Diketone biphenyl compound serving as VAV1 degradation agent and application of diketone biphenyl compound

Abstract

The invention provides a diketone biphenyl compound serving as a VAV1 degradation agent and application of the diketone biphenyl 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 diketylbenzene 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 and B-cell receptor 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 the T-cell receptor (TCR), B-cell receptor (BCR), and various cytokine receptors. In hematopoietic cells (e.g., 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 calcium ion (Ca) deficiency. 2+T cells lacking VAV1 GEF activity (VAV1 L334A / K335A) exhibit normal TCR-mediated Ca2+ activation. 2+ Flow and nuclear factor-activated T cell (NFAT) activation. This indicates that VAV1 plays an important role in both GEF activity and scaffold function 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, Represented as in This indicates that ring C and ring D form a parallel ring or a spiral ring;

[0009] The ring C is a 5-membered heteroaryl, a 4-10-membered heterocyclic alkenyl, a pyridazine, a pyrazine, or a triazine;

[0010] Ring D does not exist, or it is C. 6-10 Aryl, 5-10-membered heteroaryl, 5-10-membered heterocyclic alkyl or 5-10-membered heterocyclic alkenyl;

[0011] The phenyl group on the left is attached to a ring atom on ring C;

[0012] When ring D is absent, L1 on the right side is connected to the ring atom on ring C;

[0013] When ring D is present, L1 on the right can be connected to either the ring atom on ring C or the ring atom on ring D.

[0014] 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;

[0015] Each R 1a Each can be independently H, halogen, OH, NH2, CN, or C. 1-6 alkyl;

[0016] R2, R3, and R4 are independently H, halogen, NH2, CN, and C, respectively. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0017] Each R5 and R 51 They are independently H, halogen, oxo (=O), thio (=S), CN, and C, respectively. 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 Alkyne group or 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. 5a replace;

[0018] Each R 5a Each can be independently H, halogen, OH, NH2, CN, or C. 1-6 alkyl;

[0019] L1 represents a single bond, -O-, -NH-, or -OC. 1-3 Alkyl-, -NH-C 1-3 Alkyl- or -C 1-3 alkyl-, wherein -NH-, -OC- 1-3 Alkyl-, -NH-C 1-3 Alkyl- and -C 1-3 Alkyl groups are each independently and optionally marked with 1, 2, 3, or 4 R groups. 1L replace;

[0020] Each R 1L Each is independently H, halogen, and C. 1-3 Alkyl or C 3-6 cycloalkyl;

[0021] R6 can be H, halogen, oxo (=O), thio (=S), OH, NH2, CN, or C. 1-6 Alkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclic alkyl, 4-10 membered heterocyclic alkenyl, C 6-10 Aryl or 5-10 heteroaryl, wherein C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclic alkyl, 4-10 membered heterocyclic alkenyl, C 6-10 Aryl and 5-10 heteroaryl groups are each independently and optionally bound by 1, 2, 3 or 4 R groups. 6a replace;

[0022] Each R 6a They are, independently, H, halogen, oxo (=O), OH, NH2, CN, and C, respectively. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-8 membered heterocycloalkyl, -L2-C 3-6 Cycloalkyl or -L2-4-8-membered heterocycloalkyl, wherein C 1-6 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 4-8 membered heterocycloalkyl, -L2-C 3-6 Cycloalkyl or -L2-4-8-membered heterocycloalkyl groups are optionally surrounded by 1, 2, 3 or 4 R groups. 6a-1 replace;

[0023] Each R 6a-1 They are, independently, H, halogen, OH, NH2, CN, and C. 1-3 Alkyl or -C 1-3 Alkyl-C 1-3 Alkoxy, the C 1-3 Alkyl or -C 1-3 Alkyl-C 1-3 The alkoxy groups are optionally substituted with 1, 2, 3 or 4 R groups, respectively;

[0024] Each R is independently H, halogen, OH, NH2, or CN;

[0025] Each L2 is independently -O-, -N(R) 2L -, -S-, -S(=O)-, -S(=O)2- or -C(=O)-;

[0026] R 2L For H or C 1-3 alkyl;

[0027] R7 is H, D, halogen, or C. 1-6 alkyl;

[0028] n is 1, 2, or 3;

[0029] m can be 1, 2, 3, or 4;

[0030] The heteroatomic groups in the "heterocyclic alkyl", "heterocyclic alkenyl" and "heteroaryl" groups include N, NH, O, S, S(=O), S(=O)2 or

[0031] 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.

[0032] In an optional embodiment of the present invention, the compound represented by formula (I), its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs are included.

[0033]

[0034] in,

[0035] The ring C is a 5-membered heteroaryl, a 4-10-membered heterocyclic alkenyl, a pyridazine, a pyrazine, or a triazine;

[0036] Ring D does not exist, or it is C. 6-10 Aryl, 5-10-membered heteroaryl, 5-10-membered heterocyclic alkyl or 5-10-membered heterocyclic alkenyl;

[0037] The phenyl group on the left is attached to a ring atom on ring C;

[0038] When ring D is absent, L1 on the right side is connected to the ring atom on ring C;

[0039] When ring D is present, L1 on the right can be connected to either the ring atom on ring C or the ring atom on ring D.

[0040] 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;

[0041] Each R 1a Each can be independently H, halogen, OH, NH2, CN, or C. 1-6 alkyl;

[0042] R2, R3, and R4 are independently H, halogen, NH2, CN, and C, respectively.1-6 Alkyl or halogenated C 1-6 alkyl;

[0043] Each R5 and R 51 They are independently H, halogen, oxo (=O), thio (=S), CN, and C, respectively. 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 Alkyne group or 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. 5a replace;

[0044] Each R 5a Each can be independently H, halogen, OH, NH2, CN, or C. 1-6 alkyl;

[0045] L1 represents a single bond, -O-, -NH-, or -OC. 1-3 Alkyl-, -NH-C 1-3 Alkyl- or -C 1-3 alkyl-, wherein -NH-, -OC- 1-3 Alkyl-, -NH-C 1-3 Alkyl- and -C 1-3 Alkyl groups are each independently and optionally marked with 1, 2, 3, or 4 R groups. 1L replace;

[0046] Each R 1L Each is independently H, halogen, and C. 1-3 Alkyl or C 3-6 cycloalkyl;

[0047] R6 can be H, halogen, oxo (=O), thio (=S), OH, NH2, CN, or C. 1-6 Alkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclic alkyl, 4-10 membered heterocyclic alkenyl, C 6-10 Aryl or 5-10 heteroaryl, wherein C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclic alkyl, 4-10 membered heterocyclic alkenyl, C 6-10 Aryl and 5-10 heteroaryl groups are each independently and optionally bound by 1, 2, 3 or 4 R groups. 6a replace;

[0048] Each R 6a They are, independently, H, halogen, oxo (=O), OH, NH2, CN, and C, respectively.1-6 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 4-8 membered heterocycloalkyl, -L2-C 3-6 Cycloalkyl or -L2-4-8-membered heterocycloalkyl, wherein C 1-6 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 4-8 membered heterocycloalkyl, -L2-C 3-6 Cycloalkyl or -L2-4-8-membered heterocycloalkyl groups are optionally surrounded by 1, 2, 3 or 4 R groups. 6a-1 replace;

[0049] Each R 6a-1 They are, independently, H, halogen, OH, NH2, CN, and C. 1-3 Alkyl or -C 1-3 Alkyl-C 1-3 Alkoxy, the C 1-3 Alkyl or -C 1-3 Alkyl-C 1-3 The alkoxy groups are optionally substituted with 1, 2, 3 or 4 R groups, respectively;

[0050] Each R is independently H, halogen, OH, NH2, or CN;

[0051] Each L2 is independently -O-, -N(R) 2L -, -S-, -S(=O)-, -S(=O)2- or -C(=O)-;

[0052] R 2L For H or C 1-3 alkyl;

[0053] R7 is H, D, halogen, or C. 1-6 alkyl;

[0054] n is 1, 2, or 3;

[0055] m can be 1, 2, 3, or 4;

[0056] The heteroatomic groups in the "heterocyclic alkyl", "heterocyclic alkenyl" and "heteroaryl" groups include N, NH, O, S, S(=O), S(=O)2 or S(=O)(=NH).

[0057] The number of heteroatom groups is 1, 2, 3 or 4; when there are multiple heteroatom groups, the heteroatom groups may be the same or different.

[0058] In an optional embodiment of the present invention, the compound represented by formula (I), its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs are included.

[0059]

[0060] in,

[0061] The ring C is a 5-membered heteroaryl group;

[0062] Ring D is C 6-10 Aryl, 5-10-membered heteroaryl, 5-10-membered heterocyclic alkyl or 5-10-membered heterocyclic alkenyl;

[0063] The phenyl group on the left is attached to a ring atom on ring C;

[0064] When ring D is absent, L1 on the right side is connected to the ring atom on ring C;

[0065] When ring D is present, L1 on the right can be connected to either the ring atom on ring C or the ring atom on ring D.

[0066] 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;

[0067] Each R 1a Each can be independently H, halogen, OH, NH2, CN, or C. 1-6 alkyl;

[0068] R2, R3, and R4 are independently H, halogen, NH2, CN, and C, respectively. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0069] Each R5 and R 51 They are independently H, halogen, oxo (=O), CN, and C, respectively. 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 Alkyne group or 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. 5a replace;

[0070] Each R5a Each can be independently H, halogen, OH, NH2, CN, or C. 1-6 alkyl;

[0071] L1 represents a single bond, -O-, -NH-, or -OC. 1-3 Alkyl-, -NH-C 1-3 Alkyl- or -C 1-3 alkyl-, wherein -NH-, -OC- 1-3 Alkyl-, -NH-C 1-3 Alkyl- and -C 1-3 Alkyl groups are each independently and optionally marked with 1, 2, 3, or 4 R groups. 1L replace;

[0072] Each R 1L Each is independently H, halogen, and C. 1-3 Alkyl or C 3-6 cycloalkyl;

[0073] R6 can be H, halogen, oxometalate (=O), OH, NH2, CN, or C. 1-6 Alkyl, C 3-8 Cycloalkyl, 4-10 heterocycloalkyl, 4-10 heterocycloalkenyl, 6-10 aryl, or 5-10 heteroaryl, wherein C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclic alkyl, 4-10 membered heterocyclic alkenyl, C 6-10 Aryl and 5-10 heteroaryl groups are each independently and optionally bound by 1, 2, 3 or 4 R groups. 6a replace;

[0074] 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;

[0075] R7 is H, D, halogen, or C. 1-6 alkyl;

[0076] n is 1, 2, or 3;

[0077] m can be 1, 2, 3, or 4;

[0078] 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.

[0079] In an optional embodiment of the present invention, when the aforementioned ring D does not exist, for

[0080] In an optional embodiment of the present invention, the aforementioned ring C is E1 is O, S, or NH, and T1, T2, T3, and T4 are independently CH or N.

[0081] In an optional embodiment of the present invention, the ring C is thiophene, thiazolyl, isothiazolyl, pyrrole, pyrazolyl, imidazole, furanyl, thiadiazolyl, oxazolyl, or oxadiazolyl.

[0082] In an optional embodiment of the present invention, the above-mentioned ring C is thiophene, thiazolyl, isothiazolyl, pyrrole, pyrazolyl, imidazole, or furanyl.

[0083] In an optional embodiment of the present invention, the above for

[0084] L1 can be connected to either "#" or "*".

[0085] In an optional embodiment of the present invention, the above for

[0086] In the above formula (Ⅰ), L1 can be connected to either "#" or "*".

[0087] In an optional embodiment of the present invention, the above for

[0088] L1 can be connected to either "#" or "*".

[0089] In an optional embodiment of the present invention, the above It is a 4-6 membered heterocyclic alkenyl group.

[0090] In an optional embodiment of the present invention, the above It is dihydropyridinyl or tetrahydropyridinyl.

[0091] In an optional embodiment of the present invention, the above for

[0092] L1 can be connected to either "#" or "*".

[0093] In an optional embodiment of the present invention, the above for L1 can be connected to either "#" or "*".

[0094] In an optional embodiment of the present invention, the above Selected from the following group:

[0095] (1) for L1 can be connected to either "#" or "*"; or,

[0096] (2) for L1 can be connected to either "#" or "*";

[0097] (3) for L1 can be connected to either "#" or "*";

[0098] Each R 51 They are independently H, halogen, oxo (=O), thio (=S), CN, and C, respectively. 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 Alkyne group or 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. 5a replace;

[0099] Each R 5a Each can be independently H, halogen, OH, NH2, CN, or C. 1-6 alkyl.

[0100] In one optional embodiment of the present invention for L1 can be connected to either "#" or "*";

[0101] Each R 51 They are independently H, halogen, oxo (=O), thio (=S), CN, and C, respectively. 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 Alkyne group or 4-10 membered heterocyclic alkyl group, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6cycloalkyl, 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. 5a replace;

[0102] Each R 5a Each can be independently H, halogen, OH, NH2, CN, or C. 1-6 alkyl.

[0103] In an optional embodiment of the present invention, when the aforementioned ring D exists, for

[0104] In the above formula (Ⅰ), L1 can be connected to either the ring atom on ring C or the ring atom on ring D.

[0105] In an optional embodiment of the present invention, the above-mentioned cyclic C is a 5-membered heteroaryl group.

[0106] In an optional embodiment of the present invention, the ring C is pyrazolyl, imidazolyl, furanyl, thiophene, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, or oxadiazolyl.

[0107] In an optional embodiment of the present invention, the above-mentioned ring D is phenyl, 5-6-membered heteroaryl, 5-8-membered heterocyclic alkyl or 5-8-membered heterocyclic alkenyl.

[0108] In an optional embodiment of the present invention, the above-mentioned ring D is phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 6-membered heterocycloalkyl or 6-membered heterocycloalkenyl.

[0109] In an optional embodiment of the present invention, the ring D is phenyl, pyrazolyl, imidazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, or pyridoneyl.

[0110] In an optional embodiment of the present invention, the above for

[0111] E2 is NH, O, S; T5 and T6 are independently CH or N; E3 and E4 are NH, O, S or C (=O); X1, X2, X3 and X4 are independently CH or N; "#1" indicates that it is connected to the phenyl group on the left side of formula (I); "#2" indicates that it is connected to L1 in formula (I).

[0112] In an optional embodiment of the present invention, the above for E5 consists of NH, O, and S; T7, T8, T9, and T 10 T 11 and T 12They can be CH or N, respectively.

[0113] In an optional embodiment of the present invention, the above for

[0114]

[0115] "#1" indicates that it is connected to the phenyl group on the left side of formula (I), and "#2" indicates that it is connected to L1 in formula (I).

[0116] In one optional embodiment of the present invention, the above is

[0117] "#1" indicates that it is connected to the phenyl group on the left side of formula (I), and "#2" indicates that it is connected to L1 in formula (I);

[0118] Each R5 and R 51 They are independently H, halogen, oxo (=O), thio (=S), CN, and C, respectively. 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 Alkyne group or 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. 5a replace;

[0119] Each R 5a Each can be independently H, halogen, OH, NH2, CN, or C. 1-6 alkyl.

[0120] 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 replace.

[0121] In an optional embodiment of the present invention, R1 is Cl, F, -CH3, -C≡C-CH3,

[0122] In an optional embodiment of the present invention, R1 is Cl, F or -CH3.

[0123] In an optional embodiment of the present invention, the above-mentioned R 1a They are H or F, respectively, independently.

[0124] In an optional embodiment of the present invention, R2, R3 and R4 are each independently H.

[0125] In an optional embodiment of the present invention, each of the above R5 and R 51 They can be H, Cl, F, oxo (=O) or CH3, respectively.

[0126] In an optional embodiment of the present invention, L1 is a single bond.

[0127] In an optional embodiment of the present invention, R6 is C. 1-3 Alkyl, 4-8 membered heterocyclic alkyl, 4-8 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl, wherein C 1-3 Alkyl, 4-8 membered heterocyclic alkyl, 4-8 membered heterocyclic alkenyl, phenyl, and 5-6 membered heteroaryl groups are each independently and optionally surrounded by 1, 2, 3, or 4 R groups. 6a replace.

[0128] In an optional embodiment of the present invention, R6 is C. 1-3 Alkyl, 4-6 membered heterocyclic alkenyl or 5-6 membered heteroaryl, wherein C 1-3 Alkyl, 4-6-membered heterocyclic alkenyl, or 5-6-membered heteroaryl groups are each independently and optionally bound by 1, 2, 3, or 4 R groups. 6a replace.

[0129] In an optional embodiment of the present invention, the above-mentioned R 6a They are independently H, halogen, oxo (=O), and C, respectively. 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4-8 membered heterocycloalkyl, -L2-C 3-6 Cycloalkyl, -L2-4-8-membered heterocycloalkyl, wherein C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 4-8 membered heterocycloalkyl, -L2-C 3-6 Cycloalkyl groups and -L2-4-8-membered heterocycloalkyl groups are optionally surrounded by 1, 2, 3 or 4 R groups, respectively. 6a-1 replace.

[0130] In an optional embodiment of the present invention, the above-mentioned R 6a They are independently H, halogen, oxo (=O), and C, respectively. 1-3 Alkyl, C1-3 Alkoxy, C 3-6 Cycloalkyl, 4-8 membered heterocycloalkyl, -L2-C 3-6 Cycloalkyl, -L2-4-8-membered heterocycloalkyl, wherein C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 4-8 membered heterocycloalkyl, -L2-C 3-6 Cycloalkyl groups and -L2-4-8-membered heterocycloalkyl groups are optionally surrounded by 1, 2, 3 or 4 R groups, respectively. 6a-1 replace.

[0131] In an optional embodiment of the present invention, each of the above-mentioned R 6a-1 They can be independently H, F, Cl, OH, NH2, CN, CH3, -CH2-OH, -CH2F, -CHF2, -CF3, -CH2-CH2F, or -CH2-OCF3.

[0132] In an optional embodiment of the present invention, each of the above-mentioned L2s is independently -O-, -N(R) 2L )-、-S-、-S(=O)-、-S(=O)2- or -C(=O)-.

[0133] In an optional embodiment of the present invention, the above-mentioned R 2L It can be H or CH3.

[0134] In an optional embodiment of the present invention, each of the above-mentioned L2 is independently -O-, -NH-, -S-, -S(=O)-, -S(=O)2- or -C(=O)-.

[0135] In an optional embodiment of the present invention, each of the above L2 is independently -O-.

[0136] In an optional embodiment of the present invention, the above-mentioned R 6a They are independently H, F, oxo (=O), methyl, -CHF2, -CF3, -OCH3, -OCHF2, -OCF3, respectively.

[0137] In an optional embodiment of the present invention, the above-mentioned R 6a They are independently H, F, oxo (=O), methyl, -OCHF2, -OCF3, respectively.

[0138]

[0139] In an optional embodiment of the present invention, the above-mentioned R 6a They can be H, oxo, or CH3, respectively.

[0140] In an optional embodiment of the present invention, R6 is C. 1-3 Alkyl, 4-6 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl, wherein C 1-3 Alkyl, 4-6-membered heterocyclic alkenyl, phenyl, and 5-6-membered heteroaryl groups are each independently and optionally surrounded by 1, 2, 3, or 4 R groups. 6a replace.

[0141] In an optional embodiment of the present invention, R6 is CH3,

[0142] In an optional embodiment of the present invention, R6 is CH3,

[0143] In an optional embodiment of the present invention, R6 is CH3,

[0144] In an optional embodiment of the present invention, R6 is CH3,

[0145] In an optional embodiment of the present invention, each of the above R7 is independently H or D.

[0146] In an optional embodiment of the present invention, the above-mentioned compound, its tautomers, stereoisomers, pharmaceutically acceptable salts or prodrugs, are characterized in that the compound has the structure of the following formula (Ⅰ'):

[0147]

[0148] in,

[0149] The ring C is a 5-membered heteroaryl, a 4-10-membered heterocyclic alkenyl, a pyridazine, a pyrazine, or a triazine;

[0150] R1, R2, R3, R4, R 51 R6, R7, n and L1 are as defined in this invention.

[0151] In an optional embodiment of the present invention, the above-mentioned compound, its tautomers, stereoisomers, pharmaceutically acceptable salts or prodrugs, are characterized in that the compound has a structure of the following formula (I-1), (I-2), (I-3), (I-4) or (I-5):

[0152]

[0153] in,

[0154] E1 is O, S, or NH;

[0155] E2 can be O, S, NH, or CH2;

[0156] E3 is O, S, NH or CH2;

[0157] T1, T2, T3, and T4 are each independently CH or N; X1 and X2 are each independently CH or N, and at least one of X1 and X2 is N; R1, R2, R3, R4, R 51 R6, R7, n and L1 are as defined in this invention.

[0158] In an optional embodiment of the present invention, the above-mentioned compound, its tautomers, stereoisomers, pharmaceutically acceptable salts or prodrugs are characterized in that the compound has the structure of the following formula (I-4):

[0159]

[0160] in,

[0161] The ring C is a 5-membered heteroaryl, a 4-10-membered heterocyclic alkenyl, a pyridazine, a pyrazine, or a triazine;

[0162] Ring D is C 6-10 Aryl, 5-10-membered heteroaryl, 5-10-membered heterocyclic alkyl or 5-10-membered heterocyclic alkenyl; the phenyl group on the left is attached to a ring atom on ring C, and the L1 group on the right can be attached to either a ring atom on ring C or a ring atom on ring D.

[0163] R1, R2, R3, R4, R5, R 51 R6, R7, m, n and L1 are as defined in this invention.

[0164] In an optional embodiment of the present invention, the above-mentioned compound, its tautomers, stereoisomers, pharmaceutically acceptable salts or prodrugs, are characterized in that the compound has a structure of the following formula (I-1A'), (I-1A), (I-1B), (I-2A), (I-3A) or (I-4A):

[0165]

[0166]

[0167] in,

[0168] h can be 1, 2, 3, or 4;

[0169] E1 is O, S or NH, and T1, T2, T3 and T4 are independently CH or N;

[0170] X1 and X2 are independently CH or N, and at least one of X1 and X2 is N;

[0171] The ring C is a 5-membered heteroaryl, a 4-10-membered heterocyclic alkenyl, a pyridazine, a pyrazine, or a triazine;

[0172] Ring D is C 6-10 Aryl, 5-10-membered heteroaryl, 5-10-membered heterocyclic alkyl or 5-10-membered heterocyclic alkenyl; the phenyl group on the left is attached to a ring atom on ring C, and the L1 group on the right can be attached to either a ring atom on ring C or a ring atom on ring D.

[0173] R1, R2, R3, R4, R5, R 51 R 6a R7, m, n and L1 are as defined in this invention.

[0174] In an optional embodiment of the present invention, the above for The

[0175] It is a 5-membered heteroaryl group.

[0176] In an optional embodiment of the present invention, the above It is a thiophene group.

[0177] In an optional embodiment of the present invention, the above-mentioned R 51 Each is independently H, halogen, and C. 1-6 alkyl.

[0178] In an optional embodiment of the present invention, the above-mentioned R 51 They are H or F, respectively, independently.

[0179] In an optional embodiment of the present invention, L1 is a single bond.

[0180] In an optional embodiment of the present invention, R6 is a 4-10 membered heterocyclic alkyl group or a 4-10 membered heterocyclic alkenyl group, wherein the 4-10 membered heterocyclic alkyl group or the 4-10 membered heterocyclic alkenyl group is independently and optionally surrounded by 1, 2, 3 or 4 R6 groups. 6a replace.

[0181] In an optional embodiment of the present invention, R6 is...

[0182] In an optional embodiment of the present invention, the above-mentioned R 6a They are independently H, halogen, oxo (=O), and C, respectively. 1-6 Alkyl, C 1-6 Alkoxy

[0183] The C 1-6 Alkyl and C 1-6The alkoxy group is optionally surrounded by 1, 2, 3 or 4 R groups. 6a-1 replace.

[0184] In an optional embodiment of the present invention, the above-mentioned R 6a They are independently H, F, oxo (=O), methyl, -CHF2, CF3,

[0185] In an optional embodiment of the present invention, the above-mentioned R 6a-1 They are H, halogen, OH, and NH2, respectively.

[0186] In an optional embodiment of the present invention, the above compound has the following structure:

[0187]

[0188]

[0189]

[0190]

[0191] 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.

[0192] 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.

[0193] In an optional embodiment of the present invention, the above-mentioned drug is used to treat or prevent cancer and autoimmune diseases.

[0194] 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.

[0195] In an optional embodiment of the present invention, the aforementioned VAV1-related diseases include cancer and autoimmune diseases.

[0196] 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.

[0197] 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.

[0198] 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.

[0199] Terms and Definitions

[0200] Unless otherwise stated, the terms and definitions used in this application, including those set forth in the specification and claims, are as follows.

[0201] 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.

[0202] 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.

[0203] 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.

[0204] 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.

[0205] 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.

[0206] 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.

[0207] 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.

[0208] 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.

[0209] 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.

[0210] 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.

[0211] 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.

[0212] 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.

[0213] 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:

[0214]

[0215] Due to resonance, the hydrogen atom of nitrogen in tetrazolium can be on any of the four nitrogen atoms.

[0216] Unless otherwise specified, use wedge-shaped solid line keys. and wedge-shaped dashed key The absolute configuration of the center of a solid is represented by a straight solid line key. and straight dashed key The relative configuration of the center of a solid.

[0217] Unless otherwise stated, in this invention Represented as in It can represent either the formation of a parallel ring between ring C and ring D, or the formation of a spiral ring between ring C and ring D.

[0218] 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.

[0219] 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.

[0220] 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.

[0221] 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).

[0222] 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.

[0223] 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.

[0224] 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.

[0225] 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.

[0226] 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). C1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), etc.

[0227] The term "halogenated" is used interchangeably with the term "halogenated" when used alone or as part of other substituents.

[0228] 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.

[0229] 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.

[0230] 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.

[0231] 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.

[0232] 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).

[0233] 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.

[0234] 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.

[0235] 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. C3-8 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2]bicyclooctane, etc.

[0236] 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. C 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0237] 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.

[0238] 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" should be understood to represent a saturated ring having m to n atoms, wherein the heterocyclic atoms are 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 represent 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" represents a saturated or partially saturated ring having 4 to 10 atoms. When prefixes such as 4-8 or 4-10 are used to denote heterocyclic alkyl groups, the number of carbon atoms also implies the inclusion of heteroatoms. These include monocyclic, bicyclic, tricyclic, spirocyclic, or bridged rings. Examples of heterocyclic alkyl groups include: pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydropyridyl, tetrahydropyrrolidinyl, azaheptanyl, thiazolyl, azoleyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, azaheptanyl, diazaheptanyl, oxonitrileheptanyl, etc. The term "heterocyclic alkyl" can be used interchangeably with the term "heteroalkyl ring."

[0239] 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".

[0240] 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”.

[0241] Unless otherwise specified, the term "4-10 membered heterocyclic alkenyl" alone, or in combination with other terms, refers to an unsaturated or partially unsaturated cyclic group consisting of 4 to 10 ring atoms comprising at least one carbon-carbon double bond, but not an aromatic ring, wherein 1, 2, 3, or 4 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 "5-6 membered heterocyclic alkenyl," the heteroatom may occupy the connection position between the heterocyclic alkenyl group and the rest of the molecule. The 4-10 membered heterocyclic alkenyl includes 5-, 6-, 7-, 8-, 9-, and 10-membered heterocyclic alkenyl groups, etc.

[0242] 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.).

[0243] Unless otherwise specified, the terms "halogen" or "halogen" refer to fluorine, chlorine, bromine, and iodine.

[0244] 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.

[0245] 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.

[0246] 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).

[0247] The term "treatment" and other similar synonyms used in this article include the following meanings:

[0248] (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;

[0249] (ii) To suppress a disease or symptom, that is, to curb its development;

[0250] (iii) To alleviate a disease or symptom, that is, to cause the condition of the disease or symptom to subside; or

[0251] (iv) To alleviate the symptoms caused by the disease or condition.

[0252] The abbreviations for this invention are defined as follows:

[0253] M: Molar concentration, such as 1M hydrochloric acid, which represents a 1 mol / L hydrochloric acid solution.

[0254] N: Equivalent concentration, for example, 2N hydrochloric acid represents a 2 mol / L hydrochloric acid solution.

[0255] DMSO: Dimethyl sulfoxide

[0256] Bpin: Pinaryl borate.

[0257] Beneficial effects

[0258] According to embodiments of the present invention, the present invention has at least one of the following technical effects:

[0259] 1) The compounds of this invention can induce direct binding between VAV1 and CRBN in a dose-dependent manner;

[0260] 2) The compounds of this invention exhibit excellent degradation effects on VAV1 protein in a dose-dependent manner;

[0261] 3) In CD3 / CD28-induced Jurkat cell and T cell activation models, the compounds of this invention significantly inhibited IL-2 production, and the inhibitory function was positively correlated with the dose;

[0262] 4) The compounds of this invention exhibit excellent pharmacokinetic properties and good drug-likeness in pharmacokinetic studies in mice and rats;

[0263] 5) The compounds of this invention exhibit excellent stability in human liver microsomes, good thermodynamic solubility, no significant CYP3A4 inhibition, and a significant advantage in plasma protein binding rate, and have good drug-like properties;

[0264] 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. Detailed Implementation

[0265] 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.

[0266] Preparation of intermediate A

[0267] 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)piperidin-2,6-dione

[0268]

[0269] The synthetic route for intermediate A is shown below:

[0270]

[0271] Step 1: Synthesis of 2-(3-bromo-2-chlorophenyl)acetonitrile (intermediate A2)

[0272] 3-Bromo-2-chlorobenzyl bromide (compound 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 compound 2-(3-bromo-2-chlorophenyl)acetonitrile (intermediate A2).

[0273] LC-MS, M / Z (ESI): 230.1 [M+H] + .

[0274] Step 2: Synthesis of methyl 4-(3-bromo-2-chlorophenyl)-4-cyanobutyrate (intermediate A3)

[0275] 2-(3-bromo-2-chlorophenyl)acetonitrile (5.0 g, 21.74 mmol) (intermediate 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 compound methyl 4-(3-bromo-2-chlorophenyl)-4-cyanobutyrate (intermediate A3).

[0276] LC-MS, M / Z (ESI): 316.2 [M+H] + .

[0277] Step 3: Synthesis of 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (intermediate A4)

[0278] 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 A4).

[0279] LC-MS, M / Z (ESI): 302.1 [M+H] + .

[0280] Step 4: Synthesis of 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)piperidine-2,6-dione (intermediate A)

[0281]

[0282] Compound 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (intermediate A4) (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). After the addition was complete, 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).

[0283] LC-MS, M / Z (ESI): 350.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ10.90(s,1H),7.51(dd,1H),7.41(dd,1H),7.32(d,1H),4.25(dd, 1H),2.83–2.70(m,1H),2.56–2.50(m,1H),2.29(qd,1H),1.97–1.92(m,1H),1.30(s,12H).

[0284] Example 1: Preparation of target compound 1

[0285] 3-(2-chloro-3-(5-(2-oxopyridin-1(2H)-yl)thiophen-2-yl)phenyl)piperidin-2,6-dione

[0286]

[0287] The synthetic route for compound 1 is shown below:

[0288]

[0289] Step 1: Synthesis of 1-(5-bromothiophen-2-yl)pyridin-2(1H)-one (compounds 1-2)

[0290] 2,6-Dibromothiophene (2.0 g, 8.3 mmol) was placed in a reaction flask, followed by the addition of 2-hydroxypyridine (650 mg, 7 mmol), cuprous iodide (1.3 g, 7 mmol), potassium carbonate (2.9 g, 21 mmol), and trans-N,N'-dimethyl-1,2-cyclohexanediamine (1.2 g, 8.4 mmol), then acetonitrile (30 mL). The reaction mixture was microwaved at 100 °C for 1 h under nitrogen protection. After the reaction was complete, the reaction solution was diluted with ethyl acetate (300 mL), washed with saturated sodium chloride aqueous solution (300 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:1) to give compound 1-(5-bromothiophene-2-yl)pyridin-2(1H)-one (compound 1-2).

[0291] LC-MS, M / Z (ESI): 256.0 [M+H] + .

[0292] Step 2: Synthesis of 3-(2-chloro-3-(5-(2-oxopyridin-1(2H)-yl)thiophen-2-yl)phenyl)piperidin-2,6-dione (compound 1)

[0293]

[0294] Compound 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)piperidin-2,6-dione (intermediate A) (300 mg, 0.88 mmol) was placed in a reaction flask, followed by the addition of 1-(5-bromothiophene-2-yl)pyridin-2(1H)-one (compound 1-2) (150 mg, 0.586 mmol), potassium phosphate (370 mg, 1.76 mmol), 1,1'-bis(di-phenylphosphino)ferrocene palladium chloride (43 mg, 0.06 mmol), and 1,4-dioxane (5 mL). After the addition was complete, the reaction solution was reacted at 100 °C for 8 hours under nitrogen protection. After the reaction was complete, the reaction solution was cooled to room temperature, 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 residue was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 20:1) to give compound 3-(2-chloro-3-(5-(2-oxopyridin-1(2H)-yl)thiophen-2-yl)phenyl)piperidin-2,6-dione (compound 1).

[0295] LC-MS, M / Z (ESI): 399.1 [M+H] + .

[0296] 1 H NMR(400MHz,DMSO-d6)δ10.94(s,1H),8.26(dd,1H),7.56–7.48(m,3H),7.43–7.35(m,2H),7.30(d,1H),6.63 (d,1H),6.51–6.45(m,1H),4.36(dd,1H),2.86–2.73(m,1H),2.54(dt,1H),2.34(qd,1H),2.08–2.00(m,1H).

[0297] Example 2: Synthesis of Compound 2

[0298] 3-{2-chloro-3-[6-(2-oxopyridin-1(2H)-yl)pyridazin-3-yl]phenyl}piperidin-2,6-dione

[0299]

[0300] The synthetic route for compound 2 is as follows:

[0301]

[0302] Step 1: Synthesis of 1-(6-bromopyridazin-3-yl)pyridin-2(1H)-one (compound 2-2)

[0303] At room temperature, 3,6-dibromopyridazine (500 mg, 2.10 mmol) was dissolved in dimethyl sulfoxide (5 mL), followed by the addition of pyridin-2(1H)-one (200 mg, 2.10 mmol), potassium carbonate (580 mg, 4.20 mmol), and cuprous iodide (40.0 mg, 0.210 mmol). The reaction mixture was reacted at 120 °C for 12 hours under nitrogen protection. After the reaction was complete, the reaction mixture was slowly poured into water (50 mL), and then extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (PE:EA(V / V) = 100:1 to 1:1) to give compound 1-(6-bromopyridazine-3-yl)pyridin-2(1H)-one (compound 2-2).

[0304] LC / MS (ESI) (m / z): 252.0 (M+H) + .

[0305] Step 2: Synthesis of 3-(2-chloro-3-[6-(2-oxopyridin-1(2H)-yl)pyridazin-3-yl]phenyl)piperidin-2,6-dione (compound 2)

[0306]

[0307] At room temperature, 1-(6-bromopyridazin-3-yl)pyridin-2(1H)-one (compound 2-2) (40.0 mg, 0.160 mmol) was dissolved in 1,4-dioxane / water (1 mL / 0.1 mL), and then 3-[2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl]piperidin-2,6-dione (intermediate A) (55.0 mg, 0.160 mmol), sodium carbonate (42.0 mg, 0.400 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (12.0 mg, 0.016 mmol) were added. The reaction was carried out at 100 °C for 12 hours under liquid nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was diluted with water (10 mL). Then, it was extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (PE:EA(V / V) = 100:1 to 1:1) to give compound 3-(2-chloro-3-[6-(2-oxopyridin-1(2H)-yl)pyridazin-3-yl]phenyl)piperidin-2,6-dione (compound 2).

[0308] LC / MS (ESI) (m / z): 395.0 (M+H) + ;

[0309] 1 H NMR(400MHz,DMSO-d6)δ10.95(s,1H),8.21(d,1H),8.13(d,1H),8.05(dd,1H),7.64–7.48(m,4H),6.58 (d,1H),6.44(dd,1H),4.39(dd,1H),2.84–2.75(m,1H),2.54(dd,1H),2.36(dd,1H),2.08–2.02(m,1H).

[0310] Example 3: Preparation of Compound 3

[0311] 3-(2-chloro-3-(1'-methyl-2'-oxo-1',2',3,6-tetrahydro-2H-[1,3'-bipyridin]-4-yl)phenyl)piperidin-2,6-dione (compound 3)

[0312]

[0313] The synthetic route for target compound 3 is shown below:

[0314]

[0315] Step 1: Synthesis of compound 1-methyl-3-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)pyridin-2(1H)-one (compound 3-3)

[0316] At room temperature, 3-bromo-1-methylpyridin-2(1H)-one (3-1) (500.00 mg, 2.66 mmol) and 1,4-dioxane-8-azaspiro[4.5]decane (3-2) (456.94 mg, 3.19 mmol) were dissolved in anhydrous 1,4-dioxane solution (5 mL). Cesium carbonate (1.73 g, 5.32 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (153.87 mg, 0.27 mmol) and palladium acetate (29.85 mg, 0.13 mmol) were added. After the addition was complete, the reaction mixture was stirred at 110 °C for 12 hours under nitrogen protection. After the reaction of the raw materials was complete as monitored by TLC, stirring was stopped, the mixture was cooled to room temperature, and then water (20 mL) was added for dilution. The mixture was extracted with ethyl acetate (10 mL × 5), 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) = 30:70) to obtain compound 1-methyl-3-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)pyridin-2(1H)-one (compound 3-3).

[0317] LC-MS, M / Z (ESI): 251.2 (M+H) + )

[0318] Step 2: Synthesis of compound 1-methyl-3-(4-oxopiperidin-1-yl)pyridin-2(1H)-one (compounds 3-4)

[0319] At room temperature, compound 1-methyl-3-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)pyridin-2(1H)-one (compound 3-3) (150.00 mg, 0.60 mmol) was dissolved in a mixture of 1 mL acetone and 2 mL water, and then p-toluenesulfonic acid (20.64 mg, 0.12 mmol) was added. The reaction mixture was heated and stirred in an oil bath at 70 °C for 12 hours. 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 diluted with saturated sodium bicarbonate aqueous solution (10 mL). The solution was extracted with ethyl acetate (10 mL × 5), 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) = 10:90) to give compound 1-methyl-3-(4-oxopiperidin-1-yl)pyridin-2(1H)-one (compound 3-4).

[0320] LC-MS, M / Z (ESI): 207.1 (M+H) + )

[0321] Step 3: Synthesis of compound 1'-methyl-2'-oxo-1',2',3,6-tetrahydro-2H-[1,3'-bipyridine]-4-trifluoromethanesulfonate (compounds 3-5)

[0322] At room temperature, compound 1-methyl-3-(4-oxopiperidin-1-yl)pyridin-2(1H)-one (compound 3-4) (100.00 mg, 0.48 mmol) was dissolved in anhydrous tetrahydrofuran (1 mL), and then stirred at -78 °C for 30 minutes. Then, a tetrahydrofuran solution of bis(trimethylsilylamino)lithium (0.58 mL, 0.58 mmol) was slowly added dropwise. After the addition was completed, the mixture was stirred at -78 °C for another 30 minutes. Then, N-phenylbis(trifluoromethanesulfonyl)imide (207.85 mg, 0.58 mmol) was added. After the addition was completed, the reaction mixture was stirred for another hour and then stirred at room temperature for 12 hours. After TLC monitoring showed that the reaction of the raw materials was complete, stirring was stopped, 10 mL of saturated ammonium chloride aqueous solution was added to the reaction solution for dilution, and the mixture was extracted with ethyl acetate (5 mL × 5). The organic phase was collected and dried with anhydrous sodium sulfate. The organic phase was concentrated by vacuum distillation, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 30:70) to obtain compound 1'-methyl-2'-oxo-1',2',3,6-tetrahydro-2H-[1,3'-bipyridine]-4-trifluoromethanesulfonate (compounds 3-5).

[0323] LC-MS, M / Z (ESI): 339.5 (M+H) + )

[0324] Step 4: Synthesis of compound 3-(2-chloro-3-(1'-methyl-2'-oxo-1',2',3,6-tetrahydro-2H-[1,3'-bipyridin]-4-yl)phenyl)piperidin-2,6-dione (compound 3)

[0325]

[0326] At room temperature, compound 1'-methyl-2'-oxo-1',2',3,6-tetrahydro-2H-[1,3'-bipyridine]-4-trifluoromethanesulfonate (compounds 3-5) (20.00 mg, 0.06 mmol) and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)piperidin-2,6-dione (intermediate A) (62.01 mg, 0.18 mmol) were dissolved in toluene (0.5 mL) and water (0.2 mL). Under nitrogen protection, potassium carbonate (32.68 mg, 0.24 mmol) and tetrakis(triphenylphosphine)palladium (6.83 mg, 0.006 mmol) were added. The reaction mixture was stirred at 100 °C for 12 hours under nitrogen protection. After TLC monitoring showed that the reactants had reacted completely, stirring was stopped, the reaction solution was cooled to room temperature, and then diluted with water (20 mL). Extraction was performed with ethyl acetate (10 mL × 5). The organic phase was collected and dried over anhydrous sodium sulfate. The organic phase was concentrated by vacuum distillation. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:1) to give compound 3-(2-chloro-3-(1'-methyl-2'-oxo-1',2',3,6-tetrahydro-2H-[1,3'-bipyridin]-4-yl)phenyl)piperidin-2,6-dione (compound 3).

[0327] LC-MS, M / Z (ESI): 412.4 (M+H) + )

[0328] Example 4: Preparation of Compound 4

[0329] 3-(2-chloro-3-(1-(pyrimidin-2-ylmethyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)piperidin-2,6-dione (compound 4)

[0330]

[0331] The synthetic route for target compound 4 is shown below:

[0332]

[0333] Step 1: Synthesis of 8-(pyrimidin-2-ylmethyl)-1,4-dioxa-8-azaspiro[4.5]decane (compound 4-3)

[0334] At room temperature, compound 2-(chloromethyl)pyrimidine hydrochloride (compound 4-1) (1.00 g, 6.06 mmol) and 1,4-dioxa-8-azaspiro[4.5]decane (compound 4-2) (1.04 g, 7.27 mmol) were dissolved in anhydrous tetrahydrofuran (15 mL), and sodium iodide (90.8 mg, 0.61 mmol) and triethylamine (1.53 g, 15.15 mmol) were added. The reaction mixture was heated and stirred at 70 °C for 12 hours. After the reaction of the raw materials was completed as monitored by TLC, stirring was stopped, the reaction solution was cooled to room temperature, and then water (30 mL) was added for dilution. The solution was extracted with ethyl acetate (10 mL × 5), 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) = 20:80) to obtain compound 8-(pyrimidin-2-ylmethyl)-1,4-dioxa-8-azaspiro[4.5]decane (compound 4-3).

[0335] LC-MS, M / Z (ESI): 236.3 (M+H) + )

[0336] Step 2: Synthesis of 1-(pyrimidin-2-ylmethyl)piperidin-4-one (compound 4-4)

[0337] Compound 8-(pyrimidin-2-ylmethyl)-1,4-dioxa-8-azaspiro[4.5]decane (compound 4-3) (1.14 g, 4.85 mmol) was dissolved in a mixture of acetone (4 mL) and water (8 mL) at room temperature. Then, p-toluenesulfonic acid (146.37 mg, 0.85 mmol) was added, and the reaction mixture was stirred at 70 °C for 12 hours. After TLC monitoring showed complete reaction of the starting materials, the reaction mixture was cooled to room temperature, diluted with saturated sodium bicarbonate aqueous solution (10 mL), extracted with ethyl acetate (10 mL × 5), and the organic phase was collected and dried with anhydrous sodium sulfate. The mixture was filtered and concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate) to give compound 1-(pyrimidin-2-ylmethyl)piperidin-4-one (compound 4-4). LC-MS, M / Z (ESI): 192.4 (M+H + )

[0338] Step 3: Synthesis of 1-(pyrimidin-2-ylmethyl)-1,2,3,6-tetrahydropyridine-4-trifluoromethanesulfonate (compounds 4-5)

[0339] At room temperature, compound 1-(pyrimidin-2-ylmethyl)piperidin-4-one (compound 4-4) (200 mg, 1.05 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), and then stirred at -78 °C for 30 minutes. A tetrahydrofuran solution of bis(trimethylsilylamino)lithium (1.25 mL, 1.25 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at -78 °C for another 30 minutes. Then, N-phenylbis(trifluoromethanesulfonyl)imide (448.36 mg, 1.25 mmol) was added. After the addition was complete, the reaction mixture was stirred for another hour, and then the temperature was naturally raised to room temperature. The mixture was stirred at room temperature for another 12 hours. After TLC monitoring showed that the reaction of the raw materials was complete, stirring was stopped, and saturated ammonium chloride aqueous solution (10 mL) was added for dilution. The mixture was extracted with ethyl acetate (5 mL × 5), 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) = 60:40) to give compound 1-(pyrimidin-2-ylmethyl)-1,2,3,6-tetrahydropyridine-4-trifluoromethanesulfonate (compounds 4-5).

[0340] LC-MS, M / Z (ESI): 324.5 (M+H) + )

[0341] Step 4: Synthesis of 3-(2-chloro-3-(1-(pyrimidin-2-ylmethyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)piperidin-2,6-dione (compound 4)

[0342]

[0343] At room temperature, compound 1-(pyrimidin-2-ylmethyl)-1,2,3,6-tetrahydropyridine-4-trifluoromethanesulfonate (compounds 4-5) (50.00 mg, 0.15 mmol) and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)piperidine-2,6-dione (intermediate A) (162.22 mg, 0.46 mmol) were dissolved in a mixed solution of toluene (0.5 mL) and water (0.2 mL). Potassium carbonate (82.93 mg, 0.61 mmol) and tetra(triphenylphosphine)palladium (17.33 mg, 0.015 mmol) were added under nitrogen protection. The reaction mixture was stirred at 100 °C for 12 hours under nitrogen protection. After the reaction of the raw materials was complete as monitored by TLC, the reaction solution was cooled to room temperature, diluted with water (20 mL), extracted with ethyl acetate (10 mL × 5), the organic phase was collected and dried with anhydrous sodium sulfate, the organic phase was concentrated by vacuum distillation, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 30:70) to give compound 3-(2-chloro-3-(1-(pyrimidin-2-ylmethyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)piperidin-2,6-dione (compound 4).

[0344] LC-MS, M / Z (ESI): 397.5 (M+H) + )

[0345] Example 5: Preparation of Compound 5

[0346] 3-(2-chloro-3-(5-(3-oxomorpholino)thiophen-2-yl)phenyl)piperidin-2,6-dione (target compound 5)

[0347]

[0348] The synthetic route for compound 5 is shown below:

[0349]

[0350] Step 1: Synthesis of 4-(5-bromothiophen-2-yl)morpholin-3-one (compound 5-2)

[0351] Morpholin-3-one (2.0 g, 20.0 mmol) was placed in a reaction flask, and 2,5-dibromothiophene (14.6 g, 60.0 mmol), potassium carbonate (8.2 g, 60.0 mmol), N,N-dimethylethylenediamine (1.67 g, 20.0 mmol), cuprous iodide (3.8 g, 20.0 mmol), and acetonitrile (160 mL) were added sequentially. After the addition was complete, the reaction solution was microwaved at 100 °C for 3 hours. After the reaction was completed, the reaction solution was 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 crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 3:1) to give compound 4-(5-bromothiophene-2-yl)morpholin-3-one (compound 5-2).

[0352] LC-MS, M / Z (ESI): 261.9 [M+H] +

[0353] Step 2: Synthesis of 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)thiophene-2-yl)morpholin-3-one (compound 5-3)

[0354] 4-(5-bromothiophen-2-yl)morpholin-3-one (compound 5-2) (0.53 g, 2.03 mmol) was placed in a reaction flask, followed by the addition of pinacol diborate (1.3 g, 5.0 mmol), potassium acetate (0.75 g, 7.5 mmol), 1,1'-bis(di-phenylphosphino)ferrocene palladium chloride (0.18 g, 0.25 mmol), and 1,4-dioxane (20 mL). After the addition was complete, the reaction mixture was stirred at 100 °C for 4 hours under nitrogen protection. 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, and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 3:1) to give compound 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)thiophene-2-yl)morpholin-3-one (compound 5-3).

[0355] LC-MS, M / Z (ESI): 310.0 [M+H] +

[0356] Step 3: Synthesis of 3-(2-chloro-3-(5-(3-oxomorpholino)thiophene-2-yl)phenyl)piperidine-2,6-dione (compound 5)

[0357]

[0358] Intermediate 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)thiophen-2-yl)morpholin-3-one (compound 5-3) (180 mg, 0.58 mmol) was placed in a reaction flask, and 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (intermediate A4) (0.26 g, 0.87 mmol), potassium phosphate (0.32 g, 1.5 mmol), 1,1'-bis(di-phenylphosphino)ferrocene palladium chloride (73 mg, 0.1 mmol), and 1,4-dioxane (10 mL) were added sequentially. After the addition was complete, the reaction solution was stirred at 100 °C for 16 hours under nitrogen protection. 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 (dichloromethane:methanol (V / V) = 20:1) to give compound 3-(2-chloro-3-(5-(3-oxomorpholino)thiophene-2-yl)phenyl)piperidine-2,6-dione (compound 5).

[0359] LC-MS, M / Z (ESI): 405.1 [M+H] +

[0360] 1 H NMR(400MHz,DMSO-d6)δ10.93(s,1H),7.49(dd,1H),7.39(t,1H),7.34(dd,1H),7.21(d,1H),6.85(d,1H),4.40-4.32(m ,3H),4.10-4.05(m,2H),3.97-3.90(m,2H),2.85-2.75(m,1H),2.59-2.53(m,1H),2.39-2.31(m,1H),2.09-2.01(m,1H)

[0361] Example 6: Preparation of target compound 6

[0362] Synthesis of 3-(2-chloro-3-(5-(3-(2-hydroxypropyl-2-yl)-2-oxopyridin-1(2H)-yl)thiophen-2-yl)phenyl)piperidin-2,6-dione (compound 6)

[0363]

[0364] The synthetic route for compound 6 is shown below:

[0365]

[0366] Step 1: Synthesis of 1-(5-bromothiophen-2-yl)-3-(2-hydroxypropyl-2-yl)pyridin-2(1H)-one (compound 6-2)

[0367] 3-(2-hydroxypropyl-2-yl)pyridin-2(1H)-one (compound 6-1) (3.0 g, 19.6 mmol), 2,5-dibromothiophene (9.7 g, 40.0 mmol), and 100 mL of acetonitrile were placed in a reaction flask, followed by the addition of cuprous iodide (3.7 g, 19.6 mmol), potassium carbonate (8.3 g, 60 mmol), and N,N'-dimethylethylenediamine (2.0 g, 23.0 mmol). The mixture was deoxygenated under argon gas and reacted in a microwave oven at 90 °C for 45 minutes. After completion, the reaction solution was diluted with ethyl acetate (800 mL), washed with saturated sodium chloride aqueous solution (800 mL × 3), dried with anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 2:1) to give the intermediate 1-(5-bromothiophen-2-yl)-3-(2-hydroxypropyl-2-yl)pyridin-2(1H)-one (compound 6-2).

[0368] LC-MS, M / Z (ESI): 313.9 [M+H] + .

[0369] Step 2: Synthesis of 3-(2-hydroxypropyl-2-yl)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)thiophene-2-yl)pyridin-2(1H)-one (compound 6-3)

[0370] The intermediate 1-(5-bromothiophen-2-yl)-3-(2-hydroxypropyl-2-yl)pyridin-2(1H)-one (compound 6-2) (0.74 g, 2.36 mmol) was placed in a reaction flask, followed by the addition of pinacol diboronate (1.2 g, 4.73 mmol), potassium acetate (0.7 g, 7.08 mmol), 1,1'-bis(di-phenylphosphino)ferrocene palladium chloride (0.3 g, 0.47 mmol), and 1,4-dioxane (20 mL). After the addition was complete, the reaction mixture was stirred at 100 °C for 5 hours under nitrogen protection. The reaction solution was cooled to room temperature, then diluted with ethyl acetate (300 mL), washed with saturated sodium chloride aqueous solution (300 mL × 3), and 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 3-(2-hydroxypropyl-2-yl)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)thiophene-2-yl)pyridin-2(1H)-one (compound 6-3).

[0371] LC-MS, M / Z (ESI): 362.1 [M+H] + .

[0372] Step 3: Synthesis of 3-(2-chloro-3-(5-(3-(2-hydroxypropyl-2-yl)-2-oxopyridin-1(2H)-yl)thiophen-2-yl)phenyl)piperidin-2,6-dione (compound 6)

[0373]

[0374] Intermediate 3-(2-hydroxypropyl-2-yl)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)thiophene-2-yl)pyridin-2(1H)-one (compound 6-3) (190 mg, 0.53 mmol) was placed in a reaction flask, followed by the addition of 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (intermediate A4) (190 mg, 0.64 mmol), potassium phosphate (337 mg, 1.59 mmol), 1,1'-bis(di-phenylphosphino)ferrocene palladium chloride (43 mg, 0.06 mmol), and 1,4-dioxane (5 mL). After the addition was complete, the reaction mixture was stirred at 100 °C for 8 hours under nitrogen protection. The reaction solution was cooled to room temperature, then diluted with ethyl acetate (200 mL), washed with saturated sodium chloride aqueous solution (200 mL × 3), and the organic phase was then 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 3-(2-chloro-3-(5-(3-(2-hydroxypropyl-2-yl)-2-oxopyridin-1(2H)-yl)thiophen-2-yl)phenyl)piperidin-2,6-dione (compound 6).

[0375] LC-MS, M / Z (ESI): 457.1 [M+H] +

[0376] 1 H NMR(600MHz,DMSO-d6)δ10.92(s,1H),8.14(d,1H),7.72-7.65(m,1H),7.52(d,1H),7.44(d,1H),7.40-7.32(m,2H),7.28(d,1H), 6.49(t,1H),5.20(s,1H),4.34(dd,1H),2.83-2.68(m,1H),2.55-2.49(m,1H),2.36-2.27(m,1H),2.04-1.98(m,1H),1.46(s,6H).

[0377] The preparation methods for the following compounds are the same as those in Example 1:

[0378]

[0379]

[0380]

[0381]

[0382]

[0383]

[0384]

[0385]

[0386]

[0387]

[0388] Biological testing

[0389] Test Example 1: Compound-induced binding of VAV1 to CRBN

[0390] Experimental methods

[0391] 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 cells stably expressing VAV1-SmBiT and CRBN-LgBiT.

[0392] The cell line for LgBiT protein (HEK293-VAV1-SmBiT-CRBN-LgBiT) was cultured in DMEM medium containing 10% inactivated fetal bovine serum, 100 U / ml penicillin, and 100 μg / ml streptomycin at 37°C in a 5% CO2 incubator.

[0393] HEK293-VAV1-SmBiT-CRBN-LgBiT cells, after reaching 80-90% confluence, were passaged into individual flasks. Cells in the logarithmic growth phase were seeded into 96-well plates with 100 μL of culture medium (20,000-3,000 cells per well) and cultured overnight.

[0394] 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...

[0395] 0.031μM.

[0396] 3) Addition of the drug. Take 1 μL of the diluted compound and add it to 1 ml of complete culture medium. Mix well, then add 100 μL 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, and 0.061 nM.

[0397] 0.015nM and 0nM.

[0398] 4) Activity assay. The drug was tested 8 hours after treatment, following the instructions for the Promega NanoBiT Protein: Protein Interaction System.

[0399] 5) EC50 calculation. Fluorescence intensity (Fold change) = (Lumninence experiment - Lumininence blank) / (Lumninence DMSO -

[0400] Lumninence blank).

[0401] Experimental conclusion:

[0402] The compounds of this invention can induce direct binding between VAV1 and CRBN in a dose-dependent manner.

[0403] Test Example 2: Effect of Compounds on VAV1 Protein in HEK293 Cells

[0404] Experimental methods

[0405] 1) Cell line construction and culture. A Hibit tag was inserted into the C-terminus of VAV1, and the VAV1-Hibit tag was inserted into HEK293 cells using a lentiviral system.

[0406] The cell genome was analyzed, and a cell line stably expressing VAV1-Hibit protein was constructed. The culture medium was DMEM containing 10% inactivated fetal bovine serum, 100 U / ml penicillin, and 100 μg / ml streptomycin, and the cells were cultured in an incubator at 37°C and 5% CO2.

[0407] HEK293-VAV1-Hibit cells, after reaching 80-90% confluence, were passaged into individual flasks. Cells in the logarithmic growth phase were seeded into 96-well plates with 100 μL of culture medium (20,000-3,000 cells per well) and cultured overnight.

[0408] 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...

[0409] 0.031μM.

[0410] 3) Addition of the drug. Take 1 μL of the diluted compound and add it to 1 ml of complete culture medium. Mix well, then add 100 μL 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, and 0.061 nM.

[0411] 0.015nM and 0nM.

[0412] 6) Activity assay. The drug was tested 24 hours after treatment, using methods according to Promega's specifications. HiBiT Lytic DetectionSystem manual.

[0413] 7) DC50 calculation. Relative VAV1 (%) = (Lumninence experiment - Lumininence blank) / (Lumninence DMSO - ...

[0414] Lumninence (blank) was calculated using a fitting method based on log(inhibitor) vs. response -- Variable slope (four parameters). Experimental conclusions:

[0415] The compounds of this invention exhibit excellent degradation effects on VAV1 protein in a dose-dependent manner.

[0416] Test Example 3: Degradation of VAV1 in Jurkat Cells by Compounds

[0417] 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. When the cell density reached 1×10^6, the cells were passaged and subcultured into separate flasks. Tumor cells in the logarithmic growth phase were seeded at a density of 7×10 5 onto 12-well plates. The drug was diluted and added to the cell culture medium to final concentrations of 1000 nM, 250 nM, 62.5 nM, 15.6 nM, 3.9 nM, 0.98 nM, 0.24 nM, and 0 nM. The cells were treated with the drug for 24 hours. The cells treated with the drug for 24 hours were removed from the incubator, transferred to 1.5 mL EP tubes, and centrifuged to remove the supernatant. 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 1:1000 and Anti-GAPDH was diluted 1:5000, and incubated overnight at 4°C. The HRP secondary antibody was diluted 1:10000 and incubated at RT for 1 hour. Protein expression was detected by chemiluminescence, and gray value analysis was performed using ImageJ. The experimental results are shown in Table 1. The compounds of the present invention showed excellent degradation effects on the degradation of VAV1 protein in Jurkat cells and showed a dose-dependent manner.

[0418] Table 1 Degradation activity of compounds on VAV1 protein in Jurkat cells

[0419] Compound numbering DC50(nM) Dmax(%) Compound 1 A 98.1 Compound 6 A 97 Compound 65 A 97.7 Compound 70 A 96

[0420] *

[0421] DC50 ≤ 10 nM is designated as "A", 10 nM < DC50 ≤ 30 nM is designated as "B1", 30 nM < DC50 ≤ 100 nM is designated as "B2"; 100 nM < DC50 ≤ 1000 nM is designated as "C"; DC50 > 1000 nM is designated as "D".

[0422] Test Example 4: Inhibition of CD3 / CD28-induced Jurkat cell activation by compounds

[0423] 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. When the cell density reached 1×10^6, the cells were passaged and subcultured into separate flasks. Cells in the logarithmic growth phase were seeded at a density of 40000 onto 96-well plates and different concentrations of the compound were added. After treatment for 24 hours, 5 μg / ml CD3 antibody and 1 μg / ml CD28 antibody were added, and the cells were further cultured for 24 hours. The cell supernatant was taken for ELISA detection of the IL-2 content.

[0424] 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.

[0425] Test Example 5: Compound Inhibits CD3 / CD28-Induced Human T Cell Activation

[0426] 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. 6 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).

[0427] Experimental conclusion: In the CD3 / CD28-induced human T cell activation model, the compound of this invention significantly inhibited IL-2 production, and the inhibitory function was positively correlated with the dose.

[0428] Test Example 6: Mouse Pharmacokinetic Study

[0429] Pharmacokinetic studies were conducted in mice using male ICR mice (20-25g, fasted overnight). Three mice were administered 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.

[0430] Table 2. Mouse PK parameters of the compounds

[0431]

[0432] The results of the pharmacokinetic studies in mice showed that the compounds of this invention exhibited excellent pharmacokinetic properties and good drug-likeness.

[0433] Test Example 7: Rat Pharmacokinetic Test

[0434] 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.

[0435] 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.

[0436] Test Example 8: Human Liver Microsomal Stability Test

[0437] 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, purified water was added at a 1:1 ratio, and LC-MS / MS 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.

[0438] 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.

[0439] Test Example 9: Thermodynamic Solubility Test

[0440] 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 using 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. Thermodynamic solubility test results show that the compound of the present invention has good thermodynamic solubility and good drug-like properties.

[0441] Test Example 10: Inhibition of Cytochrome P450 by Compounds

[0442] 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.

[0443] 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.

[0444] 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.

[0445] 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.

[0446] Test Example 11: Balanced Dialysis Method for Testing Plasma Protein Binding

[0447] 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:

[0448] Unbound percentage (% Unbound) = (buffer fluid cavity peak area ratio / plasma cavity peak area ratio) × 100;

[0449] Bound rate (%Bound) = 100 - %Unbound;

[0450] Recovery (%Recovery) = (Buffer cavity peak area ratio + Plasma cavity peak area ratio) / Total sample peak area ratio × 100;

[0451] Remaining (% Remaining) = 5-hour peak area ratio / 0-hour peak area ratio × 100.

[0452] Experimental results show that the compounds of this invention have significant advantages in plasma protein binding rate.

[0453] Test Example 12: Efficacy evaluation of the compound in a mouse model of inflammatory bowel disease induced by adoptive T cell transfer

[0454] 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.

[0455] Experimental methods:

[0456] 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.

[0457] 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.

[0458] 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.

[0459] 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.

[0460] 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, Represented as in This indicates that ring C and ring D form a parallel ring or a spiral ring; The ring C is a 5-membered heteroaryl, a 4-10-membered heterocyclic alkenyl, a pyridazine, a pyrazine, or a triazine; Ring D does not exist, or it is C. 6-10 Aryl, 5-10-membered heteroaryl, 5-10-membered heterocyclic alkyl or 5-10-membered heterocyclic alkenyl; The phenyl group on the left is attached to a ring atom on ring C; When ring D is absent, L1 on the right side is connected to the ring atom on ring C; When ring D is present, L1 on the right can be connected to either the ring atom on ring C or the ring atom on ring D. 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; Each R 1a Each can be independently H, halogen, OH, NH2, CN, or C. 1-6 alkyl; R2, R3, and R4 are independently H, halogen, NH2, CN, and C, respectively. 1-6 Alkyl or halogenated C 1-6 alkyl; Each R5 and R 51 They are independently H, halogen, oxo (=O), thio (=S), CN, and C, respectively. 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 Alkyne group or 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. 5a replace; Each R 5a Each can be independently H, halogen, OH, NH2, CN, or C. 1-6 alkyl; L1 represents a single bond, -O-, -NH-, or -OC. 1-3 Alkyl-, -NH-C 1-3 Alkyl- or -C 1-3 alkyl-, wherein -NH-, -OC- 1-3 Alkyl-, -NH-C 1-3 Alkyl- and -C 1-3 Alkyl groups are each independently and optionally marked with 1, 2, 3, or 4 R groups. 1L replace; Each R 1L Each is independently H, halogen, and C. 1-3 Alkyl or C 3-6 cycloalkyl; R6 can be H, halogen, oxo (=O), thio (=S), OH, NH2, CN, or C. 1-6 Alkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclic alkyl, 4-10 membered heterocyclic alkenyl, C 6-10 Aryl or 5-10 heteroaryl, wherein C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclic alkyl, 4-10 membered heterocyclic alkenyl, C 6-10 Aryl and 5-10 heteroaryl groups are each independently and optionally bound by 1, 2, 3 or 4 R groups. 6a replace; Each R 6a They are, independently, H, halogen, oxo (=O), OH, NH2, CN, and C, respectively. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-8 membered heterocycloalkyl, -L2-C 3-6 Cycloalkyl or -L2-4-8-membered heterocycloalkyl, wherein C 1-6 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 4-8 membered heterocycloalkyl, -L2-C 3-6 Cycloalkyl or -L2-4-8-membered heterocycloalkyl groups are optionally surrounded by 1, 2, 3 or 4 R groups. 6a-1 replace; Each R 6a-1 They are, independently, H, halogen, OH, NH2, CN, and C. 1-3 Alkyl or -C 1-3 Alkyl-C 1-3 Alkoxy, the C 1-3 Alkyl or -C 1-3 Alkyl-C 1-3 The alkoxy groups are optionally substituted with 1, 2, 3 or 4 R groups, respectively; Each R is independently H, halogen, OH, NH2, or CN; Each L2 is independently -O-, -N(R) 2L -, -S-, -S(=O)-, -S(=O)2- or -C(=O)-; R 2L For H or C 1-3 alkyl; R7 is H, D, halogen, or C. 1-6 alkyl; n is 1, 2, or 3; m can be 1, 2, 3, or 4; 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, When ring D does not exist for One or more of the following conditions must be met: (1) Ring C is E1 is O, S or NH, and T1, T2, T3 and T4 are independently CH or N; (2) The ring C is thienyl, thiazolyl, isothiazolyl, pyrroleyl, pyrazolyl, imidazoleyl, furanyl, thiadiazolyl, oxazolyl, or oxadiazolyl. (3) for L1 can be connected to either "#" or "*"; (4) for L1 can be connected to either "#" or "*"; (5) It is a 4-6 membered heterocyclic alkenyl group; (6) It is dihydropyridinyl or tetrahydropyridinyl; (7) for L1 can be connected to either "#" or "*".

3. The compound, its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs according to claim 1, characterized in that, Selected from the following group: (1) for L1 can be connected to either "#" or "*"; or, (2) for L1 can be connected to either "#" or "*"; or, (3) for L1 can be connected to either "#" or "*"; or, Each R 51 They are independently H, halogen, oxo (=O), thio (=S), CN, and C, respectively. 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 Alkyne group or 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. 5a replace; Each R 5a Each can be independently H, halogen, OH, NH2, CN, or C. 1-6 alkyl.

4. The compound, its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs according to claim 1, characterized in that, for L1 can be connected to either "#" or "*"; Each R 51 They are independently H, halogen, oxo (=O), thio (=S), CN, and C, respectively. 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 Alkyne group or 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. 5a replace; Each R 5a Each can be independently H, halogen, OH, NH2, CN, or C. 1-6 alkyl.

5. The compound, its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs according to claim 1, characterized in that, When ring D exists for One or more of the following conditions must be met: (1a) L1 on the right can be connected to either the ring atom on ring C or the ring atom on ring D; (2a) Ring C is a 5-membered heteroaryl group; (3a) The ring C is pyrazolyl, imidazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, or oxadiazolyl; (4a) Ring D is phenyl, 5-6 heteroaryl, 5-8 heterocyclic alkyl or 5-8 heterocyclic alkenyl; (5a) Ring D is phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 6-membered heterocyclic alkyl or 6-membered heterocyclic alkenyl; (6a) Ring D is phenyl, pyrazolyl, imidazolyl, furanyl, thienyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl or pyridone; (7a) for E2 is NH, O, S, T5 and T6 are CH or N independently, E3 and E4 are NH, O, S or C (=O), X1, X2, X3 and X4 are CH or N independently, "#1" indicates that it is connected to the phenyl group on the left side of formula (I), and "#2" indicates that it is connected to L1 in formula (I). (8a) for E5 consists of NH, O, and S; T7, T8, T9, and T 10 T 11 and T 12 Each can be independently CH or N; (9a) for "#1" indicates that it is connected to the phenyl group on the left side of formula (I), and "#2" indicates that it is connected to L1 in formula (I).

6. The compound, its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs according to claim 1, characterized in that, for "#1" indicates that it is connected to the phenyl group on the left side of formula (I), and "#2" indicates that it is connected to L1 in formula (I); Each R5 and R 51 They are independently H, halogen, oxo (=O), thio (=S), CN, and C, respectively. 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 Alkyne group or 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. 5a replace; Each R 5a Each can be independently H, halogen, OH, NH2, CN, or C. 1-6 alkyl.

7. The compound, its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs according to claim 1, characterized in that, 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; Preferably, R1 is Cl, F, -CH3, -C≡C-CH3, Preferably, R1 is Cl, F, or -CH3.

8. The compound, its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs according to claim 1, characterized in that, Each R 1a They are H or F, respectively, independently.

9. The compound, its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs according to claim 1, characterized in that, R2, R3, and R4 are each independently H.

10. The compound, its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs according to claim 1, characterized in that, Each R5 and R 51 They can be H, Cl, F, oxo (=O) or CH3, respectively.

11. The compound, its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs according to claim 1, characterized in that, L1 is a single bond.

12. The compound, its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs according to claim 1, characterized in that, Each R 6a One or more of the following conditions must be met: 1b) Each R 6a They are independently H, halogen, oxo (=O), and C, respectively. 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4-8 membered heterocycloalkyl, -L2-C 3-6 Cycloalkyl, -L2-4-8-membered heterocycloalkyl, wherein C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 4-8 membered heterocycloalkyl, -L2-C 3-6 Cycloalkyl groups and -L2-4-8-membered heterocycloalkyl groups are optionally surrounded by 1, 2, 3 or 4 R groups, respectively. 6a-1 replace; 2b) Each R 6a-1 They can be independently H, F, Cl, OH, NH2, CN, CH3, -CH2-OH, -CH2F, -CHF2, -CF3, -CH2-CH2F or -CH2-OCF3; 3b) Each L2 is independently -O-, -N(R) 2L -, -S-, -S(=O)-, -S(=O)2- or -C(=O)-; 4b)R 2L It is H or CH3; 5b) Each L2 is independently -O-, -NH-, -S-, -S(=O)-, -S(=O)2- or -C(=O)-; 6b) Each L2 is independently -O-; 7b) Each R 6a They are independently H, F, oxo (=O), methyl, -CHF2, CF3, -OCH3, -OCHF2, -OCF3, respectively.

13. The compound, its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs according to claim 1, characterized in that, R6 is C 1-3 Alkyl, 4-8 membered heterocyclic alkyl, 4-8 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl, wherein C 1-3 Alkyl, 4-8 membered heterocyclic alkyl, 4-8 membered heterocyclic alkenyl, phenyl, and 5-6 membered heteroaryl groups are each independently and optionally surrounded by 1, 2, 3, or 4 R groups. 6a replace; Preferably, R6 is CH3, 14. The compound, its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs according to claim 1, characterized in that, Each R7 is independently H or D.

15. The compound, its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs according to claim 1, characterized in that, The compound has the following structure: (I-1), (I-2), (I-3), (I-4), or (I-5): in, E1 is O, S, or NH; E2 can be O, S, NH, or CH2; E3 is O, S, NH or CH2; T1, T2, T3, and T4 are independently CH or N; X1 and X2 are independently CH or N, and at least one of X1 and X2 is N; The ring C is a 5-membered heteroaryl, a 4-10-membered heterocyclic alkenyl, a pyridazine, a pyrazine, or a triazine; Ring D is C 6-10 Aryl, 5-10-membered heteroaryl, 5-10-membered heterocyclic alkyl or 5-10-membered heterocyclic alkenyl; the phenyl group on the left is attached to a ring atom on ring C, and the L1 group on the right can be attached to either a ring atom on ring C or a ring atom on ring D. R1, R2, R3, R4, R5, R 51 R6, R7, m, n and L1 are as described in claim 1.

16. The compound, its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs according to claim 1, characterized in that, The compound has the following structure: (Ⅰ-1A'), (Ⅰ-1A), (Ⅰ-1B), (Ⅰ-2A), (Ⅰ-3A), or (Ⅰ-4A): in, h is 1, 2, 3 or 4; E1 is O, S or NH; T1, T2, T3, and T4 are independently CH or N; X1 and X2 are independently CH or N, and at least one of X1 and X2 is N; The ring C is a 5-membered heteroaryl, a 4-10-membered heterocyclic alkenyl, a pyridazine, a pyrazine, or a triazine; Ring D is C 6-10 Aryl, 5-10-membered heteroaryl, 5-10-membered heterocyclic alkyl or 5-10-membered heterocyclic alkenyl; the phenyl group on the left is attached to a ring atom on ring C, and the L1 group on the right can be attached to either a ring atom on ring C or a ring atom on ring D. R1, R2, R3, R4, R5, R 51 R 6a R7, m, n and L1 as described in claim 1.

17. The compound, its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs according to claim 1, characterized in that, for The It is a 5-membered heteroaryl group; more preferably, It is thiophene-based; L1 is a single bond; Each R 51 Each is independently H, halogen, and C. 1-6 Alkyl groups; preferably, each R 51 Each can be H or F independently; R6 is a 4-10 membered heterocyclic alkyl group or a 4-10 membered heterocyclic alkenyl group, wherein the 4-10 membered heterocyclic alkyl group or the 4-10 membered heterocyclic alkenyl group is independently and optionally surrounded by 1, 2, 3 or 4 R6 groups. 6a Replacement; preferably, R6 is Each R 6a They are independently H, halogen, oxo (=O), and C, respectively. 1-6 Alkyl, C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group is optionally surrounded by 1, 2, 3 or 4 R groups. 6a-1 Replace; preferably, each R 6a They are independently H, F, oxo (=O), methyl, -CHF2, CF3, Each R 6a-1 They are H, halogen, OH, and NH2, respectively.

18. The compound, its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs according to claim 1, characterized in that, The compound has the following structure:

19. A pharmaceutical composition, characterized in that, The compound comprising a therapeutically effective dose of any one of claims 1-18, its tautomers, stereoisomers, pharmaceutically acceptable salts or prodrugs, and pharmaceutically acceptable excipients.

20. Use of the compound, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or pharmaceutical composition according to any one of claims 1-18 in the preparation of a medicament for the treatment or prevention of diseases associated with VAV1.

21. The use according to claim 20, characterized in that, The VAV1-related diseases include cancer and autoimmune diseases.

22. The use according to claim 20, 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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