VAV1 degradation agent

Abstract

The invention provides a VAV1 (Vinyl Acetate 1) degradation agent. Specifically provided are a compound represented by formula (I), a tautomer, a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof. The compound provided by the invention is good in drug effect and can be used for preparing drugs for treating or preventing VAV1 related diseases.

Description

TECHNICAL FIELD

[0001] 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 efficacy and can be prepared for drugs for treating or preventing VAV1 related diseases. BACKGROUND

[0002] 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 existing in human cells to destroy and degrade key proteins related to diseases, thereby achieving the effect of treating diseases. At present, molecular glue, proteolytic targeting chimera, lysosome targeting chimera, autophagy targeting chimera, autophagy linking compound and other technologies have been developed. Among them, several 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 more and more attention to the development of related drugs.

[0003] VAV family proteins, including VAV1, VAV2 and VAV3, are Rho family GTPase guanine nucleotide exchange factors (GEFs). VAV1 is a 95 kDa protein and is a positive regulator of T cell receptor and B cell receptor signaling. VAV1 is mainly expressed in human hematopoietic cells, including T cells, B cells, monocytes, natural killer (NK) cells, granulocytes and dendritic cells, while its family members VAV2 and VAV3 are more widely expressed. VAV1 is rapidly phosphorylated under 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 regulates various 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.

[0004] Whole-genome CRISPR-Cas9 screening confirmed that VAV1 is an important positive regulator of T cell activation / function, and VAV1 promotes the 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 key role in T / B lymphocyte function and antigen receptor signaling, especially in T cells. More importantly, Vav1 -deficient mouse thymocytes and splenic T cells show multiple defects in TCR-mediated signaling, such as impaired calcium (Ca 2+) and impaired activation of mobilization and transcription factors. T cells with loss of VAV1 GEF activity (VAV1 L334A / K335A) exhibited normal TCR-mediated Ca 2+ flux and nuclear factor of activated T cells (NFAT) activation. It is demonstrated that both GEF activity and scaffolding function of VAV1 play important roles in the TCR signaling pathway.

[0005] Genetic analysis found that rodents carrying VAV1 R63W variation showed lower susceptibility in experimental autoimmune encephalomyelitis (EAE) and palmitoyl-induced arthritis compared with wild type (WT). In the mouse model of antigen (methylated bovine serum albumin)-induced arthritis (AIA), VAV1 knockout mice showed less disease symptoms (such as inflammation, synovial thickening and cartilage degradation), reduced T cell proliferation and reduced joint infiltration of CD4+ T cells, neutrophils and macrophages than wild type (WT) mice. This again indicates that VAV1 plays an important role in T cell differentiation and function.

[0006] Recently, the development of a new molecular glue degrader named MRT-6160 has opened up a new path 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 the cell. 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 targeting therapy in the treatment of autoimmune diseases, and VAV1 is expected to become a key therapeutic target for various immune-mediated diseases. SUMMARY

[0007] In a first aspect of the present application, the present application provides a compound represented by formula (I), a tautomer, a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof,

[0008]

[0009] wherein,

[0010] R1 is 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 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;

[0011] Each R 1a They are, independently, H, D, halogen, OH, NH2, CN, and C. 1-6 Alkyl or halogenated C 1-6 alkyl;

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

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

[0014] R8 is H, D, halogen, or C. 1-6 alkyl;

[0015] 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;

[0016] 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;

[0017] 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;

[0018] 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 1, 2, 3 or 4 R 6c substituted C 1-6 alkoxy;

[0019] each L2is independently -0-, -N(R 2L )-, -N(R 2L )-C(=0)-, -S-, -S(=0)-, -S(=0)2- or -C(=0)-;

[0020] R 2L is H or C 1-3 alkyl;

[0021] 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;

[0022] each R is independently H, D, halogen, OH, NH2or CN;

[0023] each R 6b is independently H, D, halogen, OH, NH2, CN, C 1-6 alkyl or halogenated C 1-6 alkyl;

[0024] each R 6c is independently H, D, halogen, OH, NH2, CN or C 1-6 alkylamino;

[0025] each R 6-2 is independently H, D, halogen, OH, NH2, CN, oxo (=0), thioxo (=S), C 1-6 alkyl or halogenated C 1-6 alkyl; m is 1, 2, 3 or 4;

[0026] n is 1, 2, 3 or 4;

[0027] g is 0, 1, 2, 3 or 4;

[0028] 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.

[0029] 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,

[0030]

[0031] wherein,

[0032] 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 groups; 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 groups;

[0033] each R 1a is independently H, D, halogen, OH, NH2, CN, C 1-6 alkyl or halogenated C 1-6 alkyl;

[0034] R2, R3and R4are each independently H, D, halogen, NH2, CN, C 1-6 alkyl or halogenated C 1-6 alkyl;

[0035] each R5is independently H, D, halogen, NH2, CN or C 1-6 alkyl or halogenated C 1-6 alkyl;

[0036] R8is H, D, halogen or C 1-6 alkyl;

[0037] 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 1-3alkyl-, -NH-C 1-3 alkyl- and -C 1-3 alkyl- are each independently optionally substituted with 1, 2, 3, or 4 R 1L substituents;

[0038] each R 1L is independently H, D, halogen, C 1-3 alkyl, halogenated C 1-3 alkyl or C 3-6 cycloalkyl;

[0039] Ring A is 4-10 membered heterocycloalkyl, 5-10 membered heterocycloalkenyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

[0040] each R 6-1 is independently C 6a substituted with 1, 2, 3, or 4 R 3-6 cycloalkyl, 1, 2, 3, or 4 R 6a substituted 4-8 membered heterocycloalkyl, 1, 2, 3, or 4 R 6b substituted -L2-C 3-6 cycloalkyl, 1, 2, 3, or 4 R 6b substituted -L2-4-8 membered heterocycloalkyl, 1, 2, 3, or 4 R 6b substituted -L2-C 1-3 alkyl-C 3-6 cycloalkyl, 1, 2, 3, or 4 R 6b substituted -L2-C 1-3 alkyl-4-8 membered heterocycloalkyl, or C 6c substituted with 1, 2, 3, or 4 R 1-6 alkoxy;

[0041] each L2is independently -O-, -N(R 2L )-, -N(R 2L )-C(=O)-, -S-, -S(=O)-, -S(=O)2-, or -C(=O)-;

[0042] R 2L is H or C 1-3 alkyl;

[0043] each R 6a is 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 is independently substituted with 1, 2, 3, or 4 R

[0044] each R is independently H, halogen, OH, NH2, or CN;

[0045] each R 6b is independently H, halogen, OH, NH2, CN, C 1-6 alkyl, or haloC 1-6 alkyl;

[0046] each R 6c is independently halogen, OH, NH2, or CN;

[0047] each R 6-2 is independently H, halogen, OH, NH2, CN, oxo (=0), thioxo (=S), C 1-6 alkyl, or haloC 1-6 alkyl;

[0048] m is 1, 2, 3, or 4;

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

[0050] g is 0, 1, 2, 3, or 4;

[0051] The heteroatom groups in the "heterocycloalkyl", "heterocycloalkenyl", and "heteroaryl" groups comprise N, O, S, S(=0), S(=0)2, or 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.

[0052] 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,

[0053]

[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 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 of which is independently optionally substituted with 1, 2, 3, or 4 R 1a ;

[0056] each R 1aThey are, independently, H, halogen, OH, NH2, CN, and C. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0057] R2, R3, and R4 are independently H, halogen, NH2, CN, and C, respectively. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0058] Each R5 is independently H, halogen, NH2, CN, or C. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0059] R8 is H, D, halogen, or C. 1-6 alkyl;

[0060] 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;

[0061] Each R 1L Each is independently H, halogen, and C. 1-3 Alkyl, Halogenated C 1-3 Alkyl or C 3-6 cycloalkyl;

[0062] 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;

[0063] 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;

[0064] Each L2 is 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 alkoxy, said C 1-3 alkyl and -C 1-3 alkyl-C 1-3 alkoxy is independently substituted with 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 haloC 1-6 alkyl;

[0069] each R 6-2 is independently H, halogen, OH, NH2, CN, oxo (=O), 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(=O), S(=O)2, or S(=O)(=NH), the number of which is 1, 2, 3, or 4; when the number of the heteroatom groups is plural, the heteroatom groups are the same or different.

[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]

[0076] wherein,

[0077] R1is halogen, CN, C 1-6 alkyl, -OC 1-6 alkyl, C3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 4-10 membered heterocyclic alkyl group, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 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;

[0078] Each R 1a They are, independently, H, halogen, OH, NH2, CN, and C. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0079] R2, R3, and R4 are independently H, halogen, NH2, CN, and C, respectively. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0080] Each R5 is independently H, halogen, NH2, CN, or C. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0081] R8 is H, D, halogen, or C. 1-6 alkyl;

[0082] 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;

[0083] Each R 1L Each is independently H, halogen, and C. 1-3 Alkyl or C 3-6 cycloalkyl;

[0084] 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;

[0085] 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 3-6cycloalkyl, substituted by 1, 2, 3 or 4 R 6a substituted 4-8 membered heterocycloalkyl, substituted by 1, 2, 3 or 4 R 6b substituted -L2-C 3-6 cycloalkyl or substituted by 1, 2, 3 or 4 R 6b substituted -L2-4-8 membered heterocycloalkyl;

[0086] each L2is independently -0-, -N(R L2 )-, -S-, -S(=0)-, -S(=0)2- or -C(=0)-;

[0087] R L2 is H or C 1-3 alkyl;

[0088] each R 6a is independently H, 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 is independently substituted by 1, 2, 3 or 4 R;

[0089] each R is independently H, halogen, OH, NH2or CN;

[0090] each R 6b is independently H, halogen, OH, NH2, CN, C 1-6 alkyl or halogenated C 1-6 alkyl; each R 6-2 is independently H, halogen, OH, NH2, CN, C 1-6 alkyl or halogenated C 1-6 alkyl;

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

[0092] n is 1, 2, 3 or 4;

[0093] g is 0, 1, 2, 3 or 4;

[0094] 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.

[0095] In an optional embodiment of the present application, the above R1is F, Cl, Br, CN, C 1-3 alkyl, -OC 1-3alkyl, 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.

[0096] In an optional embodiment of the present application, each R 1a is independently H, F, Cl, OH, NH2or CN.

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

[0098] In an optional embodiment of the present application, R1is F.

[0099] In an optional embodiment of the present application, R2, R3and R4are each independently H, halogen, NH2, CN, C 1-3 alkyl or halogenated C 1-3 alkyl.

[0100] In an optional embodiment of the present application, R2, R3and R4are each independently H, F or Cl.

[0101] In an optional embodiment of the present application, R2, R3and R4are each independently H.

[0102] In an optional embodiment of the present application, each R5is independently H, halogen, NH2, CN, C 1-3 alkyl or halogenated C 1-3 alkyl.

[0103] In an optional embodiment of the present application, each R5is independently H.

[0104] In an optional embodiment of the present application, R8is H or D.

[0105] In an optional embodiment of the present application, the compound has the following formula (II):

[0106]

[0107] wherein R1is F, Cl, Br, C 1-3 alkyl;

[0108] 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 each R 1L is independently H, F, Cl, or CH3;

[0109] each independently a single or double bond, as valence bonds permit;

[0110] V1, V2, V3, V4, and V5are each independently CH, CH2, N, or NH;

[0111] V6is C, CH, or N;

[0112] each R 6-2 is independently H, D, halogen, oxo (=0), thioxo (=S), C 1-3 alkyl, or halogenated C 1-3 alkyl;

[0113] R 6-1 is C 6a substituted with 1, 2, 3, or 4 R 3-6 cycloalkyl, 4-8 membered heterocycloalkyl, aryl, or heteroaryl, each of which is substituted with 1, 2, 3, or 4 R 6a substituted with 1, 2, 3, or 4 R 6b substituted with 1, 2, 3, or 4 R 3-6 substituted with 1, 2, 3, or 4 R 6b substituted with 1, 2, 3, or 4 R 6b substituted with 1, 2, 3, or 4 R 1-3 alkyl-C 3-6 substituted with 1, 2, 3, or 4 R 6b substituted with 1, 2, 3, or 4 R 1-3 alkyl-4-8 membered heterocycloalkyl, or C 6c substituted with 1, 2, 3, or 4 R 1-6 alkoxy;

[0114] L2is -O-, -NH-, or -NH-C(=0)-;

[0115] R 6a , R 6b , R 6c as defined herein.

[0116] In an optional embodiment of the application, the above compounds have the following formula (II):

[0117]

[0118] Where R1 is F, Cl, Br, or C. 1-3 alkyl;

[0119] 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;

[0120] Each bond can be a single or double bond independently, provided that the valence bond allows it.

[0121] V1, V2, V3, V4 and V5 are each independently CH, CH2, N or NH;

[0122] V6 is C, CH, or N;

[0123] 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;

[0124] 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;

[0125] R 6a C 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.

[0126] In an optional embodiment of the present invention, the above-mentioned R 6-2 They can be H or oxo (=O) independently, respectively.

[0127] 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.

[0128] In an optional embodiment of the present application, each R is independently -CH3or -CH2-OCH3. 6a each independently -CH3or -CH2-OCH3.

[0129] In an optional embodiment of the present application, each R is independently H, D, F, OH.

[0130] In an optional embodiment of the present application, each R is independently -CH3or -CH2-OCH3. 6a each independently -CH3or -CH2-OCH3.

[0131] In an optional embodiment of the present application, the compound has the following formula (III-1):

[0132]

[0133] wherein R1is F, Cl, Br, C 1-3 alkyl;

[0134] 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 each independently H, F, Cl, or CH3. 1L

[0135] each independently a single bond or a double bond, as valence allows;

[0136] V1, V2, V3, V4, and V5are each independently CH, CH2, N, or NH;

[0137] V6is C, CH, or N;

[0138] each R 6-2 each independently H, D, halogen, oxo (=O), thioxo (=S), C 1-3 alkyl, or haloC 1-3 alkyl;

[0139] each L2is independently -O-, -NH-, or -NH-C(=O)-;

[0140] each q is independently 0, 1, 2, or 3;

[0141] 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; ​

[0142] R 6b They are, independently, H, D, halogen, OH, NH2, CN, and C. 1-6 Alkyl or halogenated C 1-6 alkyl.

[0143] In an optional embodiment of the present invention, the above-mentioned R 6-2 They can be H or oxo (=O) independently, respectively.

[0144] In an optional embodiment of the present invention, the above compound has the structure of formula (III-2):

[0145]

[0146] Where R1 is F, Cl, Br, or C. 1-3 alkyl;

[0147] 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;

[0148] Each bond can be a single or double bond independently, provided that the valence bond allows it.

[0149] V1, V2, V3, V4 and V5 are each independently CH, CH2, N or NH;

[0150] V6 is C, CH, or N;

[0151] 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 groups; preferably, each R 6-2 They can be H or oxo (=O) independently, respectively;

[0152] Each R 6-1 Each can be independently controlled by 1, 2, 3 or 4 Rs. 6c Replacement C 1-6 Alkoxy;

[0153] Each R 6c Each can be independently H, D, halogen, OH, NH2, or C. 1-3 Alkylamino.

[0154] In an optional embodiment of the present invention, the above-mentioned R 6-2They can be H or oxo (=O) independently, respectively.

[0155] In an optional embodiment of the present invention, the above-mentioned R 6-1 Each can be independently controlled by 1, 2, 3 or 4 Rs. 6c Replacement C 1-4 Alkyl group.

[0156] In an optional embodiment of the present invention, the above-mentioned R 6c They are independently H, D, F, Cl, OH, NH2 or

[0157] In an optional embodiment of the present invention, the above compound has the structure of formula (III-3):

[0158]

[0159] Where R1 is Cl;

[0160] L1 is a single bond or -O-;

[0161] Each bond can be a single or double bond independently, provided that the valence bond allows it.

[0162] V1, V2, V3, V4 and V5 are each independently CH, CH2, N or NH;

[0163] V6 is C, CH, or N;

[0164] Each R 6-2 They can be H or oxo (=O) independently, respectively;

[0165] Each R 6x Each can be independently controlled by 1, 2, 3 or 4 Rs. 6y Replaced by: C 1-4 Alkyl, C 3-4 cycloalkyl, 3-4 membered heterocyclic, -C 1-3 Alkyl-C 3-4 cycloalkyl;

[0166] Each R 6y Each can be independently H, D, halogen, OH, NH2, or C. 1-3 Alkylamino.

[0167] In an optional embodiment of the present invention, the above for

[0168] In an optional embodiment of the present invention, the above for

[0169] In an optional embodiment of the present invention, the above-mentioned R6x Each can be independently controlled by 1, 2, 3 or 4 Rs. 6y Substituted with: cyclopropyl, methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, oxecyclobutyl, -CH2-cyclopropyl.

[0170] In an optional embodiment of the present invention, the above-mentioned R 6y They are independently H, D, F, Cl, OH, NH2 or

[0171] In an optional embodiment of the present invention, the above-mentioned R 6x They are independently -CHF2, -CDF2, and -CF3, respectively.

[0172] In an optional embodiment of the present invention, the above compound has the structure of formula (Ia):

[0173]

[0174] Among them, R1, L1, R 6-1 R 6-2 g and n are as defined in this invention.

[0175] In an optional embodiment of the present invention, the above-mentioned compound has the following structure (Ib), (Ic), or (Id):

[0176]

[0177] Among them, V1, V2, V3, V4, and V5 are each independently C, CH, or N; R1, L1, and R 6-1 And n is as defined in this invention.

[0178] In an optional embodiment of the present invention, the above compound has the structure of the following formula (Ie):

[0179]

[0180] 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;

[0181] R 6-1 For 1, 2, 3 or 4 R 6a Replacement C 3-6 Cycloalkyl groups, with 1, 2, 3 or 4 R groups6a 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;

[0182] L2 is -O-, -NH-, or -NH-C(=O)-;

[0183] R 6a R 6b R 6c As defined in this invention.

[0184] In an optional embodiment of the present invention, the above-mentioned R 6-1 They are independently -OCH3, -OCHF2, -OCDF2, -OCF3, In an optional embodiment of the present invention, the above Having structure In an optional embodiment of the present invention, the above Having structure

[0185] In an optional embodiment of the present invention, the above Having structure

[0186] In an optional embodiment of the present invention, the above Having structure

[0187] In an optional embodiment of the present invention, the above Having structure

[0188] In an optional embodiment of the present invention, the above Having structure

[0189] In an optional embodiment of the present invention, the above Having structure

[0190] In an optional embodiment of the present invention, the above Having structure

[0191] In an optional embodiment of the present invention, 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.

[0192] In an optional embodiment of the present invention, the above-mentioned R 1L They can be H, F, Cl or CH3, respectively.

[0193] In an optional embodiment of the present invention, L1 is a single bond, -O-, or -CH2-.

[0194] In an optional embodiment of the present invention, the above-mentioned ring A is phenyl, 5-10 membered heterocyclic alkenyl or 5-10 membered heteroaryl.

[0195] In an optional embodiment of the present invention, the above-mentioned ring A is phenyl, 5-6 membered heterocyclic alkenyl or 5-6 membered heteroaryl.

[0196] In an optional embodiment of the present invention, the above-mentioned ring A is a 5-6 membered heterocyclic alkenyl or a 5-6 membered heteroaryl.

[0197] In an optional embodiment of the present invention, the above

[0198] In an optional embodiment of the present invention, the aforementioned ring A is In an optional embodiment of the present invention, the aforementioned ring A is

[0199] In an optional embodiment of the present invention, the aforementioned ring A is

[0200] "*" indicates a site connected to L1.

[0201] In an optional embodiment of the present invention, the aforementioned ring A is "*" indicates a site connected to L1.

[0202] In an optional embodiment of the present invention, the above-mentioned R 6-1Each independently is assigned to 1, 2, 3, or 4 R's. 6c Replacement C 1-4 Alkyl group.

[0203] In an optional embodiment of the present invention, the above-mentioned R 6-1 Each of the C atoms independently substituted with one, two, three, or four halogens 1-3 Alkyl group.

[0204] In an optional embodiment of the present invention, the above-mentioned R 6-1 Each independently represents -OCH3, The -OCH3, Each independently is assigned to 1, 2, 3, or 4 R's. 6c replace.

[0205] In an optional embodiment of the present invention, the above-mentioned R 6-1 Each independently represents -OCH3, The -OCH3, Each independently is assigned to 1, 2, 3, or 4 R's. 6c replace.

[0206] In an optional embodiment of the present invention, the above-mentioned R 6c They are independently H, D, F, Cl, OH, NH2 or

[0207] In an optional embodiment of the present invention, the above-mentioned R 6c They are D, F, Cl, OH, NH2, or...

[0208] In an optional embodiment of the present invention, the above-mentioned R 6c Each can be independently represented by D, F, Cl, OH, NH2, CH3 or

[0209] In an optional embodiment of the present invention, the above-mentioned R 6-1 They are independently -OCH3, -OCHF2, -OCDF2, -OCF3,

[0210] In an optional embodiment of the present invention, the above-mentioned R 6-1 Each is independently -OCHF2, -OCDF2, -OCF3,

[0211] In an optional embodiment of the present invention, the above-mentioned R 6-1 They are independently -OCHF2, -OCF3,

[0212] In an optional embodiment of the present invention, the above-mentioned R 6c They can be F, Cl, OH or NH2, respectively.

[0213] In an optional embodiment of the present invention, the above-mentioned R 6-1 They are independently -OCHF2 or -OCF3.

[0214] 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. 6a Replacement C 3-6 Cycloalkyl, with 1, 2, 3 or 4 R 6a Substituted 4-8 membered heterocyclic alkyl groups.

[0215] In an optional embodiment of the present invention, the above-mentioned 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.

[0216] In an optional embodiment of the present invention, the above-mentioned R 6-1 Each of the following groups is independently cyclopropyl, cyclobutyl, or azacyclobutyl, wherein the cyclopropyl, cyclobutyl, and azacyclobutyl groups are each independently bound by 1, 2, 3, or 4 R groups. 6a replace.

[0217] In an optional embodiment of the present invention, the above-mentioned R 6a Each is independently -CH3 or -CH2-OCH3, wherein -CH3 and -CH2-OCH3 are independently replaced by 1, 2, 3 or 4 Rs respectively.

[0218] In an optional embodiment of the present invention, the above-mentioned R 6a Each is independently replaced by one R.

[0219] In an optional embodiment of the present invention, each of the above R is independently H, F, Cl, OH, NH2 or CN.

[0220] 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.

[0221] In an optional embodiment of the present invention, the above-mentioned R 6-1 Each independently

[0222] In an optional embodiment of the present invention, the above-mentioned R 6-1 Each independently

[0223] 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 -L2-C 3-6 Cycloalkyl, with 1, 2, 3 or 4 R 6b Substituted -L2-4-8-membered heterocyclic alkyl group, with 1, 2, 3 or 4 R 6b Replacement -L2-C 1-3 Alkyl-C 3-6 Cycloalkyl groups or those with 1, 2, 3 or 4 R groups 6b Replacement -L2-C 1-3 Alkyl-4-8-membered heterocyclic alkyl.

[0224] In an optional embodiment of the present invention, the above-mentioned R 6-1 They are independently -L2-cyclopropyl, -L2-cyclobutyl, -L2-azacyclobutyl, -L2-cyclopentyl, -L2-oxacyclohexyl, -L2-oxacyclopentyl, -L2-tetrahydrofuranyl, -L2-tetrahydropyranyl, -L2-CH2-cyclopropyl, -L2-CH2-cyclobutyl, -L2-CH2-cyclopentyl, -L2-CH2-oxacyclopentyl, -L2-CH2-tetrahydrofuranyl, and -L2-CH2-tetrahydropyranyl. The -L2-cyclopropyl, -L2-cyclobutyl, -L2-azacyclobutyl, -L2-cyclopentyl, -L2-oxacyclopentyl, -L2-tetrahydrofuranyl, -L2-tetrahydropyranyl, -L2-CH2-cyclopropyl, -L2-CH2-cyclobutyl, -L2-CH2-cyclopentyl, -L2-CH2-oxacyclopentyl, -L2-CH2-tetrahydrofuranyl, and -L2-CH2-tetrahydropyranyl groups are each independently surrounded by 1, 2, 3, or 4 R groups. 6b replace.

[0225] In an optional embodiment of the present invention, the above-mentioned R 6-1Each of the following is independently -L2-cyclopropyl, -L2-cyclobutyl, -L2-azacyclobutyl, -L2-cyclopentyl, -L2-oxacyclopentyl, -L2-tetrahydrofuranyl, -L2-tetrahydropyranyl, -L2-CH2-cyclopropyl, -L2-CH2-cyclobutyl, -L2-CH2-cyclopentyl, -L2-CH2-oxacyclopentyl, -L2-CH2-tetrahydrofuranyl, -L2-CH2-tetrahydropyranyl, wherein -L2 -Cyclopropyl, -L2-cyclobutyl, -L2-azacyclobutyl, -L2-cyclopentyl, -L2-oxacyclopentyl, -L2-tetrahydrofuranyl, -L2-tetrahydropyranyl, -L2-CH2-cyclopropyl, -L2-CH2-cyclobutyl, -L2-CH2-cyclopentyl, -L2-CH2-oxacyclopentyl, -L2-CH2-tetrahydrofuranyl, and -L2-CH2-tetrahydropyranyl are each independently atomized by 1, 2, 3, or 4 R groups. 6b replace.

[0226] In an optional embodiment of the present invention, the above-mentioned R 6-1 Each of the following groups is independently -L2-cyclopropyl, -L2-cyclobutyl, -L2-azacyclobutyl, -L2-CH2-cyclopropyl, or -L2-CH2-cyclobutyl, wherein the -L2-cyclopropyl, -L2-cyclobutyl, -L2-azacyclobutyl, -L2-CH2-cyclopropyl, and -L2-CH2-cyclobutyl groups are each independently surrounded by 1, 2, 3, or 4 R groups. 6b replace.

[0227] 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 -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.

[0228] In an optional embodiment of the present invention, the above-mentioned R 6-1 Each independently of one R 6b Replacement -L2-C 3-6 Cycloalkyl.

[0229] In an optional embodiment of the present invention, the above-mentioned R 6-1 Each independently of one R 6b Substituted -L2-4-8-membered heterocyclic alkyl groups.

[0230] In an optional embodiment of the present invention, each of the above-mentioned L2s is independently -O-, -N(R) 2L )-、-N(R 2L -C(=O)-, -S-, -S(=O)-, -S(=O)2- or -C(=O)-.

[0231] In an optional embodiment of the present invention, each of the above-mentioned L2s is independently -O-, -N(R) 2L )-、-S-、-S(=O)-、-S(=O)2- or -C(=O)-.

[0232] In an optional embodiment of the present invention, the above-mentioned R 2L It can be H or CH3.

[0233] In an optional embodiment of the present invention, each of the above L2 is independently -O-, -NH-, -NH-C(=O)-, -S-, -S(=O)-, -S(=O)2- or -C(=O)-.

[0234] In an optional embodiment of the present invention, each of the above-mentioned L2 is independently -O-, -NH-, -S-, -S(=O)-, -S(=O)2- or -C(=O)-.

[0235] In an optional embodiment of the present invention, each of the above-mentioned L2 is independently -O- or -NH-C(=O)-.

[0236] In an optional embodiment of the present invention, each of the above L2 is independently -O-.

[0237] In an optional embodiment of the present invention, the above-mentioned R 6-1 Each R is independent 6-1 Each independently The Each independently is assigned to 1, 2, 3, or 4 R's. 6b replace.

[0238] 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.

[0239] 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.

[0240] In an optional embodiment of the present invention, the above-mentioned R 6-1 Each independently

[0241] 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.

[0242] 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

[0243] 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.

[0244] 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.

[0245] In an optional embodiment of the present invention, the above-mentioned R 6b They can be H, F, OH, NH2 or CH3, respectively.

[0246] In an optional embodiment of the present invention, the above-mentioned R 6-1 Each independently In an optional embodiment of the present invention, the above-mentioned R 6-1 Each independently

[0247] In an optional embodiment of the present invention, the above-mentioned R 6-1 Each independently

[0248] In an optional embodiment of the present invention, the above-mentioned R 6-1 Each independently

[0249] In an optional embodiment of the present invention, the above-mentioned R 6-1 They are independently -OCH3, -OCHF2, -OCDF2, -OCF3,

[0250] In an optional embodiment of the present invention, the above-mentioned R 6-1Each is independently -OCHF2, -OCDF2, -OCF3, In an optional embodiment of the present invention, the above-mentioned R 6-1 Each is independently -OCHF2, -OCDF2, -OCF3,

[0251]

[0252] In an optional embodiment of the present invention, the above-mentioned R 6-1 They are independently -OCHF2, -OCF3,

[0253] In an optional embodiment of the present invention, the above-mentioned R 6-1 They are independently -OCHF2, -OCF3,

[0254] In an optional embodiment of the present invention, the above-mentioned R 6-1 They are independently -OCHF2, -OCF3,

[0255] In an optional embodiment of the present invention, the above-mentioned 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.

[0256] In an optional embodiment of the present invention, the above-mentioned R 6-2 They can be H or oxo (=O) independently, respectively.

[0257] In an optional embodiment of the present invention, the above-mentioned R 6-2 H is used. In an optional embodiment of the present invention, the above compound has the following structure:

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265] In a second aspect, the present invention provides a pharmaceutical composition comprising: a compound as described in the first aspect of the present invention, a tautomer, a stereoisomer, a pharmaceutically acceptable salt or prodrug thereof; and a pharmaceutically acceptable excipient.

[0266] A third aspect of the present invention provides the use of compounds, tautomers, stereoisomers, pharmaceutically acceptable salts or prodrugs as described in the first aspect of the present invention, and pharmaceutical compositions as described in the second aspect, in the preparation of medicaments for the treatment and / or prevention of diseases associated with VAV1.

[0267] In an optional embodiment of the present invention, the aforementioned VAV1-related diseases include cancer and autoimmune diseases.

[0268] In an optional embodiment of the present invention, the aforementioned VAV1-related diseases include, but are not limited to, systemic lupus erythematosus, myasthenia gravis, periodontitis, type I diabetes, rheumatoid arthritis, multiple sclerosis, colitis, inflammatory bowel disease, autoimmune hepatitis, or psoriasis.

[0269] In a fourth aspect, the present invention provides a method for treating or preventing VAV1-related diseases, comprising administering to a patient an effective amount of at least one of the compound of formula (I) of the first aspect, its tautomers, stereoisomers, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition of the second aspect.

[0270] In an optional embodiment of the invention, the patient is a mammal, preferably a human.

[0271] In an optional embodiment of the present invention, the VAV1-related diseases are cancer and autoimmune diseases.

[0272] In an optional embodiment of the present invention, the VAV1-related diseases mentioned above are systemic lupus erythematosus, myasthenia gravis, periodontitis, type I diabetes, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, autoimmune hepatitis, and psoriasis.

[0273] Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.

[0274] Terms and definitions

[0275] Unless otherwise stated, the terms and definitions used in this application, including those set forth in the specification and claims, are as follows.

[0276] Those skilled in the art will understand that, according to the conventions used in the art, in the structural formula of this application, Used to describe chemical bonds, which are points where a portion or a substituent is connected to a core or skeletal structure.

[0277] Unless otherwise specified, the term "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0278] Unless otherwise specified, the term "pharmaceutically acceptable salt" means a pharmaceutically acceptable non-toxic salt of an acid or base, including salts of inorganic acids and bases, and salts of organic acids and bases.

[0279] In addition to pharmaceutically acceptable salts, the present invention also contemplates other salts. These may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts, or may be used for the identification, characterization, or purification of the compounds of the present invention.

[0280] Unless otherwise specified, the term "pharmaceutical composition" means a mixture of one or more compounds described in this text or their physiologically / pharmaceutical acceptable salts or prodrugs with other chemical components, such as physiologically / pharmaceutical acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compound to a living organism.

[0281] Unless otherwise specified, the term "excipient" refers to a pharmaceutically acceptable inert ingredient. Examples of the term "excipient" include, without limitation, binders, disintegrants, lubricants, flow aids, stabilizers, fillers, and diluents. Excipients enhance the handling properties of pharmaceutical formulations, i.e., by increasing flowability and / or adhesion, making the formulation more suitable for direct compression.

[0282] Unless otherwise specified, the term "prodrug" refers to a compound of the present invention that can be converted into a biologically active form under physiological conditions or by solvation. The prodrugs of the present invention are prepared by modifying functional groups in the compound; such modification can be performed by conventional methods or removed in vivo to obtain the parent compound. Prodrugs comprise compounds formed by attaching a hydroxyl or amino group to any group within the compound of the present invention. When a prodrug of the compound of the present invention is administered to a mammalian individual, the prodrug is cleaved to form free hydroxyl and free amino groups, respectively.

[0283] Unless otherwise specified, the term "stereoisomer" refers to isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, non-corresponding isomers, and conformational isomers.

[0284] Depending on the choice of raw materials and methods, the compounds of the present invention may exist as one or a mixture of possible isomers, for example as purely optical isomers, or as mixtures of isomers, such as racemic and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to the chiral center (or multiple chiral centers) in the molecule. The prefixes D and L or (+) and (–) are symbols used to specify the plane-polarized rotation of light induced by the compound, where (–) or L indicates that the compound is levorotatory. Compounds with the prefix (+) or D are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be called enantiomers, and mixtures of said isomers are generally referred to as mixtures of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or method. Many geometric isomers of alkenes, C=N double bonds, etc., can also exist in the compounds described herein, and all such stable isomers are considered in this invention. When the compounds described herein contain an alkene double bond, unless otherwise stated, such double bond includes E and Z geometric isomers. If the compound contains a disubstituted cycloalkyl group, the substituent of the cycloalkyl group may be in cis or trans (cis- or trans-) configuration.

[0285] When the bonds of the chiral carbon in the formulas of this invention are depicted as straight lines, it should be understood that both the (R) and (S) configurations of the chiral carbon and the resulting enantiomerically pure compounds and mixtures thereof are included within the scope of the general formula. The illustration of racemic or enantiomerically pure compounds in this document is derived from Maehr, J. Chem. Ed. 1985, 62:114-120. Unless otherwise stated, wedge-shaped and dashed bonds represent the absolute configuration of a stereocenter.

[0286] Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral formulations, or resolved using conventional techniques. Compounds of the present invention containing asymmetrically substituted carbon atoms can be separated in either an optically active or racemic form. Resolution of racemic mixtures of compounds can be performed by any of many methods known in the art. Exemplary methods include fractional recrystallization using a chiral resolving acid, which is an optically active salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or various optically active camphorsulfonic acids such as the D and L forms of β-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure α-methylbenzylamine (e.g., S and R forms or diastereoisomeric forms), 2-phenylglycine, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc. Resolution of racemic mixtures can also be achieved by elution onto a chromatographic column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). High-performance liquid chromatography (HPLC) or supercritical fluid chromatography (SFC) can be used. The specific method, elution conditions, and column selection can be chosen by those skilled in the art based on the structure of the compound and experimental results. Furthermore, any enantiomer or diastereomeric form of the compound described in this invention can be obtained through stereoorganic synthesis using optically pure starting materials or reagents with known configurations.

[0287] Unless otherwise specified, the term "tautomer" refers to a functional group isomer resulting from the rapid movement of an atom between two positions in a molecule. The compounds of this invention can exhibit tautomerism. Tautomeric compounds can exist in two or more interconvertible forms. Proton-transfer tautomers arise from the migration of covalently bonded hydrogen atoms between two atoms. Tautomers generally exist in equilibrium form, and attempts to isolate a single tautomer usually produce a mixture whose physicochemical properties are consistent with those of the mixture of compounds. The equilibrium position depends on the intramolecular chemical characteristics. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the ketone form is dominant; while in phenols, the enol form is dominant. This invention encompasses all tautomeric forms of compounds. For example... They can be transformed into each other.

[0288] Unless otherwise specified, use wedge-shaped solid line keys. and wedge-shaped dashed key The absolute configuration of the center of a solid is represented by a straight solid line key. and straight dashed key The relative configuration of the center of a solid.

[0289] The compounds of the present invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes such as deuterium (2H), tritium (3H), iodine-125 (125I), or C-14 (14C). All variations in the isotopic composition of the compounds of the present invention, regardless of radioactivity, are included within the scope of the present invention.

[0290] For pharmaceuticals or pharmacologically active agents, the term "effective amount" or "therapeutic effective amount" refers to a sufficient quantity of a drug or agent that is non-toxic but achieves the desired effect. For the oral dosage forms of this invention, the "effective amount" of one active substance in the composition refers to the quantity required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. A suitable effective amount in any given case can be determined by a person skilled in the art through routine testing.

[0291] Unless otherwise specified, the terms “active ingredient,” “therapeutic agent,” “active substance,” or “active agent” refer to a chemical entity that can effectively treat a target disorder, disease, or symptom.

[0292] Unless otherwise specified, the term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, including deuterium and hydrogen variants, provided that the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =O), it can be expressed as the oxidation of atoms such as carbon, nitrogen, and sulfur, including but not limited to C(=O), S(=O), S(=O)2, or N(=O).

[0293] Unless otherwise specified, the terms “optional” or “optionally” refer to events or conditions described below that may but are not required to occur, and the description includes both cases where said events or conditions occur and cases where said events or conditions do not occur.

[0294] The term "optionally substituted" means that it may or may not be substituted, unless otherwise specified, and the type and number of substituents may be arbitrary on the basis of chemical feasibility.

[0295] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is substituted by 0-2 Rs, the group can optionally be substituted by 0, 1, or at most two Rs, and the R in each case has independent options. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0296] Unless otherwise specified, the term "C" 1-6 "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C 1-6 Alkyl groups include C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-4 C6 and C5 alkyl groups, etc.; they can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). 1-6 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc.

[0297] Unless otherwise specified, the term "C" 1-3 "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C 1-3 Alkyl groups include C 1-2 and C 2-3 Alkyl groups, etc.; they can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). C 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), methylene (-CH2-), ethyl (Et), propyl (including n-propyl and isopropyl), etc.

[0298] The term "halogenated" is used interchangeably with the term "halogenated" when used alone or as part of other substituents.

[0299] Unless otherwise specified, "halogenated alkyl" or "halogen-substituted alkyl" means a saturated aliphatic hydrocarbon group comprising a specific number of carbon atoms, branched and straight-chained and substituted with one or more halogens.

[0300] Unless otherwise specified, "C 2-6 "Alkenyl" is used to denote a hydrocarbon group consisting of 2 to 6 carbon atoms, either straight-chain or branched, containing at least one carbon-carbon double bond. The carbon-carbon double bond can be located at any position within the group. The C... 2-6 Alkenes include C 2-4 C 2-3 C4, C3, and C2 alkenyl groups, etc.; they can be monovalent, divalent, or polyvalent. 2-6 Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, etc.

[0301] Unless otherwise specified, "C 2-6"Alkyne" is used to denote a straight-chain or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon triple bond, which can be located at any position within the group. 2-6 Alkyne groups include C 2-4 C 2-3 C4, C3, and C2 alkynyl groups, etc. They can be monovalent, divalent, or polyvalent. 2-6 Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, and pentyynyl.

[0302] Unless otherwise specified, the term "C" 1-6 "Alkoxy" refers to alkyl groups containing 1 to 6 carbon atoms that are attached to the rest of the molecule by an oxygen atom. The C 1-6 Alkoxy groups include C 1-4 C 1-3 C 1-2 C 2-6 C 2-4 C6, C5, C4, and C3 alkoxy groups, etc. 1-6 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexoxy, etc.

[0303] 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.

[0304] 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.

[0305] 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 C 3-10 C 3-8 C 3-6 C 3-5 C 4-8 C 4-6 C 4-5 C 5-8 Or C 5-6 Cycloalkyl groups, etc.; they can be monovalent, divalent, or polyvalent. C 3-8 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.

[0306] Unless otherwise specified, the term "C" 3-8 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 8 carbon atoms. 3-8 Cycloalkyl groups include C 3-6 C 3-5 C 4-8 C 4-6 C 4-5 C 5-8 Or C 5-6 Cycloalkyl groups, etc.; they can be monovalent, divalent, or polyvalent. C 3-8 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.

[0307] Unless otherwise specified, the term "C" 3-6 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, wherein the C 3-6 Cycloalkyl groups include C 3-5 C 4-5 and C 5-6 Cycloalkyl groups, etc.; they can be monovalent, divalent, or polyvalent. C 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0308] Unless otherwise specified, Cn-n+m or Cn-Cn+m includes any specific case of n to n+m carbons, such as C 1-12 Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 C 11 and C 12 It also includes any range from n to n+m, such as C 1-12 Including C 1-3 C 1-6 C 1-9 C 3-6 C 3-9 C3-12 C 6-9 C 6-12 and C 9-12 Similarly, n-membered to n+m-membered rings represent the number of atoms in the ring from n to n+m. For example, 3-12-membered rings include 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, and 12-membered rings, and also any range from n to n+m. For example, 3-12-membered rings include 3-6-membered, 3-9-membered, 5-6-membered, 5-7-membered, 6-7-membered, 6-8-membered, and 6-10-membered rings, etc.

[0309] 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".

[0310] 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".

[0311] When used alone or as part of other substituents, the term "heteroaromatic ring" refers to a monocyclic or polycyclic carbon ring in which at least one ring atom is a heteroatom independently selected from oxygen, sulfur, and nitrogen, and the remaining ring atoms are carbon atoms, wherein at least one ring is an aromatic ring. The group can be a carbon group or a heteroatom group (i.e., it can be C-linked or N-linked, whichever is possible). When one of the rings is a non-aromatic ring, the group can be linked by an aromatic ring or by a non-aromatic ring. Examples of heteroaromatic groups include, but are not limited to: imidazolyl, acridinel, carbazolyl, cenolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furanyl, thiophenyl, benzothiophenyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridinyl, pyrimidinel, pyrroleyl, N-methylpyrroleyl, and tetrahydroquinoline. The term “heteroaromatic ring” can be used interchangeably with the terms “heteroaromatic ring”, “heteroaryl”, or “heteroaromatic ring group”.

[0312] Unless otherwise specified, the term "5-6 membered heterocyclic alkenyl" alone or in combination with other terms refers to an unsaturated or partially unsaturated cyclic group consisting of 5 to 6 ring atoms comprising at least one carbon-carbon double bond, but not an aromatic ring, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen, and sulfur heteroatoms may optionally be oxidized (i.e., C(=O), NO, and S(O)p, where p is 1 or 2). Furthermore, with respect to the "5-6 membered heterocyclic alkenyl," the heteroatom may occupy the connection position between the heterocyclic alkenyl group and the rest of the molecule. The 5-6 membered heterocyclic alkenyl includes 5-membered and 6-membered heterocyclic alkenyl groups, etc.

[0313] Unless otherwise specified, the terms "5-6-membered heteroaryl" and "5-6-membered heteroaryl" are used interchangeably in this invention. The term "5-6-membered heteroaryl" refers to a monocyclic group with a conjugated π-electron system consisting of 5 to 6 ring atoms, where 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)p, where p is 1 or 2). The 5-6-membered heteroaryl can be attached to the rest of the molecule via heteroatoms or carbon atoms. The 5-6-membered heteroaryl includes both 5-membered and 6-membered heteroaryl groups. Examples of the 5-6 membered heteroaryl groups include, but are not limited to, pyrrole (including N-pyrrole, 2-pyrrole, and 3-pyrrole), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl), imidazole (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5-oxazolyl), and triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl). (and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isooxazolyl, 4-isooxazolyl and 5-isooxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).

[0314] Unless otherwise specified, the terms "halogen" or "halogen" refer to fluorine, chlorine, bromine, and iodine.

[0315] Furthermore, it should be noted that, unless otherwise explicitly stated, the descriptive phrase "...independently" used in this invention should be interpreted broadly, meaning that the described individuals are independent of each other and can independently be the same or different specific groups. More specifically, the descriptive phrase "...independently" can mean either that the specific options expressed by the same symbols in different groups do not affect each other, or that the specific options expressed by the same symbols in the same group do not affect each other.

[0316] Unless otherwise specified, the term "patient" means any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, with human being being the most preferred.

[0317] Unless otherwise specified, the term “therapeutic effective amount” means the amount of an active compound or drug that researchers, veterinarians, physicians or other clinicians are looking for in a tissue, system, animal, individual or human to elicit a biological or medical response, including one or more of the following: (1) prevention of disease: for example, prevention of disease, disorder or condition in an individual who is susceptible to disease, disorder or condition but has not yet experienced or developed the pathology or symptoms of the disease. (2) suppression of disease: for example, suppression of disease, disorder or condition in an individual who is experiencing or developing the pathology or symptoms of the disease (i.e., preventing the further development of the pathology and / or symptoms). (3) relief of disease: for example, relief of disease, disorder or condition in an individual who is experiencing or developing the pathology or symptoms of the disease (i.e., reversal of the pathology and / or symptoms).

[0318] The term "treatment" and other similar synonyms used in this article include the following meanings:

[0319] (i) To prevent the occurrence of disease or condition in mammals, especially when such mammals are susceptible to the disease or condition but have not yet been diagnosed with it;

[0320] (ii) To suppress a disease or symptom, that is, to curb its development;

[0321] (iii) To alleviate a disease or symptom, that is, to cause the condition of the disease or symptom to subside; or

[0322] (iv) To alleviate the symptoms caused by the disease or condition.

[0323] The abbreviations for this invention are defined as follows:

[0324] M: Molar concentration, such as 1M hydrochloric acid, which represents a 1 mol / L hydrochloric acid solution.

[0325] N: Equivalent concentration, for example, 2N hydrochloric acid represents a 2 mol / L hydrochloric acid solution.

[0326] DMSO: Dimethyl sulfoxide

[0327] Bpin: Pinaryl borate group

[0328] Beneficial effects

[0329] Compared to the clinically used compound MRT-6160, the present invention has at least one of the following technical effects:

[0330] 1) The compounds of this invention can induce direct binding between VAV1 and CRBN in a dose-dependent manner;

[0331] 2) The compounds of the present invention exhibit excellent degradation effects on VAV1 protein in a dose-dependent manner; the DC50 values ​​of the compounds of the present invention are less than 10 nM, and some are even less than 5 nM; the Dmax values ​​can reach more than 95%, and some even reach more than 98%, all of which are significantly better than the existing clinical compound MRT-6160.

[0332] 3) In the CD3 / CD28-induced Jurkat cell / T cell activation model, the compound of the present invention can significantly inhibit the production of IL-2, and the inhibitory function is positively correlated with the dose, which is superior to the clinical compound MRT-6160;

[0333] 4) The compound of the present invention has good pharmacokinetic properties, and is significantly superior to compound MRT-6160 in various pharmacokinetic parameters, and has good drug-like properties;

[0334] 5) The compound of the present invention has a significantly better plasma protein binding rate than compound MRT-6160, which is a significant advantage;

[0335] 6) 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, and exhibited good oral absorption characteristics and good drug-like properties.

[0336] 7) In a mouse model of inflammatory bowel disease, the test compounds of this invention showed significant relief of disease progression in an adoptive naive T cell-induced mouse enteritis model;

[0337] 8) The compounds of this invention exhibit good safety and low hepatotoxicity. Detailed Implementation

[0338] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that the following description is merely the most preferred embodiment of the present invention and should not be considered as a limitation on the scope of protection of the present invention. Based on a full understanding of the present invention, experimental methods in the following embodiments that do not specify specific conditions are generally performed under conventional conditions or as recommended by the manufacturer. Those skilled in the art can make non-essential modifications to the technical solutions of the present invention, and such modifications should be considered to be included within the scope of protection of the present invention.

[0339] Preparation of intermediate A

[0340] 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)piperidin-2,6-dione

[0341]

[0342] The synthetic route for intermediate A is shown below:

[0343]

[0344] Step 1: 2-(3-bromo-2-chlorophenyl)acetonitrile (A2)

[0345] 3-Bromo-2-chlorobenzyl bromide (A1) (9.0 g, 31.65 mmol) was placed in a reaction flask, and acetonitrile (100 mL) was added. Trimethylcyanosilane (6.3 g, 63.3 mmol) and potassium carbonate (13 g, 100 mmol) were added under ice bath conditions. After the addition was complete, the reaction solution was reacted at 80 °C for 16 h. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with ethyl acetate (500 mL), washed with saturated sodium chloride aqueous solution (500 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 10:1) to give intermediate 2-(3-bromo-2-chlorophenyl)acetonitrile (A2).

[0346] LC-MS, M / Z (ESI): 230.1 [M+H] + .

[0347] Step 2: Methyl 4-(3-bromo-2-chlorophenyl)-4-cyanobutyrate (A3)

[0348] 2-(3-bromo-2-chlorophenyl)acetonitrile (5.0 g, 21.74 mmol) (A2) was placed in a reaction flask, and methyl acrylate (3.74 g, 43.5 mmol) and tetrahydrofuran (100 mL) were added. Sodium methoxide (110 mg, 2 mmol) was then added under ice bath conditions. After the addition was complete, the reaction mixture was allowed to react at room temperature for 2 h. After the reaction was complete, the reaction mixture was diluted with ethyl acetate (500 mL), washed with sodium chloride aqueous solution (500 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 5:1) to give intermediate methyl 4-(3-bromo-2-chlorophenyl)-4-cyanobutyrate (compound A3) (5.95 g, yield: 87%).

[0349] LC-MS, M / Z (ESI): 316.2 [M+H] + .

[0350] Step 3: 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (A4)

[0351] Methyl 4-(3-bromo-2-chlorophenyl)-4-cyanobutyrate (intermediate A3) (5.9 g, 18.7 mmol) was dissolved in acetic acid (100 mL). 0.5 mL of concentrated sulfuric acid was added at 20 °C, and the reaction mixture was allowed to react at 90 °C for 6 hours. After the reaction was complete, 2.0 g of sodium acetate was added at 20 °C, and the mixture was stirred at room temperature for 30 min. The solvent was removed by vacuum distillation, followed by dilution with ethyl acetate (500 mL × 1), and then washed with saturated sodium chloride aqueous solution (500 mL × 2), saturated sodium bicarbonate aqueous solution (500 mL × 1), and saturated sodium chloride aqueous solution (500 mL × 1), respectively. The organic phase was then collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:1) to give compound 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (intermediate A4).

[0352] LC-MS, M / Z (ESI): 302.1 [M+H] + .

[0353] Step 4: 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)piperidine-2,6-dione

[0354]

[0355] Compound 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (intermediate A4) (4.6 g, 15.2 mmol) was placed in a reaction flask, followed by the addition of pinacol diboron ester (7.6 g, 30 mmol), potassium acetate (4.5 g, 45.6 mmol), 1,1'-bis(di-phenylphosphino)ferrocene palladium chloride (0.3 g, 0.45 mmol), and 1,4-dioxane (70 mL). After the addition was complete, the reaction mixture was stirred at 100 °C for 8 hours under nitrogen protection. The reaction solution was cooled to room temperature, diluted with ethyl acetate (500 mL), washed with saturated sodium chloride aqueous solution (500 mL × 3), and then the organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 1:1) to give compound 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)piperidine-2,6-dione (intermediate A).

[0356] LC-MS, M / Z (ESI): 350.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ10.90(s,1H),7.51(dd,1H),7.41(dd,1H),7.32(d,1H),4.25(dd, 1H),2.83–2.70(m,1H),2.56–2.50(m,1H),2.29(qd,1H),1.97–1.92(m,1H),1.30(s,12H).

[0357] Preparation of intermediate B1

[0358] 1-(4-Bromophenyl)-3-(difluoromethoxy)pyrazine-2(1H)-one (Intermediate B1)

[0359]

[0360] The synthetic route for intermediate B1 is shown below:

[0361]

[0362] Step 1: Synthesis of 1-(4-bromophenyl)-3-chloro-pyrazine-2(1H)-one (intermediate B1-3)

[0363] To a solution of 3-chloro-pyrazin-2(1H)-one (B1-1) (2.90 g, 22.2 mmol) and (4-bromophenyl)borondiol (B1-2) (5.35 g, 26.66 mmol) in acetonitrile (120 mL), pyridine (3.58 mL, 44.4 mmol) and copper acetate (4.84 g, 26.7 mmol) were added. The mixture was stirred in air at 30 °C for 18 hours. The reaction was confirmed to be complete by LC-MS. The reaction mixture was also diluted with 200 mL of water, extracted with ethyl acetate (100 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate. The organic layer was concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 100:0-90:10) to give 1-(4-bromophenyl)-3-chloro-pyrazin-2(1H)-one (intermediate B1-3).

[0364] LC-MS, M / Z (ESI): 285.0 [M+H] +

[0365] Step 2: Synthesis of 1-(4-bromophenyl)-3-hydroxypyrazine-2(1H)-one (intermediate B1-4)

[0366] A solution of 3.50 g (12.3 mmol) of 1-(4-bromophenyl)-3-chloro-pyrazin-2(1H)-one (intermediate B1-3) in acetic acid (50 mL) was stirred at 130 °C for 18 hours under nitrogen. The reaction was confirmed to be complete by LC-MS. The reaction solution was then directly concentrated to give 1-(4-bromophenyl)-3-hydroxy-pyrazin-2(1H)-one (intermediate B1-4).

[0367] LC-MS, M / Z (ESI): 267.1 [M+H] +

[0368] Step 3: Synthesis of 1-(4-bromophenyl)-3-(difluoromethoxy)pyrazine-2(1H)-one (intermediate B1)

[0369]

[0370] Sodium carbonate (3.97 g, 37.4 mmol) was added to a DMF (30 mL) solution of 1-(4-bromophenyl)-3-hydroxypyrazine-2(1H)-one (intermediate B1-4) (2.00 g, 7.49 mmol) and ethyl 2-bromo-2,2-difluoroacetate (1.82 g, 8.99 mmol). The mixture was stirred at 100 °C under nitrogen for 2 hours. The reaction was confirmed to be complete by LC-MS. The reaction solution was diluted with water (100 mL), extracted with ethyl acetate (50 mL × 3), and the combined organic phases were washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The organic layer was concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 100:0-75:25, gradient elution) followed by preparative HPLC (Xtimate C18, 21.2*250mm, 5μm; 10mM FA-ACN; 32-62; 60mL / min) to obtain 1-(4-bromophenyl)-3-(difluoromethoxy)pyrazin-2(1H)-one (intermediate B1).

[0371] LC-MS, M / Z (ESI): 317.0 [M+H] +

[0372] 1 ¹H NMR (400MHz, 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

[0373] 3-(2-chloro-4'-{[4-(cyclopropoxy)pyrimidin-2-yl]oxy}[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0374]

[0375] The synthetic route for compound 1 is as follows:

[0376]

[0377] Step 1: 4-(cyclopropoxy)-2-(methylthio)pyrimidine (compounds 1-3)

[0378] At room temperature, 4-chloro-2-(methylthio)pyrimidine (1-1) (500 mg, 3.11 mmol) was dissolved in N,N-dimethylformamide (5 mL), followed by the addition of cyclopropanol (1-2) (362 mg, 6.23 mmol) and cesium carbonate (2.03 g, 6.23 mmol). The reaction mixture was reacted at 80 °C for 12 hours under nitrogen protection. After the reaction was complete, the reaction mixture was slowly poured into water (10 mL), and then extracted with dichloromethane (3 × 10 mL). The organic phases were combined and washed successively with saturated sodium bicarbonate solution (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated by filtration. The crude product was purified by column chromatography (PE:EA(V / V) = 100:1 to 1:1) to give compound 4-(cyclopropoxy)-2-(methylthio)pyrimidine (compound 1-3).

[0379] LC / MS (ESI) (m / z): 183.0 (M+H) + .

[0380] Step 2: 4-(cyclopropoxy)-2-(methanesulfonyl)pyrimidine (compounds 1-4)

[0381] 4-(cyclopropoxy)-2-(methylthio)pyrimidine (compounds 1-3) (180 mg, 0.990 mmol) was dissolved in anhydrous dichloromethane (5 mL) at 0 °C, followed by the addition of m-chloroperoxybenzoic acid (85%, 603 mg, 2.97 mmol) in portions. The reaction mixture was reacted at 25 °C under nitrogen for 12 hours. After the reaction was complete, the reaction mixture was slowly poured into a saturated sodium sulfite and saturated sodium bicarbonate mixture (20 mL), and then extracted with dichloromethane (3 × 10 mL). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated by filtration. The crude product was purified by column chromatography (PE:EA(V / V) = 100:1 to 1:1) to give compounds 4-(cyclopropoxy)-2-(methanesulfonyl)pyrimidine (compounds 1-4).

[0382] LC / MS (ESI) (m / z): 215.0 (M+H) + .

[0383] Step 3: 4-(cyclopropoxy)-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenoxy]pyrimidine (compounds 1-6)

[0384] At room temperature, 4-(cyclopropoxy)-2-(methanesulfonyl)pyrimidine (compounds 1-4) (170 mg, 0.790 mmol) was dissolved in acetonitrile (2 mL), followed by the addition of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenol (compounds 1-5) (192 mg, 0.870 mmol) and potassium carbonate (165 mg, 1.19 mmol). The reaction mixture was reacted at 60 °C for 12 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water (10 mL) and then extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (PE:EA(V / V) = 100:1 to 1:1) to give compounds 4-(cyclopropoxy)-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenoxy]pyrimidine (compounds 1-6).

[0385] LC / MS (ESI) (m / z): 355. (M+H) + ;

[0386] Step 4: 3-(2-chloro-4'-{[4-(cyclopropoxy)pyrimidin-2-yl]oxy}[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (Compound 1)

[0387]

[0388] At room temperature, 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (intermediate A) (80.0 mg, 0.260 mmol) was dissolved in 1,4-dioxane / water (1 mL / 0.2 mL), and then 4-(cyclopropoxy)-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenoxy]pyrimidine (compounds 1-6) (112 mg, 0.320 mmol), sodium carbonate (70.0 mg, 0.660 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (II) (19.0 mg, 0.026 mmol) were reacted at 100 °C for 12 hours under nitrogen protection. After the reaction was complete, the reaction solution was concentrated under reduced pressure, the residue was diluted with water (10 mL), and then extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (PE:EA(V / V) = 100:1 to 1:1) to give compound 4-(cyclopropoxy)-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenoxy]pyrimidine (compound 1).

[0389] LC / MS (ESI) (m / z): 450.1 (M+H) + ;

[0390] 1 H NMR(400MHz,DMSO-d6)δ10.90(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,1 H),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).

[0391] Example 2: Preparation of Compound 2

[0392] 3-(2-chloro-4'-(3-(difluoromethoxy)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (compound 2)

[0393]

[0394] The synthetic route for compound 2 is shown below:

[0395]

[0396] Step 1: 2-Chloro-3-(difluoromethoxy)pyridine (compound 2-2)

[0397] 2-Chloropyridin-3-ol (2-1) (2.0 g, 15.4 mmol) was placed in a reaction flask, and 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 conditions. The reaction mixture 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 mixture was stirred at 100 °C for another 2 h. After completion, the reaction solution was diluted with ethyl acetate (500 mL), washed with saturated sodium chloride aqueous solution (500 mL × 3), and then the organic phase was taken, dried with anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 10:1) to give compound 2-chloro-3-(difluoromethoxy)pyridine (2-2).

[0398] LC-MS, M / Z (ESI): 180.1 [M+H] + .

[0399] Step 2: 3-(difluoromethoxy)pyridine-2-ol (compounds 2-3)

[0400] Intermediate 2-chloro-3-(difluoromethoxy)pyridine (2-2) (2.2 g, 12.2 mmol), potassium carbonate (8.43 g, 61 mmol), and acetyloxyoxime acid (2.75 g, 36.6 mmol) were dissolved in dimethyl sulfoxide (60 mL). The reaction mixture was stirred at 80 °C for 16 h under nitrogen protection. After the reaction was complete, the reaction mixture was diluted with ethyl acetate (500 mL), washed with saturated sodium chloride aqueous solution (500 mL × 3), and then the organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:1) to give compound 3-(difluoromethoxy)pyridine-2-ol (compound 2-3).

[0401] LC-MS, M / Z (ESI): 162.1 [M+H] + .

[0402] Step 3: 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 flask, 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), and then acetonitrile (10 mL). The reaction was carried out under nitrogen protection and microwaved at 100 °C for 1 h. After completion, the reaction solution was cooled to room temperature, diluted with ethyl acetate (300 mL), washed with saturated sodium chloride aqueous solution (300 mL × 3), dried with anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 1:1) to give compound 3-(difluoromethoxy)-1-(4-iodophenyl)pyridine-2(1H)-one (2-4).

[0403] LC-MS, M / Z (ESI): 364.0 [M+H] + .

[0404] Step 3: 3-(2-chloro-4'-(3-(difluoromethoxy)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (compound 2)

[0405]

[0406] Intermediate 3-(difluoromethoxy)-1-(4-iodophenyl)pyridin-2(1H)-one (2-4) (100 mg, 0.275 mmol) was placed in a reaction flask, followed by intermediate 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)piperidin-2,6-dione (intermediate A) (143 mg, 0.41 mmol), potassium phosphate (175 mg, 0.825 mmol), 1,1'-bis(di-phenylphosphino)ferrocene palladium chloride (22 mg, 0.03 mmol), and 1,4-dioxane (3 mL). The reaction solution was reacted at 100 °C for 8 hours. The reaction solution was then cooled to room temperature, diluted with ethyl acetate (100 mL), washed with saturated sodium chloride aqueous solution (100 mL × 3), and the organic phase was then collected, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 20:1) to give compound 3-(2-chloro-4'-(3-(difluoromethoxy)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (compound 2).

[0407] LC-MS, M / Z (ESI): 459.1 [M+H] + .

[0408] 1 ¹H NMR (400MHz, 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

[0409] 3-{2-chloro-4'-[3-(cyclopropoxy)-2-oxopyridin-1(2H)-yl][1,1'-biphenyl]-3-yl}piperidin-2,6-dione

[0410]

[0411] The synthetic route for compound 3 is as follows:

[0412]

[0413] Step 1: Synthesis of 3-(cyclopropoxy)-2-nitropyridine (compound 3-2)

[0414] At room temperature, 3-fluoro-2-nitropyridine (3-1) (1.00 g, 7.04 mmol) was dissolved in N,N-dimethylformamide (10 mL), followed by the addition of cesium carbonate (2.75 g, 8.45 mmol) and cyclopropanol (818 mg, 14.1 mmol). The reaction mixture was reacted at 100 °C for 3 hours under nitrogen protection. After the reaction was complete, the reaction mixture was cooled to room temperature and slowly poured into water (50 mL). The mixture was then extracted with ethyl acetate (3 × 30 mL). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated by filtration. The crude product was purified by column chromatography (PE:EA(V / V) = 100:1 to 1:1) to give compound 3-(cyclopropoxy)-2-nitropyridine (compound 3-2).

[0415] LC / MS (ESI) (m / z): 181.0 (M+H) + .

[0416] Step 2: Synthesis of 3-(cyclopropoxy)pyridine-2(1H)-one (compound 3-3)

[0417] 3-(cyclopropoxy)-2-nitropyridine (compound 3-2) (800 mg, 4.44 mmol) was dissolved in dimethyl sulfoxide (8 mL) at room temperature, followed by the addition of acetyloxyoxime acid (1.00 g, 13.3 mmol) and potassium carbonate (3.00 g, 22.2 mmol). The reaction mixture was reacted at 80 °C for 12 hours under nitrogen protection. After the reaction was complete, the reaction mixture was cooled to room temperature, diluted with water (40 mL), and extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous ammonium sulfate, and concentrated by filtration. The crude product was purified by column chromatography (DCM:MeOH (V / V) = 100:1 to 10:1) to give compound 3-(cyclopropoxy)pyridine-2(1H)-one (compound 3-3). LC / MS (ESI) (m / z): 152.0 (M+H) + .

[0418] Step 3: Synthesis of 1-(4-bromophenyl)-3-(cyclopropoxy)pyridine-2(1H)-one (compounds 3-4)

[0419] 3-(cyclopropoxy)pyridine-2(1H)-one (compound 3-3) (200 mg, 1.32 mmol) was dissolved in dimethyl sulfoxide (2 mL) at room temperature, followed by the addition of p-dibromobenzene (311 mg, 1.32 mmol), potassium carbonate (364 mg, 2.64 mmol), and cuprous iodide (25.1 mg, 0.132 mmol). The reaction mixture was reacted at 100 °C for 12 hours under nitrogen protection. After the reaction was complete, the reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated by filtration. The crude product was purified by column chromatography (PE:EA(V / V) = 100:1 to 1:1) to give compound 1-(4-bromophenyl)-3-(cyclopropoxy)pyridine-2(1H)-one (compound 3-4).

[0420] LC / MS (ESI) (m / z): 307.0 (M+H) + .

[0421] Step 4: 3-{2-chloro-4'-[3-(cyclopropoxy)-2-oxopyridin-1(2H)-yl][1,1'-biphenyl]-3-yl}piperidin-2,6-dione (compound 3)

[0422]

[0423] At room temperature, 1-(4-bromophenyl)-3-(cyclopropoxy)pyridine-2(1H)-one (compound 3-4) (100 mg, 0.326 mmol) was dissolved in 1,4-dioxane / water (1 mL / 0.1 mL), and then 3-[2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl]piperidine-2,6-dione (114 mg, 0.326 mmol), potassium phosphate (138 mg, 0.652 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (23.8 mg, 0.033 mmol) were added. The reaction mixture was reacted at 100 °C for 12 hours under nitrogen protection. After the reaction was complete, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was diluted with water (10 mL). Then, it was extracted with ethyl acetate (3 × 10 mL), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (PE:EA(V / V) = 100:1 to 1:1) to give compound 3-{2-chloro-4'-[3-(cyclopropoxy)-2-oxopyridin-1(2H)-yl][1,1'-biphenyl]-3-yl}piperidin-2,6-dione (compound 3).

[0424] LC / MS (ESI) (m / z): 449.0 (M+H) + ;

[0425] 1 H NMR(400MHz,DMSO-d6)δ10.92(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,1 H),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).

[0426] Example 4: Preparation of target compound 4

[0427] 3-(2-chloro-4'-(5-(difluoromethoxy)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (compound 4)

[0428]

[0429] The synthetic route for compound 4 is shown below:

[0430]

[0431] Step 1: 5-(difluoromethoxy)pyridine-2(1H)-one (compound 4-2)

[0432] 2-Chloro-5-(difluoromethoxy)pyridine (1.0 g, 5.54 mmol), potassium carbonate (3.83 g, 27.7 mmol), and acetoxyxamic acid (1.25 g, 16.6 mmol) were dissolved in dimethyl sulfoxide (30 mL). The reaction solution was reacted at 120 °C for 16 h under nitrogen protection. After the reaction was completed, the reaction solution was diluted with ethyl acetate (500 mL), washed with saturated sodium chloride aqueous solution (500 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:1) to give compound 5-(difluoromethoxy)pyridine-2(1H)-one (compound 4-2).

[0433] LC-MS, M / Z (ESI): 162.0 [M+H] + .

[0434] Step 3: 1-(4-bromophenyl)-5-(difluoromethoxy)pyridine-2(1H)-one (compound 4-3) 5-(difluoromethoxy)pyridine-2(1H)-one (compound 4-2) (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), and then acetonitrile (10 mL). The mixture was deoxygenated by argon and reacted in a microwave at 100 °C for 1 h. After completion, the reaction solution was diluted with ethyl acetate (300 mL), washed with saturated sodium chloride aqueous solution (300 mL × 3), dried with anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 1:1) to give compound 1-(4-bromophenyl)-5-(difluoromethoxy)pyridine-2(1H)-one (compound 4-3).

[0435] LC-MS, M / Z (ESI): 317.0 [M+H] + .

[0436] Step 3: 3-(2-chloro-4'-(5-(difluoromethoxy)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (compound 4)

[0437] Intermediate 1-(4-bromophenyl)-5-(difluoromethoxy)pyridin-2(1H)-one (compound 4-3) (120 mg, 0.38 mmol) was placed in a reaction flask, followed by intermediate 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)piperidin-2,6-dione (intermediate A) (174 mg, 0.5 mmol), potassium phosphate (242 mg, 1.14 mmol), 1,1'-bis(di-phenylphosphino)ferrocene palladium chloride (30 mg, 0.04 mmol), and 1,4-dioxane (4 mL). After the addition, the mixture was deoxygenated three times with nitrogen, and then the reaction solution was reacted at 100 °C for 8 hours. Subsequently, the solution was diluted with ethyl acetate (100 mL), washed with saturated sodium chloride aqueous solution (100 mL × 3), the organic phase was dried with anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 20:1) to give compound 3-(2-chloro-4'-(5-(difluoromethoxy)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (compound 4).

[0438] LC-MS, M / Z (ESI): 459.1 [M+H] + .

[0439] 1 H NMR(400MHz,DMSO-d6)δ10.93(s,1H),7.85(d,1H),7.65–7.44(m,5H),7.45–7.36(m,2H),7.33(dd,1H),7.0 4(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).

[0440] Example 5: Preparation of target compound 5

[0441] 3-(2-chloro-4'-(5-(difluoromethoxy)-6-oxopyridazin-1(6H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0442]

[0443] The synthetic route for compound 5 is shown below:

[0444]

[0445] Step 1: Synthesis of 2-(4-bromophenyl)-4-chloropyridazine-3(2H)-one (compound 5-2) 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) were added to a solution of 4-chloropyridazine-3(2H)-one (3.50 g, 26.8 mmol) and 4-bromo-1-iodobenzene (9.10 g, 32.2 mmol) in N,N-dimethylformamide (150 mL). The reaction mixture was stirred at 100 °C for 18 hours. The reaction was confirmed by LCMS. The reaction mixture was diluted with saturated brine (500 mL), extracted with ethyl acetate (300 mL × 3), and the organic layer was dried over anhydrous sodium sulfate. The mixture was then filtered and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 100:0-40:60) to give compound 2-(4-bromophenyl)-4-chloropyridazine-3(2H)-one (compound 5-2).

[0446] LC-MS, M / Z (ESI): 285.0 [M+H] +

[0447] Step 2: Synthesis of 2-(4-bromophenyl)-4-methoxypyridazine-3(2H)-one (compound 5-3) Sodium methoxide (1.40 mL, 7.57 mmol, 5.4 M methanol solution) was added to a tetrahydrofuran (10 mL) solution of 2-(4-bromophenyl)-4-chloropyridazine-3(2H)-one (compound 5-2) (1.90 g, 2.52 mmol). The reaction mixture was stirred at 25 °C for 1.5 h. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (100 mL × 3). The organic layers were combined and washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 100:0-50:50) to give compound 2-(4-bromophenyl)-4-methoxypyridazine-3(2H)-one (compound 5-3).

[0448] LC-MS, M / Z (ESI): 281.0 [M+H] +

[0449] Step 3: Synthesis of 2-(4-bromophenyl)-4-hydroxypyridazine-3(2H)-one (compound 5-4)

[0450] At -78°C, boron tribromide (0.709 mL, 7.47 mmol) was added to a solution of 0.600 g (1.49 mmol) of 2-(4-bromophenyl)-4-methoxypyridazine-3(2H)-one (compound 5-3) in 10 mL of dichloromethane. The resulting mixture was stirred at 25°C for 1 hour. The reaction was confirmed by LCMS. The reaction solution 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 reaction.

[0451] LC-MS, M / Z (ESI): 267.0 [M+H] +

[0452] Step 4: Synthesis of 2-(4-bromophenyl)-4-(difluoromethoxy)pyrazine-3(2H)-one (compound 5-5)

[0453] Sodium carbonate (0.833 g, 7.86 mmol) was added 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). The resulting mixture was stirred at 100 °C for 3 hours. The reaction was confirmed by LCMS. The reaction solution was directly concentrated to obtain a crude product, which was purified by preparative liquid chromatography (Prime C18, 21.2 × 250 mm 5 μm; 0.05% NH3·H2O-ACN; 38-68; 20 mL / min) to obtain compound (2-(4-bromophenyl)-4-(difluoromethoxy)pyridazin-3(2H)-one (compound 5-5)).

[0454] LC-MS, M / Z (ESI): 317.0 [M+H] +

[0455] 1 H NMR (400MHz, CD3OD): δ7.98(d,1H), δ7.70–7.61(m,2H), 7.59–7.48(m,2H).,7.25(t,1H),7.16(d,1H).

[0456] Step 5: Synthesis of 4-(difluoromethoxy)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)pyridazine-3(2H)-one (compounds 5-6)

[0457] The intermediate 2-(4-bromophenyl)-4-(difluoromethoxy)pyridazine-3(2H)-one (compound 5-5) (0.3 g, 0.95 mmol) was placed in a reaction flask, followed by the addition of pinacol diborate (0.5 g, 2 mmol), potassium acetate (0.3 g, 3 mmol), 1,1'-bis(di-phenylphosphino)ferrocene palladium chloride (73 mg, 0.1 mmol), and 1,4-dioxane (5 mL). After the addition was complete, the mixture was deoxygenated three times with nitrogen, and then reacted at 100 °C for 3 hours. The reaction solution was cooled to room temperature and then diluted with ethyl acetate (200 mL), washed with saturated sodium chloride aqueous solution (300 mL × 3), and the organic phase was then collected, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 3:1) to give compounds 4-(difluoromethoxy)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)pyridazine-3(2H)-one (compounds 5-6).

[0458] LC-MS, M / Z (ESI): 365.1 [M+H] + .

[0459] Step 6: 3-(2-chloro-4'-(5-(difluoromethoxy)-6-oxopyridazine-1(6H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0460]

[0461] Compound 4-(difluoromethoxy)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)phenyl)pyridazin-3(2H)-one (compounds 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), 1,1'-bis(di-phenylphosphino)ferrocene palladium chloride (44 mg, 0.06 mmol), and N,N-dimethylformamide (5 mL). After the addition was complete, the reaction solution was reacted at 100 °C for 2 hours under nitrogen protection. After the reaction was complete, the reaction solution was cooled to room temperature, diluted with ethyl acetate (200 mL), extracted with saturated sodium chloride aqueous solution (200 mL × 3), and then the organic phase was collected, 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 compound 3-(2-chloro-4'-(5-(difluoromethoxy)-6-oxopyridazin-1(6H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 5).

[0462] LC-MS, M / Z (ESI): 460.1 [M+H] + .

[0463] 1 H NMR(400MHz,DMSO-d6)δ10.94(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).

[0464] Example 6: Preparation of target compound 6

[0465] 3-{2-chloro-4'-[2-oxo-3-(trifluoromethoxy)pyridin-1(2H)-yl][1,1'-biphenyl]-3-yl}piperidin-2,6-dione (compound 6)

[0466]

[0467] The synthetic route for target compound 6 is shown below:

[0468]

[0469] Step 1: Synthesis of 3-(trifluoromethoxy)pyridine-2-ol (compound 6-2)

[0470] 2-Chloro-3-(trifluoromethoxy)pyridine (compound 6-1) (400 mg, 2.0 mmol), potassium carbonate (2.0 g, 14.0 mmol), and acetyloxyoxime acid (608 mg, 8.0 mmol) were dissolved in dimethyl sulfoxide (4 mL), and the mixture was purged with argon three times. The reaction solution was reacted at 100 °C for 18 h. Water (50 mL) was added to the reaction solution, and the mixture was then extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-1 / 1) to give compound 3-(trifluoromethoxy)pyridine-2-ol (compound 6-2).

[0471] LC-MS, M / Z(ESI): 180.2[M+H]+.

[0472] Step 2: Synthesis of 1-(4-bromophenyl)-3-(trifluoromethoxy)pyridine-2(1H)-one (compound 6-3)

[0473] To a solution of 1,4-dibromobenzene (350 mg, 1.48 mmol) in dioxane (3.5 mL), 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) were added, purging with argon three 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 give compound 1-(4-bromophenyl)-3-(trifluoromethoxy)pyridin-2(1H)-one (compound 6-3).

[0474] LC-MS, M / Z (ESI): 336.2 [M+H]+

[0475] 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)

[0476]

[0477] 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-dioxaborane-2-yl)phenyl]piperidin-2,6-dione (intermediate A) (550 mg, 1.57 mmol) in 1,4-dioxane (1.5 mL), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (37 mg, 0.045 mmol) and potassium carbonate (186 mg, 1.35 mmol) were added, purging with argon three times, and then stirred at 100 °C for 18 h. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (2 mL × 3). The combined organic phases were washed with saturated brine (2 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by reverse-phase preparation (column: Phenomenex Synergi C18 100×25mm×4μm; solvent: A = water + 0.1 vol% formic acid (99%), B = acetonitrile; gradient: 5%-95%, 7 min) to give compound 3-{2-chloro-4'-[2-oxo-3-(trifluoromethoxy)pyridin-1(2H)-yl][1,1'-biphenyl]-3-yl}piperidin-2,6-dione (compound 6).

[0478] 1H NMR(600MHz,DMSO-d6)δ10.96(s,1H),7.85(d,1H),7.77(d,1H),7.57(q,4H),7.46–7.40(m,2H),7.38(d,1 H),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).

[0479] LC-MS, M / Z (ESI): 476.8 [M+H]+

[0480] Example 7: Preparation of target compound 7

[0481] N-(1-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)cyclopropaneformamide (target compound 7)

[0482]

[0483] The synthetic route for target compound 7 is shown below:

[0484]

[0485] Step 1: Synthesis of 1-(4-bromophenyl)-3-nitropyridine-2(1H)-one (compound 7-3) At room temperature, (4-bromophenyl)boronic acid (1.0 g, 4.98 mmol) and 3-nitropyridine-2(1H)-one (0.5 g, 3.57 mmol) were mixed in anhydrous dichloromethane (10 mL), followed by the addition of triethylamine (0.72 g, 7.14 mmol), pyridine (0.72 g, 7.14 mmol), and copper acetate (0.72 g, 7.14 mmol). The mixture was stirred at room temperature for 12 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 5:1-1:1) to obtain compound 1-(4-bromophenyl)-3-nitropyridine-2(1H)-one (compound 7-3).

[0486] LC-MS, M / Z (ESI): 294.2 [M+H] +

[0487] Step 2: Synthesis of 3-amino-1-(4-bromophenyl)pyridine-2(1H)-one (compound 7-4)

[0488] At room temperature, 1-(4-bromophenyl)-3-nitropyridine-2(1H)-one (compound 7-3) was dissolved (0.4 g, 1.35 mmol) in methanol (20 mL). Pd / C (40 mg) was added under a nitrogen atmosphere, followed by purging with hydrogen three times. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 5 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 5:1-1:1) to give compound 3-amino-1-(4-bromophenyl)pyridine-2(1H)-one (compound 7-4).

[0489] LC-MS, M / Z (ESI): 265.2 [M+H] +

[0490] Step 3: Synthesis of N-(1-(4-bromophenyl)-2-oxo-1,2-dihydropyridin-3-yl)cyclopropaneformamide (compounds 7-5)

[0491] At room temperature, 3-amino-1-(4-bromophenyl)pyridine-2(1H)-one (compound 7-4) (0.2 g, 0.75 mmol) and cyclopropylformyl chloride (0.21 g, 1.13 mmol) were mixed in anhydrous dichloromethane (10 mL), and then triethylamine (0.16 g, 1.5 mmol) was added. The mixture was stirred at room temperature for 2 hours.

[0492] After the reaction was completed, the 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 give compound (N-(1-(4-bromophenyl)-2-oxo-1,2-dihydropyridin-3-yl)cyclopropanecarboxamide (compound 7-5).

[0493] LC-MS, M / Z (ESI): 333.2 [M+H] +

[0494] Step 4: Synthesis of N-(1-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)cyclopropaneformamide (compound 7)

[0495]

[0496] At room temperature, N-(1-(4-bromophenyl)-2-oxo-1,2-dihydropyridin-3-yl)cyclopropanecarboxamide (compound 7-5) (0.1 g, 0.3 mmol) and pinacol diborate (0.16 g, 0.6 mmol) were placed in anhydrous 1,4-dioxane (10 mL), followed by the addition of potassium acetate (0.32 g, 0.9 mmol) and Pd(dppf)Cl2 (22 mg, 0.03 mmol). The reaction mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), washed with saturated brine (20 mL), and the organic phase was concentrated to obtain the crude product, which was directly used in the next reaction step. The crude product obtained above was mixed with 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (intermediate A4) (0.11 g, 0.36 mmol) in 1,4-dioxane (10 mL), followed by the addition of potassium phosphate (0.32 g, 0.9 mmol) and Pd(dppf)Cl2 (22 mg, 0.03 mmol). The reaction mixture was heated to 90 °C and stirred for 5 h under a nitrogen atmosphere. After the reaction was completed, 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 give compound 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).

[0497] LC-MS, M / Z (ESI): 476.2 [M+H] +

[0498] 1 H NMR(400MHz,CD3OD)δ8.65(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).

[0499] Example 8: Preparation of target compound 8

[0500] 3-{2-chloro-4'-[3-(2-hydroxy-2-methylpropoxy)-2-oxopyridin-1(2H)-yl][1,1'-biphenyl]-3-yl}piperidin-2,6-dione (Compound 8)

[0501]

[0502] The synthetic route for target compound 8 is shown below:

[0503]

[0504] Step 1: Synthesis of 1-(4-bromophenyl)-3-hydroxypyridine-2(1H)-one (8-2)

[0505] To a solution of 1,4-dibromobenzene (4.25 g, 18 mmol) in 20 mL of 1,4-dioxane (20 mL), 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) were added, purging with argon three times. The reaction mixture was then stirred at 110 °C for 18 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-1 / 3) to give compound 1-(4-bromophenyl)-3-hydroxypyridine-2(1H)-one (8-2) (320 mg, yield 6.7%).

[0506] LC-MS, M / Z (ESI): 268.2 [M+H]+

[0507] Step 2: Synthesis of ethyl acetate {[1-(4-bromophenyl)-2-oxo-1,2-dihydropyridin-3-yl]oxy} (8-3)

[0508] Potassium carbonate (467 mg, 3.38 mmol) and methyl bromoacetate (282 mg, 1.69 mmol) were added to a solution of 1-(4-bromophenyl)-3-hydroxypyridin-2(1H)-one (8-2) (300 mg, 1.13 mmol) in N,N-dimethylformamide (3 mL), and the mixture was stirred at room temperature for 18 h. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-1 / 3) to obtain the product {[1-(4-bromophenyl)-2-oxo-1,2-dihydropyridin-3-yl]oxy}ethyl acetate (8-3) (310 mg, yield 78%).

[0509] LC-MS, M / Z (ESI): 354.3 [M+H]+

[0510] Step 3: Synthesis of 1-(4-bromophenyl)-3-(2-hydroxy-2-methylpropoxy)pyridine-2(1H)-one (8-4)

[0511] Ethyl ethyl acetate {[1-(4-bromophenyl)-2-oxo-1,2-dihydropyridin-3-yl]oxy} (8-3) (310 mg, 0.88 mmol) was dissolved in tetrahydrofuran (3 mL), and the mixture was purged with argon three times. At 0 °C, methyl magnesium bromide (0.88 mL, 2.64 mmol, 3 M tetrahydrofuran solution) was added dropwise to the reaction mixture, and the mixture was then brought to room temperature and stirred for 2 h. The reaction mixture was then slowly added dropwise to saturated ammonium chloride (20 mL), and extracted with ethyl acetate (10 mL * 3). The combined organic phases were washed with saturated brine (20 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-0 / 1) to give compound 1-(4-bromophenyl)-3-(2-hydroxy-2-methylpropoxy)pyridine-2(1H)-one (8-4) (200 mg, yield 67%).

[0512] LC-MS, M / Z (ESI): 340.3 [M+H]+

[0513] Step 4: Synthesis of 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)

[0514]

[0515] To a solution of 1-(4-bromophenyl)-3-(2-hydroxy-2-methylpropoxy)pyridin-2(1H)-one (8-4) (200 mg, 0.59 mmol) and 3-[2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl]piperidine-2,6-dione (827 mg, 2.37 mmol) in dioxane (3 mL), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (48 mg, 0.06 mmol) and potassium carbonate (245 mg, 1.77 mmol) were added, purging with argon three times, and then stirred at 100 °C for 18 h. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (2 mL x 3). The combined organic phases were washed with saturated brine (2 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative liquid chromatography (column: Phenomenex Synergi C18 100*25mm*4μm; solvent: A = water + 0.1 vol% formic acid (99%), B = acetonitrile; gradient: 5%-95%, 7 min) to give compound 3-{2-chloro-4'-[3-(2-hydroxy-2-methylpropoxy)-2-oxopyridin-1(2H)-yl][1,1'-biphenyl]-3-yl}piperidin-2,6-dione (compound 8).

[0516] 1 H NMR(600MHz,DMSO-d6)δ10.96(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).

[0517] LC-MS, M / Z (ESI): 481.2 [M+H]+

[0518] Example 9: Preparation of target compound 9

[0519] 3-(2-chloro-4'-(3-(difluoromethoxy)-2-oxopyrazin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (compound 9)

[0520]

[0521] The synthetic route for compound 9 is shown below:

[0522]

[0523] Step 1: Synthesis of 3-(difluoromethoxy)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)phenyl)pyrazine-2(1H)-one (compound 9-1) The intermediate 1-(4-bromophenyl)-3-(difluoromethoxy)pyrazine-2(1H)-one (intermediate B1) (80 mg, 0.25 mmol) was placed in a reaction flask, followed by the addition of pinacol diborate (128 mg, 0.51 mmol), potassium acetate (74 mg, 0.75 mmol), 1,1'-bis(di-phenylphosphino)ferrocene palladium chloride (28 mg, 0.04 mmol), and 1,4-dioxane (3 mL). After the addition was complete, the mixture was purged with nitrogen three times, and then reacted at 100 °C for 3 hours. After the reaction was complete, the reaction solution was cooled to room temperature, diluted with ethyl acetate (100 mL), washed with saturated sodium chloride aqueous solution (100 mL × 3), and then the organic phase was taken, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 3:1) to give the intermediate 3-(difluoromethoxy)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)pyrazine-2(1H)-one (9-1).

[0524] LC-MS, M / Z (ESI): 365.1 [M+H] + .

[0525] 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)

[0526]

[0527] Intermediate 3-(2-chloro-4'-(3-(difluoromethoxy)-2-oxopyrazin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-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)piperidin-2,6-dione (intermediate A4) (61 mg, 0.20 mmol), potassium phosphate (108 mg, 0.51 mmol), 1,1'-bis(di-phenylphosphino)ferrocene palladium chloride (22 mg, 0.03 mmol), and N,N-dimethylformamide (3 mL). After the addition was complete, the mixture was purged with nitrogen three times, and then reacted at 100 °C for 2 hours. The reaction solution was cooled to room temperature and then diluted with ethyl acetate (100 mL). It was extracted with saturated sodium chloride aqueous solution (100 mL × 3). The organic phase was then collected, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 20:1) to give compound 3-(2-chloro-4'-(3-(difluoromethoxy)-2-oxopyrazin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 9) (36 mg, yield: 46%).

[0528] LC-MS, M / Z (ESI): 460.1 [M+H] + .

[0529] 1 H NMR(600MHz,DMSO-d6)δ10.93(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).

[0530] Example 10: Preparation of target compound 10

[0531] 3-(2-chloro-4'-(3-(difluoromethoxy-d)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0532]

[0533] The synthetic route of Example 10 is shown below:

[0534]

[0535] Step 1: Synthesis of 1-(4-bromophenyl)-3-(difluoromethoxy-d)pyridine-2(1H)-one (compound 10-1) The intermediate 1-(4-bromophenyl)-3-hydroxypyridine-2(1H)-one (8-2) (230 mg, 0.87 mmol) was placed in a reaction flask, followed by the addition of tetrahydrofuran (8 mL). After the addition was complete, the mixture was purged with nitrogen three times. Then, 60 wt% sodium hydride (348 mg, 8.7 mmol) was slowly added at 0 °C, and the reaction was allowed to proceed for 10 minutes. Subsequently, heavy water (0.8 mL) was slowly added at 0 °C, and the reaction was allowed to proceed for 10 minutes at 0 °C. Finally, diethyl bromofluoromethylphosphonate (465 mg, 1.74 mmol) was slowly added at 0 °C, and the reaction was allowed to proceed for 10 minutes at 0 °C. After the reaction was complete, the reaction solution was diluted with ethyl acetate (200 mL), extracted with saturated sodium chloride aqueous solution (200 mL × 3), and then the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 3:1) to give the intermediate 1-(4-bromophenyl)-3-(difluoromethoxy-d)pyridine-2(1H)-one (10-1).

[0536] LC-MS, M / Z (ESI): 317.1 [M+H] +

[0537] Step 2: Synthesis of 3-(difluoromethoxy-d)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)pyridin-2(1H)-one (compound 10-2)

[0538] The intermediate 1-(4-bromophenyl)-3-(difluoromethoxy-d)pyridine-2(1H)-one (10⁻¹) (150 mg, 0.48 mmol) was placed in a reaction flask, followed by the addition of pinacol diboron ester (244 mg, 0.96 mmol), potassium acetate (141 mg, 1.44 mmol), 1,1'-bis(di-phenylphosphino)ferrocene palladium chloride (45 mg, 0.06 mmol), and 1,4-dioxane (5 mL). After the addition was complete, the mixture was purged with nitrogen three times, and then the reaction solution was reacted at 100 °C for 3 hours. After the reaction was complete, the reaction solution was cooled to room temperature, diluted with ethyl acetate (100 mL), washed with saturated sodium chloride aqueous solution (100 mL × 3), and then the organic phase was taken, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 3:1) to give the intermediate 3-(difluoromethoxy-d)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)pyridine-2(1H)-one (10-2).

[0539] LC-MS, M / Z (ESI): 365.1 [M+H] + .

[0540] 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)

[0541]

[0542] Intermediate 3-(difluoromethoxy-d)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)phenyl)pyridin-2(1H)-one (10⁻²) (120 mg, 0.33 mmol) was placed in a reaction flask, followed by the addition of 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (intermediate A4) (122 mg, 0.40 mmol), potassium phosphate (216 mg, 1.0 mmol), 1,1'-bis(di-phenylphosphino)ferrocene palladium chloride (44 mg, 0.06 mmol), and N,N-dimethylformamide (6 mL). After the addition was complete, the mixture was purged with nitrogen three times, and then reacted at 100 °C for 2 hours. After the reaction was complete, the reaction solution was diluted with ethyl acetate (100 mL), washed with saturated sodium chloride aqueous solution (100 mL × 3), and then the organic phase was taken, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 20:1) to give compound 3-(2-chloro-4'-(3-(difluoromethoxy-d)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (compound 10).

[0543] LC-MS, M / Z (ESI): 460.1 [M+H] + .

[0544] 1 H NMR(600MHz,DMSO-d6)δ10.94(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).

[0545] Example 11: Preparation of target compound 11

[0546] 3-(2-chloro-4'-(3-(2,3-dihydroxypropoxy)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (compound 11)

[0547]

[0548] The synthetic route for compound 11 is shown below:

[0549]

[0550] Step 1: Synthesis of methyl (2,2-dimethyl-1,3-dioxolane-4-yl)methanesulfonate (compound 11-2)

[0551] 2,2-Dimethyl-1,3-dioxolane-4-yl)methanol (11-1) (2.5 g, 19 mmol) was placed in a reaction flask, followed by the sequential addition of dichloromethane (50 mL) and triethylamine (5.5 mL) under ice bath conditions. After the addition was complete, methanesulfonic anhydride (4.0 mg, 22.8 mmol) was slowly added at 0 °C, and the reaction was carried out at 0 °C for 30 minutes. The reaction solution was then diluted with ethyl acetate (200 mL), washed with ice water (200 mL × 3), and the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated to give methyl (2,2-dimethyl-1,3-dioxolane-4-yl)methanesulfonate (11-2).

[0552] LC-MS, M / Z (ESI): 211.0 [M+H] + .

[0553] Step 2: Synthesis of 1-(4-bromophenyl)-3-(2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)pyridin-2(1H)-one (11-3)

[0554] The intermediate 1-(4-bromophenyl)-3-hydroxypyridine-2(1H)-one (compound 8-2) (400 mg, 1.51 mmol) was placed in a reaction flask, followed by the addition of acetonitrile (8 mL), intermediate (2,2-dimethyl-1,3-dioxolane-4-yl)methanesulfonate (11-2) (950 mg, 4.51 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (685 mg, 4.51 mmol). After the addition was complete, the mixture was purged with nitrogen three times, and then the reaction was carried out in a microwave oven at 120 °C for 3 hours. After the reaction was complete, the reaction solution was cooled to room temperature, diluted with ethyl acetate (200 mL), washed with saturated sodium chloride aqueous solution (200 mL × 3), and then the organic phase was taken, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 3:1) to give the intermediate 1-(4-bromophenyl)-3-(2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)pyridin-2(1H)-one (11-3).

[0555] LC-MS, M / Z (ESI): 380.1 [M+H] +.

[0556] Step 3: Synthesis of 3-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)pyridine-2(1H)-one (compound 11-4) The intermediate 1-(4-bromophenyl)-3-(2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)pyridine-2(1H)-one (1 1-3)(500mg, 1.32mmol) was placed in a reaction flask, followed by the addition of pinacol diboron ester (670mg, 2.64mmol), potassium acetate (388mg, 4.0mmol), 1,1'-bis(di-phenylphosphino)ferrocene palladium chloride (145mg, 0.2mmol), and 1,4-dioxane (13mL). After the addition was complete, the mixture was purged with nitrogen three times, and then reacted at 100°C for 3 hours. The mixture was then diluted with ethyl acetate (200 mL), washed with saturated sodium chloride aqueous solution (200 mL × 3), and the organic phase was then dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 3:1) to give the intermediate 3-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)pyridine-2(1H)-one (11-4).

[0557] LC-MS, M / Z (ESI): 428.0 [M+H] + .

[0558] Step 4: Synthesis of 3-(2-chloro-4'-(3-(2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (11-5)

[0559] Intermediate 3-(difluoromethoxy-d)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)phenyl)pyridin-2(1H)-one (11-4) (340 mg, 0.80 mmol) was placed in a reaction flask, followed by the addition of 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (intermediate A4) (290 mg, 0.96 mmol), potassium phosphate (510 mg, 2.4 mmol), 1,1'-bis(di-phenylphosphino)ferrocene palladium chloride (60 mg, 0.08 mmol), and N,N-dimethylformamide (8 mL). After the addition was complete, the mixture was purged with nitrogen three times, and then reacted at 100 °C for 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature, diluted with ethyl acetate (300 mL), washed with saturated sodium chloride aqueous solution (300 mL × 3), and then the organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 20:1) to give 3-(2-chloro-4'-(3-(2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (compound 11-5) (232 mg, yield: 56%).

[0560] LC-MS, M / Z (ESI): 523.1 [M+H] + .

[0561] Step 5: Synthesis of 3-(2-chloro-4'-(3-(2,3-dihydroxypropoxy)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 11)

[0562]

[0563] The intermediate 3-(2-chloro-4'-(3-(2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (11-5) (230 mg, 0.56 mmol) was placed in a reaction flask, followed by the addition of p-toluenesulfonic acid monohydrate (30 mg, 0.14 mmol) and tetrahydrofuran (8 mL). The reaction mixture was heated to 40 °C and stirred for 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature, diluted with ethyl acetate (100 mL), extracted with saturated sodium chloride aqueous solution (100 mL × 3), and then the organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 20:1) to give compound 3-(2-chloro-4'-(3-(2,3-dihydroxypropoxy)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (compound 11) (138 mg, yield: 52%).

[0564] LC-MS, M / Z (ESI): 483.1 [M+H] + .

[0565] 1 H NMR(600MHz,DMSO-d6)δ10.91(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),2.8 1–2.71(m,1H),2.55–2.48(m,1H),2.37–2.25(m,1H),2.02–1.99(m,1H).

[0566] Example 12: Preparation of target compound 12

[0567] 3-(2-chloro-4'-(3-(2-hydroxyethoxy)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (compound 12)

[0568]

[0569] The synthetic route for compound 12 is shown below:

[0570]

[0571] Step 1: Synthesis of 1-(4-bromophenyl)-3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-2(1H)-one (compound 12-1)

[0572] The intermediate 1-(4-bromophenyl)-3-hydroxypyridine-2(1H)-one (8-2) (500 mg, 1.89 mmol) was placed in a reaction flask, followed by the addition of acetonitrile (15 mL), tert-butyl-(2-iodoethoxy)dimethylsilane (1.1 g, 3.8 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (685 mg, 4.51 mmol). After the addition was complete, the mixture was deoxygenated three times with nitrogen, and then the reaction was carried out in a microwave oven at 50 °C for 3 hours. After the reaction was complete, the reaction solution was diluted with ethyl acetate (200 mL), washed with saturated sodium chloride aqueous solution (200 mL × 3), and then the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 3:1) to give the intermediate 1-(4-bromophenyl)-3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridine-2(1H)-one (12-1).

[0573] LC-MS, M / Z (ESI): 424.1 [M+H] + .

[0574] Step 2: Synthesis of 3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)pyridin-2(1H)-one (compound 12-2)

[0575] The intermediate 1-(4-bromophenyl)-3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-2(1H)-one (12-1) (450 mg, 1.06 mmol) was placed in a reaction flask, followed by the addition of pinacol diboronate (670 mg, 2.64 mmol), potassium acetate (388 mg, 4.0 mmol), 1,1'-bis(di-phenylphosphino)ferrocene palladium chloride (145 mg, 0.2 mmol), and 1,4-dioxane (13 mL). After the addition was complete, the mixture was purged with nitrogen three times, and then reacted at 100 °C for 5 hours. The mixture was then diluted with ethyl acetate (200 mL), washed with saturated sodium chloride aqueous solution (200 mL × 3), and the organic phase was then dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 3:1) to give the intermediate 3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)pyridine-2(1H)-one (12-2).

[0576] LC-MS, M / Z (ESI): 472.5 [M+H] + .

[0577] Step 4: Synthesis of 3-(4'-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-oxopyridin-1(2H)-yl)-2-chloro-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (compound 12-3)

[0578] Intermediate 3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-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)piperidin-2,6-dione (intermediate A4) (246 mg, 0.81 mmol), potassium phosphate (471 mg, 2.2 mmol), 1,1'-bis(di-phenylphosphino)ferrocene palladium chloride (60 mg, 0.08 mmol), and N,N-dimethylformamide (8 mL). After the addition was complete, the mixture was purged with nitrogen three times, and then reacted at 100 °C for 2 hours. The mixture was then diluted with ethyl acetate (300 mL), washed with saturated sodium chloride aqueous solution (300 mL × 3), and the organic phase was then dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 20:1) to give 3-(4'-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-oxopyridin-1(2H)-yl)-2-chloro-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (compound 12-3).

[0579] LC-MS, M / Z (ESI): 567.1 [M+H] + .

[0580] Step 5: Synthesis of 3-(2-chloro-4'-(3-(2-hydroxyethoxy)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (compound 12)

[0581]

[0582] The intermediate 3-(4'-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-oxopyridin-1(2H)-yl)-2-chloro-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (12-3) (220 mg, 0.39 mmol) was placed in a reaction flask, followed by the addition of 4 mL tetrahydrofuran, 0.5 mL water and 75 mg p-toluenesulfonic acid monohydrate, and reacted at 40 °C for 1 hour. After completion, the solution was diluted with ethyl acetate (100 mL), washed with saturated sodium bicarbonate aqueous solution (300 mL × 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 give 3-(2-chloro-4'-(3-(2-hydroxyethoxy)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (compound 12).

[0583] LC-MS, M / Z (ESI): 453.1 [M+H] + .

[0584] 1 H NMR(600MHz,DMSO-d6)δ10.94(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),4.9 2(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).

[0585] Example 13: Preparation of target compound 13

[0586] 3-{2-chloro-4'-[2-oxo-3-(trifluoromethoxy)pyridin-1(2H)-yl][1,1'-biphenyl]-3-yl}piperidin-2,6-dione (13)

[0587]

[0588] The synthetic route for target compound 13 is shown below:

[0589]

[0590] Step 1: Synthesis of methyl 2-((1-(4-bromophenyl)-2-oxo-1,2-dihydropyridin-3-yl)oxy)acetate (compound 13-1)

[0591] 1-(4-bromophenyl)-3-hydroxypyridin-2(1H)-one (8-2) (1.0 g, 2.0 mmol) and methyl bromoacetate (1.0 g, 2.0 mmol) were dissolved in DCM (10 mL), and DBU (1.0 g, 2.0 mmol) was added. The mixture was then stirred at room temperature for 5 h. After the reaction was complete, the reaction solution was diluted with DCM (50 mL), the organic phases were combined, washed with saturated brine (30 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0 - 1 / 1) to give compound 2-((1-(4-bromophenyl)-2-oxo-1,2-dihydropyridin-3-yl)oxy)methyl acetate (compound 13-1).

[0592] LC-MS, M / Z (ESI): 338.2 [M+H] + .

[0593] Step 2: Synthesis of 1-(4-bromophenyl)-3-(trifluoromethoxy)pyridine-2(1H)-one (compound 13-2)

[0594] To a solution of methyl 2-((1-(4-bromophenyl)-2-oxo-1,2-dihydropyridin-3-yl)oxy)acetate (compound 13-1) (220 mg, 0.6 mmol) in tetrahydrofuran (3 mL), tetraisopropyl titanate (17 mg, 0.06 mmol) was added, purging with argon three times. Ethyl magnesium bromide (1 mL, 2 mmol, 2 M tetrahydrofuran solution) was slowly added dropwise to the reaction solution at -78 °C, and the reaction was continued for 2 h. The reaction solution was then slowly added dropwise to a saturated ammonium chloride solution (20 mL), and extracted with ethyl acetate (10 mL * 3). The combined organic phases were washed with saturated brine (10 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-0 / 1) to give compound 1-(4-bromophenyl)-3-((1-hydroxycyclopropyl)methoxy)pyridine-2(1H)-one (compound 13-2).

[0595] LC-MS, M / Z (ESI): 336.2 [M+H]+

[0596] Step 3: Synthesis of N-(2-oxo-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-1,2-dihydropyridin-3-yl)cyclopropaneformamide (compound 13-3)

[0597] At room temperature, a solution of 1-(4-bromophenyl)-3-((1-hydroxycyclopropyl)methoxy)pyridine-2(1H)-one (compound 13-2) (100 mg, 0.3 mmol) in 1,4-dioxane (3 mL) was added with pinacol diborate (152 mg, 0.6 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (22 mg, 0.03 mmol), and potassium acetate (100.0 mg, 0.9 mmol). The mixture was purged with argon three times, and stirred at 100 °C for 18 h. The reaction mixture was cooled to room temperature, and water (10 mL) was added, followed by extraction with ethyl acetate (2 mL x 3). The combined organic phases were washed with saturated brine (2 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product (compound 13-3), which was used directly in the next reaction. LC-MS, M / Z (ESI): 384.2 [M+H]+

[0598] Step 4: Synthesis of 3-(2-chloro-4'-(3-((1-hydroxycyclopropyl)methoxy)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (compound 13)

[0599]

[0600] To a solution of 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (150 mg, 0.45 mmol) and 3-((1-hydroxycyclopropyl)methoxy)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)pyridin-2(1H)-one (550 mg, 1.57 mmol) in 1,4-dioxane (1.5 mL), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (37 mg, 0.045 mmol) and potassium carbonate (186 mg, 1.35 mmol) were added, purging with argon three times. The reaction mixture was stirred at 100 °C for 18 h. The reaction mixture was cooled to room temperature, water (10 mL) was added, and then extracted with ethyl acetate (2 mL * 3). The organic phases were combined and washed with saturated brine (2 mL * 2), dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative liquid chromatography (column: Phenomenex Synergi C18 100 * 25 mm * 4 μm; solvent: A = water + 0.1 vol% formic acid (99%), B = acetonitrile; gradient: 5% - 95%, 7 min) to give compound 3-(2-chloro-4'-(3-((1-hydroxycyclopropyl)methoxy)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (compound 13).

[0601] 1H NMR(600MHz,DMSO-d6)δ10.94(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),4.8 3(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).

[0602] LC-MS, M / Z (ESI): 479.1 [M+H]+

[0603] Example 14: Preparation of target compound 14:

[0604] 3-(2-chloro-4'-(3-(2-(dimethylamino)ethoxy)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (target compound 14)

[0605]

[0606] The synthetic route for compound 14 is shown below:

[0607]

[0608] Step 1: 3-(3-bromo-2-chlorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (compound 14-1)

[0609] 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione (intermediate A4) (3.0 g, 10 mmol) was placed in a reaction flask, and then 50 mL of acetonitrile, 1,5-diazabicyclo[5.4.0]-5-undecene (3.0 g, 20 mmol), and 2-(trimethylsilyl)ethoxymethyl chloride (2.5 g, 15 mmol) were added sequentially under ice bath conditions. The reaction was carried out at 45 °C for 2 h. The reaction solution was then diluted with ethyl acetate (500 mL) and extracted with ice water (500 mL × 3). The organic phase was then collected, 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 give 3-(3-bromo-2-chlorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (compound 14-1).

[0610] LC-MS, M / Z (ESI): 432.0 [M+H] + .

[0611] 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)

[0612] 1-(4-bromophenyl)-3-hydroxypyridine-2(1H)-one (intermediate 8-2) (500 mg, 1.89 mmol) was placed in a reaction flask, and compound 14-1 (1.09 g, 2.3 mmol), potassium phosphate (1.2 g, 5.67 mmol), 1,1'-bis(di-phenylphosphino)ferrocene palladium chloride (150 mg, 0.2 mmol), and 1,4-dioxane (10 mL) were added sequentially. The reaction solution was reacted at 100 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was diluted with ethyl acetate (200 mL), extracted with saturated sodium chloride aqueous solution (200 mL × 3), and then the organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 20:1) to give compound 3-(2-chloro-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).

[0613] LC-MS, M / Z (ESI): 539.0 [M+H] +

[0614] 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)

[0615] Intermediate 3-(2-chloro-4'-(3-hydroxy-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2,6-dione (compound 14-2) (660 mg, 1.23 mmol), (2-bromomethyl)dimethylamine hydrochloride (930 mg, 4.92 mmol), and cesium carbonate (2 g, 6.15 mmol) were placed in a reaction flask, and acetonitrile (10 mL) was added. The reaction solution was refluxed at 90 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was diluted with ethyl acetate (200 mL), washed with saturated sodium chloride aqueous solution (200 mL × 3), and then the organic phase was taken, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 20:1) to give compound 3-(2-chloro-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).

[0616] LC-MS, M / Z (ESI): 610.1 [M+H] +

[0617] Step 4: 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)

[0618]

[0619] The intermediate 3-(2-chloro-4'-(3-(2-(dimethylamino)ethoxy)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2,6-dione (compound 14-3) (260 mg, 0.43 mmol) was placed in a reaction flask, followed by the addition of a 1,4-dioxane solution of hydrogen chloride (5 mL, 1 mol / L). The reaction solution was then reacted at 80 °C for 2 hours under nitrogen protection. After the reaction was completed, the reaction solution was distilled under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 20:1) to give compound 3-(2-chloro-4'-(3-(2-(dimethylamino)ethoxy)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (compound 14).

[0620] LC-MS, M / Z (ESI): 480.0 [M+H] +

[0621] 1 H NMR(600MHz,DMSO-d6)δ10.92(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).

[0622] Example 15: Preparation of target compound 15

[0623] 3-(2-chloro-4'-(3-(oxetane-3-yloxy)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (target compound 15)

[0624]

[0625] The synthetic route for compound 15 is shown below:

[0626]

[0627] Step 1: Synthesis of 1-(4-bromophenyl)-3-(oxetane-3-yloxy)pyridine-2(1H)-one (compound 15-1)

[0628] Intermediate 1-(4-bromophenyl)-3-hydroxypyridine-2(1H)-one (intermediate 8-2) (280 mg, 1.06 mmol) was placed in a reaction flask, followed by the addition of acetonitrile (5 mL), 3-iodooxetane (0.97 g, 5.3 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (1.0 g, 5.6 mmol). The reaction mixture was reacted under nitrogen protection at 90 °C in a microwave oven for 5 hours. After the reaction was complete, the reaction mixture was diluted with ethyl acetate (200 mL), extracted with saturated sodium chloride aqueous solution (200 mL × 3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 2:1) to give intermediate 1-(4-bromophenyl)-3-(oxetane-3-yloxy)pyridine-2(1H)-one (compound 15-1).

[0629] LC-MS, M / Z (ESI): 322.1 [M+H] +

[0630] Step 2: Synthesis of 3-(oxacyclobutane-3-yloxy)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)pyridine-2(1H)-one (compound 15-2)

[0631] The intermediate 1-(4-bromophenyl)-3-(oxetane-3-yloxy)pyridine-2(1H)-one (compound 15-1) (140 mg, 0.435 mmol) was placed in a reaction flask, followed by the addition of pinacol diborate (222 mg, 0.87 mmol), potassium acetate (90 mg, 0.9 mmol), 1,1'-bis(di-phenylphosphino)ferrocene palladium chloride (58 mg, 0.08 mmol), and 1,4-dioxane (4 mL). The reaction solution was reacted at 100 °C for 4 hours under nitrogen protection. The reaction solution was cooled to room temperature, diluted with ethyl acetate (200 mL), washed with saturated sodium chloride aqueous solution (200 mL × 3), and then the organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 3:1) to give 3-(oxecyclobutane-3-yloxy)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)pyridine-2(1H)-one (compound 15-2).

[0632] LC-MS, M / Z (ESI): 370.2 [M+H] +

[0633] Step 4: Synthesis of 3-(2-chloro-4'-(3-(oxetane-3-yloxy)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione (compound 15)

[0634]

[0635] 3-(oxetane-3-yloxy)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)pyridin-2(1H)-one (compound 15-2) (130 mg, 0.35 mmol) was placed in a reaction flask, followed by the addition of 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (intermediate A4) (213 mg, 0.7 mmol), potassium phosphate (212 mg, 1.0 mmol), 1,1'-bis(di-phenylphosphino)ferrocene palladium chloride (30 mg, 0.04 mmol), and N,N-dimethylformamide (4 mL). The reaction mixture was stirred at 100 °C for 4 hours under nitrogen protection. The reaction solution was cooled to room temperature, diluted with ethyl acetate (200 mL), washed with saturated sodium chloride aqueous solution (200 mL × 3), and then the organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 20:1) to give compound 3-(2-chloro-4'-(3-(oxepane-3-yloxy)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (compound 15).

[0636] LC-MS, M / Z (ESI): 465.0 [M+H] +

[0637] 1 H NMR(600MHz,DMSO-d6)δ10.93(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,1 H),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).

[0638] Example 16: Preparation of target compound 16

[0639] 3-(2-chloro-4'-(3-methoxy-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (target compound compound 16)

[0640]

[0641] The synthetic route for compound 16 is shown below:

[0642]

[0643] Step 1: Synthesis of 1-(4-bromophenyl)-3-methoxypyridine-2(1H)-one (compound 16-1)

[0644] 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).

[0645] LC-MS, M / Z (ESI): 279.9 [M+H] +

[0646] 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)

[0647] 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).

[0648] LC-MS, M / Z (ESI): 328.2 [M+H] +

[0649] 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)

[0650]

[0651] 3-Methoxy-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)pyridin-2(1H)-one (compound 16-2) (130 mg, 0.40 mmol) was placed in a reaction flask, followed by the addition of 3-(3-bromo-2-chlorophenyl)piperidin-2,6-dione (intermediate A) (144 mg, 0.48 mmol), potassium phosphate (255 mg, 1.2 mmol), 1,1'-bis(di-phenylphosphino)ferrocene palladium chloride (30 mg, 0.04 mmol), and N,N-dimethylformamide (5 mL). The mixture was deoxygenated three times with nitrogen, and then reacted at 100 °C for 2 hours. The product was then diluted with ethyl acetate (100 mL), washed with saturated sodium chloride aqueous solution (100 mL × 3), and the organic phase was then dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 20:1) to give 3-(2-chloro-4'-(3-methoxy-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (compound 16).

[0652] LC-MS, M / Z (ESI): 423.1 [M+H] +

[0653] 1 H NMR (600MHz, DMSO-d) 6) δ10.94(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).

[0654] The preparation methods for the following compounds are the same as those in Example 1:

[0655]

[0656]

[0657]

[0658]

[0659]

[0660]

[0661]

[0662]

[0663]

[0664] Biological testing

[0665] Experimental Example 1: Compound-induced binding of VAV1 to CRBN

[0666] VAV1-SmBiT and CRBN-LgBiT expression plasmids were constructed separately. Using a lentiviral system, VAV1-SmBiT and CRBN-LgBiT were inserted into the genome of HEK293 cells to construct a stable cell line expressing VAV1-SmBiT and CRBN-LgBiT proteins (HEK293-VAV1-SmBiT-CRBN-LgBiT). The culture medium was DMEM containing 10% inactivated fetal bovine serum, 100 U / mL penicillin, and 100 μg / mL streptomycin. HEK293-VAV1-SmBiT-CRBN-LgBiT cells were cultured in a 37°C, 5% CO2 incubator. After passage at 80-90% confluence, the cells were divided into individual flasks for further passage. Cells in the logarithmic growth phase were used for plating. HEK293-VAV1-SmBiT-CRBN-LgBiT cells were seeded in 96-well plates with 100 μL of culture medium, 20,000-3,000 cells per well, and cultured overnight.

[0667] The test compound was dissolved in DMSO to a concentration of 10 mM. Subsequently, the compound was serially diluted with DMSO to achieve 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 test compound was added to 1 mL of complete culture medium, mixed well, and then 100 μL was added to a 96-well plate to achieve working concentrations of 1000 nM, 250 nM, 62.5 nM, 15.6 nM, 3.91 nM, 0.98 nM, 0.24 nM, 0.061 nM, 0.015 nM, and 0 nM. The assay was performed after 8 hours of treatment, following the manufacturer's instructions for the Promega NanoBiT Protein: Protein Interaction System.

[0668] EC 50 calculate:

[0669] Fluorescence intensity (Fold change) = (Lumninence experiment - Lumininence blank) / (LumninenceDMSO - Lumininence blank). Experimental conclusion: The compound of this invention can induce direct binding between VAV1 and CRBN in a dose-dependent manner.

[0670] Experimental Example 2: Effects of Compounds on VAV1 Protein in Jurkat Cells

[0671] A Hibit tag was inserted into the C-terminus of VAV1, and the VAV1-Hibit protein was inserted into the genome of Jurkat cells using a lentiviral system to construct a cell line stably expressing the VAV1-Hibit protein. The culture medium used was RPMI-1640 medium containing inactivated 10% fetal bovine serum, 100 U / mL penicillin, and 100 μg / mL streptomycin. Jurkat-VAV1-Hibit cells were cultured in a 37°C, 5% CO2 incubator. After passage, the cells were divided into individual flasks after reaching 80-90% confluence. Cells in the logarithmic growth phase were seeded into 96-well plates with 100 μL of medium at 2000-3000 cells per well, and cultured overnight.

[0672] The test compound was dissolved in DMSO to a concentration of 10 mM. Subsequently, the compound was serially diluted with DMSO to achieve 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 was added to 1 mL of complete culture medium, mixed well, and then 100 μL was added to a 96-well plate to achieve working concentrations of 1000 nM, 250 nM, 62.5 nM, 15.6 nM, 3.91 nM, 0.98 nM, 0.24 nM, 0.061 nM, 0.015 nM, and 0 nM. The compound was tested 24 hours after treatment, following the assay method described by Promega. HiBiT Lytic DetectionSystem manual.

[0673] DC 50 calculate:

[0674] Relative VAV1(%) = (Lumninence experiment - Lumininence blank) / (LumninenceDMSO - Lumininence blank), calculated by fitting log(inhibitor) vs. response -- Variable slope(fourparameters).

[0675] Experimental conclusion: The compounds of this invention exhibit excellent degradation effects on VAV1 protein in a dose-dependent manner.

[0676] Experimental Example 3: Degradation of VAV1 in Jurkat Cells by Compounds

[0677] Jurkat cells (BFN60700175, Qingqi (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 and 5% CO2, until the cell density reached 1*10⁻⁶ cells / mL. ^6 Subsequent passage and flask separation. Tumor cells in the logarithmic growth phase were passaged at 7 × 10⁻⁶ cells / vial. 5Spread on a 12-well plate. After diluting the drug, add it to the cell culture medium so that the final concentrations of the drug are 1000 nM, 250 nM, 62.5 nM, 15.6 nM, 3.9 nM, 0.98 nM, 0.24 nM, and 0 nM respectively. Treat the cells with the drug for 24 hours. After 24 hours of drug treatment, take the cells out of the incubator and transfer them into 1.5 mL Eppendorf tubes. Centrifuge to remove the supernatant. Add 150 μL of RIPA lysis buffer to each tube and incubate on ice for 30 minutes. Run a protein gel for detection. Dilute Anti-VAV1 at 1:1000 and Anti-GAPDH at 1:5000, and incubate overnight at 4°C. Dilute the HRP secondary antibody at 1:10000 and incubate at RT for 1 hour. Detect the protein expression by chemiluminescence and analyze the gray value with ImageJ. The experimental results are shown in Table 1. The compound of the present invention shows excellent degradation effect on the degradation of VAV1 protein in Jurkat cells and is dose-dependent; the DC50 value of the compound of the present invention is numerically less than 10 nM, and some are even less than 5 nM; the Dmax value can reach more than 95%, and some even reach more than 98%, all of which are significantly better than the existing clinical compound MRT-6160.

[0678] Table 1 Degradation activity of the compound on VAV1 protein in Jurkat cells

[0679]

[0680]

[0681] *DC50≤10 nM is “A”, 10 nM < DC50≤30 nM is “B1”, 30 nM < DC50≤100 nM is “B2”, 100 nM < DC50≤1000 nM is “C”, DC50 > 1000 nM is “D”.

[0682] Experimental Example 4 Inhibition of CD3 / CD28-induced activation of Jurkat cells

[0683] Culture Jurkat cells (BFN60700175, Qingqi (Shanghai) Biotechnology Development Co., Ltd.) in RPMI-1640 medium containing inactivated 10% fetal bovine serum, 100 U / mL penicillin and 100 μg / mL streptomycin in an incubator at 37°C and 5% CO2. When the cell density reaches 1*10 ^6 passages and subculture. Seed the cells in logarithmic growth phase at 40,000 per well in a 96-well plate and add different concentrations of the compound. After 24 hours of treatment, add 5 μg / mL CD3 antibody and 1 μg / mL CD28 antibody (Dynabeads TMHuman T activator CD3 / CD28 (catalog number 11161D, manufacturer: Gibco) was used to culture the cells for another 24 hours. The cell supernatant was then collected for ELISA to detect IL-2 levels.

[0684] Experimental conclusion: In the CD3 / CD28-induced Jurkat cell activation model, the compound of this invention can significantly inhibit the production of IL-2, and the inhibitory function is positively correlated with the dose.

[0685] Experimental Example 5: Compound Inhibits CD3 / CD28-Induced Human T Cell Activation

[0686] Dilute fresh blood samples with an equal volume of PBS and slowly add them to a 50 mL centrifuge tube containing 15 mL of Lymphoprep (Stemcell, #7851), taking care not to disrupt the interface. Centrifuge at 1000 g, speed 5 for 25 minutes at room temperature, without immobilizing. Collect the leukocyte matrix (PBMC), wash twice with PBS, centrifuge at 350 g for 10 minutes, and discard the supernatant. Use a T cell sorting kit (Stemcell, #17951) to sort T cells from the PBMC and adjust the cell density to 2.6 × 10⁶ cells / mL. 6 75 μL of the diluted assay compound was added to each well of a U-bottom 96-well plate (Corning, #3799), followed by 75 μL of the diluted assay compound. For the control group, 1640 complete medium containing an equal volume of DMSO was added. Cells were mixed and incubated for 24 hours. Cells were then transferred to a 96-well plate (Thermo, #167425) coated with Anti-Human CD3 (5 μg / mL, BD, #555329), and 50 μL of Anti-Human CD28 (1 μg / mL, BD, #555725) was added. Cells were mixed and incubated for another 48 hours. The supernatant was collected, and IL-2 levels were detected using an IL-2 ELISA kit (BD, #555190).

[0687] Table 2. Inhibitory effects of compounds on CD3 / CD28-induced IL-2 secretion from T cells.

[0688] Number IC 50 (nM) Compound 2 0.53 Compound 6 0.55 Compound 15 0.33

[0689] Experimental conclusion: In the CD3 / CD28-induced human T cell activation model, the compound of this invention can significantly inhibit the production of IL-2, and the inhibitory function is positively correlated with the dose, which is superior to the clinical compound MRT-6160.

[0690] Experimental Example 6: Determination of the PK properties of compounds in mice

[0691] Three male ICR mice were used. The dose was 10 mg / kg, administered by gavage to a solvent of 5% DMSO + 10% Solutol + 85% Saline. The mice were fasted overnight. Blood samples were collected before administration and at 5, 15, and 30 minutes, and at 1, 2, 4, 6, 8, and 24 hours after administration. Blood samples were centrifuged at 6800g at 2-8℃ for 6 minutes, and plasma was collected and stored at -80℃. 10 μL of plasma from each time point was added to 200 μL of methanol containing 100 ng / mL internal standard, vortexed, and centrifuged at 18000g at 2-8℃ for 7 minutes. 200 μL was transferred to a 96-well plate for LC-MS / MS quantitative analysis. The main pharmacokinetic parameters were analyzed using a non-compartmental model with WinNonlin 7.0 software. The PK parameter results of the compounds of this invention are shown in Table 3.

[0692] Table 3. Mouse PK parameters of compounds

[0693]

[0694]

[0695] Experimental conclusion: In mouse models, the compound of this invention exhibits good pharmacokinetic properties, significantly outperforming compound MRT-6160 in various pharmacokinetic parameters, and demonstrates good drug-likeness.

[0696] Experimental Example 7: Rat Pharmacokinetic Test

[0697] Pharmacokinetic studies were conducted on male SD rats (180-240g) that had been fasted overnight. Three rats were administered the drug 10mg / kg orally via gavage. Blood samples were collected before administration and at 15, 30 minutes, 1, 2, 4, 8, and 24 hours after administration. 6800g of blood samples were centrifuged at 2-8℃ for 6 minutes, and plasma was collected and stored at -80℃. Plasma samples from each time point were mixed with 3-5 times the volume of acetonitrile solution containing an internal standard, vortexed for 1 minute, centrifuged at 13000 rpm at 4℃ for 10 minutes, and the supernatant was mixed with 3 times the volume of water. An appropriate amount of the mixture was analyzed by LC-MS / MS. Key pharmacokinetic parameters were analyzed using a non-compartmental model with WinNonlin 7.0 software.

[0698] Table 4. Rats' PK parameters of the compounds

[0699]

[0700] The results of the pharmacokinetic studies in rats showed that the compound of the present invention exhibited excellent pharmacokinetic properties in rats, and was significantly superior to compound MRT-6160 in various pharmacokinetic parameters, and had good drug-like properties.

[0701] Experimental Example 8: Test for the toxicity of compounds to hepatocellular cells

[0702] The hepatotoxicity assay of the compound was performed on HepG2 (ATCC, HB-8065) ​​cells. Cell viability was measured using the CellTiter-Glo Luminescent Cell Viability Assay kit (Promega, G7573). Inhibition of HepG2 cell viability was used to characterize the toxicity of the compound. Log-phase HepG2 cells were collected, and the cell suspension concentration was adjusted to 5000 cells / well in 96-well cell culture plates. The cells were incubated overnight in a 5% CO2 incubator at 37°C. The next day, the medium was changed, and different concentrations of the compound solution were added. A negative control group (cells + DMSO) and a blank control group (medium + DMSO) were also set up. The cells were incubated for 72 hours in a 5% CO2 incubator at 37°C. After treatment, the kit instructions were followed, and the luminescence signal values ​​in different wells were detected using an EnVision plate reader (2104). The inhibitory effect of different concentrations of the compound on the viability of HepG2 cells was calculated using the following formula, with compound concentration as the X-axis and inhibition rate as the Y-axis. The toxicity effect (IC50) of the compound on HepG2 cells was calculated using GraphPad Prism 8.0 software. 50 value).

[0703]

[0704] The results of hepatotoxicity tests show that the compounds of this invention exhibit good safety and low hepatotoxicity.

[0705] Experiment Example 9: Human Liver Microsomal Stability Test

[0706] The stability assay for human liver microsomes was performed by co-incubating the compound with human liver microsomes in vitro. First, the test compound was prepared as a 10 mM stock solution in DMSO, and then diluted to 0.5 mM with acetonitrile. Human liver microsomes (Corning) were diluted with PBS to prepare a microsome / buffer solution, and this solution was used to dilute the 0.5 mM compound to prepare the working solution. The concentration of the compound in the working solution was 1.5 μM, and the concentration of human liver microsomes was 0.75 mg / mL. 30 μL of the working solution was added to each well of a deep-well plate, followed by 15 μL of preheated 6 mM NADPH solution to initiate the reaction, which was incubated at 37°C. At 0, 5, 15, 30, and 45 minutes of incubation, 135 μL of acetonitrile was added to the corresponding well to terminate the reaction. After terminating the reaction with acetonitrile at the last 45 minutes, the deep-well plate was vortexed for 10 minutes (600 rpm / min) and then centrifuged for 15 minutes. After centrifugation, the supernatant was collected, and purified water was added at a 1:1 ratio. LC-MS / MS analysis was performed to obtain the ratio of the compound peak area to the internal standard peak area at each time point. The peak area ratios of the compounds at 5, 15, 30, and 45 minutes were compared with the peak area ratio at 0 minutes to calculate the remaining percentage of the compound at each time point. T1 / 2 was calculated using Graphpad 5 software.

[0707] The results of the human liver microsome stability test show that the compound of the present invention exhibits excellent human liver microsome stability and good drug-like properties.

[0708] Experimental Example 10: Inhibition of Cytochrome P450 by Compounds

[0709] The inhibitory potential of the compounds against the cytochrome P450 (CYP450) subtype CYP3A4 (two substrates: midazolam and testosterone) was investigated. First, the test compound was prepared as a 10 mM stock solution in DMSO, and the CYP3A4 inhibitor ketoconazole was prepared as 10 mM, 2.5 mM, and 2.5 mM stock solutions in DMSO. The test compound and ketoconazole were then diluted 400-fold to a final concentration (compound: 10 μM, ketoconazole: 2.5 μM) with acetonitrile.

[0710] Prepare 4-fold final concentrations of NADPH cofactor (66.7 mg NADPH added to 10 mL of potassium phosphate buffer) and substrates using potassium phosphate buffer (0.1 M, pH 7.4). The final concentrations of CYP3A4 substrate midazolam were 320 μM and CYP3A4 substrate testosterone were 20 μM.

[0711] Prepare a 0.2 mg / mL human liver microsome solution on ice using potassium phosphate buffer. Prepare two final concentrations of the analyte and control inhibitor solutions on ice using the human liver microsome solution. Add 30 μL of the analyte and control inhibitor solutions to each well, followed by 15 μL of substrate, and perform replicates. Incubate the 96-well plate and NADPH solution at 37°C for 5 minutes. Add 15 μL of preheated 8 mM NADPH solution to the plate to initiate the reaction. Pre-incubate the CYP3A4 plate at 37°C for 5 minutes. Stop the reaction by adding 120 μL of acetonitrile. After quenching, shake the plate on a shaker (IKA, MTS2 / 4) for 10 minutes (600 rpm / min), then centrifuge for 15 minutes. After centrifugation, the supernatant was collected, purified water was added at a 1:1 ratio, and LC-MS / MS was performed to obtain the ratio of the peak area of ​​the compound to the peak area of ​​the internal standard. The peak area ratio of the compound was compared with the peak area ratio of the control inhibitor to calculate the inhibition rate.

[0712] The results of the inhibition test of the compound on cytochrome P450 showed that the compound of the present invention had no significant inhibitory effect on CYP3A4 (two substrates, midazolam and testosterone) and had good drug-like properties.

[0713] Experimental Example 11: Test of Plasma Protein Binding Using Balanced Dialysis Method

[0714] First, human or other species plasma samples were stored at -20°C, thawed in a 37°C water bath before use, and stored on wet ice. The working solution for the test compound was prepared using DMSO with a stock concentration of 10 mM and a final concentration of 2 μM. The thawed plasma was centrifuged to remove suspended impurities and precipitates, and the pH was adjusted to 7.0–8.0. The pretreated dialysis membrane was loaded into the dialysis apparatus according to the manufacturer's instructions and the assembly was completed. For the zero-point control sample, blank plasma was mixed with the working solution of the test compound and vortexed at 1000 rpm for 2 minutes to a final concentration of 2 μM. This mixture was immediately transferred to a 96-well plate as the T=0 control sample, and the remaining mixture was incubated in a constant temperature incubator. To determine the stability of the compound in plasma, the remaining mixture was incubated in a 37°C shaking incubator for 5 hours. After incubation, 50 μL of the sample was transferred to a 96-well plate for subsequent analysis. The equilibration dialysis procedure was performed by assembling the dialysis apparatus according to the manufacturer's instructions. Plasma samples were added to the dialysis chamber and dialyzed with an equal volume of PBS buffer. Experiments were conducted with replicates. The apparatus was covered with a breathable cap and incubated at 37°C and 100 rpm for 5 hours. After incubation, samples were taken from the plasma chamber and buffer chamber and transferred to 96-well plates for analysis. During sample processing, plasma or PBS was added to the collected samples and mixed for 2 minutes. 500 μL of 80% acetonitrile / methanol solution containing an appropriate internal standard was added to precipitate proteins and release compounds. After vortexing for 10 minutes, the mixture was centrifuged at 4000 rpm for 10 minutes. 100 μL of the supernatant was transferred to a new 96-well plate, and 300 μL of distilled water was added and mixed before LC-MS / MS analysis. All samples underwent automatic peak area integration. The peak areas of the analytes and internal standard were exported to an Excel spreadsheet. The free fraction, binding fraction, and recovery rate of the compounds were calculated using the following formulas:

[0715] Unbound percentage (% Unbound) = (buffer fluid cavity peak area ratio / plasma cavity peak area ratio) × 100;

[0716] Bound rate (%Bound) = 100 - %Unbound;

[0717] Recovery (%Recovery) = (Buffer cavity peak area ratio + Plasma cavity peak area ratio) / Total sample peak area ratio × 100;

[0718] Remaining (% Remaining) = 5-hour peak area ratio / 0-hour peak area ratio × 100.

[0719] Table 5. Results of plasma protein binding assay

[0720] Compound Number Species Test Concentration Free % Bound % Compound 8 Human 2 μM 24.4 75.6 Compound 12 Human 2 uM 30.0 70.0

[0721] Experimental results show that the compound of the present invention is significantly superior to compound MRT-6160 in terms of plasma protein binding rate, demonstrating a significant advantage.

[0722] Experiment Example 12: Bidirectional Osmosis Experiment in Caco-2 Cell Model

[0723] Experimental methods:

[0724] 1) Cell Culture: Caco-2 cells were purchased from the Cell Resource Center of the Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and seeded on... The upper chamber (apical side) of the multi-well plate was cultured in 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 and 5% CO2. The cell culture period was 14–28 days, during which the medium was changed regularly until a dense monolayer was formed and sufficient transepithelial electrical resistance (TEER ≥ 230 ohms·cm2) was achieved.

[0725] 2) Permeability Experiment: Caco-2 cell Transwell plates removed from the incubator were rinsed with pre-warmed transport buffer and incubated at 37°C for 30 minutes. Permeability experiments were performed in both the A→B and B→A directions: the test compound solution was added to the drug delivery end, and buffer was added to the receiving end. Initial samples (TA0 or TBO) were collected immediately, and samples were taken at time points T0 and T120. After incubating the Transwell plates at 37°C for 120 minutes, samples were collected from both the drug delivery and receiving ends and treated with quenching solution (acetonitrile, containing verapamil and glibenclamide). All samples were mixed, centrifuged, and the supernatant was diluted and analyzed by LC-MS / MS, with duplicate wells for each group.

[0726] 3) Data Analysis:

[0727] Cell compaction was determined by measuring transmembrane resistance before and after a osmosis experiment; if the resistance was below 230 Ω·cm... 2 Monolayers of cells were not included in the analysis.

[0728] Apparent permeability coefficient (Papp) calculation:

[0729]

[0730] Where: CR is the concentration at the receiving end after incubation, CD0 is the initial concentration at the drug delivery end, and VR is the solution volume at the receiving end (A→B is...).

[0731] 1.3 mL (B→A is 0.2 mL), where A is the area of ​​the monolayer cell membrane (0.33 cm2) and T is the incubation time (7200 seconds).

[0732] Efflux Ratio Calculation:

[0733]

[0734] Recovery rate calculation:

[0735]

[0736] 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.

[0737] Table 6. Results of bidirectional permeability experiments in the Caco-2 cell model.

[0738]

[0739]

[0740] 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.

[0741] Experimental Example 13: Pharmacological evaluation of the compound in a mouse model of inflammatory bowel disease induced by adoptive T cell transfer.

[0742] 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.

[0743] Experimental methods:

[0744] 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.

[0745] 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.

[0746] 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.

[0747] 4) Mice were sacrificed on day 35, and colon tissue was collected. At the endpoint, the colon was collected, its length measured, washed with PBS to remove feces, dried, and weighed. The weight-to-length ratio was calculated. At the endpoint dissection, the colon contents were cleaned and preserved for pathological scoring.

[0748] The results showed that the test compounds of the present invention significantly alleviated the disease progression in an adoptive naïve T cell-induced mouse enteritis model.

Claims

1. The compound represented by formula (Ⅰ), its tautomers, stereoisomers, pharmaceutically acceptable salts or prodrugs, in, 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 C 1-6 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; 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 R4 are independently H, D, halogen, NH2, CN, and C, respectively. 1-6 Alkyl or halogenated C 1-6 alkyl; Each R5 is independently H, D, halogen, NH2, CN, or C. 1-6 Alkyl or halogenated C 1-6 alkyl; R8 is H, D, halogen, or C. 1-6 alkyl; L1 represents a single bond, -O-, -NH-, or -OC. 1-3 Alkyl-, -NH-C 1-3 Alkyl- or -C 1-3 alkyl-, wherein -NH-, -OC- 1-3 Alkyl-, -NH-C 1-3 Alkyl- and -C 1-3 Alkyl groups are each independently and optionally marked with 1, 2, 3, or 4 R groups. 1L replace; Each R 1L Independently represented by H, D, halogen, and C respectively. 1-3 Alkyl, Halogenated C 1-3 Alkyl or C 3-6 cycloalkyl; 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; 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-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; Each L2 is independently -O-, -N(R) 2L )-、-N(R 2L -C(=O)-, -S-, -S(=O)-, -S(=O)2- or -C(=O)-; R 2L For H or C 1-3 alkyl; Each R 6a C 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; 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 6c Each can be independently H, D, halogen, OH, NH2, CN, or C. 1-6 Alkylamino; 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 group; m is 1, 2, 3 or 4; n is 1, 2, 3 or 4; g can be 0, 1, 2, 3, or 4; The heteroatomic groups in the "heterocyclic alkyl", "heterocyclic alkenyl" and "heteroaryl" include N, O, S, S(=O), S(=O)2 or S(=O)(=NH), and the number of the heteroatomic groups is 1, 2, 3 or 4; when the number of the heteroatomic groups is multiple, the heteroatomic groups may be the same or different.

2. The compound, its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs according to claim 1, characterized in that, R1 is F, Cl, Br, CN, or C. 1-3 Alkyl, -OC 1-3 Alkyl, C 3-6 cycloalkyl, C 2-4 alkenyl, C 2-4 Alkyne group or 4-6 membered heterocyclic alkyl group, wherein the C 1-3 Alkyl, -OC 1-3 Alkyl, C 3-6 cycloalkyl, C 2-4 alkenyl, C 2-4 The alkynyl or 4-6 membered heterocyclic alkyl group is independently and optionally surrounded by 1, 2, 3 or 4 R groups. 1a replace; Or, each R 1a They can be H, F, Cl, OH, NH2, or CN, respectively. Alternatively, R1 can be Cl; Alternatively, R2, R3, and R4 can be independently H, halogen, NH2, CN, and C, respectively. 1-3 Alkyl or halogenated C 1-3 Alkyl group; preferably, R2, R3 and R4 are each independently H.

3. The compound, its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs according to claim 1, characterized in that, Each R5 is independently H, halogen, NH2, CN, or C. 1-3 Alkyl or halogenated C 1-3 Alkyl group; preferably, each R5 is independently H; Alternatively, R8 can be H or D; Or, the R 6-2 For H.

4. The compound, its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs according to claim 1, characterized in that, It has any one of the following schemes 1 to 4: Scheme 1. The compound, its tautomers, stereoisomers, pharmaceutically acceptable salts or prodrugs, are characterized by having the structure of formula (II): Where R1 is F, Cl, Br, or C. 1-3 alkyl; 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; Each bond can be a single or double bond independently, provided that the valence bond allows it. V1, V2, V3, V4 and V5 are each independently CH, CH2, N or NH; V6 is 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 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; L2 is -O-, -NH-, or -NH-C(=O)-; R 6a R 6b R 6c As defined in claim 1; Scheme 2. The compound, its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs, characterized in that they have the following formula: (II) Structure: Where R1 is F, Cl, Br, or C. 1-3 alkyl; 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; Each bond can be a single or double bond independently, provided that the valence bond allows it. V1, V2, V3, V4 and V5 are each independently CH, CH2, N or NH; V6 is 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 groups; preferably, each R 6-2 They can be H or oxo (=O) independently, respectively; 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; preferably, 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; R 6a C 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 Each alkoxy group is independently substituted by one or two R groups; each R group is independently H, D, halogen, or OH; preferably, the R groups are... 6a Each R is independently -CH3 or -CH2-OCH3 substituted with one or two Rs; each R is independently H, D, F, or OH; more preferably, the Rs are... 6a They can be independently -CH2-OH, -CH2F, -CHF2, -CF3, -CH2-CH2F, or -CH2-OCF3; Scheme 3. The compound, its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs are characterized by having the following formula: (III-1) Structure: Where R1 is F, Cl, Br, or C. 1-3 alkyl; 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; Each bond can be a single or double bond independently, provided that the valence bond allows it. V1, V2, V3, V4 and V5 are each independently CH, CH2, N or NH; V6 is 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 groups; preferably, each R 6-2 They can be H or oxo (=O) independently, respectively; Each L2 is independently -O-, -NH-, or -NH-C(=O)-; q can be 0, 1, 2 or 3 independently; 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; R 6b They are, independently, H, D, halogen, OH, NH2, CN, and C. 1-6 Alkyl or halogenated C 1-6 alkyl; Scheme 4. The compound, its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs, characterized in that they have the following formula: (III-2) Structure: Where R1 is F, Cl, Br, or C. 1-3 alkyl; 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; Each bond can be a single or double bond independently, provided that the valence bond allows it. V1, V2, V3, V4 and V5 are each independently CH, CH2, N or NH; V6 is 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 groups; preferably, each R 6-2 They can be H or oxo (=O) independently, respectively; Each R 6-1 Each can be independently controlled by 1, 2, 3 or 4 Rs. 6c Replacement C 1-6 Alkoxy; preferably, each R 6-1 Each can be independently controlled by 1, 2, 3 or 4 Rs. 6c Replacement C 1-4 Alkoxy; Each R 6c Each can be independently H, D, halogen, OH, NH2, or C. 1-3 Alkylamino; preferably, each R 6c They are independently H, D, F, Cl, OH, NH2 or Scheme 5. The compound, its tautomers, stereoisomers, pharmaceutically acceptable salts or prodrugs, are characterized by having the following structure (III-3): Where R1 is Cl; L1 is a single bond or -O-; Each bond can be a single or double bond independently, provided that the valence bond allows it. V1, V2, V3, V4 and V5 are each independently CH, CH2, N or NH; V6 is C, CH, or N; Each R 6-2 They can be H or oxo (=O) independently, respectively; Preferably, the for More preferably, the for Each R 6x Each can be independently controlled by 1, 2, 3 or 4 Rs. 6y Replaced by: C 1-4 Alkyl, C 3-4 cycloalkyl, 3-4 membered heterocyclic, -C 1-3 Alkyl-C 3-4 cycloalkyl; preferably, each R 6x Each can be independently controlled by 1, 2, 3 or 4 Rs. 6y Substituted with: cyclopropyl, methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, oxecyclobutyl, -CH2-cyclopropyl; more preferably, each R 6x They are independently -CHF2, -CDF2, and -CF3, respectively. Each R 6y Each can be independently H, D, halogen, OH, NH2, or C. 1-3 Alkylamino; preferably, each R 6y They are independently H, D, F, Cl, OH, NH2 or 5. The compound, its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs according to claim 1, characterized in that, It has any of the following structures: Among them, V1, V2, V3, V4, and V5 are 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, its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs according to claim 5, characterized in that, The compound satisfies one or more of the following conditions: a) Having structure b) Having structure c) Having structure 7. The compound, its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs according to claim 1, characterized in that, 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; Or, each R 1L They can be H, F, Cl, or CH3 independently; Alternatively, L1 above can be a single bond, -O-, or -CH2-.

8. The compound, its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs according to claim 1 or 5, characterized in that, Ring A is phenyl, 5-10 membered heterocyclic alkenyl, or 5-10 membered heteroaryl; Alternatively, ring A can be phenyl, 5-6 membered heterocyclic alkenyl, or 5-6 membered heteroaryl; Alternatively, ring A is Alternatively, ring A is "*" indicates a site connected to L1.

9. The compound, its tautomer, stereoisomer, pharmaceutically acceptable salt, or prodrug according to claim 1 or 5, characterized in that, Each R 6-1 Each independently is assigned to 1, 2, 3, or 4 R's. 6c Replacement C 1-4 Alkoxy; Or, each R 6-1 Each independently represents -OCH3, The -OCH3, Each independently is assigned to 1, 2, 3, or 4 R's. 6c replace; Or, each R 6c They are independently H, D, F, Cl, OH, NH2 or Or, each R 6-1 They are independently -OCH3, -OCHF2, -OCDF2, -OCF3, 10. The compound, its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs according to claim 1 or 5, characterized in that, 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 6a Each can be independently -CH3 or -CH2-OCH3, wherein -CH3 and -CH2-OCH3 are independently replaced by 1, 2, 3 or 4 Rs, respectively; Alternatively, each R can be 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 6-1 Each independently 11. The compound, its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs according to claim 1 or 5, characterized in that, Each R 6-1 Each independently is assigned to 1, 2, 3, or 4 R's. 6b Replacement -L2-C 3-6 Cycloalkyl, with 1, 2, 3 or 4 R 6b Substituted -L2-4-8-membered heterocyclic alkyl group, with 1, 2, 3 or 4 R 6b Replacement -L2-C 1-3 Alkyl-C 3-6 Cycloalkyl groups or those with 1, 2, 3 or 4 R groups 6b Replacement -L2-C 1-3 Alkyl-4-8-membered heterocyclic alkyl; Or, each R 6-1 They are independently -L2-cyclopropyl, -L2-cyclobutyl, -L2-azacyclobutyl, -L2-cyclopentyl, -L2-oxacyclohexyl, -L2-oxacyclopentyl, -L2-tetrahydrofuranyl, -L2-tetrahydropyranyl, -L2-CH2-cyclopropyl, -L2-CH2-cyclobutyl, -L2-CH2-cyclopentyl, -L2-CH2-oxacyclopentyl, -L2-CH2-tetrahydrofuranyl, and -L2-CH2-tetrahydropyranyl. The -L2-cyclopropyl, -L2-cyclobutyl, -L2-azacyclobutyl, -L2-cyclopentyl, -L2-oxacyclopentyl, -L2-tetrahydrofuranyl, -L2-tetrahydropyranyl, -L2-CH2-cyclopropyl, -L2-CH2-cyclobutyl, -L2-CH2-cyclopentyl, -L2-CH2-oxacyclopentyl, -L2-CH2-tetrahydrofuranyl, and -L2-CH2-tetrahydropyranyl groups are each independently surrounded by 1, 2, 3, or 4 R groups. 6b replace; Alternatively, each L2 can be independently -O-, -N(R) 2L )-、-N(R 2L -C(=O)-, -S-, -S(=O)-, -S(=O)2- or -C(=O)-; Or, R 2L It is H or CH3; Alternatively, each L2 can be independently -O-, -NH-, -NH-C(=O)-, -S-, -S(=O)-, -S(=O)2- or -C(=O)-; Alternatively, each L2 can be independently -O- or -NH-C(=O)-; Or, each R 6-1 Each independently The Each independently is assigned to 1, 2, 3, or 4 R's. 6b replace; Or, each R 6b They are, independently, H, F, Cl, OH, NH2, CN, and C. 1-3 Alkyl or halogenated C 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 6-1 Each independently 12. The compound, its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs according to claim 1 or 5, characterized in that, Each R 6-1 They are independently -OCH3, -OCHF2, -OCDF2, -OCF3, 13. The compound, its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs according to claim 1, characterized in that, The compound has the following structure:

14. A pharmaceutical composition, characterized in that, The compound comprising a therapeutically effective dose of any one of claims 1-13, its tautomers, stereoisomers, pharmaceutically acceptable salts or prodrugs, and pharmaceutically acceptable excipients.

15. Use of the compound, its tautomer, stereoisomer, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition according to any one of claims 1-13 in the preparation of a medicament for the treatment and / or prevention of diseases associated with VAV1.

16. The use according to claim 15, characterized in that, VAV1-related diseases include cancer or autoimmune diseases.

17. The use according to claim 15, characterized in that, The VAV1-related diseases include systemic lupus erythematosus, myasthenia gravis, periodontitis, type 1 diabetes, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, autoimmune hepatitis, or psoriasis.

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