Biphenyl compound, and pharmaceutical composition thereof and use thereof

Abstract

The present application relates to a biphenyl compound, and a pharmaceutical composition thereof and the use thereof. Specifically, provided is a biphenyl compound as represented by formula (I), which can be used in the preparation of a drug, particularly in the preparation of a drug for preventing and / or treating diseases or conditions caused by or associated with the dysregulation of lymphocyte development or activity. Each group in formula (I) is as defined in the description.

Description

Biphenyl compounds, pharmaceutical compositions thereof and uses thereof

[0001] Cross-reference to related applications

[0002] This application is based on and claims priority to CN application No. 202411356420.3, filed on September 27, 2024, the contents of which are incorporated herein in their entirety. TECHNICAL FIELD

[0003] The present application belongs to the field of medicine, and specifically relates to a biphenyl compound, a pharmaceutical composition thereof and a use thereof, which can be used as a VAV1 degradation agent. BACKGROUND

[0004] VAV1 is a member of the VAV family, which is a group of signal transduction proteins, and is a phosphorylation-dependent GDP / GTP exchange factor (GEF) and adaptor molecule for Rho subfamily GTPases. In vertebrates, the family consists of three members - VAV1, VAV2 and VAV3. VAV1 is mainly expressed in hematopoietic stem cells, including T cells, B cells, monocytes, natural killer (NK) cells, granulocytes and dendritic cells, while family members VAV2 and VAV3 are more commonly expressed. The VAV protein family is essential for the homeostasis of the central nervous system, cardiovascular system and immune system, and is involved in the occurrence and development of autoimmune diseases, graft rejection, cancer and other diseases.

[0005] VAV1 has multiple domains, which determine its dual functions as a GEF and a scaffold protein. In the resting state, non-phosphorylated VAV1 exhibits a closed, inactive conformation: the CH-AC domain at the amino terminus and the SH3 domain at the carboxy terminus are folded towards the middle and bind to the catalytic core (DH-PH-ZF domain), which simultaneously inhibits GEF activity and linker protein function. When the AC structure of VAV1 is phosphorylated, the inhibitory folding of the protein is released, forming an open, active conformation, and performing GEF function and linker protein function. The main substrate for VAV1 to exert GEF function is Rac1, which is involved in the regulation of actin dynamics signaling pathway and cytoskeleton remodeling, and realizes the migration, adhesion and immune synapse formation of immune cells. The function of the scaffold protein: interacts with various protein complexes to form a TCR / BCR proximal complex, and plays a linker protein function to regulate T cell receptor and B cell receptor activation signal transduction.

[0006] VAV1 is a key component of the antigen receptor signaling complex and is associated with the T cell receptor (TCR) / CD3 and B cell receptor. In T cells, a 76 kDa leukocyte protein containing Src homology (SH) 2 domains (SLP76) is recruited to the transmembrane adaptor, linker for activation of T cells (LAT), through its SH2 domains, thereby activating the T cell. The LAT / SLP76 complex is a critical scaffold for other proteins in the TCR proximal signaling complex, including VAV1. VAV1 interacts with other proteins through SH2 and proline-rich region / SH3 domains. In B cells, VAV1 interacts with a signaling complex that includes a scaffolding protein homologous to SLP76, SLP65 (also known as B cell linker protein), Bruton's tyrosine kinase (BTK), Grb2, and phospholipase-gamma (PLC gamma) 2. Assembly of these protein complexes activates downstream events, including phosphorylation of PLC gamma 1 / 2; activation of Ca2+, protein kinase C (PKC), p38 mitogen-activated protein kinase (MAPK)-mediated signaling pathways; regulation of transcription factors, including nuclear factor of activated T cells (NFAT), nuclear factor kappa B (NF-KB), and activator protein-1 (AP-1). VAV1 does not depend on the "scaffolding" function of guanine nucleotide exchange factors (GEFs) and appears to depend on its participation in these antigen receptor-proximal signaling complexes. The primary function of VAV1 that depends on GEFs is to activate the Rac / Rho family GTPases. Optimal phosphorylation of VAV1 and activation of downstream signaling pathways are critical in T cells and B cells through co-stimulation of CD28 and CD19, respectively. The exact mechanism of VAV1 co-receptor activation remains to be fully determined. Although the exact role of VAV1 in human disease remains to be clinically validated, multiple lines of evidence suggest that VAV1 is associated with autoimmune and chronic inflammatory diseases, supporting its role as a therapeutic target.

[0007] Targeted protein degradation technology is a breakthrough drug development strategy for challenging drug targets. This technology can specifically recognize target proteins and directly degrade pathogenic target proteins using the intrinsic protein degradation pathway in cells. Targeted protein degradation (TPD) currently mainly degrades target proteins through ubiquitin proteasome and lysosomal degradation, and can be further divided into nearly 10 different technical routes according to the specific action principle. Among them, the molecular glue and targeted proteolysis chimera (PROTAC) technology is the fastest growing. Molecular glue is a small molecule that induces proximity, which can precisely control the timing of various biological processes, such as signal transduction, transcription, chromatin regulation, and protein folding, localization and degradation. As a proximity chemical inducer, molecular glue can promote the dimerization or co-localization of two proteins by forming a ternary complex, thereby producing a variety of biological and pharmacological functions. Generally speaking, molecular glue has small molecular weight and its physicochemical properties are easy to optimize. Molecular glue mainly induces or stabilizes the protein interaction between ubiquitin ligase and substrate protein, thereby leading to protein degradation, and can degrade inaccessible target proteins without the need for a binding pocket on the target protein. This mechanism provides a new way for targeting “undruggable” proteins, greatly expanding the scope and application prospects of drug design. VAV1 does not have a clear binding pocket, and there are many challenges in developing small molecule inhibitors. Novartis has studied VAV1 small molecule inhibitors (targeting GEF activity), but only disclosed the structure and in vitro activity information at the 2018 ACS meeting, with no subsequent research progress disclosed. Therefore, ubiquitination degradation of this type of protein through molecular glue is a good research direction. Currently, only Monte Rosa Company has developed VAV1 molecular glue MRT-6160, which is in phase 1 clinical trial, and more molecular glue with novel structure is needed to verify the druggability of the VAV1 target. SUMMARY

[0008] The present application provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

[0009] wherein:

[0010] T is

[0011] R 10 is selected from

[0012] R A is a chemical bond or R 17 ;

[0013] G 1 is N or CR 16c ;

[0014] G 2 G 3 and G 4 The same or different, and each independently constitutes NR. 18c or C(R) 18 )2;

[0015] G 5 It can be C or N;

[0016] G 6 For N or CR 16c ;

[0017] G 7 For N or CR 16d ;

[0018] It can be a single bond or a double bond;

[0019] Ring A is selected from C 3-10 Cycloalkanes, 3-10 membered heterocycles, C 6-10 Aromatic rings and 5-10 heterocyclic aromatic rings;

[0020] B represents a boron atom;

[0021] X is selected from CR X1 R X2 NR X3 , O or S;

[0022] Z is CR 4 Or N;

[0023] R 1 and R 2 They may be the same or different, and each is independently selected from H, halogen, hydroxyl, cyano, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0024] R 3 Selected from H, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, hydroxy, cyano, amino and C 3-6 cycloalkyl;

[0025] R 4 and R 5 They may be the same or different, and each is independently selected from H, halogen, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, hydroxy, cyano, amino, C 3-6 cycloalkyl and 3-6 membered heterocyclic groups, wherein the C1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-6 cycloalkyl and 3- to 6-membered heterocyclyl, which are optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, cyano, amino, oxo, C 3-6 cycloalkyl and 3- to 6-membered heterocyclyl;

[0026] R 6 , R 7 , R 8 and R 9 are identical or different and each independently selected from the group consisting of H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, hydroxyl, cyano, amino, C 3-6 cycloalkyl and 3- to 6-membered heterocyclyl;

[0027] R 11 is selected from the group consisting of H, hydroxyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, cyano, C 3-6 cycloalkyl and 3- to 6-membered heterocyclyl;

[0028] L 1 and L 2 are identical or different and each independently selected from the group consisting of a bond, C 1-6 alkylene, C(O) and C 3-6 cycloalkyl, which C 1-6 alkylene and C 3-6 cycloalkyl are optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, cyano, amino;

[0029] R 12 is selected from the group consisting of H, halogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl, cyano, NR b R c , C(O)R a , C(O)NR b Rc NR b C(O)R a NR b C(O)NR b R c S(O) 0-2 R d C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein said C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are optionally substituted with one or more R g ;

[0030] R 13 and R 14 are the same or different and each is independently selected from H, halo, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, cyano, amino, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, said C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are optionally substituted with one or more substituents selected from halo, hydroxy, C 1- 6alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, cyano, amino, oxo, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;

[0031] R 15 is selected from H, hydroxy, C 1-6 alkoxy, C 1-6 alkyl, cyano, -NR b R c , -OC(O)R a , C 3-6 cycloalkyl and 3-6 membered heterocyclyl, said C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl and 3-6 membered heterocyclyl are optionally substituted with one or more R g ;

[0032] R 16a , R 16b , R 16c and R16d the same or different, and each independently selected from the group consisting of H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, hydroxy, cyano, amino, C 3-6 cycloalkyl and 3- to 6-membered heterocyclyl;

[0033] or two adjacent R 16a , R 16b , R 16c and R 16d form, with the atoms to which they are attached, a 5- to 10-membered heterocyclic ring or a 5- to 10-membered heteroaromatic ring, which is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, cyano, amino, oxo, C 3-6 cycloalkyl and 3- to 6-membered heterocyclyl;

[0034] R 17 is selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 3-6 cycloalkyl and 3- to 6-membered heterocyclyl;

[0035] R 18a and R 18b are the same or different, and each independently selected from the group consisting of H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, hydroxy, cyano, amino, C 3-6 cycloalkyl and 3- to 6-membered heterocyclyl;

[0036] each R 18 is selected from the group consisting of H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, hydroxy, cyano, amino, C 3-6 cycloalkyl and 3- to 6-membered heterocyclyl;

[0037] R 18c is selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C3-6 cycloalkyl and 3- to 6-membered heterocyclyl;

[0038] R 19 and R 21 are the same or different and each independently selected from the group consisting of H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 cyanoalkyl, C 3-6 cycloalkyl and 3- to 6-membered heterocyclyl;

[0039] R 22 is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 cyanoalkyl, C 1-6 cyanoalkyl, C 3-6 cycloalkyl and 3- to 6-membered heterocyclyl;

[0040] R 20 and R 23 are the same or different and each independently selected from the group consisting of H, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 cyanoalkyl, C 3-6 cycloalkyl and 3- to 6-membered heterocyclyl;

[0041] R 24 and R 25 are the same or different and each independently selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 cyanoalkyl, C 1-6 cyanoalkyl, C 3-6 cycloalkyl and 3- to 6-membered heterocyclyl;

[0042] or R 24 and R 25 form together with the atom to which they are attached a 5- to 10-membered heterocyclic ring, which is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 3-6one or more substituents selected from the group consisting of halogen, deuterium, oxo, C1-6alkyl,

[0043] R g are the same or different and each is independently selected from the group consisting of halogen, deuterium, oxo, C1-6alkyl, 1-6 C1-6alkyl, C1-6haloalkyl, 1-6 C1-6alkoxy, C1-6haloalkoxy, 1-6 C1-6alkyl, C1-6haloalkyl, 1-6 C1-6alkyl, C1-6haloalkyl, 1-6 C1-6alkyl, C1-6haloalkyl, 1-6 C1-6alkyl, C1-6haloalkyl, 1-6 C1-6alkyl, C1-6haloalkyl, 1-6 C1-6alkyl, C1-6haloalkyl, 1-6 C1-6alkyl, C1-6haloalkyl, b R c , C(O)R a , C(O)NR b R c , NR b C(O)R a , NR b C(O)NR b R c , S(O) 0-2 R d , hydroxyl, cyano, amino, C1-6alkyl, 3-10 C1-6alkyl, C1-6haloalkyl, 6-10 C1-6alkyl, C1-6haloalkyl,

[0044] R a is selected from the group consisting of C1-6alkyl, 1-6 C1-6alkyl, C1-6haloalkyl, 1-6 C1-6alkyl, C1-6haloalkyl, 1-6 C1-6alkyl, C1-6haloalkyl, 1-6 C1-6alkyl, C1-6haloalkyl, 1-6 C1-6alkyl, C1-6haloalkyl, 1-6 C1-6alkyl, C1-6haloalkyl, 1-6 C1-6alkyl, C1-6haloalkyl, 3-6 C1-6alkyl, C1-6haloalkyl,

[0045] R b and R c are the same or different and each is independently selected from the group consisting of H, C1-6alkyl, 1-6 C1-6alkyl, C1-6haloalkyl, 1-6 C1-6alkyl, C1-6haloalkyl, 1-6 C1-6alkyl, C1-6haloalkyl, 1-6 C1-6alkyl, C1-6haloalkyl, 1-6 C1-6alkyl, C1-6haloalkyl, 3-6 C1-6alkyl, C1-6haloalkyl,

[0046] or R b and R cwith its attached atoms form a 3-10 membered heterocycle, which is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, oxo, amino, and cyano;

[0047] R d is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, cyano, amino, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl;

[0048] R X1 and R X2 are the same or different and each is independently selected from the group consisting of H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, hydroxyl, cyano, amino, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl;

[0049] R X3 is selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, cyano, amino, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl;

[0050] p is 0, 1, or 2;

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

[0052] t is 0, 1, 2, 3, or 4.

[0053] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0054] R B is a bond or R 16d ;

[0055] R 10 is selected from

[0056] Ring A, G 1 , G2 , G 3 , G 4 , G 5 , L 1 , L 2 , R 12 , R 13 , R 14 , R 15 , R A , R 16a , R 16b , R 16d , R 17 , R 18a , R 18b , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , r and t are as defined in the compound of Formula (I).

[0057] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is a compound of Formula (I-1) or Formula (I-2):

[0058] wherein, R 1 , R 2 , R 3 , Z, R 5 and T are as defined in Formula (I).

[0059] In some embodiments, the compound of Formula (I), Formula (I-1), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from

[0060] m is 0, 1, 2, 3, 4, 5, 6, 7, or 8;

[0061] ring A, L 1 , L 2 , R 12 , R 13 , R 14 , R 15 , R 16a , R 16b , R 16c , R 16d , R 17 , R 18 , R 18c , R 19 , R 20 , R21 , R 22 , R 23 , R 24 , R 25 , r and t are as defined herein.

[0062] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3, or 4.

[0063] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein m is 0.

[0064] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein r is 0 or 1.

[0065] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein t is 0.

[0066] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein Z is CR 4 ; R 4 as defined herein.

[0067] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein

[0068] R 10 is selected from L 1 , L 2 , R 12 , R 13 , R 14 and R 15 as defined herein.

[0069] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein L 1 and L 2 are the same or different and each is independently selected from a bond, -CH2-, -CH2F2, -CH2CH2-, -C(CH3)2-, -CH(CH3)-, and C(O).

[0070] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 12H, halogen, deuterium, C 1-3 alkyl, C 1-3 alkoxy, hydroxy, cyano, NR b R c , C(O)NR b R c , NR b C(O)R a , NR b C(O)NR b R c , C 3-6 cycloalkyl, 3-10 membered heterocyclyl, phenyl and 5-10 membered heteroaryl, wherein said C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 3-10 membered heterocyclyl, phenyl and 5-10 membered heteroaryl are optionally substituted with one or more R g ;

[0071] R a is selected from C 1-6 alkyl and C 3-6 cycloalkyl;

[0072] R b and R c are the same or different and each is independently selected from H, C 1-6 alkyl and C 3-6 cycloalkyl; or, R b and R c together with the atom to which they are attached form a 5-10 membered heterocyclic ring, said 5-10 membered heterocyclic ring is optionally substituted with one or more substituents selected from halogen, oxo and C 1-6 alkyl;

[0073] R g is as defined in formula (I).

[0074] In some embodiments, the compound of Formula (I), Formula (I-1), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein the 3-10 membered heterocyclyl is selected from 4-7 membered monocyclic heterocyclyl, 6-10 membered fused heterocyclyl, 6-10 membered spiro heterocyclyl, 6-10 membered bridged heterocyclyl, the heteroatoms in said heterocyclyl and heteroaryl are selected from N, O or S; the number of said heteroatoms can be 1, 2, 3 or 4.

[0075] In some embodiments, the compound of Formula (I), Formula (I-1), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 12 is selected from H, halogen, deuterium, C 1-3 alkyl, C 1-3 alkoxy, hydroxy, C 1-3 haloalkyl, C1-3 haloalkoxy, C 1-3 hydroxyalkyl, cyclopropyl, oxetanyl, phenyl, pyridinyl, NHCH3, N(CH3)2, C(O)N(CH3)2, NHC(O)CH3, NHC(O)NHCH3, the H on NH can be replaced by Rg; s is 0, 1, 2, or 3 (such as 0, 1, or 2); R g as defined in Formula (I).

[0076] In some embodiments, R g are the same or different and each is independently selected from halogen, C 1-6 alkyl, oxo, C 3-6 cycloalkyl, and C 1-6 haloalkyl.

[0077] In some embodiments, R g are the same or different and each is independently selected from halogen, C 1-6 alkyl, C 3-6 cycloalkyl, and C 1-6 haloalkyl.

[0078] In some embodiments, R g are the same or different and each is independently selected from F, methyl, oxo, cyclopropyl, and -CF3.

[0079] In some embodiments, R g are the same or different and each is independently selected from F, methyl, cyclopropyl, and -CF3.

[0080] In some embodiments, R 12 is selected from H, methyl, F, cyclopropyl, hydroxyl, methoxy,

[0081] In some embodiments, the compound of Formula (I), Formula (I-1), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 13 and R 14 are the same or different and each is independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl.

[0082] In some embodiments, the compound of Formula (I), Formula (I-1), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 13 and R 14the same or different, and each independently selected from H, F, methyl, -CF3, and cyclopropyl.

[0083] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 15 is selected from H, hydroxyl, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 haloalkoxy, C 1-6 haloalkyl, C 1-6 deuteroalkoxy, C 1-6 deuteroalkyl, -CH2OC 1-6 alkyl, NR b R c and -OC(O)R a ;

[0084] R a is selected from C 1-6 alkyl and C 3-6 cycloalkyl;

[0085] R b and R c are the same or different, and each independently selected from H, C 1-6 alkyl and C 3-6 cycloalkyl; or, R b and R c together with the atoms to which they are attached form a 5-10 membered heterocyclic ring, which is optionally substituted with one or more substituents selected from halogen, oxo, and C 1-6 alkyl.

[0086] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 15 is selected from H, hydroxyl, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 haloalkoxy, C 1-6 haloalkyl, C 1-6 deuteroalkoxy, C 1-6 deuteroalkyl, -CH2OC 1-6 alkyl, NR b R c and -OC(O)R a ;

[0087] R a is C 1-6 alkyl;

[0088] R b and R c are the same or different, and each independently selected from H, C1-6 Alkyl and C 3-6 Cycloalkyl.

[0089] In some embodiments, the compound represented by formula (I), formula (I-1), or formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 15 Selected from hydroxyl, C 1-6 Alkoxy groups (such as C) 1-3 alkoxy), C 1-3 Alkyl, C 1-3 Halogenated alkoxy groups, C 1-3 Haloalkyl, C 1- 3-Deuterated alkoxy, C 1-3 Deuterated alkyl, -CH2OC 1-3 Alkyl groups, NH(CH3), N(CH3)2, and -OC(O)CH3.

[0090] In some embodiments, the compound represented by formula (I), formula (I-1), or formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 15 Selected from hydroxyl, C 1-6 Alkyl group, -CH2OC 1-3 Alkyl groups, NH(CH3), N(CH3)2, and -OC(O)CH3.

[0091] In some embodiments, the compound represented by formula (I), formula (I-1), or formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 15 Selected from hydroxyl, methoxy,

[0092] In some embodiments, the compound represented by formula (I), formula (I-1), or formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 10 Selected from

[0093] Rings A and R 16a R 16b R 16c R 16d R 17 R 18 R 18c R 19 m and r are as defined in this application.

[0094] In some embodiments, the compound represented by formula (I), formula (I-1) or formula (I-2) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from benzene ring, pyrazole ring, imidazole ring, oxazole ring, isoxazole ring, thiazole ring, isothiazole ring, triazole ring, pyridine ring, pyrimidine ring and pyridazine ring.

[0095] In some embodiments, compounds of Formula (I), Formula (I-l), or Formula (I-2), or pharmaceutically acceptable salts thereof, wherein ring A is selected from a phenyl ring and a pyrazole ring.

[0096] In some embodiments, compounds of Formula (I), Formula (I-l), or Formula (I-2), or pharmaceutically acceptable salts thereof, wherein is selected from wherein, R 18 , R 18c , R 19 , m and r are as defined herein.

[0097] In some embodiments, compounds of Formula (I), Formula (I-l), or Formula (I-2), or pharmaceutically acceptable salts thereof, wherein is selected from

[0098] In some embodiments, compounds of Formula (I), Formula (I-l), or Formula (I-2), or pharmaceutically acceptable salts thereof, wherein R 16a , R 16b , R 16c and R 16d are the same or different and each is independently selected from H, halogen, C 1-6 alkyl and C 3-6 cycloalkyl.

[0099] In some embodiments, compounds of Formula (I), Formula (I-l), or Formula (I-2), or pharmaceutically acceptable salts thereof, wherein R 16a , R 16b , R 16c and R 16d are the same or different and each is independently selected from H and C 1-6 alkyl.

[0100] In some embodiments, compounds of Formula (I), Formula (I-l), or Formula (I-2), or pharmaceutically acceptable salts thereof, wherein R 16a , R 16b , R 16c and R 16d are the same or different and each is independently selected from H and methyl.

[0101] In some embodiments, compounds of Formula (I), Formula (I-l), or Formula (I-2), or pharmaceutically acceptable salts thereof, wherein R 17 is H or C 1-6 alkyl.

[0102] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 17 is H or methyl.

[0103] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein each R 18 is the same or different, and each is independently selected from H, halogen, C 1-6 alkyl, and C 3-6 cycloalkyl.

[0104] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 18c is H or C 1-6 alkyl.

[0105] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 18c is selected from H, C 1-6 alkyl, and C 3-6 cycloalkyl.

[0106] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 18c is H, methyl, isopropyl, and cyclopropyl.

[0107] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein each R 19 is the same or different, and each is independently selected from H, halogen, and C 1-6 alkyl.

[0108] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein each R 19 is the same or different, and each is independently selected from H and C 1-6 alkyl.

[0109] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein each R 19 is the same or different, and each is independently selected from H and methyl.

[0110] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from:

[0111] R 17 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 and t are as defined in the application.

[0112] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 20 is selected from hydroxy, C 1-6 alkoxy, C 1-6 haloalkoxy, and C 1-6 alkyl.

[0113] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 20 is selected from C 1-6 alkyl.

[0114] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 20 is methyl.

[0115] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 21 is selected from H, halogen, and C 1-6 alkyl.

[0116] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 21 is H.

[0117] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 22 is C 1-6 alkyl or C 3-6 cycloalkyl.

[0118] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 22 is selected from C 3-6 cycloalkyl.

[0119] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 22 is cyclopropyl.

[0120] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 23 is selected from hydroxy, C 1-6 alkoxy, C 1-6 haloalkoxy, and C 1-6 alkyl.

[0121] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 23 is selected from C 1-6 alkyl.

[0122] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 23 is methyl.

[0123] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 22 is C 1-6 alkyl or C 3-6 cycloalkyl; R 23 is selected from hydroxy, C 1-6 alkoxy, C 1-6 haloalkoxy, and C 1-6 alkyl.

[0124] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 24 and R 25 are the same or different and each independently C 1-6 alkyl or C 3-6 cycloalkyl;

[0125] or R 24 and R 25 together with the atom to which they are attached form a 5-10 membered heterocyclic ring, which is optionally substituted with one or more substituents selected from halogen, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 hydroxyalkyl.

[0126] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 24 and R 25 together with the atom to which they are attached form a 5-6 membered heterocyclic ring, which is optionally substituted with one or more substituents selected from halogen, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, and C1-6 hydroxyalkyl groups.

[0127] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 24 and R 25 together with the atoms to which they are attached form a 5-membered heterocyclic ring, for example, tetrahydrothiophene.

[0128] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein X is CR X1 R X2 , R X1 and R X2 are the same or different and each is independently selected from H, halogen, and C 1-6 alkyl.

[0129] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein X is CH2.

[0130] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2.

[0131] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein p is 1.

[0132] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 9 is selected from H, halogen, and C 1-6 alkyl.

[0133] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 9 is H.

[0134] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 11 is selected from hydroxy, C 1-6 alkoxy, C 1-6 haloalkoxy, and C 1-6 alkyl.

[0135] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 11 is selected from hydroxy and C 1-6 alkoxy.

[0136] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 11 is selected from hydroxy and methoxy.

[0137] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein T is X is CR X1 R X2 , R X1 and R X2 are the same or different and each is independently selected from H, halo, and C 1-6 alkyl; R 9 is selected from H, halo, and C 1-6 alkyl; p is 1; R 11 is selected from hydroxy, C 1-6 alkoxy, C 1-6 haloalkoxy, and C 1-6 alkyl.

[0138] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 1 is H or halo.

[0139] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 1 is H.

[0140] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 2 is halo.

[0141] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 2 is Cl.

[0142] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 3 , R 4 and R 5 are the same or different and each is independently selected from H, halo, and C 1-6 alkyl.

[0143] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 1 is H; R 2Cl; R 3 Cl; R 4 Cl; R 5 H.

[0144] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 6 R 7 R 8 are the same or different and each is independently selected from H, halogen, and C 1-6 alkyl.

[0145] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 6 R 7 R 8 are each H.

[0146] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein is selected from

[0147] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein is selected from

[0148] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein is selected from

[0149] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein T is selected from

[0150] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein T is selected from

[0151] In some embodiments, compounds of Formula (I), Formula (I-l), or Formula (I-2), or pharmaceutically acceptable salts thereof, wherein T is selected from

[0152] In some embodiments, compounds of Formula (I), Formula (I-l), or Formula (I-2), or pharmaceutically acceptable salts thereof, wherein

[0153] T is

[0154] R 10 is H or C

[0155] R 16a , R 16b , R 16c , and R 16d are the same or different and each is independently selected from H, halogen, C 1-6 alkyl, and C 3-6 cycloalkyl;

[0156] R 18c is H or C 1-6 alkyl;

[0157] each R 18 is the same or different and each is independently selected from H, halogen, C 1-6 alkyl, and C 3-6 cycloalkyl;

[0158] Z is CR 4 ;

[0159] R 1 is H or halogen;

[0160] R 2 is halogen;

[0161] R 3 , R 4 , and R 5 are the same or different and each is independently selected from H, halogen, and C 1-6 alkyl.

[0162] Exemplary specific compounds of the compounds of the present application include, but are not limited to, the structures in Table A below:

[0163] Table A

[0164] In some embodiments, compounds of the present application in Table A wherein is

[0165] In another aspect of the present application, there is provided an isotopically-labeled compound of Formula (I), Formula (I-1) or Formula (I-2) as shown in Table A, wherein the isotopic labeling is preferably deuterium (D or 2 H) for hydrogen. 1 H).

[0166] In another aspect of the present application, there is provided a pharmaceutical composition comprising at least one therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof as described above, and one or more pharmaceutically acceptable excipients.

[0167] In another aspect of the present application, there is provided an E3 ligase-molecular glue binary complex, wherein the molecular glue is a compound or a pharmaceutically acceptable salt thereof as described above.

[0168] In another aspect of the present application, there is provided an E3 ligase-molecular glue-VAV1 protein ternary complex, wherein the molecular glue is a compound or a pharmaceutically acceptable salt thereof as described above.

[0169] In another aspect of the present application, there is provided a use of a compound of Formula (I), Formula (I-1) or Formula (I-2) as shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, or a binary complex of E3 ligase-molecular glue as described above, in the manufacture of a medicament for degrading VAV1 protein.

[0170] In another aspect of the present application, there is provided a use of a compound of Formula (I), Formula (I-1) or Formula (I-2) as shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for mediating the interaction of VAV1 protein with E3 ligase, thereby increasing the degradation of VAV1 protein; preferably, the compound interacts with E3 ligase prior to the interaction of VAV1 protein with E3 ligase.

[0171] In another aspect of the present application, there is provided a use of a compound of Formula (I), Formula (I-1) or Formula (I-2) as shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for contacting with E3 ligase, interacting the contacted E3 ligase with VAV1, thereby degrading VAV1.

[0172] In another aspect of the present application, there is provided a use of a compound of Formula (I), Formula (I-1) or Formula (I-2) as shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, or a binary complex of E3 ligase-molecular glue as described above, in the manufacture of a medicament for preventing and / or treating a disease or disorder caused by or associated with a disorder in the development or activity of lymphocytes.

[0173] In the present application, the lymphocyte is a T cell.

[0174] In the present application, the lymphocyte is a B cell.

[0175] The present application also provides the use of a compound represented by formula (I), formula (I-1) or formula (I-2), a compound represented by Table A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same or the E3 ligase-molecular glue binary complex of the foregoing in the preparation of a medicament for preventing and / or treating an autoimmune disease, an inflammatory disease, a metabolic disease, a cardiovascular disease, a kidney disease, a central nervous system disease or a cancer.

[0176] The autoimmune disease described in the present application is selected from multiple sclerosis, rheumatoid arthritis, systemic lupus, thyroiditis, myasthenia gravis, type I diabetes, type II diabetes, vasculitis, pernicious anemia, dry eye, Sjoegren syndrome, uveitis, psoriasis, Graves ophthalmopathy, alopecia areata, allergic asthma, atopic dermatitis, allergic dermatitis, rhinitis, conjunctivitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, asthma, inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury, atherosclerosis, osteoarthritis, inflammatory eye disease, keratoconjunctivitis, myocarditis or hepatitis.

[0177] The present application also provides a method for degrading VAV1 protein, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound represented by formula (I), formula (I-1) or formula (I-2), a compound represented by Table A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same or the E3 ligase-molecular glue binary complex of the foregoing.

[0178] The present application also provides a method for degrading VAV1 protein, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound represented by formula (I), formula (I-1) or formula (I-2), a compound represented by Table A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same or the E3 ligase-molecular glue binary complex of the foregoing, which mediates the interaction of VAV1 protein with E3 ligase, thereby increasing the degradation of VAV1 protein.

[0179] The present application also provides a method for degrading VAV1 protein, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound represented by formula (I), formula (I-1) or formula (I-2), a compound represented by Table A or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same or the E3 ligase-molecular glue binary complex of the foregoing, which interacts with E3 ligase before the interaction of VAV1 protein with E3 ligase.

[0180] The present application also provides a method of degrading VAV1 protein, comprising: (i) contacting the compound represented by formula (I), formula (I-1) or formula (I-2), or a pharmaceutically acceptable salt thereof or the aforementioned isotopically-labeled or the aforementioned pharmaceutical composition comprising the same with an E3 ligase, and (ii) allowing the contacted E3 ligase to interact with VAV1, thereby degrading the VAV1 protein.

[0181] The present application also provides a method of preventing and / or treating a disease or disorder caused by or associated with a disorder of lymphocyte development or activity, comprising administering to a patient in need thereof a therapeutically effective amount of the compound represented by formula (I), formula (I-1) or formula (I-2), or a pharmaceutically acceptable salt thereof or the aforementioned isotopically-labeled or the aforementioned pharmaceutical composition comprising the same or the aforementioned E3 ligase-molecular glue binary complex.

[0182] The present application also provides a method of preventing and / or treating an autoimmune disease, an inflammatory disease, a metabolic disease, a cardiovascular disease, a renal disease, a central nervous system disease or a cancer, comprising administering to a patient in need thereof a therapeutically effective amount of the compound represented by formula (I), formula (I-1) or formula (I-2), or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition comprising the same or the aforementioned E3 ligase-molecular glue binary complex.

[0183] The present application also provides the compound represented by formula (I), formula (I-1) or formula (I-2), or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition or the aforementioned E3 ligase-molecular glue binary complex for use as a medicament.

[0184] The present application also provides the compound represented by formula (I), formula (I-1) or formula (I-2), or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition or the aforementioned E3 ligase-molecular glue binary complex for use as a VAV1 degrader.

[0185] The present application also provides the compound represented by formula (I), formula (I-1) or formula (I-2), or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition comprising the same or the aforementioned E3 ligase-molecular glue binary complex for use as a medicament for preventing and / or treating a disease or disorder caused by or associated with a disorder of lymphocyte development or activity.

[0186] The present application also provides the compound represented by formula (I), formula (I-1) or formula (I-2), or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition comprising the same or the aforementioned E3 ligase-molecular glue binary complex for use as a medicament for preventing and / or treating an autoimmune disease, an inflammatory disease, a metabolic disease, a cardiovascular disease, a renal disease, a central nervous system disease or a cancer.

[0187] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg - 1000 mg.

[0188] In some embodiments, the pharmaceutical composition contains 0.01 - 99.99% of the aforementioned compound or a pharmaceutically acceptable salt thereof or an isotopically-labeled material thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1 - 99.9% of the aforementioned compound or a pharmaceutically acceptable salt thereof or an isotopically-labeled material thereof. In certain embodiments, the pharmaceutical composition contains 0.5 - 99.5% of the aforementioned compound or a pharmaceutically acceptable salt thereof or an isotopically-labeled material thereof.

[0189] In some embodiments, the pharmaceutical composition contains 1 - 99% of the aforementioned compound or a pharmaceutically acceptable salt thereof or an isotopically-labeled material thereof.

[0190] In some embodiments, the pharmaceutical composition contains 0.01 - 99.99% of one or more pharmaceutically acceptable excipients, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1 - 99.9% of one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 1 - 99% of one or more pharmaceutically acceptable excipients.

[0191] As a medicament, the compounds of the present application can be administered in the form of a pharmaceutical composition. These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes depending upon whether local or systemic treatment is desired and upon the area to be treated. They can be administered topically (e.g., transdermal, transcutaneous, ophthalmic, and mucosal including intranasal, vaginal, and rectal), pulmonary (e.g., through the use of an inhaler or insufflator; intratracheal, intranasal), oral, or parenteral. Parenteral infusions include intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injections or infusion; or intracranial, e.g., intrathecal or intracerebroventricular administration. They can be administered parenterally, such as by injection or continuous infusion pump, in a single dose, or they can be administered in multiple doses.

[0192] In making the compositions of this application, the active ingredient is typically mixed with a excipient, which can take a wide variety of forms depending upon the form of composition desired for administration. By way of example, the composition can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or liquid), ointments containing, for example, up to 10% by weight of active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0193] The "excipient" of the present application refers to an ingredient other than the active ingredient, including, for example, diluents, fillers, absorbents, wetting agents, binders, disintegrants, and lubricants.

[0194] In another aspect, pharmaceutically acceptable salts of the compounds described herein can be inorganic or organic salts, acid addition salts if the compounds have a basic center, base addition salts if the compounds have an acid center, and internal salts if the compounds contain both an acid center and a basic center (e.g., a carboxylate group and a tertiary nitrogen).

[0195] In another aspect, the compounds of the present application can exist in particular geometric or stereoisomeric forms. The present application contemplates all such isomers, including those that can be produced by resolution of racemic forms. The present application also expressly includes enantiomeric mixtures, racemic mixtures, and all other mixtures, which are in each case possible, unless the context clearly indicates otherwise. Additional asymmetric carbon atoms can be present in a substituent group. All such isomers, as well as mixtures thereof, are included within the scope of the present application.

[0196] In the chemical structures of the compounds described herein, the bond indicates unspecified configuration, indicates absolute configuration, i.e., if chiral isomers are present in the chemical structure, the bond may be or both configurations, indicates the presence of an axial chirality.

[0197] The bond indicates unspecified configuration, including either the cis (E) or trans (Z) configuration.

[0198] In addition, the compounds and intermediates of the present application can exist in different tautomeric forms, and all such forms are embraced within the scope of the present application. "Tautomers" refer to different energy structures that are interconvertible by a low energy barrier. For example, prototropic tautomers (also known as proton shift tautomers) include interconversions by proton migration, such as keto-enol isomerization, imine-enamine isomerization, and lactam-lactim isomerization. All tautomeric forms of all compounds of the present application are within the scope of the present application. The name of a compound named in a single form does not exclude any tautomers.

[0199] The present application also includes isotopically-labeled compounds of the present application which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be present in compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, iodine, and chlorine, such as​2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, and the like. All isotopically-labeled compounds of this application are within the scope of the application. Isotopically-labeled compounds of this application can generally be prepared by carrying out the procedures disclosed in the schemes and examples below, by either (a) simply substituting a readily available isotopically-labeled reagent for a non-isotopically labeled reagent or (b) substituting a reagent with an active isotope. All isotopically-labeled compounds of this application are within the scope of the application.

[0200] Unless otherwise stated, when a position is designated specifically as deuterium (D), the position is understood to have deuterium in an abundance of at least 1000 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 10% deuterium incorporation). Exemplary compounds having deuterium in an abundance of at least 1000 times greater than the natural abundance of deuterium can be at least 2000 times greater than the natural abundance of deuterium, at least 3000 times greater than the natural abundance of deuterium, at least 4000 times greater than the natural abundance of deuterium, at least 5000 times greater than the natural abundance of deuterium, at least 6000 times greater than the natural abundance of deuterium, or greater. Each available hydrogen atom attached to a carbon atom can be independently replaced with a deuterium atom. Those skilled in the art could refer to the relevant literature to synthesize compounds in deuterated form. Commercially available deuterated starting materials can be used in preparing deuterated forms of the compounds, or they can be synthesized using conventional techniques employing deuterated reagents, including but not limited to deuterated borane, trideuteroborane in tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane, and the like.

[0201] A "therapeutically effective amount" of the present application refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by person of skill in the art, and includes one or more of the following: (1) preventing the disease: for example, preventing a disease, disorder or condition from occurring in an individual that is predisposed to the disease, disorder and / or condition but has not yet experienced or displayed the pathology or symptomatology of the disease; (2) inhibiting the disease: for example, arresting the development of a disease, disorder or condition (i.e., retarding the development of a pathology and / or symptomology) in an individual that is experiencing or displaying the pathology or symptomology of the disease; (3) relieving the disease: for example, relieving a disease, disorder or condition (i.e., reversing a pathology and / or symptomology) in an individual that is experiencing or displaying the pathology or symptomology of the disease. For a pharmaceutical or pharmacologically active agent, a "therapeutically effective amount" refers to a sufficient amount of the pharmaceutical or agent to provide the desired effect without undue adverse side effects. The exact amount required will vary from subject to subject, depending on the nature of the active agent, the disease or condition, the severity of the disease or condition, the age and general health of the subject, etc. Appropriate effective amounts can be determined by one of ordinary skill in the art using only routine experimentation.

[0202] The term "pharmaceutically acceptable" means, with respect to compounds, materials, compositions, and / or dosage forms of the present application, that such compounds, materials, compositions, and / or dosage forms are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio, and are effective for their intended use.

[0203] The term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine; cattle, goats, horses, or primates, and most preferably humans. Beneficial effects

[0204] The present application provides a small molecule compound that can be used as a VAV1 degrading agent, which can be used for effectively treating or preventing autoimmune diseases, inflammatory diseases, metabolic diseases, cardiovascular diseases, kidney diseases, central nervous system diseases, or cancers.

[0205] Definitions and explanations of terms

[0206] Unless otherwise indicated, the terms used in the specification and claims have the following meanings.

[0207] The term "alkyl" refers to saturated aliphatic hydrocarbon groups, which are straight-chain or branched-chain groups, preferably containing 1 to 20 carbon atoms, more preferably 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, and even more preferably 1 to 6 carbon atoms (C1-C6alkyl). Examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, hexyl, 3-methyl-hexyl, and the like. 1-6Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and various branched isomers thereof, and the like. Alkyl groups can be substituted or unsubstituted.

[0208] The term "alkoxy" refers to -O-(alkyl), where alkyl is as defined herein. Preferred are C 1-6 Alkoxy (i.e., including 1, 2, 3, 4, 5, and 6 carbon atoms). Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups can be substituted or unsubstituted.

[0209] The term "alkylene" refers to a saturated, divalent hydrocarbyl radical resulting from the removal of two H from a saturated, straight chain or branched hydrocarbon group, which can contain 1-20 carbon atoms, preferably 1-12 carbon atoms, more preferably C 1-6 Alkylene (i.e., including 1, 2, 3, 4, 5, and 6 carbon atoms). Non-limiting examples include methylene (-CH2-), ethylene (-CH2CH2-), and the like. The alkylene groups can be substituted or unsubstituted.

[0210] The term "alkenyl" is understood to preferably mean a straight-chain or branched hydrocarbyl group containing one or more double bonds and having 2 to 20 carbon atoms, preferably "C 2-10 Alkenyl." C 2-10 Alkenyl" is understood to preferably mean a straight-chain or branched monovalent hydrocarbyl group containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, for example, having 2, 3, 4, 5, or 6 carbon atoms (i.e., C 2-6 Alkenyl" is understood to preferably mean a straight-chain or branched monovalent hydrocarbyl group containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, for example, having 2, 3, 4, 5, or 6 carbon atoms (i.e., C 2-3alkenyl). It is to be understood that in case the alkenyl group comprises more than one double bond, the double bonds can be separated from each other or conjugated. The alkenyl group is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-pent-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1-methylbut-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl. The alkenyl group can be substituted or unsubstituted.

[0211] The term "alkynyl" is to be understood as meaning a straight-chain or branched one- valent hydrocarbon group which comprises one or more triple bonds and has 2 to 20 carbon atoms, preferably "C 2-10 alkynyl". The term "C 2-10 alkynyl" is to be understood as preferably meaning a straight-chain or branched one- valent hydrocarbon group which comprises one or more triple bonds and has 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, for example, 2, 3, 4, 5 or 6 carbon atoms (i.e. "C 2-6 alkynyl"). The term "C 2-3The term "alkynyl" refers to a straight or branched hydrocarbon chain that contains one or more triple bonds. The term "alkynyl" includes, but is not limited to, ethynyl, propynyl, propynyl, butynyl, butynyl, butynyl, pentynyl, pentynyl, pentynyl, pentynyl, hexynyl, hexynyl, hexynyl, hexynyl, hexynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethylbut-3-ynyl, 1,1-dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl, or 3,3-dimethylbut-1-ynyl. In particular, the alkynyl group is ethynyl, prop-1-ynyl, or prop-2-ynyl. The alkynyl group can be substituted or unsubstituted.

[0212] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably containing 3 to 14 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14) carbon atoms or 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms, more preferably containing 3 to 6 carbon atoms, which can optionally be oxidized by an oxo group (=0) that is part of the ring. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spirocyclic, fused, and bridged cycloalkyl groups.

[0213] The term "spirocycloalkyl" refers to a 5- to 20-membered, polycyclic group in which each single ring shares one carbon atom (termed a spiro atom) with the system, which can contain one or more double bonds. Preferably, 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7-, 8-, 9-, or 10-membered). Spirocycloalkyl groups are classified as mono-, bi-, or polyspirocycloalkyl groups, preferably mono- and bi-spirocycloalkyl groups, depending on the number of spiro atoms shared between rings. More preferably, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocycloalkyl groups. Non-limiting examples of spirocycloalkyl groups include:

[0214] The term "fused ring alkyl" refers to a fully carbon polycyclic group of 5 to 20 members, where each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, where one or more rings can contain one or more double bonds. Preferably, 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Can be divided into bi-, tri-, tetra-, or polycyclic fused ring alkyl, preferably bi- or tri-cyclic, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, and 6-membered / 6-membered bi-cyclic alkyl. Non-limiting examples of fused ring alkyl include:

[0215] The term "bridged ring alkyl" refers to a fully carbon polycyclic group of 5 to 20 members, where any two rings share two non-adjacent carbon atoms, which can contain one or more double bonds. Preferably, 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Can be divided into bi-, tri-, tetra-, or polycyclic bridged ring alkyl, preferably bi-, tri-, or tetra-cyclic, more preferably bi- or tri-cyclic. Non-limiting examples of bridged ring alkyl include:

[0216] The cycloalkyl ring includes cycloalkyl (including monocyclic, spirocyclic, fused, and bridged) fused to an aryl ring as described herein, where the ring that is attached to the parent structure can be a cycloalkyl ring or an aryl ring, non-limiting examples include etc.; preferably The cycloalkyl can be substituted or unsubstituted.

[0217] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic ring-like substituent containing 3 to 20 ring atoms, one or more of which are heteroatoms selected from nitrogen, oxygen, and sulfur, which can optionally be oxidized (i.e., form a sulfoxide or sulfone), but not ring moieties of -0-0-, -0-S-, or -S-S-, the remainder of which are carbon, which can optionally be oxidized, the ring carbons of which can be considered to be part of the ring. Preferably, there are 3 to 14 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14) ring atoms, of which 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms; more preferably, there are 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7, and 8), of which 1 to 3 (e.g., 1, 2, and 3) are heteroatoms; more preferably, there are 3 to 6 ring atoms, of which 1 to 3 are heteroatoms; most preferably, there are 5 or 6 ring atoms, of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclyl groups include spirocyclic, fused, and bridged heterocyclyl groups.

[0218] The term "spiroheterocyclyl" refers to a 5- to 20-membered polycyclic heterocyclic group in which each single ring shares one atom (referred to as a spiro atom) with another ring, one or more of which are heteroatoms selected from nitrogen, oxygen, and sulfur, which can optionally be oxidized (i.e., form a sulfoxide or sulfone), the remainder of which are carbon. It can contain one or more double bonds. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7-, 8-, 9-, or 10-membered). Spiroheterocyclyl groups are classified as mono-, bi-, or polyspiroheterocyclyl groups, preferably mono- and bispiroheterocyclyl groups, depending on the number of spiro atoms shared between rings. More preferably, it is a 3 / 5-, 3 / 6-, 4 / 4-, 4 / 5-, 4 / 6-, 5 / 5-, or 5 / 6- membered monospiroheterocyclyl group. Non-limiting examples of spiroheterocyclyl groups include:

[0219] The term "fused heterocyclyl" refers to a polycyclic heterocyclic radical of 5 to 20 members, each ring in the system sharing a pair of adjacent atoms with another ring in the system, one or more rings can contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, which can optionally be oxidized (i.e., form a sulfoxide or sulfone), the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Can be divided into bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclyl, preferably bicyclic or tricyclic, more preferably 3 / 4, 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 4, 5 / 5, 5 / 6, 6 / 3, 6 / 4, 6 / 5, and 6 / 6 bicyclic fused heterocyclyl, according to the number of rings comprising the ring system. Non-limiting examples of fused heterocyclyl groups include:

[0220] The term "bridged heterocyclyl" refers to a polycyclic heterocyclic radical of 5 to 14 members, any two rings sharing two non-adjacent atoms, which can contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, which can optionally be oxidized (i.e., form a sulfoxide or sulfone), the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Can be divided into bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclyl, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:

[0221] The heterocyclyl ring includes a heterocyclyl group as described herein (including monocyclic, spiro, fused, and bridged heterocyclyl) fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring that is attached to the parent structure can be a heterocyclyl ring or an aryl, heteroaryl, or cycloalkyl ring, non-limiting examples of which include:

[0222] The heterocyclyl group can be substituted or unsubstituted.

[0223] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares a pair of adjacent carbon atoms with another ring) radical that has a conjugated pi-electron system, preferably 6 to 10 members, such as phenyl and naphthyl. The aryl group can be substituted or unsubstituted.

[0224] The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10 membered (e.g., 5, 6, 7, 8, 9, or 10 membered), more preferably 5 membered or 6 membered, e.g., furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, and the like. The heteroaryl ring includes heteroaryl fused to an aryl ring as described herein, wherein the ring that is attached to the parent structure can be a heteroaryl ring or an aryl ring, non-limiting examples of which include:

[0225] and the like. The heteroaryl group can be substituted or unsubstituted.

[0226] The terms "alkyl", "alkoxy", "cycloalkyl", "heterocyclyl", "aryl", and "heteroaryl" and the like herein can be substituted or unsubstituted; when substituted, they can be substituted at any available attachment point with one or more of the same or different substituents, preferably independently optionally selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0227] The above cycloalkyl, heterocyclyl, aryl, and heteroaryl groups include residues derived from removal of one H from a ring atom of the parent ring, or two H from the same or two different ring atoms of the parent, i.e., "divalent cycloalkyl", "divalent heterocyclyl", "arylene", "heteroarylene".

[0228] Also, it will be understood by those skilled in the art that cycloalkyl, heterocyclyl, aryl, and heteroaryl are residues derived from removal of one H from a ring atom of the parent ring, i.e., cycloalkane, heterocycle, aryl ring, and heteroaryl ring. Thus, the meaning of cycloalkane, heterocycle, aryl ring, and heteroaryl ring is understood by reference to the foregoing definitions of cycloalkyl, heterocyclyl, aryl, and heteroaryl. The term "cycloalkyloxy" refers to cycloalkyl-O-, wherein cycloalkyl is as defined herein.

[0229] The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined herein.

[0230] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined herein.

[0231] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined herein.

[0232] The term "deuteroalkyl" refers to an alkyl group substituted with one or more deuterium, wherein alkyl is as defined herein.

[0233] The term "deuteroalkoxy" means an alkoxy group as defined herein substituted with one or more deuterium.

[0234] The term "hydroxyalkyl" means an alkyl group as defined herein substituted with one or more hydroxy groups.

[0235] The term "cyanoalkyl" means an alkyl group as defined herein substituted with one or more cyano groups.

[0236] The term "aminoalkyl" means an alkyl group as defined herein substituted with one or more amino groups.

[0237] The term "halogen" means F, CI, Br, or I.

[0238] The term "hydroxy" means -OH.

[0239] The term "amino" means -NH2.

[0240] The term "cyano" means -CN.

[0241] The term "nitro" means -NO2.

[0242] The term "oxo" or "keto" group means "=O" when substituted on C or

[0243] The term "carbonyl" means C=O.

[0244] The term "carboxyl" means -C(O)OH.

[0245] The term "carboxylate" means -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O-, or (cycloalkyl)C(O)O-, wherein alkyl and cycloalkyl are as defined herein.

[0246] "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "an alkyl group optionally substituted with an alkyl" means that an alkyl group can or can not be present, and that the description includes instances where the heterocycloalkyl group is substituted with an alkyl and instances where the heterocycloalkyl group is not substituted with an alkyl.

[0247] "Substituted" means that one or more H in the given structure is replaced by a particular substituent. It is understood that substituents are only in their possible chemical positions, which can be determined (by experiment or theory) by those skilled in the art without excessive effort. Further, when the group is substituted by more than one of the said substituents, the said substituents are independent of each other (i.e. the said more than one substituents can be different or the same).

[0248] Herein, when the substitution site of the substituent is indefinite, the ring intersected with the single bond of the substituent represents the ring which can be substituted by the substituent, for example, the structure formula , R 19 may be substituted at the appropriate substitution site on the pyrazole ring below, if r is 1, the structure formula can be and the like structures can be understood in the same way.

[0249] It should be understood that the singular forms "a", "an" and "the" used in this disclosure include plural referents unless otherwise specified. In addition, the term "comprising" is an open-ended term not limiting in nature, i.e. the disclosure indicates the content, but does not exclude other aspects. DETAILED DESCRIPTION

[0250] The technical solutions of the present application will be further described in detail below in combination with specific examples. It should be understood that the following examples are only illustrative and explanatory of the present application, and should not be interpreted as limiting the scope of protection of the present application. Any technology realized based on the above content of the present application is covered within the scope of protection intended by the present application.

[0251] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0252] The structure of the compound is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shift (δ) is given in units of 10 -6 (ppm). The determination of NMR is carried out by Bruker ASCEND TM -400 nuclear magnetic instrument, the determination solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS). The determination of MS is carried out by Agilent 6110, Agilent 1100, Agilent 6120, Agilent G6125B liquid chromatograph-mass spectrometer.

[0253] The HPLC determination used Shimadzu HPLC-2010C high pressure liquid chromatograph (XBRIDGE 2.1*50mm, 3.5um column).

[0254] The chiral HPLC analysis determination used THARSFC X5.

[0255] The thin layer chromatography silica gel plate used Yantai Qingdao GF254 silica gel plate, the specification of the silica gel plate used in thin layer chromatography (TLC) was 0.15mm-0.2mm, the specification of the thin layer chromatography separation and purification product was 0.4mm-0.5mm.

[0256] The column chromatography generally used Qingdao marine silica gel 200-300 mesh silica gel as the carrier.

[0257] The high performance liquid preparation used Waters 2767, Waters 2545, and innovative constant LC3000 preparative chromatograph.

[0258] The chiral preparative column chromatography used Shimadzu LC-20AP, THARSFC PREP 80.

[0259] The CombiFlash rapid preparation instrument used Combiflash Rf200 (TELEDYNE ISCO).

[0260] The pressurized hydrogenation reaction used Beijing Jiawei Kechuang Technology GCD-500G hydrogen generator.

[0261] The microwave reaction used Biotage initiator+type microwave reactor.

[0262] In the experimental examples, unless otherwise specified, the reaction was carried out under argon atmosphere or nitrogen atmosphere.

[0263] The argon atmosphere or nitrogen atmosphere refers to that the reaction bottle is connected with an about 1 liter volume argon or nitrogen balloon.

[0264] The hydrogen atmosphere refers to that the reaction bottle is connected with an about 1 liter volume hydrogen balloon.

[0265] In the experimental examples, unless otherwise specified, the reaction temperature was room temperature, and the temperature range was 20℃-30℃.

[0266] The skilled person in the art should understand that the chiral compounds which are split can be distinguished by the order of retention time in the chiral chromatographic column, therefore, the chiral compounds which are split according to the order of retention time are distinguished by the number suffix P1, P2, etc. That is, for example, the suffix P1 corresponds to the chiral compound with a certain chiral structure which is eluted out of the chiral chromatographic column earlier, and the suffix P2 corresponds to the chiral compound with a certain chiral structure which is eluted out of the chiral chromatographic column later. If the absolute configuration of the compound is listed in the structural formula, it does not mean that it directly corresponds to the compound with the number suffix P1, P2, but only indicates the two existing forms of the absolute configuration. The absolute configuration of the compound with the number suffix P1, P2 is subject to the objective corresponding absolute configuration marked by a specific retention time.

[0267] Example 1 (compound 12)

[0268] First step: synthesis of compound 12c

[0269] Compound 12a (1-(4-morpholinyl)-2-propynyl) (50 mg, 0.40 mmol) was dissolved in acetonitrile (1 mL), and compound 12b (p-bromoiodobenzene) (113 mg, 0.40 mmol), triethylamine (202.38 mg, 2.00 mmol), bis(triphenylphosphine)palladium dichloride (56.15 mg, 0.08 mmol) and cuprous iodide (15.24 mg, 0.08 mmol) were added in turn, and the reaction mixture was stirred at room temperature under nitrogen protection for 1 hour. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 40-50%) to obtain compound 12c (78 mg). MS m / z (ESI): 280.03 [M+1] +

[0270] Second step: synthesis of compound 12

[0271] Compound 12d (20 mg, 0.06 mmol, synthesis method refer to patent WO2024151547A1 specification page P184 synthesis of Intermediate A) was dissolved in 1,4-dioxane (1 mL), compound 12c (23.95 mg, 0.09 mmol), potassium phosphate (36.30 mg, 0.17 mmol) and 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(ll) (8.34 mg, 0.01 mmol) were added successively. The reaction mixture was heated to 80 °C under nitrogen protection and stirred for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-3%) to obtain the crude product, which was further purified by thin layer chromatography on silica gel plate (dichloromethane / methanol = 10 / 1) to obtain compound 12 (3.48 mg). MS m / z (ESI): 423.14 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 7.53 (s, 2H), 7.44 - 7.38 (m, 4H), 7.33 - 7.31 (m, 1H), 4.34 (dd, J = 12.4, 5.2 Hz, 1H), 3.65 - 3.59 (m, 4H), 2.83 - 2.74 (m, 2H), 2.69 - 2.66 (m, 1H), 2.36 - 2.30 (m, 2H), 2.07 - 1.96 (m, 4H), 1.46 (s, 2H).

[0272] Example 2 (compound 83)

[0273] First step: synthesis of compound 83b

[0274] Compound 83a (2-(4-bromophenyl)pyridine) (300 mg, 1.29 mmol) and meta-chloroperoxybenzoic acid (m-CPBA) (667 mg, 3.87 mmol) were added to dichloromethane (50 mL), and the reaction mixture was stirred at room temperature for 24 hours. After the reaction was completed, the reaction solution was diluted with saturated brine (20 mL), extracted with dichloromethane (10 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-50%) to obtain compound 83b (200 mg). MS m / z (ESI): 251.00 [M+1] + .

[0275] Second step: synthesis of compound 83

[0276] Compound 83b (56 mg, 0.23 mmol), compound 12d (81 mg, 0.69 mmol) were dissolved in 1,4-dioxane (5 mL), potassium phosphate (146.28 mg, 0.69 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (16.12 mg, 0.023 mmol) were added successively, the reaction mixture was heated to 90 °C under nitrogen protection and stirred for 12 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate (10 mL), and the insoluble solid was removed by filtration. The filter cake was washed with ethyl acetate (10 mL), and the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography on silica gel plate (dichloromethane / methanol = 15:1) to obtain compound 83 (35 mg). MS m / z (ESI): 392.9 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 8.42 - 8.35 (m, 1H), 7.94 (d, J = 8.3 Hz, 2H), 7.76 - 7.69 (m, 1H), 7.53 (d, J = 8.3 Hz, 2H), 7.46 - 7.35 (m, 5H), 4.38 (dd, J = 12.1, 4.9 Hz, 1H), 2.87 - 2.75 (m, 1H), 2.57 (d, J = 3.5 Hz, 1H), 2.42 - 2.30 (m, 1H), 2.13 - 2.02 (m, 1H).

[0277] Example 3 (Compound 117)

[0278] First Step: Synthesis of compound 117b

[0279] Compound 117a (4-ethynyl-1-methylpyrazole) (50 mg, 0.47 mmol) was dissolved in acetonitrile (1 mL), compound 12b (p-bromoiodobenzene) (132 mg, 0.47 mmol), triethylamine (237.80 mg, 2.35 mmol), dichlorobis(triphenylphosphine)palladium (II) (65.98 mg, 0.09 mmol) and cuprous iodide (17.90 mg, 0.09 mmol) were added successively, and the reaction mixture was stirred at room temperature under nitrogen protection for 1 hour. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0-50%) to obtain compound 117b (108 mg). MS m / z (ESI): 260.99 [M+1] +

[0280] Second Step: Synthesis of compound 117

[0281] Compound 12d (20 mg, 0.06 mmol) was dissolved in 1,4-dioxane (1 mL), and compound 117b (14.88 mg, 0.06 mmol), potassium phosphate (36.30 mg, 0.17 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (8.34 mg, 0.01 mmol) were added successively. The reaction mixture was heated to 80 °C under nitrogen protection and stirred for 16 h. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-3%) to obtain a crude product, which was further purified by thin layer chromatography on silica gel plate (dichloromethane / methanol = 10 / 1) to obtain compound 117 (4.00 mg). MS m / z (ESI): 404.11 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 8.09 (s, 1H), 7.71 (s, 1H), 7.58-7.53 (m, 2H), 7.45-7.44 (m, 1H), 7.43-7.42 (m, 1H), 7.40-7.37 (m, 1H), 7.35-7.32 (m, 1H), 4.39-4.31 (m, 1H), 3.86 (s, 3H), 2.83-2.75 (m, 1H), 2.59-2.55 (m, 1H), 2.33-2.30 (m, 1H), 2.08-2.02 (m, 1H).

[0282] Example 4 (compound 108)

[0283] First step: synthesis of compound 108b

[0284] Compound 12b (1 g, 3.5 mmol) was dissolved in N,N-dimethylformamide (10 mL), and compound 108a (3-methylaminopropylamine) (250 mg, 2.8 mmol), potassium carbonate (970 mg, 7.0 mmol), cuprous iodide (70 mg, 0.35 mmol), and D-proline (80 mg, 0.7 mmol) were added successively. The reaction mixture was heated to 90 °C under nitrogen protection and stirred for 16 h. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 10-100%) to obtain compound 108b (350 mg). MS (ES, m / z): 243.0 [M+H] + .

[0285] Second step: synthesis of compound 108d

[0286] Compound 108b (350 mg, 1.43 mmol) was dissolved in tetrahydrofuran (5 mL), and N,N'-thiocarbonyldiimidazole (307.85 mg, 1.72 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours under nitrogen protection. After the reaction was completed, the reaction mixture was concentrated under reduced pressure after cooling to room temperature, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 0-10%) to obtain compound 108d (240 mg). MS (ES, m / z): 285.0 [M+H] + .

[0287] Third step: synthesis of compound 108

[0288] Compound 12d (183.86 mg, 0.52 mmol) was dissolved in a mixed solution of 1,4-dioxane and water (10 / 1, 3 mL), and compound 108d (100 mg, 0.35 mmol), potassium phosphate (148.84 mg, 0.70 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (14.32 mg, 0.017 mmol) were sequentially added. The reaction mixture was heated to 100°C and stirred for 4 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-10%) to obtain a crude product (130 mg). The crude product was further purified by high-performance liquid chromatography (preparative column: Gemini-C18; 150 x 21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% trifluoroacetic acid); gradient: 20-95%; column temperature: 25°C; flow rate: 20 mL / min; wavelength: 214 nm) to obtain compound 108 (24.9 mg). MS m / z (ESI): 428.0 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 7.55-7.29 (m, 6H), 7.21 (d, J = 8.0 Hz, 1H), 4.33 (dd, J = 10.4, 6.0 Hz, 1H), 3.77 (s, 2H), 3.54 (s, 4H), 2.87-2.67 (m, 3H), 2.37-2.21 (m, 4H), 1.25 (s, 1H).

[0289] Example 5 (compound 55)

[0290] First step: synthesis of compound 55c

[0291] Compound 55a (propargylamine) (1.0 g, 18.16 mmol) was dissolved in dichloromethane (12 mL), triethylamine (5.51 g, 54.48 mmol) was added, and compound 55b (acetyl chloride) (1.71 g, 21.79 mmol) was added dropwise under ice bath. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain compound 55c (3.0 g), which was directly used in the next step.

[0292] Second Step: Synthesis of compound 55d

[0293] Compound 55c (3.0 g, 18.12 mmol) was dissolved in anhydrous acetonitrile (10 mL), and compound 12b (5.64 g, 19.93 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium (II) dichloride (1.33 g, 1.81 mmol), cuprous iodide (0.69 g, 3.62 mmol), and triethylamine (5.51 g, 54.48 mmol) were added in sequence. The reaction system was replaced with nitrogen, and then stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0% to 50%) to obtain compound 55d (3.3 g). MS m / z (ESI): 251.9, 253.9 [M+1, M+3] + .

[0294] Third Step: Synthesis of compound 55

[0295] Compound 55d (50 mg, 0.20 mmol) was dissolved in 1,4-dioxane (2 mL), and compound 12d (69.92 mg, 0.20 mmol), potassium phosphate tribasic (127.36 mg, 0.60 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium (II) dichloride (29.27 mg, 0.040 mmol) were added in sequence. The reaction mixture was heated to 60°C under nitrogen protection and stirred for 16 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0% to 5%) to obtain compound 55 (2.01 mg). MS m / z (ESI): 395.1 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.42 (t, J = 5.3 Hz, 1H), 7.50 (d, J = 8.3 Hz, 2H), 7.45 - 7.36 (m, 4H), 7.32 (dd, J = 7.0, 2.2 Hz, 1H), 4.35 (dd, J = 12.2, 4.8 Hz, 1H), 4.13 (d, J = 5.4 Hz, 2H), 2.38 - 2.28 (m, 2H), 2.03 - 1.98 (m, 2H), 1.86 (s, 3H).

[0296] Example 6 (Compound 101)

[0297] First Step: Synthesis of Compound 101c

[0298] Copper iodide and potassium carbonate were added successively to compound 101a (1,4-diiodobenzene) (1 g, 3.03 mmol) and compound 101b (2-pyridinone) (28.26 mg, 3.03 mmol) in dimethyl sulfoxide (20 mL) under nitrogen atmosphere. The reaction mixture was stirred at 120 °C for 3 h. The reaction was extracted with ethyl acetate (30 mL) and water (30 mL), the organic phase was separated, washed with water (30 x 2 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (ethyl acetate / petroleum ether = 0-10%) to give compound 101c (800 mg).

[0299] MS m / z (ESI): 298.0 [M+H] + .

[0300] Second Step: Synthesis of Compound 101d

[0301] Sodium bicarbonate (168 mg, 2.00 mmol) and phosphorus pentasulfide (177.8 mg, 0.80 mmol) were added successively to a solution of compound 101c (60 mg, 0.20 mmol) in 1,4-dioxane (1 mL) at room temperature, and the reaction mixture was heated to 90 °C and stirred for 16 h. After completion of the reaction, the reaction was cooled to room temperature, and the solvent was removed by concentration under reduced pressure. The residue was separated by column chromatography on silica gel (petroleum ether / ethyl acetate = 40%-50%) to give compound 101d (40 mg). MS m / z (ESI): 313.8 [M+1] + .

[0302] Third Step: Synthesis of Compound 101

[0303] Potassium phosphate (54.8 mg, 0.26 mmol) and 1,1'-bis(diphenylphosphino) ferrocene dichloride (II) (12.6 mg, 0.02 mmol) were added to a solution of compound 101d (27 mg, 0.09 mmol) and compound 12d (30 mg, 0.09 mmol) in 1,4-dioxane (200 mL) at room temperature, and the reaction mixture was heated to 80 °C under nitrogen protection for 3 days. After the reaction was completed, the reaction solution was cooled to room temperature, and the solvent was removed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 0% ~ 5%) to obtain compound 101 (6.7 mg). MS m / z (ESI): 408.9 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.06 (d, J = 5.9 Hz, 1H), 7.60 - 7.56 (m, 3H), 7.50 - 7.45 (m, 3H), 7.44 - 7.36 (m, 3H), 6.89 - 6.85 (m, 1H), 4.38 (dd, J = 12.2, 5.0 Hz, 1H), 2.86 - 2.76 (m, 1H), 2.58 - 2.57 (m, 1H), 2.40 - 2.32 (m, 1H), 2.10 - 2.04 (m, 1H).

[0304] Example 7 (compound 120)

[0305] First step: synthesis of compound 120b

[0306] Compound 120a (2 g, 14.39 mmol) and cyclopropylamine (3.29 g, 57.56 mmol) were added to a reaction bottle at room temperature, and the reaction mixture was stirred at 45 °C under nitrogen protection for 16 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate solution (100 mL), extracted with dichloromethane (100 mL x 3), and the combined organic phase was washed with saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 120b (1.80 g, crude), which was used directly in the next step without purification. MS m / z (ESI): 116.20 [M+1] + .

[0307] Second step: synthesis of compound 120c

[0308] Compound 120b (1.80 g, 15.62 mmol) was dissolved in 48% aqueous hydrobromic acid solution (20 mL) at room temperature, and the reaction mixture was stirred at 100 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 120c (1.70 g, crude product), which was used directly in the next step without purification. MS m / z (ESI): 178.10 [M+1] + .

[0309] Step 3: Synthesis of compound 120d

[0310] Compound 120c (1.60 g, 8.89 mmol) was dissolved in a mixed solution of tetrahydrofuran and water (20 mL / 10 mL) at room temperature, and potassium carbonate (6.21 g, 44.92 mmol) and di-tert-butyl dicarbonate (3.92 g, 17.97 mmol) were slowly added. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 0%-5%) to obtain compound 120d (2.20 g). MS m / z (ESI): 177.5 [M-100] + .

[0311] Step 4: Synthesis of compound 120f

[0312] Compound 120d (2.10 g, 7.54 mmol) and 120e (1.29 g, 7.54 mmol) were sequentially added to a reaction bottle at room temperature, and the reaction mixture was stirred at 100 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate solution (100 mL), extracted with dichloromethane (100 mL x 3), and the combined organic phase was washed with saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 120f (2 g, crude product), which was used directly in the next step without purification. MS m / z (ESI): 269.0 [M+1] + .

[0313] Step 5: Synthesis of compound 120g

[0314] Compound 120f (1 g, 3.71 mmol) and compound 108c (0.73 g, 4.08 mmol) were sequentially added to toluene at room temperature, and the reaction mixture was stirred at 100 °C for 5 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 0%-5%) to obtain compound 120g (150 mg). MS m / z (ESI): 313.10 [M+1] + .

[0315] Step 6: Synthesis of compound 120

[0316] Compound 120g (50 mg, 0.16 mmol) was dissolved in a mixture of 1,4-dioxane and water (5 mL / 0.5 mL) under nitrogen protection, compound 12d (84.2 mg, 0.24 mmol), potassium phosphate (68.2 mg, 0.32 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (11.7 mg, 0.02 mmol) were added successively, and the reaction mixture was stirred at 80 °C for 2 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (column: Gemini C18 150*21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 25-75%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm) to give compound 120 (9.4 mg). MS m / z (ESI): 454.00 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 7.50 - 7.20 (m, 7H), 4.36 (dd, J = 12.0, 4.8 Hz, 1H), 3.58 (d, J = 6.0 Hz, 2H), 3.42 (d, J = 6.0 Hz, 2H), 3.14 - 3.04 (m, 1H), 2.80 (d, J = 17.5, 12.9, 5.3 Hz, 1H), 2.59 - 2.52 (m, 1H), 2.41 - 2.26 (m, 1H), 2.15 - 1.99 (m, 3H), 0.93 - 0.69 (m, 4H).

[0317] Example 8 (compound 121)

[0318] First step: synthesis of compound 121b

[0319] Compound 121a (980 mg, 8.36 mmol) was added to an aqueous hydrobromic acid solution (48% wt, 10 mL), and the reaction mixture was stirred at 100 °C overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure to give compound 121b (1.50 g, crude), which was used directly in the next step without purification. MS m / z (ESI): 180.15 [M+1] + .

[0320] Second step: synthesis of compound 121c

[0321] Compound 120e (0.96 g, 5.55 mmol) was dissolved in a solution of N,N- diisopropylethylamine (2 mL), and compound 121b (1 g, 5.55 mmol) was added. The reaction mixture was stirred at 100 °C overnight. After the reaction was completed, the reaction solution was extracted with dichloromethane (20 mL x 2), and the combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane / methanol = 0-10%) to obtain compound 121c (450 mg). MS m / z (ESI): 271.05 [M+1] + .

[0322] Third step: synthesis of compound 121d

[0323] Compound 121c (450 mg, 1.66 mmol) was dissolved in a solution of toluene (5 mL), and 108c (354.8 mg, 1.99 mmol) was added. The reaction mixture was stirred at 100 °C overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (column: Gemini C18 150*21.2 mm, 5 μm; mobile phase: acetonitrile: water (0.1% trifluoroacetic acid); gradient: 40-80%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm) to obtain compound 121d (20.0 mg). MS m / z (ESI): 313.00 [M+1] + .

[0324] Fourth step: synthesis of compound 121

[0325] Compound 121d (15.0 mg, 0.05 mmol) was dissolved in a solution of 1,4-dioxane (1 mL) under nitrogen protection, and compound 12d (33.5 mg, 0.10 mmol), potassium phosphate (20.3 mg, 0.10 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (3.5 mg, 0.01 mmol) were added in sequence. The reaction mixture was stirred at 80 °C for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (column: Gemini C18 150*21.2 mm, 5 μm; mobile phase: acetonitrile: water (0.1% formic acid); gradient: 37-63%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm) to obtain compound 121 (3.3 mg). MS m / z (ESI): 455.65 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 7.44 - 7.32 (m, 5H), 7.32 - 7.27 (m, 2H), 5.68 (d, J = 6.4 Hz, 1H), 4.36 (dd, J = 12.4, 5.2 Hz, 1H), 3.62 (t, J = 6.0 Hz, 2H), 3.39 - 3.35 (m, 2H), 2.88 - 2.71 (m, 1H), 2.59 - 2.53 (m, 1H), 2.41 - 2.34 (m, 1H), 2.12 - 2.01 (m, 3H), 1.14 (d, J = 6.8 Hz, 6H).

[0326] Biological evaluation

[0327] Test Example 1. Evaluation of the degradation of VAV1 in Jurkat cells

[0328] Jurkat cells (ATCC #TIB-152) were cultured using 90% RPMI 1640 base medium (Gibco #22400-089), 10% FBS (Gibco #10099-141C) and 1% pen-strep mix (Gibco #15140-122) and seeded at 1X10 ^6The density of each well was plated in 12-well plates. After incubation in a CO2 incubator (37°C, 5% CO2) for 1 hour, 6 μL of DMSO and 100 nM, 10 nM, 1 nM of the test compound were added, respectively, with a final concentration of 0.4%. After 24 hours of continuous incubation, the cells were centrifuged, and the culture supernatant was discarded. After washing with PBS once, 50 μL of RIPA lysis buffer (Bi Yun Tian #P0013B) was added. After incubation on ice with slight shaking or shaking for 15 minutes, centrifugation was performed at 15000 rpm for 10 minutes. The total protein was quantified using a BCA kit (Bi Yun Tian #P0010). Protein electrophoresis was performed on a 4-15% gradient gel (BIO-RAD #458086), and membrane transfer was performed on a turbo (Bio-Rad #1704150) using a pre-prepared transfer bag (BIO-RAD #1704156). After blocking for 15 minutes with blocking buffer (LI-COR #927-60000), VAV1 antibody (CST #2502S) and GAPDH (CST #2118S) were incubated at 4°C overnight. After incubation with IRDye800CW labeled goat anti-rabbit secondary antibody (LI-COR #926-32211) at room temperature for 2 hours, imaging detection and capture of fluorescent signals were performed on a Li-Cor Odyssey DLX instrument, thereby obtaining VAV1 and GAPDH blot images. Thereafter, the band integral intensity of the blot image was analyzed using Image Studio software, and the internal reference GAPDH was used for normalization processing to calculate the degradation rate of VAV1. For the degradation rate, A represents a degradation rate ≥ 75%, B represents 25% ≤ degradation rate < 75%, and C represents a degradation rate < 25%. The results are shown in Table 1.

[0329] Table 1

[0330] Test Example 2. Evaluation of the degradation effect on VAV1 in Jurkat cells

[0331] Jurkat cells (ATCC #TIB-152) were cultured using 90% RPMI 1640 basic medium (Gibco #22400-089), 10% FBS (Gibco #10099-141C), and 1% penicillin-streptomycin mixture (Gibco #15140-122), and 2X10 ^5Each well was plated in 96-well plates (Greiner #655090) coated with 0.1 pg / ml poly-lysine (Sangon Biotech #E607014) at a density of 5,000 cells per well. Cells were allowed to adhere for 2 hours in a CO2 incubator (37 °C, 5% CO2) before 10 pL of each compound was added to each well at a final concentration of 0.22% DMSO and 1000 nM, 200 nM, 40 nM, 8 nM, 1.6 nM, 0.32 nM, 0.06 nM, respectively. Cells were incubated for 24 hours. Cell plates were removed and centrifuged, and cells were fixed with 4% paraformaldehyde (Beyotime-P0099-500ml) for 20 minutes, permeabilized with 0.1% Triton X-100 (Sigma #T8787-500ML) for 20 minutes, blocked with blocking buffer (LI-COR #927-60000) for 1.5 hours at room temperature, and incubated with VAV1 antibody (CST #2502S, 1:100) overnight at 4 °C. IRDye800CW-labeled goat anti-rabbit secondary antibody (LI-COR #926-32211, 1:1500) and CellTag700Stain (Li-Cor #926-41090) were incubated for 2 hours at room temperature before imaging on a Li-Cor Odyssey DLX instrument to capture luminescence signals, from which VAV1 and CellTag700Stain fluorescence signals were obtained. TM 700Stain(Li-Cor #926-41090) room temperature for 2 hours before imaging on a Li-Cor Odyssey DLX instrument to capture luminescence signals, from which VAV1 and CellTag TM 700Stain fluorescence images. The fluorescence signal intensity of each well of each cell plate was then analyzed using Image Studio software, and the background signal was subtracted to normalize the signal of the internal control CellTag TM 700Stain, and the concentration of the compound that resulted in 50% degradation of VAV1 was calculated, i.e., DC50. A indicates DC50≤50 nM, B indicates 50 nM < DC50≤500 nM, and C indicates DC50>500 nM. The results are shown in Table 2.

[0332] Table 2

[0333] The above describes exemplary embodiments of the technical solutions of the present application. It should be understood that the protection scope of the present application is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made by those skilled in the art within the spirit and principles of the present application shall be included in the protection scope of the claims of the present application.

Claims

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein: T is R 10 selected from R A is a chemical bond or R 17 ; G 1 is N or CR 16c ; G 2 , G 3 , and G 4 are the same or different and each independently NR 18c or C(R 18 )2; G 5 is C or N; G 6 is N or CR 16c ; G 7 is N or CR 16d ; is a single or double bond; Ring A is selected from C 3-10 cycloalkane, 3-10 membered heterocyclic ring, C 6-10 aromatic ring and 5-10 membered heteroaromatic ring; B is a boron atom; X is selected from CR X1 R X2 , NR X3 , O or S; Z is CR 4 or N; R 1 and R 2 are the same or different and each independently selected from H, halogen, hydroxyl, cyano, C 1-6 alkyl and C 1-6 haloalkyl; R 3 selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, hydroxy, cyano, amino and C 3-6 cycloalkyl; R 4 and R 5 are the same or different and each is independently selected from the group consisting of H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, hydroxy, cyano, amino, C 3-6 cycloalkyl, and 3- to 6-membered heterocyclyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-6 cycloalkyl, and 3- to 6-membered heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, cyano, amino, oxo, C 3-6 cycloalkyl, and 3- to 6-membered heterocyclyl; R 6 , R 7 , R 8 and R 9 are the same or different and each is independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, hydroxy, cyano, amino, C 3-6 cycloalkyl and 3-6 membered heterocyclyl; R 11 selected from H, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, cyano, C 3-6 cycloalkyl and 3-6 membered heterocyclyl; L 1 and L 2 are the same or different and each is independently selected from a chemical bond, C 1-6 alkylene, C(O), and C 3-6 cycloalkyl, said C 1-6 alkylene and C 3-6 cycloalkyl being optionally substituted with one or more substituents selected from halo, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, cyano, amino; R 12 selected from H, halogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl, cyano, NR b R c , C(O)R a , C(O)NR b R c , NR b C(O)R a , NR b C(O)NR b R c , S(O) 0-2 R d , C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are optionally substituted with one or more R g ; R 13 and R 14 are the same or different and each is independently selected from H, halo, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, cyano, amino, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, said C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl are optionally substituted with one or more substituents selected from halo, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, cyano, amino, oxo, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl; R 15 selected from H, hydroxy, C 1-6 alkyl, cyano, -NR 1-6 alkyl, cyano, -NR b R c , -OC(O)R a , C 3-6 cycloalkyl and 3- to 6-membered heterocyclyl, said C 1-6 alkyl, C 1-6 alkyl, C 3-6 alkyl, C g cycloalkyl and 3- to 6-membered heterocyclyl optionally substituted with one or more R R 16a , R 16b , R 16c and R 16d are the same or different and each is independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, hydroxy, cyano, amino, C 3-6 cycloalkyl and 3-6 membered heterocyclyl; or R 16a , R 16b , R 16c and R 16d form, together with the atoms to which they are attached, a 5-10 membered heterocyclic ring or a 5-10 membered heteroaromatic ring, which is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, cyano, amino, oxo, C 3-6 cycloalkyl and 3-6 membered heterocyclyl; R 17 selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl; R 18a and R 18b are the same or different and each is independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, hydroxy, cyano, amino, C 3-6 cycloalkyl and 3-6 membered heterocyclyl; each R is independently selected from the group consisting of H, halogen, C 18 the same or different, and each is independently selected from the group consisting of H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, hydroxy, cyano, amino, C 3-6 cycloalkyl and 3-6 membered heterocyclyl; R 18c selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl; R 19 and R 21 are the same or different and each is independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, hydroxy, cyano, amino, C 3-6 cycloalkyl and 3-6 membered heterocyclyl; R 22 selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, cyano, amino, C 3-6 cycloalkyl and 3-6 membered heterocyclyl; R 20 and R 23 are the same or different and each is independently selected from the group consisting of H, hydroxyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, cyano, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl; R 24 and R 25 are the same or different and each is independently selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, cyano, amino, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl; or R 24 and R 25 together with the atom to which they are attached form a 5-10 membered heterocyclic ring, which is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, cyano, amino, oxo, C 3-6 cycloalkyl and 3-6 membered heterocyclyl; R g are the same or different and each is independently selected from halogen, deuterium, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 haloalkoxy, C 1-6 deuteroalkoxy, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, NR b R c , C(O)R a , C(O)NR b R c , NR b C(O)R a , NR b C(O)NR b R c , S(O) 0-2 R d , hydroxy, cyano, amino, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; R a selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl; R b and R c are the same or different and each is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, cyano, amino, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl; or R b and R c together with the atom to which they are attached form a 3-10 membered heterocyclic ring, which is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, oxo, amino, and cyano; R d selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, cyano, amino, C 3-6 cycloalkyl and 3-6 membered heterocyclyl; R X1 and R X2 are the same or different and each is independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, hydroxy, cyano, amino, C 3-6 cycloalkyl and 3-6 membered heterocyclyl; R X3 selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, cyano, amino, C 3-6 cycloalkyl and 3-6 membered heterocyclyl; p is 0, 1 or 2; r is 0, 1, 2, 3 or 4; t is 0, 1, 2, 3 or 4.

2. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R B is a chemical bond or R 16d ; R 10 selected from Ring A, G 1 , G 2 , G 3 , G 4 , G 5 , L 1 , L 2 , R 12 , R 13 , R 14 , R 15 , R A , R 16a , R 16b , R 16d , R 17 , R 18a , R 18b , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , r and t are as defined in claim 1.

3. The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the compound of Formula (I) is a compound of Formula (I-1) or Formula (I-2): ###0002### (I-1) (I-2). wherein R 1 , R 2 , R 3 , Z, R 5 and T are as defined in claim 1.

4. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-3, wherein R 10 selected from m is 0, 1, 2, 3, 4, 5, 6, 7 or 8; Ring A, L 1 , L 2 , R 12 , R 13 , R 14 , R 15 , R 16a , R 16b , R 16c , R 16d , R 17 , R 18 , R 18c , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , r and t are as defined in claim 1 or 2.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein Z is CR 4 ; R 4 as defined in claim 1.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from L 1 , L 2 , R 12 , R 13 , R 14 , and R 15 as defined in any one of claims 1-4; Preferably, L 1 and L 2 are the same or different and each is independently selected from a bond, -CH2-, -CH2F2, -CH2CH2-, -C(CH3)2-, -CH(CH3)-, and C(O).

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R 12 is selected from H, halogen, deuterium, C 1-3 alkyl, C 1-3 alkoxy, hydroxyl, cyano, NR b R c , C(O)NR b R c , NR b C(O)R a , NR b C(O)NR b R c , C 3-6 cycloalkyl, 3-10 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl, wherein the C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 3-10 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl are optionally substituted with one or more R g . Preferably, the 3-10 membered heterocyclyl is selected from the group consisting of 4-7 membered monocyclic heterocyclyl, 6-10 membered fused heterocyclyl, 6-10 membered spiro heterocyclyl, 6-10 membered bridged heterocyclyl, the heteroatoms in the heterocyclyl and heteroaryl are selected from N, O or S; the number of heteroatoms can be 1, 2, 3 or 4; and / or, R 13 and R 14 are identical or different and each independently selected from the group consisting of H, halogen, C 1-6 alkyl, C 1-6 haloalkyl and C 3-6 cycloalkyl; and / or, R 15 selected from H, hydroxyl, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 haloalkoxy, C 1-6 haloalkyl, C 1-6 deuteroalkoxy, C 1-6 deuteroalkyl, -CH2OC 1-6 alkyl, NR b R c and -OC(O)R a ; and / or, R a selected from C 1-6 alkyl and C 3-6 cycloalkyl; and / or, R b and R c are the same or different and each is independently selected from the group consisting of H, C 1-6 alkyl and C 3-6 cycloalkyl; or, R b and R c together with the atom to which they are attached form a 5-10 membered heterocyclic ring, which is optionally substituted with one or more substituents selected from the group consisting of halogen, oxo and C 1-6 alkyl; R g As defined in claim 1.

8. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-5, wherein; R 10 selected from Ring A, R 16a , R 16b , R 16c , R 16d , R 17 , R 18 , R 18c , R 19 , m and r are as defined in any one of claims 1-4; Preferably, ring A is selected from the group consisting of benzene ring, pyrazole ring, imidazole ring, oxazole ring, isoxazole ring, thiazole ring, isothiazole ring, triazole ring, pyridine ring, pyrimidine ring and pyridazine ring.

9. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-5 and 8, wherein; R 16a , R 16b , R 16c and R 16d are the same or different and each independently selected from H, halogen, C 1-6 alkyl and C 3-6 cycloalkyl; and / or, R 17 is H or C 1-6 alkyl; and / or, each R is independently selected from the group consisting of H, halogen, C 18 are the same or different, and each is independently selected from the group consisting of H, halogen, C 1-6 alkyl and C 3-6 cycloalkyl; and / or, R 18c selected from H, C 1-6 alkyl and C 3-6 cycloalkyl; and / or, each R is independently selected from the group consisting of H, halogen, and C 19 are the same or different, and each is independently selected from the group consisting of H, halogen, and C 1-6 alkyl.

10. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-5, wherein R 10 selected from: R 17 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 and t are as defined in any one of claims 1-5.

11. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-5 and 10, wherein: R 17 is H or C 1-6 alkyl; and / or, R 20 selected from the group consisting of hydroxy, C 1-6 alkoxy, C 1-6 haloalkoxy and C 1-6 alkyl; and / or, R 21 selected from H, halogen and C 1-6 alkyl; and / or, R 22 is C 1-6 alkyl or C 3-6 cycloalkyl; and / or, R 23 selected from the group consisting of hydroxy, C 1-6 alkoxy, C 1-6 haloalkoxy and C 1-6 alkyl; R 24 and R 25 are the same or different and each independently C 1-6 alkyl or C 3-6 cycloalkyl; or R 24 and R 25 together with the atom to which they are attached form a 5-6 membered heterocyclic ring, which is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 hydroxyalkyl.

12. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1, 2 and 4, wherein: X is CR X1 R X2 , R X1 and R X2 are the same or different and each independently selected from H, halogen and C 1-6 alkyl; and / or, p is 1 or 2; and / or, R 9 selected from H, halogen and C 1-6 alkyl; and / or, R 11 selected from hydroxy, C 1-6 alkoxy, C 1-6 haloalkoxy and C 1-6 alkyl.

13. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-12, wherein: R 1 is H or halogen; preferably, R 1 is H.

14. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-13, wherein: R 2 is halogen; preferably, R 2 is CI.

15. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-14, wherein, R 3 , R 4 and R 5 are the same or different and each is independently selected from H, halogen and C 1-6 alkyl.

16. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-15, wherein, R 6 , R 7 and R 8 are the same or different and each is independently selected from H, halogen and C 1-6 alkyl.

17. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-16, wherein, The compound has the following structure:

18. A pharmaceutical composition comprising at least one therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof according to any one of claims 1-17, and one or more pharmaceutically acceptable excipients.

19. An E3 ligase-molecular glue binary complex, wherein, The molecular glue is a compound or pharmaceutically acceptable salt thereof according to any one of claims 1-17.

20. An E3 ligase-molecular glue-VAV1 protein ternary complex, wherein, The molecular glue is a compound or pharmaceutically acceptable salt thereof according to any one of claims 1-17.

21. Use of a compound or pharmaceutically acceptable salt thereof according to any one of claims 1-17, or a pharmaceutical composition of claim 18, or an E3 ligase-molecular glue binary complex of claim 19, in the manufacture of a medicament for degrading VAV1 protein.

22. Use of a compound or pharmaceutically acceptable salt thereof according to any one of claims 1-17, or a pharmaceutical composition of claim 18, in the manufacture of a medicament for mediating the interaction of VAV1 protein with E3 ligase, thereby increasing the degradation of VAV1 protein; preferably, the compound interacts with E3 ligase prior to the interaction of VAV1 protein with E3 ligase.

23. Use of a compound, pharmaceutically acceptable salt thereof according to any one of claims 1-17, or a pharmaceutical composition of claim 18, or an E3 ligase-molecular glue binary complex of claim 19, in the manufacture of a medicament for preventing and / or treating a disease or disorder caused by or associated with a disorder of lymphocyte development or activity, preferably, the lymphocyte is a T cell.

24. Use of a compound, a pharmaceutically acceptable salt thereof according to any one of claims 1-17 or a pharmaceutical composition of claim 18 or an E3 ligase-molecular glue binary complex of claim 19 in the manufacture of a medicament for the prevention and / or treatment of an autoimmune disease, an inflammatory disease, a metabolic disease, a cardiovascular disease, a kidney disease, a central nervous system disease or a cancer; preferably, the autoimmune disease is selected from multiple sclerosis, rheumatoid arthritis, systemic lupus, thyroiditis, myasthenia gravis, type I diabetes, type II diabetes, vasculitis, pernicious anemia, dry eye, Sjoegren syndrome, uveitis, psoriasis, Graves ophthalmopathy, alopecia areata, allergic asthma, atopic dermatitis, allergic dermatitis, rhinitis, conjunctivitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, asthma, inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury, atherosclerosis, osteoarthritis, inflammatory eye disease, keratoconjunctivitis, myocarditis or hepatitis.

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