Diketone biphenyl compound as VAV1 degradation agent, and use thereof

Abstract

Provided are a diketone biphenyl compound as a VAV1 degradation agent, and a use thereof. Specifically, provided are a compound represented by formula (I), and a tautomer, stereoisomer, pharmaceutically acceptable salt or prodrug thereof. The provided compound has good efficacy, and can be used for preparing a drug for treating or preventing VAV1-related diseases.

Description

Diketone biphenyl compounds as vav1 degraders and uses thereof

[0001] Priority information

[0002] The present disclosure claims priority to and the benefit of Chinese Patent Application No. 202411162484.X, filed August 22, 2024, Chinese Patent Application No. 202411547463.X, filed October 31, 2024, Chinese Patent Application No. 202510571153.X, filed April 30, 2025, and Chinese Patent Application No. 202511056842.3, filed July 29, 2025, all of which are incorporated herein by reference in their entirety. TECHNICAL FIELD

[0003] The present application provides diketone biphenyl compounds as VAV1 degraders and uses thereof. Specifically provided are compounds represented by formula (I), tautomers, stereoisomers, pharmaceutically acceptable salts or prodrugs thereof. The compounds provided by the present application have good drug efficacy and can be prepared for drugs for treating or preventing VAV1 related diseases. BACKGROUND

[0004] Drug-induced targeted protein degradation (TPD) technology is an emerging drug treatment strategy. This technology takes advantage of two major protein degradation systems (ubiquitin proteasome system (UPS) and lysosomal degradation system) naturally present in human cells to destroy and degrade key proteins related to diseases, thereby achieving the effect of treating diseases. Currently, molecular glue, proteolysis targeting chimera, lysosome targeting chimera, autophagy targeting chimera, autophagy linking compounds and other technologies have been developed. Among them, multiple drugs based on the principle of molecular glue have been approved for marketing, achieving good efficacy. The success of molecular glue in clinical practice and its future potential have prompted pharmaceutical companies to pay more and more attention to the development of related drugs.

[0005] VAV family proteins, including VAV1, VAV2, and VAV3, are Rho family GTPase guanine nucleotide exchange factors (GEFs). VAV1 is a 95 kDa protein that is a positive regulator of T cell receptor and B cell receptor signaling. VAV1 is mainly 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 more broadly expressed. VAV1 is rapidly phosphorylated upon a variety of stimuli, such as T cell receptor (TCR), B cell receptor (BCR), and various cytokine receptor stimulation. In hematopoietic-derived cells, such as T cells, B cells, natural killer cells, and osteoclasts, VAV1 modulates a variety of cellular functions and signaling pathways by activating certain GTPases. VAV1 -mediated functions include gene transcription, development and activation of immune cells, such as T cells and B cells.

[0006] Genome-wide CRISPR-Cas9 screening confirmed that VAV1 is an important positive regulator of T cell activation / function, and VAV1 promotes proliferation of cells sensitive to TCR signaling, such as human Jurkat T cells and primary human CD4+ and CD8+ T cells. In addition, VAV1 knockout mouse data suggest that VAV1 plays a critical role in T / B lymphocyte function and antigen receptor signaling, especially in T cells. More importantly, VAV1 -deficient mouse thymocytes and splenic T cells show multiple defects in TCR-mediated signaling, such as impaired calcium (Ca 2+ ) mobilization and transcription factor activation. Whereas T cells with loss of VAV1 GEF activity (VAV1 L334A / K335A) exhibit normal TCR-mediated Ca 2+ flux and nuclear factor of activated T cells (NFAT) activation. This indicates that both GEF activity and scaffolding function of VAV1 play important roles in the TCR signaling pathway.

[0007] Genetic analysis found that rodents carrying VAV1 R63W variation showed lower susceptibility in experimental autoimmune encephalomyelitis (EAE) and palmitoyl-induced arthritis compared to wild-type (WT). In the mouse model of antigen (methylated bovine serum albumin)-induced arthritis (AIA), VAV1 knockout mice showed less disease symptoms (such as inflammation, synovial thickening, and cartilage degradation), reduced T cell proliferation, and reduced joint infiltration of CD4+ T cells, neutrophils, and macrophages than wild-type (WT) mice. This again indicates that VAV1 plays an important role in T cell differentiation and function. Therefore, VAV1 can be a therapeutic target for immune-mediated diseases. SUMMARY

[0008] In a first aspect, the present application provides a compound represented by formula (I), a tautomer, a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof,

[0009] wherein, is represented by wherein represents that ring C and ring D form a fused ring or a spiro ring;

[0010] ring C is a 5-membered heteroaryl, a 4-10-membered heterocyclenyl, a pyridazine, a pyrazine or a triazine;

[0011] ring D is absent or is a C 6-10 aryl, 5-10-membered heteroaryl, 5-10-membered heterocycloalkyl or 5-10-membered heterocyclenyl;

[0012] the left-hand side phenyl is connected to a ring atom on ring C;

[0013] when ring D is absent, the right-hand side L1 is connected to a ring atom on ring C;

[0014] when ring D is present, the right-hand side L1 can be connected to either a ring atom on ring C or a ring atom on ring D;

[0015] R1 is H, halogen, CN, C 1-6 alkyl, -OC 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkynyl, 4-10-membered heterocycloalkyl, said C 1-6 alkyl, -OC 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkynyl and 4-10-membered heterocycloalkyl are each independently optionally substituted with 1, 2, 3 or 4 R 1a groups;

[0016] each R 1a is independently H, halogen, OH, NH2, CN or C 1-6 alkyl;

[0017] R2, R3 and R4 are each independently H, halogen, NH2, CN, C 1-6 alkyl or haloC 1-6 alkyl;

[0018] each R5 and R 51 is independently H, halogen, oxo (=O), thioxo (=S), CN, C 1-6 alkyl, -OC 1-6 alkyl, C 3-6 cycloalkyl, C 2-6alkyl, -OC 1-6 alkyl, -OC 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkynyl and 4-10 membered heterocycloalkyl are each independently optionally substituted with 1, 2, 3, or 4 R 5a substituents;

[0019] each R 5a is independently H, halogen, OH, NH2, CN, or C 1-6 alkyl;

[0020] L1is a single bond, -O-, -NH-, -O-C 1-3 alkyl-, -NH-C 1-3 alkyl-, or -C 1-3 alkyl-, wherein said -NH-, -O-C 1-3 alkyl-, -NH-C 1-3 alkyl-, and -C 1-3 alkyl- are each independently optionally substituted with 1, 2, 3, or 4 R 1L substituents;

[0021] each R 1L is independently H, halogen, C 1-3 alkyl, or C 3-6 cycloalkyl;

[0022] R6is H, halogen, oxo (=0), thioxo (=S), OH, NH2, CN, C 1-6 alkyl, C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C 6-10 aryl, or 5-10 membered heteroaryl, said C 1-6 alkyl, C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C 6-10 aryl, and 5-10 membered heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 R 6a substituents;

[0023] each R 6a is independently H, halogen, oxo (=0), OH, NH2, CN, C 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, said C 1-6 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 4-8 membered heterocycloalkyl, -L2-C 3-6cycloalkyl or -L2-4-8 membered heterocycloalkyl, respectively, is optionally substituted with 1, 2, 3, or 4 R 6a-1 substituted;

[0024] each R 6a-1 is independently H, halogen, OH, NH2, CN, C 1-3 alkyl or -C 1-3 alkyl-C 1-3 alkoxy, said C 1-3 alkyl or -C 1-3 alkyl-C 1-3 alkoxy is optionally substituted with 1, 2, 3, or 4 R;

[0025] each R is independently H, halogen, OH, NH2, or CN;

[0026] each L2is independently -O-, -N(R 2L )-, -S-, -S(=O)-, -S(=O)2-, or -C(=O)-;

[0027] R 2L is H or C 1-3 alkyl;

[0028] R7is H, D, halogen, or C 1-6 alkyl;

[0029] n is 1, 2, or 3;

[0030] m is 1, 2, 3, or 4;

[0031] The heteroatom groups in the "heterocycloalkyl", "heterocycloalkenyl", and "heteroaryl" groups comprise N, NH, O, S, S(=O), S(=O)2, or S(=O)(=NH), the number of which is 1, 2, 3, or 4; when the number of the heteroatom groups is plural, the heteroatom groups are the same or different.

[0032] In an optional embodiment of the present application, the compound represented by formula (I), a tautomer, a stereoisomer, a pharmaceutically acceptable salt, or a prodrug thereof,

[0033] wherein,

[0034] Ring C is 5-membered heteroaryl, 4-10 membered heterocycloalkenyl, pyridazine, pyrazine, or triazine;

[0035] Ring D is absent, or C 6-10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocycloalkyl, or 5-10 membered heterocycloalkenyl;

[0036] the left-hand phenyl is connected to a ring atom on ring C;

[0037] when ring D is absent, L1on the right is attached to a ring atom on ring C;

[0038] when ring D is present, L1on the right can be attached to either a ring atom on ring C or a ring atom on ring D;

[0039] R1is H, halogen, CN, C 1-6 alkyl, -OC 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkynyl, 4-10 membered heterocycloalkyl, said C 1-6 alkyl, -OC 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkynyl and 4-10 membered heterocycloalkyl are each independently optionally substituted with 1, 2, 3, or 4 R 1a substituents;

[0040] each R 1a is independently H, halogen, OH, NH2, CN, or C 1-6 alkyl;

[0041] R2, R3, and R4are each independently H, halogen, NH2, CN, C 1-6 alkyl, or haloC 1-6 alkyl;

[0042] each R5and R 51 is independently H, halogen, oxo (=0), thioxo (=S), CN, C 1-6 alkyl, -OC 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkynyl, or 4-10 membered heterocycloalkyl, said C 1-6 alkyl, -OC 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkynyl and 4-10 membered heterocycloalkyl are each independently optionally substituted with 1, 2, 3, or 4 R 5a substituents;

[0043] each R 5a is independently H, halogen, OH, NH2, CN, or C 1-6 alkyl;

[0044] L1is a single bond, -0-, -NH-, -0-C 1-3 alkyl-, -NH-C 1-3 alkyl-, or -C 1-3 alkyl-, wherein said -NH-, -0-C 1-3 alkyl-, -NH-C 1-3alkyl- and -C 1-3 alkyl- is each independently optionally substituted with 1, 2, 3, or 4 R 1L substituted;

[0045] each R 1L is each independently H, halogen, C 1-3 alkyl or C 3-6 cycloalkyl;

[0046] R6is H, halogen, oxo (=0), thioxo (=S), OH, NH2, CN, C 1-6 alkyl, C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C 6-10 aryl or 5-10 membered heteroaryl, said C 1-6 alkyl, C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C 6-10 aryl and 5-10 membered heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 R 6a substituted;

[0047] each R 6a is each independently H, halogen, oxo (=0), OH, NH2, CN, 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, said 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 are each optionally substituted with 1, 2, 3, or 4 R 6a-1 substituted;

[0048] each R 6a-1 is each independently H, halogen, OH, NH2, CN, C 1-3 alkyl or C 1-3 alkyl-C 1-3 alkoxy, said C 1-3 alkyl or C 1-3 alkyl-C 1-3 alkoxy are each optionally substituted with 1, 2, 3, or 4 R;

[0049] each R is each independently H, halogen, OH, NH2, or CN;

[0050] each L2is each independently -0-, -N(R 2L)-, -S-, -S(=O)-, -S(=O)2-, or -C(=O)-;

[0051] R 2L is H or C 1-3 alkyl;

[0052] R7is H, D, halogen or C 1-6 alkyl;

[0053] n is 1, 2 or 3;

[0054] m is 1, 2, 3 or 4;

[0055] the heteroatom groups in the "heterocycloalkyl", "heterocycloalkenyl" and "heteroaryl" groups comprise N, NH, O, S, S(=O), S(=O)2or S(=O)(=NH),

[0056] the number of the heteroatom groups is 1, 2, 3 or 4; when the number of the heteroatom groups is plural, the heteroatom groups are the same or different.

[0057] In an optional embodiment of the present application, the compound represented by formula (I), the tautomer, stereoisomer, pharmaceutically acceptable salt or prodrug thereof,

[0058] wherein,

[0059] ring C is a 5-membered heteroaryl;

[0060] ring D is C 6-10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocycloalkyl or 5-10 membered heterocycloalkenyl;

[0061] the left-hand side phenyl is connected to a ring atom on ring C;

[0062] when ring D is absent, the right-hand side L1is connected to a ring atom on ring C;

[0063] when ring D is present, the right-hand side L1may be connected to either a ring atom on ring C or a ring atom on ring D;

[0064] R1is H, halogen, CN, C 1-6 alkyl, -OC 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkynyl, 4-10 membered heterocycloalkyl, said C 1-6 alkyl, -OC 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkynyl and 4-10 membered heterocycloalkyl are each independently optionally substituted with 1, 2, 3 or 4 R 1a substituents;

[0065] each R 1a is independently H, halogen, OH, NH2, CN, or C 1-6 alkyl;

[0066] R2, R3, and R4are each independently H, halogen, NH2, CN, C 1-6 alkyl or haloC 1-6 alkyl;

[0067] each R5and R 51 is independently H, halogen, oxo (=0), CN, C 1-6 alkyl, -OC 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkynyl or 4-10 membered heterocycloalkyl, said C 1-6 alkyl, -OC 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkynyl and 4-10 membered heterocycloalkyl are each independently optionally substituted with 1, 2, 3, or 4 R 5a substituents;

[0068] each R 5a is independently H, halogen, OH, NH2, CN, or C 1-6 alkyl;

[0069] L1is a single bond, -0-, -NH-, -0-C 1-3 alkyl-, -NH-C 1-3 alkyl- or -C 1-3 alkyl-, wherein said -NH-, -0-C 1-3 alkyl-, -NH-C 1-3 alkyl- and -C 1-3 alkyl- are each independently optionally substituted with 1, 2, 3, or 4 R 1L substituents;

[0070] each R 1L is independently H, halogen, C 1-3 alkyl or C 3-6 cycloalkyl;

[0071] R6is H, halogen, oxo (=0), OH, NH2, CN, C 1-6 alkyl, C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, 6-10 membered aryl, or 5-10 membered heteroaryl, said C 1-6 alkyl, C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C 6-10R1and R2are each independently H, halogen, oxo (=0), OH, NH2, CN, C 6a substituted;

[0072] each R 6a is each independently H, halogen, oxo (=0), OH, NH2, CN, C 1-6 alkyl or haloC 1-6 alkyl;

[0073] R7is H, D, halogen or C 1-6 alkyl;

[0074] n is 1, 2 or 3;

[0075] m is 1, 2, 3 or 4;

[0076] The heteroatom groups in the "heterocycloalkyl", "heterocycloalkenyl" and "heteroaryl" include N, NH, O, S, S(=0), S(=0)2or S(=0)(=NH), the number of which is 1, 2, 3 or 4; when the number of the heteroatom groups is plural, the heteroatom groups are the same or different.

[0077] In an optional embodiment of the present application, when the above-mentioned ring D is absent,

[0078] In an optional embodiment of the present application, the above-mentioned ring C is E1is O, S or NH, T1, T2, T3and T4are each independently CH or N.

[0079] In an optional embodiment of the present application, the above-mentioned ring C is thienyl, thiazolyl, isothiazolyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thiadiazolyl, oxazolyl, oxadiazolyl.

[0080] In an optional embodiment of the present application, the above-mentioned ring C is thienyl, thiazolyl, isothiazolyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl.

[0081] In an optional embodiment of the present application, the above-mentioned L1may be connected to "#" or "*".

[0082] In an optional embodiment of the present application, the above-mentioned L1in the above-mentioned formula (I) can be connected to "#" or "*".

[0083] ​​​In an optional embodiment of the application, the above In an optional embodiment of the application, the above L1may be attached to "#" or "*".

[0084] In an optional embodiment of the application, the above is 4-6 membered heterocycloalkenyl.

[0085] In an optional embodiment of the application, the above is dihydropyridinyl or tetrahydropyridinyl.

[0086] In an optional embodiment of the application, the above In an optional embodiment of the application, the above L1may be attached to "#" or "*".

[0087] In an optional embodiment of the application, the above In an optional embodiment of the application, the above L1may be attached to "#" or "*".

[0088] In an optional embodiment of the application, the above is selected from the group consisting of:

[0089] (1) In an optional embodiment of the application, the above

[0090] L1may be attached to "#" or "*"; or,

[0091] (2) In an optional embodiment of the application, the above L1may be attached to "#" or "*";

[0092] (3) In an optional embodiment of the application, the above L1may be attached to "#" or "*";

[0093] each R 51 are each independently H, halogen, oxo (=0), thioxo (=S), CN, C 1-6 alkyl, -OC 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkynyl or 4-10 membered heterocycloalkyl, said C 1-6 alkyl, -OC 1-6 alkyl, C 3-6 cycloalkyl, C 2-6The 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;

[0094] Each R 5a Each can be independently H, halogen, OH, NH2, CN, or C. 1-6 alkyl.

[0095] In one optional embodiment of the present invention for L1 can be connected to either "#" or "*";

[0096] 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;

[0097] Each R 5a Each can be independently H, halogen, OH, NH2, CN, or C. 1-6 alkyl.

[0098] In an optional embodiment of the present invention, when the aforementioned ring D exists, for

[0099] In the above formula (Ⅰ), L1 can be connected to either the ring atom on ring C or the ring atom on ring D.

[0100] In an optional embodiment of the present invention, the above-mentioned cyclic C is a 5-membered heteroaryl group.

[0101] In an optional embodiment of the present invention, the ring C is pyrazolyl, imidazolyl, furanyl, thiophene, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, or oxadiazolyl.

[0102] 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.

[0103] In an optional embodiment of the present application, ring D is phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 6-membered heterocycloalkyl, or 6-membered heterocycloalkenyl.

[0104] In an optional embodiment of the present application, ring D is phenyl, pyrazolyl, imidazolyl, furanyl, thienyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, or pyridonyl.

[0105] In an optional embodiment of the present application, ring D is phenyl, pyrazolyl, imidazolyl, furanyl, thienyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, or pyridonyl. E2 is NH, O, or S, T5 and T6 are each independently CH or N, E3 and E4 are NH, O, S, or C(=O), X1, X2, X3, and X4 are each independently CH or N, "#1" indicates the connection to the left phenyl group in formula (I), and "#2" indicates the connection to L1 in formula (I).

[0106] In an optional embodiment of the present application, ring D is phenyl, pyrazolyl, imidazolyl, furanyl, thienyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, or pyridonyl. E5 is NH, O, or S, T7, T8, T9, T 10 , T 11 , and T 12 are each independently CH or N.

[0107] In an optional embodiment of the present application, ring D is phenyl, pyrazolyl, imidazolyl, furanyl, thienyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, or pyridonyl. "#1" indicates the connection to the left phenyl group in formula (I), and "#2" indicates the connection to L1 in formula (I).

[0108] In an optional embodiment of the present application, ring D is phenyl, pyrazolyl, imidazolyl, furanyl, thienyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, or pyridonyl. "#1" indicates the connection to the left phenyl group in formula (I), and "#2" indicates the connection to L1 in formula (I).

[0109] each R5 and R 51 are each independently H, halogen, oxo (=O), thioxo (=S), CN, C 1-6 alkyl, -OC 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkynyl, or 4-10 membered heterocycloalkyl, said C 1-6 alkyl, -OC 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkynyl, and 4-10 membered heterocycloalkyl are each independently optionally substituted with 1, 2, 3, or 4 R 5a ;​​​

[0110] each R 5a is independently H, halogen, OH, NH2, CN, or C 1-6 alkyl.

[0111] In an optional embodiment of the present application, each R1is H, F, Cl, CN, C 1-3 alkyl, C 2-4 alkenyl, C 3-4 cycloalkyl, or 4-6 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 R 1-3 alkyl, C 2-4 alkenyl, C 3-4 cycloalkyl, and 4-6 membered heterocycloalkyl, each of which is independently optionally substituted with 1, 2, 3, or 4 R 1a substituents.

[0112] In an optional embodiment of the present application, each R1is Cl, F, -CH3, -C≡C-CH3,

[0113] In an optional embodiment of the present application, each R1is Cl, F, or -CH3.

[0114] In an optional embodiment of the present application, each R 1a is independently H or F.

[0115] In an optional embodiment of the present application, each of R2, R3, and R4is independently H.

[0116] In an optional embodiment of the present application, each of R5and R 51 is independently H, Cl, F, oxo (=0), or CH3.

[0117] In an optional embodiment of the present application, L1is a single bond.

[0118] In an optional embodiment of the present application, R6is C 1-3 alkyl, 4-8 membered heterocycloalkyl, 4-8 membered heterocycloalkenyl, phenyl, or 5-6 membered heteroaryl, each of which is independently optionally substituted with 1, 2, 3, or 4 R 1-3 alkyl, 4-8 membered heterocycloalkyl, 4-8 membered heterocycloalkenyl, phenyl, and 5-6 membered heteroaryl, each of which is independently optionally substituted with 1, 2, 3, or 4 R 6a substituents.

[0119] In an optional embodiment of the present application, R6is C 1-3 alkyl, 4-6 membered heterocycloalkenyl, or 5-6 membered heteroaryl, each of which is independently optionally substituted with 1, 2, 3, or 4 R 1-3 alkyl, 4-6 membered heterocycloalkenyl, or 5-6 membered heteroaryl, each of which is independently optionally substituted with 1, 2, 3, or 4 R 6a substituents.

[0120] In an optional embodiment of the present application, each R 6a is independently H, halogen, oxo (=0), C 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, said C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 4-8 membered heterocycloalkyl, -L2-C 3-6 cycloalkyl, -L2-4-8 membered heterocycloalkyl, is each optionally substituted with 1, 2, 3 or 4 R 6a-1 substituents.

[0121] In an optional embodiment of the present application, each R 6a is independently H, halogen, oxo (=0), C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 4-8 membered heterocycloalkyl, -L2-C 3-6 cycloalkyl, -L2-4-8 membered heterocycloalkyl, said C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 4-8 membered heterocycloalkyl, -L2-C 3-6 cycloalkyl, -L2-4-8 membered heterocycloalkyl, is each optionally substituted with 1, 2, 3 or 4 R 6a-1 substituents.

[0122] In an optional embodiment of the present application, each R 6a-1 is independently H, F, CI, OH, NH2, CN, CH3, -CH2-OH, -CH2F, -CHF2, -CF3, -CH2-CH2F or -CH2-OCF3.

[0123] In an optional embodiment of the present application, each L2is independently -0-, -N(R 2L )-, -S-, -S(=0)-, -S(=0)2- or -C(=0)-.

[0124] In an optional embodiment of the present application, each R 2L is H or CH3.

[0125] In an optional embodiment of the present application, each L2is independently -0-, -NH-, -S-, -S(=0)-, -S(=0)2- or -C(=0)-.

[0126] In an optional embodiment of the present application, each L2is independently -O-.

[0127] In an optional embodiment of the present application, each R 6a is independently H, F, oxo (=0), methyl, -CHF2, -CF3, -OCH3, -OCHF2, -OCF3,

[0128] In an optional embodiment of the present application, each R 6a is independently H, F, oxo (=0), methyl, -OCHF2, -OCF3,

[0129] In an optional embodiment of the present application, each R 6a is independently H, oxo or CH3.

[0130] In an optional embodiment of the present application, R6is C 1-3 alkyl, 4-6 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl, said C 1-3 alkyl, 4-6 membered heterocycloalkenyl, phenyl and 5-6 membered heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 R 6a substituents.

[0131] In an optional embodiment of the present application, R6is CH3,

[0132] In an optional embodiment of the present application, R6is CH3, In an optional embodiment of the present application, R6is CH3,

[0133] In an optional embodiment of the present application, R6is CH3,

[0134] In an optional embodiment of the present application, each R7is independently H or D.

[0135] In an optional embodiment of the present application, the compound, tautomer, stereoisomer, pharmaceutically acceptable salt or prodrug thereof is characterized in that the compound has the following formula (I’):

[0136] wherein,

[0137] The ring C is a 5-membered heteroaryl, a 4-10-membered heterocyclic alkenyl, a pyridazine, a pyrazine, or a triazine;

[0138] R1, R2, R3, R4, R 51 R6, R7, n and L1 are as defined in this invention.

[0139] 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):

[0140] in,

[0141] E1 is O, S, or NH;

[0142] E2 can be O, S, NH, or CH2;

[0143] E3 is O, S, NH or CH2;

[0144] 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.

[0145] 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):

[0146] in,

[0147] The ring C is a 5-membered heteroaryl, a 4-10-membered heterocyclic alkenyl, a pyridazine, a pyrazine, or a triazine;

[0148] 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.

[0149] R1, R2, R3, R4, R5, R 51 R6, R7, m, n and L1 are as defined in this invention.

[0150] In an optional embodiment of the present application, the above-mentioned compound, its tautomer, stereoisomer, pharmaceutically acceptable salt or prodrug is characterized in that the compound has the following formula (I-1A'), (I-1A), (I-1B), (I-2A), (I-3A) or (I-4A):

[0151] wherein,

[0152] h is 1, 2, 3 or 4;

[0153] E1is O, S or NH, T1, T2, T3and T4are independently CH or N;

[0154] X1and X2are independently CH or N, and at least one of X1and X2is N;

[0155] Ring C is 5-membered heteroaryl, 4-10 membered heterocyclenyl, pyridazine, pyrazine or triazine;

[0156] Ring D is C 6-10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocycloalkyl or 5-10 membered heterocyclenyl; the left-hand phenyl is connected to a ring atom on Ring C, and the right-hand L1may be connected to either a ring atom on Ring C or a ring atom on Ring D;

[0157] R1, R2, R3, R4, R5, R 51 , R 6a , R7, m, n and L1are as defined in the present application.

[0158] In an optional embodiment of the present application, the above-mentioned compound, its tautomer, stereoisomer, pharmaceutically acceptable salt or prodrug is characterized in that the compound has the following formula (I-1A'), (I-1A), (I-1B), (I-1A'), (I-1A), (I-1B), (I-2A), (I-3A) or (I-4A): is 5-membered heteroaryl.

[0159] In an optional embodiment of the present application, the above-mentioned compound, its tautomer, stereoisomer, pharmaceutically acceptable salt or prodrug is characterized in that the compound has the following formula (I-1A'), (I-1A), (I-1B), (I-1A'), (I-1A), (I-1B), (I-2A), (I-3A) or (I-4A):

[0160] In an optional embodiment of the present application, each R 51 is independently H, halogen, C 1-6 alkyl.

[0161] In an optional embodiment of the present application, each R 51 is independently H or F.

[0162] In an optional embodiment of the present application, L1is a single bond.

[0163] ​​​In an optional embodiment of the present application, each R6is independently H, halogen, OH, NH2. 6a substituted.

[0164] In an optional embodiment of the present application, each R6is

[0165] In an optional embodiment of the present application, each R 6a is independently H, halogen, oxo (=0), C 1-6 alkyl, C 1-6 alkoxy, said C 1-6 alkyl and C 1-6 alkoxy are each optionally substituted with 1, 2, 3, or 4 R 6a-1 substituted.

[0166] In an optional embodiment of the present application, each R 6a is independently H, F, oxo (=0), methyl, -CHF2, CF3,

[0167] In an optional embodiment of the present application, each R 6a-1 is independently H, halogen, OH, NH2.

[0168] In an optional embodiment of the present application, the compound has the following structure:

[0169] In a second aspect of the present application, there is provided a pharmaceutical composition comprising: a compound, a tautomer, a stereoisomer, a pharmaceutically acceptable salt, or a prodrug thereof as described in the first aspect of the present application; and a pharmaceutically acceptable excipient.

[0170] In a third aspect of the present application, there is provided use of a compound, a tautomer, a stereoisomer, a pharmaceutically acceptable salt, or a prodrug thereof as described in the first aspect of the present application, and a pharmaceutical composition as described in the second aspect of the present application, in the manufacture of a medicament for treating or preventing a disease associated with VAV1.

[0171] In an optional embodiment of the present application, the medicament is used for treating or preventing cancer and autoimmune diseases.

[0172] In an optional embodiment of the present application, the above-mentioned medicament is used for treating or preventing a VAV1 -related disease, including 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.

[0173] In an optional embodiment of the present application, the above-mentioned VAV1 -related disease includes cancer and autoimmune disease.

[0174] In an optional embodiment of the present application, the above-mentioned VAV1 -related disease includes systemic lupus erythematosus, myasthenia gravis, periodontitis, type I diabetes, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, inflammatory bowel disease, autoimmune hepatitis, or psoriasis.

[0175] In an optional embodiment of the present application, the above-mentioned VAV1 -related disease includes but not limited to systemic lupus erythematosus, myasthenia gravis, periodontitis, type I diabetes, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, inflammatory bowel disease, autoimmune hepatitis, psoriasis, and the like.

[0176] Additional aspects and advantages of the present application will be in part apparent and in part pointed out hereinafter.

[0177] Terms and Definitions

[0178] Unless otherwise defined, all terms used in connection with the present application, including the present specification and claims, are intended to have the meaning commonly used by those skilled in the art.

[0179] As will be understood by those skilled in the art, in the structural formulae of the present application, is used to depict a chemical bond, which is the point of attachment of a moiety or substituent to a core structure or backbone structure.

[0180] Unless otherwise specified, the term "pharmaceutically acceptable" in reference to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio.

[0181] Unless otherwise specified, the term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable, non-toxic acid or base salt, including salts of inorganic acids and bases, salts of organic acids and bases.

[0182] In addition to pharmaceutically acceptable salts, other salts are also contemplated. They can serve as intermediates in the purification of the compounds or in the preparation of other pharmaceutically acceptable salts, or they can be useful in the identification, characterization, or purification of the compounds of the present application.

[0183] The term "pharmaceutical composition" means, unless otherwise noted, a mixture of one or more of the compounds described herein, or a physiologically / pharmaceutically acceptable salt or prodrug thereof, with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compound to the organism.

[0184] The term "excipient" refers to a pharmaceutically acceptable inert ingredient, unless otherwise noted. Examples of classes of excipients include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, and diluents. Excipients can enhance the handling properties of a pharmaceutical formulation, i.e., make the formulation more amenable to direct compression by increasing flow and / or cohesion.

[0185] The term "prodrug" means, unless otherwise noted, a compound that can be converted under physiological conditions or by solvolysis to a biologically or pharmaceutically active compound of this application. A prodrug is prepared by modifying functional groups in the compound in a manner that the modifications can be reversed in vivo to provide the parent compound. Prodrugs include compounds wherein a hydroxy or amino group is bonded to any group that, when administered to a mammalian subject, is cleaved to form a free hydroxyl or amino group.

[0186] The term "stereoisomer" means, unless otherwise noted, isomers that have the same molecular formula but different structures resulting from the spatial arrangement of atoms. Stereoisomers include enantiomeric or optical isomers, atropisomers, and conformational isomers.

[0187] Depending on the choice of starting materials and methods, the compounds of the application can be present in the form of one or more of possible isomers, such as geometric or stereoisomers, for example as pure optical isomers, or as mixtures of different isomers, such as racemates, diastereomeric mixtures, and enantiomeric mixtures. When describing compounds having optical activity, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to a single reference plane. The prefixes D and L or (+) and (-) are used to designate the plane polarized light that the compound will cause to rotate. (-) or L means that the compound is levorotatory. A compound of the prefix (+) or D is dextrorotatory. Except for these stereoisomers, these compounds are identical and indistinguishable from one another. Specific stereoisomers are also referred to as enantiomers, and mixtures of such isomers are often referred to as enantiomeric mixtures. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, and such mixtures can occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. Many geometric isomers of olefins, C=N double bonds, and the like can also exist; all such stable isomers are contemplated in the present application. When the compounds described herein contain olefinic double bonds, unless otherwise specified, both E and Z geometric isomers are encompassed. If the compounds contain a di-substituted cycloalkyl ring, the substituents can be in the cis- or trans- (or, alternatively, the Z- or E-) configuration. When bonds to a chiral carbon are depicted as straight lines in the formulas of the application, it is understood that both the (R) and (S) configurations, and the enantiomerically pure compounds and mixtures thereof, are included within the scope of the general formula. The graphic representation of racemates or enantiomerically pure compounds herein is from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise indicated, a wedge and hashed bond represents the absolute configuration at a single stereogenic center.

[0188] When bonds to a chiral carbon are depicted as straight lines in the formulas of the application, it is understood that both the (R) and (S) configurations, and the enantiomerically pure compounds and mixtures thereof, are included within the scope of the general formula. The graphic representation of racemates or enantiomerically pure compounds herein is from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise indicated, a wedge and hashed bond represents the absolute configuration at a single stereogenic center.

[0189] Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Compounds of the application containing asymmetrically substituted carbon atoms can exist in optically active forms or as racemates. Resolution of racemic mixtures of compounds can be achieved by any of a number of methods known in the art. Exemplary methods include fractional crystallization using chiral resolving acids, which are optically active, salt-forming organic acids. Suitable resolving agents for fractional crystallization methods are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as β- camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include α-methyl- benzylamine (e.g., S and R forms or diastereomeric pure forms), 2-phenylglycinol, norephedrine, ephedrine, N- methyl-ephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like, in stereoisomerically pure form. Resolution of racemic mixtures can also be achieved by elution on chiral chromatographic columns packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). High performance liquid chromatography (HPLC) methods can be employed as well as supercritical fluid chromatography (SFC). The choice of the particular method and elution conditions, as well as the choice of the chromatographic column, can be selected by one skilled in the art based on the structure of the compound and the results of the test. Further, any enantiomer or diastereomer of a compound described herein can be obtained by stereospecific synthesis from an optically pure starting material or reagent of known configuration.

[0190] Unless otherwise specified, the term "tautomers" refers to isomers of a functional group that result from the rapid movement of a certain atom between two positions in a molecule. Compounds of the application can exhibit tautomerism. Tautomeric compounds can exist in two or more interconvertible forms. Proton- shifting tautomers result from the migration of a hydrogen atom covalently bonded between two atoms. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer usually result in a mixture whose physical and chemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates; in phenols, the enol form predominates. The present application includes all tautomeric forms of the compounds. For example may interconvert.

[0191] In examples of the present application, a proton can occupy two or more positions in a ring system of a heterocyclic ring, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H- isoindole, tetrazole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or spatially fixed in one form by appropriate substitution. For example:

[0192] The hydrogen on the nitrogen of the tetrazole can be on any one of the four nitrogens due to resonance.

[0193] Unless otherwise indicated, the use of the term "wedge" is intended to indicate a solid line and the use of the term "wedge" is intended to indicate a dashed line to represent the absolute configuration of a stereocenter, the use of the term "straight" is intended to indicate a solid line and the use of the term "straight" is intended to indicate a dashed line to represent the relative configuration of a stereocenter.

[0194] Unless otherwise indicated, the use of the term "wedge" is intended to indicate a solid line to represent the absolute configuration of a stereocenter, the use of the term "straight" is intended to indicate a solid line wherein may indicate either a fused or spiro ring.

[0195] The compounds of the present application can contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds can be radiolabeled with radioactive isotopes such as for example deuterium (2H), tritium (3H), iodine-125 (125I) or C-14 (14C). All isotopic variations of the compounds of the present application, whether radioactive or not, are encompassed within the scope of the present application.

[0196] The term "effective amount" or "therapeutically effective amount" in reference to a drug or a pharmacological agent means a nontoxic but sufficient amount of the drug or agent to provide the desired effect. For oral dosage forms of the present application, an "effective amount" of one active agent in a composition means the amount needed to provide the desired effect in conjunction with the other active agent in the composition. The determination of an effective amount is dependent on the age and general condition of the recipient, on the particular active agent, and an appropriate effective amount for a given case can be determined by one of ordinary skill in the art using routine testing.

[0197] The term "active ingredient", "therapeutic agent", "active agent" or "active agent" means a chemical entity that is effective in treating a disorder, disease or condition of interest, unless otherwise specified.

[0198] The term "substituted" means that any one or more hydrogen atoms on the particular atom is replaced with a substituent group, including heavy hydrogen and variations of hydrogen, as long as the valency of the particular atom is not exceeded and the substituted compound is stable. When the substituent is oxo (i.e., =0), it can be represented as oxidation of carbon, nitrogen and sulfur atoms, including but not limited to C(=O), S(=O), S(=O)2 or N(=O), unless otherwise specified.

[0199] The term "optionally" or "optional" means that the subsequently described event or circumstance may, but need not, occur, and the description includes instances where the event or circumstance occurs and instances where it does not, unless otherwise indicated.

[0200] The term "optionally substituted" means that the group can or can not be substituted and that the nature and number of substituents, when present, can be any that are chemically possible.

[0201] When any variable (e.g., R) occurs more than one time in a compound or substituent, its definition in each instance is independent of the definition of the other occurrences. Thus, for example, if a group is substituted with 0-2 R groups, then the group can optionally be substituted with up to two R groups, and each R group is selected independently of the other. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0202] The term "C 1-6 "alkyl" is used to denote a straight or branched saturated carbon hydride group consisting of from 1 to 6 carbon atoms. The C 1-6 alkyl group includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C6and C5alkyl, etc.; which can be monovalent (e.g., methyl), divalent (e.g., methylene) or multivalent (e.g., methine). Examples of C

[0203] The term "C 1-3 "alkyl" is used to denote a straight or branched saturated carbon hydride group consisting of from 1 to 3 carbon atoms. The C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl, etc.; which can be monovalent (e.g., methyl), divalent (e.g., methylene) or multivalent (e.g., methine). Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), etc.

[0204] The term "halo" is used interchangeably with the term "halogen substituted" when used alone or as part of another substituent.

[0205] 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.

[0206] 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.

[0207] 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.

[0208] 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.

[0209] 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 2-3Examples of C1-3 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy).

[0210] 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.

[0211] 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.

[0212] Unless otherwise specified, the term "C" 3-8 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 8 carbon atoms, including monocyclic and bicyclic systems, wherein bicyclic systems include spirocyclic, fused, and bridged rings. The C 3-8 Cycloalkyl groups include C 3-6 C 3-5 C 4-8 C 4-6 C 4-5 C 5-8 Or C 5-6 Cycloalkyl groups, etc.; they can be monovalent, divalent, or polyvalent. C 3-8 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2]bicyclooctane, etc.

[0213] Unless otherwise specified, the term "C" 3-6Cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which is a monocyclic and bicyclic ring system, said C 3-6 Cycloalkyl includes C 3-5 , C 4-5 , and C 5-6 cycloalkyl and the like; which can be monovalent, divalent or multivalent. C 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0214] Unless otherwise specified, Cn-n+m or Cn-Cn+m includes any one particular case of n to n+m carbons, for example C 1-12 includes C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , and C 12 also includes any one range of n to n+m, for example C 1-12 includes 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 and the like; and likewise, n-membered to n+m-membered means the number of atoms in the ring is n to n+m, for example 3-12 membered ring includes 3 membered ring, 4 membered ring, 5 membered ring, 6 membered ring, 7 membered ring, 8 membered ring, 9 membered ring, 10 membered ring, 11 membered ring, and 12 membered ring, also includes any one range of n to n+m, for example 3-12 membered ring includes 3-6 membered ring, 3-9 membered ring, 5-6 membered ring, 5-7 membered ring, 6-7 membered ring, 6-8 membered ring, and 6-10 membered ring, and the like.

[0215] The term "heterocycloalkyl" when used alone or as part of another substituent refers to a cycloalkyl group in which one or more (in some embodiments 1 to 3) carbon atoms are replaced by a heteroatom such as, but not limited to, N, NH, O, S, P, S(=0), S(=0)2, or S(=0)(=NH). The term "m- to n-membered heterocycloalkyl" is understood to mean a saturated ring having m to n atoms, wherein the hetero ring atoms are selected from N, NH, O, S, P, S(=0), S(=0)2, or S(=0)(=NH), preferably from N, O, or S. For example, the term "4- to 8-membered heterocycloalkyl" is understood to mean 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. A "4- to 10-membered heterocyclyl" is understood to mean a saturated or partially saturated ring having 4 to 10 atoms. When a prefix such as 4- to 8-membered or 4- to 10-membered is used to denote a heterocycloalkyl group, the number of carbons also means to include the heteroatoms. Single-, bi-, tri-, spiro-, or bridged rings are included. Examples of heterocycloalkyl groups are: pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydropyridinyl, tetrahydropyrrolyl, azetidinyl, thiazolidinyl, oxazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, diazepanyl, oxazepanyl, and the like. The term "heterocycloalkyl" can be used interchangeably with the term "heteroalkyl ring".

[0216] The term "aromatic ring" when used alone or as part of another substituent refers to a monocyclic or polycyclic carbocyclic ring having 6 to 20 carbon atoms, wherein at least one ring is aromatic. When one of the rings is non-aromatic, the group can be attached through the aromatic ring or through the non-aromatic ring. Examples of aryl groups include, but are not limited to: phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl, and acenaphthyl. The term "aromatic ring" can be used interchangeably with the term "aryl".

[0217] The term "heteroaromatic ring," by itself or in combination with other terms, means a monocyclic or polycyclic carbocyclic ring in which at least one ring atom is a heteroatom independently selected from oxygen, sulfur and nitrogen, the remainder of the ring atoms being carbon, wherein at least one ring is aromatic. The group can be carbon-based or heteroatom-based (i.e., it can be C-attached or N-attached, as is possible). When one of the rings is non-aromatic, the group can be attached through an aromatic ring, as well as through a non-aromatic ring. Examples of heteroaryl groups include, but are not limited to, imidazolyl, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furanyl, thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, N-methylpyrrolyl and tetrahydroquinoline. The term "heteroaromatic ring" can be used interchangeably with the terms "heteroaromatic ring," "heteroaryl" or "heteroaryl group."

[0218] The term "4-10 membered heterocyclenyl," by itself or in combination with other terms, means an unsaturated or partially unsaturated cyclic group consisting of 4 to 10 ring atoms, but not an aromatic ring, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, the remainder of which are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen and sulfur heteroatoms are optionally oxidized (i.e., C(=O), NO and S(O)p, where p is 1 or 2), unless otherwise specified. Further, with respect to the "5-6 membered heterocyclenyl," a heteroatom can occupy the position of attachment of the heterocyclenyl group to the remainder of the molecule. The 4-10 membered heterocyclenyl group includes 5-, 6-, 7-, 8-, 9- and 10-membered heterocyclenyl groups, and the like.

[0219] Unless otherwise specified, the terms "5-10 membered heteroaromatic ring" and "5-10 membered heteroaryl" are used interchangeably throughout the application, and the term "5-10 membered heteroaryl" means a monocyclic ring group consisting of 5 to 10 ring atoms having a conjugated pi-electron system, 1, 2, 3, or 4 of which are heteroatoms independently selected from O, S, and N, with the remainder being carbon atoms. Where the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, where p is 1 or 2). The 5-10 membered heteroaryl can be attached to the remainder of the molecule through a heteroatom or carbon atom. The 5-10 membered heteroaryl includes 5-, 6-, 7-, 8-, 9-, and 10-membered heteroaryl groups. Examples of the 5-10 membered heteroaryl groups include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5-oxazolyl, etc.), triazolyl (1H-1, 2, 3-triazolyl, 2H-1, 2, 3-triazolyl, 1H-1, 2, 4-triazolyl, and 4H-1, 2, 4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl, and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, etc.), thiophenyl (including 2-thiophenyl and 3-thiophenyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl, and 4-pyridyl, etc.), pyrazinyl, or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).

[0220] Unless otherwise specified, the term "halo" or "halogen" is fluorine, chlorine, bromine, and iodine.

[0221] Further, it is noted that the descriptive manner "independently" as employed in the present application is to be interpreted broadly, unless explicitly indicated otherwise, and means that each individual described is independent of the other, and can be the same or different specific group independently. In more detail, the descriptive manner "independently" can mean that the specific options expressed between the same symbols in different groups do not influence each other, or that the specific options expressed between the same symbols in the same group do not influence each other.

[0222] Unless otherwise specified, the term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine; cattle, sheep, horses, or primates, and most preferably humans.

[0223] The term "therapeutically effective amount" means, unless otherwise indicated, an amount of an active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of: (1) preventing the disease: for example, preventing a disease, disorder or condition from occurring in an individual that is predisposed or susceptible to the disease, disorder and condition but has not yet been diagnosed with the disease pathology or symptoms; (2) inhibiting the disease: for example, arresting the development of a disease, disorder or condition in an individual that is experiencing or displaying the pathology or symptoms of the disease, disorder or condition (i.e., halting the pathology and / or symptoms); (3) relieving the disease: for example, causing the regression of the pathology and / or symptoms in an individual that is experiencing or displaying the pathology or symptoms of the disease, disorder or condition (i.e., reversing the pathology and / or symptoms).

[0224] The terms "treat" and other similar synonymous terms as used herein include the following meanings:

[0225] (i) preventing the disease or condition from occurring in a mammal, in particular, when such mammal is predisposed or susceptible to the disease or condition but has not yet been diagnosed as having it;

[0226] (ii) inhibiting the disease or condition, i.e., arresting its development;

[0227] (iii) relieving the disease or condition, i.e., causing the regression of the state of the disease or condition; or

[0228] (iv) relieving the symptoms caused by the disease or condition.

[0229] Abbreviations used in the present invention are defined as follows:

[0230] M: molar concentration, e.g., 1 M hydrochloric acid means 1 mol / L hydrochloric acid solution

[0231] N: normality, e.g., 2 N hydrochloric acid means 2 mol / L hydrochloric acid solution

[0232] DMSO: dimethyl sulfoxide

[0233] Bpin: pinacol boronate. Beneficial effects

[0234] According to the embodiments of the present invention, the present invention has at least one of the following technical effects:

[0235] 1) The compounds of the present invention can induce the direct binding of VAV1 to CRBN in a dose-dependent manner;

[0236] 2) The compounds of the present invention exhibit excellent degradation effect on VAV1 protein in a dose-dependent manner;

[0237] 3) In CD3 / CD28 induced Jurkat cell and T cell activation model, the compounds of the present application can significantly inhibit the production of IL-2, and the inhibition function is positively correlated with the dosage;

[0238] 4) The compounds of the present application show excellent pharmacokinetic properties and good drugability in mouse and rat pharmacokinetic tests;

[0239] 5) The compounds of the present application show excellent human liver microsomal stability, good thermodynamic solubility, no obvious CYP3A4 inhibition, and significant advantages in plasma protein binding rate, and good drugability;

[0240] 6) The test compound group of the present application shows significant alleviation of disease progression in the adoptive naive T cell induced mouse enteritis model. DETAILED DESCRIPTION

[0241] The present application will be further described in conjunction with specific examples. It should be understood that the following description is merely the most preferred embodiment of the present application, and should not be considered as a limitation to the scope of protection of the present application. Based on a full understanding of the present application, the experimental methods in the following examples, which are not specified with specific conditions, can be made non-essential changes by the person skilled in the art according to the conventional conditions or the conditions recommended by the manufacturer, and such changes should be considered to be included in the scope of protection of the present application.

[0242] Preparation of intermediate A

[0243] 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)piperidine-2,6-dione

[0244] The synthetic route of intermediate A is as follows:

[0245] First step: synthesis of 2-(3-bromo-2-chlorophenyl)acetonitrile (intermediate A2)

[0246] Into a reaction flask was placed 3-bromo-2-chlorobenzyl bromide (compound Al) (9.0 g, 31.65 mmol), acetonitrile (100 mL), trimethylsilyl cyanide (6.3 g, 63.3 mmol), and potassium carbonate (13 g, 100 mmol). After the addition was complete, the reaction mixture was heated at 80 °C for 16 h. After the reaction was complete, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (500 mL), washed with saturated aqueous sodium chloride (500 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate (v / v) = 10: 1) to give 2-(3-bromo-2-chlorophenyl)acetonitrile (intermediate A2).

[0247] LC-MS, M / Z (ESI): 230.1 [M+H] + .

[0248] Second Step: Synthesis of methyl 4-(3-bromo-2-chlorophenyl)-4-cyanobutanoate (intermediate A3)

[0249] Into a reaction flask was placed 2-(3-bromo-2-chlorophenyl)acetonitrile (5.0 g, 21.74 mmol) (intermediate A2), methyl acrylate (3.74 g, 43.5 mmol), and tetrahydrofuran (100 mL), followed by sodium methoxide (110 mg, 2 mmol) under ice bath. After the addition was complete, the reaction mixture was stirred at room temperature for 2 h. After the reaction was complete, the reaction mixture was diluted with ethyl acetate (500 mL), washed with aqueous sodium chloride (500 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate (v / v) = 5: 1) to give methyl 4-(3-bromo-2-chlorophenyl)-4-cyanobutanoate (intermediate A3).

[0250] LC-MS, M / Z (ESI): 316.2 [M+H] + .

[0251] Third Step: Synthesis of 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (intermediate A4)

[0252] Methyl 4-(3-bromo-2-chlorophenyl)-4-cyanobutanoate (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, after the addition, the reaction liquid was reacted at 90 °C for 6 hours. After the reaction was completed, 2.0 g of sodium acetate was added at 20 °C, and stirred at room temperature for 30 min, after completion, the solvent was removed by reduced pressure distillation, then diluted with ethyl acetate (500 mL), washed with saturated sodium chloride aqueous solution (500 mL x 1), saturated sodium bicarbonate aqueous solution (500 mL x 2), saturated sodium chloride aqueous solution (500 mL x 1) respectively, then the organic phase was 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 obtain compound 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (Intermediate A4).

[0253] LC-MS, M / Z (ESI): 302.1 [M+H] + .

[0254] Fourth step: synthesis of 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione (Intermediate A)

[0255] Compound 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (Intermediate A4) (4.6 g, 15.2 mmol) was placed in a reaction bottle, then pinacol diboronic acid (7.6 g, 30 mmol), potassium acetate (4.5 g, 45.6 mmol) and 1,1'-bis (di-phenylphosphino) ferrocene palladium chloride (0.3 g, 0.45 mmol), 1,4-dioxane (70 mL) were added, after the addition, the reaction liquid was stirred at 100 °C for 8 hours under nitrogen protection. The reaction liquid was cooled to room temperature, diluted with ethyl acetate (500 mL), washed with saturated sodium chloride aqueous solution (500 mL x 3), then the organic phase was 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 obtain compound 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione (Intermediate A).

[0256] LC-MS, M / Z (ESI): 350.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.90 (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).

[0257] Example 1: Preparation of the target compound 1

[0258] 3-(2-chloro-3-(5-(2-oxopyridin-1(2H)-yl)thiophen-2-yl)phenyl)piperidine-2,6-dione

[0259] The synthetic route of compound 1 is shown as follows:

[0260] First step: synthesis of 1-(5-bromothiophen-2-yl)pyridin-2(1H)-one (compound 1-2)

[0261] Put 2,6-dibromothiophene (2.0 g, 8.3 mmol) in a reaction bottle, then add 2-hydroxypyridine (650 mg, 7 mmol), cuprous iodide (1.3 g, 7 mmol), potassium carbonate (2.9 g, 21 mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (1.2 g, 8.4 mmol), then add acetonitrile (30 mL), and microwave at 100 ℃ for 1 h under nitrogen protection. After completion, dilute the reaction solution with ethyl acetate (300 mL), wash with saturated aqueous sodium chloride solution (300 mL x 3), dry the organic phase with anhydrous sodium sulfate, filter and concentrate, and purify the residue by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 1:1) to obtain compound 1-(5-bromothiophen-2-yl)pyridin-2(1H)-one (compound 1-2).

[0262] LC-MS, M / Z (ESI): 256.0 [M+H] + .

[0263] Second step: synthesis of 3-(2-chloro-3-(5-(2-oxopyridin-1(2H)-yl)thiophen-2-yl)phenyl)piperidine-2,6-dione (compound 1)

[0264] Compound 3-(2-chloro-3-(5-(2-oxopyridin-1(2H)-yl)thiophen-2-yl)phenyl)piperidine- 2,6-dione (Compound 1) was synthesized by putting compound 3-(2-chloro-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione (Intermediate A) (300 mg, 0.88 mmol) into a reaction flask, then adding 1-(5-bromothiophen-2-yl)pyridin-2(1H)-one (Compound 1-2) (150 mg, 0.586 mmol), potassium phosphate (370 mg, 1.76 mmol) and 1,1'-bis(di-phenylphosphino)ferrocene palladium chloride (43 mg, 0.06 mmol), 1,4-dioxane (5 mL), after adding, the reaction was carried out at 100 °C for 8 hours under nitrogen protection. After the reaction was completed, the reaction was cooled to room temperature, diluted with ethyl acetate (200 mL), washed with saturated aqueous sodium chloride solution (200 mL x 3), then the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 20:1) to obtain compound 3-(2-chloro-3-(5-(2-oxopyridin-1(2H)-yl)thiophen-2-yl)phenyl)piperidine- 2,6-dione (Compound 1).

[0265] LC-MS, M / Z (ESI): 399.1 [M+H] + .

[0266] 1 H NMR (400 MHz, DMSO-d6) δ 10.94 (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).

[0267] Example 2: Synthesis of Compound 2

[0268] 3-{2-chloro-3-[6-(2-oxopyridin-1(2H)-yl)pyridazin-3-yl]phenyl}piperidine-2,6-dione

[0269] The synthetic route of compound 2 is as follows:

[0270] First step: Synthesis of 1-(6-bromopyridazin-3-yl)pyridin-2(1H)-one (Compound 2-2)

[0271] Compound 2-2) was obtained by dissolving 3,6-dibromopyridazine (500 mg, 2.10 mmol) into dimethyl sulfoxide (5 mL) at room temperature, then adding pyridine-2(lH)-one (200 mg, 2.10 mmol), potassium carbonate (580 mg, 4.20 mmol) and cuprous iodide (40.0 mg, 0.210 mmol), and reacting the mixture under nitrogen protection at 120 °C for 12 hours. After the reaction was completed, the reaction solution was slowly poured into water (50 mL), then extracted with ethyl acetate (3 x 20 mL), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the obtained crude product was purified by column chromatography (PE:EA (V / V) = 100:1 to 1:1) to obtain compound l-(6-bromopyridazin-3-yl)pyridine-2(lH)-one (compound 2-2).

[0272] LC / MS (ESI) (m / z): 252.0 (M+H) + .

[0273] Second Step: Synthesis of 3-(2-chloro-3-[6-(2-oxopyridin-l(2H)-yl)pyridazin-3-yl]phenyl)piperidine-2,6-dione (Compound 2)

[0274] Compound 2-2) was obtained by dissolving 3,6-dibromopyridazine (500 mg, 2.10 mmol) into dimethyl sulfoxide (5 mL) at room temperature, then adding pyridine-2(lH)-one (200 mg, 2.10 mmol), potassium carbonate (580 mg, 4.20 mmol) and cuprous iodide (40.0 mg, 0.210 mmol), and reacting the mixture under nitrogen protection at 120 °C for 12 hours. After the reaction was completed, the reaction solution was slowly poured into water (50 mL), then extracted with ethyl acetate (3 x 20 mL), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the obtained crude product was purified by column chromatography (PE:EA (V / V) = 100:1 to 1:1) to obtain compound l-(6-bromopyridazin-3-yl)pyridine-2(lH)-one (compound 2-2).

[0275] LC / MS (ESI) (m / z): 395.0 (M+H) + ;

[0276] 1 H NMR (400 MHz, DMSO-d6) δ 10.95 (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).

[0277] Example 3: Preparation of compound 3

[0278] 3-(2-chloro-3-(1'-methyl-2'-oxo-1',2',3,6-tetrahydro-2H-[1,3'-bipyridinyl]-4- yl)phenyl)piperidine-2,6-dione (compound 3)

[0279] The synthetic route of the target compound 3 is shown as follows:

[0280] First step: synthesis of compound 1-methyl-3-(1,4-dioxa-8-azaspiro[4.5]dec-8- yl)pyridin-2(1H)-one (compound 3-3)

[0281] Compound 3-bromo-1-methylpyridin-2(1H)-one (3-1) (500.00 mg, 2.66 mmol) and 1,4-dioxa-8-azaspiro[4.5]decane (3-2) (456.94 mg, 3.19 mmol) were dissolved in anhydrous 1,4-dioxane solution (5 mL) at room temperature, and cesium carbonate (1.73 g, 5.32 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (153.87 mg, 0.27 mmol) and palladium acetate (29.85 mg, 0.13 mmol) were added under nitrogen protection. After the addition was completed, the reaction solution was stirred at 110°C for 12 hours under nitrogen protection. TLC monitoring showed that the raw material was completely reacted, then the stirring was stopped, cooled to room temperature, then diluted with water (20 mL), extracted with ethyl acetate (10 mL x 5), the organic phase was collected and dried with anhydrous sodium sulfate, the organic phase was concentrated by reduced pressure distillation, and the residue was separated and 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]dec-8-yl)pyridin-2(1H)-one (compound 3-3).

[0282] LC-MS, M / Z (ESI): 251.2 (M+H + )

[0283] Step 2: Synthesis of compound 1-methyl-3-(4-oxopiperidin-1-yl)pyridin-2(1H)-one (compound 3-4)

[0284] Compound 1-methyl-3-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)pyridin-2(1H)-one (compound 3-3) (150.00 mg, 0.60 mmol) was dissolved in a mixture of 1 mL of acetone and 2 mL of water at room temperature, then p-toluenesulfonic acid (20.64 mg, 0.12 mmol) was added, and the reaction solution was heated and stirred in a 70 °C oil bath for 12 hours. TLC monitoring showed that the raw material was completely reacted, and then the stirring was stopped, the reaction solution was cooled to room temperature, and then diluted with saturated aqueous sodium bicarbonate solution (10 mL), extracted with ethyl acetate (10 mL x 5), the organic phase was collected and dried with anhydrous sodium sulfate, the organic phase was concentrated by reduced pressure distillation, and the residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 10:90) to obtain compound 1-methyl-3-(4-oxopiperidin-1-yl)pyridin-2(1H)-one (compound 3-4).

[0285] LC-MS, M / Z (ESI): 207.1 (M+H + )

[0286] Step 3: Synthesis of compound 1'-methyl-2'-oxo-1',2',3,6-tetrahydro-2H-[1,3'-bipyridinyl]-4- trifluoromethanesulfonate (compound 3-5)

[0287] 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) at room temperature, then stirred for 30 minutes at -78 °C, and then slowly added dropwise with a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (0.58 mL, 0.58 mmol), after the addition was completed, the reaction solution was continued to be stirred at -78 °C for 30 minutes, then N-phenylbis(trifluoromethanesulfonyl)imide (207.85 mg, 0.58 mmol) was added, after the addition was completed, the reaction solution was continued to be stirred for 1 hour and then the temperature was raised to room temperature and stirred for 12 hours. TLC monitoring showed that the raw material was completely reacted, and then the stirring was stopped, the reaction solution was diluted with 10 mL of saturated aqueous ammonium chloride solution, extracted with ethyl acetate (5 mL x 5), the organic phase was collected and dried with anhydrous sodium sulfate, the organic phase was concentrated by reduced pressure distillation, and the residue was separated and 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'-bipyridinyl]-4-trifluoromethanesulfonate (compound 3-5).

[0288] LC-MS, M / Z (ESI): 339.5 (M+H + )

[0289] Step 4: Synthesis of compound 3-(2-chloro-3-(1'-methyl-2'-oxo-1',2',3,6-tetrahydro- 2H-[1,3'-bipyridinyl]-4-yl)phenyl)piperidine-2,6-dione (Compound 3)

[0290] Compound 1'-methyl-2'-oxo-1',2',3,6-tetrahydro-2H-[1,3'-bipyridinyl]-4- trifluoromethanesulfonate (Compound 3-5) (20.00 mg, 0.06 mmol) and 3-(2-chloro-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-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 solution was stirred at 100 °C under nitrogen protection for 12 hours. TLC monitoring showed that the raw material was completely reacted, the stirring was stopped, the reaction solution was cooled to room temperature, then diluted with water (20 mL), extracted with ethyl acetate (10 mL x 5), the organic phase was collected and dried with anhydrous sodium sulfate, the organic phase was concentrated by reduced pressure distillation, the residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 1:1) to obtain compound 3-(2-chloro-3-(1'-methyl-2'-oxo-1',2',3,6-tetrahydro-2H-[1,3'-bipyridinyl]-4-yl)phenyl)piperidine-2,6-dione (Compound 3)

[0291] LC-MS, M / Z (ESI): 412.4 (M+H + )

[0292] Example 4: Preparation of compound 4

[0293] 3-(2-chloro-3-(1-(pyrimidin-2-ylmethyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)piperidine- 2,6-dione (Compound 4)

[0294] The synthetic route of the target compound 4 is shown below:

[0295] Step 1: Synthesis of 8-(pyrimidin-2-ylmethyl)-1,4-dioxa-8-azaspiro[4.5]decane (Compound 4-3)

[0296] 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) at room temperature, sodium iodide (90.8 mg, 0.61 mmol) and triethylamine (1.53 g, 15.15 mmol) were added, and the reaction solution was heated and stirred at 70 °C for 12 hours. After TLC monitoring showed that the reaction was completed, the stirring was stopped, the reaction solution was cooled to room temperature, then diluted with water (30 mL), extracted with ethyl acetate (10 mL x 5), the organic phase was collected and dried with anhydrous sodium sulfate, the organic phase was concentrated under reduced pressure, and 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).

[0297] LC-MS, M / Z (ESI): 236.3 (M+H + )

[0298] Second step: synthesis of 1-(pyrimidin-2-ylmethyl)piperidin-4-one (compound 4-4)

[0299] 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 mixed solution 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 solution was stirred at 70 °C for 12 hours. After TLC monitoring showed that the reaction was completed, the reaction solution was cooled to room temperature, then diluted with saturated aqueous sodium bicarbonate solution (10 mL), extracted with ethyl acetate (10 mL x 5), the organic phase was collected and dried with anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate) to obtain compound 1-(pyrimidin-2-ylmethyl)piperidin-4-one (compound 4-4). LC-MS, M / Z (ESI): 192.4 (M+H + )

[0300] Third step: synthesis of 1-(pyrimidin-2-ylmethyl)-1,2,3,6-tetrahydropyridine-4-trifluoromethanesulfonate (compound 4-5)

[0301] Compound 1-(pyrimidin-2-ylmethyl)piperidin-4-one (compound 4-4) (200 mg, 1.05 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL) at room temperature, then stirred at -78 °C for 30 minutes, and a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1.25 mL, 1.25 mmol) was added dropwise slowly. After the addition was completed, the reaction solution was continuously stirred at -78 °C for 30 minutes, and N-phenylbis(trifluoromethanesulfonyl)imide (448.36 mg, 1.25 mmol) was added. After the addition was completed, the reaction solution was continuously stirred for 1 hour, and then naturally warmed to room temperature. The reaction solution was continuously stirred at room temperature for 12 hours. After TLC monitoring showed that the raw material was completely reacted, the stirring was stopped, saturated aqueous ammonium chloride solution (10 mL) was added for dilution, and ethyl acetate (5 mL x 5) was used for extraction. The organic phase was collected and dried with anhydrous sodium sulfate, and the organic phase was concentrated by reduced pressure distillation. The residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 60:40) to obtain compound 1-(pyrimidin-2-ylmethyl)-1,2,3,6-tetrahydropyridine-4-trifluoromethanesulfonate (compound 4-5).

[0302] LC-MS, M / Z (ESI): 324.5 (M+H + )

[0303] Fourth step: synthesis of 3-(2-chloro-3-(1-(pyrimidin-2-ylmethyl)-1,2,3,6- tetrahydropyridin-4-yl)phenyl)piperidine-2,6-dione (compound 4)

[0304] Compound 1-(pyrimidin-2-ylmethyl)-1,2,3,6-tetrahydropyridine-4-trifluoromethanesulfonate (compound 4-5) (50.00 mg, 0.15 mmol) and 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione (intermediate A) (162.22 mg, 0.46 mmol) were dissolved in a mixture of toluene (0.5 mL) and water (0.2 mL) at room temperature, potassium carbonate (82.93 mg, 0.61 mmol) and tetrakis(triphenylphosphine)palladium (17.33 mg, 0.015 mmol) were added under nitrogen protection, and the reaction solution was stirred at 100 °C for 12 hours under nitrogen protection. TLC monitoring showed that the raw material was completely reacted, the reaction solution was cooled to room temperature, diluted with water (20 mL), extracted with ethyl acetate (10 mL x 5), the organic phase was collected and dried with anhydrous sodium sulfate, the organic phase was concentrated by reduced pressure distillation, and the residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 30:70) to obtain compound 3-(2-chloro-3-(1-(pyrimidin-2-ylmethyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)piperidine-2,6-dione (compound 4).

[0305] LC-MS, M / Z (ESI): 397.5 (M+H + )

[0306] Example 5: Preparation of compound 5

[0307] 3-(2-chloro-3-(5-(3-oxomorpholino)thiophen-2-yl)phenyl)piperidine-2,6-dione (target compound 5)

[0308] The synthetic route of compound 5 is shown below:

[0309] First step: synthesis of 4-(5-bromothiophen-2-yl)morpholine-3-one (compound 5-2)

[0310] 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).

[0311] LC-MS, M / Z (ESI): 261.9 [M+H] +

[0312] 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)

[0313] 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).

[0314] LC-MS, M / Z (ESI): 310.0 [M+H] +

[0315] Step 3: Synthesis of 3-(2-chloro-3-(5-(3-oxomorpholino)thiophene-2-yl)phenyl)piperidine-2,6-dione (compound 5)

[0316] Intermediate 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)morpholine- 3-one (compound 5-3) (180 mg, 0.58 mmol) was placed in a reaction flask, followed by the addition of 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (Intermediate A4) (0.26 g, 0.87 mmol), potassium phosphate (0.32 g, 1.5 mmol) and 1,1'-bis(di- phenylphosphino)ferrocene palladium chloride (73 mg, 0.1 mmol), 1,4-dioxane (10 mL), after the addition, the reaction was stirred at 100 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction was diluted with ethyl acetate (200 mL), washed with saturated sodium chloride aqueous solution (200 mL x 3), then the organic phase was 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 obtain compound 3-(2-chloro-3-(5-(3-oxomorpholino)thiophen-2-yl)phenyl)piperidine-2,6-dione (compound 5).

[0317] LC-MS, M / Z (ESI): 405.1 [M+H] +

[0318] 1 H NMR (400 MHz, DMSO-d6) δ 10.93 (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)

[0319] Example 6: Preparation of target compound 6

[0320] Synthesis of 3-(2-chloro-3-(5-(3-(2-hydroxypropan-2-yl)-2-oxopyridin-1(2H)-yl)thiophen- 2-yl)phenyl)piperidine-2,6-dione (compound 6)

[0321] The synthesis route of compound 6 is shown as follows:

[0322] First step: synthesis of 1-(5-bromothiophen-2-yl)-3-(2-hydroxypropan-2-yl)pyridin-2(1H)- one (compound 6-2)

[0323] A reaction flask was charged with 3-(2-hydroxypropan-2-yl)pyridin-2(lH)-one (compound 6-1) (3.0 g, 19.6 mmol), 2,5-dibromothiophene (9.7 g, 40.0 mmol), 100 mL of acetonitrile, followed by cuprous iodide (3.7 g, 19.6 mmol), potassium carbonate (8.3 g, 60 mmol), N,N'-dimethylethylenediamine (2.0 g, 23.0 mmol), and the reaction was purged with argon. The reaction was heated at 90 °C for 45 min in a microwave reactor. After completion, the reaction was diluted with ethyl acetate (800 mL) and washed with saturated aqueous sodium chloride (800 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 2: 1) to give intermediate 1-(5-bromothiophen-2-yl)-3-(2-hydroxypropan-2-yl)pyridin-2(lH)-one (compound 6-2).

[0324] LC-MS, M / Z (ESI): 313.9 [M+H] + .

[0325] Step 2: Synthesis of 3-(2-hydroxypropan-2-yl)-l-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)thiophen-2-yl)pyridin-2(lH)-one (compound 6-3)

[0326] A reaction flask was charged with intermediate 1-(5-bromothiophen-2-yl)-3-(2-hydroxypropan-2-yl)pyridin-2(lH)-one (compound 6-2) (0.74 g, 2.36 mmol), bis(pinacolato)diboron (1.2 g, 4.73 mmol), potassium acetate (0.7 g, 7.08 mmol), and l,l'-bis(diphenylphosphino)ferrocene palladium(II) chloride (0.3 g, 0.47 mmol), and 1,4-dioxane (20 mL). After addition, the reaction was stirred at 100 °C for 5 h under nitrogen. The reaction was cooled to room temperature, diluted with ethyl acetate (300 mL), and washed with saturated aqueous sodium chloride (300 mL x 3). The organic phase was 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 intermediate 3-(2-hydroxypropan-2-yl)-l-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)thiophen-2-yl)pyridin-2(lH)-one (compound 6-3).

[0327] LC-MS, M / Z (ESI): 362.1 [M+H] + .

[0328] Step 3: Synthesis of 3-(2-chloro-3-(5-(3-(2-hydroxypropan-2-yl)-2-oxopyridin-1(2H)-yl)thiophen-2-yl)phenyl)piperidine-2,6-dione (Compound 6)

[0329] Intermediate 3-(2-hydroxypropan-2-yl)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-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)piperidine-2,6-dione (Intermediate A4) (190 mg, 0.64 mmol), potassium phosphate (337 mg, 1.59 mmol) and 1,1'-bis(di-phenylphosphino)ferrocene palladium chloride (43 mg, 0.06 mmol), 1,4-dioxane (5 mL), after the addition, the reaction was stirred at 100 °C for 8 hours under nitrogen protection. The reaction was cooled to room temperature, then diluted with ethyl acetate (200 mL), washed with saturated aqueous sodium chloride solution (200 mL x 3), then the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 20:1) to obtain 3-(2-chloro-3-(5-(3-(2-hydroxypropan-2-yl)-2-oxopyridin-1(2H)-yl)thiophen-2-yl)phenyl)piperidine-2,6-dione (Compound 6).

[0330] LC-MS, M / Z (ESI): 457.1 [M+H] +

[0331] 1 H NMR (600 MHz, DMSO-d6) δ 10.92 (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).

[0332] The following compounds were prepared according to the method described in Reference Example 1:

[0333] Biological test

[0334] Test Example 1: Compound-induced binding of VAV1 to CRBN

[0335] Experimental method

[0336] 1) Cell line construction and culture. VAV1-SmBiT expression plasmid and CRBN-LgBiT expression plasmid were constructed respectively, and VAV1-SmBiT and CRBN-LgBiT were inserted into the genome of HEK293 cells using a lentivirus system to construct a cell line (HEK293-VAV1-SmBiT-CRBN-LgBiT) stably expressing VAV1-SmBiT and CRBN-LgBiT proteins. The culture medium used for culture was DMEM medium containing inactivated 10% fetal bovine serum, 100 U / ml penicillin and 100 μg / ml streptomycin. HEK293-VAV1-SmBiT-CRBN-LgBiT cells were cultured in a 37°C, 5% CO2 incubator, and the cells were subcultured when the confluence rate reached 80-90%. Cells in the logarithmic growth phase were used for plating, and HEK293-VAV1-SmBiT-CRBN-LgBiT cells were plated in a 96-well plate with 100ul medium, 20000-3000 cells per well, and incubated overnight.

[0337] 2) Compound dilution. The compound was dissolved in DMSO to a concentration of 10 mM. Then the compound was gradiently diluted with DMSO to concentrations of 2000 μM, 500 μM, 125 μM, 32.25 μM, 7.81 μM, 1.95 μM, 0.49 μM, 0.12 μM and 0.031 μM, respectively.

[0338] 3) Drug addition. 1 μL of the diluted compound was added to 1 ml of complete medium, mixed well, and then 100 μL was added to a 96-well plate, with a working concentration of 1000 nM, 250 nM, 62.5 nM, 15.6 nM, 3.91 nM, 0.98 nM, 0.24 nM, 0.061 nM, 0.015 nM and 0 nM.

[0339] 4) Activity detection. Detection was performed 8 hours after drug treatment, and the detection method was according to the promega company NanoBiT Protein: Protein Interaction System instruction.

[0340] 5) EC50 calculation. Fluorescence intensity (Fold change) = (Lumninence experiment - Lumninence blank) / (Lumninence DMSO - Lumninence blank).

[0341] Experimental conclusion:

[0342] The compound of the application can induce the direct binding of VAV1 and CRBN in a dose-dependent manner.

[0343] Test example 2: Effect of the compound on VAV1 protein of HEK293 cells

[0344] Experimental method

[0345] 1) Cell line construction and culture. The C-terminal of VAV1 is inserted into Hibit tag, and VAV1-Hibit is inserted into the genome of HEK293 cells by using a lentiviral system to construct a cell line stably expressing VAV1-Hibit protein. The culture medium used for culture is DMEM medium containing inactivated 10% fetal bovine serum, 100 U / ml penicillin and 100 μg / ml streptomycin, and the HEK293-VAV1-Hibit cells are cultured in a 37°C, 5% CO2 incubator. The cell confluence rate reaches 80-90% after subculture. Cells in the logarithmic growth phase are used for plating, and HEK293-VAV1-Hibit cells are plated in a 96-well plate, 100ul medium, 20000-3000 cells per well, and incubated overnight.

[0346] 2) Compound dilution. The compound is dissolved in DMSO to make its concentration 10 mM. Then the compound is gradient diluted with DMSO to make its concentration 2000 μM, 500 μM, 125 μM, 32.25 μM, 7.81 μM, 1.95 μM, 0.49 μM, 0.12 μM and 0.031 μM, respectively.

[0347] 3) Drug administration. Take 1 μL of the diluted compound and add it to 1 ml of complete medium, mix well, and then take 100 μL and add it to a 96-well plate, with a working concentration of 1000 nM, 250 nM, 62.5 nM, 15.6 nM, 3.91 nM, 0.98 nM, 0.24 nM, 0.061 nM, 0.015 nM and 0 nM.

[0348] 6) Activity detection. Detection is performed 24 hours after drug treatment, and the detection method is according to the promega company HiBiT Lytic Detection System instruction.

[0349] 7) DC50 calculation. Relative VAV1 (%) = (Lumninence experiment - Lumninence blank) / (Lumninence DMSO - Lumninence blank), calculated using a log(inhibitor) vs. response - Variable slope (four parameters) fit.

[0350] Experimental conclusion:

[0351] The compound of the present application shows excellent degradation effect on VAV1 protein and dose dependence.

[0352] Test example 3: degradation of compounds on VAV1 of Jurkat cells

[0353] Jurkat cells were cultured in RPMI-1640 medium containing inactivated 10% fetal bovine serum, 100 U / ml penicillin and 100 μg / ml streptomycin in a 37℃, 5% CO2 incubator, and the cell density reached 1*10^6, then subcultured and divided into bottles. The tumor cells in the logarithmic growth phase were plated in 12-well plates at 7*10 5 The drug was diluted and added to the cell culture medium to make the final concentration of the drug 1000 nM, 250 nM, 62.5 nM, 15.6 nM, 3.9 nM, 0.98 nM, 0.24 nM and 0 nM. The drug was treated for 24 hours. The cells treated with the drug for 24 hours were taken out of the incubator and transferred to a 1.5 mL EP tube, 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 gel was run for detection. Anti-VAV1 was diluted 1:1000, Anti-GAPDH was diluted 1:5000, and HRP secondary antibody was diluted 1:10000, and incubated at 4℃ overnight. RT for 1 hour. Chemiluminescence was used to detect protein expression, and ImageJ was used for gray value analysis. The experimental results are shown in Table 1. The compound of the present application shows excellent degradation effect on VAV1 protein in Jurkat cells and dose dependence.

[0354] Table 1 degradation activity of compounds on VAV1 protein in Jurkat cells

[0355] *

[0356] DC50≤10nM is "A", 10nM<DC50≤30nM is "B1", 30nM<DC50≤100nM is "B2"; 100nM<DC50≤1000nM is "C"; DC50>1000nM is "D".

[0357] Test Example 4: Compound inhibits CD3 / CD28-induced Jurkat cell activation

[0358] Jurkat cells were cultured in RPMI-1640 medium containing inactivated 10% fetal bovine serum, 100 U / ml penicillin and 100 μg / ml streptomycin at 37°C in a 5% CO2 incubator, and subcultured and split when the cell density reached 1*10^6. Cells in logarithmic growth phase were plated at 40000 cells per well in a 96-well plate, and different concentrations of compounds were added. After 24 hours of treatment, 5 ug / ml CD3 antibody and 1 ug / ml CD28 antibody were added, and the cells were incubated for another 24 hours. The cell supernatant was taken and subjected to ELISA to detect the IL-2 content.

[0359] Experimental conclusion: In the CD3 / CD28-induced Jurkat cell activation model, the compound of the present application can significantly inhibit the production of IL-2, and the inhibition function is positively correlated with the dose.

[0360] Test Example 5: Compound inhibits CD3 / CD28-induced human T cell activation

[0361] Fresh blood samples were diluted with an equal volume of PBS, then slowly added to a 50 mL centrifuge tube containing 15 mL Lymphoprep (Stemcell, #7851), taking care not to break the interface, and centrifuged at 1000g, 5 min, at room temperature, without using the brake. The white blood cell layer (PBMC) was collected, washed twice with PBS, and centrifuged at 350g for 10 min, and the supernatant was discarded. T cells were sorted from PBMC using a T cell sorting kit (Stemcell, #17951), and the cell density was adjusted to 2.6*10 6 / mL, 75 μL was added to each well of a U-bottom 96-well plate (Corning, #3799), and 75 μL of the diluted test compound was added, and an equal amount of DMSO was added to the blank group, and mixed well and incubated for 24 hours. Then the cells were transferred to a 96-well plate coated with Anti-Human CD3 (5 μg / mL, BD, #555329), and 50 μL Anti-Human CD28 (1 μg / mL, BD, #555725) was added, mixed well, and incubated for another 48 hours. Finally, the supernatant was collected, and the IL-2 level was detected using an IL-2 ELISA kit (BD, #555190).

[0362] Experimental conclusion: In the CD3 / CD28-induced human T cell activation model, the compound of the present application can significantly inhibit the production of IL-2, and the inhibition function is positively correlated with the dose

[0363] Test Example 6: Mouse pharmacokinetic test

[0364] Mouse pharmacokinetic test, using male ICR mice, 20-25g, fasting overnight. Take 3 mice, oral gavage administration of 10mg / kg. Before administration and after administration of 15, 30 minutes and 1, 2, 4, 8, 24 hours of blood sampling. Blood samples 6800g, 2-8℃ centrifugation for 6 minutes, collect plasma, stored at-80℃. Take the plasma at each time point, add 3-5 times the amount of internal standard acetonitrile solution mixing, vortex mixing 1 minute, 13000r / min 4℃ centrifugation for 10 minutes, add 3 times the amount of water mixing, take the appropriate amount of mixed solution for LC-MS / MS analysis. The main pharmacokinetic parameters were analyzed by WinNonlin 7.0 software non-compartment model.

[0365] Table 2 Compound mouse PK parameters

[0366] The results of the mouse pharmacokinetic test show that the compounds of the present application exhibit excellent pharmacokinetic properties and good drug development.

[0367] Test Example 7: Rat pharmacokinetic test

[0368] Rat pharmacokinetic test, using male SD rats, 180-240g, fasting overnight. Take 3 rats, oral gavage administration of 10mg / kg. Before administration and after administration of 15, 30 minutes and 1, 2, 4, 8, 24 hours of blood sampling. Blood samples 6800g, 2-8℃ centrifugation for 6 minutes, collect plasma, stored at-80℃. Take the plasma at each time point, add 3-5 times the amount of internal standard acetonitrile solution mixing, vortex mixing 1 minute, 13000r / min 4℃ centrifugation for 10 minutes, add 3 times the amount of water mixing, take the appropriate amount of mixed solution for LC-MS / MS analysis. The main pharmacokinetic parameters were analyzed by WinNonlin 7.0 software non-compartment model.

[0369] The results of the rat pharmacokinetic test show that the compounds of the present application exhibit excellent rat pharmacokinetic properties and good drug development.

[0370] Test Example 8: Human liver microsome stability test

[0371] Human liver microsomal stability test was performed by co-incubation of the compound with human liver microsomes in vitro. First, the compound to be tested was prepared into a 10 mM stock solution in DMSO solvent, and then the compound was diluted to 0.5 mM using acetonitrile. Human liver microsomes (Corning) were diluted into a microsome / buffer solution using PBS, and the solution was used to dilute the 0.5 mM compound into a working solution, with a compound concentration of 1.5 μM and a human liver microsome concentration of 0.75 mg / mL. A deep well plate was taken, 30 μL of the working solution was added to each well, and then 15 μL of preheated 6 mM NADPH solution was added to start the reaction, and incubation was performed at 37°C. At 0, 5, 15, 30, and 45 minutes of incubation, 135 μL of acetonitrile was added to the corresponding wells to terminate the reaction. After the reaction was terminated at the last 45-minute time point using acetonitrile, the deep well plate was vortexed for 10 minutes (600 rpm / min) and then centrifuged for 15 minutes. After centrifugation, the supernatant was taken, 1:1 purified water was added, and LC-MS / MS detection was performed, obtaining the peak area ratio of the compound to the internal standard at each time point. The peak area ratios of the compound at 5, 15, 30, and 45 minutes were compared with the peak area ratio at 0 minutes, and the remaining percentage of the compound at each time point was calculated. Graphpad 5 software was used to calculate T1 / 2.

[0372] The results of the human liver microsomal stability test show that the compounds of the present application exhibit excellent human liver microsomal stability and good drugability.

[0373] Test Example 9: Thermodynamic solubility test

[0374] In this example, the solubility of the compound was evaluated using a standardized in vitro method. The control compounds progesterone and diclofenac were purchased from Sigma. PBS (pH 7.4), FaSSIF, FeSSIF, and FaSSGF buffers were all freshly prepared in the laboratory according to standard formulations and used within the specified time. The solubility determination procedure was as follows: about 1 mg of the compound was weighed into a glass bottle, the corresponding buffer (1 mL / mg) was added, a stirring rod was added and the bottle was sealed, and the bottle was shaken at 25°C and 1100 rpm for 24 hours. After incubation, the stirring rod was removed, the sample was filtered under vacuum, and gradient dilution was performed at 100, 1000, and 10000 times. The diluent was a mixture of water / acetonitrile (1:1) containing an internal standard. The standard was dissolved in DMSO and diluted in the same way to concentrations of 10, 1, and 0.1 μg / mL. All samples were placed in an autosampler, and LC-MS / MS was used for analysis. Data processing was performed using Excel software, and the solubility was calculated by comparison with the standard. The results of the thermodynamic solubility test show that the compounds of the present application have good thermodynamic solubility and good drugability.

[0375] Test Example 10: Inhibition test of the compound on cytochrome P450

[0376] The inhibitory potential of the test compound on cytochrome P450 (CYP450) subtypes CYP3A4 (two substrates, midazolam and testosterone) was detected. The test compound was first prepared into a 10 mM stock solution in DMSO solvent, and the CYP3A4 inhibitor ketoconazole was prepared into a 10 mM, 2.5 mM, 2.5 mM stock solution in DMSO solvent. The test compound and ketoconazole were diluted 400 times with acetonitrile to a final concentration (compound: 10 μM, ketoconazole: 2.5 μM).

[0377] The NADPH cofactor (66.7 mg NADPH in 10 mL potassium phosphate buffer) and the substrate were prepared in a 4-fold final concentration of potassium phosphate buffer (0.1 M, pH 7.4), and the CYP3A4 substrate midazolam was prepared to a final concentration of 320 μM, and the CYP3A4 substrate testosterone was prepared to a final concentration of 20 μM.

[0378] The human liver microsomal solution was prepared in potassium phosphate buffer on ice, at a concentration of 0.2 mg / mL. The test compound and control inhibitor solution were prepared in a 2-fold final concentration in human liver microsomal solution on ice. 30 μL of the test compound and control inhibitor solution were added to the test wells, respectively, and 15 μL of the substrate was added, and the operation was performed in duplicate. The 96-well assay plate and NADPH solution were incubated at 37°C for 5 minutes, and 15 μL of preheated 8 mM NADPH solution was added to the assay plate to start the reaction. The CYP3A4 assay plate was pre-incubated at 37°C for 5 minutes. The reaction was terminated by adding 120 μL of acetonitrile, and after quenching, the plate was shaken on a shaker (IKA, MTS2 / 4) for 10 minutes (600 rpm / min), and then centrifuged for 15 minutes. After centrifugation, the supernatant was taken, and after 1:1 addition of purified water, LC-MS / MS detection 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, and the inhibition rate was calculated.

[0379] The results of the cytochrome P450 inhibition test of the compound showed that the compound of the present application had no significant CYP3A4 (two substrates, midazolam and testosterone) inhibition effect, and had good drug property.

[0380] Test Example 11: Test of plasma protein binding by equilibrium dialysis method

[0381] 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 both the plasma and buffer chambers 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. The mixture was vortexed for 10 minutes and 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 standards were exported to an Excel spreadsheet. The free, bound, and recovered rates of the compounds were calculated using the following formulas: Free rate (%Unbound) = (buffer chamber peak area ratio / plasma chamber peak area ratio) × 100; Bound rate (%Bound) = 100 - %Unbound; Recovery rate (%Recovery) = (buffer chamber peak area ratio + plasma chamber peak area ratio) / total sample peak area ratio × 100; Remaining amount (%Remaining) = 5-hour peak area ratio / 0-hour peak area ratio × 100.

[0382] Experimental results show that the compounds of this invention have significant advantages in plasma protein binding rate.

[0383] Test Example 12: Efficacy evaluation of the compound in a mouse model of inflammatory bowel disease induced by adoptive T cell transfer

[0384] 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.

[0385] Experimental Methods:

[0386] 1) Isolate spleen from BALB / c donor mice, prepare single cell suspension, sort CD4 + CD25 - cells by EasySep kit, stain and sort CD4 + CD45RB + cells by flow cytometry, wash with PBS and resuspend to 1.5 x 10 6 / mL. Then transfer to immunodeficient recipient mice (CB17-SCID mice) via tail vein injection.

[0387] 2) Randomly group the recipient mice on day 15 after cell transfer, and give them compounds or control solvent respectively. Test compounds are administered by oral gavage, at a dose range of 0.1-10 mg / kg, once daily for 20 days.

[0388] 3) During the experiment, record the changes in body weight, stool character and activity of the mice. After cell inoculation, perform DAI scoring twice a week for the first and second weeks, and three times a week for the third to fifth weeks. The DAI score is the sum of the body weight loss and stool consistency scores, through the changes in animal body weight and stool consistency.

[0389] 4) Sacrifice the mice on day 35, and collect the colon tissues. At the endpoint, collect the colon, measure the length, wash with PBS and remove the feces, weigh after blotting, and calculate the weight to length ratio. At the endpoint dissection, clean the colon contents, and save for pathological scoring.

[0390] The results show that the test compound group of the present application significantly alleviates the disease progression of the mouse intestinal inflammation model induced by adoptive naive T cells.

Claims

1. A compound represented by Formula (I), a tautomer, a stereoisomer, a pharmaceutically acceptable salt, or a prodrug thereof, ###00001### (I) wherein, denoted as wherein represents that ring C and ring D form a fused ring or a spiro ring; ring C is a 5-membered heteroaryl group, a 4-10-membered heterocycloalkenyl group, a pyridazine, a pyrazine or a triazine; D is absent, C, N, O or S 6-10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocycloalkyl, or 5-10 membered heterocycloalkenyl; the left-hand side phenyl group is connected to a ring atom of ring C; when ring D is absent, the right-hand side L1 is connected to a ring atom of ring C; when ring D is present, the right-hand side L1 can be connected to either a ring atom of ring C or a ring atom of ring D; R1is H, halogen, CN, C 1-6 alkyl, -OC 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkynyl, 4-10 membered heterocycloalkyl, said C 1-6 alkyl, -OC 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkynyl and 4-10 membered heterocycloalkyl are each independently optionally substituted with 1, 2, 3, or 4 R 1a substituents; each R is independently H, halogen, OH, NH2, CN, or C1-C6 alkyl; 1a each R is independently H, halogen, OH, NH2, CN, or C1-C6 alkyl; 1-6 alkyl; R2, R3and R4are each independently H, halogen, NH2, CN, C 1-6 alkyl or haloC 1-6 alkyl; each R5and R 51 are independently H, halogen, oxo (=0), thioxo (=S), CN, C 1-6 alkyl, -OC 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkynyl or 4-10 membered heterocycloalkyl, said C 1-6 alkyl, -OC 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkynyl and 4-10 membered heterocycloalkyl are each independently optionally substituted with 1, 2, 3, or 4 R 5a substituents; each R is independently H, halogen, OH, NH2, CN, or C1-C6 alkyl; 5a each R is independently H, halogen, OH, NH2, CN, or C1-C6 alkyl; 1-6 alkyl; L1is a single bond, -O-, -NH-, -O-C 1-3 alkyl-, -NH-C 1-3 alkyl- or -C 1-3 alkyl-, wherein said -NH-, -O-C 1-3 alkyl-, -NH-C 1-3 alkyl- and -C 1-3 alkyl- are each independently optionally substituted with 1, 2, 3 or 4 R 1L substituents; each R is independently H, halogen, C 1L each R is independently H, halogen, C 1-3 alkyl or C 3-6 cycloalkyl; R6is H, halogen, oxo (=0), thioxo (=S), OH, NH2, CN, C 1-6 alkyl, C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C 6-10 aryl or 5-10 membered heteroaryl, said C 1-6 alkyl, C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C 6-10 aryl and 5-10 membered heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 R 6a substituents; 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 is independently H, halogen, OH, NH2, CN, C 6a-1 each R is independently H, halogen, OH, NH2, CN, C 1-3 alkyl or -C 1-3 alkyl-C 1-3 alkyl-C 1-3 alkyl or -C 1-3 alkyl-C 1-3 alkyl-C each R is independently H, halogen, OH, NH2 or CN; each L2is independently -O-, -N(R 2L )-, -S-, -S(=O)-, -S(=O)2-, or -C(=O)-; R 2L is H or C 1-3 alkyl; R7is H, D, halogen or C 1-6 alkyl; n is 1, 2 or 3; m is 1, 2, 3 or 4; the heteroatom groups in the "heterocycloalkyl group", "heterocycloalkenyl group" and "heteroaryl group" comprise N, NH, O, S, S(=O), S(=O)2 or S(=O)(=NH), and the number of the heteroatom groups is 1, 2, 3 or 4; when the number of the heteroatom groups is plural, the heteroatom groups are the same or different.

2. The compound, a tautomer, a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof according to claim 1, characterized in that, when ring D is absent, one or more of the following conditions are met: (1) Ring C is E1 is O, S or NH, T1, T2, T3 and T4 are independently CH or N; (2) ring C is a thienyl group, a thiazolyl group, an isothiazolyl group, a pyrrolyl group, a pyrazolyl group, an imidazolyl group, a furanyl group, a thiadiazolyl group, an oxazolyl group, an oxadiazolyl group; (3) For L1 can be connected to "#" or "*"; (4) For L1 can be connected to "#" or "*"; (5) is a 4-6-membered heterocycloalkenyl group; (6) is a dihydropyridyl group or a tetrahydropyridyl group; (7) For L1 can be connected to "#" or "*".

3. The compound, tautomer, stereoisomer, pharmaceutically acceptable salt, or prodrug thereof of claim 1, wherein, selected from the group consisting of: (1) For L1 can be connected to "#" or "*"; or, (2) For L1 can be connected to "#" or "*"; or, (3) For L1 can be connected to "#" or "*"; or, each R is independently H, halogen, oxo (=0), thioxo (=S), CN, C 51 is independently H, halogen, oxo (=0), thioxo (=S), CN, C 1-6 alkyl, -OC 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkynyl or 4-10 membered heterocycloalkyl, said C 1-6 alkyl, -OC 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkynyl and 4-10 membered heterocycloalkyl are each independently optionally substituted with 1, 2, 3, or 4 R 5a substituents; each R is independently H, halogen, OH, NH2, CN, or C1-C6 alkyl. 5a each R is independently H, halogen, OH, NH2, CN, or C1-C6 alkyl. 1-6 alkyl.

4. The compound, tautomer, stereoisomer, pharmaceutically acceptable salt, or prodrug thereof of claim 1, wherein, For L1 can be connected with "#" or "*". each R is independently H, halogen, oxo (=0), thioxo (=S), CN, C 51 each R is independently H, halogen, oxo (=0), thioxo (=S), CN, C 1-6 alkyl, -OC 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkynyl or 4-10 membered heterocycloalkyl, said C 1-6 alkyl, -OC 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkynyl and 4-10 membered heterocycloalkyl are each independently optionally substituted with 1, 2, 3, or 4 R 5a substituents; each R is independently H, halogen, OH, NH2, CN, or C1-C6 alkyl. 5a each R is independently H, halogen, OH, NH2, CN, or C1-C6 alkyl. 1-6 alkyl.

5. The compound, tautomer, stereoisomer, pharmaceutically acceptable salt, or prodrug thereof of claim 1, wherein when ring D is present, For satisfy one or more of the following conditions: (1a) the right-hand side L1 can be connected to either a ring atom of ring C or a ring atom of ring D; (2a) ring C is a 5-membered heteroaryl group; (3a) ring C is a pyrazolyl group, an imidazolyl group, a furanyl group, a thienyl group, a thiazolyl group, an oxazolyl group, an isothiazolyl group, an isoxazolyl group, a thiadiazolyl group, an oxadiazolyl group; (4a) ring D is a phenyl group, a 5-6-membered heteroaryl group, a 5-8-membered heterocycloalkyl group or a 5-8-membered heterocycloalkenyl group; (5a) ring D is a phenyl group, a 5-membered heteroaryl group, a 6-membered heteroaryl group, a 6-membered heterocycloalkyl group or a 6-membered heterocycloalkenyl group; (6a) ring D is a phenyl group, a pyrazolyl group, an imidazolyl group, a furanyl group, a thienyl group, a thiazolyl group, an oxazolyl group, an isothiazolyl group, an isoxazolyl group, a thiadiazolyl group, an oxadiazolyl group or a pyridonyl group; (7a) For E2 is NH, O or 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" represents connection to the left-hand side phenyl group in formula (I), and "#"2" represents connection to L1 in formula (I); (8a) For E5 is NH, O, S, T7, T8, T9, T 10 , T 11 and T 12 are each independently CH or N; (9a) For "#1" represents connection to the left-hand side phenyl group in formula (I), and "#2" represents connection to L1 in formula (I).

6. The compound, tautomer, stereoisomer, pharmaceutically acceptable salt, or prodrug thereof of claim 1, wherein For "1" indicates the connection to the left phenyl group in formula (I), and "#2" indicates the connection to L1in formula (I); each R5and R 51 are independently H, halogen, oxo (=0), thioxo (=S), CN, C 1-6 alkyl, -OC 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkynyl or 4-10 membered heterocycloalkyl, said C 1-6 alkyl, -OC 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkynyl and 4-10 membered heterocycloalkyl are each independently optionally substituted with 1, 2, 3, or 4 R 5a substituents; each R is independently H, halogen, OH, NH2, CN, or C1-C6 alkyl. 5a each R is independently H, halogen, OH, NH2, CN, or C1-C6 alkyl. 1-6 alkyl.

7. The compound, tautomer, stereoisomer, pharmaceutically acceptable salt, or prodrug thereof of claim 1, wherein R1is H, F, CI, CN, C 1-3 alkyl, C 2-4 alkynyl, C 3-4 cycloalkyl or 4-6 membered heterocycloalkyl, said C 1-3 alkyl, C 2-4 alkynyl, C 3- 4cycloalkyl and 4-6 membered heterocycloalkyl are each independently optionally substituted with 1, 2, 3, or 4 R 1a substituents; More preferably, R1is Cl, F, -CH3, -C≡C-CH3, More preferably, R1 is Cl, F or -CH3.

8. The compound, tautomer, stereoisomer, pharmaceutically acceptable salt, or prodrug thereof of claim 1, wherein, Each R 1a They are H or F, respectively, independently.

9. The compound, tautomer, stereoisomer, pharmaceutically acceptable salt, or prodrug thereof of claim 1, wherein, R2, R3 and R4 are independently H.

10. The compound, tautomer, stereoisomer, pharmaceutically acceptable salt, or prodrug thereof of claim 1, wherein, each R5and R 51 are independently H, Cl, F, oxo (=0) or CH3, respectively.

11. The compound, tautomer, stereoisomer, pharmaceutically acceptable salt, or prodrug thereof, of claim 1, wherein, L1 is a single bond.

12. The compound, tautomer, stereoisomer, pharmaceutically acceptable salt, or prodrug thereof, of claim 1, wherein, each R 6a satisfies one or more of the following conditions: 1 b) each R 6a is independently H, halogen, oxo (=0), C 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, said C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 4-8 membered heterocycloalkyl, -L2-C 3-6 cycloalkyl, -L2-4-8 membered heterocycloalkyl, each optionally substituted with 1, 2, 3 or 4 R 6a-1 substituents; 2b) each R 6a-1 are independently H, F, CI, OH, NH2, CN, CH3, -CH2-OH, -CH2F, -CHF2, -CF3, -CH2-CH2F, or -CH2-OCF3, respectively. 3b) each L2is independently -O-, -N(R 2L )-, -S-, -S(=O)-, -S(=O)2-, or -C(=O)-; 4b) R 2L is H or CH3; 5b) each L2is independently -O-, -NH-, -S-, -S(=O)-, -S(=O)2-, or -C(=O)-; 6b) each L2is independently -O-; 7b) each R 6a are each independently H, F, oxo (=0), methyl, -CHF2, CF3, -OCH3, -OCHF2, -OCF3, 13. The compound, tautomer, stereoisomer, pharmaceutically acceptable salt, or prodrug thereof, of claim 1, wherein, R6is C 1-3 alkyl, 4-8 membered heterocycloalkyl, 4-8 membered heterocycloalkenyl, phenyl, or 5-6 membered heteroaryl, each of which is independently optionally substituted with 1, 2, 3, or 4 R 1-3 alkyl, 4-8 membered heterocycloalkyl, 4-8 membered heterocycloalkenyl, phenyl, and 5-6 membered heteroaryl is independently optionally substituted with 1, 2, 3, or 4 R 6a substituents; More preferably, R6 is CH3, 14. The compound, tautomer, stereoisomer, pharmaceutically acceptable salt, or prodrug thereof, of claim 1, wherein, each R7is independently H or D.

15. The compound, tautomer, stereoisomer, pharmaceutically acceptable salt, or prodrug thereof, of claim 1, wherein, The compound has the following formula (I-1), (I-2), (I-3), (I-4) or (I-5) structure: wherein, E1is O, S, or NH; E2is O, S, NH, or CH2; E3is O, S, NH, or CH2; T1, T2, T3, and T4are each independently CH or N; X1and X2are each independently CH or N, and at least one of X1and X2is N; Ring C is 5-membered heteroaryl, 4-10 membered heterocyclenyl, pyridazine, pyrazine, or triazine; Ring D is C 6-10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocycloalkyl, or 5-10 membered heterocycloalkenyl; the left-hand phenyl group is attached to a ring atom on ring C, and the right-hand L1group can be attached either to a ring atom on ring C or to 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, tautomer, stereoisomer, pharmaceutically acceptable salt, or prodrug thereof, of claim 1, wherein, The compounds have the following formula (I-1A'), (I-1A), (I-1B), (I-2A), (I-3A) or (I-4A): wherein, h is 1, 2, 3, or 4; E1is O, S, or NH; T1, T2, T3, and T4are each independently CH or N; X1and X2are each independently CH or N, and at least one of X1and X2is N; Ring C is 5-membered heteroaryl, 4-10 membered heterocyclenyl, pyridazine, pyrazine, or triazine; Ring D is C 6-10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocycloalkyl, or 5-10 membered heterocycloalkenyl; the left-hand phenyl group is attached to a ring atom on ring C, and the right-hand L1group can be attached either to a ring atom on ring C or to a ring atom on ring D; R1, R2, R3, R4, R5, R 51 , R 6a , R7, m, n and L1 are as described in claim 1.

17. The compound, tautomer, stereoisomer, pharmaceutically acceptable salt, or prodrug thereof, of claim 1, wherein For The is a 5-membered heteroaryl; more preferably, is a thienyl group; L1is a single bond; each R 51 are each independently H, halogen, C 1-6 alkyl; more preferably, each R 51 are each independently H or F; R6is 4-10 membered heterocycloalkyl or 4-10 membered heterocycloalkenyl, each independently optionally substituted with 1, 2, 3, or 4 R 6a substituents; more preferably, R6is each R 6a is independently H, halogen, oxo (=0), C 1-6 alkyl, C 1-6 alkoxy, said C 1-6 alkyl and C 1-6 alkoxy are each optionally substituted with 1, 2, 3, or 4 R 6a-1 ; more preferably, each R 6a is independently H, F, oxo (=0), methyl, -CHF2, CF3, Each R 6a-1 They are H, halogen, OH, and NH2, respectively.

18. The compound, tautomer, stereoisomer, pharmaceutically acceptable salt, or prodrug thereof, of claim 1, wherein, The compound has the structure:

19. A pharmaceutical composition comprising, a therapeutically effective amount of a compound according to any one of claims 1-18, a tautomer, stereoisomer, pharmaceutically acceptable salt, or prodrug thereof, and a pharmaceutically acceptable excipient.

20. Use of a compound according to any one of claims 1-18, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof, or a pharmaceutical composition according to claim 19, in the manufacture of a medicament for treating or preventing a VAV1 -associated disease.

21. Use according to claim 20, characterized in that, The VAV1 -associated disease includes cancer and autoimmune disease.

22. The use according to claim 20, characterized in that, The VAV1 -associated disease includes systemic lupus erythematosus, myasthenia gravis, periodontitis, type I diabetes, rheumatoid arthritis, multiple sclerosis, inflammatory enteritis, inflammatory bowel disease, autoimmune hepatitis, or psoriasis. The VAV1 -associated disease includes systemic lupus erythematosus, myasthenia gravis, periodontitis, type I diabetes, rheumatoid arthritis, multiple sclerosis, inflammatory enteritis, inflammatory bowel disease, autoimmune hepatitis, or psoriasis.

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