0 mg), which was the crude product.

[0247] LC-MS (m / z): 313.0 [M+H] + .

[0248] Step 4: Synthesis of diethyl difluoro(1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indol-8-yl)methyl)phosphonate (1-4)

[0249] Cadmium powder (739.0 mg, 6.60 mmol) was added to a 50 mL three-necked flask, followed by 5 mL of anhydrous N,N-dimethylformamide solution containing diethyl bromofluoromethyl phosphate (1.60 g, 5.99 mmol). The mixture was then reacted at 40 °C for 2 hours. In a separate three-necked flask, cuprous chloride (446.0 mg, 4.51 mmol) and crude compounds 1-3 (936.0 mg) were dissolved in 15 mL of anhydrous N,N-dimethylformamide. The yellow solution from the cadmium powder flask was filtered through a filter and slowly injected into the reaction mixture in the second flask. The reaction mixture was then reacted at 40 °C for 16 hours. Add ethyl acetate (30 mL) and water (30 mL), filter with diatomaceous earth, extract the filtrate with ethyl acetate (30 mL × 3), wash the combined organic phases with saturated sodium chloride solution (30 mL), dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography (ethyl acetate:methanol = 97:3 as eluent) to give compounds 1-4 (275.0 mg), with a two-step yield of 31.9%.

[0250] LC-MS (m / z): 373.0 [M+H] + .

[0251] Step 5: Synthesis of diethyl difluoro(1-thio-1,2,3,4-tetrahydropyrazine[1,2-a]indol-8-yl)methyl)phosphonate (1-5)

[0252] Compounds 1-4 (275.0 mg, 0.74 mmol) were dissolved in toluene (8 mL), and Lawson's reagent (327.0 mg, 0.81 mmol) was added. The mixture was reacted at 110 °C for 2 hours. After the reaction was complete as monitored by LC-MS, the solution was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate:methanol = 90:10 as eluent) to give compounds 1-5 (283.0 mg), in 98.6% yield.

[0253] LC-MS (m / z): 389.0 [M+H] + .

[0254] Step 6: Synthesis of diethyl difluoro(1-(methylthio)-3,4-dihydropyrazine[1,2-a]indol-8-yl)methyl)phosphonate (1-6)

[0255] Compounds 1-5 (283.0 mg, 0.73 mmol) were dissolved in dichloromethane (6 mL), and iodomethane (207.0 mg, 1.46 mmol) was added. The mixture was reacted at 25 °C for 5 hours. After the reaction was complete as monitored by LC-MS, the solution was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate:methanol = 90:10 as eluent) to give compounds 1-6 (90.0 mg), in a yield of 30.7%.

[0256] LC-MS (m / z): 403.0 [M+H] + .

[0257] Step 7: Synthesis of compound (1-(((3S,6S,10aS)-3-((3R,4S or 3S,4R)-3-cyano-4-phenylpyrrolidine-1-carbonyl)-5-oxodecahydropyrrolo[1,2-a]azo-6-yl)amino)-3,4-dihydropyrazine[1,2-a]indol-8-yl)difluoromethyl)phosphonate diethyl ester (1-7)

[0258] Compounds 1-6 (70.0 mg, 0.17 mmol) and compound (3R,4S or 3S,4R)-1-((3S,6S,10aS)-6-amino-5-oxodecahydropyrrolo[1,2-a]azacyclobutane-3-carbonyl)-4-phenylpyrrolidin-3-onitrile (M1) (150.0 mg, 0.39 mmol) were dissolved in acetonitrile (3 mL) and heated to 90 °C in a sealed tube for 16 hours. After the reaction was complete as monitored by LC-MS, the solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol = 90:10 as eluent) to give compound 1-7 (20.0 mg), yield 16.0%.

[0259] LC-MS (m / z): 735.0 [M+H] + .

[0260] Step 8: Synthesis of compound (1-(((3S,6S,10aS)-3-(3R,4S or 3S,4R)-3-cyano-4-phenylpyrrolidine-1-carbonyl)-5-oxodecahydropyrrolo[1,2-a]azo-6-yl)amino)-3,4-dihydropyrazine[1,2-a]indol-8-yl)difluoromethyl)phosphonic acid (1)

[0261] Compounds 1-7 (20.0 mg, 0.027 mmol) were dissolved in anhydrous dichloromethane (2 mL). The reaction solution was cooled to 0 °C, and trimethylbromosilane (1 mL) was added dropwise. The reaction solution was then incubated at 25 °C for 16 hours. After the reaction was confirmed to be complete by LC-MS, the solution was concentrated under reduced pressure. A mixture of acetonitrile (4 mL) and water (1 mL) was added, and the reaction solution was incubated at 25 °C for 10 minutes. The solution was then concentrated under reduced pressure, and compound 1 (2.1 mg) was obtained by HPLC purification, with a yield of 11.5%.

[0262] LC-MS (m / z): 679.0 [M+H] + .

[0263] 1H NMR(600MHz,DMSO-d6)δ7.80–7.51(m,2H),7.51–7.17(m,8H),5.27–5.04 (m,1H),4.90–4.50(m,2H),4.40–4.21(m,1H),4.15–3.93(m,2H),3.88–3 .67(m,4H),3.65–3.49(m,3H),2.40–2.21(m,1H),2.12–1.97(m,3H),1.9 6–1.77(m,3H),1.75–1.62(m,3H),1.62–1.53(m,1H),0.88–0.78(m,1H).

[0264] Example 33: Synthesis of (difluoro(1-(((3S,6S,10aS)-5-oxo-3-((R)-2-phenylmorpholine-4-carbonyl)decahydropyrrolo[1,2-a]azo-6-yl)amino)-3,4-dihydropyrazino[1,2-a]indol-8-yl)methyl)phosphonic acid (33)

[0265]

[0266] Step 1: Synthesis of compound difluoro(1-((3S,6S,10aS)-5-oxo-3-((R)-2-phenylmorpholine-4-carbonyl)decahydropyrrole[1,2-a]azooctyl-6-yl)amino)-3,4-dihydropyrazine[1,2-a]indol-8-yl)methyl)phosphonate ethyl ester (33-1)

[0267] Compounds 1-6 were prepared according to steps 1-6 of Example 1.

[0268] Compound M3 (200.0 mg, 0.54 mmol) and compounds 1-6 (140.0 mg, 0.35 mmol) were dissolved in a mixed solution of acetonitrile (2 mL) and N,N-dimethylformamide (1 mL). The mixture was heated to 90 °C in a sealed tube and reacted for 16 hours. After the reaction was confirmed to be complete by LC-MS, the solution was concentrated under reduced pressure and purified by silica gel column chromatography (using dichloromethane:methanol = 90:10 as eluent) to give compound 33-1 (160.0 mg), in a yield of 65.6%.

[0269] LC-MS (m / z): 698.0 [M+H] + .

[0270] Step 2: Synthesis of (difluoro(1-(((3S,6S,10aS)-5-oxo-3-((R)-2-phenylmorpholine-4-carbonyl)decahydropyrrolo[1,2-a]azo-6-yl)amino)-3,4-dihydropyrazino[1,2-a]indol-8-yl)methyl)phosphonic acid (33)

[0271] Compound 33-1 (160.0 mg, 0.23 mmol) was dissolved in anhydrous dichloromethane (6 mL). The reaction solution was cooled to 0 °C, and trimethylbromosilane (1 mL) was added dropwise. The reaction solution was then incubated at 25 °C for 16 hours. After the reaction was confirmed to be complete by LC-MS, the solution was concentrated under reduced pressure. A mixture of acetonitrile (8 mL) and water (2 mL) was added, and the reaction solution was incubated at 25 °C for 10 minutes. The solution was then concentrated under reduced pressure and purified by reverse-phase column chromatography (methanol:water = 80:20 as eluent) to give compound 33 (83.0 mg), with a yield of 53.9%.

[0272] LC-MS (m / z): 670.0 [M+H] + .

[0273] 1 H NMR(600MHz, Methanol-d4)δ7.85(d,J=9.0Hz,1H),7.65(d,J=8.8Hz,1H),7.49–7.02(m,7 H),5.40–5.05(m,2H),4.84–4.71(m,1H),4.72–4.39(m,2H),4.32–3.99(m,2H),3.91–3.81 (m,1H),3.78–3.67(m,1H),3.55–3.37(m,1H),3.28–3.19(m,1H),3.09–2.95(m,1H),2.84– 2.70(m,1H),2.69–2.58(m,1H),2.55–2.29(m,1H),2.24–2.14(m,1H),2.14–1.61(m,10H).

[0274] Example 35: Synthesis of (difluoro(1-(((5S,8S,10aR)-6-oxo-8-((R)-2-phenylmorpholine-4-carboxyl)-3-propionyldecahydropyrrole[1,2-a][1,5]diazol-5-yl)amino)-3,4-dihydropyrazole[1,2-a]indole-8-yl)methyl)phosphoric acid)(35)

[0275]

[0276] Step 1: Synthesis of compound difluoro(1-(((5S,8S,10aR)-6-oxo-8-((R)-2-phenylmorpholine-4-carbonyl)-3-propionyldecahydropyrrolo[1,2-a][1,5]diazaoct-5-yl)amino)-3,4-dihydropyrazino[1,2a]indol-8-yl)methyl)phosphonate ethyl ester (35-1)

[0277] Compounds 1-6 were prepared according to steps 1-6 of Example 1.

[0278] Compound M2 (169.0 mg, 0.40 mmol) and compounds 1-6 (160.0 mg, 0.40 mmol) were dissolved in acetonitrile (3 mL), and the mixture was heated to 90 °C in a sealed tube for 16 hours. After the reaction was confirmed to be complete by LC-MS, the solution was concentrated under reduced pressure and purified by silica gel column chromatography (using dichloromethane:methanol = 90:10 as eluent) to give compound 35-1 (145.0 mg), with a yield of 48.1%.

[0279] LC-MS (m / z): 755.0 [M+H] + .

[0280] Step 2: Synthesis of difluoro(1-(((5S,8S,10aR)-6-oxo-8-((R)-2-phenylmorpholine-4-formyl)-3-propionyldecahydropyrrole[1,2-a][1,5]diazol-5-yl)amino)-3,4-dihydropyrazole[1,2-a]indol-8-yl)methyl)phosphoric acid)(35)

[0281] Compound 35-1 (145.0 mg, 0.19 mmol) was dissolved in anhydrous dichloromethane (2 mL). The reaction solution was cooled to 0 °C, and trimethylbromosilane (1 mL) was added dropwise. The reaction solution was then incubated at 25 °C for 16 hours. After the reaction was confirmed to be complete by LC-MS, the solution was concentrated under reduced pressure. A mixture of acetonitrile (4 mL) and water (1 mL) was added, and the reaction solution was incubated at 25 °C for 10 minutes. The solution was then concentrated under reduced pressure and purified by reverse-phase column chromatography (methanol:water = 50:50 as eluent) to give compound 35 (71.3 mg), with a yield of 51.6%.

[0282] LC-MS (m / z): 727.0 [M+H] + .

[0283] 1 H NMR(600MHz,DMSO-d6)δ7.63(s,2H),7.44–7.01(m,8H),4.93(s,1H),4.84–4.68(m,1H) ,4.37(d,J=12.1Hz,2H),4.21(dd,J=39.7,13.4Hz,2H),4.02(s,3H),3.72(s,3H),3.56( s,2H),3.13(s,1H),2.86(s,1H),2.60(d,J=22.3Hz,2H),2.40(d,J=19.5Hz,2H),2.32– 2.19(m,1H),2.04–1.85(m,2H),1.68(d,J=48.3Hz,3H),1.23(s,1H),1.18–0.95(m,4H).

[0284] Example 45: Synthesis of ((((1-((((3S,6S,10aS)-3-((3R,4S or 3S,4R)-3-cyano-4-phenylpyrrolidine-1-carbonyl)-5-oxodecahydropyrrolo[1,2-a]azolin-6-yl)amino)-3,4-dihydropyrazino[1,2-a]indol-8-yl)difluoromethyl)phosphoryl)bis(oxy)bis(methylene)bis(2,2-dimethylpropionate) (45)

[0285]

[0286] Step 1: Synthesis of compound ((((1-((((3S,6S,10aS)-3-((3R,4S or 3S,4R)-3-cyano-4-phenylpyrrolidine-1-carbonyl)-5-oxodecahydropyrrolo[1,2-a]azolin-6-yl)amino)-3,4-dihydropyrazino[1,2-a]indol-8-yl)difluoromethyl)phosphoryl)bis(oxy)bis(methylene)bis(2,2-dimethylpropionate) (45)

[0287] Compound 1 (388.0 mg, 0.57 mmol) was dissolved in water (10 mL). The reaction solution was cooled to 0 °C, and an aqueous solution of sodium hydroxide (41.0 mg, 1.03 mmol) was added dropwise (2 mL). After the addition was complete, the pH of the solution was approximately 9. Silver nitrate (213.0 mg, 1.25 mmol) was added, and the mixture was reacted at 0 °C for 2 hours. The mixture was filtered, the solid was collected, dried, and dissolved in toluene (3 mL). Methyl iodide tervastatin (414.0 mg, 1.71 mmol) was added, and the mixture was reacted at 25 °C for 16 hours. After the reaction was confirmed to be complete by LC-MS, the mixture was filtered, concentrated under reduced pressure, and purified by HPLC to obtain compound 45 (7.4 mg), with a yield of 1.4%.

[0288] LC-MS (m / z): 907.0 [M+H] + .

[0289] Example 93: Synthesis of (1-(((3S,6R,10aS)-3-(3R,4S or 3S,4R)-3-cyano-4-phenylpyrrolidine-1-carbonyl)-5-oxodecahydropyrrolo[1,2-a]azolin-6-yl)amino)-4,9-dihydro-3H-pyrido[3,4-b]indol-7-yl)difluoromethyl)phosphonic acid (93)

[0290]

[0291] Step 1: Synthesis of compound methyl 6-bromo-3-formyl-1H-indole-2-carboxylate (93-1)

[0292] Compound 93-SM (5.00 g, 19.68 mmol) was dissolved in anhydrous N,N-dimethylformamide (50 mL), and phosphorus oxychloride (6.04 g, 39.36 mmol) was added at 0 °C. The mixture was then reacted at 100 °C for 4 hours. After the reaction was confirmed to be complete by LC-MS, the reaction solution was cooled and then slowly added dropwise to ice water. A large amount of solid precipitated out. The solid was filtered and dried to give compound 93-1 (4.80 g), with a yield of 86.5%.

[0293] LC-MS (m / z): 280.0 / 282.0 [M–H] – .

[0294] Step 2: Synthesis of compound (E)-6-bromo-3-(2-nitrovinyl)-1H-indole-2-carboxylic acid methyl ester (93-2)

[0295] Compound 93-1 (1.60 g, 5.67 mmol) was dissolved in nitromethane (16 mL), and ammonium acetate (1.31 g, 17.01 mmol) was added. The reaction mixture was placed at 80 °C for 1 hour. After the reaction was complete as monitored by LC-MS, water (30 mL) was added, and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 70:30 as eluent) to give compound 93-2 (840.0 mg), in a yield of 45.6%.

[0296] LC-MS (m / z): 323.0 / 325.0 [M–H] – .

[0297] Step 3: Synthesis of compound methyl 6-bromo-3-(2-nitroethyl)-1H-indole-2-carboxylate (93-3)

[0298] Compound 93-2 (840.0 mg, 2.58 mmol) was dissolved in tetrahydrofuran (15 mL) and methanol (3 mL). Sodium borohydride (195.0 mg, 5.16 mmol) was slowly added in portions at 0 °C, and the reaction mixture was reacted at 0 °C for 0.5 h. After the reaction was complete as monitored by LC-MS, water (30 mL) was added, and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 70:30 as eluent) to give compound 93-3 (691.0 mg), in 81.8% yield.

[0299] LC-MS (m / z): 325.0 / 327.0 [M–H] – .

[0300] Step 4: Synthesis of compound methyl 3-(2-aminoethyl)-6-bromo-1H-indole-2-carboxylate (93-4)

[0301] Compound 93-3 (691.0 mg, 2.11 mmol) was dissolved in ethanol (15 mL) and water (5 mL). Iron powder (591.0 mg, 10.55 mmol) and ammonium chloride (591.0 mg, 10.55 mmol) were added, and the reaction mixture was placed at 80 °C for 2 hours. After the reaction was complete as monitored by LC-MS, the mixture was filtered through diatomaceous earth. Water (30 mL) was added to the filtrate, and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 93-4 (670.0 mg), which was the crude product.

[0302] LC-MS (m / z): 297.0 / 299.0 [M+H] + .

[0303] Step 5: Synthesis of compound 7-bromo-2,3,4-9-tetrahydro-1H-pyrido[3,4-b]indol-1-one (93-5)

[0304] The crude product of compound 93-4 (670.0 mg) was dissolved in methanol (10 mL), and sodium methoxide (243.0 mg, 4.50 mmol) was added. The reaction mixture was placed at 60 °C for 0.5 h. After the reaction was complete as monitored by LC-MS, water (30 mL) was added, and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 93-5 (560.0 mg), which was the crude product.

[0305] LC-MS (m / z): 265.0 / 267.0 [M+H] + .

[0306] 1 H NMR(600MHz,)δ11.76(s,1H),7.65(t,J=2.6Hz,1H),7.58(d,J=8.5Hz,1H),7.54( d,J=1.8Hz,1H),7.19(dd,J=8.5,1.8Hz,1H),3.50(m,2H),2.92(t,J=6.9Hz,2H).

[0307] Step 6: Synthesis of compound 7-iodo-2,3,4-9-tetrahydro-1H-pyrido[3,4-b]indol-1-one (93-6)

[0308] The crude product of compound 93-5 (560.0 mg) was dissolved in anhydrous N,N-dimethylformamide (10 mL), and N,N'-dimethylethylenediamine (37.0 mg, 0.42 mmol), cuprous iodide (80.0 mg, 0.42 mmol), and potassium iodide (701.0 mg, 4.22 mmol) were added. The mixture was placed in a sealed tube, purged with nitrogen three times, and reacted at 110 °C for 16 hours. After the reaction was complete as monitored by LC-MS, water (30 mL) was added, and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 93-6 (600.0 mg), which was the crude product.

[0309] LC-MS (m / z): 313.0 [M+H] + .

[0310] Step 7: Synthesis of diethyl difluoro(1-oxo-2,3,4-9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)methyl)phosphonate (93-7)

[0311] Cadmium powder (688.0 mg, 6.14 mmol) was added to a 50 mL three-necked flask, followed by 8 mL of anhydrous N,N-dimethylformamide solution containing diethyl bromofluoromethyl phosphate (1.54 g, 5.76 mmol). The mixture was then reacted at 40 °C for 2 hours. In a separate three-necked flask, cuprous chloride (285.0 mg, 2.88 mmol) and the crude product of compound 93-6 (600.0 mg) were dissolved in 15 mL of anhydrous N,N-dimethylformamide. The yellow solution from the cadmium powder flask was filtered through a filter and slowly injected into the reaction mixture in the second flask. The reaction mixture was then reacted at 55 °C for 16 hours. Add ethyl acetate (30 mL) and water (30 mL), filter with diatomaceous earth, extract the filtrate with ethyl acetate (30 mL × 3), wash the combined organic phases with saturated sodium chloride solution (30 mL), dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography (ethyl acetate as eluent) to give compound 93-7 (320.0 mg), with a four-step yield of 40.7%.

[0312] LC-MS (m / z): 373.0 [M+H] + .

[0313] Step 8: Synthesis of diethyl difluoro(1-thio-2,3,4-9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)methyl)phosphonate (93-8)

[0314] Compound 93-7 (320.0 mg, 0.86 mmol) was dissolved in tetrahydrofuran (8 mL), and Lawson's reagent (365.0 mg, 0.90 mmol) was added. The mixture was reacted at 60 °C for 1 hour. After the reaction was completed as monitored by LC-MS, the solution was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 30:70 as eluent) to give compound 93-8 (330.0 mg), with a yield of 98.8%.

[0315] LC-MS (m / z): 389.0 [M+H] + .

[0316] Step 9: Synthesis of diethyl difluoro(1-(methylthio)-4,9-dihydro-3H-pyrido[3,4-b]indol-7-yl)methyl)phosphonate (93-9)

[0317] Compound 93-8 (330.0 mg, 0.85 mmol) was dissolved in dichloromethane (8 mL), and iodomethane (362.0 mg, 2.55 mmol) was added. The mixture was reacted at 25 °C for 20 hours. After the reaction was complete as monitored by LC-MS, the solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol = 96:4 as eluent) to give compound 93-9 (300.0 mg), in 87.5% yield.

[0318] LC-MS (m / z): 403.0 [M+H] + .

[0319] Step 10: Synthesis of compound (1-(((3S,6R,10aS)-3-((3R,4S or 3S,4R)-3-cyano-4-phenylpyrrolidine-1-carbonyl)-5-oxodecahydropyrrolo[1,2-a]azolin-6-yl)amino)-4,9-dihydro-3H-pyrido[3,4-b]indol-7-yl)difluoromethyl)phosphonate diethyl ester (93-10)

[0320] Compound 93-9 (50.0 mg, 0.12 mmol) and compound (3R,4S or 3S,4R)-1-((3S,6S,10aS)-6-amino-5-oxodecahydropyrrolo[1,2-a]azacyclobutane-3-carbonyl)-4-phenylpyrrolidin-3-onitrile (M1, 68.0 mg, 0.18 mmol) were dissolved in acetonitrile (5 mL) and heated to 80 °C in a sealed tube for 2 hours. After the reaction was confirmed to be complete by LC-MS, the solution was concentrated under reduced pressure to give compound 93-10 (80.0 mg), which was the crude product.

[0321] LC-MS (m / z): 735.0 [M+H] + .

[0322] Step 11: Synthesis of compound (1-(((3S,6R,10aS)-3-(3R,4S or 3S,4R)-3-cyano-4-phenylpyrrolidine-1-carbonyl)-5-oxodecahydropyrrolo[1,2-a]azolin-6-yl)amino)-4,9-dihydro-3H-pyrido[3,4-b]indol-7-yl)difluoromethyl)phosphonic acid (93)

[0323] The crude product of compound 93-10 (80.0 mg) was dissolved in anhydrous dichloromethane (6 mL). The reaction solution was cooled to 0 °C, and trimethylbromosilane (1 mL) was added dropwise. The reaction solution was then incubated at 25 °C for 16 hours. After the reaction was confirmed to be complete by LC-MS, the solution was concentrated under reduced pressure. A mixed solution of acetonitrile (4 mL) and water (1 mL) was added, and the reaction solution was incubated at 25 °C for 10 minutes. The solution was then concentrated under reduced pressure, and compound 93 (28.5 mg) was obtained by HPLC purification. The two-step yield was 35.0%.

[0324] LC-MS (m / z): 679.0 [M+H] + .

[0325] 1 H NMR(600MHz, Methanol-d4)δ7.86–7.67(m,1H),7.60–7.40(m,2H),7.40–7.21(m,5H),5.16–4.96(m,1H),4.81–4.62(m,2H),4.55–4.37(m,1H),4.22 –3.73(m,3H),3.73–3.45(m,3H),3.45–3.33(m,1H),2.72–2.46(m,2H),2. 45–2.24(m,3H),2.15–1.86(m,5H),1.86–1.70(m,3H),1.70–1.49(m,1H).

[0326] Example 94: Synthesis of ((((1-(((3S,6R,10aS)-3-((3R,4S or 3S,4R)-3-cyano-4-phenylpyrrolidine-1-carbonyl)-5-oxodecahydropyrrolo[1,2-a]azocine-6-yl)amino)-4,9-dihydro-3H-pyrido[3,4-b]indol-7-yl)difluoromethyl)phosphoryl)bis(oxy))bis(methylene)bis(2,2-dimethylpropionate) (Compound 94)

[0327]

[0328] Compound 93 (50.0 mg, 0.07 mmol) was dissolved in water (4 mL). The reaction solution was cooled to 0 °C, and an aqueous solution of sodium hydroxide (41.00 mg, 0.133 mmol) was added dropwise (1 mL). After the addition was complete, the pH of the solution was approximately 9. Silver nitrate (30.00 mg, 0.18 mmol) was added, and the reaction was carried out at 0 °C for 2 hours. The mixture was filtered, the solid was collected, and the water was removed by vacuum drying. The resulting solid was dissolved in acetonitrile (4 mL), and methyl iodide tervastatin (170.00 mg, 0.70 mmol) was added. The reaction was carried out at 25 °C for 16 hours. After the reaction was monitored by LC-MS to be complete, the mixture was filtered, concentrated under reduced pressure, and purified by preparative TLC (dichloromethane:methanol = 10:1) to obtain compound 94 (7.0 mg), with a yield of 11.0%.

[0329] LC-MS (m / z): 907.0 [M+H] + .

[0330] Example 98: Synthesis of S,S'-(((((1-(((3S,6R,10aS)-3-((3R,4S or 3S,4R)-3-cyano-4-phenylpyrrolidine-1-carbonyl)-5-oxodecahydropyrrolo[1,2-a]acoxin-6-yl)amino)-4,9-dihydro-3H-pyrido[3,4-b]indol-7-yl)difluoromethyl)phosphoryl)bis(oxy))bis(ethane-2,1-diyl))dibutane thioester (compound 98)

[0331]

[0332] Compound 93 (50.0 mg, 0.07 mmol) was dissolved in water (4 mL). The reaction solution was cooled to 0 °C, and an aqueous solution of sodium hydroxide (41.00 mg, 0.133 mmol) was added dropwise (1 mL). After the addition was complete, the pH of the solution was approximately 9. Silver nitrate (30.00 mg, 0.70 mmol) was added, and the reaction was carried out at 0 °C for 2 hours. The mixture was filtered, the solid was collected, and the water was removed by vacuum drying. The resulting solid was dissolved in acetonitrile (4 mL), and ethyl thiobutyrate (181.00 mg, 0.70 mmol) was added. The mixture was then reacted at 25 °C for 16 hours. After the reaction was confirmed to be complete by LC-MS, the mixture was filtered, concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain compound 98 (1.0 mg), with a yield of 1.5%.

[0333] LC-MS (m / z): 939.0 [M+H] + .

[0334] Example 101: Synthesis of (1-(((3S,6R,10aS)-3-(3R,4S or 3S,4R)-3-cyano-4-phenylpyrrolidine-1-carbonyl)-5-oxodecahydropyrrolo[1,2-a]azo-6-yl)amino)-9H-pyrido[3,4-b]indol-7-yl)difluoromethyl)phosphonic acid (101)

[0335]

[0336] Step 1: Synthesis of compound (1-(((3S,6R,10aS)-3-(3R,4S or 3S,4R)-3-cyano-4-phenylpyrrolidine-1-carbonyl)-5-oxodecahydropyrrolo[1,2-a]azolin-6-yl)amino)-9H-pyrido[3,4-b]indol-7-yl)difluoromethyl)phosphonate diethyl ester (101-1)

[0337] Compounds 93-10 were prepared according to steps 1-10 of Example 93.

[0338] Compound 93-10 (180.0 mg, 0.24 mmol) was dissolved in anhydrous 1,4-dioxane (6 mL), and DDQ (109.0 mg, 0.48 mmol) was added at 0 °C. The reaction mixture was then incubated at 25 °C for 3 hours. After the reaction was complete as monitored by LCMS, water (10 mL) was added, and the aqueous phase was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (using dichloromethane:methanol = 96:4 as the eluent) to give compound 101-1 (130.0 mg), with a yield of 45.6%.

[0339] LC-MS (m / z): 733.0 [M+H] + .

[0340] Step 2: Synthesis of compound (1-(((3S,6R,10aS)-3-(3R,4S or 3S,4R)-3-cyano-4-phenylpyrrolidine-1-carbonyl)-5-oxodecahydropyrrolo[1,2-a]azo-6-yl)amino)-9H-pyrido[3,4-b]indol-7-yl)difluoromethyl)phosphonic acid (101)

[0341] Compound 101-1 (130.0 mg, 0.18 mmol) was dissolved in anhydrous dichloromethane (6 mL). The reaction solution was cooled to 0 °C, and trimethylbromosilane (1 mL) was added dropwise. The reaction solution was then incubated at 25 °C for 16 hours. After the reaction was confirmed to be complete by LC-MS, the solution was concentrated under reduced pressure. A mixture of acetonitrile (4 mL) and water (1 mL) was added, and the reaction solution was incubated at 25 °C for 10 minutes. The solution was then concentrated under reduced pressure and purified by reverse-phase column chromatography (methanol:water = 70:30 as eluent) to give compound 101 (70.0 mg), with a yield of 57.4%.

[0342] LC-MS (m / z): 677.0 [M+H] + .

[0343] Example 102: Synthesis of ((1-(((3S,6R,10aS)-3-(3R,4S or 3S,4R)-3-cyano-4-phenylpyrrolidine-1-carbonyl)-5-oxodecahydropyrrolo[1,2-a]azolin-6-yl)amino)-9H-pyrido[3,4-b]indol-7-yl)difluoromethyl)phosphoryl)bis(oxy)bis(methylene)bis(2,2-dimethylpropionate) (102)

[0344]

[0345] Step 1: Synthesis of compound ((1-(((3S,6R,10aS)-3-(3R,4S or 3S,4R)-3-cyano-4-phenylpyrrolidine-1-carbonyl)-5-oxodecahydropyrrolo[1,2-a]azolin-6-yl)amino)-9H-pyrido[3,4-b]indol-7-yl)difluoromethyl)phosphoryl)bis(oxy)bis(methylene)bis(2,2-dimethylpropionate) (102)

[0346] Compound 101 (50.0 mg, 0.07 mmol) was dissolved in water (6 mL). The reaction solution was cooled to 0 °C, and an aqueous solution of sodium hydroxide (6.0 mg, 0.13 mmol) was added dropwise (2 mL). After the addition was complete, the pH of the solution was approximately 9. Silver nitrate (28.00 mg, 0.16 mmol) was added, and the mixture was reacted at 0 °C for 2 hours. The mixture was filtered, and the solid was collected and dried under an oil pump. The dried solid was dissolved in toluene (3 mL), and methyl iodide tervastatin (51.0 mg, 0.21 mmol) was added. The mixture was reacted at 25 °C for 16 hours. After the reaction was confirmed to be complete by LC-MS, the mixture was filtered, concentrated under reduced pressure, and purified by preparative TLC (petroleum ether: ethyl acetate = 15:85 as eluent) to obtain compound 102 (7.7 mg), with a yield of 12.2%.

[0347] LC-MS (m / z): 905.0 [M+H] +.

[0348] 1 H NMR(600MHz,DMSO-d6)δ11.80–11.60(m,1H),8.24(t,J=9.4Hz,1H),7.84–7.76(m,1H),7.74(s, 1H),7.49–7.24(m,7H),6.81–6.60(m,1H),5.80–5.54(m,4H),5.41–5.26(m,2H),4.64–4.36(m,2 H),4.35–4.14(m,1H),4.13–3.94(m,1H),3.94–3.75(m,1H),3.71–3.59(m,1H),3.59–3.46(m,1H ),2.35–2.15(m,1H),2.16–1.83(m,6H),1.81–1.52(m,4H),1.45(t,J=7.2Hz,1H),1.13(s,18H).

[0349] Example 113: Synthesis of compound ((4-(((3S,6R,10aS)-3-((3R,4S or 3S,4R)-3-cyano-4-phenylpyrrolidine-1-carboxyl)-5-oxodecahydropyrrolo[1,2-a]azacyclooctyl-6-yl)amino)-5H-pyrimido[5,4-b]indol-7-yl)difluoromethyl)phosphonic acid (113)

[0350]

[0351] Step 1: Synthesis of compound N-(5-bromo-2-cyanophenyl)acetamide (113-1)

[0352] Compound 2-amino-4-bromobenzonitrile (113-SM, 3.00 g, 15.3 mmol) was dissolved in acetic anhydride (15 mL), and the reaction solution was placed at 100 °C for 1 hour. After the reaction was complete as monitored by LC-MS, it was cooled to room temperature, water (20 mL) was added, and stirring was continued for 0.5 hours. The mixture was filtered to obtain a filter cake, which was then dried to give compound 113-1 (3.45 g), with a yield of 94.7%.

[0353] LC-MS (m / z): 239.0 / 241 [M+H] + .

[0354] 1 H NMR (600MHz, DMSO-d6) δ10.28(s,1H),7.91(d,J=1.9Hz,1H),7.77(d,J=8.3Hz,1H),7.55(dd,J=8.4,1.9Hz,1H),2.12(s,3H).

[0355] Step 2: Synthesis of compound N-(2-cyano-5-iodophenyl)acetamide (113-2)

[0356] Compound 113-1 (1.50 g, 6.30 mmol) was dissolved in anhydrous 1,4-dioxane (15 mL), and N,N'-dimethylethylenediamine (554.0 mg, 6.30 mmol), cuprous iodide (1.20 g, 6.30 mmol), and potassium iodide (3.14 g, 18.9 mmol) were added to a sealed tube. The tube was purged with nitrogen three times and reacted at 110 °C for 16 hours. After the reaction was complete as monitored by LC-MS, water (30 mL) was added, and the aqueous phase was extracted with dichloromethane (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 113-2 (1.62 g), which was the crude product.

[0357] LC-MS (m / z): 287.0 [M+H] + .

[0358] Step 3: Synthesis of compound ethyl 1-acetyl-3-amino-6-iodo-1H-indole-2-carboxylate (113-3)

[0359] Potassium tert-butoxide (1.27 g, 11.3 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and the reaction solution was cooled to 0 °C. Compound 113-2 (1.62 g, 5.66 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) and added dropwise to the aforementioned reaction solution. After stirring at 0 °C for 0.5 hours, an anhydrous tetrahydrofuran solution of ethyl bromoacetate (1.42 g, 8.49 mmol) was added (5 mL), and the reaction solution was placed at 25 °C for 3 hours. After the reaction was monitored by LC-MS to be complete, the reaction was quenched with an aqueous solution of saturated ammonium chloride (20 mL). The aqueous phase was extracted with ethyl acetate (30 mL × 3), and the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 70:30 as eluent) to give compound 113-3 (1.53 g), with a two-step yield of 72.7%.

[0360] LC-MS (m / z): 373.0 [M+H] + .

[0361] 1H NMR (600MHz, DMSO-d6) δ8.45(d,J=1.5Hz,1H),7.79(d,J=8.3Hz,1H),7.64(dd,J=8.3 ,1.5Hz,1H),6.77(s,2H),4.30(q,J=7.2Hz,2H),2.37(s,3H),1.31(t,J=7.1Hz,3H).

[0362] Step 4: Synthesis of compound 1-acetyl-3-(((dimethylamino)methylene)amino)-6-iodo-1H-indole-2-carboxylic acid ethyl ester (113-4)

[0363] Compound 113-3 (1.71 g, 4.60 mmol) was dissolved in N,N-dimethylformamide (10 mL), and N,N-dimethylformamide dimethyl acetal (2.17 g, 18.2 mmol) was added. The reaction mixture was placed at 100 °C for 1 hour. After the reaction was confirmed to be complete by LC-MS, the solution was concentrated under reduced pressure to obtain compound 113-4 (2.00 g), which was the crude product.

[0364] LC-MS (m / z): 428.0 [M+H] + .

[0365] Step 5: Synthesis of compound 7-iodo-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one (113-5)

[0366] The crude product of compound 113-4 (2.00 g) was dissolved in ethanol (15 mL), and ammonia (15 mL) was added. The mixture was heated to 70 °C for 2 hours in a sealed tube. After the reaction was complete as monitored by LC-MS, the mixture was concentrated under reduced pressure. Dichloromethane (10 mL) was added to the residue, and the mixture was filtered to obtain a filter cake. The filter cake was dried to give compound 113-5 (860.0 mg), with a two-step yield of 60.1%.

[0367] LC-MS (m / z): 312.0 [M+H] + .

[0368] 1 H NMR (600MHz, DMSO-d6) δ12.17(brs,2H),8.02(s,1H),7.88(d,J=1.5Hz,1H),7.81(d,J=8.4Hz,1H),7.52(dd,J=8.3,1.5Hz,1H).

[0369] Step 6: Synthesis of compound (3R,4S or 3S,4R)-1-((3S,6R,10aS)-6-((7-iodo-5H-pyrimidino[5,4-b]indol-4-yl)amino)-5-oxodecahydropyrrolo[1,2-a]azacyclobutane-3-carbonyl)-4-phenylpyrrolidin-3-nitrile (113-6)

[0370] Compound 113-5 (350.0 mg, 1.13 mmol) and benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (999.0 mg, 2.26 mmol) were dissolved in N,N-dimethylformamide (10 mL), DBU (258.0 mg, 1.70 mmol) was added, and the mixture was reacted at 25 °C for 0.5 hours. The trifluoroacetate of compound (3R,4S or 3S,4R)-1-((3S,6S,10aS)-6-amino-5-oxodecahydropyrrolo[1,2-a]azacyclobutane-3-carbonyl)-4-phenylpyrrolidin-3-onitrile (M1, 1.68 g, 3.39 mmol) was dissolved in N,N-dimethylformamide (10 mL) and added to the above reaction solution, followed by the addition of N,N-diisopropylethylamine (729.0 mg, 5.65 mmol), and the reaction was carried out at 60 °C for 18 hours. After the reaction was monitored by LC-MS to be complete, water (30 mL) was added, and the aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (using dichloromethane:methanol = 98:2 as eluent) to give compound 113-6 (300.0 mg), with a yield of 39.4%.

[0371] LC-MS (m / z): 674.0 [M+H] + .

[0372] Step 7: Synthesis of compound diethyl(4-(((3S,6R,10aS)-3-((3R,4S or 3S,4R)-3-cyano-4-phenylpyrrolidine-1-formyl)-5-oxodecahydropyrrolo[1,2-a]azacyclooctyl-6-yl)amino)-5H-pyrimido[5,4-b]indol-7-yl)difluoromethyl)phosphate (113-7)

[0373] Cadmium powder (167.0 mg, 1.49 mmol) was added to a 50 mL three-necked flask, followed by 5 mL of anhydrous N,N-dimethylformamide solution containing diethyl bromofluoromethyl phosphate (360.0 mg, 1.35 mmol). The mixture was then reacted at 40 °C for 2 hours. In a separate three-necked flask, cuprous chloride (67.0 mg, 0.68 mmol) and compound 113-6 (300.0 mg, 0.45 mmol) were dissolved in 10 mL of anhydrous N,N-dimethylformamide. The yellow solution from the cadmium powder flask was filtered through a filter and slowly injected into the reaction mixture in the second flask. The reaction mixture was then reacted at 55 °C for 16 hours. After the reaction was monitored by LC-MS to be complete, ethyl acetate (30 mL) and water (30 mL) were added. The mixture was filtered through diatomaceous earth, and the filtrate was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane:methanol = 95:5 as eluent) to give compound 113-7 (150.0 mg), with a yield of 45.5%.

[0374] LC-MS (m / z): 734.0 [M+H] + .

[0375] Step 8: Synthesis of compound ((4-(((3S,6R,10aS)-3-((3R,4S or 3S,4R)-3-cyano-4-phenylpyrrolidine-1-formyl)-5-oxodecahydropyrrolo[1,2-a]azacyclooctyl-6-yl)amino)-5H-pyrimido[5,4-b]indol-7-yl)difluoromethyl)phosphonic acid (113)

[0376] Compound 113-7 (150.0 mg, 0.20 mmol) was dissolved in anhydrous dichloromethane (8 mL). The reaction solution was cooled to 0 °C, and trimethylbromosilane (2 mL) was added dropwise. The reaction solution was incubated at 25 °C for 16 hours, followed by incubation at 40 °C for 2 hours. After the reaction was confirmed to be complete by LC-MS, the solution was concentrated under reduced pressure, and a mixture of acetonitrile (8 mL) and water (2 mL) was added. The reaction solution was incubated at 25 °C for 30 minutes, concentrated under reduced pressure, and purified by reverse-phase column chromatography (methanol as eluent) to give compound 113 (30.0 mg), with a yield of 22.2%.

[0377] LC-MS (m / z): 678.0 [M+H] + .

[0378] Example 114: Synthesis of compound (4-((3S,6R,10aS)-3-(3R,4S or 3S,4R)-3-cyano-4-phenylpyrrolidine-1-carbonyl)-5-oxodecahydropyrrolo[1,2-a]azo-6-yl)amino)-5H-pyrimido[5,4-b]indol-7-yl)difluoromethyl)phosphoryl)bis(oxy)bis(methylene)bis(2,2-dimethylpropionate) (114)

[0379]

[0380] Compound 113 (30.0 mg, 0.044 mmol) was dissolved in water (3 mL). The reaction solution was cooled to 0 °C, and an aqueous solution of sodium hydroxide (3.2 mg, 0.08 mmol) was added dropwise (1 mL). After the addition was complete, the pH of the solution was approximately 9. Silver nitrate (17.0 mg, 0.10 mmol) was added, and the mixture was reacted at 0 °C for 2 hours. The mixture was filtered, and the solid was collected and dried under an oil pump. The dried solid was dissolved in toluene (3 mL), and methyl iodide tervastatin (31.0 mg, 0.13 mmol) was added. The mixture was reacted at 25 °C for 16 hours. After the reaction was confirmed to be complete by LC-MS, the mixture was filtered, concentrated under reduced pressure, and purified by preparative TLC (ethyl acetate as eluent) to give compound 114 (2.2 mg), with a yield of 5.5%.

[0381] LC-MS (m / z): 906.0 [M+H] + .

[0382] Example 123: Synthesis of compound ((1-(((5S,8S,10aR)-8-(dimethylcarbamoyl)-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazin-5-yl)amino)-9H-pyrido[3,4-b]indol-7-yl)difluoromethyl)phosphonic acid (123)

[0383]

[0384] Step 1: Synthesis of compound methyl(5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazo-8-carboxylic acid (123-1)

[0385] Compound M2-1 (0.250 g, 0.733 mmol) and 123-SM (168.00 mg, 0.949 mmol) were dissolved in anhydrous dichloromethane (10 mL). The reaction mixture was cooled to 0 °C, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.211 g, 1.10 mmol) and 1-hydroxybenzotriazole (0.109 g, 0.807 mmol) were added. The mixture was reacted at 25 °C for 2 hours. After the reaction was complete as monitored by LC-MS, water (50 mL) was added, and the mixture was extracted with DCM (10 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 50:50 as eluent) to give compound 123-1 (0.350 g), yield 95.6%.

[0386] LC-MS (m / z): 501.0 [M+H] + .

[0387] Step 2: Synthesis of compound ((5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazo-8-carboxylic acid (123-2)

[0388] Compound 123-1 (0.350 g, 0.700 mmol) was dissolved in tetrahydrofuran (4 mL). The reaction solution was cooled to 0 °C, and an aqueous solution of lithium hydroxide (59.0 mg, 1.40 mmol) (4 mL) was added dropwise. The mixture was allowed to react at room temperature for 2 hours. After the reaction was confirmed to be complete by LC-MS, 1.0 M dilute hydrochloric acid was added to the reaction solution to adjust the pH of the aqueous phase to acidic. The aqueous phase was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 123-2 (0.330 g), with a yield of 96.7%.

[0389] LC-MS (m / z): 487.0 [M+H] + .

[0390] Step 3: Synthesis of compound (5S,8S,10aR)-8-(dimethylcarbamoyl)-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazo-5-yl)tert-butyl carbamate (123-3)

[0391] Compound 123-2 (501.0 mg, 1.03 mmol) and dimethylamine (210.0 mg, 2.58 mmol) were dissolved in N,N-dimethylformamide (8 mL). The reaction solution was cooled to 0 °C, and diisopropylethylamine (666.0 mg, 5.15 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (587.0 mg, 1.55 mmol) were added sequentially. The mixture was reacted at 25 °C for 1 hour. After the reaction was complete as monitored by LC-MS, water (20 mL) was added, and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate as eluent) to give compound 123-3 (500.0 mg), with a yield of 94.5%.

[0392] LC-MS (m / z): 514.0 [M+H] + .

[0393] Step 4: Synthesis of compound (5S,8S,10aR)-5-amino-N,N-dimethyl-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazo-8-carboxamide (123-4)

[0394] Compound 123-3 (500.0 mg, 0.97 mmol) was dissolved in anhydrous dichloromethane (7 mL). The reaction solution was cooled to 0 °C, and trifluoroacetic acid (1.66 g, 14.56 mmol) was added. The reaction solution was then placed at 25 °C for 1 hour. After the reaction was confirmed to be complete by LC-MS, the solution was concentrated under reduced pressure. The pH of the aqueous phase was adjusted to alkaline with saturated sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 123-4 (400.0 mg), with a yield of 99.5%.

[0395] LC-MS (m / z): 414.0 [M+H] + .

[0396] Step 5: Synthesis of compound (1-(((5S,8S,10aR)-8-(dimethylcarbamoyl)-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazin-5-yl)amino)-4,9-dihydro-3H-pyrido[3,4-b]indol-7-yl)difluoromethyl)phosphonate diethyl ester (123-5)

[0397] Compounds 93-9 were prepared according to steps 1-9 of Example 93.

[0398] Compound 93-9 (100.0 mg, 0.25 mmol) and compound 123-4 (145.0 mg, 0.35 mmol) were dissolved in acetonitrile (6 mL), and the mixture was heated to 80 °C in a sealed tube for 1 hour. After the reaction was confirmed to be complete by LC-MS, the mixture was concentrated under reduced pressure to obtain compound 123-5 (190.0 mg), which was the crude product.

[0399] LC-MS (m / z): 768.0 [M+H] + .

[0400] Step 6: Synthesis of compound (1-(((5S,8S,10aR)-8-(dimethylcarbamoyl)-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazin-5-yl)amino)-9H-pyrido[3,4-b]indol-7-yl)difluoromethyl)phosphonate diethyl ester (123-6)

[0401] The crude product of compound 123-5 (190.0 mg) was dissolved in anhydrous 1,4-dioxane (10 mL), and DDQ (114.0 mg, 0.50 mmol) was added at 0 °C. The reaction mixture was then incubated at 25 °C for 3 hours. After the reaction was complete as monitored by LCMS, water (10 mL) was added, and the aqueous phase was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol = 96:4 as eluent) to give compound 123-6 (130.0 mg), with a two-step yield of 48.6%.

[0402] LC-MS (m / z): 766.0 [M+H] + .

[0403] Step 7: Synthesis of compound ((1-(((5S,8S,10aR)-8-(dimethylcarbamoyl)-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazin-5-yl)amino)-9H-pyrido[3,4-b]indol-7-yl)difluoromethyl)phosphonic acid (123)

[0404] Compound 123-6 (130.0 mg, 0.17 mmol) was dissolved in anhydrous dichloromethane (6 mL). The reaction solution was cooled to 0 °C, and trimethylbromosilane (1 mL) was added dropwise. The reaction solution was then incubated at 25 °C for 16 hours. After the reaction was confirmed to be complete by LC-MS, the solution was concentrated under reduced pressure. A mixture of acetonitrile (4 mL) and water (1 mL) was added, and the reaction solution was incubated at 25 °C for 10 minutes. The solution was then concentrated under reduced pressure and purified by reverse-phase column chromatography (methanol:water = 70:30 as eluent) to give compound 123 (70.0 mg), with a yield of 57.8%.

[0405] 1 H NMR(600MHz,Methanol-d4)δ7.91(s,2H),7.73(s,1H),7.55–7.50(m,1H),7.50–7.43( m,2H),7.36(s,1H),7.22–7.11(m,1H),5.64–5.25(m,1H),4.94(t,J=8.5Hz,1H),4.77 (s,2H),4.43(s,1H),4.26–3.87(m,2H),3.10(d,J=11.2Hz,3H),2.88(d,J=5.5Hz,3H) ,2.49(d,J=16.9Hz,3H),2.42(q,J=7.1Hz,2H),2.32–2.16(m,2H),2.07–1.87(m,2H).

[0406] LC-MS (m / z): 710.0 [M+H] + .

[0407] Example 133: Synthesis of (1-(((5S,8S,10aR)-8-(dimethylcarbamoyl)-3-(5-methylbenzo[d]isoxazole-3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazooctyl-5-yl)amino)-9H-pyrido[3,4-b]indol-7-yl)difluoromethyl)phosphoryl)bis(oxy))bis(methylene)bis(2,2-dimethylpropionate) (133)

[0408]

[0409] Compound 123 (70.0 mg, 0.09 mmol) was dissolved in water (6 mL). The reaction solution was cooled to 0 °C, and an aqueous solution of sodium hydroxide (7.00 mg, 0.16 mmol) was added dropwise (2 mL). After the addition was complete, the pH of the solution was approximately 9. Silver nitrate (34.0 mg, 0.20 mmol) was added, and the mixture was reacted at 0 °C for 2 hours. The mixture was filtered, and the solid was collected and dried under an oil pump. The dried solid was dissolved in toluene (3 mL), and methyl iodide tervastatin (65.0 mg, 0.27 mmol) was added. The mixture was reacted at 25 °C for 16 hours. After the reaction was confirmed to be complete by LC-MS, the mixture was filtered, concentrated under reduced pressure, and purified by preparative TLC (ethyl acetate as eluent) to give compound 133 (7.5 mg), with a yield of 8.9%.

[0410] LC-MS (m / z): 938.0 [M+H] + .

[0411] Example 143: Synthesis of compound (1-((3S,6R,10aS)-3-(3R,4S or 3S,4R)-3-cyano-4-phenylpyrrolidine-1-carbonyl)-5-oxodecahydropyrrolo[1,2-a]azo-6-yl)amino)-9H-pyrido[3,4-b]indol-7-yl)difluoromethyl)phosphoryl)bis(oxy)bis(methylene)diisopropylbis(carbonate) (143)

[0412]

[0413] Compound 101 (100.0 mg, 0.15 mmol) was dissolved in water (6 mL). The reaction solution was cooled to 0 °C, and an aqueous solution of sodium hydroxide (11.0 mg, 0.27 mmol) was added dropwise (2 mL). After the addition was complete, the pH of the solution was approximately 9. Silver nitrate (56.0 mg, 0.33 mmol) was added, and the mixture was reacted at 0 °C for 2 hours. The mixture was filtered, and the solid was collected and dried under an oil pump. The dried solid was dissolved in toluene (3 mL), and iodomethyl isopropyl carbonate (110.0 mg, 0.45 mmol) was added. The mixture was reacted at 25 °C for 16 hours. After the reaction was confirmed to be complete by LC-MS, the mixture was filtered, concentrated under reduced pressure, and purified by preparative TLC (petroleum ether: ethyl acetate = 15:85 as eluent) to give compound 143 (2.0 mg), with a yield of 1.5%.

[0414] LC-MS (m / z): 909.0 [M+H] + .

[0415] Bioactivity test

[0416] Test Example 1: Fluorescence polarization screening experiment of the compounds of this invention

[0417] 1. Main reagents and consumables

[0418]

[0419]

[0420] 2. Reagent preparation

[0421] 1) Prepare the test buffer (10mL system) according to the table below:

[0422]

[0423] 2) Prepare the working concentrations of each component using the test buffer according to the table below (final volume: 50 μL):

[0424] reagents Working concentration Sample volume Final concentration DMSO — 5μL 10％ STAT6 protein 2.5μM 10 μL 500nM 5-FAM 125nM 5μL 12.5nM Test buffer — 30μL —

[0425] "—" indicates that there is no relevant data.

[0426] 3) The STAT6 protein expression plasmid pT7-TrxA-6×His-STAT6 (human-derived) used in this experiment was induced to express protein using Rosetta (DE3) strain, 0.2 mM IPTG concentration, 16℃, for 20 h. The protein was purified using Ni NTA Beads kit to obtain purified STAT6 protein.

[0427] 3. Fluorescence polarization activity detection

[0428] 1) Compound dilution: Add 2 μL of 10 mM compound stock solution to 198 μL of DMSO to obtain a 100 μM compound dilution. Then, perform a 3-fold serial dilution by adding 30 μL of the 100 μM compound dilution to 60 μL of DMSO to obtain 8 concentrations. Then, add 5 μL of each concentration of the test compound to a 96-well black plate, and set up two negative controls (DMSO final concentration 10%).

[0429] 2) Compound and protein incubation: Then add 30 μL of test buffer and 10 μL of 2.5 μM STAT6 protein to the 96-well black plate, centrifuge at 1000 rpm for 1 min at room temperature, and incubate at 25 °C with shaking for 45 min.

[0430] 3) Substrate reaction: Add 5 μL of 125 nM substrate 5-FAM-ApYKPFQDLI-NH2 to the 96-well black plate, centrifuge at 1000 rpm for 1 min at room temperature, and then incubate at 25 °C in the dark with shaking for 30 min.

[0431] 4) Transfer the reaction system from the 96-well black plate to the 384-well black plate at a rate of 20 μL per well. Detect the absorbance at 485 / 535 nm using a microplate reader and calculate the fluorescence polarization mP value using software.

[0432] 5) Data Processing: The group containing only 5-FAM substrate (without STAT6 protein) was used as a negative control, and the DMSO control group was used as a positive control. The inhibition rate (%) of the compound on the binding of STAT6 to 5-FAM-ApYKPFQDLI-NH2 was calculated using the formula "Inhibition rate (%) = (1 - (Experimental group value - Negative control group value) / (Positive control group value - Negative control group value)) * 100%". Then, the IC50 of the compound was obtained by fitting the data using Graphpad Prism 8 software. 50 value.

[0433] Table 1 shows the fluorescence polarization experiment results of the compounds of this invention on STAT6 protein.

[0434] Table 1. Fluorescence polarization experiment results of the compounds of the present invention.

[0435] Compound numbering <![CDATA[STAT6 IC 50 (nM)]]> 1 181.37 93 39.7 101 63.5 113 117.8 123 155

[0436] Test Example 2: Experiment with the compound p-STAT6 of this invention

[0437] (1) Cells

[0438] Cell Name source BEAS-2B Shanghai Jihe Biotechnology Co., Ltd.

[0439] (2) Reagents and Consumables

[0440]

[0441]

[0442] (3) Compound preparation

[0443] Take an appropriate amount of the test compound and dissolve it in DMSO to 10 mM. Take an appropriate amount of the 10 mM test compound stock solution and perform a 4-fold serial dilution with DMSO to obtain the compound stock solution.

[0444] (4) Experimental methods

[0445] When the BEAS-2B cell density reaches 70%-80%, the cells are seeded into plates, with 1 x 10⁶ cells per well in a 24-well plate. 5Cells were cultured overnight in DMEM medium (containing 2% FBS). Cells in the drug-treated group were pretreated with the drug (1 μM) for 3 h, while the blank group and the IL-4 single-drug group received an equal volume of DMSO. After 3 h of pretreatment, except for the blank group, each well was treated with 2 ng / ml IL-4 for 30 min, followed by cell harvesting. The supernatant was discarded, and the cells were washed once with PBS. 100 μL of RIPA lysis buffer (containing a protease inhibitor mixture, PMSF, and 1.5x protein loading buffer) was added to each well. The cell lysis buffer was boiled at 100 °C for 10 min and stored at -20 °C.

[0446] Equal volumes of protein samples and protein molecular weight standards were loaded into the wells of an SDS-PAGE gel and electrophoresed at 100V. After electrophoresis, the PVDF membrane was transferred at a constant current of 300mA. After transfer, the membrane was removed and blocked with 5% skim milk PBST solution at room temperature for 1 hour. After blocking, the corresponding primary antibody incubation solution (primary antibody dilution ratio 1:1000, 5% BSA + PBST) was added, and the membrane was incubated overnight at 4°C with gentle shaking. After incubation, the membrane was washed four times with PBST for 5 minutes each time. Secondary antibody incubation solution (secondary antibody dilution ratio 1:2000, 5% skim milk + PBST) was added, and the membrane was incubated at room temperature for 1 hour. The membrane was washed four times with PBST for 5 minutes each time. Development and exposure were performed according to the method provided by the ECL chemiluminescence detection kit. The development results were analyzed using ImagJ software to calculate the grayscale molecular weight, inhibition rate, and IC50. 50 .

[0447] The inhibition rate is calculated as follows:

[0448] Inhibition rate (%) = 100 - (gray value of the treated group - gray value of the blank group) / (gray value of the IL-4 monotherapy group - gray value of the blank group) × 100%

[0449] Table 2 shows the results of the degree of inhibition of STAT6 phosphorylation in cells by the compounds of this invention.

[0450] Table 2. Inhibition of cellular pSTAT6 activity by the compounds of this invention.

[0451] Compound numbering pSTAT6 inhibition rate (1 μM) 45 >90％ 102 >90％ 114 >90％ 133 >90％ 143 >90％

Claims

1. A ternary fused-ring compound having the structure shown in formula (I), or its pharmaceutically acceptable salt, isotope derivative, solvate, or its stereoisomer, geometric isomer, tautomer, or its prodrug molecule or metabolite: in, It can be a single bond or a double bond; It is a 9-membered aromatic heterocycle; X 1 Selected from CR 5 Or N; X 2 Selected from C(R) 5 ) f or N(R) 5 ) g ;X 3 X 4 X 5 Each is independently selected from C or N; X 7 Selected from C(R) 5 ) h or N(R) 5 ) i ;X 6 Selected from CR 11 、N(R 11 ) j , S, O or Se; f and h are each independently selected from 1 or 2; g, i, and j are each independently selected from 0 or 1; p is selected from 1 or 2; s is selected from 0, 1, 2, 3, 4 or 5; n is selected from 0, 1, 2, and 3; R 1 R 6 Each is independently selected from R g CR 1a R 2a P(O)OR 1b OR 2b CR 1a R 2a P(O)OR 1b NHR 2b , CR 1a R 2a P(O)(OR 1b )(NH(AA)C(O)OR 1c )、CR 1a R 2a P(O)(NHR 2c )(NH(AA)C(O)OR 1c )、CR 1a R 2a P(O)(NH(AA)C(O)OR 1c )(NH(AA)C(O)OR 1c )、P(O)OR 1b OR 2b 、 P(O)(OR). 1b )(NH(AA)C(O)OR 1c )、P(O)(NHR 2c )(NH(AA)C(O)OR 1c ) or P(O)(NH(AA)C(O)OR 1c )(NH(AA)C(O)OR 1c ); R 1a R 2a Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 1-4 Hydroxyalkyl; or, R 1a and R 2a It forms C3-C6 cycloalkyl or 3-6 membered heterocyclic groups with the atoms it is attached to; R 1b and R 2b are each independently selected from -R 1aa 、-R 1aa -OC(O)-R 1ab 、-R 1aa -C(O)O-R 1ab 、-R 1aa -OC(O)O-R 1ab 、-R 1aa -O-R 1ab 、-R 1aa -SC(O)O-R 1ab 、-R 1aa -SC(O)-R 1ab 、-R 1aa -S-R 1ab 、-R 1aa -O-R 1ab 、-R[[ID=�9]] 1aa -S-R 1ab -S-R 1ac 、-R 1aa -S-R 1ab -O-R 1ac 、-R 1aa -OC(O)NH-R 1ab 、-R 1aa -OC(O)NR 1ab R 1ac 、-R 1aa -OC(O)-R 1ab -O-R 1ac 、-R 1aa -OC(O)O-R 1ab -O-R 1ac 、-R 1aa -SC(O)O-R 1ab -O-R 1ac 、-R 1aa -SC(O)-R 1ab -O-R 1ac or -R 1aa -OC(O)-(NH(AA)C(O)OR 1c ); R 1aa R 1ab R 1ac Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-20 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, 5-7 membered heterocyclic group, C 6-12 Aryl, 5-12 heteroaryl, -C 1-20 Alkylene C 2-6 alkynyl group, -C 1-20 Alkylene C 3-12 cycloalkyl, -C 1-20 Alkylene C 6-12 Aryl or C 1-20 Alkylene C 2-10 heteroaryl, the C 1-20 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 5-7 membered heterocyclic group, C 6-12 Aryl, 5-12 heteroaryl, C 1-20 Alkylene C 2-6 alkynyl group, C 1-20 Alkylene C 3-12 cycloalkyl, C 1-20 Alkylene C 6-12 Aryl or C 1-20 Alkylene C 2-10 Heteroaryl groups, optionally further reacted with one or more R groups h 、-Si(R h )3 or C(O)OR h replace; R 1c R 2c Each C is independently selected from hydrogen, deuterium, or may be optionally substituted with one or more substituent groups. 1-6 Alkyl, 5-7 membered heterocyclic, C 6-12 Aryl, 5-12 heteroaryl, C 1-4 Alkylene C 6-12 Aryl or C 1-4 Alkylene C 2-10 Heteroaryl groups, wherein the substituents are selected from deuterium, halogen, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups; AA is selected from residues of natural or non-natural amino acids, wherein the residues of the natural or non-natural amino acids are in the α or β configuration; R 2 Each C group is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, or optionally substituted with one or more substituents. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 The substituent is an alkylamine group or a 4-10 membered heterocyclic group, wherein the substituent is selected from deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl or C 1-4 Halogenated alkoxy groups; Or, two Rs 2 And the atoms they are attached to cyclize to form C3-C6 cycloalkyl groups, C 6-12 Aryl or 3-6 membered heterocyclic groups, wherein the C3-C6 cycloalkyl group, C 6-12 The aryl or 3-6 membered heterocyclic group may optionally be further surrounded by one or more groups selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Substituents of haloalkyl groups; R 2A R 2B Each C group is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, or optionally substituted with one or more substituents. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 The substituent is an alkylamine group or a 4-10 membered heterocyclic group, wherein the substituent is selected from deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl or C 1-4 Halogenated alkoxy groups; Or, R 2A and R 2B Together with the atoms they are attached to, they form C7-C. 10 Cycloalkyl or 7-10 membered heterocyclic groups, wherein the C7-C 10 Cycloalkyl or 7-10 membered heterocyclic groups may optionally be selected from one or more R 3 Or R 4 Substitution of groups; Or, R 2 With R 2A And the atoms they are attached to cyclize to form C3-C6 cycloalkyl groups, C 6-12 Aryl or 3-6 membered heterocyclic groups, wherein the C3-C6 cycloalkyl group, C 6-12 The aryl or 3-6 membered heterocyclic group may optionally be further surrounded by one or more groups selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Substituents of haloalkyl groups; The R 3 R 4 Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, or optionally influenced by one or more R groups. Y Replacement C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-NH(CO)(CO)-, C 1-6 Alkyl (CO)-, C 1-6 Alkyl (CO)(CO)-, C 6-12 Aryl(CO)-, C 6-12 Aryl(CO)(CO)-, C 6-12 aryl-NH(CO)(CO)-, 5-12-membered heteroaryl(CO)-, 5-12-membered heteroaryl(CO)(CO)-, 5-12-membered heteroaryl-NH(CO)(CO)-, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 Alkylamine group, 4-10 membered heterocyclic group, C 6-12 Aryl, 5-12 heteroaryl, -C 1-6 Alkylene C 6-12 Aryl or C 1-6 Alkylene-C 2-10 Mixed aromatics; Or, R 3 and R 4 The atoms attached to them together form a C3-C6 cycloalkyl or a 3-6 membered heterocyclic group, wherein the C3-C6 cycloalkyl or 3-6 membered heterocyclic group may optionally be bonded by one or more R Y1 Or R Y2 replace; R Y1 R Y2 Each is independently selected from deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl or C 1-4 Halogenated alkoxy groups; Each R 5 Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl or C 1-6 Halogenated alkyl; or two R 5 The atoms to which they are attached cyclize to form C3-C6 cycloalkyl or 3-6 membered heterocyclic groups, wherein the C3-C6 cycloalkyl or 3-6 membered heterocyclic group may optionally be further cyclically bonded by one or more elements selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Substituents of haloalkyl groups; R 7 R 8 Each is independently selected from hydrogen, deuterium, or optionally converted by one or more R. Z Replacement C 1-6 Alkyl, 5-12 membered heterocyclic, 5-12 membered cycloalkyl, C 6-12 Aryl, 5-12 heteroaryl, C 1-4 Alkylene C 6-12 Aryl or C 1-4 Alkylene C 2-10 Mixed aromatics; Or, R 7 and R 8 Together with the atoms they are attached to, they form a 4-14 membered heterocyclic group or a 5-12 membered heteroaryl group, wherein the 4-14 membered heterocyclic group or the 5-12 membered heteroaryl group may optionally be further bonded by one or more R groups. Z replace; R 11 Selected from hydrogen or deuterium; R Y Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, imino, or optionally by one or more R groups. Q Replacement C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 Alkylamine group, 4-10 membered heterocyclic group, C 6-12 Aryl, 5-12 heteroaryl, -NR a R b -OR a -C(O)R a -C(O)OR a -NHC(O)OR a -NR b C(O)OR a -NR b C(O)R a -NR a C(O)NR b R c -C(O)NR a R b -S(O)R c -S(O)2R c -S(O)=NHR c -S(O)NR c R d or -S(O)2NR c R d ; R Z Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, imino, or optionally by one or more R groups. Q Replacement C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 Alkylamine group, 4-10 membered heterocyclic group, C 6-12 Aryl, 5-12 heteroaryl, -NR a R b -OR a -C(O)R a -C(O)OR a -NHC(O)OR a -NR b C(O)OR a -NR b C(O)R a -NR a C(O)NR b R c -C(O)NR a R b -S(O)R c -S(O)2R c -S(O)=NHR c -S(O)NR c R d or -S(O)2NR c R d ; R Q Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, imino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 Alkylamine group, 4-10 membered heterocyclic group, C 6-12 Aryl, 5-12 heteroaryl, -NR e R f -OR e -C(O)R e -C(O)OR e -NHC(O)OR e -NHC(O)R e -NR e C(O)OR f -NR e C(O)R f -NR g C(O)NR e R f -C(O)NR e R f -S(O)R e -S(O)2R e -S(O)=NHR e -S(O)NR e R f or -S(O)2NR e R f ; R a R b R c R d R e R f R g R h Each C group is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, imino, or optionally substituted with one or more substituents. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 Alkylamine group, 4-10 membered heterocyclic group, C 6-12 Aryl, 5-12 heteroaryl, C 1-4 Alkylene C 6-12 Aryl or C 1-4 Alkylene C 2-10 Heteroaryl groups, wherein the substituents are selected from deuterium, halogen, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy, phenyl, or benzyl; The condition is that the compound of formula (I) is not selected from any one or more of the following compounds, or isomers or mixtures of isomers of any one of the following compounds:

2. The compound of claim 1, or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or its stereoisomer, geometric isomer, tautomer, or its prodrug molecule or metabolite, characterized in that, The compound has the structure shown in the following formulas: (IIA-a1), (IIA-b1), (IIA-c1), (IIA-d1), (IIA-e1), (IIA-f1), (IIA-a2), (IIA-b2), (IIA-c2), (IIA-d2), (IIA-e2), (IIA-f2), (IIIA-a1), (IIIA-b1), (IIIA-c1), (IVA-a1), (IVA-b1), (IVA-c1), (VA-a1), (VA-b1), (VA-c1), (VIA-a1), (VIA-b1), or (VIA-c1): in, Z is selected from S, O, -S(=O)-, -S(=O)2-, -S(=O)=NH, CHR 10 CR 9 R 10 or NR 10 ; Y is selected from CHR 9 CR 9 R 10 or NR 9 ; R 2 Each C group is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, or optionally substituted with one or more substituents. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 The substituent is an alkylamine group or a 4-10 membered heterocyclic group, wherein the substituent is selected from deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl or C 1-4 Halogenated alkoxy groups; Or, two Rs 2 And the atoms they are attached to cyclize to form C3-C6 cycloalkyl groups, C 6-12 Aryl or 3-6 membered heterocyclic groups, wherein the C3-C6 cycloalkyl group, C 6-12 The aryl or 3-6 membered heterocyclic group may optionally be further surrounded by one or more groups selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Substituents of haloalkyl groups; R 3 R 4 Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, or optionally influenced by one or more R groups. Y Replacement C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-NH(CO)(CO)-, C 1-6 Alkyl (CO)-, C 1-6 Alkyl (CO)(CO)-, C 6-12 Aryl(CO)-, C 6-12 Aryl(CO)(CO)-, C 6-12 aryl-NH(CO)(CO)-, 5-12-membered heteroaryl(CO)-, 5-12-membered heteroaryl(CO)(CO)-, 5-12-membered heteroaryl-NH(CO)(CO)-, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 Alkylamine group, 4-10 membered heterocyclic group, C 6-12 Aryl, 5-12 heteroaryl, C 1-6 Alkylene C 6-12 Aryl or C 1-6 Alkylene C 2-10 Mixed aromatics; Or, R 3 and R 4 The atoms attached to them together form a C3-C6 cycloalkyl or a 3-6 membered heterocyclic group, wherein the C3-C6 cycloalkyl or 3-6 membered heterocyclic group may optionally be bonded by one or more R Y1 Or R Y2 replace; R 5 Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl or C 1-6 Halogenated alkyl; or two R 5 The atoms to which they are attached cyclize to form C3-C6 cycloalkyl or 3-6 membered heterocyclic groups, wherein the C3-C6 cycloalkyl or 3-6 membered heterocyclic group may optionally be further cyclically bonded by one or more elements selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Substituents of haloalkyl groups; R 9 R 10 Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, or optionally influenced by one or more R groups. Y Replacement C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-NH(CO)(CO)-, C 1-6 Alkyl (CO)-, C 1-6 Alkyl (CO)(CO)-, C 6-12 Aryl(CO)-, C 6-12 Aryl(CO)(CO)-, C 6-12 aryl-NH(CO)(CO)-, 5-12-membered heteroaryl(CO)-, 5-12-membered heteroaryl(CO)(CO)-, 5-12-membered heteroaryl-NH(CO)(CO)-, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 Alkylamine group, 4-10 membered heterocyclic group, C 6-12 Aryl, 5-12 heteroaryl, C 1-6 Alkylene C 6-12 Aryl or C 1-6 Alkylene C 2-10 Mixed aromatics; Or, R 9 and R 10 The atoms attached to them together form a C3-C6 cycloalkyl or a 3-6 membered heterocyclic group, wherein the C3-C6 cycloalkyl or 3-6 membered heterocyclic group may optionally be bonded by one or more R Y1 Or R Y2 replace; R Y1 R Y2 Each is independently selected from deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl or C 1-4 Halogenated alkoxy groups; R Y Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, imino, or optionally by one or more R groups. Q Replacement C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 Alkylamine group, 4-10 membered heterocyclic group, C 6-12 Aryl, 5-12 heteroaryl, -NR a R b -OR a -C(O)R a -C(O)OR a -NHC(O)OR a -NR b C(O)OR a -NR b C(O)R a -NR a C(O)NR b R c -C(O)NR a R b -S(O)R c -S(O)2R c -S(O)=NHR c -S(O)NR c R d or -S(O)2NR c R d ; s、R 1 R 6 R 7 R 8 R Q R a R b R c R d The definition is as described in claim 1.

3. The compound of claim 2, or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or its stereoisomer, geometric isomer, tautomer, or its prodrug molecule or metabolite, characterized in that, The compound has the following formula (IIA-1), (IIA-2), (IIA-3), (IIA-4), (IIA-5), (IIA-6), (IIA-7), (IIA-8), (IIA-9), (IIA-10), (IIA-11), (IIA-12), (IIA -13), (IIA-14), (IIA-15), (IIA-16), (IIA-17), (IIA-18), (IIIA-1), (IIIA-2), (IIIA-3), (IIIA-4), (IIIA-5), (IIIA-6), (IIIA-7), ( IIIA-8), (IIIA-9), (IVA-1), (IVA-2), (IVA-3), (IVA-4), (IVA-5), (IVA-6), (IVA-7), (IVA-8), (IVA-9), (VA-1), (VA-2), (VA-3), (VA- 4), (VA-5), (VA-6), (VA-7), (VA-8), (VA-9), (VIA-1), (VIA-2), (VIA-3), (VIA-4), (VIA-5), (VIA-6), (VIA-7), (VIA-8) or (VIA-9) as shown: Among them, s, R 1 R 2 R 5 R 6 R 7 R 8 R 9 R 10 R Y1 R Y2 The definition is as described in claim 2.

4. The compound of claim 3, or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or its stereoisomer, geometric isomer, tautomer, or its prodrug molecule or metabolite, characterized in that, The R 9 and R 10 Each is independently selected from hydrogen, deuterium, or optionally converted by one or more R. Y Replacement C 1-6 Alkyl, C 1-6 Alkyl-NH(CO)(CO)-, C 1-6 Alkyl (CO)-, C 1-6 Alkyl (CO)(CO)-, C 6-12 Aryl(CO)-, C 6-12 Aryl(CO)(CO)-, C 6-12 Aryl-NH(CO)(CO)-, 5-12-membered heteroaryl(CO)-, 5-12-membered heteroaryl(CO)(CO)-, 5-12-membered heteroaryl-NH(CO)(CO)-, wherein R Y Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, imino, or C. 1-6 alkyl.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule or metabolite thereof, characterized in that, The R 2 Selected from hydrogen or hydroxyl; the R 5 Each is independently selected from hydrogen, halogen, or C. 1-6 Alkyl; or, two Rs 5 The atoms to which they are attached cyclize to form C3-C6 cycloalkyl groups, wherein the C3-C6 cycloalkyl groups may optionally be further cyclically bonded by one or more atoms selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C6, and C6. 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 The alkyl halogroup is substituted by a substituent.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule or metabolite thereof, characterized in that, The R 1 Or R 6 Independently selected 7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule or metabolite thereof, characterized in that, The Selected from:

8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule or metabolite thereof, characterized in that, The compound is selected from the following structural compounds:

9. A pharmaceutical composition, characterized in that, The pharmaceutical composition contains a therapeutically effective amount of any one of the compounds of claims 1-8 or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule or metabolite thereof.

10. Use of any compound of claims 1-8 or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, or pharmaceutical composition of claim 9 in the preparation of a medicament for treating STAT6-mediated diseases or conditions and related diseases or conditions.

11. The method according to claim 10, characterized in that, The STAT6-mediated diseases or conditions and related diseases or conditions are tumors or type II inflammation-related diseases. The type II inflammation-related diseases are selected from atopic dermatitis, bullous pemphigoid, nodular prurigo, chronic spontaneous urticaria, eosinophilic esophagitis, food allergy, chronic rhinosinusitis with nasal polyps (CRSwNP), chronic rhinosinusitis without nasal polyps (CRSsNP), NSAID-exacerbated respiratory disease (NSAID-ERD / AERD), and other related conditions. Allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), eosinophilic granulomatous polyangiitis (EGPA), or allergic bronchopulmonary aspergillosis; the tumor is selected from lymphoma, solitary fibrous tumor, colon cancer, esophageal cancer, breast cancer, bile duct cancer, liver cancer, kidney cancer, gastric cancer, head and neck squamous cell carcinoma, prostate cancer, lung cancer, non-small cell lung cancer (NSCLC), acute B-lymphoblastic leukemia, bladder cancer, pancreatic cancer, osteosarcoma, myeloma, glioma, ovarian cancer, or skin cancer.

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