Three-membered ring compound and pharmaceutical use thereof

Abstract

Provided are a three-membered ring compound having a structure as represented by formula (I) or (II), or a pharmaceutically acceptable salt, isotope derivative, solvate, stereoisomer, geometric isomer, tautomer, prodrug molecule or metabolite thereof, and a pharmaceutical composition thereof and the use thereof. The compound can efficiently degrade STAT6 proteins, can be used in the preparation of a drug for preventing and treating inflammatory diseases, and can be used in the preparation of anti-tumor drugs.

Description

Three-membered cyclic compounds and their pharmaceutical applications Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to three-membered ring compounds, their preparation methods and their pharmaceutical applications. Specifically, it relates to the compounds shown in formulas (I) and (II) or their pharmaceutically acceptable salts, isotope derivatives, solvates, or their stereoisomers, geometric isomers, tautomers, or their 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] KT-621 is the first STAT6 drug to enter clinical trials. It is an oral PROTAC targeted degrader developed by Kymera. In preclinical models, it has shown similar activity to dupilumab and has the potential to treat a variety of allergic and atopic diseases, including atopic dermatitis, asthma, and chronic obstructive pulmonary disease.

[0006] Protein-targeted chimeric degradation (PROTAC) technology recruits E3 ubiquitin ligases to ubiquitinate target proteins, which are then degraded via the proteasome pathway. Compared to traditional small molecule inhibitors, PROTAC molecules exhibit higher affinity for target proteins, down to the micromolar level, and offer advantages such as low dosage, low risk of drug resistance, and high safety.

[0007] Therefore, developing a novel targeted STAT6 degrader is of great significance for the prevention or treatment of STAT6-related diseases. Summary of the Invention

[0008] The technical problem to be solved by the present invention is to provide a novel three-membered ring compound that can be used as a STAT6 degrading agent for the preparation of drugs for treating STAT6-mediated diseases or symptoms and related diseases or symptoms.

[0009] On the one hand, the present invention provides three-membered ring compounds of formulas (I) and (II), or their pharmaceutically acceptable salts, isotope derivatives, solvates, or their stereoisomers, geometric isomers, tautomers, or their prodrug molecules or metabolites:

[0010] in,

[0011] It can be a single bond or a double bond;

[0012] Ring A is C 6-12 Aryl, 5 to 14 membered monocyclic, bicyclic or tricyclic heteroaryl, 5 to 14 membered monocyclic, bicyclic or tricyclic saturated or partially unsaturated heterocyclic groups;

[0013] Ring B is a 4- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group or a 5- to 6-membered heteroaryl group;

[0014] The ring C is a 5-8 member saturated or partially unsaturated carbocyclic group or heterocyclic group;

[0015] Each R 1 Each is independently selected from hydrogen, deuterium, halogen, oxo group, thio group, and C. 1-6 Alkyl or C 1-6 alkoxy group, or two R atoms bonded to the same carbon atom 1 The carbon atoms bonded to it form 3-6 membered cycloalkyl groups;

[0016] Each R 2 Each is independently selected from hydrogen, deuterium, halogen, oxo group, thio group, and C. 1-6 alkylamine group, C 1-6 Cycloalkyl, 3-8 membered heterocyclic or C 1- 6-alkyl; the C 1-6 alkylamine group, C 1-6 cycloalkyl or C 1-6 The alkyl group may optionally be further substituted with substituents selected from the following groups: hydrogen, deuterium, halogen, cyano, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C 3-6 cycloalkyl;

[0017] Or two R atoms bonded to the same atom 2 The atoms bonded to it form 3-8 membered heterocyclic groups or C 3-8 cycloalkyl; the 3-8 membered heterocyclic group or C 3-8 The cycloalkyl group may optionally be further substituted with substituents selected from the following groups: hydrogen, deuterium, halogen, cyano, oxo, C 1-6 Alkyl, C1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C 3-6 cycloalkyl;

[0018] Each R 3 Each is independently selected from hydrogen, deuterium, halogen, oxo group, thio group, and C. 1-6 alkylamine or C 1-6 alkyl;

[0019] R 4 Selected from hydrogen, deuterium, halogen, or methyl;

[0020] R 5 Selected from hydrogen,

[0021] X and Y are each independently selected from C, CH, N, O, S, or NR. 6 ;

[0022] R 6 Selected from hydrogen, C 1-6 Deuterated alkyl, C 3-6 cycloalkyl or C 1-6 alkyl;

[0023] X 2 Selected from N or CH;

[0024] L 1 Selected from key or -Q-;

[0025] L is selected from the following structures, starting from the *** end: -Cy-, -Cy-Ak-, -Cy-Ak-Cy-, -Cy-Ak-Cy-Q-, -Cy-Ak-Cy-Cy-Q-, -Cy-Ak-Cy-Ak-, -Cy-Cy-, -Cy-Cy -Q-, -Cy-Cy-Ak-, -Cy-Cy-Ak-Q-, -Cy-Cy-Ak-Cy-Q-, -Cy-Cy-Cy- or -Cy-Cy-Cy-Q-;

[0026] L X Selected from the following structures, starting from the end connected to G: key, -Ak-Q-, -Q-Ak-, -Ak-Q-Ak-, -Q-Ak-Q- or -Ak-Q-Ak-Q-;

[0027] Each Cy is independently selected from C 4-12 Saturated or partially unsaturated monocyclic or bicyclic carbocyclic groups, 4-12 membered saturated or partially unsaturated monocyclic or bicyclic heterocyclic groups, C 6-12 Aryl or 5-12 membered monocyclic or bicyclic heteroaryl; the C 4-12Saturated or partially unsaturated monocyclic or bicyclic carbocyclic groups, 4-12 membered saturated or partially unsaturated monocyclic or bicyclic heterocyclic groups, C 6-12 The aryl or 5-12 membered monocyclic or bicyclic heteroaryl group may optionally be further substituted by one or more substituents selected from the following groups: hydrogen, deuterium, halogen, cyano, oxo, thio, C 1-6 alkylamine group, C 1- 6-cycloalkyl, C 1-6 Alkoxy or C 1-6 Alkyl, the C 1-6 alkylamine group, C 1-6 cycloalkyl, C 1-6 Alkoxy or C 1-6 The alkyl group may optionally be further substituted with substituents selected from the following groups: hydrogen, deuterium, halogen, cyano, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1- 6-Haloalkoxy or C 3-6 cycloalkyl;

[0028] Each Ak is independently C 1-10 A straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein the hydrocarbon chain may optionally be replaced by 1-3 halogens;

[0029] Each Q is independently selected from -O-, -C(O)-, -C(S)-, -C(R')2-, -NR'-, -S-, -S(O)-, -S(O)2-, -NR'C(O)- or -C(O)NR'-;

[0030] Each R' is independently selected from hydrogen, halogen, or C. 1-6 alkyl;

[0031] G is hydrogen, halogen, or...

[0032] Ring D is C 3-6 Elemental saturated or partially unsaturated carbon cyclogroups, C 6-12 Aryl, 4- to 6-membered monocyclic saturated or partially unsaturated heterocyclic groups, or 5- to 12-membered heteroaryl groups;

[0033] Each R D Each is independently selected from hydrogen, halogen, cyano, oxo, C 1-6 alkylamine group, C 1-6 Alkyl or C 1-6 Alkoxy;

[0034] a, b, c, and d are each independently selected from 0, 1, 2, 3, 4, 5, or 6.

[0035] In some embodiments of the present invention, each Cy is independently selected from C. 4-12 Saturated or partially unsaturated monocyclic or bicyclic carbocyclic groups, 4-12 membered saturated or partially unsaturated monocyclic or bicyclic heterocyclic groups, C 6-12 Aryl or 5-12 membered monocyclic or bicyclic heteroaryl; the C 4-12 Saturated or partially unsaturated monocyclic or bicyclic carbocyclic groups, 4-12 membered saturated or partially unsaturated monocyclic or bicyclic heterocyclic groups, C 6-12 The aryl or 5-12 membered monocyclic or bicyclic heteroaryl group may optionally be further substituted by one or more substituents selected from the following groups: hydrogen, deuterium, halogen, cyano, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C 3-6 Cycloalkyl.

[0036] In some embodiments of the present invention, the ring C is selected from...

[0037] In some embodiments of the present invention, the compound has the structure shown in formula (III) or (IV):

[0038] Among them, ring D is a 5-membered heteroaryl group;

[0039] L XA Selected from -C(O)-, -C(S)-, -C(R')2-, -S(O)- or -S(O)2-;

[0040] L XB Selected from key or C 1-5 Straight-chain or branched saturated or unsaturated hydrocarbon chains;

[0041] R 1 R 2 R 3 R 4 R 5 R D ,R',a,b,c,d,X,Y,X 2 L, L 1 The definitions of ring A and ring B are as described in general formulas (I) and (II).

[0042] In some embodiments of the present invention, the compound has a structure as shown in formula (IIIA), (IIIB), (IVA), or (IVB):

[0043] Among them, ring E is a 5-6 member saturated or partially unsaturated heterocyclic group or heteroaryl group;

[0044] R 1 R 2 R 3 R 4 R 5 R D a, b, c, d, X, Y, X 2 L, L 1 L XA L XB The definitions of ring B and ring D are as described in general formulas (III) and (IV).

[0045] In some embodiments of the present invention, the compound has a structure as shown in formula (IIIa), (IIIb), (IIIc), (IIId), (IVa), (IVb), (IVc), or (IVd):

[0046] Wherein, Cy 1 Each is selected independently from C 4-12 Saturated or partially unsaturated monocyclic or bicyclic carbocyclic groups, 4-12 membered saturated or partially unsaturated monocyclic or bicyclic heterocyclic groups, C 6-12 Aryl or 5-12 membered monocyclic or bicyclic heteroaryl;

[0047] Cy 2 Cy 3 Each is independently selected from C 4-12 Saturated or partially unsaturated monocyclic or bicyclic carbocyclic groups, 4-12 member saturated or partially unsaturated monocyclic or bicyclic heterocyclic groups;

[0048] The Cy 1 Cy 2 Cy 3 Each can also be independently influenced by 1-3 groups selected from hydrogen, deuterium, halogen, cyano, oxo, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C 3-6 Substituents of cycloalkyl groups;

[0049] L m Each can be selected independently from the key or -C 1-3 alkylene-;

[0050] L n Each group is independently selected from the following groups, from Cy 2 or Cy 3 The first segment of the connection is: key, -C(O)-, -O-, -N(R) Ln )-、-C 1-3 alkylene- or -C 1-3 Alkylene-N(R) Ln )-, the C 1-3 The alkylene group may also be optionally replaced by 1-3 halogens;

[0051] R Ln Each is independently selected from hydrogen or C 1-6 alkyl;

[0052] R 1 R 2 R 3 R 4 R 5 R D a, b, c, d, X, Y, X 2 L 1 L XA L XB The definitions of rings A, B, and D are as described in general formulas (III) and (IV).

[0053] In some embodiments of the present invention, the compound has a structure as shown in formula (III-1), (III-2), (III-3), (III-4), (IV-1), (IV-2), (IV-3), or (IV-4):

[0054] Wherein, Cy 1 Each is selected independently from C 4-12 Saturated or partially unsaturated monocyclic or bicyclic carbocyclic groups, 4-12 membered saturated or partially unsaturated monocyclic or bicyclic heterocyclic groups, C 6-12 Aryl or 5-12 membered monocyclic or bicyclic heteroaryl;

[0055] Cy 2 Cy 3 Each is independently selected from C 4-12 Saturated or partially unsaturated monocyclic or bicyclic carbocyclic groups, 4-12 member saturated or partially unsaturated monocyclic or bicyclic heterocyclic groups;

[0056] The Cy 1 Cy 2 Cy 3 Each can also be independently influenced by 1-3 groups selected from hydrogen, deuterium, halogen, cyano, oxo, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C 3-6 Substituents of cycloalkyl groups;

[0057] L m Selected from key or -C 1-3 alkylene-;

[0058] L n Selected from the following groups, from Cy 2 or Cy 3 The first segment of the connection is: key, -C(O)-, -O-, -N(R) Ln )-、-C 1-3 alkylene- or -C 1-3 Alkylene-N(R) Ln )-, the C 1-3 The alkylene group may also be optionally replaced by 1-3 halogens;

[0059] R Ln Selected from hydrogen or C 1-6 alkyl;

[0060] Ring E is a 5-6 member saturated or partially unsaturated heterocyclic group or heteroaryl group;

[0061] R 1 R 2 R 3 R 4 R 5 R D a, b, c, d, X, Y, X 2 L 1 L XA L XB The definitions of ring B and ring D are as described in general formulas (III) and (IV).

[0062] In some embodiments of the present invention, the Selected from

[0063] Among them, R 4 Selected from hydrogen, deuterium, or fluorine;

[0064] R 2a Selected from hydrogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl or C 1-6 cycloalkyl;

[0065] R 2b R 2c Each is independently selected from hydrogen and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl or C 1-6cycloalkyl;

[0066] Or R 2b R 2c The N atoms they are connected to form 3-8 membered heterocyclic groups;

[0067] R 6 Selected from hydrogen, C 1-6 Deuterated alkyl, C 3-6 cycloalkyl or C 1-6 alkyl.

[0068] In some embodiments of the present invention, the Selected from

[0069] In some embodiments of the present invention, the Selected from

[0070] The Selected from

[0071] Among them, each R 10 Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl or C 1-6 Alkoxy;

[0072] Each R 11 Each is independently selected from hydrogen or C. 1-6 alkyl;

[0073] Each R 12 R 13 Each is independently selected from hydrogen or C. 1-6 alkyl;

[0074] Or, R 12 R 13 It forms C with the carbon atom it is attached to. 3-6 cycloalkyl;

[0075] r can be selected from 0, 1, 2 or 3.

[0076] In some embodiments of the present invention, the Selected from the following structures:

[0077] Among them, each R 10 Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl or C 1-6 Alkoxy;

[0078] Each R 11 Each is independently selected from hydrogen or C. 1-6 alkyl;

[0079] Each R 12 R 13 Each is independently selected from hydrogen or C. 1-6 alkyl;

[0080] Or, R 12 R 13 It forms C with the carbon atom it is attached to. 3-6 cycloalkyl;

[0081] r can be selected from 0, 1, 2 or 3.

[0082] In some embodiments of the present invention, L is selected from the following structures:

[0083] Among them, each R cy1 Each is independently selected from hydrogen, deuterium, halogen, cyano, oxo, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy or C 3-6 cycloalkyl;

[0084] Each R cy2 R cy3 Each is independently selected from hydrogen, deuterium, halogen, cyano, oxo, or C. 1-6 alkyl;

[0085] Each R Ln Each is independently selected from hydrogen or C. 1-6 alkyl;

[0086] c1, c2, and c3 are selected from 0, 1, 2, or 3;

[0087] n is selected from 0, 1, 2, or 3;

[0088] m is selected from 1 or 2;

[0089] The The chain can optionally be further replaced by 1-3 halogens.

[0090] In some embodiments of the present invention, the Selected from the following structures:

[0091] In some embodiments of the present invention, the compound is selected from the following structural compounds:

[0092] On the other hand, the present invention provides a pharmaceutical composition containing 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 or metabolite thereof.

[0093] 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-related diseases or conditions and related diseases or conditions.

[0094] 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 for the treatment of STAT6-related diseases or conditions and related diseases or conditions.

[0095] In another aspect, the present invention provides a method for treating and / or preventing diseases, comprising administering to 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 as described above.

[0096] In some implementations, the disease being treated and / or prevented is a STAT6-related disease or condition and related diseases or conditions.

[0097] In some implementations, the STAT6-related diseases or conditions and related diseases or conditions are tumors or type II inflammation-related diseases.

[0098] In some implementations, the type II inflammation-related disease is 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; 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.

[0099] The "compounds represented by the above general formulas" in this invention refers to compounds selected from any one or more of the general formulas (I), (II), (III), (IV), (IIIA), (IIIB), (IVA), (IVB), (IIIa), (IIIb), (IIIc), (IIId), (IVa), (IVb), (IVc), (IVd), (III-1), (III-2), (III-3), (III-4), (IV-1), (IV-2), (IV-3), or (IV-4).

[0100] Unless otherwise stated, the general chemical terms used in the structural formulas have their usual meanings.

[0101] For example, unless otherwise stated, the term "halogen" as used in this invention refers to fluorine, chlorine, bromine, or iodine.

[0102] The term "hydrocarbon chain" refers to a straight or branched hydrocarbon chain consisting only of carbon and hydrogen, linking two structural segments together. It may be saturated or contain one or more carbon-carbon double or triple bonds.

[0103] The term "alkyl" includes monovalent saturated hydrocarbon groups, whether straight-chain or branched. Examples of 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.

[0104] 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-.

[0105] The term "alkoxy" refers to the oxygen ether form of the aforementioned straight-chain or branched alkyl group, i.e., -O-alkyl.

[0106] The term "halogenated alkyl" refers to an alkyl group in which one or more H atoms have been replaced by halogen atoms.

[0107] The term "deuterated alkyl" refers to an alkyl group in which one or more H atoms have been replaced by deuterium atoms.

[0108] The term "haloalkoxy" refers to a group consisting of -O-haloalkyl groups.

[0109] The term "deuterated alkoxy" refers to an alkoxy group in which one or more H atoms have been replaced by deuterium atoms.

[0110] 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.

[0111] The term "thioyl" refers to a sulfur atom in the form of a divalent substituent, which forms a thiocarbonyl group when attached to a carbon atom.

[0112] The term "cycloalkyl" refers to a cyclic system having at least one cycloalkyl group. Preferably, C 3-12 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.

[0113] 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.

[0114] 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, P, 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, P, 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.

[0115] The term "carbocyclic" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group. The partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group is a saturated cycloalkyl group or may optionally contain one, two, or more double and / or triple bonds on its ring, thereby forming a so-called cycloalkenyl or cycloynyl group. Preferably, the carbocyclic group is a cycloalkyl group, i.e., a saturated monocyclic or polycyclic cyclic hydrocarbon group, more preferably a saturated monocyclic hydrocarbon group. For example, non-limiting examples of monocyclic carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, cyclooctatetraenyl, etc.

[0116] The term "heterocyclic group" refers to a ring system having at least one cyclic alkyl or cyclic alkenyl group containing a heteroatom selected from N, O, P, 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 containing 3-14 cyclic atoms of C, N, O, P, 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. Heterocyclic groups also include cyclic systems in which the above-mentioned heterocyclic ring is fused with one or more cycloalkyl, aryl, or heteroaryl groups, including but not limited to: dihydroindolyl, isodihydroindolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinone, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydrobenzopyranyl, tetrahydropyranopyridyl, tetrahydropyrrolopyrazolyl, etc.

[0117] 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.

[0118] The term "cyano" refers to the -CN group.

[0119] The term "medicinal salt" refers to salt prepared from a pharmaceutically acceptable, non-toxic alkali or acid.

[0120] 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.

[0121] 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.

[0122] 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.

[0123] 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.

[0124] 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.

[0125] 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.

[0126] Unless otherwise stated, the term "isomer" is intended to include geometric isomers, cis-trans isomers, stereo isomers, enantiomers, optical isomers, diastereomers and tautomers.

[0127] 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.

[0128] 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 14 C). 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.

[0129] 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.

[0130] 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.

[0131] 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.

[0132] 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.

[0133] 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.

[0134] 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.

[0135] 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.

[0136] 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.

[0137] 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.

[0138] 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.

[0139] 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.

[0140] The term "STAT6" refers to member 6 of the family of signal transduction and transcription activator factors.

[0141] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0142] This invention, based on the STAT6 target, developed a series of novel three-membered cyclic compounds and conducted related biological experiments. The results showed that the compounds exhibited significant STAT6 protein degradation activity, good subtype selectivity, and low hERG toxicity. Furthermore, the compounds demonstrated stable in vitro liver microsomal metabolism with minimal species variation, significantly superior to the positive control, and showed great promise for clinical application. In addition, the synthetic routes provided by this invention are novel, safe, environmentally friendly, and feasible for production. Detailed Implementation

[0143] 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.

[0144] Unless otherwise stated, all temperatures in this invention refer to degrees Celsius.

[0145] The following abbreviations are used in this invention: EA: Ethyl acetate; DCM: Dichloromethane; rt.: Room temperature; HATU: 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate; DIPEA: N,N-diisopropylethylamine; ACN: Acetonitrile; TLC: Thin-layer chromatography; LC-MS: Liquid chromatography-mass spectrometry; THF: Tetrahydrofuran; DMF: N,N-Dimethylformamide; Pd(dppf)Cl2: [1,1'-bis(diphenylphosphine)ferrocene]palladium dioxide; L-proline: L-proline; CuI: Cuprous iodide K2CO3: Potassium carbonate; DMSO: Dimethyl sulfoxide; B2Pin2: 4,4,5,5-Tetramethyl-2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)-1,3,2-dioxaborane; KOAc: Potassium acetate; dioxane: 1,4-dioxane; NBS: N-bromosuccinimide; Ac2O: Acetic anhydride; t-BuOK: Potassium tert-butoxide; DMFDMA: N,N-dimethylformamide dimethyl acetal; NH3·H2O: Ammonia; EtOH: Ethanol; sealed tube: Sealed tube; BOP: (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; DBU: 1,8-diazacyclo[5,4,0]undecene-7; Me2NH: Dimethylamine; XPhos Pd G3: Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II); K3PO4: potassium phosphate; TFA: trifluoroacetic acid; NaBH3CN: sodium cyanoborohydride; HOAc / AcOH: acetic acid; Pd2(dba)3: tris(dibenzylidene indacetone)dipalladium; XPhos: 2-dicyclohexylphosphino-2',4',6'-triisopropyl-2'-biphenyl Benzene; RuPhos: 2-Dicyclohexylphospho-2',6'-diisopropoxy-1,1'-biphenyl; DCE: 1,2-dichloroethane; NaBH(OAc)3: sodium triacetoxyborohydride; LHMDS: lithium bis(trimethylsilylamino)amine; Ruphos-Pd-G2: chloro(2-dicyclohexylphospho-2',6'-di-isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II); Tol: toluene.

[0146] Preparation Example 1: Synthesis of intermediate 3-(1H-pyrazol-1-yl)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-3,6-dihydropyridin-1(2H)-yl)propane-1-one (INT1)

[0147] Step 1: Synthesis of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1,2,3,6-tetrahydropyridine

[0148] Compound INT1-1 (3.00 g, 9.70 mmol) was dissolved in DCM (10 mL), and hydrochloric acid (4 M in EA, 10 mL) was added. The reaction solution was placed at 25 °C and reacted for 15 min. After TLC monitoring showed no residue, the reaction solution was concentrated under reduced pressure to obtain crude compound INT1-2 (2.60 g).

[0149] LC-MS (m / z): 210.0 [M+H] + .

[0150] Step 2: Synthesis of 3-(1H-pyrazol-1-yl)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-3,6-dihydropyridin-1(2H)-yl)propane-1-one

[0151] 3-(1-pyrazolyl)propionic acid (1.15 g, 8.18 mmol) was dissolved in acetonitrile (15 mL), and DIPEA (3.17 g, 24.54 mmol) was added. HATU (4.04 g, 10.63 mmol) was added in portions under ice bath conditions. After the reaction solution was brought to room temperature and stirred for 5 minutes, crude compound INT1-2 (2.00 g) was added, and the reaction solution was placed at 25 °C for 15 minutes. Once the reaction was complete as monitored by LC-MS, a saturated ammonium chloride solution was added to quench the reaction. The mixture was extracted with ethyl acetate, washed with saturated brine, concentrated under reduced pressure, and purified by column chromatography (DCM:EA = 1:1 as eluent) to give compound INT1 (850.0 mg), yield 31.4%.

[0152] LC-MS (m / z): 332.0 [M+H] + .

[0153] 1 H NMR(600MHz,DMSO-d6)δ7.75–7.61(m,1H),7.46–7.33(m,1H),6.63–6.46(m,1H),6.22–6.13(m,1H),4.36 –4.28(m,2H),3.97–3.87(m,2H),3.52–3.40(m,2H),2.93–2.86(m,2H),2.19–2.09(m,2H),1.21(s,12H).

[0154] Preparation Example 2: Synthesis of intermediate 2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acetaldehyde (INT2)

[0155] Step 1: Synthesis of compound 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0156] 7-Bromo-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (500.0 mg, 2.20 mmol) was dissolved in THF (20 mL). Under nitrogen protection, NaH (60%) (440.0 mg, 11.01 mmol) was added in portions at 0 °C, and the reaction was carried out at room temperature for 1 hour. The temperature was then raised to 60 °C, and 3-bromopiperidin-2,6-dione (1268.0 mg, 6.60 mmol) was added. The mixture was vigorously vented, and the mixture was stirred at 60 °C for another 1 hour. After the reaction was confirmed to be complete by LC-MS, the temperature was lowered, and the reaction was quenched with saturated ammonium chloride solution. 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 pulping (petroleum ether:ethyl acetate = 1:8) to give compound INT2-1 (420.0 mg), with a yield of 56.7%.

[0157] LC-MS (m / z): 338.0 / 340.0 [M+H] + .

[0158] 1 H NMR (600MHz, DMSO-d6) δ11.14(s,1H),7.25(d,J=8.1Hz,1H),7.17(d,J=7.9Hz,1H),6.99(t,J=8.0Hz,1H),5.42(dd,J=12 .9,5.4Hz,1H),3.64(s,3H),2.96–2.84(m,1H),2.77–2.66(m,1H),2.63(ddd,J=17.0,4.4,2.2Hz,1H),2.08–2.00(m,1H).

[0159] Step 2: Synthesis of compound 3-(4-(2-ethoxyvinyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0160] Compound INT2-1 (400.0 mg, 1.18 mmol), 1-ethoxyvinyl-2-boronic acid pinacol ester (282.0 mg, 1.42 mmol), Pd(dppf)Cl2 (86.0 mg, 0.12 mmol), and cesium fluoride (358.0 mg, 2.37 mmol) were dissolved in DMF / water (8 mL / 2 mL). The mixture was purged with nitrogen three times, heated to 60 °C, and 3-bromopiperidine-2,6-dione (1268.0 mg, 6.60 mmol) was added, followed by vigorous flaring. The mixture was stirred at 80 °C for 1 hour. After the reaction was confirmed to be complete by LC-MS, the mixture was cooled, and the reaction was quenched with water. The aqueous phase was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (10 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 = 1:2) to give compound INT2-2 (138.0 mg), in a yield of 35.5%.

[0161] LC-MS (m / z): 330.0 [M+H] + .

[0162] Step 3: Synthesis of 2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acetaldehyde

[0163] Compound INT2-2 (138.0 mg, 0.42 mmol) was dissolved in formic acid (2 mL) and reacted at 30 °C for 2 hours under nitrogen protection. After the reaction was complete as monitored by LC-MS, the solution was concentrated under reduced pressure to give compound INT2 (102.0 mg), in a yield of 80.1%.

[0164] LC-MS (m / z): 302.0 [M+H] + .

[0165] Preparation Example 3: Synthesis of intermediate compound 4-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester (INT3)

[0166] Step 1: Synthesis of compound 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0167] Compound 2-bromo-5-iodoanisole (5.00 g, 15.9 mmol), 1-tert-butoxycarbonylpiperazine (7.12 g, 31.9 mmol), cuprous iodide (608 mg, 3.20 mmol), potassium carbonate (6.62 g, 47.9 mmol), and L-proline (367 mg, 3.20 mmol) were purged three times with nitrogen in dimethyl sulfoxide (50 mL). The reaction was then stirred at 80 °C for 16 h under nitrogen protection. After the reaction was confirmed to be complete by LC-MS, water was added to quench the reaction. The aqueous phase was extracted with ethyl acetate (20 mL × 3), and the combined organic phases were washed with saturated brine (10 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 = 5:1) to give compound INT3-1 (3.00 g), in a yield of 51.1%.

[0168] LC-MS (m / z): 371.0 / 373.0 [M+H] + .

[0169] Step 2: Synthesis of tert-butyl piperazine-1-carboxylate

[0170] A mixture of compound INT3-1 (3.00 g, 8.0 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,3,2-dioxaborane (2.36 g, 9.2 mmol), Pd(dppf)Cl2 (584.0 mg, 0.8 mmol), and potassium acetate (2.35 g, 2.4 mmol) in dioxane (80 mL) was purged three times with nitrogen. The mixture was then stirred at 120 °C for 2 hours under nitrogen protection. After the reaction was complete as monitored by LC-MS, the reaction mixture was filtered and concentrated under reduced pressure to give the residue. Column chromatography purification (petroleum ether: ethyl acetate = 3:1) gave compound INT3 (1.04 g) in a yield of 26.3%.

[0171] LC-MS (m / z): 419.0 [M+H] + .

[0172] Preparation Example 4: Synthesis of the intermediate compound 3-(3-fluoro-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)piperidin-1-yl)phenyl)piperidin-2,6-dione (INT4)

[0173] Step 1: Synthesis of methyl 2-(4-(4-(4-chlorophenyl)piperidin-1-yl)-3-fluorophenyl)acetate (INT4-1)

[0174] Methyl 2-(4-bromo-3-fluorophenyl)acetate (1.00 g, 4.05 mmol), 4-(4-chlorophenyl)piperidine (792.5 mg, 4.05 mmol), Pd2(dba)3 (183.1 mg, 0.20 mmol), XPhos (233.6 mg, 0.49 mmol), and Cs2CO3 (3.96 g, 12.15 mmol) were dissolved in toluene (12 mL) and reacted at 100 °C for 2 hours under a nitrogen atmosphere. The reaction solution was concentrated, and the residue was purified by column chromatography (EA:PE = 0%–20%) to give compound INT4-1 (350.0 mg), in a yield of 23.9%.

[0175] LC-MS (m / z): 362.0 [M+H] + .

[0176] Step 2: Synthesis of 3-(4-(4-(4-chlorophenyl)piperidin-1-yl)-3-fluorophenyl)piperidin-2,6-dione (INT4-2)

[0177] INT4-1 (350.0 mg, 0.97 mmol) was dissolved in THF (10 mL), and acrylamide (68.9 mg, 0.97 mmol) was added. Under nitrogen protection and in an ice-water bath, a 1 M, 1.16 mL solution of t-BuOK THF was slowly added dropwise, and the reaction was carried out at 50 °C for 0.5 hours. The reaction solution was poured into a saturated NH4Cl aqueous solution (50 mL), extracted with EA (50 mL × 3), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (EA:PE = 0%–65%) to obtain INT4-2 (154.0 mg), with a yield of 39.7%.

[0178] LC-MS (m / z): 401.0 [M+H] + .

[0179] Step 3: Synthesis of 3-(3-fluoro-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)piperidin-1-yl)phenyl)piperidin-2,6-dione (INT4)

[0180] INT4-2 (154.0 mg, 0.38 mmol) was dissolved in dioxane (3 mL), and XPhos Pd G3 (33.8 mg, 0.04 mmol), pinacol diborate (144.7 mg, 0.57 mmol), and potassium acetate (111.9 mg, 1.14 mmol) were added. The mixture was reacted at 80 °C for 2 hours under nitrogen protection. The reaction solution was concentrated and purified by column chromatography (MeOH:DCM = 0%–7%) to give INT4 (105.0 mg), with a yield of 55.5%.

[0181] LC-MS (m / z): 493.0 [M+H] + .

[0182] Preparation Example 5: Synthesis of intermediate compound 3-((4-(4-(2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)piperazin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione (INT5)

[0183] Step 1: Synthesis of compound 4-(2,3-difluorophenyl)piperazine-1-carboxylic acid tert-butyl ester (INT5-1)

[0184] Compound 1,2-difluoro-3-iodobenzene (5.00 g, 20.83 mmol) was dissolved in anhydrous 1,4-dioxane (50 mL), and N-tert-butoxycarbonylpiperazine (5.82 g, 31.25 mmol), tris(dibenzylacetone)dipalladium (1.91 g, 2.08 mmol), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (1.94 g, 4.17 mmol), and cesium carbonate (20.36 g, 62.50 mmol) were added. The reaction mixture was placed at 100 °C for 16 hours under nitrogen protection. After the reaction was complete as monitored by LCMS, the reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 90:10 as eluent) to give INT5-1 (8.40 g), the crude product.

[0185] LC-MS (m / z): 299.0 [M+H] + .

[0186] Step 2: Synthesis of compound 4-(4-bromo-2,3-difluorophenyl)piperazine-1-carboxylic acid tert-butyl ester (INT5-2)

[0187] The crude product of compound INT5-1 (8.40 g) was dissolved in dichloromethane (100 mL), and N-bromosuccinimide (4.08 g, 22.93 mmol) was added. The reaction mixture was placed at 25 °C for 1 hour. After the reaction was completed as monitored by LC-MS, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 95:5 as eluent) to give INT5-2 (7.80 g), with a two-step yield of 99.17%.

[0188] LC-MS(m / z):321.0 / 323.0[M+H-56] + .

[0189] Step 3: Synthesis of compound 1-(4-bromo-2,3-difluorophenyl)piperazine (INT5-3)

[0190] Compound INT5-2 (7.80 g, 20.68 mmol) was dissolved in dichloromethane (30 mL), and a solution of hydrochloric acid in ethyl acetate (30 mL, 4.0 M in ethyl acetate) was added. The reaction mixture was placed at 25 °C and reacted for 0.5 hours. After the reaction was monitored by LC-MS to be complete, the solution was concentrated under reduced pressure to obtain INT5-3 (6.80 g), which was the crude product.

[0191] LC-MS (m / z): 277.0 / 279.0 [M+H] + .

[0192] Step 4: Synthesis of compound 1-(4-bromo-2,3-difluorophenyl)-4-(2-fluoro-5-methoxy-4-nitrophenyl)piperazine (INT5-4)

[0193] Compound INT5-3 (1.60 g, 5.77 mmol) was dissolved in acetonitrile (15 mL), and 3,4-difluoro-6-nitrobenzene ether (873.5 mg, 4.62 mmol) and potassium carbonate (3.99 g, 28.87 mmol) were added. The reaction mixture was placed at 80 °C for 16 hours. After the reaction was confirmed to be complete by LC-MS, the mixture was filtered, the filter cake was washed with water, and dried to give INT5-4 (1.16 g), with a yield of 45.02%.

[0194] LC-MS (m / z): 446.0 / 448.0 [M+H] + .

[0195] Step 5: Synthesis of compound 4-(4-(4-bromo-2,3-difluorophenyl)piperazin-1-yl)-5-fluoro-2-methoxyaniline (INT5-5)

[0196] Compound INT5-4 (1.16 g, 2.60 mmol) was dissolved in a mixed solution of ethanol (10 mL) and water (10 mL), and reduced iron powder (725.8 mg, 13.00 mmol) and ammonium chloride (208.57 mg, 3.90 mmol) were added. The reaction solution 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, and the filtrate 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 give INT5-5 (250.0 mg), with a yield of 23.10%.

[0197] LC-MS (m / z): 416.0 / 418.0 [M+H] + .

[0198] Step 6: Synthesis of compound 3-((4-(4-bromo-2,3-difluorophenyl)piperazin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione (INT5-6)

[0199] Compound INT5-5 (250.0 mg, 0.60 mmol) was dissolved in anhydrous N,N-dimethylformamide (3 mL), and 3-bromopiperidin-2,6-dione (138.9 mg, 0.72 mmol) and sodium bicarbonate (100.9 mg, 1.20 mmol) were added. The reaction mixture was placed at 80 °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. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 60:40 as eluent) to give INT5-6 (200.0 mg), with a yield of 63.15%.

[0200] LC-MS (m / z): 527.0 / 529.0 [M+H] + .

[0201] Step 7: Synthesis of compound 3-((4-(4-(2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)piperazin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione (INT5)

[0202] Compound INT5-6 (190.0 mg, 0.36 mmol) was dissolved in 1,4-dioxane (3 mL), and XPhos-Pd-G3 (45.7 mg, 0.54 mmol), pinacol diborate (274.5 mg, 1.08 mmol), and potassium acetate (106.1 mg, 1.08 mmol) were added. The reaction mixture was placed at 100 °C for 3 hours under nitrogen protection. 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 silica gel column chromatography (dichloromethane:ethyl acetate = 80:20 as eluent) to give INT5 (32.4 mg), with a yield of 15.66%.

[0203] LC-MS (m / z): 575.0 [M+H] + .

[0204] Preparation Example 6: Synthesis of 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-3,6-dihydropyridin-1(2H)-yl)-3-(1H-1,2,3-triazol-1-yl)prop-1-one (INT6)

[0205] Step 1: Synthesis of ethyl 3-(1H-1,2,3-triazol-1-yl)propionate (INT6-1)

[0206] Compound 1H-1,2,3-triazole (5.00 g, 72.39 mmol), pyridine (0.57 g, 7.24 mmol), and ethyl acrylate (5.00 g, 72.39 mmol) were mixed in a sealed tube, and the reaction mixture was placed at 90 °C for 20 hours. After the reaction was complete as monitored by LCMS, the mixture was purified by silica gel column chromatography (dichloromethane:methanol = 90:10 as eluent) to give compound INT6-1 (3.60 g), with a yield of 29.39%.

[0207] LC-MS (m / z): 170.0 [M+H] + .

[0208] Step 2: Synthesis of 3-(1H-1,2,3-triazol-1-yl)propionic acid (INT6-2)

[0209] Compound INT6-1 (3.60 g, 21.28 mmol) was dissolved in a mixed solvent of tetrahydrofuran (20 mL) and water (20 mL), and lithium hydroxide monohydrate (1.79 g, 42.56 mmol) was added. The reaction solution was placed at 25 °C and reacted for 16 hours. After the reaction was confirmed to be complete by LC-MS, the pH of the aqueous phase was adjusted to 5 by adding hydrochloric acid aqueous solution (1.0 M), and the solution was lyophilized in a vacuum freeze dryer to remove water, yielding compound INT6-2 (4.80 g), which was the crude product.

[0210] LC-MS (m / z): 142.0 [M+H] + .

[0211] Step 3: Synthesis of 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-3,6-dihydropyridin-1(2H)-yl)-3-(1H-1,2,3-triazol-1-yl)prop-1-one (INT6)

[0212] The crude product of the above compound INT6-2 (4.80 g) was dissolved in acetonitrile (50 mL), and N,N-diisopropylethylamine (5.94 g, 58.67 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (11.15 g, 29.33 mmol) were added. The reaction system was stirred at 25 °C for 10 minutes, and then 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,2,3,6-tetrahydropyridine (4.09 g, 19.56 mmol) was added. The reaction solution was reacted at 25 °C for 0.5 hours. After the reaction was monitored by LC-MS to be complete, water (30 mL) was added, and the mixture was extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by reversed-phase column chromatography (water:methanol = 20:80 as eluent) to give compound INT6 (0.18 g), with a two-step yield of 2.55%.

[0213] LC-MS (m / z): 333.0 [M+H] + .

[0214] Preparation Example 7: Synthesis of 2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)acetaldehyde (INT7)

[0215] Step 1: Synthesis of 3-(4-bromo-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione (INT7-1)

[0216] The compound 4-bromo-3-methyl-1H-indazole (2.00 g, 9.48 mmol) was dissolved in a mixed solution of anhydrous tetrahydrofuran (15 mL) and anhydrous DMSO (15 mL). Sodium hydride (60%, 1.14 g, 28.43 mmol) was added at 0 °C. The reaction system was heated to 25 °C and stirred for 30 minutes. Then, 3-bromopiperidine-2,6-dione (2.73 g, 14.21 mmol) and potassium iodide (1.26 g, 7.58 mmol) were added, and the reaction was continued at 25 °C for 4 hours. After the reaction was monitored by LC-MS until it was complete, the reaction was quenched with saturated ammonium chloride aqueous solution (20 mL), 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, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:ethyl acetate = 70:30 as eluent) to give compound INT7-1 (2.60 g), yield 85.17%.

[0217] LC-MS (m / z): 322.0 / 324.0 [M+H] + .

[0218] Step 2: Synthesis of (E)-3-(4-(2-ethoxyvinyl)-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione (INT7-2)

[0219] Compound INT7-1 (2.60 g, 8.07 mmol) was dissolved in 1,4-dioxane (35 mL), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.59 g, 0.81 mmol), cesium fluoride (2.45 g, 16.14 mmol), and (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (2.40 g, 12.11 mmol) were added. The reaction mixture was placed at 100 °C for 3 hours under nitrogen protection. After the reaction was confirmed to be complete by LC-MS, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:ethyl acetate = 80:20 as eluent) to give compound INT7-2 (2.30 g), with a yield of 90.95%.

[0220] LC-MS (m / z): 314.0 [M+H] + .

[0221] Step 3: Synthesis of 2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)acetaldehyde (INT7)

[0222] Compound INT7-2 (2.30 g, 7.34 mmol) was dissolved in formic acid (20 mL), and the reaction solution was placed at 35 °C for 0.5 h. After the reaction was completed as monitored by LC-MS, the reaction solution was concentrated under reduced pressure to obtain compound INT7 (2.20 g).

[0223] LC-MS (m / z): 286.0 [M+H] + .

[0224] Preparation Example 9: Synthesis of 1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-carboxaldehyde (INT9)

[0225] Compound INT2-1 (600.0 mg, 1.77 mmol), tert-butyl isocyanate (294.0 mg, 3.54 mmol), palladium acetate (20.0 mg, 0.09 mmol), tricyclohexylphosphine (37.0 mg, 0.13 mmol), sodium carbonate (188.0 mg, 1.77 mmol), and triethylsilane (616.0 mg, 5.31 mmol) were dissolved in DMF (10 mL). Under nitrogen protection, the reaction mixture was stirred at 65 °C for 10 hours. After the reaction was confirmed to be complete by LC-MS, 3.0 M hydrochloric acid aqueous solution (3 mL) was added, and the reaction mixture was stirred at 65 °C for another 0.5 hours. Subsequently, water (20 mL) was added to quench the reaction. The aqueous phase was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (using dichloromethane:methanol = 95:5 as eluent) to give INT9 (458.0 mg), with a yield of 89.8%.

[0226] LC-MS (m / z): 288.0 [M+H] + .

[0227] Example 2: Synthesis of 3-(4-(2-(4-(4-(7-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-8-fluoro-2-methyl-1-oxo-2,3,4,9-tetrahydro-1H-pyridino[3,4-b]indol-5-yl)-3-methoxyphenyl)piperazin-1-yl)ethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Compound 2)

[0228] Step 1: Synthesis of 7-bromo-5-chloro-8-fluoro-2-methyl-2,3,4,9-tetrahydro-1H-pyridine[3,4-b]indol-1-one (2-1)

[0229] N-methylpyrrolidone (344.8 mg, 3.48 mmol) and DMF (1.34 mL, 17.40 mmol) were dissolved in DCE (15 mL). POCl3 (1.62 mL, 17.4 mmol) was added dropwise under an ice-water bath. The reaction was carried out at 80 °C for 6 hours under nitrogen protection. The reaction solution was concentrated to remove the solvent, diluted with water (10 mL), and then added to a solution of 3-bromo-5-chloro-2-fluorophenylhydrazine hydrochloride (2-SM, 800.0 mg, 2.90 mmol) in EtOH (20 mL). The reaction was carried out at 80 °C for 1 hour, followed by the addition of concentrated hydrochloric acid (10 mL). The solution was transferred to a sealed tube and reacted at 100 °C for another hour. The reaction solution was cooled to room temperature, filtered, and the filter cake was purified by column chromatography (MeOH:DCM = 10%) to give 2-1 (152.0 mg), with a yield of 15.8%.

[0230] LC-MS (m / z): 333.0 [M+H] + .

[0231] 1 H NMR (600MHz, DMSO-d6) δ12.76(s,1H),7.36(d,J=4.9Hz,1H),3.68(t,J=7.1Hz,2H),3.25(t,J=7.1Hz,2H),3.02(s,3H).

[0232] Step 2: Synthesis of 7-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-chloro-8-fluoro-2-methyl-2,3,4,9-tetrahydro-1H-pyridin[3,4-b]indol-1-one (2-2)

[0233] 2-1 (150.0 mg, 0.45 mmol), INT1 (180.0 mg, 0.54 mmol), Pd(dppf)Cl2 (32.9 mg, 45.0 μmmol), and K2CO3 (186.6 mg, 1.35 mmol) were dissolved in a mixed solvent of dioxane (4 mL) and water (0.4 mL). The mixture was reacted at 90 °C for 16 hours under nitrogen protection. The reaction solution was concentrated and purified by column chromatography (MeOH:DCM = 3%) to give 2-2 (82.0 mg), in a yield of 40.0%.

[0234] LC-MS (m / z): 456.0 [M+H] + .

[0235] Step 3: Synthesis of 4-(4-(7-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-8-fluoro-2-methyl-1-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-5-yl)-3-methoxyphenyl)piperazine-1-carboxylic acid tert-butyl ester (2-3)

[0236] 2-2 (82.0 mg, 0.18 mmol), INT3 (88.1 mg, 0.21 mmol), XPhos Pd G3 (14.9 mg, 17.5 μmol), and potassium phosphate (111.8 mg, 0.53 mmol) were dissolved in a mixed solvent of dioxane (3 mL) and water (0.6 mL). The mixture was reacted at 80 °C for 1 hour under nitrogen protection. The reaction solution was concentrated and purified by column chromatography (MeOH:DCM = 5%) to obtain crude 2-3 (132.0 mg).

[0237] LC-MS (m / z): 712.0 [M+H] + .

[0238] Step 4: Synthesis of 7-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-8-fluoro-5-(2-methoxy-4-(piperazin-1-yl)phenyl)-2-methyl-2,3,4,9-tetrahydro-1H-pyridin[3,4-b]indol-1-one (2-4)

[0239] Dissolve crude product 2-3 (132.0 mg) in DCM (2 mL), add TFA (2 mL), and react at room temperature for 0.5 hours. Concentrate the reaction solution to obtain crude product 2-4 (205.0 mg), which can be used directly in the next step.

[0240] LC-MS (m / z): 612.0 [M+H] + .

[0241] Step 5: Synthesis of 3-(4-(2-(4-(4-(7-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-8-fluoro-2-methyl-1-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-5-yl)-3-methoxyphenyl)piperazin-1-yl)ethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (compound 2)

[0242] Compound 2-4 (205.0 mg) crude product and INT2 (63.3 mg, 0.21 mmol) were dissolved in a mixed solvent of THF (4 mL) and DMSO (1 mL). AcOH (31.5 mg, 0.53 mmol) was added, and the mixture was stirred at room temperature for 10 minutes. Then, NaBH(OAc)3 (194.2 mg, 0.88 mmol) was added, and the reaction was continued at room temperature for 0.5 hours. The reaction solution was quenched with sodium bicarbonate aqueous solution, extracted with DCM / MeOH (10:1, 20 mL × 2), the organic phase was concentrated, and purified by column chromatography (MeOH:DCM = 8%) to give compound 2 (91.0 mg), with a three-step yield of 58.0%.

[0243] LC-MS (m / z): 897.0 [M+H] + .

[0244] 1 H NMR (600MHz, DMSO-d6) δ12.13–12.00(m,1H),11.10(s,1H),7.77–7.65(m,1H),7.48–7.29(m,1H),7.05(d,J=8.2Hz,1H),7. 01–6.92(m,3H),6.78–6.65(m,1H),6.62(s,1H),6.56(d,J=8.4Hz,1H),6.24–6.15(m,1H),6.13–6.02(m,1H),5.38(dd,J=1 3.5,5.1Hz,1H),4.39–4.22(m,4H),3.67–3.60(m,7H),3.57–3.54(m,1H),3.51–3.41(m,2H),3.33–3.30(m,2H),3.26–3.22 (m,4H),3.19–3.03(m,2H),3.00–2.93(m,5H),2.93–2.84(m,1H),2.77–2.58(m,8H),2.34–2.17(m,2H),2.03–1.98(m,1H).

[0245] Example 10: Synthesis of 3-(4-(2-(4-(4-(8-(1-(3-(1H-pyrazol-1-yl)propyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(dimethylamino)-5H-pyrimidino[5,4-b]indol-6-yl)-3-methoxyphenyl)piperazin-1-yl)ethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (compound 10)

[0246] Step 1: Synthesis of 2-amino-5-bromo-3-chlorobenzonitrile (10-1)

[0247] 2-Amino-3-chlorobenzonitrile (5.00 g, 32.77 mmol) was dissolved in ACN (100 mL), and NBS (6.42 g, 36.04 mmol) was added under ice-water bath conditions. The mixture was reacted at room temperature for 1 hour. The reaction solution was concentrated, and the residue was dissolved in EA (100 mL). The residue was washed with water (100 mL) and saturated brine (50 mL), filtered, and the filtrate was concentrated to give crude compound 10-1 (8.70 g), which was used directly in the next step.

[0248] Step 2: Synthesis of N-(4-bromo-2-chloro-6-cyanophenyl)acetamide (10-2)

[0249] 8.70 g of crude 10⁻¹ was dissolved in acetic anhydride (33 mL) and reacted at 100 °C for 16 hours. After the reaction solution cooled to room temperature, it was concentrated to dryness, dissolved in methanol (50 mL), and excess K₂CO₃ was added. The mixture was stirred at room temperature for 10 minutes, then DCM (100 mL) was added. The mixture was filtered, the filtrate was concentrated, and purified by column chromatography (EA:PE = 50%) to obtain 3.64 g of 10⁻², with a two-step yield of 40.6%.

[0250] LC-MS (m / z): 275.0 [M+H] + .

[0251] 1 H NMR (600MHz, DMSO-d6) δ10.28(s,1H),8.24(d,J=2.2Hz,1H),8.21(d,J=2.3Hz,1H),2.11(s,3H).

[0252] Step 3: Synthesis of ethyl 3-amino-5-bromo-7-chloro-1H-indole-2-carboxylate (10-3)

[0253] Potassium tert-butoxide (2.99 g, 26.62 mmol) was dissolved in anhydrous THF (40 mL). Under nitrogen protection and in an ice-water bath, a 10⁻² (3.64 g, 13.31 mmol) THF solution (20 mL) was slowly added dropwise. After reacting at this temperature for 0.5 hours, ethyl bromoacetate (3.33 g, 19.96 mmol) THF solution (10 mL) was slowly added dropwise to the reaction solution under an ice-water bath. After reacting at room temperature for 1.5 hours, potassium tert-butoxide (1.00 g, 8.91 mmol) THF solution (10 mL) was added again under an ice-water bath, and the reaction was continued at room temperature for another hour. The reaction solution was quenched with saturated ammonium chloride, extracted with EA (100 mL × 2), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and purified by column chromatography (EA:PE = 15%) to obtain 10⁻³ (1.50 g), yield 35.5%.

[0254] LC-MS (m / z): 319.0 [M+H] + .

[0255] 1 H NMR (600MHz, DMSO-d6) δ10.76(s,1H),8.06(d,J=1.8Hz,1H),7.48(d,J=1.8Hz,1H),5.85(s,2H),4.31(q,J=7.1Hz,2H),1.34(t,J=7.1Hz,3H).

[0256] Step 4: Synthesis of ethyl 5-bromo-7-chloro-3-(((dimethylamino)methylene)amino)-1H-indole-2-carboxylate (10-4)

[0257] 10⁻³ (1.50 g, 4.72 mmol) was dissolved in DMF (20 mL), and DMF-DMA (2.81 g, 23.6 mmol) was added. The mixture was reacted at 100 °C for 0.5 h. The reaction solution was concentrated to obtain crude 10⁻⁴ (2.50 g), which was used directly in the next step.

[0258] LC-MS (m / z): 374.0 [M+H] + .

[0259] Step 5: Synthesis of 8-bromo-6-chloro-5H-pyrimido[5,4-b]indole-4-ol (10-5)

[0260] In a sealed tube, crude 10⁻⁴ (2.50 g) was dissolved in EtOH (10 mL), and ammonia (10 mL) was added. The mixture was then reacted at 70 °C for 3 hours. After the reaction solution cooled to room temperature, it was concentrated to dryness, and DCM (50 mL) was added. The mixture was stirred at room temperature for 0.5 hours, filtered, and the filter cake was dried to obtain 10⁻⁵ (1.26 g). The two-step yield was 89.4%.

[0261] LC-MS (m / z): 300.0 [M+H] + .

[0262] 1 H NMR (600MHz, DMSO-d6) δ11.10(brs,2H),8.11(d,J=1.8Hz,1H),8.07(s,1H),7.75(d,J=1.9Hz,1H).

[0263] Step 6: Synthesis of 8-bromo-6-chloro-N,N-dimethyl-5H-pyrimido[5,4-b]indole-4-amine (10-6)

[0264] 10⁻⁵ (298.5 mg, 1.00 mmol) and BOP (884.6 mg, 2.00 mmol) were dissolved in DMF (8 mL), and DBU (228.3 mg, 1.50 mmol) was added dropwise. The mixture was allowed to react at room temperature for 10 minutes. A THF solution of dimethylamine (2.0 M, 4 mL) and DIPEA (0.87 mL, 5.00 mmol) were added to the reaction mixture, transferred to a sealed tube, and reacted at 60 °C for 0.5 hours. After the reaction mixture cooled to room temperature, it was concentrated to dryness, diluted with DCM (30 mL), washed with water (15 mL) and saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (MeOH:DCM = 12%) to obtain 10⁻⁶ (238.0 mg), with a yield of 73.1%.

[0265] LC-MS (m / z): 327.0 [M+H] + .

[0266] 1 H NMR (600MHz, DMSO-d6) δ11.04(s,1H),8.45(s,1H),8.19(d,J=1.8Hz,1H),7.84(d,J=1.8Hz,1H),3.36(s,6H).

[0267] Step 7: Synthesis of 1-(5-(6-chloro-4-(dimethylamine)-5H-pyrimidino[5,4-b]indol-8-yl)-3,6-dihydropyridin-1(2H)-yl)-3-(1H-pyrazol-1-yl)propane-1-one (10-7)

[0268] 10⁻⁶ (238.0 mg, 0.73 mmol), INT₁ (241.8 mg, 0.73 mmol), Pd(dppf)Cl₂ (53.4 mg, 0.07 mmol), and K₂CO₃ (302.7 mg, 2.19 mmol) were dissolved in a mixed solvent of dioxane (6 mL) and water (1.5 mL). The mixture was reacted at 80 °C for 2.5 h under nitrogen protection. The reaction solution was concentrated and purified by column chromatography (MeOH:DCM = 5%) to give 10⁻⁷ (243.0 mg), in a yield of 74.0%.

[0269] LC-MS (m / z): 450.0 [M+H] + .

[0270] 1 H NMR(600MHz,DMSO-d6)δ11.28–10.68(m,1H),8.49–8.39(m,1H),8.17–7.97(m,1H),7 .85–7.70(m,2H),7.49–7.39(m,1H),6.49–6.40(m,1H),6.29–6.15(m,1H),4.51–4.4 3(m,1H),4.41–4.35(m,3H),3.62(t,J=5.8Hz,1H),3.57(t,J=5.8Hz,1H),3.35(s,6H ),3.09(t,J=7.0Hz,1H),3.00(t,J=7.0Hz,1H),2.35–2.32(m,1H),2.29–2.24(m,1H).

[0271] Step 8: Synthesis of 4-(4-(8-(1-(3-(1H-pyrazol-1-yl)propyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(dimethylamino)-5H-pyrimidino[5,4-b]indol-6-yl)-3-methoxyphenyl)piperazine-1-carboxylic acid tert-butyl ester (10-8)

[0272] 10⁻⁷ (243.0 mg, 0.54 mmol), INT₃ (271.1 mg, 0.65 mmol), XPhos Pd G₃ (91.4 mg, 0.11 mmol), and potassium phosphate (343.9 mg, 1.62 mmol) were dissolved in a mixed solvent of dioxane (10 mL) and water (2 mL). The mixture was reacted at 80 °C for 1 hour under nitrogen protection. The reaction solution was concentrated and purified by column chromatography (MeOH:DCM = 5%) to give 10⁻⁸ (241.0 mg), in a yield of 63.2%.

[0273] LC-MS (m / z): 706.0 [M+H] + .

[0274] 1 H NMR (600MHz, DMSO-d6) δ10.01–9.92(m,1H),8.48–8.34(m,1H),8.11–7.91(m,1H),7.74(d,J=2.3Hz ,1H),7.58–7.40(m,2H),7.37–7.31(m,1H),6.76–6.72(m,1H),6.73–6.63(m,1H),6.40–6.29(m,1H) ,6.24–6.16(m,1H),4.51–4.41(m,2H),4.40–4.33(m,2H),3.84–3.77(m,3H),3.66–3.55(m,2H),3. 53–3.46(m,4H),3.31(s,6H),3.27–3.22(m,4H),3.13–2.96(m,2H),2.36–2.21(m,2H),1.44(s,9H).

[0275] Step 9: Synthesis of 1-(5-(4-(dimethylamine)-6-(2-methoxy-4-(piperazin-1-)phenyl)-5H-pyrimidino[5,4-b]indol-8-yl)-3,6-dihydropyridin-1(2H)-yl)-3-(1H-pyrazol-1-yl)propane-1-one (10-9)

[0276] 10⁻⁸ (241.0 mg, 0.34 mmol) was dissolved in DCM (5 mL), and TFA (5 mL) was added. The mixture was allowed to react at room temperature for 1 hour. The reaction solution was concentrated to obtain crude 10⁻⁹ (475.0 mg), which was used directly in the next step.

[0277] LC-MS (m / z): 606.0 [M+H] + .

[0278] Step 10: Synthesis of 3-(4-(2-(4-(4-(8-(1-(3-(1H-pyrazol-1-yl)propyl)-1,2,5,6-tetrahydropyridin-3-yl)-4-(dimethylamino)-5H-pyrimidino[5,4-b]indol-6-yl)-3-methoxyphenyl)piperazin-1-yl)ethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (10)

[0279] 10⁻⁹ (475.0 mg) crude product and INT₂ (98.0 mg, 0.32 mmol) were dissolved in a mixed solvent of THF (4 mL) and DMSO (1 mL). KOAc (94.2 mmol, 0.96 mmol) and HOAc (96.0 mg, 1.60 mmol) were added, and the mixture was stirred at room temperature for 0.5 hours. Then, NaBH₃CN (60.3 mg, 0.96 mmol) was added, and the reaction was continued at room temperature for 1 hour. The reaction solution was quenched with water, concentrated, and the residue was diluted with DCM / MeOH (10:1, 30 mL). The residue was washed with water (10 mL), the organic phase was concentrated, and purified by column chromatography (MeOH:DCM = 8%) to give compound 10 (34.0 mg), with a yield of 11.9%.

[0280] LC-MS (m / z): 891.0 [M+H] + .

[0281] 1 H NMR(600MHz,DMSO-d6)δ11.12(s,1H),10.02–9.91(m,1H),8.46–8.38(m,1H),8.13–7.95(m,1H),7.83–7.68(m,1H),7.57–7.39 (m,2H),7.37–7.28(m,1H),7.02–6.94(m,3H),6.77–6.65(m,2H),6.40–6.32(m,1H),6.24–6.18(m,1H),5.48–5.32(m,1H),4.5 3–4.42(m,2H),4.42–4.30(m,2H),3.83–3.73(m,3H),3.69–3.48(m,6H),3.32–3.29(m,10H),3.16–3.12(m,1H),3.09(t,J=7.0 Hz,1H),3.00(t,J=7.0Hz,1H),2.95–2.82(m,1H),2.78–2.59(m,8H),2.37–2.32(m,1H),2.29–2.24(m,1H),2.07–1.99(m,1H).

[0282] Example 13: Synthesis of 3-(4-(2-(4-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-2-methyl-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-8-yl)-3-methoxyphenyl)piperazin-1-yl)ethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (compound 13)

[0283] Step 1: Synthesis of methyl 2-azido-3-(4-bromo-2-chlorophenyl)acrylate (13-1)

[0284] 4-Bromo-2-chlorobenzaldehyde (2.50 g, 11.39 mmol) was dissolved in MeOH (50 mL), and ethyl 2-azidoethyl acetate (4.30 g, 33.30 mmol) was added. MeOH (50 mL) containing dissolved MeONa (5 M, 9.10 mL) was added dropwise at -10 °C, and the reaction was allowed to proceed at room temperature for 12 hours. The reaction mixture was quenched by adding 300 mL of saturated ammonium chloride aqueous solution at 0 °C. The mixture was filtered, the solid was washed with ice water (30 mL), dried under vacuum, and the residue was purified by column chromatography (EA:PE = 0%–20%) to give 13-1 (1.60 g), yield 44.3%.

[0285] 1 H NMR (600MHz, DMSO-d6) δ8.13(d,J=8.4Hz,1H),7.85(d,J=1.8Hz,1H),7.68–7.61(m,1H),7.03(s,1H),3.88(s,3H).

[0286] Step 2: Synthesis of methyl 6-bromo-4-chloro-1H-indole-2-carboxylate (13-2)

[0287] 13-1 (1.60 g, 5.05 mmol) was dissolved in xylene (50 mL) and refluxed at 150 °C for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the solid was washed with petroleum ether (30 mL) to obtain crude 13-2 (1.20 g).

[0288] LC-MS (m / z): 288.0 [MH] - .

[0289] 1 H NMR (600MHz, DMSO-d6) δ12.48(s,1H),7.59(s,1H),7.39(d,J=1.8Hz,1H),7.13(s,1H),3.90(s,3H).

[0290] Step 3: Synthesis of methyl 6-bromo-4-chloro-3-formyl-1H-indole-2-carboxylate (13-3)

[0291] DMF (2.78 g, 38.10 mmol) was added to DCE (15 mL), and POCl3 (5.84 g, 38.10 mmol) was added dropwise at 0 °C. The mixture was stirred at room temperature for 0.5 hours. Crude 13-2 (1.10 g, 3.81 mmol) was added, and the reaction was carried out at 80 °C for 16 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure. The residue was purified by column chromatography (EA:PE = 0%–65%) to give 13-3 (402.0 mg), with a two-step yield of 27.4%.

[0292] LC-MS (m / z): 316.0 [MH] - .

[0293] Step 4: Synthesis of methyl 6-bromo-4-chloro-3-((methylamino)methyl)-1H-indole-2-carboxylate (13-4)

[0294] 13-3 (325.0 mg, 1.03 mmol) and methylamine hydrochloride (102.8 mg, 1.55 mmol) were added to methanol (10 mL), stirred at room temperature for 10 minutes, and then NaBH3CN (129.5 mg, 2.06 mmol) was added. The reaction mixture was reacted at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, washed with water (30 mL), and the residue was purified by column chromatography (MeOH:DCM = 0%–5%) to give 13-4 (253.0 mg), with a yield of 74.3%.

[0295] LC-MS (m / z): 333.0 [M+H] + .

[0296] 1 H NMR (600MHz, DMSO-d6) δ13.24(s,1H),10.62(s,1H),7.70(d,J=1.8Hz,1H),7.53(d,J=1.2Hz,1H),3.98(s,3H).

[0297] Step 5: Synthesis of 6-bromo-8-chloro-2-methyl-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (13-5)

[0298] 13-4 (184.0 mg, 0.55 mmol) was added to methanol (10 mL), followed by THF (10 mL) and LiOH·H2O (46.2 mg, 1.10 mmol). The mixture was reacted at 40 °C for 1 hour. The reaction solution was concentrated, and the residue was purified by column chromatography (MeOH:DCM = 0%–7%) to obtain 13-5 (155.0 mg), with a yield of 93.2%.

[0299] LC-MS (m / z): 301.0 [M+H]+ .

[0300] Step 6: Synthesis of 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-8-chloro-2-methyl-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (13-6)

[0301] 13-5 (155.0 mg, 0.52 mmol), INT1 (258.4 mg, 0.78 mmol), Pd(dppf)Cl2 (36.6 mg, 0.05 mmol), and K2CO3 (215.6 mg, 1.56 mmol) were dissolved in a mixed solvent of dioxane (5 mL) and water (1 mL). The mixture was reacted at 80 °C for 1 hour under nitrogen protection. The reaction solution was concentrated, and the residue was purified by column chromatography (MeOH:DCM = 0%–7%) to give 13-6 (138.0 mg), with a yield of 62.9%.

[0302] LC-MS (m / z): 424.0 [M+H] + .

[0303] Step 7: Synthesis of 4-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-2-methyl-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-8-yl)-3-methoxyphenyl)piperazine-1-carboxylic acid tert-butyl ester (13-7)

[0304] 13-6 (128.0 mg, 0.30 mmol), INT3 (150.6 mg, 0.36 mmol), XPhos Pd G3 (50.8 mg, 0.06 mmol), and potassium phosphate (191.0 mg, 0.90 mmol) were dissolved in a mixed solvent of dioxane (3 mL) and water (0.6 mL). The mixture was reacted at 80 °C for 1 hour under nitrogen protection. The reaction solution was concentrated, and the residue was purified by column chromatography (MeOH:DCM = 0%–12%) to give 13-7 (113.0 mg), with a yield of 55.0%.

[0305] LC-MS (m / z): 680.0 [M+H] + .

[0306] Step 8: Synthesis of 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-8-(2-methoxy-4-(piperazin-1-yl)phenyl)-2-methyl-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one trifluoroacetate (13-8)

[0307] Dissolve 13-7 (113.0 mg, 0.34 mmol) in DCM (5 mL), add TFA (5 mL), and react at room temperature for 1 hour. Concentrate the reaction solution to obtain crude 13-8 (112.0 mg), which can be used directly in the next step.

[0308] LC-MS (m / z): 580.0 [M+H] + .

[0309] Step 9: Synthesis of 3-(4-(2-(4-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-2-methyl-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-8-yl)-3-methoxyphenyl)piperazin-1-yl)ethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (13)

[0310] Crude product 13-8 (112.0 mg, 0.16 mmol) and INT2 (69.3 mg, 0.23 mmol) were dissolved in a mixed solvent of MeOH (5 mL). KOAc (37.3 mmol, 0.38 mmol) and HOAc (0.4 mL) were added, and the mixture was stirred at room temperature for 0.5 hours. Then, NaBH3CN (28.9 mg, 0.46 mmol) was added, and the reaction was continued at room temperature for 1 hour. The reaction solution was quenched with water, concentrated, and the residue was purified by column chromatography (MeOH:DCM = 0%–14%) to give 13 (11.5 mg), with a yield of 8.0%.

[0311] LC-MS (m / z): 865.0 [M+H] + .

[0312] 1H NMR (600MHz, DMSO-d6) δ11.86–11.81(m,1H),11.11(s,1H),7.73–7.62(m,1H),7.43–7.40(m,1H),7.35–7.32(m,1H ),7.18(s,1H),7.11–7.09(m,1H),7.02–6.96(m,3H),6.71–6.63(m,2H),6.30–6.28(m,1H),6.21–6.19(m,1H),5.41 –5.37(m,1H),4.40–4.33(m,4H),4.03–4.01(m,2H),3.71–3.70(m,3H),3.64–3.60(m,4H),3.57–3.55(m,1H),3.32– 3.09(m,9H),3.04–2.98(m,5H),2.93–2.87(m,1H),2.75–2.62(m,5H),2.31(s,1H),2.24(s,1H),2.01–1.98(m,1H).

[0313] Example 15: Synthesis of 3-(4-(2-(4-(4-(6-1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2-methyl-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-8-yl)-3-methoxyphenyl)piperazin-1-yl)ethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (compound 15)

[0314] Step 1: Synthesis of methyl 2-azido-3-(4-bromo-2-chloro-5-fluorophenyl)acrylate (15-1)

[0315] 10.0 g (42.11 mmol) of 2-chloro-4-bromo-5-fluorobenzaldehyde was dissolved in 140 mL of MeOH, and 21.75 g (168.46 mmol) of ethyl 2-azidoethyl acetate was added. 150 mL of MeOH containing 5 M (34.10 mL) was added dropwise at -10 °C, and the reaction was allowed to proceed at room temperature for 12 hours. The reaction mixture was quenched in 300 mL of saturated ammonium chloride solution at 0 °C, filtered, and the solid was washed with 200 mL of ice water and dried under vacuum to give 15-1 (6.50 g), a yield of 46.4%.

[0316] Step 2: Synthesis of methyl 6-bromo-4-chloro-7-fluoro-1H-indole-2-carboxylate (15-2)

[0317] 15-1 (6.50 g, 19.43 mmol) was dissolved in xylene (210 mL) and refluxed at 150 °C for 2 hours. After the reaction solution cooled to room temperature, it was filtered, and the solid was washed with petroleum ether (100 mL) to give 15-2 (2.90 g), with a yield of 48.7%.

[0318] LC-MS (m / z): 304.0, 306.0 [MH] - .

[0319] 1 H NMR (600MHz, DMSO-d6) δ13.14(s,1H),7.48(d,J=4.9Hz,1H),7.19(d,J=2.8Hz,1H),3.91(s,3H).

[0320] Step 3: Synthesis of methyl 6-bromo-4-chloro-7-fluoro-3-formyl-1H-indole-2-carboxylate (15-3)

[0321] DMF (1.26 mL, 16.31 mmol) was added to DCE (20 mL). POCl3 (1.52 mL, 16.31 mmol) was added dropwise to the reaction solution under ice-water bath conditions. After reacting at room temperature for 0.5 hours, 15-2 (1.00 g, 3.26 mmol) was added to the reaction solution. The reaction was carried out at 90 °C for 16 hours under nitrogen protection. The reaction solution was concentrated, and the residue was diluted with water (50 mL). Extraction was performed using EA (50 mL × 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography (EA:PE = 40%) to obtain crude 15-3 (421.0 mg).

[0322] LC-MS (m / z): 334.0 [MH] - .

[0323] Step 4: Synthesis of methyl 6-bromo-4-chloro-7-fluoro-3-((methylamino)methyl)-1H-indole-2-carboxylate (15-4)

[0324] Crude product 15-3 (421.0 mg) and methylamine hydrochloride (170.1 mg, 2.52 mmol) were dissolved in MeOH (10 mL), 2 drops of acetic acid were added, followed by NaBH3CN (158.3 mg, 2.52 mmol), and the mixture was reacted at room temperature for 16 hours. The reaction solution was quenched with water, concentrated to dryness, and purified by column chromatography to obtain crude product 15-4 (201.0 mg).

[0325] LC-MS (m / z): 351.0 [M+H] + .

[0326] Step 5: Synthesis of 6-bromo-8-chloro-5-fluoro-2-methyl-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (15-5)

[0327] Crude 15-4 (201.0 mg) was dissolved in a mixed solvent of THF (2 mL) and methanol (2 mL), and an aqueous solution of LiOH·H2O (48.3 mg, 1.15 mmol) (2 mL) was added. The mixture was reacted at room temperature for 16 hours. The pH of the reaction solution was adjusted to approximately 4 with dilute hydrochloric acid, extracted with EA (10 mL), the organic phase was concentrated, and purified by column chromatography (MeOH:DCM = 4%) to obtain 15-5 (15.0 mg). The three-step yield was 1.4%.

[0328] LC-MS (m / z): 319.0 [M+H] + .

[0329] 1 H NMR (600MHz, DMSO-d6) δ12.98 (s, 1H), 7.48 (d, J = 4.9Hz, 1H), 4.60 (s, 2H), 3.10 (s, 3H).

[0330] Step 6: Synthesis of 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-8-chloro-5-fluoro-2-methyl-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (15-6)

[0331] 15-5 (15.0 mg, 47.3 μmmol), INT1 (18.8 mg, 56.8 μmmol), Pd(dppf)Cl2 (3.5 mg, 4.7 μmmol), and K2CO3 (19.6 mg, 0.14 mmol) were dissolved in a mixed solvent of dioxane (1 mL) and water (0.2 mL). The mixture was reacted at 80 °C for 16 hours under nitrogen protection. The reaction solution was concentrated and purified by column chromatography (MeOH:DCM = 5%) to obtain crude 15-6 (33.0 mg).

[0332] LC-MS (m / z): 442.0 [M+H] + .

[0333] Step 7: Synthesis of 4-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2-methyl-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-8-yl)-3-methoxyphenyl)piperazine-1-carboxylic acid tert-butyl ester (15-7)

[0334] 15-6 (33.0 mg), INT3 (37.5 mg, 89.6 μmol), XPhos Pd G3 (12.6 mg, 14.9 μmol), and potassium phosphate (47.6 mg, 0.22 mmol) were dissolved in a mixed solvent of dioxane (1 mL) and water (0.2 mL). The mixture was reacted at 80 °C for 1 hour under nitrogen protection. The reaction solution was concentrated and purified by column chromatography (MeOH:DCM = 10%) to give 15-7 (16.0 mg), with a yield of 48.5%.

[0335] LC-MS (m / z): 698.0 [M+H] + .

[0336] Step 8: Synthesis of 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-8-(2-methoxy-4-(piperazin-1-yl)phenyl)-2-methyl-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (15-8)

[0337] Dissolve 15-7 (16.0 mg, 22.9 μmol) in DCM (1 mL), add TFA (1 mL), and react at room temperature for 0.5 hours. Concentrate the reaction solution to obtain crude 15-8 (12.0 mg), which can be used directly in the next step.

[0338] LC-MS (m / z): 598.0 [M+H] + .

[0339] Step 9: Synthesis of 3-(4-(2-(4-(4-(6-1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2-methyl-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-8-yl)-3-methoxyphenyl)piperazin-1-yl)ethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (15)

[0340] 15-8 (12.0 mg) crude product and INT2 (7.6 mg, 25.2 μmol) were dissolved in a mixed solvent of THF (0.8 mL) and DMSO (0.2 mL). KOAc (6.7 mmol, 68.7 μmol) and 2 drops of acetic acid were added, and the mixture was stirred at room temperature for 1 hour. Then, NaBH3CN (4.3 mg, 68.7 μmol) was added, and the reaction was continued at room temperature for 0.5 hours. The reaction solution was quenched with water, concentrated, and the residue was diluted with DCM / MeOH (10:1, 5 mL), washed with water (5 mL), concentrated, and purified by column chromatography (MeOH:DCM = 8%) to give 15 (12.0 mg), with a two-step yield of 59.3%.

[0341] LC-MS (m / z): 883.0 [M+H] + .

[0342] 1 H NMR(600MHz,DMSO-d6)δ12.34–12.32(m,1H),11.11(s,1H),7.73–7.70(m,1H),7.43–7.37(m,1H),7.16–7.15(m,1H),7.00 –6.86(m,4H),6.67(s,1H),6.61–6.59(m,1H),6.21–6.17(m,1H),6.14–6.11(m,1H),5.40–5.37(m,1H),4.38–4.34(m,3H) ,4.29(s,1H),4.05–4.02(m,2H),3.72–3.69(m,3H),3.65–3.62(m,4H),3.58–3.56(m,1H),3.30–3.24(m,4H),3.16–3.13( m,2H),3.01–2.95(m,5H),2.92–2.87(m,1H),2.73–2.61(m,8H),2.35–2.30(m,1H),2.28–2.24(m,1H),2.01–2.00(m,1H).

[0343] Example 16: Synthesis of 3-(4-(2-(4-(4-(6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2-methyl-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-8-yl)-3-methoxyphenyl)piperazin-1-yl)ethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (compound 16)

[0344] Step 1: Synthesis of 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-8-chloro-5-fluoro-2-methyl-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (16-1)

[0345] Intermediate 15-5 is prepared according to steps 1 to 5 of Example 15.

[0346] Intermediate 15-5 (150.0 mg, 0.47 mmol), INT6 (190.0 mg, 0.57 mmol), 1'-bis(diphenylphosphino)ferrocene]palladium dichloride (36.0 mg, 0.049 mmol), and potassium carbonate (198.0 mg, 1.43 mmol) were dissolved in a mixed solution of 1,4-dioxane (8 mL) and water (1.5 mL). The reaction mixture was placed at 90 °C for 1 hour under nitrogen protection. After the reaction was complete as monitored by LC-MS, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol = 70:30 as eluent) to give compound 16-1 (60.0 mg), in a yield of 28.9%.

[0347] LC-MS (m / z): 443.0 [M+H] + .

[0348] Step 2: Synthesis of 4-(4-(6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2-methyl-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-8-yl)-3-methoxyphenyl)piperazine-1-carboxylic acid tert-butyl ester (16-2)

[0349] Compound 16-1 (60.0 mg, 0.14 mmol), INT3 (85.0 mg, 0.20 mmol), Xphos-Pd-G3 (17.0 mg, 0.02 mmol), and potassium phosphate (86.0 mg, 0.41 mmol) were dissolved in a mixed solution of 1,4-dioxane (3 mL) and water (0.5 mL). The reaction mixture was placed at 90 °C for 1 hour under nitrogen protection. After the reaction was complete as monitored by LC-MS, the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (using dichloromethane:methanol = 95:5 as eluent) to give compound 16-2 (80.0 mg), in a yield of 81.9%.

[0350] LC-MS (m / z): 699.0 [M+H] + .

[0351] Step 3: Synthesis of 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-8-(2-methoxy-4-(piperazin-1-yl)phenyl)-2-methyl-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (16-3)

[0352] 16-2 (80.0 mg, 0.11 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (0.5 mL) was added. The reaction mixture was placed at 25 °C and reacted for 1 hour. After the reaction was monitored by LC-MS to be complete, the solution was concentrated under reduced pressure to obtain compound 16-3 (100.0 mg), which was the crude product.

[0353] LC-MS (m / z): 599.0 [M+H] + .

[0354] Step 4: Synthesis of 3-(4-(2-(4-(4-(6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2-methyl-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-8-yl)-3-methoxyphenyl)piperazin-1-yl)ethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (compound 16)

[0355] The crude product of compound 16-3 (100.0 mg) and INT2 (52.0 mg, 0.17 mmol) were dissolved in a mixed solution of tetrahydrofuran (2 mL) and dimethyl sulfoxide (2 mL). Acetic acid (21.0 mg, 0.35 mmol) and sodium triacetoxyborohydride (122.0 mg, 0.58 mmol) were added, and the reaction solution was placed at 25 °C for 1 hour. After the reaction was complete as monitored by LC-MS, water (10 mL) was added to quench the reaction. The aqueous phase was extracted with dichloromethane (20 mL × 6). The combined organic phases were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by HPLC to give the formate of compound 16 (30.9 mg), with a two-step yield of 31.8%.

[0356] LC-MS (m / z): 884.0 [M+H] + .

[0357] 1H NMR (600MHz, DMSO-d6) δ12.33(d,J=11.1Hz,1H),11.11(s,1H),8.16(s,1H),8.14–8.08(m,1H),7.72–7.63(m,1H),7.1 8–7.13(m,1H),7.02–6.84(m,4H),6.67(d,J=2.5Hz,1H),6.60(dd,J=8.4,2.2Hz,1H),6.17–6.09(m,1H),5.38(dd,J=12 .8,5.5Hz,1H),4.70–4.52(m,2H),4.38–4.27(m,2H),4.08–3.98(m,2H),3.75–3.66(m,3H),3.66–3.57(m,5H),3.29–3. 19(m,4H),3.17–3.05(m,4H),3.01(s,3H),2.94–2.84(m,1H),2.77–2.58(m,8H),2.37–2.20(m,2H),2.05–1.95(m,1H).

[0358] Example 19: Synthesis of 3-(4-(4-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2-methyl-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-8-yl)-3-methylphenyl)piperidin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione (compound 19)

[0359] Step 1: Synthesis of 4-(4-chloro-3-methylphenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (19-1)

[0360] 4-Bromo-1-chloro-2-toluene (19-SM, 3.00 g, 14.70 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (5.45 g, 17.64 mmol), 1'-bis(diphenylphosphine)ferrocene]palladium dichloride (1.08 g, 1.48 mmol), and potassium carbonate (6.09 g, 43.8 mmol) were dissolved in a mixed solution of 1,4-dioxane (30 mL) and water (8 mL). The reaction mixture was placed at 80 °C for 2 hours under nitrogen protection. After the reaction was complete as monitored by LC-MS, the mixture was filtered through diatomaceous earth, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 90:10 as eluent) to give compound 19-1 (4.40 g), yield 97.5%.

[0361] LC-MS (m / z): 252.0 [M+H-56] + .

[0362] 1 H NMR (600MHz, DMSO-d6) δ7.42(d,J=2.4Hz,1H),7.36(d,J=8.3Hz,1H),7.27(dd,J=8.4,2.4Hz,1H),6. 23–6.09(m,1H),4.03–3.93(m,2H),3.56–3.46(m,2H),2.48–2.38(m,2H),2.33(s,3H),1.42(s,9H).

[0363] Step 2: Synthesis of tert-butyl 4-(4-chloro-3-methylphenyl)piperidine-1-carboxylate (19-2)

[0364] Compound 19-1 (3.40 g, 11.07 mmol) was dissolved in tetrahydrofuran (30 mL), and palladium on carbon (10%, 1.17 g, 1.10 mmol) was added. The mixture was reacted at 25 °C for 5 hours under a hydrogen atmosphere. After the reaction was confirmed to be complete by LCMS, the reaction solution was filtered and concentrated under reduced pressure to obtain compound 19-2 (3.40 g), which was the crude product.

[0365] LC-MS (m / z): 254.0 [M+H-56] + .

[0366] Step 3: Synthesis of 4-(4-chloro-3-methylphenyl)piperidine hydrochloride (19-3)

[0367] The crude product of compound 19-2 (3.40 g) was dissolved in dichloromethane (30 mL), and a dioxane solution of hydrogen chloride (4.0 M, 11 mL, 44.00 mmol) was added. The reaction mixture was 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 to obtain compound 19-3 (2.50 g), which was the crude product.

[0368] LC-MS (m / z): 210.0 [M+H] + .

[0369] Step 4: Synthesis of 3-(4-(4-(-4-chloro-3-methylphenyl)piperidin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione (19-4)

[0370] The following were added: 19-3 (1.04 g, 4.24 mmol), INT2-1 (1.20 g, 3.55 mmol), Ruphos-Pd-G2 (275.0 mg, 0.35 mmol), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (250.0 mg, 0.53 mmol) and Molecular sieve (2.0 g) was dissolved in toluene (40 mL), and a tetrahydrofuran solution of LHMDS (1.0 M, 30 mL, 30.00 mmol) was added dropwise at 0 °C. Under nitrogen protection, the reaction mixture was heated to 100 °C and reacted for 1.5 h. After the reaction was confirmed to be complete by LC-MS, the reaction was quenched by adding a saturated aqueous solution of ammonium chloride (30 mL) at 0 °C. Water (30 mL) was added, and the aqueous phase was extracted with ethyl acetate (60 mL × 3). The combined organic phases were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate as eluent) to give compound 19-4 (800.0 mg), with a yield of 48.4%.

[0371] LC-MS (m / z): 467.0 [M+H] + .

[0372] Step 5: Synthesis of 3-(3-methyl-4-(4-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)piperidin-1-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione (19-5)

[0373] Compound 19-4 (400.0 mg, 0.86 mmol), pinacol diborate (874.0 mg, 3.44 mmol), potassium acetate (253.0 mg, 2.58 mmol), and Xphos-Pd-G3 (73.0 mg, 0.086 mmol) were dissolved in anhydrous 1,4-dioxane (6 mL). The reaction mixture was placed at 80 °C for 1.5 h under nitrogen protection. After the reaction was complete as monitored by LC-MS, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (using ethyl acetate as eluent) to give compound 19-5 (310.0 mg), with a yield of 64.6%.

[0374] LC-MS (m / z): 559.0 [M+H] + .

[0375] Step 6: Synthesis of 3-(4-(4-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2-methyl-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-8-yl)-3-methylphenyl)piperidin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione (compound 19)

[0376] Intermediate 15-6 is prepared according to steps 1 to 6 of Example 15.

[0377] Intermediates 15-6 (30.0 mg, 0.068 mmol), 19-5 (46.0 mg, 0.082 mmol), XPhos-Pd-G3 (9.0 mg, 0.011 mmol), and cesium fluoride (31.0 mg, 0.20 mmol) were dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (0.6 mL). The reaction mixture was placed at 80 °C for 2 hours under nitrogen protection. After the reaction was confirmed to be complete by LC-MS, the reaction mixture was concentrated under reduced pressure. The residue was purified by HPLC to give compound 19 (17.0 mg), with a yield of 29.9%.

[0378] LC-MS (m / z): 838.0 [M+H] + .

[0379] 1 H NMR(600MHz,DMSO-d6)δ12.53–12.44(m,1H),11.10(s,1H),7.75–7.66(m,1H),7.47–7.35(m,1H),7.33 –7.21(m,3H),7.06–6.86(m,4H),6.23–6.13(m,2H),5.37(dd,J=12.8,5.5Hz,1H),4.41–4.28(m,4H),3 .92(s,2H),3.71(s,3H),3.60(dt,J=37.7,5.8Hz,2H),3.26(d,J=10.9Hz,2H),3.02–2.94(m,5H),2.95 –2.83(m,3H),2.77–2.67(m,2H),2.65–2.57(m,1H),2.34–2.24(m,2H),2.16(s,3H),2.04–1.91(m,5H).

[0380] Example 23: Synthesis of 3-(4-(4-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2-methyl-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-8-yl)-3-methoxyphenyl)piperidin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione (compound 23)

[0381] Step 1: Synthesis of 4-(4-chloro-3-methoxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (23-1)

[0382] 4-Bromo-1-chloro-2-methoxybenzene (23-SM, 3.50 g, 15.80 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (5.86 g, 18.96 mmol), [1'-bis(diphenylphosphine)ferrocene]palladium dichloride (1.16 g, 1.58 mmol), and potassium carbonate (6.55 g, 47.40 mmol) were dissolved in 1,4-dioxane (35 mL). The reaction mixture was placed at 80 °C for 2 hours under nitrogen protection. After the reaction was complete as monitored by LC-MS, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 90:10 as eluent) to give compound 23-1 (5.07 g), yield 99.0%.

[0383] LC-MS (m / z): 324.0 [M+H] + .

[0384] Step 2: Synthesis of tert-butyl 4-(4-chloro-3-methoxyphenyl)piperidine-1-carboxylate (23-2)

[0385] Compound 23-1 (2.50 g, 7.72 mmol) was dissolved in tetrahydrofuran (20 mL), and palladium on carbon (10%, 250.0 mg, 0.24 mmol) was added. The mixture was reacted at 25 °C for 3 hours under a hydrogen atmosphere. After the reaction was confirmed to be complete by LC-MS, the reaction solution was filtered and concentrated under reduced pressure to obtain compound 23-2 (2.61 g), which was the crude product.

[0386] LC-MS (m / z): 326.0 [M+H] + .

[0387] Step 3: Synthesis of 4-(4-chloro-3-methoxyphenyl)piperidine hydrochloride (23-3)

[0388] The crude product of compound 23-2 (2.61 g) was dissolved in dichloromethane (20 mL), and an ethyl acetate solution of hydrogen chloride (4.0 M, 10 mL, 40.00 mmol) was added. The reaction solution was placed at 25 °C for 1 hour. After the reaction was confirmed to be complete by LC-MS, the reaction solution was concentrated to obtain compound 23-3 (1.91 g), which was the crude product.

[0389] LC-MS (m / z): 226.0 [M+H] + .

[0390] Step 4: Synthesis of 3-(4-(4-(-4-chloro-3-methoxyphenyl)piperidin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione (23-4)

[0391] The following were added: 23-3 (1.30 g, 4.61 mmol), INT2-1 (1.30 g, 3.84 mmol), Ruphos-Pd-G2 (300.0 mg, 0.38 mmol), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (271.0 mg, 0.58 mmol) and Molecular sieve (2.0 g) was dissolved in anhydrous toluene (15 mL), and a tetrahydrofuran solution of LHMDS (1.0 M, 19.2 mL, 19.20 mmol) was added dropwise at 0 °C. Under nitrogen protection, the reaction solution was heated to 100 °C and reacted for 1 hour. After the reaction was complete as monitored by LC-MS, the reaction solution was cooled to room temperature, and the reaction was quenched by adding a saturated aqueous solution of ammonium chloride (30 mL) at 0 °C. Water (30 mL) was added, and the aqueous phase was extracted with ethyl acetate (60 mL × 3). The combined organic phases were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate as eluent) to give compound 23-4 (1.00 g), yield 54.1%.

[0392] LC-MS (m / z): 483.0 [M+H] + .

[0393] Step 5: Synthesis of 3-(4-(4-(4-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)piperidin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione (23-5)

[0394] Compound 23-4 (500.0 mg, 1.04 mmol), pinacol diborate (528.0 mg, 2.08 mmol), Xphos-Pd-G3 (88.0 mg, 0.10 mmol), and potassium acetate (306.0 mg, 3.12 mmol) were dissolved in 1,4-dioxane (10 mL). The reaction mixture was placed at 80 °C for 1 hour under nitrogen protection. After the reaction was complete as monitored by LC-MS, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate as eluent) to give compound 23-5 (390.0 mg), with a yield of 65.2%.

[0395] LC-MS (m / z): 575.0 [M+H] + .

[0396] Step 6: Synthesis of 3-(4-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2-methyl-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-8-yl)-3-methoxyphenyl)piperidin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione (compound 23)

[0397] Intermediate 15-6 is prepared according to steps 1 to 6 of Example 15.

[0398] Intermediates 15-6 (30.0 mg, 0.07 mmol) and 23-5 (80.0 mg, 0.14 mmol) were dissolved in a mixed solution of 1,4-dioxane (5 mL) and water (1 mL). Xphos-Pd-G3 (6.0 mg, 7.0 μmol) and cesium fluoride (32.0 mg, 0.21 mmol) were added. The reaction mixture was incubated at 80 °C for 1 hour under nitrogen protection. After the reaction was confirmed to be complete by LC-MS, the reaction solution was concentrated under reduced pressure. The residue was purified by HPLC to give compound 23 (19.0 mg), with a yield of 31.7%.

[0399] LC-MS (m / z): 854.0 [M+H] + .

[0400] 1H NMR (600MHz, DMSO-d6) δ12.40(d,J=12.5Hz,1H),11.10(s,1H),7.72(dd,J=15.1,2.2Hz,1H),7.40(dd,J=34.6,1.8Hz,1H),7.29(dd,J=7.7,2.1Hz, 1H),7.08(d,J=2.8Hz,1H),7.05–6.96(m,3H),6.92(dd,J=21.1,7.0Hz,2 H),6.22–6.11(m,2H),5.37(dd,J=13.0,5.4Hz,1H),4.37(q,J=6.7,6.2Hz ,3H),4.30(s,1H),4.02(d,J=2.7Hz,2H),3.75(d,J=5.7Hz,3H),3.71(s, 3H),3.64(t,J=5.9Hz,1H),3.58(t,J=5.8Hz,1H),3.27(d,J=11.0Hz,2H), 3.01(s,3H),2.97(dt,J=9.5,7.1Hz,2H),2.89(dt,J=12.9,7.3Hz,3H),2. 83–2.66(m,2H),2.67–2.59(m,1H),2.41–2.21(m,2H),2.06–1.92(m,5H).

[0401] Example 31: Synthesis of 3-(4-(2-(4-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2-methyl-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-8-yl)-5-chloro-2-fluorophenyl)piperazin-1-yl)ethyl)-3-methyl-1H-indazol-1-yl)-2,6-dione (compound 31)

[0402] Step 1: Synthesis of 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (31-1)

[0403] Intermediate 15-6 is prepared according to steps 1 to 6 of Example 15.

[0404] Intermediate 15-6 (100.0 mg, 0.23 mmol), pinacol diborate (115.1 mg, 0.45 mmol), Xphos-Pd-G3 (19.4 mg, 0.023 mmol), and potassium acetate (67.6 mg, 0.69 mmol) were dissolved in a mixed solution of 1,4-dioxane (3 mL). The reaction mixture was placed at 80 °C for 2 hours under nitrogen protection. After the reaction was complete as monitored by LC-MS, the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (using dichloromethane:methanol = 95:5 as eluent) to give compound 31-1 (110.0 mg), with a yield of 90.1%.

[0405] LC-MS (m / z): 534.0 [M+H] + .

[0406] Step 2: Synthesis of 4-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2-methyl-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-8-yl)-5-chloro-2-fluorophenyl)piperazine-1-carboxylic acid tert-butyl ester (31-2)

[0407] 4-(4-bromo-5-chloro-2-fluorophenyl)piperazine-1-carboxylic acid tert-butyl ester (80.9 mg, 0.21 mmol), 31-1 (110.0 mg, 0.21 mmol), [1'-bis(diphenylphosphino)ferrocene]palladium dichloride (15.1 mg, 0.021 mmol), and potassium carbonate (85.3 mg, 0.62 mmol) were dissolved in a mixed solution of 1,4-dioxane (4 mL) and water (1 mL). The reaction mixture was placed at 80 °C for 2 hours under nitrogen protection. After the reaction was complete as monitored by LC-MS, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 95:5 as eluent) to give compound 31-2 (120.0 mg), with a yield of 81.0%.

[0408] LC-MS (m / z): 720.0 [M+H] + .

[0409] Step 3: Synthesis of 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-8-(2-chloro-5-fluoro-4-(piperazin-1-yl)phenyl)-5-fluoro-2-methyl-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (31-3)

[0410] Compound 31-2 (120.0 mg, 0.17 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (2 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 obtain compound 31-3 (100.0 mg), which was the crude product.

[0411] LC-MS (m / z): 620.0 [M+H] + .

[0412] Step 4: Synthesis of 3-(4-(2-(4-(4-(6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2-methyl-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-8-yl)-3-methoxyphenyl)piperazin-1-yl)ethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (compound 31)

[0413] The crude product of compound 31-3 (100.0 mg) and intermediate INT7 (69.0 mg, 0.24 mmol) were dissolved in a mixed solution of tetrahydrofuran (2 mL) and dimethyl sulfoxide (2 mL). Acetic acid (48.5 mg, 0.81 mmol) and potassium acetate (47.5 mg, 0.48 mmol) were added, and the reaction solution was placed at 25 °C for 1 hour. Then, sodium triacetoxyborohydride (170.0 mg, 0.81 mmol) was added, and the reaction was continued at 25 °C for 1 hour. After the reaction was complete as monitored by LC-MS, water (10 mL) was added to quench the reaction. The aqueous phase was extracted with dichloromethane (20 mL × 6). The combined organic phases were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel plate preparation (dichloromethane:methanol = 95:5 as eluent) to give compound 31 (7.5 mg), with a two-step yield of 5.2%.

[0414] LC-MS (m / z): 889.0 [M+H] + .

[0415] 1H NMR(600MHz,DMSO-d6)δ12.56(d,J=10.7Hz,1H),11.06(s,1H),7.71(dd,J=14.7,2.2Hz,1H),7.46–7.26(m,4H) ,7.19(d,J=8.1Hz,1H),7.06–6.93(m,2H),6.24–6.13(m,2H),5.73(dd,J=11.8,5.1Hz,1H),4.36(q,J=5.2,3.8H z,3H),4.08(s,2H),3.64(s,1H),3.57(t,J=5.9Hz,1H),3.25–3.13(m,6H),3.01(s,3H),2.97(dt,J=9.7,7.0Hz, 2H),2.88–2.83(m,1H),2.72(t,J=11.6Hz,6H),2.66(s,3H),2.54(s,3H),2.36–2.27(m,2H),2.24–2.18(m,1H).

[0416] Example 39: Synthesis of 3-((4-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2-methyl-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-8-yl)-2,3-difluorophenyl)piperazin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione (compound 39)

[0417] Intermediate 15-6 is prepared according to steps 1 to 6 of Example 15.

[0418] 15-6 (20.5 mg, 0.046 mmol), INT5 (32.0 mg, 0.056 mmol), XPhos-Pd-G3 (6.0 mg, 0.007 mmol), and cesium fluoride (21.2 mg, 0.14 mmol) were dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (0.6 mL). The reaction mixture was placed at 80 °C for 2 hours under nitrogen protection. After the reaction was confirmed to be complete by LC-MS, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (using dichloromethane:methanol = 95:5 as eluent) to give compound 39 (12.1 mg), with a yield of 30.8%.

[0419] LC-MS (m / z): 854.0 [M+H] + .

[0420] 1H NMR(600MHz,DMSO-d6)δ12.61(s,1H),10.87(s,1H),7.76–7.68(m,1H),7.45–7.27(m,2H),7.14–6.96(m,2H) ,6.70(d,J=8.0Hz,1H),6.59(d,J=14.1Hz,1H),6.24–6.13(m,2H),5.15(d,J=6.9Hz,1H),4.41–4.24(m,5H), 4.25–4.18(m,2H),3.82(s,3H),3.67–3.54(m,2H),3.31–3.23(m,4H),3.16–3.08(m,4H),3.04(s,3H),3.03– 2.92(m,2H),2.86–2.76(m,1H),2.59–2.51(m,1H),2.37–2.22(m,2H),2.18–2.09(m,1H),1.99–1.90(m,1H).

[0421] Example 47: Synthesis of 3-(4-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2-methyl-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-8-yl)-2,3-difluorophenyl)piperazin-1-yl)piperidin-1-yl)-3-fluorophenyl)piperidin-2,6-dione (compound 47)

[0422] Step 1: Synthesis of 3-(4-(4-(2,3-difluoro-4-(4,4,5,5-tetramethyl-1,2l3,3-trioxopentane-2-yl)phenyl)piperazin-1-yl)piperidin-1-yl)-3-fluorophenyl)piperidin-2,6-dione (47-1)

[0423] 47-SM (100.0 mg, 0.18 mmol) was dissolved in 1,4-dioxane (5 mL), and pinacol diboronate (90.0 mg, 0.35 mmol), DPPF palladium dichloride (13.0 mg, 0.02 mmol), and potassium acetate (35.0 mg, 0.35 mmol) were added. The reaction was carried out at 100 °C for 6 hours under nitrogen protection. After the reaction was complete as monitored by LC-MS, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 97:3 as eluent) to give 47-1 (70.0 mg, purity 40%), yield: 25.9%.

[0424] LC-MS (m / z): 618.0 [M+H] + .

[0425] Step 2: Synthesis of 3-(4-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2-methyl-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-8-yl)-2,3-difluorophenyl)piperazin-1-yl)piperidin-1-yl)-3-fluorophenyl)piperidin-2,6-dione (47)

[0426] 15-6 (20.0 mg, 0.05 mmol) and 47-1 (30.5 mg, 0.05 mmol) were dissolved in 1,4-dioxane (3 mL), and X-Phos-Pd-G3 (3.80 mg, 0.01 mmol), cesium fluoride (14.0 mg, 0.09 mmol), and water (0.3 mL) were added. The reaction was carried out under nitrogen protection and stirred at 110 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was separated by HPLC to obtain 47 (5.0 mg), with a yield of 12.5%.

[0427] LC-MS (m / z): 892.0 [M+H] + .

[0428] 1 H NMR (600MHz, DMSO-d6) δ12.59(d,J=12.0Hz,1H),10.82(s,1H),8.15(s,0.5H),7.74–7.69(m,1H),7.44–7.35(m,1H),7.28(q,J=8.1Hz,1H),7.10( d,J=6.0Hz,0.5H),7.05–7.02(m,1H),7.02–7.00(m,1H),6.98–6.94(m,2 H),6.22–6.14(m,2H),4.39–4.29(m,4H),4.21–4.17(m,2H),3.83–3.78( m,1H),3.64(t,J=6.0Hz,1H),3.58(t,J=6.0Hz,1H),3.42(d,J=10.8Hz,2 H),3.16(s,4H),3.03(s,3H),3.00–2.94(m,2H),2.73(t,J=4.8Hz,4H),2 .71–2.60(m,4H),2.44–2.40(m,1H),2.35–2.31(m,1H),2.26(s,1H),2.2 4–2.16(m,1H),2.04–1.97(m,1H),1.94–1.88(m,2H),1.67–1.59(m,2H).

[0429] Example 51: Synthesis of 3-(4-(4-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2-methyl-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-8-yl)phenyl)piperidin-1-yl)-3-fluorophenyl)piperidin-2,6-dione (compound 51)

[0430] Intermediate 15-6 is prepared according to steps 1 to 6 of Example 15.

[0431] 15-6 (65.0 mg, 0.15 mmol), INT4 (83.6 mg, 0.17 mmol), XPhos Pd G3 (12.2 mg, 14.5 μmol), and CsF (66.0 mg, 0.43 mmol) were dissolved in a mixed solvent of dioxane (2 mL) and water (0.4 mL). The mixture was reacted at 80 °C for 2 hours under nitrogen protection. The reaction solution was concentrated, and the concentrate was purified by column chromatography (MeOH:DCM = 10%), followed by preparative purification by high performance liquid chromatography (0.1% HCO2H aqueous solution: acetonitrile) to give compound 51 (2.9 mg), with a yield of 2.6%.

[0432] LC-MS (m / z): 772.0 [M+H] + .

[0433] 1 H NMR(600MHz,DMSO-d6)δ12.55(brs,1H),10.83(s,1H),7.75–7.64(m,1H),7.62–7.51(m,2H),7.48–7.33 (m,3H),7.18–6.93(m,4H),6.23–6.13(m,2H),4.44–4.23(m,6H),3.94–3.79(m,1H),3.70–3.54(m,2H), 3.53–3.43(m,2H),3.05(s,3H),3.01–2.93(m,2H),2.82(t,J=11.5Hz,2H),2.79–2.73(m,1H),2.70–2.5 9(m,1H),2.57–2.52(m,1H),2.37–2.27(m,2H),2.25–2.15(m,1H),2.06–1.99(m,1H),1.99–1.81(m,4H).

[0434] Example 56: Synthesis of 3-(4-(4-(4-(8-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-9-fluoro-2-methyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indol-6-yl)phenyl)piperidin-1-yl)-3-fluorophenyl)piperidin-2,6-dione (compound 56)

[0435] Step 1: Synthesis of (4-bromo-2-chloro-5-fluorophenyl)hydrazine hydrochloride (56-1)

[0436] 4-Bromo-2-chloro-5-fluoroaniline (9.00 g, 40.10 mmol) was dissolved in an aqueous hydrochloric acid solution (6.0 M, 100 mL). An aqueous sodium nitrite solution (3.30 g, 48.12 mmol, dissolved in 22 mL of water) was slowly added dropwise at 0 °C. The reaction mixture was kept at 0 °C for 1 hour. Subsequently, SnCl₂·2H₂O (18.00 g, 80.12 mmol, dissolved in 60 mL of 6 M hydrochloric acid solution) was slowly added dropwise at 0 °C. The reaction mixture was kept at room temperature for 1 hour. After the reaction was complete, the mixture was filtered. The filter cake was washed three times with petroleum ether and dried to obtain 56-1 (13.00 g), which was the crude product.

[0437] LC-MS (m / z): 239.0 / 241.0 [M+H] + .

[0438] Step 2: Synthesis of ethyl 2-(2-(4-bromo-2-chloro-5-fluorophenyl)hydrazine)propionate (56-2)

[0439] The crude product of compound 56-1 (7.00 g) was dissolved in ethanol (70 mL), and ethyl pyruvate (2.65 g, 22.83 mmol) was slowly added dropwise at 0 °C. The reaction solution was kept at 0 °C for 1 hour. After the reaction was completed, the solution was concentrated under reduced pressure to obtain 56-2 (9.60 g), which was the crude product.

[0440] LC-MS (m / z): 337.0 / 339.0 [M+H] + .

[0441] Step 3: Synthesis of ethyl 5-bromo-7-chloro-4-fluoro-1H-indole-2-carboxylate (56-3)

[0442] 56-2 (9.60 g, 28.44 mmol) was dissolved in Eaton reagent (60 mL), and the reaction mixture was placed at 45 °C for 2 hours. After the reaction was complete as monitored by LC-MS, the reaction mixture was cooled to room temperature and slowly poured into a saturated sodium bicarbonate aqueous solution. The aqueous phase was extracted with ethyl acetate (60 mL × 3). The combined organic phases were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 85:15 as eluent) to give 56-3 (900.0 mg), with a three-step yield of 12.6%.

[0443] LC-MS (m / z): 318.0 / 320.0 [MH] - .

[0444] 1 H NMR (600MHz, DMSO-d6) δ12.41(s,1H),7.93(d,J=6.6Hz,1H),7.39(d,J=9.1Hz,1H),4.38(q,J=7.1Hz,2H),1.36(t,J=7.1Hz,3H).

[0445] Step 4: Synthesis of ethyl 5-bromo-1-(2-((tert-butoxycarbonyl)amino)ethyl)-7-chloro-4-fluoro-1H-indole-2-carboxylate (56-4)

[0446] 56-3 (900.0 mg, 2.81 mmol), N-tert-butyloxycarbonyl-bromoethylamine (1.13 g, 5.06 mmol), potassium iodide (513.0 mg, 3.09 mmol), and cesium carbonate (2.11 g, 6.46 mmol) were dissolved in DMF (15 mL), and the reaction mixture was placed at 60 °C for 3 hours. After the reaction was complete as monitored by LC-MS, water (20 mL) was added to quench the reaction. The aqueous phase was extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 80:20 as eluent) to give 56-4 (1.00 g), with a yield of 88.5%.

[0447] LC-MS (m / z): 463.0 / 465.0 [M+H] + .

[0448] Step 5: Synthesis of ethyl 1-(2-aminoethyl)-5-bromo-7-chloro-4-fluoro-1H-indole-2-carboxylate (56-5)

[0449] 56-4 (1.00 g, 2.16 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (2.46 g, 21.60 mmol) was slowly added dropwise at 0 °C. The reaction solution was kept at room temperature for 2 hours. After the reaction was confirmed to be complete by LC-MS, the solution was concentrated under reduced pressure to obtain 56-5 (1.00 g), which was the crude product.

[0450] LC-MS (m / z): 363.0 / 365.0 [M+H] + .

[0451] Step 6: Synthesis of 8-bromo-6-chloro-9-fluoro-3,4-dihydropyrazino[1,2-a]indole-1(2H)-one (56-6)

[0452] The crude compound 56-5 (1.00 g) was dissolved in a mixed solution of tetrahydrofuran (10 mL) and water (5 mL). Sodium bicarbonate (2.43 g, 27.50 mmol) was added in three portions, and the reaction mixture was placed at 60 °C for 2 hours. After the reaction was confirmed to be complete by LC-MS, water (20 mL) was added to quench the reaction. The aqueous phase was extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 56-6 (700.0 mg), which was the crude product.

[0453] LC-MS (m / z): 317.0 / 319.0 [M+H] + .

[0454] 1 H NMR (600MHz, DMSO-d6) δ8.34(d,J=3.1Hz,1H),7.91(d,J=6.7Hz,1H),7.81(d,J=9.7Hz,1H),4.28(t,J=5.8Hz,2H),3.62(dq,J=5.2,3.3Hz,2H).

[0455] Step 7: Synthesis of 8-bromo-6-chloro-9-fluoro-2-methyl-3,4-dihydropyrazino[1,2-a]indole-1(2H)-one (56-7)

[0456] NaH (132.0 mg, 3.31 mmol) was suspended in DMF (6 mL). A DMF solution (6 mL) of 56-6 (700.0 mg, 2.20 mmol) was slowly added dropwise at 0 °C. The reaction mixture was heated to room temperature and reacted for 0.5 hours. Iodomethane (406.0 mg, 2.86 mmol) was then added, and the reaction mixture was allowed to continue reacting at room temperature for 1 hour. After the reaction was confirmed to be complete by LC-MS, water (20 mL) was added to quench the reaction. The aqueous phase was extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 56-7 (734.0 mg), the crude product.

[0457] LC-MS (m / z): 331.0 / 333.0 [M+H] + .

[0458] Step 8: Synthesis of 8-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-6-chloro-9-fluoro-2-methyl-3,4-dihydropyrazine[1,2-a]indole-1(2H)-one (56-8)

[0459] 56-7 (120.0 mg, 0.36 mmol), INT1 (214.6 mg, 0.65 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (26.3 mg, 0.04 mmol), and potassium carbonate (149.2 mg, 1.08 mmol) were dissolved in a mixed solvent of 1,4-dioxane (5 mL) and water (1 mL). The reaction mixture was placed at 80 °C for 1 hour under nitrogen protection. After the reaction was complete as monitored by LC-MS, the residue was purified by silica gel column chromatography (using dichloromethane:methanol = 97:3 as eluent) to give 56-8 (150.0 mg), with a yield of 91.5%.

[0460] LC-MS (m / z): 456.0 [M+H] + .

[0461] Step 9: Synthesis of 3-(4-(4-(4-(8-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-9-fluoro-2-methyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indol-6-yl)phenyl)piperidin-1-yl)-3-fluorophenyl)piperidin-2,6-dione (56)

[0462] 56-8 (40.0 mg, 0.09 mmol), INT4 (59.1 mg, 0.12 mmol), XPhos Pd G3 (9.0 mg, 0.01 mmol), and cesium fluoride (41.0 mg, 0.27 mmol) were dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (0.6 mL). The reaction mixture was placed at 80 °C for 1 hour under nitrogen protection. After the reaction was complete as monitored by LC-MS, the reaction solution was concentrated under reduced pressure and purified by HPLC to obtain 56-8 (8.0 mg), with a yield of 11.3%.

[0463] LC-MS (m / z): 786.0 [M+H] + .

[0464] 1 H NMR(600MHz, DMSO-d6)δ10.83(s,1H),7.70(dd,J=20.8,2.2Hz,1H),7.57–7.45(m,3H),7.45–7.30(m,4H),7.11–7.02(m, 2H),6.98(dd,J=8.3,2.0Hz,1H),6.17(dt,J=28.7,2.1Hz,1H),5.95(d,J=4.8Hz,1H),4.44–4.28(m,4H),4.23(s,1H),4. 13(s,1H),3.82(q,J=5.4Hz,3H),3.61(t,J=5.9Hz,1H),3.54(t,J=5.8Hz,1H),3.50(d,J=11.3Hz,2H),3.02(s,3H),2.95 (t,J=7.0Hz,1H),2.89(t,J=7.0Hz,1H),2.82(t,J=11.4Hz,2H),2.77–2.60(m,2H),2.32–2.16(m,3H),2.07–1.83(m,6H).

[0465] Example 65: Synthesis of 3-(4-(2-(4-(4-(8-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-9-fluoro-2-methyl-1-oxo-1,2,3,4-tetrahydropyrazine[1,2-a]indol-6-yl)-3-methoxyphenyl)piperazin-1-yl)ethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione formate (compound 65 formate)

[0466] Step 1: Synthesis of 4-(4-(8-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-9-fluoro-2-methyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indol-6-yl)-3-methoxyphenyl)piperazine-1-carboxylic acid tert-butyl ester (65-1)

[0467] Intermediates 56-8 are prepared according to steps 1 to 8 of Example 56.

[0468] 56-8 (70.0 mg, 0.15 mmol), INT3 (90.0 mg, 0.21 mmol), XPhos Pd G3 (13.0 mg, 0.02 mmol), and potassium phosphate (96.0 mg, 0.45 mmol) were dissolved in a mixed solvent of 1,4-dioxane (5 mL) and water (1 mL). The mixture was reacted at 80 °C for 1 hour under nitrogen protection. After the reaction was complete as monitored by LC-MS, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (using dichloromethane:methanol = 95:5 as eluent) to give 65-1 (80.0 mg), with a yield of 74.8%.

[0469] LC-MS (m / z): 712.0 [M+H] + .

[0470] Step 2: Synthesis of 8-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-9-fluoro-6-(2-methoxy-4-(piperazin-1-yl)phenyl)-2-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (65-2)

[0471] Dissolve 65-1 (80.0 mg, 0.11 mmol) in dichloromethane (5 mL), add trifluoroacetic acid (5 mL), and react at room temperature for 1 hour. After the reaction is complete as monitored by LC-MS, concentrate under reduced pressure, add methanol (10 mL × 3), and concentrate three times under reduced pressure to remove the residual trifluoroacetic acid, yielding crude 65-2 (80.0 mg), which can be used directly in the next step.

[0472] LC-MS (m / z): 612.0 [M+H] + .

[0473] Step 3: Synthesis of 3-(4-(2-(4-(4-(8-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-9-fluoro-2-methyl-1-oxo-1,2,3,4-tetrahydropyrazine[1,2-a]indol-6-yl)-3-methoxyphenyl)piperazin-1-yl)ethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione formate (compound 65 formate).

[0474] The crude product of compound 65-2 (80.0 mg) and INT2 (51.0 mg, 0.17 mmol) were dissolved in MeOH (5 mL), potassium acetate (26.0 mmol, 0.26 mmol) and acetic acid (0.4 mL) were added, and the mixture was stirred at room temperature for 0.5 hours. Then, NaBH3CN (20.5 mg, 0.33 mmol) was added, and the reaction was continued at room temperature for 1 hour. The reaction solution was quenched with water, concentrated, and the residue was separated by HPLC to obtain the formate of compound 65 (7.2 mg), with a two-step yield of 6.2%.

[0475] LC-MS (m / z): 897.0 [M+H] + .

[0476] 1 H NMR (600MHz, DMSO-d6) δ11.11(s,1H),8.18(s,1H),7.70(dd,J=18.9,2.2Hz,1H),7.51–7.29(m,2H),7.15–7.06(m,2H),6.99(d,J=5.4Hz,2H),6.95 (dd,J=5.9,3.1Hz,1H),6.62(dd,J=12.8,2.2Hz,1H),6.53(dt,J=9.0,2. 6Hz,1H),6.17(dt,J=22.2,2.1Hz,1H),5.91(s,1H),5.50–5.22(m,1H),4. 33(dt,J=11.5,6.9Hz,4H),4.28–4.05(m,2H),3.79(t,J=6.1Hz,2H),3.6 5(s,2H),3.64(s,1H),3.62(s,3H),3.52(d,J=6.8Hz,1H),3.28–3.20(m,6 H),3.14(t,J=8.1Hz,2H),2.98(s,3H),2.94(t,J=7.0Hz,1H),2.89(t,J= 7.4Hz,1H),2.76–2.59(m,8H),2.22(d,J=40.1Hz,2H),2.06–1.94(m,1H).

[0477] Example 107: Synthesis of 3-(4-(2-(4-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2-methyl-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-8-yl)-3-(methoxy-d3)phenyl)piperazin-1-yl)ethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (compound 107 formate)

[0478] Step 1: Synthesis of 1-bromo-4-iodo-2-(methoxy-d3)benzene (107-1)

[0479] Sodium hydride (60%, 0.58 g, 14.5 mmol) was suspended in anhydrous N,N-dimethylformamide (5 mL). A solution of 2-bromo-5-iodophenol (2.18 g, 7.27 mmol) in N,N-dimethylformamide (20 mL) was added at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, followed by the addition of deuterated iodomethane (2.1 g, 14.5 mmol). The reaction mixture was then stirred at 25 °C for 1 h. After LC-MS monitoring confirmed complete reaction, the reaction was quenched at 0 °C with saturated ammonium chloride aqueous solution (10 mL) and water (10 mL). The aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 98:2 as eluent) to give 107-1 (2.05 g), yield 89.5%.

[0480] LC-MS (m / z): 316.0 / 318.0 [M+H] + .

[0481] 1 H NMR (600MHz, Chloroform-d) δ7.24 (d, J = 8.0Hz, 1H), 7.18–7.14 (m, 2H).

[0482] Step 2: Synthesis of tert-butyl 4-(4-bromo-3-(methoxy-d3)phenyl)piperazine-1-carboxylate (107-2)

[0483] 107-1 (1.00 g, 3.17 mmol), N-tert-butyloxycarbonylpiperazine (1.18 g, 6.34 mmol), L-proline (72.0 mg, 0.63 mmol), cuprous iodide (120.0 mg, 0.63 mmol), and potassium carbonate (1.30 g, 9.51 mmol) were dissolved in anhydrous dimethyl sulfoxide (10 mL). The reaction mixture was stirred at 80 °C for 14 hours under nitrogen protection. After the reaction was confirmed to be complete by LC-MS, water (20 mL) was added to quench the reaction. The aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 80:20 as eluent) to give 107-2 (1.02 g), with a yield of 86.3%.

[0484] LC-MS (m / z): 374.0 / 376.0 [M+H] + .

[0485] 1 H NMR(600MHz,Chloroform-d)δ7.37(d,J=8.7Hz,1H),6.47(d,J=2.6Hz,1H),6.40( dd,J=8.7,2.6Hz,1H),3.58(t,J=5.2Hz,4H),3.12(t,J=5.1Hz,4H),1.48(s,9H).

[0486] Step 3: Synthesis of tert-butyl piperazine-1-carboxylate (107-3)

[0487] 107-2 (1.02 g, 2.73 mmol), pinacol diborate (1.70 g, 6.69 mmol), potassium acetate (788.0 mg, 8.04 mmol), and [1'-bis(diphenylphosphine)ferrocene]palladium dichloride (294.0 mg, 0.40 mmol) were dissolved in anhydrous 1,4-dioxane (10 mL). The reaction mixture was placed at 120 °C for 2 hours under nitrogen protection. After the reaction was complete as monitored by LC-MS, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 80:20 as eluent) to give 107-3 (651.0 mg), with a yield of 56.7%.

[0488] LC-MS (m / z): 295.0 [M+H] + .

[0489] Step 4: Synthesis of 4-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2-methyl-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-8-yl)-3-(methoxy-d3)phenyl)piperazine-1-carboxylic acid tert-butyl ester (107-4)

[0490] 15-6 (40.0 mg, 0.09 mmol), 107-3 (56.8 mg, 0.13 mmol), Xphos-Pd-G3 (11.4 mg, 0.013 mmol), and potassium phosphate (57.0 mg, 0.27 mmol) were dissolved in a mixed solution of 1,4-dioxane (3 mL) and water (0.5 mL). The reaction mixture was placed at 90 °C for 1 hour under nitrogen protection. After the reaction was complete as monitored by LC-MS, the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (using dichloromethane:methanol = 95:5 as eluent) to obtain 107-4 (66.7 mg), the crude product.

[0491] LC-MS (m / z): 701.0 [M+H] + .

[0492] Step 5: Synthesis of 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-8-(2-(methoxy-d3)-4-(piperazin-1-yl)phenyl)-2-methyl-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (107-5)

[0493] The crude product of compound 107-4 (66.7 mg) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (0.5 mL) was added. The reaction mixture was placed at 25 °C and reacted for 1 hour. After the reaction was monitored by LC-MS to be complete, the solution was concentrated under reduced pressure to obtain 107-5 (100.0 mg), which was the crude product.

[0494] LC-MS (m / z): 601.0 [M+H] + .

[0495] Step 6: Synthesis of 3-(4-(2-(4-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2-methyl-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-8-yl)-3-(methoxy-d3)phenyl)piperazin-1-yl)ethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (107 formate)

[0496] The crude product of compound 107-5 (100.0 mg) and INT2 (40.6 mg, 0.13 mmol) were dissolved in a mixed solution of tetrahydrofuran (2 mL) and dimethyl sulfoxide (2 mL). Acetic acid (16.0 mg, 0.27 mmol) and sodium triacetoxyborohydride (95.4 mg, 0.45 mmol) were added, and the reaction solution was placed at 25 °C for 1 hour. After the reaction was complete as monitored by LC-MS, water (10 mL) was added to quench the reaction. The aqueous phase was extracted with dichloromethane (20 mL × 6). The combined organic phases were washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by HPLC to obtain the formate of compound 107 (41.8 mg), with a three-step yield of 49.5%.

[0497] LC-MS (m / z): 886.0 [M+H] + .

[0498] 1 H NMR (600MHz, DMSO-d6) δ12.40–12.20(m,1H),11.11(s,1H),8.15(s,1H),7.76–7.67(m,1H),7.48–7.32(m,1H),7.15(d,J=8 .2Hz,1H),7.05–6.83(m,4H),6.68–6.63(m,1H),6.59(dd,J=8.5,2.3Hz,1H),6.25–6.15(m,1H),6.15–6.09(m,1H),5.38(dd ,J=12.9,5.5Hz,1H),4.39–4.23(m,4H),4.08–3.98(m,2H),3.67–3.59(m,4H),3.57(t,J=5.8Hz,1H),3.29–3.25(m,4H),3.1 8–3.10(m,2H),3.01(s,3H),3.01–2.93(m,2H),2.94–2.85(m,1H),2.76–2.60(m,8H),2.34–2.20(m,2H),2.07–1.97(m,1H).

[0499] Example 115: Synthesis of 3-(4-(2-(4-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2-methyl-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-8-yl)-3-methoxyphenyl)-4-oxo-1,4-azaphosphine-1-yl)ethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione formate (compound 115 formate)

[0500] Step 1: Synthesis of diethyl (4-bromo-3-methoxyphenyl)phosphonate (115-1)

[0501] 1-Bromo-4-iodo-2-methoxybenzene (3.42 g, 10.96 mmol), diethyl phosphonate (1.38 g, 10.00 mmol), 1'-bis(diphenylphosphino)ferrocene]palladium dichloride (732.0 mg, 1.00 mmol), potassium acetate (98.0 mg, 1.00 mmol), and triethylamine (1.20 g, 11.88 mmol) were dissolved in tetrahydrofuran (20 mL). The reaction mixture was placed at 68 °C for 17 hours under nitrogen protection. After the reaction was complete as monitored by LC-MS, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 50:50 as eluent) to give 115-1 (2.76 g), yield 85.7%.

[0502] LC-MS (m / z): 323.0 / 325.0 [M+H] + .

[0503] 1 H NMR(600MHz,DMSO-d6)δ7.77(dd,J=7.9,4.6Hz,1H),7.27(dd,J=14.4,1.6Hz,1H),7.2 1(ddd,J=12.7,7.9,1.6Hz,1H),4.10–3.96(m,4H),3.92(s,3H),1.24(t,J=7.0Hz,6H).

[0504] Step 2: Synthesis of (4-bromo-3-methoxyphenyl)divinylphosphine oxide (115-2)

[0505] 115-1 (1.80 g, 5.59 mmol) was dissolved in a mixed solution of thionyl chloride (10 mL) and DMF (2 mL), and the reaction solution was placed at 110 °C for 2 hours. After the reaction was complete as monitored by LC-MS, the solution was concentrated under reduced pressure, and the residue was dissolved in anhydrous tetrahydrofuran (20 mL). Vinyl magnesium bromide (1.0 M in tetrahydrofuran, 17 mL, 17.0 mmol) was added dropwise at –78 °C, and the reaction solution was placed at –78 °C for 1.0 hour. After the reaction was complete as monitored by LC-MS, the reaction was quenched by adding saturated ammonium chloride aqueous solution (20 mL) and water (20 mL) at –78 °C. The aqueous phase was extracted with ethyl acetate (40 mL × 3), and the combined organic phases were washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (using dichloromethane:methanol = 90:10 as eluent) to give 115-2 (1.50 g), with a yield of 93.8%.

[0506] LC-MS (m / z): 287.0 / 289.0 [M+H] + .

[0507] 1 H NMR(600MHz,DMSO-d6)δ7.76(dd,J=7.9,3.2Hz,1H),7.31(dd,J=12.4,1.6Hz,1H),7.20(ddd,J =11.3,7.9,1.6Hz,1H),6.72(ddd,J=26.1,18.6,12.6Hz,2H),6.33–6.05(m,4H),3.91(s,3H).

[0508] Step 3: Synthesis of 1-benzyl-4-(4-bromo-3-methoxyphenyl)-1,4-azaphosphine-4-oxide (115-3)

[0509] 115-2 (1.50 g, 5.24 mmol) was dissolved in a mixed solution of tetrahydrofuran (10 mL) and water (10 mL), and benzylamine (617.0 mg, 5.77 mmol) was added. The reaction mixture was placed at 80 °C for 15 hours. After the reaction was complete as monitored by LC-MS, water (10 mL) was added, and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 95:5 as eluent) to give 115-3 (1.30 g), with a yield of 63.1%.

[0510] LC-MS (m / z): 394.0 / 396.0 [M+H] + .

[0511] Step 4: Synthesis of 4-(4-bromo-3-methoxyphenyl)-1,4-azaphosphine-4-oxide hydrochloride (115-4)

[0512] 115-3 (700.0 mg, 1.78 mmol) was dissolved in 1,2-dichloroethane (6 mL), and 1-chloroethyl chloroformate (506.0 mg, 3.56 mmol) and N,N-diisopropylethylamine (460.0 mg, 3.56 mmol) were added. The reaction mixture was placed at 25 °C and reacted for 0.5 h. After the reaction was confirmed to be complete by LC-MS, the mixture was concentrated under reduced pressure. The residue was dissolved in methanol (5 mL), and the reaction mixture was placed at 70 °C and reacted for 2 h. After the reaction was confirmed to be complete by LC-MS, the mixture was concentrated under reduced pressure to obtain 115-4 (576.0 mg), which was the crude product.

[0513] LC-MS (m / z): 304.0 / 306.0 [M+H]+ .

[0514] Step 5: Synthesis of 4-(4-bromo-3-methoxyphenyl)-1,4-azaphosphine-1-carboxylic acid tert-butyl ester 4-oxide (115-5)

[0515] The crude product of compound 115-4 (576.0 mg) was dissolved in dichloromethane (10 mL), and triethylamine (576.0 mg, 5.70 mmol) and di-tert-butyl dicarbonate (828.0 mg, 3.80 mmol) were added. The reaction mixture was placed at 25 °C for 1.5 h. After the reaction was complete as monitored 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 brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 95:5 as eluent) to give 115-5 (564.0 mg), with a two-step yield of 78.6%.

[0516] LC-MS(m / z):348.0.0 / 350.0[M+H-56] + .

[0517] 1 H NMR(600MHz, DMSO-d6)δ7.77(dd,J=8.0,3.0Hz,1H),7.40(dd,J=12.0,1.6Hz,1H),7.35–7.28(m,1H), 3.93(s,3H),3.91–3.79(m,2H),3.64–3.44(m,2H),2.32–2.17(m,2H),1.96–1.84(m,2H),1.43(s,9H).

[0518] Step 6: Synthesis of 4-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-1,4-azaphosphine-1-carboxylic acid tert-butyl ester 4-oxide (115-6)

[0519] 115-5 (500.0 mg, 1.24 mmol), pinacol diborate (770.0 mg, 3.03 mmol), potassium acetate (366.0 mg, 3.73 mmol), and 1'-bis(diphenylphosphino)ferrocene]palladium dichloride (182.0 mg, 0.25 mmol) were dissolved in anhydrous 1,4-dioxane (10 mL). The reaction mixture was placed at 115 °C for 5.5 hours under nitrogen protection. After the reaction was complete as monitored by LC-MS, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (using dichloromethane:methanol = 95:5 as eluent) to obtain 115-6 (600.0 mg), the crude product.

[0520] LC-MS (m / z): 452.0 [M+H] + .

[0521] Step 7: Synthesis of 4-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2-methyl-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-8-yl)-3-methoxyphenyl)-1,4-azaphosphine-1-carboxylic acid 4-oxide tert-butyl ester (115-7)

[0522] Intermediate 15-6 is prepared according to steps 1 to 6 of Example 15.

[0523] Intermediates 15-6 (100.0 mg, 0.23 mmol), 115-6 (192.0 mg, 0.43 mmol), Xphos-Pd-G3 (28.0 mg, 0.03 mmol), and potassium phosphate (144.0 mg, 0.68 mmol) were dissolved in a mixed solution of 1,4-dioxane (3 mL) and water (0.5 mL). The reaction mixture was placed at 90 °C for 1 hour under nitrogen protection. After the reaction was complete as monitored by LC-MS, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (using dichloromethane:methanol = 95:5 as eluent) to give compound 115-7 (177.0 mg), the crude product.

[0524] LC-MS (m / z): 731.0 [M+H] + .

[0525] Step 8: Synthesis of 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-8-(2-methoxy-4-(4-oxo-1,4-azaphosphine-4-yl)phenyl)-2-methyl-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (115-8)

[0526] The crude product of compound 115-7 (177.0 mg) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 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 mixture was concentrated under reduced pressure to obtain 115-8 (200.0 mg), which was the crude product.

[0527] LC-MS (m / z): 631.0 [M+H] + .

[0528] Step 9: Synthesis of 3-(4-(2-(4-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2-methyl-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-8-yl)-3-methoxyphenyl)-4-oxo-1,4-azaphosphine-1-yl)ethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione formate (compound 115 formate).

[0529] The crude product of compound 115-8 (200.0 mg) and INT2 (81.6 mg, 0.27 mmol) were dissolved in a mixed solution of tetrahydrofuran (2 mL) and dimethyl sulfoxide (2 mL). Potassium acetate (66.0 mg, 0.67 mmol) and acetic acid (0.4 mL) were added, and the mixture was stirred at 25 °C for 0.5 hours. Then, NaBH3CN (28.5 mg, 0.45 mmol) was added, and the reaction mixture was kept at 25 °C for another hour. After the reaction was confirmed to be complete by LC-MS, water (2 mL) was added to quench the reaction, and the mixture was concentrated under reduced pressure. The residue was purified by HPLC to obtain the formate of compound 115 (23.4 mg), with a three-step yield of 11.1%.

[0530] LC-MS (m / z): 916.0 [M+H] + .

[0531] 1 H NMR(600MHz,DMSO-d6)δ12.56–12.35(m,1H),11.11(s,1H),8.17(s,1H),7.75–7.68(m,1H),7.55–7.34(m,4H), 7.07–6.90(m,4H),6.23–6.13(m,2H),5.38(dd,J=12.9,5.5Hz,1H),4.42–4.27(m,4H),4.05–4.00(m,2H),3.85 –3.77(m,3H),3.67–3.61(m,1H),3.61(s,3H),3.57(t,J=5.8Hz,2H),3.16–3.04(m,5H),3.04–2.94(m,9H),2.9 4–2.83(m,1H),2.83–2.74(m,2H),2.76–2.66(m,1H),2.65–2.58(m,1H),2.35–2.24(m,2H),2.05–1.98(m,1H).

[0532] Example 125: Synthesis of 3-(4-(2-(4-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2-methyl-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-8-yl)-5-chloro-2-fluorophenyl)piperazin-1-yl)ethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (compound 125)

[0533] Step 1: Synthesis of 1-(4-bromo-5-chloro-2-fluorophenyl)piperazine (125-1)

[0534] 4-(4-bromo-5-chloro-2-fluorophenyl)piperazine-1-carboxylic acid tert-butyl ester (125-SM, 180.0 mg, 0.46 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (2 mL) was added. The reaction mixture was placed at 25 °C and reacted for 1 hour. After the reaction was monitored by LC-MS to be complete, the solution was concentrated under reduced pressure to obtain 125-1 (160.0 mg), which was the crude product.

[0535] LC-MS (m / z): 293.0 [M+H] + .

[0536] Step 2: Synthesis of 3-(4-(2-(4-(4-bromo-5-chloro-2-fluorophenyl)piperazin-1-yl)ethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (125-2)

[0537] The crude product of compound 125-1 (160.0 mg) and intermediate INT7 (52.0 mg, 0.41 mmol) were dissolved in a mixed solution of tetrahydrofuran (2 mL) and dimethyl sulfoxide (2 mL). Acetic acid (0.5 mL) and potassium acetate (120.0 mg, 1.23 mmol) were added, and the reaction solution was placed at 25 °C for 1 hour. Then, sodium cyanoborohydride (51.0 mg, 0.82 mmol) was added, and the reaction was continued at 25 °C for 2 hours. After the reaction was confirmed to be complete by LC-MS, water (10 mL) was added to quench the reaction. The aqueous phase was extracted with ethyl acetate (20 mL × 6). The combined organic phases were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel plate preparation (dichloromethane:methanol = 95:5 as eluent) to give 125-2 (180.0 mg), with a two-step yield of 67.7%.

[0538] LC-MS (m / z): 578.0 [M+H] + .

[0539] Step 3: Synthesis of 3-(4-(2-(4-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2-methyl-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-8-yl)-5-chloro-2-fluorophenyl)piperazin-1-yl)ethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (compound 125)

[0540] Intermediate 31-1 is prepared according to step 1 of Example 31.

[0541] Intermediate 31-1 (64.0 mg, 0.11 mmol), 125-2 (60.0 mg, 0.11 mmol), [1'-bis(diphenylphosphine)ferrocene]palladium dichloride (8.2 mg, 0.011 mmol), and cesium fluoride (33.9 mg, 0.22 mmol) were dissolved in a mixed solution of DMF (4 mL) and water (1 mL). The reaction mixture was placed at 80 °C for 2 hours under nitrogen protection. After the reaction was complete as monitored by LC-MS, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (using dichloromethane:methanol = 95:5 as eluent) to give compound 125 (6.2 mg), with a yield of 6.2%.

[0542] LC-MS (m / z): 905.0 [M+H] + .

[0543] 1 H NMR(600MHz,DMSO-d6)δ12.56(s,1H),11.10(s,1H),7.71(dd,J=14.8,2.2Hz,1H),7.46–7.3 0(m,2H),7.19(d,J=8.1Hz,1H),7.06–6.92(m,4H),6.23–6.13(m,2H),5.38(dd,J=12.9,5.4H z,1H),4.42–4.25(m,4H),4.08(s,2H),3.66–3.53(m,5H),3.21–3.09(m,6H),3.01(s,3H),3. 01–2.94(m,2H),2.93–2.85(m,1H),2.76–2.61(m,8H),2.35–2.23(m,2H),2.03–1.95(m,1H).

[0544] Example 126: Synthesis of 3-(4-(2-(4-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2-methyl-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-8-yl)-3-(trifluoromethoxy)phenyl)piperazin-1-yl)ethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione formate (compound 126 formate)

[0545] Step 1: Synthesis of 4-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2-methyl-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-8-yl)-3-(trifluoromethoxy)phenyl)piperazine-1-carboxylic acid tert-butyl ester (126-1)

[0546] 126-SM (132.0 mg, 0.28 mmol), 15-6 (60.0 mg, 0.14 mmol), XPhos-Pd-G3 (12.0 mg, 0.014 mmol), and potassium phosphate (89.0 mg, 0.42 mmol) were dissolved in a mixed solvent of 1,4-dioxane (5 mL) and water (1 mL). The reaction mixture was placed at 80 °C for 1 hour under nitrogen protection. After the reaction was complete as monitored by LC-MS, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 95:5) to give 126-1 (69.0 mg), with a yield of 65.7%.

[0547] LC-MS (m / z): 752.0 [M+H] + .

[0548] Step 2: Synthesis of 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2-methyl-8-(4-(piperazin-1-yl)-2-(trifluoromethoxy)phenyl)-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (126-2)

[0549] Dissolve 126-1 (69.0 mg, 0.09 mmol) in dichloromethane (5 mL), add trifluoroacetic acid (1 mL), and react the mixture at 25 °C for 1 hour. After the reaction is complete as monitored by LC-MS, concentrate the reaction mixture under reduced pressure to obtain crude 126-2 (60.0 mg), which can be used directly in the next step.

[0550] LC-MS (m / z): 652.0 [M+H] + .

[0551] Step 3: Synthesis of 3-(4-(2-(4-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2-methyl-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-8-yl)-3-(trifluoromethoxy)phenyl)piperazin-1-yl)ethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione formate (126 formate)

[0552] The crude product of compound 126-2 (60.0 mg) and INT2 (42.0 mg, 0.14 mmol) were dissolved in a mixed solution of dimethyl sulfoxide (2 mL) and tetrahydrofuran (2 mL), followed by the addition of acetic acid (0.4 mL) and sodium triacetoxyborohydride (95.0 mg, 0.45 mmol). The reaction mixture was stirred at 25 °C for 1 hour. After the reaction was confirmed to be complete by LC-MS, water (10 mL) was added to quench the reaction. The aqueous phase was extracted with ethyl acetate (10 mL × 3), and the combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC to give the formate of 126 (23.3 mg), with a two-step yield of 27.6%.

[0553] LC-MS (m / z): 937.0 [M+H] + .

[0554] 1 ¹H NMR (600MHz, DMSO-d6) δ 12.55–12.45 (m, 1H), 11.10 (s, 1H), 8.18 (s, 0.33H, formic acid), 7.77–7.66 (m, 1H), 7.49–7.34 (m, 2H), 7.11–6.90 (m, 6H), 6.24–6.08 (m, 2H), 5.41–5.33 (m, 1H), 4.41–4.26 (m,4H),4.09(s,2H),3.65–3.55(m,5H),3.30–3.28(m,4H),3.16–3.11(m,2H),3.01(s,3H),3 .01–2.92(m,2H),2.91–2.84(m,1H),2.74–2.60(m,8H),2.36–2.25(m,2H),2.04–1.96(m,1H).

[0555] Example 128: Synthesis of 3-(4-(2-(5-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2-methyl-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-8-yl)-3-methoxyphenyl)-2,5-diazabicyclo[2.2.1]hept-2-yl)ethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione formate (compound 128 formate)

[0556] Step 1: Synthesis of tert-butyl 5-(4-bromo-3-methoxyphenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (128-1)

[0557] 2-Bromo-5-iodoanisole (0.90 g, 2.91 mmol), tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.75 g, 3.78 mmol), cuprous iodide (110.5 mg, 0.58 mmol), potassium carbonate (1.20 g, 8.73 mmol), and L-proline (66.81 mg, 0.58 mmol) were dissolved in dimethyl sulfoxide (50 mL). Under nitrogen protection, the reaction mixture was stirred at 80 °C for 16 hours. After the reaction was confirmed to be complete by LC-MS, water (20 mL) was added to quench the reaction. The aqueous phase was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 85:15 as eluent) to give 128-1 (0.67 g), yield 61.0%.

[0558] LC-MS (m / z): 383.0 [M+H] + .

[0559] Step 2: Synthesis of 5-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (128-2)

[0560] 128-1 (0.20 g, 0.52 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,3,2-dioxaborane (0.27 g, 1.05 mmol), [1'-bis(diphenylphosphine)ferrocene]palladium dichloride (73.1 mg, 0.10 mmol), and potassium acetate (0.15 g, 1.56 mmol) were dissolved in dioxane (2 mL). Under nitrogen protection, the reaction mixture was stirred at 120 °C for 2 hours. After the reaction was complete as monitored by LC-MS, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 75:25 as eluent) to give 128-2 (56.0 mg), with a yield of 25.1%.

[0561] LC-MS (m / z): 431.0 [M+H] + .

[0562] Step 3: Synthesis of 5-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2-methyl-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-8-yl)-3-methoxyphenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (128-3)

[0563] 128-2 (56.0 mg, 0.13 mmol), 15-6 (40.0 mg, 0.09 mmol), Xphos-Pd-G3 (11.4 mg, 0.013 mmol), and potassium phosphate (57.0 mg, 0.26 mmol) were dissolved in a mixed solution of 1,4-dioxane (2.5 mL) and water (0.5 mL). The reaction mixture was placed at 90 °C for 1 hour under nitrogen protection. After the reaction was complete as monitored by LC-MS, the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (using dichloromethane:methanol = 95:5 as eluent) to give 128-3 (60 mg), with a yield of 95.2%.

[0564] LC-MS (m / z): 710.0 [M+H] + .

[0565] Step 4: Synthesis of 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-8-(4-(2,5-diazabicyclo[2.2.1]hept-2-yl)-2-methoxyphenyl)-5-fluoro-2-methyl-1,4-dihydropyrrolo[3,4-b]indol-3(2H)-one (128-4)

[0566] 128-3 (60.0 mg, 0.084 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (2 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 obtain 128-4 (70.0 mg), which was the crude product.

[0567] LC-MS (m / z): 610.0 [M+H] + .

[0568] Step 5: Synthesis of 3-(4-(2-(5-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2-methyl-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-8-yl)-3-methoxyphenyl)-2,5-diazabicyclo[2.2.1]hept-2-yl)ethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione formate (128 formate)

[0569] The crude product of compound 128-4 (70.0 mg) and INT2 (40.6 mg, 0.13 mmol) were dissolved in a mixed solution of tetrahydrofuran (2 mL) and dimethyl sulfoxide (1 mL). Acetic acid (95.4 mg, 0.45 mmol) was added, followed by sodium triacetoxyborohydride (170.0 mg, 0.81 mmol). The reaction mixture was placed at 25 °C for 1 hour. After the reaction was complete as monitored by LC-MS, water (10 mL) was added to quench the reaction. The aqueous phase was extracted with dichloromethane (20 mL × 6). The combined organic phases were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by HPLC to obtain the formate of 128 (36.1 mg), with a two-step yield of 48.0%.

[0570] LC-MS (m / z): 895.0 [M+H] + .

[0571] 1H NMR (600MHz, DMSO-d6) δ12.35–12.26(m,1H),11.09(s,1H),8.15(s,1H, formic acid),7.71(dd,J=16.9,2.2Hz,1H),7.40(dd,J=36.7,1.7Hz,1H),7.08(d ,J=8.1Hz,1H),7.01–6.93(m,2H),6.93–6.83(m,2H),6.29–6.23(m,2H) ,6.23–6.09(m,2H),5.36(dd,J=13.0,5.4Hz,1H),4.45–4.27(m,6H),4.0 4(d,J=2.9Hz,2H),3.69–3.66(m,4H),3.58–3.55(m,4H),3.41–3.38(m, 2H),3.27–3.24(m,2H),3.00(s,3H),2.99–2.95(m,3H),2.93–2.84(m,1 H),2.82–2.76(m,2H),2.75–2.68(m,1H),2.68–2.59(m,2H),2.35–2.24 (m,2H),2.01–1.95(m,1H),1.91(d,J=9.0Hz,1H),1.81(d,J=9.0Hz,1H).

[0572] Example 129: Synthesis of 3-(4-(2-(3-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2-methyl-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-8-yl)-3-methoxyphenyl)-3,8-diazabicyclo[3.2.1]octane-8-yl)ethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione formate (compound 129 formate)

[0573] Step 1: Synthesis of tert-butyl 3-(4-bromo-3-methoxyphenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (129-1)

[0574] Compounds 2-bromo-5-iodoanisole (1.40 g, 4.70 mmol), tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.50 g, 7.07 mmol), cuprous iodide (178.0 mg, 0.94 mmol), potassium carbonate (1.94 g, 14.10 mmol), and L-proline (108.0 mg, 0.94 mmol) were dissolved in dimethyl sulfoxide (50 mL). The reaction mixture was stirred at 80 °C for 16 hours under nitrogen protection. After the reaction was confirmed to be complete by LC-MS, water (20 mL) was added to quench the reaction. The aqueous phase was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 85:15 as eluent) to give 129-1 (0.63 g), yield 35.0%.

[0575] LC-MS (m / z): 397.0 / 399.0 [M+H] + .

[0576] Step 2: Synthesis of 3-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (129-2)

[0577] 129-1 (0.63 g, 1.59 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,3,2-dioxaborane (0.80 g, 3.18 mmol), [1'-bis(diphenylphosphine)ferrocene]palladium dichloride (232.4 mg, 0.33 mmol), and potassium acetate (0.47 g, 4.77 mmol) were dissolved in dioxane (10 mL). Under nitrogen protection, the reaction mixture was stirred at 120 °C for 2 hours. After the reaction was complete as monitored by LC-MS, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 75:25 as eluent) to give 129-2 (189.0 mg) in 26.8% yield.

[0578] LC-MS (m / z): 445.0 [M+H] + .

[0579] Step 3: Synthesis of 3-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2-methyl-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-8-yl)-3-methoxyphenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (129-3)

[0580] 129-2 (60.4 mg, 0.14 mmol), 15-6 (40.0 mg, 0.09 mmol), Xphos-Pd-G3 (17.0 mg, 0.02 mmol), and potassium phosphate (86.5 mg, 0.41 mmol) were dissolved in a mixed solution of 1,4-dioxane (2.5 mL) and water (0.5 mL). The reaction mixture was placed at 90 °C for 1 hour under nitrogen protection. After the reaction was complete as monitored by LC-MS, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (using dichloromethane:methanol = 95:5 as eluent) to give 129-3 (61.0 mg), with a yield of 93.8%.

[0581] LC-MS (m / z): 724.0 [M+H] + .

[0582] Step 4: Synthesis of 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-8-(4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-2-methoxyphenyl)-5-fluoro-2-methyl-1,4-dihydropyrrolo[3,4-b]indol-3(2H)-one (129-4)

[0583] 129-3 (61.0 mg, 0.084 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (2 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 obtain 129-4 (60.0 mg), which was the crude product.

[0584] LC-MS (m / z): 624.0 [M+H] + .

[0585] Step 5: Synthesis of 3-(4-(2-(3-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2-methyl-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-8-yl)-3-methoxyphenyl)-3,8-diazabicyclo[3.2.1]octane-8-yl)ethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione formate (129 formate)

[0586] The crude product of compound 129-4 (60.0 mg) and INT2 (50.7 mg, 0.17 mmol) were dissolved in a mixed solution of tetrahydrofuran (2 mL) and dimethyl sulfoxide (1 mL). Acetic acid (95.4 mg, 0.45 mmol) was added, followed by sodium triacetoxyborohydride (171.0 mg, 0.81 mmol). The reaction mixture was placed at 25 °C for 1 hour. After the reaction was confirmed to be complete by LC-MS, water (10 mL) was added to quench the reaction. The aqueous phase was extracted with dichloromethane (20 mL × 6). The combined organic phases were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by HPLC to obtain the formate of 129 (56.0 mg), with a two-step yield of 73.7%.

[0587] LC-MS (m / z): 909.0 [M+H] + .

[0588] 1H NMR (600MHz, DMSO-d6) δ12.35–12.26(m,1H),11.10(s,1H),8.14(s,1H, formic acid),7.71(dd,J=15.8,2.2Hz,1H),7.40(dd,J=32.9,1.8Hz,1H),7.1 2(d,J=8.2Hz,1H),7.02–6.94(m,3H),6.92–6.83(m,1H),6.54–6.49( m,1H),6.49–6.44(m,1H),6.22–6.15(m,1H),6.14–6.08(m,1H),5.37( dd,J=12.8,5.5Hz,1H),4.40–4.26(m,4H),4.06(s,2H),3.72–3.67(m,4H),3.66–3.59(m,4H),3.60–3.55(m,1H),3.50–3.43(m,2H),3.17–3 .08(m,2H),3.01(s,3H),2.99–2.95(m,2H),2.95–2.87(m,3H),2.76– 2.60(m,5H),2.35–2.23(m,2H),2.03–1.89(m,3H),1.73–1.65(m,2H).

[0589] Example 132: Synthesis of 3-(4-(2-(4-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2-methyl-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-8-yl)-3-(difluoromethoxy)phenyl)piperazin-1-yl)ethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione formate (compound 132 formate)

[0590] Step 1: Synthesis of 4-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2-methyl-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-8-yl)-3-(difluoromethoxy)phenyl)piperazine-1-carboxylic acid tert-butyl ester (132-1)

[0591] 15-6 (40.0 mg, 0.08 mmol), 132-SM (58.0 mg, 0.10 mmol), XPhos-Pd-G3 (7.0 mg, 0.01 mmol), and potassium phosphate (35.0 mg, 0.16 mmol) were dissolved in a mixed solvent of 1,4-dioxane (5 mL) and water (0.5 mL). The mixture was reacted at 90 °C for 2 hours under nitrogen protection. After the reaction was complete as monitored by LC-MS, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (using dichloromethane:methanol = 90:10 as eluent) to give 132-1 (60.0 mg), with a yield of 94.2%.

[0592] LC-MS (m / z): 734.0 [M+H] + .

[0593] Step 2: Synthesis of 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-8-(2-(difluoromethoxy)-4-(piperazin-1-yl)phenyl)-5-fluoro-2-methyl-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (132-2)

[0594] Dissolve 132-1 (46.0 mg, 0.06 mmol) in dichloromethane (3 mL), add trifluoroacetic acid (0.5 mL), and react at room temperature for 2 hours. After the reaction is complete as monitored by LC-MS, concentrate under reduced pressure to obtain crude 132-2 (40.0 mg), which can be used directly in the next step.

[0595] LC-MS (m / z): 634.0 [M+H] + .

[0596] Step 3: Synthesis of 3-(4-(2-(4-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2-methyl-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-8-yl)-3-(difluoromethoxy)phenyl)piperazin-1-yl)ethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione formate (132 formate)

[0597] The crude product of compound 132-2 (40.0 mg) and INT2 (29.0 mg, 0.09 mmol) were dissolved in a mixed solution of tetrahydrofuran (2 mL) and dimethyl sulfoxide (2 mL). Acetic acid (11.0 mg, 0.19 mmol) and sodium borohydride acetate (67.0 mg, 0.32 mmol) were added, and the mixture was reacted at room temperature for 2 hours. After the reaction was confirmed to be complete by LC-MS, the reaction solution was quenched with water, concentrated, and the residue was purified by HPLC to obtain 132 (5.0 mg) formate. The two-step yield was 10.0%.

[0598] LC-MS (m / z): 919.0 [M+H] + .

[0599] 1 ¹H NMR (600MHz, DMSO-d⁶) δ 12.45 (d, J = 8.8 Hz, 1H), 11.11 (s, 1H), 8.14 (s, 0.33H, formic acid), 7.71 (dd, J = 18.5, 2.2 Hz, 1H), 7.45–7.32 (m, 2H), 7.10–6.91 (m, 6H), 6.84 (s, 1H), 6.23–6.07 (m, 2H), 5.38 (dd, J = 12.9, 5.6 Hz, 1H), 4.4 1–4.26(m,4H),4.10(s,2H),3.67–3.59(m,4H),3.57(t,J=5.8Hz,1H),3.31–3.27(m,4H),3.18–3.09(m,2H), 3.01(s,3H),3.01–2.92(m,2H),2.92–2.86(m,1H),2.75–2.59(m,8H),2.34–2.24(m,2H),2.05–1.97(m,1H).

[0600] Example 133: Synthesis of 3-(4-(2-(2-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2-methyl-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-8-yl)-3-methoxyphenyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)ethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione formate (compound 133 formate)

[0601] Step 1: Synthesis of 2-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2-methyl-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-8-yl)-3-methoxyphenyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-carboxylic acid tert-butyl ester (133-1)

[0602] 133-SM (60.0 mg, 0.14 mmol), 15-6 (40.0 mg, 0.09 mmol), XPhos-Pd-G3 (8.0 mg, 0.009 mmol), and potassium phosphate (57.0 mg, 0.27 mmol) were dissolved in a mixed solvent of 1,4-dioxane (5 mL) and water (1 mL). The reaction mixture was placed at 80 °C for 1 hour under nitrogen protection. After the reaction was complete as monitored by LC-MS, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 95:5) to give 133-1 (60.0 mg), with a yield of 92.3%.

[0603] LC-MS (m / z): 721.0 [M+H] + .

[0604] Step 2: Synthesis of 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-8-(4-(5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-2-methoxyphenyl)-5-fluoro-2-methyl-1,4-dihydropyrrolo[3,4-b]indol-3(2H)-one (133-2)

[0605] Dissolve 133-1 (60.0 mg, 0.08 mmol) in dichloromethane (5 mL), add trifluoroacetic acid (1 mL), and react the mixture at 25 °C for 1 hour. After the reaction is complete as monitored by LC-MS, concentrate the reaction mixture under reduced pressure to obtain crude product 133-2 (60.0 mg), which can be used directly in the next step.

[0606] LC-MS (m / z): 621.0 [M+H] + .

[0607] Step 3: Synthesis of 3-(4-(2-(2-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2-methyl-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-8-yl)-3-methoxyphenyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)ethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione formate (133 formate)

[0608] The crude product of compound 133-2 (60.0 mg) and INT2 (42.0 mg, 0.14 mmol) were dissolved in a mixed solution of dimethyl sulfoxide (2 mL) and tetrahydrofuran (2 mL). Acetic acid (0.4 mL) and sodium triacetoxyborohydride (95.0 mg, 0.45 mmol) were then added, and the mixture was stirred at 25 °C for 1 hour. After the reaction was complete as monitored by LC-MS, water (10 mL) was added to quench the reaction. The aqueous phase was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC to give the formate of 133 (25.7 mg), with a two-step yield of 35.5%.

[0609] LC-MS (m / z): 906.0 [M+H] + .

[0610] 1H NMR (600MHz, DMSO-d6) δ12.44(t,J=10.8Hz,1H),11.11(s,1H),8.34(s,1H),8.16(s,1H, formic acid),7.72(dd,J=14.9,2.1Hz,1H),7.55(d,J=4.1Hz,1 H),7.49–7.34(m,3H),7.04–6.92(m,4H),6.26–6.07(m,2H),5.38(dt, J=11.4,5.6Hz,1H),4.44–4.27(m,4H),4.04(d,J=2.7Hz,2H),3.89(d,J =9.8Hz,3H),3.80(d,J=5.4Hz,3H),3.69–3.62(m,4H),3.62–3.54(m,1H),3.19(dt,J=9.6,5.8Hz,2H),3.08(dt,J=15.9,7.9Hz,2H),3.02–2.9 5(m,5H),2.89(dt,J=18.1,5.8Hz,1H),2.72(qt,J=13.1,5.1Hz,1H),2.66–2.59(m,2H),2.33(dd,J=38.7,32.7Hz,2H),2.01(d,J=7.5Hz,1H).

[0611] Example 134: Synthesis of 3-(4-((7-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2-methyl-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-8-yl)-3-methoxyphenyl)-2,7-diazaspiro[3.5]non-2-yl)methyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (compound 134)

[0612] Step 1: Synthesis of 7-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2-methyl-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-8-yl)-3-methoxyphenyl)-2,7-diazaspiro[3,5]nonane-2-carboxylic acid tert-butyl ester (134-1)

[0613] 134-SM (62.0 mg, 0.14 mmol), 15-6 (40.0 mg, 0.09 mmol), XPhos-Pd-G3 (8.0 mg, 0.009 mmol), and potassium phosphate (57.0 mg, 0.27 mmol) were dissolved in a mixed solvent of 1,4-dioxane (5 mL) and water (1 mL). The reaction mixture was placed at 80 °C for 1 hour under nitrogen protection. After the reaction was complete as monitored by LC-MS, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 95:5) to obtain 134-1 (60.0 mg), with a yield of 90.3%.

[0614] LC-MS (m / z): 738.0 [M+H] + .

[0615] Step 2: Synthesis of 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-8-(2-methoxy-4-(2,7-diazaspiro[3.5]non-7-yl)phenyl)-2-methyl-1,4-dihydropyrrolo[3,4-b]indol-3(2H)-one (134-2)

[0616] Dissolve 134-1 (60.0 mg, 0.08 mmol) in dichloromethane (5 mL), add trifluoroacetic acid (1 mL), and react the mixture at 25 °C for 1 hour. After the reaction is complete as monitored by LC-MS, concentrate the reaction mixture under reduced pressure to obtain crude product 134-2 (60.0 mg), which can be used directly in the next step.

[0617] LC-MS (m / z): 638.0 [M+H] + .

[0618] Step 3: Synthesis of 3-(4-((7-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-1,2,5,6-tetrahydropyridin-3-yl)-5-fluoro-2-methyl-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-8-yl)-3-methoxyphenyl)-2,7-diazaspiro[3.5]non-2-yl)methyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (134)

[0619] The crude product of compound 134-2 (30.0 mg, 0.05 mmol) and INT9 (28.0 mg, 0.10 mmol) were dissolved in a mixed solution of dimethyl sulfoxide (2 mL) and tetrahydrofuran (2 mL), followed by the addition of acetic acid (0.4 mL) and sodium triacetoxyborohydride (53.0 mg, 0.25 mmol). The reaction mixture was stirred at 25 °C for 1 hour. After the reaction was confirmed to be complete by LC-MS, water (10 mL) was added to quench the reaction. The aqueous phase was extracted with ethyl acetate (10 mL × 3), and the combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC to give 134 (2.5 mg), with a yield of 5.6%.

[0620] LC-MS (m / z): 909.0 [M+H] + .

[0621] 1 H NMR (600MHz, DMSO-d6) δ12.38–12.22(m,1H),11.11(s,1H),7.71(dd,J=16.7,2.2Hz,1H),7.45–7.34(m,1H),7.11(d,J=8.1Hz,1H),7 .10–7.01(m,1H),6.99–6.92(m,2H),6.92–6.83(m,1H),6.63(s,1H),6.58–6.53(m,1H),6.27–6.05(m,2H),5.48–5.30(m,1H),4.39–4 .24(m,4H),4.02(s,2H),3.88–3.79(m,2H),3.72–3.65(m,6H),3.66–3.60(m,1H),3.59–3.52(m,2H),3.25–3.13(m,4H),3.03(s,3H), 3.01–2.93(m,5H),2.93–2.84(m,1H),2.77–2.65(m,1H),2.65–2.60(m,1H),2.33–2.23(m,2H),2.04–1.96(m,1H),1.87–1.74(m,4H).

[0622] Bioactivity test

[0623] Test Example 1: Western blot assay to examine STAT6 protein content in A549, BEAS-2B, or PBMC cells.

[0624] The compounds of this invention were prepared according to the methods described in the examples.

[0625] (1) Cells

[0626] (2) Reagents and Consumables

[0627] (3) Compound preparation

[0628] 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 10-fold serial dilution with DMSO to obtain the compound stock solutions (10, 1, 0.1, 0.01, 0.001, 0.0001, 0.00001 mM).

[0629] (4) Experimental methods

[0630] ① When the A549 or BEAS-2B cell density reaches 70%-80%, plate the cells, using 1.5 x 10⁶ cells per well in a 24-well plate. 5 Cells were cultured overnight in 10% FBS DMEM. Cells in the drug-treated groups were treated with different concentrations of the compound (final concentrations of 10, 1, 0.1, 0.01, 0.001, 0.0001, and 0.00001 μM) for 24 h, while the blank group received an equal volume of DMSO. The supernatant was discarded, and the cells were washed once with PBS. 100 μL of RIPA lysis buffer (containing cocktail, PMSF, and 1.5x protein loading buffer) was added to each well. The cell lysis buffer was heated at 95 °C for 15 min and stored at -20 °C.

[0631] After PBMC cell density recovery, they were plated in 24-well plates with 1.2 x 10⁶ cells per well. 6 Cells were cultured in 10% FBS RPMI-1640 for 30 min. Cells in the drug-treated groups were treated with different concentrations of the compound (final concentrations of 10, 1, 0.1, 0.01, 0.001, 0.0001, and 0.00001 μM) for 24 h, while the blank group received an equal volume of DMSO. After cell collection, the supernatant was discarded by centrifugation. Each sample was then treated with 80 μL of RIPA lysis buffer (containing a cocktail, PMSF) and 20 μL of SDS-PAGE protein loading buffer (5X). The cell lysis buffer was heated at 95 °C for 15 min and stored at -20 °C.

[0632] ② Load an equal volume of protein sample into the wells of an SDS-PAGE gel and perform electrophoresis at 100V. After electrophoresis, transfer the PVDF membrane at a constant current of 300mA. After transfer, remove the PVDF membrane and block it with 5% skim milk PBST solution at room temperature for 1 hour. After blocking, add the corresponding primary antibody incubation solution (primary antibody dilution ratio 1:1000, 5% BSA + PBST) to the antibody incubation chamber and incubate overnight at 4°C with gentle shaking. After incubation, wash the membrane four times with PBST for 5 minutes each time. Add secondary antibody incubation solution (secondary antibody dilution ratio 1:5000, 5% skim milk + PBST), incubate at room temperature for 1 hour, wash the membrane four times with PBST for 5 minutes each time, and develop and expose according to the method provided by the ECL chemiluminescence detection kit. Use Image Lab software to perform grayscale analysis on the development results and calculate the degradation rate, Dmax, and DC. 50 .

[0633] The degradation rate was calculated as follows:

[0634] Degradation rate (%) = 100% - (Gray value of the treatment group / Gray value of the blank group) × 100%

[0635] Dmax refers to the maximum level of degradation a compound can achieve in cells, that is, the maximum percentage reduction in the level of a target protein at a specific concentration; DC 50 This indicates the concentration of the compound at which half of the maximum degradation effect is achieved.

[0636] Table 1 shows the degradation results of STAT6 protein after 24 hours of treatment with different compounds.

[0637] The degradation rate (%) of STAT6 in A549 cells is represented by the following letters: A (≥80%); B (20%-80%); C (≤20%); / indicates not measured.

[0638] STAT6 DCs in PBMC cells 50 (nM) is represented by the following letters: A (<1nM); B (1-10nM); C (10-100nM); D (>100nM); / indicates not measured.

[0639] In PBMC cells, STAT6 Dmax (%) is represented by the following letters: A (>90%); B (80%-90%); C (50%-80%); D (<50%); / indicates not measured.

[0640] Table 1. STAT6 protein degradation results

[0641] Test Example 2: Detection of STAT6 degradation activity in A549-STAT6-FLAG cells

[0642] Construction of A549-STAT6-FLAG cell line

[0643] (1) Main reagents and consumables

[0644] (2) Experimental steps

[0645] 293T cells were plated in 100mm culture dishes with 90% confluence and packaged with STAT6-3xFLAG lentivirus. After 24 hours, the cell supernatant containing STAT6-3xFLAG lentivirus was collected and filtered using a 0.45µm syringe filter. The lentivirus solution was stored at -80°C.

[0646] A549 cells, 10 4 Cells were seeded in 6-well plates, and 1 mL of STAT6-3xFLAG lentiviral solution and 1 mg / mL polybrene were added. The medium was replaced with fresh medium after 24 hours. After cell expansion, a portion of cells was harvested to verify STAT6 overexpression efficiency. Western blotting confirmed the successful construction of the A549-STAT6-FLAG cell line.

[0647] STAT6 degradation activity assay

[0648] (1) Main reagents and consumables

[0649] (2) Experimental steps

[0650] The compound was dissolved in DMSO to prepare a 10 mM stock solution. Store at -20°C protected from light.

[0651] A549-STAT6-FLAG cells were plated. The stock solution was diluted with DMSO to obtain a 1 μM compound dilution, which was then serially diluted using RPMI-1640 medium (containing 10% FBS). The test compounds at these serial concentrations were added to the cell culture system. A DMSO group (final DMSO concentration 1‰) was also included. 24 h after drug administration, the cell supernatant was discarded, and NP-40 lysis buffer (containing PMSF) was added to each well of the cell culture plate. Lysis was performed on ice for 30 min, and the plates were stored at -80°C.

[0652] Incubate 100 µL of FLAG capture antibody (1:2000, containing 1x coating buffer) in each well of the ELISA plate overnight at 4°C. Discard the FLAG capture antibody and wash three times with 1x PBST. Incubate 200 µL of 1x blocking buffer (1x PBST, containing 5% skim milk) in each well of the ELISA plate for 1 h at room temperature. Discard the 5% skim milk and wash once with 1x PBST. Incubate 100 µL of cell lysis buffer in each well of the ELISA plate, and add 100 µL of NP-40 lysis buffer to the negative control group. Incubate overnight at 4°C. Discard the sample and wash three times with 1x PBST. Add 100 µL of FLAG detection antibody (1:1000, containing 1x blocking buffer) to each well of the ELISA plate and incubate for 2 h at room temperature. Discard the FLAG detection antibody and wash three times with 1x PBST. Add 100 μL of HRP-labeled secondary antibody (1:5000, containing 1x blocking buffer) to each well of the ELISA plate and incubate at room temperature for 1 hour. Discard the HRP-labeled secondary antibody and wash 5 times with 1x PBST. Add 100 μL of TMB chromogenic buffer to each well of the ELISA plate and incubate at room temperature in the dark for 15-20 minutes. Add 100 μL of ELISA stop solution to each well of the ELISA plate.

[0653] Use an ELISA reader to read the OD values ​​at wavelengths of 450nm-570nm. The formula for calculating the relative content of STAT6 is: Relative content (%) = (Experimental group - Negative control) / (Positive control - Negative control) * 100%.

[0654] Table 2 shows the degradation results of STAT6 protein after 24 hours of treatment with different compounds.

[0655] STAT6 DCs in A549-STAT6-FLAG cells 50 (nM) is represented by the following letters: A (<1nM); B (1-10nM); C (10-100nM); D (>100nM); / indicates not measured.

[0656] In A549-STAT6-FLAG cells, STAT6 Dmax (%) is represented by the following letters: A (>80%); B (50%-80%); C (<50%); / indicates not measured.

[0657] Table 2. STAT6 protein degradation results

[0658] Test Example 3: Western Blot (WB) assay for STAT1-5 in PBMC cells (selective assay)

[0659] The compounds of this invention were prepared according to the methods described in the examples.

[0660] (1) Cells

[0661] (2) Reagents and Consumables

[0662] (3) Compound preparation

[0663] 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 serial dilution with DMSO to obtain compound stock solutions (100, 1, 0.01 μM).

[0664] (4) Experimental methods

[0665] ① After PBMC cell density recovery, seed the cells into plates, 1.2*10 cells per well in a 24-well plate. 6 Cells were cultured in 10% FBS RPMI-1640 for 30 min. Cells in the drug-treated groups were administered different concentrations of the compound (final concentrations of 1000, 10, and 0.1 nM), while the blank group received an equal volume of DMSO. Treatment lasted 24 h. After cell collection, the supernatant was discarded by centrifugation, and 100 μL of RIPA lysis buffer (containing cocktail, PMSF, and 1.5x protein loading buffer) was added to each well. The cell lysis buffer was heated at 95 °C for 15 min and stored at -20 °C.

[0666] ② Load equal volumes of protein sample into the wells of an SDS-PAGE gel and perform electrophoresis at 100V. After electrophoresis, transfer the PVDF membrane at a constant current of 300mA. After transfer, remove the PVDF membrane and block it with 5% skim milk PBST solution at room temperature for 1 hour. After blocking, add the corresponding primary antibody incubation solution (primary antibody dilution ratio 1:1000, 5% BSA + PBST) to the antibody incubation chamber and incubate overnight at 4°C with gentle shaking. After incubation, wash the membrane four times with PBST for 5 minutes each time. Add secondary antibody incubation solution (secondary antibody dilution ratio 1:5000, 5% skim milk + PBST), incubate at room temperature for 1 hour, wash the membrane four times with PBST for 5 minutes each time, and develop and expose according to the method provided in the ECL chemiluminescence detection kit. Use Image Lab software to perform grayscale analysis on the development results and calculate the degradation rate, Dmax, and DC. 50 .

[0667] The degradation rate was calculated as follows:

[0668] Degradation rate (%) = 100% - (Gray value of the treatment group / Gray value of the blank group) × 100%

[0669] Dmax refers to the maximum level of degradation a compound can achieve in cells, that is, the maximum percentage reduction in the level of a target protein at a specific concentration; DC 50 This indicates the concentration of the compound at which half of the maximum degradation effect is achieved.

[0670] Table 3 shows the degradation results of STAT1-5 protein after 24 hours of treatment with different compounds.

[0671] Table 3. STAT1-5 protein degradation results

[0672] As can be seen from Table 3, compound 15 has no degradation activity against STAT1-5 and exhibits good subtype selectivity.

[0673] Test Example 4: In vitro metabolic stability

[0674] (1) Main reagent materials

[0675] (2) Incubation system

[0676] (3) Experimental methods

[0677] 1 μM of the test sample and the positive control testosterone were incubated with microsomes in the presence of NADPH for 120 min, and a negative control group was set up (the test sample was incubated with microsomes in the absence of any coenzyme for 120 min). Samples were taken at 0 min and 120 min, and 300 μL of pre-cooled methanol solution containing internal standard (rameltein: 1.000 ng / mL) was added to the sample. The sample was vortexed (2500 rpm, 1 min), centrifuged (4700 rpm, 4℃) for 10 min, and 50.0 μL of the supernatant was added to 200 μL of pure water in a 96-well plate. The plate was vortexed (1000 rpm, 10 min), sealed, and analyzed by LC-MS / MS. The parental remaining amount of the test substance or probe substrate was detected by LC-MS / MS. The metabolic stability of the test substance was expressed as a percentage of the parental remaining amount of the test substance at each time point relative to the parental amount before incubation (0 min). The data were calculated according to the following formula: Parental remaining percentage (% of 0 min) = T x Maternal mass / T0 maternal mass × 100; T x T1: Any incubation time point; T0: 0-minute incubation time point. The test results are shown in Table 4 below.

[0678] Table 4. Results of the in vitro metabolic stability of the compounds.

[0679] *The control compound is compound I-628, disclosed in Kymera's patent WO2025049820A1.

[0680] As shown in Table 4, compounds 13 and 16 exhibit good in vitro metabolic stability and show little species difference, which is significantly better than the positive control compound I-628.

[0681] Test Example 5: hERG Toxicity Test

[0682] The inhibitory effect of the compound on human hERG ion channels stably expressed in HEK293 cells was tested using conventional patch-clamp techniques. The compound was prepared at a concentration of 10 μM. Each cell served as a control. Perfusion was performed using a gravity-based perfusion system. After the current stabilized, the hERG current before and after the addition of the compound was compared, and the blocking effect of the compound on the hERG current was calculated. The results are shown in Table 5.

[0683] Table 5. Blocking effect of compounds on hERG current (10 μM)

[0684] As can be seen from the data in Table 5, the compounds of the present invention have a low hERG inhibition rate, indicating a low risk of cardiotoxicity.

Claims

1. A three-membered ring compound having the structure shown in formula (I) or (II), 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; Ring A is C 6-12 Aryl, 5 to 14 membered monocyclic, bicyclic or tricyclic heteroaryl, 5 to 14 membered monocyclic, bicyclic or tricyclic saturated or partially unsaturated heterocyclic groups; Ring B is a 4- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group or a 5- to 6-membered heteroaryl group; The ring C is a 5-8 member saturated or partially unsaturated carbocyclic group or heterocyclic group; Each R 1 Each is independently selected from hydrogen, deuterium, halogen, oxo group, thio group, and C. 1-6 Alkyl or C 1-6 alkoxy group, or two R atoms bonded to the same carbon atom 1 The carbon atoms bonded to it form 3-6 membered cycloalkyl groups; Each R 2 Each is independently selected from hydrogen, deuterium, halogen, oxo group, thio group, and C. 1-6 alkylamine group, C 1-6 Cycloalkyl, 3-8 membered heterocyclic or C 1-6 Alkyl; the C 1-6 alkylamine group, C 1-6 cycloalkyl or C 1-6 The alkyl group may optionally be further substituted with substituents selected from the following groups: hydrogen, deuterium, halogen, cyano, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C 3-6 cycloalkyl; Or two R atoms bonded to the same atom 2 The atoms bonded to it form 3-8 membered heterocyclic groups or C 3-8 cycloalkyl; the 3-8 membered heterocyclic group or C 3-8 The cycloalkyl group may optionally be further substituted with substituents selected from the following groups: hydrogen, deuterium, halogen, cyano, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C 3-6 cycloalkyl; Each R 3 Each is independently selected from hydrogen, deuterium, halogen, oxo group, thio group, and C. 1-6 alkylamine or C 1-6 alkyl; R 4 Selected from hydrogen, deuterium, halogen, or methyl; R 5 Selected from hydrogen, X and Y are each independently selected from C, CH, N, O, S, or NR. 6 ; R 6 Selected from hydrogen, C 1-6 Deuterated alkyl, C 3-6 cycloalkyl or C 1-6 alkyl; X 2 Selected from N or CH; L 1 Selected from key or -Q-; L is selected from the following structures, starting from the *** end: -Cy-, -Cy-Ak-, -Cy-Ak-Cy-, -Cy-Ak-Cy-Q-, -Cy-Ak-Cy-Cy-Q-, -Cy-Ak-Cy-Ak-, -Cy-Cy-, -Cy-Cy -Q-, -Cy-Cy-Ak-, -Cy-Cy-Ak-Q-, -Cy-Cy-Ak-Cy-Q-, -Cy-Cy-Cy- or -Cy-Cy-Cy-Q-; L X Selected from the following structures, starting from the end connected to G: key, -Ak-Q-, -Q-Ak-, -Ak-Q-Ak-, -Q-Ak-Q- or -Ak-Q-Ak-Q-; Each Cy is independently selected from C 4-12 Saturated or partially unsaturated monocyclic or bicyclic carbocyclic groups, 4-12 membered saturated or partially unsaturated monocyclic or bicyclic heterocyclic groups, C 6-12 Aryl or 5-12 membered monocyclic or bicyclic heteroaryl; the C 4-12 Saturated or partially unsaturated monocyclic or bicyclic carbocyclic groups, 4-12 membered saturated or partially unsaturated monocyclic or bicyclic heterocyclic groups, C 6-12 The aryl or 5-12 membered monocyclic or bicyclic heteroaryl group may optionally be further substituted by one or more substituents selected from the following groups: hydrogen, deuterium, halogen, cyano, oxo, thio, C 1-6 alkylamine group, C 1-6 cycloalkyl, C 1-6 Alkoxy or C 1-6 Alkyl, the C 1-6 alkylamine group, C 1-6 cycloalkyl, C 1-6 Alkoxy or C 1-6 The alkyl group may optionally be further substituted with substituents selected from the following groups: hydrogen, deuterium, halogen, cyano, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C 3-6 cycloalkyl; Each Ak is independently C 1-10 A straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein the hydrocarbon chain may optionally be replaced by 1-3 halogens; Each Q is independently selected from -O-, -C(O)-, -C(S)-, -C(R')2-, -NR'-, -S-, -S(O)-, -S(O)2-, -NR'C(O)- or -C(O)NR'-; Each R' is independently selected from hydrogen, halogen, or C. 1-6 alkyl; G is hydrogen, halogen, or... Ring D is C 3-6 Elemental saturated or partially unsaturated carbon cyclogroups, C 6-12 Aryl, 4- to 6-membered monocyclic saturated or partially unsaturated heterocyclic groups, or 5- to 12-membered heteroaryl groups; Each R D Each is independently selected from hydrogen, halogen, cyano, oxo, C 1-6 alkylamine group, C 1-6 Alkyl or C 1-6 Alkyl groups; a, b, c, and d are each independently selected from 0, 1, 2, 3, 4, 5, or 6.

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, Each Cy is independently selected from C 4-12 Saturated or partially unsaturated monocyclic or bicyclic carbocyclic groups, 4-12 membered saturated or partially unsaturated monocyclic or bicyclic heterocyclic groups, C 6-12 Aryl or 5-12 membered monocyclic or bicyclic heteroaryl; the C 4-12 Saturated or partially unsaturated monocyclic or bicyclic carbocyclic groups, 4-12 membered saturated or partially unsaturated monocyclic or bicyclic heterocyclic groups, C 6-12 The aryl or 5-12 membered monocyclic or bicyclic heteroaryl group may optionally be further substituted by one or more substituents selected from the following groups: hydrogen, deuterium, halogen, cyano, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C 3-6 Cycloalkyl.

3. The compound as described in claim 1 or 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 ring C is selected from 4. The compound according to any one of claims 1 to 3, or its pharmaceutically acceptable salt, isotope derivative, solvate, or its stereoisomer, geometric isomer, tautomer, or its prodrug molecule or metabolite, characterized in that, The compound has the structure shown in formula (III) or (IV): Among them, ring D is a 5-membered heteroaryl group; L XA Selected from -C(O)-, -C(S)-, -C(R')2-, -S(O)- or -S(O)2-; L XB Selected from key or C 1-5 Straight-chain or branched saturated or unsaturated hydrocarbon chains; R 1 R 2 R 3 R 4 R 5 R D ,R',a,b,c,d,X,Y,X 2 L, L 1 The definitions of ring A and ring B are as described in claim 1.

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 compound has a structure as shown in formula (IIIA), (IIIB), (IVA), or (IVB): Among them, ring E is a 5-6 member saturated or partially unsaturated heterocyclic group or heteroaryl group; R 1 R 2 R 3 R 4 R 5 R D a, b, c, d, X, Y, X 2 L, L 1 L XA L XB The definitions of ring B and ring D are as described in claim 4.

6. 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 compound has the structure shown in formula (IIIa), (IIIb), (IIIc), (IIId), (IVa), (IVb), (IVc), or (IVd): Wherein, Cy 1 Each is selected independently from C 4-12 Saturated or partially unsaturated monocyclic or bicyclic carbocyclic groups, 4-12 membered saturated or partially unsaturated monocyclic or bicyclic heterocyclic groups, C 6-12 Aryl or 5-12 membered monocyclic or bicyclic heteroaryl; Cy 2 Cy 3 Each is independently selected from C 4-12 Saturated or partially unsaturated monocyclic or bicyclic carbocyclic groups, 4-12 member saturated or partially unsaturated monocyclic or bicyclic heterocyclic groups; The Cy 1 Cy 2 Cy 3 Each can also be independently influenced by 1-3 groups selected from hydrogen, deuterium, halogen, cyano, oxo, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C 3-6 Substituents of cycloalkyl groups; L m Each can be selected independently from the key or -C 1-3 alkylene-; L n Each group is independently selected from the following groups, from Cy 2 or Cy 3 The first segment of the connection is: key, -C(O)-, -O-, -N(R) Ln )-、-C 1-3 alkylene- or -C 1-3 Alkylene-N(R) Ln )-, the C 1-3 The alkylene group may also be optionally replaced by 1-3 halogens; R Ln Each is independently selected from hydrogen or C 1-6 alkyl; R 1 R 2 R 3 R 4 R 5 R D a, b, c, d, X, Y, X 2 L 1 L XA L XB The definitions of ring A, ring B, and ring D are as described in claim 4.

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 compound has a structure as shown in formula (III-1), (III-2), (III-3), (III-4), (IV-1), (IV-2), (IV-3), or (IV-4): Wherein, Cy 1 Each is selected independently from C 4-12 Saturated or partially unsaturated monocyclic or bicyclic carbocyclic groups, 4-12 membered saturated or partially unsaturated monocyclic or bicyclic heterocyclic groups, C 6-12 Aryl or 5-12 membered monocyclic or bicyclic heteroaryl; Cy 2 Cy 3 Each is independently selected from C 4-12 Saturated or partially unsaturated monocyclic or bicyclic carbocyclic groups, 4-12 member saturated or partially unsaturated monocyclic or bicyclic heterocyclic groups; The Cy 1 Cy 2 Cy 3 Each can also be independently influenced by 1-3 groups selected from hydrogen, deuterium, halogen, cyano, oxo, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C 3-6 Substituents of cycloalkyl groups; L m Selected from key or -C 1-3 alkylene-; L n Selected from the following groups, from Cy 2 or Cy 3 The first segment of the connection is: key, -C(O)-, -O-, -N(R) Ln )-、-C 1-3 alkylene- or -C 1-3 Alkylene-N(R) Ln )-, the C 1-3 The alkylene group may also be optionally replaced by 1-3 halogens; R Ln Selected from hydrogen or C 1-6 alkyl; Ring E is a 5-6 member saturated or partially unsaturated heterocyclic group or heteroaryl group; R 1 R 2 R 3 R 4 R 5 R D a, b, c, d, X, Y, X 2 L 1 L XA L XB The definitions of ring B and ring D are as described in claim 4.

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 Selected from Among them, R 4 Selected from hydrogen, deuterium, or fluorine; R 2a Selected from hydrogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl or C 1-6 cycloalkyl; R 2b R 2c Each is independently selected from hydrogen and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl or C 1-6 cycloalkyl; Or R 2b R 2c The N atoms they are connected to form 3-8 membered heterocyclic groups; R 6 Selected from hydrogen, C 1-6 Deuterated alkyl, C 3-6 cycloalkyl or C 1-6 alkyl.

9. The compound according to any one of claims 4 to 8, 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 10. The compound of claim 5 or 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 Selected from The Selected from Among them, each R 10 Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl or C 1-6 Alkyl groups; Each R 11 Each is independently selected from hydrogen or C. 1-6 alkyl; Each R 12 R 13 Each is independently selected from hydrogen or C. 1-6 alkyl; Or, R 12 R 13 It forms C with the carbon atom it is attached to. 3-6 cycloalkyl; r can be selected from 0, 1, 2 or 3.

11. The compound according to any one of claims 1 to 9, 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 the following structures: Among them, each R 10 Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl or C 1-6 Alkyl groups; Each R 11 Each is independently selected from hydrogen or C. 1-6 alkyl; Each R 12 R 13 Each is independently selected from hydrogen or C. 1-6 alkyl; Or, R 12 R 13 It forms C with the carbon atom it is attached to. 3-6 cycloalkyl; r can be selected from 0, 1, 2 or 3.

12. The compound according to any one of claims 1 to 11, 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 L is selected from the following structures: Among them, each R cy1 Each is independently selected from hydrogen, deuterium, halogen, cyano, oxo, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy or C 3-6 cycloalkyl; Each R cy2 R cy3 Each is independently selected from hydrogen, deuterium, halogen, cyano, oxo, or C. 1-6 alkyl; Each R Ln Each is independently selected from hydrogen or C. 1-6 alkyl; c1, c2, and c3 are selected from 0, 1, 2, or 3; n is selected from 0, 1, 2, or 3; m is selected from 1 or 2; The The chain can optionally be further replaced by 1-3 halogens.

13. The compound according to any one of claims 1 to 12, 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 the following structures:

14. [Revised according to Rule 91, Amended 30.04.2026] The compound of any one of claims 1 to 13, 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:

15. A pharmaceutical composition, characterized in that, The pharmaceutical composition contains a therapeutically effective amount of any one of the compounds of claims 1-14 or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or its stereoisomer, geometric isomer, tautomer, or its prodrug molecule or metabolite.

16. Use of any compound of claims 1 to 14 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 15 in the preparation of a medicament for treating STAT6-related diseases or conditions and related diseases or conditions.

17. Use of the compound of any one of claims 1 to 14 or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, or the pharmaceutical composition of claim 15 for the treatment of STAT6-related diseases or conditions and related diseases or conditions.

18. A method of treating and / or preventing a disease, comprising administering to a subject a therapeutically effective amount of any one of claims 1 to 14, 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 15 thereof.

19. The method according to claim 18, characterized in that, The diseases to be treated and / or prevented are STAT6-related diseases or conditions and related diseases or conditions.

20. The use according to claim 16 or 17, or the method according to claim 19, characterized in that, The STAT6-related diseases or conditions and related diseases or conditions are tumors or type II inflammation-related diseases.

21. The use or method according to claim 20, characterized in that, 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), 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; the tumors are selected from lymphoma, solitary fibrous tumors, 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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