VAV1 degrader

Abstract

The present invention provides a VAV1 degrader, and specifically provides a compound represented by formula (I), and a tautomer, stereoisomer, pharmaceutically acceptable salt or prodrug thereof. The compound provided by the present invention has good efficacy, and can be used for preparing a drug for treatment or prevention of VAV1-related diseases.

Description

Vav1 degraders

[0001] Priority information

[0002] The present disclosure claims priority to and the benefit of Chinese Patent Application No. 202411348783.2, filed September 25, 2024, Chinese Patent Application No. 202411546123.5, filed October 31, 2024, Chinese Patent Application No. 202411646151.4, filed November 15, 2024, Chinese Patent Application No. 202411959696.0, filed December 27, 2024, Chinese Patent Application No. 202510121475.4, filed January 24, 2025, Chinese Patent Application No. 202510309221.5, filed March 14, 2025, and Chinese Patent Application No. 202510525464.2, filed April 24, 2025, and incorporates by reference the entire contents of each of the foregoing applications. TECHNICAL FIELD

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

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

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

[0006] Genome-wide CRISPR-Cas9 screens confirmed that VAV1 is an important positive regulator of T cell activation / function, and that VAV1 promotes proliferation of cells sensitive to TCR signaling pathways, such as human Jurkat T cells and primary human CD4+ and CD8+ T cells. In addition, VAV1 knockout mouse data suggest that VAV1 plays a critical role in T / B lymphocyte function and antigen receptor signaling, particularly in T cells. More importantly, Vav1 -deficient mouse thymocytes and splenic T cells show multiple defects in TCR-mediated signaling, such as impaired calcium (Ca 2+ ) mobilization and transcription factor activation. Whereas T cells with loss of VAV1 GEF activity (VAV1 L334A / K335A) exhibit normal TCR-mediated Ca 2+ flux and nuclear factor of activated T cells (NFAT) activation. This indicates that both GEF activity and scaffolding function of VAV1 play important roles in the TCR signaling pathway.

[0007] Genetic analysis found that rodents carrying the VAV1 R63W mutation exhibited lower susceptibility in experimental autoimmune encephalomyelitis (EAE) and palmitoyl-induced arthritis compared to wild-type (WT). In the mouse model of antigen (methylated bovine serum albumin)-induced arthritis (AIA), VAV1 knockout mice exhibited less 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 than wild-type (WT) mice. This again indicates that VAV1 plays an important role in T cell differentiation and function.

[0008] Recently, the development of a new molecular glue degrader named MRT-6160 has opened up new avenues for targeting the VAV1 protein, which was previously considered "undruggable". MRT-6160 can effectively link the VAV1 protein with E3 ubiquitin ligase (such as Cereblon), inducing the degradation and clearance of VAV1 by the ubiquitin-proteasome system of cells. In clinical phase I trials, MRT-6160 showed excellent efficacy: not only did it achieve over 90% efficient degradation of the VAV1 protein, but it also significantly inhibited downstream immune activity, reducing the production of most inflammatory cytokines by up to 99%. At the same time, the drug has good safety and tolerability, laying a solid foundation for subsequent clinical development. This breakthrough highlights the great potential of VAV1-targeted therapy in the treatment of autoimmune diseases, and VAV1 is expected to become a key therapeutic target for various immune-mediated diseases. SUMMARY

[0009] In a first aspect, the present application provides a compound represented by formula (I), a tautomer, a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof,

[0010] wherein,

[0011] R1is halogen, CN, C 1-6 alkyl, -OC 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl or 4-10 membered heterocycloalkyl, each independently optionally substituted with 1, 2, 3 or 4 R 1-6 alkyl, -OC 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 4-10 membered heterocycloalkyl, each independently optionally substituted with 1, 2, 3 or 4 R 1a ;

[0012] each R 1a is independently H, D, halogen, OH, NH2, CN, C 1-6 alkyl or halogenated C 1-6 alkyl;

[0013] R2, R3and R4are each independently H, D, halogen, NH2, CN, C 1-6 alkyl or halogenated C 1-6 alkyl;

[0014] each R5is independently H, D, halogen, NH2, CN or C 1-6 alkyl or halogenated C 1-6 alkyl;

[0015] R8is H, D, halogen, or C 1-6 alkyl;

[0016] L1is a single bond, -O-, -NH-, -O-C 1-3 alkyl-, -NH-C 1-3 alkyl-, or -C 1-3 alkyl-, wherein said -NH-, -O-C 1-3 alkyl-, -NH-C 1-3 alkyl-, and -C 1-3 alkyl- are each independently optionally substituted with 1, 2, 3, or 4 R 1L substituents;

[0017] each R 1L is independently H, D, halogen, C 1-3 alkyl, haloC 1-3 alkyl, or C 3-6 cycloalkyl;

[0018] Ring A is 4-10 membered heterocycloalkyl, 5-10 membered heterocycloalkenyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

[0019] each R 6-1 is independently C 6a alkyl substituted with 1, 2, 3, or 4 R 3-6 cycloalkyl substituted with 1, 2, 3, or 4 R 6a 4-8 membered heterocycloalkyl substituted with 1, 2, 3, or 4 R 6b -L2-C 3-6 cycloalkyl substituted with 1, 2, 3, or 4 R 6b -L2-4-8 membered heterocycloalkyl substituted with 1, 2, 3, or 4 R 6b -L2-C 1-3 alkyl-C 3-6 cycloalkyl substituted with 1, 2, 3, or 4 R 6b -L2-C 1-3 alkyl-4-8 membered heterocycloalkyl substituted with 1, 2, 3, or 4 R 6c C 1-6 alkoxy;

[0020] each L2is independently -O-, -N(R 2L )-, -N(R 2L )-C(=O)-, -S-, -S(=O)-, -S(=O)2-, or -C(=O)-;

[0021] R 2L is H or C 1-3 alkyl;

[0022] each R6a C, each independently 1-3 Alkyl or -C 1-3 Alkyl-C 1-3 Alkoxy, the C 1-3 Alkyl and -C 1-3 Alkyl-C 1-3 The alkoxy groups are independently substituted by 1, 2, 3 or 4 R groups;

[0023] Each R is independently H, D, halogen, OH, NH2, or CN;

[0024] Each R 6b They are, independently, H, D, halogen, OH, NH2, CN, and C. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0025] Each R 6c Each can be independently H, D, halogen, OH, NH2, CN, or C. 1-6 Alkylamino;

[0026] Each R 6-2 They are, independently, H, D, halogen, OH, NH2, CN, oxo (=O), thio (=S), and C. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0027] m can be 1, 2, 3, or 4;

[0028] n is 1, 2, 3 or 4;

[0029] g can be 0, 1, 2, 3, or 4;

[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 compound represented by formula (I), its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs are included.

[0032] in,

[0033] R1 is a halogen, CN, or C. 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group or 4-10 membered heterocyclic alkyl group, wherein the C1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, 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;

[0034] Each R 1a They are, independently, H, D, halogen, OH, NH2, CN, and C. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0035] R2, R3, and R4 are independently H, D, halogen, NH2, CN, and C, respectively. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0036] Each R5 is independently H, D, halogen, NH2, CN, or C. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0037] R8 is H, D, halogen, or C. 1-6 alkyl;

[0038] 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;

[0039] Each R 1L Independently represented by H, D, halogen, and C respectively. 1-3 Alkyl, Halogenated C 1-3 Alkyl or C 3-6 cycloalkyl;

[0040] Ring A is a 4-10 membered heterocyclic alkyl, a 5-10 membered heterocyclic alkenyl, a 6-10 membered aryl, or a 5-10 membered heteroaryl;

[0041] Each R 6-1 Each independently is assigned to 1, 2, 3, or 4 R's. 6a Replacement C 3-6 Cycloalkyl groups, with 1, 2, 3 or 4 R groups 6a Substituted 4-8 membered heterocyclic alkyl groups, with 1, 2, 3 or 4 R groups 6b Replacement -L2-C3-6 cycloalkyl, which is substituted by 1, 2, 3 or 4 R 6b substituted -L2-4-8 membered heterocycloalkyl, which is substituted by 1, 2, 3 or 4 R 6b substituted -L2-C 1-3 alkyl-C 3-6 cycloalkyl, which is substituted by 1, 2, 3 or 4 R 6b substituted -L2-C 1-3 alkyl-4-8 membered heterocycloalkyl or substituted by 1, 2, 3 or 4 R 6c substituted C 1-6 alkoxy;

[0042] each L2is independently -0-, -N(R 2L )-, -N(R 2L )-C(=0)-, -S-, -S(=0)-, -S(=0)2- or -C(=0)-;

[0043] R 2L is H or C 1-3 alkyl;

[0044] each R 6a is independently C 1-3 alkyl or -C 1-3 alkyl-C 1-3 alkoxy, which C 1-3 alkyl and -C 1-3 alkyl-C 1-3 alkoxy is independently substituted by 1, 2, 3 or 4 R;

[0045] each R is independently H, halogen, OH, NH2or CN;

[0046] each R 6b is independently H, halogen, OH, NH2, CN, C 1-6 alkyl or halogenated C 1-6 alkyl;

[0047] each R 6c is independently halogen, OH, NH2or CN;

[0048] each R 6-2 is independently H, halogen, OH, NH2, CN, oxo (=0), thioxo (=S), C 1-6 alkyl or halogenated C 1-6 alkyl;

[0049] m is 1, 2, 3 or 4;

[0050] n is 1, 2, 3 or 4;

[0051] g is 0, 1, 2, 3 or 4;

[0052] The heteroatom groups in the "heterocycloalkyl", "heterocycloalkenyl" and "heteroaryl" groups comprise N, O, S, S(=O), S(=O)2or S(=O)(=NH), the number of which is 1, 2, 3 or 4; when the number of the heteroatom groups is plural, the heteroatom groups are the same or different.

[0053] In an optional embodiment of the present application, the above-mentioned compound represented by the formula (I), a tautomer, a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof,

[0054] wherein,

[0055] R1is halogen, CN, C 1-6 alkyl, -OC 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl or 4-10 membered heterocycloalkyl, each of which is independently optionally substituted by 1, 2, 3 or 4 R 1-6 alkyl, -OC 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 4-10 membered heterocycloalkyl, each of which is independently optionally substituted by 1, 2, 3 or 4 R 1a substituents;

[0056] each R 1a is independently H, halogen, OH, NH2, CN, C 1-6 alkyl or halogenated C 1-6 alkyl;

[0057] R2, R3and R4are each independently H, halogen, NH2, CN, C 1-6 alkyl or halogenated C 1-6 alkyl;

[0058] each R5is independently H, halogen, NH2, CN or C 1-6 alkyl or halogenated C 1-6 alkyl;

[0059] R8is H, D, halogen or C 1-6 alkyl;

[0060] L1is a single bond, -O-, -NH-, -O-C 1-3 alkyl-, -NH-C 1-3 alkyl- or -C 1-3 alkyl-, wherein the -NH-, -O-C 1-3 alkyl-, -NH-C 1-3 alkyl- and -C1-3 alkyl is independently optionally substituted by 1, 2, 3, or 4 R 1L substituents;

[0061] each R 1L is independently H, halogen, C 1-3 alkyl, halogenated C 1-3 alkyl or C 3-6 cycloalkyl;

[0062] Ring A is a 4-10 membered heterocycloalkyl, 5-10 membered heterocycloalkenyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

[0063] each R 6-1 is independently C 1-3 alkyl substituted by 1, 2, 3, or 4 R 6a substituents; 3-6 cycloalkyl substituted by 1, 2, 3, or 4 R 6a substituents; 4-8 membered heterocycloalkyl substituted by 1, 2, 3, or 4 R 6b substituents; -L2-C 3-6 cycloalkyl or -L2-4-8 membered heterocycloalkyl substituted by 1, 2, 3, or 4 R 6b substituents;

[0064] each L2is independently -O-, -N(R 2L )-, -N(R 2L )-C(=O)-, -S-, -S(=O)-, -S(=O)2-, or -C(=O)-;

[0065] R 2L is H or C 1-3 alkyl;

[0066] each R 6a is independently C 1-3 alkyl or -C 1-3 alkyl-C 1-3 alkyl, and -C 1-3 alkyl and -C 1-3 alkyl-C 1-3 alkyl is independently optionally substituted by 1, 2, 3, or 4 R

[0067] each R is independently H, halogen, OH, NH2, or CN;

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

[0069] each R 6-2each independently H, halogen, OH, NH2, CN, oxo (=0), thioxo (=S), C 1-6 alkyl or haloC 1-6 alkyl;

[0070] m is 1, 2, 3 or 4;

[0071] n is 1, 2, 3 or 4;

[0072] g is 0, 1, 2, 3 or 4;

[0073] The heteroatom groups in the "heterocycloalkyl", "heterocycloalkenyl" and "heteroaryl" groups comprise N, O, S, S(=0), S(=0)2or S(=0)(=NH), the number of which is 1, 2, 3 or 4; when the number of the heteroatom groups is plural, the heteroatom groups are the same or different.

[0074] In an optional embodiment of the present application, the above-mentioned compound represented by formula (I), a tautomer, a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof,

[0075] wherein,

[0076] R1is halogen, CN, C 1-6 alkyl, -OC 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 4-10 membered heterocycloalkyl, the C 1-6 alkyl, -OC 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 4-10 membered heterocycloalkyl are each independently optionally substituted by 1, 2, 3 or 4 R 1a substituents;

[0077] each R 1a is each independently H, halogen, OH, NH2, CN, C 1-6 alkyl or haloC 1-6 alkyl;

[0078] R2, R3and R4are each independently H, halogen, NH2, CN, C 1-6 alkyl or haloC 1-6 alkyl;

[0079] each R5is each independently H, halogen, NH2, CN or C 1-6 alkyl or haloC 1-6 alkyl;

[0080] R8 is H, D, halogen, or C. 1-6 alkyl;

[0081] 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... 1-3 Alkyl-, -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;

[0082] Each R 1L Each is independently H, halogen, and C. 1-3 Alkyl or C 3-6 cycloalkyl;

[0083] Ring A is a 4-10 membered heterocyclic alkyl, a 5-10 membered heterocyclic alkenyl, a 6-10 membered aryl, or a 5-10 membered heteroaryl;

[0084] Each R 6-1 Each of the C atoms independently substituted with one, two, three, or four halogens 1-3 alkoxy group, with 1, 2, 3 or 4 R groups 6a Replacement C 3-6 Cycloalkyl, with 1, 2, 3 or 4 R 6a Substituted 4-8 membered heterocyclic alkyl groups, with 1, 2, 3 or 4 R groups 6b Replacement -L2-C 3-6 Cycloalkyl groups or those with 1, 2, 3 or 4 R groups 6b Substituted -L2-4-8-membered heterocyclic alkyl groups;

[0085] Each L2 is independently -O-, -N(R) L2 -, -S-, -S(=O)-, -S(=O)2- or -C(=O)-;

[0086] R L2 For H or C 1-3 alkyl;

[0087] Each R 6a H and C are independent of each other. 1-3 Alkyl or -C 1-3 Alkyl-C 1-3 Alkoxy, the C 1-3 Alkyl and -C 1-3 Alkyl-C 1-3 The alkoxy groups are independently substituted by 1, 2, 3 or 4 R groups;

[0088] Each R is independently H, halogen, OH, NH2, or CN;

[0089] each R 6b is independently H, halogen, OH, NH2, CN, C 1-6 alkyl or haloC 1-6 alkyl; each R 6-2 is independently H, halogen, OH, NH2, CN, C 1-6 alkyl or haloC 1-6 alkyl;

[0090] m is 1, 2, 3 or 4;

[0091] n is 1, 2, 3 or 4;

[0092] g is 0, 1, 2, 3 or 4;

[0093] The heteroatom groups in the "heterocycloalkyl", "heterocycloalkenyl" and "heteroaryl" groups comprise N, O, S, S(=O), S(=O)2or S(=O)(=NH), the number of which is 1, 2, 3 or 4; when the number of the heteroatom groups is plural, the heteroatom groups are the same or different.

[0094] In an optional embodiment of the present application, each R1is F, Cl, Br, CN, C 1-3 alkyl, -OC 1-3 alkyl, C 3-6 cycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl or 4-6 membered heterocycloalkyl, the C 1-3 alkyl, -OC 1-3 alkyl, C 3-6 cycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl or 4-6 membered heterocycloalkyl is independently optionally substituted with 1, 2, 3 or 4 R 1a groups.

[0095] In an optional embodiment of the present application, each R 1a is independently H, F, Cl, OH, NH2or CN.

[0096] In an optional embodiment of the present application, R1is Cl.

[0097] In an optional embodiment of the present application, R1is F.

[0098] In an optional embodiment of the present application, each of R2, R3and R4is independently H, halogen, NH2, CN, C 1-3 alkyl or haloC 1-3 alkyl.

[0099] In an optional embodiment of the present invention, R2, R3 and R4 are independently H, F or Cl, respectively.

[0100] In an optional embodiment of the present invention, R2, R3 and R4 are each independently H.

[0101] In an optional embodiment of the present invention, each of the above R5 is independently H, halogen, NH2, CN, or C. 1-3 Alkyl or halogenated C 1-3 alkyl.

[0102] In an optional embodiment of the present invention, each of the above R5 is independently H.

[0103] In an optional embodiment of the present invention, R8 is H or D.

[0104] In an optional embodiment of the present invention, the above compound has the structure of formula (II):

[0105] Where R1 is F, Cl, Br, or C. 1-3 alkyl;

[0106] L1 is a single bond, -O-, -NH-, -O-CH2-, -NH-CH2-, or -CH2-, wherein -NH-, -O-CH2-, -NH-CH2-, and -CH2- are each independently and optionally influenced by 1, 2, 3, or 4 R bonds. 1L Replace; each R 1L They can be H, F, Cl, or CH3 independently;

[0107] Each bond can be a single or double bond independently, provided that the valence bond allows it.

[0108] V1, V2, V3, V4 and V5 are each independently CH, CH2, N or NH;

[0109] V6 is C, CH, or N;

[0110] Each R 6-2 They are independently H, D, halogen, oxo (=O), thio (=S), and C, respectively. 1-3 Alkyl or halogenated C 1-3 alkyl;

[0111] R 6-1 For 1, 2, 3 or 4 R 6a Replacement C 3-6 Cycloalkyl groups, with 1, 2, 3 or 4 R groups 6a Substituted 4-8 membered heterocyclic alkyl groups, with 1, 2, 3 or 4 R groups 6b Replacement -L2-C 3-6Cycloalkyl groups, with 1, 2, 3 or 4 R groups 6b Substituted -L2-4-8-membered heterocyclic alkyl groups, with 1, 2, 3 or 4 R groups 6b Replacement -L2-C 1-3 Alkyl-C 3-6 Cycloalkyl groups, with 1, 2, 3 or 4 R groups 6b Replacement -L2-C 1-3 Alkyl-4-8-membered heterocyclic alkyl groups or those with 1, 2, 3 or 4 R groups 6c Replacement C 1-6 Alkoxy;

[0112] L2 is -O-, -NH-, or -NH-C(=O)-;

[0113] R 6a R 6b R 6c As defined in this invention.

[0114] In an optional embodiment of the present invention, the above compound has the structure of formula (II):

[0115] Where R1 is F, Cl, Br, or C. 1-3 alkyl;

[0116] L1 is a single bond, -O-, -NH-, -O-CH2-, -NH-CH2-, or -CH2-, wherein -NH-, -O-CH2-, -NH-CH2-, and -CH2- are each independently and optionally influenced by 1, 2, 3, or 4 R bonds. 1L Replace; each R 1L They can be H, F, Cl, or CH3 independently;

[0117] Each bond can be a single or double bond independently, provided that the valence bond allows it.

[0118] V1, V2, V3, V4 and V5 are each independently CH, CH2, N or NH;

[0119] V6 is C, CH, or N;

[0120] Each R 6-2 They are independently H, D, halogen, oxo (=O), thio (=S), and C, respectively. 1-3 Alkyl or halogenated C 1-3 alkyl;

[0121] R 6-1 For 1, 2, 3 or 4 R 6a Replacement C 3-6 Cycloalkyl groups, with 1, 2, 3 or 4 R groups 6aSubstituted 4-8 membered heterocyclic alkyl groups;

[0122] R 6a C, each independently 1-3 Alkyl or -C 1-2 Alkyl-C 1-2 Alkoxy, the C 1-3 Alkyl and -C 1-3 Alkyl-C 1-3 The alkoxy group is independently substituted by one or two R groups; each R group is independently H, D, halogen, or OH.

[0123] In an optional embodiment of the present invention, the above-mentioned R 6-2 They can be H or oxo (=O) independently, respectively.

[0124] In an optional embodiment of the present invention, the above-mentioned R 6-1 For 1 or 2 R 6a Replacement C 3-6 Cycloalkyl groups, with 1, 2, 3 or 4 R groups 6a Substituted 4-5 membered heterocyclic alkyl groups.

[0125] In an optional embodiment of the present invention, the above-mentioned R 6a They are independently -CH3 or -CH2-OCH3 substituted with 1 or 2 Rs, respectively.

[0126] In an optional embodiment of the present invention, each of the above R is independently H, D, F, or OH.

[0127] In an optional embodiment of the present invention, the above-mentioned R 6a They can be independently -CH2-OH, -CH2F, -CHF2, -CF3, -CH2-CH2F, or -CH2-OCF3.

[0128] In an optional embodiment of the present invention, the above compound has the structure of formula (III-1):

[0129] Where R1 is F, Cl, Br, or C. 1-3 alkyl;

[0130] L1 is a single bond, -O-, -NH-, -O-CH2-, -NH-CH2-, or -CH2-, wherein -NH-, -O-CH2-, -NH-CH2-, and -CH2- are each independently and optionally influenced by 1, 2, 3, or 4 R bonds. 1L Replace; each R 1L They can be H, F, Cl, or CH3 independently;

[0131] Each bond can be a single or double bond independently, provided that the valence bond allows it.

[0132] V1, V2, V3, V4 and V5 are each independently CH, CH2, N or NH;

[0133] V6 is C, CH, or N;

[0134] Each R 6-2 They are independently H, D, halogen, oxo (=O), thio (=S), and C, respectively. 1-3 Alkyl or halogenated C 1-3 alkyl;

[0135] Each L2 is independently -O-, -NH-, or -NH-C(=O)-;

[0136] q can be 0, 1, 2 or 3 independently;

[0137] Y1, Y2, Y3, Y4, Y5 and Y6 are each independently a single bond, O or CH2, and at least two of Y1, Y2, Y3, Y4, Y5 and Y6 are CH2;

[0138] R 6b They are, independently, H, D, halogen, OH, NH2, CN, and C. 1-6 Alkyl or halogenated C 1-6 alkyl.

[0139] In an optional embodiment of the present invention, the above-mentioned R 6-2 They can be H or oxo (=O) independently, respectively.

[0140] In an optional embodiment of the present invention, the above compound has the structure of formula (III-2):

[0141] Where R1 is F, Cl, Br, or C. 1-3 alkyl;

[0142] L1 is a single bond, -O-, -NH-, -O-CH2-, -NH-CH2-, or -CH2-, wherein -NH-, -O-CH2-, -NH-CH2-, and -CH2- are each independently and optionally influenced by 1, 2, 3, or 4 R bonds. 1L Replace; each R 1L They can be H, F, Cl, or CH3 independently;

[0143] Each bond can be a single or double bond independently, provided that the valence bond allows it.

[0144] V1, V2, V3, V4 and V5 are each independently CH, CH2, N or NH;

[0145] V6 is C, CH, or N;

[0146] each R 6-2 independently H, D, halogen, oxo (=0), thioxo (=S), C 1-3 alkyl or halogenated C 1-3 alkyl; preferably, each R 6-2 independently H or oxo (=0);

[0147] each R 6-1 independently substituted with 1, 2, 3 or 4 R 6c substituted C 1-6 alkoxy;

[0148] each R 6c independently H, D, halogen, OH, NH2or C 1-3 alkylamino.

[0149] In an optional embodiment of the present application, each R 6-2 independently H or oxo (=0).

[0150] In an optional embodiment of the present application, each R 6-1 independently substituted with 1, 2, 3 or 4 R 6c substituted C 1-4 alkoxy.

[0151] In an optional embodiment of the present application, each R 6c independently H, D, F, Cl, OH, NH2or

[0152] In an optional embodiment of the present application, the above compound has the following formula (III-3):

[0153] wherein R1is Cl;

[0154] L1is a single bond or -0-;

[0155] each independently a single bond or a double bond, as valence allows;

[0156] V1, V2, V3, V4and V5are each independently CH, CH2, N or NH;

[0157] V6is C, CH or N;

[0158] each R 6-2 independently H or oxo (=0).

[0159] each R 6x independently substituted with 1, 2, 3 or 4 R 6ysubstituted: C 1-4 alkyl, C 3-4 cycloalkyl, 3-4 membered heterocyclyl, -C 1-3 alkyl-C 3-4 cycloalkyl;

[0160] each R 6y is independently H, D, halogen, OH, NH2, or C 1-3 alkylamino.

[0161] In an optional embodiment of the present application, each R is

[0162] In an optional embodiment of the present application, each R is

[0163] In an optional embodiment of the present application, each R 6x is independently substituted with 1, 2, 3, or 4 R 6y substituted: cyclopropyl, methyl, ethyl, propyl, isopropyl, t-butyl, isobutyl, oxetanyl, -CH2-cyclopropyl.

[0164] In an optional embodiment of the present application, each R 6y is independently H, D, F, Cl, OH, NH2, or

[0165] In an optional embodiment of the present application, each R 6x is independently -CHF2, -CDF2, -CF3,

[0166] In an optional embodiment of the present application, the above compound has the following structure of Formula (Ia):

[0167] wherein R1, L1, R 6-1 , R 6-2 , g, and n are as defined in the present application.

[0168] In an optional embodiment of the present application, the above compound has the following structure of Formula (Ib), (Ic), or (Id):

[0169] wherein V1, V2, V3, V4, V5 are each independently C, CH, or N; R1, L1, R 6-1 , and n are as defined in the present application.

[0170] In an optional embodiment of the present invention, the above compound has the structure of the following formula (Ie):

[0171] L1 is a single bond, -O-, -NH-, -O-CH2-, -NH-CH2-, or -CH2-, wherein -NH-, -O-CH2-, -NH-CH2-, and -CH2- are each independently and optionally influenced by 1, 2, 3, or 4 R bonds. 1L Replace; each R 1L They can be H, F, Cl, or CH3 independently;

[0172] R 6-1 For 1, 2, 3 or 4 R 6a Replacement C 3-6 Cycloalkyl groups, with 1, 2, 3 or 4 R groups 6a Substituted 4-8 membered heterocyclic alkyl groups, with 1, 2, 3 or 4 R groups 6b Replacement -L2-C 3-6 Cycloalkyl groups, with 1, 2, 3 or 4 R groups 6b Substituted -L2-4-8-membered heterocyclic alkyl groups, with 1, 2, 3 or 4 R groups 6b Replacement -L2-C 1-3 Alkyl-C 3-6 Cycloalkyl groups, with 1, 2, 3 or 4 R groups 6b Replacement -L2-C 1-3 Alkyl-4-8-membered heterocyclic alkyl groups or those with 1, 2, 3 or 4 R groups 6c Replacement C 1-6 Alkoxy;

[0173] L2 is -O-, -NH-, or -NH-C(=O)-;

[0174] R 6a R 6b R 6c As defined in this invention.

[0175] In an optional embodiment of the present invention, the above-mentioned R 6-1 They are independently -OCH3, -OCHF2, -OCDF2, -OCF3,

[0176] In an optional embodiment of the present invention, the above Having structure

[0177] In an optional embodiment of the present invention, the above Having structure

[0178] In an optional embodiment of the application, the above has the structure

[0179] In an optional embodiment of the application, the above has the structure

[0180] In an optional embodiment of the application, the above has the structure

[0181] In an optional embodiment of the application, the above has the structure

[0182] In an optional embodiment of the application, the above has the structure

[0183] In an optional embodiment of the application, the above has the structure

[0184] In an optional embodiment of the application, the above L1is a single bond, -O-, -NH-, -O-CH2-, -NH-CH2-, or -CH2-, wherein said -NH-, -O-CH2-, -NH-CH2-, and -CH2- are each independently optionally substituted with 1, 2, 3, or 4 R 1L substituents.

[0185] In an optional embodiment of the application, the above each R 1L is independently H, F, Cl, or CH3.

[0186] In an optional embodiment of the application, the above L1is a single bond, -O-, or -CH2-.

[0187] In an optional embodiment of the application, the above ring A is phenyl, 5-10 membered heterocycloalkenyl, or 5-10 membered heteroaryl.

[0188] In an optional embodiment of the application, the above ring A is phenyl, 5-6 membered heterocycloalkenyl, or 5-6 membered heteroaryl.

[0189] In an optional embodiment of the application, the above ring A is 5-6 membered heterocycloalkenyl or 5-6 membered heteroaryl.

[0190] In an optional embodiment of the present application, the above ring A is

[0191] In an optional embodiment of the present application, the above ring A is In an optional embodiment of the present application, the above ring A is

[0192] In an optional embodiment of the present application, the above ring A is " " indicates the site of attachment to L1.

[0193] In an optional embodiment of the present application, the above ring A is " " indicates the site of attachment to L1.

[0194] In an optional embodiment of the present application, each R 6-1 is independently C 6c alkyl substituted with 1, 2, 3, or 4 R 1-4 alkoxy.

[0195] In an optional embodiment of the present application, each R 6-1 is independently C 1-3 alkyl substituted with 1, 2, 3, or 4 halo.

[0196] In an optional embodiment of the present application, each R 6-1 is independently -OCH3, -OCH3, is independently substituted with 1, 2, 3, or 4 R 6c .

[0197] In an optional embodiment of the present application, each R 6-1 is independently -OCH3, -OCH3, is independently substituted with 1, 2, 3, or 4 R 6c .

[0198] In an optional embodiment of the present application, each R 6c is independently H, D, F, Cl, OH, NH2, or

[0199] In an optional embodiment of the present application, each R 6c is independently D, F, Cl, OH, NH2, or

[0200] In an optional embodiment of the application, each R 6c is independently D, F, Cl, OH, NH2, CH3, or

[0201] In an optional embodiment of the application, each R 6-1 is independently -OCH3, -OCHF2, -OCDF2, -OCF3,

[0202] In an optional embodiment of the application, each R 6-1 is independently -OCHF2, -OCDF2, -OCF3,

[0203] In an optional embodiment of the application, each R 6-1 is independently -OCHF2, -OCF3,

[0204] In an optional embodiment of the application, each R 6c is independently F, Cl, OH, or NH2.

[0205] In an optional embodiment of the application, each R 6-1 is independently -OCHF2, or -OCF3.

[0206] In an optional embodiment of the application, each R 6-1 is independently C 6a cycloalkyl, 4-8 membered heterocycloalkyl. 3-6 substituted with 1, 2, 3, or 4 R 6a substituted with 1, 2, 3, or 4 R

[0207] In an optional embodiment of the application, each R 6-1 is independently cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, each independently substituted with 1, 2, 3, or 4 R 6a substituted with 1, 2, 3, or 4 R 6-1 substituted with 1, 2, 3, or 4 R 6a substituted with 1, 2, 3, or 4 R

[0208] In an optional embodiment of the application, each R 6a is independently cyclopropyl, cyclobutyl, azetidinyl, each independently substituted with 1, 2, 3, or 4 R 6a substituted with 1, 2, 3, or 4 R6a each independently -CH3or -CH2-OCH3, said -CH3and -CH2-OCH3are each independently substituted with 1, 2, 3, or 4 R.

[0210] In an optional embodiment of the present application, each R 6a is each independently substituted with 1 R.

[0211] In an optional embodiment of the present application, each R is each independently H, F, Cl, OH, NH2, or CN.

[0212] In an optional embodiment of the present application, each R 6a is each independently -CH2-OH, -CH2F, -CHF2, -CF3, -CH2-CH2F, or -CH2-OCF3.

[0213] In an optional embodiment of the present application, each R 6-1 is each independently

[0214] In an optional embodiment of the present application, each R 6-1 is each independently

[0215] In an optional embodiment of the present application, each R 6-1 is each independently substituted with 1, 2, 3, or 4 R 6b -L2-C 3-6 cycloalkyl, -L2-4-8 membered heterocycloalkyl, -L2-C 6b alkyl, -L2-C 6b alkyl, -L2-C 1-3 alkyl, -L2-C 3-6 alkyl, -L2-C 6b alkyl, -L2-C 1-3 alkyl, -L2-C

[0216] In an optional embodiment of the present application, each R 6-1independently -L2-cyclopropyl, -L2-cyclobutyl, -L2-azetidinyl, -L2-cyclopentyl, -L2- oxolanyl, -L2-tetrahydrofuranyl, -L2-tetrahydropyranyl, -L2-CH2-cyclopropyl, -L2- CH2-cyclobutyl, -L2-CH2-cyclopentyl, -L2-CH2-oxolanyl, -L2-CH2-tetrahydrofuranyl, -L2-CH2-tetrahydropyranyl, which -L2-cyclopropyl, -L2-cyclobutyl, -L2-azetidinyl, -L2-cyclopentyl, -L2-oxolanyl, -L2-tetrahydrofuranyl, -L2-tetrahydropyranyl, -L2-CH2-cyclopropyl, -L2-CH2-cyclobutyl, -L2-CH2-cyclopentyl, -L2-CH2-oxolanyl, -L2-CH2-tetrahydrofuranyl, and -L2-CH2-tetrahydropyranyl is independently substituted with 1, 2, 3, or 4 R 6b substituents.

[0217] In an optional embodiment of the application, each R 6-1 independently -L2-cyclopropyl, -L2-cyclobutyl, -L2-azetidinyl, -L2-cyclopentyl, -L2- oxolanyl, -L2-tetrahydrofuranyl, -L2-tetrahydropyranyl, -L2-CH2-cyclopropyl, -L2- CH2-cyclobutyl, -L2-CH2-cyclopentyl, -L2-CH2-oxolanyl, -L2-CH2-tetrahydrofuranyl, -L2-CH2-tetrahydropyranyl, which -L2-cyclopropyl, -L2-cyclobutyl, -L2-azetidinyl, -L2-cyclopentyl, -L2-oxolanyl, -L2-tetrahydrofuranyl, -L2-tetrahydropyranyl, -L2-CH2-cyclopropyl, -L2-CH2-cyclobutyl, -L2-CH2-cyclopentyl, -L2-CH2-oxolanyl, -L2-CH2-tetrahydrofuranyl, and -L2-CH2-tetrahydropyranyl is independently substituted with 1, 2, 3, or 4 R 6b substituents.

[0218] In an optional embodiment of the application, each R 6-1 independently -L2-cyclopropyl, -L2-cyclobutyl, -L2-azetidinyl, -L2-CH2-cyclopropyl, or -L2-CH2-cyclobutyl, which -L2-cyclopropyl, -L2-cyclobutyl, -L2-azetidinyl, -L2-CH2-cyclopropyl, and -L2-CH2-cyclobutyl is independently substituted with 1, 2, 3, or 4 R 6b substituents.

[0219] In an optional embodiment of the application, each R 6-1 independently -L2-C 6b substituted with 1, 2, 3, or 4 R3-6 cycloalkyl or 4-8 membered heterocycloalkyl substituted with 1, 2, 3, or 4 R 6b substituted -L2-4-8 membered heterocycloalkyl.

[0220] In an optional embodiment of the application, each R 6-1 is independently H or R 6b substituted -L2-C 3-6 cycloalkyl.

[0221] In an optional embodiment of the application, each R 6-1 is independently H or R 6b substituted -L2-4-8 membered heterocycloalkyl.

[0222] In an optional embodiment of the application, each L2is independently -O-, -N(R 2L )-, -N(R 2L )-C(=O)-, -S-, -S(=O)-, -S(=O)2-, or -C(=O)-.

[0223] In an optional embodiment of the application, each L2is independently -O-, -N(R 2L )-, -S-, -S(=O)-, -S(=O)2-, or -C(=O)-.

[0224] In an optional embodiment of the application, each R 2L is H or CH3.

[0225] In an optional embodiment of the application, each L2is independently -O-, -NH-, -NH-C(=O)-, -S-, -S(=O)-, -S(=O)2-, or -C(=O)-.

[0226] In an optional embodiment of the application, each L2is independently -O-, -NH-, -S-, -S(=O)-, -S(=O)2-, or -C(=O)-.

[0227] In an optional embodiment of the application, each L2is independently -O- or -NH-C(=O)-.

[0228] In an optional embodiment of the application, each L2is independently -O-.

[0229] In an optional embodiment of the application, each R 6-1 is independently H or R 6-1 is independently H or R is independently H or R Each independently is assigned to 1, 2, 3, or 4 R's. 6b replace.

[0230] In an optional embodiment of the present invention, the above-mentioned R 6-1 Each independently The Each independently is assigned to 1, 2, 3, or 4 R's. 6b replace.

[0231] In an optional embodiment of the present invention, the above-mentioned R 6-1 Each independently The Each independently is assigned to 1, 2, 3, or 4 R's. 6b replace.

[0232] In an optional embodiment of the present invention, the above-mentioned R 6-1 Each independently

[0233] In an optional embodiment of the present invention, the above-mentioned R 6-1 Each independently The Each independently of 1, 2, 3 or 4 R 6b replace.

[0234] In an optional embodiment of the present invention, the above-mentioned R 6-1 Each independently is assigned to 1, 2, 3, or 4 R's. 6b Replacement

[0235] In an optional embodiment of the present invention, the above-mentioned R 6b They are, independently, H, F, Cl, OH, NH2, CN, and C. 1-3 Alkyl or halogenated C 1-3 alkyl.

[0236] In an optional embodiment of the present invention, the above-mentioned R 6b They can be H, F, Cl, OH, NH2, CN or CH3, respectively.

[0237] In an optional embodiment of the present invention, the above-mentioned R 6b They can be H, F, OH, NH2 or CH3, respectively.

[0238] In an optional embodiment of the present invention, the above-mentioned R 6-1 Each independently

[0239] In an optional embodiment of the application, each R 6-1 are each independently

[0240] In an optional embodiment of the application, each R 6-1 are each independently

[0241] In an optional embodiment of the application, each R 6-1 are each independently

[0242] In an optional embodiment of the application, each R 6-1 are each independently -OCH3, -OCHF2, -OCDF2, -OCF3,

[0243] In an optional embodiment of the application, each R 6-1 are each independently -OCHF2, -OCDF2, -OCF3,

[0244] In an optional embodiment of the application, each R 6-1 are each independently -OCHF2, -OCDF2, -OCF3,

[0245] In an optional embodiment of the application, each R 6-1 are each independently -OCHF2, -OCF3,

[0246] In an optional embodiment of the application, each R 6-1 are each independently -OCHF2, -OCF3,

[0247] In an optional embodiment of the application, each R 6-1 are each independently -OCHF2, -OCF3,

[0248] In an optional embodiment of the application, each R 6-2 are each independently H, D, halogen, oxo (=0), thioxo (=S), C1-3 alkyl or haloC 1-3 alkyl.

[0249] In an optional embodiment of the present application, each R 6-2 is independently H or oxo (=0).

[0250] In an optional embodiment of the present application, R 6-2 is H. In an optional embodiment of the present application, the compound has the following structure:

[0251] In a second aspect of the present application, there is provided a pharmaceutical composition comprising: a compound, a tautomer, a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof according to the first aspect of the present application; and a pharmaceutically acceptable excipient.

[0252] In a third aspect of the present application, there is provided a use of a compound, a tautomer, a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof according to the first aspect of the present application and a pharmaceutical composition according to the second aspect of the present application in the manufacture of a medicament for treating and / or preventing a VAV1 -related disease.

[0253] In an optional embodiment of the present application, the VAV1 -related disease comprises cancer and autoimmune diseases.

[0254] In an optional embodiment of the present application, the VAV1 -related disease comprises, but is not limited to, systemic lupus erythematosus, myasthenia gravis, periodontitis, type I diabetes, rheumatoid arthritis, multiple sclerosis, colitis, inflammatory bowel disease, inflammatory bowel disease, autoimmune hepatitis or psoriasis.

[0255] In a fourth aspect of the present application, there is provided a method for treating or preventing a VAV1 -related disease, comprising administering to a patient an effective amount of at least one of a compound of formula (I), a tautomer, a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof according to the first aspect of the present application or a pharmaceutical composition according to the second aspect of the present application.

[0256] In an optional embodiment of the present application, the patient is a mammal, preferably a human.

[0257] In an optional embodiment of the present application, the VAV1 -related disease is cancer and autoimmune diseases.

[0258] In an optional embodiment of the application, the VAVl-related disease described above is systemic lupus erythematosus, myasthenia gravis, periodontitis, type I diabetes mellitus, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, inflammatory bowel disorder, autoimmune hepatitis, psoriasis.

[0259] Additional aspects and advantages of the application will be set forth in part in the following description, will become apparent from the following description, or will be learned through practice of the application.

[0260] Terms and Definitions

[0261] Unless otherwise defined, all terms used in connection with the application, including the patent specification and claims, are intended to have the meanings ascribed to them below.

[0262] As will be understood by those skilled in the art, in the structural formulae herein, is used to depict a chemical bond, which is the point of attachment of a moiety or substituent to a core or backbone structure.

[0263] Unless otherwise specified, the term "pharmaceutically acceptable" pertains to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0264] Unless otherwise specified, the term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable, non-toxic acid or base salt, including salts of inorganic acids and bases, salts of organic acids and bases.

[0265] In addition to pharmaceutically acceptable salts, other salts are also contemplated. They can serve as intermediates in the purification of the compounds or in the preparation of other pharmaceutically acceptable salts, or they can be useful in the identification, characterization, or purification of the compounds of the application.

[0266] Unless otherwise specified, the term "pharmaceutical composition" denotes a mixture of one or more of the compounds described herein, or physiologically / pharmaceutically acceptable salts or prodrugs thereof, with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compound to an organism.

[0267] Unless otherwise specified, the term "excipient" refers to a pharmaceutically acceptable inert ingredient. Examples of classes of excipients, without limitation, include binders, disintegrants, lubricants, glidants, stabilizers, fillers, and diluents. Excipients can enhance the handling properties of a pharmaceutical formulation, i.e., make the formulation more amenable to direct compression by increasing flow and / or cohesion.

[0268] The term "prodrug" means, unless otherwise apparent from context, compounds that can be converted under physiological conditions or by solvo lysis into compounds of this application that have biological activity. The prodrugs of this application are prepared by modifying functional groups in such a way that their solubility characteristics are altered but undergo in vivo conversion by metabolic processes or through hydrolysis under physiological conditions to give the parent compound or a compound of this application. Prodrugs include compounds of this application wherein a hydroxy or amino group is bonded to any group that, when administered to a mammalian subject, is cleaved to form a free hydroxyl or aminogroup.

[0269] The term "stereoisomers" means isomers that have the same molecular formula but different structures, resulting from a difference in the arrangement of atoms in space. Stereoisomers include enantiomeric or optical isomers, diastereomeric isomers, and conformational isomers.

[0270] Depending on the choice of raw materials and methods, the compounds of the application can be present in the form of one or more of the possible isomers or as a mixture of isomers, for example, as pure optical isomers, or as a mixture of isomers, such as, for example, as racemates or as mixtures of diastereomeric isomers, depending on the number of asymmetric carbon atoms. When describing compounds having optical activity, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to one chiral center (or multiple chiral centers) in the molecule. The prefixes D and L or (+) and (-) are used to designate the optical rotation of a compound, where (-) or L indicates that the compound is levorotatory. A compound with the prefix (+) or D is dextrorotary. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers are also referred to as enantiomers, and mixtures of such isomers are often referred to as enantiomeric mixtures. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, and such racemic mixtures or racemates can occur in chemical reactions or methods having no stereoselectivity or stereospecificity. Many geometric isomers of olefins, C=N double bonds, and the like can also exist in the compounds described herein, and all such isomers are contemplated in this application. When the compounds described herein contain olefinic double bonds, unless identified otherwise, such double bonds are understood to include both E and Z geometric isomers. If a compound contains a disubstituted cycloalkyl ring, the substituents on the ring can be in the cis- or trans- (or, alternatively, the Z- or E-) configuration.

[0271] When bonds to a chiral carbon in a formula of this application are depicted as straight lines, it is understood that both the (R) and (S) configurations of the chiral carbon and the enantiomerically pure compounds and mixtures resulting therefrom are included within the scope of the formula. The graphical representation of racemates or enantiomerically pure compounds herein is from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise indicated, a wedge and a dashed line represent the absolute configuration of a stereocenter.

[0272] Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Compounds of the application containing asymmetrically substituted carbon atoms can exist in optically active form or as racemic mixtures. Resolution of racemic mixtures into their individual components can be achieved by any of a number of methods known in the art. Exemplary methods include fractional recrystallization using chiral resolving acids, which are optically active, salt-forming organic acids. Suitable resolving agents for fractional recrystallization procedures are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, binaroyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids. Other resolving agents suitable for fractional crystallization procedures include the stereoisomerically pure forms of alpha-methylbenzylamine (e.g., the S and R forms or the diastereomeric pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like. Resolution of racemic mixtures can also be achieved by elution of chromatography columns packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). High performance liquid chromatography (HPLC) methods can be employed as well as supercritical fluid chromatography (SFC). The choice of the particular method and elution conditions, choice of chromatography column can be selected by one skilled in the art based on the structure of the compound and test results. Further, optically pure starting materials or reagents of known configuration can be used to obtain any enantiomer or diastereomer of a compound described herein by stereo-organic synthesis.

[0273] Unless otherwise stated, the term "tautomers" refers to isomers of a functional group that result from the movement of a certain atom in the molecule between two positions. Compounds of the application can exhibit tautomerism. Tautomeric compounds can exist in two or more interconvertible forms. Proton-shift tautomers result from the migration of a hydrogen atom covalently bonded between two atoms. Tautomers generally exist in equilibrium and attempts to isolate a single tautomer usually result in a mixture whose physical properties are consistent with a mixture of compounds. The position of the equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates; in phenols, the enol form predominates. The present application includes all tautomeric forms of the compounds. For example may interconvert.

[0274] Unless otherwise stated, a solid wedge and a dashed wedge indicate the absolute configuration of a stereogenic center, a solid straight line and a dashed straight line indicate the relative configuration of a stereogenic center.

[0275] The compounds of the present application can contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds can be labeled with radioactive isotopes, such as deuterium (2H), tritium (3H), iodine-125 (125I) or C-14 (14C). All isotopic variations of the compounds of the present application, whether radioactive or not, are encompassed within the scope of the present application.

[0276] The term "effective amount" or "therapeutically effective amount" with respect to a drug or pharmacological agent means a nontoxic but sufficient amount of the drug or agent to provide the desired effect. For oral dosage forms of the present application, an "effective amount" of one active agent in a composition means the amount needed to achieve the desired effect in conjunction with the other active agent in the composition. The determination of an effective amount is dependent on the age and general condition of the recipient, on the particular active agent, and an appropriate effective amount for a given case can be determined by one of ordinary skill in the art using routine testing.

[0277] The term "active ingredient," "therapeutic agent," "active agent," or "active agent" means a chemical entity that is effective in treating a disorder, disease, or condition of interest, unless otherwise specified.

[0278] The term "substituted," unless otherwise specified, means that any one or more hydrogen atoms on the particular atom indicated in the expression in which it appears are replaced with a substituent group, including variants of hydrogen, provided that the valency of the particular atom is not exceeded and that the substituted compound is stable. When the substituent is oxo (i.e., =0), it can be represented as oxidation of carbon, nitrogen, and sulfur atoms, including but not limited to C(=0), S(=0), S(=0)2, or N(=0).

[0279] The term "optionally" or "optional," unless otherwise specified, means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0280] The term "optionally substituted" means that the group can or can not be substituted and that the types and number of substituents are optional on a chemical basis.

[0281] When any variable (e.g., R) occurs more than one time in a compound, its definition in each instance is independent of the definition of the other occurrences. Thus, for example, if a group is substituted with 0-2 R groups, then the group can optionally be substituted with zero, one, or two R groups, and at each occurrence R is selected independently. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0282] Unless otherwise indicated, the term "C 1-6 "alkyl" is used to denote a straight or branched saturated hydrocarbon group containing from one to six carbon atoms. The C 1-6 alkyl group includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C6and C5alkyl groups and the like; which can be monovalent, divalent or multivalent. The C 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, and the like.

[0283] Unless otherwise indicated, the term "C 1-3 "alkyl" is used to denote a straight or branched saturated hydrocarbon group containing from one to three carbon atoms. The C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups and the like; which can be monovalent, divalent or multivalent. The 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), and the like.

[0284] The term "halo" is used interchangeably with the term "halogen substituted" when used alone or as part of another substituent.

[0285] Unless otherwise indicated, "haloalkyl" or "halogen substituted alkyl" refers to branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted by one or more halogens.

[0286] Unless otherwise indicated, "C 2-6 "alkenyl" is used to denote a straight or branched hydrocarbon group containing from two to six carbon atoms, comprising at least one carbon-carbon double bond, which can be located in any position on the group. The C 2-6 alkenyl group includes C 2-4 , C 2-3 , C4, C3and C2alkenyl groups and the like; which can be monovalent, divalent or multivalent. The C 2-6 Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, and the like.

[0287] Unless otherwise indicated, "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.

[0288] Unless otherwise specified, the term "C" 1-3 "Alkoxy" refers to alkyl groups containing 1, 2, or 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 C3 and C2 alkoxy groups, etc. 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), etc.

[0289] 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, -NHCH(CH3)2, etc.

[0290] Unless otherwise specified, the term "C" 3-12 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 12 carbon atoms. 3-12 Cycloalkyl groups include C3-10 , 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 and the like; which can be monovalent, divalent or multivalent.C 3- Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.

[0291] Unless otherwise specified, the term "C 3-8 cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 8 carbon atoms. The C 3-8 cycloalkyl group includes C 3-6 , C 3-5 , C 4-8 , C 4-6 , C 4-5 , C 5-8 or C 5-6 cycloalkyl and the like; which can be monovalent, divalent or multivalent.C 3-8 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.

[0292] Unless otherwise specified, the term "C 3-6 cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms. The C 3-6 cycloalkyl group includes C 3-5 , C 4-5 and C 5-6 cycloalkyl and the like; which can be monovalent, divalent or multivalent.C 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

[0293] Unless otherwise specified, Cn-n+m or Cn-Cn+m includes any one particular case of n to n+m carbons, for example C 1-12 includes C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , and C 12 also includes any one range of n to n+m, for example C 1-12 includes C 1- 3, C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12Similarly, 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.

[0294] 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 substituted with heteroatoms, such as, but not limited to, N, O, S, and P. The terms "mn-membered heterocyclic alkyl" or "C m-n "Heterocyclic alkyl" should be understood to mean a saturated ring having m to n atoms, wherein the heterocyclic atoms are selected from N, O, S, and P, preferably from N, O, or S. For example, the terms "4-8-membered heterocyclic alkyl" or "C4-C8 heterocyclic alkyl" should be understood to mean 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, and P, preferably from N, O, or S. "4-10-membered heterocyclic alkyl" means a saturated ring having 4 to 10 atoms. Ring. 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. Examples of heterocyclic alkyl groups are: pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydropyridyl, tetrahydropyrrolidinyl, azaheptanyl, thiazolyl, azoleyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, azaheptanyl, diazaheptanyl, oxonitroheptanyl, etc. The term "heterocyclic alkyl" can be used interchangeably with the term "heteroalkyl ring".

[0295] 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".

[0296] The term "heteroaromatic ring," by itself or in combination with another term, means a monocyclic or polycyclic carbocyclic ring in which at least one ring atom is a heteroatom independently selected from oxygen, sulfur and nitrogen, the remainder of the ring atoms being carbon, wherein at least one ring is aromatic. The group can be carbon-based or heteroatom-based (i.e., it can be C-attached or N-attached, as is possible). When one of the rings is non-aromatic, the group can be attached through an aromatic ring, as well as through a non-aromatic ring. Examples of heteroaryl groups include, but are not limited to, imidazolyl, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furanyl, thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, N-methylpyrrolyl and tetrahydroquinoline. The term "heteroaromatic ring" can be used interchangeably with the terms "heteroaromatic ring," "heteroaryl" or "heteroaryl group."

[0297] The term "5-6 membered heterocyclenyl," by itself or in combination with other terms, means an unsaturated or partially unsaturated cyclic group consisting of 5 to 6 ring atoms, but not an aromatic ring, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, the remainder of which are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen and sulfur heteroatoms are optionally oxidized (i.e., C(=O), NO and S(O)p, where p is 1 or 2). Furthermore, for this "5-6 membered heterocyclenyl," a heteroatom can occupy the position of attachment of the heterocyclenyl group to the rest of the molecule. The 5-6 membered heterocyclenyl group includes 5-membered and 6-membered heterocyclenyl groups, and the like.

[0298] Unless otherwise specified, the terms "5-6 membered heteroaromatic ring" and "5-6 membered heteroaryl" are used interchangeably throughout the application, and the term "5-6 membered heteroaryl" means a monocyclic ring group consisting of 5 to 6 ring atoms having a conjugated pi-electron system, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the remainder carbon atoms. Of the nitrogen atoms, one can optionally be quaternized, and the nitrogen and sulfur heteroatoms can 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 remainder of the molecule by a heteroatom or carbon atom. The 5-6 membered heteroaryl includes 5-membered and 6-membered heteroaryls. Examples of the 5-6 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.), triazolyl (1H-1, 2, 3-triazolyl, 2H-1, 2, 3-triazolyl, 1H-1, 2, 4-triazolyl and 4H-1, 2, 4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, etc.), thiophenyl (including 2-thiophenyl and 3-thiophenyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).

[0299] Unless otherwise specified, the term "halo" or "halogen" is fluorine, chlorine, bromine and iodine.

[0300] Further, it should be noted that the description manner "independently" employed in the present application should be interpreted in a broad sense, unless explicitly indicated otherwise, that is, each individual described is independent of each other, and can be independently the same or different specific groups. In more detail, the description manner "independently" can mean that in different groups, the specific options expressed between the same symbols do not affect each other, or it can mean that in the same group, the specific options expressed between the same symbols do not affect each other.

[0301] Unless otherwise specified, the term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine; cattle, sheep, horses, or primates, and most preferably humans.

[0302] The term "therapeutically effective amount" means, unless otherwise indicated, an amount of an active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of: (1) preventing the disease: for example, preventing a disease, disorder, or condition from occurring in an individual that is predisposed to the disease, disorder, or condition but has not yet been diagnosed with the disease pathology or symptoms of the disorder; (2) inhibiting the disease: for example, arresting the development of a disease, disorder, or condition in an individual that is experiencing or displaying the pathology or symptoms of the disease, disorder, or condition (i.e., halting the progression of the pathology and / or symptoms); (3) relieving the disease: for example, causing the regression of a disease, disorder, or condition in an individual that is experiencing or displaying the pathology or symptoms of the disease, disorder, or condition (i.e., reversing the pathology and / or symptoms).

[0303] The terms "treat" and other similar synonymous terms as used herein include the following meanings:

[0304] (i) preventing the disease or condition from occurring in a mammal, in particular, when such mammal is predisposed or has a predisposition to the disease or condition but has not yet been diagnosed as having it;

[0305] (ii) inhibiting the disease or condition, i.e., arresting its development;

[0306] (iii) relieving the disease or condition, i.e., causing the state of the disease or condition to regress; or

[0307] (iv) alleviating the symptoms of the disease or condition.

[0308] Abbreviations used in the present invention are defined as follows:

[0309] M: molar concentration, e.g., 1 M hydrochloric acid means 1 mol / L hydrochloric acid solution

[0310] N: normality, e.g., 2 N hydrochloric acid means 2 mol / L hydrochloric acid solution

[0311] DMSO: dimethyl sulfoxide

[0312] Bpin: pinacol boronate group Beneficial effects

[0313] The present invention has at least one of the following technical effects relative to the clinically used compound MRT-6160:

[0314] 1) The compounds of the present invention can induce the direct binding of VAV1 to CRBN in a dose-dependent manner;

[0315] 2) The compound of the present application shows excellent degradation effect on VAV1 protein in a dose-dependent manner; the DC50 value of the compound of the present application is less than 10 nM, and even less than 5 nM; the Dmax value of the compound of the present application can reach more than 95%, and even more than 98%, which are significantly better than the existing clinical compound MRT-6160;

[0316] 3) In the CD3 / CD28-induced Jurkat cell / T cell activation model, the compound of the present application can significantly inhibit the production of IL-2, and the inhibition function is positively correlated with the dose, which is better than the compound MRT-6160;

[0317] 4) The compound of the present application has good pharmacokinetic properties, which are significantly better than the compound MRT-6160 in various pharmacokinetic parameters, and has good drugability;

[0318] 5) The compound of the present application is significantly better than the compound MRT-6160 in terms of plasma protein binding rate, which has a significant advantage;

[0319] 6) The bidirectional permeability test results in the Caco-2 cell model show that the permeability of the compound of the present application in the in vitro model is significantly better than that of the compound MRT-6160, there is no obvious efflux, and the compound of the present application shows good oral absorption characteristics and good drugability;

[0320] 7) In the mouse inflammatory bowel disease model, the test compound group of the present application shows significant relief of the disease progression of the mouse intestinal inflammation model induced by adoptive primary T cells;

[0321] 8) The compound of the present application shows good safety and small hepatotoxicity. DETAILED DESCRIPTION

[0322] The present application will be further described in conjunction with specific examples. It should be understood that the following description is only the most preferred embodiment of the present application, and should not be considered as a limitation on the scope of protection of the present application. Based on a full understanding of the present application, the experimental methods not specified in the following examples are generally carried out under conventional conditions, or under the conditions recommended by the manufacturer, and the person skilled in the art can make non-essential changes to the technical solutions of the present application, which should be considered as included in the protection scope of the present application.

[0323] Preparation of intermediate A

[0324] 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)piperidine-2,6-dione

[0325] The synthesis route of intermediate A is as shown below:

[0326] First step: 2-(3-bromo-2-chlorophenyl)acetonitrile (A2)

[0327] Put 3-bromo-2-chlorobenzyl (A1) (9.0 g, 31.65 mmol) into a reaction flask, add acetonitrile (100 mL), and then add trimethylsilyl cyanide (6.3 g, 63.3 mmol), potassium carbonate (13 g, 100 mmol) under ice bath. After the addition, the reaction solution is reacted at 80°C for 16 h. After the reaction is completed, the reaction solution is cooled to room temperature, diluted with ethyl acetate (500 mL), washed with saturated aqueous sodium chloride solution (500 mL x 3), and then dried with anhydrous sodium sulfate. After filtration and concentration, the residue is purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 10:1) to obtain intermediate 2-(3-bromo-2-chlorophenyl)acetonitrile (A2).

[0328] LC-MS, M / Z (ESI): 230.1 [M+H] + .

[0329] Second step: methyl 4-(3-bromo-2-chlorophenyl)-4-cyanobutanoate (A3)

[0330] Put 2-(3-bromo-2-chlorophenyl)acetonitrile (5.0 g, 21.74 mmol) (A2) into a reaction flask, add methyl acrylate (3.74 g, 43.5 mmol), and then add tetrahydrofuran (100 mL), followed by sodium methoxide (110 mg, 2 mmol) under ice bath. After the addition, the reaction solution is reacted at room temperature for 2 h. After the reaction is completed, the reaction solution is diluted with ethyl acetate (500 mL), washed with aqueous sodium chloride solution (500 mL x 3), and then dried with anhydrous sodium sulfate. After filtration and concentration, the residue is purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 5:1) to obtain intermediate methyl 4-(3-bromo-2-chlorophenyl)-4-cyanobutanoate (compound A3) (5.95 g, yield: 87%).

[0331] LC-MS, M / Z (ESI): 316.2 [M+H] + .

[0332] Third step: 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (A4)

[0333] Methyl 4-(3-bromo-2-chlorophenyl)-4-cyanobutanoate (Intermediate A3) (5.9 g, 18.7 mmol) was dissolved in acetic acid (100 mL), 0.5 mL of concentrated sulfuric acid was added at 20 °C, after the addition, the reaction liquid was reacted at 90 °C for 6 hours. After the reaction was completed, 2.0 g of sodium acetate was added at 20 °C, and stirred at room temperature for 30 min, after completion, the solvent was removed by reduced pressure distillation, then diluted with ethyl acetate (500 mL), washed with saturated sodium chloride aqueous solution (500 mL x 1), saturated sodium bicarbonate aqueous solution (500 mL x 2), saturated sodium chloride aqueous solution (500 mL x 1) respectively, then the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 1:1) to obtain compound 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (Intermediate A4).

[0334] LC-MS, M / Z (ESI): 302.1 [M+H] + .

[0335] Fourth step: 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine- 2,6-dione

[0336] Compound 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (Intermediate A4) (4.6 g, 15.2 mmol) was placed in a reaction bottle, then pinacol diboronic acid (7.6 g, 30 mmol), potassium acetate (4.5 g, 45.6 mmol) and 1,1'-bis (di-phenylphosphino) ferrocene palladium chloride (0.3 g, 0.45 mmol), 1,4-dioxane (70 mL) were added, after the addition, the reaction liquid was stirred at 100 °C for 8 hours under nitrogen protection. The reaction liquid was cooled to room temperature, diluted with ethyl acetate (500 mL), washed with saturated sodium chloride aqueous solution (500 mL x 3), then the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 1:1) to obtain compound 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione (Intermediate A).

[0337] LC-MS, M / Z (ESI): 350.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 7.51 (dd, 1H), 7.41 (dd, 1H), 7.32 (d, 1H), 4.25 (dd, 1H), 2.83 - 2.70 (m, 1H), 2.56 - 2.50 (m, 1H), 2.29 (qd, 1H), 1.97 - 1.92 (m, 1H), 1.30 (s, 12H).

[0338] Preparation of intermediate B1

[0339] 1-(4-bromophenyl)-3-(difluoromethoxy)pyrazin-2(lH)-one (intermediate B1)

[0340] The synthesis route of intermediate B1 is shown below:

[0341] First step: synthesis of 1-(4-bromophenyl)-3-chloro-pyrazin-2(lH)-one (intermediate B1-3)

[0342] To a solution of 3-chloro-pyrazin-2(lH)-one (B1-1) (2.90 g, 22.2 mmol) and (4-bromophenyl) boronic acid (B1-2) (5.35 g, 26.66 mmol) in acetonitrile (120 mL) was added pyridine (3.58 mL, 44.4 mmol) and copper acetate (4.84 g, 26.7 mmol). The mixture was stirred at 30 °C in air atmosphere for 18 hours. LCMS showed the reaction was complete. The reaction was also diluted with water (200 mL), extracted with ethyl acetate (100 mL x 3), the organic phase was combined and dried over anhydrous sodium sulfate. The organic layer was concentrated and the crude product was purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 100:0-90:10) to give 1-(4-bromophenyl)-3-chloro-pyrazin-2(lH)-one (intermediate B1-3).

[0343] LC-MS, M / Z (ESI): 285.0 [M+H] +

[0344] Second step: synthesis of 1-(4-bromophenyl)-3-hydroxy-pyrazin-2(lH)-one (intermediate B1-4)

[0345] A solution of 1-(4-bromophenyl)-3-chloro-pyrazin-2(lH)-one (intermediate B1-3) (3.50 g, 12.3 mmol) in acetic acid (50 mL) was stirred at 130 °C under nitrogen atmosphere for 18 hours. LCMS showed the reaction was complete. The reaction was directly concentrated to give 1-(4-bromophenyl)-3-hydroxy-pyrazin-2(lH)-one (intermediate B1-4).

[0346] LC-MS, M / Z (ESI): 267.1 [M+H] +

[0347] Third Step: Synthesis of 1-(4-bromophenyl)-3-(difluoromethoxy)pyrazin-2(lH)-one (Intermediate B1)

[0348] To a solution of 1-(4-bromophenyl)-3-hydroxy-pyrazin-2(lH)-one (Intermediate B1-4) (2.00 g, 7.49 mmol) and ethyl 2-bromo-2,2-difluoroacetate (1.82 g, 8.99 mmol) in DMF (30 mL) was added sodium carbonate (3.97 g, 37.4 mmol). The mixture was stirred at 100 °C under nitrogen for 2 hours. LCMS showed the reaction was complete. The reaction was diluted with water (100 mL), extracted with ethyl acetate (50 mL x 3), the combined organic phase was washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The organic layer was concentrated, the crude product was purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 100:0-75:25, gradient elution) and then by prep-HPLC (Xtimate C18, 21.2*250mm, 5μm; 10mM FA-ACN; 32-62; 60mL / min) to give 1-(4-bromophenyl)-3-(difluoromethoxy)pyrazin-2(lH)-one (Intermediate B1).

[0349] LC-MS, M / Z (ESI): 317.0 [M+H] +

[0350] 1 H NMR (400 MHz, DMSO-d6): 7.80-7.74 (m, 2H), 7.63 (t, 1H), 7.54 (d, 1H), 7.51-7.46 (m, 2H), 6.99 (d, 1H). Example 1: Preparation of Compound 1

[0351] 3-(2-Chloro-4'-{[4-(cyclopropoxy)pyrimidin-2-yl]oxy}[l,l'-biphenyl]-3-yl)piperidine- 2,6-dione

[0352] The synthesis route of Compound 1 is as follows:

[0353] First Step: 4-(Cyclopropoxy)-2-(methylthio)pyrimidine (Compound 1-3)

[0354] Compound 1-3) (180 mg, 0.990 mmol) was dissolved in anhydrous dichloromethane (5 mL), then m-chloroperoxybenzoic acid (85%, 603 mg, 2.97 mmol) was added portionwise, and the reaction was allowed to react at 25°C for 12 hours under nitrogen. After the reaction was completed, the reaction solution was slowly poured into a mixed solution of saturated sodium sulfite and saturated sodium bicarbonate (20 mL), then extracted with dichloromethane (3 x 10 mL), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude product was purified by column chromatography (PE:EA (V / V) = 100:1 to 1:1) to obtain compound 4-(cyclopropoxy)-2-(methylsulfonyl)pyrimidine (compound 1-4).

[0355] LC / MS (ESI) (m / z): 183.0 (M+H) + .

[0356] Second step: 4-(cyclopropoxy)-2-(methylsulfonyl)pyrimidine (compound 1-4)

[0357] Compound 1-3) (180 mg, 0.990 mmol) was dissolved in anhydrous dichloromethane (5 mL), then m-chloroperoxybenzoic acid (85%, 603 mg, 2.97 mmol) was added portionwise, and the reaction was allowed to react at 25°C for 12 hours under nitrogen. After the reaction was completed, the reaction solution was slowly poured into a mixed solution of saturated sodium sulfite and saturated sodium bicarbonate (20 mL), then extracted with dichloromethane (3 x 10 mL), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude product was purified by column chromatography (PE:EA (V / V) = 100:1 to 1:1) to obtain compound 4-(cyclopropoxy)-2-(methylsulfonyl)pyrimidine (compound 1-4).

[0358] LC / MS (ESI) (m / z): 183.0 (M+H) + .

[0359] Third step: 4-(cyclopropoxy)-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrimidine (compound 1-6)

[0360] Compound 1-4 (170 mg, 0.790 mmol) was dissolved in acetonitrile (2 mL) at room temperature, then 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (Compound 1-5) (192 mg, 0.870 mmol) and potassium carbonate (165 mg, 1.19 mmol) were added, and the reaction was reacted at 60 °C for 12 hours. After the reaction was completed, the reaction was concentrated under reduced pressure, the residue was diluted with water (10 mL), then extracted with ethyl acetate (3 x 10 mL), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude product was purified by column chromatography (PE:EA (V / V) = 100:1 to 1:1) to obtain Compound 4-(cyclopropoxy)-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrimidine (Compound 1-6).

[0361] LC / MS (ESI) (m / z): 355. (M+H) + ;

[0362] Fourth Step: 3-(2-chloro-4'-{[4-(cyclopropoxy)pyrimidin-2-yl]oxy}[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 1)

[0363] Compound 1-6) (112 mg, 0.320 mmol), sodium carbonate (70.0 mg, 0.660 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (19.0 mg, 0.026 mmol) were added, and the reaction was reacted at 100 °C for 12 hours under nitrogen protection. After the reaction was completed, the reaction was concentrated under reduced pressure, the residue was diluted with water (10 mL), then extracted with ethyl acetate (3 x 10 mL), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude product was purified by column chromatography (PE:EA (V / V) = 100:1 to 1:1) to obtain Compound 4-(cyclopropoxy)-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrimidine (Compound 1).

[0364] LC / MS (ESI) (m / z): 450.1 (M+H) + ;

[0365] 1 H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.35 (d, 1H), 7.47 - 7.42 (m, 2H), 7.40 - 7.31 (m, 3H), 7.30 - 7.26 (m, 2H), 6.75 (d, 1H), 4.33 (dd, 1H), 4.24 - 4.19 (m, 1H), 2.81 - 2.73 (m, 1H), 2.52 (dd, 1H), 2.32 (dd, 1H), 2.04 (dd, 1H), 0.80 - 0.70 (m, 4H).

[0366] Example 2: Preparation of compound 2

[0367] 3-(2-chloro-4'-(3-(difluoromethoxy)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine- 2,6-dione (compound 2)

[0368] The synthetic route of compound 2 is shown as follows:

[0369] First step: 2-chloro-3-(difluoromethoxy)pyridine (compound 2-2)

[0370] 2-chloropyridin-3-ol (2-1) (2.0 g, 15.4 mmol) was placed in a reaction flask, N,N- dimethylformamide (100 mL) was added, potassium carbonate (2.55 g, 18.5 mmol) and sodium 2-chloro-2,2-difluoroacetate (4.73 g, 30.5 mmol) were added under ice bath, the reaction solution was stirred at 100 °C for 2 h, then potassium carbonate (2.55 g, 18.5 mmol) and sodium 2-chloro-2,2-difluoroacetate (4.73 g, 30.5 mmol) were added, and the stirring was continued at 100 °C for 2 h. After completion, the reaction solution was diluted with ethyl acetate (500 mL), washed with saturated aqueous sodium chloride solution (500 mL x 3), then the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 10:1) to obtain compound 2-chloro-3-(difluoromethoxy)pyridine (2-2).

[0371] LC-MS, M / Z (ESI): 180.1 [M+H] + .

[0372] Second step: 3-(difluoromethoxy)pyridin-2-ol (compound 2-3)

[0373] Intermediate 2-chloro-3-(difluoromethoxy)pyridine (2-2) (2.2 g, 12.2 mmol), potassium carbonate (8.43 g, 61 mmol), acetoxy hydroxamic acid (2.75 g, 36.6 mmol) were dissolved in dimethyl sulfoxide (60 mL), and the reaction was stirred at 80 °C for 16 h under nitrogen protection. After the reaction was completed, the reaction was diluted with ethyl acetate (500 mL), washed with saturated aqueous sodium chloride solution (500 mL x 3), and then the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 1:1) to obtain compound 3-(difluoromethoxy)pyridin-2-ol (compound 2-3).

[0374] LC-MS, M / Z (ESI): 162.1 [M+H] + .

[0375] Third step: 3-(difluoromethoxy)-1-(4-iodophenyl)pyridin-2(1H)-one (compound 2-4) 3-(difluoromethoxy)pyridin-2-ol (2-3) (450 mg, 2.8 mmol) was placed in a reaction bottle, followed by the addition of 1,4-diiodobenzene (1.4 g, 4.2 mmol), cuprous iodide (0.54 g, 2.8 mmol), potassium carbonate (1.2 g, 8.4 mmol), and N,N'-dimethylethylenediamine (0.3 g, 3.4 mmol), followed by the addition of acetonitrile (10 mL), and the reaction was carried out by microwave at 100 °C for 1 h under nitrogen protection. After completion, the reaction was cooled to room temperature, diluted with ethyl acetate (300 mL), washed with saturated aqueous sodium chloride solution (300 mL x 3), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 1:1) to obtain compound 3-(difluoromethoxy)-1-(4-iodophenyl)pyridin-2(1H)-one (2-4).

[0376] LC-MS, M / Z (ESI): 364.0 [M+H] + .

[0377] Third step: 3-(2-chloro-4'-(3-(difluoromethoxy)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 2)

[0378] Intermediate 3-(difluoromethoxy)-l-(4-iodophenyl)pyridin-2(lH)-one (2-4) (100 mg, 0.275 mmol) was placed in a reaction flask followed by the addition of intermediate 3-(2-chloro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione (Intermediate A) (143 mg, 0.41 mmol), potassium phosphate (175 mg, 0.825 mmol) and l,l'-bis(di-phenylphosphino)ferrocene palladium chloride (22 mg, 0.03 mmol), 1,4-dioxane (3 mL), the reaction was heated at 100 °C for 8 h. The reaction was then cooled to room temperature, diluted with ethyl acetate (100 mL), washed with saturated aqueous sodium chloride solution (100 mL x 3), then the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, the residue was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 20:1) to give compound 3-(2-chloro-4'-(3-(difluoromethoxy)-2-oxopyridin-l(2H)-yl)-[l,l'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 2).

[0379] LC-MS, M / Z (ESI): 459.1 [M+H] + .

[0380] 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.68 (dd, 1H), 7.58 - 7.50 (m, 4H), 7.45 - 7.35 (m, 4H), 7.17 (t, 1H), 6.33 (t, 1H), 4.35 (dd, 1H), 2.83 - 2.72 (m, 1H), 2.58 - 2.49 (m, 1H), 2.33 (qd, 1H), 2.08 - 2.00 (m, 1H). Example 3: Preparation of Compound 3

[0381] 3-{2-chloro-4'-[3-(cyclopropoxy)-2-oxopyridin-l(2H)-yl][l,l'-biphenyl]-3-yl}piperidine-2,6-dione

[0382] The synthetic route of Compound 3 is as follows:

[0383] First Step: Synthesis of 3-(cyclopropoxy)-2-nitropyridine (Compound 3-2)

[0384] Compound 3-2) was synthesized. LC / MS (ESI) (m / z): 152.0 (M+H)

[0385] LC / MS (ESI) (m / z): 181.0 (M+H) + .

[0386] Second Step: Synthesis of 3-(cyclopropoxy)pyridin-2(lH)-one (Compound 3-3)

[0387] Compound 3-2) was synthesized. LC / MS (ESI) (m / z): 152.0 (M+H) + .

[0388] Third Step: Synthesis of l-(4-bromophenyl)-3-(cyclopropoxy)pyridin-2(lH)-one (Compound 3-4)

[0389] To a solution of 3-(cyclopropoxy)pyridin-2(lH)-one (compound 3-3) (200 mg, 1.32 mmol) in dimethyl sulfoxide (2 mL) was added p-dibromobenzene (311 mg, 1.32 mmol), potassium carbonate (364 mg, 2.64 mmol) and cuprous iodide (25.1 mg, 0.132 mmol) at room temperature. The reaction was stirred at 100 °C for 12 h under nitrogen atmosphere. After completion of the reaction, the reaction was cooled to room temperature, diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude was purified by column chromatography (PE:EA (V / V) = 100:1 to 1:1) to give 1-(4-bromophenyl)-3-(cyclopropoxy)pyridin-2(lH)-one (compound 3-4).

[0390] LC / MS (ESI) (m / z): 307.0 (M+H) + .

[0391] Fourth Step: 3-{2-chloro-4'-[3-(cyclopropoxy)-2-oxopyridin-l(2H)-yl][l,l'-biphenyl]-3-yl}piperidine-2,6-dione (compound 3)

[0392] To a solution of l-(4-bromophenyl)-3-(cyclopropoxy)pyridin-2(lH)-one (compound 3-4) (100 mg, 0.326 mmol) in 1,4-dioxane / water (1 mL / 0.1 mL) was added 3-[2-chloro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]piperidine-2,6-dione (114 mg, 0.326 mmol), potassium phosphate (138 mg, 0.652 mmol) and l,l'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (23.8 mg, 0.033 mmol) at room temperature. The reaction was stirred at 100 °C for 12 h under nitrogen atmosphere. After completion of the reaction, the reaction was cooled to room temperature, concentrated under reduced pressure, diluted with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude was purified by column chromatography (PE:EA (V / V) = 100:1 to 1:1) to give 3-{2-chloro-4'-[3-(cyclopropoxy)-2-oxopyridin-l(2H)-yl][l,l'-biphenyl]-3-yl}piperidine-2,6-dione (compound 3).

[0393] LC / MS (ESI) (m / z): 449.0 (M+H)+ ;

[0394] 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.55-7.50 (m, 2H), 7.49-7.44 (m, 2H), 7.41-7.33 (m, 3H), 7.30 (dd, 1H), 7.17 (dd, 1H), 6.28 (t, 1H), 4.35 (dd, 1H), 3.81-3.77 (m, 1H), 2.80-2.74 (m, 1H), 2.35-2.29 (m, 1H), 2.04 (dd, 1H), 1.97 (d, 1H), 0.80-0.74 (m, 2H), 0.69 (d, 2H).

[0395] Example 4: Preparation of the target compound 4

[0396] 3-(2-chloro-4'-(5-(difluoromethoxy)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine- 2,6-dione (Compound 4)

[0397] The synthetic route of Compound 4 is shown as follows:

[0398] First step: 5-(difluoromethoxy)pyridin-2(1H)-one (Compound 4-2)

[0399] 2-chloro-5-(difluoromethoxy)pyridine (1.0 g, 5.54 mmol), potassium carbonate (3.83 g, 27.7 mmol), acetoxyhydroxamic acid (1.25 g, 16.6 mmol) were dissolved in dimethyl sulfoxide (30 mL), and the reaction solution was reacted at 120°C for 16 h under nitrogen protection. After completion, the reaction solution was diluted with ethyl acetate (500 mL), washed with saturated aqueous sodium chloride solution (500 mL x 3), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product which was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 1:1) to obtain Compound 5-(difluoromethoxy)pyridin-2(1H)-one (Compound 4-2).

[0400] LC-MS, M / Z (ESI): 162.0 [M+H] + .

[0401] Step 3: 1-(4-bromophenyl)-5-(difluoromethoxy)pyridin-2(lH)-one (Compound 4-3) Intermediate 1-(4-bromophenyl)-5-(difluoromethoxy)pyridin-2(lH)-one (Compound 4-3) (320 mg, 1.99 mmol) was placed in a reaction flask, followed by the addition of 1,4-dibromobenzene (567 g, 2.4 mmol), cuprous iodide (0.38 g, 2 mmol), potassium carbonate (0.84 g, 6 mmol), N,N'-dimethylethylenediamine (0.2 g, 2.4 mmol), followed by the addition of acetonitrile (10 mL), argon deoxygenation, 100 °C microwave reaction for 1 h. After completion, the reaction was diluted with ethyl acetate (300 mL), washed with saturated aqueous sodium chloride solution (300 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 1:1) to obtain Compound 1-(4-bromophenyl)-5-(difluoromethoxy)pyridin-2(lH)-one (Compound 4-3).

[0402] LC-MS, M / Z (ESI): 317.0 [M+H] + .

[0403] Step 3: 3-(2-chloro-4'-(5-(difluoromethoxy)-2-oxopyridin-l(2H)-yl)-[l,l'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 4)

[0404] Intermediate 1-(4-bromophenyl)-5-(difluoromethoxy)pyridin-2(lH)-one (Compound 4-3) (120 mg, 0.38 mmol) was placed in a reaction flask, followed by the addition of Intermediate 3-(2-chloro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)piperidine-2,6-dione (Intermediate A) (174 mg, 0.5 mmol), potassium phosphate (242 mg, 1.14 mmol) and l,l'-bis(di-phenylphosphino)ferrocene palladium chloride (30 mg, 0.04 mmol), 1,4-dioxane (4 mL), after addition, nitrogen deoxygenation 3 times, then the reaction was reacted at 100 °C for 8 h. Then diluted with ethyl acetate (100 mL), washed with saturated aqueous sodium chloride solution (100 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, the residue was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 20:1) to obtain Compound 3-(2-chloro-4'-(5-(difluoromethoxy)-2-oxopyridin-l(2H)-yl)-[l,l'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 4).

[0405] LC-MS, M / Z (ESI): 459.1 [M+H] + .

[0406] 1 H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 7.85 (d, 1H), 7.65 - 7.44 (m, 5H), 7.45 - 7.36 (m, 2H), 7.33 (dd, 1H), 7.04 (t, 1H), 6.54 (d, 1H), 4.35 (dd, 1H), 2.84 - 2.72 (m, 1H), 2.58 - 2.48 (m, 1H), 2.33 (dq, 1H), 2.08 - 2.00 (m, 1H).

[0407] Example 5: Preparation of the target compound 5

[0408] 3-(2-chloro-4'-(5-(difluoromethoxy)-6-oxopyridazin-l(6H)-yl)-[l,l'-biphenyl]-3-yl)piperidine- 2,6-dione

[0409] The synthetic route of compound 5 is shown as follows:

[0410] Step 1: Synthesis of 2-(4-bromophenyl)-4-chloropyridazin-3(2H)-one (compound 5-2) To a solution of 4-chloropyridazin-3(2H)-one (3.50 g, 26.8 mmol) and 4-bromo-l- iodobenzene (9.10 g, 32.2 mmol) in N,N-dimethylformamide (150 mL) was added potassium carbonate (7.41 g, 53.6 mmol), cuprous iodide (1.02 g, 5.36 mmol) and 2,5-diazahexane (0.470 g, 5.36 mmol). The reaction was stirred at 100 °C for 18 hours. LCMS detection showed the reaction was completed. The reaction was diluted with saturated brine (500 mL) and extracted with ethyl acetate (300 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel column separation (petroleum ether: ethyl acetate (V / V) = 100:0-40:60) to give compound 2-(4-bromophenyl)-4-chloropyridazin-3(2H)-one (compound 5-2).

[0411] LC-MS, M / Z (ESI): 285.0 [M+H] +

[0412] Second Step: Synthesis of 2-(4-bromophenyl)-4-methoxypyridazine-3(2H)-one (Compound 5-3) To a solution of 2-(4-bromophenyl)-4-chloropyridazine-3(2H)-one (Compound 5-2) (1.90 g, 2.52 mmol) in tetrahydrofuran (10 mL) was added sodium methoxide (1.40 mL, 7.57 mmol, 5.4 M in methanol). The reaction was stirred at 25 °C for 1.5 h. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 100:0 to 50:50) to give Compound 2-(4-bromophenyl)-4-methoxypyridazine-3(2H)-one (Compound 5-3).

[0413] LC-MS, M / Z (ESI): 281.0 [M+H] +

[0414] Third Step: Synthesis of 2-(4-bromophenyl)-4-hydroxypyridazine-3(2H)-one (Compound 5-4)

[0415] To a solution of 2-(4-bromophenyl)-4-methoxypyridazine-3(2H)-one (Compound 5-3) (0.600 g, 1.49 mmol) in dichloromethane (10 mL) was added boron tribromide (0.709 mL, 7.47 mmol) at -78 °C. The resulting mixture was stirred at 25 °C for 1 h. LCMS indicated the reaction was completed. The reaction was quenched with methanol and concentrated under reduced pressure to give 2-(4-bromophenyl)-4-hydroxypyridazine-3(2H)-one (Compound 5-4), which was used directly in the next step.

[0416] LC-MS, M / Z (ESI): 267.0 [M+H] +

[0417] Fourth Step: Synthesis of 2-(4-bromophenyl)-4-(difluoromethoxy)pyridazine-3(2H)-one (Compound 5-5)

[0418] To a solution of 2-(4-bromophenyl)-4-hydroxypyridazin-3(2H)-one (compound 5-4) (0.420 g, 1.57 mmol) and ethyl 2-bromo-2,2-difluoroacetate (0.319 g, 1.57 mmol) in N,N-dimethylformamide (10 mL) was added sodium carbonate (0.833 g, 7.86 mmol), the resulting mixture was stirred at 100 °C for 3 h. LCMS detection showed the reaction was completed. The reaction was directly concentrated to get the crude product, which was purified by preparative liquid chromatography (Prime C18, 21.2 x 250 mm 5 um; 0.05% NH3.H2O-ACN; 38-68; 20 mL / min) to give compound (2-(4-bromophenyl)-4-(difluoromethoxy)pyridazin-3(2H)-one (compound 5-5).

[0419] LC-MS, M / Z (ESI): 317.0 [M+H] +

[0420] 1 H NMR (400 MHz, CD3OD): δ 7.98 (d, 1H), δ 7.70-7.61 (m, 2H), 7.59-7.48 (m, 2H.), 7.25 (t, 1H), 7.16 (d, 1H).

[0421] Fifth Step: Synthesis of 4-(difluoromethoxy)-2-(4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)pyridazin-3(2H)-one (compound 5-6)

[0422] The intermediate 2-(4-bromophenyl)-4-(difluoromethoxy)pyridazin-3(2H)-one (compound 5-5) (0.3 g, 0.95 mmol) was placed in a reaction flask, then pinacol diborane (0.5 g, 2 mmol), potassium acetate (0.3 g, 3 mmol) and 1,1'-bis(di-phenylphosphino)ferrocene palladium chloride (73 mg, 0.1 mmol), 1,4-dioxane (5 mL) were added, after addition, nitrogen was deoxygenated for 3 times, then reacted at 100 °C for 3 hours. The reaction was cooled to room temperature, then diluted with ethyl acetate (200 mL), washed with saturated aqueous sodium chloride solution (300 mL x 3), then the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 3:1) to give compound 4-(difluoromethoxy)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridazin-3(2H)-one (compound 5-6).

[0423] LC-MS, M / Z (ESI): 365.1 [M+H] +.

[0424] Step 6: 3-(2-chloro-4'-(5-(difluoromethoxy)-6-oxopyridazin-l(6H)-yl)-[l,l'-biphenyl]-3- yl)piperidine-2,6-dione

[0425] Compound 4-(difluoromethoxy)-2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl) pyridazine-3(2H)-one (Compound 5-6) (230 mg, 0.63 mmol) was placed in a reaction flask, followed by the addition of 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (Intermediate A4) (229 mg, 0.76 mmol), potassium phosphate (400 mg, 1.89 mmol) and l,l'-bis(di-phenylphosphino)ferrocene palladium chloride (44 mg, 0.06 mmol), N,N-dimethylformamide (5 mL), after the addition was completed, the reaction was reacted at 100 °C for 2 hours under nitrogen protection. After the reaction was completed, the reaction was cooled to room temperature, diluted with ethyl acetate (200 mL), extracted with saturated aqueous sodium chloride solution (200 mL x 3), then the organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 20: 1) to obtain compound 3-(2-chloro-4'-(5-(difluoromethoxy)-6-oxopyridazin-l(6H)-yl)-[l,l'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 5).

[0426] LC-MS, M / Z (ESI): 460.1 [M+H] + .

[0427] 1 H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.09 (d, 1H), 7.74 - 7.30 (m, 8H), 7.28 (d, 1H), 4.36 (dd, 1H), 2.84 - 2.73 (m, 1H), 2.59 - 2.50 (m, 1H), 2.34 (qd, 1H), 2.10 - 2.02 (m, 1H).

[0428] Example 6: Preparation of target compound 6

[0429] 3-{2-chloro-4'-[2-oxo-3-(trifluoromethoxy)pyridin-l(2H)-yl][l,l'-biphenyl]-3-yl}piperidine- 2,6-dione (Compound 6)

[0430] The synthetic route of target compound 6 is shown below:

[0431] Step 1: Synthesis of 3-(trifluoromethoxy)pyridin-2-ol (Compound 6-2)

[0432] 2-chloro-3-(trifluoromethoxy)pyridine (Compound 6-1) (400 mg, 2.0 mmol), potassium carbonate (2.0 g, 14.0 mmol), acetoxy hydroxamic acid (608 mg, 8.0 mmol) were dissolved in dimethyl sulfoxide (4 mL), replaced with argon for 3 times, and the reaction was carried out at 100 °C for 18 h. Water (50 mL) was added to the reaction solution, which was then extracted with ethyl acetate (50 mL x 3). The organic phase was combined, washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-1 / 1) to obtain 3-(trifluoromethoxy)pyridin-2-ol (Compound 6-2).

[0433] LC-MS, M / Z (ESI): 180.2 [M+H]+.

[0434] Step 2: Synthesis of 1-(4-bromophenyl)-3-(trifluoromethoxy)pyridin-2(1H)-one (Compound 6-3)

[0435] To a solution of 1,4-dibromobenzene (350 mg, 1.48 mmol) in dioxane (3.5 mL) was added 3-(trifluoromethoxy)pyridin-2-ol (Compound 6-2) (266 mg, 1.48 mmol), cuprous iodide (57 mg, 0.3 mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (42 mg, 0.3 mmol), and potassium carbonate (410 mg, 3.0 mmol), replaced with argon for 3 times, and then stirred at 100 °C for 18 h. The reaction solution was concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-1 / 3) to obtain 1-(4-bromophenyl)-3-(trifluoromethoxy)pyridin-2(1H)-one (Compound 6-3).

[0436] LC-MS, M / Z (ESI): 336.2 [M+H]+

[0437] Step 3: Synthesis of 3-{2-chloro-4'-[2-oxo-3-(trifluoromethoxy)pyridin-1(2H)-yl][1,1'-biphenyl]-3-yl}piperidine-2,6-dione (Compound 6)

[0438] To a solution of 1-(4-bromophenyl)-3-(trifluoromethoxy)pyridin-2(1H)-one (compound 6-3) (150 mg, 0.45 mmol) and 3-[2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine-2,6-dione (Intermediate A) (550 mg, 1.57 mmol) in 1,4-dioxane (1.5 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (37 mg, 0.045 mmol) and potassium carbonate (186 mg, 1.35 mmol), replaced with argon for three times, then stirred at 100 °C for 18 h. The reaction was poured into water (10 mL), then extracted with ethyl acetate (2 mL x 3). The organic phase was combined, washed with saturated brine (2 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by reverse phase preparation (column: Phenomenex Synergi C18 100 x 25 mm x 4 µm; solvent: A = water + 0.1 volume% formic acid (99%), B = acetonitrile; gradient: 5% - 95%, 7 minutes) to give 3-{2-chloro-4'-[2-oxo-3-(trifluoromethoxy)pyridin-1(2H)-yl][1,1'-biphenyl]-3-yl}piperidine-2,6-dione (compound 6).

[0439] 1 H NMR (600 MHz, DMSO-d6) δ 10.96 (s, 1H), 7.85 (d, 1H), 7.77 (d, 1H), 7.57 (q, 4H), 7.46 - 7.40 (m, 2H), 7.38 (d, 1H), 6.40 (t, 1H), 4.40 - 4.35 (m, 1H), 2.84 - 2.77 (m, 1H), 2.55 (d, 1H), 2.39 - 2.31 (m, 1H), 2.09 - 2.03 (m, 1H).

[0440] LC-MS, M / Z (ESI): 476.8 [M+H]+

[0441] Example 7: Preparation of target compound 7

[0442] N-(1-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)cyclopropanecarboxamide (target compound 7)

[0443] The synthetic route of target compound 7 is shown as follows:

[0444] First Step: Synthesis of 1-(4-bromophenyl)-3-nitropyridin-2(lH)-one (Compound 7-3)

[0445] LC-MS, M / Z (ESI): 294.2 [M+H] +

[0446] Second Step: Synthesis of 3-amino-l-(4-bromophenyl)pyridin-2(lH)-one (Compound 7-4)

[0447] At room temperature, 1-(4-bromophenyl)-3-nitropyridin-2(lH)-one (Compound 7-3) (0.4 g, 1.35 mmol) was dissolved in methanol (20 mL), Pd / C (40 mg) was added under nitrogen atmosphere, then replaced with hydrogen gas for three times, the reaction solution was stirred at room temperature for 5 hours under hydrogen atmosphere. After the reaction was completed, it was concentrated under reduced pressure, and the obtained crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 5: 1-1: 1) to obtain compound 3-amino-l-(4-bromophenyl)pyridin-2(lH)-one (Compound 7-4).

[0448] LC-MS, M / Z (ESI): 265.2 [M+H] +

[0449] Third Step: Synthesis of N-(l-(4-bromophenyl)-2-oxo-l,2-dihydropyridin-3-yl)cyclopropanecarboxamide (Compound 7-5)

[0450] To a stirred solution of 3-amino-1-(4-bromophenyl)pyridin-2(1H)-one (compound 7-4) (0.2 g, 0.75 mmol) and cyclopropylcarbonyl chloride (0.21 g, 1.13 mmol) in dry dichloromethane (10 mL) was added triethylamine (0.16 g, 1.5 mmol) at room temperature and stirred for 2 h at room temperature. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to get the crude product which was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 5:1 to 1:1) to get N-(1-(4-bromophenyl)-2-oxo-1,2-dihydropyridin-3-yl)cyclopropanecarboxamide (compound 7-5).

[0451] LC-MS, M / Z (ESI): 333.2 [M+H] +

[0452] Fourth Step: Synthesis of N-(1-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)cyclopropanecarboxamide (compound 7)

[0453] To a stirred solution of N-(1-(4-bromophenyl)-2-oxo-1,2-dihydropyridin-3-yl)cyclopropanecarboxamide (compound 7-5) (0.1 g, 0.3 mmol) and bis(pinacolato)diboron (0.16 g, 0.6 mmol) in dry 1,4-dioxane (10 mL) was added potassium acetate (0.32 g, 0.9 mmol) and Pd(dppf)Cl2(22 mg, 0.03 mmol) at room temperature and stirred for 2 h at 90 °C under nitrogen atmosphere. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL) and washed with saturated brine (20 mL). The organic layer was concentrated under reduced pressure to get the crude product which was used directly for the next step. The above obtained crude product was mixed with 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (intermediate A4) (0.11 g, 0.36 mmol) in 1,4-dioxane (10 mL) and then added potassium phosphate (0.32 g, 0.9 mmol) and Pd(dppf)Cl2(22 mg, 0.03 mmol) and stirred for 5 h at 90 °C under nitrogen atmosphere. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 5:1 to 1:1) to get N-(1-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)cyclopropanecarboxamide (compound 7).

[0454] LC-MS, M / Z (ESI): 476.2 [M+H] +

[0455] 1 H NMR (400 MHz, CD3OD) δ 8.65 (s, 1H), 8.43 (d, 1H), 8.02 (s, 1H), 7.55 (d, 2H), 7.47 (d, 2H), 7.36 (dt, 2H), 7.13 (d, 1H), 6.35 (t, 1H), 4.34 (dd, 1H), 2.86 - 2.79 (m, 1H), 2.75-2.71 (m, 1H), 2.41 - 2.27 (m, 2H), 1.65 - 1.61 (m, 1H), 1.11 - 1.07 (m, 2H), 0.88 (dd, 2H).

[0456] Example 8: Preparation of the target compound 8

[0457] 3-{2-chloro-4'-[3-(2-hydroxy-2-methylpropoxy)-2-oxopyridin-1(2H)-yl][1,1'-biphenyl]-3-yl}piperidine-2,6-dione (Compound 8)

[0458] The synthetic route of the target compound 8 is shown as follows:

[0459] First step: synthesis of 1-(4-bromophenyl)-3-hydroxypyridin-2(1H)-one (8-2)

[0460] To a solution of 1,4-dibromobenzene (4.25 g, 18 mmol) in 1,4-dioxane (20 mL) was added 2,3-dihydroxypyridine (8-1) (2 g, 18 mmol), cuprous iodide (686 mg, 3.6 mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (1.0 g, 7.2 mmol) and potassium phosphate (7.6 g, 36 mmol), and the reaction solution was replaced with argon for three times, then the reaction solution was stirred at 110 °C for 18 h. The reaction solution was cooled to room temperature, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-1 / 3) to obtain compound 1-(4-bromophenyl)-3-hydroxypyridin-2(1H)-one (8-2) (320 mg, yield 6.7%).

[0461] LC-MS, M / Z (ESI): 268.2 [M+H]+

[0462] Second step: synthesis of {[1-(4-bromophenyl)-2-oxo-1,2-dihydropyridin-3-yl]oxy}acetic acid ethyl ester (8-3)

[0463] To a solution of 1-(4-bromophenyl)-3-hydroxypyridin-2(lH)-one (8-2) (300 mg, 1.13 mmol) in N,N-dimethylformamide (3 mL) was added potassium carbonate (467 mg, 3.38 mmol) and methyl bromoacetate (282 mg, 1.69 mmol) and stirred at room temperature for 18 h. The reaction was poured into water (50 mL) and extracted with ethyl acetate (20 mL*3). The organic phase was combined and washed with saturated brine (20 mL*2), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-1 / 3) to give { [l-(4-bromophenyl)-2-oxo-l,2-dihydropyridin-3-yl]oxy} ethyl acetate (8-3) (310 mg, yield 78%).

[0464] LC-MS, M / Z (ESI): 354.3 [M+H]+

[0465] Third Step: Synthesis of 1-(4-bromophenyl)-3-(2-hydroxy-2-methylpropoxy)pyridin-2(lH)-one (8-4)

[0466] { [l-(4-bromophenyl)-2-oxo-l,2-dihydropyridin-3-yl]oxy} ethyl acetate (8-3) (310 mg, 0.88 mmol) was dissolved in tetrahydrofuran (3 mL) and replaced with argon three times, methyl magnesium bromide (0.88 mL, 2.64 mmol, 3M in tetrahydrofuran) was added dropwise into the reaction solution at 0 °C, then the temperature was raised to room temperature and stirred for 2 h. The reaction solution was slowly dropped into saturated ammonium chloride (20 mL) and extracted with ethyl acetate (10 mL*3). The organic phase was combined and washed with saturated brine (20 mL*2), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-0 / 1) to give compound 1-(4-bromophenyl)-3-(2-hydroxy-2-methylpropoxy)pyridin-2(lH)-one (8-4) (200 mg, yield 67%).

[0467] LC-MS, M / Z (ESI): 340.3 [M+H]+

[0468] Fourth Step: Synthesis of 3-{2-chloro-4'-[3-(2-hydroxy-2-methylpropoxy)-2-oxopyridin-l(2H)-yl][l,l'-biphenyl]-3-yl}piperidine-2,6-dione (Compound 8)

[0469] To a solution of 1-(4-bromophenyl)-3-(2-hydroxy-2-methylpropoxy)pyridin-2(lH)-one (8-4) (200 mg, 0.59 mmol) and 3-[2-chloro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]piperidine-2,6-dione (827 mg, 2.37 mmol) in dioxane (3 mL) was added [l,l'-bis(diphenylphosphino)ferrocene]palladium dichloride (48 mg, 0.06 mmol) and potassium carbonate (245 mg, 1.77 mmol), replaced with argon for three times, then stirred at 100 °C for 18 h. The reaction was poured into water (10 mL), then extracted with ethyl acetate (2 mL*3). The organic phase was combined, washed with saturated brine (2 mL*2), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by preparative liquid chromatography (column: Phenomenex Synergi C18 100*25mm*4μm; solvent: A = water + 0.1 volume% formic acid (99%), B = acetonitrile; gradient: 5% - 95%, 7 minutes) to give 3-{2-chloro-4'-[3-(2-hydroxy-2-methylpropoxy)-2-oxopyridin-l(2H)-yl][l,l'-biphenyl]-3-yl}piperidine-2,6-dione (Compound 8).

[0470] 1 H NMR (600 MHz, DMSO-d6) δ 10.96 (s, 1H), 7.58 - 7.47 (m, 4H), 7.46 - 7.36 (m, 3H), 7.30 (d, 1H), 6.93 (d, 1H), 6.25 (t, 1H), 4.71 (s, 1H), 4.39 - 4.34 (m, 1H), 3.67 (s, 2H), 2.85 - 2.77 (m, 1H), 2.55 (d, 1H), 2.39 - 2.32 (m, 1H), 2.09 - 2.04 (m, 1H), 1.20 (s, 6H).

[0471] LC-MS, M / Z (ESI): 481.2 [M+H]+

[0472] Example 9: Preparation of the target compound 9

[0473] 3-(2-chloro-4'-(3-(difluoromethoxy)-2-oxopyrazin-l(2H)-yl)-[l,l'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 9)

[0474] The synthetic route of Compound 9 is shown as follows:

[0475] Step 1: Synthesis of 3-(2-chloro-4'-(3-(difluoromethoxy)-2-oxopyrazin-1(2H)-yl)- [1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 9)

[0476] LC-MS, M / Z (ESI): 365.1 [M+H] + .

[0477] Step 2: Synthesis of 3-(2-chloro-4'-(3-(difluoromethoxy)-2-oxopyrazin-1(2H)-yl)- [1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 9)

[0478] Intermediate 3-(2-chloro-4'-(3-(difluoromethoxy)-2-oxopyrazin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 9-1) (63 mg, 0.17 mmol) was placed in a reaction flask, followed by the addition of 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (Intermediate A4) (61 mg, 0.20 mmol), potassium phosphate (108 mg, 0.51 mmol) and 1,1'-bis(di-phenylphosphino)ferrocene palladium chloride (22 mg, 0.03 mmol), N,N-dimethylformamide (3 mL), after addition, replaced with nitrogen for 3 times, then reacted at 100 °C for 2 hours. The reaction solution was cooled to room temperature, then diluted with ethyl acetate (100 mL), extracted with saturated aqueous sodium chloride solution (100 mL x 3), then the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, the obtained residue was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 20:1) to obtain Compound 3-(2-chloro-4'-(3-(difluoromethoxy)-2-oxopyrazin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 9) (36 mg, yield: 46%).

[0479] LC-MS, M / Z (ESI): 460.1 [M+H] + .

[0480] 1 H NMR (600 MHz, DMSO-d6) δ 10.93 (s, 1H), 7.62 (t, 1H), 7.60 (d, 1H), 7.60-7.54 (m, 4H), 7.44-7.37 (m, 2H), 7.35 (dd, 1H), 6.98 (d, 1H), 4.35 (dd, 1H), 2.82-2.73 (m, 1H), 2.56-2.50 (m, 1H), 2.32 (qd, 1H), 2.05-2.01 (m, 1H).

[0481] Example 10: Preparation of target compound 10

[0482] 3-(2-chloro-4'-(3-(difluoromethoxy-d)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione

[0483] The synthetic route of Example 10 is shown as follows:

[0484] Step 1: Synthesis of 1-(4-bromophenyl)-3-(difluoromethoxy-d)pyridin-2(lH)-one (Compound 10-1) Intermediate 1-(4-bromophenyl)-3-hydroxypyridin-2(lH)-one (8-2) (230 mg, 0.87 mmol) was placed in a reaction flask, then tetrahydrofuran (8 mL) was added, after addition, replaced with nitrogen for 3 times, then 60 wt% sodium hydride (348 mg, 8.7 mmol) was slowly added at 0°C, and reacted for 10 minutes. Then heavy water (0.8 mL) was slowly added at 0°C, after addition, reacted for 10 minutes at 0°C, then diethyl bromofluoromethylphosphonate (465 mg, 1.74 mmol) was slowly added at 0°C, after addition, reacted for 10 minutes at 0°C. After the reaction was completed, the reaction solution was diluted with ethyl acetate (200 mL), extracted with saturated aqueous sodium chloride solution (200 mL x 3), then the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 3:1) to obtain intermediate 1-(4-bromophenyl)-3-(difluoromethoxy-d)pyridin-2(lH)-one (10-1).

[0485] LC-MS, M / Z (ESI): 317.1 [M+H] +

[0486] Step 2: Synthesis of 3-(difluoromethoxy-d)-l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)pyridin-2(lH)-one (Compound 10-2)

[0487] Intermediate 1-(4-bromophenyl)-3-(difluoromethoxy-d)pyridin-2(lH)-one (10-1) (150 mg, 0.48 mmol) was placed in a reaction flask, then pinacol diboronic acid (244 mg, 0.96 mmol), potassium acetate (141 mg, 1.44 mmol) and l, l'-bis(di-phenylphosphino)ferrocene palladium chloride (45 mg, 0.06 mmol) were added, 1,4-dioxane (5 mL) was added, after addition, replaced with nitrogen for 3 times, then the reaction solution was reacted at 100°C for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with ethyl acetate (100 mL), washed with saturated aqueous sodium chloride solution (100 mL x 3), then the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 3:1) to obtain intermediate 3-(difluoromethoxy-d)-l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)pyridin-2(lH)-one (10-2).

[0488] LC-MS, M / Z (ESI): 365.1 [M+H] + .

[0489] Step 3: Synthesis of 3-(2-chloro-4'-(3-(difluoromethoxy-d)-2-oxopyridin-1(2H)-yl)- [1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 10)

[0490] Intermediate 3-(difluoromethoxy-d)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)pyridin-2(1H)-one (10-2) (120 mg, 0.33 mmol) was placed in a reaction flask, followed by 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (Intermediate A4) (122 mg, 0.40 mmol), potassium phosphate (216 mg, 1.0 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium chloride (44 mg, 0.06 mmol), N,N-dimethylformamide (6 mL), after addition, replaced with nitrogen for 3 times, then reacted at 100 °C for 2 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate (100 mL), washed with saturated aqueous sodium chloride solution (100 mL x 3), then the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 20:1) to obtain 3-(2-chloro-4'-(3-(difluoromethoxy-d)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3- yl)piperidine-2,6-dione (Compound 10).

[0491] LC-MS, M / Z (ESI): 460.1 [M+H] + .

[0492] 1 H NMR (600 MHz, DMSO-d6) δ 10.94 (s, 1H), 7.69 (dd, 1H), 7.55 (q, 4H), 7.47 - 7.33 (m, 4H), 6.35 (t, 1H), 4.36 (dd, 1H), 2.84 - 2.73 (m, 1H), 2.58 - 2.51 (m, 1H), 2.34 (qd, 1H), 2.07 - 2.01 (m, 1H).

[0493] Example 11: Preparation of the target compound 11

[0494] 3-(2-chloro-4'-(3-(2,3-dihydroxypropoxy)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3- yl)piperidine-2,6-dione (Compound 11)

[0495] The synthetic route of Compound 11 is shown as follows:

[0496] Step 1: Synthesis of methyl (2,2-dimethyl-1,3-dioxolan-4-yl)methanesulfonate (compound 11-2)

[0497] Put 2,2-dimethyl-1,3-dioxolan-4-yl)methanol (11-1) (2.5 g, 19 mmol) into a reaction flask, then add dichloromethane (50 mL) and triethylamine (5.5 mL) successively under ice bath, after addition, slowly add methanesulfonic anhydride (4.0 mg, 22.8 mmol) at 0 °C, then react at 0 °C for 30 minutes. Then dilute the reaction solution with ethyl acetate (200 mL), wash with ice water (200 mL x 3), then take the organic phase, dry over anhydrous sodium sulfate, concentrate to obtain methyl (2,2-dimethyl-1,3-dioxolan-4-yl)methanesulfonate (11-2).

[0498] LC-MS, M / Z (ESI): 211.0 [M+H] + .

[0499] Step 2: Synthesis of 1-(4-bromophenyl)-3-(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyridin-2(1H)-one (11-3)

[0500] Put intermediate 1-(4-bromophenyl)-3-hydroxypyridin-2(1H)-one (compound 8-2) (400 mg, 1.51 mmol) into a reaction flask, then add acetonitrile (8 mL), intermediate methyl (2,2-dimethyl-1,3-dioxolan-4-yl)methanesulfonate (11-2) (950 mg, 4.51 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (685 mg, 4.51 mmol) successively, after addition, replace with nitrogen for 3 times, then react at 120 °C for 3 hours under microwave. After the reaction is completed, cool the reaction solution to room temperature, dilute with ethyl acetate (200 mL), wash with saturated aqueous sodium chloride solution (200 mL x 3), then take the organic phase, dry over anhydrous sodium sulfate, filter and concentrate to obtain a residue, which is purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 3:1) to obtain intermediate 1-(4-bromophenyl)-3-(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyridin-2(1H)-one (11-3).

[0501] LC-MS, M / Z (ESI): 380.1 [M+H] + .

[0502] Step 3: Synthesis of 3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-1-(4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridin-2(1H)-one (Compound 11-4) Intermediate 1-(4-bromophenyl)-3-(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyridin- 2(1H)-one (11-3) (500 mg, 1.32 mmol) was placed in a reaction flask, followed by addition of pinacol diboronic acid (670 mg, 2.64 mmol), potassium acetate (388 mg, 4.0 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium chloride (145 mg, 0.2 mmol), 1,4-dioxane (13 mL), after addition, nitrogen was replaced for 3 times, followed by reaction at 100 °C for 3 hours. Then diluted with ethyl acetate (200 mL), washed with saturated aqueous sodium chloride solution (200 mL x 3), then the organic phase was dried over anhydrous sodium sulfate, concentrated by filtration, the obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 3:1) to obtain intermediate 3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-1-(4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridin-2(1H)-one (11-4).

[0503] LC-MS, M / Z (ESI): 428.0 [M+H] + .

[0504] Step 4: Synthesis of 3-(2-chloro-4'-(3-(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-2- oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (11-5)

[0505] Intermediate 3-(difluoromethoxy-d)-l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)pyridin-2(lH)-one (11-4) (340 mg, 0.80 mmol) was placed in a reaction flask, followed by the addition of 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (Intermediate A4) (290 mg, 0.96 mmol), potassium phosphate (510 mg, 2.4 mmol) and l,l'-bis(di-phenylphosphino)ferrocene palladium chloride (60 mg, 0.08 mmol), N,N-dimethylformamide (8 mL), after addition, nitrogen was replaced for 3 times, then reacted at 100 °C for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with ethyl acetate (300 mL), washed with saturated aqueous sodium chloride solution (300 mL x 3), then the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, the obtained residue was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 20: 1) to obtain 3-(2-chloro-4'-(3-(2,2-dimethyl-l,3-dioxolan-4-yl)methoxy)-2-oxopyridin-l(2H)-yl)- [l,l'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 11-5) (232 mg, yield: 56%).

[0506] LC-MS, M / Z (ESI): 523.1 [M+H] + .

[0507] Fifth step: synthesis of 3-(2-chloro-4'-(3-(2,3-dihydroxypropoxy)-2-oxopyridin-l(2H)-yl)- [l,l'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 11)

[0508] Intermediate 3-(2-chloro-4'-(3-(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (11-5) (230 mg, 0.56 mmol) was placed in a reaction flask, followed by p-toluenesulfonic acid monohydrate (30 mg, 0.14 mmol), tetrahydrofuran (8 mL), and the reaction was stirred at 40 °C for 2 hours. After the reaction was completed, the reaction was cooled to room temperature, diluted with ethyl acetate (100 mL), extracted with saturated aqueous sodium chloride solution (100 mL x 3), and then the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue, which was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 20:1) to give compound 3-(2-chloro-4'-(3-(2,3-dihydroxypropoxy)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 11) (138 mg, yield: 52%).

[0509] LC-MS, M / Z (ESI): 483.1 [M+H] + .

[0510] 1 H NMR (600 MHz, DMSO-d6) δ 10.91 (s, 1H), 7.51 (d, 2H), 7.45 (d, 2H), 7.41 - 7.29 (m, 3H), 7.25 (dd, 1H), 6.89 (dd, 1H), 6.21 (t, 1H), 5.01 (s, 1H), 4.67 (s, 1H), 4.33 (dd, 1H), 3.91 (dd, 1H), 3.83 - 3.71 (m, 2H), 3.40 (d, 2H), 2.81 - 2.71 (m, 1H), 2.55 - 2.48 (m, 1H), 2.37 - 2.25 (m, 1H), 2.02 - 1.99 (m, 1H).

[0511] Example 12: Preparation of the target compound 12

[0512] 3-(2-chloro-4'-(3-(2-hydroxyethoxy)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 12)

[0513] The synthetic route of compound 12 is shown below:

[0514] First step: synthesis of 1-(4-bromophenyl)-3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-2(1H)-one (compound 12-1)

[0515] Intermediate 1-(4-bromophenyl)-3-hydroxypyridin-2(lH)-one (8-2) (500 mg, 1.89 mmol) was placed in a reaction flask, followed by acetonitrile (15 mL), tert-butyl-(2-iodoethoxy)dimethylsilane (1.1 g, 3.8 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (685 mg, 4.51 mmol), after addition, nitrogen was replaced for 3 times, then reacted at 50 °C for 3 hours under microwave. After the reaction was completed, the reaction solution was diluted with ethyl acetate (200 mL), washed with saturated aqueous sodium chloride solution (200 mL x 3), then the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 3: 1) to obtain intermediate 1-(4-bromophenyl)-3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-2(lH)-one (12-1).

[0516] LC-MS, M / Z (ESI): 424.1 [M+H] + .

[0517] Second step: synthesis of 3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-l-(4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)pyridin-2(lH)-one (compound 12-2)

[0518] Intermediate 1-(4-bromophenyl)-3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-2(lH)- one (12-1) (450 mg, 1.06 mmol) was placed in a reaction flask, followed by pinacol diborane (670 mg, 2.64 mmol), potassium acetate (388 mg, 4.0 mmol) and l,l'-bis(di- phenylphosphino)ferrocene palladium chloride (145 mg, 0.2 mmol), 1,4-dioxane (13 mL), after addition, nitrogen was replaced for 3 times, then reacted at 100 °C for 5 hours. Then diluted with ethyl acetate (200 mL), washed with saturated aqueous sodium chloride solution (200 mL x 3), then the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 3: 1) to obtain intermediate 3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-l-(4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)pyridin-2(lH)-one (12-2).

[0519] LC-MS, M / Z (ESI): 472.5 [M+H] + .

[0520] Step 4: Synthesis of 3-(4'-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-oxopyridin-1(2H)-yl)-2-chloro-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 12-3)

[0521] Intermediate 3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridin-2(1H)-one (12-2) (350 mg, 0.74 mmol) was placed in a reaction flask, followed by the addition of 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (Intermediate A4) (246 mg, 0.81 mmol), potassium phosphate (471 mg, 2.2 mmol) and 1,1'-bis(di-phenylphosphino)ferrocene palladium chloride (60 mg, 0.08 mmol), N,N-dimethylformamide (8 mL), after addition, nitrogen was replaced for 3 times, followed by reaction at 100 °C for 2 hours. Then diluted with ethyl acetate (300 mL), washed with saturated aqueous sodium chloride solution (300 mL x 3), then the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 20:1) to obtain 3-(4'-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-oxopyridin-1(2H)-yl)-2-chloro-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 12-3).

[0522] LC-MS, M / Z (ESI): 567.1 [M+H] + .

[0523] Step 5: Synthesis of 3-(2-chloro-4'-(3-(2-hydroxyethoxy)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 12)

[0524] Intermediate 3-(4'-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-oxopyridin-1(2H)-yl)-2-chloro-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (12-3) (220 mg, 0.39 mmol) was placed in a reaction flask, followed by the addition of 4 mL of tetrahydrofuran, 0.5 mL of water, and 75 mg of p-toluenesulfonic acid monohydrate, and reacted at 40°C for 1 hour. After completion, it was diluted with ethyl acetate (100 mL), washed with saturated aqueous sodium bicarbonate solution (300 mL x 3), and then the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 20:1) to obtain 3-(2-chloro-4'-(3-(2-hydroxyethoxy)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 12).

[0525] LC-MS, M / Z (ESI): 453.1 [M+H] + .

[0526] 1 H NMR (600 MHz, DMSO-d6) δ 10.94 (s, 1H), 7.53 (d, 2H), 7.47 (d, 2H), 7.45-7.33 (m, 3H), 7.27 (d, 1H), 6.92 (d, 1H), 6.23 (t, 1H), 4.92 (t, 1H), 4.35 (dd, 1H), 3.93 (t, 2H), 3.71 (q, 2H), 2.82-2.73 (m, 1H), 2.55-2.51 (m, 1H), 2.37-2.29 (m, 1H), 2.07-2.01 (m, 1H).

[0527] Example 13: Preparation of the target compound 13

[0528] 3-{2-chloro-4'-[2-oxo-3-(trifluoromethoxy)pyridin-1(2H)-yl][1,1'-biphenyl]-3-yl}piperidine-2,6-dione (13)

[0529] The synthetic route of the target compound 13 is shown below:

[0530] First step: synthesis of methyl 2-((1-(4-bromophenyl)-2-oxo-1,2-dihydropyridin-3-yl)oxy)acetate (Compound 13-1)

[0531] Methyl 2-((l-(4-bromophenyl)-2-oxo-l,2-dihydropyridin-3-yl)oxy)acetate (compound 13-1) was prepared according to the procedure described in Scheme 13-1. To a solution of l-(4-bromophenyl)-3-hydroxypyridin-2(lH)-one (8-2) (1.0 g, 2.0 mmol) and methyl bromoacetate (1.0 g, 2.0 mmol) in DCM (10 mL) was added DBU (1.0 g, 2.0 mmol) and stirred at room temperature for 5 h. After the reaction was completed, the reaction solution was diluted with DCM (50 mL), and the organic phase was combined and washed with saturated brine (30 mL*2), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-1 / 1) to give methyl 2-((l-(4-bromophenyl)-2-oxo-l,2-dihydropyridin-3-yl)oxy)acetate (compound 13-1).

[0532] LC-MS, M / Z (ESI): 338.2 [M+H] + .

[0533] Second Step: Synthesis of l-(4-bromophenyl)-3-(trifluoromethoxy)pyridin-2(lH)-one (compound 13-2)

[0534] To a solution of methyl 2-((l-(4-bromophenyl)-2-oxo-l,2-dihydropyridin-3- yl)oxy)acetate (compound 13-1) (220 mg, 0.6 mmol) in tetrahydrofuran (3 mL) was added tetraisopropyl titanate (17 mg, 0.06 mmol), and the reaction solution was replaced with argon three times, and ethyl magnesium bromide (1 mL, 2 mmol, 2M in tetrahydrofuran) was slowly added dropwise to the reaction solution at -78°C, and the reaction was continued for 2 h. The reaction solution was slowly added dropwise to a saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (10 mL*3). The organic phase was combined and washed with saturated brine (10 mL*2), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-0 / 1) to give l-(4-bromophenyl)-3-((l-hydroxycyclopropyl)methoxy)pyridin-2(lH)-one (compound 13-2).

[0535] LC-MS, M / Z (ESI): 336.2 [M+H]+

[0536] Third Step: Synthesis of N-(2-oxo-l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)- 1,2-dihydropyridin-3-yl)cyclopropanecarboxamide (compound 13-3)

[0537] To a solution of 1-(4-bromophenyl)-3-((1-hydroxycyclopropyl)methoxy)pyridin-2(1H)-one (compound 13-2) (100 mg, 0.3 mmol) in 1,4-dioxane (3 mL) was added pinacol diborane (152 mg, 0.6 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (22 mg, 0.03 mmol) and potassium acetate (100.0 mg, 0.9 mmol) at room temperature, and the reaction was purged with argon for three times. The reaction was stirred at 100 °C for 18 h. The reaction was cooled to room temperature, water (10 mL) was added, and then extracted with ethyl acetate (2 mL*3). The organic phase was combined and washed with saturated brine (2 mL*2), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product (compound 13-3), which was used directly in the next step.

[0538] LC-MS, M / Z (ESI): 384.2 [M+H]+

[0539] Fourth Step: Synthesis of 3-(2-chloro-4'-(3-((1-hydroxycyclopropyl)methoxy)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 13)

[0540] To a solution of 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (150 mg, 0.45 mmol) and 3-((1-hydroxycyclopropyl)methoxy)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridin-2(1H)-one (550 mg, 1.57 mmol) in 1,4-dioxane (1.5 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (37 mg, 0.045 mmol) and potassium carbonate (186 mg, 1.35 mmol), and the reaction was purged with argon for three times. The reaction was stirred at 100 °C for 18 h. The reaction was cooled to room temperature, water (10 mL) was added, and then extracted with ethyl acetate (2 mL*3). The organic phase was combined and washed with saturated brine (2 mL*2), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by preparative liquid chromatography (column: Phenomenex Synergi C18 100*25mm*4um; Solvent: A = water + 0.1 volume% formic acid (99%), B = acetonitrile; Gradient: 5% - 95%, 7 minutes) to give 3-(2-chloro-4'-(3-((1-hydroxycyclopropyl)methoxy)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 13).

[0541] 1H NMR (600 MHz, DMSO-d6) δ 10.94 (s, 1H), 7.58-7.48 (m, 4H), 7.46-7.31 (m, 4H), 6.85-6.82 (m, 1H), 6.25-6.21 (m, 1H), 4.83 (s, 2H), 4.40-4.35 (m, 1H), 2.88-2.74 (m, 1H), 2.58-2.51 (m, 3H), 2.39-2.29 (m, 1H), 2.08 (s, 1H), 1.01-0.96 (m, 3H).

[0542] LC-MS, M / Z (ESI): 479.1 [M+H]+

[0543] Example 14: Preparation of target compound 14:

[0544] 3-(2-chloro-4'-(3-(2-(dimethylamino)ethoxy)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3- yl)piperidine-2,6-dione (target compound 14)

[0545] The synthetic route of compound 14 is shown as follows:

[0546] First step: 3-(3-bromo-2-chlorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine- 2,6-dione (compound 14-1)

[0547] 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (Intermediate A4) (3.0 g, 10 mmol) was placed in a reaction flask, then 50 mL of acetonitrile, 1,5-diazabicyclo[5.4.0]-5-undecene (3.0 g, 20 mmol), 2-(trimethylsilyl)ethoxymethyl chloride (2.5 g, 15 mmol) were added successively under ice bath, and the reaction was carried out at 45°C for 2 h, then the reaction solution was diluted with ethyl acetate (500 mL), extracted with ice water (500 mL x 3), then the organic phase was dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 5:1) to obtain 3-(3-bromo-2-chlorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (compound 14-1).

[0548] LC-MS, M / Z (ESI): 432.0 [M+H] + .

[0549] Step 2: Synthesis of 3-(2-chloro-4'-(3-hydroxy-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (Compound 14-2)

[0550] Into a reaction vial was placed 1-(4-bromophenyl)-3-hydroxypyridin-2(1H)-one (Intermediate 8-2) (500 mg, 1.89 mmol), followed by Compound 14-1 (1.09 g, 2.3 mmol), potassium phosphate (1.2 g, 5.67 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium chloride (150 mg, 0.2 mmol), 1,4-dioxane (10 mL), and the reaction was stirred at 100 °C for 16 h under nitrogen. After the reaction was completed, the reaction was diluted with ethyl acetate (200 mL), extracted with saturated aqueous sodium chloride solution (200 mL x 3), and then the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 20:1) to give 3-(2-chloro-4'-(3-hydroxy-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (Compound 14-2).

[0551] LC-MS, M / Z (ESI): 539.0 [M+H] +

[0552] Step 3: Synthesis of 3-(2-chloro-4'-(3-(2-(dimethylamino)ethoxy)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (Compound 14-3)

[0553] Intermediate 3-(2-chloro-4'-(3-(2-(dimethylamino)ethoxy)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 14) was synthesized by placing intermediate 3-(2-chloro-4'-(3-hydroxy-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (Compound 14-2) (660 mg, 1.23 mmol), (2-bromomethyl)dimethylamine hydrochloride (930 mg, 4.92 mmol), cesium carbonate (2 g, 6.15 mmol) into a reaction flask, adding acetonitrile (10 mL), and refluxing the reaction under nitrogen at 90 °C for 16 hours. After the reaction was completed, the reaction was diluted with ethyl acetate (200 mL), washed with saturated aqueous sodium chloride solution (200 mL x 3), and then the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 20:1) to obtain Compound 3-(2-chloro-4'-(3-(2-(dimethylamino)ethoxy)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (Compound 14-3).

[0554] LC-MS, M / Z (ESI): 610.1 [M+H] +

[0555] Fourth Step: Synthesis of 3-(2-chloro-4'-(3-(2-(dimethylamino)ethoxy)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 14)

[0556] Intermediate 3-(2-chloro-4'-(3-(2-(dimethylamino)ethoxy)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 14) was synthesized by placing intermediate 3-(2-chloro-4'-(3-hydroxy-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (Compound 14-2) (660 mg, 1.23 mmol), (2-bromomethyl)dimethylamine hydrochloride (930 mg, 4.92 mmol), cesium carbonate (2 g, 6.15 mmol) into a reaction flask, adding acetonitrile (10 mL), and refluxing the reaction under nitrogen at 90 °C for 16 hours. After the reaction was completed, the reaction was diluted with ethyl acetate (200 mL), washed with saturated aqueous sodium chloride solution (200 mL x 3), and then the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 20:1) to obtain Compound 3-(2-chloro-4'-(3-(2-(dimethylamino)ethoxy)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (Compound 14-3).

[0557] LC-MS, M / Z (ESI): 480.0 [M+H] +

[0558] 1H NMR (600 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.52 (d, 2H), 7.47 (d, 2H), 7.42-7.35 (m, 3H), 7.33 (dd, 1H), 7.08 (dd, 1H), 6.28 (t, 1H), 4.37-4.31 (m, 2H), 3.49-3.44 (m, 2H), 3.11-3.02 (m, 1H), 2.82 (s, 6H), 2.78-2.74 (m, 1H), 2.55-2.50 (m, 1H), 2.37-2.27 (m, 1H), 2.05-2.00 (m, 1H).

[0559] Example 15: Preparation of target compound 15

[0560] 3-(2-chloro-4'-(3-(oxetan-3-yloxy)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine- 2,6-dione (target compound 15)

[0561] The synthetic route of compound 15 is shown as follows:

[0562] First step: synthesis of 1-(4-bromophenyl)-3-(oxetan-3-yloxy)pyridin-2(1H)-one (compound 15-1)

[0563] The intermediate 1-(4-bromophenyl)-3-hydroxypyridin-2(1H)-one (intermediate 8-2) (280 mg, 1.06 mmol) was placed in a reaction bottle, followed by the addition of acetonitrile (5 mL), 3-iodooxetane (0.97 g, 5.3 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (1.0 g, 5.6 mmol) in sequence. The reaction was carried out at 90 °C under microwave for 5 hours under nitrogen protection. After the reaction was completed, the reaction solution was diluted with ethyl acetate (200 mL), extracted with saturated aqueous sodium chloride solution (200 mL x 3), and then the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 2:1) to obtain intermediate 1-(4-bromophenyl)-3-(oxetan-3-yloxy)pyridin-2(1H)-one (compound 15-1).

[0564] LC-MS, M / Z (ESI): 322.1 [M+H] +

[0565] Step 2: Synthesis of 3-(oxetan-3-yloxy)-l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)pyridin-2(lH)-one (Compound 15-2)

[0566] Intermediate l-(4-bromophenyl)-3-(oxetan-3-yloxy)pyridin-2(lH)-one (Compound 15-1) (140 mg, 0.435 mmol) was placed in a reaction flask, followed by addition of pinacol diboronic acid (222 mg, 0.87 mmol), potassium acetate (90 mg, 0.9 mmol) and l, l'-bis(di-phenylphosphino)ferrocene palladium chloride (58 mg, 0.08 mmol), 1,4-dioxane (4 mL), and the reaction was allowed to react at 100 °C for 4 hours under nitrogen protection. The reaction was cooled to room temperature, diluted with ethyl acetate (200 mL), washed with saturated aqueous sodium chloride solution (200 mL x 3), and then the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 3: 1) to obtain 3-(oxetan-3-yloxy)-l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)pyridin-2(lH)-one (Compound 15-2).

[0567] LC-MS, M / Z (ESI): 370.2 [M+H] +

[0568] Step 4: Synthesis of 3-(2-chloro-4'-(3-(oxetan-3-yloxy)-2-oxopyridin-l(2H)-yl)-[l,l'-biphenyl]-3-yl)piperidine-2,6-dione (Compound 15)

[0569] A reaction flask was charged with 3-(oxetan-3-yloxy)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridin-2(1H)-one (compound 15-2) (130 mg, 0.35 mmol), 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (Intermediate A4) (213 mg, 0.7 mmol), potassium phosphate (212 mg, 1.0 mmol) and 1,1'-bis(di-phenylphosphino)ferrocene palladium chloride (30 mg, 0.04 mmol), N,N-dimethylformamide (4 mL), and the reaction was stirred at 100 °C for 4 h under nitrogen. The reaction was cooled to room temperature, diluted with ethyl acetate (200 mL), washed with saturated aqueous sodium chloride solution (200 mL x 3), then the organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 20:1) to give 3-(2-chloro-4'-(3-(oxetan-3-yloxy)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 15).

[0570] LC-MS, M / Z (ESI): 465.0 [M+H] +

[0571] 1 H NMR (600 MHz, DMSO-d6) δ 10.93 (s, 1H), 7.54 (d, 2H), 7.48 (d, 2H), 7.44-7.32 (m, 4H), 6.64 (d, 1H), 6.20 (t, 1H), 5.24-5.16 (m, 1H), 4.88 (t, 2H), 4.59-4.50 (m, 2H), 4.35 (dd, 1H), 2.83-2.74 (m, 1H), 2.57-2.50 (m, 1H), 2.39-2.28 (m, 1H), 2.07-2.01 (m, 1H).

[0572] Example 16: Preparation of target compound 16

[0573] 3-(2-chloro-4'-(3-methoxy-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (target compound compound 16)

[0574] The synthetic route of compound 16 is shown below:

[0575] First step: synthesis of 1-(4-bromophenyl)-3-methoxypyridin-2(1H)-one (compound 16-1)

[0576] Intermediate 1-(4-bromophenyl)-3-hydroxypyridine-2(1H)-one (intermediate 8-2) (180 mg, 0.68 mmol) was placed in a reaction flask, followed by the addition of acetonitrile (6 mL). After the addition was complete, the mixture was deoxygenated three times with nitrogen. Then, 1,8-diazabicyclo[5.4.0]undecene (310 mg, 2.0 mmol) and iodomethane (240 mg, 1.7 mmol) were slowly added at 0 °C. After the addition was complete, the mixture was microwaved at 70 °C for 3 hours. After the reaction was complete, the reaction solution was diluted with ethyl acetate (200 mL) and 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 (petroleum ether:ethyl acetate (V / V) = 2:1) to give 1-(4-bromophenyl)-3-methoxypyridine-2(1H)-one (compound 16-1).

[0577] LC-MS, M / Z (ESI): 279.9 [M+H] +

[0578] Step 2: Synthesis of 3-methoxy-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)pyridin-2(1H)-one (compound 16-2)

[0579] 1-(4-bromophenyl)-3-methoxypyridin-2(1H)-one (compound 16-1) (170 mg, 0.60 mmol) was placed in a reaction flask, followed by the addition of pinacol diborate (310 mg, 1.21 mmol), potassium acetate (160 mg, 1.8 mmol), 1,1'-bis(di-phenylphosphino)ferrocene palladium chloride (45 mg, 0.06 mmol), and 1,4-dioxane (6 mL). After the addition was complete, the mixture was deoxygenated three times with nitrogen, and then reacted at 100 °C for 4 hours. Subsequently, the solution was diluted with ethyl acetate (100 mL), extracted with saturated sodium chloride aqueous solution (100 mL × 3), and the organic phase was then dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 2:1) to give 3-methoxy-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)pyridine-2(1H)-one (compound 16-2).

[0580] LC-MS, M / Z (ESI): 328.2 [M+H] +

[0581] Step 3: Synthesis of 3-(2-chloro-4'-(3-methoxy-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 16)

[0582] Into a reaction flask was placed 3-methoxy-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridin-2(1H)-one (compound 16-2) (130 mg, 0.40 mmol), followed by 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (intermediate A) (144 mg, 0.48 mmol), potassium phosphate (255 mg, 1.2 mmol) and 1,1'-bis(di-phenylphosphino)ferrocene palladium chloride (30 mg, 0.04 mmol), N,N-dimethylformamide (5 mL), deoxygenated with nitrogen for 3 times, followed by reaction at 100 °C for 2 hours. Then diluted with ethyl acetate (100 mL), washed with saturated aqueous sodium chloride solution (100 mL x 3), then the organic phase was dried over anhydrous sodium sulfate, concentrated by filtration, the crude product was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 20:1) to give 3-(2-chloro-4'-(3-methoxy-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 16).

[0583] LC-MS, M / Z (ESI): 423.1 [M+H] +

[0584] 1 H NMR (600 MHz, DMSO-d 6) δ 10.94 (s, 1H), 7.54 (d, 2H), 7.48 (d, 2H), 7.45-7.33 (m, 3H), 7.30-7.23 (m, 1H), 6.90 (d, 1H), 6.26 (t, 1H), 4.36 (dd, 1H), 3.74 (s, 3H), 2.83-2.73 (m, 1H), 2.58-2.51 (m, 1H), 2.38-2.29 (m, 1H), 2.08-2.02 (m, 1H).

[0585] The following compounds were prepared according to the method of Example 1:

[0586] Biological test

[0587] Example 1: Compound induces the binding of VAV1 to CRBN

[0588] VAV1-SmBiT expression plasmid and CRBN-LgBiT expression plasmid were constructed respectively, and VAV1-SmBiT and CRBN-LgBiT were inserted into the genome of HEK293 cells by using a lentivirus system to construct a cell line (HEK293-VAV1-SmBiT-CRBN-LgBiT) stably expressing VAV1-SmBiT and CRBN-LgBiT proteins. The culture medium used for culture was DMEM medium containing inactivated 10% fetal bovine serum, 100 U / mL penicillin and 100 μg / mL streptomycin, and the HEK293-VAV1-SmBiT-CRBN-LgBiT cells were cultured in a 37°C, 5% CO2 incubator. After the cell confluence rate reached 80-90%, the cells were subcultured. Cells in the logarithmic growth phase were used for plating, and the HEK293-VAV1-SmBiT-CRBN-LgBiT cells were plated in a 96-well plate, 100 μL of culture medium, 20,000-30,000 cells per well, and incubated overnight.

[0589] The test compound was dissolved in DMSO to a concentration of 10 mM. Then the compound was gradiently diluted with DMSO to concentrations of 2000 μM, 500 μM, 125 μM, 32.25 μM, 7.81 μM, 1.95 μM, 0.49 μM, 0.12 μM and 0.031 μM, respectively. 1 μL of the diluted test compound was added to 1 mL of complete medium, mixed well, and then 100 μL was added to a 96-well plate, and the working concentration reached 1000 nM, 250 nM, 62.5 nM, 15.6 nM, 3.91 nM, 0.98 nM, 0.24 nM, 0.061 nM, 0.015 nM and 0 nM. Drug treatment was performed for 8 hours for detection, and the detection method was according to the promega company NanoBiT Protein: Protein Interaction System instruction.

[0590] EC 50 Calculation:

[0591] Fluorescence intensity (Fold change) = (Lumninence experiment - Lumninence blank) / (Lumninence DMSO - Lumninence blank). Experimental conclusion: The compound of the present application can induce the direct binding of VAV1 and CRBN in a dose-dependent manner.

[0592] Experimental Example 2: Effect of the compound on VAV1 protein of Jurkat cells

[0593] The C-terminal of VAV1 is inserted into the Hibit tag, and the VAV1-Hibit is inserted into the genome of HEK293 cells by using a lentivirus system to construct a cell line stably expressing VAV1-Hibit protein. The culture medium used for culture is DMEM culture medium containing inactivated 10% fetal bovine serum, 100 U / mL penicillin and 100 μg / mL streptomycin, and Jurkat-VAV1-Hibit cells are cultured in a 37℃, 5% CO2 incubator. After the cell confluence rate reaches 80-90%, the cells are subcultured. Cells in the logarithmic growth phase are used for plating, and Jurkat-VAV1-Hibit cells are plated in a 96-well plate, 100 μL of culture medium, 20,000-30,000 cells per well, and incubated overnight.

[0594] The test compound is dissolved in DMSO to a concentration of 10 mM. Then the compound is gradiently diluted with DMSO to concentrations of 2000 μM, 500 μM, 125 μM, 32.25 μM, 7.81 μM, 1.95 μM, 0.49 μM, 0.12 μM and 0.031 μM. 1 μL of the diluted compound is added to 1 mL of complete medium, mixed well, and then 100 μL is added to a 96-well plate, and the working concentration is 1000 nM, 250 nM, 62.5 nM, 15.6 nM, 3.91 nM, 0.98 nM, 0.24 nM, 0.061 nM, 0.015 nM and 0 nM. The drug treatment is detected after 24 hours, and the detection method is according to the promega company HiBiT Lytic Detection System instruction.

[0595] DC 50 Calculation:

[0596] Relative VAV1 (%) = (Lumninence experiment - Lumninence blank) / (Lumninence DMSO - Lumninence blank), calculated according to log(inhibitor) vs.response--Variable slope(four parameters) fitting.

[0597] Experimental conclusion: The compound of the present application shows excellent degradation effect on VAV1 protein, and shows dose-dependent.

[0598] Experimental example 3: degradation of compound on Jurkat cell VAV1

[0599] Jurkat cells (BFN60700175, Qiang (Shanghai) Biotechnology Development Co., Ltd.) were cultured in RPMI-1640 medium containing inactivated 10% fetal bovine serum, 100 U / mL penicillin and 100 μg / mL streptomycin at 37°C in a 5% CO2 incubator, and the cell density reached 1*10 ^6 Subsequent passage and bottle. The tumor cells in the logarithmic growth phase were plated at 7*10 5 onto 12-well plates. After dilution, the drugs were added to the cell culture medium to make the final concentration of the drugs 1000 nM, 250 nM, 62.5 nM, 15.6 nM, 3.9 nM, 0.98 nM, 0.24 nM and 0 nM, respectively. The drug treatment was 24 hours. After 24 hours of drug treatment, the cells were taken out of the incubator and transferred to 1.5 mL EP tubes, and the supernatant was centrifuged. 150 μL of RIPA lysis buffer was added to each tube, and it was incubated on ice for 30 minutes. The protein gel was run for detection. After dilution of Anti-VAV1 1:1000 and Anti-GAPDH 1:5000, it was incubated at 4°C overnight. The HRP secondary antibody was diluted at 1:10000, and it was incubated at RT for 1 hour. The protein expression was detected by chemiluminescence, and the gray value was analyzed by ImageJ. The experimental results are shown in Table 1. The compounds of the present application showed excellent degradation effect on VAV1 protein in Jurkat cells in a dose-dependent manner; the DC50 value of the compounds of the present application was less than 10 nM, and even some were less than 5 nM; the Dmax value of the compounds of the present application could reach more than 95%, and even some reached more than 98%, which was significantly better than the existing clinical compound MRT-6160.

[0600] Table 1 Degradation activity of compounds on VAV1 protein in Jurkat cells DC50≤10 nM is "A", 10 nM<DC50≤30 nM is "B1", 30 nM<DC50≤100 nM is "B2", 100 nM<DC50≤1000 nM is "C", and DC50>1000 nM is "D".

[0601] Experimental Example 4 Inhibition of CD3 / CD28-induced Jurkat cell activation by compounds

[0602] Jurkat cells (BFN60700175, Qiang (Shanghai) Biotechnology Development Co., Ltd.) were cultured in RPMI-1640 medium containing inactivated 10% fetal bovine serum, 100 U / mL penicillin and 100 μg / mL streptomycin at 37°C in a 5% CO2 incubator, and the cell density reached 1*10 ^6Subculture and plating. Cells in log phase were plated at 40000 cells per well in 96-well plates and treated with different concentrations of compounds. After 24 hours of treatment, 5 μg / mL CD3 antibody and 1 μg / mL CD28 antibody (Dynabeads TM Human T activator CD3 / CD28, Cat. No. 11161D, Gibco) were added, and the cells were incubated for another 24 hours. The cell supernatant was collected and subjected to ELISA to detect the IL-2 content.

[0603] Experimental conclusion: In the CD3 / CD28-induced Jurkat cell activation model, the compound of the present application can significantly inhibit the production of IL-2, and the inhibition function is positively correlated with the dose.

[0604] Experimental Example 5: Inhibition of CD3 / CD28-induced human T cell activation by the compound

[0605] Fresh blood samples were diluted with an equal volume of PBS, slowly added to a 50 mL centrifuge tube containing 15 mL Lymphoprep (Stemcell, #7851), and centrifuged at 1000 g, 5 min, and 25 min at room temperature, without breaking the interface. The white blood cell layer (PBMC) was collected, washed twice with PBS, and centrifuged at 350 g for 10 min, and the supernatant was discarded. T cells were sorted from PBMC using a T cell sorting kit (Stemcell, #17951), and the cell density was adjusted to 2.6 x 10 6 / mL, 75 μL was added to each well of a U-bottom 96-well plate (Corning, #3799), and 75 μL of the diluted test compound was added, and an equal amount of DMSO was added to the blank group. After mixing, the cells were incubated for 24 hours. Then the cells were transferred to a 96-well plate coated with Anti-Human CD3 (5 μg / mL, BD, #555329), and 50 μL of Anti-Human CD28 (1 μg / mL, BD, #555725) was added, and the mixture was incubated for another 48 hours. Finally, the supernatant was collected, and the IL-2 level was detected using an IL-2 ELISA kit (BD, #555190).

[0606] Table 2 Inhibition of CD3 / CD28-induced T cell IL-2 secretion by the compound

[0607] Experimental conclusion: In the CD3 / CD28-induced human T cell activation model, the compound of the present application can significantly inhibit the production of IL-2, and the inhibition function is positively correlated with the dose, which is superior to the compound MRT-6160.

[0608] Example 6: Determination of the PK properties of the compound in mice

[0609] Male ICR mice, 3 animals, 10 mg / kg, gavage, vehicle: 5% DMSO + 10% Solutol + 85% Saline, overnight fast, blood sampling time points: pre-dose, and 5, 15, 30 min, and 1, 2, 4, 6, 8, 24 h post-dose. Blood samples were centrifuged at 6800 g for 6 min at 2-8°C, and the plasma was collected and stored at -80°C. 10 μL of plasma from each time point was added to 200 μL of methanol containing 100 ng / mL of internal standard, vortexed and mixed, and then centrifuged at 18000 g for 7 min at 2-8°C. 200 μL was transferred to a 96-well injection plate, and LC-MS / MS quantitative analysis was performed. The main pharmacokinetic parameters were analyzed by WinNonlin 7.0 software using a non-compartment model. The PK parameter results of the compounds of the present application are shown in Table 3.

[0610] Table 3. Compound mouse PK parameters

[0611] Experimental conclusion: In the mouse model, the compounds of the present application have good pharmacokinetic properties, and are significantly superior to compound MRT-6160 in various pharmacokinetic parameters, and have good drug properties.

[0612] Experimental Example 7: Rat pharmacokinetic test

[0613] The rat pharmacokinetic test used male SD rats, 180-240 g, overnight fast. 3 rats were orally administered 10 mg / kg by gavage. Blood sampling was performed before administration and at 15, 30 min, and 1, 2, 4, 8, 24 h after administration. Blood samples were centrifuged at 6800 g for 6 min at 2-8°C, and the plasma was collected and stored at -80°C. The plasma at each time point was mixed with 3-5 times the amount of an internal standard-containing acetonitrile solution, vortexed for 1 min, and centrifuged at 13000 rpm for 10 min at 4°C. The supernatant was mixed with 3 times the amount of water, and an appropriate amount of the mixture was subjected to LC-MS / MS analysis. The main pharmacokinetic parameters were analyzed by WinNonlin 7.0 software using a non-compartment model.

[0614] Table 4. Compound rat PK parameters

[0615] The rat pharmacokinetic test results showed that the compounds of the present application exhibited excellent rat pharmacokinetic properties, and were significantly superior to compound MRT-6160 in various pharmacokinetic parameters, and had good drug properties.

[0616] Experimental Example 8: Compound hepatocyte toxicity test

[0617] The compound hepatotoxicity test was performed on HepG2 (ATCC, HB-8065) cells, and the cell viability was determined using the CellTiter-Glo Luminescent Cell Viability Assay kit (Promega, G7573) to characterize the toxicity of the compound by inhibiting the viability of HepG2 cells. The logarithmic phase HepG2 cells were collected, and the cell suspension concentration was adjusted to 5000 cells / well in a 96-well cell culture plate, and the cells were incubated in a 5% CO2, 37°C cell incubator overnight. The next day, different concentrations of compound solutions were added, and negative control groups (cells + DMSO) and blank control groups (medium + DMSO) were set up, and incubated in a 5% CO2, 37°C cell incubator for 72 hours. After the treatment was completed, the kit instructions were followed, and the luminescence signal values in different wells were detected on the EnVision plate reader (2104). The inhibition of the viability of HepG2 cells by different concentrations of compounds was calculated according to the following formula: compound concentration as X axis, inhibition rate as Y axis, and the toxicity of the compound to HepG2 (IC 50 value) was calculated by software GraphPad Prism 8.0.

[0618] The results of the hepatotoxicity test showed that the compounds of the present application exhibited good safety and low hepatotoxicity.

[0619] Example 9: Human liver microsomal stability test

[0620] Human liver microsomal stability test was detected by co-incubation of compound with human liver microsomes in vitro. First, the compound to be tested was prepared into a 10 mM stock solution in DMSO solvent, and then the compound was diluted to 0.5 mM using acetonitrile. Human liver microsomes (Corning) were diluted into a microsomal / buffer solution using PBS, and the solution was used to dilute the 0.5 mM compound into a working solution, with a compound concentration of 1.5 μM and a human liver microsomal concentration of 0.75 mg / mL. A deep well plate was taken, 30 μL of the working solution was added to each well, and then 15 μL of preheated 6 mM NADPH solution was added to start the reaction, and incubation was carried out at 37°C. At 0, 5, 15, 30, and 45 minutes of incubation, 135 μL of acetonitrile was added to the corresponding wells to terminate the reaction. After the reaction was terminated at the last 45-minute time point with acetonitrile, the deep well plate was vortexed for 10 minutes (600 rpm / min) and then centrifuged for 15 minutes. After centrifugation, the supernatant was taken, 1:1 purified water was added, and LC-MS / MS detection was performed to obtain the peak area ratio of the compound to the internal standard at each time point. The peak area ratios of the compound at 5, 15, 30, and 45 minutes were compared with the peak area ratio at 0 minutes, and the remaining percentage of the compound at each time point was calculated. Graphpad 5 software was used to calculate T1 / 2.

[0621] The results of the human liver microsomal stability test showed that the compounds of the present application exhibited excellent human liver microsomal stability and good drugability.

[0622] Experimental Example 10: Inhibition test of compound on cytochrome P450

[0623] The inhibition potential of the compound on cytochrome P450 (CYP450) subtype CYP3A4 (two substrates, midazolam and testosterone) was detected. First, the compound to be tested was prepared into a 10 mM stock solution in DMSO solvent, and the CYP3A4 inhibitor ketoconazole was prepared into 10 mM, 2.5 mM, and 2.5 mM stock solutions in DMSO solvent. The compound to be tested and ketoconazole were diluted to a final concentration of 400 times (compound: 10 μM, ketoconazole: 2.5 μM) using acetonitrile.

[0624] The 4-fold final concentration of NADPH cofactor (66.7 mg of NADPH was added to 10 mL of potassium phosphate buffer) and substrates were prepared using potassium phosphate buffer (0.1 M, pH 7.4), and the final concentration of the CYP3A4 substrate midazolam was 320 μM, and the final concentration of the CYP3A4 substrate testosterone was 20 μM.

[0625] The human liver microsomal solution was prepared with potassium phosphate buffer on ice, with a concentration of 0.2 mg / mL. The 2-fold final concentration of the test compound and control inhibitor solution was prepared with the human liver microsomal solution on ice. 30 μL of the test compound and control inhibitor solution was added to the test well, respectively, and 15 μL of the substrate was added, with a duplicate well operation. The 96-well assay plate and NADPH solution were incubated at 37°C for 5 minutes, and 15 μL of the preheated 8 mM NADPH solution was added to the assay plate to initiate the reaction. The CYP3A4 assay plate was pre-incubated at 37°C for 5 minutes. The reaction was terminated by adding 120 μL of acetonitrile, and after quenching, the plate was shaken on a shaker (IKA, MTS2 / 4) for 10 minutes (600 rpm / min), and then centrifuged for 15 minutes. After centrifugation, the supernatant was taken, and after 1:1 addition of purified water, LC-MS / MS detection was performed to obtain the ratio of the compound peak area to the internal standard peak area. The peak area ratio of the compound was compared with the peak area ratio of the control inhibitor, and the inhibition rate was calculated.

[0626] The results of the cytochrome P450 inhibition test of the compound show that the compound of the present application has no obvious CYP3A4 (2 substrates, midazolam and testosterone) inhibition effect, and has good drug property.

[0627] Experimental Example 11: Test of plasma protein binding by equilibrium dialysis method

[0628] First, human or other species plasma samples were stored in -20 °C refrigerator, thawed in 37 °C water bath before use and kept on wet ice for standby. Test compound working solution was prepared using DMSO, stock concentration was 10 mM, final concentration was 2 μΜ. Thawed plasma was centrifuged to remove suspended impurities and precipitates, and the pH was adjusted to the range of 7.0-8.0. According to the manufacturer's instructions, the pretreated dialysis membrane was installed in the dialysis device and the installation was completed. When preparing the zero-time control sample, the blank plasma was mixed with the test compound working solution, and the vortex mixer was used to mix at 1000 rpm for 2 minutes to make the final concentration 2 μΜ, and immediately transferred to a 96-well plate as the T=0 time point control sample, and the remaining mixture was placed in an incubator for continued incubation. To determine the stability of the compound in the plasma, the remaining mixture was incubated in a 37 °C constant temperature shaking incubator for 5 hours, and 50 μL of sample was transferred to a 96-well plate for subsequent analysis after incubation. The dialysis device was assembled according to the manufacturer's instructions, the plasma sample was added to the dialysis cavity, and dialysis was performed with an equal volume of PBS buffer. The experiment was repeated, the air-permeable cover was used to cover the device, and the device was incubated at 37 °C and 100 rpm for 5 hours. After incubation, samples were taken from the plasma cavity and the buffer cavity and transferred to a 96-well plate for analysis. During sample processing, 500 μL of 80% acetonitrile / methanol solution containing appropriate internal standards was added to the collected samples and mixed for 2 minutes. The protein was precipitated and the compound was released by vortex mixing for 10 minutes, and then centrifuged at 4000 rpm for 10 minutes. 100 μL of supernatant was transferred to a new 96-well plate, mixed with 300 μL of distilled water, and then analyzed by LC-MS / MS. All samples were automatically peak area integrated, and the analyte peak area and internal standard peak area were exported to an Excel table to calculate the free rate, binding rate and recovery rate of the compound, as follows:

[0629] Free rate (% Unbound) = (buffer cavity peak area ratio / plasma cavity peak area ratio) x 100;

[0630] Binding rate (% Bound) = 100 - % Unbound;

[0631] Recovery rate (% Recovery) = (buffer cavity peak area ratio + plasma cavity peak area ratio) / total sample peak area ratio x 100;

[0632] Remaining amount (% Remaining) = 5-hour peak area ratio / 0-hour peak area ratio x 100.

[0633] Table 5 Plasma protein binding test results

[0634] The experimental results show that the compound has significant advantages in plasma protein binding rate compared with compound MRT-6160.

[0635] Experimental Example 12: Bidirectional permeability experiment in Caco-2 cell model

[0636] Experimental method:

[0637] 1) Cell culture: Caco-2 cells were purchased from the Cell Resource Center of Shanghai Life Science Research Institute, Chinese Academy of Sciences, and inoculated in the apical side of the multi-well plate with DMEM medium (containing 10% fetal bovine serum, 0.1 mg / ml streptomycin, 100 units of penicillin and 1X non-essential amino acids) at 37°C, 5% CO2. The cell culture period was 14-28 days, and the culture medium was replaced regularly during the period until a dense monolayer was formed and had sufficient trans-epithelial electrical resistance (TEER≥230 ohms·cm2).

[0638] 2) Permeability experiment: the Caco-2 cell Transwell plate taken out from the incubator was rinsed with preheated transport buffer and incubated at 37°C for 30 minutes. The A→B and B→A direction permeability experiments were carried out respectively: the test compound solution was added to the drug administration end, and the buffer was added to the receiving end, and the initial sample (TA0 or TB0) was immediately collected, and the T0 and T120 time point samples were set. After the Transwell plate was incubated at 37°C for 120 minutes, the samples at the drug administration end and the receiving end were collected, and the quenching solution (acetonitrile containing verapamil and glibenclamide) was added for treatment. All samples were mixed and centrifuged, and the supernatant was diluted and analyzed by LC-MS / MS. Each group had double repeated wells.

[0639] 3) Data analysis:

[0640] Cell density determination: the transmembrane resistance value was determined before and after the permeability experiment, and the monolayer cells below 230Ω·cm 2 were not included in the analysis. The apparent permeability coefficient (Papp) was calculated:

[0641] Wherein: CR is the concentration of the receiving end after incubation, CD0 is the initial concentration of the drug administration end, VR is the solution volume of the receiving end (A→B is

[0642] 1.3mL, B→A is 0.2mL), A is the monolayer cell membrane area (0.33cm2), and T is the incubation time (7200 seconds).

[0643] Efflux ratio (Efflux Ratio) calculation:

[0644] Recovery (Recovery) calculation:​

[0645] Where: CR is the concentration at the receiving end after incubation, VR is the solution volume at the receiving end (1.3 mL for A→B, 0.2 mL for B→A), CD is the concentration at the administration end after incubation, VD is the solution volume at the administration end (0.2 mL for A→B, 1.3 mL for B→A), and CD0 is the initial concentration at the administration end.

[0646] Table 6. Results of bidirectional permeability experiments in the Caco-2 cell model.

[0647] The results of the bidirectional permeability test in the Caco-2 cell model showed that the compound of the present invention had significantly better permeability than compound MRT-6160 in the in vitro model, with no obvious efflux, exhibiting good oral absorption characteristics and good drug-like properties.

[0648] Experimental Example 13: Pharmacological evaluation of the compound in a mouse model of inflammatory bowel disease induced by adoptive T cell transfer.

[0649] 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.

[0650] Experimental methods:

[0651] 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.

[0652] 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.

[0653] 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.

[0654] 4) At day 35, mice were sacrificed and colonic tissue was collected. At endpoint, colons were harvested, measured for length, washed in PBS and fecal material removed, blotted dry and weighed, and the weight to length ratio was calculated. At endpoint dissection, colonic contents were cleaned and saved for histological scoring.

[0655] The results show that the test compound set of the present application significantly ameliorated disease progression in the adoptive naive T cell-induced mouse model of colitis.

Claims

1. A compound represented by Formula (I), a tautomer, a stereoisomer, a pharmaceutically acceptable salt, or a prodrug thereof, ###0001### (I) wherein, R1is halogen, CN, C 1-6 alkyl, -OC 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl or 4-10 membered heterocycloalkyl, said C 1-6 alkyl, -OC 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 4-10 membered heterocycloalkyl are each independently optionally substituted with 1, 2, 3, or 4 R 1a substituents; Each R 1a They are, independently, H, D, halogen, OH, NH2, CN, and C. 1-6 Alkyl or halogenated C 1-6 alkyl; R2, R3, and R4are each independently H, D, halogen, NH2, CN, C 1-6 alkyl or haloC 1-6 alkyl; each R5is independently H, D, halogen, NH2, CN, or C 1-6 alkyl or haloC 1-6 alkyl; R8is H, D, halogen or C 1-6 alkyl; L1is a single bond, -O-, -NH-, -O-C 1-3 alkyl-, -NH-C 1-3 alkyl- or -C 1-3 alkyl-, wherein said -NH-, -O-C 1-3 alkyl-, -NH-C 1-3 alkyl- and -C 1-3 alkyl- are each independently optionally substituted with 1, 2, 3, or 4 R 1L substituents; each R independently is H, D, halogen, C 1L each independently is H, D, halogen, C 1-3 alkyl, haloC 1-3 alkyl or C 3-6 cycloalkyl; ring A is a 4-10 membered heterocycloalkyl, a 5-10 membered heterocycloalkenyl, a 6-10 membered aryl, or a 5-10 membered heteroaryl; each R 6-1 is independently substituted C 6a alkyl, C 3-6 cycloalkyl, 4-8 membered heterocycloalkyl, aryl, or heteroaryl, each of which is substituted with 1, 2, 3, or 4 R 6a substituted C 6b substituted -L2-C 3-6 substituted -L2-C 6b substituted -L2-C 6b substituted -L2-C 1-3 substituted -L2-C 3-6 substituted -L2-C 6b substituted -L2-C 1-3 substituted -L2-C 6c substituted -L2-C 1-6 substituted -L2-C each L2is independently -O-, -N(R 2L )-, -N(R 2L )-C(=O)-, -S-, -S(=O)-, -S(=O)2-, or -C(=O)-; R 2L is H or C 1-3 alkyl; each R 6a are each independently C 1-3 alkyl or -C 1-3 alkyl-C 1-3 alkoxy, said C 1-3 alkyl and -C 1-3 alkyl-C 1-3 alkoxy are each independently substituted with 1, 2, 3, or 4 R; each R is independently H, D, halogen, OH, NH2, or CN; Each R 6b They are, independently, H, D, halogen, OH, NH2, CN, and C. 1-6 Alkyl or halogenated C 1-6 alkyl; each R is independently H, D, halogen, OH, NH2, CN, or C1-6alkyl; 6c each R is independently H, D, halogen, OH, NH2, CN, or C1-6alkyl; 1-6 alkylamino; each R 6-2 are each independently H, D, halogen, OH, NH2, CN, oxo (=0), thioxo (=S), C 1-6 alkyl or haloC 1-6 alkyl; m is 1, 2, 3, or 4; n is 1, 2, 3, or 4; g is 0, 1, 2, 3, or 4; the heteroatom groups in the "heterocycloalkyl", "heterocycloalkenyl", and "heteroaryl" comprise N, O, S, S(=O), S(=O)2, or S(=O)(=NH), the number of the heteroatom groups is 1, 2, 3, or 4; when the number of the heteroatom groups is plural, the heteroatom groups are the same or different.

2. The compound, tautomer, stereoisomer, pharmaceutically acceptable salt, or prodrug thereof of claim 1, wherein, R1is F, CI, Br, CN, C 1-3 alkyl, -OC 1-3 alkyl, C 3-6 cycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl or 4-6 membered heterocycloalkyl, said C 1-3 alkyl, -OC 1-3 alkyl, C 3-6 cycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl or 4-6 membered heterocycloalkyl are each independently optionally substituted with 1, 2, 3, or 4 R 1a substituents; Or, each R 1a They can be H, F, Cl, OH, NH2, or CN, respectively. or, R1is Cl; or R2, R3and R4are each independently H, halogen, NH2, CN, C 1-3 alkyl or haloC 1-3 alkyl; more preferably, R2, R3and R4are each independently H.

3. The compound, tautomer, stereoisomer, pharmaceutically acceptable salt, or prodrug thereof of claim 1, wherein, each R5is independently H, halo, NH2, CN, C 1-3 alkyl or haloC 1-3 alkyl; more preferably, each R5is independently H; or, the R8is H or D; or said R 6-2 is H.

4. The compound, tautomer, stereoisomer, pharmaceutically acceptable salt, or prodrug thereof of claim 1, wherein, has any one of the following schemes 1-4: Scheme 1. The compound, its tautomer, stereoisomer, pharmaceutically acceptable salt, or prodrug, characterized by having the following formula (II): wherein R1is F, CI, Br, C 1-3 alkyl; L1is a single bond, -O-, -NH-, -O-CH2-, -NH-CH2-, or -CH2-, wherein the -NH-, -O-CH2-, -NH-CH2-, and -CH2- are each independently optionally substituted with 1, 2, 3, or 4 R 1L substituents; each R 1L is independently H, F, Cl, or CH3; each independently is a single bond or a double bond, as valence allows; V1, V2, V3, V4, and V5are each independently CH, CH2, N, or NH; V6is C, CH, or N; Each R 6-2 They are independently H, D, halogen, oxo (=O), thio (=S), and C, respectively. 1-3 Alkyl or halogenated C 1-3 alkyl; R 6-1 substituted by 1, 2, 3 or 4 R 6a substituted by 1, 2, 3 or 4 R 3-6 substituted by 1, 2, 3 or 4 R 6a substituted by 1, 2, 3 or 4 R 6b substituted by 1, 2, 3 or 4 R 3-6 substituted by 1, 2, 3 or 4 R 6b substituted by 1, 2, 3 or 4 R 6b substituted by 1, 2, 3 or 4 R 1-3 substituted by 1, 2, 3 or 4 R 3-6 substituted by 1, 2, 3 or 4 R 6b substituted by 1, 2, 3 or 4 R 1-3 substituted by 1, 2, 3 or 4 R 6c substituted by 1, 2, 3 or 4 R 1-6 substituted by 1, 2, 3 or 4 R L2is -O-, -NH-, or -NH-C(=O)-; R 6a , R 6b , R 6c as defined in claim 1 ; Scheme 2. The compound, tautomer, stereoisomer, pharmaceutically acceptable salt, or prodrug thereof, characterized by having the following formula (II): wherein R1is F, CI, Br, C 1-3 alkyl; L1is a single bond, -O-, -NH-, -O-CH2-, -NH-CH2-, or -CH2-, wherein the -NH-, -O-CH2-, -NH-CH2-, and -CH2- are each independently optionally substituted with 1, 2, 3, or 4 R 1L substituents; each R 1L is independently H, F, Cl, or CH3; each independently is a single bond or a double bond, as valence allows; V1, V2, V3, V4, and V5are each independently CH, CH2, N, or NH; V6is C, CH, or N; each R 6-2 are each independently H, D, halogen, oxo (=0), thioxo (=S), C 1-3 alkyl or haloC 1-3 alkyl; preferably, each R 6-2 are each independently H or oxo (=0); R 6-1 substituted by 1, 2, 3 or 4 R 6a substituted by 1, 2, 3 or 4 R 3-6 substituted by 1, 2, 3 or 4 R 6a substituted by 1, 2, 3 or 4 R 6-1 substituted by 1, 2, 3 or 4 R 6a substituted by 1, 2, 3 or 4 R 3-6 substituted by 1, 2, 3 or 4 R 6a substituted by 1, 2, 3 or 4 R R 6a are each independently C 1-3 alkyl or -C 1-2 alkyl-C 1-2 alkoxy, said C 1-3 alkyl and -C 1-3 alkyl-C 1-3 alkoxy are each independently substituted with 1 or 2 R; each R is independently H, D, halogen, OH; preferably, the R 6a are each independently -CH3or -CH2-OCH3substituted with 1 or 2 R; each R is independently H, D, F, OH; more preferably, the R 6a are each independently -CH2-OH, -CH2F, -CHF2, -CF3, -CH2-CH2F, or -CH2-OCF3; Scheme 3. The compound, a tautomer, a stereoisomer, a pharmaceutically acceptable salt, or a prodrug thereof, characterized by having the following formula (III-1): wherein R1is F, CI, Br, C 1-3 alkyl; L1is a single bond, -O-, -NH-, -O-CH2-, -NH-CH2-, or -CH2-, wherein the -NH-, -O-CH2-, -NH-CH2-, and -CH2- are each independently optionally substituted with 1, 2, 3, or 4 R 1L each R 1L is independently H, F, Cl, or CH3; each independently is a single bond or a double bond, as valence allows; V1, V2, V3, V4, and V5are each independently CH, CH2, N, or NH; V6is C, CH, or N; each R 6-2 are each independently H, D, halogen, oxo (=0), thioxo (=S), C 1-3 alkyl or haloC 1-3 alkyl; preferably, each R 6-2 are each independently H or oxo (=0); each L2is independently -O-, -NH-, or -NH-C(=O)-; q is independently 0, 1, 2, or 3; Y1, Y2, Y3, Y4, Y5, and Y6are each independently a single bond, O, or CH2, and at least two of Y1, Y2, Y3, Y4, Y5, and Y6are CH2; R 6b are each independently H, D, halogen, OH, NH2, CN, C 1-6 alkyl or haloC 1-6 alkyl; Scheme 4. The compound, its tautomer, stereoisomer, pharmaceutically acceptable salt, or prodrug, characterized by having the following formula (III-2): wherein R1is F, CI, Br, C 1-3 alkyl; L1is a single bond, -O-, -NH-, -O-CH2-, -NH-CH2-, or -CH2-, wherein the -NH-, -O-CH2-, -NH-CH2-, and -CH2- are each independently optionally substituted with 1, 2, 3, or 4 R 1L each R 1L is independently H, F, Cl, or CH3; each independently is a single bond or a double bond, as valence allows; V1, V2, V3, V4, and V5are each independently CH, CH2, N, or NH; V6is C, CH, or N; each R 6-2 are each independently H, D, halogen, oxo (=0), thioxo (=S), C 1-3 alkyl or haloC 1-3 alkyl; preferably, each R 6-2 are each independently H or oxo (=0); each R 6-1 is independently substituted with 1, 2, 3, or 4 R 6c substituted C 1-6 alkyl; preferably, each R 6-1 is independently substituted with 1, 2, 3, or 4 R 6c substituted C 1-4 alkyl; preferably, each R each R 6c are each independently H, D, halogen, OH, NH2, or C 1-3 alkylamino; preferably, each R 6c are each independently H, D, F, Cl, OH, NH2, or Scheme 5. The compound, its tautomer, stereoisomer, pharmaceutically acceptable salt, or prodrug, characterized by having the following formula (III-3): wherein, R1is Cl; L1is a single bond or -O-; each independently is a single bond or a double bond, as valence allows; V1, V2, V3, V4, and V5are each independently CH, CH2, N, or NH; V6is C, CH, or N; Each R 6-2 They can be H or oxo (=O) independently, respectively; Preferably, said For More preferably, said For each R 6x is independently substituted with 1, 2, 3, or 4 R 6y substituted: C 1-4 alkyl, C 3-4 cycloalkyl, 3-4 membered heterocyclyl, -C 1-3 alkyl-C 3-4 cycloalkyl; preferably, each R 6x is independently substituted with 1, 2, 3, or 4 R 6y substituted: cyclopropyl, methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, oxetanyl, -CH2-cyclopropyl; more preferably, each R 6x is independently -CHF2, -CDF2, -CF3, each R 6y are each independently H, D, halogen, OH, NH2, or C 1-3 alkylamino; preferably, each R 6y are each independently H, D, F, Cl, OH, NH2, or 5. The compound, tautomer, stereoisomer, pharmaceutically acceptable salt, or prodrug thereof of claim 1, wherein having any one of the following structures: wherein, V1, V2, V3, V4, V5are each independently C, CH, or N; R1, L1, R 6-1 , R 6-2 , g and n are as defined in claim 1.

6. The compound, tautomer, stereoisomer, pharmaceutically acceptable salt, or prodrug thereof of claim 5, wherein, the compound satisfies one or more of the following conditions: a) Having a structure b) Having a structure c) Having a structure 7. The compound, tautomer, stereoisomer, pharmaceutically acceptable salt, or prodrug thereof, of claim 1, wherein L1is a single bond, -O-, -NH-, -O-CH2-, -NH-CH2-, or -CH2-, wherein the -NH-, -O-CH2-, -NH-CH2-, and -CH2- are each independently optionally substituted with 1, 2, 3, or 4 R 1L substituted; Or, each R 1L They can be H, F, Cl, or CH3 independently; or, the above L1is a single bond, -O-, or -CH2-.

8. The compound, tautomer, stereoisomer, pharmaceutically acceptable salt, or prodrug thereof, of claim 1 or 5, wherein, ring A is a phenyl, a 5-10 membered heterocycloalkenyl, or a 5-10 membered heteroaryl; or, ring A is a phenyl, a 5-6 membered heterocycloalkenyl, or a 5-6 membered heteroaryl; Alternatively, ring A is Alternatively, ring A is "*" indicates the site connected with L1.

9. The compound, tautomer, stereoisomer, pharmaceutically acceptable salt, or prodrug thereof, of claim 1 or 5, wherein, each R 6-1 are each independently substituted C 6c alkyl; and each R 1-4 alkoxy; or each R is independently -OCH3, 6-1 each R is independently -OCH3, said -OCH3, each independently is substituted with 1, 2, 3, or 4 R 6c substituted; or each R is independently H, D, F, Cl, OH, NH2, or 6c are each independently H, D, F, Cl, OH, NH2, or or each R is independently -OCH3, -OCHF2, -OCDF2, -OCF3, 6-1 are each independently -OCH3, -OCHF2, -OCDF2, -OCF3, 10. The compound, tautomer, stereoisomer, pharmaceutically acceptable salt, or prodrug thereof, of claim 1 or 5, wherein, Each R 6-1 Each independently is assigned to 1, 2, 3, or 4 R's. 6a Replacement C 3-6 Cycloalkyl, with 1, 2, 3 or 4 R 6a Substituted 4-8 membered heterocyclic alkyl groups; Or, each R 6-1 Each of the following groups is independently composed of cyclopropyl, cyclobutyl, azacyclobutyl, and oxacyclobutyl, wherein the cyclopropyl, cyclobutyl, azacyclobutyl, and oxacyclobutyl groups are independently separated by 1, 2, 3, or 4 R groups. 6a replace; or each R is independently -CH3or -CH2-OCH3, said -CH3and -CH2-OCH3are each independently substituted with 1, 2, 3, or 4 R; 6a each R is independently -CH3or -CH2-OCH3, said -CH3and -CH2-OCH3are each independently substituted with 1, 2, 3, or 4 R; or, each R is independently H, F, Cl, OH, NH2, or CN; Or, each R 6a They can be independently -CH2-OH, -CH2F, -CHF2, -CF3, -CH2-CH2F, or -CH2-OCF3; or each R is independently 6-1 each R is independently 11. The compound, tautomer, stereoisomer, pharmaceutically acceptable salt, or prodrug thereof, of claim 1 or 5, wherein, each R 6-1 are each independently -L2-C 6b substituted -L2-C 3-6 cycloalkyl, -L2-C 6b substituted -L2-C 6b substituted -L2-C 1-3 alkyl-C 3-6 cycloalkyl or -L2-C 6b substituted -L2-C 1- 3 alkyl-4-8 membered heterocycloalkyl; or each R 6-1 is independently -L2-cyclopropyl, -L2-cyclobutyl, -L2-azetidinyl, -L2-cyclopentyl, -L2- oxanyl, -L2-oxolanyl, -L2-tetrahydrofuranyl, -L2-tetrahydropyranyl, -L2-CH2-cyclopropyl, -L2-CH2-cyclobutyl, -L2-CH2-cyclopentyl, -L2-CH2-oxolanyl, -L2-CH2-tetrahydrofuranyl, -L2-CH2-tetrahydropyranyl, each of which is independently substituted with 1, 2, 3, or 4 R 6b substituents; or each L2is independently -O-, -N(R 2L )-, -N(R 2L )-C(=O)-, -S-, -S(=O)-, -S(=O)2-, or -C(=O)-; or R 2L is H or CH3; or, each L2is independently -O-, -NH-, -NH-C(=O)-, -S-, -S(=O)-, -S(=O)2-, or -C(=O)-; or, each L2is independently -O- or -NH-C(=O)-; or, each L2is independently -O- or -NH-C(=O)-; or each R is independently 6-1 each R is independently The each independently is substituted with 1, 2, 3, or 4 R 6b substituted; or each R is independently H, F, Cl, OH, NH2, CN, C 6b is independently H, F, Cl, OH, NH2, CN, C 1-3 alkyl or haloC 1-3 alkyl; Or, each R 6b They can be H, F, Cl, OH, NH2, CN, or CH3, respectively. Or, each R 6b They can be H, F, OH, NH2 or CH3, respectively. or each R is independently 6-1 each R is independently 12. The compound, tautomer, stereoisomer, pharmaceutically acceptable salt, or prodrug thereof, of claim 1 or 5, wherein, each R is independently -OCH3, -OCHF2, -OCDF2, -OCF3, 6-1 each R is independently -OCH3, -OCHF2, -OCDF2, -OCF3, 13. The compound, tautomer, stereoisomer, pharmaceutically acceptable salt, or prodrug thereof, of claim 1, wherein, The compound has the structure:

14. A pharmaceutical composition, characterized by, A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1-13, a tautomer, a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof, and a pharmaceutically acceptable excipient.

15. Use of a compound according to any one of claims 1-13, a tautomer, a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof, or a pharmaceutical composition according to claim 14 in the manufacture of a medicament for the treatment and / or prevention of a VAV1 -related disease.

16. Use according to claim 15, characterized in that, The VAV1 -related disease comprises a cancer or an autoimmune disease.

17. Use according to claim 15, characterized in that, The VAV1 -related disease comprises systemic lupus erythematosus, myasthenia gravis, periodontitis, type I diabetes, rheumatoid arthritis, multiple sclerosis, inflammatory enteritis, inflammatory bowel disease, autoimmune hepatitis, or psoriasis. The VAV1 -related disease comprises systemic lupus erythematosus, myasthenia gravis, periodontitis, type I diabetes, rheumatoid arthritis, multiple sclerosis, inflammatory enteritis, inflammatory bowel disease, autoimmune hepatitis, or psoriasis.

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