Compounds as VAV1 degradation agents and uses thereof

Abstract

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

Description

Technical Field

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

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

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

[0004] Genome-wide CRISPR-Cas9 screening confirmed that VAV1 is a crucial positive regulator of T cell activation / function. VAV1 promotes the proliferation of cells sensitive to the TCR signaling pathway, such as human Jurkat T cells and primary human CD4+ and CD8+ T cells. Furthermore, data from VAV1 knockout mice indicate that VAV1 plays a key role in T / B lymphocyte function and antigen receptor signaling, particularly in T cells. More importantly, VAV1-deficient mouse thymocytes and spleen T cells exhibit multiple defects in TCR-mediated signaling, such as calcium ion (Ca) deficiency. 2+T cells exhibit impaired mobilization and transcription factor activation. In contrast, T cells lacking VAV1 GEF activity (VAV1 L334A / K335A) show normal TCR-mediated Ca2+ activation. 2+ Flow and nuclear factor-activated T cell (NFAT) activation. This indicates that VAV1 plays an important role in both GEF activity and scaffold function in the TCR signaling pathway.

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

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

[0007]

[0008] in,

[0009] R1 is a halogen, OCF3, CN, or C. 2-6 Alkyl, -OC 2-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 4-10 membered heterocyclic alkyl group, wherein the C 2-6 Alkyl, -OC 2-6 Alkyl, C 3-6 cycloalkyl, C 2-6 The alkynyl group and the 4-10 membered heterocyclic alkyl group are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. 1a replace;

[0010] Each R 1a They are, independently, H, halogen, OH, NH2, CN, and C. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0011] R2, R3, and R4 are independently H, halogen, NH2, CN, and C, respectively. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0012] X1 is either N or CR5;

[0013] X2 is N or CR 51 ;

[0014] X3 is either N or CR7;

[0015] X4 is N or CR 71 ;

[0016] R5, R 51 R7 and R 71 Each can be independently H, halogen, NH2, CN, or C. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0017] R8 is H, D, halogen, or C. 1-6 alkyl;

[0018] L1 represents a single bond, -O-, -NH-, or -OC. 1-3 Alkyl-, -NH-C 1-3 Alkyl-, -C 1-3 Alkyl- or -C 3-6 cycloalkyl-, wherein -NH-, -OC- 1-3 Alkyl-, -NH-C 1-3 Alkyl-, -C 1-3 Alkyl- and -C 3-6 Cycloalkyl groups – each independently and optionally marked with 1, 2, 3, or 4 R's 1L replace;

[0019] Each R 1L Each is independently H, halogen, and C. 1-3 Alkyl or C 3-6 cycloalkyl;

[0020] R6 represents CN, -C 0-3 Alkyl-P(=O)(R) 61 )2、-C 0-3 Alkyl-(N=)S(=O)(R 61 )2、-C 0-3 Alkyl-S(=O)(=NR) 62 )R 63 C 1-6 Alkyl, 4-10-membered heterocyclic alkyl, 5-10-membered heterocyclic alkenyl, 6-10-membered aryl or 5-10-membered heteroaryl, wherein C 1-6 Alkyl, 4-10-membered heterocyclic alkyl, 5-10-membered heterocyclic alkenyl, 6-10-membered aryl, and 5-10-membered heteroaryl groups are each independently and optionally bounded by 1, 2, 3, 4, 5, 6, 7, or 8 R groups. 6a replace;

[0021] R61 R 62 and R 63 H and C are independent of each other. 1-6 Alkyl or C 3-6 cycloalkyl;

[0022] Each R 6a The independent components are H, halogen, oxo (=O), thio (=S), OH, NH2, CN, and C, respectively. 1-6 Alkyl, Halogenated C 1-6 Alkyl or C 3-6 cycloalkyl;

[0023] Or, two Rs 61 Together with the N, P, or S atoms to which they are attached, they form a 4-10 membered heterocyclic alkyl group, wherein the 4-10 membered heterocyclic alkyl group is optionally surrounded by 1, 2, 3, or 4 R atoms. 6b replace;

[0024] Or, R 62 With R 63 Together with the N and S atoms attached thereto, they form a 5-10 membered heterocyclic alkenyl group, which is optionally surrounded by 1, 2, 3 or 4 R atoms. 6b replace;

[0025] Each R 6b They are, independently, H, halogen, oxo (=O), OH, NH2, CN, and C, respectively. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-6 cycloalkyl, -L2-C 1-6 Alkyl, -L2-C 3-6 Cycloalkyl or -L2-4-8-membered heterocycloalkyl, wherein C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-6 cycloalkyl, -L2-C 1-6 Alkyl, -L2-C 3-6 The cycloalkyl or -L2-4-8-membered heterocycloalkyl groups are each optionally substituted by 1, 2, 3 or 4 Rs, independently;

[0026] Each L2 is independently -O-, -N(R) 2L -, -S-, -S(=O)-, -S(=O)2- or -C(=O)-;

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

[0028] Each R is independently H, halogen, OH, NH2, or CN;

[0029] When R1 is a halogen, R6 is -C.0-3 Alkyl P(=O)(R) 61 )2、-C 0-3 Alkyl-(N=)S(=O)(R 61 )2、-C 0-3 Alkyl-S(=O)(=NR) 62 )R 63 , 4-10-membered heterocyclic alkyl or 5-10-membered heterocyclic alkenyl, wherein at least one of the 4-10-membered heterocyclic alkyl and 5-10-membered heterocyclic alkenyl is substituted with a thio (C=S);

[0030] The heteroatomic groups in the "heterocyclic alkyl", "heterocyclic alkenyl" and "heteroaryl" include N, O, S, S(=O), S(=O)2 or S(=O)(=NH), and the number of the heteroatomic groups is 1, 2, 3 or 4; when the number of the heteroatomic groups is multiple, the heteroatomic groups may be the same or different.

[0031] In an optional embodiment of the present invention, the above-mentioned compound, its tautomers, stereoisomers, pharmaceutically acceptable salts or prodrugs, wherein the compound has the structure of formula (II):

[0032]

[0033] in,

[0034] R1 is a halogen, OCF3, CN, or C. 2-6 Alkyl, -OC 2-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 4-10 membered heterocyclic alkyl group, wherein the C 2-6 Alkyl, -OC 2-6 Alkyl, C 3-6 cycloalkyl, C 2-6 The alkynyl group and the 4-10 membered heterocyclic alkyl group are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. 1a replace;

[0035] Each R 1a They are, independently, H, halogen, OH, NH2, CN, and C. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0036] R2, R3, and R4 are independently H, halogen, NH2, CN, and C, respectively. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0037] X1 is either N or CR5;

[0038] X2 is N or CR51 ;

[0039] X3 is either N or CR7;

[0040] X4 is N or CR 71 ;

[0041] R5, R 51 R7 and R 71 Each can be independently H, halogen, NH2, CN, or C. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0042] R8 is H, D, halogen, or C. 1-6 alkyl;

[0043] L1 represents a single bond, -O-, -NH-, or -OC. 1-3 Alkyl-, -NH-C 1-3 Alkyl- or -C 1-3 alkyl-, wherein -NH-, -OC- 1-3 Alkyl-, -NH-C 1-3 Alkyl- and -C 1-3 Alkyl groups are each independently and optionally marked with 1, 2, 3, or 4 R groups. 1L replace;

[0044] Each R 1L Each is independently H, halogen, and C. 1-3 Alkyl or C 3-6 cycloalkyl;

[0045] R6 represents CN, -C 0-3 Alkyl-P(=O)(R) 61 )2、-C 0-3 Alkyl-(N=)S(=O)(R 61 )2、-C 0-3 Alkyl-S(=O)(=NR) 62 )R 63 C 1-6 Alkyl, 4-10-membered heterocyclic alkyl, 5-10-membered heterocyclic alkenyl, 6-10-membered aryl or 5-10-membered heteroaryl, wherein C 1-6 Alkyl, 4-10-membered heterocyclic alkyl, 5-10-membered heterocyclic alkenyl, 6-10-membered aryl, and 5-10-membered heteroaryl are each independently and optionally bound by 1, 2, 3, or 4 Rs. 6a replace;

[0046] R 61 R 62 and R 63 H or C, independently respectively 1-6 alkyl;

[0047] Each R6a The independent components are H, halogen, oxo (=O), thio (C=S), OH, NH2, CN, and C, respectively. 1-6 Alkyl, Halogenated C 1-6 Alkyl or C 3-6 cycloalkyl;

[0048] Or, two Rs 61 Together with the P or S atoms to which they are attached, they form a 5-10 membered heterocyclic alkyl group, wherein the 5-10 membered heterocyclic alkyl group is optionally surrounded by 1, 2, 3 or 4 R atoms. 6b replace;

[0049] Each R 6b They are, independently, H, halogen, oxo (=O), OH, NH2, CN, and C, respectively. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-6 cycloalkyl, -L2-C 1-6 Alkyl, -L2-C 3-6 Cycloalkyl or -L2-4-8-membered heterocycloalkyl, wherein C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-6 cycloalkyl, -L2-C 1-6 Alkyl, -L2-C 3-6 The cycloalkyl or -L2-4-8-membered heterocycloalkyl groups are each optionally substituted by 1, 2, 3 or 4 Rs, independently;

[0050] Each L2 is independently -O-, -N(R) 2L -, -S-, -S(=O)-, -S(=O)2- or -C(=O)-;

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

[0052] Each R is independently H, halogen, OH, NH2, or CN;

[0053] When R1 is a halogen, R6 is -C. 0-3 Alkyl P(=O)(R) 61 )2、-C 0-3 Alkyl-(N=)S(=O)(R 61 )2、-C 0-3 Alkyl-S(=O)(=NR) 62 )R 63 Alternatively, a 5-10 membered heterocyclic alkenyl group, wherein at least one of the 5-10 membered heterocyclic alkenyl groups is substituted with a thio (C=S);

[0054] The heteroatomic groups in the "heterocyclic alkyl", "heterocyclic alkenyl" and "heteroaryl" include N, O, S, S(=O), S(=O)2 or S(=O)(=NH), and the number of the heteroatomic groups is 1, 2, 3 or 4; when the number of the heteroatomic groups is multiple, the heteroatomic groups may be the same or different.

[0055] In an optional embodiment of the present invention, the above-described compound, its tautomers, stereoisomers, pharmaceutically acceptable salts or prodrugs, wherein the compound has the structure of formula (I)

[0056]

[0057] in,

[0058] R1 is a halogen, OCF3, CN, or C. 2-6 Alkyl, -OC 2-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 4-10 membered heterocyclic alkyl group, wherein the C 2-6 Alkyl, -OC 2-6 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 [membered alkyl groups].

[0059] R 1a replace;

[0060] Each R 1a They are, independently, H, halogen, OH, NH2, CN, and C. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0061] R2, R3, and R4 are independently H, halogen, NH2, CN, and C, respectively. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0062] R5 and R7 can be independently H, halogen, NH2, CN, or C, respectively. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0063] R8 is H, D, halogen, or C. 1-6 alkyl;

[0064] L1 represents a single bond, -O-, -NH-, or -OC. 1-3 Alkyl-, -NH-C 1-3 Alkyl- or -C 1-3 Alkyl groups, wherein the -NH- and -OC- are... 1-3Alkyl-, -NH-C 1-3 Alkyl- and -C 1-3 The alkyl group is independently and optionally surrounded by 1, 2, 3 or 4 R groups. 1L replace;

[0065] Each R 1L Each is independently H, halogen, and C. 1-3 Alkyl or C 3-6 cycloalkyl;

[0066] R6 is -P (=O)(R 61 )2、-(N=)S(=O)(R 61 )2、-S(=O)(=NR 62 )R 63 CN, C 1-6 Alkyl, 4-10-membered heterocyclic alkyl, 5-10-membered heterocyclic alkenyl, 6-10-membered aryl or 5-10-membered heteroaryl, wherein C 1-6 Alkyl, 4-10-membered heterocyclic alkyl, 5-10-membered heterocyclic alkenyl, 6-10-membered aryl, and 5-10-membered heteroaryl are each independently and optionally bound by 1, 2, 3, or 4 Rs. 6a replace;

[0067] R 61 R 62 and R 63 H or C, independently respectively 1-6 alkyl;

[0068] Each R 6a They are, independently, H, halogen, oxo (=O), OH, NH2, CN, and C, respectively. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0069] Or, two Rs 61 Together with the P or S atoms to which they are attached, they form 5-10 membered heterocyclic alkyl groups;

[0070] When R1 is a halogen, R6 is -P (=O)(R 61 )2、-(N=)S(=O)(R 61 )2 or -S(=O)(=NR 62 )R 63 ;

[0071] The heteroatomic groups in the "heterocyclic alkyl", "heterocyclic alkenyl" and "heteroaryl" include N, O, S, S(=O), S(=O)2 or S(=O)(=NH), and the number of the heteroatomic groups is 1, 2, 3 or 4; when the number of the heteroatomic groups is multiple, the heteroatomic groups may be the same or different.

[0072] In an optional embodiment of the present invention, R1 is Cl, CN, -OCF3, C 2-4 alkynyl group, C 3-4 Cycloalkyl or 4-6 membered heterocycloalkyl, wherein C 2-4 alkynyl group, C 3-4 Cycloalkyl and 4-6 membered heterocycloalkyl groups are each independently and optionally bound by 1, 2, 3 or 4 R groups. 1a replace.

[0073] In an optional embodiment of the present invention, R1 is Cl, CN, -OCF3, -C≡C-CH3, In an optional embodiment of the present invention, the above-mentioned R 1a They are H or F, respectively, independently.

[0074] In an optional embodiment of the present invention, R2, R3 and R4 are each independently H.

[0075] In an optional embodiment of the present invention, the above-mentioned R5, R 51 R7 and R 71 Each is independently represented by H.

[0076] In an optional embodiment of the present invention, R5 and R7 are each independently H.

[0077] In an optional embodiment of the present invention, R8 is H or D.

[0078] In an optional embodiment of the present invention, L1 is a single bond, -C 1-3 Alkyl-, -OC 1-3 Alkyl-, -C 3-6 Cycloalkyl-.

[0079] In an optional embodiment of the present invention, L1 is a single bond, -CH2-, -O-CH2-, or...

[0080] In an optional embodiment of the present invention, L1 is a single bond, -CH2-, or -O-CH2-.

[0081] In an optional embodiment of the present invention, R6 is a 4-8-membered heterocyclic alkyl, a 5-8-membered heterocyclic alkenyl, or a 5-6-membered heteroaryl, wherein the 4-8-membered heterocyclic alkyl, 5-8-membered heterocyclic alkenyl, and 5-6-membered heteroaryl are each independently and optionally surrounded by 1, 2, 3, 4, or 5 R6 groups. 6a replace.

[0082] In an optional embodiment of the present invention, the above-mentioned R 6a It can be independently H, oxo (=O), thio (=S), CH3, -CH2CH3, CHF2, CF3 or cyclopropyl.

[0083] In an optional embodiment of the present invention, the above-mentioned R 6a Each of the above R groups is independently H, oxo (=O), thio (=S), CH3, CHF2, or cyclopropyl. In an optional embodiment of the invention, each of the above R groups is... 6a They can be H, oxo (=O), CH3 or CHF2, respectively.

[0084] In an optional embodiment of the present invention, R6 is...

[0085]

[0086] In an optional embodiment of the present invention, R6 is...

[0087] In an optional embodiment of the present invention, R6 is...

[0088] In an optional embodiment of the present invention, when R1 is Cl, R6 is -C. 0-3 Alkyl-P(=O)(R) 61 )2、-C 0-3 Alkyl-(N=)S(=O)(R 61 )2 or -C 0-3 Alkyl-S(=O)(=NR) 62 )R 63 .

[0089] In an optional embodiment of the invention, when R1 is Cl, R6 is a 5-8 membered heterocyclic alkenyl group, wherein at least one of the 5-8 membered heterocyclic alkenyl groups is substituted with a thio (=S). In an optional embodiment of the invention, when R1 is Cl, R6 is -P (=O)(R 61 )2、-(N=)S(=O)(R 61 )2 or -S(=O)(=NR 62 )R 63 .

[0090] In an optional embodiment of the present invention, R6 is -C. 0-3 Alkyl-P(=O)(R) 61 )2、-C 0-3 Alkyl-(N=)S(=O)(R 61 )2 or -C 0-3 Alkyl-S(=O)(=NR) 62 )R 63 .

[0091] In an optional embodiment of the present invention, R6 is -P(=O)(R 61 )2、-(N=)S(=O)(R 61 )2 or -S(=O)(=NR 62 )R 63 .

[0092] In an optional embodiment of the present invention, the above-mentioned R 61 R 62 and R 63 Each can be independently H, CH3, -CH2CH3, or cyclopropyl.

[0093] In an optional embodiment of the present invention, the above-mentioned R 61 R 62 and R 63 They are H or CH3, respectively, independently.

[0094] In an optional embodiment of the present invention, R6 is...

[0095] In an optional embodiment of the present invention, R6 is...

[0096] In an optional embodiment of the present invention, R6 is...

[0097] In an optional embodiment of the present invention, the above two Rs 61 Together with the P or S atoms to which they are attached, they form a 4-6 membered heterocyclic alkyl group, wherein the 4-6 membered heterocyclic alkyl group is optionally surrounded by 1, 2, 3 or 4 R atoms. 6b replace.

[0098] In an optional embodiment of the present invention, the above two Rs 61 Together with the P or S atom it is attached to, they form a heterocyclic alkyl group, wherein the heterocyclic alkyl group is a 5-6 membered heterocyclic alkyl group.

[0099] In an optional embodiment of the present invention, the above-mentioned R 62 With R 63 Together with the N and S atoms attached thereto, they form a 5-10 membered heterocyclic alkenyl group, which is optionally surrounded by 1, 2, 3 or 4 R atoms. 6b replace.

[0100] In an optional embodiment of the present invention, the above-mentioned R 6b They are, independently, H, halogen, oxo (=O), OH, NH2, CN, and C, respectively. 1-3 Alkyl, Halogenated C 1-6 Alkyl, C 3-6cycloalkyl, -L2-C 1-3 Alkyl, -L2-C 3-5 Cycloalkyl or -L2-4-6-membered heterocycloalkyl, wherein C 1-3 Alkyl, Halogenated C 1-6 Alkyl, C 3-6 cycloalkyl, -L2-C 1-3 Alkyl, -L2-C 3-5 The cycloalkyl or -L2-4-6-membered heterocycloalkyl groups are each optionally substituted by 1, 2, 3 or 4 Rs, respectively.

[0101] In an optional embodiment of the present invention, the above-mentioned R 6b H and -C (=O)-C are independently represented respectively. 1-3 Alkyl, or -C(=O)-C 3-5 Cycloalkyl.

[0102] In an optional embodiment of the present invention, the above-mentioned R 6b They are independently H, -C(=O)-CH3, -C(=O)-CH2CH3 or -C(=O)-cyclopropyl.

[0103] In an optional embodiment of the present invention, each of the above-mentioned L2s is independently -O-, -N(R) 2L )- or -C(=O)-.

[0104] In an optional embodiment of the present invention, the above-mentioned R 2L For H.

[0105] In an optional embodiment of the present invention, R6 is -C. 0-3 Alkyl-P(=O)(R) 61 )2 or -C 0-3 Alkyl-(N=)S(=O)(R 61 )2, where two R 61 When R6 forms a heterocyclic alkyl group together with the P or S atom it is attached to, R6 is...

[0106] In an optional embodiment of the present invention, R6 is -C. 0-3 Alkyl-S(=O)(=NR) 62 )R 63 , where R 62 With R 63 When R6 forms a 5-10 membered heterocyclic alkenyl group together with the N and S atoms it is attached to, R6 is

[0107] In an optional embodiment of the present invention, R6 is -C. 0-3 Alkyl-P(=O)(R) 61)2、-C 0-3 Alkyl-(N=)S(=O)(R 61 2. 4-10-membered heterocyclic alkyl or 5-10-membered heterocyclic alkenyl, wherein two R 61 When R6 forms a heterocyclic alkyl group together with the P or S atom it is attached to, R6 is...

[0108] In an optional embodiment of the present invention, R6 is -C. 0-3 Alkyl-P(=O)(R) 61 )2、-C 0-3 Alkyl-(N=)S(=O)(R 61 )2 or 5-10 membered heterocyclic alkenyl groups, wherein two R 61 When R6 forms a heterocyclic alkyl group together with the P or S atoms it is attached to, R6 is...

[0109]

[0110] In an optional embodiment of the present invention, R6 is...

[0111] In an optional embodiment of the present invention, R6 is...

[0112] In an optional embodiment of the present invention, the above-mentioned two R 61 When R6 forms a heterocyclic alkyl group together with the P or S atoms it is attached to, R6 is...

[0113] In an optional embodiment of the present invention, R6 is... In an optional embodiment of the present invention, R6 is... In an optional embodiment of the present invention, R6 is...

[0114] In an optional embodiment of the present invention, the aforementioned R6 is a 5-8 membered heterocyclic alkenyl group, wherein the 5-8 membered heterocyclic alkenyl group is surrounded by 1, 2, 3 or 4 R groups. 6a Replacement, where at least one R 6a It is thiolated (=S).

[0115] In an optional embodiment of the present invention, when R1 is Cl, R6 is In an optional embodiment of the present invention, when R1 is Cl, R6 is

[0116] In an optional embodiment of the present invention, the above-mentioned compound is selected from the following structures:

[0117]

[0118] R1 and R8 are defined as described in this invention, wherein L1 and R6 satisfy one or more of the following conditions:

[0119] (1c) L1 is a single bond, -CH2-, -O-CH2- or...

[0120] (2c) R6 is a 4-8 membered heterocyclic alkyl, a 5-8 membered heterocyclic alkenyl, or a 5-6 membered heteroaryl, wherein the 4-8 membered heterocyclic alkyl, the 5-8 membered heterocyclic alkenyl, and the 5-6 membered heteroaryl are each independently selected by 1, 2, 3, 4, or 5 R6 groups. 6a Replace; the R 6a They can be independently H, oxo (=O), thio (=S), CH3, -CH2CH3, CHF2, CF3 or cyclopropyl;

[0121] (3c)R6 is

[0122] (4c)R6 is -C 0-3 Alkyl-P(=O)(R) 61 )2、-C 0-3 Alkyl-(N=)S(=O)(R 61 )2 or -C 0-3 Alkyl-S(=O)(=NR) 62 )R 63 The R 61 R 62 and R 63 Each can be independently H, CH3, -CH2CH3, or cyclopropyl;

[0123] (5c)R6 is

[0124] (6c)R6 is -C 0-3 Alkyl-P(=O)(R) 61 )2、-C 0-3 Alkyl-(N=)S(=O)(R 61 )2, two R 61Together with the P or S atoms to which they are attached, they form a heterocyclic alkyl group, wherein the heterocyclic alkyl group is a 5-6 membered heterocyclic alkyl group, and the 5-6 membered heterocyclic alkyl group is optionally surrounded by 1, 2, 3 or 4 R atoms. 6b Replace; each of the R 6b They are, independently, H, halogen, oxo (=O), OH, NH2, CN, and C, respectively. 1-3 Alkyl, -L2-C 1-3 Alkyl, -L2-C 3-5 Cycloalkyl or -L2-4-6-membered heterocycloalkyl; wherein L2 is -O-, -NH- or -C(=O)-;

[0125] (7c)R6 is The R 6b Hydrogen, L2-C 1-3 Alkyl, L2-C 3-5 Cycloalkyl, L2-4-6-membered heterocycloalkyl, wherein L2 is -C(=O)-;

[0126] (8c)R6 is The R 6b For hydrogen,

[0127] (9c)R6 is -C 0-3 Alkyl-S(=O)(=NR) 62 )R 63 The R 62 With R 63 Together with the N and S atoms attached thereto, they form 4-10 membered heterocyclic alkyl groups, wherein the 5-10 membered heterocyclic alkyl groups are optionally bound by 1, 2, 3 or 4 R atoms. 6b When replacing, R6 is

[0128] (10c)R6 is

[0129] In an optional embodiment of the present invention, the above-mentioned compound is selected from the following structures:

[0130]

[0131] R1 and R8 are defined as described in this invention, wherein L1 and R6 satisfy one or more of the following conditions:

[0132] (1c)L1 is a single bond, -CH2- or -O-CH2-;

[0133] (2c) R6 is a 4-8 membered heterocyclic alkyl, a 5-8 membered heterocyclic alkenyl, or a 5-6 membered heteroaryl, wherein the 4-8 membered heterocyclic alkyl, the 5-8 membered heterocyclic alkenyl, and the 5-6 membered heteroaryl are each independently selected by 1, 2, 3, or 4 R6 groups.6a Replace; the R 6a They can be independently H, oxo (=O), thio (C=S), CH3, CHF2, or cyclopropyl;

[0134] (3c)R6 is

[0135] (4c)R6 is -C 0-3 Alkyl-P(=O)(R) 61 )2、-C 0-3 Alkyl-(N=)S(=O)(R 61 )2 or -C 0-3 Alkyl-S(=O)(=NR) 62 )R 63 The R 61 R 62 and R 63 They can be H or CH3 independently, respectively;

[0136] (5c)R6 is

[0137] (6c)R6 is -C 0-3 Alkyl-P(=O)(R) 61 )2、-C 0-3 Alkyl-(N=)S(=O)(R 61 )2, two R 61 Together with the P or S atoms to which they are attached, they form a heterocyclic alkyl group, wherein the heterocyclic alkyl group is a 5-6 membered heterocyclic alkyl group, and the 5-6 membered heterocyclic alkyl group is optionally surrounded by 1, 2, 3 or 4 R atoms. 6b Replace; each of the R 6b They are, independently, H, halogen, oxo (=O), OH, NH2, CN, and C, respectively. 1-3 Alkyl, -L2-C 1-3 Alkyl, -L2-C 3-5 Cycloalkyl or -L2-4-6-membered heterocycloalkyl; wherein L2 is -O-, -NH- or -C(=O)-;

[0138] (7c)R6 is The R 6b Hydrogen, L2-C 1-3 Alkyl, L2-C 3-5 Cycloalkyl, L2-4-6-membered heterocycloalkyl, wherein L2 is -C(=O)-;

[0139] (8c)R6 is The R 6b For hydrogen,

[0140] (9c)R6 is

[0141] In an optional embodiment of the present invention, the above-mentioned compound is selected from the following structures:

[0142]

[0143] The definitions of L1 and R8 are as described in this invention, wherein R6 satisfies one or more of the following conditions:

[0144] (1d)R6 is -C 0-3 Alkyl-P(=O)(R) 61 )2、-C 0-3 Alkyl-(N=)S(=O)(R 61 )2 or -C 0-3 Alkyl-S(=O)(=NR) 62 )R 63 ;

[0145] (2d)R6 is

[0146]

[0147] (3d)R6 is a 4-8 membered heterocyclic alkyl group or a 5-6 membered heterocyclic alkenyl group, wherein at least one of the 4-8 membered heterocyclic alkyl group and the 5-6 membered heterocyclic alkenyl group is substituted with a thio (C=S);

[0148] (4d)R6 is

[0149] In an optional embodiment of the present invention, the above-mentioned compound is selected from the following structures:

[0150]

[0151] Where R6 is -C 0-3 Alkyl-P(=O)(R) 61 )2、-C 0-3 Alkyl-(N=)S(=O)(R 61 )2 or -C 0-3 Alkyl-S(=O)(=NR) 62 )R 63 ;

[0152] And / or, R6 is

[0153] And / or, R6 is a 5-6 membered heterocyclic alkenyl group, wherein at least one of the 5-6 membered heterocyclic alkenyl groups is substituted with a thio (C=S);

[0154] And / or, R6 is

[0155] The definition of R8 is as defined in this invention.

[0156] In an optional embodiment of the present invention, L1 is a single bond, and R6 is selected from...

[0157] In an optional embodiment of the present invention, R6 is...

[0158] In an optional embodiment of the present invention, R6 is...

[0159] In an optional embodiment of the present invention, R6 is...

[0160] In an optional embodiment of the present invention, R6 is...

[0161] In an optional embodiment of the present invention, R6 is...

[0162] In an optional embodiment of the present invention, R6 is...

[0163] In an optional embodiment of the present invention:

[0164] (1e) R6 is a 4-8-membered heterocyclic alkyl, a 5-8-membered heterocyclic alkenyl, or a 5-6-membered heteroaryl, wherein the 4-8-membered heterocyclic alkyl, 5-8-membered heterocyclic alkenyl, and 5-6-membered heteroaryl are each independently selected by 1, 2, 3, 4, or 5 R6 groups. 6a Replace; or,

[0165] (2e)R6 is -C 0-3 Alkyl-P(=O)(R) 61 )2、-C 0-3 Alkyl-(N=)S(=O)(R 61 )2 or -C 0-3 Alkyl-S(=O)(=NR) 62 )R 63 The

[0166] R 61 R 62 and R 63 H and C are independent of each other. 1-6 Alkyl or C3-6 cycloalkyl; or,

[0167] (3e)R6 is -C 0-3 Alkyl-P(=O)(R) 61 )2、-C 0-3 Alkyl-(N=)S(=O)(R 61 )2, the two R 61 Together with the P or S atoms to which they are attached, they form a 4-6 membered heterocyclic alkyl group, wherein the 4-6 membered heterocyclic alkyl group is optionally surrounded by 1, 2, 3 or 4 R atoms. 6b Replace; or,

[0168] (4e)R6 is -C 0-3 Alkyl-S(=O)(=NR) 62 )R 63 The R 62 With R 63 Together with the N and S atoms attached thereto, they form a 5-10 membered heterocyclic alkenyl group, which is optionally surrounded by 1, 2, 3 or 4 R atoms. 6b Replace; or,

[0169] (5e) R6 is a 4-8 membered heterocyclic alkyl group or a 5-8 membered heterocyclic alkenyl group, wherein the 4-8 membered heterocyclic alkyl group and the 5-8 membered heterocyclic alkenyl group are separated by 1, 2, 3, 4, 5 or 6 R groups. 6a Replacement, where at least one R 6a It is thiolated (=S).

[0170] In an optional embodiment of the present invention:

[0171] (1f)R6 is

[0172] Better place,

[0173] or,

[0174] (2f)R6 is or,

[0175] (3f)R6 is Ideally, R6 is or,

[0176] (4f)R6 is or

[0177] (5f)R6 is Ideally, R6 is

[0178] In an optional embodiment of the present invention:

[0179] R6 is selected from -(N=)S(=O)(R 61 )2, 4-7 membered heterocyclic alkyl groups, 5-6 membered heterocyclic alkenyl groups; the R 61 Each is independently CH3, CHF2, or cyclopropyl; the 4-7 membered heterocyclic alkyl group and the 5-6 membered heterocyclic alkenyl group are optionally surrounded by 1, 2, 3, 4, or 5 R groups. 6a Replacement, where at least one R 6a Selected from thiocyanates (C=S); or, two Rs 61 Together with the S atom it is attached to, they form a 5-6 membered heterocyclic alkyl group, which is optionally surrounded by 1, 2, 3 or 4 R atoms. 6b replace;

[0180] R6 is selected from

[0181] Preferably, R6 is selected from

[0182] Better yet, R6 is selected from

[0183] In an optional embodiment of the present invention, the above compound has the following structure:

[0184]

[0185]

[0186] In a second aspect, the present invention provides a pharmaceutical composition comprising: a compound as described in the first aspect of the present invention, a tautomer, a stereoisomer, a pharmaceutically acceptable salt or prodrug thereof; and a pharmaceutically acceptable excipient.

[0187] In a third aspect of the present invention, the use of the compounds, tautomers, stereoisomers, pharmaceutically acceptable salts or prodrugs described in the first aspect of the present invention, and the pharmaceutical compositions described in the second aspect of the present invention in the preparation of medicaments for the treatment or prevention of diseases related to VAV1.

[0188] In an optional embodiment of the present invention, the aforementioned VAV1-related diseases include cancer and autoimmune diseases.

[0189] In an optional embodiment of the present invention, the above-mentioned drug is used to treat or prevent cancer and autoimmune diseases.

[0190] In an optional embodiment of the present invention, the above-mentioned drug is used for the treatment or prevention of, but not limited to, systemic lupus erythematosus, myasthenia gravis, periodontitis, type I diabetes, rheumatoid arthritis, multiple sclerosis, colitis, inflammatory bowel disease, autoimmune hepatitis, or psoriasis.

[0191] In an optional embodiment of the present invention, the aforementioned VAV1-related diseases include systemic lupus erythematosus, myasthenia gravis, periodontitis, type I diabetes, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, autoimmune hepatitis, or psoriasis.

[0192] In an optional embodiment of the present invention, the aforementioned VAV1-related diseases include, but are not limited to, systemic lupus erythematosus, myasthenia gravis, periodontitis, type I diabetes, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, autoimmune hepatitis, psoriasis, etc.

[0193] Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.

[0194] Terms and Definitions

[0195] Unless otherwise stated, the terms and definitions used in this application, including those set forth in the specification and claims, are as follows.

[0196] Those skilled in the art will understand that, according to the conventions used in the art, in the structural formula of this application, Used to describe chemical bonds, which are points where a portion or a substituent is connected to a core or skeletal structure.

[0197] Unless otherwise specified, the term "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0198] Unless otherwise specified, the term "pharmaceutically acceptable salt" means a pharmaceutically acceptable non-toxic salt of an acid or base, including salts of inorganic acids and bases, and salts of organic acids and bases.

[0199] In addition to pharmaceutically acceptable salts, the present invention also contemplates other salts. These may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts, or may be used for the identification, characterization, or purification of the compounds of the present invention.

[0200] Unless otherwise specified, the term "pharmaceutical composition" means a mixture of one or more compounds described in this text or their physiologically / pharmaceutical acceptable salts or prodrugs with other chemical components, such as physiologically / pharmaceutical acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compound to a living organism.

[0201] Unless otherwise specified, the term "excipient" refers to a pharmaceutically acceptable inert ingredient. Examples of the term "excipient" include, without limitation, binders, disintegrants, lubricants, flow aids, stabilizers, fillers, and diluents. Excipients enhance the handling properties of pharmaceutical formulations, i.e., by increasing flowability and / or adhesion, making the formulation more suitable for direct compression.

[0202] Unless otherwise specified, the term "prodrug" refers to a compound of the present invention that can be converted into a biologically active form under physiological conditions or by solvation. The prodrugs of the present invention are prepared by modifying functional groups in the compound; such modification can be performed by conventional methods or removed in vivo to obtain the parent compound. Prodrugs comprise compounds formed by attaching a hydroxyl or amino group to any group within the compound of the present invention. When a prodrug of the compound of the present invention is administered to a mammalian individual, the prodrug is cleaved to form free hydroxyl and free amino groups, respectively.

[0203] Unless otherwise specified, the term "stereoisomer" refers to isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, non-corresponding isomers, and conformational isomers.

[0204] Depending on the choice of raw materials and methods, the compounds of the present invention may exist as one or a mixture of possible isomers, for example as purely optical isomers, or as mixtures of isomers, such as racemic and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to the chiral center (or multiple chiral centers) in the molecule. The prefixes D and L or (+) and (–) are symbols used to specify the plane-polarized rotation of light induced by the compound, where (–) or L indicates that the compound is levorotatory. Compounds with the prefix (+) or D are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be called enantiomers, and mixtures of said isomers are generally referred to as mixtures of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or method. Many geometric isomers of alkenes, C=N double bonds, etc., can also exist in the compounds described herein, and all such stable isomers are considered in this invention. When the compounds described herein contain an alkene double bond, unless otherwise stated, such double bond includes E and Z geometric isomers. If the compound contains a disubstituted cycloalkyl group, the substituent of the cycloalkyl group may be in cis or trans (cis- or trans-) configuration.

[0205] When the bonds of the chiral carbon in the formulas of this invention are depicted as straight lines, it should be understood that both the (R) and (S) configurations of the chiral carbon and the resulting enantiomerically pure compounds and mixtures thereof are included within the scope of the general formula. The illustration of racemic or enantiomerically pure compounds in this document is derived from Maehr, J. Chem. Ed. 1985, 62:114-120. Unless otherwise stated, wedge-shaped and dashed bonds represent the absolute configuration of a stereocenter.

[0206] Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral formulations, or resolved using conventional techniques. Compounds of the present invention containing asymmetrically substituted carbon atoms can be separated in either an optically active or racemic form. Resolution of racemic mixtures of compounds can be performed by any of many methods known in the art. Exemplary methods include fractional recrystallization using a chiral resolving acid, which is an optically active salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or various optically active camphorsulfonic acids such as the D and L forms of β-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure α-methylbenzylamine (e.g., S and R forms or diastereoisomeric forms), 2-phenylglycine, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc. Resolution of racemic mixtures can also be achieved by elution onto a chromatographic column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). High-performance liquid chromatography (HPLC) or supercritical fluid chromatography (SFC) can be used. The specific method, elution conditions, and column selection can be chosen by those skilled in the art based on the structure of the compound and experimental results. Furthermore, any enantiomer or diastereomeric form of the compound described in this invention can be obtained through stereoorganic synthesis using optically pure starting materials or reagents with known configurations.

[0207] Unless otherwise specified, the term "tautomer" refers to a functional group isomer resulting from the rapid movement of an atom between two positions in a molecule. The compounds of this invention can exhibit tautomerism. Tautomeric compounds can exist in two or more interconvertible forms. Proton-transfer tautomers arise from the migration of covalently bonded hydrogen atoms between two atoms. Tautomers generally exist in equilibrium form, and attempts to isolate a single tautomer usually produce a mixture whose physicochemical properties are consistent with those of the mixture of compounds. The equilibrium position depends on the intramolecular chemical characteristics. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the ketone form is dominant; while in phenols, the enol form is dominant. This invention encompasses all tautomeric forms of compounds. For example... They can be transformed into each other.

[0208] Unless otherwise specified, use wedge-shaped solid line keys. and wedge-shaped dashed key The absolute configuration of the center of a solid is represented by a straight solid line key. and straight dashed key Represents the relative configuration of the center of a solid.

[0209] The compounds of the present invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes such as deuterium (2H), tritium (3H), iodine-125 (125I), or C-14 (14C). All variations in the isotopic composition of the compounds of the present invention, regardless of radioactivity, are included within the scope of the present invention.

[0210] For pharmaceuticals or pharmacologically active agents, the term "effective amount" or "therapeutic effective amount" refers to a sufficient quantity of a drug or agent that is non-toxic but achieves the desired effect. For the oral dosage forms of this invention, the "effective amount" of one active substance in the composition refers to the quantity required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. A suitable effective amount in any given case can be determined by a person skilled in the art through routine testing.

[0211] Unless otherwise specified, the terms “active ingredient,” “therapeutic agent,” “active substance,” or “active agent” refer to a chemical entity that can effectively treat a target disorder, disease, or condition.

[0212] Unless otherwise specified, the term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, including deuterium and hydrogen variants, provided that the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =O), it can be expressed as the oxidation of atoms such as carbon, nitrogen, and sulfur, including but not limited to C(=O), S(=O), S(=O)2, or N(=O).

[0213] Unless otherwise specified, the terms “optional” or “optionally” refer to events or conditions described below that may but are not required to occur, and the description includes both cases where said events or conditions occur and cases where said events or conditions do not occur.

[0214] The term "optionally substituted" means that it may or may not be substituted, unless otherwise specified, and the type and number of substituents may be arbitrary on the basis of chemical feasibility.

[0215] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is substituted by 0-2 Rs, the group can optionally be substituted by at most two Rs, and the Rs in each case have independent options. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0216] Unless otherwise specified, the term "D" is used to denote the isotope deuterium (D). 2 H).

[0217] Unless otherwise specified, the term "C" 1-6 "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C 1-6 Alkyl groups include C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-4 C6 and C5 alkyl groups, etc.; they can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). 1-6 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc.

[0218] Unless otherwise specified, the term "C" 1-3 "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C 1-3 Alkyl groups include C 1-2 and C 2-3 Alkyl groups, etc.; they can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). C 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), methylene (-CH2-), ethyl (Et), propyl (including n-propyl and isopropyl), etc.

[0219] The term "halogenated" is used interchangeably with the term "halogenated" when used alone or as part of other substituents.

[0220] 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.

[0221] 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.

[0222] 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 pentyynyl. Unless otherwise specified, the term "C" refers to... 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.

[0223] Unless otherwise specified, the term "C" 1-3 "Alkoxy" refers to alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule by an oxygen atom. The C 1-3 Alkoxy groups include C 1-2 C 2-3 Examples of C1-3 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy).

[0224] 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.

[0225] 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 C 3-12 Cycloalkyl groups include 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.

[0226] 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.

[0227] Unless otherwise specified, the term "C" 3-6 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which can be monocyclic or bicyclic. 3-6 Cycloalkyl groups include C 3-5 C 4-5 and C 5-6 Cycloalkyl groups, etc.; they can be monovalent, divalent, or polyvalent. C 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0228] Unless otherwise specified, Cn-n+m or Cn-Cn+m includes any specific case of n to n+m carbons, such as C 1-12 Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 C 11 and C 12It also includes any range from n to n+m, such as C 1-12 Including C 1-3 C 1-6 C 1-9 C 3-6 C 3-9 C 3-12 C 6-9 C 6-12 and C 9-12 Similarly, n-membered to n+m-membered rings represent the number of atoms in the ring from n to n+m. For example, 3-12-membered rings include 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, and 12-membered rings, and also any range from n to n+m. For example, 3-12-membered rings include 3-6-membered, 3-9-membered, 5-6-membered, 5-7-membered, 6-7-membered, 6-8-membered, and 6-10-membered rings, etc.

[0229] When used alone or as part of other substituents, the term "heterocyclic alkyl" refers to a cycloalkyl group in which one or more (in some embodiments, 1 to 3) carbon atoms are replaced by heteroatoms, such as, but not limited to, N, NH, O, S, P, S(=O), S(=O)2, or S(=O)(=NH). The term "mn-membered heterocyclic alkyl" should be understood to represent a saturated ring having m to n atoms, wherein the heterocyclic atom is selected from N, NH, O, S, P, S(=O), S(=O)2, or S(=O)(=NH), preferably from N, O, or S. For example, the term "4-8-membered heterocyclic alkyl" should be understood to represent a saturated or partially saturated ring having 4 to 8 atoms, wherein 1, 2, 3, or 4 ring atoms are selected from N, O, S, P, preferably from N, O, or S. "4-10-membered heterocyclic alkyl" represents a saturated ring having 4 to 10 atoms. When prefixes such as 4-8 or 4-10 are used to denote heterocyclic alkyl groups, the number of carbon atoms also implies the inclusion of heteroatoms. These include monocyclic, bicyclic, tricyclic, spirocyclic, or bridged rings. Examples of heterocyclic alkyl groups include: pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydropyridyl, tetrahydropyrrolidinyl, azaheptanyl, thiazolyl, azoleyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, azaheptanyl, diazaheptanyl, oxonitrileheptanyl, etc. The term "heterocyclic alkyl" can be used interchangeably with the term "heteroalkyl ring."

[0230] When used alone or as part of other substituents, the term "aromatic ring" refers to a monocyclic or polycyclic carbon ring having 6 to 20 carbon atoms, wherein at least one ring is an aromatic ring. When one of the rings is a non-aromatic ring, the group can be linked by either an aromatic or non-aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, 2,3-dihydroindenyl, biphenyl, phenanthryl, anthraceneyl, and acenaphthene. The term "aromatic ring" may be used interchangeably with the term "aryl".

[0231] When used alone or as part of other substituents, the term "heteroaromatic ring" refers to a monocyclic or polycyclic carbon ring in which at least one ring atom is a heteroatom independently selected from oxygen, sulfur, and nitrogen, and the remaining ring atoms are carbon atoms, wherein at least one ring is an aromatic ring. The group can be a carbon group or a heteroatom group (i.e., it can be C-linked or N-linked, whichever is possible). When one of the rings is a non-aromatic ring, the group can be linked by an aromatic ring or by a non-aromatic ring. Examples of heteroaromatic groups include, but are not limited to: imidazolyl, acridinel, carbazolyl, cenolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furanyl, thiophenyl, benzothiophenyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridinyl, pyrimidinel, pyrroleyl, N-methylpyrroleyl, and tetrahydroquinoline. The term “heteroaromatic ring” can be used interchangeably with the terms “heteroaromatic ring”, “heteroaryl”, or “heteroaromatic ring group”.

[0232] Unless otherwise specified, the term "5-6 membered heterocyclic alkenyl" on its own or in combination with other terms refers to an unsaturated or partially unsaturated cyclic group consisting of 5 to 6 ring atoms, comprising at least one carbon-carbon double bond, but not an aromatic ring, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen, and sulfur heteroatoms may optionally be oxidized (i.e., C(=O), NO, and S(O)p, where p is 1 or 2). Furthermore, with respect to the "5-6 membered heterocyclic alkenyl," the heteroatom may occupy the connection position between the heterocyclic alkenyl group and the rest of the molecule. The 5-6 membered heterocyclic alkenyl includes 5-membered and 6-membered heterocyclic alkenyl groups, etc.

[0233] Unless otherwise specified, the terms "5-6-membered heteroaryl" and "5-6-membered heteroaryl" are used interchangeably in this invention. The term "5-6-membered heteroaryl" refers to a monocyclic group with a conjugated π-electron system consisting of 5 to 6 ring atoms, where 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)p, where p is 1 or 2). The 5-6-membered heteroaryl can be attached to the rest of the molecule via heteroatoms or carbon atoms. The 5-6-membered heteroaryl includes both 5-membered and 6-membered heteroaryl groups. Examples of the 5-6 membered heteroaryl groups include, but are not limited to, pyrrole (including N-pyrrole, 2-pyrrole, and 3-pyrrole), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl), imidazole (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5-oxazolyl), and triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl). (and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isooxazolyl, 4-isooxazolyl and 5-isooxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).

[0234] Unless otherwise specified, the terms "halogen" or "halogen" refer to fluorine, chlorine, bromine, and iodine.

[0235] Furthermore, it should be noted that, unless otherwise explicitly stated, the descriptive phrase "...independently" used in this invention should be interpreted broadly, meaning that the described individuals are independent of each other and can independently be the same or different specific groups. More specifically, the descriptive phrase "...independently" can mean either that the specific options expressed by the same symbols in different groups do not affect each other, or that the specific options expressed by the same symbols in the same group do not affect each other.

[0236] Unless otherwise specified, the term "patient" means any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, with human being being the most preferred.

[0237] Unless otherwise specified, the term “therapeutic effective amount” means the amount of an active compound or drug that researchers, veterinarians, physicians or other clinicians are looking for in a tissue, system, animal, individual or human to elicit a biological or medical response, including one or more of the following: (1) prevention of disease: for example, prevention of disease, disorder or condition in an individual who is susceptible to disease, disorder or condition but has not yet experienced or developed the pathology or symptoms of the disease. (2) suppression of disease: for example, suppression of disease, disorder or condition in an individual who is experiencing or developing the pathology or symptoms of the disease (i.e., preventing the further development of the pathology and / or symptoms). (3) relief of disease: for example, relief of disease, disorder or condition in an individual who is experiencing or developing the pathology or symptoms of the disease (i.e., reversal of the pathology and / or symptoms).

[0238] The term "treatment" and other similar synonyms used in this article include the following meanings:

[0239] (i) To prevent the occurrence of disease or condition in mammals, especially when such mammals are susceptible to the disease or condition but have not yet been diagnosed with it;

[0240] (ii) To suppress a disease or symptom, that is, to curb its development;

[0241] (iii) To alleviate a disease or symptom, that is, to cause the condition of the disease or symptom to subside; or

[0242] (iv) To alleviate the symptoms caused by the disease or condition.

[0243] The abbreviations of this invention are defined as follows:

[0244] DC 50 The half-maximum degradation concentration refers to the concentration at which a compound achieves half of its maximum degradation effect.

[0245] M: Molar concentration, such as 1M hydrochloric acid, which represents a 1 mol / L hydrochloric acid solution.

[0246] N: Equivalent concentration, for example, 2N hydrochloric acid represents a 2 mol / L hydrochloric acid solution.

[0247] DMSO: Dimethyl sulfoxide

[0248] Bpin: Pinaryl borate.

[0249] Beneficial effects

[0250] According to embodiments of the present invention, the present invention has at least one of the following technical effects:

[0251] 1) The compounds of this invention can induce direct binding between VAV1 and CRBN in a dose-dependent manner;

[0252] 2) The compounds of this invention exhibit excellent degradation effects on VAV1 protein in a dose-dependent manner;

[0253] 3) In CD3 / CD28-induced Jurkat cell and T cell activation models, the compounds of this invention significantly inhibited IL-2 production, and the inhibitory function was positively correlated with the dose;

[0254] 4) The compounds of this invention exhibit excellent pharmacokinetic properties and good drug-likeness in pharmacokinetic studies in mice and rats;

[0255] 5) The compounds of this invention exhibit excellent stability in human liver microsomes, good thermodynamic solubility, no significant CYP3A4 inhibition, and a significant advantage in plasma protein binding rate, and have good drug-like properties;

[0256] 6) The test compound group of the present invention showed significant relief of disease progression in an adoptive naïve T cell-induced mouse enteritis model. Detailed Implementation

[0257] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that the following description is merely the most preferred embodiment of the present invention and should not be considered as a limitation on the scope of protection of the present invention. Based on a full understanding of the present invention, experimental methods in the following embodiments that do not specify specific conditions are generally performed under conventional conditions or as recommended by the manufacturer. Those skilled in the art can make non-essential modifications to the technical solutions of the present invention, and such modifications should be considered to be included within the scope of protection of the present invention.

[0258] Preparation of intermediate A

[0259] 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)piperidin-2,6-dione

[0260]

[0261] The synthetic route for intermediate A is shown below:

[0262]

[0263] Step 1: 2-(3-bromo-2-chlorophenyl)acetonitrile (A2)

[0264] 3-Bromo-2-chlorobenzyl bromide (A1) (9.0 g, 31.65 mmol) was placed in a reaction flask, and acetonitrile (100 mL) was added. Trimethylcyanosilane (6.3 g, 63.3 mmol) and potassium carbonate (13 g, 100 mmol) were added under ice bath conditions. The reaction solution was reacted at 80 °C for 16 h. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with ethyl acetate (500 mL), washed with saturated sodium chloride aqueous solution (500 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 10:1) to give 2-(3-bromo-2-chlorophenyl)acetonitrile (A2).

[0265] LC-MS, M / Z (ESI): 230.1 [M+H] + .

[0266] Step 2: Methyl 4-(3-bromo-2-chlorophenyl)-4-cyanobutyrate (A3)

[0267] 2-(3-bromo-2-chlorophenyl)acetonitrile (5.0 g, 21.74 mmol) (A2) was placed in a reaction flask, and methyl acrylate (3.74 g, 43.5 mmol) and tetrahydrofuran (100 mL) were added. Sodium methoxide (110 mg, 2 mmol) was then added under ice bath conditions, and the reaction mixture was allowed to react at room temperature for 2 h. After the reaction was complete, the reaction mixture was diluted with ethyl acetate (500 mL), washed with sodium chloride aqueous solution (500 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 5:1) to give methyl 4-(3-bromo-2-chlorophenyl)-4-cyanobutyrate (A3) (5.95 g, yield: 87%).

[0268] LC-MS, M / Z (ESI): 316.2 [M+H] + .

[0269] Step 3: 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (A4)

[0270] Methyl 4-(3-bromo-2-chlorophenyl)-4-cyanobutyrate (A3) (5.9 g, 18.7 mmol) was dissolved in acetic acid (100 mL), and 0.5 mL of concentrated sulfuric acid was added at 20 °C. The reaction mixture was reacted at 90 °C for 6 hours. After the reaction was complete, 2.0 g of sodium acetate was added at 20 °C, and the mixture was stirred at room temperature for 30 min. The solvent was removed by vacuum distillation, and then diluted with ethyl acetate (500 mL). The solution was then washed with saturated sodium chloride aqueous solution (500 mL × 1), saturated sodium bicarbonate aqueous solution (500 mL × 2), and saturated sodium chloride aqueous solution (500 mL × 1), respectively. The organic phase was then collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:1) to give compound 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (A4).

[0271] LC-MS, M / Z (ESI): 302.1 [M+H] + .

[0272] 1 H NMR(400MHz,DMSOd6)δ10.93(s,1H),7.71(dd,1H),7.37(dd,1H),7.27(t,1H),4 .31(dd,1H),2.77(ddd,1H),2.58–2.49(m,1H),2.31(qd,1H),2.04–1.95(m,1H).

[0273] Step 4: 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)piperidine-2,6-dione

[0274]

[0275] Compound 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (A4) (4.6 g, 15.2 mmol) was placed in a reaction flask, followed by the addition of pinacol diboron ester (7.6 g, 30 mmol), potassium acetate (4.5 g, 45.6 mmol), 1,1'-bis(di-phenylphosphino)ferrocene palladium chloride (0.3 g, 0.45 mmol), and 1,4-dioxane (70 mL). The reaction mixture was stirred at 100 °C for 8 hours under nitrogen protection. The reaction solution was cooled to room temperature, diluted with ethyl acetate (500 mL), washed with saturated sodium chloride aqueous solution (500 mL × 3), and then the organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 1:1) to give compound 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)piperidine-2,6-dione (intermediate A).

[0276] LC-MS, M / Z (ESI): 350.2 [M+H] + .

[0277] Example 1: Preparation of target compound 1

[0278] 3-[2-chloro-4'-(dimethylphosphoryl)[1,1'-biphenyl]-3-yl]piperidin-2,6-dione (compound 1)

[0279]

[0280] The synthetic route for target compound 1 is shown below:

[0281]

[0282] Step 1: (4-Bromophenyl)di(methyl)(oxo)-λ 5 Synthesis of phosphine (compounds 1-2)

[0283] 4-Bromo-iodobenzene (1.0 g, 3.5 mmol), dimethylphosphine oxide (900 mg, 10.5 mmol), triethylamine (1.8 g, 17.5 mmol), tris(dibenzylideneacetone)dipalladium (300 mg, 0.3 mmol), and 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (350 mg, 0.6 mmol) were dissolved in 1,4-dioxane (15 mL). The reaction mixture was heated to 60 °C and stirred overnight under nitrogen protection. After the reaction was complete, the reaction mixture was diluted with saturated brine (60 mL) and then extracted with ethyl acetate (50 mL × 2). The organic phases were combined, dried over sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 1) to give compound (4-bromophenyl)di(methyl)(oxo)-λ. 5 - Phosphine (compounds 1-2).

[0284] LC-MS,M / Z(ESI):233.2 / 235.2[M+H] +

[0285] Step 2: Dimethyl(oxo)[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl]-λ 5 Synthesis of phosphine (compounds 1-3)

[0286] (4-bromophenyl)di(methyl)(oxo)-λ 5Phosphine (compounds 1-2) (250 mg, 1.0 mmol), bis-pinacolborate (893 mg, 3.5 mmol), potassium acetate (330 mg, 3.5 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (40 mg, 0.07 mmol) were dissolved in anhydrous 1,4-dioxane (5 mL). The reaction mixture was stirred at 60 °C for 2 h under nitrogen protection. The reaction mixture was dissolved in ethyl acetate (50 mL), washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 1) to give compound dimethyl(oxo)[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl]-λ 5 - Phosphine (compounds 1-3).

[0287] LC-MS, M / Z (ESI): 281.2 [M+H]+

[0288] Step 3: Synthesis of 3-[2-chloro-4'-(dimethylphosphoryl)[1,1'-biphenyl]-3-yl]piperidine-2,6-dione (compound 1)

[0289]

[0290] 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (intermediate A4) (70 mg, 0.25 mmol), dimethyl(oxo)[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl]-λ 5 Phosphorus (compounds 1-3) (100 mg, 0.36 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (31 mg, 0.04 mmol), and potassium phosphate (88 mg, 0.82 mmol) were dissolved in anhydrous N,N-dimethylformamide (1.5 mL). The reaction solution was stirred at 100 °C for 4 h. After the reaction was complete, the reaction solution was cooled to room temperature and filtered. The mother liquor was purified by preparative liquid chromatography (column: Phenomenex Synergi C18 100*25 mm*4 μm; solvent: A = water + 0.1 v / v formic acid (99%), B = acetonitrile; gradient: 5%-95%, 7 min) to give compound 3-[2-chloro-4'-(dimethylphosphoryl)[1,1'-biphenyl]-3-yl]piperidin-2,6-dione (compound 1).

[0291] LC-MS, M / Z (ESI): 376.2 [M+H] +

[0292] 1H NMR (400MHz, DMSO-d6) δ10.93(s,1H),7.86-7.30(m,7H),4.35-4.31(m,1H),2.79-1.65(m,10H).

[0293] Example 2: Preparation of Compound 2

[0294] 3-(2-chloro-4'-((dimethyl(oxo)-λ) 6 (-sulfoxide)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (compound 2)

[0295]

[0296] The synthetic route for target compound 2 is shown below:

[0297]

[0298] Step 1: Compound ((4-bromophenyl)imino)dimethyl-λ 6 Synthesis of thiophene (compound 2-1)

[0299] At room temperature, p-bromoiodobenzene (600.00 mg, 2.12 mmol) and dimethylsulfinylimide (237.06 mg, 2.54 mmol) were dissolved in anhydrous 1,4-dioxane solution (6 mL), followed by the addition of cesium carbonate (967.41 mg, 2.97 mmol), tris(dibenzylideneacetone)dipalladium (58.26 mg, 0.06 mmol), and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (72.25 mg, 0.12 mmol). The reaction mixture was stirred at 110 °C for 12 hours under nitrogen protection. After the reaction of the starting materials was complete as monitored by TLC, stirring was stopped, the reaction solution was cooled to room temperature, and then diluted with water (20 mL). Extraction was performed with ethyl acetate (10 mL × 5), the organic phase was collected, dried with anhydrous sodium sulfate, and concentrated by vacuum distillation. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 100:50) to give the compound ((4-bromophenyl)imino)dimethyl-λ. 6 -Thione (compound 2-1).

[0300] LC-MS, M / Z (ESI): 249.9 [M+H] +

[0301] Step 2: Compound dimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)imino)-λ 6 Synthesis of thiophene (compound 2-2)

[0302] At room temperature, the compound ((4-bromophenyl)imino)dimethyl-λ 6 Thione (compound 2-1) (300 mg, 1.21 mmol) and pinacol diboronate (460.52 mg, 1.81 mmol) were dissolved in anhydrous 1,4-dioxane solution (5 mL), and potassium acetate (355.95 mg, 3.62 mmol) and 1,1-bis(diphenylphosphine)diferropalladium dichloride (88.46 mg, 0.12 mmol) were added. The reaction solution was stirred in an oil bath at 90 °C for 12 hours under nitrogen protection. After the reaction of the reactants was complete as monitored by TLC, stirring was stopped, the reaction solution was cooled to room temperature, and then diluted with water (20 mL). Extraction was performed with ethyl acetate (10 mL × 5), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 100:3) to give the compound dimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)imino)-λ 6 -Thione (compound 2-2).

[0303] LC-MS, M / Z (ESI): 296.0 [M+H] +

[0304] Step 3: Compound 3-(2-chloro-4'-((dimethyl(oxo)-λ) 6 Synthesis of (-sulfoxide)amino)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 2)

[0305]

[0306] At room temperature, the compound dimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)imino)-λ 6-Thione (compound 2-2) (150.00 mg, 0.51 mmol) and compound 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (intermediate A4) (153.73 mg, 0.51 mmol) were dissolved in anhydrous N,N-dimethylformamide (2 mL), potassium phosphate (323.58 mg, 1.52 mmol) and 1,1-bis(diphenylphosphine)diferro-palladium dichloride (37.18 mg, 0.05 mmol) were added, and the reaction solution was stirred at 100 °C for 12 hours under nitrogen protection. After the reaction of the starting materials was complete as monitored by TLC, stirring was stopped, the reaction solution was cooled to room temperature, and then diluted with water (15 mL). Extraction was performed with ethyl acetate (5 mL × 5), the organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 100:50) to give compound 3-(2-chloro-4'-((dimethyl(oxo)-λ)). 6 -sulfoxide)amino)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 2).

[0307] LC-MS, M / Z (ESI): 391.0 [M+H] +

[0308] 1 H NMR(400MHz,DMSO-d6)δ10.92(s,1H),7.39–7.31(m,1H),7.31–7.26(m,2H),7.26–7.21(m,2H),7.03– 6.95(m,2H),4.33(dd,1H),3.26(s,6H),2.78(ddd,1H),2.56(t,1H),2.32(qd,1H),2.10–1.96(m,1H).

[0309] Example 3: Preparation of target compound 3

[0310] 3-(2-chloro-4'-((S-methylsulfonylimino)methyl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (compound 3)

[0311]

[0312] The synthetic route for compound 3 is shown below:

[0313]

[0314] Step 1: Synthesis of (4-bromobenzyl)(methyl)thione (compound 3-2)

[0315] 1-Bromo-4-(bromomethyl)benzene (3-1) (3.0 g, 12.09 mmol) was placed in a reaction flask, and ethanol (100 mL) was added. Sodium methanethiol (4.2 g, 60 mmol) was added under ice bath conditions, and the reaction mixture was stirred under reflux for 16 h. After completion, the reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 10:1) to give compound (4-bromobenzyl)(methyl)thione (compound 3-2).

[0316] LC-MS, M / Z (ESI): 217.0 [M+H] + .

[0317] Step 2: (4-Bromobenzyl)(imino)(methyl)-λ 6 Synthesis of thiophene (3-3)

[0318] Intermediate (4-bromobenzyl)(methyl)thione (3-2) (2.2 g, 10.2 mmol), iodophenyl diacetic acid (8.1 g, 25 mmol), and ammonium carbonate (3.8 g, 40 mmol) were dissolved in methanol (100 mL). The reaction mixture was reacted at room temperature for 2 h under nitrogen protection. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (500 mL), washed with saturated sodium chloride aqueous solution (500 mL × 3), and then the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:2) to give compound (4-bromobenzyl)(imino)(methyl)-λ. 66 -Thione (3-3) (0.62 g, yield: 25%).

[0319] LC-MS, M / Z (ESI): 248.1 [M+H] + .

[0320] Step 3: Synthesis of 3-(2-chloro-4'-((S-methylsulfonylimino)methyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 3)

[0321]

[0322] The intermediate (4-bromobenzyl)(imino)(methyl)-λ 6Thione (3-3) (100 mg, 0.40 mmol) was placed in a reaction flask, followed by the addition of intermediate 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)piperidine-2,6-dione (intermediate A) (205 mg, 0.60 mmol), potassium phosphate (255 mg, 1.20 mmol), 1,1'-bis(di-phenylphosphino)ferrocene palladium chloride (30 mg, 0.04 mmol), and 1,4-dioxane (4 mL). The reaction mixture was stirred at 100 °C for 8 hours under nitrogen protection. The reaction solution was cooled to room temperature, diluted with ethyl acetate (100 mL), washed with saturated sodium chloride aqueous solution (100 mL × 3), and then the organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 20:1) to give compound 3-(2-chloro-4'-((S-methylsulfonylimino)methyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 3).

[0323] LC-MS, M / Z (ESI): 391.1 [M+H] + .

[0324] 1 H NMR(400MHz,DMSO-d6)δ10.90(s,1H),7.49(d,2H),7.42–7.36(m,3H),7.34(dd,1H),7.29(dd,1H),4.47–4.35( m,2H),4.32(dd,1H),3.66(s,1H),2.84–2.67(m,4H),2.56–2.47(m,1H),2.39–2.22(m,1H),2.07–1.96(m,1H).

[0325] Example 4: Preparation of target compound 4

[0326] 3-(2-chloro-4'-(2-thiopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0327]

[0328] The synthetic route for compound 4 is shown below:

[0329]

[0330] Step 1: 1-(4-bromophenyl)pyridine-2(1H)-thione (compound 4-2)

[0331] 1-(4-bromophenyl)pyridine-2(1H)-one (compound 4-1) (300 mg, 1.20 mmol) was placed in a reaction flask, followed by the addition of Lawson's reagent (1.0 g, 2.4 mmol) and toluene (10 mL). The reaction mixture was refluxed at 110 °C for 2 hours under nitrogen protection. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (300 mL), extracted with saturated sodium chloride aqueous solution (300 mL × 3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 20:1) to give compound 1-(4-bromophenyl)pyridine-2(1H)-thione (compound 4-2).

[0332] LC-MS, M / Z (ESI): 265.9 [M+H] + .

[0333] Step 2: 3-(2-chloro-4'-(2-thiopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (compound 4)

[0334]

[0335] Intermediate 1-(4-bromophenyl)pyridine-2(1H)-thione (4-2) (120 mg, 0.45 mmol) was placed in a reaction flask, followed by the addition of 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)piperidine-2,6-dione (intermediate A) (210 mg, 0.60 mmol), potassium phosphate (286 mg, 1.35 mmol), 1,1'-bis(di-phenylphosphino)ferrocene palladium chloride (36 mg, 0.05 mmol) and 1,4-dioxane (4 mL). After the addition was complete, the reaction mixture was stirred at 100 °C for 6 hours under nitrogen protection. The reaction solution was cooled to room temperature, and then diluted with ethyl acetate (200 mL). The solution was washed with saturated sodium chloride aqueous solution (200 mL × 3). The organic phase was then collected, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 10:1) to give compound 3-(2-chloro-4'-(2-thiopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (compound 4).

[0336] LC-MS, M / Z (ESI): 409.0 [M+H] + .

[0337] 1H NMR(400MHz,DMSO-d6)δ10.93(s,1H),8.06–8.02(m,1H),7.60–7.51(m,3H),7.51–7.28(m,6H),6. 85(td,1H),4.42–4.32(m,1H),2.85–2.73(m,1H),2.54(dt,1H),2.34(ddd,1H),2.10–2.01(m,1H).

[0338] Example 5: Synthesis of Compound 5

[0339] 3-{2-chloro-4'-[1-methyl-5-thioalkyl-3-(trifluoromethyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl][1,1'-biphenyl]-3-yl}piperidin-2,6-dione

[0340]

[0341] The synthetic route for compound 5 is as follows:

[0342]

[0343] Step 1: 2-[(4-bromophenyl)aminothioyl]-2-methylhydrazine-1-carboxylic acid tert-butyl ester (compound 5-3)

[0344] At room temperature, tert-butyl 2-methylhydrazine-1-carboxylic acid (5-2) (303 mg, 2.07 mmol) was dissolved in anhydrous dichloromethane (10 mL), and then 1-bromo-4-isothiocyanobenzene (5-1) (500 mg, 1.73 mmol) was slowly added at 0°C. After the addition was complete, the reaction mixture was stirred at 25°C for 12 hours. After the reaction was completed, the reaction mixture was concentrated, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate (V / V) = 100:1 to 1:1) to give compound 2-[(4-bromophenyl)aminothioyl]-2-methylhydrazine-1-carboxylic acid tert-butyl ester (compound 5-3).

[0345] LC / MS (ESI) (m / z): 360.0 (M+H) + .

[0346] Step 2: N-(4-bromophenyl)-1-methylhydrazine-1-thioamide (compound 5-4)

[0347] At room temperature, tert-butyl 2-[(4-bromophenyl)aminothioyl]-2-methylhydrazine-1-carboxylic acid (compound 5-3) (620 mg, 1.73 mmol) was dissolved in dichloromethane (10 mL), followed by the addition of trifluoroacetic acid (5 mL). The reaction was carried out at 25 °C for 1 hour. After the reaction was complete, the reaction solution was concentrated to obtain N-(4-bromophenyl)-1-methylhydrazine-1-thioamide (compound 5-4).

[0348] LC / MS(ESI)(m / z): 260(M+H) + .

[0349] Step 3: 4-(4-bromophenyl)-2-methyl-5-(trifluoromethyl)-2,4-dihydro-3H-1,2,4-triazol-3-thione (compound 5-5)

[0350] At room temperature, N-(4-bromophenyl)-1-methylhydrazine-1-thioamide (compound 5-4) (450 mg, 1.73 mmol) was dissolved in trifluoroacetic acid (3 mL), followed by the addition of trifluoroacetic anhydride (484 mg, 2.31 mmol). The reaction mixture was stirred at 80 °C for 4 hours under nitrogen protection. After the reaction was complete, the reaction mixture was concentrated, and the crude product was diluted with ethyl acetate (20 mL). It was then washed successively with saturated sodium bicarbonate solution (20 mL), water (20 mL), and saturated brine (20 mL). The organic phase was concentrated, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate (V / V) = 100:1 to 1:1) to give compound 4-(4-bromophenyl)-2-methyl-5-(trifluoromethyl)-2,4-dihydro-3H-1,2,4-triazol-3-thione (compound 5-5).

[0351] LC / MS (ESI) (m / z): 339.0 (M+H) + .

[0352] Step 4: 3-{2-chloro-4'-[1-methyl-5-thioalkyl-3-(trifluoromethyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl][1,1'-biphenyl]-3-yl}piperidin-2,6-dione (compound 5)

[0353]

[0354] At room temperature, 4-(4-bromophenyl)-2-methyl-5-(trifluoromethyl)-2,4-dihydro-3H-1,2,4-triazol-3-thione (compound 5-5) (100 mg, 0.300 mmol) was dissolved in N,N-dimethylformamide (1 mL), and then 3-[2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl]piperidine-2,6-dione (intermediate A) (207 mg, 0.590 mmol), potassium phosphate (126 mg, 0.590 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (II) (22.0 mg, 0.030 mmol) were added. The reaction mixture was stirred at 100 °C for 12 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with water (10 mL), and then extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine (10 mL), dried with anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (petroleum ether: ethyl acetate (V / V) = 100:1 to 1:1) to give compound 3-{2-chloro-4'-[1-methyl-5-thioalkyl-3-(trifluoromethyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl][1,1'-biphenyl]-3-yl}piperidine-2,6-dione (compound 5).

[0355] LC / MS (ESI) (m / z): 481.0 (M+H) + ;

[0356] 1 H NMR(400MHz,DMSO-d6)δ10.93(s,1H),7.60(q,4H),7.43–7.37(m,3H),4.35(dd,1H), 3.82(s,3H),2.82–2.74(m,1H),2.55–2.49(m,1H),2.32(dd,1H),2.06–2.01(m,1H).

[0357] Example 6: Preparation of target compound 6

[0358] 3-{2-chloro-4'-[(1-oxo-1λ] 6 [-Thiocyclopropane-1-methylene)amino][1,1'-biphenyl]-3-yl}piperidine-2,6-dione (compound 6)

[0359]

[0360] The synthetic route for target compound 6 is shown below:

[0361]

[0362] Step 1: 1-[(4-bromophenyl)imino]-1λ 6 Synthesis of thiocyclopentane-1-one (6-2)

[0363] 4-Bromo-iodobenzene (800 mg, 2.8 mmol), 1-imino-1λ 6 Thionylpropane-1-one (6-1) (388 mg, 3.2 mmol), cesium carbonate (1.4 g, 4.2 mmol), tris(dibenzylacetone)dipalladium (260 mg, 0.3 mmol), and 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (350 mg, 0.6 mmol) were dissolved in 1,4-dioxane (10 mL). The reaction mixture was stirred at 100 °C for 5 h under nitrogen protection. After the reaction was complete, the reaction mixture was cooled to room temperature, diluted with a saline solution (60 mL), and then extracted with ethyl acetate (50 mL * 2). The organic phases were combined, dried over sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 3 / 1) to give compound 1-[(4-bromophenyl)imino]-1λ. 6 -Thiocyclopentane-1-one (6-2).

[0364] LC-MS,M / Z(ESI):274.2 / 276.2[M+H]+

[0365] Step 2: 1-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl]imino}-1λ 6 Synthesis of thiocyclopentane-1-one (6-3)

[0366] 1-[(4-bromophenyl)imino]-1λ 6 Thionitropentan-1-one (6-2) (200 mg, 0.7 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis-1,3,2-dioxaborane (893 mg, 3.5 mmol), potassium acetate (330 mg, 3.5 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (II) (40 mg, 0.07 mmol) were dissolved in anhydrous 1,4-dioxane (5 mL). The reaction mixture was stirred at 60 °C for 2 h under nitrogen protection. The reaction solution was cooled to room temperature, and ethyl acetate (20 mL) was added. The mixture was then washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 2 / 1) to give compound 1-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl]imino}-1λ 6 -Thiocyclopentane-1-one (6-3).

[0367] LC-MS, M / Z (ESI): 322.2 [M+H]+

[0368] Step 3: 3-{2-chloro-4'-[(1-oxo-1λ] 6 Synthesis of thiocyclopropane-1-methylene)amino][1,1'-biphenyl]-3-yl}piperidine-2,6-dione (compound 6)

[0369]

[0370] 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (A4) (100 mg, 0.33 mmol), 1-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl]imino}-1λ 6 Thionitropentan-1-one (6-3) (200 mg, 0.6 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (II) (31 mg, 0.04 mmol), and potassium phosphate (88 mg, 0.82 mmol) were dissolved in anhydrous N,N-dimethylformamide (1.5 mL). The reaction mixture was stirred at 100 °C for 4 h. After the reaction was complete, the reaction mixture was cooled to room temperature, filtered, and then the filtrate was purified by preparative liquid chromatography (column: Phenomenex Synergi C18 100*25 mm*4 μm; solvent: A = water + 0.1 vol% formic acid (99%), B = acetonitrile; gradient: 5%-95%, 7 min) to give compound 3-{2-chloro-4'-[(1-oxo-1λ 6 -Thiocyclopropane-1-methylene)amino][1,1'-biphenyl]-3-yl}piperidine-2,6-dione (compound 6).

[0371] 1 H NMR (400MHz, DMSO-d6) δ10.93(s,1H),7.36-6.90(m,7H),4.35-4.31(m,1H),3.30-2.00(m,12H).

[0372] LC-MS, M / Z (ESI): 417.20 [M+H] +

[0373] Example 7: Preparation of target compound 7

[0374] 3-[2-chloro-4'-(1,3-dimethyl-5-thionyl-1,5-dihydro-4H-1,2,4-triazol-4-yl)[1,1'-biphenyl]-3-yl]piperidin-2,6-dione

[0375]

[0376] The synthetic route for target compound 7 is shown below:

[0377]

[0378] Step 1: Synthesis of 4-(4-bromophenyl)-2,5-dimethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (7-1)

[0379] 4-(4-bromophenyl)-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (compound 7-1) (156.0 mg, 0.61 mmol) was dissolved in N,N-dimethylformamide (8.0 mL). Sodium hydroxide (49.1 mg, 1.23 mmol, 60%) was added at 0 °C under nitrogen protection. After stirring for 10 minutes, iodomethane (261.5 mg, 1.84 mmol) was added, and the mixture was allowed to return to room temperature and stirred overnight. After the reaction was completed, the reaction solution was cooled to 0°C, and the reaction was quenched with water (15 mL). The mixture was extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with water (20 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 1:2) to give compound 4-(4-bromophenyl)-2,5-dimethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (7-2).

[0380] LC-MS,M / Z(ESI):268.1 / 270.1[M+H] + .

[0381] Step 2: Synthesis of 4-(4-bromophenyl)-2,5-dimethyl-2,4-dihydro-3H-1,2,4-triazol-3-thione (7-3) 4-(4-bromophenyl)-2,5-dimethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (7-2) (143.5 mg, 0.54 mmol) was dissolved in toluene (10 mL), Lawson's reagent (324.7 mg, 0.80 mmol) was added, and the reaction mixture was heated to 100 °C and stirred overnight. After the reaction was completed, the mixture was cooled to room temperature, dried over water (10 mL) and anhydrous sodium sulfate, filtered and concentrated, and the reaction solution was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 8:1) to give compound 4-(4-bromophenyl)-2,5-dimethyl-2,4-dihydro-3H-1,2,4-triazol-3-thione (7-3) (78.5 mg, yield 51.2%).

[0382] LC-MS,M / Z(ESI):284.1 / 286.1[M+H] + .

[0383] Step 3: Synthesis of 2,5-dimethyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-thione (7-4) 4-(4-bromophenyl)-2,5-dimethyl-2,4-dihydro-3H-1,2,4-triazol-3-thione (7-3) (39.8 mg, 0.14 mmol) was dissolved in 1,4-dioxane (6 mL). Under nitrogen protection, pinacol diborate (55.0 mg, 0.22 mmol) and anhydrous potassium acetate (42.0 mg, 0.43 mmol) were added, followed by 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (10.5 mg, 0.014 mmol). The reaction mixture was reacted at 100 °C for 3.5 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure, diluted with dichloromethane (20 mL), washed with water (10 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude compound 2,5-dimethyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-thione (7-4).

[0384] LC-MS, M / Z(ESI): 332.1[M+H]+.

[0385] Step 4: Synthesis of 3-[2-chloro-4'-(1,3-dimethyl-5-thionyl-1,5-dihydro-4H-1,2,4-triazol-4-yl)[1,1'-biphenyl]-3-yl]piperidine-2,6-dione (compound 7)

[0386]

[0387] 2,5-Dimethyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-thione (7-4) (45.7 mg, 0.14 mmol) was dissolved in 1,4-dioxane (10 mL), and 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (86 mg, 0.28 mmol) and potassium phosphate (76.0 mg, 0.36 mmol) were added. Then, 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (10.5 mg, 0.014 mmol) was added. The reaction mixture was stirred at 100 °C for 12 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 10:1) to give compound 3-[2-chloro-4'-(1,3-dimethyl-5-thionyl-1,5-dihydro-4H-1,2,4-triazol-4-yl)[1,1'-biphenyl]-3-yl]piperidine-2,6-dione (compound 7).

[0388] LC-MS, M / Z (ESI): 427.1 [M+H] + .

[0389] 1 H NMR(600MHz,DMSOd6)δ10.94(s,1H),7.61(d,2H),7.54(d,2H),7.42(dt,3H),4.37(dd,1H),3.71 (s,3H),2.84–2.77(m,1H),2.58–2.53(m,1H),2.38-2.30(m,1H),2.17(s,3H),2.10–2.04(m,1H).

[0390] Example 8: Preparation of target compound 8

[0391] 3-[2-chloro-4'-(4-methyl-5-oxo-7-thioalkyl-4,6-diazaspiro[2,4]hept-6-yl)[1,1'-biphenyl]-3-yl]piperidin-2,6-dione (compound 8)

[0392]

[0393] The synthetic route for target compound 8 is shown below:

[0394]

[0395] Step 1: Synthesis of 6-(4-bromophenyl)-4-methyl-7-thionyl-4,6-diazaspiro[2.4]hepta-5-one (8-1)

[0396] At room temperature, 1-(methylamino)cyclopropane-1-carboxylic acid (180 mg, 1.65 mmol), triethylamine (167 mg, 1.65 mmol), and DMAP (15 mg, 0.07 mmol) were added to a DMSO (10 mL) solution of 4-bromophenyl isothiocyanate (5-1) (300 mg, 1.4 mmol). The reaction solution was heated to 65 °C and stirred for 12 h. After the reaction was completed, the solution was cooled to room temperature, and the solution was diluted with dichloromethane (100 mL). The solution was washed with saturated sodium bicarbonate aqueous solution (50 mL * 2). The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0 to 1 / 1) to obtain compound 6-(4-bromophenyl)-4-methyl-7-thiomethylene-4,6-diazaspiro[2.4]hepta-5-one (compound 8-1).

[0397] LC-MS, M / Z (ESI): 311.1 [M+H] +

[0398] Step 2: Synthesis of 4-methyl-7-thioalkyl-6-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]-4,6-diazaspiro[2,4]hepta-5-one (8-2)

[0399] At room temperature, a solution of 6-(4-bromophenyl)-4-methyl-7-thionyl-4,6-diazaspiro[2,4]hepta-5-one ((8-1) (150 mg, 0.48 mmol)) in 1,4-dioxane (5 mL) was reacted with pinacol ester of borate (203 mg, 0.8 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (22 mg, 0.03 mmol) and potassium acetate (150.0 mg, 1.5 mmol). The reaction solution was then reacted under argon atmosphere. The mixture was stirred at 100°C for 18 h under protective conditions. The reaction solution was poured into water (10 mL), and then extracted with ethyl acetate (2 mL * 3). The organic phases were combined and washed with saturated brine (2 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 4-methyl-7-thioalkyl-6-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphanecyclopentan-2-yl)phenyl]-4,6-diazaspiro[2,4]hepta-5-one (8-2) (crude product), which was directly used in the next reaction.

[0400] LC-MS, M / Z (ESI): 359.2 [M+H] +

[0401] Step 3: Synthesis of 3-[2-chloro-4'-(4-methyl-5-oxo-7-thioalkyl-4,6-diazaspiro[2,4]hept-6-yl)[1,1'-biphenyl]-3-yl]piperidine-2,6-dione (compound 8)

[0402]

[0403] To a solution of crude 4-methyl-7-thioalkyl-6-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]-4,6-diazaspiro[2,4]hepta-5-one (8-2) (150 mg, 0.48 mmol) and 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (177 mg, 0.58 mmol) in 1,4-dioxane (5 mL), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (22 mg, 0.03 mmol) and potassium phosphate (186 mg, 1.35 mmol) were added. The reaction mixture was stirred at 100 °C for 18 h under argon protection. The reaction mixture was then poured into water (10 mL) and extracted with ethyl acetate (2 mL x 3). After the organic phases were combined, they were washed with saturated brine (2 mL * 2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product. The crude product was purified by paper cup liquid chromatography (column: Phenomenex Synergi C18 100 * 25 mm * 4 μm; solvent: A = water + 0.1 vol% formic acid (99%), B = acetonitrile; gradient: 5% - 95%, 7 min) to obtain compound 3-[2-chloro-4'-(4-methyl-5-oxo-7-thioalkyl-4,6-diazaspiro[2,4]hept-6-yl)[1,1'-biphenyl]-3-yl]piperidin-2,6-dione (compound 8).

[0404] 1 H NMR(400MHz,DMSO-d6)10.94(s,1H),7.54(d,2H),7.47–7.36(m,5H),4.37(dd,1H),3.13(s,3H),2.85– 2.76(m,1H),2.61–2.52(m,1H),2.35(dt,1H),2.09–2.03(m,1H),1.96–1.90(m,2H),1.52-1.49(m,2H)

[0405] LC-MS, M / Z (ESI): 454.1 [M+H] +

[0406] Example 9: Preparation of target compound 9

[0407] 3-(2-chloro-4'-{[cyclopropyl(methyl)(oxo)-λ]6 [-thioalkyl]amino}[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (compound 9)

[0408]

[0409] The synthetic route for target compound 9 is shown below:

[0410]

[0411] Step 1: 1-Bromo-4-{[cyclopropyl(methyl)(oxo)-λ} 6 Synthesis of β-thioalkyl]amino}benzene (9-1)

[0412] At room temperature, p-bromoiodobenzene (200.00 mg, 0.71 mmol) and cyclopropyl(imino)(methyl)-L6 sulfamethoxam (95 mg, 0.8 mmol) were dissolved in anhydrous 1,4-dioxane solution (6 mL), followed by the addition of cesium carbonate (461 mg, 1.4 mmol), tris(dibenzylideneacetone)dipalladium (58.26 mg, 0.06 mmol), and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (72.25 mg, 0.12 mmol). The reaction mixture was stirred at 110 °C for 12 hours under nitrogen protection. After the reaction of the starting materials was complete as monitored by TLC, stirring was stopped, the reaction solution was cooled to room temperature, and then diluted with water (20 mL). Extraction was performed with ethyl acetate (10 mL × 5), the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 100:50) to give compound 1-bromo-4-{[cyclopropyl(methyl)(oxo)-λ}. 6 [-thioalkyl]amino}benzene (compound 9-1).

[0413] LC-MS, M / Z (ESI): 274.2 [M+H] +

[0414] Step 2: 2-(4-{[cyclopropyl(methyl)(oxo)-λ] 6 Synthesis of (9-2)-thioalkyl]amino}phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane

[0415] At room temperature, to 1-bromo-4-{[cyclopropyl(methyl)(oxo)-λ 6[-thioalkyl]amino}benzene (9-1) (70 mg, 0.26 mmol) was reacted with 1,4-dioxane (3 mL) of pinacol diborate (131 mg, 0.52 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (22 mg, 0.03 mmol), and potassium acetate (90.0 mg, 0.9 mmol) under nitrogen protection and stirred at 100 °C for 18 h. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (2 mL * 3). The organic phases were combined, washed with saturated brine (2 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 2-(4-{[cyclopropyl(methyl)(oxo)-λ 6 [-thioalkyl]amino}phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (9-2) (crude product) is used directly in the next reaction.

[0416] LC-MS, M / Z (ESI): 322.2 [M+H] +

[0417] Step 3: 3-(2-chloro-4'-{[cyclopropyl(methyl)(oxo)-λ] 6 Synthesis of [-thioalkyl]amino}[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 9)

[0418]

[0419] To a solution of crude 2-(4-{[cyclopropyl(methyl)(oxo)-λ6-thioalkyl]amino}phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (9-2) (70 mg, 0.26 mmol) and 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (intermediate A4) (118 mg, 0.39 mmol) in 1,4-dioxane (5 mL), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (22 mg, 0.03 mmol) and potassium phosphate (186 mg, 1.35 mmol) were added. The reaction mixture was stirred at 100 °C for 18 h under nitrogen protection. The reaction mixture was poured into water (10 mL) and then extracted with ethyl acetate (2 mL x 3). The combined organic phases were washed with saturated brine (2 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative liquid chromatography (column: Phenomenex Synergi C18 100*25mm*4μm; solvent: A = water + 0.1 vol% formic acid (99%), B = acetonitrile; gradient: 5%-95%, 7 min) to give compound 3-(2-chloro-4'-{[cyclopropyl(methyl)(oxo)-λ 6[-thioalkyl]amino}[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 9).

[0420] 1H NMR(400MHz,DMSO-d6)δ10.90(s,1H),7.39-7.32(m,2H),7.27(dd,2H),7.21(t,2H),6.98(d,1H),4.31(dd,1H),3.20(s,3H),2.85-2.81 (m,1H),2.79–2.73(m,1H),2.55–2.50(m,1H),2.32–2.27(m,1H),2.05–2.00(m,1H),1.18(dt,1H),1.13–1.08(m,1H),1.07–0.98(m,2H).

[0421] LC-MS, M / Z (ESI): 417.1 [M+H] +

[0422] Example 10: Preparation of compound 10:

[0423] 3-(2-chloro-4'-{[4-(cyclopropanecarbonyl)-1-oxo-1λ] 6 [-Thiomorpholine-1-methylene]amino}[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (compound 10)

[0424]

[0425] Referring to compound 3-{2-chloro-4'-[(1-oxo-1λ] in Example 6 6 The preparation method of 3-(2-chloro-4'-{[4-(cyclopropanecarbonyl)-1-oxo-1λ}piperidine-2,6-dione (compound 6) was used to synthesize 3-(2-chloro-4'-{[4-(cyclopropanecarbonyl)-1-oxo-1λ}piperidine-2,6-dione). 6 [1,1'-Biphenyl]-3-yl)piperidin-2,6-dione (compound 10); LC-MS, M / Z (ESI): 500.1 [M+H] + .

[0426] Example 11: Preparation of compound 11:

[0427] 3-[2-chloro-4'-(3,4,4-trimethyl-5-oxo-2-thioalkylimidazolidine-1-yl)[1,1'-biphenyl]-3-yl]piperidin-2,6-dione (compound 11)

[0428]

[0429] 3-[2-chloro-4'-(3,4,4-trimethyl-5-oxo-2-thioalkyl-4,6-diazaspiro[2,4]hept-6-yl)[1,1'-biphenyl]-3-yl]piperidin-2,6-dione (compound 8) was synthesized using the same method as in Example 8 to obtain 3-[2-chloro-4'-(3,4,4-trimethyl-5-oxo-2-thioalkylimidazolidine-1-yl)[1,1'-biphenyl]-3-yl]piperidin-2,6-dione (compound 11); LC-MS, M / Z (ESI): 456.1 [M+H] + .

[0430] The preparation methods for the following compounds are the same as those in Example 1:

[0431]

[0432]

[0433]

[0434]

[0435]

[0436] Biological testing

[0437] Test Example 1: Compound-induced binding of VAV1 to CRBN

[0438] Experimental methods

[0439] 1) Cell line construction and culture. VAV1-SmBiT and CRBN-LgBiT expression plasmids were constructed separately. Using a lentiviral system, VAV1-SmBiT and CRBN-LgBiT were inserted into the genome of HEK293 cells to construct cells stably expressing VAV1-SmBiT and CRBN-LgBiT.

[0440] The LgBiT protein cell line (HEK293-VAV1-SmBiT-CRBN-LgBiT) was cultured in DMEM medium containing 10% inactivated fetal bovine serum, 100 U / mL penicillin, and 100 μg / mL streptomycin. HEK293-VAV1-SmBiT-CRBN-LgBiT cells were cultured at 37°C with 5% CO2. After passage to 80-90% confluence, the cells were divided into individual flasks. Cells in the logarithmic growth phase were seeded into 96-well plates with 100 μL of medium at 20,000-3,000 cells per well, and cultured overnight.

[0441] 2) Compound dilution. The compound was dissolved in DMSO to a concentration of 10 mM. Subsequently, the compound was serially diluted with DMSO to concentrations of 2000 μM, 500 μM, 125 μM, 32.25 μM, 7.81 μM, 1.95 μM, 0.49 μM, 0.12 μM, and...

[0442] 0.031μM.

[0443] 3) Addition of the drug. Take 1 μL of the diluted compound and add it to 1 mL of complete culture medium. Mix well, then add 100 μL to a 96-well plate to achieve working concentrations of 1000 nM, 250 nM, 62.5 nM, 15.6 nM, 3.91 nM, 0.98 nM, 0.24 nM, 0.061 nM, and 0.015 nM.

[0444] nM and 0nM.

[0445] 4) Activity assay. The drug was tested 8 hours after treatment, following the instructions for the Promega NanoBiT Protein: Protein Interaction System.

[0446] 5) EC 50 Calculation. Fluorescence intensity (Fold change) = (Lumninence experiment - Lumininence blank) / (Lumninence DMSO -

[0447] Lumninence blank).

[0448] Experimental conclusion: The compounds of this invention can induce direct binding between VAV1 and CRBN in a dose-dependent manner.

[0449] Test Example 2: Effect of Compounds on VAV1 Protein in HEK293 Cells

[0450] Experimental methods

[0451] 1) Cell line construction and culture. A Hibit tag was inserted into the C-terminus of VAV1, and the VAV1-Hibit tag was inserted into HEK293 cells using a lentiviral system.

[0452] The cell genome was analyzed, and a cell line stably expressing VAV1-Hibit protein was constructed. The culture medium was DMEM containing 10% inactivated fetal bovine serum, 100 U / mL penicillin, and 100 μg / mL streptomycin, and the cells were cultured in an incubator at 37°C and 5% CO2.

[0453] HEK293-VAV1-Hibit cells, after reaching 80-90% confluence, were passaged into individual flasks. Cells in the logarithmic growth phase were seeded into 96-well plates with 100 μL of culture medium, 20,000-3,000 cells per well, and cultured overnight.

[0454] 2) Compound dilution. The compound was dissolved in DMSO to a concentration of 10 mM. Subsequently, the compound was serially diluted with DMSO to concentrations of 2000 μM, 500 μM, 125 μM, 32.25 μM, 7.81 μM, 1.95 μM, 0.49 μM, 0.12 μM, and...

[0455] 0.031μM.

[0456] 3) Addition of the drug. Take 1 μL of the diluted compound and add it to 1 mL of complete culture medium. Mix well, then add 100 μL to a 96-well plate to achieve working concentrations of 1000 nM, 250 nM, 62.5 nM, 15.6 nM, 3.91 nM, 0.98 nM, 0.24 nM, 0.061 nM, and 0.015 nM.

[0457] nM and 0nM.

[0458] 6) Activity assay. The drug was tested 24 hours after treatment, using methods according to Promega's specifications. HiBiT Lytic DetectionSystem manual.

[0459] 7) DC 50 Calculate. Relative VAV1(%) = (Lumninence experiment - Lumininence blank) / (Lumninence DMSO -

[0460] Lumninence blank), calculated using a log(inhibitor) vs. response--Variable slope (four parameters). Experimental conclusion: The compounds of this invention exhibit excellent degradation effects on VAV1 protein in a dose-dependent manner.

[0461] Test Example 3: Degradation of VAV1 in Jurkat Cells by Compounds

[0462] Jurkat cells were cultured in RPMI-1640 medium containing inactivated 10% fetal bovine serum, 100 U / ml penicillin and 100 μg / ml streptomycin in an incubator at 37°C and 5% CO2. When the cell density reached 1×10^6, the cells were passaged and subcultured. Tumor cells in the logarithmic growth phase were seeded at a density of 7×10 5 onto a 12-well plate. The drug was diluted and added to the cell culture medium to final concentrations of 1000 nM, 250 nM, 62.5 nM, 15.6 nM, 3.9 nM, 0.98 nM, 0.24 nM and 0 nM, respectively. The cells were treated with the drug 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 the supernatant was removed by centrifugation. 150 μL of RIPA lysis buffer was added to each tube and incubated on ice for 30 minutes. Protein gels were run for detection. Anti-VAV1 was diluted 1:1000 and Anti-GAPDH was diluted 1:5000, and incubated overnight at 4°C. The HRP secondary antibody was diluted 1:10000 and incubated at RT for 1 hour. Protein expression was detected by chemiluminescence, and gray value analysis was performed using ImageJ. The experimental results are shown in Table 1.

[0463] Table 1 Degradation activity of the compound on VAV1 protein in Jurkat cells.

[0464] Compound numbering <![CDATA[DC 50 (nM)]]> Dmax Compound 2 B2 - Compound 4 B1 93％ Compound 5 B1 99％ Compound 6 B 1 93％ Compound 8 A 95％ Compound 9 A 95.2％ Compound 10 A 95％ Compound 11 A 96％

[0465] *

[0466] DC50 ≤ 10 nM is designated as "A", 10 nM < DC50 ≤ 30 nM is designated as "B1", 30 nM < DC50 ≤ 100 nM is designated as "B2", 100 nM < DC50 ≤ 1000 nM is designated as "C", and DC50 > 1000 nM is designated as "D".

[0467] Experimental conclusion: The compound of the present invention shows excellent degradation effect on the degradation of VAV1 protein in Jurkat cells and is dose-dependent. Test example 4: Inhibition of CD3 / CD28-induced activation of Jurkat cells by the compound

[0468] Jurkat cells were cultured in RPMI-1640 medium containing inactivated 10% fetal bovine serum, 100 U / mL penicillin and 100 μg / mL streptomycin in an incubator at 37°C and 5% CO2. When the cell density reached 1×10^6, the cells were passaged and subcultured. Cells in the logarithmic growth phase were seeded at a density of 40000 onto a 96-well plate, and different concentrations of the compound were added. After treatment for 24 hours, 5 μg / mL CD3 antibody and 1 μg / mL CD28 antibody were added, and the cells were cultured for another 24 hours. The cell supernatant was taken and the IL-2 content was detected by ELISA.

[0469] Experimental conclusion: In the CD3 / CD28-induced Jurkat cell activation model, the compound of this invention can significantly inhibit the production of IL-2, and the inhibitory function is positively correlated with the dose.

[0470] Test Example 5: Compound Inhibits CD3 / CD28-Induced Human T Cell Activation

[0471] Dilute fresh blood samples with an equal volume of PBS and slowly add them to a 50 mL centrifuge tube containing 15 mL of Lymphoprep (Stemcell, #7851), taking care not to disrupt the interface. Centrifuge at 1000 g, speed 5 for 25 minutes at room temperature, without immobilizing. Collect the leukocyte matrix (PBMC), wash twice with PBS, centrifuge at 350 g for 10 minutes, and discard the supernatant. Use a T cell sorting kit (Stemcell, #17951) to sort T cells from the PBMC and adjust the cell density to 2.6 × 10⁶ cells / mL. 6 75 μL of the diluted assay compound was added to each well of a U-bottom 96-well plate (Corning, #3799), followed by 75 μL of the diluted assay compound. For the control group, 1640 complete medium containing an equal volume of DMSO was added. Cells were mixed and incubated for 24 hours. Cells were then transferred to a 96-well plate (Thermo, #167425) coated with Anti-Human CD3 (5 μg / mL, BD, #555329), and 50 μL of Anti-Human CD28 (1 μg / mL, BD, #555725) was added. Cells were mixed and incubated for another 48 hours. The supernatant was collected, and IL-2 levels were detected using an IL-2 ELISA kit (BD, #555190).

[0472] Experimental conclusion: In the CD3 / CD28-induced human T cell activation model, the compound of this invention can significantly inhibit the production of IL-2, and the inhibitory function is positively correlated with the dose.

[0473] Test Example 6: Mouse Pharmacokinetic Study

[0474] Pharmacokinetic studies were conducted in mice using male ICR mice (20-25g, fasted overnight). Three mice were administered 10mg / kg orally via gavage. Blood samples were collected before administration and at 15, 30 minutes, 1, 2, 4, 8, and 24 hours after administration. 6800g of blood samples were centrifuged at 2-8℃ for 6 minutes, and plasma was collected and stored at -80℃. Plasma samples from each time point were mixed with 3-5 times the volume of acetonitrile solution containing an internal standard, vortexed for 1 minute, centrifuged at 13000 rpm at 4℃ for 10 minutes, and the supernatant was mixed with 3 times the volume of water. An appropriate amount of the mixture was analyzed by LC-MS / MS. Key pharmacokinetic parameters were analyzed using a non-compartmental model with WinNonlin 7.0 software.

[0475] Table 2. Mouse p-values ​​of the compounds

[0476]

[0477] The results of the pharmacokinetic studies in mice showed that the compounds of this invention exhibited excellent pharmacokinetic properties and good drug-likeness.

[0478] Test Example 7: Rat Pharmacokinetic Test

[0479] Pharmacokinetic studies were conducted on male SD rats (180-240g) that had been fasted overnight. Three rats were administered the drug 10mg / kg orally via gavage. Blood samples were collected before administration and at 15, 30 minutes, 1, 2, 4, 8, and 24 hours after administration. 6800g of blood samples were centrifuged at 2-8℃ for 6 minutes, and plasma was collected and stored at -80℃. Plasma samples from each time point were mixed with 3-5 times the volume of acetonitrile solution containing an internal standard, vortexed for 1 minute, centrifuged at 13000 rpm at 4℃ for 10 minutes, and the supernatant was mixed with 3 times the volume of water. An appropriate amount of the mixture was analyzed by LC-MS / MS. Key pharmacokinetic parameters were analyzed using a non-compartmental model with WinNonlin 7.0 software.

[0480] The results of the pharmacokinetic studies in rats showed that the compound of the present invention exhibited excellent pharmacokinetic properties in rats and good drug-likeness.

[0481] Test Example 8: Human Liver Microsomal Stability Test

[0482] The stability assay for human liver microsomes was performed by co-incubating the compound with human liver microsomes in vitro. First, the test compound was prepared as a 10 mM stock solution in DMSO, and then diluted to 0.5 mM with acetonitrile. Human liver microsomes (Corning) were diluted with PBS to prepare a microsome / buffer solution, and this solution was used to dilute the 0.5 mM compound to prepare the working solution. The concentration of the compound in the working solution was 1.5 μM, and the concentration of human liver microsomes was 0.75 mg / mL. 30 μL of the working solution was added to each well of a deep-well plate, followed by 15 μL of preheated 6 mM NADPH solution to initiate the reaction, which was incubated at 37°C. At 0, 5, 15, 30, and 45 minutes of incubation, 135 μL of acetonitrile was added to the corresponding well to terminate the reaction. After terminating the reaction with acetonitrile at the last 45 minutes, the deep-well plate was vortexed for 10 minutes (600 rpm / min) and then centrifuged for 15 minutes. After centrifugation, the supernatant was collected, and purified water was added at a 1:1 ratio. LC-MS / MS analysis was performed to obtain the ratio of the compound peak area to the internal standard peak area at each time point. The peak area ratios of the compounds at 5, 15, 30, and 45 minutes were compared with the peak area ratio at 0 minutes to calculate the remaining percentage of the compound at each time point. T1 / 2 was calculated using Graphpad 5 software.

[0483] The results of the human liver microsome stability test show that the compound of the present invention exhibits excellent human liver microsome stability and good drug-like properties.

[0484] Test Example 9: Thermodynamic Solubility Test

[0485] This embodiment uses a standardized in vitro method to assess the solubility of the compounds. The control compounds, progesterone and diclofenac, were purchased from Sigma-Aldrich. PBS (pH 7.4), FaSSIF, FeSSIF, and FaSSGF buffers were freshly prepared in the laboratory according to standard formulations and used within the specified time. The solubility determination procedure was as follows: approximately 1 mg of the compound was weighed into a glass vial, the corresponding buffer (1 mL / mg) was added, a stir bar was added, and the vial was sealed. The vial was incubated at 25°C and 1100 rpm for 24 hours. After incubation, the stir bar was removed, and the sample was vacuum filtered and serially diluted 100, 1000, and 10000 times using a water / acetonitrile (1:1, including internal standard) mixture. The standards were dissolved in DMSO and diluted in the same manner to concentrations of 10, 1, and 0.1 μg / mL. All samples were placed in an autosampler and analyzed using LC-MS / MS. Data processing was performed using Excel software, and solubility was calculated by comparison with standards.

[0486] Thermodynamic solubility test results show that the compound of the present invention has good thermodynamic solubility and good drug-like properties.

[0487] Test Example 10: Inhibition of Cytochrome P450 by Compounds

[0488] The inhibitory potential of the compounds against the cytochrome P450 (CYP450) subtype CYP3A4 (two substrates: midazolam and testosterone) was investigated. First, the test compound was prepared as a 10 mM stock solution in DMSO, and the CYP3A4 inhibitor ketoconazole was prepared as 10 mM, 2.5 mM, and 2.5 mM stock solutions in DMSO. The test compound and ketoconazole were then diluted 400-fold to a final concentration (compound: 10 μM, ketoconazole: 2.5 μM) with acetonitrile.

[0489] Prepare 4-fold final concentrations of NADPH cofactor (66.7 mg NADPH added to 10 mL of potassium phosphate buffer) and substrates using potassium phosphate buffer (0.1 M, pH 7.4). The final concentrations of CYP3A4 substrate midazolam were 320 μM and CYP3A4 substrate testosterone were 20 μM.

[0490] Prepare a 0.2 mg / mL human liver microsome solution on ice using potassium phosphate buffer. Prepare two final concentrations of the analyte and control inhibitor solutions on ice using the human liver microsome solution. Add 30 μL of the analyte and control inhibitor solutions to each well, followed by 15 μL of substrate, and perform replicates. Incubate the 96-well plate and NADPH solution at 37°C for 5 minutes. Add 15 μL of preheated 8 mM NADPH solution to the plate to initiate the reaction. Pre-incubate the CYP3A4 plate at 37°C for 5 minutes. Stop the reaction by adding 120 μL of acetonitrile. After quenching, shake the plate on a shaker (IKA, MTS2 / 4) for 10 minutes (600 rpm / min), then centrifuge for 15 minutes. After centrifugation, the supernatant was collected, purified water was added at a 1:1 ratio, and LC-MS / MS was performed to obtain the ratio of the peak area of ​​the compound to the peak area of ​​the internal standard. The peak area ratio of the compound was compared with the peak area ratio of the control inhibitor to calculate the inhibition rate.

[0491] The results of the inhibition test on cytochrome P450 showed that the compound of the present invention had no significant inhibitory effect on CYP3A4 (two substrates, midazolam and testosterone) and had good drug-like properties.

[0492] Test Example 11: Balanced Dialysis Method for Testing Plasma Protein Binding

[0493] First, human or other species plasma samples were stored at -20°C, thawed in a 37°C water bath before use, and stored on wet ice. The working solution for the test compound was prepared using DMSO with a stock concentration of 10 mM and a final concentration of 2 μM. The thawed plasma was centrifuged to remove suspended impurities and precipitates, and the pH was adjusted to 7.0–8.0. The pretreated dialysis membrane was loaded into the dialysis apparatus according to the manufacturer's instructions and the assembly was completed. For the zero-point control sample, blank plasma was mixed with the working solution of the test compound and vortexed at 1000 rpm for 2 minutes to a final concentration of 2 μM. This mixture was immediately transferred to a 96-well plate as the T=0 control sample, and the remaining mixture was incubated in a constant temperature incubator. To determine the stability of the compound in plasma, the remaining mixture was incubated in a 37°C shaking incubator for 5 hours. After incubation, 50 μL of the sample was transferred to a 96-well plate for subsequent analysis. The equilibration dialysis procedure was performed by assembling the dialysis apparatus according to the manufacturer's instructions. Plasma samples were added to the dialysis chamber and dialyzed with an equal volume of PBS buffer. Experiments were conducted with replicates. The apparatus was covered with a breathable cap and incubated at 37°C and 100 rpm for 5 hours. After incubation, samples were taken from the plasma chamber and buffer chamber and transferred to 96-well plates for analysis. During sample processing, plasma or PBS was added to the collected samples and mixed for 2 minutes. 500 μL of 80% acetonitrile / methanol solution containing an appropriate internal standard was added to precipitate proteins and release compounds. After vortexing for 10 minutes, the mixture was centrifuged at 4000 rpm for 10 minutes. 100 μL of the supernatant was transferred to a new 96-well plate, and 300 μL of distilled water was added and mixed before LC-MS / MS analysis. All samples underwent automatic peak area integration. The peak areas of the analytes and internal standard were exported to an Excel spreadsheet. The free fraction, binding fraction, and recovery rate of the compounds were calculated using the following formulas:

[0494] Unbound percentage (% Unbound) = (buffer fluid cavity peak area ratio / plasma cavity peak area ratio) × 100;

[0495] Bound rate (%Bound) = 100 - %Unbound;

[0496] Recovery (%Recovery) = (Buffer cavity peak area ratio + Plasma cavity peak area ratio) / Total sample peak area ratio × 100;

[0497] Remaining (% Remaining) = 5-hour peak area ratio / 0-hour peak area ratio × 100.

[0498] Experimental results show that the compounds of this invention have significant advantages in plasma protein binding rate.

[0499] Test Example 12: Efficacy evaluation of the compound in a mouse model of inflammatory bowel disease induced by adoptive T cell transfer

[0500] 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.

[0501] Experimental methods:

[0502] 1) Spleens were isolated from BALB / c donor mice, and single-cell suspensions were prepared. CD4 cells were then sorted using the EasySep kit. + CD25 - Cells were stained and then sorted by flow cytometry for CD4+. + CD45RB + Cells were washed with PBS and resuspended to 1.5 × 10⁻⁶. 6 / mL. It was then transferred to immunodeficient recipient mice (CB17-SCID mice) via tail vein injection.

[0503] 2) Recipient mice were randomly assigned to either the compound or the control solvent starting on day 15 after cell transfer. The test compound was administered orally via gavage at doses ranging from 0.1 to 10 mg / kg once daily for 20 days.

[0504] 3) During the experiment, record changes in mouse body weight, fecal characteristics, and activity levels. After cell inoculation, perform DAI scoring twice weekly for weeks 1 and 2, and three times weekly for weeks 3 to 5. The DAI score is the sum of the scores for weight loss and fecal consistency, based on changes in animal body weight and fecal consistency.

[0505] 4) Mice were sacrificed on day 35, and colon tissue was collected. At the endpoint, the colon was collected, its length measured, washed with PBS to remove feces, dried, and weighed. The weight-to-length ratio was calculated. At the endpoint dissection, the colon contents were cleaned and preserved for pathological scoring.

[0506] The results showed that the compounds of this invention significantly alleviated the disease progression in an adoptive naïve T cell-induced mouse enteritis model.

Claims

1. The compound represented by formula (II), its tautomers, stereoisomers, pharmaceutically acceptable salts or prodrugs, in, R1 is a halogen, OCF3, CN, or C. 2-6 Alkyl, -OC 2-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 4-10 membered heterocyclic alkyl group, wherein the C 2-6 Alkyl, -OC 2-6 Alkyl, C 3-6 cycloalkyl, C 2-6 The alkynyl group and the 4-10 membered heterocyclic alkyl group are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. 1a replace; Each R 1a They are, independently, H, halogen, OH, NH2, CN, and C. 1-6 Alkyl or halogenated C 1-6 alkyl; R2, R3, and R4 are independently H, halogen, NH2, CN, and C, respectively. 1-6 Alkyl or halogenated C 1-6 alkyl; X1 is either N or CR5; X2 is N or CR 51 ; X3 is either N or CR7; X4 is N or CR 71 ; R5, R 51 R7 and R 71 Each can be independently H, halogen, NH2, CN, or C. 1-6 Alkyl or halogenated C 1-6 alkyl; R8 is H, D, halogen, or C. 1-6 alkyl; L1 represents a single bond, -O-, -NH-, or -OC. 1-3 Alkyl-, -NH-C 1-3 Alkyl-, -C 1-3 Alkyl- or -C 3-6 cycloalkyl-, wherein -NH-, -OC- 1-3 Alkyl-, -NH-C 1-3 Alkyl-, -C 1-3 Alkyl- and -C 3-6 Cycloalkyl groups – each independently and optionally marked with 1, 2, 3, or 4 R's 1L replace; Each R 1L Each is independently H, halogen, and C. 1-3 Alkyl or C 3-6 cycloalkyl; R6 represents CN, -C 0-3 Alkyl-P(=O)(R) 61 )2、-C 0-3 Alkyl-(N=)S(=O)(R 61 )2、-C 0-3 Alkyl-S(=O)(=NR) 62 )R 63 C 1-6 Alkyl, 4-10-membered heterocyclic alkyl, 5-10-membered heterocyclic alkenyl, 6-10-membered aryl or 5-10-membered heteroaryl, wherein C 1-6 Alkyl, 4-10-membered heterocyclic alkyl, 5-10-membered heterocyclic alkenyl, 6-10-membered aryl, and 5-10-membered heteroaryl groups are each independently and optionally bounded by 1, 2, 3, 4, 5, 6, 7, or 8 R groups. 6a replace; R 61 R 62 and R 63 H and C are independent of each other. 1-6 Alkyl or C 3-6 cycloalkyl; Each R 6a The independent components are H, halogen, oxo (=O), thio (=S), OH, NH2, CN, and C, respectively. 1-6 Alkyl, Halogenated C 1-6 Alkyl or C 3-6 cycloalkyl; Or, two Rs 61 Together with the P or S atoms to which they are attached, they form a 4-10 membered heterocyclic alkyl group, wherein the 4-10 membered heterocyclic alkyl group is optionally surrounded by 1, 2, 3 or 4 R atoms. 6b replace; Or, R 62 With R 63 Together with the N and S atoms attached thereto, they form a 5-10 membered heterocyclic alkenyl group, which is optionally surrounded by 1, 2, 3 or 4 R atoms. 6b replace; Each R 6b They are, independently, H, halogen, oxo (=O), OH, NH2, CN, and C, respectively. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-6 cycloalkyl, -L2-C 1-6 Alkyl, -L2-C 3-6 Cycloalkyl or -L2-4-8-membered heterocycloalkyl, wherein C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-6 cycloalkyl, -L2-C 1-6 Alkyl, -L2-C 3-6 The cycloalkyl or -L2-4-8-membered heterocycloalkyl groups are each optionally substituted by 1, 2, 3 or 4 Rs, independently; Each L2 is independently -O-, -N(R) 2L -, -S-, -S(=O)-, -S(=O)2- or -C(=O)-; R 2L For H or C 1-3 alkyl; Each R is independently H, halogen, OH, NH2, or CN; The condition is that when R1 is a halogen, R6 is -C. 0-3 Alkyl P(=O)(R) 61 )2、-C 0-3 Alkyl-(N=)S(=O)(R 61 )2、-C 0-3 Alkyl-S(=O)(=NR) 62 )R 63 The 4-10-membered heterocyclic alkyl group or the 5-10-membered heterocyclic alkenyl group is at least substituted with one of the thio groups (C=S). The heteroatomic groups in the "heterocyclic alkyl", "heterocyclic alkenyl" and "heteroaryl" include N, O, S, S(=O), S(=O)2 or S(=O)(=NH), and the number of the heteroatomic groups is 1, 2, 3 or 4; when the number of the heteroatomic groups is multiple, the heteroatomic groups may be the same or different.

2. The compound, its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs according to claim 1, characterized in that, It satisfies one or more of the following conditions: (1) R1 is Cl, CN, -OCF3, C 2-4 alkynyl group, C 3-4 Cycloalkyl or 4-6 membered heterocycloalkyl, wherein C 2-4 alkynyl group, C 3-4 Cycloalkyl and 4-6 membered heterocycloalkyl groups are each independently and optionally bound by 1, 2, 3 or 4 R groups. 1a replace; (2) Each R 1a Each can be H or F independently; (3) R6 is a 4-8-membered heterocyclic alkyl, a 5-8-membered heterocyclic alkenyl, or a 5-6-membered heteroaryl, wherein the 4-8-membered heterocyclic alkyl, the 5-8-membered heterocyclic alkenyl, and the 5-6-membered heteroaryl are each independently selected by 1, 2, 3, 4, or 5 R6 groups. 6a replace; (4) Each R 6a They can be independently H, oxo (=O), thio (=S), CH3, -CH2CH3, CHF2, CF3 or cyclopropyl; (5) R6 is -C 0-3 Alkyl-P(=O)(R) 61 )2、-C 0-3 Alkyl-(N=)S(=O)(R 61 )2 or -C 0-3 Alkyl-S(=O)(=NR) 62 )R 63 ; (6)R 61 R 62 and R 63 Each can be independently H, CH3, -CH2CH3, or cyclopropyl; (7) Two Rs 61 Together with the P or S atoms to which they are attached, they form a 4-6 membered heterocyclic alkyl group, wherein the 4-6 membered heterocyclic alkyl group is optionally surrounded by 1, 2, 3 or 4 R atoms. 6b replace; (8)R 62 With R 63 Together with the N and S atoms attached thereto, they form a 5-10 membered heterocyclic alkenyl group, wherein the 5-10 membered heterocyclic alkenyl group is optionally separated by 1, 2, 3, or 4 Rs 6b replace; (9) Each R 6b They are, independently, H, halogen, oxo (=O), OH, NH2, CN, and C, respectively. 1-3 Alkyl, Halogenated C 1-6 Alkyl, C 3-6 cycloalkyl, -L2-C 1-3 Alkyl, -L2-C 3-5 Cycloalkyl or -L2-4-6-membered heterocycloalkyl, wherein C 1-3 Alkyl, Halogenated C 1-6 Alkyl, C 3-6 cycloalkyl, -L2-C 1-3 Alkyl, -L2-C 3-5 The cycloalkyl or -L2-4-6-membered heterocycloalkyl groups are each optionally substituted by 1, 2, 3 or 4 Rs, independently; (10) Each L2 is independently -O-, -N(R) 2L - or -C(=O)-; (11)R 2L For H; (12) R6 is a 4-8 membered heterocyclic alkyl group or a 5-8 membered heterocyclic alkenyl group, wherein the 4-8 membered heterocyclic alkyl group and the 5-8 membered heterocyclic alkenyl group are surrounded by 1, 2, 3, 4, 5 or 6 R groups. 6a Replacement, where at least one R 6a It is thiolated (=S); (13) L1 is selected from the following group: single bond, -C 1-3 Alkyl-, -OC 1-3 Alkyl-, -C 3-6 Cycloalkyl-.

3. The compound, its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs according to claim 1, characterized in that, It satisfies one or more of the following conditions: (1a) R1 is Cl, CN, -OCF3, -C≡C-CH3, (2a) R2, R3 and R4 are each independently H; (3a)R5、R 51 R7 and R 71 Each is independently represented by H; (4a) L1 is a single bond, -CH2-, -O-CH2- or (5a)R6 is (6a)R6 is (7a) Each R 6b H and -C (=O)-C are independently represented respectively. 1-3 Alkyl, or -C(=O)-C 3-5 cycloalkyl; (8a) Each R 6b They are independently H, -C(=O)-CH3, -C(=O)-CH2CH3 or -C(=O)-cyclopropyl; (9a) When R6 is -C 0-3 Alkyl-P(=O)(R) 61 )2、-C 0-3 Alkyl-(N=)S(=O)(R 61 2. 4-10-membered heterocyclic alkyl or 5-10-membered heterocyclic alkenyl, wherein two R 61 When R6 forms a heterocyclic alkyl group together with the P or S atom it is attached to, R6 is... (10a)R6 is (11a) R8 is H or D; (12a)R6 is -C 0-3 Alkyl-S(=O)(=NR) 62 )R 63 , where R 62 With R 63 When R6 forms a 5-10 membered heterocyclic alkenyl group together with the N and S atoms it is attached to, R6 is 4. The compound, its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs according to claim 1, characterized in that, It satisfies one or more of the following conditions: (1b) When R1 is Cl, R6 is -C 0-3 Alkyl-P(=O)(R) 61 )2、-C 0-3 Alkyl-(N=)S(=O)(R 61 )2 or -C 0-3 Alkyl-S(=O)(=NR) 62 )R 63 (2b) When R1 is Cl, R6 is a 4-8 membered heterocyclic alkyl or a 5-8 membered heterocyclic alkenyl, wherein the 4-8 membered heterocyclic alkyl and the 5-8 membered heterocyclic alkenyl are at least substituted by a thio (=S). (3b)R6 is (4b) When R1 is Cl, R6 is 5. The compound, its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs according to claim 1, characterized in that, The compound is selected from the following structures: The definitions of R1 and R8 are as described in claim 1, wherein L1 and R6 satisfy one or more of the following conditions: (1c) L1 is a single bond, -CH2-, -O-CH2- or... (2c) R6 is a 4-8 membered heterocyclic alkyl, a 5-8 membered heterocyclic alkenyl, or a 5-6 membered heteroaryl, wherein the 4-8 membered heterocyclic alkyl, the 5-8 membered heterocyclic alkenyl, and the 5-6 membered heteroaryl are each independently selected by 1, 2, 3, 4, or 5 R6 groups. 6a Replace; the R 6a They can be independently H, oxo (=O), thio (=S), CH3, -CH2CH3, CHF2, CF3 or cyclopropyl; (3c)R6 is (4c)R6 is -C 0-3 Alkyl-P(=O)(R) 61 )2、-C 0-3 Alkyl-(N=)S(=O)(R 61 )2 or -C 0-3 Alkyl-S(=O)(=NR) 62 )R 63 The R 61 R 62 and R 63 Each can be independently H, CH3, -CH2CH3, or cyclopropyl; (5c)R6 is (6c)R6 is -C 0-3 Alkyl-P(=O)(R) 61 )2、-C 0-3 Alkyl-(N=)S(=O)(R 61 )2, two R 61 Together with the P or S atoms to which they are attached, they form a heterocyclic alkyl group, wherein the heterocyclic alkyl group is a 4-6 membered heterocyclic alkyl group, and the 4-6 membered heterocyclic alkyl group is optionally surrounded by 1, 2, 3 or 4 R atoms. 6b Replace; each of the R 6b They are, independently, H, halogen, oxo (=O), OH, NH2, CN, and C, respectively. 1-3 Alkyl, -L2-C 1-3 Alkyl, -L2-C 3-5 Cycloalkyl or -L2-4-6-membered heterocycloalkyl; wherein L2 is -O-, -NH- or -C(=O)-; (7c)R6 is The R 6b Hydrogen, L2-C 1-3 Alkyl, L2-C 3-5 Cycloalkyl, L2-4-6-membered heterocycloalkyl, wherein L2 is -C(=O)-; (8c)R6 is The R 6b For hydrogen, (9c)R6 is -C 0-3 Alkyl-S(=O)(=NR) 62 )R 63 The R 62 With R 63 Together with the N and S atoms attached thereto, they form a 5-10 membered heterocyclic alkenyl group, wherein the 5-10 membered heterocyclic alkyl group is optionally surrounded by 1, 2, 3 or 4 R atoms. 6b When replacing, R6 is (10c)R6 is 6. The compound, its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs according to claim 1, characterized in that, The compound is selected from the following structures: The definitions of L1 and R8 are as described in claim 1, wherein R6 satisfies one or more of the following conditions: (1d)R6 is -C 0-3 Alkyl-P(=O)(R) 61 )2、-C 0-3 Alkyl-(N=)S(=O)(R 61 )2 or -C 0-3 Alkyl-S(=O)(=NR) 62 )R 63 ; (2d)R6 is (3d)R6 is a 4-8 membered heterocyclic alkyl group or a 5-6 membered heterocyclic alkenyl group, wherein the 4-8 membered heterocyclic alkyl group and the 5-6 membered heterocyclic alkenyl group are at least substituted by a thio (=S); (4d)R6 is 7. The compound, its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs according to claim 1, characterized in that, It satisfies one or more of the following conditions: (1e) R6 is a 4-8-membered heterocyclic alkyl, a 5-8-membered heterocyclic alkenyl, or a 5-6-membered heteroaryl, wherein the 4-8-membered heterocyclic alkyl, 5-8-membered heterocyclic alkenyl, and 5-6-membered heteroaryl are each independently selected by 1, 2, 3, 4, or 5 R6 groups. 6a Replace; or, (2e)R6 is -C 0-3 Alkyl-P(=O)(R) 61 )2、-C 0-3 Alkyl-(N=)S(=O)(R 61 )2 or -C 0-3 Alkyl-S(=O)(=NR) 62 )R 63 The R 61 R 62 and R 63 H and C are independent of each other. 1-6 Alkyl or C 3-6 cycloalkyl; or, (3e)R6 is -C 0-3 Alkyl-P(=O)(R) 61 )2、-C 0-3 Alkyl-(N=)S(=O)(R 61 )2, the two R 61 Together with the P or S atoms to which they are attached, they form a 4-6 membered heterocyclic alkyl group, wherein the 4-6 membered heterocyclic alkyl group is optionally surrounded by 1, 2, 3 or 4 R atoms. 6b Replace; or, (4e)R6 is -C 0-3 Alkyl-S(=O)(=NR) 62 )R 63 The R 62 With R 63 Together with the N and S atoms attached thereto, they form a 5-10 membered heterocyclic alkenyl group, which is optionally surrounded by 1, 2, 3 or 4 R atoms. 6b Replace; or, (5e) R6 is a 4-8 membered heterocyclic alkyl group or a 5-8 membered heterocyclic alkenyl group, wherein the 4-8 membered heterocyclic alkyl group and the 5-8 membered heterocyclic alkenyl group are separated by 1, 2, 3, 4, 5 or 6 R groups. 6a Replacement, where at least one R 6a It is thiolated (=S).

8. The compound, its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs according to claim 1, characterized in that, It satisfies one or more of the following conditions: (1f)R6 is Ideally, R6 is or, (2f)R6 is or, (3f)R6 is Ideally, R6 is or, (4f)R6 is or, (5f)R6 is Ideally, R6 is 9. The compound, its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs according to claim 1, characterized in that, R6 is selected from -(N=)S(=O)(R 61 )2, 4-7 membered heterocyclic alkyl groups, 5-6 membered heterocyclic alkenyl groups; the R 61 Each is independently CH3, CHF2, or cyclopropyl; the 4-7 membered heterocyclic alkyl group and the 5-6 membered heterocyclic alkenyl group are optionally surrounded by 1, 2, 3, 4, or 5 R groups. 6a Replacement, where at least one R 6a Selected from thiocyanates (C=S); or, two Rs 61 Together with the S atom it is attached to, they form a 5-6 membered heterocyclic alkyl group, which is optionally surrounded by 1, 2, 3 or 4 R atoms. 6b replace; R6 is selected from Preferably, R6 is selected from Better yet, R6 is selected from 10. The compound, its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs according to claim 1, characterized in that, The compound has the following structure:

11. A pharmaceutical composition, characterized in that, The compound comprising a therapeutically effective dose of any one of claims 1-10, its tautomers, stereoisomers, pharmaceutically acceptable salts or prodrugs, and pharmaceutically acceptable excipients.

12. Use of the compound, its tautomer, stereoisomer, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition according to any one of claims 1-10 in the preparation of a medicament for the treatment or prevention of diseases associated with VAV1.

13. The use according to claim 12, characterized in that, VAV1-related diseases include cancer or autoimmune diseases.

14. The use according to claim 12, characterized in that, The VAV1-related diseases include systemic lupus erythematosus, myasthenia gravis, periodontitis, type 1 diabetes, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, autoimmune hepatitis, or psoriasis.

Images