Tricyclic compound and medical use thereof

Abstract

The present invention relates to the technical field of medicine, and specifically relates to a Cbl-b small molecule inhibitor, a preparation method therefor, and the medical use thereof. Provided in the present invention are a Cbl-b small molecule inhibitor represented by formula (I), a composition thereof and the use thereof. The compound can be used for treating or preventing Cbl-b mediated diseases or disorders and related diseases or disorders.

Description

Three-membered fused-ring compounds and their pharmaceutical uses Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a ternary fused-ring compound of formula (I) or its pharmaceutically acceptable salt, isotope derivative, solvate, or its stereoisomer, geometric isomer, tautomer, or its prodrug molecule or metabolite, as well as its preparation method and its application in the preparation of drugs for treating related diseases. Background Technology

[0002] As representatives of numerous transmembrane receptor-ligand pairs regulating T-cell antigen responses, the anti-programmed cell death 1 (PD-1) / PD-1 ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) checkpoints have seen their emergence and success with immune checkpoint protein inhibitors (ICIs) significantly altering the treatment paradigm for cancer patients. While many patients derive clinical benefit from ICI therapy, a significant number develop resistance to this treatment or acquire resistance after an initial response. Resistance mechanisms are diverse, including insufficient T-cell antigen recognition, impaired T-cell migration and / or infiltration, and T-cell exhaustion / decreased cytotoxicity, most of which are related to T-cell activation. Therefore, T-cell activation is crucial for the antitumor effects of ICIs.

[0003] Downstream protein ubiquitination in immune signaling pathways is crucial for the positive and negative regulation of almost all immune responses, particularly T cell activation. Numerous studies have shown that ubiquitination exerts various cellular and molecular effects by controlling protein function, localization, and stability. Regulation of ubiquitin-dependent pathways can significantly alter T cell activation and enhance anti-tumor responses. The ubiquitin system is widely distributed in eukaryotes and is a precise intracellular protein degradation regulatory system that maintains cellular homeostasis by regulating the protein "production-degradation" balance. The ubiquitin system consists of ubiquitin, the 26S proteasome, and various enzymes (E1, E2, E3, and deubiquitinases, etc.). Ubiquitin is a small protein molecule composed of 76 amino acids with a highly conserved sequence. It typically labels proteins to be degraded by covalently linking a ubiquitin chain to a lysine residue in the substrate protein. Protein ubiquitination is completed through an E1-E2-E3 cascade reaction involving ubiquitin activator E1, ubiquitin conjugate E2, and ubiquitin ligase E3. Subsequently, the ubiquitinated protein is degraded by the 26S proteasome.

[0004] The human genome encodes approximately 35 E2-binding enzymes and over 500 E3 ligases. Casitas B-cell lymphoma (Cbl) proteins are among the most characteristic E3 ubiquitin ligase families, comprising three members: Cbl, Cbl-b, and Cb1-c. Cbl proteins participate in signal transduction regulation in numerous physiological and pathological processes, and are associated with tumorigenesis and progression, hematopoietic development, and T-cell receptor regulation. Among the three Cbl family members, Cb1-b plays a central role in regulating effector T-cell function. It is highly expressed in immune cells and promotes adaptive and innate immune tolerance. Previous studies have shown that Cbl-b is involved in the expression of depleted CD8+ PD-1 and TIM-3. + Upregulation in T cells and Cbl-b deficiency can effectively reverse T cell exhaustion and restore the function of effector cells in the blood. Cbl-b-deficient T cells have a stronger tumor clearance rate compared to wild-type cells. Mice treated with Cbl-b inhibitors develop strong immune memory, and tumor growth is completely suppressed upon reimplantation into tumors. Furthermore, studies have shown that Cbl-b inhibition can reduce PD-1 expression, and its combination with anti-PD-1 monoclonal antibodies produces a synergistic effect. Therefore, as a potential target for immunomodulatory therapy, targeting Cb1-b may provide a new therapeutic option for tumor immunotherapy. Summary of the Invention

[0005] The technical problem to be solved by the present invention is to provide a novel ternary fused-ring compound that can be used as a small molecule inhibitor of Cbl-b for the preparation of drugs for treating Cbl-b-mediated diseases or symptoms and related diseases or symptoms.

[0006] To solve the above-mentioned technical problems, the present invention provides the following technical solution:

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

[0008] Among them, R 1 Selected from hydroxyl or

[0009] m and n are each independently selected from 1, 2, or 3;

[0010] X 1 Selected from S, O, NR Z1 CR Z1 or CR Z1 R Z2 ;

[0011] X 2X 3 X 4 Each is independently selected from N or C;

[0012] Z 1 Selected from CR Z1 R Z2 -(CO)-, -(C=NR) Z1 )-、NR Z1 -C(R) Z1 )=C(R Z2 )-、-N=C(R Z2 )-、-C(R Z1 )=N-、-O-CR Z1 R Z2 -、-CR Z1 R Z2 -CO-、-CR Z1 R Z2 -CR Z3 R Z4 -or-NR Z3 -CR Z1 R Z2 -;

[0013] Z 2 Selected from S, -C(R) Z1 )=C(R Z2 )-、-N=C(R Z2 - or -C(R) Z1 ) = N-;

[0014] Y 1 Y 2 Y 3 Y 4 Each is independently selected from N or CR 5 ;

[0015] Ring A is selected from 5-6-membered heteroaryl or 5-6-membered heterocyclic groups, wherein the 5-6-membered heteroaryl or 5-6-membered heterocyclic group is optionally further surrounded by one or more R groups. 6 replace;

[0016] R Z1 R Z2 R Z3 R Z4 R 2 R 2’ R 3 R 3’ R 4 R 4’ R 5 R 6 Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 alkylamine group, C 1-6 alkyl ester group, C 1-6 Alkyl acyl, C 1-6 Alkylamide group, C 1-6 alkylsulfonamide group, C 1-6 Phosphoryl group or 3-8 membered heterocyclic group; the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 alkylamine group, C 1- 6-alkyl ester group, C 1-6 Alkyl acyl, C 1-6 Alkylamide group, C 1-6 alkylsulfonamide group, C 1-6 The phosphoryl group or 3-8 membered heterocyclic group may optionally be further surrounded by one or more R groups. a Replaced;

[0017] Or, the R Z1 R Z2 Together with the atoms they are attached to, they form C 3-12 Cycloalkyl or 4-12 membered heterocyclic groups, wherein the C3-C 12 Cycloalkyl groups, 4-12 membered heterocyclic groups optionally further modified by one or more R groups a Replaced;

[0018] Or, the R Z3 R Z4 Together with the atoms they are attached to, they form C 3-12 Cycloalkyl or 4-12 membered heterocyclic groups, wherein the C3-C 12 Cycloalkyl groups, 4-12 membered heterocyclic groups optionally further modified by one or more R groups a Replaced;

[0019] Or, the R 2 R 2’ Together with the atoms they are attached to, they form C 3-12 Cycloalkyl or 4-12 membered heterocyclic groups, wherein the C3-C 12 Cycloalkyl groups, 4-12 membered heterocyclic groups optionally further modified by one or more R groups a Replaced;

[0020] Or, the R 3 R 3’ Together with the atoms they are attached to, they form C 3-12 Cycloalkyl or 4-12 membered heterocyclic groups, wherein the C3-C 12 Cycloalkyl groups, 4-12 membered heterocyclic groups optionally further modified by one or more R groups a Replaced;

[0021] Or, the R 4 R 4’ Together with the atoms they are attached to, they form a 4-12 membered heterocyclic group, which may optionally be further bonded by one or more R atoms. a Replaced;

[0022] R a Independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 alkylamine group, C 1-6 Alkyl acyl or 3-8 membered heterocyclic group; the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 alkylamine group, C 1-6 The alkyl acyl group or a 3-8 membered heterocyclic group may optionally be further selected from one or more groups selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, or C. 1-6 The alkoxy group is replaced by a substituent.

[0023] In some embodiments, the compound has a structure as shown in formula (II) or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule or metabolite thereof:

[0024] Where m, n, X 1 X 2 X 3 X 4 Y 1 Y 2 Y 3 Y4 Z 1 Z 2 R 1 R 2 R 2’ R 3 R 3’ R 6 The definition is as stated in general formula (I).

[0025] In some implementations, the Selected from:

[0026] In some implementations, the Selected from

[0027] In some embodiments, the compound has a structure as shown in formula (III) or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule or metabolite thereof:

[0028] Among them, X 1 X 2 X 3 X 4 Y 1 Y 2 Y 3 Y 4 Z 1 Z 2 R 1 R 2 R 2’ R 3 R 3’ R 6 The definition is as stated in general formula (I).

[0029] In some embodiments, the compound has a structure as shown in formula (IV) or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule or metabolite thereof:

[0030] Where p is selected from 0, 1, 2 or 3;

[0031] X 1 X 2 X 3 X 4 Z 1 Z 2 Y 1 R 1R 2 R 2’ R 3 R 3’ R 5 R 6 The definition is as stated in general formula (I).

[0032] In some implementations, the Selected from The X 1 Z 1 R Z1 R Z2 The definition is as stated in general formula (I).

[0033] In some embodiments, the compound has a structure as shown in formula (Va), (Vb), (Vc), or (Vd), or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule or metabolite thereof:

[0034] Among them, X 1 Selected from S or NR Z1 ;

[0035] p is selected from 0, 1, 2, or 3;

[0036] Z 1 Y 1 R 1 R 2 R 2’ R 3 R 3’ R 5 R 6 R Z1 R Z2 The definition is as stated in general formula (I).

[0037] In some implementations, the R 3 R 3’ Each is independently selected from hydrogen and C. 1-6 Alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclic groups, wherein the C 1- 6-alkyl, C 3-6 The cycloalkyl or 3-6 membered heterocyclic group may optionally be further selected from one or more groups selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl groups are substituted.

[0038] In some implementations, the Selected from The values ​​q and r are each independently selected from 0, 1, 2, or 3; the value s is selected from 1, 2, or 3; the value R... a Independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy groups.

[0039] In some implementations, the Selected from The values ​​q and r are each independently selected from 0, 1, 2, or 3; the value R... a Independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy groups.

[0040] In some embodiments, the compound has a structure as shown in formula (VIa), (VIb), (VIc), (VId), or (VIe), or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule or metabolite thereof:

[0041] Among them, X 1 Selected from S or NH;

[0042] p, q, and r are each independently selected from 0, 1, 2, or 3;

[0043] s is selected from 1, 2, or 3;

[0044] Z 1 Y 1 R 1 R 2 R 2’ R 5 R 6 R Z1 R Z2 R a The definition is as stated in general formula (I).

[0045] In some embodiments, the compound has a structure as shown in formulas (VIIa), (VIIb), (VIIc), (VIId), (VIIe), (VIIf), (VIIg), (VIIh), (VIIi), (VIIj), (VIIk), (VIIm), or (VIIn), or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule or metabolite thereof:

[0046] Among them, p, q, and r are each independently selected from 0, 1, 2, or 3;

[0047] s is selected from 1, 2, or 3;

[0048] Y 1 R 1 R 2 R 2’ R 5 R 6 R Z1 R Z2 R a The definition is as stated in general formula (I).

[0049] In some implementations, the R 1 Selected from The R 4 R 4’ Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl or C 3-8 cycloalkyl, the C 1-6 Alkyl or C 3-8 The cycloalkyl group may optionally be further divided by one or more radicals selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C 3-8 Substituents of cycloalkyl groups;

[0050] Or, the R 4 R 4’ The atoms attached to it together form a 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group is optionally further bonded by one or more elements selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, oxo, C 1-6 alkylamine group, C 1-6 Alkyl, C 3-8 cycloalkyl or C 1-6 Alkoxy; the C 1-6 Alkyl, C 3-8 cycloalkyl or C 1-6alkoxy groups may optionally be further divided by one or more groups selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, or C. 1-6 The alkoxy group is replaced by a substituent.

[0051] In some implementations, the R 1 Selected from The R 4 R 4’ Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl or C 3-8 cycloalkyl, the C 1-6 Alkyl or C 3-8 The cycloalkyl group may optionally be further divided by one or more radicals selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C. 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 The substituents of the haloalkoxy group are replaced.

[0052] In some implementations, the R 1 Selected from The R 4 R 4’ The atoms attached to it together form a 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group is optionally further bonded by one or more elements selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, oxo, C 1-6 Alkyl, C 3- 8-cycloalkyl or C 1-6 Alkoxy; the C 1-6 Alkyl, C 3-8 cycloalkyl or C 1-6 alkoxy groups may optionally be further divided by one or more groups selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, or C. 1-6 The alkoxy group is replaced by a substituent.

[0053] In some implementations, the R 1 Selected from Preferably, the R 1 Selected from

[0054] In some implementations, the R 1 Selected from

[0055] In some implementations, the R 1 Selected from

[0056] In some embodiments, the compound has a structure as shown in formulas (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), (VIIIi), (VIIIj), (VIIIk), (VIIIm), or (VIIIn), or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule or metabolite thereof:

[0057] In this context, p and q are each independently selected from 0, 1, 2, or 3;

[0058] s is selected from 1, 2, or 3;

[0059] Y 1 R 2 R 2’ R 5 R 6 R Z1 R Z2 R a The definition is as stated in general formula (I).

[0060] In some implementations, the Selected from

[0061] In some implementations, the Selected from Preferred

[0062] In some implementations, the R 5 Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 3-6 Cycloalkyl.

[0063] In some implementations, the R 5 Selected from hydrogen or cyclopropyl.

[0064] In some implementations, the R 6 Selected from hydrogen, deuterium, and C 1-3 Alkyl or C 3-6 Cycloalkyl.

[0065] In some implementations, the R 6 Selected from methyl.

[0066] In some implementations, the R Z2 Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 3-6 Cycloalkyl.

[0067] In some implementations, the R Z1 Selected from hydrogen; the R Z2 Selected from hydrogen or fluorine.

[0068] In some implementations, the Selected from

[0069] In some embodiments, the compound of the present invention, or its pharmaceutically acceptable salt, isotope derivative, solvate, or its stereoisomer, geometric isomer, tautomer, or its prodrug molecule or metabolite, is selected from the following structures:

[0070] On the other hand, the present invention provides a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (I), (II), (III), (IV), (Va) to (Vd), (VIa) to (VIe), (VIIa) to (VIIn), (VIIIa) to (VIIIn) or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule or metabolite thereof.

[0071] In another aspect, the present invention provides the use of compounds of formulas (I), (II), (III), (IV), (Va) to (Vd), (VIa) to (VIe), (VIIa) to (VIIn), (VIIIa) to (VIIIn) as described above, or their pharmaceutically acceptable salts, isotope derivatives, solvates, or their stereoisomers, geometric isomers, tautomers, or their prodrug molecules, metabolites, or the pharmaceutical compositions described above, in the preparation of medicaments for treating Cbl-b-mediated diseases or conditions and related diseases or conditions.

[0072] In another aspect, the present invention provides the use of compounds of formulas (I), (II), (III), (IV), (Va) to (Vd), (VIa) to (VIe), (VIIa) to (VIIn), (VIIIa) to (VIIIn) as described above, or their pharmaceutically acceptable salts, isotope derivatives, solvates, or their stereoisomers, geometric isomers, tautomers, or their prodrug molecules, metabolites, or the pharmaceutical compositions described above, in the treatment of Cbl-b mediated diseases or conditions and related diseases or conditions.

[0073] The present invention also provides a method for treating a disease or symptom, the method comprising administering to a patient in need a therapeutically effective amount of a compound of formulas (I), (II), (III), (IV), (Va)–(Vd), (VIa)–(VIe), (VIIa)–(VIIn), (VIIIa)–(VIIIn) as described above, or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, or a pharmaceutical composition thereof described above, wherein the disease treated and / or prevented is a Cbl-b mediated disease or symptom and related diseases or symptom.

[0074] In some implementations, the Cbl-b-mediated disease or condition and related diseases or conditions are tumors.

[0075] Furthermore, the tumor is selected from lymphoma, solitary fibrous tumor, colon cancer, esophageal cancer, breast cancer, bile duct cancer, liver cancer, kidney cancer, gastric cancer, esophagogastric junction cancer, melanoma, pleural mesothelioma, urothelial carcinoma, cervical cancer, diffuse large B-cell lymphoma (DLBCL), Richter syndrome, 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.

[0076] Unless otherwise stated, the general chemical terms used in the structural formulas have their usual meanings.

[0077] For example, unless otherwise stated, the term "halogen" as used in this invention refers to fluorine, chlorine, bromine, or iodine.

[0078] In this invention, unless otherwise stated, "alkyl" includes straight-chain or branched monovalent saturated hydrocarbon groups. For example, alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc. Similarly, "C 1-6 "alkyl" 1-6"" refers to a group consisting of 1, 2, 3, 4, 5 or 6 carbon atoms arranged in a straight or branched form.

[0079] The term "alkoxy" refers to the oxygen ether form of the aforementioned straight-chain or branched alkyl group, i.e., -O-alkyl.

[0080] The term "halogenated alkyl" refers to an alkyl group in which one or more H atoms have been replaced by halogen atoms.

[0081] The term "haloalkoxy" refers to an alkoxy group in which one or more H atoms have been replaced by halogen atoms.

[0082] 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.

[0083] The term "cycloalkyl" refers to a cyclic system having at least one cycloalkyl group. Preferably, C 3-12 Cycloalkyl, wherein the "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.

[0084] The term "alkenyl" refers to an alkyl group having one or more carbon-carbon double bonds, such as vinyl, propenyl, 1,3-butadiene, cis-butenyl, trans-butenyl, etc.

[0085] The term "alkynyl" refers to an alkyl group having one or more carbon-carbon triple bonds, such as ethynyl, propynyl, etc.

[0086] The term "alkathioyl" refers to a straight-chain or branched alkyl group linked by sulfur atoms, i.e., -S-alkyl, such as C 1-6 Alkylthio groups include, but are not limited to, methylthio, ethylthio, propylthio (including n-propylthio and isopropylthio), butylthio (including n-butylthio, isobutylthio, sec-butylthio, and tert-butylthio), pentylthio (including n-pentylthio, isopentylthio, and neopentylthio), and hexylthio (n-hexylthio, 2-methylpentylthio, 3-methylpentylthio, 2,3-dimethylbutylthio, and 2,2-dimethylbutylthio).

[0087] The term "alkylsulfonyl" refers to a straight-chain or branched alkyl group linked by a sulfone group, i.e., -SO2-alkyl, such as C 1-6Alkyl sulfone groups, including but not limited to methyl sulfone, ethyl sulfone, propane sulfone (including n-propane sulfone and isopropane sulfone), butyl sulfone (including n-butyl sulfone, isobutyl sulfone, sec-butyl sulfone, and tert-butyl sulfone), pentyl sulfone (including n-pentyl sulfone, isopentyl sulfone, and neopentyl sulfone), and hexyl sulfone (n-hexyl sulfone, 2-methylpentyl sulfone, 3-methylpentyl sulfone, 2,3-dimethylbutyl sulfone, and 2,2-dimethylbutyl sulfone), etc.

[0088] The term "alkylamine" refers to an open-chain alkyl group containing a nitrogen atom, such as C... 1-6 Alkylamine groups, including but not limited to methylamino, ethylamino, isopropylamino, dimethylamino, methylethylamino, diethylamino, etc.

[0089] The term "alkyl ester group" refers to a straight-chain or branched alkyl group linked by an ester group, i.e., -alkyl-CO2-, such as C 1-6 Alkyl ester group, including but not limited to methyl ester group, ethyl ester group, propyl ester group (including n-propyl ester group and isopropyl ester group), butyl ester group (including n-butyl ester group, isobutyl ester group, sec-butyl ester group, and tert-butyl ester group), pentyl ester group (including n-pentyl ester group, isopentyl ester group, and neopentyl ester group), and hexyl ester group (n-hexyl ester group, 2-methylpentyl ester group, 3-methylpentyl ester group, 2,3-dimethylbutyl ester group, and 2,2-dimethylbutyl ester group), etc.

[0090] The term "alkyl acyl" refers to a straight-chain or branched alkyl group linked by an acyl group, i.e., -alkyl-CO-, such as C 1-6 Alkyl groups, including but not limited to formyl, acetyl, propionyl (including n-propionyl and isopropionyl), butyryl (including n-butyryl, isobutyryl, sec-butyryl, and tert-butyryl), valeryl (including n-valeryl, isovaleryl, and neovaleryl), and hexanoyl (n-hexanoyl, 2-methylvaleryl, 3-methylvaleryl, 2,3-dimethylbutyryl, and 2,2-dimethylbutyryl).

[0091] The term "alkylamide group" refers to a straight-chain or branched alkyl group linked by an amide group, i.e., -alkyl-CONH-, such as C 1-6 Alkylamide groups include, but are not limited to, formamido, acetamido, propionamido (including n-propionamido and isopropionamido), butyamido (including n-butyamido, isobutyamido, sec-butyamido, and tert-butyamido), pentamido (including n-pentamido, isovaleramido, and neopentamido), and hexamido (n-hexamido, 2-methylpentamido, 3-methylpentamido, 2,3-dimethylbutyamido, and 2,2-dimethylbutyamido).

[0092] The term "alkylsulfonamide" refers to a straight-chain or branched alkyl group linked by a sulfonamide group, i.e., -alkyl-SO2N-, such as C 1-6Alkyl sulfonamide groups include, but are not limited to, methanesulfonamide, ethanesulfonamide, propanesulfonamide (including n-propanesulfonamide and isopropanesulfonamide), butanesulfonamide (including n-butanesulfonamide, isobutanesulfonamide, sec-butanesulfonamide, and tert-butanesulfonamide), pentasulfonamide (including n-pentanesulfonamide, isopentanesulfonamide, and neopentanesulfonamide), and hexanesulfonamide (n-hexanesulfonamide, 2-methylpentanesulfonamide, 3-methylpentanesulfonamide, 2,3-dimethylbutanesulfonamide, and 2,2-dimethylbutanesulfonamide).

[0093] The term "phosphoryl group" refers to -PO2-, such as C 1-6 Phosphoryl groups include, but are not limited to, methylphosphoryl, ethphosphoryl, propionic phosphoryl (including n-propionic phosphoryl and isopropionic phosphoryl), butylphosphoryl (including n-butylphosphoryl, isobutylphosphoryl, sec-butylphosphoryl, and tert-butylphosphoryl), pentaphosphoryl (including n-pentaphosphoryl, isopentapionic phosphoryl, and neopentaphosphoryl), and hexophosphoryl (n-hexophosphoryl, 2-methylpentaphosphoryl, 3-methylpentaphosphoryl, 2,3-dimethylbutionic phosphoryl, and 2,2-dimethylbutionic phosphoryl).

[0094] 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.

[0095] The term "heteroaryl" in this invention, unless otherwise stated, refers to a monocyclic or polycyclic (e.g., fused bicyclic) aromatic heterocycle having at least one heteroatom selected from N, O, and / or S, wherein the nitrogen or sulfur heteroatom is selectively oxidized, and the nitrogen heteroatom is selectively quaternized. Preferably, it is a 5-14 membered heteroaryl, wherein "5-14" in 5-14 membered heteroaryl refers to a heteroaryl containing 5-14 cyclic atoms of C, N, O, or S. More preferably, it is a 5-10 membered heteroaryl, and even more preferably, it is a 5-6 membered heteroaryl. Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrroloyl, thiazolyl, thiadiazolyl, triazolyl, pyridinyl, pyridazinyl, indolyl, azaindolyl, indolyl, benzimidazolyl, benzofuranyl, benzothiophene, benzoisoxazolyl, benzothiazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyladenine, quinolinyl, or isoquinolinyl. The heteroaryl group may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring.

[0096] The term "heterocyclic group" refers to a ring system having at least one cyclic alkyl or cyclic alkenyl group containing a heterocycle, wherein the heteroatom is selected from N, O, and / or S. The heterocyclic group can include monocyclic or polycyclic groups (e.g., having 2, 3, or 4 fused rings, spirocyclic, bridged rings, etc.). The heterocyclic group can be connected to other parts of the compound via cyclic carbon atoms or cyclic heteroatoms. Preferably, it is a 3-14 membered heterocyclic group, where "3-14" refers to a heterocyclic group consisting of 3-14 cyclic atoms of C, N, O, or S; more preferably, it is a 3-8 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, azacyclic butyl, pyrrolyl, piperidinyl, 1,2,3,6-tetrahydropyridine, piperazine, oxoperazine, oxoperridinyl, tetrahydrofuranyl, dioxopentyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, and tetrahydrooxadiazolyl. The heterocyclic group may be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group.

[0097] The term "medicinal salt" refers to salt prepared from a pharmaceutically acceptable, non-toxic alkali or acid.

[0098] 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.

[0099] When the compounds provided by this invention are bases, 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, etc.

[0100] 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.

[0101] 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.

[0102] Unless otherwise stated, this invention includes any possible tautomers and their pharmaceutical salts, and mixtures thereof, when the compounds shown in formulas (I), (II), (III), (IV), (Va)~(Vd), (VIa)~(VIe), (VIIa)~(VIIn), (VIIIa)~(VIIIn) are present.

[0103] 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.

[0104] In this invention, "solvent" is selected from hydrates, ethanol compounds, methanol compounds, acetone compounds, diethyl ether compounds, or isopropanol compounds.

[0105] 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.

[0106] 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.

[0107] 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.

[0108] 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.

[0109] 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.

[0110] 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.

[0111] 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.

[0112] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0113] This invention, based on the Cbl-b target design, develops a novel ternary fused-ring compound as a Cbl-b inhibitor. Related biological experiments have shown that the compound exhibits significant IL-2 release-activating activity in Jurkat cells, along with good metabolic stability, and demonstrates good tumor-suppressing effects in animal models of solid tumors such as colorectal cancer, showing great promise for clinical application. Furthermore, the synthetic route provided by this invention is novel, safe, environmentally friendly, and feasible for production. Detailed Implementation

[0114] 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.

[0115] Unless otherwise stated, all temperatures in this invention refer to degrees Celsius.

[0116] (S)-3-methylpiperidine hydrochloride was purchased from Shanghai Bide Pharmaceutical Technology Co., Ltd., with a purity of 98%.

[0117] Explanation of abbreviations for solvents or materials used:

[0118] NaH: Sodium hydride; DMF: N,N-dimethylformamide; KOH: Potassium hydroxide; EtOH: Ethanol; H2O: Water; HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate; DIPEA: N,N-diisopropylethylamine; NaOH: Sodium hydroxide; H2O2: Hydrogen peroxide; DCM: Dichloromethane; AcOH: Acetic acid; NH4Cl: Ammonium chloride; EA: Ethyl acetate; Na2SO4: Sodium sulfate ; PE: petroleum ether; K2CO3: potassium carbonate; MeOH: methanol; Pd(OAc)2: palladium acetate; XPhos: 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl; Cs2CO3: cesium carbonate; dioxane: dioxane; Cu2O: cuprous oxide; NH3·H2O: ammonia; ACN: acetonitrile; KI: potassium iodide; TPFPB: tris(pentafluorophenyl)borane; POCl3: phosphorus oxychloride; NaBH4: sodium borohydride; x mL×y: y times, x each time mL; LC-MS: liquid chromatography-mass spectrometry; DMSO: dimethyl sulfoxide; Na2S2O3: sodium thiosulfate; DMF-DMA: N,N-dimethylformamide dimethyl acetal; P(Cy)3: tricyclohexylphosphine; K3PO4: potassium phosphate; Tol: toluene; THF: tetrahydrofuran; DMC: dimethyl carbonate; (1R,2R)-DMCHDA: (1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine; NaBH3CN: sodium cyanoborohydride; Ruphos-Pd-G3: (2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′- Biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate; Ruphos: 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl; PMBNH2: 4-methoxybenzylamine; SEMCl: 2-(trimethylsilyl)ethoxymethyl chloride; Tf2O: trifluoromethanesulfonic anhydride; TFA: trifluoroacetic acid; NaHCO3: sodium bicarbonate; Pd(PPh3)4: tetrakis(triphenylphosphine)palladium; KF: potassium fluoride; Pd2(dba)3: tris(dibenzylideneacetone)dipalladium; DMP: Dess-Martin oxidant; PBr3: phosphorus tribromide.

[0119] Furthermore, all operations involving easily oxidized or hydrolyzed raw materials are performed under nitrogen protection. Unless otherwise stated, the raw materials used in this invention are commercially available and can be used directly without further purification.

[0120] All reaction raw materials and common intermediates involved in the embodiments of the present invention can be obtained commercially or by self-production. The preparation process of raw materials and common intermediates that need to be self-produced is described in detail below.

[0121] Preparation of common intermediate INT1

[0122] Step 1: Synthesis of 1-(3-bromophenyl)-3-methylcyclobutane-1-carboxynitrile (INT1-b)

[0123] A DMF (10 mL) solution of INT1-a (1.00 g, 5.10 mmol) and 1,3-dibromo-2-methylpropane (1.10 g, 5.10 mmol) was slowly added to an anhydrous DMF (10 mL) solution of NaH (449.0 mg, 11.22 mmol) under ice-water bath conditions, and the reaction was allowed to proceed at room temperature for 1 hour. The reaction mixture was quenched with saturated NH4Cl solution, diluted with water (50 mL), extracted with EA (50 mL × 2), and the organic phases were combined and washed with water (50 mL × 3) and saturated brine (20 mL). The mixture was dried over anhydrous Na2SO4, filtered, concentrated, and the residue was purified by column chromatography (EA:PE = 6%) to give compound INT1-b (1.01 g), with a yield of 79.2%.

[0124] Step 2: Synthesis of 1-(3-bromophenyl)-3-methylcyclobutane-1-carboxylic acid (INT1-c)

[0125] INT1-b (1.01 g, 4.04 mmol) was dissolved in EtOH (25 mL), and a solution of KOH (2.26 g, 40.40 mmol) in water (5 mL) was added. The mixture was reacted at 85 °C for 7 hours, then the reaction solution was transferred to a sealed tube and reacted at 100 °C for 16 hours. After the reaction solution cooled to room temperature, the pH was adjusted to <4 with dilute hydrochloric acid (2N), and the mixture was extracted with EA (50 mL × 2). The organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous Na2SO4, filtered, concentrated, and the residue was purified by column chromatography (EA:PE = 35%) to give compound INT1-c (849.0 mg), with a yield of 78.1%.

[0126] LC-MS (m / z): 267.0 / 269.0 [MH] - .

[0127] Step 3: Synthesis of 5-(1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazol-3-thiol (INT1-d)

[0128] INT1-c (849.0 mg, 3.15 mmol), 4-methylaminothiourea (497.9 mg, 4.73 mmol), and DIPEA (1.65 mL, 9.46 mmol) were dissolved in DMF (10 mL), and HATU (1.56 g, 4.10 mmol) was added. The mixture was allowed to react at room temperature for 0.5 hours. NaOH aqueous solution (1 N, 6.3 mL) was added to the reaction solution, and the temperature was raised to 50 °C for 16 hours. After the reaction solution cooled to room temperature, it was adjusted to neutral with saturated NH4Cl aqueous solution, extracted with EA (20 mL × 4), and the organic phases were combined. The mixture was washed with saturated brine (20 mL), dried over anhydrous Na2SO4, filtered, concentrated, and the residue was purified by column chromatography (EA:DCM = 10%) to give compound INT1-d (684.0 mg), with a yield of 64.2%.

[0129] LC-MS (m / z): 338.0 / 340.0 [M+H] + .

[0130] Step 4: Synthesis of 3-(1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (INT1)

[0131] INT1-d (684.0 mg, 2.02 mmol) was added to a mixed solvent of DCM (6.8 mL) and AcOH (0.68 mL). H2O2 aqueous solution (30% w / w, 0.55 mL) was added under ice-water bath conditions, and the reaction was allowed to proceed at room temperature for 16 hours. The reaction solution was adjusted to pH > 10 with NaOH aqueous solution (2.5 N), extracted with DCM (20 mL × 2), and the organic phases were combined. The mixture was washed with saturated brine (20 mL), dried over anhydrous Na2SO4, filtered, concentrated, and the residue was purified by column chromatography (MeOH:DCM = 5%) to give intermediate INT1 (397.0 mg), yield 64.1%.

[0132] LC-MS (m / z): 306.0 / 308.0 [M+H] + .

[0133] Step 5: Chiral decomposition of INT1

[0134] INT1 (132.6 g) was chirally resolved (chiral column CHIRALPAK IN (IN00CE-DV002), mobile phase Hexane:EtOAc:DEA = 20:80:0.1), finally yielding 3-((1s,3s)-1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (s,s-INT1, 20.6 g) and 3-((1r,3r)-1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (r,r-INT1, 111.5 g).

[0135] s,s-INT1: 1 H NMR(600MHz,Chloroform-d)δ8.04(s,1H),7.38-7.34(m,2H),7.18(t,J=7.9Hz,1H),7.09(dt,J=7.7,1.4Hz,1H),3.21(s ,3H),3.12(td,J=8.2,2.6Hz,3H),2.57(dp,J=16.9,9.0,7.9Hz,2H),2.26(td,J=9.4,2.5Hz,3H),1.12(d,J=6.6Hz,3H).

[0136] r,r-INT1: 1 H NMR(600MHz,Chloroform-d)δ7.98(s,1H),7.53(s,1H),7.39(d,J=7.4Hz,1H),7.25-7.17( m,2H),3.18(d,J=1.2Hz,3H),2.85-2.76(m,2H),2.69-2.60(m,3H),1.14(d,J=5.6Hz,3H).

[0137] Preparation of common intermediate INT2

[0138] INT1 (153.1 mg, 0.50 mmol), Cu2O (35.8 mg, 0.25 mmol), NH3·H2O (25% w / w, 0.75 mL), and ACN (0.75 mL) were added to a sealed tube and reacted at 110 °C for 3.5 hours. After the reaction solution cooled to room temperature, it was filtered. The filtrate was diluted with DCM (10 mL), washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous Na2SO4, filtered, concentrated, and the residue was purified by column chromatography (MeOH:DCM = 4%) to give intermediate INT2 (92.0 mg), with a yield of 75.9%.

[0139] LC-MS (m / z): 243.0 [M+H] + .

[0140] Preparation of common intermediate INT3

[0141] INT3-a (2.24 g, 16.50 mmol), potassium (bromomethyl)trifluoroborate (3.01 g, 15.00 mmol), K2CO3 (4.15 g, 30.00 mmol), and KI (249.0 mg, 1.50 mmol) were added to ACN (50 mL), and the mixture was reacted at 80 °C for 16 hours. The reaction mixture was filtered while hot, the filter cake was washed with hot ACN, and the filtrate was concentrated to give intermediate INT3 (2.09 g), with a yield of 63.6%.

[0142] Preparation of the common intermediate INT4

[0143] Step 1: Synthesis of methyl 2-(3-bromophenyl)-2-cyclobutylacetate (INT4-b)

[0144] INT4-a: methyl 3-bromophenylacetate (11.71 g, 51.11 mmol) was added to anhydrous DMF (60 mL). The reaction solution was cooled to 0 °C, and NaH (2.45 g, 61.33 mmol) was added in portions. The reaction was allowed to proceed for 0.5 h. Cyclobutyl bromide (6.90 g, 51.11 mmol) was added, and the reaction was allowed to proceed to room temperature for 16 h. The reaction solution was quenched with saturated NH4Cl solution (20 mL) and water (50 mL), extracted with EA (40 mL × 3), and the organic phases were combined. The mixture was washed with water (40 mL × 3) and saturated brine (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give INT4-b (12.94 g), with a yield of 89.4%.

[0145] LC-MS (m / z): 283.0 / 285.0 [M+H] + .

[0146] Step 2: Synthesis of 2-(3-bromophenyl)-2-cyclobutylacetic acid (INT4-c)

[0147] INT4-b (12.94 g, 45.71 mmol) and KOH (3.84 g, 68.56 mmol) were added to a mixed solvent of EtOH (15 mL) and water (15 mL), and the mixture was heated to 90 °C and reacted for 8 hours. After the reaction solution cooled to room temperature, dilute hydrochloric acid (2N) was added to adjust the pH to 1–2, and the mixture was stirred for 10 minutes. The solution was extracted with DCM (40 mL × 3), the organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain crude INT4-c (12.40 g).

[0148] LC-MS (m / z): 267.0 / 269.0 [MH] - .

[0149] Step 3: Synthesis of 5-((3-bromophenyl)(cyclobutyl)methyl)-4-methyl-4H-1,2,4-triazol-3-thiol (INT4-d)

[0150] Crude INT4-c (12.40 mg, 45.71 mmol), 4-methylaminothiourea (7.21 g, 60.57 mmol), HATU (22.59 g, 59.42 mmol), and DIPEA (17.72 g, 137.10 mmol) were added to anhydrous DMF (80 mL) and reacted at room temperature for 2 hours. An aqueous solution of NaOH (3.66 g, 91.42 mmol) (50 mL) was added, and the mixture was heated to 50 °C and reacted for 18 hours. The pH of the reaction mixture was adjusted to approximately 5 with dilute hydrochloric acid (2N), and water (100 mL) was added. The mixture was stirred, filtered, and the filter cake was washed with water (100 mL) and dried to obtain INT4-d (13.00 g). The two-step yield was 84.1%.

[0151] LC-MS (m / z): 336.0 / 338.0 [MH] - .

[0152] Step 4: Synthesis of 3-((3-bromophenyl)(cyclobutyl)methyl)-4-methyl-4H-1,2,4-triazole (INT4-e)

[0153] INT4-d (13.00 mg, 38.43 mmol) was added to a mixed solvent of DCM (80 mL) and acetic acid (8 mL). The reaction solution was cooled to 0 °C, and H2O2 (21.80 g, 30% w / w, 192.13 mmol) was slowly added dropwise. The mixture was then brought to room temperature and reacted for 16 hours. An aqueous solution of Na2S2O3 was added to the reaction solution and stirred for 10 minutes. The pH was adjusted to 8–9 with saturated NaHCO3 solution. The mixture was extracted with DCM (20 mL × 2), and the organic phases were combined. The mixture was washed with water (30 mL × 2) and saturated brine (30 mL), dried over anhydrous Na2SO4, filtered, concentrated, and the residue was purified by column chromatography (MeOH:DCM = 6%) to give INT4-e (6.10 g), with a yield of 51.8%.

[0154] LC-MS (m / z): 306.0 / 308.0 [M+H] + .

[0155] Step 5: Synthesis of 3-(cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)aniline (INT4)

[0156] INT4-e (6.10 g, 19.92 mmol) and Cu2O (572.0 mg, 4.00 mmol) were added to a mixed solvent of ammonia (20 mL) and ACN (20 mL). The reaction solution was placed in a sealed tube under nitrogen protection and reacted at 90 °C for 16 hours. After the reaction solution cooled to room temperature, it was concentrated, and the residue was purified by column chromatography (MeOH:DCM = 9%) to give INT4 (3.00 g), with a yield of 62.1%.

[0157] LC-MS (m / z): 243.0 [M+H] + .

[0158] Preparation of common intermediate INT5

[0159] Step 1: Synthesis of methyl 2-(2,6-dichloropyridin-4-yl)acetate (INT5-b)

[0160] INT5-a: 2,6-dichloro-4-methylpyridine (16.0 g, 98.76 mmol) was dissolved in anhydrous THF (250 mL). LDA (2 M, 98.76 mL, 197.52 mmol) was slowly added dropwise at -78 °C. After 1 hour, a solution of DMC (22.2 g, 246.89 mmol) in anhydrous THF (80 mL) was added dropwise. After the addition was complete, the temperature was slowly raised to 0 °C and the reaction continued for 1 hour. The reaction solution was quenched in NH4Cl solution (500 mL) and extracted with EA (200 mL × 3). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous Na2SO4, filtered, concentrated, and the residue was purified by column chromatography (EA:PE = 30%) to give methyl 2-(2,6-dichloropyridin-4-yl)acetate (15.6 g), yield 71.8%.

[0161] LC-MS (m / z): 220.0 [M+H] + .

[0162] Step 2: Synthesis of methyl 2-(2-chloro-6-cyclopropylpyridin-4-yl)acetate (INT5-c)

[0163] INT5-b (14.6 g, 66.35 mmol), cyclopropylboronic acid (6.7 g, 72.98 mmol), Pd(OAc)2 (1.5 g, 6.63 mmol), P(Cy)3 (3.7 g, 13.27 mmol), and K3PO4 (49.3 g, 232.22 mmol) were dissolved in a mixed solvent of toluene (200 mL) and water (10 mL), and reacted at 100 °C under nitrogen protection for 16 hours. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with DCM (30 mL × 3), the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (EA:PE = 20%) to give INT5-c (10.3 g), with a yield of 69.1%.

[0164] LC-MS (m / z): 226.0 [M+H] + .

[0165] Step 3: Synthesis of methyl 1-(2-chloro-6-cyclopropylpyridin-4-yl)-3-methylcyclobutane-1-carboxylate (INT5-d)

[0166] INT5-c (10.3 g, 45.86 mmol) was dissolved in anhydrous DMF (100 mL). NaH (60% w / w, 4.6 g, 114.66 mmol) was added in portions at 0 °C. After stirring for 1 hour, a solution of 1,3-dibromo-2-methylpropane (10.9 g, 50.45 mmol) in anhydrous DMF (15 mL) was added dropwise. After the addition was complete, the mixture was slowly heated to room temperature and reacted under nitrogen protection for 16 hours. The reaction solution was quenched in water (200 mL), adjusted to neutral with dilute hydrochloric acid (2N), and extracted with EA (100 mL × 3). The combined organic phases were washed with water (200 mL) and saturated brine (200 mL), dried over anhydrous Na₂SO₄, filtered, concentrated, and the residue was purified by column chromatography (EA:PE = 10%) to give INT5-d (6.9 g), with a yield of 55.7%.

[0167] LC-MS (m / z): 280.0 [M+H] + .

[0168] Step 4: Synthesis of 1-(2-chloro-6-cyclopropylpyridin-4-yl)-3-methylcyclobutane-1-carboxylic acid (INT5-e)

[0169] INT5-d (6.9 g, 24.66 mmol) was dissolved in a mixed solvent of THF (120 mL) and MeOH (120 mL), and an aqueous solution of NaOH (2 N, 61.7 mL) was added. The reaction was carried out at room temperature for 1.5 hours. After concentration, the pH of the reaction solution was adjusted to 1-2 with dilute hydrochloric acid (2 N), and extracted with EA (100 mL × 3). The organic phases were combined and washed with water (200 mL) and saturated brine (200 mL). The mixture was dried over anhydrous Na2SO4, filtered, and concentrated to obtain crude INT5-e (6.3 g).

[0170] LC-MS (m / z): 266.0 [M+H] + .

[0171] Step 5: Synthesis of 5-(1-(2-chloro-6-cyclopropylpyridin-4-yl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazol-3-thiol (INT5-f)

[0172] Crude INT5-e and 4-methylaminothiourea were dissolved in DMF (60 mL) at 0 °C. HATU (13.6 g, 35.84 mmol) and DIPEA (9.3 g, 71.69 mmol) were added sequentially, and the mixture was slowly heated to room temperature and reacted for 2 hours. A NaOH aqueous solution (1 N, 47.8 mL, 47.79 mmol) was added dropwise, and the mixture was reacted at 50 °C for 16 hours. The reaction mixture was poured into water (50 mL), and the pH was adjusted to approximately 5 with dilute hydrochloric acid (2 N). Extraction was performed using EA (100 mL × 3). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain crude INT5-f (14.0 g).

[0173] LC-MS (m / z): 335.0 [M+H] + .

[0174] Step 6: Synthesis of 2-chloro-6-cyclopropyl-4-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine (INT5)

[0175] The crude INT5-f was dissolved in a mixed solvent of DCM (50 mL), water (25 mL), and AcOH (5 mL), and H2O2 (30% w / w, 9.5 g, 83.62 mmol) was added. The reaction mixture was reacted at room temperature for 4 hours. The reaction solution was poured into water (50 mL), extracted with DCM (50 mL × 3), and the organic phases were combined and washed with saturated brine (50 mL). The mixture was dried over anhydrous Na2SO4, filtered, concentrated, and the residue was purified by column chromatography (MeOH:DCM:EA = 10:45:45) to give INT5 (1.4 g), with a three-step yield of 14.3%.

[0176] LC-MS (m / z): 303.0 [M+H] + .

[0177] 1 H NMR(600MHz,DMSO-d6)δ8.45-8.32(m,1H),7.32-7.10(m,1H),7.08-6.90(m,1H),3.24-3.19(m,3H),3.06-2 .82(m,2H),2.56-2.50(m,2H),2.37-2.06(m,2H),1.09-1.04(m,3H),0.99-0.94(m,2H),0.90-0.86(m,2H).

[0178] Preparation of the common intermediate INT6

[0179] Step 1: Synthesis of methyl 5-(3-bromophenyl)spiro[2,3]hexane-5-carboxylic acid (INT6-b)

[0180] INT6-a: methyl 2-(3-bromophenyl)acetate (25.0 g, 109.1 mmol) was dissolved in anhydrous DMF (250 mL). NaH (60% w / w, 10.9 g, 272.8 mmol) was added in portions. After stirring for 1 hour, an anhydrous DMF solution of 1,1-bis(bromomethyl)cyclopropane (27.4 g, 120.1 mmol) (50 mL) was slowly added dropwise. After the addition was complete, the mixture was slowly heated to room temperature and reacted under nitrogen protection for 16 hours. The reaction solution was quenched in saturated NH4Cl solution (500 mL), extracted with EA (200 mL × 3), and the organic phases were combined and washed with saturated brine (200 mL). The mixture was dried over anhydrous Na2SO4, filtered, concentrated, and the residue was purified by column chromatography (EA:DCM = 50%) to give INT6-b (15.0 g), with a yield of 46.6%.

[0181] Step 2: Synthesis of 5-(3-bromophenyl)spiro[2.3]hexane-5-carboxylic acid (INT6-c)

[0182] INT6-b (15.0 g, 50.82 mmol) was dissolved in a mixed solvent of MeOH (60 mL) and THF (60 mL), and an aqueous solution of NaOH (4.1 g, 101.63 mmol) (30 mL) was added. The reaction was carried out at room temperature for 16 hours. The pH of the reaction solution was adjusted to 1-2 with dilute hydrochloric acid (2N), concentrated, and the precipitated solid was filtered and dried to obtain crude INT6-c (14.0 g).

[0183] LC-MS (m / z): 279.0 / 281.0 [MH] - .

[0184] Step 3: Synthesis of 5-(5-(3-bromophenyl)spiro[2.3]hexane-5-yl)-4-methyl-4H-1,2,4-triazol-3-thiol (INT6-d)

[0185] INT6-c crude product (14.0 g) and N-methylhydrazine thioamide (6.3 g, 59.75 mmol) were dissolved in DMF (140 mL) at 0 °C. DIPEA (19.3 g, 149.39 mmol) and HATU (28.4 g, 74.69 mmol) were added sequentially. After reacting at room temperature for 2 hours, NaOH aqueous solution (1 N, 149.4 mL, 149.39 mmol) was added dropwise to the reaction solution, and the reaction was continued at 50 °C for 16 hours. The pH of the reaction solution was adjusted to approximately 5 with dilute hydrochloric acid (2 N), the precipitated solid was filtered, and dried to obtain INT6-d crude product (26.0 g).

[0186] LC-MS (m / z): 350.0 / 352.0 [M+H] + .

[0187] Step 4: Synthesis of 3-(5-(3-bromophenyl)spiro[2.3]hexane-5-yl)-4-methyl-4H-1,2,4-triazole (INT6-e)

[0188] Crude INT6-d (26.0 g) was dissolved in a mixed solvent of DCM (100 mL), water (50 mL), and AcOH (10 mL). H2O2 (30% w / w, 16.8 g, 148.45 mmol) was added, and the reaction was carried out at room temperature for 16 hours. The reaction solution was poured into water (200 mL), extracted with DCM (100 mL × 3), and the organic phases were combined and washed with Na2S2O3 (50 mL) and saturated brine (50 mL). The mixture was dried over anhydrous Na2SO4, filtered, concentrated, and the residue was purified by column chromatography (MeOH:DCM:EA = 10:45:45) to give INT6-e (9.6 g), with a three-step yield of 59.4%.

[0189] LC-MS (m / z): 318.0 / 320.0 [M+H] + .

[0190] Step 5: Synthesis of 3-(5-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[2,3]hexane-5-yl)aniline (INT6)

[0191] INT6-e (2.0 g, 6.28 mmol) was dissolved in ACN (7 mL) and concentrated ammonia (7 mL), and Cu2O (179.9 mg, 1.26 mmol) was added. The mixture was then sealed in a tube at 100 °C for 16 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (MeOH:DCM:concentrated ammonia = 9:90:1) to give INT6 (1.8 g), with a yield of 98.2%.

[0192] LC-MS (m / z): 255.0 [M+H] + .

[0193] Example 1: Synthesis of (S)-2-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((3-methylpiperidin-1-yl)methyl)-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (1)

[0194] Step 1: Synthesis of ethyl 7-bromo-3-formyl-1H-indole-2-carboxylate (1-2)

[0195] POCl3 (628.5 mg, 4.10 mmol) was added dropwise to anhydrous DMF at 0 °C. After reacting at this temperature for 1 hour, an anhydrous DMF solution of ethyl 7-bromo-1H-indole-2-carboxylic acid (1.00 g, 3.73 mmol) was added, and the reaction was carried out at 60 °C for 4.5 hours. The reaction solution was slowly poured into ice water (20 mL) and stirred. The pH was adjusted to 8-9 by adding saturated NaHCO3 solution. The mixture was extracted with EA (20 mL × 3), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous Na2SO4, filtered, concentrated, and the residue was purified by column chromatography (EA:PE = 16%) to give compounds 1-2 (653.0 mg), with a yield of 59.1%.

[0196] LC-MS (m / z): 296.0 / 298.0 [M+H] + .

[0197] Step 2: Synthesis of 7-bromo-3-formyl-1H-indole-2-carboxylic acid (1-3)

[0198] Compounds 1-2 (200.0 mg, 0.67 mmol) and KOH (41.7 mg, 0.74 mmol) were added to a mixed solvent of EtOH (3 mL) and water (1 mL), and the mixture was heated to 70 °C and reacted for 1 hour. After the reaction mixture cooled to room temperature, dilute hydrochloric acid (2 M) was added to adjust the pH to 1–2, and the mixture was stirred for 10 minutes. The reaction mixture was filtered, the filter cake was washed with water (10 mL), and dried to give compound 1-3 (179.0 mg), with a yield of 99.0%.

[0199] LC-MS (m / z): 266.0 / 268.0 [MH] - .

[0200] Step 3: Synthesis of 7-bromo-3-(((3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)amino)methyl)-1H-indole-2-carboxylic acid (1-4)

[0201] Compounds 1-3 (110.0 mg, 0.41 mmol), INT2 (99.4 mg, 0.41 mmol), and TPFPB (2.0 mg, 4.0 μmol) were added to anhydrous EtOH (4 mL). The reaction mixture was reacted at room temperature for 1 hour under nitrogen protection. The reaction mixture was then cooled to 0 °C, and NaBH4 (31.0 mg, 0.82 mmol) was added. The mixture was then heated to room temperature for 1 hour. The pH of the reaction mixture was adjusted to 6–7 with dilute hydrochloric acid (2 M), concentrated under reduced pressure, and water (10 mL) was added. The mixture was stirred, filtered, and the filter cake was washed with water (10 mL) and dried to give compound 1-4 (108.0 mg), with a yield of 53.3%.

[0202] LC-MS (m / z): 492.0 / 494.0 [MH] - .

[0203] Step 4: Synthesis of 5-bromo-2-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (1-5)

[0204] Compounds 1-4 (108.0 mg, 0.22 mmol), HATU (124.6 mg, 0.33 mmol), and DIPEA (56.5 mg, 0.44 mol) were added to anhydrous DMF (2 mL) and reacted at 80 °C for 1 hour. After the reaction mixture cooled to room temperature, it was diluted with water (15 mL), extracted with EA (20 mL × 2), and the organic phases were combined. The mixture was washed with water (10 mL × 3) and saturated brine (20 mL), dried over anhydrous Na₂SO₄, filtered, concentrated, and the residue was purified by column chromatography (MeOH:DCM = 10%) to give compounds 1-5 (87.0 mg), with a yield of 83.6%.

[0205] LC-MS (m / z): 476.0 / 478.0 [M+H] + .

[0206] Step 5: Synthesis of (S)-2-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((3-methylpiperidin-1-yl)methyl)-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (1)

[0207] Compounds 1-5 (87.0 mg, 0.18 mmol), INT3 (80.0 mg, 0.36 mmol), Pd(OAc)2 (4.1 mg, 0.02 mmol), XPhos (17.4 mg, 0.04 mmol), and Cs2CO3 (119.0 mg, 0.36 mmol) were added to a mixed solvent of dioxane (4 mL) and water (0.4 mL). The reaction solution was placed at 90 °C for 16 hours under nitrogen protection. After the reaction solution cooled to room temperature, it was diluted with water (5 mL), extracted with EA (10 mL × 2), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (MeOH:DCM = 11%) to give compound 1 (25.5 mg), yield 27.4%.

[0208] LC-MS (m / z): 509.0 [M+H] + .

[0209] 1 H NMR(600MHz,DMSO-d6)δ11.67(s,1H),8.51-8.18(m,1H),7.99-7.57(m,3H ),7.48-7.33(m,1H),7.28-6.80(m,3H),5.04(s,2H),3.86-3.66(m,1H),3. 30-3.07(m,4H),2.96-2.75(m,3H),2.65-2.52(m,3H),2.43-2.19(m,1H),1 .99-1.81(m,1H),1.72-1.38(m,5H),1.16-1.04(m,3H),0.94-0.71(m,4H).

[0210] Example 2: Synthesis of (S)-8-fluoro-2-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((3-methylpiperidin-1-yl)methyl)-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (2)

[0211] Step 1: Synthesis of ethyl 7-bromo-4-fluoro-1H-indole-2-carboxylate (2-2)

[0212] 2-1:(2-bromo-5-fluorophenyl)hydrazine hydrochloride (5.00 g, 20.70 mmol) was dissolved in EtOH (20 mL) at 0 °C. A solution of ethyl 2-oxopropionate (2.50 g, 21.74 mmol) in EtOH (5 mL) was added, and the mixture was slowly heated to room temperature for 16 hours. Then, Eaton's reagent (6.30 g, 20.72 mmol) was added to the reaction solution, and the reaction was carried out at 50 °C for 4 hours. The reaction solution was quenched by slowly adding Na₂CO₃ solution (200 mL), and the pH was adjusted to approximately 8 with NaOH solution. Extraction was performed using EA (100 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous Na₂SO₄, filtered, concentrated, and the residue was purified by column chromatography (EA:PE = 30%) to give 2-2 (450.0 mg), with a yield of 7.6%.

[0213] LC-MS (m / z): 284.0 / 286.0 [MH] - .

[0214] Step 2: Synthesis of ethyl 7-bromo-4-fluoro-3-formyl-1H-indole-2-carboxylate (2-3)

[0215] POCl3 (964.6 mg, 6.29 mmol) was added dropwise to anhydrous DMF (0.5 mL, 6.29 mmol) at 0 °C. After the addition was complete, the reaction was continued for 1 hour. Then, 2-2 (450.0 mg, 1.57 mmol) of anhydrous DMF (5 mL) solution was added, and the reaction was raised to 90 °C and reacted for 16 hours. The reaction solution was slowly poured into water (50 mL) to quench the reaction, and saturated NaHCO3 solution was added to adjust the pH to 7-8. The solution was extracted with EA (50 mL × 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous Na2SO4, filtered, concentrated, and the residue was purified by column chromatography (EA:PE = 20%) to give 2-3 (175.0 mg), with a yield of 35.4%.

[0216] LC-MS (m / z): 314.0 / 316.0 [M+H] + .

[0217] Step 3: Synthesis of 7-bromo-4-fluoro-3-formyl-1H-indole-2-carboxylic acid (2-4)

[0218] Dissolve 2-3 (175.0 mg, 0.56 mmol) in EtOH (2 mL), add KOH (34.4 mg, 0.61 mmol) in water (0.5 mL), and react at 70 °C for 1 hour. Cool the reaction solution to room temperature, add dilute hydrochloric acid (2N) to adjust the pH to 1-2, filter, wash the filter cake with water (10 mL), and dry to obtain crude 2-4 (210.0 mg).

[0219] LC-MS (m / z): 284.0 / 286.0 [MH] - .

[0220] Step 4: Synthesis of 7-bromo-4-fluoro-3-(((3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)amino)methyl)-1H-indole-2-carboxylic acid (2-5)

[0221] Crude product 2-4 (210.0 mg), INT2 (177.9 mg, 0.73 mmol), and TFPPB (3.8 mg, 0.01 mmol) were added to anhydrous EtOH (5 mL). After reacting for 1 hour under nitrogen protection at room temperature, NaBH4 (55.6 mg, 1.47 mmol) was added in portions at 0 °C, and the reaction was continued at room temperature for 15 minutes. The pH of the reaction solution was adjusted to about 5 with dilute hydrochloric acid (2N), and extracted with DCM (50 mL × 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain crude product 2-5 (320.0 mg).

[0222] LC-MS (m / z): 510.0 / 512.0 [MH] - .

[0223] Step 5: Synthesis of 5-bromo-8-fluoro-2-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (2-6)

[0224] Crude product 2-5 (320.0 mg), HATU (356.2 mg, 0.94 mmol), and DIPEA (161.4 mg, 1.25 mmol) were added to anhydrous DMF (5 mL). The reaction solution was placed at 80 °C for 2 hours under nitrogen protection. After the reaction solution cooled to room temperature, it was diluted with water (50 mL), extracted with DCM (30 mL × 2), and the organic phases were combined. The mixture was washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous Na₂SO₄, filtered, concentrated, and the residue was purified by column chromatography (MeOH:DCM = 10%) to give 2-6 (183.0 mg), with a three-step yield of 66.4%.

[0225] LC-MS (m / z): 494.0 / 496.0 [M+H] + .

[0226] Step 6: Synthesis of (S)-8-fluoro-2-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((3-methylpiperidin-1-yl)methyl)-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (2)

[0227] 2-6 (183.0 mg, 0.37 mmol), INT3 (162.2 mg, 0.74 mmol), Pd(OAc)2 (8.3 mg, 0.04 mmol), XPhos (35.3 mg, 0.07 mmol), and Cs2CO3 (241.2 mg, 0.74 mmol) were added to a mixed solvent of dioxane (4 mL) and water (1 mL), and reacted at 90 °C under nitrogen protection for 16 hours. The reaction solution was filtered, concentrated, and the residue was purified by column chromatography (MeOH:DCM = 10%) to give 2 (22.4 mg), with a yield of 11.5%.

[0228] LC-MS (m / z): 527.0 [M+H] + .

[0229] 1H NMR(600MHz,DMSO-d6)δ12.06(s,1H),8.39-8.27(m,1H),7.92-7.72(m,2H),7.44-7.34(m,1H),7.21 -7.15(m,1H),7.07-6.86(m,2H),5.17-5.09(m,2H),3.79-3.70(m,2H),3.27-3.23(m,3H),3.16-3.1 0(m,1H),2.90-2.87(m,1H),2.86-2.79(m,2H),2.59-2.54(m,2H),2.42-2.24(m,1H),1.97-1.86(m, 1H),1.68-1.54(m,4H),1.51-1.40(m,1H),1.14-1.08(m,3H),0.92-0.83(m,1H),0.82-0.78(m,3H).

[0230] Example 25: Synthesis of 2-(3-(cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-5-(((S)-3-methylpiperidin-1-yl)methyl)-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (25)

[0231] Step 1: Synthesis of 7-bromo-3-(((3-(cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)amino)methyl)-1H-indole-2-carboxylic acid (25-1)

[0232] Add 1-3 (250.0 mg, 0.93 mmol), INT4 (255.9 mg, 0.93 mmol), and TPFPB (4.8 mg, 9.30 μmol) to EtOH (4 mL). After reacting for 1 hour at room temperature under nitrogen protection, add NaBH4 (70.0 mg, 1.87 mmol) in portions at 0 °C, and then raise the temperature to room temperature and react for another hour. Adjust the pH of the reaction solution to approximately 5 with dilute hydrochloric acid (2N), extract with DCM (10 mL × 2), combine the organic phases, wash with water (10 mL × 2) and saturated brine (20 mL), dry with anhydrous Na2SO4, filter, concentrate, and obtain crude product 25-1 (416.0 mg).

[0233] LC-MS (m / z): 492.0 / 494.0 [MH] - .

[0234] Step 2: Synthesis of 5-bromo-2-(3-(cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (25-2)

[0235] Crude 25-1 (416.0 mg), HATU (480.0 mg, 1.26 mmol), and DIPEA (217.6 mg, 1.68 mol) were added to anhydrous DMF (10 mL) and reacted at 80 °C for 1 hour. The reaction solution was diluted with water (20 mL), extracted with EA (30 mL × 2), and the organic phases were combined and washed with water (20 mL × 3) and saturated brine (20 mL). The mixture was dried over anhydrous Na₂SO₄, filtered, concentrated, and the residue was purified by column chromatography (MeOH:DCM = 10%) to give 25-2 (149.0 mg), with a two-step yield of 33.5%.

[0236] LC-MS (m / z): 476.0 / 478.0 [M+H] + .

[0237] Step 3: Synthesis of 2-(3-(cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-5-(((S)-3-methylpiperidin-1-yl)methyl)-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (25)

[0238] 25-2 (149.0 mg, 0.31 mmol), INT3 (137.1 mg, 0.63 mmol), Pd(OAc)2 (7.0 mg, 0.03 mmol), XPhos (29.8 mg, 0.06 mmol), and Cs2CO3 (203.8 mg, 0.63 mmol) were added to a mixed solvent of dioxane (4 mL) and water (0.4 mL), and reacted at 90 °C under nitrogen protection for 16 hours. The reaction solution was diluted with water (5 mL), extracted with EA (10 mL × 2), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (MeOH:DCM = 8%) to obtain 25-2 (45.3 mg), yield 28.5%.

[0239] LC-MS (m / z): 509.0 [M+H] + .

[0240] 1H NMR (600MHz, DMSO-d6) δ11.72(s,1H),8.33(s,1H),7.82-7.78(m,1H),7.76(s,1H),7.64(d,J=7.8Hz,1H),7.34 (t,J=7.8Hz,1H),7.23(d,J=7.2Hz,1H),7.13(t,J=7.8Hz,1H),6.96(d,J=7.2Hz,1H),4.99(d,J=7.8Hz,2H),4.2 0(d,J=10.8Hz,1H),3.79(s,2H),3.38-3.31(m,2H),3.25-3.18(m,2H),2.90-2.82(m,2H),2.14-2.06(m,1H),1. 99-1.92(m,1H),1.88-1.77(m,4H),1.75-1.63(m,3H),1.62-1.56(m,2H),1.51-1.42(m,1H),0.90-0.78(m,4H).

[0241] Example 26: Synthesis of (S)-3-(6-cyclopropyl-4-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-6-((3-methylpiperidin-1-yl)methyl)-3,5-dihydro-4H-pyrimidino[5,4-b]indol-4-one (26)

[0242] Step 1: Synthesis of ethyl 3-amino-7-bromo-1H-indole-2-carboxylate (26-2)

[0243] 26-1: 3-bromo-2-fluorobenzonitrile (5.00 g, 25.00 mmol), glycine ethyl ester hydrochloride (3.49 g, 25.00 mmol), and K₂CO₃ (8.64 g, 62.50 mmol) were added to DMSO (40 mL), and the mixture was reacted at 100 °C for 16 hours. The reaction solution was diluted with water (50 mL), extracted with EA (40 mL × 3), and the organic phases were combined and washed with water (40 mL × 3) and saturated brine (30 mL). The mixture was dried over anhydrous Na₂SO₄, filtered, concentrated, and the residue was purified by column chromatography (EA:PE = 25%) to give 26-2 (980.0 mg), with a yield of 13.9%.

[0244] LC-MS (m / z): 283.0 / 285.0 [M+H] + .

[0245] Step 2: Synthesis of ethyl 7-bromo-3-(((dimethylamino)methylene)amino)-1H-indole-2-carboxylate (26-3)

[0246] 26-2 (980 mg, 3.46 mmol) and DMF-DMA (4.13 g, 34.62 mmol) were added to DMF (4 mL), and the mixture was heated to 60 °C and reacted for 16 hours. The reaction solution was concentrated to obtain crude 26-3 (1.30 g).

[0247] LC-MS (m / z): 338.0 / 340.0 [M+H] + .

[0248] Step 3: Synthesis of 6-bromo-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one (26-4)

[0249] 1.30 g of crude 26-3 was added to a mixed solvent of concentrated ammonia (10 mL) and EtOH (10 mL), and the mixture was heated to 70 °C and reacted for 6 hours. The reaction solution was then added to water (20 mL), filtered, the filter cake was washed with water (10 mL), and dried to obtain crude 26-4 (940.0 mg).

[0250] LC-MS (m / z): 264.0 / 266.0 [M+H] + .

[0251] Step 4: Synthesis of (S)-6-((3-methylpiperidin-1-yl)methyl)-3,5-dihydro-4H-pyrimidino[5,4-b]indol-4-one (26-5)

[0252] 26-4 (940.0 mg, 3.46 mmol), INT3 (1.52 g, 6.92 mmol), Pd(OAc)2 (77.7 mg, 0.35 mmol), XPhos (330.0 mg, 0.69 mmol), and Cs2CO3 (3.38 g, 10.38 mmol) were added to a mixed solvent of dioxane (15 mL) and water (1.5 mL). The reaction mixture was sealed in a tube at 120 °C under nitrogen protection for 16 hours. After the reaction solution was cooled to room temperature, it was diluted with water (20 mL), extracted with EA (20 mL × 3), and the organic phases were combined and washed with water (20 mL × 2) and saturated brine (20 mL). The mixture was dried over anhydrous Na2SO4, filtered, concentrated, and the residue was purified by column chromatography (MeOH:DCM:concentrated ammonia = 11:88:1) to give 26-5 (480.0 mg), with a three-step yield of 46.8%.

[0253] LC-MS (m / z): 297.0 [M+H] + .

[0254] Step 5: Synthesis of (S)-3-(6-cyclopropyl-4-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-6-((3-methylpiperidin-1-yl)methyl)-3,5-dihydro-4H-pyrimidino[5,4-b]indol-4-one (26)

[0255] 26-5 (200.0 mg, 0.68 mmol), INT5 (204.3 mg, 0.68 mmol), CuI (64.3 mg, 0.34 mmol), (1R,2R)-DMCHDA (96.0 mg, 0.68 mmol), and K2CO3 (186.6 mg, 1.35 mmol) were added to anhydrous dioxane (5 mL), and the mixture was sealed and reacted at 120 °C for 20 hours under nitrogen protection. The reaction solution was diluted with water (10 mL), extracted with EA (10 mL × 2), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous Na2SO4, filtered, concentrated, and the residue was purified by column chromatography (MeOH:DCM:concentrated ammonia = 9:90:1) to give 26-5 (82.1 mg), yield 21.6%.

[0256] LC-MS (m / z): 563.0 [M+H] + .

[0257] 1 H NMR(600MHz,DMSO-d6)δ11.91(s,1H),8.47-8.34(m,2H),7.94(d,J=7.8Hz,1H),7.5 3-7.36(m,3H),7.31-7.22(m,1H),3.82(s,2H),3.30(s,3H),2.99-2.77(m,4H),2.6 5-2.56(m,2H),2.42-2.30(m,1H),2.27-2.20(m,1H),1.94-1.87(m,1H),1.68-1.53 (m,4H),1.50-1.38(m,1H),1.14-1.06(m,3H),1.02-0.97(m,4H),0.90-0.77(m,4H).

[0258] Example 27: Synthesis of (S)-2-(6-cyclopropyl-4-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-5-((3-methylpiperidin-1-yl)methyl)-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (27)

[0259] Step 1: Synthesis of ethyl 7-bromo-3-(((4-methoxybenzyl)amino)methyl)-1H-indole-2-carboxylate (27-1)

[0260] Dissolve 1-2 (500.0 mg, 1.69 mmol) in a mixed solvent of DCM (2 mL) and MeOH (2 mL), add PMBNH2 (347.5 mg, 2.50 mmol), stir at room temperature for 1 hour, then add NaBH3CN (318.3 mg, 5.10 mmol), and react at room temperature for 0.5 hours. Concentrate the reaction solution, and purify the residue by column chromatography (EA:PE = 60%) to give 27-1 (450.0 mg), yield 63.9%.

[0261] LC-MS (m / z): 417.0 / 419.0 [M+H] + .

[0262] Step 2: Synthesis of 7-bromo-3-(((4-methoxybenzyl)amino)methyl)-1H-indole-2-carboxylic acid (27-2)

[0263] Dissolve 27-1 (450.0 mg, 1.08 mmol) in a mixed solvent of THF (2 mL) and MeOH (2 mL), add 1 mL of NaOH (107.8 mg, 2.70 mmol) aqueous solution, and react at room temperature for 2 hours. Concentrate the reaction solution, dilute with water (10 mL), adjust the pH to about 3 with dilute hydrochloric acid (2N), filter and dry the precipitated solid to obtain crude 27-2 (370.0 mg).

[0264] LC-MS (m / z): 389.0 / 391.0 [M+H] + .

[0265] Step 3: Synthesis of 5-bromo-2-(4-methoxybenzyl)-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (27-3)

[0266] 27-2 (350.0 mg) was dissolved in ACN (20 mL), and HATU (1.5 g, 4.1 mmol) was added. The mixture was reacted at 80 °C for 16 hours. The reaction solution was cooled to 0 °C and water (20 mL) was added. After stirring for 0.5 hours, a solid precipitated out. The solid was filtered and dried to obtain crude 27-3 (207.0 mg).

[0267] LC-MS (m / z): 371.0 / 373.0 [M+H] + .

[0268] Step 4: Synthesis of 5-bromo-2-(4-methoxybenzyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (27-4)

[0269] 27-3 (207.0 mg) and SEMCl (139.4 mg, 0.84 mmol) were dissolved in anhydrous DMF (3 mL). NaH (60% w / w, 26.8 mg, 1.12 mmol) was added at 0 °C, and the reaction was carried out at room temperature for 3 hours under nitrogen protection. The reaction solution was quenched in NH4Cl solution (10 mL), extracted with EA (30 mL × 3), the organic phases were combined and washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered, concentrated, and the residue was purified by column chromatography (EA:PE = 20%) to give 27-4 (250.0 mg), with a three-step yield of 46.2%.

[0270] LC-MS (m / z): 501.0 / 503.0 [M+H] + .

[0271] Step 5: Synthesis of (S)-2-(4-methoxybenzyl)-5-((3-methylpiperidin-1-yl)methyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (27-5)

[0272] 27-4 (250.0 mg, 0.50 mmol), INT3 (218.5 mg, 1.00 mmol), Pd(OAc)2 (11.2 mg, 0.005 mmol), XPhos (47.5 mg, 0.10 mmol), and Cs2CO3 (324.9 mg, 1.00 mmol) were dissolved in a mixed solvent of dioxane (4 mL) and water (1 mL), and reacted at 90 °C under nitrogen protection for 16 hours. The reaction solution was filtered, concentrated, and the residue was purified by column chromatography (EA:PE = 40%) to give 27-5 (150.0 mg), with a yield of 56.4%.

[0273] LC-MS (m / z): 534.0 [M+H] + .

[0274] Step 6: Synthesis of (S)-5-((3-methylpiperidin-1-yl)methyl)-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (27-6)

[0275] 27-5 (110.0 mg, 0.21 mmol) and Tf₂O (69.8 mg, 0.25 mmol) were dissolved in TFA (2 mL) and reacted at 80 °C for 2 hours. The reaction solution was concentrated, and the residue was dissolved in methanol (5 mL) and water (10 mL). The pH was adjusted to approximately 7 with a saturated NaHCO₃ solution, concentrated, and the precipitated solid was filtered, washed with water, and dried to obtain crude 27-6 (90.0 mg).

[0276] LC-MS (m / z): 284.0 [M+H] + .

[0277] Step 7: Synthesis of (S)-2-(6-cyclopropyl-4-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-5-((3-methylpiperidin-1-yl)methyl)-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (27)

[0278] 27-6 (45.0 mg), INT5 (57.7 mg, 0.20 mmol), Ruphos-Pd-G3 (26.6 mg, 0.03 mmol), Ruphos (29.6 mg, 0.06 mmol), and Cs₂CO₃ (155.2 mg, 0.50 mmol) were dissolved in anhydrous dioxane (2 mL) and reacted at 100 °C under nitrogen protection for 16 hours. The reaction solution was filtered through diatomaceous earth, concentrated, and the residue was purified by column chromatography (DCM:MeOH:concentrated ammonia = 90:9:1) to give 27-6 (6.8 mg), with a two-step yield of 6.0%.

[0279] LC-MS (m / z): 550.0 [M+H] + .

[0280] 1H NMR (600MHz, DMSO-d6) δ11.63(s,1H),8.45-8.32(m,1H),8.21-8.02(m,1H),7.69(d,J=7.8Hz,1H),7.22(d,J=7. 2Hz,1H),7.12(t,J=7.8Hz,1H),7.06-6.85(m,1H),5.06-5.00(m,2H),3.76-3.70(m,2H),3.29-3.25(m,3H),2.8 7-2.80(m,3H),2.63-2.54(m,3H),2.35-2.23(m,1H),2.13-2.05(m,1H),1.94-1.85(m,1H),1.67-1.54(m,4H),1 .49-1.42(m,1H),1.13-1.08(m,3H),1.06-1.02(m,2H),0.98-0.93(m,2H),0.89-0.83(m,1H),0.81-0.78(m,3H).

[0281] Example 28: Synthesis of (S)-2-(3-(5-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[2.3]hexane-5-yl)phenyl)-5-((3-methylpiperidin-1-yl)methyl)-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (28)

[0282] Step 1: Synthesis of ethyl 7-bromo-3-(((3-(5-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[2.3]hexyl-5-yl)phenyl)amino)methyl)-1H-indole-2-carboxylate (28-1)

[0283] Dissolve 1-2 (500.0 mg, 1.69 mmol) and INT6 (429.5 mg, 1.69 mmol) in MeOH (5 mL), add 1 drop of AcOH, stir for 1 hour, then add NaBH3CN (212.2 mg, 3.38 mmol), and continue stirring for 2 hours. Pour the reaction solution into water (30 mL), adjust the pH to 7-8 with NaHCO3 solution, extract with EA (20 mL × 3), wash with saturated brine (10 mL), dry with anhydrous Na2SO4, filter, concentrate, and purify the residue by column chromatography (MeOH:DCM = 10%) to obtain 28-1 (490.0 mg), yield 54.3%.

[0284] LC-MS (m / z): 534.0 / 536.0 [M+H] + .

[0285] Step 2: Synthesis of 7-bromo-3-(((3-(5-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[2.3]hexane-5-yl)phenyl)amino)methyl)-1H-indole-2-carboxylic acid (28-2)

[0286] Dissolve 28-1 (490.0 mg, 0.92 mmol) in a mixed solvent of MeOH (2 mL) and THF (2 mL), add 1 mL of an aqueous solution of NaOH (73.3 mg, 1.83 mmol), and react at room temperature for 2 hours. Pour the reaction solution into water (20 mL), adjust the pH to 3-4 with dilute hydrochloric acid (2N), extract with EA (20 mL × 3), combine the organic phases, wash with saturated brine (10 mL), dry with anhydrous Na2SO4, filter, concentrate, and obtain crude 28-2 (400.0 mg).

[0287] LC-MS (m / z): 506.0 / 508.0 [M+H] + .

[0288] Step 3: Synthesis of 5-bromo-2-(3-(5-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[2.3]hexyl-5-yl)phenyl)-1,4-dihydropyrrolo[3,4-b]indol-3(2H)-one (28-3)

[0289] 28-2 (400.0 mg) was dissolved in DMF (6 mL), and DIPEA (204.2 mg, 1.58 mmol) and HATU (450.0 mg, 1.18 mmol) were added. The mixture was reacted at 80 °C for 1 hour. The reaction solution was poured into water (80 mL), extracted with EA (30 mL × 3), and the organic phases were combined and washed with water (10 mL) and saturated brine (10 mL). The mixture was dried over anhydrous Na2SO4, filtered, concentrated, and the residue was purified by column chromatography (MeOH:DCM:concentrated ammonia = 9:90:1) to give 28-3 (250.0 mg), with a two-step yield of 52.9%.

[0290] LC-MS (m / z): 488.0 / 490.0 [M+H] + .

[0291] Step 4: Synthesis of (S)-2-(3-(5-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[2.3]hex-5-yl)phenyl)-5-((3-methylpiperidin-1-yl)methyl)-1,4-dihydropyrrolo[3,4-b]indol-3(2H)-one (28)

[0292] 28-3 (250.0 mg, 0.51 mmol) was dissolved in a mixed solvent of dioxane (4.2 mL) and water (0.8 mL). INT3 (224.3 mg, 1.02 mmol), Pd(OAc)2 (11.5 mg, 0.05 mmol), Xphos (48.8 mg, 0.10 mmol), and Cs2CO3 (333.6 mg, 1.02 mmol) were added, and the reaction was carried out at 90 °C for 16 hours under nitrogen protection. The reaction solution was concentrated, and the residue was purified by column chromatography (MeOH:DCM:concentrated ammonia = 9:90:1) to give 28-3 (177.2 mg), with a yield of 66.5%.

[0293] LC-MS (m / z): 521.0 [M+H] + .

[0294] 1 H NMR (600MHz, DMSO-d6) δ11.70(s,1H),8.40(s,1H),7.99(s,1H),7.72(d,J=8.4Hz,1H),7.63(d,J=7.8Hz, 1H),7.41(t,J=7.8Hz,1H),7.21(d,J=7.2Hz,1H),7.12(t,J=7.2Hz,1H),6.93(d,J=7.8Hz,1H),5.03(s,2 H),3.72(s,2H),3.26(s,3H),3.20(d,J=12.0Hz,2H),2.90-2.79(m,2H),2.75(d,J=12.0Hz,2H),1.94-1. 85(m,1H),1.69-1.54(m,4H),1.51-1.40(m,1H),0.90-0.77(m,4H),0.64-0.59(m,2H),0.52-0.46(m,2H).

[0295] Example 29: Synthesis of 5-((3,3-dimethylpyrrolo-1-yl)methyl)-2-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (29)

[0296] Step 1: Synthesis of 5-(hydroxymethyl)-2-(4-methoxybenzyl)-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (29-1)

[0297] 27-3 (2.0 g, 5.39 mmol), (tributyltin)methanol (3.46 g, 10.77 mmol), and Pd(PPh3)4 (622.5 mg, 0.54 mmol) were dissolved in anhydrous dioxane (30 mL) and reacted at 110 °C under nitrogen protection for 16 hours. The reaction solution was quenched with saturated KF solution (150 mL), extracted with EA (50 mL × 3), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous Na2SO4, filtered, concentrated, and the residue was purified by column chromatography (MeOH:DCM = 10%) to give 29-1 (774.0 mg), yield 44.6%.

[0298] LC-MS (m / z): 323.0 [M+H] + .

[0299] Step 2: Synthesis of 2-(4-methoxybenzyl)-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indole-5-carboxaldehyde (29-2)

[0300] 29-1 (724.0 mg, 2.25 mmol) was dissolved in DCM (15 mL), and methyl phthalate (1.43 g, 3.37 mmol) was added. The mixture was reacted at room temperature for 1 hour. The reaction solution was poured into a saturated NaHCO3 / Na2S2O3 solution (15 / 15 mL), extracted with DCM (30 mL × 3), and the organic phases were combined and washed with saturated brine (20 mL). The mixture was dried over anhydrous Na2SO4, filtered, concentrated, and the residue was purified by column chromatography (MeOH:DCM = 5%) to give 29-2 (705.0 mg), with a yield of 91.5%.

[0301] LC-MS (m / z): 321.0 [M+H] + .

[0302] 1 H NMR (400MHz, DMSO-d6) δ12.28(s,1H),10.33(s,1H),8.03(d,J=7.6Hz,1H),7.87(d,J=7.2Hz,1H),7.33 (t,J=7.6Hz,1H),7.25(d,J=8.4Hz,2H),6.92(d,J=8.4Hz,2H),4.67(s,2H),4.39(s,2H),3.73(s,3H).

[0303] Step 3: Synthesis of 5-((3,3-dimethylpyrrolo-1-yl)methyl)-2-(4-methoxybenzyl)-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (29-3)

[0304] 29-2 (100.0 mg, 0.31 mmol) and 3,3-dimethylpyrrolidine hydrochloride (63.5 mg, 0.47 mmol) were dissolved in a mixed solvent of MeOH (2.5 mL) and DCM (2.5 mL). One drop of AcOH was added dropwise, and the mixture was stirred for 1 hour. Then, NaBH3CN (58.9 mg, 0.94 mmol) was added, and the reaction was continued at room temperature for 16 hours. The pH of the reaction solution was adjusted to 7–8 with saturated NaHCO3 solution. The mixture was extracted with DCM (30 mL × 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous Na2SO4, filtered, concentrated, and the residue was purified by column chromatography (MeOH:DCM:concentrated ammonia = 9:90:1) to give 29-3 (110.0 mg), with a yield of 43.7%.

[0305] LC-MS (m / z): 404.0 [M+H] + .

[0306] Step 4: Synthesis of 5-((3,3-dimethylpyrrolo-1-yl)methyl)-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (29-4)

[0307] 29-3 (110.0 mg, 0.27 mmol) was dissolved in TFA (1.0 mL), and Tf2O (92.3 mg, 0.33 mmol) was added. The reaction mixture was reacted at 80 °C for 1 hour. The reaction solution was concentrated, and the residue was dissolved in MeOH (5 mL). The pH was adjusted to 7–8 with saturated NaHCO3 solution, and the mixture was extracted with DCM (30 mL × 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous Na2SO4, filtered, concentrated, and the residue was purified by column chromatography (MeOH:DCM = 10%) to give 29-4 (60.0 mg), with a yield of 77.7%.

[0308] LC-MS (m / z): 284.0 [M+H] + .

[0309] Step 5: Synthesis of 5-((3,3-dimethylpyrrolo-1-yl)methyl)-2-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (29)

[0310] 29-4 (60.0 mg, 0.21 mmol), INT1 (84.3 mg, 0.28 mmol), Pd2(dba)3 (19.4 mg, 0.02 mmol), Xphos (12.3 mg, 0.02 mmol), and Cs2CO3 (172.5 mg, 0.53 mmol) were dissolved in anhydrous dioxane (5 mL) and reacted at 100 °C under nitrogen protection for 16 hours. The reaction solution was filtered through diatomaceous earth, washed with 10% MeOH in DCM solution (10 mL × 3), the filtrate was concentrated, and the residue was prepared by reverse-phase reaction (ACN: 0.1% formic acid solution = 95%) to give 29 (27.8 mg), yield 25.8%.

[0311] LC-MS (m / z): 509.0 [M+H] + .

[0312] 1 H NMR (400MHz, DMSO-d6) δ12.03-11.84(m,1H),8.39-8.30(m,1H),7.87-7. 69(m,3H),7.44-7.33(m,2H),7.22-7.14(m,1H),7.10-7.05(m,1H),5.11- 5.01(m,2H),4.28-4.08(m,2H),3.28-3.23(m,3H),3.02-2.82(m,4H),2. 69-2.54(m,4H),2.37-2.26(m,1H),1.69-1.59(m,2H),1.14-1.01(m,9H).

[0313] Example 30: Synthesis of (R)-2-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((2-methylmorpholine)methyl)-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (30)

[0314] Step 1: Synthesis of (R)-2-(4-methoxybenzyl)-5-((2-methylmorpholino)methyl)-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (30-1)

[0315] 29-2 (200.0 mg, 0.62 mmol) and (R)-2-methylmorpholine hydrochloride (128.9 mg, 0.94 mmol) were dissolved in a mixed solvent of MeOH (2.5 mL) and DCM (2.5 mL). One drop of AcOH was added dropwise, and the mixture was stirred for 1 hour. Then, NaBH3CN (117.7 mg, 1.87 mmol) was added, and the reaction was continued at room temperature for 16 hours. The pH of the reaction solution was adjusted to 7-8 with NaHCO3 solution, and the mixture was extracted with DCM (30 mL × 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous Na2SO4, filtered, concentrated, and the residue was purified by column chromatography (MeOH:DCM = 5%) to give 30-1 (123.0 mg), with a yield of 48.6%.

[0316] LC-MS (m / z): 406.0 [M+H] + .

[0317] Step 2: Synthesis of (R)-5-((2-methylmorpholine)methyl)-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (30-2)

[0318] 30-1 (123.0 mg, 0.30 mmol) was dissolved in TFA (1.0 mL), and Tf2O (102.7 mg, 0.36 mmol) was added. The mixture was reacted at 80 °C for 1 hour. The reaction solution was concentrated, and the residue was dissolved in MeOH (5 mL). The pH was adjusted to 7–8 with NaHCO3 solution, and the mixture was extracted with DCM (30 mL × 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous Na2SO4, filtered, concentrated, and the residue was purified by column chromatography (MeOH:DCM = 10%) to give 30-2 (60.0 mg), with a yield of 69.3%.

[0319] LC-MS (m / z): 286.0 [M+H] + .

[0320] Step 3: Synthesis of (R)-2-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((2-methylmorpholine)methyl)-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (30)

[0321] 30-2 (96.6 mg, 0.32 mmol), Pd2(dba)3 (19.3 mg, 0.02 mmol), Xphos (12.2 mg, 0.02 mmol), and Cs2CO3 (171.3 mg, 0.53 mmol) were dissolved in anhydrous dioxane (5 mL) and reacted at 100 °C under nitrogen protection for 16 hours. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed with 10% MeOH in DCM solution (10 mL × 3). The filtrate was concentrated, and the residue was prepared by reverse-phase reaction (ACN: 10 mmol NH4HCO3 solution = 95%) to give 30 (33.2 mg), with a yield of 30.9%.

[0322] LC-MS (m / z): 511.0 [M+H] + .

[0323] 1 H NMR (400MHz, DMSO-d6) δ11.87-11.67(m,1H),8.41-8.25(m,1H),7.88-7.70(m,2H),7.69-7. 61(m,1H),7.44-7.36(m,1H),7.25-7.19(m,1H),7.16-7.09(m,1H),7.07-6.85(m,1H),5.12- 4.96(m,2H),3.82-3.66(m,3H),3.54-3.43(m,2H),3.30-3.20(m,3H),2.94-2.64(m,4H),2. 60-2.54(m,2H),2.43-2.19(m,1H),2.13-2.03(m,1H),1.83-1.72(m,1H),1.17-0.94(m,6H).

[0324] Example 31: Synthesis of 5-((2-azabicyclo[2.1.1]hex-2-yl)methyl)-2-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (31)

[0325] Step 1: Synthesis of 5-(bromomethyl)-2-(4-methoxybenzyl)-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (31-1)

[0326] 29-1 (152.0 mg, 0.47 mmol) was dissolved in anhydrous DCM (2 mL), and PBr3 (255.3 mg, 0.94 mmol) was added at 0 °C. The reaction mixture was kept at this temperature for 1 hour. The reaction solution was concentrated, and the residue was purified by column chromatography (EA:DCM = 30%) to give 31-1 (165.0 mg), with a yield of 85.2%.

[0327] LC-MS (m / z): 385.0 / 387.0 [M+H] + .

[0328] Step 2: Synthesis of 5-((2-azabicyclo[2.1.1]hex-2-yl)methyl)-2-(4-methoxybenzyl)-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (31-2)

[0329] 31-1 (155.0 mg, 0.40 mmol) was dissolved in ACN (3 mL), and 2-azabicyclo[2.1.1]hexane hydrochloride (57.7 mg, 0.48 mmol) and DIPEA (156.0 mg, 1.21 mmol) were added. The mixture was reacted at 80 °C for 16 hours. The reaction solution was poured into water (20 mL), extracted with EA (15 mL × 3), and the organic phases were combined and washed with saturated brine (10 mL). The mixture was dried over anhydrous Na2SO4, filtered, concentrated, and the residue was purified by column chromatography (MeOH:DCM:concentrated ammonia = 9:90:1) to give 31-2 (115.0 mg), with a yield of 69.3%.

[0330] LC-MS (m / z): 388.0 [M+H] + .

[0331] Step 3: Synthesis of 5-((2-azabicyclo[2.1.1]hex-2-yl)methyl)-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (31-3)

[0332] 31-2 (115.0 mg, 0.30 mmol) was dissolved in TFA (1 mL), and Tf2O (100.5 mg, 0.36 mmol) was added. The mixture was reacted at 80 °C for 1 hour. The reaction solution was concentrated, and the residue was dissolved in MeOH (5 mL). The pH was adjusted to 7–8 with NaHCO3 solution, and the mixture was extracted with DCM (30 mL × 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous Na2SO4, filtered, concentrated, and the residue was purified by column chromatography (MeOH:DCM:concentrated ammonia = 19:80:1) to give 31-3 (45.0 mg), with a yield of 56.7%.

[0333] LC-MS (m / z): 268.0 [M+H]+ .

[0334] Step 4: Synthesis of 5-((2-azabicyclo[2.1.1]hex-2-yl)methyl)-2-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (31)

[0335] 31-3 (45.0 mg, 0.17 mmol), INT1 (67.0 mg, 0.22 mmol), Pd2(dba)3 (15.4 mg, 0.02 mmol), Xphos (9.7 mg, 0.02 mmol), and Cs2CO3 (137.1 mg, 0.42 mmol) were dissolved in anhydrous dioxane (5 mL) and reacted at 100 °C under nitrogen protection for 16 hours. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed with 10% MeOH in DCM solution (10 mL × 3). The filtrate was concentrated, and the residue was purified by column chromatography (MeOH:DCM = 20%) and reverse-phase preparation (acetonitrile:0.1% formic acid aqueous solution = 95%) to obtain 31 (12.1 mg), with a yield of 14.6%.

[0336] LC-MS (m / z): 493.0 [M+H] + .

[0337] 1 H NMR(400MHz,DMSO-d6)δ8.38-8.29(m,1H),8.25-8.18(m,1H),7.88-7.73(m,2H),7.6 9-7.63(m,1H),7.46-7.34(m,2H),7.19-7.12(m,1H),7.07-7.00(m,1H),5.09-5.01(m ,2H),4.13-4.06(m,2H),3.58-3.54(m,2H),3.25-3.23(m,3H),2.92-2.84(m,2H),2.7 6-2.68(m,3H),2.59-2.54(m,2H),1.73(s,2H),1.61-1.52(m,2H),1.17-1.03(m,3H).

[0338] Example 32: Synthesis of 5-(((cyclopropylmethyl)(methyl)amino)methyl)-2-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (32)

[0339] Step 1: Synthesis of 5-(((cyclopropylmethyl)amino)methyl)-2-(4-methoxybenzyl)-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (32-1)

[0340] 29-2 (300.0 mg, 0.94 mmol) and cyclopropyl methylamine (99.9 mg, 1.40 mmol) were dissolved in a mixed solvent of DCM (4 mL) and MeOH (4 mL). One drop of AcOH was added, and the mixture was stirred at room temperature for 30 minutes. Then, NaBH3CN (176.6 mg, 2.81 mmol) was added, and the mixture was heated to 60 °C and reacted for 3 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (MeOH:DCM = 10%) to give 32-1 (330.0 mg), with a yield of 93.9%.

[0341] LC-MS (m / z): 376.0 [M+H] + .

[0342] Step 2: Synthesis of 5-(((cyclopropylmethyl)(methyl)amino)methyl)-2-(4-methoxybenzyl)-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (32-2)

[0343] 32-1 (330.0 mg, 0.88 mmol) and formaldehyde aqueous solution (107.0 mg, 1.32 mmol, 37 wt.%) were dissolved in a mixed solvent of DCM (2.5 mL) and MeOH (2.5 mL). One drop of AcOH was added, and the mixture was stirred at room temperature for 30 minutes. Then, NaBH3CN (165.7 mg, 2.64 mmol) was added, and the reaction was continued for 2 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (MeOH:DCM = 10%) to give 32-2 (240.0 mg), with a yield of 70.1%.

[0344] LC-MS (m / z): 390.0 [M+H] + .

[0345] Step 3: Synthesis of 5-(((cyclopropylmethyl)(methyl)amino)methyl)-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (32-3)

[0346] 32-2 (240.0 mg, 0.62 mmol) was dissolved in TFA (1 mL), and Tf2O (208.6 mg, 0.29 mmol) was added. The reaction mixture was reacted at 80 °C for 1 hour. The reaction solution was concentrated, redissolved in methanol (5 mL), and the pH was adjusted to 7–8 with ammonia. The solution was concentrated under reduced pressure, and the residue was purified by column chromatography (MeOH:DCM:concentrated ammonia = 9:90:1) to give 32-3 (110.0 mg), with a yield of 66.3%.

[0347] LC-MS (m / z): 270.0 [M+H] + .

[0348] Step 4: Synthesis of 5-(((cyclopropylmethyl)(methyl)amino)methyl)-2-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (32)

[0349] 32-3 (110.0 mg, 0.37 mmol), INT1 (147.8 mg, 0.48 mmol), Pd2(dba)3 (34.0 mg, 0.03 mmol), Xantphos (21.5 mg, 0.04 mmol), and cesium carbonate (302.4 mg, 0.93 mmol) were dissolved in anhydrous dioxane (3 mL) and reacted at 100 °C under nitrogen protection for 16 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (MeOH:DCM:concentrated ammonia = 9:90:1) and reverse-phase preparation (ACN:0.1% formic acid aqueous solution = 95%) to give 32-3 (40.0 mg), with a yield of 19.8%.

[0350] LC-MS (m / z): 495.0 [M+H] + .

[0351] 1 H NMR(400MHz,DMSO-d6)δ11.67(s,1H),8.39-8.28(m,1H),7.90-7.85(m,1H),7.83-7.74(m,1H),7.68-7 .63(m,1H),7.44-7.35(m,1H),7.29-7.25(m,1H),7.17-7.11(m,1H),7.07-6.86(m,1H),5.09-4.98(m,2 H),3.93-3.88(m,2H),3.27-3.23(m,3H),3.17-3.12(m,1H),2.93-2.83(m,2H),2.59-2.54(m,2H),2.41 -2.36(m,2H),2.30(s,3H),1.15-1.05(m,3H),0.99-0.89(m,1H),0.53-0.42(m,2H),0.14-0.04(m,2H).

[0352] Example 33: Synthesis of 2-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((3-(methylamino)azacyclobutane-1-yl)methyl)-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (33) formate

[0353] Step 1: Synthesis of (1-((2-(4-methoxybenzyl)-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-5-yl)methyl)azacyclobutane-3-yl)(methyl)carbamate tert-butyl ester (33-1)

[0354] 29-2 (200.0 mg, 0.62 mmol) and tert-butyl aziridine-3-yl(methyl)carbamate hydrochloride (208.6 mg, 0.94 mmol) were dissolved in a mixed solvent of DCM (2.5 mL) and MeOH (2.5 mL). One drop of AcOH was added, and the mixture was stirred at room temperature for 30 minutes. Then, NaBH3CN (117.7 mg, 1.87 mmol) was added, and the reaction was continued for 16 hours. The reaction solution was quenched with NaHCO3 aqueous solution (20 mL), extracted with DCM (50 mL × 3), washed with saturated brine (50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (MeOH:DCM = 10%) to give 33-1 (120.0 mg), with a yield of 39.2%.

[0355] LC-MS (m / z): 491.0 [M+H] + .

[0356] Step 2: Synthesis of 5-((3-(methylamino)azacyclobutane-1-yl)methyl)-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (33-2)

[0357] 33-1 (120.0 mg, 0.24 mmol) was dissolved in TFA (1 mL), and Tf2O (82.8 mg, 0.29 mmol) was added. The reaction mixture was reacted at 80 °C for 1 hour. The reaction solution was concentrated, redissolved in methanol (5 mL), and the pH was adjusted to 7–8 with ammonia. The solution was concentrated under reduced pressure, and the residue was purified by reversed-phase column chromatography (water:MeOH = 5%–95%, containing 1% formic acid) to obtain crude 33-2 (140.0 mg).

[0358] LC-MS (m / z): 271.0 [M+H] + .

[0359] Step 3: Synthesis of methyl(1-((3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indole-5-yl)methyl)azacyclobutane-3-yl)tert-butyl carbamate (33-3A) and 5-((3-((tert-butoxycarbonyl)(methyl)amino)azacyclobutane-1-yl)methyl)-3-oxo-2,3-dihydropyrrolo[3,4-b]indole-4(1H)-tert-butyl carbamate (33-3B)

[0360] Crude product 33-2 (140.0 mg) was dissolved in DCM (2 mL), and TEA (262.0 mg, 2.59 mmol), DMAP (6.3 mg, 0.05 mmol), and Boc2O (113.0 mg, 0.52 mmol) were added sequentially. The reaction was carried out at room temperature for 16 hours. The reaction solution was quenched with NaHCO3 aqueous solution (2 mL), concentrated under reduced pressure, and the residue was purified by column chromatography (MeOH:DCM = 10%) to obtain a mixture of 33-3A and 33-3B (90.0 mg), which was used directly in the next step without further processing.

[0361] 33-3A: LC-MS (m / z): 371.0 [M+H] + .

[0362] 33-3B: LC-MS (m / z): 471.0 [M+H] + .

[0363] Step 4: Synthesis of methyl(1-((2-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-5-yl)methyl)azacyclobutane-3-yl)tert-butyl carbamate (33-4)

[0364] The mixture of 33-3A and 33-3B from the previous step (90.0 mg), INT1 (96.7 mg, 0.32 mmol), Pd2(dba)3 (22.3 mg, 0.02 mmol), Xantphos (14.1 mg, 0.02 mmol), and cesium carbonate (197.9 mg, 0.61 mmol) were dissolved in anhydrous dioxane (3 mL) and reacted at 100 °C under nitrogen protection for 16 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (MeOH:DCM = 10%) to give 33-4 (50.0 mg), with a three-step yield of 34.3%.

[0365] LC-MS (m / z): 596.0 [M+H] + .

[0366] Step 5: Synthesis of 2-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((3-(methylamino)azacyclobutane-1-yl)methyl)-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one(33)formate

[0367] 33-4 (50.0 mg, 0.08 mmol) was dissolved in MeOH (2 mL), and a dioxane solution of HCl (4 M, 1 mL) was added. The reaction was carried out at room temperature for 3 hours. The reaction solution was concentrated, and the residue was prepared by reverse phase (ACN: 0.1% formic acid aqueous solution = 15%–95%) to give 33-formate (5.2 mg), yield 12.5%.

[0368] LC-MS (m / z): 496.0 [M+H] + .

[0369] 1 ¹H NMR (400MHz, DMSO-d6) δ 11.83 (s, 1H), 8.40–8.29 (m, 1H), 8.26 (s, 1H, formic acid HC=O), 7.89–7.72 (m, 2H), 7.67–7.61 (m, 1H), 7.45–7.35 (m, 1H), 7.27–7.17 (m, 1H), 7.14–7.09 (m, 1H), 7.06–6.86 ( m,1H),5.08-4.98(m,2H),3.91(s,2H),3.50-3.45(m,2H),3.41-3.36(m,1H),3.28-3.21(m,3 H),3.17-3.09(m,1H),3.02-2.80(m,4H),2.60-2.54(m,2H),2.27(s,3H),1.15-1.02(m,3H).

[0370] Example 34: Synthesis of 5-((2,6-diazaspiro[3,4]octane-6-yl)methyl)-2-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one(34)formate

[0371] Step 1: Synthesis of tert-butyl 6-((2-(4-methoxybenzyl)-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-5-yl)methyl)-2,6-diazaspiro[3,4]octane-2-carboxylate (34-1)

[0372] 29-2 (200.0 mg, 0.62 mmol) and tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate (198.8 mg, 0.94 mmol) were dissolved in a mixed solvent of DCM (2.5 mL) and MeOH (2.5 mL). One drop of AcOH was added, and the mixture was stirred at room temperature for 30 minutes. Then, NaBH3CN (117.7 mg, 1.87 mmol) was added, and the reaction was allowed to proceed at room temperature for 16 hours. The reaction solution was quenched with NaHCO3 aqueous solution (20 mL), extracted with DCM (50 mL × 3), washed with saturated brine (50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (MeOH:DCM = 10%) to give 34-1 (210.0 mg), with a yield of 65.1%.

[0373] LC-MS (m / z): 517.0 [M+H] + .

[0374] Step 2: Synthesis of 5-((2,6-diazaspiro[3,4]octane-6-yl)methyl)-1,4-dihydropyrrolo[3,4-b]indol-3(2H)-one (34-2)

[0375] 34-1 (210.0 mg, 0.41 mmol) was dissolved in TFA (1 mL), and Tf2O (137.6 mg, 0.49 mmol) was added. The mixture was reacted at 80 °C for 1 hour. The reaction solution was concentrated, redissolved in methanol (5 mL), and the pH was adjusted to 7–8 with ammonia. The solution was concentrated under reduced pressure, and the residue was purified by reversed-phase column chromatography (water:MeOH = 5%–95%, containing 1% formic acid) to obtain crude 34-2 (170.0 mg).

[0376] LC-MS (m / z): 297.0 [M+H] + .

[0377] Step 3: Synthesis of 6-((3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-5-yl)methyl)-2,6-diazaspiro[3,4]octane-2-carboxylic acid tert-butyl ester (34-3)

[0378] Crude product 34-2 (170.0 mg) was dissolved in DCM (2 mL), and TEA (290.2 mg, 2.87 mmol), DMAP (7.0 mg, 0.06 mmol), and Boc2O (150.2 mg, 0.67 mmol) were added sequentially. The reaction was carried out at room temperature for 16 hours. The reaction solution was quenched with NaHCO3 aqueous solution (2 mL), concentrated under reduced pressure, and the residue was purified by column chromatography (MeOH:DCM = 10%) to give 34-3 (40.0 mg), with a yield of 24.8%.

[0379] LC-MS (m / z): 397.0 [M+H] + .

[0380] Step 4: Synthesis of 6-((2-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-5-yl)methyl)-2,6-diazaspiro[3,4]octane-2-carboxylic acid tert-butyl ester (34-4)

[0381] 34-3 (40.0 mg, 0.10 mmol), INT1 (40.2 mg, 0.13 mmol), Pd2(dba)3 (9.2 mg, 0.01 mmol), Xantphos (5.8 mg, 0.01 mmol), and cesium carbonate (82.2 mg, 0.25 mmol) were dissolved in anhydrous dioxane (2 mL) and reacted at 100 °C for 16 hours under nitrogen protection. The reaction solution was concentrated, and the residue was purified by column chromatography (MeOH:DCM = 15%) to give 34-4 (50.0 mg), with a yield of 79.7%.

[0382] LC-MS (m / z): 622.0 [M+H] + .

[0383] Step 5: Synthesis of 5-((2,6-diazaspiro[3,4]octane-6-yl)methyl)-2-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one(34)formate

[0384] 34-4 (50.0 mg, 0.08 mmol) was dissolved in a 4 M, 2 mL solution of dioxane in HCl and reacted at room temperature for 3 hours. The reaction solution was concentrated, and the residue was prepared by reverse-phase reaction (ACN: 0.1% formic acid aqueous solution = 15%–95%) to give 34-formate (10.9 mg), yield 26.0%.

[0385] LC-MS (m / z): 522.0 [M+H] + .

[0386] 1¹H NMR (400MHz, DMSO-d⁶) δ 11.79 (s, 1H), 8.38–8.28 (m, 1H), 8.30 (s, 1H, formic acid HClO), 7.89–7.80 (m, 2H), 7.65 (d, J = 8.0 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.23 (d, J = 7.2 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 7.08 (d, J = 7.6 Hz, 1H), 5.09– 5.02(m,2H),3.91-3.86(m,2H),3.83-3.78(m,2H),3.76-3.71(m,2H),3.24(s,3H),2.95-2.83(m,3H),2.77- 2.72(m,2H),2.70-2.65(m,2H),2.35-2.33(m,1H),2.05-1.96(m,2H),1.27-1.22(m,1H),1.16-1.04(m,3H).

[0387] Example 35: Synthesis of 5-((2-azabicyclo[2.2.1]heptane-2-yl)methyl)-2-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1,4-dihydropyrrolo[3,4-b]indole-3(2H)-one (35)

[0388] Step 1: Synthesis of 5-((2-azabicyclo[2.2.1]heptane-2-yl)methyl)-2-(4-methoxybenzyl)-1,4-dihydropyrrolo[3,4-b]indol-3(2H)-one (35-1)

[0389] 31-1 (119.4 mg, 0.31 mmol) was dissolved in ACN (3 mL), and 2-azabicyclo[2.2.1]heptane hydrochloride (50.0 mg, 0.37 mmol) and DIPEA (120.2 mg, 0.93 mmol) were added. The reaction mixture was reacted at 80 °C under nitrogen protection for 16 hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography (MeOH:DCM = 9%) to give 35-1 (104.0 mg), with a yield of 83.6%.

[0390] LC-MS (m / z): 402.0 [M+H] + .

[0391] Step 2: Synthesis of 5-((2-azabicyclo[2.2.1]heptane-2-yl)methyl)-1,4-dihydropyrrolo[3,4-b]indol-3(2H)-one (35-2)

[0392] 35-1 (134.0 mg, 0.33 mmol) was dissolved in TFA (3 mL), and Tf2O (84.5 mg, 0.31 mmol) was added. The reaction was carried out at 80 °C under nitrogen protection for 1 hour. The reaction solution was concentrated under reduced pressure, and MeOH (10 mL × 2) and ammonia (4 mL) were added and then concentrated again. The residue was purified by column chromatography (MeOH:DCM = 10%) to give 35-2 (39.0 mg), with a yield of 53.5%.

[0393] LC-MS (m / z): 282.0 [M+H] + .

[0394] Step 3: Synthesis of 5-((2-azabicyclo[2.2.1]heptane-2-yl)methyl)-2-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1,4-dihydropyrrolo[3,4-b]indol-3(2H)-one (35-3)

[0395] 35-2 (39.0 mg, 0.14 mmol) was dissolved in dioxane (2 mL), and INT1 (55.1 mg, 0.18 mmol), Pd2(dba)3 (12.8 mg, 14.0 μmol), Xantphos (8.1 mg, 14.0 μmol), and Cs2CO3 (136.8 mg, 0.42 mmol) were added. The mixture was reacted at 100 °C under nitrogen protection for 16 hours. The reaction solution was concentrated, methanol (10 mL) was added, and the mixture was filtered. The filtrate was concentrated and purified by reverse-phase preparation (ACN: 0.1% formic acid aqueous solution = 70%) to obtain 35-2 (18.3 mg), with a yield of 26.1%.

[0396] LC-MS (m / z): 507.0 [M+H] + .

[0397] 1H NMR (400MHz, DMSO-d6) δ8.29(s,1H),8.23(s,1H),7.87(s,1H),7.81(d,J=8.0Hz,1H),7.62(d,J=8.0Hz,1H),7.42-7 .37(m,1H),7.30(d,J=7.2Hz,1H),7.14-7.10(m,1H),7.05-7.03(m,1H),5.03-5.02(m,2H),4.01-3.90(m,2H),3.31( s,2H),3.27(s,3H),2.89-2.88(m,2H),2.75-2.73(m,1H),2.57-2.55(s,2H),2.34-2.32(m,1H),2.22(d,J=9.2Hz,1H ),1.83-1.81(m,1H),1.72-1.69(m,1H),1.53-1.50(m,1H),1.46-1.39(m,1H),1.30-1.25(m,2H),1.12-1.09(m,3H).

[0398] Example 36: Synthesis of 5-((2-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-5-yl)methyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-nitrile (36)

[0399] Step 1: Synthesis of tert-butyl 6,7-dihydrothiopheno[3,2-c]pyridine-5(4H)-carboxylate (36-2)

[0400] 36-1: 4,5,6,7-tetrahydrothiopheno[3,2-c]pyridine hydrochloride (5.00 g) was dissolved in DCM (70 mL), and TEA (3.17 g, 31.31 mmol) and Boc2O (6.83 g, 31.31 mmol) were added sequentially. The reaction was carried out at room temperature for 3 hours. The reaction solution was quenched with NaHCO3 aqueous solution (200 mL), extracted with DCM (100 mL × 3), washed with saturated brine (100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (EA:PE = 20%) to obtain 36-2 (7.30 g), crude product.

[0401] LC-MS (m / z): 140.0 [M+H-Boc] + .

[0402] Step 2: Synthesis of tert-butyl 2-bromo-6,7-dihydrothiopheno[3,2-c]pyridine-5(4H)-carboxylate (36-3)

[0403] Crude 36-2 (7.30 g) was dissolved in ACN (100 mL), and NBS (5.97 g, 33.55 mmol) was added. The reaction mixture was reacted at room temperature for 3 hours. The reaction solution was quenched in water (150 mL), extracted with EA (100 mL × 3), washed with saturated brine (100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (EA:PE = 10%) to obtain 36-3 (8.10 g), with a two-step yield of 89.4%.

[0404] LC-MS (m / z): 261.0 / 263.0 [M+H- t Bu] + .

[0405] 1 H NMR (600MHz, DMSO-d6) δ7.02 (s, 1H), 4.36 (s, 2H), 3.61 (t, J = 5.4Hz, 2H), 2.70 (t, J = 5.4Hz, 2H), 1.42 (s, 9H).

[0406] Step 3: Synthesis of tert-butyl 2-cyano-6,7-dihydrothiophene[3,2-c]pyridine-5(4H)-carboxylate (36-4)

[0407] 36-3 (4.00 g, 12.57 mmol) was dissolved in anhydrous DMF (60 mL), and zinc cyanide (2.95 g, 25.14 mmol) and Pd(PPh3)4 (726.3 mg, 0.63 mmol) were added sequentially. The reaction was carried out at 110 °C under nitrogen protection for 16 hours. After the reaction solution cooled to room temperature, an aqueous solution (100 mL) and EA (100 mL) were added and stirred thoroughly. The mixture was filtered through diatomaceous earth, and the filtrate was extracted with EA (100 mL × 3), washed with saturated brine (100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (EA:PE = 30%) to give 36-4 (900.0 mg), with a yield of 24.1%.

[0408] LC-MS (m / z): 165.0 [M+H-Boc] + .

[0409] Step 4: Synthesis of 4,5,6,7-tetrahydrothiopheno[3,2-c]pyridine-2-nitrile (36-5)

[0410] 36-4 (800.0 mg, 3.03 mmol) was dissolved in DCM (8 mL), and a 4 M, 4 mL solution of dioxane in HCl was added. The mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated, reconstituted with methanol (5 mL), and then NaHCO3 solid was added. The mixture was stirred at room temperature for 20 minutes, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (MeOH:DCM = 10%) to give 36-5 (270.0 mg), with a yield of 54.3%.

[0411] LC-MS (m / z): 165.0 [M+H] + .

[0412] Step 5: Synthesis of 5-((4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)methyl)-4,5,6,7-tetrahydrothiopheno[3,2-c]pyridine-2-nitrile (36-6)

[0413] Dissolve 36-5 (270.0 mg, 1.64 mmol) in ACN (5 mL), then add potassium carbonate (435.1 mg, 2.47 mmol) and 2-(chloromethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (454.4 mg, 3.29 mmol) sequentially, and react at room temperature for 5 hours. Filter the reaction solution, and concentrate the filtrate under reduced pressure to obtain crude 36-6 (750.0 mg).

[0414] LC-MS (m / z): No corresponding mass-to-nucleus ratio was detected.

[0415] Step 6: Synthesis of 5-((2-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-5-yl)methyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-nitrile (36)

[0416] Dissolve 1-5 (50.0 mg, 0.10 mmol) in a mixed solvent of dioxane (0.9 mL) and water (0.1 mL), then add crude 36-6 (95.8 mg), Pd2(dba)3 (9.6 mg, 0.01 mmol), Xphos (10.0 mg, 0.02 mmol), and cesium carbonate (102.6 mg, 0.31 mmol) sequentially. React at 100 °C under nitrogen protection for 2 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (MeOH:DCM = 8%) to give 36 (33.7 mg), yield 56.0%.

[0417] LC-MS (m / z): 574.0 [M+H] + .

[0418] 1 H NMR(600MHz,DMSO-d6)δ11.79(s,1H),8.37-8.28(m,1H),7.85-7.66(m,4H),7 .43-7.35(m,1H),7.28-7.25(m,1H),7.18-7.12(m,1H),7.06-6.86(m,1H),5.0 6-5.01(m,2H),3.98(s,2H),3.53(s,2H),3.27-3.22(m,3H),3.15-2.95(m,1H ),2.91-2.84(m,5H),2.58-2.53(m,2H),2.37-2.25(m,1H),1.13-1.08(m,3H).

[0419] Example 37: Synthesis of 7-((2-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-5-yl)methyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine-2-nitrile (37)

[0420] Step 1: Synthesis of 2-bromo-[1,2,4]triazolo[1,5-a]pyrazine (37-2)

[0421] 37-1: [1,2,4]triazolo[1,5-a]pyrazin-2-amine (2.50 g, 18.50 mmol) was dissolved in AcOH (80 mL), and water (80 mL) and HBr aqueous solution (48 wt.%, 20 mL) were added. The mixture was stirred at 0 °C for 1 hour. Then CuBr (3.18 g, 22.20 mmol) was added, followed by dropwise addition of NaNO2 (2.55 g, 37.00 mmol) aqueous solution (10 mL). The reaction mixture was reacted at 80 °C for 2 hours. The reaction solution was concentrated under reduced pressure, and the pH was adjusted to approximately 8 with saturated NaHCO3 solution. Water (50 mL) was added, and the mixture was extracted with EA (100 mL × 3). The combined organic phases were washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (MeOH:DCM = 8%) to obtain 37-2 (1.20 g), with a yield of 32.6%.

[0422] LC-MS (m / z): 199.0 / 201.0 [M+H] + .

[0423] Step 2: Synthesis of 2-bromo-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine (37-3)

[0424] Lithium chloride (2.50 g, 58.98 mmol) was dissolved in THF (25 mL), and sodium borohydride (2.23 g, 58.98 mmol) was added. The mixture was stirred at 60 °C for 8 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure to obtain crude lithium borohydride (4.80 g).

[0425] 37-2 (1.00 g, 5.02 mmol) was dissolved in EtOH (20 mL), and crude lithium borohydride (4.80 g) was added. The reaction was carried out at 50 °C under nitrogen protection for 2 hours. The reaction was quenched by adding saturated ammonium chloride aqueous solution (150 mL), diluted with water (200 mL), and the pH was adjusted to 1-2 with dilute hydrochloric acid (1 N). The mixture was washed with EA (150 mL × 2), and the pH of the aqueous phase was adjusted to about 8 with saturated NaHCO3 solution. The mixture was extracted with DCM (150 mL × 3), and the organic phases were combined and washed with saturated brine (100 mL × 2). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain crude 37-3 (574.0 mg).

[0426] LC-MS (m / z): 203.0 / 205.0 [M+H] + .

[0427] Step 3: Synthesis of 5-((2-bromo-5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)methyl)-2-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1,4-dihydropyrrolo[3,4-b]indol-3(2H)-one (37-4)

[0428] Dissolve 31-1 (58.0 mg, 0.12 mmol) in ACN (3 mL), add crude 37-3 (26.4 mg) and DIPEA (93.1 mg, 0.72 mmol), and react at 40 °C under nitrogen protection for 2 hours. Concentrate the reaction solution and purify by column chromatography (MeOH:DCM = 5%) to obtain crude 37-4 (78.0 mg).

[0429] LC-MS (m / z): 612.0 / 614.0 [M+H] + .

[0430] Step 6: Synthesis of 7-((2-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-3-oxo-1,2,3,4-tetrahydropyrrolo[3,4-b]indol-5-yl)methyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine-2-nitrile (37)

[0431] Crude product 37-4 (78.0 mg) was dissolved in DMF (1 mL), and zinc cyanide (17.6 mg, 0.15 mmol), zinc powder (0.8 mg, 12.0 μmol), Pd2(dba)3 (11.0 mg, 12.0 μmol), and dppf (13.3 mg, 24.0 μmol) were added. The reaction was carried out at 120 °C under nitrogen protection for 3 hours. The reaction solution was concentrated, purified by column chromatography (MeOH:DCM = 10%), and then purified by preparative chromatography (ACN: 0.1% formic acid aqueous solution = 90%) to obtain 37 (15.90 mg), with a two-step yield of 24.1%.

[0432] LC-MS (m / z): 559.0 [M+H] + .

[0433] 1 H NMR(600MHz,DMSO-d6)δ11.84(s,1H),8.37-8.29(m,1H),7.83-7.69(m,3H),7.41-7.36(m ,1H),7.29(d,J=6.6Hz,1H),7.18-7.15(m,1H),7.05-6.86(m,1H),5.04-5.03(m,2H),4.22 (t,J=5.4Hz,2H),4.07(s,2H),3.90(s,2H),3.27-3.23(m,3H),3.14-3.11(m,1H),3.07(t, J=5.4Hz,2H),2.89-2.86(m,1H),2.56-2.55(m,2H),2.36-2.25(m,1H),1.12-1.09(m,3H).

[0434] Biological tests

[0435] Example 1: Jurkat cell IL-2 release and activation experiment

[0436] The following experimental steps were used in this experiment:

[0437] (1) Jurkat cells were seeded into 96-well plates (1 x 10⁻⁶ cells per well). 6 (cells / mL, 90μL);

[0438] (2) Prepare a 10 mM DMSO solution of the compound to be tested, and then dilute it 4 times with DMSO to obtain 8 concentrations of compound solution, and then dilute it 100 times with RPMI 1640 empty medium.

[0439] (3) Add the compound solutions diluted at different concentrations to the well plates inoculated with cells (10 μL / well) and incubate at 37°C and 5% CO2 for 0.5 hours;

[0440] (4) Dilute the CD3 / CD28 activator 100 times with RPMI 1640 medium to obtain the CD3 / CD28 activator working solution. Add 10 μL of the CD3 / CD28 activator working solution to the cells and incubate at 37°C and 5% CO2 for 24 hours;

[0441] (5) Collect cell supernatant, dilute with RPMI 1640 medium, and measure IL-2 level according to the instructions of IL-2 ELISA kit (Invitrogen, catalog number EK101B);

[0442] (6) Fit EC using the log (agonist) vs. response-variable slope four-parameter method in GraphPad software. 50 The values ​​are shown in Table 1.

[0443] Table 1. Activation of IL-2 release from Jurkat cells by the compounds.

Claims

1. A ternary fused-ring compound having the structure shown in formula (I), or its pharmaceutically acceptable salt, isotope derivative, solvate, or its stereoisomer, geometric isomer, tautomer, or its prodrug molecule or metabolite: in, R 1 Selected from hydroxyl or m and n are each independently selected from 1, 2, or 3; X 1 Selected from S, O, NR Z1 CR Z1 or CR Z1 R Z2 ; X 2 X 3 X 4 Each is independently selected from N or C; Z 1 selected from CR Z1 R Z2 , -(CO)-, -(C=NR Z1 ), NR Z1 , -C(R Z1 )=C(R Z2 )-, -N=C(R Z2 )-, -C(R Z1 )=N-, -O-CR Z1 R Z2 -, -CR Z1 R Z2 -CO-, -CR Z1 R Z2 -CR Z3 R Z4 - or -NR Z3 -CR Z1 R Z2 -; Z 2 Selected from S, -C(R) Z1 )=C(R Z2 )-、-N=C(R Z2 - or -C(R) Z1 ) = N-; Y 1 Y 2 Y 3 Y 4 Each is independently selected from N or CR 5 ; Ring A is selected from 5-6-membered heteroaryl or 5-6-membered heterocyclic groups, wherein the 5-6-membered heteroaryl or 5-6-membered heterocyclic group is optionally further surrounded by one or more R groups. 6 replace; R Z1 R Z2 R Z3 R Z4 R 2 R 2’ R 3 R 3’ R 4 R 4’ R 5 R 6 Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 alkylamine group, C 1-6 alkyl ester group, C 1-6 Alkyl acyl, C 1-6 Alkylamide group, C 1-6 alkylsulfonamide group, C 1-6 Phosphoryl group or 3-8 membered heterocyclic group; the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 alkylamine group, C 1- 6-alkyl ester group, C 1-6 Alkyl acyl, C 1-6 Alkylamide group, C 1-6 alkylsulfonamide group, C 1-6 The phosphoryl group or 3-8 membered heterocyclic group may optionally be further surrounded by one or more R groups. a Replaced; Or, the R Z1 R Z2 Together with the atoms they are attached to, they form C 3-12 Cycloalkyl or 4-12 membered heterocyclic groups, wherein the C3-C 12 Cycloalkyl groups, 4-12 membered heterocyclic groups optionally further modified by one or more R groups a Replaced; Or, the R Z3 R Z4 Together with the atoms they are attached to, they form C 3-12 Cycloalkyl or 4-12 membered heterocyclic groups, wherein the C3-C 12 Cycloalkyl groups, 4-12 membered heterocyclic groups optionally further modified by one or more R groups a Replaced; Or, the R 2 R 2’ Together with the atoms they are attached to, they form C 3-12 Cycloalkyl or 4-12 membered heterocyclic groups, wherein the C3-C 12 Cycloalkyl groups, 4-12 membered heterocyclic groups optionally further modified by one or more R groups a Replaced; Or, the R 3 R 3’ Together with the atoms they are attached to, they form C 3-12 Cycloalkyl or 4-12 membered heterocyclic groups, wherein the C3-C 12 Cycloalkyl groups, 4-12 membered heterocyclic groups optionally further modified by one or more R groups a Replaced; Or, the R 4 R 4’ Together with the atoms they are attached to, they form a 4-12 membered heterocyclic group, which may optionally be further bonded by one or more R atoms. a Replaced; R a Independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 alkylamine group, C 1-6 Alkyl acyl or 3-8 membered heterocyclic group; the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl sulfone group, C 1-6 Alkylthio, C 1-6 alkylamine group, C 1-6 The alkyl acyl group or a 3-8 membered heterocyclic group may optionally be further selected from one or more groups selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, or C. 1-6 The alkoxy group is replaced by a substituent.

2. The compound of any one of claims 1, 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 (II): Where m, n, X 1 X 2 X 3 X 4 Y 1 Y 2 Y 3 Y 4 Z 1 Z 2 R 1 R 2 R 2’ R 3 R 3’ R 6 The definition is as described in claim 1.

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 Selected from: Preferably, the 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): Among them, X 1 X 2 X 3 X 4 Y 1 Y 2 Y 3 Y 4 Z 1 Z 2 R 1 R 2 R 2’ R 3 R 3’ R 6 The definition is 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 the structure shown in formula (IV): Where p is selected from 0, 1, 2 or 3; X 1 X 2 X 3 X 4 Z 1 Z 2 Y 1 R 1 R 2 R 2’ R 3 R 3’ R 5 R 6 The definition is as described in claim 1.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule or metabolite thereof, characterized in that, The Selected from The X 1 Z 1 R Z1 R Z2 The definition is as described in claim 1.

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 (Va), (Vb), (Vc), or (Vd): Among them, X 1 Selected from S or NR Z1 ; p is selected from 0, 1, 2, or 3; Z 1 Y 1 R 1 R 2 R 2’ R 3 R 3’ R 5 R 6 R Z1 R Z2 The definition is as described in claim 1.

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 R 3 R 3’ Each is independently selected from hydrogen and C. 1-6 Alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-6 The cycloalkyl or 3-6 membered heterocyclic group may optionally be further selected from one or more groups selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl groups are substituted.

9. The compound according to any one of claims 1 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 The values ​​q and r are each independently selected from 0, 1, 2, or 3; the value s is selected from 1, 2, or 3; the value R... a Independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy groups.

10. 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 compound has a structure as shown in formula (VIa), (VIb), (VIc), (VId), or (VIe): Among them, X 1 Selected from S or NH; p, q, and r are each independently selected from 0, 1, 2, or 3; s is selected from 1, 2, or 3; Z 1 Y 1 R 1 R 2 R 2’ R 5 R 6 R Z1 R Z2 R a The definition is as described in claim 1.

11. The compound according to any one of claims 1 to 10, 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 formulas (VIIa), (VIIb), (VIIc), (VIId), (VIIe), (VIIf), (VIIg), (VIIh), (VIIi), (VIIj), (VIIk), (VIIm), or (VIIn): Among them, p, q, and r are each independently selected from 0, 1, 2, or 3; s is selected from 1, 2, or 3; Y 1 R 1 R 2 R 2’ R 5 R 6 R Z1 R Z2 R a The definition is as described in claim 1.

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 R 1 Selected from The R 4 R 4’ Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl or C 3-8 cycloalkyl, the C 1-6 Alkyl or C 3-8 The cycloalkyl group may optionally be further divided by one or more radicals selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C 3-8 Substituents of cycloalkyl groups. Or, the R 4 R 4’ The atoms attached to it together form a 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group is optionally further bonded by one or more elements selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, oxo, C 1-6 alkylamine group, C 1-6 Alkyl, C 3-8 cycloalkyl or C 1-6 Alkoxy; the C 1-6 Alkyl, C 3-8 cycloalkyl or C 1-6 alkoxy groups may optionally be further divided by one or more groups selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, or C. 1-6 The alkoxy group is replaced by a substituent.

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 R 1 Selected from Preferably, the R 1 Selected from 14. The compound according to 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 has the structure shown in formulas (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), (VIIIi), (VIIIj), (VIIIk), (VIIIm), or (VIIIn): In this context, p and q are each independently selected from 0, 1, 2, or 3; s is selected from 1, 2, or 3; Y 1 R 2 R 2’ R 5 R 6 R Z1 R Z2 R a The definition is as described in claim 1.

15. The compound according to 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 or metabolite thereof, characterized in that, The Selected from 16. The compound according to any one of claims 1 to 15, 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 Preferred 17. The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule or metabolite thereof, characterized in that, The R 5 Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 3-6 cycloalkyl; preferably, the R 5 Selected from hydrogen or cyclopropyl.

18. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule or metabolite thereof, characterized in that, The R 6 Selected from hydrogen, deuterium, and C 1-3 Alkyl or C 3-6 cycloalkyl; preferably, the R 6 Selected from methyl.

19. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule or metabolite thereof, characterized in that, The R Z2 Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 3-6 Cycloalkyl.

20. The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule or metabolite thereof, characterized in that, The R Z1 Selected from hydrogen; the R Z2 Selected from hydrogen or fluorine.

21. The compound according to any one of claims 1 to 20, or its pharmaceutically acceptable salt, isotope derivative, solvate, or its stereoisomer, geometric isomer, tautomer, or its prodrug molecule or metabolite, characterized in that, The Selected from 22. The compound according to any one of claims 1 to 21, or its pharmaceutically acceptable salt, isotope derivative, solvate, or its stereoisomer, geometric isomer, tautomer, or its prodrug molecule or metabolite, characterized in that, Selected from the following structures:

23. A pharmaceutical composition, characterized in that, The pharmaceutical composition contains a therapeutically effective amount of any one of claims 1 to 22, or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule or metabolite thereof.

24. Use of any compound of claims 1 to 22 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 23 in the preparation of a medicament for treating Cbl-b mediated diseases or conditions and related diseases or conditions.

25. Use of any compound of claims 1 to 22 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 23 in the treatment of Cbl-b mediated diseases or conditions and related diseases or conditions.

26. 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 22 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 23 thereof, wherein the disease being treated and / or prevented is a Cbl-b mediated disease or condition and related diseases or conditions.

27. The use as described in claims 24 and 25, or the method as described in claim 26, characterized in that, The Cbl-b-mediated diseases or conditions and related diseases or conditions are tumors, selected from lymphoma, solitary fibrous tumors, colon cancer, esophageal cancer, breast cancer, bile duct cancer, liver cancer, kidney cancer, gastric cancer, esophagogastric junction cancer, melanoma, pleural mesothelioma, urothelial carcinoma, cervical cancer, diffuse large B-cell lymphoma (DLBCL), Richter syndrome, 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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