Benzoheterocycle compound as VAV1 degradation agent and application thereof

Abstract

The invention provides a benzoheterocycle compound serving as a VAV1 degradation agent and application of the benzoheterocycle compound. Specifically provided are a compound represented by formula (I), a tautomer, a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof. The compound provided by the invention is good in drug effect and can be used for preparing drugs for treating or preventing VAV1 related diseases.

Description

Technical Field

[0001] This invention provides a class of benzo[a]heterocyclic compounds as VAV1 degrading agents and their uses. Specifically, it provides compounds of formula (I), their tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs. The compounds provided by this invention have good pharmacological efficacy and can be used to prepare drugs for the treatment or prevention of VAV1-related diseases. Background Technology

[0002] Drug-induced targeted protein degradation (TPD) is an emerging therapeutic strategy. This technology utilizes two naturally occurring protein degradation systems within human cells—the ubiquitin-proteasome system (UPS) and the lysosomal degradation system—to break down and degrade key disease-related proteins, thereby achieving therapeutic effects. Currently, technologies such as molecular glues, proteolytic targeted chimeras, lysosomal targeted chimeras, autophagy targeted chimeras, and autophagy-linked compounds have been developed. Several drugs based on the molecular glue principle have been approved for marketing, demonstrating good efficacy. The clinical success and future potential of molecular glues have prompted pharmaceutical companies to increasingly focus on the development of related drugs.

[0003] The VAV family of proteins, including VAV1, VAV2, and VAV3, are Rho family GTPases and guanylate exchange factors (GEFs). VAV1 is a 95 kDa protein and a positive regulator of T cell receptor (TCR) and B cell receptor (BCR) signaling. VAV1 is primarily expressed in human hematopoietic cells, including T cells, B cells, monocytes, natural killer (NK) cells, granulocytes, and dendritic cells, while its family members VAV2 and VAV3 are expressed more broadly. VAV1 is rapidly phosphorylated in response to various stimuli, such as those from T cell receptors, B cell receptors, and various cytokine receptors. In hematopoietic cells (such as T cells, B cells, natural killer cells, and osteoclasts), VAV1 regulates various cellular functions and signaling pathways by activating certain GTPases. VAV1-mediated functions include gene transcription and the development and activation of immune cells, such as T cells and B cells.

[0004] Genome-wide CRISPR-Cas9 screening confirmed that VAV1 is a crucial positive regulator of T cell activation / function. VAV1 promotes the proliferation of cells sensitive to the TCR signaling pathway, such as human Jurkat T cells and primary human CD4+ and CD8+ T cells. Furthermore, data from VAV1 knockout mice indicate that VAV1 plays a key role in T / B lymphocyte function and antigen receptor signaling, particularly in T cells. More importantly, VAV1-deficient mouse thymocytes and spleen T cells exhibit multiple defects in TCR-mediated signaling, such as impaired calcium (Ca2+) mobilization and transcription factor activation. In contrast, T cells lacking VAV1 GEF activity (VAV1 L334A / K335A) exhibit normal TCR-mediated Ca2+ influx and nuclear factor-activated T cell (NFAT) activation. This demonstrates that both VAV1 GEF activity and scaffold function play important roles in the TCR signaling pathway.

[0005] Genetic analysis revealed that rodents carrying the VAV1 R63W variant exhibited lower susceptibility to experimental autoimmune encephalomyelitis (EAE) and palmitoyl-induced arthritis compared to wild-type (WT) mice. In an antigen-induced arthritis (AIA) mouse model, VAV1 knockout mice showed fewer disease symptoms (such as inflammation, synovial thickening, and cartilage degradation), reduced T cell proliferation, and decreased joint infiltration of CD4+ T cells, neutrophils, and macrophages compared to wild-type (WT) mice. This further demonstrates the crucial role of VAV1 in T cell differentiation and function. Therefore, VAV1 may serve as a therapeutic target for immune-mediated diseases. Summary of the Invention

[0006] In a first aspect, the present invention provides compounds of formula (I), their tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs.

[0007]

[0008] in,

[0009] Ring A is a 7-12 membered heterocyclic alkyl, a 7-12 membered heterocyclic alkenyl, a 7-12 membered heteroaryl, a 5-6 membered sulfur-containing heterocyclic alkyl, a 5-6 membered sulfur-containing heterocyclic alkenyl, or a 5-10 membered sulfur-containing heteroaryl;

[0010] R1 is H, D, halogen, CN, or C. 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 Alkyne group, 4-10 membered heterocyclic alkyl group, wherein the C 1-6 Alkyl, -OC 1-6Alkyl, C 3-6 cycloalkyl, C 2-6 The alkynyl group and the 4-10 membered heterocyclic alkyl group are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. 1a replace;

[0011] Each R 1a Each can be independently H, halogen, OH, NH2, CN, or C. 1-6 alkyl;

[0012] R2, R3, and R4 are independently H, D, halogen, NH2, CN, and C, respectively. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0013] Each R5 is independently H, D, halogen, NH2, CN, or C. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0014] Each R6 is independently H, D, halogen, oxo (=O), thio (=S), nitrile (=N), OH, NH2, CN, -P (=O)(OH)2, C 1-6 Alkyl, C 1-6 Alkoxy, -C 0-6 Alkyl-P(=O)(C 1-6 Alkyl)2, -C 0-6 Alkyl-C(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)OC 1-6 Alkyl, -C 0-6 Alkyl-SC 1-6 Alkyl, -C 0-6 Alkyl-S(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-S(=O)2-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)-NR 6b R 6c -C 0-6 Alkyl-OC(=O)-NR 6b R 6c -C 0-6 Alkyl-C 3-8 cycloalkyl, -C 0-6 Alkyl-4-10 membered heterocyclic alkyl, -C 0-6 alkyl-4-10-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-10 heteroaryl, -OC 3-8 cycloalkyl, -L1-C 3-8 Cycloalkyl, -L1-4-10 heterocycloalkyl, or -L1-5-10 heteroaryl, wherein C1-6 Alkyl, C 1-6 Alkoxy, -C 0-6 Alkyl-P(=O)(C 1-6 Alkyl)2, -C 0-6 Alkyl-C(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)OC 1-6 Alkyl, -C 0-6 Alkyl-SC 1-6 Alkyl, -C 0-6 Alkyl-S(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-S(=O)2-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)-NR 6b R 6c -C 0-6 Alkyl-OC(=O)-NR 6b R 6c -C 0-6 Alkyl-C 3-8 cycloalkyl, -C 0-6 Alkyl-4-10 membered heterocyclic alkyl, -C 0-6 alkyl-4-10-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-10 heteroaryl, -OC 3-8 cycloalkyl, -L1-C 3-8 Cycloalkyl, -L1-4-10 heterocycloalkyl, and -L1-5-10 heteroaryl groups are each independently and optionally bound by 1, 2, 3, or 4 R groups. 6a replace;

[0015] Alternatively, the two R6 atoms and the ring atoms they are attached to form a ring, which is C. 3-8 Cycloalkyl or 5-10 membered heterocycloalkyl; wherein, the C 3-8 Cycloalkyl or 5-10 membered heterocyclic alkyl groups are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. 6a replace;

[0016] Each L1 is independently -O-, -N(R) 1L )-、-N(R 1L -C(=O)-, -S-, -S(=O)-, -S(=O)2- or -C(=O)-;

[0017] R 1L For H or C 1-3 alkyl;

[0018] Each R 6aThey are, independently, H, D, halogen, oxo (=O), thio (=S), OH, NH2, CN, and C. 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 Alkyl-C 1-3 Alkoxy or C 1-6 Alkylamino, the C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 Alkyl-C 1-3 Alkoxy, C 1-6 The alkylamino groups can be independently substituted by 1, 2, 3 or 4 R groups;

[0019] R 6b and R 6c H or C, independently respectively 1-6 alkyl;

[0020] Or, R 6b R 6c Together with the nitrogen atom to which it is attached, it forms a 4-7 membered heterocyclic alkyl group, optionally substituted with 1, 2, 3, or 4 Rs; each R is independently H, halogen, OH, NH2, CN, or C. 1-3 alkyl;

[0021] R7 is H, D, halogen, or C. 1-6 alkyl;

[0022] m is 1, 2, or 3;

[0023] n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0024] The term "sulfur-containing" in "5-6 member sulfur-containing heterocyclic alkyl", "5-6 member sulfur-containing heterocyclic alkenyl" or "5-10 member sulfur-containing heteroaryl" refers to the presence of S, S(=O), S(=O)2 or S(=O)(=NH);

[0025] The heteroatomic groups in the "heterocyclic alkyl", "heterocyclic alkenyl" and "heteroaryl" include N, NH, O, S, S(=O), S(=O)2 or S(=O)(=NH), and the number of the heteroatomic groups is 1, 2, 3 or 4; when the number of the heteroatomic groups is multiple, the heteroatomic groups may be the same or different.

[0026] In an optional embodiment of the present invention, the compound represented by formula (I), its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs are included.

[0027]

[0028] in,

[0029] Ring A is a 7-12 membered heterocyclic alkyl, a 7-12 membered heterocyclic alkenyl, a 7-12 membered heteroaryl, a 5-6 membered sulfur-containing heterocyclic alkyl, a 5-6 membered sulfur-containing heterocyclic alkenyl, or a 5-10 membered sulfur-containing heteroaryl;

[0030] R1 is H, D, halogen, CN, or C. 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 Alkyne group, 4-10 membered heterocyclic alkyl group, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 The alkynyl group and the 4-10 membered heterocyclic alkyl group are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. 1a replace;

[0031] Each R 1a Each can be independently H, halogen, OH, NH2, CN, or C. 1-6 alkyl;

[0032] R2, R3, and R4 are independently H, D, halogen, NH2, CN, and C, respectively. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0033] Each R5 is independently H, D, halogen, NH2, CN, or C. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0034] Each R6 is independently H, D, halogen, oxo (=O), thio (=S), nitrile (=N), OH, NH2, CN, -P (=O)(OH)2, C 1-6 Alkyl, C 1-6 Alkoxy, -C 0-6 Alkyl-P(=O)(C 1-6 Alkyl)2, -C 0-6 Alkyl-C(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)OC 1-6 Alkyl, -C 0-6 Alkyl-SC 1-6 Alkyl, -C 0-6 Alkyl-S(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-S(=O)2-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)-NR 6b R 6c -C 0-6 Alkyl-OC(=O)-NR6b R 6c -C 0-6 Alkyl-C 3-8 cycloalkyl, -C 0-6 Alkyl-4-10 membered heterocyclic alkyl, -C 0-6 alkyl-4-10-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-10 heteroaryl, -OC 3-8 cycloalkyl, -L1-C 3-8 Cycloalkyl, -L1-4-10 heterocycloalkyl, or -L1-5-10 heteroaryl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, -C 0-6 Alkyl-P(=O)(C 1-6 Alkyl)2, -C 0-6 Alkyl-C(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)OC 1-6 Alkyl, -C 0-6 Alkyl-SC 1-6 Alkyl, -C 0-6 Alkyl-S(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-S(=O)2-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)-NR 6b R 6c -C 0-6 Alkyl-OC(=O)-NR 6b R 6c -C 0-6 Alkyl-C 3-8 cycloalkyl, -C 0-6 Alkyl-4-10 membered heterocyclic alkyl, -C 0-6 alkyl-4-10-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-10 heteroaryl, -OC 3-8 cycloalkyl, -L1-C 3-8 Cycloalkyl, -L1-4-10 heterocycloalkyl, and -L1-5-10 heteroaryl groups are each independently and optionally bound by 1, 2, 3, or 4 R groups. 6a replace;

[0035] Alternatively, the two R6 atoms and the ring atoms they are attached to form a ring, which is C. 3-8 Cycloalkyl or 5-10 membered heterocyclic alkyl;

[0036] Each L1 is independently -O-, -N(R) 1L )-、-N(R 1L-C(=O)-, -S-, -S(=O)-, -S(=O)2- or -C(=O)-;

[0037] R 1L For H or C 1-3 alkyl;

[0038] Each R 6a They are, independently, H, D, halogen, oxo (=O), thio (=S), OH, NH2, CN, and C. 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 Alkyl-C 1-3 Alkoxy or C 1-6 Alkylamino, the C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 Alkyl-C 1-3 Alkoxy, C 1-6 The alkylamino groups can be independently substituted by 1, 2, 3 or 4 R groups;

[0039] R 6b and R 6c H or C, independently respectively 1-6 alkyl;

[0040] Or, R 6b R 6c Together with the nitrogen atom to which it is attached, it forms a 4-7 membered heterocyclic alkyl group, optionally substituted with 1, 2, 3, or 4 Rs; each R is independently H, halogen, OH, NH2, CN, or C. 1-3 alkyl;

[0041] R7 is H, D, halogen, or C. 1-6 alkyl;

[0042] m is 1, 2, or 3;

[0043] n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0044] The term "sulfur-containing" in "5-6 member sulfur-containing heterocyclic alkyl", "5-6 member sulfur-containing heterocyclic alkenyl" or "5-10 member sulfur-containing heteroaryl" refers to the presence of S, S(=O), S(=O)2 or S(=O)(=NH);

[0045] The heteroatomic groups in the "heterocyclic alkyl", "heterocyclic alkenyl" and "heteroaryl" include N, NH, O, S, S(=O), S(=O)2 or S(=O)(=NH), and the number of the heteroatomic groups is 1, 2, 3 or 4; when the number of the heteroatomic groups is multiple, the heteroatomic groups may be the same or different.

[0046] In an optional embodiment of the present invention, the compound represented by formula (I), its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs are included.

[0047]

[0048] in,

[0049] Ring A is a 7-12 membered heterocyclic alkyl, a 7-12 membered heterocyclic alkenyl, a 7-12 membered heteroaryl, a 5-6 membered sulfur-containing heterocyclic alkyl, a 5-6 membered sulfur-containing heterocyclic alkenyl, or a 5-10 membered sulfur-containing heteroaryl;

[0050] R1 is H, halogen, CN, or C. 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 Alkyne group, 4-10 membered heterocyclic alkyl group, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 The alkynyl group and the 4-10 membered heterocyclic alkyl group are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. 1a replace;

[0051] Each R 1a Each can be independently H, halogen, OH, NH2, CN, or C. 1-6 alkyl;

[0052] R2, R3, and R4 are independently H, halogen, NH2, CN, and C, respectively. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0053] Each R5 is independently H, halogen, NH2, CN, or C. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0054] Each R6 is independently H, halogen, oxo (=O), thio (=S), OH, NH2, CN, -P (=O)(OH)2, C 1-6 Alkyl, C 1-6 Alkoxy, -C 0-6 Alkyl-P(=O)(C 1-6 Alkyl)2, -C 0-6 Alkyl-C(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)-NR 6b R 6c -C 0-6 Alkyl-OC(=O)-NR 6b R 6c -C0-6 Alkyl-C 3-8 cycloalkyl, -C 0-6 Alkyl-4-10 membered heterocyclic alkyl, -C 0-6 alkyl-4-10-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-10 heteroaryl, -OC 3-8 cycloalkyl, -L1-C 3-8 Cycloalkyl or -L1-4-10-membered heterocycloalkyl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, -C 0-6 Alkyl-P(=O)(C 1-6 Alkyl)2, -C 0-6 Alkyl-C(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)-NR 6b R 6c -C 0-6 Alkyl-OC(=O)-NR 6b R 6c -C 0-6 Alkyl-C 3-8 cycloalkyl, -C 0-6 Alkyl-4-10 membered heterocyclic alkyl, -C 0-6 alkyl-4-10-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-10 heteroaryl, -OC 3-8 cycloalkyl, -L1-C 3-8 Cycloalkyl and -L1-4-10-membered heterocycloalkyl groups are each independently and optionally bound by 1, 2, 3 or 4 R groups. 6a replace;

[0055] Each L1 is independently -O-, -N(R) 1L )-、-N(R 1L -C(=O)-, -S-, -S(=O)-, -S(=O)2- or -C(=O)-;

[0056] R 1L For H or C 1-3 alkyl;

[0057] Each R 6a The independent components are H, halogen, oxo (=O), thio (=S), OH, NH2, CN, and C, respectively. 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 Alkyl-C 1-3 Alkoxy or C 1-6 Alkylamino, the C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3Alkyl-C 1-3 Alkoxy and C 1-6 The alkylamino groups can be independently substituted by 1, 2, 3 or 4 R groups;

[0058] R 6b and R 6c H or C, independently respectively 1-6 alkyl;

[0059] Or, R 6b R 6c Together with the nitrogen atom to which it is attached, it forms a 4-7 membered heterocyclic alkyl group, optionally substituted with 1, 2, 3, or 4 Rs; each R is independently H, halogen, OH, NH2, CN, or C. 1-3 alkyl;

[0060] R7 is H, D, halogen, or C. 1-6 alkyl;

[0061] m is 1, 2, or 3;

[0062] n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0063] The term "sulfur-containing" in "5-6 member sulfur-containing heterocyclic alkyl", "5-6 member sulfur-containing heterocyclic alkenyl" or "5-10 member sulfur-containing heteroaryl" refers to the presence of S, S(=O), S(=O)2 or S(=O)(=NH);

[0064] The heteroatomic groups in the "heterocyclic alkyl", "heterocyclic alkenyl" and "heteroaryl" groups include N, NH, O, S, S(=O), S(=O)2 or

[0065] S(=O)(=NH), wherein the number of heteroatomic groups is 1, 2, 3 or 4; when the number of heteroatomic groups is multiple, the heteroatomic groups may be the same or different.

[0066] In an optional embodiment of the present invention, the compound represented by formula (I), its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs are included.

[0067]

[0068] in,

[0069] Ring A is a 7-12 membered heterocyclic alkyl, a 7-12 membered heterocyclic alkenyl, a 7-12 membered heteroaryl, a 5-6 membered sulfur-containing heterocyclic alkyl, a 5-6 membered sulfur-containing heterocyclic alkenyl, or a 5-10 membered sulfur-containing heteroaryl;

[0070] R1 is H, halogen, CN, or C. 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 cycloalkyl, C2-6 Alkyne group, 4-10 membered heterocyclic alkyl group, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 The alkynyl group and the 4-10 membered heterocyclic alkyl group are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. 1a replace;

[0071] Each R 1a Each can be independently H, halogen, OH, NH2, CN, or C. 1-6 alkyl;

[0072] R2, R3, and R4 are independently H, halogen, NH2, CN, and C, respectively. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0073] Each R5 is independently H, halogen, NH2, CN, or C. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0074] Each R6 is independently H, halogen, oxo (=O), thio (=S), OH, NH2, CN, -P (=O)(OH)2, C 1-6 Alkyl, C 1-6 Alkoxy, -C 0-6 Alkyl-P(=O)(C 1-6 Alkyl)2, -C 0-6 Alkyl-C 3-8 cycloalkyl, -C 0-6 Alkyl-4-10 membered heterocyclic alkyl, -C 0-6 alkyl-4-10-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-10 heteroaryl, -OC 3-8 cycloalkyl, -L1-C 3-8 Cycloalkyl or -L1-4-10-membered heterocycloalkyl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, -C 0-6 Alkyl-P(=O)(C 1-6 Alkyl)2, -C 0-6 Alkyl-C 3-8 cycloalkyl, -C 0-6 Alkyl-4-10 membered heterocyclic alkyl, -C 0-6 alkyl-4-10-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-10 heteroaryl, -OC 3-8 cycloalkyl, -L1-C 3-8 Cycloalkyl and -L1-4-10-membered heterocycloalkyl groups are each independently and optionally bound by 1, 2, 3 or 4 R groups.6a replace;

[0075] Each L1 is independently -O-, -N(R) 1L )-、-N(R 1L -C(=O)-, -S-, -S(=O)-, -S(=O)2- or -C(=O)-;

[0076] R 1L For H or C 1-3 alkyl;

[0077] Each R 6a The independent components are H, halogen, oxo (=O), thio (=S), OH, NH2, CN, and C, respectively. 1-6 Alkyl, -C 1-3 Alkyl-C 1-3 Alkoxy or C 1-6 Alkylamino, the C 1-6 Alkyl, -C 1-3 Alkyl-C 1-3 Alkoxy and C 1-6 The alkylamino group is independently substituted by 1, 2, 3 or 4 Rs; each R is independently H, halogen, OH, NH2 or CN;

[0078] R7 is H, D, halogen, or C. 1-6 alkyl;

[0079] m is 1, 2, or 3;

[0080] n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0081] The term "sulfur-containing" in "5-6 member sulfur-containing heterocyclic alkyl", "5-6 member sulfur-containing heterocyclic alkenyl" or "5-10 member sulfur-containing heteroaryl" refers to the presence of S, S(=O), S(=O)2 or S(=O)(=NH);

[0082] The heteroatomic groups in the "heterocyclic alkyl", "heterocyclic alkenyl" and "heteroaryl" include N, NH, O, S, S(=O), S(=O)2 or S(=O)(=NH), and the number of the heteroatomic groups is 1, 2, 3 or 4; when the number of the heteroatomic groups is multiple, the heteroatomic groups may be the same or different.

[0083] In an optional embodiment of the present invention, the compound represented by formula (I), its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs are included.

[0084]

[0085] in,

[0086] Ring A is a 7-12 membered heterocyclic alkyl, a 7-12 membered heterocyclic alkenyl, a 7-12 membered heteroaryl, a 5-6 membered sulfur-containing heterocyclic alkyl, a 5-6 membered sulfur-containing heterocyclic alkenyl, or a 5-10 membered sulfur-containing heteroaryl;

[0087] R1 is H, halogen, CN, or C. 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 Alkyne group, 4-10 membered heterocyclic alkyl group, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 The alkynyl group and the 4-10 membered heterocyclic alkyl group are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. 1a replace;

[0088] Each R 1a Each can be independently H, halogen, OH, NH2, CN, or C. 1-6 alkyl;

[0089] R2, R3, and R4 are independently H, halogen, NH2, CN, and C, respectively. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0090] Each R5 is independently H, halogen, NH2, CN, or C. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0091] Each R6 is independently H, halogen, oxo (=O), thio (=S), OH, NH2, CN, -P (=O)(OH)2, C 1-6 Alkyl, C 1-6 Alkoxy, -C 0-6 Alkyl-P(=O)(C 1-6 Alkyl)2, -C 0-6 Alkyl-C 3-8 cycloalkyl, -C 0-6 Alkyl-4-10 membered heterocyclic alkyl, -C 0-6 alkyl-4-10-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-10 heteroaryl, -OC 3-8 cycloalkyl, -L1-C 3-8 Cycloalkyl or -L1-4-10-membered heterocycloalkyl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, -C 0-6 Alkyl-P(=O)(C 1-6 Alkyl)2, -C 0-6 Alkyl-C 3-8 cycloalkyl, -C0-6 Alkyl-4-10 membered heterocyclic alkyl, -C 0-6 alkyl-4-10-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-10 heteroaryl, -OC 3-8 cycloalkyl, -L1-C 3-8 Cycloalkyl and -L1-4-10-membered heterocycloalkyl groups are each independently and optionally bound by 1, 2, 3 or 4 R groups. 6a replace;

[0092] Each L1 is independently -O-, -N(R) 1L )-、-N(R 1L -C(=O)-, -S-, -S(=O)-, -S(=O)2- or -C(=O)-;

[0093] R 1L For H or C 1-3 alkyl;

[0094] Each R 6a The independent components are H, halogen, oxo (=O), thio (=S), OH, NH2, CN, and C, respectively. 1-6 Alkyl, Halogenated C 1-6 Alkyl or -C 1-3 Alkyl-C 1-3 Alkoxy, the C 1-6 Alkyl, Halogenated C 1-6 Alkyl and -C 1-3 Alkyl-C 1-3 The alkoxy groups are independently substituted by 1, 2, 3 or 4 R groups;

[0095] Each R is independently H, halogen, OH, NH2, or CN;

[0096] R7 is H, D, halogen, or C. 1-6 alkyl;

[0097] m is 1, 2, or 3;

[0098] n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0099] The term "sulfur-containing" in "5-6 member sulfur-containing heterocyclic alkyl", "5-6 member sulfur-containing heterocyclic alkenyl" or "5-10 member sulfur-containing heteroaryl" refers to the presence of S, S(=O), S(=O)2 or S(=O)(=NH);

[0100] The heteroatomic groups in the "heterocyclic alkyl", "heterocyclic alkenyl" and "heteroaryl" groups include N, NH, O, S, S(=O), S(=O)2 or

[0101] S(=O)(=NH), wherein the number of heteroatomic groups is 1, 2, 3 or 4; when the number of heteroatomic groups is multiple, the heteroatomic groups may be the same or different.

[0102] In an optional embodiment of the present invention, the compound represented by formula (I), its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs are included.

[0103]

[0104] in,

[0105] Ring A is a 7-12 membered heterocyclic alkyl, a 7-12 membered heterocyclic alkenyl, a 7-12 membered heteroaryl, a 5-6 membered sulfur-containing heterocyclic alkyl, a 5-6 membered sulfur-containing heterocyclic alkenyl, or a 5-10 membered sulfur-containing heteroaryl;

[0106] R1 is H, halogen, CN, or C. 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 Alkyne group, 4-10 membered heterocyclic alkyl group, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 The alkynyl group and the 4-10 membered heterocyclic alkyl group are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. 1a replace;

[0107] Each R 1a Each can be independently H, halogen, OH, NH2, CN, or C. 1-6 alkyl;

[0108] R2, R3, and R4 are independently H, halogen, NH2, CN, and C, respectively. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0109] Each R5 is independently H, halogen, NH2, CN, or C. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0110] Each R6 is independently H, halogen, oxo (=O), thio (=S), OH, NH2, CN, C 1-6 Alkyl, C 1-6 Alkoxy, -C 0-6 Alkyl-C 3-8 cycloalkyl, -C 0-6 Alkyl-4-10 membered heterocyclic alkyl, -C 0-6 alkyl-4-10-membered heterocyclic alkenyl, -C 0-6Alkyl-5-10 heteroaryl, -OC 3-8 cycloalkyl, -L1-C 3-8 Cycloalkyl or -L1-4-10-membered heterocycloalkyl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, -C 0-6 Alkyl-C 3-8 cycloalkyl, -C 0-6 Alkyl-4-10 membered heterocyclic alkyl, -C 0-6 alkyl-4-10-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-10 heteroaryl, -OC 3-8 cycloalkyl, -L1-C 3-8 Cycloalkyl and -L1-4-10-membered heterocycloalkyl groups are each independently and optionally bound by 1, 2, 3 or 4 R groups. 6a replace;

[0111] Each L1 is independently -O-, -N(R) 1L )-、-N(R 1L -C(=O)-, -S-, -S(=O)-, -S(=O)2- or -C(=O)-;

[0112] R 1L For H or C 1-3 alkyl;

[0113] Each R 6a The independent components are H, halogen, oxo (=O), thio (=S), OH, NH2, CN, and C, respectively. 1-6 Alkyl, Halogenated C 1-6 Alkyl or -C 1-3 Alkyl-C 1-3 Alkoxy, the C 1-6 Alkyl, Halogenated C 1-6 Alkyl and -C 1-3 Alkyl-C 1-3 The alkoxy groups are independently substituted by 1, 2, 3 or 4 R groups;

[0114] Each R is independently H, halogen, OH, NH2, or CN;

[0115] R7 is H, D, halogen, or C. 1-6 alkyl;

[0116] m is 1, 2, or 3;

[0117] n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0118] The term "sulfur-containing" in "5-6 member sulfur-containing heterocyclic alkyl", "5-6 member sulfur-containing heterocyclic alkenyl" or "5-10 member sulfur-containing heteroaryl" refers to the presence of S, S(=O), S(=O)2 or S(=O)(=NH);

[0119] The heteroatomic groups in the "heterocyclic alkyl", "heterocyclic alkenyl" and "heteroaryl" include N, NH, O, S, S(=O), S(=O)2 or S(=O)(=NH), and the number of the heteroatomic groups is 1, 2, 3 or 4; when the number of the heteroatomic groups is multiple, the heteroatomic groups may be the same or different.

[0120] In an optional embodiment of the present invention, the compound represented by formula (I), its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs are included.

[0121]

[0122] in,

[0123] Ring A is a 7-12 membered heterocyclic alkyl, a 7-12 membered heterocyclic alkenyl, a 7-12 membered heteroaryl, a 5-6 membered sulfur-containing heterocyclic alkyl, a 5-6 membered sulfur-containing heterocyclic alkenyl, or a 5-10 membered sulfur-containing heteroaryl;

[0124] R1 is H, halogen, CN, or C. 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 Alkyne group, 4-10 membered heterocyclic alkyl group, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 The alkynyl group and the 4-10 membered heterocyclic alkyl group are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. 1a replace;

[0125] Each R 1a Each can be independently H, halogen, OH, NH2, CN, or C. 1-6 alkyl;

[0126] R2, R3, and R4 are independently H, halogen, NH2, CN, and C, respectively. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0127] Each R5 is independently H, halogen, NH2, CN, or C. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0128] Each R6 is independently H, halogen, oxo (=O), thio (=S), OH, NH2, CN, C1-6 Alkyl, C 1-6 Alkoxy, -C 0-6 Alkyl-C 3-8 cycloalkyl, -C 0-6 Alkyl-4-10 membered heterocyclic alkyl, -C 0-6 alkyl-4-10-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-10 heteroaryl or -OC 3-8 cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, -C 0-6 Alkyl-C 3-8 cycloalkyl, -C 0-6 Alkyl-4-10 membered heterocyclic alkyl, -C 0-6 alkyl-4-10-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-10 heteroaryl and -OC 3-8 The cycloalkyl group is independently and optionally surrounded by 1, 2, 3 or 4 R groups. 6a replace;

[0129] Each R 6a The independent components are H, halogen, oxo (=O), thio (=S), OH, NH2, CN, and C, respectively. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0130] R7 is H, D, halogen, or C. 1-6 alkyl;

[0131] m is 1, 2, or 3;

[0132] n is 1, 2, 3, 4, 5, 6, 7 or 8;

[0133] The term "sulfur-containing" in "5-6 member sulfur-containing heterocyclic alkyl", "5-6 member sulfur-containing heterocyclic alkenyl" or "5-10 member sulfur-containing heteroaryl" refers to the presence of S, S(=O), S(=O)2 or S(=O)(=NH);

[0134] The heteroatomic groups in the "heterocyclic alkyl", "heterocyclic alkenyl" and "heteroaryl" groups include N, NH, O, S, S(=O), S(=O)2 or

[0135] S(=O)(=NH), wherein the number of heteroatomic groups is 1, 2, 3 or 4; when the number of heteroatomic groups is multiple, the heteroatomic groups may be the same or different.

[0136] In an optional embodiment of the present invention, the compound represented by formula (I), its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs are included.

[0137]

[0138] in,

[0139] Ring A is a 7-10 member heterocyclic alkyl, 7-10 member heterocyclic alkenyl, 7-10 member heteroaryl, 5-6 member sulfur-containing heterocyclic alkyl, 5-6 member sulfur-containing heterocyclic alkenyl or 5-10 member sulfur-containing heteroaryl;

[0140] R1 is H, halogen, CN, or C. 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 Alkyne group, 4-10 membered heterocyclic alkyl group, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 The alkynyl group and the 4-10 membered heterocyclic alkyl group are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. 1a replace;

[0141] Each R 1a Each can be independently H, halogen, OH, NH2, CN, or C. 1-6 alkyl;

[0142] R2, R3, and R4 are independently H, halogen, NH2, CN, and C, respectively. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0143] Each R5 is independently H, halogen, NH2, CN, or C. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0144] Each R6 is independently H, halogen, oxo (=O), thio (=S), OH, NH2, CN, C 1-6 Alkyl, -C 0-6 Alkyl-C 3-8 cycloalkyl, -C 0-6 Alkyl-4-10 membered heterocyclic alkyl, -C 0-6 alkyl-4-10-membered heterocyclic alkenyl or -C 0-6 alkyl-5-10 heteroaryl, wherein C 1-6 Alkyl, -C 0-6 Alkyl-C 3-8 cycloalkyl, -C 0-6 Alkyl-4-10 membered heterocyclic alkyl, -C 0-6 alkyl-4-10-membered heterocyclic alkenyl and -C 0-6 The alkyl-5-10 heteroaryl groups are independently and optionally surrounded by 1, 2, 3 or 4 R groups. 6a replace;

[0145] Each R 6a The independent components are H, halogen, oxo (=O), thio (=S), OH, NH2, CN, and C, respectively. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0146] R7 is H, D, halogen, or C. 1-6 alkyl;

[0147] m is 1, 2, or 3;

[0148] n is 1, 2, 3 or 4;

[0149] The term "sulfur-containing" in "5-6 member sulfur-containing heterocyclic alkyl", "5-6 member sulfur-containing heterocyclic alkenyl" or "5-10 member sulfur-containing heteroaryl" refers to the presence of S, S(=O), S(=O)2 or S(=O)(=NH);

[0150] The heteroatomic groups in the "heterocyclic alkyl", "heterocyclic alkenyl" and "heteroaryl" include N, NH, O, S, S(=O), S(=O)2 or S(=O)(=NH), and the number of the heteroatomic groups is 1, 2, 3 or 4; when the number of the heteroatomic groups is multiple, the heteroatomic groups may be the same or different.

[0151] In an optional embodiment of the present invention, the compound represented by formula (I), its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs are included.

[0152]

[0153] in,

[0154] Ring A is a 7-10 membered heterocyclic alkyl, a 7-10 membered heterocyclic alkenyl, a 5-6 membered sulfur-containing heterocyclic alkyl, a 5-6 membered sulfur-containing heterocyclic alkenyl, or a 5-10 membered sulfur-containing heteroaryl;

[0155] R1 is H, halogen, CN, or C. 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 Alkyne group, 4-10 membered heterocyclic alkyl group, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 The alkynyl group and the 4-10 membered heterocyclic alkyl group are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. 1a replace;

[0156] Each R 1a They are, independently, H, halogen, OH, NH2, CN, and C. 1-6Alkyl or halogenated C 1-6 alkyl;

[0157] R2, R3, and R4 are independently H, halogen, NH2, CN, and C, respectively. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0158] Each R5 is independently H, halogen, NH2, CN, or C. 1-6 alkyl;

[0159] R6 can be H, halogen, oxometalate (=O), OH, NH2, CN, or C. 1-6 Alkyl, -C 0-6 Alkyl-C 3-8 cycloalkyl, -C 0-6 Alkyl-4-10 membered heterocyclic alkyl, -C 0-6 alkyl-4-10-membered heterocyclic alkenyl or -C 0-6 alkyl-5-10 heteroaryl, wherein C 1-6 Alkyl, -C 0-6 Alkyl-C 3-8 cycloalkyl, -C 0-6 Alkyl-4-10 membered heterocyclic alkyl, -C 0-6 alkyl-4-10-membered heterocyclic alkenyl and -C 0-6 The alkyl-5-10 heteroaryl groups are independently and optionally surrounded by 1, 2, 3 or 4 R groups. 6a replace;

[0160] Each R 6a They are, independently, H, halogen, oxo (=O), OH, NH2, CN, and C, respectively. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0161] R7 is H, D, halogen, or C. 1-6 alkyl;

[0162] m is 1, 2, or 3;

[0163] n is 1, 2, 3 or 4;

[0164] The term "sulfur-containing" in "5-6 member sulfur-containing heterocyclic alkyl", "5-6 member sulfur-containing heterocyclic alkenyl" or "5-10 member sulfur-containing heteroaryl" refers to the presence of S, S(=O), S(=O)2 or S(=O)(=NH);

[0165] The heteroatomic groups in the "heterocyclic alkyl", "heterocyclic alkenyl" and "heteroaryl" include N, NH, O, S, S(=O), S(=O)2 or S(=O)(=NH), and the number of the heteroatomic groups is 1, 2, 3 or 4; when the number of the heteroatomic groups is multiple, the heteroatomic groups may be the same or different.

[0166] In an optional embodiment of the present invention, R1 is H, F, Cl, CN, or C. 1-3 Alkyl, C 2-4 alkynyl group, C 3-4 Cycloalkyl or 4-6 membered heterocycloalkyl, wherein C 1-3 Alkyl, C 2-4 alkynyl group, C 3-4 Cycloalkyl and 4-6 membered heterocycloalkyl groups are each independently and optionally bound by 1, 2, 3 or 4 R groups. 1a

[0167] replace.

[0168] In an optional embodiment of the present invention, R1 is Cl, F, -CH3, -C≡C-CH3,

[0169] In an optional embodiment of the present invention, R1 is Cl, F or -CH3.

[0170] In an optional embodiment of the present invention, the above-mentioned R 1a They are H or F, respectively, independently.

[0171] In an optional embodiment of the present invention, R2, R3 and R4 are each independently H.

[0172] In an optional embodiment of the present invention, each of the above R5 is independently H.

[0173] In an optional embodiment of the present invention, each of the above R7 is independently H or D.

[0174] In an optional embodiment of the present invention, R6 is H, F, Cl, oxo (=O), nitrified (=N), or C. 1-3 Alkyl, C 1-3 Alkoxy, -C 0-6 Alkyl-P(=O)(C 1-3 Alkyl)2, -C 0-6 Alkyl-C(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)OC 1-6 Alkyl, -C 0-6 Alkyl-S(=O)2-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)-NR 6b R 6c -C 0-6 Alkyl-OC(=O)-NR 6b R 6c -C 0-6 Alkyl-C 3-6cycloalkyl, -C 0-6 Alkyl-4-6-membered heterocyclic alkyl, -C 0-6 alkyl-4-6-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-6-membered heteroaryl, -L1-C 3-6 Cycloalkyl, -L1-4-6 heterocycloalkyl or -L1-5-6 heteroaryl, wherein C 1-3 Alkyl, C 1-3 Alkoxy, -C 0-6 Alkyl-P(=O)(C 1-3 Alkyl)2, -C 0-6 Alkyl-C(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)OC 1-6 Alkyl, -C 0-6 Alkyl-S(=O)2-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)-NR 6b R 6c -C 0-6 Alkyl-OC(=O)-NR 6b R 6c -C 0-6 Alkyl-C 3-6 cycloalkyl, -C 0-6 alkyl-4-6-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-6-membered heteroaryl, -L1-C 3-6 Cycloalkyl, -L1-4-6 heterocycloalkyl, and -L1-5-6 heteroaryl groups are each independently and optionally bound by 1, 2, 3, or 4 R groups. 6a replace.

[0175] In an optional embodiment of the present invention, R6 is H, F, Cl, oxo (=O), or C. 1-3 Alkyl, C 1-3 Alkoxy, -C 0-6 Alkyl-P(=O)(C 1-3 Alkyl)2, -C 0-6 Alkyl-C(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-C 3-6 cycloalkyl, -C 0-6 Alkyl-4-6-membered heterocyclic alkyl, -C 0-6 alkyl-4-6-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-6-membered heteroaryl, -L1-C 3-6 Cycloalkyl or -L1-4-6-membered heterocycloalkyl, wherein C 1-3 Alkyl, C 1-3 Alkoxy, -C 0-6Alkyl-P(=O)(C 1-3 Alkyl)2, -C 0-6 Alkyl-C(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-C 3-6 cycloalkyl, -C 0-6 alkyl-4-6-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-6-membered heteroaryl, -L1-C 3-6 Cycloalkyl and -L1-4-6-membered heterocycloalkyl groups are each independently and optionally bound by 1, 2, 3 or 4 R groups. 6a Substitution. In an optional embodiment of the invention, R6 is H, F, Cl, oxo (=O), C. 1-3 Alkyl, C 1-3 Alkoxy, -C 0-6 Alkyl-P(=O)(C 1-3 Alkyl)2, -C 0-6 Alkyl-C 3-6 cycloalkyl, -C 0-6 Alkyl-4-6-membered heterocyclic alkyl, -C 0-6 alkyl-4-6-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-6-membered heteroaryl, -L1-C 3-6 Cycloalkyl or -L1-4-6-membered heterocycloalkyl, wherein C 1-3 Alkyl, C 1-3 Alkoxy, -C 0-6 Alkyl-P(=O)(C 1-3 Alkyl)2, -C 0-6 Alkyl-C 3-6 cycloalkyl, -C 0-6 alkyl-4-6-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-6-membered heteroaryl, -L1-C 3-6 Cycloalkyl and -L1-4-6-membered heterocycloalkyl groups are each independently and optionally bound by 1, 2, 3 or 4 R groups. 6a replace.

[0176] In an optional embodiment of the present invention, R6 is H, Cl, oxo (=O), or C. 1-3 Alkyl, C 1-3 Alkoxy, -C 0-6 Alkyl-P(=O)(C 1-3 Alkyl)2, -C 0-6 Alkyl-C 3-6 cycloalkyl, -C 0-6 Alkyl-4-6-membered heterocyclic alkyl, -C 0-6 alkyl-4-6-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-6-membered heteroaryl, -L1-C 3-6Cycloalkyl or -L1-4-6-membered heterocycloalkyl, wherein C 1-3 Alkyl, C 1-3 Alkoxy, -C 0-6 Alkyl-P(=O)(C 1-3 Alkyl)2, -C 0-6 Alkyl-C 3-6 cycloalkyl, -C 0-6 alkyl-4-6-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-6-membered heteroaryl, -L1-C 3-6 Cycloalkyl and -L1-4-6-membered heterocycloalkyl groups are each independently and optionally bound by 1, 2, 3 or 4 R groups. 6a replace.

[0177] In an optional embodiment of the present invention, R6 is H, Cl, oxo (=O), or C. 1-3 Alkyl, C 1-3 Alkoxy, -C 0-6 Alkyl-C 3-6 cycloalkyl, -C 0-6 Alkyl-4-6-membered heterocyclic alkyl, -C 0-6 alkyl-4-6-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-6-membered heteroaryl, -L1-C 3-6 Cycloalkyl or -L1-4-6-membered heterocycloalkyl, wherein C 1-3 Alkyl, C 1-3 Alkoxy, -C 0-6 Alkyl-C 3-6 cycloalkyl, -C 0-6 alkyl-4-6-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-6-membered heteroaryl, -L1-C 3-6 Cycloalkyl and -L1-4-6-membered heterocycloalkyl groups are each independently and optionally bound by 1, 2, 3 or 4 R groups. 6a replace.

[0178] In an optional embodiment of the present invention, the above-mentioned R 1L It can be H or CH3.

[0179] In an optional embodiment of the present invention, each of the above L1 is independently -O-, -NH-, -NH-C(=O)-, -S-, -S(=O)-, -S(=O)2- or -C(=O)-.

[0180] In an optional embodiment of the present invention, each of the above L1 is independently -O- or -NH-C(=O)-.

[0181] In an optional embodiment of the present invention, R6 is H, Cl, oxo (=O), or C. 1-3 Alkyl, C 1-3Alkoxy, -C 0-6 Alkyl-C 3-6 cycloalkyl, -C 0-6 alkyl-4-6-membered heterocyclic alkenyl or -C 0-6 alkyl-5-6-membered heteroaryl, wherein C 1-3 Alkyl, C 1-3 Alkoxy, -C 0-6 Alkyl-C 3-6 cycloalkyl, -C 0-6 alkyl-4-6-membered heterocyclic alkenyl and -C 0-6 The alkyl-5-6-membered heteroaryl groups are independently and optionally bound by 1, 2, 3 or 4 R groups. 6a replace.

[0182] In an optional embodiment of the present invention, R6 is H, Cl, oxo (=O), or C. 1-3 Alkyl, -C 0-6 Alkyl-C 3-6 cycloalkyl, -C 0-6 alkyl-4-6-membered heterocyclic alkenyl or -C 0-6 Alkyl-5-6-membered heteroaryl, C 1-3 Alkyl, -C 0-6 Alkyl-C 3-6 cycloalkyl, -C 0-6 alkyl-4-6-membered heterocyclic alkenyl and -C 0-6 The alkyl-5-6-membered heteroaryl groups are independently and optionally bound by 1, 2, 3 or 4 R groups. 6a replace.

[0183] In an optional embodiment of the present invention, R6 is H, Cl, oxo (=O), or C. 1-3 Alkyl, -C 0-6 Alkyl-C 3-6 cycloalkyl or -C 0-6 Alkyl-5-6-membered heteroaryl, C 1-3 Alkyl, -C 0-6 Alkyl-C 3-6 cycloalkyl and -C 0-6 The alkyl-5-6-membered heteroaryl groups are independently and optionally bound by 1, 2, 3 or 4 R groups. 6a replace.

[0184] In an optional embodiment of the present invention, R6 is H, F, Cl, oxo (=O), -CH3, -CH2-CH3, -CH(CH3)2, -CH2CH(CH3)2, -OCH3, -O-CH2CH(CH3)2, The -CH3, -CH2-CH3, -CH(CH3)2, -CH2CH(CH3)2, -OCH3, -O-CH2CH(CH3)2, Each of the 1, 2, 3, or 4 R's can be independently selected. 6a replace.

[0185] In an optional embodiment of the present invention, R6 is H, F, Cl, oxo (=O), -CH3, -CH2-CH3, -CH(CH3)2, -CH2CH(CH3)2, -OCH3, -O-CH2CH(CH3)2, The -CH3, -CH2-CH3, -CH(CH3)2, -CH2CH(CH3)2, -OCH3, -O-CH2CH(CH3)2, Each of the 1, 2, 3, or 4 R's can be independently selected. 6a replace.

[0186] In an optional embodiment of the present invention, R6 is H, F, Cl, oxo (=O), -CH3, -CH2-CH3, -CH(CH3)2, -CH2CH(CH3)2, -OCH3, -O-CH2CH(CH3)2, The -CH3, -CH2-CH3, -CH(CH3)2, -CH2CH(CH3)2, -OCH3, -O-CH2CH(CH3)2, Each of the 1, 2, 3, or 4 R's can be independently selected. 6a replace.

[0187] In an optional embodiment of the present invention, R6 is H, Cl, oxo (=O), -CH3, -CH2-CH3, -CH2CH(CH3)2, -OCH3, -O-CH2CH(CH3)2, The -CH3, -CH2-CH3, -CH2CH(CH3)2, -OCH3, -O-CH2CH(CH3)2, Each of the 1, 2, 3, or 4 R's can be independently selected. 6a replace.

[0188] In an optional embodiment of the present invention, R6 is H, Cl, oxo (=O), -CH3, -CH2-CH3, -CH2CH(CH3)2, -OCH3,

[0189] The -CH3, -CH2-CH3, -CH2CH(CH3)2, -OCH3, Each of the 1, 2, 3, or 4 R's can be independently selected. 6a replace.

[0190] In an optional embodiment of the present invention, R6 is H, Cl, oxo(=O), -CH3, -OCH3, The -CH3, -OCH3, Each of the 1, 2, 3, or 4 R's can be independently selected. 6a replace.

[0191] In an optional embodiment of the present invention, R6 is H, Cl, oxo (=O), -CH3, The -CH3, Each of the 1, 2, 3, or 4 R's can be independently selected. 6a replace.

[0192] In an optional embodiment of the present invention, R6 is H, Cl, oxo (=O), -CH3, The -CH3, Each of the 1, 2, 3, or 4 R's can be independently selected. 6a replace.

[0193] In an optional embodiment of the present invention, the above-mentioned R 6a The independent components are H, D, F, Cl, Br, oxo (=O), thio (=S), OH, NH2, CN, and C, respectively. 1-3 Alkyl, C 1-3 Alkoxy, -C 1-3 Alkyl-C 1-3 Alkoxy or C 1-3 Alkylamino, the C 1-3 Alkyl, C 1-6 Alkoxy, -C 1-3 Alkyl-C 1-3 Alkoxy and C 1-3 The alkylamino group is independently substituted by 1, 2, 3 or 4 Rs.

[0194] In an optional embodiment of the present invention, the above-mentioned R 6aThe independent components are H, F, Cl, Br, oxo (=O), thio (=S), OH, NH2, CN, and C, respectively. 1-3 Alkyl, C 1-3 Alkoxy, -C 1-3 Alkyl-C 1-3 Alkoxy or C 1-3 Alkylamino, the C 1-3 Alkyl, C 1-6 Alkoxy, -C 1-3 Alkyl-C 1-3 Alkoxy and C 1-3 The alkylamino group is independently substituted by 1, 2, 3 or 4 Rs.

[0195] In an optional embodiment of the present invention, the above-mentioned R 6a The independent components are H, F, Cl, Br, oxo (=O), thio (=S), OH, NH2, CN, and C, respectively. 1-3 Alkyl, -C 1-3 Alkyl-C 1-3 Alkoxy or C 1-3 Alkylamino, the C 1-3 Alkyl, -C 1-3 Alkyl-C 1-3 Alkoxy and C 1-3 The alkylamino group is independently substituted by 1, 2, 3 or 4 Rs.

[0196] In an optional embodiment of the present invention, each of the above R is independently H, F, Cl, Br, OH, NH2, CN or CH3.

[0197] In an optional embodiment of the present invention, each of the above R is independently H, F, Cl, Br, OH, NH2 or CN.

[0198] In an optional embodiment of the present invention, the above-mentioned R 6a Each can be independently H, D, F, OH, CN, NH2, oxo (=O), CH3, -O-CH3, -O-CHF2, -CH2-OH, -CH2F, -CHF2, -CF3, -CH2-CH2F, -CH2-OCF3, or

[0199] In an optional embodiment of the present invention, the above-mentioned R 6a Each of these can be independently represented as H, F, OH, CN, NH2, oxo (=O), CH3, -O-CH3, -O-CHF2, -CH2-OH, -CH2F, -CHF2, -CF3, -CH2-CH2F, -CH2-OCF3, or In an optional embodiment of the present invention, the above-mentioned R 6aEach can be independently H, F, OH, CN, oxo (=O), CH3, -CH2-OH, -CH2F, -CHF2, -CF3, -CH2-CH2F, -CH2-OCF3, or

[0200] In an optional embodiment of the present invention, the above-mentioned R 6a They can be independently H, F, OH, CN, oxo (=O), CH3, -CH2-OH, -CH2F, -CHF2, -CF3, -CH2-CH2F or -CH2-OCF3.

[0201] In an optional embodiment of the present invention, the above-mentioned R 6a They can be H, F, CN, oxo (=O) or CH3, respectively.

[0202] In an optional embodiment of the present invention, the above-mentioned R 6a They can be H, CN, oxo (=O), or CH3, respectively.

[0203] In an optional embodiment of the present invention, the above-mentioned R 6a They can be H, CN, or CH3 independently.

[0204] In an optional embodiment of the present invention, R6 is H, F, Cl, oxo(=O), -CH3, -CD3, -CHF2, -CF3, -CH2CHF2, -CH2CF3, -OCH3, -OCHF2, -OCF3, -CH(CH3)2, -CH2C(CH3)2OH, -CH2CH2OH, -O-CH2C(CH3)2OH,

[0205] In an optional embodiment of the present invention, R6 is H, F, Cl, oxo (=O), -CH3, -CHF2, -CF3, -CH2CHF2, -CH2CF3, -OCH3, -OCHF2, -OCF3, -CH(CH3)2, -CH2C(CH3)2OH, -CH2CH2OH, -O-CH2C(CH3)2OH,

[0206] In an optional embodiment of the present invention, R6 is H, F, Cl, oxo (=O), -CH3, -CHF2, -CF3, -CH2CHF2, -CH2CF3, -OCH3, -OCHF2, -OCF3, -CH(CH3)2, -CH2C(CH3)2OH, -CH2CH2OH, -O-CH2C(CH3)2OH,

[0207] In an optional embodiment of the present invention, R6 is H, Cl, oxo (=O), -CH3, -CHF2, -CF3, -CH2CHF2, -CH2CF3, -OCHF2, -OCF3, -CH2C(CH3)2OH, -CH2CH2OH, -O-CH2C(CH3)2OH, In an optional embodiment of the present invention, R6 is H, Cl, oxo (=O), -CH3, -CHF2, -CF3, -CH2CHF2, -CH2CF3, -OCHF2, -OCF3, -CH2C(CH3)2OH, -O-CH2C(CH3)2OH, In an optional embodiment of the present invention, R6 is H, Cl, oxo(=O), -CH3, -CHF2, -CH2CHF2, -CH2CF3, -OCHF2, -OCF3, -CH2C(CH3)2OH, In an optional embodiment of the present invention, R6 is H, Cl, oxo (=O), -CH3, -CH2CF3, -OCHF2, -OCF3,

[0208] In an optional embodiment of the present invention, R6 is H, Cl, oxo(=O), -CH3, -CH2CF3,

[0209] In an optional embodiment of the present invention, R6 is H, Cl, oxo (=O), -CH3,

[0210] In an optional embodiment of the present invention, the above-mentioned ring A is a 7-12 membered heterocyclic alkyl group, wherein the 7-12 membered heterocyclic alkyl group is a monocyclic, fused, spirocyclic, or bridged ring.

[0211] In an optional embodiment of the present invention, the above-mentioned ring A is a 7-12 membered heterocyclic alkenyl group, wherein the 7-12 membered heterocyclic alkenyl group is a monocyclic, fused, spirocyclic, or bridged ring.

[0212] In an optional embodiment of the present invention, ring A is a 7-12 membered heterocyclic alkyl group, wherein the 7-12 membered heterocyclic alkyl group is a fused ring, a spiro ring, or a bridged ring.

[0213] In an optional embodiment of the present invention, the above-mentioned ring A is a 7-12 membered heterocyclic alkenyl group, wherein the 7-12 membered heterocyclic alkenyl group is a fused ring, a spiro ring, or a bridged ring.

[0214] In an optional embodiment of the present invention, the above-mentioned ring A is a 7-12 member heteroaryl group, and the 7-12 member heteroaryl group is a fused ring.

[0215] In an optional embodiment of the present invention, the above-mentioned ring A is a 7-10 membered heterocyclic alkyl group, wherein the 7-10 membered heterocyclic alkyl group is a fused ring, a spiro ring, or a bridged ring.

[0216] In an optional embodiment of the present invention, the above-mentioned ring A is a 7-10 membered heterocyclic alkenyl group, wherein the 7-10 membered heterocyclic alkenyl group is a fused ring, a spiro ring, or a bridged ring.

[0217] In an optional embodiment of the present invention, the above-mentioned ring A is a 7-10 member heteroaryl group, wherein the 7-10 member heteroaryl group is a fused ring.

[0218] In an optional embodiment of the present invention, the above-mentioned ring A is a 5-6 member sulfur-containing heterocyclic alkyl group, a 5-6 member sulfur-containing heterocyclic alkenyl group, or a 5-6 member sulfur-containing heteroaryl group.

[0219] In an optional embodiment of the present invention, ring A is a 7-9 membered heterocyclic alkyl group, a 7-9 membered heterocyclic alkenyl group, a 5-6 membered sulfur-containing heterocyclic alkyl group, a 5-6 membered sulfur-containing heterocyclic alkenyl group, or a 5-6 membered sulfur-containing heteroaryl group.

[0220] In an optional embodiment of the present invention, ring A is...

[0221] In an optional embodiment of the present invention, ring A is...

[0222]

[0223] In an optional embodiment of the present invention, ring A is...

[0224] In an optional embodiment of the present invention, ring A is...

[0225] In an optional embodiment of the present invention, ring A is...

[0226] In an optional embodiment of the present invention, ring A is...

[0227] In one optional embodiment of the present invention for

[0228] In one optional embodiment of the present invention for

[0229] In one optional embodiment of the present invention for

[0230] In one optional embodiment of the present invention for

[0231]

[0232] In one optional embodiment of the present invention for

[0233]

[0234] In one optional embodiment of the present invention for

[0235] In one optional embodiment of the present invention for

[0236] In one optional embodiment of the present invention for

[0237] In one optional embodiment of the present invention for

[0238] In an optional embodiment of the present invention, the above compound has an (IA) structure:

[0239]

[0240] The rings A, R1, R2, R3, R4, R5, R6, R7, m, and n mentioned therein have the definitions as described in this invention.

[0241] In an optional embodiment of the present invention, the above compound has a (Ⅰ') structure:

[0242]

[0243] in,

[0244] It can be represented as a single bond or a double bond;

[0245] T represents O, S, and NR. x C(R) x 2. N or CR x ;

[0246] E1 is a single bond, O, S, NR6, or C(R6)2;

[0247] E2 and E3 are independently O, S, NR6 or C(R6)2, respectively;

[0248] R x and R y Each is independently R6, and in this case, E1 is O, S, NR6 or C(R6)2;

[0249] Or, R x and R y Together with the attached ring atom, it forms a ring substituted with 1, 2, 3 or 4 R6 atoms, wherein the ring is a 5-6 membered heterocyclic alkyl, 5-6 membered heterocyclic alkenyl, 5-6 membered heteroaryl or phenyl; E1 is a single bond, O, S, NR6 or C(R6)2;

[0250] m, R1, R2, R3, R4, R5, R6 and R7 are as defined in this invention.

[0251] In an optional embodiment of the present invention, the above compound has a (Ⅰ-1) structure:

[0252]

[0253] in,

[0254] E1 is a single bond, O, S, NR6, or C(R6)2;

[0255] E2 and E3 are independently O, S, NR6 or C(R6)2, respectively;

[0256] R x and R y Each is independently R6, and in this case, E1 is O, S, NR6 or C(R6)2;

[0257] Or, R x and R y Together with the attached ring atom, it forms a heterocycle substituted with 1, 2, 3 or 4 R6 atoms, wherein the heterocycle is a 5-6 membered heterocyclic alkyl, 5-6 membered heterocyclic alkenyl or 5-6 membered heteroaryl; E1 is a single bond, O, S, NR6 or C(R6)2;

[0258] m, R1, R2, R3, R4, R5, R6 and R7 are as defined in this invention.

[0259] In an optional embodiment of the present invention, the above compound has a (Ⅰ-2) structure:

[0260]

[0261] in,

[0262] E1 is a single bond, O, S, NR6, or C(R6)2;

[0263] E2 and E3 are independently O, S, NR6 or C(R6)2, respectively;

[0264] R x and R y Each is independently R6, and in this case, E1 is O, S, NR6 or C(R6)2;

[0265] Or, R x and R y Together with the attached ring atom, it forms a ring substituted with 1, 2, 3 or 4 R6 atoms, wherein the ring is a 5-6 membered heterocyclic alkyl, 5-6 membered heterocyclic alkenyl or 5-6 membered heteroaryl or phenyl; E1 is a single bond, O, S, NR6 or C(R6)2;

[0266] m, R1, R2, R3, R4, R5, R6 and R7 are as defined in this invention.

[0267] In an optional embodiment of the present invention, the above compound has a (Ⅰ-1A) structure:

[0268]

[0269] in,

[0270] E1 is O, S, NR6 or C(R6)2;

[0271] E2 and E3 are independently O, S, NR6 or C(R6)2, respectively;

[0272] m, R1, R2, R3, R4, R5, R6 and R7 are as defined in claim 1.

[0273] In an optional embodiment of the present invention, the above-mentioned compound has a (I-1B) or (I-1C) structure:

[0274]

[0275]

[0276] in,

[0277] It can be represented as a single bond or a double bond;

[0278] E1 is a single bond, O, S, NR6, or C(R6)2;

[0279] E2 and E3 are independently O, S, NR6 or C(R6)2, respectively;

[0280] T1, T2 and T3 are independently C(=O), O, S, NR6, C(R6)2, N or CR6, respectively;

[0281] T4, T5, T6 and T7 are independently C(=O), O, S, NR6, C(R6)2, N or CR6, respectively;

[0282] m, R1, R2, R3, R4, R5, R6 and R7 are as defined in this invention.

[0283] In an optional embodiment of the present invention, the above compound has a (Ⅰ-2A) structure:

[0284]

[0285] in,

[0286] It can be represented as a single bond or a double bond;

[0287] E1 is a single bond, O, S, NR6, or C(R6)2;

[0288] E2 and E3 are independently O, S, NR6 or C(R6)2, respectively;

[0289] T4, T5, T6 and T7 are independently C(=O), O, S, NR6, C(R6)2, N or CR6, respectively;

[0290] m, R1, R2, R3, R4, R5, R6 and R7 are as defined in this invention.

[0291] In an optional embodiment of the present invention, the above-mentioned R x For H, F, Cl, oxo (=O), C 1-3 Alkyl, C 1-3 Alkoxy, -C 0-6 Alkyl-P(=O)(C 1-3 Alkyl)2, -C 0-6 Alkyl-C(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)OC 1-6 Alkyl, -C 0-6 Alkyl-S(=O)2-C 1-6 Alkyl, -C0-6 Alkyl-C(=O)-NR 6b R 6c -C 0-6 Alkyl-OC(=O)-NR 6b R 6c -C 0-6 Alkyl-C 3-6 cycloalkyl, -C 0-6 Alkyl-4-6-membered heterocyclic alkyl, -C 0-6 alkyl-4-6-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-6-membered heteroaryl, -L1-C 3-6 Cycloalkyl, -L1-4-6 heterocycloalkyl or -L1-5-6 heteroaryl, wherein C 1-3 Alkyl, C 1-3 Alkoxy, -C 0-6 Alkyl-P(=O)(C 1-3 Alkyl)2, -C 0-6 Alkyl-C(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)OC 1-6 Alkyl, -C 0-6 Alkyl-S(=O)2-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)-NR 6b R 6c -C 0-6 Alkyl-OC(=O)-NR 6b R 6c -C 0-6 Alkyl-C 3-6 cycloalkyl, -C 0-6 alkyl-4-6-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-6-membered heteroaryl, -L1-C 3-6 Cycloalkyl, -L1-4-6 heterocycloalkyl, and -L1-5-6 heteroaryl groups are each independently and optionally bound by 1, 2, 3, or 4 R groups. 6a replace.

[0292] In an optional embodiment of the present invention, the above-mentioned R x For H, F, Cl, oxo (=O), C 1-3 Alkyl, C 1-3 Alkoxy, -C 0-6 Alkyl-P(=O)(C 1-3 Alkyl)2, -C 0-6 Alkyl-C(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-C 3-6 cycloalkyl, -C 0-6Alkyl-4-6-membered heterocyclic alkyl, -C 0-6 alkyl-4-6-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-6-membered heteroaryl, -L1-C 3-6 Cycloalkyl or -L1-4-6-membered heterocycloalkyl, wherein C 1-3 Alkyl, C 1-3 Alkoxy, -C 0-6 Alkyl-P(=O)(C 1-3 Alkyl)2, -C 0-6 Alkyl-C(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-C 3-6 cycloalkyl, -C 0-6 alkyl-4-6-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-6-membered heteroaryl, -L1-C 3-6 Cycloalkyl or -L1-4-6-membered heterocycloalkyl groups are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. 6a replace.

[0293] In an optional embodiment of the present invention, the above-mentioned R x For H, F, Cl, oxo (=O), C 1-3 Alkyl, C 1-3 Alkoxy, -C 0-6 Alkyl-P(=O)(C 1-3 Alkyl)2, -C 0-6 Alkyl-C 3-6 cycloalkyl, -C 0-6 Alkyl-4-6-membered heterocyclic alkyl, -C 0-6 alkyl-4-6-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-6-membered heteroaryl, -L1-C 3-6 Cycloalkyl or -L1-4-6-membered heterocycloalkyl, wherein C 1-3 Alkyl, C 1-3 Alkoxy, -C 0-6 Alkyl-P(=O)(C 1-3 Alkyl)2, -C 0-6 Alkyl-C 3-6 cycloalkyl, -C 0-6 alkyl-4-6-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-6-membered heteroaryl, -L1-C 3-6 Cycloalkyl or -L1-4-6-membered heterocycloalkyl groups are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. 6a replace.

[0294] In an optional embodiment of the present invention, the above-mentioned R x For H, Cl, oxo (=O), C 1-3 Alkyl, C1-3 Alkoxy, -C 0-6 Alkyl-P(=O)(C 1-3 Alkyl)2, -C 0-6 Alkyl-C 3-6 cycloalkyl, -C 0-6 Alkyl-4-6-membered heterocyclic alkyl, -C 0-6 alkyl-4-6-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-6-membered heteroaryl, -L1-C 3-6 Cycloalkyl or -L1-4-6-membered heterocycloalkyl, wherein C 1-3 Alkyl, C 1-3 Alkoxy, -C 0-6 Alkyl-P(=O)(C 1-3 Alkyl)2, -C 0-6 Alkyl-C 3-6 cycloalkyl, -C 0-6 alkyl-4-6-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-6-membered heteroaryl, -L1-C 3-6 Cycloalkyl or -L1-4-6-membered heterocycloalkyl groups are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. 6a replace.

[0295] In an optional embodiment of the present invention, the above-mentioned R x For H, Cl, oxo (=O), C 1-3 Alkyl, C 1-3 Alkoxy, -C 0-6 Alkyl-C 3-6 cycloalkyl, -C 0-6 Alkyl-4-6-membered heterocyclic alkyl, -C 0-6 alkyl-4-6-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-6-membered heteroaryl, -L1-C 3-6 Cycloalkyl or -L1-4-6-membered heterocycloalkyl, wherein C 1-3 Alkyl, C 1-3 Alkoxy, -C 0-6 Alkyl-C 3-6 cycloalkyl, -C 0-6 alkyl-4-6-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-6-membered heteroaryl, -L1-C 3-6 Cycloalkyl or -L1-4-6-membered heterocycloalkyl groups are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. 6a replace.

[0296] In an optional embodiment of the present invention, the above-mentioned R x For H, Cl, oxo (=O), C 1-3 Alkyl, C 1-3 Alkoxy, -C0-6 Alkyl-C 3-6 cycloalkyl, -C 0-6 alkyl-4-6-membered heterocyclic alkenyl or -C 0-6 alkyl-5-6-membered heteroaryl, wherein C 1-3 Alkyl, C 1-3 Alkoxy, -C 0-6 Alkyl-C 3-6 cycloalkyl, -C 0-6 alkyl-4-6-membered heterocyclic alkenyl and -C 0-6 The alkyl-5-6-membered heteroaryl groups are independently and optionally bound by 1, 2, 3 or 4 R groups. 6a replace.

[0297] In an optional embodiment of the present invention, the above-mentioned R x For H, F, Cl, oxo (=O), -CH3, -CH2-CH3, -CH(CH3)2, -CH2CH(CH3)2, -OCH3, -O-CH2CH(CH3)2, The -CH3, -CH2-CH3, -CH(CH3)2, -CH2CH(CH3)2, -OCH3, -O-CH2CH(CH3)2, Each of the 1, 2, 3, or 4 R's can be independently selected. 6a replace.

[0298] In an optional embodiment of the present invention, the above-mentioned R x For H, F, Cl, oxo (=O), -CH3, -CH2-CH3, -CH(CH3)2, -CH2CH(CH3)2, -OCH3, -O-CH2CH(CH3)2, The -CH3, -CH2-CH3, -CH(CH3)2, -CH2CH(CH3)2, -OCH3, -O-CH2CH(CH3)2, Each of the 1, 2, 3, or 4 R's can be independently selected. 6a replace.

[0299] In an optional embodiment of the present invention, the above-mentioned R x For H, F, Cl, oxo (=O), -CH3, -CH2-CH3, -CH(CH3)2, -CH2CH(CH3)2, -OCH3, -O-CH2CH(CH3)2, The -CH3, -CH2-CH3, -CH(CH3)2, -CH2CH(CH3)2, -OCH3, -O-CH2CH(CH3)2, Each of the 1, 2, 3, or 4 R's can be independently selected. 6a replace.

[0300] In an optional embodiment of the present invention, the above-mentioned R x For H, Cl, oxo (=O), -CH3, -CH2-CH3, -CH2CH(CH3)2, -OCH3, -O-CH2CH(CH3)2, The -CH3, -CH2-CH3, -OCH3, -O-CH2CH(CH3)2, Each of the 1, 2, 3, or 4 R's can be independently selected. 6a replace.

[0301] In an optional embodiment of the present invention, the above-mentioned R x For H, Cl, oxo (=O), -CH3, -CH2-CH3, -CH2CH(CH3)2, -OCH3, The -CH3, -CH2-CH3, -OCH3, Each of the 1, 2, 3, or 4 R's can be independently selected. 6a replace.

[0302] In an optional embodiment of the present invention, the above-mentioned R x For H, Cl, oxo (=O), -CH3, -OCH3, The -CH3, -OCH3, and

[0303] Each of the 1, 2, 3, or 4 R's can be independently selected. 6a replace.

[0304] In an optional embodiment of the present invention, the above-mentioned R 6a Each can be independently H, F, OH, CN, oxo (=O), CH3, -CH2-OH, -CH2F, -CHF2, -CF3, -CH2-CH2F, -CH2-OCF3, or

[0305] In an optional embodiment of the present invention, the above-mentioned R 6aThey can be independently H, F, OH, CN, oxo (=O), CH3, -CH2-OH, -CH2F, -CHF2, -CF3, -CH2-CH2F or -CH2-OCF3.

[0306] In an optional embodiment of the present invention, the above-mentioned R 6a They can be H, F, CN, oxo (=O) or CH3, respectively.

[0307] In an optional embodiment of the present invention, the above-mentioned R x For H, F, Cl, oxo (=O), -CH3, -CHF2, -CF3, -CH2CHF2, -CH2CF3, -OCH3, -OCHF2, -OCF3, -CH2C(CH3)2OH, -CH2CH2OH, -O-CH2C(CH3)2OH,

[0308] In an optional embodiment of the present invention, the above-mentioned R x For H, F, Cl, oxo (=O), -CH3, -CHF2, -CF3, -CH2CHF2, -CH2CF3, -OCH3, -OCHF2, -OCF3, -CH2C(CH3)2OH, -CH2CH2OH, -O-CH2C(CH3)2OH,

[0309] In an optional embodiment of the present invention, the above-mentioned R x For H, F, Cl, oxo (=O), -CH3, -CHF2, -CF3, -CH2CHF2, -CH2CF3, -OCH3, -OCHF2, -OCF3, -CH2C(CH3)2OH, -CH2CH2OH, -O-CH2C(CH3)2OH,

[0310] In an optional embodiment of the present invention, the above-mentioned R x The following are possible combinations of hydroxyl groups: H, Cl, oxo (=O), -CH3, -CHF2, -CF3, -CH2CHF2, -CH2CF3, -OCHF2, -OCF3, -CH2C(CH3)2OH, -CH2CH2OH, -O-CH2C(CH3)2OH.

[0311] In an optional embodiment of the present invention, the above-mentioned R xThe following are possible combinations of hydroxyl groups: H, Cl, oxo (=O), -CH3, -CHF2, -CF3, -CH2CHF2, -CH2CF3, -OCHF2, -OCF3, -CH2C(CH3)2OH, -O-CH2C(CH3)2OH. In an optional embodiment of the present invention, the above-mentioned R x For H, Cl, oxo (=O), -CH3, -CHF2, -CH2CHF2, -CH2CF3, -OCHF2, -OCF3, -CH2C(CH3)2OH, In an optional embodiment of the present invention, the above-mentioned R x For H, Cl, oxo (=O), -CH3, -CH2CF3, -OCHF2, -OCF3,

[0312] In an optional embodiment of the present invention, the above for

[0313] In an optional embodiment of the present invention, the above for

[0314] In an optional embodiment of the present invention, the above for

[0315] In an optional embodiment of the present invention, the above for

[0316] In an optional embodiment of the present invention, the above for

[0317] In an optional embodiment of the present invention, the above for

[0318] In an optional embodiment of the present invention, the above for

[0319] In an optional embodiment of the present invention, the above for

[0320] In an optional embodiment of the present invention, the above for

[0321] In an optional embodiment of the present invention, the above for

[0322] In an optional embodiment of the present invention, the above for

[0323] In an optional embodiment of the present invention, the above for

[0324] In an optional embodiment of the present invention, the above for

[0325] In an optional embodiment of the present invention, the above for

[0326]

[0327] In an optional embodiment of the present invention, R1 is H, D, halogen, CN, or C. 1-6 Alkyl, the C 1-6 Alkyl groups are optionally surrounded by 1, 2, 3 or 4 R's. 1a Replace; each R 1a Each can be independently H, halogen, CN, or C. 1-6 alkyl.

[0328] In an optional embodiment of the present invention, the above-mentioned compound has the structure shown in formula (I-3):

[0329]

[0330] Wherein, R1 is H, D, halogen, or C. 1-3 Alkyl group; preferably, R1 is a halogen;

[0331] R2, R3, R4 and R7 are H, D or halogens; preferably, R2, R3, R4 and R7 are H;

[0332] m is 1, 2, or 3;

[0333] Each R5 is independently H, D, halogen, NH2, CN, or C. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0334] E1 is a single bond, O, S, or C(R6)2;

[0335] E2 and E3 are independently O, S, or C(R6)2; and ring A is a 6-7 membered heterocyclic alkyl group;

[0336] R6 can be H, D, halogen, oxometalate (=O), OH, NH2, CN, or C. 1-6 Alkyl, C 1-6 Alkoxy, -C 0-6 Alkyl-C(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)OC 1-6 Alkyl, -C 0-6 Alkyl-SC 1-6 Alkyl, -C 0-6 Alkyl-S(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-S(=O)2-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)-NR 6b R 6c -C 0-6 Alkyl-OC(=O)-NR 6b R 6c -C 0-6 Alkyl-C 3-8 cycloalkyl, -C 0-6 Alkyl-4-8-membered heterocyclic alkyl, -C 0-6 alkyl-4-8-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-8-membered heteroaryl, -OC 3-8 cycloalkyl, -L1-C 3-8 Cycloalkyl, -L1-4-8 heterocycloalkyl, or -L1-5-8 heteroaryl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, -C 0-6 Alkyl-C(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)OC 1-6 Alkyl, -C 0-6 Alkyl-SC 1-6 Alkyl, -C 0-6 Alkyl-S(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-S(=O)2-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)-NR 6b R 6c -C 0-6 Alkyl-OC(=O)-NR 6b R6c -C 0-6 Alkyl-C 3-8 cycloalkyl, -C 0-6 Alkyl-4-10 membered heterocyclic alkyl, -C 0-6 alkyl-4-8-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-8-membered heteroaryl, -OC 3-8 cycloalkyl, -L1-C 3-8 Cycloalkyl, -L1-4-8 heterocycloalkyl, and -L1-5-8 heteroaryl groups are each independently and optionally bound by 1, 2, 3, or 4 R groups. 6a replace;

[0337] Each L1 is independently -O-, -S-, -S(=O)-, -S(=O)2- or -C(=O)-;

[0338] Alternatively, the two R6 atoms and the ring atoms they are attached to form a ring, which is C. 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl; wherein, the C 3-8 Cycloalkyl or 5-10 membered heterocyclic alkyl groups are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. 6a replace;

[0339] Each R 6a They are, independently, H, D, halogen, oxo (=O), thio (=S), OH, NH2, CN, and C. 1-4 Alkyl, C 1-4 Alkoxy, -C 1-3 Alkyl-C 1-3 Alkoxy or C 1-4 Alkylamino; the C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 Alkyl-C 1-3 Alkoxy, C 1-6 The alkylamino groups can be independently substituted by 1, 2, 3 or 4 R groups;

[0340] Each R is independently H, halogen, OH, NH2, CN, or C. 1-3 alkyl;

[0341] R 6b and R 6c H or C, independently respectively 1-6 alkyl.

[0342] In an optional embodiment of the present invention, the above-mentioned compound has the structure shown in formula (I-4):

[0343]

[0344] Wherein, R1 is H, D, halogen, or C. 1-3 Alkyl group; preferably, R1 is a halogen;

[0345] R2, R3, R4 and R7 are H, D or halogens; preferably, R2, R3, R4 and R7 are H;

[0346] m is 1, 2, or 3;

[0347] Each R5 is independently H, D, halogen, NH2, CN, or C. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0348] E1 is a single bond, O, S, or C(R6)2;

[0349] E2 and E3 are independently O, S or C(R6)2, respectively;

[0350] n is 1, 2, or 3;

[0351] R6 can be H, D, halogen, oxometalate (=O), OH, NH2, CN, or C. 1-6 Alkyl, C 1-6 Alkoxy, -C 0-6 Alkyl-C(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)OC 1-6 Alkyl, -C 0-6 Alkyl-SC 1-6 Alkyl, -C 0-6 Alkyl-S(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-S(=O)2-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)-NR 6b R 6c -C 0-6 Alkyl-OC(=O)-NR 6b R 6c -C 0-6 Alkyl-C 3-8 cycloalkyl, -C 0-6 Alkyl-4-8-membered heterocyclic alkyl, -C 0-6 alkyl-4-8-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-8-membered heteroaryl, -OC 3-8 cycloalkyl, -L1-C 3-8 Cycloalkyl, -L1-4-8 heterocycloalkyl, or -L1-5-8 heteroaryl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, -C 0-6 Alkyl-C(=O)-C1-6 Alkyl, -C 0-6 Alkyl-C(=O)OC 1-6 Alkyl, -C 0-6 Alkyl-SC 1-6 Alkyl, -C 0-6 Alkyl-S(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-S(=O)2-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)-NR 6b R 6c -C 0-6 Alkyl-OC(=O)-NR 6b R 6c -C 0-6 Alkyl-C 3-8 cycloalkyl, -C 0-6 Alkyl-4-10 membered heterocyclic alkyl, -C 0-6 alkyl-4-8-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-8-membered heteroaryl, -OC 3-8 cycloalkyl, -L1-C 3-8 Cycloalkyl, -L1-4-8 heterocycloalkyl, and -L1-5-8 heteroaryl groups are each independently and optionally bound by 1, 2, 3, or 4 R groups. 6a replace;

[0352] Each L1 is independently -O-, -S-, -S(=O)-, -S(=O)2- or -C(=O)-;

[0353] Each R 6a They are, independently, H, D, halogen, oxo (=O), thio (=S), OH, NH2, CN, and C. 1-4 Alkyl, C 1-4 Alkoxy, -C 1-3 Alkyl-C 1-3 Alkoxy or C 1-4 Alkylamino; the C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 Alkyl-C 1-3 Alkoxy, C 1-6 The alkylamino groups can be independently substituted by 1, 2, 3 or 4 R groups;

[0354] Each R is independently H, halogen, OH, NH2, CN, or C. 1-3 alkyl.

[0355] In an optional embodiment of the present invention, the above-mentioned compound has the structure shown in formula (I-5):

[0356]

[0357] Wherein, R1 is H, D, halogen, or C. 1-3 Alkyl group; preferably, R1 is a halogen;

[0358] R2, R3, R4 and R7 are H, D or halogens; preferably, R2, R3, R4 and R7 are H;

[0359] m is 1, 2, or 3;

[0360] Each R5 is independently H, D, halogen, NH2, CN, or C. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0361] E1 is a single bond, O, S, or C(R6)2;

[0362] E2 and E3 are independently O, S or C(R6)2, respectively;

[0363] n is 1, 2, or 3;

[0364] R6 can be H, D, halogen, oxometalate (=O), OH, NH2, CN, or C. 1-6 Alkyl, C 1-6 Alkoxy, -C 0-6 Alkyl-C(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)OC 1-6 Alkyl, -C 0-6 Alkyl-SC 1-6 Alkyl, -C 0-6 Alkyl-S(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-S(=O)2-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)-NR 6b R 6c -C 0-6 Alkyl-OC(=O)-NR 6b R 6c -C 0-6 Alkyl-C 3-8 cycloalkyl, -C 0-6 Alkyl-4-8-membered heterocyclic alkyl, -C 0-6 alkyl-4-8-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-8-membered heteroaryl, -OC 3-8 cycloalkyl, -L1-C 3-8 Cycloalkyl, -L1-4-8 heterocycloalkyl, or -L1-5-8 heteroaryl, wherein C 1-6 Alkyl, C 1-6Alkoxy, -C 0-6 Alkyl-C(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)OC 1-6 Alkyl, -C 0-6 Alkyl-SC 1-6 Alkyl, -C 0-6 Alkyl-S(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-S(=O)2-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)-NR 6b R 6c -C 0-6 Alkyl-OC(=O)-NR 6b R 6c -C 0-6 Alkyl-C 3-8 cycloalkyl, -C 0-6 Alkyl-4-10 membered heterocyclic alkyl, -C 0-6 alkyl-4-8-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-8-membered heteroaryl, -OC 3-8 cycloalkyl, -L1-C 3-8 Cycloalkyl, -L1-4-8 heterocycloalkyl, and -L1-5-8 heteroaryl groups are each independently and optionally bound by 1, 2, 3, or 4 R groups. 6a replace;

[0365] Each L1 is independently -O-, -S-, -S(=O)-, -S(=O)2- or -C(=O)-;

[0366] R 6T For H, D, halogens, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl-OH, C 1-6 Alkoxy, -C 0-6 Alkyl-C 1-6 Alkoxy, -C 0-6 Alkyl-halogenated C 1-6 Alkoxy, -C 0-6 Alkyl-C(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)-NR 6b R 6c -C 0-6 Alkyl-OC(=O)-NR 6b R 6c -C 0-6 Alkyl-S(=O)2-C 1-6 Alkyl, -C0-6 Alkyl-NR 6b R 6c -C 0-6 Alkyl-C 3-6 cycloalkyl, -C 0-6 alkyl-4-6-membered heterocyclic group; wherein the -C 0-6 Alkyl-C 3-6 cycloalkyl, -C 0-6 The alkyl-4-6-membered heterocyclic groups are independently and optionally surrounded by 1, 2, 3 or 4 R groups. 6a replace;

[0367] Each R 6a They are, independently, H, D, halogen, oxo (=O), thio (=S), OH, NH2, CN, and C. 1-4 Alkyl, C 1-4 Alkoxy, -C 1-3 Alkyl-C 1-3 Alkoxy or C 1-4 Alkylamino; the C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 Alkyl-C 1-3 Alkoxy, C 1-6 The alkylamino groups can be independently substituted by 1, 2, 3 or 4 R groups;

[0368] Each R is independently H, halogen, OH, NH2, CN, or C. 1-3 alkyl.

[0369] In an optional embodiment of the present invention, the above-mentioned R 6T For H, -CH3, -CD3, -CHF2, -CF3, -CH2CHF2, -CH2CF3, -OCH3, -OCHF2, -OCF3, -CH(CH3)2, -CH2C(CH3)2OH, -CH2CH2OH, -O-CH2C(CH3)2OH, In an optional embodiment of the present invention, the above compound has the structure shown in formula (I-6):

[0370]

[0371] Wherein, R1 is H, D, halogen, or C. 1-3 Alkyl group; preferably, R1 is a halogen;

[0372] R2, R3, R4 and R7 are H, D or halogens; preferably, R2, R3, R4 and R7 are H;

[0373] m is 1, 2, or 3;

[0374] Each R5 is independently H, D, halogen, NH2, CN, or C. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0375] E1 is a single bond, O, S, or C(R6)2;

[0376] E2 and E3 are independently O, S or C(R6)2, respectively;

[0377] n is 1, 2, or 3;

[0378] R6 can be H, D, halogen, oxometalate (=O), OH, NH2, CN, or C. 1-6 Alkyl, C 1-6 Alkoxy, -C 0-6 Alkyl-C(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)OC 1-6 Alkyl, -C 0-6 Alkyl-SC 1-6 Alkyl, -C 0-6 Alkyl-S(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-S(=O)2-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)-NR 6b R 6c -C 0-6 Alkyl-OC(=O)-NR 6b R 6c -C 0-6 Alkyl-C 3-8 cycloalkyl, -C 0-6 Alkyl-4-8-membered heterocyclic alkyl, -C 0-6 alkyl-4-8-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-8-membered heteroaryl, -OC 3-8 cycloalkyl, -L1-C 3-8 Cycloalkyl, -L1-4-8 heterocycloalkyl, or -L1-5-8 heteroaryl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, -C 0-6 Alkyl-C(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)OC 1-6 Alkyl, -C 0-6 Alkyl-SC 1-6 Alkyl, -C 0-6 Alkyl-S(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-S(=O)2-C1-6 Alkyl, -C 0-6 Alkyl-C(=O)-NR 6b R 6c -C 0-6 Alkyl-OC(=O)-NR 6b R 6c -C 0-6 Alkyl-C 3-8 cycloalkyl, -C 0-6 Alkyl-4-10 membered heterocyclic alkyl, -C 0-6 alkyl-4-8-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-8-membered heteroaryl, -OC 3-8 cycloalkyl, -L1-C 3-8 Cycloalkyl, -L1-4-8 heterocycloalkyl, and -L1-5-8 heteroaryl groups are each independently and optionally bound by 1, 2, 3, or 4 R groups. 6a replace;

[0379] Each L1 is independently -O-, -S-, -S(=O)-, -S(=O)2- or -C(=O)-;

[0380] Each R 6a They are, independently, H, D, halogen, oxo (=O), thio (=S), OH, NH2, CN, and C. 1-4 Alkyl, C 1-4 Alkoxy, -C 1-3 Alkyl-C 1-3 Alkoxy or C 1-4 Alkylamino; the C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 Alkyl-C 1-3 Alkoxy, C 1-6 The alkylamino groups can be independently substituted by 1, 2, 3 or 4 R groups;

[0381] Each R is independently H, halogen, OH, NH2, CN, or C. 1-3 alkyl.

[0382] In an optional embodiment of the present invention, the above compound has the following structure:

[0383]

[0384]

[0385]

[0386]

[0387]

[0388]

[0389]

[0390] In a second aspect, the present invention provides a pharmaceutical composition comprising: a compound as described in the first aspect of the present invention, a tautomer, a stereoisomer, a pharmaceutically acceptable salt or prodrug thereof; and a pharmaceutically acceptable excipient.

[0391] In a third aspect of the present invention, the use of the compounds, tautomers, stereoisomers, pharmaceutically acceptable salts or prodrugs described in the first aspect of the present invention, and the pharmaceutical compositions described in the second aspect of the present invention in the preparation of medicaments for the treatment or prevention of diseases related to VAV1.

[0392] In an optional embodiment of the present invention, the aforementioned VAV1-related diseases include cancer and autoimmune diseases.

[0393] In an optional embodiment of the present invention, the above-mentioned drug is used to treat or prevent cancer and autoimmune diseases.

[0394] In an optional embodiment of the present invention, the aforementioned VAV1-related diseases include systemic lupus erythematosus, myasthenia gravis, periodontitis, type I diabetes, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, autoimmune hepatitis, or psoriasis.

[0395] In an optional embodiment of the present invention, the above-mentioned drug is used for the treatment or prevention of, but not limited to, systemic lupus erythematosus, myasthenia gravis, periodontitis, type I diabetes, rheumatoid arthritis, multiple sclerosis, colitis, inflammatory bowel disease, autoimmune hepatitis, or psoriasis.

[0396] In an optional embodiment of the present invention, the aforementioned VAV1-related diseases include, but are not limited to, systemic lupus erythematosus, myasthenia gravis, periodontitis, type I diabetes, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, autoimmune hepatitis, psoriasis, etc.

[0397] Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.

[0398] Terms and Definitions

[0399] Unless otherwise stated, the terms and definitions used in this application, including those set forth in the specification and claims, are as follows.

[0400] Those skilled in the art will understand that, according to the conventions used in the art, in the structural formula of this application, Used to describe chemical bonds, which are points where a portion or a substituent is connected to a core or skeletal structure.

[0401] Unless otherwise specified, the term "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0402] Unless otherwise specified, the term "pharmaceutically acceptable salt" means a pharmaceutically acceptable non-toxic salt of an acid or base, including salts of inorganic acids and bases, and salts of organic acids and bases.

[0403] In addition to pharmaceutically acceptable salts, the present invention also contemplates other salts. These may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts, or may be used for the identification, characterization, or purification of the compounds of the present invention.

[0404] Unless otherwise specified, the term "pharmaceutical composition" means a mixture of one or more compounds described in this text or their physiologically / pharmaceutical acceptable salts or prodrugs with other chemical components, such as physiologically / pharmaceutical acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compound to a living organism.

[0405] Unless otherwise specified, the term "excipient" refers to a pharmaceutically acceptable inert ingredient. Examples of the term "excipient" include, without limitation, binders, disintegrants, lubricants, flow aids, stabilizers, fillers, and diluents. Excipients enhance the handling properties of pharmaceutical formulations, i.e., by increasing flowability and / or adhesion, making the formulation more suitable for direct compression.

[0406] Unless otherwise specified, the term "prodrug" refers to a compound of the present invention that can be converted into a biologically active form under physiological conditions or by solvation. The prodrugs of the present invention are prepared by modifying functional groups in the compound; such modification can be performed by conventional methods or removed in vivo to obtain the parent compound. Prodrugs comprise compounds formed by attaching a hydroxyl or amino group to any group within the compound of the present invention. When a prodrug of the compound of the present invention is administered to a mammalian individual, the prodrug is cleaved to form free hydroxyl and free amino groups, respectively.

[0407] Unless otherwise specified, the term "stereoisomer" refers to isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, non-corresponding isomers, and conformational isomers.

[0408] Depending on the choice of raw materials and methods, the compounds of the present invention may exist as one or a mixture of possible isomers, for example as purely optical isomers, or as mixtures of isomers, such as racemic and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to the chiral center (or multiple chiral centers) in the molecule. The prefixes D and L or (+) and (–) are symbols used to specify the plane-polarized rotation of light induced by the compound, where (–) or L indicates that the compound is levorotatory. Compounds with the prefix (+) or D are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be called enantiomers, and mixtures of said isomers are generally referred to as mixtures of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or method. Many geometric isomers of alkenes, C=N double bonds, etc., can also exist in the compounds described herein, and all such stable isomers are considered in this invention. When the compounds described herein contain an alkene double bond, unless otherwise stated, such double bond includes E and Z geometric isomers. If the compound contains a disubstituted cycloalkyl group, the substituent of the cycloalkyl group may be in cis or trans (cis- or trans-) configuration.

[0409] When the bonds of the chiral carbon in the formulas of this invention are depicted as straight lines, it should be understood that both the (R) and (S) configurations of the chiral carbon and the resulting enantiomerically pure compounds and mixtures thereof are included within the scope of the general formula. The illustration of racemic or enantiomerically pure compounds in this document is derived from Maehr, J. Chem. Ed. 1985, 62:114-120. Unless otherwise stated, wedge-shaped and dashed bonds represent the absolute configuration of a stereocenter.

[0410] Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral formulations, or resolved using conventional techniques. Compounds of the present invention containing asymmetrically substituted carbon atoms can be separated in either an optically active or racemic form. Resolution of racemic mixtures of compounds can be performed by any of many methods known in the art. Exemplary methods include fractional recrystallization using a chiral resolving acid, which is an optically active salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or various optically active camphorsulfonic acids such as the D and L forms of β-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure α-methylbenzylamine (e.g., S and R forms or diastereoisomeric forms), 2-phenylglycine, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc. Resolution of racemic mixtures can also be achieved by elution onto a chromatographic column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). High-performance liquid chromatography (HPLC) or supercritical fluid chromatography (SFC) can be used. The specific method, elution conditions, and column selection can be chosen by those skilled in the art based on the structure of the compound and experimental results. Furthermore, any enantiomer or diastereomeric form of the compound described in this invention can be obtained through stereoorganic synthesis using optically pure starting materials or reagents with known configurations.

[0411] Unless otherwise specified, the term "tautomer" refers to a functional group isomer resulting from the rapid movement of an atom between two positions in a molecule. The compounds of this invention can exhibit tautomerism. Tautomeric compounds can exist in two or more interconvertible forms. Proton-transfer tautomers arise from the migration of covalently bonded hydrogen atoms between two atoms. Tautomers generally exist in equilibrium form, and attempts to isolate a single tautomer usually produce a mixture whose physicochemical properties are consistent with those of the mixture of compounds. The equilibrium position depends on the intramolecular chemical characteristics. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the ketone form is dominant; while in phenols, the enol form is dominant. This invention encompasses all tautomeric forms of compounds. For example... They can be transformed into each other.

[0412] In examples of the present invention, the proton can occupy two or more positions in the cyclic form of the heterocyclic system, for example, 1H- and 3H-imidazolium, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, tetrazolium, and 1H- and 2H-pyrazole. The tautomer form can be in equilibrium or spatially fixed in one form through appropriate substitution. For example:

[0413]

[0414] Due to resonance, the hydrogen atom of nitrogen in tetrazolium can be on any of the four nitrogen atoms.

[0415] Unless otherwise specified, use wedge-shaped solid line keys ( ) and wedge-shaped dashed key ( The absolute configuration of a solid center is represented by a straight solid line key ( ). ) and straight dashed key ( ) indicates the relative configuration of the solid center.

[0416] The compounds of the present invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes such as deuterium (2H), tritium (3H), iodine-125 (125I), or C-14 (14C). All variations in the isotopic composition of the compounds of the present invention, regardless of radioactivity, are included within the scope of the present invention.

[0417] For pharmaceuticals or pharmacologically active agents, the term "effective amount" or "therapeutic effective amount" refers to a sufficient quantity of a drug or agent that is non-toxic but achieves the desired effect. For the oral dosage forms of this invention, the "effective amount" of one active substance in the composition refers to the quantity required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. A suitable effective amount in any given case can be determined by a person skilled in the art through routine testing.

[0418] Unless otherwise specified, the terms “active ingredient,” “therapeutic agent,” “active substance,” or “active agent” refer to a chemical entity that can effectively treat a target disorder, disease, or condition.

[0419] Unless otherwise specified, the term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, including deuterium and hydrogen variants, provided that the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =O), it can be expressed as the oxidation of atoms such as carbon, nitrogen, and sulfur, including but not limited to C(=O), S(=O), S(=O)2, or N(=O).

[0420] Unless otherwise specified, the terms “optional” or “optionally” refer to events or conditions described below that may but are not required to occur, and the description includes both cases where said events or conditions occur and cases where said events or conditions do not occur.

[0421] The term "optionally substituted" means that it may or may not be substituted, unless otherwise specified, and the type and number of substituents may be arbitrary on the basis of chemical feasibility.

[0422] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is substituted by 0-2 Rs, the group can optionally be substituted by at most two Rs, and the Rs in each case have independent options. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0423] Unless otherwise specified, the term "C" 1-6 "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C 1-6 Alkyl groups include C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-4 C1-C6 and C5 alkyl groups, etc.; they can be monovalent (such as methyl), divalent (such as methylene), or polyvalent (such as methine). Examples of C1-6 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl, and t-butyl), pentyl (including n-pentyl, isopentyl, and neopentyl), hexyl, etc.

[0424] Unless otherwise specified, the term "C" 1-3 "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C 1-3 Alkyl groups include C 1-2 and C 2-3 Alkyl groups, etc.; they can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). C 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), etc.

[0425] The term "halogenated" is used interchangeably with the term "halogenated" when used alone or as part of other substituents.

[0426] Unless otherwise specified, "halogenated alkyl" or "halogen-substituted alkyl" means a saturated aliphatic hydrocarbon group comprising a specific number of carbon atoms, branched and straight-chained and substituted with one or more halogens.

[0427] Unless otherwise specified, "C 2-6"Alkenyl" is used to denote a hydrocarbon group consisting of 2 to 6 carbon atoms, either straight-chain or branched, containing at least one carbon-carbon double bond. The carbon-carbon double bond can be located at any position within the group. The C... 2-6 Alkenes include C 2-4 C 2-3 C4, C3, and C2 alkenyl groups, etc.; they can be monovalent, divalent, or polyvalent. 2-6 Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, etc.

[0428] Unless otherwise specified, "C 2-6 "Alkyne" is used to denote a straight-chain or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon triple bond, which can be located at any position within the group. 2-6 Alkyne groups include C 2-4 C 2-3 C4, C3, and C2 alkynyl groups, etc. They can be monovalent, divalent, or polyvalent. 2-6 Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, and penynyl.

[0429] Unless otherwise specified, the term "C" 1-6 "Alkoxy" refers to alkyl groups containing 1 to 6 carbon atoms that are attached to the rest of the molecule by an oxygen atom. The C 1-6 Alkoxy groups include C 1-4 C 1-3 C 1-2 C 2-6 C 2-4 C6, C5, C4, and C3 alkoxy groups, etc. 1-6 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexoxy, etc.

[0430] Unless otherwise specified, the term "C" 1-3 "Alkoxy" refers to alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule by an oxygen atom. The C 1-3 Alkoxy groups include C 1-2 C 2-3 Examples of C1-3 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy).

[0431] Unless otherwise specified, the term "C" 1-3"Alkylamino" refers to alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule via an amino group. The C 1-3 Alkylamino groups include C 1-2 C3 and C2 alkylamino groups, etc. C 1-3 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -NHCH2CH2CH3, -NHCHCH3)2, etc.

[0432] Unless otherwise specified, the term "C" 3-12 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 12 carbon atoms, including monocyclic and bicyclic systems, wherein bicyclic systems include spirocyclic, fused, and bridged rings. The C3-12 cycloalkyl group includes C 3-10 C 3-8 C 3-6 C 3-5 C 4-8 C 4-6 C 4-5 C 5-8 Or C 5-6 Cycloalkyl groups, etc.; they can be monovalent, divalent, or polyvalent. C 3-8 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2]bicyclooctane, etc.

[0433] Unless otherwise specified, the term "C" 3-8 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 8 carbon atoms, including monocyclic and bicyclic systems, wherein bicyclic systems include spirocyclic, fused, and bridged rings. The C 3-8 Cycloalkyl groups include C 3-6 C 3-5 C 4-8 C 4-6 C 4-5 C 5-8 Or C 5-6 Cycloalkyl groups, etc.; they can be monovalent, divalent, or polyvalent. C 3-8 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2]bicyclooctane, etc.

[0434] Unless otherwise specified, the term "C" 3-6 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which can be monocyclic or bicyclic. 3-6 Cycloalkyl groups include C 3-5 C 4-5 and C 5-6 Cycloalkyl groups, etc.; they can be monovalent, divalent, or polyvalent. C3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0435] Unless otherwise specified, Cn-n+m or Cn-Cn+m includes any specific case of n to n+m carbons, such as C 1-12 Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 C 11 and C 12 It also includes any range from n to n+m, such as C 1-12 Including C 1-3 C 1-6 C 1-9 C 3-6 C 3-9 C 3-12 C 6-9 C 6-12 and C 9-12 Similarly, n-membered to n+m-membered rings represent the number of atoms in the ring from n to n+m. For example, 3-12-membered rings include 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, and 12-membered rings, and also any range from n to n+m. For example, 3-12-membered rings include 3-6-membered, 3-9-membered, 5-6-membered, 5-7-membered, 6-7-membered, 6-8-membered, and 6-10-membered rings, etc.

[0436] When used alone or as part of other substituents, the term "heterocyclic alkyl" refers to a cycloalkyl group in which one or more (in some embodiments, 1 to 3) carbon atoms are replaced by heteroatoms, such as, but not limited to, N, NH, O, S, P, S(=O), S(=O)2, or S(=O)(=NH). The term "mn-membered heterocyclic alkyl" refers to a cycloalkyl group in which the heterocyclic atom is selected from N, NH, O, S, P, S(=O), S(=O)2, or S(=O)(=NH), preferably from N, O, or S. For example, the term "4-8-membered heterocyclic alkyl" should be understood to indicate a saturated ring having 4 to 8 atoms, wherein 1, 2, 3, or 4 ring atoms are selected from N, O, S, P, preferably from N, O, or S. "4-10-membered heterocyclic alkyl" indicates a saturated ring having 4 to 10 atoms. When prefixes such as 4-8 or 4-10 are used to indicate a heterocyclic alkyl group, the number of carbon atoms also implies the inclusion of heteroatoms. Heterocyclic alkyl groups include monocyclic, bicyclic, tricyclic, spirocyclic, and bridged rings. Examples of heterocyclic alkyl groups include: pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydropyridyl, tetrahydropyrrolidinyl, azacyclic butyl, thiazoalkyl, azolealkyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, azacyclic heptyl, diazacyclic heptyl, oxonyl heterocyclic heptyl, etc. The term "heterocyclic alkyl" may be used interchangeably with the term "heteroalkyl ring".

[0437] When used alone or as part of other substituents, the term "aromatic ring" refers to a monocyclic or polycyclic carbon ring having 6 to 20 carbon atoms, wherein at least one ring is an aromatic ring. When one of the rings is a non-aromatic ring, the group can be linked by either an aromatic or non-aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, 2,3-dihydroindenyl, biphenyl, phenanthryl, anthraceneyl, and acenaphthene. The term "aromatic ring" may be used interchangeably with the term "aryl".

[0438] When used alone or as part of other substituents, the term "heteroaromatic ring" refers to a monocyclic or polycyclic carbon ring in which at least one ring atom is a heteroatom independently selected from oxygen, sulfur, and nitrogen, and the remaining ring atoms are carbon atoms, wherein at least one ring is an aromatic ring. The group can be a carbon group or a heteroatom group (i.e., it can be C-linked or N-linked, whichever is possible). When one of the rings is a non-aromatic ring, the group can be linked by an aromatic ring or by a non-aromatic ring. Examples of heteroaromatic groups include, but are not limited to: imidazolyl, acridinel, carbazolyl, cenolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furanyl, thiophenyl, benzothiophenyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridinyl, pyrimidinel, pyrroleyl, N-methylpyrroleyl, and tetrahydroquinoline. The term “heteroaromatic ring” can be used interchangeably with the terms “heteroaromatic ring”, “heteroaryl”, or “heteroaromatic ring group”.

[0439] Unless otherwise specified, the term "5-6 membered heterocyclic alkenyl" on its own or in combination with other terms refers to an unsaturated or partially unsaturated cyclic group consisting of 5 to 6 ring atoms, comprising at least one carbon-carbon double bond, but not an aromatic ring, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen, and sulfur heteroatoms may optionally be oxidized (i.e., C(=O), NO, and S(O)p, where p is 1 or 2). Furthermore, with respect to the "5-6 membered heterocyclic alkenyl," the heteroatom may occupy the connection position between the heterocyclic alkenyl group and the rest of the molecule. The 5-6 membered heterocyclic alkenyl includes 5-membered and 6-membered heterocyclic alkenyl groups, etc.

[0440] Unless otherwise specified, the terms "5-10-membered heteroaryl ring" and "5-10-membered heteroaryl" are used interchangeably in this invention. The term "5-10-membered heteroaryl" refers to a monocyclic group consisting of 5 to 10 ring atoms with a conjugated π-electron system, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)p, where p is 1 or 2). The 5-10-membered heteroaryl group can be attached to the rest of the molecule via a heteroatom or a carbon atom. The 5-10-membered heteroaryl group includes 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, and 10-membered heteroaryl groups. Examples of the 5-10 membered heteroaryl groups include, but are not limited to, pyrrole (including N-pyrrole, 2-pyrrole, and 3-pyrrole), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl), imidazole (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5-oxazolyl), and triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl). (e.g., 4H-1,2,4-triazolyl, tetrazolyl, isoxazolyl (3-isooxazolyl, 4-isooxazolyl and 5-isooxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).

[0441] Unless otherwise specified, the terms "halogenated," "halogenated group," or "halogen" refer to fluorine, chlorine, bromine, and iodine; wherein, "halogenated" indicates substitution by one or more halogens, generally preferably one, two, three, or four; for example, "halogenated C 1-6 "alkyl" indicates a C that has been substituted with one or more halogens. 1-6 alkyl.

[0442] Furthermore, it should be noted that, unless otherwise explicitly stated, the descriptive phrase "...independently" used in this invention should be interpreted broadly, meaning that the described individuals are independent of each other and can independently be the same or different specific groups. More specifically, the descriptive phrase "...independently" can mean either that the specific options expressed by the same symbols in different groups do not affect each other, or that the specific options expressed by the same symbols in the same group do not affect each other.

[0443] Unless otherwise specified, the term "patient" means any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, with human being being the most preferred.

[0444] Unless otherwise specified, the term “therapeutic effective amount” means the amount of an active compound or drug that researchers, veterinarians, physicians or other clinicians are looking for in a tissue, system, animal, individual or human to elicit a biological or medical response, including one or more of the following: (1) prevention of disease: for example, prevention of disease, disorder or condition in an individual who is susceptible to disease, disorder or condition but has not yet experienced or developed the pathology or symptoms of the disease. (2) suppression of disease: for example, suppression of disease, disorder or condition in an individual who is experiencing or developing the pathology or symptoms of the disease (i.e., preventing the further development of the pathology and / or symptoms). (3) relief of disease: for example, relief of disease, disorder or condition in an individual who is experiencing or developing the pathology or symptoms of the disease (i.e., reversal of the pathology and / or symptoms).

[0445] The term "treatment" and other similar synonyms used in this article include the following meanings:

[0446] (i) To prevent the occurrence of disease or condition in mammals, especially when such mammals are susceptible to the disease or condition but have not yet been diagnosed with it;

[0447] (ii) To suppress a disease or symptom, that is, to curb its development;

[0448] (iii) To alleviate a disease or symptom, that is, to cause the condition of the disease or symptom to subside; or

[0449] (iv) To alleviate the symptoms caused by the disease or condition.

[0450] The abbreviations of this invention are defined as follows:

[0451] M: Molar concentration, such as 1M hydrochloric acid, which represents a 1 mol / L hydrochloric acid solution.

[0452] N: Equivalent concentration, for example, 2N hydrochloric acid represents a 2 mol / L hydrochloric acid solution.

[0453] DMSO: Dimethyl sulfoxide

[0454] Bpin: Pinaryl borate ester group.

[0455] Beneficial effects

[0456] According to embodiments of the present invention, the present invention has at least one of the following technical effects:

[0457] 1) The compounds of this invention can induce direct binding between Vav1 and CRBN in a dose-dependent manner;

[0458] 2) The compounds of this invention exhibit excellent degradation effects on Vav1 protein in a dose-dependent manner;

[0459] 3) In the CD3 / CD28-induced Jurkat cell / T cell activation model, the compounds of this invention significantly inhibited the production of IL-2, and the inhibitory function was positively correlated with the dose;

[0460] 4) The compounds of this invention exhibit excellent pharmacokinetic properties and good drug-likeness in pharmacokinetic studies in mice and rats;

[0461] 5) The compounds of this invention exhibit excellent stability in human liver microsomes, good thermodynamic solubility, no significant CYP3A4 inhibitory effect, and a significant advantage in plasma protein binding rate, and have good drug-like properties;

[0462] 6) The test compound group of the present invention showed significant relief of disease progression in an adoptive naïve T cell-induced mouse enteritis model.

[0463] 7). Detailed Implementation

[0464] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that the following description is merely the most preferred embodiment of the present invention and should not be considered as a limitation on the scope of protection of the present invention. Based on a full understanding of the present invention, experimental methods in the following embodiments that do not specify specific conditions are generally performed under conventional conditions or as recommended by the manufacturer. Those skilled in the art can make non-essential modifications to the technical solutions of the present invention, and such modifications should be considered to be included within the scope of protection of the present invention.

[0465] Preparation of intermediate A

[0466] 3-(3-Bromo-2-chlorophenyl)piperidine-2,6-dione (Intermediate A)

[0467]

[0468] The synthetic route for intermediate A is shown below:

[0469]

[0470] Step 1: 2-(3-bromo-2-chlorophenyl)acetonitrile (A2)

[0471] 3-Bromo-2-chlorobenzyl bromide (A1) (9.0 g, 31.65 mmol) was placed in a reaction flask, and acetonitrile (100 mL) was added. Trimethylcyanosilane (6.3 g, 63.3 mmol) and potassium carbonate (13 g, 100 mmol) were added under ice bath conditions. After the addition was complete, the reaction solution was reacted at 80 °C for 16 h. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with ethyl acetate (500 mL), washed with saturated sodium chloride aqueous solution (500 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 10:1) to give intermediate 2-(3-bromo-2-chlorophenyl)acetonitrile (A2).

[0472] LC-MS, M / Z (ESI): 230.1 [M+H] + .

[0473] Step 2: Methyl 4-(3-bromo-2-chlorophenyl)-4-cyanobutyrate (A3)

[0474] 2-(3-bromo-2-chlorophenyl)acetonitrile (5.0 g, 21.74 mmol) (A2) was placed in a reaction flask, and methyl acrylate (3.74 g, 43.5 mmol) and tetrahydrofuran (100 mL) were added. Sodium methoxide (110 mg, 2 mmol) was then added under ice bath conditions. After the addition was complete, the reaction mixture was allowed to react at room temperature for 2 h. After the reaction was complete, the reaction mixture was diluted with ethyl acetate (500 mL), washed with sodium chloride aqueous solution (500 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 5:1) to give intermediate methyl 4-(3-bromo-2-chlorophenyl)-4-cyanobutyrate (compound A3) (5.95 g, yield: 87%).

[0475] LC-MS, M / Z (ESI): 316.2 [M+H] + .

[0476] Step 3: 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (Intermediate A)

[0477] Methyl 4-(3-bromo-2-chlorophenyl)-4-cyanobutyrate (intermediate A3) (5.9 g, 18.7 mmol) was dissolved in acetic acid (100 mL). 0.5 mL of concentrated sulfuric acid was added at 20 °C, and the reaction mixture was allowed to react at 90 °C for 6 hours. After the reaction was complete, 2.0 g of sodium acetate was added at 20 °C, and the mixture was stirred at room temperature for 30 min. The solvent was removed by vacuum distillation, followed by dilution with ethyl acetate (500 mL × 1), and then washed with saturated sodium chloride aqueous solution (500 mL × 2), saturated sodium bicarbonate aqueous solution (500 mL × 1), and saturated sodium chloride aqueous solution (500 mL × 1), respectively. The organic phase was then collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:1) to give compound 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (intermediate A).

[0478] LC-MS, M / Z (ESI): 302.1 [M+H] + .

[0479] 1 H NMR(400MHz,DMSOd6)δ10.93(s,1H),7.71(dd,1H),7.37(dd,1H),7.27(t,1H),4.31(dd,1H),2.77(dd d,1H),2.58–2.49(m,1H),2.31(qd,1H),2.04–1.95(m,1H).

[0480] Preparation of intermediate A'

[0481] 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)piperidin-2,6-dione

[0482]

[0483] The synthetic route for intermediate A' is shown below:

[0484]

[0485] Step 1: Synthesis of 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)piperidine-2,6-dione (intermediate A')

[0486]

[0487] Compound 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (A) (4.6 g, 15.2 mmol) was placed in a reaction flask, followed by the addition of pinacol diboron ester (7.6 g, 30 mmol), potassium acetate (4.5 g, 45.6 mmol), 1,1'-bis(di-phenylphosphino)ferrocene palladium chloride (0.3 g, 0.45 mmol), and 1,4-dioxane (70 mL). The reaction mixture was stirred at 100 °C for 8 hours under nitrogen protection. The reaction solution was cooled to room temperature, diluted with ethyl acetate (500 mL), washed with saturated sodium chloride aqueous solution (500 mL × 3), and then the organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 1:1) to give compound 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)piperidine-2,6-dione (intermediate A').

[0488] LC-MS, M / Z (ESI): 350.2 [M+H] + .

[0489] Example 1: Preparation of target compound 1

[0490] 3-[2-chloro-3-(2-oxo-1a,2,3,7b-tetrahydro-1H-cyclopropane[c]quinolin-6-yl)phenyl]piperidin-2,6-dione (Compound 1)

[0491]

[0492] The synthetic route for compound 1 is shown below:

[0493]

[0494] Step 1: Synthesis of 6-bromo-1-[(4-methoxyphenyl)methyl]quinoline-2(1H)-one (compound 1-2) At room temperature, potassium carbonate (4.6 g, 33.5 mmol) and 4-methoxybenzyl chloride (5.2 g, 33.5 mmol) were added to a solution of 6-bromoquinoline-2(1H)-one (5.0 g, 22.3 mmol) in N,N-dimethylformamide (20 mL). The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was added to water and stirred for 1 h. The mixture was filtered, the solid was collected and dried to obtain compound 6-bromo-1-[(4-methoxyphenyl)methyl]quinoline-2(1H)-one (compound 1-2).

[0495] Step 2: Synthesis of 6-bromo-3-[(4-methoxyphenyl)methyl]-1,1a,3,7b-tetrahydro-2H-cyclopropane[c]quinoline-2-one (compounds 1-3)

[0496] Trimethyl sulfoxide (3.8 g, 17.4 mmol) and DMSO (20 mL) were added sequentially to a 100 mL single-necked flask. Then, potassium tert-butoxide (17.4 mL, 1 mol / L, 17.4 mmol) was added at 0 °C. After stirring at room temperature for 1 h, 6-bromo-1-[(4-methoxyphenyl)methyl]quinoline-2(1H)-one (compounds 1-2) (3.0 g, 8.7 mmol) was added. The reaction mixture was heated to 80 °C and stirred overnight. The reaction solution was cooled to room temperature and then purified by preparative liquid chromatography (column: YMC-Triart Prep C18 (30 mm × 40 cm, 7 μm); mobile phase: A = 0.1% formic acid, B = acetonitrile; gradient: 10%-100%) to give compound 6-bromo-3-[(4-methoxyphenyl)methyl]-1,1a,3,7b-tetrahydro-2H-cyclopropane[c]quinoline-2-one (compounds 1-3).

[0497] Step 3: Synthesis of 6-bromo-1,1a,3,7b-tetrahydro-2H-cyclopropane[c]quinoline-2-one (compounds 1-4)

[0498] At room temperature, trifluoroacetic acid (5 mL) and anisole (0.2 mL) were added to 250 mg (0.7 mmol) of 6-bromo-3-[(4-methoxyphenyl)methyl]-1,1a,3,7b-tetrahydro-2H-cyclopropane[c]quinoline-2-one. The mixture was heated to 50 °C and stirred overnight. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography to give compounds 6-bromo-1,1a,3,7b-tetrahydro-2H-cyclopropane[c]quinoline-2-one (compounds 1-4).

[0499] Step 4: Synthesis of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,1a,3,7b-tetrahydro-2H-cyclopropane[c]quinoline-2-one (compounds 1-5)

[0500] Add 6-bromo-1,1a,3,7b-tetrahydro-2H-cyclopropane[c]quinoline-2-one (compounds 1-4) (100 mg, 0.4 mmol), bis-pinacol boronic acid ester (160 mg, 0.6 mmol), Pd(dppf)Cl2 (31 mg, 0.04 mmol), potassium acetate (82 mg, 0.8 mmol), and 1,4-dioxane (10 mL) to a 100 mL single-necked flask in sequence. Heat the reaction solution to 70 °C under nitrogen protection and stir overnight. After the reaction is complete, cool the reaction solution to room temperature and proceed directly to the next step of feeding.

[0501] Step 5: Synthesis of 3-[2-chloro-3-(2-oxo-1a,2,3,7b-tetrahydro-1H-cyclopropane[c]quinolin-6-yl)phenyl]piperidine-2,6-dione (compound 1)

[0502]

[0503] 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (intermediate A) (200 mg, 0.7 mmol), Pd(dppf)Cl2 (31 mg, 0.04 mmol), and potassium carbonate (116 mg, 0.8 mmol) were added to the reaction solution from the previous step. The reaction solution was heated to 100 °C overnight under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by preparative chromatography to give compound 3-[2-chloro-3-(2-oxo-1a,2,3,7b-tetrahydro-1H-cyclopropane[c]quinoline-6-yl)phenyl]piperidin-2,6-dione (compound 1).

[0504] 1 H NMR (400MHz, DMSO-d6) δ10.90(s,1H),10.05(s,1H),7.39-7.26(m,4H),7.12(d,1H),6.89(d,1H),4.32-4.28(m,1H),3.34-3. 29(m,1H),2.80-2.71(m,1H),2.59-2.52(m,1H),2.34-2.26(m,1H),2.04-1.96(m,2H),1.60-1.55(m,1H),0.59-0.55(m,1H).

[0505] LC / MS (ESI) (m / z): 381.3 (M+H) +

[0506] Example 2: Preparation of target compound 2

[0507] 3-[2-chloro-3-(1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-5'-yl)phenyl]piperidine-2,6-dione (compound 2)

[0508]

[0509] The synthetic route for target compound 2 is shown below:

[0510]

[0511] Step 1: Synthesis of 5'-bromo-1'-methylspiro[cyclopropane-1,3'-indole]-2'(1'H)-one (2-2)

[0512] 5'-Bromospiro[cyclopropane-1,3'-indole]-2'(1'H)-one (compound 2-1) (1.0 g, 4.2 mmol) was dissolved in tetrahydrofuran (15 mL), and the solution was cooled to 0 °C. Sodium hydroxide (504 mg, 12.6 mmol) was added in three portions, followed by dropwise addition of iodomethane (1.8 g, 12.6 mmol) after 10 min. The reaction mixture was stirred overnight at room temperature. The reaction was quenched with a saturated saline solution (20 mL), and then extracted with ethyl acetate (50 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 5'-bromo-1'-methylspiro[cyclopropane-1,3'-indole]-2'(1'H)-one (compound 2-2), which was used directly in the next reaction.

[0513] LC-MS,M / Z(ESI):252.2 / 254.2[M+H]+

[0514] Step 2: Synthesis of 1'-methyl-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one (compounds 2-3)

[0515] 5'-bromo-1'-methylspiro[cyclopropane-1,3'-indole]-2'(1'H)-one (compound 2-2) (1.1 g, 4.2 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis-1,3,2-dioxaborane (3.2 g, 12.6 mmol), potassium acetate (1.2 g, 12.6 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (II) (307 mg, 0.4 mmol) were dissolved in anhydrous 1,4-dioxane (12 mL). The reaction mixture was stirred at 60 °C for 2 h under nitrogen protection. The reaction solution was diluted with ethyl acetate (50 mL), then washed with saturated brine (10 mL * 2), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 1) to give compound 1'-methyl-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one (compound 2-3).

[0516] LC-MS, M / Z (ESI): 300.2 [M+H]+

[0517] Step 3: Synthesis of 3-[2-chloro-3-(1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-5'-yl)phenyl]piperidine-2,6-dione (compound 2)

[0518]

[0519] 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (100 mg, 0.33 mmol), 1'-methyl-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one (120 mg, 0.40 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (31 mg, 0.04 mmol), and potassium phosphate (88 mg, 0.82 mmol) were dissolved in anhydrous N,N-dimethylformamide (1.5 mL), and the reaction mixture was stirred at 100 °C for 4 h. The reaction solution was cooled to room temperature and filtered. The filtrate was purified by preparative liquid chromatography (column: Phenomenex Synergi C18 100*25mm*4μm; solvent: A = water + 0.1 vol% formic acid (99%), B = acetonitrile; gradient: 5%-95%, 7 min) to give compound 3-[2-chloro-3-(1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-5'-yl)phenyl]piperidine-2,6-dione (compound 2) (20 mg, yield 15%).

[0520] LC-MS, M / Z (ESI): 395.20 [M+H]+

[0521] 1 H NMR(400MHz,DMSO-d6)δ11.50(s,1H),7.42-7.05(m,6H),4.01-3.96(m,1H),3.33-3.05(m,5H),2.21-1.46(m,6H)

[0522] Example 3: Preparation of target compound 3

[0523] 3-[2-chloro-3-(1'-methyl-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-5'-yl)phenyl]piperidine-2,6-dione (compound 3)

[0524]

[0525] The synthetic route for target compound 3 is shown below:

[0526]

[0527] Step 1: Synthesis of 1'-methyl-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-indole](3-1)

[0528] 1'-Methyl-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)spiro[cyclopropane-1,3'-indole]-2'(1'H)-one (300 mg, 1 mmol) was dissolved in anhydrous tetrahydrofuran (3 mL). Under nitrogen protection, a borane dimethyl sulfide solution (10 M, 1 mL, 10 mmol) was slowly added dropwise. The reaction mixture was stirred at 60 °C for 2 h. The reaction mixture was cooled to room temperature, and the reaction was quenched by slowly adding methanol (10 mL). The mixture was then concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 100 / 1) to give compound 1'-methyl-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-indole] (compound 3-1).

[0529] LC-MS, M / Z (ESI): 286.2 [M+H]+

[0530] Step 2: Synthesis of 3-[2-chloro-3-(1'-methyl-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-5'-yl)phenyl]piperidine-2,6-dione (compound 4)

[0531]

[0532] 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (100 mg, 0.33 mmol), 1'-methyl-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-indole] (compound 3-1) (200 mg, 0.70 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride(II) (31 mg, 0.04 mmol), and potassium phosphate (88 mg, 0.82 mmol) were dissolved in anhydrous N,N-dimethylformamide (1.5 mL), and the reaction mixture was stirred at 100 °C for 4 h. The reaction solution was cooled to room temperature and filtered. The filtrate was purified by high-performance preparative liquid chromatography (column: Phenomenex Synergi C18100*25mm*4um; solvent: A = water + 0.1 vol% formic acid (99%), B = acetonitrile; gradient: 5%-95%, 7 min) to give compound 3-[2-chloro-3-(1'-methyl-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-5'-yl)phenyl]piperidine-2,6-dione (compound 3) (20 mg, yield 15%).

[0533] 1H NMR (400MHz, DMSO-d6) δ10.88(s,1H),7.30-6.50(m,6H),4.29-4.25(m,1H),2.79-1.98(m,8H),1.20-0.96(m,5H)

[0534] LC-MS, M / Z (ESI): 381.20 [M+H]+

[0535] Example 4: Preparation of target compound 4

[0536] 3-[2-chloro-3-(2-methyl-1-benzothiophene-5-yl)phenyl]piperidin-2,6-dione (compound 4)

[0537]

[0538] The synthetic route for target compound 4 is shown below:

[0539]

[0540] Step 1: Synthesis of 5-bromo-2-methyl-1-benzothiophene (4-2)

[0541] 5-Bromo-1-benzothiophene (4-1) (1 g, 4.7 mmol) was dissolved in tetrahydrofuran (10 mL) solution, purged three times with argon gas, and then lithium diisopropylamino (2.5 mL, 5 mmol, 2 M tetrahydrofuran solution) was slowly added dropwise at -78 °C, with stirring continued for 0.5 h. Iodomethane (1 g, 7.1 mmol) was added dropwise to the reaction solution at -78 °C, with stirring continued for 2 h. The reaction solution was slowly added dropwise to ice water (50 mL), and extracted with ethyl acetate (10 mL * 3). The combined organic phases were washed with saturated brine (10 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-50 / 1) to give compound 5-bromo-2-methyl-1-benzothiophene (4-2) (1 g, yield 93.8%).

[0542] LC-MS, M / Z (ESI): 228.3 [M+H]+

[0543] Step 2: Synthesis of 4,4,5,5-tetramethyl-2-(2-methyl-1-benzothiophene-5-yl)-1,3,2-dioxoboronane (4-3)

[0544] To a solution of 5-bromo-2-methyl-1-benzothiophene (4-2) (1 g, 4.4 mmol) in 1,4-dioxane (10 mL), pinacol borate (2.2 g, 8.8 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (327 mg, 0.4 mmol), and potassium acetate (1.3 g, 13.2 mmol) were added, purging with argon three times, and then stirred at 110 °C for 18 h. Water (50 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-20 / 1) to give compound 4,4,5,5-tetramethyl-2-(2-methyl-1-benzothiophene-5-yl)-1,3,2-dioxoborane (4-3) (220 mg, yield 18.2%).

[0545] LC-MS, M / Z (ESI): 274.3 [M+H]+

[0546] Step 3: Synthesis of 3-[2-chloro-3-(2-methyl-1-benzothiophene-5-yl)phenyl]piperidine-2,6-dione (compound 4)

[0547]

[0548] To a solution of 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (intermediate A) (50 mg, 0.17 mmol) in 1,4-dioxane (1 mL), 4,4,5,5-tetramethyl-2-(2-methyl-1-benzothiophene-5-yl)-1,3,2-dioxoboronane (compound 4-3) (113 mg, 0.41 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (13 mg, 0.017 mmol), and potassium carbonate (91 mg, 0.66 mmol) were added. The reaction mixture was stirred at 100 °C for 8 h under nitrogen protection. After the reaction was complete, the reaction mixture was cooled to room temperature, water (10 mL) was added, and then extracted with ethyl acetate (2 mL * 3). The combined organic phases were washed with saturated brine (2 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative liquid chromatography (column: Phenomenex Synergi C18 100*25mm*4μm; solvent: A = water + 0.1 vol% formic acid (99%), B = acetonitrile; gradient: 5%-95%, 7 min) to give compound 3-[2-chloro-3-(2-methyl-1-benzothiophene-5-yl)phenyl]piperidine-2,6-dione (compound 4) (6.5 mg, yield 10%).

[0549] 1 H NMR (400MHz, DMSO-d6) δ10.93(s,1H),7.93(d,1H),7.72(d,1H),7.43–7.34(m,3H),7.31–7.26(m,1H),7. 18(s,1H),4.38–4.32(m,1H),2.85–2.74(m,1H),2.62–2.51(m,4H),2.37–2.31(m,1H),2.09–2.00(m,1H).

[0550] LC-MS, M / Z (ESI): 370.3 [M+H]+

[0551] Example 5: Preparation of target compound 5

[0552] 3-[2-chloro-3-(2-oxo-2,3,4,5-tetrahydro-1H-1-benzoza-7-yl)phenyl]piperidin-2,6-dione (compound 5)

[0553]

[0554] The synthetic route for target compound 5 is shown below:

[0555]

[0556] Step 1: Synthesis of 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,3,4,5-tetrahydro-2H-1-benzoza-2-one (compound 5-2)

[0557] To a solution of 7-bromo-1,3,4,5-tetrahydro-2H-1-benzoza-2-one (5-1) (500 mg, 2.1 mmol) in dioxane (5 mL), pinacol borate (1.1 g, 4.2 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (170 mg, 0.21 mmol), and potassium acetate (613 g, 6.2 mmol) were added. The reaction mixture was stirred at 110 °C for 18 h under nitrogen protection. The reaction mixture was cooled to room temperature, water (50 mL) was added, and then extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-20 / 1) to give compound 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,3,4,5-tetrahydro-2H-1-benzoza-2-one (5-2).

[0558] LC-MS, M / Z (ESI): 288.3 [M+H]+

[0559] Step 2: Synthesis of 3-[2-chloro-3-(2-oxo-2,3,4,5-tetrahydro-1H-1-benzoza-7-yl)phenyl]piperidine-2,6-dione (compound 5)

[0560]

[0561] To a solution of 1,4-dioxane (1 mL) of 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (intermediate A) (100 mg, 0.33 mmol), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,3,4,5-tetrahydro-2H-1-benzoza-2-one (compound 5-2) (190 mg, 0.66 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (27 mg, 0.033 mmol), and potassium carbonate (137 mg, 0.99 mmol) were added. The reaction mixture was stirred at 100 °C for 8 h. After cooling to room temperature, water (10 mL) was added, followed by extraction with ethyl acetate (2 mL x 3). The combined organic phases were washed with saturated brine (2 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative liquid chromatography (column: Phenomenex Synergi C18 100*25mm*4μm; solvent: A = water + 0.1 vol% formic acid (99%), B = acetonitrile; gradient: 5%-95%, 7 min) to give compound 3-[2-chloro-3-(2-oxo-2,3,4,5-tetrahydro-1H-1-benzoza-7-yl)phenyl]piperidin-2,6-dione (compound 5) (10.5 mg, yield 8%).

[0562] 1 H NMR(400MHz,DMSO-d6)δ10.92(s,1H),9.63(s,1H),7.44–7.18(m,5H),7.03(d,1H),4.37– 4.28(m,1H),2.86–2.67(m,3H),2.59–2.48(m,1H),2.38–2.28(m,1H),2.24–1.98(m,5H).

[0563] LC-MS, M / Z (ESI): 383.2 [M+H]+

[0564] Example 6: Preparation of target compound 6

[0565] 5-[2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl]-1-methyl-1,3-dihydro-2H-2λ6,1-benzothiazol-2,2-dione (compound 6)

[0566]

[0567] The synthetic route for target compound 6 is shown below:

[0568]

[0569] Step 1: Synthesis of 7-bromo-1,3,4,5-tetrahydro-2H-1-benzoza-2-thione (6-1)

[0570] Triethylamine (1.58 g, 15.6 mmol) and phosphorus pentasulfide (1.3 g, 6.9 mmol) were added to a solution of 7-bromo-1,3,4,5-tetrahydro-2H-1-benzoza-2-thione (5-1) (1.5 g, 6.2 mmol) in acetonitrile (4.5 mL), and the mixture was stirred at 90 °C for 6 h. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-20 / 1) to give compound 7-bromo-1,3,4,5-tetrahydro-2H-1-benzoza-2-thione (6-1) (200 mg, yield 12.5%).

[0571] LC-MS, M / Z (ESI): 258.3 [M+H]+

[0572] Step 2: Synthesis of 8-bromo-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-1-one (6-2)

[0573] 7-Bromo-1,3,4,5-Tetrahydro-2H-1-benzoza-2-thione (6-1) (200 mg, 0.78 mmol) and methyl hydrazine carbamate (3) (141 mg, 1.56 mmol) were dissolved in n-butanol (3 mL). The reaction mixture was placed in a microwave-safe tube, sealed, and stirred at 140 °C for 48 h. Water (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-1 / 1) to give compound 8-bromo-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-1-one (6-2) (110 mg, yield 50.3%).

[0574] LC-MS, M / Z (ESI): 282.2 [M+H]+

[0575] Step 3: Synthesis of 8-bromo-2-methyl-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-1-one (6-3)

[0576] At 0 °C, potassium carbonate (148 mg, 1.07 mmol) and methyl iodide (61 mg, 0.43 mmol) were added to a solution of 8-bromo-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-1-one (6-2) (100 mg, 0.36 mmol) in N,N-dimethylformamide (1 mL), and the mixture was stirred at room temperature for 2 h. Water (10 mL) was added to the reaction mixture, and the mixture was then extracted with ethyl acetate (5 mL × 3). The combined organic phases were washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-1 / 1) to give compound 8-bromo-2-methyl-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-1-one (6-3) (100 mg, yield 95%).

[0577] LC-MS, M / Z (ESI): 296.3 [M+H]+

[0578] Step 4: Synthesis of 5-[2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl]-1-methyl-1,3-dihydro-2H-2λ6,1-benzothiazol-2,2-dione (compound 6)

[0579]

[0580] To a solution of 1,4-dioxane (1 mL) of 8-bromo-2-methyl-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-1-one (6-3) (100 mg, 0.34 mmol), 3-[2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl]piperidin-2,6-dione (intermediate A') (238 mg, 0.68 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (28 mg, 0.034 mmol), and potassium carbonate (117 mg, 0.85 mmol) were added, purging with argon three times, and the mixture was stirred at 100 °C for 18 h. The reaction mixture was then poured into water (10 mL) and extracted with ethyl acetate (2 mL × 3). The organic phases were combined and washed with saturated brine (2 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative liquid chromatography (column: Phenomenex Synergi C18 100 × 25 mm × 4 μm; solvent: A = water + 0.1 vol% formic acid (99%), B = acetonitrile; gradient: 5%-95%, 7 min) to give compound 5-[2-chloro-3-(2,6-dioxoperidin-3-yl)phenyl]-1-methyl-1,3-dihydro-2H-2λ. 6 1-Benzothiazol-2,2-dione (compound 6) (12.5 mg, yield 8%).

[0581] 1 H NMR (400MHz, DMSO-d6) δ10.94(s,1H),7.60–7.55(m,1H),7.48–7.44(m,2H),7.43–7.33(m,3H),4.39–4.32(m ,1H),3.39(s,3H),2.85–2.75(m,1H),2.70(t,2H),2.60–2.51(m,3H),2.40–2.29(m,1H),2.15–2.02(m,3H).

[0582] LC-MS, M / Z (ESI): 437.3 [M+H]+

[0583] Example 7: Preparation of target compound 7

[0584] 3-{2-chloro-3-[2-oxo-1-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-1-benzoza-7-yl]phenyl}piperidin-2,6-dione (compound 7)

[0585]

[0586] The synthetic route for target compound 7 is shown below:

[0587]

[0588] Step 1: Synthesis of 7-bromo-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzoza-2-one (7-1)

[0589] To a solution of 7-bromo-1,3,4,5-tetrahydro-2H-1-benzoza-2-one (5-1) (500 mg, 2.08 mmol) in N,N-dimethylformamide (7.5 mL), trifluoroethyl trifluoromethanesulfonate (870 mg, 3.75 mmol) and cesium carbonate (1.02 g, 3.12 mmol) were added, and the mixture was stirred at 40 °C for 5 h. Water (50 mL) was added to the reaction mixture, and the mixture was then extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-20 / 1) to give compound 7-bromo-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzoza-2-one (7-1) (620 mg, yield 90%).

[0590] LC-MS, M / Z (ESI): 324.2 [M+H]+

[0591] Step 2: Synthesis of 3-{2-chloro-3-[2-oxo-1-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-1-benzoza-7-yl]phenyl}piperidine-2,6-dione (compound 7)

[0592]

[0593] To a solution of 7-bromo-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzoza-2-one (7-1) (100 mg, 0.31 mmol) in 1,4-dioxane (1 mL), 3-[2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl]piperidin-2,6-dione (intermediate A') (217 mg, 0.62 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (25 mg, 0.031 mmol), and potassium carbonate (107 mg, 0.78 mmol) were added, purging with argon three times, and the mixture was stirred at 100 °C for 18 h. The reaction mixture was then poured into water (10 mL) and extracted with ethyl acetate (2 mL × 3). The organic phases were combined and washed with saturated brine (2 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative liquid chromatography (column: Phenomenex Synergi C18 100*25mm×4μm; solvent: A = water + 0.1 v / v formic acid (99%), B = acetonitrile; gradient: 5%-95%, 7 min) to give compound 3-{2-chloro-3-[2-oxo-1-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-1-benzoza-7-yl]phenyl}piperidin-2,6-dione (compound 7) (18.2 mg, yield 12%).

[0594] 1 H NMR(400MHz,DMSO-d6)δ10.93(s,1H),7.57(d,1H),7.45–7.33(m,5H),4.39–4.31( m,1H),2.86–2.68(m,3H),2.59–2.51(m,2H),2.40–2.18(m,4H),2.15–1.95(m,3H).

[0595] LC-MS, M / Z (ESI): 465.2 [M+H]+

[0596] Example 8: Preparation of target compound 8

[0597] 3-[2-chloro-3-(11-oxo-7,11-dihydro-6H-pyrido[2,1-d][1,5]benzoxazono-3-yl)phenyl]piperidin-2,6-dione (compound 8)

[0598]

[0599] The synthetic route for target compound 8 is shown below:

[0600]

[0601] Step 1: Synthesis of 2-[2-(5-bromo-2-iodophenoxy)ethyl]-6-methoxypyridine (8-2)

[0602] 2-(6-methoxypyridin-2-yl)ethane-1-ol (8-1) (1 g, 6.5 mmol), 5-bromo-2-iodophenol (2.3 g, 7.8 mmol), and triphenylphosphine (5.1 g, 19.5 mmol) were dissolved in tetrahydrofuran (15 mL), and the mixture was purged with nitrogen three times. Then, diisopropyl azodicarbonate (3.9 g, 19.5 mmol) was slowly added dropwise at 0 °C, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was directly concentrated to obtain a crude product, which was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 3 / 1) to give compound 2-[2-(5-bromo-2-iodophenoxy)ethyl]-6-methoxypyridine (8-2) (1.5 g, yield 54%).

[0603] LC-MS,M / Z(ESI):434.2 / 436.2[M+H]+

[0604] Step 2: Synthesis of 6-[2-(5-bromo-2-iodophenoxy)ethyl]pyridine-2(1H)-one (8-3)

[0605] 2-[2-(5-bromo-2-iodophenoxy)ethyl]-6-methoxypyridine (8-2) (1 g, 2.3 mmol), sodium iodide (1.2 g, 3.5 mmol), and trimethylchlorosilane (800 mg, 3.5 mmol) were dissolved in acetonitrile (15 mL). The reaction mixture was heated to 90 °C and stirred for 2 h under nitrogen protection. The reaction mixture was cooled to room temperature, diluted with water (10 mL), and then filtered to obtain a black crude product. The crude product was washed with a small amount of acetonitrile to obtain compound 6-[2-(5-bromo-2-iodophenoxy)ethyl]pyridine-2(1H)-one (8-3) (800 mg, yield 83%).

[0606] LC-MS,M / Z(ESI):420.2 / 422.2[M+H]+

[0607] Step 3: Synthesis of 3-bromo-6,7-dihydro-11H-pyrido[2,1-d][1,5]benzoxazono-11-one (8-4)

[0608] 6-[2-(5-bromo-2-iodophenoxy)ethyl]pyridin-2(1H)-one (8-3) (800 mg, 1.9 mmol), potassium phosphate (1.2 g, 5.7 mmol), (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (50 mg, 0.4 mmol), and cuprous iodide (720 mg, 3.8 mmol) were dissolved in anhydrous nitrogen and N-dimethylformamide (80 mL). The mixture was heated to 110 °C and stirred for 5 h under nitrogen protection. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 0 / 1) to give compound 3-bromo-6,7-dihydro-11H-pyrido[2,1-d][1,5]benzoxazazepone-11-one (8-4) (100 mg, 18% yield).

[0609] LC-MS,M / Z(ESI):292.2 / 294.2[M+H]+

[0610] Step 4: Synthesis of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-6,7-dihydro-11H-pyrido[2,1-d][1,5]benzoxazon-11-one (8-5)

[0611] 3-Bromo-6,7-dihydro-11H-pyrido[2,1-d][1,5]benzoxazon-11-one (8-4) (100 mg, 0.34 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis-1,3,2-dioxaborane (893 mg, 3.5 mmol), potassium acetate (330 mg, 3.5 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (II) (40 mg, 0.07 mmol) were dissolved in anhydrous 1,4-dioxane (5 mL). The reaction mixture was stirred at 80 °C for 1 h under nitrogen protection. The reaction solution was directly concentrated to obtain the crude product, which was then purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 6 / 5) to give compound 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-6,7-dihydro-11H-pyrido[2,1-d][1,5]benzoxazon-11-one (8-5) (100 mg, yield 87%).

[0612] LC-MS, M / Z (ESI): 340.2 [M+H]+

[0613] Step 5: Synthesis of 3-[2-chloro-3-(11-oxo-7,11-dihydro-6H-pyrido[2,1-d][1,5]benzoxazono-3-yl)phenyl]piperidin-2,6-dione (compound 8)

[0614]

[0615] 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (50 mg, 0.15 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-6,7-dihydro-11H-pyrido[2,1-d][1,5]benzoxazon-11-one (100 mg, 0.3 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (31 mg, 0.04 mmol), and potassium phosphate (88 mg, 0.82 mmol) were dissolved in anhydrous nitrogen and dimethylformamide (1.5 mL) and stirred at 110 °C for 4 h. The reaction solution was cooled to room temperature, filtered, and then the filtrate was purified by preparative high performance liquid chromatography (column: Phenomenex Synergi C18 100*25mm*4μm; solvent: A = water + 0.1 vol% formic acid (99%), B = acetonitrile; gradient: 5%-95%, 7 min) to give compound 3-[2-chloro-3-(11-oxo-7,11-dihydro-6H-pyrido[2,1-d][1,5]benzoxazono-3-yl)phenyl]piperidin-2,6-dione (compound 8) (3 mg, yield 5%).

[0616] 1 H NMR (400MHz, DMSO-d6) δ10.93(s,1H),7.62-7.23(m,7H),6.45-6.32(m,2H),4.40-4.23(m,3H),2.85-1.94(m,6H).

[0617] LC-MS, M / Z (ESI): 435.20 [M+H]+

[0618] Example 9: Preparation of target compound 9

[0619] 3-{2-chloro-3-[2-(2-hydroxy-2-methylpropyl)-1-oxo-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-8-yl]phenyl}piperidin-2,6-dione (compound 9)

[0620]

[0621] The synthetic route for target compound 9 is shown below:

[0622]

[0623] Step 1: Synthesis of methyl (8-bromo-1-oxo-5,6-dihydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-2(4H)-yl)acetate (9-1)

[0624] Potassium carbonate (444 mg, 3.21 mmol) and methyl bromoacetate (196 mg, 1.29 mmol) were added to a solution of 8-bromo-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-1-one (6-2) (300 mg, 1.07 mmol) in N,N-dimethylformamide (3 mL). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-1 / 3) to give compound (8-bromo-1-oxo-5,6-dihydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-2(4H)-yl)methyl acetate (9-1) (230 mg, yield 61%).

[0625] LC-MS, M / Z (ESI): 354.3 [M+H]+

[0626] Step 2: Synthesis of 8-bromo-2-(2-hydroxy-2-methylpropyl)-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-1-one (9-2)

[0627] Methyl (8-bromo-1-oxo-5,6-dihydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-2(4H)-yl)acetate (9-1) (200 mg, 0.57 mmol) was dissolved in tetrahydrofuran (2 mL), and the mixture was purged with argon three times. At 0 °C, methyl magnesium bromide (0.2 mL, 0.6 mmol, 3 M tetrahydrofuran solution) was added dropwise to the reaction mixture, and the mixture was then brought to room temperature and stirred for 2 h. The reaction mixture was then slowly added dropwise to saturated ammonium chloride (20 mL), and extracted with ethyl acetate (10 mL * 3). The combined organic phases were washed with saturated brine (20 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-0 / 1) to give compound 8-bromo-2-(2-hydroxy-2-methylpropyl)-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-1-one (9-2) (130 mg, yield 65%).

[0628] LC-MS, M / Z (ESI): 354.2 [M+H]+

[0629] Step 3: Synthesis of 3-{2-chloro-3-[2-(2-hydroxy-2-methylpropyl)-1-oxo-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-8-yl]phenyl}piperidine-2,6-dione (compound 9)

[0630] To a solution of 1,4-dioxane (1.5 mL) of 8-bromo-2-(2-hydroxy-2-methylpropyl)-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-1-one (9-2) (100 mg, 0.28 mmol) in 1,4-dioxane (1.5 mL), 3-[2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl]piperidin-2,6-dione (347 mg, 0.99 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (23 mg, 0.028 mmol), and potassium carbonate (118 mg, 0.85 mmol) were added, purging with argon three times, and the mixture was stirred at 100 °C for 18 h. The reaction solution was cooled to room temperature, poured into water (10 mL), and then extracted with ethyl acetate (2 mL * 3). After the organic phases were combined, the mixture was washed with saturated brine (2 mL * 2), dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then subjected to reverse-phase preparation (column: Phenomenex Synergi C18 100 * 25 mm * 4 μm; solvent: A = water + 0.1 vol% formic acid (99%), B = acetonitrile; gradient: 5% - 95%, 7 min) to give compound 3-{2-chloro-3-[2-(2-hydroxy-2-methylpropyl)-1-oxo-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-8-yl]phenyl}piperidin-2,6-dione (compound 9) (7.4 mg, purity 91.2%, yield 4.8%).

[0631] 1 H NMR(400MHz,DMSO-d6)δ10.96(s,1H),7.56(s,1H),7.51–7.25(m,5H),4.75(s,1H), 4.36(d,1H),3.58(d,2H),2.86–2.53(m,6H),2.37–1.98(m,6H),1.44–0.94(m,4H).

[0632] LC-MS, M / Z (ESI): 494.9 [M+H]+

[0633] Example 10: Preparation of target compound 10

[0634] 3-{2-chloro-3-[2-(2,2-difluoroethyl)-1-oxo-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-8-yl]phenyl}piperidin-2,6-dione (compound 10)

[0635]

[0636] The synthetic route for target compound 10 is shown below:

[0637]

[0638] Step 1: Synthesis of 8-bromo-2-(2,2-difluoroethyl)-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-1-one (10-1)

[0639] To a solution of 8-bromo-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-1-one (6-2) (200 mg, 0.71 mmol) in N,N-dimethylformamide (3 mL), 2,2-difluoroethyltrifluoromethanesulfonate (275 mg, 1.29 mmol) and cesium carbonate (696 mg, 2.14 mmol) were added, and the mixture was stirred at 40 °C for 5 h. Water (50 mL) was added to the reaction mixture, and the mixture was then extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-1 / 1) to give compound 8-bromo-2-(2,2-difluoroethyl)-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-1-one (compound 10-1) (220 mg, yield 90%).

[0640] LC-MS, M / Z (ESI): 346.2 [M+H]+

[0641] Step 2: Synthesis of 3-{2-chloro-3-[2-(2,2-difluoroethyl)-1-oxo-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-8-yl]phenyl}piperidine-2,6-dione (compound 10)

[0642] To a solution of 1,4-dioxane (1.5 mL) of 8-bromo-2-(2,2-difluoroethyl)-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-1-one (10⁻¹) (100 mg, 0.28 mmol) in 1,4-dioxane (1.5 mL), 3-[2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl]piperidin-2,6-dione (711 mg, 2.03 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (47 mg, 0.058 mmol), and potassium carbonate (241 mg, 1.74 mmol) were added, purging with argon three times, and the mixture was stirred at 100 °C for 18 h. The reaction mixture was cooled to room temperature, poured into water (10 mL), and then extracted with ethyl acetate (2 mL x 3). After the organic phases were combined, the mixture was washed with saturated brine (2 mL * 2), dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then subjected to reverse-phase preparation (column: Phenomenex Synergi C18 100 * 25 mm * 4 μm; solvent: A = water + 0.1 vol% formic acid (99%), B = acetonitrile; gradient: 5% - 95%, 7 min) to give compound 3-{2-chloro-3-[2-(2,2-difluoroethyl)-1-oxo-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-8-yl]phenyl}piperidin-2,6-dione (compound 10) (17.4 mg, purity 98.4%, yield 6%).

[0643] 1 H NMR(400MHz,DMSO-d6)δ10.96(s,1H),7.58(d,1H),7.50–7.30(m,5H),6.51–6.17(m,1H),4.36(dd, 1H),4.28–4.15(m,2H),2.87–2.67(m,3H),2.63–2.52(m,3H),2.42–2.30(m,1H),2.16–2.01(m,3H).

[0644] LC-MS, M / Z (ESI): 486.9 [M+H]+

[0645] Example 11: Synthesis of target compound 11

[0646] 3-[2-chloro-3-(2-methyl-1-oxo-2,4-dihydro-1H,6H-[1,2,4]triazolo[4,3-a][4,1]benzoxazolo-8-yl)phenyl]piperidin-2,6-dione (compound 11)

[0647]

[0648] The synthetic route for compound 11 is as follows:

[0649]

[0650] Step 1: 7-Bromo-1,5-dihydro-4,1-benzoxazono-2(3H)-one (Compound 11-2)

[0651] At room temperature, (2-amino-5-bromophenyl)methanol (compound 11-1) (2.00 g, 9.88 mmol) was dissolved in anhydrous toluene (20 mL), followed by the addition of sodium hydroxide (60%, 472 mg, 11.9 mmol) and ethyl chloroacetate (1.21 g, 9.88 mmol). The reaction mixture was reacted at 80 °C for 1 hour under nitrogen protection. After the reaction was complete, the reaction mixture was slowly poured into water (50 mL), filtered, and the filter cake was collected and dried to give compound 7-bromo-1,5-dihydro-4,1-benzoxazazepone-2(3H)-one (compound 11-2).

[0652] LC / MS (ESI) (m / z): 240.7 (MH) + .

[0653] Step 2: 7-Bromo-1,5-dihydro-4,1-benzoxaza-2(3H)-thione (compound 11-3)

[0654] At room temperature, 7-bromo-1,5-dihydro-4,1-benzoxazaze-2(3H)-one (compound 11-2) (400 mg, 1.65 mmol) was dissolved in acetonitrile (20 mL), and Lawson's reagent (1.00 g, 2.48 mmol) was added. The reaction solution was reacted at 100 °C for 1 hour under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature and poured into a saturated sodium bicarbonate aqueous solution (40 mL). After stirring for 0.5 hours, the mixture was filtered and the filter cake was collected to obtain compound 7-bromo-1,5-dihydro-4,1-benzoxazaze-2(3H)-thione (compound 11-3).

[0655] LC / MS (ESI) (m / z): 257 (MH) + .

[0656] Step 3: 8-Bromo-2,4-dihydro-1H,6H-[1,2,4]triazolo[4,3-a][4,1]benzoxazazepone-1-one (compound 11-4)

[0657] 7-Bromo-1,5-dihydro-4,1-benzoxazazole-2(3H)-thione (compound 11-3) (400 mg, 1.55 mmol) was dissolved in n-butanol (4 mL) at room temperature, and then methyl hydrazide (279 mg, 3.10 mmol) reaction solution was added and the reaction was carried out at 140 °C for 48 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by column chromatography (PE:EA = 100:1 to 0:1) to give compound 8-bromo-2,4-dihydro-1H,6H-[1,2,4]triazolo[4,3-a][4,1]benzoxazazole-1-one (compound 11-4).

[0658] LC / MS(ESI)(m / z): 283(M+H) + .

[0659] Step 4: 8-Bromo-2-methyl-2,4-dihydro-1H,6H-[1,2,4]triazolo[4,3-a][4,1]benzoxazolo-1-one (compounds 11-5)

[0660] At room temperature, 8-bromo-2,4-dihydro-1H,6H-[1,2,4]triazolo[4,3-a][4,1]benzoxazon-1-one (compound 11-4) (220 mg, 0.780 mmol) was dissolved in N,N-dimethylformamide (2 mL), followed by the addition of potassium carbonate (323 mg, 2.34 mmol) and methyl iodoforme (166 mg, 1.17 mmol). The reaction mixture was incubated at 40 °C for 1 hour. After the reaction was complete, the reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (3 × 20 mL), and the combined organic phases were washed with saturated brine (20 mL), dried, filtered, and concentrated. The crude product was purified by column chromatography (PE:EA = 100:1 to 0:1) to give compound 8-bromo-2-methyl-2,4-dihydro-1H,6H-[1,2,4]triazolo[4,3-a][4,1]benzoxazolane-1-one (compound 11-5).

[0661] LC / MS(ESI)(m / z): 297(M+H) + .

[0662] Step 5: 2-Methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-2,4-dihydro-1H,6H-[1,2,4]triazolo[4,3-a][4,1]benzoxazolazo-1-one (compound 11-6)

[0663] At room temperature, 8-bromo-2-methyl-2,4-dihydro-1H,6H-[1,2,4]triazolo[4,3-a][4,1]benzoxazon-1-one (compound 11-5) (100 mg, 0.340 mmol) was dissolved in 1,4-dioxane (1 mL), followed by the addition of potassium carbonate (140 mg, 1.02 mmol), diboron dipinalyl (258 mg, 1.02 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (24.0 mg, 0.034 mmol). The reaction mixture was reacted at 100 °C for 12 hours under nitrogen protection. After the reaction was complete, the resulting reaction solution (compound 11-6) was used directly for the next reaction.

[0664] LC / MS (ESI) (m / z): 344.0 (M+H) + .

[0665] Step 6: 3-[2-chloro-3-(2-methyl-1-oxo-2,4-dihydro-1H,6H-[1,2,4]triazolo[4,3-a][4,1]benzoxazolo-8-yl)phenyl]piperidin-2,6-dione (compound 11)

[0666]

[0667] At room temperature, potassium carbonate (140 mg, 1.01 mmol), 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (intermediate A) (102 mg, 0.340 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (23.8 mg, 0.034 mmol) were added to the reaction solution from the previous step. The resulting reaction solution was stirred at 100 °C for 12 hours under nitrogen protection. After the reaction was complete, the reaction solution was cooled to room temperature, concentrated under reduced pressure, diluted with water (10 mL), extracted with ethyl acetate (3 × 10 mL), and the organic phases were combined, washed successively with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (PE:EA = 100:1 to 0:1) to give compound 3-[2-chloro-3-(2-methyl-1-oxo-2,4-dihydro-1H,6H-[1,2,4]triazolo[4,3-a][4,1]benzoxazono-8-yl)phenyl]piperidin-2,6-dione (compound 11). LC / MS (ESI) (m / z): 439.1 (M+H) + ;

[0668] 1H NMR(400MHz,DMSO-d6)δ10.91(s,1H),7.81–7.78(m,1H),7.60(dd,2H),7.38(dd,2H),7.33(dd,1H),4.63(s ,2H),4.44(s,2H),4.33(dd,1H),3.42(s,3H),2.76(dd,1H),2.55–2.49(m,1H),2.31(dd,1H),2.01(dd,1H).

[0669] Example 12: Preparation of target compound 12

[0670] 3-[2-chloro-3-(1-oxo-1,5-dihydro-7H-pyrido[1,2-a][4,1]benzoxazono-9-yl)phenyl]piperidin-2,6-dione (compound 12)

[0671]

[0672] The synthetic route for target compound 12 is shown below:

[0673]

[0674] Step 1: Synthesis of 2-{[(5-bromo-2-iodophenyl)methoxy]methyl}-6-methoxypyridine (12-2)

[0675] 4-Bromo-2-(bromomethyl)-1-iodobenzene (2 g, 5.3 mmol) and (6-methoxypyridin-2-yl)methanol (0.89 g, 6.4 mmol) were dissolved in tetrahydrofuran (20 mL), and sodium hydrogen (276 mg, 7 mmol) was added in portions at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 5 / 1) to give compound 2-{[(5-bromo-2-iodophenyl)methoxy]methyl}-6-methoxypyridine (12-2).

[0676] LC-MS,M / Z(ESI):434.2 / 436.2[M+H]+

[0677] Step 2: Synthesis of 6-{[(5-bromo-2-iodophenyl)methoxy]methyl}pyridin-2(1H)-one (12-3)

[0678] 2-{[(5-bromo-2-iodophenyl)methoxy]methyl}-6-methoxypyridine (12-2) (1 g, 2.3 mmol), sodium iodide (1.2 g, 3.5 mmol), and trimethylchlorosilane (800 mg, 3.5 mmol) were dissolved in acetonitrile (15 mL). The reaction mixture was heated to 80 °C and stirred for 2 h under nitrogen protection. After the reaction was complete, the reaction mixture was cooled to room temperature, diluted with water (10 mL), filtered, and the filter cake was collected and washed with a small amount of acetonitrile to obtain compound 6-{[(5-bromo-2-iodophenyl)methoxy]methyl}pyridine-2(1H)-one (12-3).

[0679] LC-MS,M / Z(ESI):422.2 / 424.2[M+H]+

[0680] Step 3: Synthesis of 9-bromo-7H-pyrido[1,2-a][4,1]benzoxazono-1(5H)-one (12-4)

[0681] 6-{[(5-bromo-2-iodophenyl)methoxy]methyl}pyridin-2(1H)-one (12-3) (800 mg, 1.9 mmol), potassium phosphate (1.2 g, 5.7 mmol), (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (50 mg, 0.4 mmol), and cuprous iodide (720 mg, 3.8 mmol) were dissolved in anhydrous nitrogen and N-dimethylformamide (80 mL). The reaction mixture was heated to 110 °C and stirred for 5 h under nitrogen protection. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 0 / 1) to give compound 9-bromo-7H-pyrido[1,2-a][4,1]benzoxazazepone-1(5H)-one (12-4).

[0682] LC-MS,M / Z(ESI):292.2 / 294.2[M+H]+

[0683] Step 4: Synthesis of 9-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-7H-pyrido[1,2-a][4,1]benzoxazono-1(5H)-one (12-5)

[0684] 9-Bromo-7H-pyrido[1,2-a][4,1]benzoxazon-1(5H)-one (12-4) (100 mg, 0.34 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis-1,3,2-dioxaborane (893 mg, 3.5 mmol), potassium acetate (330 mg, 3.5 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (II) (40 mg, 0.07 mmol) were dissolved in anhydrous 1,4-dioxane (5 mL). The reaction mixture was stirred at 80 °C for 1 h under nitrogen protection. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1.2 / 1) to give compound 9-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-7H-pyrido[1,2-a][4,1]benzoxazon-1(5H)-one (12-5).

[0685] LC-MS, M / Z (ESI): 340.2 [M+H]+

[0686] Step 5: Synthesis of 3-[2-chloro-3-(1-oxo-1,5-dihydro-7H-pyrido[1,2-a][4,1]benzoxazono-9-yl)phenyl]piperidin-2,6-dione (compound 12)

[0687]

[0688] 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (intermediate A) (50 mg, 0.15 mmol), 9-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-7H-pyrido[1,2-a][4,1]benzoxazon-1(5H)-one (compound 12-5) (100 mg, 0.3 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride(II) (31 mg, 0.04 mmol), and potassium phosphate (88 mg, 0.82 mmol) were dissolved in anhydrous 1,4-dioxane (1.5 mL), and the reaction mixture was stirred at 110 °C for 4 h. The reaction solution was cooled to room temperature, filtered, and the filtrate was collected and concentrated under reduced pressure. The crude product was then purified by reverse-phase preparative purification (column: Phenomenex Synergi C18 100*25mm*4μm; solvent: A = water + 0.1 vol% formic acid (99%), B = acetonitrile; gradient: 5%-95%, 7 min) to obtain compound 3-[2-chloro-3-(1-oxo-1,5-dihydro-7H-pyrido[1,2-a][4,1]benzoxazono-9-yl)phenyl]piperidin-2,6-dione (compound 12).

[0689] 1 H NMR (400MHz, DMSO-d6) δ10.95(s,1H),7.72-7.36(m,7H),6.61-6.51(m,2H),4.67-3.83(m,5H),2.81-1.99(m,4H).

[0690] LC-MS, M / Z (ESI): 435.20 [M+H]+

[0691] Example 13: Preparation of target compound 13

[0692] 3-[2-chloro-3-(1-oxo-6,7-dihydro-1H-pyrido[1,2-a][3,1]benzoxazono-9-yl)phenyl]piperidin-2,6-dione (compound 13)

[0693]

[0694] The synthetic route for target compound 13 is shown below:

[0695]

[0696] Step 1: Synthesis of (5-bromo-2-iodophenyl)acetic acid (13-2)

[0697] To a solution of (3-bromophenyl)acetic acid (13-1) (2 g, 9.3 mmol) in N,N-dimethylformamide (20 mL), elemental iodine (1.78 g, 7 mmol), palladium acetate (202 mg, 0.9 mmol), and diacetic acid iodobenzene (2.25 g, 7 mmol) were added. The reaction mixture was stirred at 60 °C for 24 h under nitrogen protection. The reaction mixture was then poured into a mixture of water (100 mL) and ethyl acetate (50 mL), filtered, and the filtrate was collected and separated. The aqueous phase was further extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium thiosulfate solution (30 mL x 2), washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound (5-bromo-2-iodophenyl)acetic acid (13-2).

[0698] LC-MS, M / Z (ESI): 339.6 [MH]-

[0699] Step 2: Synthesis of 2-(5-bromo-2-iodophenyl)ethane-1-ol (13-3)

[0700] (5-Bromo-2-iodophenyl)acetic acid (13-2) (3 g, 8.8 mmol) was dissolved in tetrahydrofuran (30 mL), and argon gas was purged three times. Borane-tetrahydrofuran solution (18 mL, 18 mmol, 1 M concentration) was added dropwise to the reaction solution at 0 °C, and the mixture was refluxed overnight. The reaction solution was slowly added dropwise to ice water (50 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0 - 1 / 1) to give compound 2-(5-bromo-2-iodophenyl)ethane-1-ol (13-3).

[0701] LC-MS, M / Z (ESI): 328.3 [M+H]+

[0702] Step 3: Synthesis of 6-[2-(5-bromo-2-iodophenyl)ethoxy]pyridine-2(1H)-one (13-4)

[0703] 2-(5-bromo-2-iodophenyl)ethane-1-ol (13-3) (400 mg, 1.22 mmol), 2,6-dihydroxypyridine (163 mg, 1.47 mmol), and triphenylphosphine (642 mg, 2.45 mmol) were dissolved in tetrahydrofuran (4 mL). Diisopropyl azodicarbonate (495 mg, 2.45 mmol) was added dropwise to the reaction mixture at 0 °C, and the mixture was stirred at room temperature for 18 h. The reaction mixture was then poured into water (50 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-1 / 1) to give compound 6-[2-(5-bromo-2-iodophenyl)ethoxy]pyridine-2(1H)-one (13-4) (210 mg, yield 40.9%).

[0704] LC-MS, M / Z (ESI): 422.3 [M+H]+

[0705] Step 4: Synthesis of 9-bromo-6,7-dihydro-1H-pyrido[1,2-a][3,1]benzoxazon-1-one (13-5)

[0706] To a solution of 6-[2-(5-bromo-2-iodophenyl)ethoxy]pyridin-2(1H)-one (13-4) (200 mg, 0.48 mmol) in 1,4-dioxane (10 mL), cuprous iodide (18 mg, 0.096 mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (13 mg, 0.096 mmol), and potassium carbonate (131 mg, 0.96 mmol) were added. The reaction mixture was stirred at 100 °C for 18 h under argon protection. The reaction mixture was concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-0 / 1) to obtain 9-bromo-6,7-dihydro-1H-pyrido[1,2-a][3,1]benzoxazazepone-1-one (13-5) (30 mg, yield 21.6%).

[0707] LC-MS, M / Z (ESI): 294.3 [M+H]+

[0708] Step 5: Synthesis of 3-[2-chloro-3-(1-oxo-6,7-dihydro-1H-pyrido[1,2-a][3,1]benzoxazono-9-yl)phenyl]piperidin-2,6-dione (compound 13)

[0709]

[0710] To a solution of 9-bromo-6,7-dihydro-1H-pyrido[1,2-a][3,1]benzoxazon-1-one (13-5) (30 mg, 0.1 mmol) and 3-[2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl]piperidin-2,6-dione (180 mg, 0.5 mmol) in 1,4-dioxane (0.5 mL), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (8 mg, 0.01 mmol) and potassium carbonate (43 mg, 0.3 mmol) were added. The reaction mixture was stirred at 100 °C for 18 h under argon protection. The reaction mixture was cooled to room temperature, poured into water (10 mL), and then extracted with ethyl acetate (2 mL x 3). After combining the organic phases, the mixture was washed with saturated brine (2 mL * 2), dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then subjected to reverse-phase preparation (column: Phenomenex Synergi C18 100 * 25 mm * 4 μm; solvent: A = water + 0.1 vol% formic acid (99%), B = acetonitrile; gradient: 5% - 95%, 7 min) to give compound 3-[2-chloro-3-(1-oxo-6,7-dihydro-1H-pyrido[1,2-a][3,1]benzoxazono-9-yl)phenyl]piperidin-2,6-dione (compound 13).

[0711] 1H NMR(600MHz,DMSO-d6)δ10.95(s,1H),7.58(d,1H),7.55–7.49(m,2H),7.46–7.41(m,2H),7.41–7.37(m,2H),6.42(d,1H),6.09(d,1 H),4.46–4.42(m,1H),4.39–4.29(m,2H),2.97–2.91(m,2H),2.84–2.77(m,1H),2.55(d,1H),2.39–2.33(m,1H),2.09–2.04(m,1H).

[0712] LC-MS, M / Z (ESI): 435.0 [M+H]+

[0713] Example 14: Preparation of target compound 14

[0714] 3-(2-chloro-3-{2-[(1-hydroxycyclopropyl)methyl]-1-oxo-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-8-yl}phenyl)piperidin-2,6-dione (compound 14)

[0715]

[0716] The synthetic route for target compound 14 is shown below:

[0717]

[0718] Step 1: Synthesis of ethyl acetate (8-bromo-1-oxo-5,6-dihydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-2(4H)-yl) (compound 14-1)

[0719] Potassium carbonate (296 mg, 2.14 mmol) and ethyl bromoacetate (179 mg, 1.07 mmol) were added to a solution of 8-bromo-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-1-one (6-2) (200 mg, 0.71 mmol) in N,N-dimethylformamide (2 mL), and the mixture was stirred at room temperature for 18 h. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-1 / 3) to obtain ethyl acetate (8-bromo-1-oxo-5,6-dihydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-2(4H)-yl) (compound 14-1).

[0720] LC-MS, M / Z (ESI): 368.3 [M+H]+

[0721] Step 2: Synthesis of 8-bromo-2-[(1-hydroxycyclopropyl)methyl]-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-1-one (compound 14-2)

[0722] To a solution of ethyl acetate (220 mg, 0.6 mmol) of (8-bromo-1-oxo-5,6-dihydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-2(4H)-yl) (compound 14-1) in tetrahydrofuran (3 mL), tetraisopropyl titanate (17 mg, 0.06 mmol) was added, purging with argon three times. Ethyl magnesium bromide (1 mL, 2 mmol, 2 M tetrahydrofuran solution) was slowly added dropwise to the reaction solution at 0 °C, and the reaction was continued for 2 h. The reaction solution was then slowly added dropwise to a saturated ammonium chloride solution (20 mL), and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-0 / 1) to give 8-bromo-2-[(1-hydroxycyclopropyl)methyl]-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-1-one (compound 14-2) (60 mg, yield 30%).

[0723] LC-MS, M / Z (ESI): 352.2 [M+H]+

[0724] Step 3: Synthesis of 3-(2-chloro-3-{2-[(1-hydroxycyclopropyl)methyl]-1-oxo-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-8-yl}phenyl)piperidine-2,6-dione (compound 14)

[0725]

[0726] To a solution of 8-bromo-2-[(1-hydroxycyclopropyl)methyl]-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-1-one (compound 14-2) (60 mg, 0.17 mmol) in 1,4-dioxane (1.5 mL), 3-[2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl]piperidin-2,6-dione (299 mg, 0.86 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (14 mg, 0.017 mmol), and potassium carbonate (71 mg, 0.51 mmol) were added, purging with argon three times, and the mixture was stirred at 100 °C for 18 h. The reaction mixture was then poured into water (10 mL) and extracted with ethyl acetate (2 mL × 3). After the organic phases were combined, the mixture was washed with saturated brine (2 mL × 2), dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then subjected to reverse-phase preparation (column: Phenomenex Synergi C18 100*25mm*4μm; solvent: A = water + 0.1 vol% formic acid (99%), B = acetonitrile; gradient: 5%-95%, 7 min) to obtain the product 3-(2-chloro-3-{2-[(1-hydroxycyclopropyl)methyl]-1-oxo-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-8-yl}phenyl)piperidin-2,6-dione (compound 14).

[0727] 1 H NMR(600MHz,DMSO-d6)δ10.95(s,1H),7.57(d,1H),7.50–7.34(m,5H),4.74(s,2H),4.38–4.33(m,1H),2.83–2.7 7(m,1H),2.71(t,2H),2.61–2.52(m,5H),2.39–2.31(m,1H),2.15–2.09(m,2H),2.08–2.02(m,1H),0.97(t,3H).

[0728] LC-MS, M / Z (ESI): 493.3 [M+H]+

[0729] Example 15: Preparation of target compound 15

[0730] 3-(2-chloro-3-(2-(3-hydroxycyclobutyl)-1-oxo-2,4,5,6-tetrahydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azacycloheptane-8-yl)phenyl)piperidine-2,6-dione (compound 15)

[0731]

[0732] The synthetic route for target compound 15 is shown below:

[0733]

[0734] Step 1: Synthesis of 8-bromo-2-(3-oxocyclobutyl)-2,4,5,6-tetrahydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azacycloheptane-1-one (compound 15-1)

[0735] At 0 °C, potassium carbonate (148 mg, 1.07 mmol) and 3-bromocyclobutane-1-one (6-2) (100 mg, 0.36 mmol) were added to a solution of 8-bromo-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-1-one (6-2) (100 mg, 0.36 mmol) in N,N-dimethylformamide (1 mL). The reaction mixture was stirred at 80 °C for 5 h. The reaction mixture was cooled to room temperature, water (10 mL) was added, and then extracted with ethyl acetate (5 mL * 3). The combined organic phases were washed with saturated brine (5 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-1 / 1) to give compound 8-bromo-2-(3-oxocyclobutyl)-2,4,5,6-tetrahydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azacycloheptane-1-one (compound 15-1).

[0736] LC-MS, M / Z (ESI): 348.3 [M+H]+

[0737] Step 2: Synthesis of 8-bromo-2-(3-hydroxycyclobutyl)-2,4,5,6-tetrahydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azacycloheptane-1-one (15-2)

[0738] 8-Bromo-2-(3-oxocyclobutyl)-2,4,5,6-tetrahydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azacycloheptan-1-one (compound 15-1) (100 mg, 0.34 mmol) was dissolved in a MeOH / THF (10 mL / 10 mL) mixture. Sodium borohydride (20 mg, 0.51 mmol) was added at 0 °C, and the reaction mixture was stirred at 25 °C for 8 h. The reaction mixture was poured into a saturated ammonium chloride aqueous solution (20 mL), and then extracted with ethyl acetate (20 mL * 3). The combined organic phases were washed with saturated brine (2 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-1 / 1) to give compound 8-bromo-2-(3-hydroxycyclobutyl)-2,4,5,6-tetrahydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azacycloheptane-1-one (compound 15-2).

[0739] LC-MS, M / Z (ESI): 350.2 [M+H]+

[0740] Step 3: Synthesis of 2-(3-hydroxycyclobutyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-2,4,5,6-tetrahydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azacycloheptane-1-one (15-3)

[0741] At room temperature, 1,4-dioxane (3 mL) of 8-bromo-2-(3-hydroxycyclobutyl)-2,4,5,6-tetrahydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azacycloheptan-1-one (compound 15-2) (80 mg, 0.34 mmol) was added to pinacol diborate (152 mg, 0.6 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (22 mg, 0.03 mmol), and potassium acetate (100.0 mg, 0.9 mmol). The reaction mixture was stirred at 100 °C for 18 h under nitrogen protection. The reaction mixture was then poured into water (10 mL) and extracted with ethyl acetate (2 mL x 3). After combining the organic phases, the mixture was washed with saturated brine (2 mL * 2), dried with anhydrous sodium sulfate, filtered, and concentrated to obtain compound 2-(3-hydroxycyclobutyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-2,4,5,6-tetrahydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azacycloheptane-1-one (compound 15-3), which was directly used in the next step of the reaction.

[0742] LC-MS, M / Z (ESI): 384.2 [M+H]+

[0743] Step 4: Synthesis of 3-(2-chloro-3-(2-(3-hydroxycyclobutyl)-1-oxo-2,4,5,6-tetrahydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azacycloheptane-8-yl)phenyl)piperidine-2,6-dione (compound 15)

[0744]

[0745] To a solution of crude 2-(3-hydroxycyclobutyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-2,4,5,6-tetrahydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azacycloheptane-1-one (80 mg, 0.34 mmol) and 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (intermediate A) (154 mg, 0.51 mmol) in 1,4-dioxane (1.5 mL), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (22 mg, 0.03 mmol) and potassium carbonate (186 mg, 1.35 mmol) were added, purging with argon three times, and then stirred at 100 °C for 18 h. The reaction mixture was poured into water (10 mL) and then extracted with ethyl acetate (2 mL * 3). After the organic phases were combined, the mixture was washed with saturated brine (2 mL * 2), dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by reverse-phase preparation (column: Phenomenex Synergi C18 100 * 25 mm * 4 μm; solvent: A = water + 0.1 vol% formic acid (99%), B = acetonitrile; gradient: 5% - 95%, 7 min) to obtain compound 3-(2-chloro-3-(2-(2-hydroxyethyl)-1-oxo-2,4,5,6-tetrahydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azacycloheptane-8-yl)phenyl)piperidine-2,6-dione (compound 15).

[0746] LC-MS, M / Z (ESI): 493.2 [M+H]+

[0747] Example 16: Preparation of target compound 16

[0748] 3-(2-chloro-3-(2-(2-hydroxyethyl)-1-oxo-2,4,5,6-tetrahydro-1H-benzo[1,2,4]triazolo[4,3-a]azacycloheptane-8-yl)phenyl)piperidine-2,6-dione (compound 16)

[0749]

[0750] The synthetic route for target compound 16 is shown below:

[0751]

[0752] Step 1: Synthesis of 8-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2,4,5,6-tetrahydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azacycloheptan-1-one (16-1)

[0753] At room temperature, potassium carbonate (148 mg, 1.07 mmol) and tert-butyl(2-iodoethoxy)dimethylsilane (61 mg, 0.43 mmol) were added to a solution of 8-bromo-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-1-one (compound 6-2) (100 mg, 0.36 mmol) in N,N-dimethylformamide (1 mL). The reaction mixture was stirred at 80 °C for 5 h. The reaction mixture was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (5 mL * 3). The combined organic phases were washed with saturated brine (5 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-1 / 1) to give compound 8-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2,4,5,6-tetrahydro-1H-benzo[1,2,4]triazolo[4,3-a]azacycloheptane-1-one (compound 16-1).

[0754] LC-MS, M / Z (ESI): 438.3 [M+H]+

[0755] Step 2: Synthesis of 2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-2,4,5,6-tetrahydro-1H-benzo[1,2,4]triazolo[4,3-a]azacycloheptane-1-one (compound 16-2)

[0756] To a solution of 1,4-dioxane (1 mL) of 8-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2,4,5,6-tetrahydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azacycloheptan-1-one (compound 16-1) (100 mg, 0.34 mmol) in 1,4-dioxane (1 mL), pinacol diborate (152 mg, 0.6 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (22 mg, 0.03 mmol), and potassium acetate (100.0 mg, 0.9 mmol) were added. The reaction mixture was stirred at 100 °C for 18 h under nitrogen protection. The reaction mixture was cooled to room temperature, poured into water (10 mL), and then extracted with ethyl acetate (2 mL * 3). After combining the organic phases, the mixture was washed with saturated brine (2 mL * 2), dried with anhydrous sodium sulfate, filtered, and concentrated to obtain compound 2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-2,4,5,6-tetrahydro-1H-benzo[1,2,4]triazolo[4,3-a]azacycloheptane-1-one (compound 16-2), which was directly used in the next step of the reaction.

[0757] LC-MS, M / Z (ESI): 486.2 [M+H]+

[0758] Step 3: Synthesis of 3-(3-(2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-oxo-2,4,5,6-tetrahydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azacycloheptane-8-yl)-2-chlorophenyl)piperidine-2,6-dione (compound 16-3)

[0759] To a solution of crude 2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-2,4,5,6-tetrahydro-1H-benzo[1,2,4]triazolo[4,3-a]azacycloheptane-1-one (compound 16-2) (100 mg, 0.34 mmol) and 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (intermediate A) (154 mg, 0.51 mmol) in 1,4-dioxane (1 mL), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (37 mg, 0.045 mmol) and potassium carbonate (186 mg, 1.35 mmol) were added. The reaction mixture was stirred at 100 °C for 18 h under nitrogen protection. The reaction solution was cooled to room temperature, poured into water (10 mL), and then extracted with ethyl acetate (2 mL * 3). The combined organic phases were washed with saturated brine (2 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-0 / 1) to give compound 3-(3-(2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-oxo-2,4,5,6-tetrahydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azacycloheptane-8-yl)-2-chlorophenyl)piperidine-2,6-dione (compound 16-3).

[0760] LC-MS, M / Z (ESI): 581.2 [M+H]+

[0761] Step 4: Synthesis of 3-(2-chloro-3-(2-(2-hydroxyethyl)-1-oxo-2,4,5,6-tetrahydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azacycloheptane-8-yl)phenyl)piperidine-2,6-dione (compound 16)

[0762]

[0763] To a solution of 100 mg (0.34 mmol) of 3-(3-(2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-oxo-2,4,5,6-tetrahydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azacycloheptane-8-yl)-2-chlorophenyl)piperidin-2,6-dione (compound 16-3) in tetrahydrofuran (1 mL), TBAF (0.7 mL, 1 M in THF) was added, and the mixture was stirred at room temperature for 18 h. The reaction mixture was poured into water (10 mL) and then extracted with ethyl acetate (2 mL x 3). The combined organic phases were washed with saturated brine (2 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative liquid chromatography (column: Phenomenex Synergi C18 100*25mm*4um; solvent: A = water + 0.1 vol% formic acid (99%), B = acetonitrile; gradient: 5%-95%, 7 min) to give compound 5-[2-chloro-3-(2,6-dioxoperidin-3-yl)phenyl]-1-methyl-1,3-dihydro-2H-2λ 6 ,1-Benzothiazol-2,2-dione (compound 16).

[0764] 1 H NMR(400MHz,DMSO-d6)δ8.02(d,1H),7.68(d,1H),7.44(d,1H),7.37–7.33(m,2H),7.30(d,1H),7.23(d,1H) ,4.32(dd,1H),4.05(dd,4H),3.29(s,1H),2.81(dt,1H),2.76–2.62(m,5H),2.41–2.27(m,2H),2.22(dd,2H)

[0765] LC-MS, M / Z(ESI): 467.3[M+H]+.

[0766] Example 17: Preparation of target compound 17

[0767] 3-{2-chloro-3-[2-(2-methoxyethyl)-1-oxo-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-8-yl]phenyl}piperidin-2,6-dione (compound 17)

[0768]

[0769] The synthetic route for target compound 17 is shown below:

[0770]

[0771] Step 1: Synthesis of 8-bromo-2-(2-methoxyethyl)-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzozazepine-1-one (17-1)

[0772] At room temperature, potassium carbonate (148 mg, 1.07 mmol) and 1-bromo-2-methoxyethane (61 mg, 0.43 mmol) were added to a solution of 8-bromo-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-1-one (6-2) (100 mg, 0.36 mmol) in N,N-dimethylformamide (1 mL). The reaction mixture was stirred at 80 °C for 5 h. After cooling to room temperature, water (10 mL) was added, followed by extraction with ethyl acetate (5 mL * 3). The combined organic phases were washed with saturated brine (5 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0 to 1 / 1) to give compound 8-bromo-2-(2-methoxyethyl)-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzozazepine-1-one (17-1).

[0773] LC-MS, M / Z (ESI): 338.3 [M+H]+

[0774] Step 2: Synthesis of 2-(2-methoxyethyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-1-one (17-2)

[0775] To a solution of 1,4-dioxane (1 mL) of 8-bromo-2-(2-methoxyethyl)-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzozazepine-1-one (17-1) (100 mg, 0.34 mmol) in 1,4-dioxane (1 mL), pinacol diborate (152 mg, 0.6 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (22 mg, 0.03 mmol), and potassium acetate (100.0 mg, 0.9 mmol) were added. The reaction mixture was stirred at 100 °C for 18 h under nitrogen protection. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (2 mL * 3). The combined organic phases were washed with saturated brine (2 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product (17-2), which was used directly in the next reaction.

[0776] LC-MS, M / Z (ESI): 386.2 [M+H]+

[0777] Step 3: Synthesis of 3-{2-chloro-3-[2-(2-methoxyethyl)-1-oxo-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-8-yl]phenyl}piperidine-2,6-dione (17)

[0778]

[0779] To a solution of crude 2-(2-methoxyethyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-1-one (17-2) (100 mg, 0.34 mmol) and 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (intermediate A) (154 mg, 0.51 mmol) in 1,4-dioxane (2 mL), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (37 mg, 0.045 mmol) and potassium carbonate (186 mg, 1.35 mmol) were added. The reaction mixture was stirred at 100 °C for 18 h under nitrogen protection. The reaction solution was poured into water (10 mL), and then extracted with ethyl acetate (2 mL * 3). The organic phases were combined and washed with saturated brine (2 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0 to 0 / 1) to give compound 3-{2-chloro-3-[2-(2-methoxyethyl)-1-oxo-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-8-yl]phenyl}piperidin-2,6-dione (compound 17).

[0780] 1 H NMR(400MHz,DMSO-d6)δ10.93(s,1H),7.56(d,1H),7.44(d,2H),7.41–7.34(m,3H),4.34(dd,1H),3.88(t,2H),3.64(t,2 H),3.26(s,3H),2.82–2.75(m,1H),2.67(t,2H),2.55(dt,3H),2.37–2.31(m,1H),2.12–2.07(m,2H),2.06–2.01(m,1H).

[0781] LC-MS, M / Z (ESI): 481.2 [M+H]+

[0782] Example 18: Preparation of target compound 18

[0783] 3-[2-chloro-3-(1-oxo-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-8-yl)phenyl]piperidin-2,6-dione (compound 18)

[0784]

[0785] The synthetic route for target compound 18 is shown below:

[0786]

[0787] To a solution of 8-bromo-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-1-one (6-2) (100 mg, 0.36 mmol) in dioxane (1 mL), 3-[2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl]piperidin-2,6-dione (intermediate A') (374 mg, 1.07 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (29 mg, 0.036 mmol), and potassium carbonate (123 mg, 0.89 mmol) were added. The reaction mixture was stirred at 100 °C for 18 h under nitrogen protection. The reaction mixture was then poured into water (10 mL) and extracted with ethyl acetate (2 mL x 3). The organic phases were combined and washed with saturated brine (2 mL * 2), dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative liquid chromatography (column: Phenomenex Synergi C18 100 * 25 mm * 4 μm; solvent: A = water + 0.1 vol% formic acid (99%), B = acetonitrile; gradient: 5% - 95%, 7 min) to give compound 3-[2-chloro-3-(1-oxo-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-8-yl)phenyl]piperidin-2,6-dione (compound 18).

[0788] 1 H NMR (400MHz, DMSO-d6) δ11.74(s,1H),10.92(s,1H),7.58(d,1H),7.49–7.34(m,5H),4.38–4.32(m,1H),2.83 –2.77(m,1H),2.71–2.66(m,2H),2.58–2.52(m,2H),2.36–2.30(m,1H),2.12–2.06(m,2H),2.01–1.96(m,2H).

[0789] LC-MS, M / Z (ESI): 423.3 [M+H]+

[0790] Example 19: Preparation of target compound 19

[0791] 3-[3-(1-acetyl-2,3,4,5-tetrahydro-1H-1-benzoza-7-yl)-2-chlorophenyl]piperidin-2,6-dione (target compound 19)

[0792]

[0793] The synthetic route for compound 19 is shown below:

[0794]

[0795] Step 1: Synthesis of 7-bromo-2,3,4,5-tetrahydro-1H-1-benzozazepine (compound 19-1)

[0796] At 0 °C, 200 mg (0.72 mmol) of 8-bromo-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-1-one (compound 5-1) in 3 mL of THF was added to BH3·THF (2.1 mL, 2.1 mmol), and the mixture was heated to 70 °C and stirred under reflux for 8 h. After the reaction was complete, the reaction solution was cooled to room temperature, and the reaction was quenched by slow dropwise addition of methanol (1 mL). The solution was then evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate (V / V) = 1:0 to 1:1) to obtain compound 7-bromo-2,3,4,5-tetrahydro-1H-1-benzozazaporide (compound 19-1).

[0797] LC-MS, M / Z (ESI): 226.1 [M+H] +

[0798] Step 2: Synthesis of 1-(7-bromo-2,3,4,5-tetrahydro-1H-1-benzoza-1-yl)ethyl-1-one (compound 19-2)

[0799] At room temperature, TEA (179 mg, 1.77 mmol) and DMAP (11 mg, 0.09 mmol) were added to a DCM (5 mL) solution of 7-bromo-2,3,4,5-tetrahydro-1H-1-benzozazaporide (compound 19-1) (200 mg, 0.88 mmol), followed by the addition of acetic anhydride (135 mg, 1.32 mmol). The reaction was carried out at room temperature for 12 h. After the reaction was completed, DCM (20 mL) was added to dilute the reaction solution, and the organic phase was washed with saturated NH4Cl aqueous solution. The solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate (V / V) = 1:0 to 1:1) to obtain compound 7-bromo-2,3,4,5-tetrahydro-1H-1-benzozazaporide (compound 19-2).

[0800] LC-MS, M / Z (ESI): 268.1 [M+H] +

[0801] Step 3: Synthesis of 1-[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-2,3,4,5-tetrahydro-1H-1-benzozazapor-1-yl] ethyl-1-one (compound 19-3) at room temperature: 1,4-dioxane (3 mL) of 1-(7-bromo-2,3,4,5-tetrahydro-1H-1-benzozazapor-1-yl) ethyl-1-one (compound 19-2) (80 mg, 0.29 mmol) was added to pinacol diborate (152 mg, 0.6 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (22 mg, 0.03 mmol), and potassium acetate (100 mg, 0.9 mmol). The reaction mixture was stirred at 100 °C for 18 h under nitrogen protection. Pour the reaction solution into water (10 mL), and then extract with ethyl acetate (2 mL * 3). Combine the organic phases, wash with saturated brine (2 mL * 2), dry with anhydrous sodium sulfate, filter and concentrate to obtain the crude product, which is directly used in the next step.

[0802] LC-MS, M / Z (ESI): 316.2 [M+H] +

[0803] Step 4: Synthesis of 3-[3-(1-acetyl-2,3,4,5-tetrahydro-1H-1-benzoza-7-yl)-2-chlorophenyl]piperidine-2,6-dione (compound 19)

[0804]

[0805] To a solution of crude 1-[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-2,3,4,5-tetrahydro-1H-1-benzozazepine-1-yl]ethyl-1-one (compound 19-3) (80 mg, 0.29 mmol) and 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (intermediate A) (154 mg, 0.51 mmol) in 1,4-dioxane (1.5 mL), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (22 mg, 0.03 mmol) and potassium carbonate (186 mg, 1.35 mmol) were added. The reaction mixture was stirred at 100 °C for 18 h under nitrogen protection. The reaction mixture was then poured into water (10 mL) and extracted with ethyl acetate (2 mL x 3). The organic phases were combined and washed with saturated brine (2 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative liquid chromatography (column: Phenomenex Synergi C18 100 * 25 mm * 4 μm; solvent: A = water + 0.1 vol% formic acid (99%), B = acetonitrile; gradient: 5% - 95%, 7 min) to give the product 3-[3-(1-acetyl-2,3,4,5-tetrahydro-1H-1-benzoza-7-yl)-2-chlorophenyl]piperidin-2,6-dione (compound 19).

[0806] 1 H NMR(400MHz,DMSO-d6)10.92(s,1H),7.65-7.47(m,1H),7.42-7.10(m,5H),4.52(d,1H),4.33(d,1H ),2.90-2.63(m,3H),2.60-2.49(m,3H),2.38-2.23(m,1H),1.97(d,2H),1.76(d,3H),1.27(d,2H).

[0807] LC-MS, M / Z (ESI): 411.1 [M+H] +

[0808] Example 20: Preparation of target compound 20

[0809] 3-(2-chloro-3-{2-[2-(dimethylamino)ethyl]-1-oxo-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-8-yl}phenyl)piperidine-2,6-dione (target compound 20)

[0810]

[0811] The synthetic route for compound 20 is shown below:

[0812]

[0813] Step 1: Synthesis of 8-bromo-2-[2-(dimethylamino)ethyl]-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzozazepine-1-one (compound 20-1)

[0814] At 0 °C, DBU (218 mg, 1.44 mmol) and 2-bromo-N,N-dimethylformamide (61 mg, 1.1 mmol) were added to a solution of 8-bromo-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-1-one (compound 6-2) (200 mg, 0.72 mmol) in N,N-dimethylformamide (3 mL), and the mixture was heated to 80 °C and stirred for 5 h. Water (10 mL) was added to the reaction mixture, and the mixture was then extracted with ethyl acetate (5 mL * 3). The combined organic phases were washed with saturated brine (5 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate (V / V) = 1:0 to 1:1) to give compound 8-bromo-2-[2-(dimethylamino)ethyl]-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzozazepine-1-one (compound 20-1).

[0815] LC-MS, M / Z (ESI): 351.3 [M+H] +

[0816] Step 2: Synthesis of 2-[2-(dimethylamino)ethyl]-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzozazepine-1-one (compound 20-2)

[0817] At room temperature, 1,4-dioxane (3 mL) of 8-bromo-2-(3-hydroxycyclobutyl)-2,4,5,6-tetrahydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azacycloheptan-1-one (compound 20-1) (100 mg, 0.29 mmol) was added to pinacol diborate (152 mg, 0.6 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (22 mg, 0.03 mmol), and potassium acetate (100 mg, 0.9 mmol). The mixture was purged with argon three times and stirred at 100 °C for 18 h. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (2 mL x 3). The combined organic phases were washed with saturated brine (2 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude compound 20-2, which was directly added to the next step.

[0818] LC-MS, M / Z (ESI): 399.2 [M+H] +

[0819] Step 3: Synthesis of 3-(2-chloro-3-{2-[2-(dimethylamino)ethyl]-1-oxo-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-8-yl}phenyl)piperidine-2,6-dione (compound 20)

[0820]

[0821] To a solution of crude 2-[2-(dimethylamino)ethyl]-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzozazepine-1-one (compound 20-2) (100 mg, 0.29 mmol) and 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (intermediate A) (154 mg, 0.51 mmol) in dioxane (1.5 mL), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (22 mg, 0.03 mmol) and potassium carbonate (186 mg, 1.35 mmol) were added, purging with argon three times, and then stirred at 100 °C for 18 h. The reaction mixture was poured into water (10 mL) and then extracted with ethyl acetate (2 mL * 3). The organic phases were combined, washed with saturated brine (2 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was subjected to reverse-phase preparation (column: Phenomenex Synergi C18 100 * 25 mm * 4 μm; solvent: A = water + 0.1 vol% formic acid (99%), B = acetonitrile; gradient: 5% - 95%, 7 min) to give the product 3-(2-chloro-3-(2-(2-hydroxyethyl)-1-oxo-2,4,5,6-tetrahydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azacycloheptane-8-yl)phenyl)piperidin-2,6-dione (compound 20).

[0822] 1 H NMR(400MHz,DMSO-d6)10.93(s,1H),7.58-7.54(m,1H),7.44(d,2H),7.39-7.35(m,3H),4.34(d,1H),3.81(t,2H),2.81- 2.75(m,1H),2.66(t,2H),2.59(t,2H),2.57-2.54(m,3H),2.37-2.30(m,1H),2.18(d,6H),2.09(d,2H),2.06-2.00(m,1H)

[0823] LC-MS, M / Z (ESI): 494.2 [M+H] +

[0824] Example 21: Preparation of target compound 21

[0825] {2-Chloro-3-[2-(2H3)methyl-1-oxo-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-8-yl]phenyl}piperidin-2,6-dione (target compound 21)

[0826]

[0827] The synthetic route for compound 21 is shown below:

[0828]

[0829] Step 1: 8-Bromo-2-( 2 Synthesis of methyl-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzozazepine-1-one (compound 21-2): At 0 °C, potassium carbonate (100 mg, 0.72 mmol) and deuterated iodomethane (78 mg, 0.54 mmol) were added to a solution of 8-bromo-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzozazepine-1-one (intermediate 6-2) (100 mg, 0.36 mmol) in N,N-dimethylformamide (3 mL), and the mixture was heated to 80 °C and stirred for 5 h. Water (10 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (5 mL * 3). The combined organic phases were washed with saturated brine (5 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate (V / V) = 1:0-1:1) to give compound 8-bromo-2-(2H3)methyl-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzozazepine-1-one (compound 21-1).

[0830] LC-MS, M / Z (ESI): 291.3 [M+H] +

[0831] Step 2: Synthesis of 2-(2H3)methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzozazepine-1-one (compound 21-2)

[0832] At room temperature, 1,4-dioxane (3 mL) of 8-bromo-2-(2H3)methyl-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzozazepine-1-one (compound 21-1) (100 mg, 0.29 mmol) was added to pinacol diborate (152 mg, 0.6 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (22 mg, 0.03 mmol), and potassium acetate (100 mg, 0.9 mmol). The mixture was purged with argon three times and stirred at 100 °C for 18 h. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (2 mL x 3). The combined organic phases were washed with saturated brine (2 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude compound 21-2, which was directly added to the next step.

[0833] LC-MS, M / Z (ESI): 339.2 [M+H] +

[0834] Step 3: Synthesis of 3-{2-chloro-3-[2-(2H3)methyl-1-oxo-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-8-yl]phenyl}piperidine-2,6-dione (compound 21)

[0835]

[0836] To a solution of crude 2-(2H3)methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzozazepine-1-one (compound 21-2) (100 mg, 0.29 mmol) and 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (intermediate A) (154 mg, 0.51 mmol) in dioxane (1.5 mL), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (22 mg, 0.03 mmol) and potassium carbonate (186 mg, 1.35 mmol) were added, purging with argon three times, and then stirred at 100 °C for 18 h. The reaction mixture was poured into water (10 mL) and then extracted with ethyl acetate (2 mL * 3). After the organic phases were combined, the mixture was washed with saturated brine (2 mL * 2), dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then subjected to reverse-phase preparation (column: Phenomenex Synergi C18 100 * 25 mm * 4 μm; solvent: A = water + 0.1 vol% formic acid (99%), B = acetonitrile; gradient: 5% - 95%, 7 min) to obtain the product 3-{2-chloro-3-[2-(2H3)methyl-1-oxo-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-8-yl]phenyl}piperidin-2,6-dione (compound 21-) (74.1 mg, yield 85%).

[0837] 1 H NMR(400MHz,DMSO-d6)10.93(s,1H),7.59-7.53(m,1H),7.44(s,2H),7.42-7.32(m,3H),4.36-4.3 2(m,1H),2.82-2.74(m,1H),2.71-2.68(m,2H),2.54(t,3H),2.35-2.31(m,1H),2.09-2.01(m,3H)

[0838] LC-MS, M / Z (ESI): 440.0 [M+H] +

[0839] Example 22: Preparation of target compound 22

[0840] 3-(2-chloro-3-{2-[2-(methanesulfonyl)ethyl]-1-oxo-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-8-yl}phenyl)piperidin-2,6-dione (target compound 22)

[0841]

[0842] The synthetic route for compound 22 is shown below:

[0843]

[0844] Step 1: Synthesis of 8-bromo-2-[2-(methanesulfonyl)ethyl]-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzozazepine-1-one (compound 22-1)

[0845] At 0 °C, cesium carbonate (234 mg, 0.72 mmol) and 1-bromo-2-(methanesulfonyl)ethane (101 mg, 0.54 mmol) were added to a solution of 8-bromo-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-1-one (compound 6-2) (100 mg, 0.36 mmol) in N,N-dimethylformamide (3 mL), and the mixture was heated to 80 °C and stirred for 5 h. Water (10 mL) was added to the reaction mixture, and the mixture was then extracted with ethyl acetate (5 mL * 3). The combined organic phases were washed with saturated brine (5 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-1 / 1) to give compound 8-bromo-2-[2-(methanesulfonyl)ethyl]-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzozazepine-1-one (compound 22-1).

[0846] LC-MS, M / Z (ESI): 386.1 [M+H] +

[0847] Step 2: Synthesis of 2-[2-(methanesulfonyl)ethyl]-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzozazepine-1-one (compound 22-2)

[0848] At room temperature, 1,4-dioxane (3 mL) of 8-bromo-2-[2-(methanesulfonyl)ethyl]-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzozazepine-1-one (compound 22-1) (110 mg, 0.29 mmol) was added to pinacol diboronate (152 mg, 0.6 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (22 mg, 0.03 mmol), and potassium acetate (100 mg, 0.9 mmol). The reaction mixture was stirred at 100 °C for 18 h under nitrogen protection. The reaction mixture was poured into water (10 mL) and then extracted with ethyl acetate (2 mL x 3). The combined organic phases were washed with saturated brine (2 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude compound 22-2, which was directly added to the next step.

[0849] LC-MS, M / Z (ESI): 434.2 [M+H] +

[0850] Step 3: Synthesis of 3-(2-chloro-3-{2-[2-(methanesulfonyl)ethyl]-1-oxo-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-8-yl}phenyl)piperidine-2,6-dione (compound 22)

[0851]

[0852] To a solution of crude 2-[2-(methanesulfonyl)ethyl]-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzozazepine-1-one (compound 22-2) (100 mg, 0.29 mmol) and 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (intermediate A) (154 mg, 0.51 mmol) in 1,4-dioxane (1.5 mL), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (22 mg, 0.03 mmol) and potassium carbonate (186 mg, 1.35 mmol) were added. The reaction mixture was stirred at 100 °C for 18 h under nitrogen protection. The reaction mixture was poured into water (10 mL) and then extracted with ethyl acetate (2 mL * 3). The organic phases were combined and washed with saturated brine (2 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative liquid chromatography (column: Phenomenex Synergi C18 100 * 25 mm * 4 μm; solvent: A = water + 0.1 vol% formic acid (99%), B = acetonitrile; gradient: 5% - 95%, 7 min) to give the product 3-(2-chloro-3-{2-[2-(methanesulfonyl)ethyl]-1-oxo-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzozaza-8-yl}phenyl)piperidin-2,6-dione (compound 22).

[0853] 1 H NMR (400MHz, DMSO-d6)10.92(s,1H),7.55(d,J=8.4Hz,1H),7.45(d,J=7.6Hz,2H),7.42-7.32(m,3H),4.36-4.32(m,1H),4.19(t,J=6.8Hz, 2H),3.56(t,J=6.8Hz,2H),3.06(s,3H),2.82-2.75(m,1H),2.69(t,J=6.8Hz,2H),2.57-2.53(m,3H),2.35-2.31(m,1H),2.12-2.01(m,3H).

[0854] LC-MS, M / Z (ESI): 529.1 [M+H] +

[0855] Example 23: Preparation of target compound 23

[0856] 3-{2-chloro-3-[1-(cyclopropanecarbonyl)-2,3,4,5-tetrahydro-1H-1-benzoza-7-yl]phenyl}piperidin-2,6-dione (compound 23)

[0857]

[0858] The synthetic route for target compound 23 is shown below:

[0859]

[0860] Step 1: Synthesis of (7-bromo-2,3,4,5-tetrahydro-1H-1-benzoza-1-yl)(cyclopropyl)methyl ketone (23-1)

[0861] At room temperature, triethylamine (179 mg, 1.77 mmol) and 4-dimethylaminopyridine (11 mg, 0.09 mmol) were added to a solution of 7-bromo-2,3,4,5-tetrahydro-1H-1-benzozazaphene (19-1) (200 mg, 0.88 mmol) in dichloromethane (5 mL), followed by the addition of acetic anhydride (135 mg, 1.32 mmol). The reaction mixture was stirred at room temperature for 12 h. After the reaction was complete, the solution was diluted with dichloromethane (20 mL), washed with saturated ammonium chloride aqueous solution, and the organic phase was collected and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0 to 1 / 1) to give the compound (7-bromo-2,3,4,5-tetrahydro-1H-1-benzozazaphene-1-yl)(cyclopropyl) methyl ketone (23-1).

[0862] LC-MS, M / Z (ESI): 294.1 [M+H]+

[0863] Step 2: Synthesis of cyclopropyl [7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-2,3,4,5-tetrahydro-1H-1-benzozazepine-1-yl] ketone (23-2)

[0864] At room temperature, 152 mg (0.6 mmol) of pinacol diborate, 22 mg (0.03 mmol) of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, and 100.0 mg (0.9 mmol) of potassium acetate were added to 1,4-dioxane (3 mL) of (7-bromo-2,3,4,5-tetrahydro-1H-1-benzoza-1-yl)(cyclopropyl)methyl ketone (23-1) (80 mg, 0.29 mmol). The reaction mixture was stirred at 100 °C for 18 h under nitrogen protection. The reaction mixture was cooled to room temperature, poured into water (10 mL), and then extracted with ethyl acetate (2 mL * 3). After combining the organic phases, the mixture was washed with saturated brine (2 mL * 2), dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude compound cyclopropyl[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-2,3,4,5-tetrahydro-1H-1-benzozazepine-1-yl] ketone (23-2), which was directly used in the next step of the reaction.

[0865] LC-MS, M / Z (ESI): 316.2 [M+H]+

[0866] Step 3: Synthesis of 3-{2-chloro-3-[1-(cyclopropanecarbonyl)-2,3,4,5-tetrahydro-1H-1-benzoza-7-yl]phenyl}piperidine-2,6-dione (compound 23-2)

[0867]

[0868] To a solution of crude cyclopropyl[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-2,3,4,5-tetrahydro-1H-1-benzozazepine-1-yl] ketone (23-2) (180 mg, 0.6 mmol) and 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (230 mg, 0.9 mmol) in 1,4-dioxane (1.5 mL), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (44 mg, 0.06 mmol) and potassium phosphate (380 mg, 1.8 mmol) were added. The reaction mixture was stirred at 100 °C for 18 h under nitrogen protection. The reaction mixture was cooled to room temperature, poured into water (10 mL), and then extracted with ethyl acetate (2 mL x 3). The organic phases were combined and washed with saturated brine (2 mL * 2), dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by paper cup liquid chromatography (column: Phenomenex Synergi C18 100 * 25 mm * 4 μm; solvent: A = water + 0.1 vol% formic acid (99%), B = acetonitrile; gradient: 5% - 95%, 7 min) to give compound 3-{2-chloro-3-[1-(cyclopropanecarbonyl)-2,3,4,5-tetrahydro-1H-1-benzoza-7-yl]phenyl}piperidin-2,6-dione (compound 23).

[0869] 1 H NMR(400MHz,DMSO-d6)δ10.91(s,1H),7.42–7.27(m,6H),4.56(d,1H),4. 35-4.1(m,1H),2.84–2.74(m,2H),2.73-2.71(m,1H),2.63–2.50(m,2H), 2.37–2.27(m,1H),2.08–1.99(m,1H),1.93(d,1H),1.77–1.67(m,2H),1. 40–1.30(m,2H),0.84-0.81(m,2H),0.67-0.65(m,1H),0.60-0.58(m,1H)

[0870] LC-MS, M / Z (ESI): 437.2 [M+H]+

[0871] Example 24: Preparation of target compound 24

[0872] 3-[2-chloro-3-(1-propionyl-2,3,4,5-tetrahydro-1H-1-benzoza-7-yl)phenyl]piperidin-2,6-dione (compound 24)

[0873]

[0874] The synthetic route for target compound 24 is shown below:

[0875]

[0876] Step 1: Synthesis of 1-(7-bromo-2,3,4,5-tetrahydro-1H-1-benzoza-1-yl)prop-1-one (24-1)

[0877] At room temperature, triethylamine (179 mg, 1.77 mmol) and 4-dimethylaminopyridine (11 mg, 0.09 mmol) were added to a solution of 7-bromo-2,3,4,5-tetrahydro-1H-1-benzozazaphene (19-1) (200 mg, 0.88 mmol) in dichloromethane (5 mL), followed by the addition of propionyl chloride (135 mg, 1.32 mmol). The reaction was carried out at room temperature for 5 h. After the reaction was complete, the reaction solution was diluted with dichloromethane (20 mL), and the organic phase was washed with saturated ammonium chloride aqueous solution. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0 to 1 / 1) to give compound 1-(7-bromo-2,3,4,5-tetrahydro-1H-1-benzozaza-1-yl)prop-1-one (24-1).

[0878] LC-MS, M / Z (ESI): 268.1 [M+H]+

[0879] Step 3: Synthesis of 1-[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-2,3,4,5-tetrahydro-1H-1-benzozazepine-1-yl]prop-1-one (24-2)

[0880] At room temperature, 1,4-dioxane (3 mL) of 1-(7-bromo-2,3,4,5-tetrahydro-1H-1-benzoza-1-yl)prop-1-one (24-1) (80 mg, 0.29 mmol) was mixed with pinacol diborate (152 mg, 0.6 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (22 mg, 0.03 mmol), and potassium acetate (100.0 mg, 0.9 mmol). The reaction mixture was stirred at 100 °C for 18 h under nitrogen protection. The reaction mixture was then poured into water (10 mL) and extracted with ethyl acetate (2 mL x 3). After combining the organic phases, the mixture was washed with saturated brine (2 mL * 2), dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude compound 1-[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborphanecyclopentan-2-yl)-2,3,4,5-tetrahydro-1H-1-benzozazepine-1-yl]prop-1-one (24-2), which was directly used in the next reaction step.

[0881] LC-MS, M / Z (ESI): 316.2 [M+H]+

[0882] Step 3: 3-[2-chloro-3-(1-propionyl-2,3,4,5-tetrahydro-1H-1-benzoza-7-yl)phenyl]piperidin-2,6-dione (compound 24)

[0883]

[0884] To a solution of crude 1-[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-2,3,4,5-tetrahydro-1H-1-benzozazepine-1-yl]prop-1-one (24-2) (160 mg, 0.6 mmol) and 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (intermediate A) (230 mg, 0.9 mmol) in 1,4-dioxane (1.5 mL), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (44 mg, 0.06 mmol) and potassium phosphate (381 mg, 1.8 mmol) were added. The reaction mixture was stirred at 100 °C for 18 h under nitrogen protection. The reaction mixture was then poured into water (10 mL) and extracted with ethyl acetate (2 mL x 3). The organic phases were combined and washed with saturated brine (2 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative liquid chromatography (column: Phenomenex Synergi C18 100 * 25 mm * 4 μm; solvent: A = water + 0.1 v / v formic acid (99%), B = acetonitrile; gradient: 5% - 95%, 7 min) to give compound 3-[2-chloro-3-(1-propionyl-2,3,4,5-tetrahydro-1H-1-benzoza-7-yl)phenyl]piperidin-2,6-dione (compound 24).

[0885] 1 H NMR(400MHz,DMSO-d6)10.91(s,1H),7.44–7.31(m,5H),7.28(d,1H),4.54(d,1H),4.35-4.31(m,1H),2.79-2.76(m,2H),2.66(t,1H),2.57- 2.53(m,2H),2.35-2.31(m,1H),2.25-2.3(m,1H),2.07-2.02(m,1H),1 .91(d,1H),1.86-1.82(m,1H),1.73(s,2H),1.32(d,1H),0.92(q,3H).

[0886] LC-MS, M / Z (ESI): 425.1 [M+H]+

[0887] Example 25: Preparation of target compound 25

[0888] 3-(2-chloro-3-{2-[2-(difluoromethoxy)ethyl]-1-oxo-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-8-yl}phenyl)piperidin-2,6-dione (compound 25)

[0889]

[0890] The synthetic route for target compound 25 is shown below:

[0891]

[0892] Step 1: Synthesis of 8-bromo-2-(2-{[tert-butyldi(methyl)silyl]oxy}ethyl)-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzozazepine-1-one (25-1)

[0893] At room temperature, potassium carbonate (493 mg, 3.6 mmol) and tert-butyl(2-iodoethoxy)dimethylsilane (764 mg, 2.67 mmol) were added to a solution of 8-bromo-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-1-one (6-2) (500 mg, 1.78 mmol) in N,N-dimethylformamide (10 mL), and the mixture was heated to 80 °C and stirred for 5 h. The reaction mixture was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (5 mL x 3). The combined organic phases were washed with saturated brine (5 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0 to 1 / 1) to give compound 8-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2,4,5,6-tetrahydro-1H-benzo[1,2,4]triazolo[4,3-a]azacycloheptane-1-one (compound 25-1).

[0894] LC-MS, M / Z (ESI): 438.3 [M+H]+

[0895] Step 2: Synthesis of 8-bromo-2-(2-hydroxyethyl)-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzozazepine-1-one (25-2) At room temperature, water (0.5 mL) and p-toluenesulfonic acid hydrate (295 mg, 1.55 mmol) were added to a tetrahydrofuran (5 mL) solution of 8-bromo-2-(2-{[tert-butyldi(methyl)silyl]oxy}ethyl)-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzozazepine-1-one (25-1) (340 mg, 0.78 mmol), and then heated to 50 °C and stirred for 5 h. The reaction solution was cooled to room temperature, water (10 mL) was added, and then extracted with ethyl acetate (5 mL * 3). The organic phases were combined and washed with saturated brine (5 mL * 2), dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0 to 1 / 1) to give compound 8-bromo-2-(2-hydroxyethyl)-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzozazepine-1-one (25-2) (260 mg, yield 99%).

[0896] LC-MS, M / Z (ESI): 324.1 [M+H]+

[0897] Step 3: Synthesis of 8-bromo-2-[2-(difluoromethoxy)ethyl]-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzozazepine-1-one (25-3)

[0898] At room temperature, cuprous iodide (13 mg, 0.07 mmol) was added to a solution of 8-bromo-2-(2-hydroxyethyl)-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzozazepine-1-one (25-2) (110 mg, 0.34 mmol) in acetonitrile (5 mL). The mixture was heated to 50 °C under nitrogen protection. Then, a solution of 2,2-difluoro-2-(fluorosulfonyl)acetic acid (2.32 g, 13.0 mmol) in acetonitrile (100 mL) was slowly added to the reaction mixture under nitrogen protection. The resulting reaction mixture was stirred at 50 °C for 12 hours. The reaction mixture was quenched with saturated sodium bicarbonate (10 mL), water (50 mL) was added, and then extracted with ethyl acetate (25 mL * 3). The combined organic phases were washed with saturated brine (50 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0 to 1 / 1) to give compound 8-bromo-2-[2-(difluoromethoxy)ethyl]-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzozazepine-1-one (25-3) (90 mg, yield 70%).

[0899] LC-MS, M / Z (ESI): 374.1 [M+H]+

[0900] Step 4: Synthesis of 2-[2-(difluoromethoxy)ethyl]-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborphanecyclopentan-2-yl)-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-1-one (25-4)

[0901] To a solution of 8-bromo-2-[2-(difluoromethoxy)ethyl]-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzozazepine-1-one (25-3) (90 mg, 0.24 mmol) in 1,4-dioxane (1 mL), pinacol diboronate (122 mg, 0.5 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (22 mg, 0.03 mmol), and potassium acetate (72.0 mg, 0.72 mmol) were added. The reaction mixture was stirred at 100 °C for 18 h under nitrogen protection. The reaction mixture was cooled to room temperature, water (10 mL) was added, and then extracted with ethyl acetate (2 mL x 3). After combining the organic phases, the mixture was washed with saturated brine (2 mL * 2), dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude compound 2-[2-(difluoromethoxy)ethyl]-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-1-one (compound 25-4), which was directly used in the next step of the reaction.

[0902] LC-MS, M / Z (ESI): 422.2 [M+H]+

[0903] Step 5: Synthesis of 3-(2-chloro-3-{2-[2-(difluoromethoxy)ethyl]-1-oxo-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-8-yl}phenyl)piperidine-2,6-dione (compound 25)

[0904]

[0905] To a solution of crude 2-[2-(difluoromethoxy)ethyl]-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-1-one (25-4) (100 mg, 0.3 mmol) and 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (154 mg, 0.51 mmol) in 1,4-dioxane (1 mL), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (37 mg, 0.045 mmol) and potassium phosphate (186 mg, 1.35 mmol) were added. The reaction mixture was stirred at 100 °C for 18 h under nitrogen protection. The reaction mixture was poured into water (10 mL) and then extracted with ethyl acetate (2 mL * 3). The organic phases were combined and washed with saturated brine (2 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-0 / 1) to give compound 3-(2-chloro-3-{2-[2-(difluoromethoxy)ethyl]-1-oxo-2,4,5,6-tetrahydro-1H-[1,2,4]triazolo[4,3-a][1]benzoza-8-yl}phenyl)piperidin-2,6-dione (compound 25).

[0906] 1 H NMR(400MHz,DMSO-d6)δ10.92(s,1H),7.57–7.54(m,1H),7.45(s,2H),7.41-7.36(m,3H),6.81-7.73(m,1H),4.37-4.31(m,1H),4.1 4(t,2H),3.99(t,2H),2.81–2.75(m,1H),2.67(t,2H),2.59-2.53(m,3H),2.37–2.30(m,1H),2.12–2.07(m,2H),2.06–2.01(m,1H).

[0907] LC-MS, M / Z (ESI): 517.1 [M+H]+

[0908] Example 26: Preparation of target compound 26

[0909] 3-[2-chloro-3-(2-methyl-1-oxo-1,2,4,5-tetrahydro[1,2,4]triazolo[4,3-a]quinolin-7-yl)phenyl]piperidin-2,6-dione (compound 26)

[0910]

[0911] The synthetic route for target compound 26 is shown below:

[0912]

[0913] Step 1: Synthesis of 6-bromo-3,4-dihydroquinoline-2(1H)-thione (26-1)

[0914] Triethylamine (1.58 g, 15.6 mmol) and phosphorus pentasulfide (1.3 g, 6.9 mmol) were added to a solution of 6-bromo-3,4-dihydroquinoline-2(1H)-one (1-1) (1.5 g, 6.2 mmol) in acetonitrile (4.5 mL), and the mixture was stirred at 90 °C for 6 h. The reaction solution was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0 to 20 / 1) to give the compound 6-bromo-3,4-dihydroquinoline-2(1H)-thione (26-1).

[0915] LC-MS, M / Z (ESI): 242.3 [M+H]+

[0916] Step 2: Synthesis of 7-bromo-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoline-1(2H)-one (26-2)

[0917] 6-Bromo-3,4-dihydroquinoline-2(1H)-thione (26-1) (200 mg, 0.78 mmol) and methyl hydrazine carbamate (3) (141 mg, 1.56 mmol) were dissolved in n-butanol (3 mL), and the reaction mixture was placed in a microwave tube and reacted at 140 °C for 48 h. Water (20 mL) was added to the reaction mixture, and then it was extracted with ethyl acetate (10 mL * 3). The organic phases were combined, washed with saturated brine (10 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0 to 1 / 1) to give compound 7-bromo-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoline-1(2H)-one (26-2).

[0918] LC-MS, M / Z (ESI): 266.2 [M+H]+

[0919] Step 3: Synthesis of 7-bromo-2-methyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoline-1(2H)-one (26-3)

[0920] At 0 °C, potassium carbonate (148 mg, 1.07 mmol) and methyl iodide (61 mg, 0.43 mmol) were added to a solution of 7-bromo-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoline-1(2H)-one (26-2) (100 mg, 0.36 mmol) in N,N-dimethylformamide (1 mL), and the mixture was stirred at room temperature for 2 h. Water (10 mL) was added to the reaction mixture, and the mixture was then extracted with ethyl acetate (5 mL x 3). The combined organic phases were washed with saturated brine (5 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0 to 1 / 1) to give compound 7-bromo-2-methyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoline-1(2H)-one (26-3) (100 mg, yield 95%).

[0921] LC-MS, M / Z (ESI): 280.3 [M+H]+

[0922] Step 4: Synthesis of 2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborphanecyclopentan-2-yl)-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoline-1(2H)-one (26-4)

[0923] At room temperature, 1,4-dioxane (3 mL) of 7-bromo-2-methyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoline-1(2H)-one (26-3) (80 mg, 0.29 mmol) was added to a 1,4-dioxane (3 mL) of 1,4-dioxane (152 mg, 0.6 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (22 mg, 0.03 mmol), and potassium acetate (100.0 mg, 0.9 mmol). The reaction mixture was stirred at 100 °C for 18 h under nitrogen protection. The reaction mixture was poured into water (10 mL) and then extracted with ethyl acetate (2 mL x 3). The combined organic phases were washed with saturated brine (2 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product (26-4), which was used directly in the next reaction.

[0924] LC-MS, M / Z (ESI): 328.2 [M+H]+

[0925] Step 5: Synthesis of 3-[2-chloro-3-(2-methyl-1-oxo-1,2,4,5-tetrahydro[1,2,4]triazolo[4,3-a]quinolin-7-yl)phenyl]piperidin-2,6-dione (compound 26)

[0926]

[0927] To a solution of crude 2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoline-1(2H)-one (26-4) (100 mg, 0.34 mmol) in 1,4-dioxane (1 mL), 3-[2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)phenyl]piperidin-2,6-dione (intermediate A') (238 mg, 0.68 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (28 mg, 0.034 mmol) and potassium phosphate (117 mg, 0.85 mmol) were added. The reaction mixture was stirred at 100 °C for 18 h under nitrogen protection. The reaction mixture was poured into water (10 mL) and then extracted with ethyl acetate (2 mL * 3). The organic phases were combined, washed with saturated brine (2 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative liquid chromatography (column: Phenomenex Synergi C18100 * 25 mm * 4 μm; solvent: A = water + 0.1 vol% formic acid (99%), B = acetonitrile; gradient: 5%-95%, 7 min) to give compound 3-[2-chloro-3-(2-methyl-1-oxo-1,2,4,5-tetrahydro[1,2,4]triazolo[4,3-a]quinolin-7-yl)phenyl]piperidin-2,6-dione (compound 26) (79.2 mg, yield 38%).

[0928] 1 H NMR (400MHz, DMSO-d6) δ10.91(s,1H),8.26(d,1H),7.40–7.35(m,4H),7.31(d,1H),4.35-4.31(m,1H),3.01( t,2H),2.88(t,2H),2.79-2.73(m,1H),2.56–2.51(m,1H),2.48(s,3H),2.35–2.29(m,1H),2.05–2.01(m,1H)

[0929] LC-MS, M / Z (ESI): 423.1 [M+H]+

[0930] Example 27: Synthesis of target compound 27

[0931] 3-(3-(1-acetyl-1,2,3,5-tetrahydrobenzo[e][1,4]oxaza-7-yl)-2-chlorophenyl)piperidin-2,6-dione

[0932]

[0933] The synthetic route for target compound 27 is shown below:

[0934]

[0935] Step 1: Synthesis of compound 1-(7-bromo-2,3-dihydrobenzo[e][1,4]oxaza-1(5H)-yl)ethane-1-one (27-2)

[0936] At room temperature, 7-bromo-1,2,3,5-tetrahydro-4,1-benzoxazol (200 mg, 0.88 mmol), triethylamine (266.18 mg, 2.63 mmol), and 4-dimethylaminopyridine (10.71 mg, 0.09 mmol) were dissolved in dichloromethane (5 mL), followed by the addition of acetic anhydride (179 mg, 1.75 mmol). The reaction mixture was stirred at room temperature for 12 hours. After TLC monitoring showed that the reactants had reacted completely, stirring was stopped, and the reaction mixture was concentrated by vacuum distillation. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 90:10) to give compound 1-(7-bromo-2,3-dihydrobenzo[e][1,4]oxaza-1(5H)-yl)ethane-1-one (compound 27-2).

[0937] LC-MS, M / Z (ESI): 270.0 (M+H) + )

[0938] Step 2: Synthesis of compound 1-(7-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentan-2-yl)-2,3-dihydrobenzo[e][1,4]oxazacyclopentan-1(5H)-yl)ethane-1-one (compound 27-3)

[0939] At room temperature, 1-(7-bromo-2,3-dihydrobenzo[e][1,4]oxaza-1(5H)-yl)ethane-1-one (27-1) (100 mg, 0.37 mmol), pinacol diboronate (141 mg, 0.56 mmol), anhydrous potassium acetate (109 mg, 1.11 mmol), and 1,1-bis(diphenylphosphine)diberberine palladium dichloride (27.1 mg, 0.04 mmol) were dissolved in anhydrous 1,4-dioxane (3 mL) and heated and stirred at 100 °C for 6 hours under nitrogen protection. After TLC monitoring showed that the reaction of the raw materials was complete, stirring was stopped, the reaction solution was cooled to room temperature, and then water (10 mL) was added for dilution. The solution was extracted with ethyl acetate (4 mL × 3), the organic phase was collected and dried with anhydrous sodium sulfate, and the organic phase was concentrated by vacuum distillation. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 80:20) to obtain compound 1-(7-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentan-2-yl)-2,3-dihydrobenzo[e][1,4]oxazacyclopentan-1(5H)-yl)ethane-1-one (compound 27-3).

[0940] LC-MS, M / Z (ESI): 318.2 (M+H) + )

[0941] Step 3: Synthesis of compound 3-(3-(1-acetyl-1,2,3,5-tetrahydrobenzo[e][1,4]oxaza-7-yl)-2-chlorophenyl)piperidine-2,6-dione (compound 27)

[0942]

[0943] At room temperature, compound 1-(7-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentan-2-yl)-2,3-dihydrobenzo[e][1,4]oxazacyclopentan-1(5H)-yl)ethane-1-one (compound 27-3) (80 mg, 0.25 mmol) and 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (91.6 mg, 0.30 mmol) were dissolved in anhydrous 1,4-dioxane (2 mL), followed by the addition of 1,1-bis(diphenylphosphine)diferro-palladium dichloride (18.3 mg, 0.03 mmol) and potassium phosphate (132.7 mg, 0.63 mmol). The reaction mixture was heated and stirred at 100 °C for 6 hours under nitrogen protection. After the reaction of the raw materials was confirmed to be complete by TLC monitoring, stirring was stopped, the reaction solution was cooled to room temperature, and then water (15 mL) was added for dilution. The solution was extracted with ethyl acetate (5 mL × 3), the organic phase was collected and dried with anhydrous sodium sulfate, and the organic phase was concentrated by vacuum distillation. The residue was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 100:4) to give compound 3-(3-(1-acetyl-1,2,3,5-tetrahydrobenzo[e][1,4]oxaza-7-yl)-2-chlorophenyl)piperidine-2,6-dione (compound 27) (10 mg, yield 9.6%).

[0944] LC-MS, M / Z (ESI): 413.1 (M+H) + )

[0945] 1 H NMR(600MHz,DMSO-d6)δ10.92(s,1H),7.52–7.36(m,5H),7.34(dd,1H),4.69–4.53(m,3H),4.35(dd,1H),3.96(d, 1H),3.66–3.59(m,1H),2.82–2.76(m,2H),2.57–2.51(m,1H),2.36–2.29(m,1H),2.08–2.01(m,1H),1.93(d,3H).

[0946] Example 28: Preparation of target compound 28

[0947] 2-(8-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)-1-oxo-5,6-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azacycloheptane-2(4H)-yl)-N,N-dimethylacetamide (target compound 28)

[0948]

[0949] The synthetic route for compound 28 is shown below:

[0950]

[0951] Step 1: Synthesis of compound 2-(8-bromo-1-oxo-5,6-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azacycloheptane-2(4H)-yl)-N,N-dimethylacetamide (compound 28-1)

[0952] At room temperature, 8-bromo-2,4,5,6-tetrahydro-1H-benzo[1,2,4]triazolo[4,3-a]azacycloheptane-1-one (intermediate 6-2) (300 mg, 1.07 mmol) and 2-chloro-N,N-dimethylacetamide (195 mg, 1.61 mmol) were dissolved in N,N-dimethylformamide (3 mL) solution, and then cesium carbonate (698 mg, 2.14 mmol) was added. After the addition was completed, the reaction solution was heated and stirred in an oil bath at 80 °C for 4 hours. After the reaction of the raw materials was confirmed to be complete by TLC monitoring, stirring was stopped, the mixture was cooled to room temperature, and then water (10 mL) was added for dilution. The mixture was extracted with ethyl acetate (4 mL × 3), the organic phase was collected and dried with anhydrous sodium sulfate, and the organic phase was concentrated by vacuum distillation. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 80:20) to obtain compound 2-(8-bromo-1-oxo-5,6-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azacycloheptane-2(4H)-yl)-N,N-dimethylacetamide (compound 28-1).

[0953] LC-MS, M / Z (ESI): 366.4 [M+H] +

[0954] Step 2: Synthesis of N,N-dimethyl-2-(1-oxo-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-5,6-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azacycloheptane-2(4H)-yl)acetamide (compound 28-2).

[0955] At room temperature, compound 2-(8-bromo-1-oxo-5,6-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azacycloheptane-2(4H)-yl)-N,N-dimethylacetamide (compound 28-1) (280 mg, 0.77 mmol), pinacol diboronate (292 mg, 1.15 mmol), anhydrous potassium acetate (225.7 mg, 2.30 mmol), and 1,1-bis(diphenylphosphine)diberberine palladium dichloride (56 mg, 0.08 mmol) were dissolved in anhydrous 1,4-dioxane (3 mL) solution. Nitrogen purging was performed, and the mixture was stirred at 100 °C for 6 hours under nitrogen protection. The mixture was monitored by TLC. After the reaction of the raw materials was complete, stirring was stopped, the mixture was cooled to room temperature, and then water (10 mL) was added for dilution. The mixture was extracted with ethyl acetate (4 mL × 3), the organic phase was collected and dried with anhydrous sodium sulfate, and the organic phase was concentrated by vacuum distillation. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 80:20), and a white solid was obtained, which is compound N,N-dimethyl-2-(1-oxo-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-5,6-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azacycloheptane-2(4H)-yl)acetamide (compound 28-2).

[0956] LC-MS, M / Z (ESI): 413.4 [M+H] +

[0957] Step 3: Synthesis of compound 2-(8-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)-1-oxo-5,6-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azacycloheptane-2(4H)-yl)-N,N-dimethylacetamide (compound 28)

[0958]

[0959] At room temperature, compound N,N-dimethyl-2-(1-oxo-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-5,6-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azacycloheptane-2(4H)-yl)acetamide (compound 28-2) (200 mg, 0.49 mmol) and 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (intermediate A) (220 mg, 0.73 mmol) were dissolved in anhydrous 1,4-dioxane (2 mL) solution, purged with nitrogen, and then 1,1-bis(diphenylphosphine)diferro-palladium dichloride (35 mg, 0.05 mmol) and potassium phosphate (309 mg, 1.46 mmol) were added. The mixture was heated and stirred in an oil bath at 100 °C for 6 hours under nitrogen protection. After the reaction of the raw materials was confirmed to be complete by TLC monitoring, stirring was stopped, the mixture was cooled to room temperature, and then water (15 mL) was added for dilution. The mixture was extracted with ethyl acetate (5 mL × 3), the organic phase was collected and dried with anhydrous sodium sulfate, and the organic phase was concentrated by vacuum distillation. The residue was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 100:4) to obtain compound 2-(8-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)-1-oxo-5,6-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azacycloheptane-2(4H)-yl)-N,N-dimethylacetamide (compound 28).

[0960] LC-MS, M / Z (ESI): 508.2 [M+H] +

[0961] 1 H NMR(600MHz,DMSO-d6)δ10.93(s,1H),7.57-7.54(m,1H),7.49-7.45(m,2H),7.44-7.35(m,3H),4.68(s,2H),4.35(dd,1H),3.03(s, 3H),2.84(s,3H),2.83-2.76(m,1H),2.72-2.67(m,2H),2.59-2.53(m,3H),2.39-2.30(m,1H),2.14-2.08(m,2H),2.07-2.03(m,1H)

[0962] Example 29: Preparation of target compound 29

[0963] 3-(2-chloro-3-(2-(oxecyclobutan-3-yl)-1-oxo-2,4,5,6-tetrahydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azacycloheptane-8-yl)phenyl)piperidin-2,6-dione (target compound 29)

[0964]

[0965] The synthetic route for compound 29 is shown below:

[0966]

[0967] Step 1: Synthesis of compound 8-bromo-2-(oxetane-3-yl)-2,4,5,6-tetrahydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azacycloheptane-1-one (compound 29-1)

[0968] At room temperature, 8-bromo-2,4,5,6-tetrahydro-1H-benzo[1,2,4]triazolo[4,3-a]azacycloheptane-1-one (intermediate 6-2) (200 mg, 0.71 mmol) and 3-iodooxetane (197 mg, 1.07 mmol) were dissolved in N,N-dimethylformamide (2 mL) solution, followed by the addition of cesium carbonate (698 mg, 2.14 mmol). After the addition was complete, the mixture was heated and stirred in an oil bath at 80 °C for 4 hours. TLC monitoring showed that the reaction of the starting materials was complete. Afterward, stop stirring, cool to room temperature, then add water (10 mL) to dilute, extract with ethyl acetate (4 mL × 3), collect the organic phase and dry with anhydrous sodium sulfate, concentrate the organic phase by vacuum distillation, and purify the residue by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 70:30) to obtain compound 8-bromo-2-(oxecyclobutan-3-yl)-2,4,5,6-tetrahydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azacycloheptane-1-one (compound 29-1).

[0969] LC-MS, M / Z (ESI): 337.2 [M+H] +

[0970] Step 2: Synthesis of compound 3-(2-chloro-3-(2-(oxetane-3-yl)-1-oxo-2,4,5,6-tetrahydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azacycloheptane-8-yl)phenyl)piperidine-2,6-dione (compound 29)

[0971]

[0972] At room temperature, compound 8-bromo-2-(oxetane-3-yl)-2,4,5,6-tetrahydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azacycloheptane-1-one (compound 29-1) (120 mg, 0.36 mmol) and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)piperidine-2,6-dione (intermediate A') (249.6 mg, 0.71 mmol) were dissolved in anhydrous 1,4-dioxane (2 mL) solution, purged with nitrogen, and then 1,1-bis(diphenylphosphine)diberberine palladium dichloride (26 mg, 0.04 mmol) and potassium phosphate (227 mg, 1 mL) were added. 0.07 mmol), heated and stirred in an oil bath at 100 °C for 6 hours under nitrogen protection. After the reaction was complete as monitored by TLC, stirring was stopped, and the mixture was cooled to room temperature. Then, water (15 mL) was added for dilution, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phase was collected and dried with anhydrous sodium sulfate. The organic phase was concentrated by vacuum distillation. The residue was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 100:2) to obtain compound 3-(2-chloro-3-(2-(oxecyclobutan-3-yl)-1-oxo-2,4,5,6-tetrahydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azacycloheptane-8-yl)phenyl)piperidine-2,6-dione (compound 29).

[0973] LC-MS, M / Z (ESI): 479.1 [M+H] +

[0974] 1 H NMR(600MHz, DMSO-d6)δ10.92(s,1H),7.60-7.50(m,1H),7.44(d,2H),7.42-7.32(m,3H),5.44-5.37(m,1H),4.93-4.81(m,4H),4.34(dd, 1H),2.82-2.74(m,1H),2.73-2.68(m,2H),2.65-2.60(m,2H),2.56-2 .50(m,1H),2.38-2.28(m,1H),2.15-2.09(m,2H),2.07-2.02(m,1H).

[0975] Example 30: Preparation of target compound 30

[0976] 2-(8-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)-1-oxo-5,6-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azacycloheptane-2(4H)-yl)dimethylcarbamate

[0977] (Target compound 30)

[0978]

[0979] The synthetic route for compound 30 is shown below:

[0980]

[0981] Step 1: Synthesis of 8-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2,4,5,6-tetrahydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azacycloheptane-1-one (compound 30-1)

[0982] 8-Bromo-2,4,5,6-Tetrahydro-1H-benzo[1,2,4]triazolo[4,3-a]azacycloheptane-1-one (intermediate 6-2) (500 mg, 1.79 mmol) was placed in a reaction flask, followed by acetonitrile (10 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.8 g, 5.38 mmol), and tert-butyl-(2-iodoethoxy)dimethylsilane (1.0 g, 3.58 mmol) in sequence. After the addition was complete, the mixture was deoxygenated three times with nitrogen, and then the reaction was carried out at 80 °C for 16 hours. After the reaction was complete, the reaction solution was diluted with ethyl acetate (500 mL), extracted with saturated sodium chloride aqueous solution (500 mL × 3), and then the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 2:1) to give the intermediate 8-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2,4,5,6-tetrahydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azacycloheptane-1-one (compound 30-1).

[0983] LC-MS, M / Z (ESI): 438.0 [M+H] +

[0984] Step 2: Synthesis of 8-bromo-2-(2-hydroxyethyl)-2,4,5,6-tetrahydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azacycloheptane-1-one (compound 30-2)

[0985] 8-Bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2,4,5,6-tetrahydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azacycloheptan-1-one (compound 30-1) (460 mg, 1.05 mmol) was placed in a reaction flask, followed by the addition of tetrahydrofuran / water (8 mL: 2 mL) and p-toluenesulfonic acid monohydrate (190 mg, 1.0 mmol). After the addition was complete, the mixture was deoxygenated three times with nitrogen, and then the reaction was carried out at room temperature for 1 hour. After the reaction was completed, the reaction solution was diluted with ethyl acetate (200 mL), extracted with saturated sodium chloride aqueous solution (200 mL × 3), and then the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 0:1) to give the intermediate 8-bromo-2-(2-hydroxyethyl)-2,4,5,6-tetrahydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azacycloheptane-1-one (compound 30-2) (317 mg, yield 93%).

[0986] LC-MS, M / Z (ESI): 324.1 [M+H] +

[0987] Step 3: Synthesis of ethyl 2-(8-bromo-1-oxo-5,6-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azacycloheptane-2(4H)-yl)dimethylcarbamate (compound 30-3)

[0988] 8-Bromo-2-(2-hydroxyethyl)-2,4,5,6-tetrahydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azacycloheptane-1-one (compound 30-2) (310 mg, 0.96 mmol) was placed in a reaction flask, followed by the addition of acetonitrile (8 mL), N,N'-carbonyldiimidazole (320 mg, 2.0 mmol), and triethylamine (0.3 g, 3 mmol). After the addition was complete, the mixture was deoxygenated three times with nitrogen and reacted at room temperature for 0.5 hours. Then, dimethylamine (0.25 g, 5 mmol) was added to the reaction solution, and the mixture was reacted at room temperature for 1 hour after the addition was complete. After the reaction was completed, the reaction solution was diluted with ethyl acetate (200 mL), extracted with saturated sodium chloride aqueous solution (200 mL × 3), and then the organic phase was taken, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 1:1) to give intermediate 2-(8-bromo-1-oxo-5,6-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azacycloheptane-2(4H)-yl)dimethylcarbamate (30-3).

[0989] LC-MS, M / Z (ESI): 395.0 [M+H] +

[0990] Step 4: Synthesis of ethyl 2-(8-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)-1-oxo-5,6-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azacycloheptane-2(4H)-yl)dimethylcarbamate (compound 30)

[0991]

[0992] 2-(8-bromo-1-oxo-5,6-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azacycloheptane-2(4H)-yl)dimethylcarbamate (compound 30-3) (300 mg, 0.76 mmol) was placed in a reaction flask, followed by the addition of 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (intermediate A) (400 mg, 1.14 mmol), potassium phosphate (480 mg, 2.28 mmol), [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (52 mg, 0.08 mmol), and 1,4-dioxane (5 mL). After the addition was complete, the mixture was deoxygenated three times with nitrogen, and then reacted at 100 °C for 4 hours. The reaction mixture was then diluted with ethyl acetate (200 mL), extracted with saturated sodium chloride aqueous solution (200 mL × 3), and the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 20:1) to give compound 2-(8-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)-1-oxo-5,6-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azacycloheptane-2(4H)-yl)dimethylcarbamate (compound 30) (63 mg, yield 15%).

[0993] LC-MS, M / Z (ESI): 538.1 [M+H] +

[0994] 1 H NMR(600MHz,DMSO-d6)δ10.92(s,1H),7.57-7.51(m,1H),7.47-7.43(m,2H),7.43-7.33(m,3H),4.35(dd,1H),4. 24(t,2H),3.97(t,2H),2.84-2.75(m,6H),2.68(t,2H),2.61-2.50(m,4H),2.39-2.29(m,1H),2.12-2.02(m,3H).

[0995] Example 31: Preparation of target compound 31:

[0996] 3-(2-chloro-3-(2-(1-methylazacyclobutane-3-yl)-1-oxo-2,4,5,6-tetrahydro-1H-benzo[f][1,2,4]triazolo[4,3-a]aza -8-yl)phenyl)piperidin-2,6-dione (target compound 31)

[0997]

[0998] The synthetic route for compound 31 is shown below:

[0999]

[1000] Step 1: Synthesis of tert-butyl 3-(8-bromo-1-oxo-5,6-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azapyrrol-2(4H)-yl)azacyclobutane-1-carboxylate (compound 31-1)

[1001] 8-Bromo-2,4,5,6-Tetrahydro-1H-benzo[f][1,2,4]triazolo[4,3-a]aza -1-one (intermediate 6-2) (240 mg, 0.86 mmol) was dissolved in N,N-dimethylformamide (4 mL), potassium carbonate (296 mg, 2.14 mmol) and tert-butyl 3-iodoazacyclobutane-1-carboxylate (365 mg, 1.29 mmol) were added, and the reaction was carried out at 80 °C for 5 hours. After the reaction was completed, water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 1:1) to give tert-butyl 3-(8-bromo-1-oxo-5,6-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azapyro-2(4H)-yl)azacyclobutane-1-carboxylate (compound 31-1).

[1002] LC-MS,M / Z(ESI):435.1 / 437.1[M+H] +

[1003] Step 2: 2-(azacyclobutane-3-yl)-8-bromo-2,4,5,6-tetrahydro-1H-benzo[f][1,2,4]triazolo[4,3-a]aza Synthesis of 1-one (31-2)

[1004] 270 mg (0.62 mmol) of tert-butyl 3-(8-bromo-1-oxo-5,6-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azapyrrolidone-2(4H)-yl)azacyclobutane-1-carboxylate (31-1) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (3 mL) was added. The reaction was carried out at room temperature for 1 hour. After the reaction was completed, the reaction solvent was removed by vacuum distillation. The crude product was diluted with dichloromethane (20 mL), and the pH was adjusted to 8 at 0 °C with saturated sodium bicarbonate aqueous solution (10 mL). The mixture was separated, extracted with dichloromethane (10 mL × 2), and the organic phases were combined and dried over anhydrous sodium sulfate. The solution was filtered and concentrated to give compound 2-(azacyclobutane-3-yl)-8-bromo-2,4,5,6-tetrahydro-1H-benzo[f][1,2,4]triazolo[4,3-a]azapyrrolidone-2(4H)-yl) ... -1-keto (compound 31-2).

[1005] LC-MS,M / Z(ESI):335.1 / 337.1[M+H] +

[1006] Step 3: 8-Bromo-2-(1-methylazacyclobutane-3-yl)-2,4,5,6-tetrahydro-1H-benzo[f][1,2,4]triazolo[4,3-a]aza Synthesis of 1-one (31-3)

[1007] 2-(azacyclobutane-3-yl)-8-bromo-2,4,5,6-tetrahydro-1H-benzo[f][1,2,4]triazolo[4,3-a]aza 1-one (132 mg, 0.40 mmol) was dissolved in trifluoroethanol (10 mL), and paraformaldehyde (60 mg, 2.0 mmol) was added at room temperature. The reaction was carried out under nitrogen protection at room temperature for 10 minutes, followed by a reaction at 78 °C for 0.5 hours. After cooling to room temperature, sodium borohydride (30 mg, 0.79 mmol) was added, and the reaction was carried out at 78 °C for 3 hours. After the reaction was completed, the mixture was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 1:1) to give 8-bromo-2-(1-methylazacyclobutane-3-yl)-2,4,5,6-tetrahydro-1H-benzo[f][1,2,4]triazolo[4,3-a]aza -1-keto (compound 31-3).

[1008] LC-MS,M / Z(ESI):349.1 / 351.1[M+H] +

[1009] Step 4: 2-(1-methylazacyclobutane-3-yl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxoborazecyclopentane-2-yl)-2,4,5,6-tetrahydro-1H-benzo[f][1,2,4]triazolo[4,3-a]aza Synthesis of 1-one (compound 31-4)

[1010] 8-Bromo-2-(1-methylazacyclobutane-3-yl)-2,4,5,6-tetrahydro-1H-benzo[f][1,2,4]triazolo[4,3-a]aza -1-one (31-3) (50 mg, 0.14 mmol) was dissolved in dioxane (6 mL), and pinacol diboronate (55 mg, 0.22 mmol) and anhydrous potassium acetate (42 mg, 0.43 mmol) were added under nitrogen protection. Then 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (10 mg, 0.014 mmol) was added. The reaction was carried out at 100 °C for 3.5 hours under nitrogen protection. After the reaction was completed, the product was concentrated, diluted with dichloromethane (20 mL), washed with water (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product 2-(1-methylazacyclobutane-3-yl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxoborazecyclopentane-2-yl)-2,4,5,6-tetrahydro-1H-benzo[f][1,2,4]triazolo[4,3-a]aza -1-keto (compounds 31-4).

[1011] LC-MS, M / Z (ESI): 397.1 [M+H] +

[1012] Step 5: 3-(2-chloro-3-(2-(1-methylazacyclobutane-3-yl)-1-oxo-2,4,5,6-tetrahydro-1H-benzo[f][1,2,4]triazolo[4,3-a]aza Synthesis of 8-yl)phenyl)piperidine-2,6-dione (compound 31)

[1013]

[1014] 2-(1-methylazacyclobutane-3-yl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxoborazecyclopentane-2-yl)-2,4,5,6-tetrahydro-1H-benzo[f][1,2,4]triazolo[4,3-a]aza 1-one (55 mg, 0.14 mmol) was dissolved in 1,4-dioxane (10 mL), and 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (intermediate A) (86 mg, 0.28 mmol) and potassium phosphate (76 mg, 0.36 mmol) were added. Then, 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (11 mg, 0.014 mmol) was added. The reaction solution was reacted at 100 °C for 12 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 10:1) to give compound 3-(2-chloro-3-(2-(1-methylazacyclobutane-3-yl)-1-oxo-2,4,5,6-tetrahydro-1H-benzo[f][1,2,4]triazolo[4,3-a]aza -8-yl)phenyl)piperidine-2,6-dione (compound 31).

[1015] LC-MS, M / Z (ESI): 492.1 [M+H] +

[1016] 1 H NMR(600MHz,DMSO-d6)δ10.93(s,1H),7.56(d,1H),7.45(s,1H),7.43-7.33(m,4H),4.77(dt,1H),4.35(dd,1H),3.65(t,2H),3.33(t,2H ),2.82-2.76(m,1H),2.70(t,2H),2.61(t,2H),2.58-2.53(m,1H),2.40-2.34(m,1H),2.31(s,3H),2.15-2.07(m,2H),2.07-2.02(m,1H).

[1017] Example 32: Preparation of target compound 32

[1018] 1-((8-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)-1-oxo-5,6-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a]aza -2(4H)-yl)methyl)cyclopropaneformonitrile (target compound 32)

[1019]

[1020] The synthetic route for compound 32 is shown below:

[1021]

[1022] Step 1: 1-((8-bromo-1-oxo-5,6-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a]aza) Synthesis of -2(4H)-yl)methyl)cyclopropaneformonitrile (32-1)

[1023] 8-Bromo-2,4,5,6-Tetrahydro-1H-benzo[f][1,2,4]triazolo[4,3-a]aza 1-Keto (intermediate 6-2) (240 mg, 0.86 mmol) was dissolved in N,N-dimethylformamide (4 mL), potassium carbonate (296 mg, 2.14 mmol) and 1-(bromomethyl)cyclopropaneformonitrile (206 mg, 1.29 mmol) were added, and the reaction was carried out at 80 °C for 5 hours. After the reaction was completed, water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 1:2) to give 1-((8-bromo-1-oxo-5,6-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a]aza) -2(4H)-yl)methyl)cyclopropaneformonitrile (compound 32-1).

[1024] LC-MS,M / Z(ESI):359.1 / 361.1[M+H] +

[1025] Step 2: 1-((1-oxo-8-(4,4,5,5-tetramethyl-1,3,2-dioxoborazecyclopentan-2-yl)-5,6-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a]aza Synthesis of -2(4H)-yl)methyl)cyclopropaneformonitrile (compound 32-2)

[1026] 1-((8-bromo-1-oxo-5,6-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a]aza) -2(4H)-yl)methyl)cyclopropaneformonitrile (compound 32-1) (145 mg, 0.41 mmol) was dissolved in dioxane (6 mL), and pinacol diboronate (153 mg, 0.60 mmol) and anhydrous potassium acetate (120 mg, 1.23 mmol) were added under nitrogen protection, followed by 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (29 mg, 0.04 mmol). The reaction was carried out at 100 °C for 3.5 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and the crude product was diluted with dichloromethane (20 mL), washed with water (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product 1-((1-oxo-8-(4,4,5,5-tetramethyl-1,3,2-dioxoborazecyclopentan-2-yl)-5,6-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a]aza -2(4H)-yl)methyl)cyclopropaneformonitrile (compound 32-2) is used directly in the next reaction.

[1027] LC-MS, M / Z (ESI): 407.1 [M+H] +

[1028] Step 3: 1-((8-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)-1-oxo-5,6-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a]aza Synthesis of -2(4H)-yl)methyl)cyclopropaneformonitrile (compound 32)

[1029]

[1030] 1-((1-oxo-8-(4,4,5,5-tetramethyl-1,3,2-dioxoboronacyclopentan-2-yl)-5,6-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a]aza -2(4H)-yl)methyl)cyclopropaneformonitrile (compound 32-2) (57 mg, 0.14 mmol) was dissolved in 1,4-dioxane (10 mL), 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (intermediate A) (86 mg, 0.28 mmol) and potassium phosphate (76 mg, 0.36 mmol) were added, followed by 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (10 mg, 0.014 mmol). The reaction was carried out at 100 °C for 12 hours under nitrogen protection. After the reaction was complete, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 10:1) to give compound 1-((8-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)-1-oxo-5,6-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a]aza -2(4H)-yl)methyl)cyclopropaneformonitrile (compound 32) (27.9 mg, yield 39.7%).

[1031] LC-MS, M / Z (ESI): 502.1 [M+H] +

[1032] 1 H NMR(400MHz,DMSO-d6)δ10.93(s,1H),7.65-7.56(m,1H),7.52-7.46(m,2H),7.45-7.32(m,3H),4.36(dd,1H),3.93(s,2H) ,2.85-2.75(m,1H),2.71(t,2H),2.63(t,2H),2.59-2.55(m,1H),2.42-2.29(m,1H),2.21-2.02(m,3H),1.39-1.20(m,4H).

[1033] Example 33: Preparation of target compound 33

[1034] methyl 8-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)-3,4,5-6-tetrahydro-1H-benzo[b]azacycloheptan-1(2H)-carboxylate

[1035]

[1036] The synthetic route for compound 33 is shown below:

[1037]

[1038] Step 1: Synthesis of methyl 7-bromo-2,3,4-5-tetrahydro-1H-benzo[b]azacycloheptan-1-carboxylate (33-1)

[1039] 120 mg (0.53 mmol) of 7-bromo-2,3,4,5-tetrahydro-1H-benzo[b]azacyclobutane (compound 19-1) was placed in a reaction flask, followed by the addition of 2 mL of pyridine. Methyl chloroformate (0.2 g, 2.12 mmol) was slowly added at 0 °C under nitrogen protection. After the addition was complete, the reaction mixture was heated to 80 °C and stirred for 1 hour. After the reaction was complete, the reaction mixture was quenched with methanol (0.2 mL) in an ice-water bath, then diluted with ethyl acetate (200 mL), washed with saturated sodium chloride aqueous solution (200 mL × 3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 10:1) to give the intermediate methyl 7-bromo-2,3,4,5-tetrahydro-1H-benzo[b]azacycloheptan-1-carboxylic acid (compound 33-1).

[1040] LC-MS, M / Z (ESI): 284.0 [M+H] + .

[1041] Step Two:

[1042] Synthesis of methyl 8-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)-3,4,5-6-tetrahydro-1H-benzo[b]azacycloheptan-1(2H)-carboxylate (compound 33)

[1043]

[1044] The intermediate methyl 7-bromo-2,3,4-5-tetrahydro-1H-benzo[b]azacycloheptan-1-carboxylate (compound 33-1) (80 mg, 0.28 mmol) was placed in a reaction flask, followed by the addition of 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)piperidine-2,6-dione (intermediate A') (148 mg, 0.42 mmol), potassium phosphate (178 mg, 0.84 mmol), [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (20 mg, 0.03 mmol), and 1,4-dioxane (3 mL). After the addition was complete, the reaction mixture was stirred at 100 °C for 8 hours under nitrogen protection. After the reaction was complete, the reaction solution was diluted with ethyl acetate (200 mL), washed with saturated sodium chloride aqueous solution (200 mL × 3), and then the organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 20:1) to give compound methyl 8-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)-3,4,5-6-tetrahydro-1H-benzo[b]azacycloheptane-1(2H)-formate.

[1045] (Compound 33).

[1046] LC-MS, M / Z (ESI): 427.1 [M+H] + .

[1047] 1 H NMR(600MHz,DMSO-d6)δ10.92(s,1H),7.40–7.28(m,4H),7.27–7.21(m,2H),4.44–4.18(m,2H),3.70(s,1 H),3.56(s,3H),2.84–2.68(m,4H),2.56–2.50(m,2H),2.36–2.28(m,1H),2.06–2.01(m,1H),1.76(s,2H).

[1048] Example 34: Preparation of target compound 34:

[1049] 3-(2-chloro-3-(1-oxo-5,6-dihydro-1H,4H-benzo[f][1,2,4]oxadiazolo[4,3-a]azacycloheptane-8-yl)phenyl)piperidine-2,6-dione (target compound 34)

[1050]

[1051] The synthetic route of Example 34 is shown below:

[1052]

[1053] Step 1: Synthesis of 7-bromo-1,3,4-5-tetrahydro-2H-benzo[b]azacycloheptan-2-one oxime (compound 34-1)

[1054] 7-Bromo-1,3,4-5-tetrahydro-2H-benzo[b]azacyclopenten-2-thionone (compound 6-1) (600 mg, 2.353 mmol) was placed in a reaction flask, followed by ethanol (20 mL) and hydroxylamine aqueous solution (1.56 mL, 23 mmol, 50 wt%). After the addition was complete, the mixture was deoxygenated three times with nitrogen, and then reacted at 50 °C for 1 hour. After the reaction was complete, the reaction solution was diluted with ethyl acetate (500 mL) and washed with saturated sodium chloride aqueous solution (500 mL × 3). The organic phase was then collected, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 1:1) to give the intermediate 7-bromo-1,3,4-5-tetrahydro-2H-benzo[b]azacycloheptan-2-one oxime (compound 34-1).

[1055] LC-MS, M / Z (ESI): 255.0 [M+H] +

[1056] Step 2: Synthesis of 3-(oxacyclobutane-3-yloxy)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)pyridine-2(1H)-one (compound 34-2)

[1057] The intermediate 7-bromo-1,3,4-5-tetrahydro-2H-benzo[b]azacycloheptan-2-one oxime (compound 34-1) (500 mg, 1.96 mmol) was placed in a reaction flask, followed by the addition of acetonitrile (15 mL), N,N'-carbonyldiimidazole (650 mg, 4 mmol) and triethylamine (1.0 g, 10 mmol) in sequence. After the addition was complete, the mixture was deoxygenated three times with nitrogen, and then reacted at 60 °C for 2 hours. The product was then diluted with ethyl acetate (200 mL), washed with saturated sodium chloride aqueous solution (200 mL × 3), and the organic phase was then dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 3:1) to give the intermediate 3-(oxecyclobutane-3-yloxy)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)pyridine-2(1H)-one (compound 34-2).

[1058] LC-MS, M / Z (ESI): 280.9 [M+H] +

[1059] Step 4: Synthesis of 3-(2-chloro-3-(1-oxo-5,6-dihydro-1H,4H-benzo[f][1,2,4]oxadiazolo[4,3-a]azacycloheptane-8-yl)phenyl)piperidine-2,6-dione (compound 34)

[1060]

[1061] Intermediate 3-(oxecyclobutane-3-yloxy)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)pyridine-2(1H)-one (34-2) (120 mg, 0.43 mmol) was placed in a reaction flask, followed by the addition of 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)piperidine-2,6-dione (intermediate A') (300 mg, 0.86 mmol), potassium fluoride (70 mg, 1.2 mmol), palladium acetate (18 mg, 0.08 mmol), and acetonitrile (4 mL). After the addition was complete, the mixture was deoxygenated three times with nitrogen, and then reacted at 80 °C for 16 hours. The reaction solution was then diluted with ethyl acetate (200 mL), washed with saturated sodium chloride aqueous solution (200 mL × 3), and the organic phase was then dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 20:1) to give compound 3-(2-chloro-3-(1-oxo-5,6-dihydro-1H,4H-benzo[f][1,2,4]oxadiazolo[4,3-a]azacycloheptane-8-yl)phenyl)piperidine-2,6-dione (compound 34).

[1062] LC-MS, M / Z (ESI): 424.1 [M+H] +

[1063] 1 H NMR(600MHz,DMSO-d6)δ10.93(s,1H),7.59(d,1H),7.52-7.46(m,2H),7.44-7.37(m,2H),7.34(dd,1H),4.34(d d,1H),2.85-2.75(m,3H),2.66(t,2H),2.56-2.51(m,1H),2.33(ddd,1H),2.15-2.09(m,2H),2.05-2.01(m,1H).

[1064] Example 35: Preparation of target compound 35

[1065] 3-{2-chloro-3-[1-(1-methyl-1H-pyrazole-4-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoza-7-yl]phenyl}piperidin-2,6-dione (compound 35)

[1066]

[1067] The synthetic route for target compound 35 is shown below:

[1068]

[1069] Step 1: Synthesis of (7-bromo-2,3,4,5-tetrahydro-1H-1-benzoza-1-yl)(1-methyl-1H-pyrazol-4-yl) ketone (35-1)

[1070] At room temperature, 2.0 mL of thionyl chloride and 1 drop of DMF were added to a DCM (5 mL) solution of 1-methyl-1H-pyrazole-4-carboxylic acid (200 mg, 1.6 mmol), and the mixture was then heated to 45 °C and stirred under reflux for 2 h. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain crude 1-methyl-1H-pyrazole-4-formyl chloride.

[1071] At room temperature, crude 1-methyl-1H-pyrazole-4-carboxyl chloride (200 mg, 1.6 mmol) obtained above was added to a pyridine (5 mL) solution of 7-bromo-2,3,4,5-tetrahydro-1H-1-benzozazaporin (19-1) (226 mg, 1.0 mmol). The reaction solution was heated to 80 °C and reacted for 12 h. After the reaction was completed, the reaction solution was cooled to room temperature, and dichloromethane (20 mL) was added to dilute the reaction solution. The solution was washed with saturated ammonium chloride (10 mL), and the organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-1 / 1) to obtain the compound (7-bromo-2,3,4,5-tetrahydro-1H-1-benzozazaporin-1-yl)(1-methyl-1H-pyrazole-4-yl) methyl ketone (35-1).

[1072] LC-MS, M / Z (ESI): 334.1 [M+H]+

[1073] Step 2: Synthesis of (1-methyl-1H-pyrazol-4-yl)[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-2,3,4,5-tetrahydro-1H-1-benzozazepine-1-yl] methyl ketone (35-2)

[1074] At room temperature, 1,4-dioxane (3 mL) of (7-bromo-2,3,4,5-tetrahydro-1H-1-benzoza-1-yl)(1-methyl-1H-pyrazol-4-yl) methyl ketone (35-1) (130 mg, 0.39 mmol) was mixed with pinacol diborate (203 mg, 0.8 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (22 mg, 0.03 mmol), and potassium acetate (120.0 mg, 1.2 mmol). The reaction mixture was stirred at 100 °C for 18 h under nitrogen protection. The reaction mixture was poured into water (10 mL), then extracted with ethyl acetate (2 mL * 3). The organic phases were combined and washed with saturated brine (2 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain (1-methyl-1H-pyrazol-4-yl)[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-2,3,4,5-tetrahydro-1H-1-benzozazepine-1-yl] methyl ketone (35-2) (crude product), which was directly used in the next step of the reaction.

[1075] LC-MS, M / Z (ESI): 382.2 [M+H]+

[1076] Step 3: Synthesis of 3-{2-chloro-3-[1-(1-methyl-1H-pyrazole-4-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoza-7-yl]phenyl}piperidine-2,6-dione (compound 35)

[1077]

[1078] To a solution of crude (1-methyl-1H-pyrazol-4-yl)[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-2,3,4,5-tetrahydro-1H-1-benzozazepine-1-yl] methyl ketone (35-2) (130 mg, 0.39 mmol) and 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (177 mg, 0.58 mmol) in 1,4-dioxane (5 mL), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (22 mg, 0.03 mmol) and potassium phosphate (186 mg, 1.35 mmol) were added. The reaction mixture was stirred at 100 °C for 18 h under nitrogen protection. The reaction mixture was then poured into water (10 mL) and extracted with ethyl acetate (2 mL x 3). The organic phases were combined and washed with saturated brine (2 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative liquid chromatography (column: Phenomenex Synergi C18 100 x 25 mm x 4 μm; solvent: A = water + 0.1 vol% formic acid (99%), B = acetonitrile; gradient: 5%-95%, 7 min) to give compound 3-{2-chloro-3-[1-(1-methyl-1H-pyrazole-4-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoza-7-yl]phenyl}piperidin-2,6-dione (compound 35) (23.3 mg, yield 13%).

[1079] 1 H NMR(400MHz,DMSO-d6)10.92(s,1H),7.40(d,2H),7.37(d,2H),7.21(s,2H),7.12(d,1H),6.62(s,1H),4.74(d,1H),4.34(dd,1 H),3.66(s,3H),2.85–2.69(m,4H),2.53(dd,1H),2.33(dt,1H),2.06–2.01(m,1H),1.94(s,1H),1.84–1.74(m,2H),1.39(d,1H)

[1080] LC-MS, M / Z(ESI): 477.1[M+H]+.

[1081] Example 36: Preparation of target compound 36

[1082] 3-(2-chloro-3-(1-((2-hydroxyethyl)sulfonyl)-2,3,4-5-tetrahydro-1H-benzo[b]azacycloheptane-7-yl)phenyl)piperidine-2,6-dione (compound 36)

[1083]

[1084] The synthetic route of Example 36 is shown below:

[1085]

[1086] Step 1: Synthesis of methyl 2-((7-bromo-2,3,4,5-tetrahydro-1H-benzo[b]azacycloheptan-1-yl)sulfonyl)acetate (36-1) 7-bromo-2,3,4,5-tetrahydro-1H-benzo[b]azacyclobutane (intermediate 19-1) (500 mg, 2.22 mmol) was placed in a reaction flask, followed by the addition of pyridine (0.9 mL) and 1,2-dichloroethane (12 mL). After the addition was complete, the mixture was deoxygenated three times with nitrogen. Then, methyl 2-(chlorosulfonyl)acetate (950 mg, 5.55 mmol) was slowly added under an ice-water bath. After the addition was complete, the reaction mixture was reacted at 60 °C for 1 hour. After the reaction was complete, the reaction solution was quenched with methanol (0.5 mL) in an ice-water bath, then diluted with ethyl acetate (300 mL), washed with saturated sodium chloride aqueous solution (300 mL × 3), and then the organic phase was taken, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 5:1) to give intermediate 2-((7-bromo-2,3,4-5-tetrahydro-1H-benzo[b]azacycloheptane-1-yl)sulfonyl)methyl acetate (compound 36-1).

[1087] LC-MS, M / Z (ESI): 362.0 [M+H] + .

[1088] Step 2: Synthesis of 2-((7-bromo-2,3,4,5-tetrahydro-1H-benzo[b]azacycloheptane-1-yl)sulfonyl)ethanol-1-ol (compound 36-2): The intermediate 2-((7-bromo-2,3,4,5-tetrahydro-1H-benzo[b]azacycloheptane-1-yl)sulfonyl)methyl acetate (compound 36-1) (630 mg, 1.74 mmol) and calcium chloride (190 mg, 1.74 mmol) were added to tetrahydrofuran (9 mL), and sodium borohydride (265 mg, 7.0 mmol) was added under ice bath conditions. After the addition was complete, the mixture was refluxed at 80 °C for two days. After the reaction was completed, the reaction solution was diluted with ethyl acetate (200 mL), washed with saturated sodium chloride aqueous solution (200 mL × 3), and then the organic phase was taken, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 2:1) to give compound 2-((7-bromo-2,3,4,5-tetrahydro-1H-benzo[b]azacycloheptane-1-yl)sulfonyl)ethanol-1-ol (compound 36-2).

[1089] LC-MS, M / Z (ESI): 334.0 [M+H] +.

[1090] Step 3: Synthesis of 7-bromo-1-((2-((tert-butyldimethylsilyl)oxy)ethyl)sulfonyl)-2,3,4-5-tetrahydro-1H-benzo[b]azacyclobutane (compound 36-3) The intermediate 2-((7-bromo-2,3,4,5-tetrahydro-1H-benzo[b]azacycloheptane-1-yl)sulfonyl)ethanol-1-ol (compound 36-2) (410 mg, 1.23 mmol) and imidazole (251 mg, 3.69 mmol) were added to acetonitrile (10 mL), and tert-butyldimethylchlorosilane (371 mg, 2.46 mmol) was added under ice bath. After the addition was complete, the reaction was carried out at room temperature for 4 h. After the reaction was completed, the reaction solution was diluted with ethyl acetate (300 mL), washed with saturated sodium chloride aqueous solution (300 mL × 3), and then the organic phase was taken, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 5:1) to give compound 7-bromo-1-((2-((tert-butyldimethylsilyl)oxy)ethyl)sulfonyl)-2,3,4-5-tetrahydro-1H-benzo[b]azacyclobutane (compound 36-3).

[1091] LC-MS, M / Z (ESI): 448.0 [M+H] + .

[1092] Step 4: Synthesis of 3-(3-(1-((2-((tert-butyldimethylsilyl)oxy)ethyl)sulfonyl)-2,3,4-5-tetrahydro-1H-benzo[b]aziro-7-yl)-2-chlorophenyl)piperidine-2,6-dione (compound 36-4) The intermediate 7-bromo-1-((2-((tert-butyldimethylsilyl)oxy)ethyl)sulfonyl)-2,3,4-5-tetrahydro-1H-benzo[b]azirobutane (compound 36-3) (250 mg, 0.56 mmol) l) Place the mixture in a reaction flask, then add 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)piperidine-2,6-dione (intermediate A') (235 mg, 0.67 mmol), potassium phosphate (356 mg, 1.68 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (82 mg, 0.11 mmol), and 1,4-dioxane (6 mL). After the addition is complete, deoxygenate the mixture three times with nitrogen, and then react at 100 °C for 8 hours. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with ethyl acetate (300 mL), washed with saturated sodium chloride aqueous solution (300 mL × 3), and then the organic phase was taken, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 20:1) to give compound 3-(3-(1-((2-((tert-butyldimethylsilyl)oxy)ethyl)sulfonyl)-2,3,4-5-tetrahydro-1H-benzo[b]azon-7-yl)-2-chlorophenyl)piperidine-2,6-dione (compound 36-4).

[1093] LC-MS, M / Z (ESI): 591.0 [M+H] + .

[1094] Step 5: 3-(2-chloro-3-(1-((2-hydroxyethyl)sulfonyl)-2,3,4-5-tetrahydro-1H-benzo[b]azacycloheptane-7-yl)phenyl)piperidin-2,6-dione

[1095]

[1096] The intermediate 3-(3-(1-((2-((tert-butyldimethylsilyl)oxy)ethyl)sulfonyl)-2,3,4-5-tetrahydro-1H-benzo[b]azapyridine-7-yl)-2-chlorophenyl)piperidine-2,6-dione (compound 36-4) (89 mg, 0.15 mmol) was placed in a reaction flask, followed by the addition of trifluoroacetic acid (5 mL). After the addition was complete, the reaction was carried out at room temperature for 1 hour. After the reaction was completed, the solvent was removed by vacuum distillation, and the residue was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 20:1) to give compound 3-(2-chloro-3-(1-((2-hydroxyethyl)sulfonyl)-2,3,4-5-tetrahydro-1H-benzo[b]azapyridine-7-yl)phenyl)piperidine-2,6-dione (compound 36).

[1097] LC-MS, M / Z (ESI): 477.0 [M+H] + .

[1098] The preparation methods for the following compounds are as described in Examples 1, 4, 5, 6, 7, or 8:

[1099]

[1100]

[1101]

[1102]

[1103]

[1104]

[1105]

[1106]

[1107]

[1108]

[1109]

[1110]

[1111] Biological testing

[1112] Experimental Example 1: Compound-induced binding of VAV1 to CRBN

[1113] Experimental methods

[1114] 1) Cell line construction and culture. VAV1-SmBiT and CRBN-LgBiT expression plasmids were constructed separately. Using a lentiviral system, VAV1-SmBiT and CRBN-LgBiT were inserted into the genome of HEK293 cells to construct a stable cell line expressing VAV1-SmBiT and CRBN-LgBiT proteins (HEK293-VAV1-SmBiT-CRBN-LgBiT). The culture medium was DMEM containing 10% inactivated fetal bovine serum, 100 U / ml penicillin, and 100 μg / ml streptomycin. HEK293-VAV1-SmBiT-CRBN-LgBiT cells were cultured in a 37°C, 5% CO2 incubator. After passage at 80-90% confluence, the cells were divided into individual flasks for further passage. Cells in the logarithmic growth phase were used for plating. HEK293-VAV1-SmBiT-CRBN-LgBiT cells were seeded in 96-well plates with 100 μL of culture medium, 20,000-3,000 cells per well, and cultured overnight.

[1115] 2) Compound dilution. The compound was dissolved in DMSO to a concentration of 10 mM. Subsequently, the compound was serially diluted with DMSO to concentrations of 2000 μM, 500 μM, 125 μM, 32.25 μM, 7.81 μM, 1.95 μM, 0.49 μM, 0.12 μM and 0.031 μM.

[1116] 3) Adding the drug. Take 1 μL of the diluted compound and add it to 1 ml of complete culture medium. After mixing, take 100 μL and add it to a 96-well plate to achieve working concentrations of 1000 nM, 250 nM, 62.5 nM, 15.6 nM, 3.91 nM, 0.98 nM, 0.24 nM, 0.061 nM, 0.015 nM and 0 nM.

[1117] 4) Activity assay. The drug was tested 8 hours after treatment, following the instructions for the Promega NanoBiT Protein: Protein Interaction System.

[1118] 5) EC50 calculation. Fluorescence intensity (Fold change) = (Lumninence experiment - Lumininence blank) / (Lumninence DMSO - Lumininence blank).

[1119] Experimental conclusion:

[1120] The compounds of this invention can induce direct binding between VAV1 and CRBN in a dose-dependent manner.

[1121] Experimental Example 2:

[1122] Experimental methods

[1123] 1) Cell line construction and culture. A Hibit tag was inserted into the C-terminus of VAV1, and the VAV1-Hibit protein was inserted into the genome of HEK293 cells using a lentiviral system to construct a cell line stably expressing the VAV1-Hibit protein. The culture medium was DMEM containing 10% inactivated fetal bovine serum, 100 U / ml penicillin, and 100 μg / ml streptomycin. HEK293-VAV1-Hibit cells were cultured in a 37°C, 5% CO2 incubator. After passage, the cells were divided into flasks after reaching 80-90% confluence. Cells in the logarithmic growth phase were seeded into 96-well plates with 100 μL of medium at 20,000-3,000 cells per well, and cultured overnight.

[1124] 2) Compound dilution. The compound was dissolved in DMSO to a concentration of 10 mM. Subsequently, the compound was serially diluted with DMSO to concentrations of 2000 μM, 500 μM, 125 μM, 32.25 μM, 7.81 μM, 1.95 μM, 0.49 μM, 0.12 μM and 0.031 μM.

[1125] 3) Adding the drug. Take 1 μL of the diluted compound and add it to 1 ml of complete culture medium. After mixing, take 100 μL and add it to a 96-well plate to achieve working concentrations of 1000 nM, 250 nM, 62.5 nM, 15.6 nM, 3.91 nM, 0.98 nM, 0.24 nM, 0.061 nM, 0.015 nM and 0 nM.

[1126] 4) Activity assay. The drug was tested 24 hours after treatment, using methods according to Promega's specifications. HiBiT Lytic Detection System Manual.

[1127] 5) DC50 calculation. Relative VAV1(%) = (Lumninence experiment - Lumininence blank) / (LumninenceDMSO - Lumininence blank), calculated using the fitting method based on log(inhibitor) vs. response -- Variable slope (four parameters).

[1128] Experimental conclusion:

[1129] The compounds of this invention exhibit excellent degradation effects on VAV1 protein in a dose-dependent manner.

[1130] Experimental Example 3: Degradation of VAV1 in Jurkat Cells by the Compound

[1131] Jurkat cells were cultured in RPMI-1640 medium containing inactivated 10% fetal bovine serum, 100 U / ml penicillin and 100 μg / ml streptomycin in an incubator at 37°C and 5% CO2. After the cell density reached 1×10^6, the cells were passaged and subcultured into flasks. Tumor cells in the logarithmic growth phase were seeded at 7×10 5 onto a 12-well plate. The drug was diluted and added to the cell culture medium to make the final concentrations of the drug be 1000 nM, 250 nM, 62.5 nM, 15.6 nM, 3.9 nM, 0.98 nM, 0.24 nM and 0 nM respectively. The cells treated with the drug for 24 hours were taken out of the incubator and transferred into 1.5 mL EP tubes, and the supernatant was removed by centrifugation. 150 μL of RIPA lysis buffer was added to each tube and incubated on ice for 30 minutes. Protein gels were run for detection. Anti-VAV1 was diluted at 1:1000, Anti-GAPDH was diluted at 1:5000, and incubated overnight at 4°C. The HRP secondary antibody was diluted at 1:10000 and incubated at RT for 1 hour. Protein expression was detected by chemiluminescence, and gray value analysis was performed using ImageJ. It can be seen from Table 1 that the compound of the present invention shows excellent degradation effect on the degradation of VAV1 protein in Jurkat cells and is dose-dependent.

[1132] Table 1 Degradation Activity of the Compound on VAV1 Protein in Jurkat Cells

[1133]

[1134]

[1135] *DC50≤10 nM is “A”, 10 nM < DC50≤30 nM is “B1”, 30 nM < DC50≤100 nM is “B2”, 100 nM < DC50≤1000 nM is “C”, DC50 > 1000 nM is “D”.

[1136] Experimental Example 4: Inhibition of CD3 / CD28-induced Activation of Jurkat Cells by the Compound

[1137] Jurkat cells were cultured in RPMI-1640 medium containing inactivated 10% fetal bovine serum, 100 U / ml penicillin, and 100 μg / ml streptomycin at 37°C in a 5% CO2 incubator. After reaching a cell density of 1*10^6, the cells were passaged and aliquoted. Cells in logarithmic growth phase were seeded at 40,000 cells per well in 96-well plates, and different concentrations of the compounds were added. After 24 hours of treatment, 5 μg / ml CD3 antibody and 1 μg / ml CD28 antibody were added, and the cells were cultured for another 24 hours. The cell supernatant was then collected for ELISA to detect IL-2 levels.

[1138] Experimental conclusion: In the CD3 / CD28-induced Jurkat cell activation model, the compound of this invention can significantly inhibit the production of IL-2, and the inhibitory function is positively correlated with the dose.

[1139] Experimental Example 5: Compound Inhibits CD3 / CD28-Induced Human T Cell Activation

[1140] Dilute fresh blood samples with an equal volume of PBS and slowly add them to a 50 mL centrifuge tube containing 15 mL of Lymphoprep (Stemcell, #7851), taking care not to disrupt the interface. Centrifuge at 1000 g, speed 5 for 25 minutes at room temperature, without immobilizing. Collect the leukocyte matrix (PBMC), wash twice with PBS, centrifuge at 350 g for 10 minutes, and discard the supernatant. Use a T cell sorting kit (Stemcell, #17951) to sort T cells from the PBMC and adjust the cell density to 2.6 × 10⁶ cells / mL. 8 75 μL of the diluted assay compound was added to each well of a U-bottom 96-well plate (Corning, #3799), followed by 75 μL of the diluted assay compound. For the control group, 1640 complete medium containing an equal volume of DMSO was added. Cells were mixed and incubated for 24 hours. Cells were then transferred to a 96-well plate (Thermo, #167425) coated with Anti-Human CD3 (5 μg / mL, BD, #555329), and 50 μL of Anti-Human CD28 (1 μg / mL, BD, #555725) was added. Cells were mixed and incubated for another 48 hours. The supernatant was collected, and IL-2 levels were detected using an IL-2 ELISA kit (BD, #555190).

[1141] Experimental conclusion: In the CD3 / CD28-induced human T cell activation model, the compound of this invention can significantly inhibit the production of IL-2, and the inhibitory function is positively correlated with the dose.

[1142] Example 6: Determination of the PK properties of the compound in mice

[1143] Three male ICR mice were used. The dose was 10 mg / kg, administered by gavage to a solvent of 5% DMSO + 10% Solutol + 85% Saline. The mice were fasted overnight. Blood samples were collected before administration and at 5, 15, and 30 minutes, and at 1, 2, 4, 6, 8, and 24 hours after administration. Blood samples were centrifuged at 6800g at 2-8℃ for 6 minutes, and plasma was collected and stored at -80℃. 10 μL of plasma from each time point was added to 200 μL of methanol containing 100 ng / mL internal standard, vortexed, and centrifuged at 18000g at 2-8℃ for 7 minutes. 200 μL was transferred to a 96-well plate for LC-MS / MS quantitative analysis. The main pharmacokinetic parameters were analyzed using a non-compartmental model with WinNonlin 7.0 software. The PK parameter results of the compounds of this invention are shown in Table 2.

[1144] Table 2. Mouse p-values ​​of the compounds

[1145]

[1146] Experimental conclusion: In mouse models, the compounds of this invention exhibit good pharmacokinetic properties.

[1147] Test Example 7: Rat Pharmacokinetic Test

[1148] Pharmacokinetic studies were conducted on male SD rats (180-240g) that had been fasted overnight. Three rats were administered the drug 10mg / kg orally via gavage. Blood samples were collected before administration and at 15, 30 minutes, 1, 2, 4, 8, and 24 hours after administration. 6800g of blood samples were centrifuged at 2-8℃ for 6 minutes, and plasma was collected and stored at -80℃. Plasma samples from each time point were mixed with 3-5 times the volume of acetonitrile solution containing an internal standard, vortexed for 1 minute, centrifuged at 13000 rpm at 4℃ for 10 minutes, and the supernatant was mixed with 3 times the volume of water. An appropriate amount of the mixture was analyzed by LC-MS / MS. Key pharmacokinetic parameters were analyzed using a non-compartmental model with WinNonlin 7.0 software.

[1149] The results of the pharmacokinetic studies in rats showed that the compound of the present invention exhibited excellent pharmacokinetic properties in rats and good drug-likeness.

[1150] Test Example 8: Human Liver Microsomal Stability Test

[1151] The stability assay for human liver microsomes was performed by co-incubating the compound with human liver microsomes in vitro. First, the test compound was prepared as a 10 mM stock solution in DMSO, and then diluted to 0.5 mM with acetonitrile. Human liver microsomes (Corning) were diluted with PBS to prepare a microsome / buffer solution, and this solution was used to dilute the 0.5 mM compound to prepare the working solution. The concentration of the compound in the working solution was 1.5 μM, and the concentration of human liver microsomes was 0.75 mg / mL. 30 μL of the working solution was added to each well of a deep-well plate, followed by 15 μL of preheated 6 mM NADPH solution to initiate the reaction, which was incubated at 37°C. At 0, 5, 15, 30, and 45 minutes of incubation, 135 μL of acetonitrile was added to the corresponding well to terminate the reaction. After terminating the reaction with acetonitrile at the last 45 minutes, the deep-well plate was vortexed for 10 minutes (600 rpm / min) and then centrifuged for 15 minutes. After centrifugation, the supernatant was collected, and purified water was added at a 1:1 ratio. LC-MS / MS analysis was performed to obtain the ratio of the compound peak area to the internal standard peak area at each time point. The peak area ratios of the compounds at 5, 15, 30, and 45 minutes were compared with the peak area ratio at 0 minutes to calculate the remaining percentage of the compound at each time point. T1 / 2 was calculated using Graphpad 5 software.

[1152] The results of the human liver microsome stability test show that the compound of the present invention exhibits excellent human liver microsome stability and good drug-like properties.

[1153] Test Example 9: Thermodynamic Solubility Test

[1154] This embodiment uses a standardized in vitro method to assess the solubility of the compounds. The control compounds, progesterone and diclofenac, were purchased from Sigma-Aldrich. PBS (pH 7.4), FaSSIF, FeSSIF, and FaSSGF buffers were freshly prepared in the laboratory according to standard formulations and used within the specified time. The solubility determination procedure was as follows: approximately 1 mg of the compound was weighed into a glass vial, the corresponding buffer (1 mL / mg) was added, a stir bar was added, and the vial was sealed. The vial was incubated at 25°C and 1100 rpm for 24 hours. After incubation, the stir bar was removed, and the sample was vacuum filtered and serially diluted 100, 1000, and 10000 times with a water / acetonitrile (1:1, including internal standard) mixture. The standards were dissolved in DMSO and diluted in the same manner to concentrations of 10, 1, and 0.1 μg / mL. All samples were placed in an autosampler and analyzed using LC-MS / MS. Data processing was performed using Excel software, and solubility was calculated by comparison with standards.

[1155] Thermodynamic solubility test results show that the compound of the present invention has good thermodynamic solubility and good drug-like properties.

[1156] Test Example 10: Inhibition of Cytochrome P450 by Compounds

[1157] The inhibitory potential of the compounds against the cytochrome P450 (CYP450) subtype CYP3A4 (two substrates: midazolam and testosterone) was investigated. First, the test compound was prepared as a 10 mM stock solution in DMSO, and the CYP3A4 inhibitor ketoconazole was prepared as 10 mM, 2.5 mM, and 2.5 mM stock solutions in DMSO. The test compound and ketoconazole were then diluted 400-fold to a final concentration (compound: 10 μM, ketoconazole: 2.5 μM) with acetonitrile.

[1158] Prepare 4-fold final concentrations of NADPH cofactor (66.7 mg NADPH added to 10 mL of potassium phosphate buffer) and substrates using potassium phosphate buffer (0.1 M, pH 7.4). The final concentrations of CYP3A4 substrate midazolam were 320 μM and CYP3A4 substrate testosterone were 20 μM.

[1159] Prepare a 0.2 mg / mL human liver microsome solution on ice using potassium phosphate buffer. Prepare two final concentrations of the analyte and control inhibitor solutions on ice using the human liver microsome solution. Add 30 μL of the analyte and control inhibitor solutions to each well, followed by 15 μL of substrate, and perform replicates. Incubate the 96-well plate and NADPH solution at 37°C for 5 minutes. Add 15 μL of preheated 8 mM NADPH solution to the plate to initiate the reaction. Pre-incubate the CYP3A4 plate at 37°C for 5 minutes. Stop the reaction by adding 120 μL of acetonitrile. After quenching, shake the plate on a shaker (IKA, MTS2 / 4) for 10 minutes (600 rpm / min), then centrifuge for 15 minutes. After centrifugation, the supernatant was collected, purified water was added at a 1:1 ratio, and LC-MS / MS was performed to obtain the ratio of the peak area of ​​the compound to the peak area of ​​the internal standard. The peak area ratio of the compound was compared with the peak area ratio of the control inhibitor to calculate the inhibition rate.

[1160] The results of the inhibition test of the compound on cytochrome P450 showed that the compound of the present invention had no significant inhibitory effect on CYP3A4 (two substrates, midazolam and testosterone) and had good drug-like properties.

[1161] Test Example 11: Balanced Dialysis Method for Testing Plasma Protein Binding

[1162] First, human or other species plasma samples were stored at -20°C, thawed in a 37°C water bath before use, and stored on wet ice. The working solution for the test compound was prepared using DMSO with a stock concentration of 10 mM and a final concentration of 2 μM. The thawed plasma was centrifuged to remove suspended impurities and precipitates, and the pH was adjusted to 7.0–8.0. The pretreated dialysis membrane was loaded into the dialysis apparatus according to the manufacturer's instructions and the assembly was completed. For the zero-point control sample, blank plasma was mixed with the working solution of the test compound and vortexed at 1000 rpm for 2 minutes to a final concentration of 2 μM. This mixture was immediately transferred to a 96-well plate as the T=0 control sample, and the remaining mixture was incubated in a constant temperature incubator. To determine the stability of the compound in plasma, the remaining mixture was incubated in a 37°C shaking incubator for 5 hours. After incubation, 50 μL of the sample was transferred to a 96-well plate for subsequent analysis. The equilibration dialysis procedure was performed by assembling the dialysis apparatus according to the manufacturer's instructions. Plasma samples were added to the dialysis chamber and dialyzed with an equal volume of PBS buffer. Experiments were conducted with replicates. The apparatus was covered with a breathable cap and incubated at 37°C and 100 rpm for 5 hours. After incubation, samples were taken from the plasma chamber and buffer chamber and transferred to 96-well plates for analysis. During sample processing, plasma or PBS was added to the collected samples and mixed for 2 minutes. 500 μL of 80% acetonitrile / methanol solution containing an appropriate internal standard was added to precipitate proteins and release compounds. After vortexing for 10 minutes, the mixture was centrifuged at 4000 rpm for 10 minutes. 100 μL of the supernatant was transferred to a new 96-well plate, and 300 μL of distilled water was added and mixed before LC-MS / MS analysis. All samples underwent automatic peak area integration. The peak areas of the analytes and internal standard were exported to an Excel spreadsheet. The free fraction, binding fraction, and recovery rate of the compounds were calculated using the following formulas:

[1163] Unbound percentage (% Unbound) = (buffer fluid cavity peak area ratio / plasma cavity peak area ratio) × 100;

[1164] Bound rate (%Bound) = 100 - %Unbound;

[1165] Recovery (%Recovery) = (Buffer cavity peak area ratio + Plasma cavity peak area ratio) / Total sample peak area ratio × 100;

[1166] Remaining (% Remaining) = 5-hour peak area ratio / 0-hour peak area ratio × 100.

[1167] Table 3. Results of plasma protein binding assay

[1168]

[1169] Experimental results show that the compounds of this invention have significant advantages in plasma protein binding rate.

[1170] Test Example 12: Efficacy evaluation of the compound in a mouse model of inflammatory bowel disease induced by adoptive T cell transfer

[1171] This embodiment aims to evaluate the therapeutic potential of the compound in a mouse model of inflammatory bowel disease. The model used was an adoptive T-cell transfer-induced inflammatory bowel disease model, which has good clinical relevance.

[1172] Experimental methods:

[1173] 1) Spleens were isolated from BALB / c donor mice, and single-cell suspensions were prepared. CD4 cells were then sorted using the EasySep kit. + CD25 - Cells were stained and then sorted by flow cytometry for CD4+. + CD45RB + Cells were washed with PBS and resuspended to 1.5 × 10⁻⁶. 6 / mL. It was then transferred to immunodeficient recipient mice (CB17-SCID mice) via tail vein injection.

[1174] 2) Recipient mice were randomly assigned to either the compound or the control solvent starting on day 15 after cell transfer. The test compound was administered orally via gavage at doses ranging from 0.1 to 10 mg / kg once daily for 20 days.

[1175] 3) During the experiment, record changes in mouse body weight, fecal characteristics, and activity levels. After cell inoculation, perform DAI scoring twice weekly for weeks 1 and 2, and three times weekly for weeks 3 to 5. The DAI score is the sum of the scores for weight loss and fecal consistency, based on changes in animal body weight and fecal consistency.

[1176] 4) Mice were sacrificed on day 35, and colon tissue was collected. At the endpoint, the colon was collected, its length measured, washed with PBS to remove feces, dried, and weighed. The weight-to-length ratio was calculated. At the endpoint dissection, the colon contents were cleaned and preserved for pathological scoring.

[1177] The results showed that the test compounds of the present invention significantly alleviated the disease progression in an adoptive naïve T cell-induced mouse enteritis model.

Claims

1. The compound represented by formula (Ⅰ), its tautomers, stereoisomers, pharmaceutically acceptable salts or prodrugs, in, Ring A is a 7-12 membered heterocyclic alkyl, a 7-12 membered heterocyclic alkenyl, a 7-12 membered heteroaryl, a 5-6 membered sulfur-containing heterocyclic alkyl, a 5-6 membered sulfur-containing heterocyclic alkenyl, or a 5-10 membered sulfur-containing heteroaryl; R1 is H, D, halogen, CN, or C. 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 Alkyne group, 4-10 membered heterocyclic alkyl group, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 The alkynyl group and the 4-10 membered heterocyclic alkyl group are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. 1a replace; Each R 1a Each can be independently H, halogen, OH, NH2, CN, or C. 1-6 alkyl; R2, R3, and R4 are independently H, D, halogen, NH2, CN, and C, respectively. 1-6 Alkyl or halogenated C 1-6 alkyl; Each R5 is independently H, D, halogen, NH2, CN, or C. 1-6 Alkyl or halogenated C 1-6 alkyl; Each R6 is independently H, D, halogen, oxo (=O), thio (=S), nitrile (=N), OH, NH2, CN, -P (=O)(OH)2, C 1-6 Alkyl, C 1-6 Alkoxy, -C 0-6 Alkyl-P(=O)(C 1-6 Alkyl)2, -C 0-6 Alkyl-C(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)OC 1-6 Alkyl, -C 0-6 Alkyl-SC 1-6 Alkyl, -C 0-6 Alkyl-S(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-S(=O)2-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)-NR 6b R 6c -C 0-6 Alkyl-OC(=O)-NR 6b R 6c -C 0-6 Alkyl-C 3-8 cycloalkyl, -C 0-6 Alkyl-4-10 membered heterocyclic alkyl, -C 0-6 alkyl-4-10-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-10 heteroaryl, -OC 3-8 cycloalkyl, -L1-C 3-8 Cycloalkyl, -L1-4-10 heterocycloalkyl, or -L1-5-10 heteroaryl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, -C 0-6 Alkyl-P(=O)(C 1-6 Alkyl)2, -C 0-6 Alkyl-C(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)OC 1-6 Alkyl, -C 0-6 Alkyl-SC 1-6 Alkyl, -C 0-6 Alkyl-S(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-S(=O)2-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)-NR 6b R 6c -C 0-6 Alkyl-OC(=O)-NR 6b R 6c -C 0-6 Alkyl-C 3-8 cycloalkyl, -C 0-6 Alkyl-4-10 membered heterocyclic alkyl, -C 0-6 alkyl-4-10-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-10 heteroaryl, -OC 3-8 cycloalkyl, -L1-C 3-8 Cycloalkyl, -L1-4-10 heterocycloalkyl, and -L1-5-10 heteroaryl groups are each independently and optionally bound by 1, 2, 3, or 4 R groups. 6a replace; Alternatively, the two R6 atoms and the ring atoms they are attached to form a ring, which is C. 3-8 Cycloalkyl or 5-10 membered heterocycloalkyl; wherein, the C 3-8 Cycloalkyl or 5-10 membered heterocyclic alkyl groups are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. 6a replace; Each L1 is independently -O-, -N(R) 1L )-、-N(R 1L -C(=O)-, -S-, -S(=O)-, -S(=O)2- or -C(=O)-; R 1L For H or C 1-3 alkyl; Each R 6a They are, independently, H, D, halogen, oxo (=O), thio (=S), OH, NH2, CN, and C. 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 Alkyl-C 1-3 Alkoxy or C 1-6 Alkylamino, the C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 Alkyl-C 1-3 Alkoxy, C 1-6 The alkylamino groups can be independently substituted by 1, 2, 3 or 4 R groups; R 6b and R 6c H or C, independently respectively 1-6 alkyl; Or, R 6b R 6c Together with the nitrogen atom to which it is attached, it forms a 4-7 membered heterocyclic alkyl group, which may be optionally substituted with 1, 2, 3 or 4 R atoms; Each R is independently H, halogen, OH, NH2, CN, or C. 1-3 alkyl; R7 is H, D, halogen, or C. 1-6 alkyl; m is 1, 2, or 3; n is 1, 2, 3, 4, 5, 6, 7 or 8; The "sulfur-containing" in "5-6 member sulfur-containing heterocyclic alkyl", "5-6 member sulfur-containing heterocyclic alkenyl" or "5-10 member sulfur-containing heteroaryl" refers to the presence of S, S(=O), S(=O)2 or S(=O)(=NH); The heteroatomic groups in the "heterocyclic alkyl", "heterocyclic alkenyl" and "heteroaryl" include N, NH, O, S, S(=O), S(=O)2 or S(=O)(=NH), and the number of the heteroatomic groups is 1, 2, 3 or 4; when the number of the heteroatomic groups is multiple, the heteroatomic groups may be the same or different.

2. The compound, its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs according to claim 1, characterized in that, It satisfies one or more of the following conditions: (1) R1 is H, F, Cl, CN, C 1-3 Alkyl, C 2-4 alkynyl group, C 3-4 Cycloalkyl or 4-6 membered heterocycloalkyl, wherein C 1-3 Alkyl, C 2-4 alkynyl group, C 3-4 Cycloalkyl and 4-6 membered heterocycloalkyl groups are each independently and optionally bound by 1, 2, 3 or 4 R groups. 1a replace; (2) Each R 1a Each can be H or F independently; (3) R6 is H, F, Cl, oxo (=O), nitro (=N), C 1-3 Alkyl, C 1-3 Alkoxy, -C 0-6 Alkyl-P(=O)(C 1-3 Alkyl)2, -C 0-6 Alkyl-C(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)OC 1-6 Alkyl, -C 0-6 Alkyl-S(=O)2-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)-NR 6b R 6c , -C 0-6 Alkyl-OC(=O)-NR 6b R 6c -C 0-6 Alkyl-C 3-6 cycloalkyl, -C 0-6 Alkyl-4-6-membered heterocyclic alkyl, -C 0-6 alkyl-4-6-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-6-membered heteroaryl, -L1-C 3-6 Cycloalkyl, -L1-4-6 heterocycloalkyl or -L1-5-6 heteroaryl, wherein C 1-3 Alkyl, C 1-3 Alkoxy, -C 0-6 Alkyl-P(=O)(C 1-3 Alkyl)2, -C 0-6 Alkyl-C(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)OC 1-6 Alkyl, -C 0-6 Alkyl-S(=O)2-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)-NR 6b R 6c -C 0-6 Alkyl-OC(=O)-NR 6b R 6c -C 0-6 Alkyl-C 3-6 cycloalkyl, -C 0-6 alkyl-4-6-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-6-membered heteroaryl, -L1-C 3-6 Cycloalkyl, -L1-4-6 heterocycloalkyl, and -L1-5-6 heteroaryl groups are each independently and optionally bound by 1, 2, 3, or 4 R groups. 6a replace; (4)R 6a The independent components are H, D, F, Cl, Br, oxo (=O), thio (=S), OH, NH2, CN, and C, respectively. 1-3 Alkyl, C 1-3 Alkoxy, -C 1-3 Alkyl-C 1-3 Alkoxy or C 1-3 Alkylamino, the C 1-3 Alkyl, C 1-6 Alkoxy, -C 1-3 Alkyl-C 1-3 Alkoxy and C 1-3 The alkylamino group is independently substituted by 1, 2, 3 or 4 R groups; (5) Each R is independently H, F, Cl, Br, OH, NH2, CN or CH3; (6)R 6b and R 6c They are H or CH3, respectively, independently.

3. The compound, its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs according to claim 1, characterized in that, It satisfies one or more of the following conditions: (1a) R1 is Cl, F or -CH3; (2a) R2, R3 and R4 are each independently H; (3a) Each R5 is independently H; (4a) Each R7 is independently H or D; (5a)R 1L It is H or CH3; (6a) Each L1 is independently -O-, -NH-, -NH-C(=O)-, -S-, -S(=O)-, -S(=O)2- or -C(=O)-; (7a) Each L1 is independently -O- or -NH-C(=O)-; (8a) R6 can be H, F, Cl, oxo (=O), -CH3, -CH2-CH3, -CH(CH3)2, -CH2CH(CH3)2, -OCH3, -O-CH2CH(CH3)2. -CH3, -CH2-CH3, -CH(CH3)2, -CH2CH(CH3)2, -OCH3, -O-CH2CH(CH3)2, Each of the 1, 2, 3, or 4 R's can be independently selected. 6a replace; (9a)R 6a Each can be independently represented by H, D, F, OH, CN, NH2, oxo (=O), CH3, -O-CH3, -O-CHF2, CH2-OH, -CH2F, -CHF2, -CF3, -CH2-CH2F, -CH2-OCF3, or 4. The compound, its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs according to claim 1, characterized in that, It satisfies one or more of the following conditions: (1b) R6 is H, F, Cl, oxo (=O), -CH3, -CD3, -CHF2, -CF3, -CH2CHF2, -CH2CF3, -OCH3, -OCHF2, -OCF3, -CH(CH3)2, -CH2C(CH3)2OH, -CH2CH2OH, -O-CH2C(CH3)2OH, (2b) Ring A is a 7-12 membered heterocyclic alkyl group, wherein the 7-12 membered heterocyclic alkyl group is a monocyclic, fused, spirocyclic, or bridged ring; (3b) Ring A is a 7-12 membered heterocyclic alkenyl group, wherein the 7-12 membered heterocyclic alkenyl group is a monocyclic, fused, spirocyclic, or bridged ring; (4b) Ring A is a 7-12 membered heteroaryl group, wherein the 7-12 membered heteroaryl group is a fused ring; (5b) Ring A is a 5-6 member sulfur-containing heterocyclic alkyl group, a 5-6 member sulfur-containing heterocyclic alkenyl group, or a 5-6 member sulfur-containing heteroaryl group.

5. The compound, its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs according to claim 1, characterized in that, (1c) Ring A is (2c) for (3c) for (4c) for (4c) for The R6 therein has the definition as described in claim 1.

6. The compound, its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs according to claim 1, characterized in that, The compound has an (IA) structure: The rings A, R1, R2, R3, R4, R5, R6, R7, m, and n therein have the definitions as described in claim 1.

7. The compound, its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs according to claim 1, characterized in that, The compound has an (Ⅰ') structure: in, It can be represented as a single bond or a double bond; T represents O, S, and NR. x C(R) x 2. N or CR x ; E1 is a single bond, O, S, NR6, or C(R6)2; E2 and E3 are independently O, S, NR6 or C(R6)2, respectively; R x and R y Each is independently R6, and in this case, E1 is O, S, NR6 or C(R6)2; Or, R x and R y Together with the attached ring atom, it forms a ring substituted with 1, 2, 3 or 4 R6 atoms, said ring being a 5-6 membered heterocyclic alkyl, 5-6 membered heterocyclic alkenyl, 5-6 membered heteroaryl or phenyl; E1 is a single bond, O, S, NR6 or C(R6)2; m, R1, R2, R3, R4, R5, R6 and R7 are as defined in claim 1.

8. The compound, its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs according to claim 7, characterized in that, The compound has a (Ⅰ-1) structure: in, E1 is a single bond, O, S, NR6, or C(R6)2; E2 and E3 are independently O, S, NR6 or C(R6)2, respectively; R x and R y Each is independently R6, and in this case, E1 is O, S, NR6 or C(R6)2; Or, R x and R y Together with the attached ring atom, it forms a heterocycle substituted with 1, 2, 3, or 4 R6 atoms, said heterocycle being a 5-6 membered heterocyclic alkyl, 5-6 membered heterocyclic alkenyl, or 5-6 membered heteroaryl; E1 is a single bond, O, S, NR6, or C(R6)2; m, R1, R2, R3, R4, R5, R6, and R7 are as defined in claim 1.

9. The compound, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs according to claim 7, characterized in that, The compound has a (Ⅰ-2) structure: in, E1 is a single bond, O, S, NR6, or C(R6)2; E2 and E3 are independently O, S, NR6 or C(R6)2, respectively; R x and R y Each is independently R6, and in this case, E1 is O, S, NR6 or C(R6)2; Or, R x and R y Together with the attached ring atom, it forms a ring substituted with 1, 2, 3 or 4 R6 atoms, said ring being a 5-6 membered heterocyclic alkyl, 5-6 membered heterocyclic alkenyl or 5-6 membered heteroaryl or phenyl; E1 is a single bond, O, S, NR6 or C(R6)2; m, R1, R2, R3, R4, R5, R6 and R7 are as defined in claim 1.

10. The compound, its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs according to claim 7, characterized in that, The compound has the (Ⅰ-1A) structure: in, E1 is O, S, NR6 or C(R6)2; E2 and E3 are independently O, S, NR6 or C(R6)2, respectively; m, R1, R2, R3, R4, R5, R6 and R7 are as defined in claim 1.

11. The compound, its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs according to claim 7, characterized in that, The compound has a (Ⅰ-1B), (Ⅰ-1C), or (Ⅰ-2A) structure: in, It can be represented as a single bond or a double bond; E1 is a single bond, O, S, NR6, or C(R6)2; E2 and E3 are independently O, S, NR6 or C(R6)2, respectively; T1, T2 and T3 are independently C(=O), O, S, NR6, C(R6)2, N or CR6, respectively; T4, T5, T6 and T7 are independently C(=O), O, S, NR6, C(R6)2, N or CR6, respectively; m, R1, R2, R3, R4, R5, R6 and R7 are as defined in claim 1.

12. The compound, its tautomer, stereoisomer, pharmaceutically acceptable salt, or prodrug according to any one of claims 7-11, characterized in that, It satisfies one or more of the following conditions: (1d)R x For H, F, Cl, oxo (=O), C 1-3 Alkyl, C 1-3 Alkoxy, -C 0-6 Alkyl-P(=O)(C 1-3 Alkyl)2, -C 0-6 Alkyl-C(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)OC 1-6 Alkyl, -C 0-6 Alkyl-S(=O)2-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)-NR 6b R 6c -C 0-6 Alkyl-OC(=O)-NR 6b R 6c -C 0-6 Alkyl-C 3-6 cycloalkyl, -C 0-6 Alkyl-4-6-membered heterocyclic alkyl, -C 0-6 alkyl-4-6-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-6-membered heteroaryl, -L1-C 3-6 Cycloalkyl, -L1-4-6 heterocycloalkyl or -L1-5-6 heteroaryl, wherein C 1-3 Alkyl, C 1-3 Alkoxy, -C 0-6 Alkyl-P(=O)(C 1-3 Alkyl)2, -C 0-6 Alkyl-C(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)OC 1-6 Alkyl, -C 0-6 Alkyl-S(=O)2-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)-NR 6b R 6c -C 0-6 Alkyl-OC(=O)-NR 6b R 6c -C 0-6 Alkyl-C 3-6 cycloalkyl, -C 0-6 alkyl-4-6-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-6-membered heteroaryl, -L1-C 3-6 Cycloalkyl, -L1-4-6 heterocycloalkyl, and -L1-5-6 heteroaryl groups are each independently and optionally bound by 1, 2, 3, or 4 R groups. 6a replace; (2d)R x For H, F, Cl, oxo (=O), -CH3, -CH2-CH3, -CH(CH3)2, -CH2CH(CH3)2, -OCH3, -O-CH2CH(CH3)2, -CH3, -CH2-CH3, -CH(CH3)2, -CH2CH(CH3)2, -OCH3, -O-CH2CH(CH3)2, Each of the 1, 2, 3, or 4 R's can be independently selected. 6a replace; (3d)R 6a Each can be independently H, D, F, OH, CN, NH2, oxo (=O), CH3, -O-CH3, -O-CHF2, -CH2-OH, -CH2F, -CHF2, -CF3, -CH2-CH2F, -CH2-OCF3, or (4d)R x is H, F, Cl, oxo(=O), -CH3, -CHF2, -CF3, -CH2CHF2, -CH2CF3, -OCH3, -OCHF2, -OCF3, -CH2C(CH3)2OH, -CH2CH2OH, -O-CH2C(CH3)2OH, (5d) for (6d) for Preferably, for (7d) for Preferably, Selected from (8d) for Preferably, Selected from (10d) for Preferably, for (5d)R1 is H, D, halogen, CN, C 1-6 Alkyl, the C 1-6 Alkyl groups are optionally surrounded by 1, 2, 3 or 4 R's. 1a Replace; each R 1a Each can be independently H, halogen, CN, or C. 1-6 alkyl.

13. The compound, its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs according to claim 1, characterized in that, The compound satisfies any of the following definitions (a)-(d): (a) The compound has the structure shown in formula (I-3): Wherein, R1 is H, D, halogen, or C. 1-3 Alkyl group; preferably, R1 is a halogen; R2, R3, R4 and R7 are H, D or halogens; preferably, R2, R3, R4 and R7 are H; m is 1, 2, or 3; Each R5 is independently H, D, halogen, NH2, CN, or C. 1-6 Alkyl or halogenated C 1-6 alkyl; E1 is a single bond, O, S, or C(R6)2; E2 and E3 are independently O, S, or C(R6)2; and ring A is a 6-7 membered heterocyclic alkyl group; R6 can be H, D, halogen, oxometalate (=O), OH, NH2, CN, or C. 1-6 Alkyl, C 1-6 Alkoxy, -C 0-6 Alkyl-C(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)OC 1-6 Alkyl, -C 0-6 Alkyl-SC 1-6 Alkyl, -C 0-6 Alkyl-S(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-S(=O)2-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)-NR 6b R 6c -C 0-6 Alkyl-OC(=O)-NR 6b R 6c -C 0-6 Alkyl-C 3-8 cycloalkyl, -C 0-6 Alkyl-4-8-membered heterocyclic alkyl, -C 0-6 alkyl-4-8-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-8-membered heteroaryl, -OC 3-8 cycloalkyl, -L1-C 3-8 Cycloalkyl, -L1-4-8 heterocycloalkyl, or -L1-5-8 heteroaryl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, -C 0-6 Alkyl-C(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)OC 1-6 Alkyl, -C 0-6 Alkyl-SC 1-6 Alkyl, -C 0-6 Alkyl-S(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-S(=O)2-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)-NR 6b R 6c -C 0-6 Alkyl-OC(=O)-NR 6b R 6c -C 0-6 Alkyl-C 3-8 cycloalkyl, -C 0-6 Alkyl-4-10 membered heterocyclic alkyl, -C 0-6 alkyl-4-8-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-8-membered heteroaryl, -OC 3-8 cycloalkyl, -L1-C 3-8 Cycloalkyl, -L1-4-8 heterocycloalkyl, and -L1-5-8 heteroaryl groups are each independently and optionally bound by 1, 2, 3, or 4 R groups. 6a replace; Each L1 is independently -O-, -S-, -S(=O)-, -S(=O)2- or -C(=O)-; Alternatively, the two R6 atoms and the ring atoms they are attached to form a ring, which is C. 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl; wherein, the C 3-8 Cycloalkyl or 5-10 membered heterocyclic alkyl groups are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. 6a Replace; each R 6a They are, independently, H, D, halogen, oxo (=O), thio (=S), OH, NH2, CN, and C. 1-4 Alkyl, C 1-4 Alkoxy, -C 1-3 Alkyl-C 1-3 Alkoxy or C 1-4 Alkylamino; the C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 Alkyl-C 1-3 Alkoxy, C 1-6 The alkylamino groups can be independently substituted by 1, 2, 3 or 4 R groups; Each R is independently H, halogen, OH, NH2, CN, or C. 1-3 alkyl; R 6b and R 6c H or C, independently respectively 1-6 alkyl; (b) The compound has the structure shown in formula (I-4): Wherein, R1 is H, D, halogen, or C. 1-3 Alkyl group; preferably, R1 is a halogen; R2, R3, R4 and R7 are H, D or halogens; preferably, R2, R3, R4 and R7 are H; m is 1, 2, or 3; Each R5 is independently H, D, halogen, NH2, CN, or C. 1-6 Alkyl or halogenated C 1-6 alkyl; E1 is a single bond, O, S, or C(R6)2; E2 and E3 are independently O, S or C(R6)2, respectively; n is 1, 2, or 3; R6 can be H, D, halogen, oxometalate (=O), OH, NH2, CN, or C. 1-6 Alkyl, C 1-6 Alkoxy, -C 0-6 Alkyl-C(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)OC 1-6 Alkyl, -C 0-6 Alkyl-SC 1-6 Alkyl, -C 0-6 Alkyl-S(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-S(=O)2-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)-NR 6b R 6c -C 0-6 Alkyl-OC(=O)-NR 6b R 6c -C 0-6 Alkyl-C 3-8 cycloalkyl, -C 0-6 Alkyl-4-8-membered heterocyclic alkyl, -C 0-6 alkyl-4-8-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-8-membered heteroaryl, -OC 3-8 cycloalkyl, -L1-C 3-8 Cycloalkyl, -L1-4-8 heterocycloalkyl, or -L1-5-8 heteroaryl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, -C 0-6 Alkyl-C(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)OC 1-6 Alkyl, -C 0-6 Alkyl-SC 1-6 Alkyl, -C 0-6 Alkyl-S(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-S(=O)2-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)-NR 6b R 6c -C 0-6 Alkyl-OC(=O)-NR 6b R 6c -C 0-6 Alkyl-C 3-8 cycloalkyl, -C 0-6 Alkyl-4-10 membered heterocyclic alkyl, -C 0-6 alkyl-4-8-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-8-membered heteroaryl, -OC 3-8 cycloalkyl, -L1-C 3-8 Cycloalkyl, -L1-4-8 heterocycloalkyl, and -L1-5-8 heteroaryl groups are each independently and optionally bound by 1, 2, 3, or 4 R groups. 6a replace; Each L1 is independently -O-, -S-, -S(=O)-, -S(=O)2- or -C(=O)-; Each R 6a They are, independently, H, D, halogen, oxo (=O), thio (=S), OH, NH2, CN, and C. 1-4 Alkyl, C 1-4 Alkoxy, -C 1-3 Alkyl-C 1-3 Alkoxy or C 1-4 Alkylamino; the C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 Alkyl-C 1-3 Alkoxy, C 1-6 The alkylamino groups can be independently substituted by 1, 2, 3 or 4 R groups; Each R is independently H, halogen, OH, NH2, CN, or C. 1-3 alkyl; (c) The compound has the structure shown in formula (I-5): Wherein, R1 is H, D, halogen, or C. 1-3 Alkyl group; preferably, R1 is a halogen; R2, R3, R4 and R7 are H, D or halogens; preferably, R2, R3, R4 and R7 are H; m is 1, 2, or 3; Each R5 is independently H, D, halogen, NH2, CN, or C. 1-6 Alkyl or halogenated C 1-6 alkyl; E1 is a single bond, O, S, or C(R6)2; E2 and E3 are independently O, S or C(R6)2, respectively; n is 1, 2, or 3; R6 can be H, D, halogen, oxometalate (=O), OH, NH2, CN, or C. 1-6 Alkyl, C 1-6 Alkoxy, -C 0-6 Alkyl-C(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)OC 1-6 Alkyl, -C 0-6 Alkyl-SC 1-6 Alkyl, -C 0-6 Alkyl-S(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-S(=O)2-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)-NR 6b R 6c -C 0-6 Alkyl-OC(=O)-NR 6b R 6c -C 0-6 Alkyl-C 3-8 cycloalkyl, -C 0-6 Alkyl-4-8-membered heterocyclic alkyl, -C 0-6 alkyl-4-8-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-8-membered heteroaryl, -OC 3-8 cycloalkyl, -L1-C 3-8 Cycloalkyl, -L1-4-8 heterocycloalkyl, or -L1-5-8 heteroaryl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, -C 0-6 Alkyl-C(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)OC 1-6 Alkyl, -C 0-6 Alkyl-SC 1-6 Alkyl, -C 0-6 Alkyl-S(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-S(=O)2-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)-NR 6b R 6c -C 0-6 Alkyl-OC(=O)-NR 6b R 6c -C 0-6 Alkyl-C 3-8 cycloalkyl, -C 0-6 Alkyl-4-10 membered heterocyclic alkyl, -C 0-6 alkyl-4-8-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-8-membered heteroaryl, -OC 3-8 cycloalkyl, -L1-C 3-8 Cycloalkyl, -L1-4-8 heterocycloalkyl, and -L1-5-8 heteroaryl groups are each independently and optionally bound by 1, 2, 3, or 4 R groups. 6a replace; Each L1 is independently -O-, -S-, -S(=O)-, -S(=O)2- or -C(=O)-; R 6T For H, D, halogens, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl-OH, C 1-6 Alkoxy, -C 0-6 Alkyl-C 1-6 Alkoxy, -C 0-6 Alkyl-halogenated C 1-6 Alkoxy, -C 0-6 Alkyl-C(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)-NR 6b R 6c -C 0-6 Alkyl-OC(=O)-NR 6b R 6c -C 0-6 Alkyl-S(=O)2-C 1-6 Alkyl, -C 0-6 Alkyl-NR 6b R 6c -C 0-6 Alkyl-C 3-6 cycloalkyl, -C 0-6 alkyl-4-6-membered heterocyclic group; wherein the -C 0-6 Alkyl-C 3-6 cycloalkyl, -C 0-6 The alkyl-4-6-membered heterocyclic groups are independently and optionally surrounded by 1, 2, 3 or 4 R groups. 6a Replace; each R 6a They are, independently, H, D, halogen, oxo (=O), thio (=S), OH, NH2, CN, and C. 1-4 Alkyl, C 1-4 Alkoxy, -C 1-3 Alkyl-C 1-3 Alkoxy or C 1-4 Alkylamino; the C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 Alkyl-C 1-3 Alkoxy, C 1-6 The alkylamino groups can be independently substituted by 1, 2, 3 or 4 R groups; Each R is independently H, halogen, OH, NH2, CN, or C. 1-3 alkyl; Ideally, R 6T For H, -CH3, -CD3, -CHF2, -CF3, -CH2CHF2, -CH2CF3, -OCH3, -OCHF2, -OCF3, -CH(CH3)2, -CH2C(CH3)2OH, -CH2CH2OH, -O-CH2C(CH3)2OH, (d) The compound has the structure shown in formula (I-6): Wherein, R1 is H, D, halogen, or C. 1-3 Alkyl group; preferably, R1 is a halogen; R2, R3, R4 and R7 are H, D or halogens; preferably, R2, R3, R4 and R7 are H; m is 1, 2, or 3; Each R5 is independently H, D, halogen, NH2, CN, or C. 1-6 Alkyl or halogenated C 1-6 alkyl; E1 is a single bond, O, S, or C(R6)2; E2 and E3 are independently O, S or C(R6)2, respectively; n is 1, 2, or 3; R6 can be H, D, halogen, oxometalate (=O), OH, NH2, CN, or C. 1-6 Alkyl, C 1-6 Alkoxy, -C 0-6 Alkyl-C(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)OC 1-6 Alkyl, -C 0-6 Alkyl-SC 1-6 Alkyl, -C 0-6 Alkyl-S(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-S(=O)2-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)-NR 6b R 6c -C 0-6 Alkyl-OC(=O)-NR 6b R 6c -C 0-6 Alkyl-C 3-8 cycloalkyl, -C 0-6 Alkyl-4-8-membered heterocyclic alkyl, -C 0-6 alkyl-4-8-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-8-membered heteroaryl, -OC 3-8 cycloalkyl, -L1-C 3-8 Cycloalkyl, -L1-4-8 heterocycloalkyl, or -L1-5-8 heteroaryl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, -C 0-6 Alkyl-C(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)OC 1-6 Alkyl, -C 0-6 Alkyl-SC 1-6 Alkyl, -C 0-6 Alkyl-S(=O)-C 1-6 Alkyl, -C 0-6 Alkyl-S(=O)2-C 1-6 Alkyl, -C 0-6 Alkyl-C(=O)-NR 6b R 6c -C 0-6 Alkyl-OC(=O)-NR 6b R 6c -C 0-6 Alkyl-C 3-8 cycloalkyl, -C 0-6 Alkyl-4-10 membered heterocyclic alkyl, -C 0-6 alkyl-4-8-membered heterocyclic alkenyl, -C 0-6 Alkyl-5-8-membered heteroaryl, -OC 3-8 cycloalkyl, -L1-C 3-8 Cycloalkyl, -L1-4-8 heterocycloalkyl, and -L1-5-8 heteroaryl groups are each independently and optionally bound by 1, 2, 3, or 4 R groups. 6a replace; Each L1 is independently -O-, -S-, -S(=O)-, -S(=O)2- or -C(=O)-; Each R 6a They are, independently, H, D, halogen, oxo (=O), thio (=S), OH, NH2, CN, and C. 1-4 Alkyl, C 1-4 Alkoxy, -C 1-3 Alkyl-C 1-3 Alkoxy or C 1-4 Alkylamino; the C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-3 Alkyl-C 1-3 Alkoxy, C 1-6 The alkylamino groups can be independently substituted by 1, 2, 3 or 4 R groups; Each R is independently H, halogen, OH, NH2, CN, or C. 1-3 alkyl.

14. The compound, its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs according to claim 1, characterized in that, The compound has the following structure:

15. A pharmaceutical composition, characterized in that, The compound comprising a therapeutically effective dose of any one of claims 1-13, its tautomers, stereoisomers, pharmaceutically acceptable salts or prodrugs, and pharmaceutically acceptable excipients.

16. Use of the compound, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or pharmaceutical composition according to any one of claims 1-14 in the preparation of a medicament for the treatment or prevention of diseases associated with VAV1.

17. The use according to claim 16, characterized in that, The VAV1-related diseases include cancer and autoimmune diseases.

18. The use according to claim 16, characterized in that, The VAV1-related diseases include systemic lupus erythematosus, myasthenia gravis, periodontitis, type 1 diabetes, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, autoimmune hepatitis, or psoriasis.

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