Piperidinedione compound, and pharmaceutical composition and use thereof

Abstract

The present application relates to a piperidinedione compound, and a pharmaceutical composition and use thereof. Specifically, provided is a piperidinedione compound represented by formula (I), which can be used for preparing a drug, especially for preparing a drug for preventing and / or treating diseases or conditions caused by or relating to lymphocyte development or activity disorders. Each group in formula (I) is as defined in the description.

Description

Piperidinedione compounds, pharmaceutical compositions thereof and uses thereof

[0001] Cross-reference to related applications

[0002] This application is based on the application with CN application number 202411291232.7, application date September 14, 2024, the application with CN application number 202411582839.0, application date November 7, 2024, and the application with CN application number 202511270335.X, application date September 5, 2025, and claims priority thereto, the contents of all applications are hereby incorporated by reference in their entirety. TECHNICAL FIELD

[0003] The present application belongs to the field of medicine, and specifically relates to a piperidinedione 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 the family members VAV2 and VAV3 are more universally 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 amino-terminal CH-AC domain and the carboxy-terminal SH3 domain fold inward and bind to the catalytic core (DH-PH-ZF domain), which simultaneously inhibits GEF activity and adaptor protein function. When the AC structure of VAV1 is phosphorylated, the inhibitory folding within the protein is released, forming an open, active conformation that performs GEF and adaptor protein functions. The main substrate for VAV1 to perform GEF function is Rac1, which is involved in regulating actin dynamics signaling pathways and cytoskeleton remodeling, enabling immune cell migration, adhesion, and immune synapse formation. The function of the scaffold protein: interacts with various protein complexes to form a TCR / BCR proximal complex, performs the function of an adaptor protein, and regulates T cell receptor and B cell receptor activation signaling.

[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), 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 activation of 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 lysosome, and can be further divided into nearly 10 different technical routes according to the specific action principle, among which the molecular glue and targeted proteolysis chimera (PROTAC) technologies are 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] Z is CR 4 or N;

[0011] T is

[0012] is a single bond or a double bond;

[0013] X is selected from CR X1 R X2 , C=O, CR 6c , N and NR X3 , when X is selected from CR X1 RX2 C=O and NR X3 hour, For a single bond, when X is CR 6c Or N, It is a double bond;

[0014] Y is CR 6d Or N;

[0015] R 1 and R 2 They may be the same or different, and each is independently selected from H, deuterium, halogen, hydroxyl, cyano, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0016] Or R 1 and R 2 The atoms bonded to it form C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, wherein the C 3-8 Cycloalkyl groups and 3-8-membered heterocyclic groups are optionally selected from halogens, hydroxyl groups, and C. 1-6 One or more substituents in the alkyl group are substituted;

[0017] R 3 Selected from H, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, hydroxyl, cyano, amino, C 3-8 cycloalkyl and C 3-8 Halogenated cycloalkyl groups;

[0018] 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 3-8 cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-8 Cycloalkyl groups and 3-8 membered heterocyclic groups are optionally selected from halogens, hydroxyl groups, C... 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, cyano, amino, oxo, C 3-6 The cycloalkyl group and one or more substituents of the 3-6 membered heterocyclic group are substituted;

[0019] R6a 6b 6c 6d R and R are the same or different and each is independently selected from H, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, hydroxy, cyano, amino, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl;

[0020] R 7 is selected from absent, H, oxo, L 1 -R 9 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-12 membered heteroaryl, C(O)R a , C(O)NR b R c , NR b R c , NR b C(O)R a , NR b C(O)NR b R c , and S(O) 0-2 R d wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, and 5-12 membered heteroaryl is optionally substituted with one or more R g ;

[0021] R X1 and R X2 are the same or different and each is independently selected from absent, H, halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, hydroxy, cyano, amino, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl;

[0022] R X3 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, cyano, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl;

[0023] ​​​Or, R 7 and R X1 R 7 and R 6c R 7 and R 6d Any group of atoms bonded to it forms a 5-12 membered heterocyclic group or a 5-12 membered heteroaryl group, wherein the 5-12 membered heterocyclic group or the 5-12 membered heteroaryl group is optionally bonded to one or more R groups. 8 Replaced when R 7 and R X1 When forming a 5-12 membered heterocyclic group or a 5-12 membered heteroaryl group, R X2 It can be non-existent;

[0024] Or, R 7 and R X3 The atoms bonded to it form a 5-12 membered heterocyclic group or a 5-12 membered heteroaryl group, wherein the 5-12 membered heterocyclic group or the 5-12 membered heteroaryl group is optionally bonded to one or more R groups. 8 Replaced;

[0025] R 8 Selected from H, halogen, oxo, L 1 -R 9 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, hydroxyl, cyano, amino, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-12 heteroaryl, =NR 10 C(O)R a C(O)NR b R c NR b R c NR b C(O)R a NR b C(O)NR b R c and S(O) 0-2 R d The C mentioned therein 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl and 5-12 heteroaryl groups are optionally coupled with one or more R groups. g Replaced;

[0026] L 1 C1-6 Alkylene, C 2-6 imide or C 2-6 Idemynyl group, where C 1-6 Alkylene, C 2-6 imide and C 2-6 One, two, or three CH2 groups in the ynethynyl group may be optionally and independently selected from -O-, -S-, and -NR. L1 -、C(O),C 3-8 The group substitution in the cycloalkyl or 3-8 membered heterocyclic group, wherein the C 1-6 Alkylene, C 2-6 imide or C 2-6 The ethynyl group is optionally selected from halogen, hydroxyl, amino, cyano, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 The alkyl group is replaced by one or more substituents in the cycloalkyl and 3-8 membered heterocyclic groups;

[0027] R L1 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups;

[0028] R 9 Selected from H, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-12 heteroaryl, C(O)R a C(O)NR b R c NR b R c NR b C(O)R a NR b C(O)NR b R c and S(O) 0-2 R d The C mentioned therein 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl and 5-12 heteroaryl groups are optionally coupled with one or more R groups. g Replaced;

[0029] R g Whether the same or different, each is independently selected from halogens, hydroxyl groups, and C. 1-6 Alkyl, C 1-6alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are optionally substituted with one or more R a , C(O)NR b R c , NR b R c , NR b C(O)R a , NR b C(O)NR b R c and S(O) 0-2 R d wherein said C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are optionally substituted with one or more R v ;

[0030] R v is selected from halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, hydroxy, cyano, amino, C 3-8 cycloalkyl and 3-8 membered heterocyclyl;

[0031] R 10 is selected from H, C 1-6 alkyl, cyano, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclyl;

[0032] R a is selected from 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, C 3-8 cycloalkyl and 3-8 membered heterocyclyl;

[0033] R b and R c are the same or different, each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C3-8 cycloalkyl and 3-8 membered heterocyclyl;

[0034] or R b and R c together with the nitrogen atom to which they are attached form a 5-10 membered heterocyclyl, said 5-10 membered heterocyclyl being optionally substituted with one or more of halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, hydroxy, cyano, and amino;

[0035] R d is 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 3-8 cycloalkyl and 3-8 membered heterocyclyl.

[0036] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are the same or different and each is independently selected from H, halo, hydroxy, cyano, C 1-6 alkyl and C 1-6 haloalkyl.

[0037] In some embodiments, R 1 and R 2 are the same or different and each is independently selected from H, deuterium and halo.

[0038] In some embodiments, R L1 is selected from H and C 1-6 alkyl, preferably H.

[0039] In some embodiments, R g are the same or different and each is independently selected from halo, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, oxo, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein said C 1-6 alkyl, C 1-6 alkoxy, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl is optionally substituted with one or more R v .

[0040] In some embodiments, R v is selected from C1-6 alkyl.

[0041] In some implementation schemes, R 10 Selected from H, C 1-6 Alkyl and cyano groups.

[0042] In some implementation schemes, R 10 Selected from H, methyl, and cyano groups.

[0043] In some implementation schemes, R a Selected from C 1-6 Alkoxy, C 1-6 Alkyl groups and 3-8 membered heterocyclic groups.

[0044] In some implementation schemes, R b and R c Whether the two are the same or different, they are each independently selected from H and C. 1-6 alkyl.

[0045] In some embodiments, the compound or a pharmaceutically acceptable salt thereof satisfies one or more of the following conditions:

[0046] (1) The C 1-6 The alkyl group is methyl, ethyl, n-propyl, or isopropyl;

[0047] (2) The C 1-6 The alkylene group is methylene (-CH2-), ethylene (-CH2CH2-), or propylene (-CH2CH2CH2-);

[0048] (3) The halogen is fluorine, chlorine, bromine or iodine, for example chlorine;

[0049] (4) The C 3-12 Cycloalkyl group is C 3-6 Cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and again, cyclopropyl;

[0050] (5) The heteroatoms in the 3-12 membered heterocyclic group, 3-8 membered heterocyclic group, and 3-6 membered heterocyclic group are N, O, or S; the number of heteroatoms can be 1, 2, or 3, for example, azirrobutyl, oxobutyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyranyl, tetrahydropyrroleyl, tetrahydrothiaranyl, piperidinyl, piperazineyl, etc.

[0051] (6) The heteroatoms in the 5-12-membered heteroaryl and 5-10-membered heteroaryl groups are N, O, or S; the number of heteroatoms can be 1, 2, or 3, for example, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, triazolyl, indoleyl, pyridinyl, quinolinyl, etc.

[0052] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein T is selected from:

[0053] Rings A and B are the same or different, each independently 5-12 membered heterocyclyl or 5-12 membered heteroaryl;

[0054] n is 0, 1, 2, 3, or 4;

[0055] R 6a , R 6b , R 6c , R 6d , R 7 , and R 8 are as defined above.

[0056] In some embodiments, n is 0, 1, or 2.

[0057] In some embodiments, n is 0 or 1.

[0058] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein Z is CR 4 ; R 4 are as defined above.

[0059] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein Y is CR 6d ; R 6d are as defined above.

[0060] In some embodiments, the compound of Formula (I) is a compound according to Formula (II), Formula (III), or Formula (IV):

[0061] wherein,

[0062] Rings A, B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6a , R 6b , R 6d , R 7 , R 8 , and n are as defined above.

[0063] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein T is selected from:

[0064] p is 0, 1 or 2; q is 0, 1 or 2; G is NR 8 , O or S; R 7 , R 8 , R 10 and n are as defined for compounds of formula (I).

[0065] In some embodiments, compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein T is selected from:

[0066] p is 0, 1 or 2; q is 0, 1 or 2; G is NR 8 , O or S; R 7 , R 8 , R 10 and n are as defined for compounds of formula (I).

[0067] In some embodiments, compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein T is selected from:

[0068] p is 0, 1 or 2; q is 0, 1 or 2; G is NR 8 , O or S, preferably NH, O or S; R 7 , R 8 , R 10 and n are as defined above.

[0069] In some embodiments, T is selected from

[0070] In some embodiments, T is selected from

[0071] In some embodiments, compounds of formula (III) or pharmaceutically acceptable salts thereof, wherein is selected from:

[0072] p is 0, 1 or 2; q is 0, 1 or 2; G is NR 8 , O or S; R 8 , R 10 and n are as defined for compounds of formula (I).

[0073] In some embodiments, compounds of formula (III) or pharmaceutically acceptable salts thereof, wherein is selected from: p is 0, 1, or 2; q is 0, 1, or 2; G is NR 8 , O, or S; R 8 , R 10 , and n are defined as for a compound of Formula (I).

[0074] In some embodiments, a compound of Formula (III) or a pharmaceutically acceptable salt thereof, wherein is selected from:

[0075] p is 0, 1, or 2; q is 0, 1, or 2; G is NR 8 , O, or S; R 8 , R 10 , and n are defined as above.

[0076] In some embodiments, a compound of Formula (IV) or a pharmaceutically acceptable salt thereof, wherein is selected from: q is 0, 1, or 2; R 8 , and n are defined as above.

[0077] In some embodiments, a compound of Formula (I), Formula (II), Formula (III), and Formula (IV) or a pharmaceutically acceptable salt thereof, wherein: is R 1 is defined as above.

[0078] In some embodiments, a compound of Formula (I), Formula (II), Formula (III), and Formula (IV) or a pharmaceutically acceptable salt thereof, wherein R 1 is H, deuterium, or halogen.

[0079] In some embodiments, a compound of Formula (I), Formula (II), Formula (III), and Formula (IV) or a pharmaceutically acceptable salt thereof, wherein R 1 is H or halogen, preferably H or F.

[0080] In some embodiments, a compound of Formula (I), Formula (II), Formula (III), and Formula (IV) or a pharmaceutically acceptable salt thereof, wherein R 1 is H.

[0081] In some embodiments, a compound of Formula (I), Formula (II), Formula (III), and Formula (IV) or a pharmaceutically acceptable salt thereof, wherein R 2 is halogen.

[0082] In some embodiments, compounds of Formula (I), Formula (II), Formula (III), and Formula (IV), or pharmaceutically acceptable salts thereof, wherein R 2 is Cl.

[0083] In some embodiments, compounds of Formula (I), Formula (II), Formula (III), and Formula (IV), or pharmaceutically acceptable salts thereof, 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.

[0084] In some embodiments, R 3 is selected from H and C 1-6 alkyl.

[0085] In some embodiments, R 3 is H.

[0086] In some embodiments, R 4 and R 5 are the same or different and each is independently selected from H and C 1-6 alkyl.

[0087] In some embodiments, R 4 and R 5 are H.

[0088] In some embodiments, compounds of Formula (I), Formula (II), Formula (III), and Formula (IV), or pharmaceutically acceptable salts thereof, wherein R 6a , R 6b , R 6c , and R 6d are the same or different and each is independently selected from H, halogen, and C 1-6 alkyl.

[0089] In some embodiments, R 6a , R 6b , R 6c , and R 6d are the same or different and each is independently selected from H and C 1-6 alkyl.

[0090] In some embodiments, R 6a , R 6b , R 6c , and R 6d are H.

[0091] In some embodiments, compounds of Formula (I) and Formula (II), or pharmaceutically acceptable salts thereof, wherein R 7 is selected from absent, H, oxo, L1 -R 9 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups are optionally coupled with one or more R groups. g Replaced;

[0092] L 1 C 1-6 Alkylene, wherein C 1-6 One, two, or three CH2 groups in the alkylene group may optionally and independently be selected from -O-, -S-, or -NR. L1 -、C(O),C 3-8 The group substitution in the cycloalkyl or 3-8 membered heterocyclic group, wherein the C 1-6 Alkyl groups are optionally selected from halogens, hydroxyl groups, amino groups, cyano groups, and C. 1-6 One or more substituents in the alkyl group are substituted;

[0093] R 9 Selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, C(O)R a C(O)NR b R c NR b C(O)R a and NR b C(O)NR b R c The C mentioned therein 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups are optionally coupled with one or more R groups. g Replaced;

[0094] R a R b R c R L1 and R g As defined above.

[0095] In some embodiments, the compounds represented by formulas (I), (II), (III), and (IV), or pharmaceutically acceptable salts thereof, wherein L1 -CH2-, -CH2CH2-, -CH(CH3)-, -CH2C(O)-, -CH2CH2O-, and -CH2CH2NH-.

[0096] In some embodiments, compounds of Formula (I) and Formula (II), or pharmaceutically acceptable salts thereof, wherein R 7 is selected from H, L 1 -R 9 , C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyano, and amino;

[0097] L 1 is selected from -CH2-, -CH2CH2-, -CH(CH3)-, -CH2C(O)-, -CH2CH2O-, and -CH2CH2NH-;

[0098] R 9 is selected from C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, C(O)R a , C(O)NR b R c , NR b C(O)R a , and NR b C(O)NR b R c , wherein said C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl is optionally substituted with one or more R g ;

[0099] R a , R b , R c , and R g are as defined above.

[0100] In some embodiments, compounds of Formula (I) and Formula (II), or pharmaceutically acceptable salts thereof, wherein R 7 is selected from C 3-8 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, wherein said C 3-8cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are optionally substituted with one or more R g substituted;

[0101] R g as defined above.

[0102] In some embodiments, R 7 is selected from the group consisting of absent, H, oxo, L 1 -R 9 , C 1-6 alkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein said C 1-6 alkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are optionally substituted with one or more R g substituted.

[0103] In some embodiments, R 7 is selected from the group consisting of H, C 1-6 alkylene-5 membered heteroaryl, C 1-6 alkyl and C 6-10 aryl, wherein said 5 membered heteroaryl is optionally substituted with one or more C 1-6 alkyl.

[0104] In some embodiments, R 7 is selected from the group consisting of H, C 1-6 alkylene-pyrazolyl, C 1-6 alkyl and phenyl, wherein said pyrazolyl is optionally substituted with one or more C 1-6 alkyl.

[0105] In some embodiments, R 7 is C 1-6 alkylene-5 membered heteroaryl, wherein said 5 membered heteroaryl is optionally substituted with one or more C 1-6 alkyl.

[0106] In some embodiments, R 7 is C 1-6 alkylene-pyrazolyl, wherein said pyrazolyl is optionally substituted with one or more C 1-6 alkyl.

[0107] In some embodiments, R 7 is selected from the group consisting of H, methyl, cyclopropyl,

[0108] In some embodiments, R7 H, methyl,

[0109] In some embodiments, R 7 is

[0110] In some embodiments, R 8 is selected from H, halo, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cyano, C 1- 6alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =NR 10 , C(O)R a , C(O)NR b R c , NR b R c , NR b C(O)R a , and NR b C(O)NR b R c wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl is optionally substituted with one or more R g , R a , R b , R c , R 10 , and R g are as defined above.

[0111] In some embodiments, R 8 is selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 3-8 alkynyl, cyano, C 6-10 cycloalkyl, 3-8 membered heterocyclyl, C a (O)R b , C(O)NR c R b , and NR a C(O)R 1-6 wherein said C 2-6 alkyl, C 3-8 alkenyl, C 6-10 alkynyl, C cycloalkyl, 3-8 membered heterocyclyl, and Caryl is optionally substituted with one or more R g substituents.

[0112] In some embodiments, R 8 is selected from H and C(O)-C 1-6 alkyl.

[0113] In some embodiments, R 8 is selected from H, methyl, isopropyl, chloro, ethynyl, cyano,

[0114] In some embodiments, R 8 is selected from H and

[0115] In some embodiments, R 8 is H.

[0116] In some embodiments, the compound of Formula (I), Formula (II), Formula (III), and Formula (IV), or a pharmaceutically acceptable salt thereof, wherein R a is C 1-3 alkyl, C 1-3 haloalkyl, or C

[0117] R b and R c are the same or different, each being independently selected from H or C 1-3 alkyl;

[0118] or R b and R c together with the nitrogen atom to which they are attached form a 5-10 membered heterocyclyl, said 5-10 membered heterocyclyl being optionally substituted with one or more substituents selected from halo, oxo, and C 1-3 alkyl;

[0119] R d is selected from C 1-3 alkyl, C 1-3 haloalkyl, and C 3-6 cycloalkyl.

[0120] In some embodiments, the compound of Formula (I), Formula (II), Formula (III), and Formula (IV), or a pharmaceutically acceptable salt thereof, wherein R g are the same or different, each being independently selected from halo, hydroxyl, C 1-6 alkyl, cyano, oxo, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, C(O)R a , C(O)NR b R c , NRb R c , b C(O)R a , b C(O)NR b R c wherein the C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are optionally substituted with one or more R v ;

[0121] R a is C 1-3 alkoxy or C 1-3 haloalkoxy;

[0122] R b and R c are the same or different, each being independently selected from H or C 1-3 alkyl;

[0123] or R b and R c together with the nitrogen atom to which they are attached form a 5-10 membered heterocyclyl, said 5-10 membered heterocyclyl being optionally substituted with one or more selected from the group consisting of halogen, oxo and C 1-3 alkyl;

[0124] R v is selected from halogen, oxo and C 1-6 alkyl.

[0125] In some embodiments, T is selected from

[0126] In some embodiments, T is selected from

[0127] In some embodiments, T is selected from

[0128] In some embodiments, T is selected from

[0129] R 7 is selected from H, C 1-6 alkylene-pyrazolyl, C 1-6 alkyl and phenyl, wherein the pyrazolyl is optionally substituted with one or more C 1-6 alkyl;

[0130] R 8 selected from H and C(O)-C 1-6 alkoxy;

[0131] R 1 is H or halogen;

[0132] R 2 is halogen;

[0133] R 3 selected from H and C 1-6 alkyl;

[0134] R 4 and R 5 are the same or different, and each is independently selected from H and C 1-6 alkyl;

[0135] n is 0, 1 or 2.

[0136] Exemplary specific compounds of the compounds shown herein include, but are not limited to, the structures in Table A below:

[0137] Table A

[0138] In some embodiments, the compounds in Table A herein are wherein is

[0139] In another aspect of the present application, there are provided isotopically labeled compounds of the compounds shown in Formula (I), Formula (II), Formula (III) and Formula (IV), and Table A, wherein the isotopic label is preferably deuterium (D or 2 H) for hydrogen (H). 1 H).

[0140] 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.

[0141] In another aspect of the present application, there is also provided an E3 ligase-molecular glue binary complex, wherein the molecular glue is a compound or a pharmaceutically acceptable salt thereof as described above.

[0142] In another aspect of the present application, there is also 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.

[0143] In another aspect, the present application provides the use of a compound of Formula (I), Formula (II), Formula (III), and Formula (IV), 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 manufacture of a medicament for degrading VAV1 protein.

[0144] In another aspect, the present application provides the use of a compound of Formula (I), Formula (II), Formula (III), and Formula (IV), 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.

[0145] In another aspect, the present application provides the use of a compound of Formula (I), Formula (II), Formula (III), and Formula (IV), 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.

[0146] In another aspect, the present application provides the use of a compound of Formula (I), Formula (II), Formula (III), and Formula (IV), 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 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.

[0147] In the present application, the lymphocytes are T cells.

[0148] In the present application, the lymphocytes are B cells.

[0149] In another aspect, the present application provides the use of a compound of Formula (I), Formula (II), Formula (III), and Formula (IV), 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 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.

[0150] 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.

[0151] The present application also provides a method of degrading VAV1 protein, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I), Formula (II), Formula (III), and Formula (IV), or a pharmaceutically acceptable salt thereof, or an isotopically-labeled form of the foregoing, or a pharmaceutical composition comprising the same, or the E3 ligase-molecular glue binary complex of the foregoing.

[0152] The present application also provides a method of degrading VAV1 protein, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I), Formula (II), Formula (III), and Formula (IV), or a pharmaceutically acceptable salt thereof, or an isotopically-labeled form of the foregoing, or a pharmaceutical composition comprising the same, said compound mediating the interaction of VAV1 protein with an E3 ligase, thereby increasing degradation of VAV1 protein.

[0153] The present application also provides a method of degrading VAV1 protein, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I), Formula (II), Formula (III), and Formula (IV), or a pharmaceutically acceptable salt thereof, or an isotopically-labeled form of the foregoing, or a pharmaceutical composition comprising the same, said compound interacting with an E3 ligase prior to the interaction of VAV1 protein with the E3 ligase.

[0154] The present application also provides a method of degrading VAV1 protein, comprising: (i) contacting said compound of Formula (I), Formula (II), Formula (III), and Formula (IV), or a pharmaceutically acceptable salt thereof, or an isotopically-labeled form of the foregoing, or a pharmaceutical composition comprising the same, with an E3 ligase, (ii) allowing the contacted E3 ligase to interact with VAV1, thereby degrading VAV1 protein.

[0155] The present application also provides a method for preventing and / or treating a disease or disorder caused by or related to a disorder of lymphocyte development or activity, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I), Formula (II), Formula (III), and Formula (IV), a compound of Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, or the E3 ligase-molecular glue binary complex.

[0156] The present application also provides a method 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, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I), Formula (II), Formula (III), and Formula (IV), a compound of Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, or the E3 ligase-molecular glue binary complex.

[0157] The present application also provides a compound of Formula (I), Formula (II), Formula (III), and Formula (IV), a compound of Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, or the E3 ligase-molecular glue binary complex, for use as a medicament.

[0158] The present application also provides a compound of Formula (I), Formula (II), Formula (III), and Formula (IV), a compound of Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, or the E3 ligase-molecular glue binary complex, for use as a VAV1 degrader.

[0159] The present application also provides a compound of Formula (I), Formula (II), Formula (III), and Formula (IV), a compound of Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, or the E3 ligase-molecular glue binary complex, for use as a medicament for preventing and / or treating a disease or disorder caused by or related to a disorder of lymphocyte development or activity.

[0160] The present application also provides a compound of Formula (I), Formula (II), Formula (III), and Formula (IV), a compound of Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, or the 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.

[0161] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

[0162] In some embodiments, the pharmaceutical composition contains 0.01-99.99% of the foregoing compound, or a pharmaceutically acceptable salt thereof, or an isotopically-labeled version thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the foregoing compound, or a pharmaceutically acceptable salt thereof, or an isotopically-labeled version thereof. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the foregoing compound, or a pharmaceutically acceptable salt thereof, or an isotopically-labeled version thereof.

[0163] In some embodiments, the pharmaceutical composition contains 1-99% of the foregoing compound, or a pharmaceutically acceptable salt thereof, or an isotopically-labeled version thereof.

[0164] 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.

[0165] 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.

[0166] In preparing the compositions of this application, the active ingredient will generally be mixed with a carrier, excipient or diluent, and as such compositions can be in unit dosage form, in admixture with non-toxic pharmaceutically acceptable auxiliary substances such as diluents, fillers, binders, disintegrating agents, and lubricants, etc. The compositions can be in unit, bulk or multiple doses.

[0167] As used herein, "excipient" means an ingredient other than the active ingredients. It includes diluents, fillers, absorbents, wetting agents, binders, disintegrating agents, lubricants, and the like.

[0168] 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 acidic center, and internal salts if the compounds contain both an acidic center and a basic center (e.g., a carboxylate group and a tertiary nitrogen).

[0169] 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 a racemic form. For example, cis and trans isomers, (-)- and (+)-enantiomeric forms, (R)- and (S)-enantiomeric forms, diastereomeric forms, (D)- isomer forms, (L)-isomer forms, racemic mixtures and other mixtures, and enantiomeric or diastereomeric enrichments thereof, are all contemplated by the present application. 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.

[0170] In the chemical structures of the compounds described herein, a bond indicates unspecified configuration, indicates absolute configuration, i.e., if chiral isomers are present in the chemical structure, a bond may be or both configurations, indicates the presence of an axial chirality.

[0171] a bond indicates unspecified configuration, including either the cis (E) or trans (Z) configuration.

[0172] In addition, the compounds and intermediates of the present application can also exist in different tautomeric forms and all such forms are encompassed by the scope of the present application. "Tautomers" refer to different energy structures that can interconvert via a low energy barrier. For example, prototropic tautomers (also known as proton-shift tautomers) include interconversions via 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.

[0173] 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 the application are included within the scope of the application, whether radioactive or not.

[0174] 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 have deuterium in an abundance of 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 will be able to synthesize compounds in deuterated form by reference to the literature. In making the deuterated forms of the compounds, the commercially available deuterated starting materials can be used, 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.

[0175] 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.

[0176] "Pharmaceutically acceptable" means, within the scope of sound medical judgment, that the compounds, materials, compositions, and / or dosage forms are suitable for use in contact with the tissues of a patient without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio, and effective for their intended use.

[0177] "Patient" means any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, goats, horses, or primates, most preferably humans. Beneficial effects

[0178] The present application provides a small molecule compound as a VAV1 degrader, 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.

[0179] Definitions and explanations of terms

[0180] Unless otherwise indicated, the terms used in the specification and claims have the following meanings.

[0181] 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 alkyl groups containing 1 to 6 carbon atoms (C1-C6-alkyl), even more preferably 1 to 4 carbon atoms (C1-C4-alkyl), and in particular 1 to 3 carbon atoms (C1-C3-alkyl), very particularly 1 or 2 carbon atoms (C1-C2-alkyl), such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, 2-pentyl, 3-pentyl or 2-methyl-2-butyl. 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.

[0182] The term "alkoxy" refers to -O-(alkyl), where alkyl is as defined herein. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propyloxy, and butyloxy. Alkoxy groups can be substituted or unsubstituted.

[0183] The term "alkylene" refers to a saturated, divalent hydrocarbyl radical resulting from the removal of two H from a saturated, straight chain or branched chain hydrocarbon group, which can contain 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms. Non-limiting examples include methylene (-CH2-), ethylene (-CH2CH2-), and the like. The alkylene group can be substituted or unsubstituted.

[0184] The term "alkenyl" is understood to preferably mean a straight-chain or branched monovalent hydrocarbon group which contains one or more double bonds and has 2 to 20 carbon atoms, preferably "C 2-10 alkenyl". "C 2-10 The term "alkenyl" is understood to preferably mean a straight-chain or branched monovalent hydrocarbon group which contains one or more double 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 alkenyl". "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.

[0185] 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.

[0186] 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.

[0187] 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) in 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:

[0188] 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:

[0189] 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:

[0190] 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.

[0191] 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 members of -O-O-, -O-S-, or -S-S-, the remainder of which are carbon, which can optionally be oxidized, the ring carbons of which are 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.

[0192] 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) in the system, 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:

[0193] The term "fused heterocyclyl" refers to a polycyclic heterocyclic group 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 groups according to the number of rings comprising the ring system, 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 groups. Non-limiting examples of fused heterocyclyl groups include:

[0194] The term "bridged heterocyclyl" refers to a polycyclic heterocyclic group 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 groups according to the number of rings comprising the ring system, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:

[0195] The heterocyclyl ring includes heterocyclyl groups as described herein (including monocyclic, spiroheterocyclic, fused heterocyclic, and bridged heterocyclic) 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: The heterocyclyl group can be substituted or unsubstituted.

[0196] 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) ring having a conjugated pi-electron system, preferably 6 to 10 members, such as phenyl and naphthyl. The aryl group can be substituted or unsubstituted.

[0197] 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. Heteroaryl 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 rings connected together can be a heteroaryl ring or an aryl ring, non-limiting examples of which include: and the like. Heteroaryl can be substituted or unsubstituted.

[0198] The terms "alkyl", "alkoxy", "cycloalkyl", "heterocyclyl", "aryl", and "heteroaryl" and the like herein can be substituted or unsubstituted; when substituted, it 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.

[0199] The above cycloalkyl, heterocyclyl, aryl, and heteroaryl include residues derived from removal of one H from a ring atom of the parent, or two H from the same or two different ring atoms of the parent, i.e., "divalent cycloalkyl", "divalent heterocyclyl", "arylene", "heteroarylene".

[0200] The term "cycloalkyloxy" refers to cycloalkyl-O-, wherein cycloalkyl is as defined herein.

[0201] The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined herein.

[0202] The term "haloalkyl" refers to alkyl substituted with one or more halogens, wherein alkyl is as defined herein.

[0203] The term "haloalkoxy" refers to alkoxy substituted with one or more halogens, wherein alkoxy is as defined herein.

[0204] The term "hydroxyalkyl" refers to alkyl substituted with one or more hydroxy groups, wherein alkyl is as defined herein.

[0205] The term "cyanoalkyl" refers to alkyl substituted with one or more cyano groups, wherein alkyl is as defined herein.

[0206] The term "aminoalkyl" refers to alkyl substituted with one or more amino groups, wherein alkyl is as defined herein.

[0207] The term "halogen" refers to F, Cl, Br, or I.

[0208] The term "hydroxyl group" refers to -OH.

[0209] The term "amino" refers to -NH2.

[0210] The term "cyano" refers to -CN.

[0211] The term "nitro" refers to -NO2.

[0212] The term "oxo" or "oxo" refers to "=O" when it substitutes on C, and "=O" when it substitutes on N.

[0213] The term "carbonyl" refers to C=O.

[0214] The term "carboxyl group" refers to -C(O)OH.

[0215] The term “carboxylic acid ester group” refers to -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.

[0216] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes situations in which the event or environment may or may not occur. For example, "optionally alkyl-substituted heterocyclic alkyl group" means that an alkyl group may but does not have to be present, and the description includes cases where the heterocyclic alkyl group is substituted with an alkyl group and cases where the heterocyclic alkyl group is not substituted with an alkyl group.

[0217] "Substituted" means that one or more H atoms in the given structure are replaced by specific substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (through experiment or theory) possible or impossible substitutions without much effort. Furthermore, when the group is replaced by more than one of the substituents, the substituents are independent of each other (i.e., the more than one substituent can be different or the same).

[0218] In this text, when the substitution site of the substituent is indeterminate, the ring intersecting the single bond of the substituent represents a ring in which the substituent can be substituted. For example, in the structural formula... In the middle, R 8 Substitution can be performed at suitable sites on the right-hand ring. If n is 1 or 2, the structure can be... Please refer to this definition for understanding other similar structures.

[0219] It should be understood that the singular forms "a," "an," and "the" used in the present disclosure include plural referents unless otherwise stated. In addition, the term "comprising" is to be construed as open-ended, i.e., as "including but not limited to," unless otherwise indicated. DETAILED DESCRIPTION

[0220] 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 illustratively described and explained the present application, and should not be interpreted as limiting the scope of protection of the present application. Any technology achieved based on the above content of the present application is covered within the scope intended to be protected by the present application.

[0221] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0222] 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, and 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, and Agilent G6125B liquid chromatography-mass spectrometry.

[0223] The determination of HPLC uses Shimadzu HPLC-2010C high pressure liquid chromatograph (XBRIDGE 2.1*50mm, 3.5um chromatographic column).

[0224] The determination of chiral HPLC analysis uses THARSFC X5.

[0225] The thin layer chromatography silica gel plate uses Yantai Qingdao GF254 silica gel plate, and the silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.2mm, and the specification adopted for the thin layer chromatography separation and purification product is 0.4mm-0.5mm.

[0226] Column chromatography generally uses Qingdao Marine silica gel 200-300 mesh silica gel as the carrier.

[0227] High performance liquid preparation uses Waters 2767, Waters 2545, and innovative constant LC3000 preparative chromatograph.

[0228] Chiral preparative column chromatography uses Shimadzu LC-20AP, THARSFC PREP 80.

[0229] Combiflash Rf200 (TELEDYNE ISCO) was used for the combiFlash flash system.

[0230] Beijing Jiawei Kechuang Technology GCD-500G hydrogen generator was used for the pressurized hydrogenation reaction.

[0231] Biotage initiator+ microwave reactor was used for the microwave reaction.

[0232] Unless otherwise specified, the reactions in the experimental examples were carried out under an argon or nitrogen atmosphere.

[0233] The argon or nitrogen atmosphere refers to that the reaction bottle is connected to an about 1 liter argon or nitrogen balloon.

[0234] The hydrogen atmosphere refers to that the reaction bottle is connected to an about 1 liter hydrogen balloon.

[0235] Unless otherwise specified, the reaction temperature in the experimental examples is room temperature, and the temperature range is 20-30°C.

[0236] Those skilled in the art should understand that the chiral compounds separated by the retention time in the chiral chromatographic column can be distinguished by the order of the retention time, therefore, the chiral compounds separated by the order of the retention time are distinguished by the number suffixes P1, P2, etc. For example, the suffix P1 corresponds to the chiral compound with a certain chiral structure eluted out of the chiral chromatographic column earlier, and the suffix P2 corresponds to the chiral compound with a certain chiral structure eluted out of the chiral chromatographic column later. If the absolute configuration of a 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 based on the objective corresponding absolute configuration marked by the specific retention time.

[0237] Example 1 (compound 39)

[0238] Step 1: synthesis of compound 39

[0239] Compound 39b (5-bromopyrazolo[l,5-a]pyridine) (50 mg, 0.25 mmol) was dissolved in 1,4-dioxane (4 mL), and compound 39a (87 mg, 0.25 mmol, synthesis method refer to WO2024151547A1 specification page P184 synthesis of intermediate A), potassium phosphate (159.2 mg, 0.75 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (18.3 mg, 0.025 mmol) were added successively. The reaction mixture was heated to 100 °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%) and thin layer chromatography silica gel plate (dichloromethane / methanol = 10 / 1) to obtain compound 39 (31.6 mg).

[0240] MS m / z (ESI): 340.0 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 8.74 (d, J = 7.2 Hz, 1H), 8.05 (d, J = 2.2 Hz, 1H), 7.73 (d, J = 0.9 Hz, 1H), 7.53 - 7.29 (m, 3H), 6.92 (dd, J = 7.2, 1.9 Hz, 1H), 6.68 (d, J = 1.7 Hz, 1H), 4.37 (dd, J = 12.2, 5.0 Hz, 1H), 2.89 - 2.73 (m, 1H), 2.58-2.51 (m, 1H), 2.35 (qd, J = 12.8, 4.3 Hz, 1H), 2.11 - 2.00 (m, 1H).

[0241] Example 2 (Compound 41)

[0242] First step: synthesis of compound 41

[0243] Compound 39a (100 mg, 0.29 mmol) was dissolved in 1,4-dioxane (5 mL), and compound 41b (7-bromoimidazo[l,2-a]pyridine) (57.1 mg, 0.29 mmol), potassium phosphate (184.7 mg, 0.87 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (21.2 mg, 0.029 mmol) were added successively. The reaction mixture was heated to 100 °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 = 0-5%) to obtain compound 41 (10.1 mg). MS m / z (ESI): 340.0 [M+1]+ . 1 H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 8.61 (d, J = 7.0 Hz, 1H), 8.01 (s, 1H), 7.64 (s, 1H), 7.56 (s, 1H), 7.46 - 7.39 (m, 3H), 6.96 (dd, J = 7.0, 1.6 Hz, 1H), 4.37 (dd, J = 12.2, 5.0 Hz, 1H), 2.86 - 2.71 (m, 1H), 2.57-2.50 (m, 1H), 2.35 (dt, J = 12.5, 8.5 Hz, 1H), 2.12 - 2.03 (m, 1H).

[0244] Example 3 (Compound 47)

[0245] First Step: Synthesis of compound 47c

[0246] Under nitrogen protection, diisopropylamine lithium (1.9 mL, 3.80 mmol, 2M in tetrahydrofuran) was added to tetrahydrofuran (20 mL) at -65 °C, a solution of compound 47a (4-bromo-2-methylpyridine) (500 mg, 2.19 mmol) in tetrahydrofuran (4 mL) was added dropwise, after reaction at -65 °C for 40 minutes, a solution of 47b (2-(ethoxymethylidene)malonic acid diethyl ester) (755 mg, 3.49 mmol) in tetrahydrofuran (2 mL) was added dropwise within 20 minutes. The mixture was slowly warmed to 25 °C, stirred for 2.5 hours, the reaction was quenched with saturated aqueous ammonium chloride (25 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (30 mL) again, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure, the residue was dissolved in toluene (4 mL), after stirring at 60 °C for 12 hours, the reaction was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0% - 60%) to give compound 47c (230 mg). MS m / z (ESI): 296.0, 298.0 [M+1, M+3] + .

[0247] Second Step: Synthesis of compound 47d

[0248] Compound 47c (150 mg, 0.51 mmol) was dissolved in 6N hydrochloric acid (3 mL). The reaction was heated to 100 °C under nitrogen protection and stirred for 12 hours. After the reaction was completed, it was cooled to 0 °C, adjusted to pH 10 with 1N NaOH, extracted with ethyl acetate (30 mL x 3), the combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%-60%) to obtain compound 47d (40 mg). MS m / z (ESI): 223.9, 225.9 [M+1, M+3] + .

[0249] Third step: synthesis of compound 47

[0250] Compound 39a (63 mg, 0.18 mmol) was dissolved in 1,4-dioxane (2 mL), and compound 47d (40 mg, 0.18 mmol), potassium phosphate (114.6 mg, 0.54 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (13 mg, 0.018 mmol) were added in turn. The reaction mixture was heated to 100 °C under nitrogen protection and stirred for 16 hours. After the reaction was completed, the reaction was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 70-100%) to obtain compound 47 (31.28 mg). MS m / z (ESI): 367.1 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 8.98 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 4.0 Hz, 1H), 7.79 (t, J = 8.0 Hz, 1H), 7.49 (s, 3H), 7.25 (dd, J = 8.0, 4.0 Hz, 1H), 6.90 (d, J = 8.0 Hz, 1H), 6.48 (d, J = 4.0 Hz, 1H), 4.38 (dd, J = 12.0, 8.0 Hz, 1H), 2.88 - 2.75 (m, 1H), 2.67-2.56 (m, 1H), 2.40-2.33 (m, 1H), 2.10-2.01 (m, 1H).

[0251] Example 4 (compound 40)

[0252] First step: synthesis of compound 40

[0253] Compound 39a (100 mg, 0.29 mmol) was dissolved in 1,4-dioxane (10 mL), and compound 40a (7-bromoimidazo[l,5-a]pyridine) (57.14 mg, 0.29 mmol), potassium phosphate (184.67 mg, 0.87 mmol), and l,l'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (21.22 mg, 0.029 mmol) were added successively. The reaction mixture was heated to 100 °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 = 0-15%) and thin layer chromatography silica gel plate (methanol / dichloromethane = 1 / 20) to obtain compound 40 (16.1 mg). MS m / z (ESI): 340.0 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.55 - 8.29 (m, 2H), 7.58 (s, 1H), 7.47 - 7.30 (m, 4H), 6.71 (d, J = 7.3 Hz, 1H), 4.36 (dd, J = 12.2, 4.8 Hz, 1H), 2.89 - 2.72 (m, 1H), 2.55 (d, J = 19.4 Hz, 1H), 2.34 (dt, J = 12.6, 8.8 Hz, 1H), 2.06 (dd, J = 10.1, 4.8 Hz, 1H).

[0254] Example 5 (Compound 11)

[0255] First Step: Synthesis of compound 11b

[0256] Compound 11a ((l-methyl-lH-pyrazol-3-yl)methanol) (1 g, 8.92 mmol) was dissolved in tetrahydrofuran (20 mL) under ice bath condition, and then carbon tetrabromide (3.55 g, 10.7 mmol) and triphenylphosphine (3.51 g, 13.38 mmol) were added portionwise, after which the reaction solution was slowly warmed to room temperature, and then stirred at room temperature for 4 h. The reaction solution was concentrated under reduced pressure, and purified by silica gel column chromatography (methanol / dichloromethane = 0-10%) to obtain compound 11b (1.1 g). MS m / z (ESI): 175.0 [M+1] + .

[0257] Second Step: Synthesis of compound 11d

[0258] Compound 11c (4-bromopyridin-2(lH)-one) (170 mg, 0.98 mmol) was dissolved in N,N-dimethylformamide (4 mL), then compound 11b (150 mg, 0.98 mmol) and sodium hydride (47 mg, 1.96 mmol) were added under ice-bath condition, after which the reaction solution was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate (20 mL x 2), the combined organic phase was washed with saturated brine (30 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1-1 / 1) to obtain 11d (196 mg). MS m / z (ESI): 267.9 [M+1] + .

[0259] Third step: synthesis of compound 11

[0260] Compound 11d (40 mg, 0.15 mmol) was dissolved in 1,4-dioxane (2 mL), and compound 39a (52 mg, 0.15 mmol), potassium phosphate (96 mg, 0.45 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (11 mg, 0.015 mmol) were sequentially added. The reaction mixture was heated to 100°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. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-5%) to obtain compound 11 (20 mg). MS m / z (ESI): 411.0 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 7.73 (d, J = 7.0 Hz, 1H), 7.64 (d, J = 2.1 Hz, 1H), 7.41 (d, J = 4.7 Hz, 2H), 7.33 (t, J = 4.7 Hz, 1H), 6.37 (d, J = 1.8 Hz, 1H), 6.27 (dd, J = 7.0, 2.0 Hz, 1H), 6.20 (d, J = 2.2 Hz, 1H), 5.06 (s, 2H), 4.34 (dd, J = 12.3, 4.9 Hz, 1H), 3.81 (s, 3H), 2.74-2.85 (m, 1H), 2.54-2.58 (m, 1H), 2.22-2.38 (m, 1H), 2.07-1.97 (m, 1H).

[0261] Example 6 (Compound 1)

[0262] First step: synthesis of compound 1

[0263] Compound 1a (4-pyridineboronic acid) (10 mg, 0.081 mmol) was dissolved in 1,4-dioxane (1 mL), and compound 1b (24.51 mg, 0.081 mmol) (synthesis method, refer to patent WO2024151547A1 specification page 184 Intermediate AA-1), potassium phosphate (51.58 mg, 0.24 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (11.85 mg, 0.016 mmol) were added sequentially. The reaction mixture was heated to 80°C under nitrogen protection and stirred for 2 days. 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 compound 1 (3.20 mg). MS m / z (ESI): 301.0 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.68 (s, 2H), 7.46-7.44 (m, 4H), 7.37-7.35 (m, 1H), 4.36 (dd, J = 4.0, 12.0 Hz, 1H), 2.88-2.77 (m, 1H), 2.57-2.56 (m, 1H), 2.36-2.32 (m, 1H), 2.07-1.97 (m, 1H).

[0264] The following compounds can be synthesized according to the preparation method of the above examples.

[0265] Biological evaluation

[0266] Test Example 1. Evaluation of degradation of VAV1 in Jurkat cells

[0267] Jurkat cells (ATCC #TIB-152) were cultured using 90% RPMI 1640 base medium (Gibco #22400-089), 10% FBS (Gibco #10099-141C), and 1% penicillin-streptomycin mixture (Gibco #15140-122), and 1X10 ^6Each well was plated in 12-well plates. After incubation in a CO2 incubator (37 °C, 5% CO2) for 1 hour, 6 μL of DMSO at a final concentration of 0.4% and 100 nM, 10 nM, 1 nM of the test compound were added, respectively, and the cells were incubated for another 24 hours. After centrifugation, the culture supernatant was discarded. The cells were washed once with PBS and 50 μL of RIPA lysis buffer (Bi Yun Tian #P0013B) was added. After incubation on ice for 15 minutes with slight shaking or shaking, the cells were centrifuged 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 the 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 overnight at 4 °C. After incubation with IRDye800CW labeled goat anti-rabbit secondary antibody (LI-COR #926-32211) at room temperature for 2 hours, the captured fluorescent signal was detected by imaging on a Li-Cor Odyssey DLX instrument, and thus VAV1 and GAPDH blot images were obtained. 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 a degradation rate of 25%≤ degradation rate < 75%, and C represents a degradation rate < 25%. The results are shown in Table 1.

[0268] Table 1

[0269] Test Example 2. Evaluation of the degradation effect on VAV1 in Jurkat cells

[0270] 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 TM TM

[0271] Table 2

[0272] The above has exemplarily described the 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 modification, equivalent replacement, improvement, etc. made by those skilled in the art within the spirit and principle 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: Z is CR 4 or N; T is is a single or double bond; X is selected from CR X1 R X2 , C=0, CR 6c , N and NR X3 , when X is selected from CR X1 R X2 , C=0 and NR X3 , is a single bond when X is CR 6c or N, is a double bond; Y is CR 6d or N; R 1 and R 2 are the same or different and each is independently selected from H, deuterium, halogen, hydroxyl, cyano, C 1-6 alkyl and C 1-6 haloalkyl; or R 1 and R 2 with the atom to which they are attached form a C 3-8 cycloalkyl or 3-8 membered heterocyclyl, wherein said C 3-8 cycloalkyl and 3-8 membered heterocyclyl are optionally substituted with one or more substituents selected from halogen, hydroxy, and C 1-6 alkyl; 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, C 3-8 cycloalkyl and C 3-8 halocycloalkyl; 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 3-8 cycloalkyl, and 3-8 membered heterocyclyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-8 cycloalkyl, and 3-8 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 3-6 membered heterocyclyl; R 6a , R 6b , R 6c and R 6d 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 3-8 cycloalkyl and 3-8 membered heterocyclyl; R 7 is selected from the group consisting of absent, H, oxo, L 1 -R 9 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 ycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-12 membered heteroaryl, C(O)R a , C(O)NR b R c , NR b R c , NR b C(O)R a , NR b C(O)NR b R c , and S(O) 0-2 R d , wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 ycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, and 5-12 membered heteroaryl is optionally substituted with one or more R g ; R X1 and R X2 are the same or different and each is independently selected from the group consisting of absent, H, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, hydroxy, cyano, amino, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl; R X3 selected from H, C 1-6 alkyl, C 1-6 haloalkyl, cyano, C 3-8 cycloalkyl and 3-8 membered heterocyclyl; or R 7 and R X1 , R 7 and R 6c , R 7 and R 6d form, together with the atom to which they are attached, a 5-12 membered heterocyclyl or 5-12 membered heteroaryl, which is optionally substituted with one or more R 8 ; and when R 7 and R X1 form a 5-12 membered heterocyclyl or 5-12 membered heteroaryl, R X2 may be absent; or R 7 and R X3 with the atom to which it is attached forms a 5-12 membered heterocyclyl or 5-12 membered heteroaryl, which is optionally substituted with one or more R 8 substituents; R 8 is selected from H, halogen, oxo, L 1 -R 9 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, hydroxyl, cyano, amino, C 1-6 alkoxy, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-12 membered heteroaryl, =NR 10 , C(O)R a , C(O)NR b R c , NR b R c , NR b C(O)R a , NR b C(O)NR b R c and S(O) 0-2 R d , wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl and 5-12 membered heteroaryl are optionally substituted with one or more R g ; L 1 is C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene, wherein 1, 2 or 3 CH2in the C 1-6 alkylene, C 2-6 alkenylene and C 2-6 alkynylene are optionally and each independently replaced with a moiety selected from the group consisting of -0-, -S-, -NR L1 -, C(O), C 3-8 cycloalkyl or 3-8 membered heterocyclyl, said C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl; R L1 selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclyl; R 9 is selected from the group consisting of H, C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-10 aryl, 5- to 12-membered heteroaryl, C(O)R a , C(O)NR b R c , NR b R c , NR b C(O)R a , NR b C(O)NR b R c and S(O) 0-2 R d wherein said C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-10 aryl and 5- to 12-membered heteroaryl are optionally substituted with one or more R g ; R g the same or different, each independently selected from halogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, cyano, oxo, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, C(O)R a , C(O)NR b R c , NR b R c , NR b C(O)R a , NR b C(O)NR b R c and S(O) 0-2 R d wherein said C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are optionally substituted with one or more R v ; R v selected from halogen, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, hydroxy, cyano, amino, C 3-8 cycloalkyl and 3-8 membered heterocyclyl; R 10 selected from H, C 1-6 alkyl, cyano, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclyl; R a selected from 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, C 3-8 cycloalkyl and 3-8 membered heterocyclyl; R b and R c are the same or different, each being independently selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl; Or R b and R c Together with the nitrogen atom attached thereto, a 5-10 member heterocyclic group is formed, wherein the 5-10 member heterocyclic group is optionally selected from halogen, oxo, C... 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 1-6 aminoalkyl, C 1-6 One or more substitutions of hydroxyalkyl, hydroxy, cyano, and amino; 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 3-8 cycloalkyl and 3-8 membered heterocyclyl.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are the same or different and each is independently selected from H, halogen, hydroxyl, cyano, C 1-6 alkyl and C 1-6 haloalkyl.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein T is selected from the group consisting of: wherein: ring A and ring B are the same or different, each independently a 5-12 membered heterocyclyl or a 5-12 membered heteroaryl; n is 0, 1, 2, 3 or 4; R 6a , R 6b , R 6c , R 6d , R 7 and R 8 are as defined in claim 1 or 2.

4. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein Z is CR 4 ; R 4 as defined in claims 1-3. or Y is CR 6d ; R 6d as defined in claims 1-3.

5. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound according to Formula (II), Formula (III), or Formula (IV): wherein, Ring A, Ring B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6a , R 6b , R 6d , R 7 , R 8 and n are as defined in claims 1-4.

6. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-5, wherein T is selected from: Preferably, T is selected from Preferably, T is selected from p is 0, 1 or 2; q is 0, 1 or 2; G is NR 8 , O or S, preferably NH, O or S; R 7 , R 8 , R 10 and n are as defined in claims 1 to 5.

7. The compound according to any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein: For R 1 As defined in any one of claims 1-6.

8. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-7, wherein: R 1 is H, deuterium or halogen; preferably, R 1 is H.

9. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-8, wherein: R 2 is halogen; preferably, R 2 is CI.

10. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-9, 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.

11. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-10, wherein, R 6a , R 6b , R 6c and R 6d are the same or different and each is independently selected from H, halogen and C 1-6 alkyl.

12. The compound according to any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from the group consisting of absent, H, oxo, L 1 -R 9 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl is optionally substituted with one or more R g ; Preferably, R 7 Selected from non-existent, H, oxo, L 1 -R 9 C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6- 10 aryl and 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups are optionally coupled with one or more R groups. g Replaced; R is selected from the group consisting of H, C 7 alkylene-5-membered heteroaryl, C 1-6 alkylene-5-membered heteroaryl, C 1-6 alkylene-5-membered heteroaryl, C 6-10 aryl, wherein said 5-membered heteroaryl is optionally substituted by one or more C 1-6 alkyl; R is selected from the group consisting of H, C 7 alkyl, C 1-6 alkylene-pyrazolyl, C 1-6 alkyl and phenyl, wherein said pyrazolyl is optionally substituted by one or more C 1-6 alkyl; R is preferably C 7 alkylene-5-membered heteroaryl, wherein said 5-membered heteroaryl is optionally substituted by one or more C 1-6 alkylene-5-membered heteroaryl, wherein said 5-membered heteroaryl is optionally substituted by one or more C 1-6 alkylene-5-membered heteroaryl, wherein said 5-membered heteroaryl is optionally substituted by one or more C L 1 is C 1-6 alkylene, wherein 1, 2 or 3 CH2in the alkylene group are optionally and each independently replaced by a moiety selected from the group consisting of -0-, -S-, -NR 1-6 -0-, -S-, -NR L1 -C(O), -C 3-8 alkylene, wherein 1, 2 or 3 CH2in the alkylene group are optionally and each independently replaced by a moiety selected from the group consisting of -0-, -S-, -NR 1-6 alkylene, wherein 1, 2 or 3 CH2in the alkylene group are optionally and each independently replaced by a moiety selected from the group consisting of -0-, -S-, -NR 1-6 alkyl; Preferably, L 1 is selected from: -CH2-, -CH2CH2-, -CH(CH3)-, -CH2C(O)-, -CH2CH2O- and -CH2CH2NH-; R 9 selected from C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, C(O)R a , C(O)NR b R c , NR b C(O)R a and NR b C(O)NR b R c wherein said C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are optionally substituted with one or more R g ; R a , R b , R c , R L1 and R g are as defined in claims 1-11.

13. The compound according to any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein R 8 is selected from H, halo, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cyano, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =NR 10 , C(O)R a , C(O)NR b R c , NR b R c , NR b C(O)R a and NR b C(O)NR b R c , wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are optionally substituted with one or more R g ; R is selected from H, halogen, C 8 alkyl, C 1-6 alkenyl, C 2-6 alkynyl, cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6- 10 aryl, C(O)R a , C(O)NR b R c and NR b C(O)R a , wherein said C 1-6 alkyl, C 2-6 alkenyl, C 3-8 alkynyl, cycloalkyl, 3-8 membered heterocyclyl and C 6-10 aryl are optionally substituted with one or more R g ; R a , R b , R c , R 10 and R g are as defined in claims 1-12.

14. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-13, wherein, The compound has the following structure:

15. A pharmaceutical composition comprising at least one therapeutically effective amount of a compound according to any one of claims 1-14, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

16. An E3 ligase-molecular glue binary complex, wherein, said molecular glue is a compound according to any one of claims 1-14, or a pharmaceutically acceptable salt thereof.

17. An E3 ligase-molecular glue-VAV1 protein ternary complex, wherein, said molecular glue is a compound according to any one of claims 1-14, or a pharmaceutically acceptable salt thereof.

18. Use of a compound according to any one of claims 1-14, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 15, or an E3 ligase-molecular glue binary complex according to claim 16, in the manufacture of a medicament for degrading VAV1 protein.

19. Use of a compound according to any one of claims 1-14, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 15, in the manufacture of a medicament for mediating the interaction of VAV1 protein with E3 ligase, thereby increasing the degradation of VAV1 protein; preferably, said compound interacts with E3 ligase prior to the interaction of VAV1 protein with E3 ligase.

20. Use of a compound according to any one of claims 1-14, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 15, or an E3 ligase-molecular glue binary complex according to claim 16, 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, preferably T cells.

21. Use of a compound, a pharmaceutically acceptable salt thereof according to any one of claims 1-14 or a pharmaceutical composition of claim 15 or an E3 ligase-molecular glue binary complex of claim 16 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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