Piperidine diketone compound, and pharmaceutical composition and application thereof

Abstract

The invention relates to a piperidinedione compound as well as a pharmaceutical composition and application thereof, and particularly provides a piperidinedione compound shown in a formula (I) which can be used for preparing medicines, especially medicines for preventing and / or treating diseases or symptoms caused by or related to lymphocyte development or activity disorder. Each group in the formula (I) is as defined in the specification.

Description

[0001] Cross-references to related applications

[0002] This application is based on and claims priority to CN application No. 202411291232.7 filed on September 14, 2024, CN application No. 202411582839.0 filed on November 7, 2024, and CN application No. 202511270335.X filed on September 5, 2025, and all the contents of these applications are incorporated herein by reference in their entirety. Technical Field

[0003] This application belongs to the pharmaceutical field, specifically relating to a piperidine dione compound, its pharmaceutical composition and uses, which can be used as a VAV1 degrading agent. Background Technology

[0004] VAV1 is a member of the VAV family, a group of signal transduction proteins that act as phosphorylation-dependent GDP / GTP exchange factors (GEFs) and adaptor molecules for Rho subfamily GTPases. In vertebrates, this family consists of three members: VAV1, VAV2, and VAV3. VAV1 primarily encodes and expresses GEFs in human hematopoietic stem cells, including T cells, B cells, monocytes, natural killer (NK) cells, granulocytes, and dendritic cells, while family members VAV2 and VAV3 are more commonly expressed. The VAV protein family is crucial for the homeostasis of the central nervous system, cardiovascular system, and immune system, and is involved in the development and progression of diseases such as autoimmune diseases, transplant rejection, and cancer.

[0005] VAV1 possesses multiple domains, determining its dual function as a GEF (gastrointestinal fibroblast) and scaffold protein. In its resting state, unphosphorylated VAV1 exhibits a closed, inactive conformation: the N-terminal CH-AC domain and the C-terminal SH3 domain fold inwards to bind to the catalytic core (DH-PH-ZF domain), simultaneously inhibiting GEF activity and adaptor protein function. When the AC structure of VAV1 is phosphorylated, the inhibitory folds within the protein are released, forming an open, active conformation, enabling it to perform both GEF and adaptor protein functions. The primary substrate for VAV1's GEF function is Rac1, which participates in regulating actin dynamics signaling pathways and cytoskeleton remodeling, facilitating immune cell migration, adhesion, and immune synapse formation. As a scaffold protein, it interacts with various protein complexes to form the TCR / BCR proximal complex, performing adaptor protein function and regulating T cell and B cell receptor activation signal transduction.

[0006] VAV1 is a key component of the antigen receptor signaling complex and is associated with the T cell receptor (TCR) / CD3 and B cell receptor. In T cells, a 76 kDa leukocyte protein containing Src homology (SH) 2 domains (SLP76) is recruited to the transmembrane adaptor, linker for activation of T cells (LAT), through its SH2 domains, thereby activating the T cell. The LAT / SLP76 complex is a critical scaffold for other proteins in the TCR proximal signaling complex, including VAV1. VAV1 interacts with other proteins through SH2 and proline-rich region / SH3 domains. In B cells, VAV1 interacts with a signaling complex that includes a scaffolding protein homologous to SLP76, SLP65 (also known as B-cell linker), 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 (TPD) is a breakthrough drug development strategy for challenging drug targets. This technology specifically recognizes target proteins and directly degrades pathogenic target proteins using inherent intracellular protein degradation pathways. TPD currently primarily degrades target proteins through ubiquitin-proteasomes and lysosomes, and can be further subdivided into nearly 10 different technical routes based on specific mechanisms of action. Among these, molecular glues and targeted protein hydrolysis chimeras (PROTACs) are the most rapidly developing technologies. Molecular glues are small molecules that induce proximity, allowing for precise time-controlled processing of various biological processes, such as signal transduction, transcription, chromatin regulation, and protein folding, localization, and degradation. As a chemical inducer of proximity, molecular glues can promote the dimerization or co-localization of two proteins by forming ternary complexes, thereby generating a variety of biological and pharmacological functions. Generally, molecular glues have a small molecular weight, making their physicochemical properties easy to optimize. Molecular glues mainly induce or stabilize protein interactions between ubiquitin ligases and substrate proteins, leading to protein degradation. They can degrade inaccessible target proteins without requiring a binding pocket on the target protein. This mechanism provides a new avenue for targeting undruggable proteins, greatly expanding the scope and application prospects of drug design. However, VAV1 lacks a defined binding pocket, posing significant challenges to the development of small molecule inhibitors. Novartis has investigated small molecule inhibitors of VAV1 (targeting GEF activity), but only disclosed structural and in vitro activity information at the 2018 ACS meeting, with no further research progress reported. Therefore, ubiquitination degradation of this type of protein via molecular gels is a promising research direction. Currently, only Monte Rosa's VAV1 molecular gel MRT-6160 is in development and has entered Phase 1 clinical trials. More structurally novel molecular gels are needed to validate the druggability of the VAV1 target. Summary of the Invention

[0008] This application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0009]

[0010] in:

[0011] Z is CR 4 Or N;

[0012] T is

[0013] It can be a single bond or a double bond;

[0014] X is selected from CR X1 R X2 C=O, CR 6c , N and NR X3When X is selected from CR X1 R X2 C=O and NR X3 hour, For a single bond, when X is CR 6c Or N, It is a double bond;

[0015] Y is CR 6d Or N;

[0016] 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;

[0017] 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;

[0018] 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;

[0019] 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;

[0020] R 6a R 6b R 6c and R 6d They may be the same or different, and each is independently selected from H, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, hydroxyl, cyano, amino, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups;

[0021] R 7 Selected from non-existent, H, oxo, L 1 -R 9 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, 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- 2R d The C mentioned therein 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, 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;

[0022] R X1 and R X2 Same or different, and each independently selected from non-existent, H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, hydroxyl, cyano, amino, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups;

[0023] R X3 Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, cyano, C 3-8cycloalkyl and 3-8 membered heterocyclic groups;

[0024] 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;

[0025] 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;

[0026] 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;

[0027] L 1 C 1-6 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;

[0028] 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;

[0029] 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;

[0030] R g Whether the same or different, each is independently selected from halogens, hydroxyl groups, and C.1-6 Alkyl, C 1-6 Alkoxy, cyano, oxo, 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 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 1-6 Alkoxy, C 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. v replace;

[0031] 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, hydroxyl, cyano, amino, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups;

[0032] 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 heterocyclic groups;

[0033] R a Selected from C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, 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 heterocyclic groups;

[0034] 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, C1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups;

[0035] 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;

[0036] 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 heterocyclic groups.

[0037] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 They may be the same or different, and each is independently selected from H, halogen, hydroxyl, cyano, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0038] In some implementation schemes, R 1 and R 2 They may be the same or different, and each is independently selected from H, deuterium and halogens.

[0039] In some implementation schemes, R L1 Selected from H and C 1-6 Alkyl group, preferably H.

[0040] In some implementation schemes, R g Whether the same or different, each is independently selected from halogens, hydroxyl groups, and C. 1-6 Alkyl, C 1-6 Alkoxy, oxo, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 heteroaryl groups are optionally coupled with one or more R groups. v replace..

[0041] In some implementation schemes, R v Selected from C 1-6 alkyl.

[0042] In some implementation schemes, R 10 Selected from H, C 1-6 Alkyl and cyano groups.

[0043] In some implementation schemes, R 10 Selected from H, methyl, and cyano groups.

[0044] In some implementation schemes, R a Selected from C 1-6 Alkoxy, C 1-6 Alkyl groups and 3-8 membered heterocyclic groups.

[0045] 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.

[0046] In some embodiments, the compound or a pharmaceutically acceptable salt thereof satisfies one or more of the following conditions:

[0047] (1) The C 1-6 The alkyl group is methyl, ethyl, n-propyl, or isopropyl;

[0048] (2) The C 1-6 The alkylene group is methylene (-CH2-), ethylene (-CH2CH2-), or propylene (-CH2CH2CH2-);

[0049] (3) The halogen is fluorine, chlorine, bromine or iodine, for example chlorine;

[0050] (4) The C 3-12 Cycloalkyl group is C 3-6 Cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and again, cyclopropyl;

[0051] (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.

[0052] (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.

[0053] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein T is selected from:

[0054]

[0055] Ring A and ring B may be the same or different, and each is independently a 5-12 membered heterocyclic group or a 5-12 membered heteroaryl group;

[0056] n can be 0, 1, 2, 3, or 4;

[0057] R 6a R 6b R 6c R 6d R 7 and R 8 As defined above.

[0058] In some implementations, n is 0, 1, or 2.

[0059] In some implementations, n is 0 or 1.

[0060] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein Z is CR 4 ;R 4 As defined above.

[0061] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein Y is a CR 6d ;R 6d As defined above.

[0062] In some embodiments, the compound represented by formula (I) is a compound described in formula (II), formula (III), or formula (IV):

[0063]

[0064] in,

[0065] Ring A, Ring B, R 1 R 2 R 3 R 4 R 5 R 6a R 6b R 6d R 7 R8 And n is as defined above.

[0066] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein T is selected from:

[0067]

[0068]

[0069] 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 is as defined by compound of formula (I).

[0070] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein T is selected from:

[0071]

[0072] 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 is as defined by compound of formula (I).

[0073] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein T is selected from:

[0074]

[0075] 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 is as defined above.

[0076] In some implementations, T is selected from

[0077] In some implementations, T is selected from

[0078] In some embodiments, the compound represented by formula (III) or a pharmaceutically acceptable salt thereof, wherein Selected from:

[0079]

[0080]

[0081] 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 is as defined by compound of formula (I).

[0082] In some embodiments, the compound represented by formula (III) or a pharmaceutically acceptable salt thereof, wherein Selected from:

[0083]

[0084] 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 is as defined by compound of formula (I).

[0085] In some embodiments, the compound represented by formula (III) or a pharmaceutically acceptable salt thereof, wherein Selected from:

[0086] 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 is as defined above.

[0087] In some embodiments, the compound represented by formula (IV) or a pharmaceutically acceptable salt thereof, wherein Selected from: q is 0, 1, or 2; R 8 And n is as defined above.

[0088] In some embodiments, the compounds represented by formulas (I), (II), (III), and (IV), or pharmaceutically acceptable salts thereof, wherein: for R 1 As defined above.

[0089] In some embodiments, the compounds represented by formulas (I), (II), (III), and (IV), or pharmaceutically acceptable salts thereof, wherein R 1 It can be H, deuterium, or halogen.

[0090] In some embodiments, the compounds represented by formulas (I), (II), (III), and (IV), or pharmaceutically acceptable salts thereof, wherein R 1 It is H or a halogen, preferably H or F.

[0091] In some embodiments, the compounds represented by formulas (I), (II), (III), and (IV), or pharmaceutically acceptable salts thereof, wherein R 1 For H.

[0092] In some embodiments, the compounds represented by formulas (I), (II), (III), and (IV), or pharmaceutically acceptable salts thereof, wherein R 2 It is a halogen.

[0093] In some embodiments, the compounds represented by formulas (I), (II), (III), and (IV), or pharmaceutically acceptable salts thereof, wherein R 2 It is Cl.

[0094] In some embodiments, the compounds represented by formulas (I), (II), (III), and (IV), or pharmaceutically acceptable salts thereof, wherein R 3 R 4 and R 5 They may be the same or different, and each is independently selected from H, halogens, and C. 1-6 alkyl.

[0095] In some implementation schemes, R 3 Selected from H and C 1-6 alkyl.

[0096] In some implementation schemes, R 3 For H.

[0097] In some implementation schemes, R 4 and R 5 They are the same or different, and each is independently selected from H and C. 1-6 alkyl.

[0098] In some implementation schemes, R 4 and R 5 For H.

[0099] In some embodiments, the compounds represented by formulas (I), (II), (III), and (IV), or pharmaceutically acceptable salts thereof, wherein R 6a R 6b R 6c and R 6d They may be the same or different, and each is independently selected from H, halogens, and C. 1-6 alkyl.

[0100] In some implementation schemes, R 6a R 6b R 6c and R 6d They are the same or different, and each is independently selected from H and C. 1-6 alkyl.

[0101] In some implementation schemes, R 6a R 6b R 6c and R 6d For H.

[0102] In some embodiments, the compounds represented by formulas (I) and (II) or their pharmaceutically acceptable salts, wherein R 7 Selected from non-existent, H, oxo, L 1 -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;

[0103] 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-, 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 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;

[0104] 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)NRb 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;

[0105] R a R b R c R L1 and R g As defined above.

[0106] In some embodiments, the compounds represented by formulas (I), (II), (III), and (IV), or pharmaceutically acceptable salts thereof, wherein L 1 Selected from: -CH2-, -CH2CH2-, -CH(CH3)-, -CH2C(O)-, -CH2CH2O- and -CH2CH2NH-.

[0107] In some embodiments, the compounds represented by formulas (I) and (II) or their pharmaceutically acceptable salts, wherein R 7 Selected from H, L 1 -R 9 C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 alkynyl group, wherein the C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group may be optionally replaced by one or more substituents selected from halogen, hydroxyl, cyano and amino groups;

[0108] L 1 Selected from: -CH2-, -CH2CH2-, -CH(CH3)-, -CH2C(O)-, -CH2CH2O- and -CH2CH2NH-;

[0109] 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, C6-10 Aryl and 5-10 heteroaryl groups are optionally coupled with one or more R groups. g Replaced;

[0110] R a R b R c and R g As defined above.

[0111] In some embodiments, the compounds represented by formulas (I) and (II) or their pharmaceutically acceptable salts, wherein R 7 Selected from C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl, wherein the 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;

[0112] R g As defined above.

[0113] In some implementation schemes, 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 What it replaced.

[0114] In some implementation schemes, R 7 Selected from H, C 1-6 alkylene-5-membered heteroaryl, C 1-6 Alkyl and C 6-10 aryl, wherein the 5-membered heteroaryl group is optionally substituted with one or more C 1-6 Alkyl groups are substituted.

[0115] In some implementation schemes, R 7 Selected from H, C 1-6 alkylene-pyrazolyl, C 1-6 alkyl and phenyl, wherein the pyrazolyl group is optionally surrounded by one or more C24 groups. 1-6 Alkyl groups are substituted.

[0116] In some implementation schemes, R 7 C1-6 alkylene-5-membered heteroaryl, wherein the 5-membered heteroaryl group is optionally oxidized by one or more C14 groups. 1-6 Alkyl groups are substituted.

[0117] In some implementation schemes, R 7 C 1-6 alkylene-pyrazolyl, wherein the pyrazolyl group is optionally surrounded by one or more C16 groups. 1-6 Alkyl groups are substituted.

[0118] In some implementation schemes, R 7 Selected from H, methyl, cyclopropyl,

[0119] In some implementation schemes, R 7 Selected from H, methyl,

[0120] In some implementation schemes, R 7 for

[0121] In some implementation schemes, R 8 Selected from H, halogen, 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 heterocyclic groups, C 6-10 Aryl, 5-10 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 The C mentioned therein 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 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; R a R b R c R 10 and R g As defined above.

[0122] In some implementation schemes, R 8 Selected from H, halogens, C 1-6 Alkyl, C 2-6 alkynyl, cyano, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, C(O)R a C(O)NR b R c and NR b C(O)R a The C mentioned therein 1-6 Alkyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups and C 6-10 aryl groups are optionally influenced by one or more R groups. g What it replaced.

[0123] In some implementation schemes, R 8 Selected from H and C(O)-C 1-6 Alkyl group.

[0124] In some implementation schemes, R 8 Selected from H, methyl, isopropyl, chloro, ethynyl, cyano,

[0125] In some implementation schemes, R 8 Selected from H and

[0126] In some implementation schemes, R 8 For H.

[0127] In some embodiments, the compounds represented by formulas (I), (II), (III), and (IV), or pharmaceutically acceptable salts thereof, wherein R a C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups;

[0128] R b and R c Whether the two are the same or different, each is independently selected from H or C. 1-3 alkyl;

[0129] 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, and C. 1-3 One or more substitutions in alkyl groups;

[0130] R d Selected from C 1-3Alkyl, C 1-3 Halogenated alkyl and C 3-6 Cycloalkyl.

[0131] In some embodiments, the compounds represented by formulas (I), (II), (III), and (IV), or pharmaceutically acceptable salts thereof, wherein R g Whether the same or different, each is independently selected from halogens, hydroxyl groups, and C. 1-6 Alkyl, cyano, oxo, 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 R c NR b C(O)R a and NR b C(O)NR b R c The C mentioned therein 1-6 Alkyl, C 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. v replace;

[0132] R a C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups;

[0133] R b and R c Whether the two are the same or different, each is independently selected from H or C. 1-3 alkyl;

[0134] 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, and C. 1-3 One or more substitutions in alkyl groups;

[0135] R v Selected from halogens, oxometalates, and C 1-6 alkyl.

[0136] In some implementations, T is selected from

[0137]

[0138]

[0139]

[0140] In some implementations, T is selected from

[0141] In some implementations, T is selected from

[0142] In some implementations, T is selected from

[0143] R 7 Selected from H, C 1-6 alkylene-pyrazolyl, C 1-6 alkyl and phenyl, wherein the pyrazolyl group is optionally surrounded by one or more C24 groups. 1-6 Alkyl groups are substituted;

[0144] R 8 Selected from H and C(O)-C 1-6 Alkoxy;

[0145] R 1 It is H or halogen;

[0146] R 2 It is a halogen;

[0147] R 3 Selected from H and C 1-6 alkyl;

[0148] R 4 and R 5 They are the same or different, and each is independently selected from H and C. 1-6 alkyl;

[0149] n is 0, 1, or 2.

[0150] Exemplary specific compounds shown in this application include, but are not limited to, the structures in Table A below:

[0151] Table A

[0152]

[0153]

[0154]

[0155]

[0156]

[0157] In some embodiments, the compounds in Form A of this application include for

[0158] In another aspect, this application provides isotope labels for the compounds shown in Table A, as represented by formulas (I), (II), (III), and (IV), wherein the isotope labels are preferably deuterium (D or... 2 H) replaces hydrogen ( 1 H).

[0159] In another aspect, this application provides a pharmaceutical composition comprising at least a therapeutically effective amount of the aforementioned compound or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0160] In another aspect, this application also provides an E3 ligase-molecular glue binary complex, wherein the molecular glue is the aforementioned compound or a pharmaceutically acceptable salt thereof.

[0161] In another aspect, this application also provides an E3 ligase-molecular glue-VAV1 protein ternary complex, wherein the molecular glue is the aforementioned compound or a pharmaceutically acceptable salt thereof.

[0162] In another aspect, this application also provides the use of the compounds of formula (I), formula (II), formula (III) and formula (IV), the compounds shown in Table A, or pharmaceutically acceptable salts thereof or pharmaceutical compositions containing them, or the aforementioned E3 ligase-molecular glue binary complexes, in the preparation of a medicament for degrading VAV1 protein.

[0163] In another aspect, this application also provides the use of compounds of formulas (I), (II), (III) and (IV), compounds shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of a medicament for mediating the interaction between VAV1 protein and E3 ligase, thereby increasing the degradation of VAV1 protein; preferably, the compounds interact with E3 ligase prior to the interaction between VAV1 protein and E3 ligase.

[0164] In another aspect, this application also provides the use of compounds of formulas (I), (II), (III) and (IV), compounds shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing thereof, in the preparation of a medicament for contacting an E3 ligase, thereby causing the contacted E3 ligase to interact with VAV1 and degrade VAV1.

[0165] In another aspect, this application also provides the use of compounds of formulas (I), (II), (III) and (IV), compounds shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, or the aforementioned E3 ligase-molecular glue binary complexes, in the preparation of medicaments for the prevention and / or treatment of diseases or conditions caused by or related to lymphocyte developmental or activity disorders.

[0166] In this application, the lymphocytes mentioned are T cells.

[0167] In this application, the lymphocytes mentioned are B cells.

[0168] This application also provides the use of compounds of formulas (I), (II), (III) and (IV), compounds shown in Table A, or pharmaceutically acceptable salts thereof or pharmaceutical compositions comprising them, or the aforementioned E3 ligase-molecular glue binary complexes, in the preparation of medicaments for the prevention and / or treatment of autoimmune diseases, inflammatory diseases, metabolic diseases, cardiovascular diseases, kidney diseases, central nervous system diseases, or cancer.

[0169] The autoimmune diseases described in this application are selected from multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, thyroiditis, myasthenia gravis, type I diabetes, type II diabetes, vasculitis, pernicious anemia, dry eye syndrome, 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.

[0170] This application also provides a method for degrading VAV1 protein, comprising administering to a patient a therapeutically effective amount of a compound of formula (I), formula (II), formula (III) and formula (IV), shown in Table A, or a pharmaceutically acceptable salt thereof, or the aforementioned isotopic label, or the aforementioned pharmaceutical composition comprising the aforementioned, or the aforementioned E3 ligase-molecular glue binary complex.

[0171] This application also provides a method for degrading VAV1 protein, comprising administering to a patient a therapeutically effective amount of a compound of formula (I), formula (II), formula (III) and formula (IV), shown in Table A, or a pharmaceutically acceptable salt thereof, or a aforementioned isotopic label thereof, or a aforementioned pharmaceutical composition comprising the thereof, wherein the compound mediates the interaction between VAV1 protein and E3 ligase, thereby increasing the degradation of VAV1 protein.

[0172] This application also provides a method for degrading VAV1 protein, comprising administering to a patient a therapeutically effective amount of a compound of formula (I), formula (II), formula (III) and formula (IV), shown in Table A, or a pharmaceutically acceptable salt thereof, or a aforementioned isotopic label thereof, or a aforementioned pharmaceutical composition comprising the thereof, wherein the compound interacts with the E3 ligase prior to the interaction of the VAV1 protein with the E3 ligase.

[0173] This application also provides a method for degrading VAV1 protein, comprising: (i) contacting the compounds of formulas (I), (II), (III) and (IV), the compounds shown in Table A, or pharmaceutically acceptable salts thereof, or the aforementioned isotope labels, or the aforementioned pharmaceutical compositions containing them, with an E3 ligase; and (ii) causing the contacted E3 ligase to interact with VAV1, thereby degrading the VAV1 protein.

[0174] This application also provides a method for preventing and / or treating diseases or conditions caused by or related to lymphocyte developmental or activity disorders, comprising administering to a patient a therapeutically effective amount of a compound of formula (I), formula (II), formula (III) and formula (IV), shown in Table A, or a pharmaceutically acceptable salt thereof, or the aforementioned isotope label, or the aforementioned pharmaceutical composition comprising the aforementioned, or the aforementioned E3 ligase-molecular glue binary complex.

[0175] This application also provides a method for preventing and / or treating autoimmune diseases, inflammatory diseases, metabolic diseases, cardiovascular diseases, kidney diseases, central nervous system diseases, or cancer, comprising administering to a patient a therapeutically effective amount of a compound of formula (I), formula (II), formula (III), and formula (IV), shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the aforementioned compounds, or the aforementioned E3 ligase-molecular glue binary complex.

[0176] This application also provides compounds of formulas (I), (II), (III) and (IV), shown in Table A, or pharmaceutically acceptable salts thereof, or the aforementioned pharmaceutical compositions or the aforementioned E3 ligase-molecular glue binary complexes, for use as pharmaceuticals.

[0177] This application also provides compounds of formulas (I), (II), (III) and (IV), compounds shown in Table A, or pharmaceutically acceptable salts thereof, or the aforementioned pharmaceutical compositions or the aforementioned E3 ligase-molecular glue binary complexes, which are used as VAV1 degrading agents.

[0178] This application also provides a compound of formula (I), formula (II), formula (III) and formula (IV), a compound shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above, or the above E3 ligase-molecular glue binary complex, which is used as a medicament for the prevention and / or treatment of diseases or conditions caused by or related to lymphocyte development or activity disorders.

[0179] This application also provides a compound of formula (I), formula (II), formula (III) and formula (IV), a compound shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above, or the above E3 ligase-molecular glue binary complex, which is used as a medicament for the prevention and / or treatment of autoimmune diseases, inflammatory diseases, metabolic diseases, cardiovascular diseases, kidney diseases, central nervous system diseases, or cancer.

[0180] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0181] In some embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or a pharmaceutically acceptable salt thereof or an isotopic label thereof, based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or a pharmaceutically acceptable salt thereof or an isotopic label thereof. In some embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or a pharmaceutically acceptable salt thereof or an isotopic label thereof.

[0182] In some embodiments, the pharmaceutical composition contains 1% to 99% of the aforementioned compound or a pharmaceutically acceptable salt thereof or an isotopic label thereof.

[0183] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% pharmaceutically acceptable one or more excipients based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% pharmaceutically acceptable one or more excipients. In some embodiments, the pharmaceutical composition contains 1% to 99% pharmaceutically acceptable one or more excipients.

[0184] When administered as a medicine, the compounds of this application may be given in the form of pharmaceutical compositions. These compositions may be prepared in a manner well known in the pharmaceutical art and may be administered via a variety of routes, depending on whether local or systemic treatment is required and the area to be treated. Administration may be local (e.g., transdermal, skin, eye, and mucous membrane delivery, including intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or blowing of powders or aerosols, including via nebulizers; intratracheal, intranasal), oral, or parenteral administration. Parenteral administration includes intravenous, intra-arterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranial, such as intrathecal or intraventricular administration. Parenteral administration may be in the form of a single large dose or via, for example, a continuous infusion pump.

[0185] In preparing the compositions of this application, the active ingredient is typically mixed with excipients, and the compositions may be in the following forms: tablets, pills, powders, lozenges, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or soluble in liquid solvents), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0186] The term "excipients" as used in this application refers to components other than the active ingredient, such as diluents, fillers, absorbents, wetting agents, binders, disintegrants, and lubricants.

[0187] On the other hand, pharmaceutically acceptable salts of the compounds described in this application may be inorganic or organic salts. If these compounds have a basic center, they may form acid addition salts; if these compounds have an acidic center, they may form base addition salts; and if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they may also form inner salts.

[0188] On the other hand, the compounds of this application may exist in specific geometric or stereoisomeric forms. For example, cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, racemic mixtures and other mixtures, as well as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this application. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this application.

[0189] In the chemical structure of the compound described in this application, the bond... This indicates that no configuration has been specified. or Indicates absolute configuration, that is, if chiral isomers exist in the chemical structure, the bonds... It can be or Or simultaneously include and Two configurations, This indicates the presence of axial chirality.

[0190] key This indicates that the configuration is not specified, including cis (E) or trans (Z) configurations.

[0191] Furthermore, the compounds and intermediates of this application may also exist in different tautomer forms, and all such forms are included within the scope of this application. "Tautomer" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton transfer, such as keto-enol isomerization, imine-enamine isomerization, and lactam-lactamimide isomerization. All tautomer forms of all compounds in this application are within the scope of this application. The name of a compound named in a single manner does not exclude any tautomer.

[0192] This application also includes compounds of this application with the same structure as described herein, but with one or more atoms replaced by isotopes of atoms having atomic weights or mass numbers different from those commonly found in nature. Examples of isotopes that can be incorporated into the compounds of this application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, 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, etc. All isotopic variations of the compounds in this application, regardless of radioactivity, are included within the scope of this application.

[0193] Unless otherwise specified, when a position is specifically designated as deuterium (D), that position should be understood as having a deuterium abundance at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 10% deuterium doping). The natural abundance of deuterium in the example compounds can be at least 1000 times, at least 2000 times, at least 3000 times, at least 4000 times, at least 5000 times, at least 6000 times, or higher. Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize the deuterated form of the compound by referring to relevant literature. Commercially available deuterated starting materials can be used to prepare compounds in their deuterated form, or they can be synthesized using conventional techniques with deuterated reagents, including but not limited to deuterated boranes, trideuterated borane tetrahydrofuran solutions, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane.

[0194] The "therapeutic effective amount" in this application refers to the amount of an active compound or drug that researchers, veterinarians, physicians, or other clinicians seek in tissues, systems, animals, individuals, or humans to elicit a biological or medical response. It includes one or more of the following: (1) prevention of disease: e.g., prevention of disease, disorder, or condition in individuals susceptible to disease, disorder, or symptom but not yet experiencing or exhibiting the pathology or symptoms of the disease; (2) inhibition of disease: e.g., inhibition of disease, disorder, or symptom in individuals experiencing or exhibiting the pathology or symptoms of the disease, disorder, or symptom (i.e., prevention of further development of the pathology and / or symptoms); (3) relief of disease: e.g., relief of disease, disorder, or symptom in individuals experiencing or exhibiting the pathology or symptoms of the disease, disorder, or symptom (i.e., reversal of the pathology and / or symptoms). For the purposes of a drug or pharmacologically active agent, "therapeutic effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but achieves the desired effect. The determination of an effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. The appropriate effective amount in a particular case can be determined by a person skilled in the art based on routine testing.

[0195] "Pharmaceutical acceptable" in this application means that these compounds, materials, compositions, and / or dosage forms are suitable for contact with patient tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, within reasonable medical judgment, have a reasonable benefit / risk ratio, and are effective for their intended use.

[0196] In this application, "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, with human being being the most preferred.

[0197] Beneficial effects

[0198] This application provides a small molecule compound that can be used as a VAV1 degrader. Such compounds or pharmaceutical compositions can be used to effectively treat or prevent autoimmune diseases, inflammatory diseases, metabolic diseases, cardiovascular diseases, kidney diseases, central nervous system diseases, or cancer.

[0199] Terminology Definitions and Explanations

[0200] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0201] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms (C 1-6 Alkyl groups. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-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 their various branched isomers. Alkyl groups can be substituted or unsubstituted.

[0202] The term "alkoxy" refers to -O- (alkyl), where alkyl is defined as described herein. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups can be substituted or unsubstituted.

[0203] The term "alkylene" refers to a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a saturated straight-chain or branched hydrocarbon group, which may contain 1-20 carbon atoms, preferably 1-12 carbon atoms. Non-limiting examples include methylene (-CH2-), ethylene (-CH2CH2-), etc. The alkylene group may be substituted or unsubstituted.

[0204] The term "alkenyl" should be understood to preferably refer to a linear or branched hydrocarbon group containing one or more double bonds and having 2 to 20 carbon atoms, preferably "C". 2-10 "Alkenyl". "C" 2-10 "Alkenyl" should be understood to preferably represent a straight or branched monovalent hydrocarbon group containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, for example, having 2, 3, 4, 5, or 6 carbon atoms (i.e., C...). 2-6alkenyl), having 2 or 3 carbon atoms (i.e., C24, C34, C4 ... 2-3 Alkenyl). It should be understood that when the alkenyl group contains more than one double bond, the double bonds may be separable 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)- Pentyl-1-enyl, (Z)-pentyl-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-methyl But-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 may be substituted or unsubstituted.

[0205] The term "alkynyl" should be understood to refer to a straight or branched monovalent hydrocarbon group containing one or more triple bonds and having 2 to 20 carbon atoms, preferably "C". 2-10 "Alkyne group". The term "C" 2-10 "Alkyne" should be understood to preferably represent a straight or branched monovalent hydrocarbon group containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, for example, having 2, 3, 4, 5, or 6 carbon atoms (i.e., "C"). 2-6 The alkynyl group ("C") has 2 or 3 carbon atoms ("C") 2-3The alkynyl group is, for example, ethynyl, prop-1-alkynyl, prop-2-alkynyl, but-1-alkynyl, but-2-alkynyl, but-3-alkynyl, pent-1-alkynyl, pent-2-alkynyl, pent-3-alkynyl, pent-4-alkynyl, hex-1-alkynyl, hex-2-alkynyl, hex-3-alkynyl, hex-4-alkynyl, hex-5-alkynyl, 1-methylprop-2-alkynyl, 2-methylbut-3-alkynyl, 1-methylbut-3-alkynyl, 1-methylbut-2-alkynyl, 3-methylbut-1-alkynyl, 1-ethylprop-2-alkynyl, 3-methylpent-4-alkynyl, 2-methylpent-4-alkynyl, 1-methylpent-4-alkynyl, 2-methyl The alkynyl group can be pentyl-3-ynyl, 1-methylpentyl-3-ynyl, 4-methylpentyl-2-ynyl, 1-methylpentyl-2-ynyl, 4-methylpentyl-1-ynyl, 3-methylpentyl-1-ynyl, 2-ethylbutyl-3-ynyl, 1-ethylbutyl-3-ynyl, 1-ethylbutyl-2-ynyl, 1-propylpropyl-2-ynyl, 1-isopropylpropyl-2-ynyl, 2,2-dimethylbutyl-3-ynyl, 1,1-dimethylbutyl-3-ynyl, 1,1-dimethylbutyl-2-ynyl, or 3,3-dimethylbutyl-1-ynyl. Specifically, the alkynyl group is ethynyl, propyl-1-ynyl, or propyl-2-ynyl. The alkynyl group can be substituted or unsubstituted.

[0206] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 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 3 to 6 carbon atoms, wherein the ring atoms may optionally be oxidized, and the oxidizing group (=O) on the ring is part of the ring. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl includes spirocyclic, fused-ring, and bridged-ring cycloalkyl.

[0207] The term "spirocycloalkyl" refers to a 5- to 20-membered polycyclic group in which each monocyclic ring in the system shares a carbon atom (called a spiro atom), and may 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). Spirocycloalkyl groups are classified as monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups based on the number of shared spiro atoms between rings, with monospirocycloalkyl and bispirocycloalkyl groups being preferred. More preferably, it is a 3 / 5-membered, 3 / 6-membered, 4 / 4-membered, 4 / 5-membered, 4 / 6-membered, 5 / 5-membered, or 5 / 6-membered monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include:

[0208]

[0209] The term "fused cycloalkyl" refers to a 5- to 20-membered polycyclic aromatic hydrocarbon group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may 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). Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 3 / 4-membered, 3 / 5-membered, 3 / 6-membered, 4 / 4-membered, 4 / 5-membered, 4 / 6-membered, 5 / 4-membered, 5 / 5-membered, 5 / 6-membered, 6 / 3-membered, 6 / 4-membered, 6 / 5-membered, and 6 / 6-membered bicyclic alkyl groups. Non-limiting examples of fused cycloalkyl groups include:

[0210]

[0211] The term "bridged cycloalkyl" refers to a 5- to 20-membered polycyclic carbon group in which any two rings share two non-directly bonded carbon atoms, and may 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). Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

[0212]

[0213] The cycloalkyl ring comprises a cycloalkyl group (including monocyclic, spirocyclic, fused, and bridged rings) fused to an aryl ring as described herein, wherein the ring attached to the parent structure may be a cycloalkyl ring or an aryl ring, and non-limiting examples include... etc.; preferred The cycloalkyl group may be substituted or unsubstituted.

[0214] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent containing 3 to 20 ring atoms, one or more of which are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), but does not include the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon, wherein the ring carbon atoms may optionally be oxidized, and the oxidized group (=O) on the ring is part of the ring. Preferably, it contains 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, it contains 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; even more preferably, it contains 3 to 6 ring atoms, of which 1 to 3 are heteroatoms; most preferably, it contains 5 or 6 ring atoms, of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups.

[0215] The term "spiroheterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each monocyclic ring in the system shares one atom (called a spiro atom), wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. It may 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). Spiroheterocyclic groups are classified into monospirocyclic, bispirocyclic, or polyspirocyclic groups according to the number of shared spiro atoms between rings, with monospirocyclic and bispirocyclic groups being preferred. More preferably, it is a 3- / 5-membered, 3- / 6-membered, 4- / 4-membered, 4- / 5-membered, 4- / 6-membered, 5- / 5-membered, or 5- / 6-membered monospirocyclic group. Non-limiting examples of spirocyclic groups include:

[0216]

[0217] The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, 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 bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

[0218]

[0219] The term "bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two non-directly connected atoms. It may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0220]

[0221] The heterocyclic ring comprises a heterocyclic group (including monocyclic, spirocyclic, fused heterocyclic, and bridged heterocyclic rings) fused to an aryl, heteroaryl, or cycloalkyl ring as described herein, wherein the ring connected to the parent structure may be a heterocyclic ring, or an aryl, heteroaryl, or cycloalkyl ring, and non-limiting examples include:

[0222] The heterocyclic group may be substituted or unsubstituted.

[0223] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl group can be substituted or unsubstituted.

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

[0225]

[0226] Etc. Heteroaryl groups can be substituted or unsubstituted.

[0227] The terms “alkyl,” “alkoxy,” “cycloalkyl,” “heterocyclic,” “aryl,” and “heteroaryl” used herein may be substituted or unsubstituted; when substituted, they may be substituted at any usable linking point, and the substituents are preferably independently selected independently from one or more of the same or different substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0228] The aforementioned cycloalkyl, heterocyclic, aryl, and heteroaryl groups include residues derived from removing one H from a parent ring atom, or residues derived from removing two H from the same or two different ring atoms of the parent, namely "divalent cycloalkyl", "divalent heterocyclic", "arylene", and "heteroarylene".

[0229] The term “cycloalkyloxy” refers to cycloalkyl-O-, where the cycloalkyl group is as defined herein.

[0230] The term “heterocyclic oxy group” refers to a heterocyclic group -O-, wherein the heterocyclic group is as defined herein.

[0231] The term “halogenated alkyl” refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined herein.

[0232] The term “haloalkoxy” refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group is as defined herein.

[0233] The term "hydroxyalkyl" refers to an alkyl group that is substituted with one or more hydroxyl groups, wherein the alkyl group is as defined herein.

[0234] The term "cyanoalkyl" refers to an alkyl group that is substituted with one or more cyano groups, wherein the alkyl group is as defined herein.

[0235] The term "aminoalkyl" refers to an alkyl group that is substituted with one or more amino groups, wherein the alkyl group is as defined herein.

[0236] The term "halogen" refers to F, Cl, Br, or I.

[0237] The term "hydroxyl group" refers to -OH.

[0238] The term "amino" refers to -NH2.

[0239] The term "cyano" refers to -CN.

[0240] The term "nitro" refers to -NO2.

[0241] The term "oxo" or "oxo" refers to "=O" when it substitutes on C, and "=O" when it substitutes on N.

[0242] The term "carbonyl" refers to C=O.

[0243] The term "carboxyl group" refers to -C(O)OH.

[0244] 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.

[0245] "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.

[0246] "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).

[0247] In this text, when the substitution site of the substituent is indeterminate, the loop intersecting the single bond of the substituent represents a loop 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.

[0248] It should be understood that the singular form used in this disclosure, such as "a," includes plural references, unless otherwise specified. Furthermore, the term "comprising" is an expansive limitation and not a closed one, meaning it includes only what is specified in this disclosure but does not exclude other aspects. Detailed Implementation

[0249] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0250] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0251] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ ohms. -6 The measurements are given in units of ppm. NMR determinations were performed using Bruker Ascend. TM -400 NMR was used, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD) as the solvents, and tetramethylsilane (TMS) as the internal standard. MS measurements were performed using an Agilent 6110, Agilent 1100, Agilent 6120, or Agilent G6125B liquid chromatography-mass spectrometry system.

[0252] HPLC determinations were performed using a Shimadzu HPLC-2010C high-performance liquid chromatograph (XBRIDGE 2.1*50mm, 3.5um column).

[0253] Chiral HPLC analysis was performed using THARSFC X5.

[0254] The silica gel plates used for thin-layer chromatography are GF254 silica gel plates from Yantai Qingdao. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

[0255] Column chromatography typically uses Qingdao marine silica gel 200-300 mesh as the carrier.

[0256] High-performance liquid chromatography (HPLC) was performed using Waters 2767, Waters 2545, and the innovative Hengtong LC3000 preparative chromatograph.

[0257] Chiral preparative column chromatography was performed using Shimadzu LC-20AP and THARSFC PREP 80.

[0258] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0259] The pressurized hydrogenation reaction uses a Beijing Jiawei Kechuang Technology GCD-500G hydrogen generator.

[0260] The microwave reaction uses a Biotage initiator+ type microwave reactor.

[0261] Unless otherwise specified in the experimental examples, the reactions were carried out under an argon or nitrogen atmosphere.

[0262] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of about 1 liter.

[0263] A hydrogen atmosphere refers to a reaction vessel connected to a hydrogen balloon with a volume of approximately 1 liter.

[0264] Unless otherwise specified in the experimental examples, the reaction temperature is room temperature, ranging from 20℃ to 30℃.

[0265] Those skilled in the art should understand that chiral compounds can be distinguished by their retention times in a chiral chromatographic column. Therefore, chiral compounds separated according to their retention times are correspondingly distinguished by suffixes such as P1, P2, etc. That is, for example, suffix P1 corresponds to a chiral compound with a certain chiral structure that was eluted earlier from the chiral chromatographic column, while suffix P2 corresponds to a chiral compound with a certain chiral structure that was eluted later from the chiral chromatographic column. If the absolute configuration of a compound is listed in the structural formula, it does not imply a direct correspondence with the compounds suffixed P1 or P2; it merely indicates two possible forms of absolute configuration. The absolute configuration of compounds suffixed P1 or P2 is based on the objectively corresponding absolute configuration marked by a specific retention time.

[0266] Example 1 (compound 39)

[0267]

[0268] Step 1: Synthesis of Compound 39

[0269] Compound 39b (5-bromopyrazolo[1,5-a]pyridine) (50 mg, 0.25 mmol) was dissolved in 1,4-dioxane (4 mL), followed by the addition of compound 39a (87 mg, 0.25 mmol, synthetic method referred to the synthesis of intermediate A on page 184 of patent WO2024151547A1), potassium phosphate (159.2 mg, 0.75 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (18.3 mg, 0.025 mmol). Under nitrogen protection, the reaction mixture was heated to 100 °C and stirred for 16 hours. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-3%) and thin-layer chromatography on silica gel plates (dichloromethane / methanol = 10 / 1) to give compound 39 (31.6 mg).

[0270] MS m / z(ESI): 340.0 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.95(s,1H),8.74(d,J=7.2Hz,1H),8.05(d,J=2.2Hz,1H),7.73(d,J=0.9Hz,1H),7.53–7.29(m,3H),6.92(dd,J=7.2,1.9H z,1H),6.68(d,J=1.7Hz,1H),4.37(dd,J=12.2,5.0Hz,1H),2.89–2.73(m ,1H),2.58-2.51(m,1H),2.35(qd,J=12.8,4.3Hz,1H),2.11–2.00(m,1H).

[0271] Example 2 (compound 41)

[0272]

[0273] Step 1: Synthesis of Compound 41

[0274] Compound 39a (100 mg, 0.29 mmol) was dissolved in 1,4-dioxane (5 mL), followed by the sequential addition of compound 41b (7-bromoimidazolo[1,2-a]pyridine) (57.1 mg, 0.29 mmol), potassium phosphate (184.7 mg, 0.87 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (21.2 mg, 0.029 mmol). Under nitrogen protection, the reaction mixture was heated to 100 °C and stirred for 16 hours. After the reaction was complete, the 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 give compound 41 (10.1 mg). MS m / z (ESI): 340.0 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.95(s,1H),8.61(d,J=7.0Hz,1H),8.01(s,1H),7.64(s,1H),7.56(s,1H),7.46–7.39(m,3H),6.96(dd,J=7 .0,1.6Hz,1H),4.37(dd,J=12.2,5.0Hz,1H),2.86–2.71(m,1H),2.57-2.50(m,1H),2.35(dt,J=12.5,8.5Hz,1H),2.12–2.03(m,1H).

[0275] Example 3 (compound 47)

[0276]

[0277] Step 1: Synthesis of compound 47c

[0278] Under nitrogen protection, lithium diisopropylamino (1.9 mL, 3.80 mmol, 2 M tetrahydrofuran) was added to 20 mL tetrahydrofuran 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 reacting at -65 °C for 40 minutes, a solution of 47b (diethyl 2-(ethoxymethylene)malonate) (755 mg, 3.49 mmol) in tetrahydrofuran (2 mL) was added dropwise over 20 minutes. The mixture was slowly heated to 25 °C and stirred for 2.5 hours. The reaction was quenched with a saturated ammonium chloride aqueous solution (25 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was dissolved in toluene (4 mL). After stirring at 60 °C for 12 hours, the reaction mixture 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] + .

[0279] Step 2: Synthesis of compound 47d

[0280] Compound 47c (150 mg, 0.51 mmol) was dissolved in 6N hydrochloric acid (3 mL). The reaction was carried out under nitrogen protection at 100 °C with stirring for 12 hours. After the reaction was completed, the mixture was cooled to 0 °C, the pH was adjusted to 10 with 1N NaOH, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–60%) to give compound 47d (40 mg). MS m / z (ESI): 223.9, 225.9 [M+1, M+3] + .

[0281] Step 3: Synthesis of Compound 47

[0282] Compound 39a (63 mg, 0.18 mmol) was dissolved in 1,4-dioxane (2 mL), followed by the addition of compound 47d (40 mg, 0.18 mmol), potassium phosphate (114.6 mg, 0.54 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (13 mg, 0.018 mmol). The reaction mixture was heated to 100 °C and stirred for 16 hours under nitrogen protection. After the reaction was complete, the solution 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 give compound 47 (31.28 mg). MS m / z (ESI): 367.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.95(s,1H),8.98(d,J=8.0Hz,1H),7.84(d,J=4.0Hz,1H),7.79(t,J=8.0Hz,1H),7.49(s,3H),7.25(dd,J=8.0,4.0Hz,1H),6 .90(d,J=8.0Hz,1H),6.48(d,J=4.0Hz,1H),4.38(dd,J=12.0,8.0Hz,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).

[0283] Example 4 (compound 40)

[0284]

[0285] Step 1: Synthesis of Compound 40

[0286] Compound 39a (100 mg, 0.29 mmol) was dissolved in 1,4-dioxane (10 mL), followed by the sequential addition of compound 40a (7-bromoimidazolo[1,5-a]pyridine) (57.14 mg, 0.29 mmol), potassium phosphate (184.67 mg, 0.87 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (21.22 mg, 0.029 mmol). Under nitrogen protection, the reaction mixture was heated to 100 °C and stirred for 16 hours. After complete reaction, 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 on silica gel plates (methanol / dichloromethane = 1 / 20) to give compound 40 (16.1 mg). MS m / z (ESI): 340.0 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ10.94(s,1H),8.55–8.29(m,2H),7.58(s,1H),7.47–7.30(m,4H),6.71(d,J=7.3Hz,1H),4.36(dd, J=12.2,4.8Hz,1H),2.89–2.72(m,1H),2.55(d,J=19.4Hz,1H),2.34(dt,J=12.6,8.8Hz,1H),2.06(dd,J=10.1,4.8Hz,1H).

[0287] Example 5 (compound 11)

[0288]

[0289] Step 1: Synthesis of compound 11b

[0290] Compound 11a ((1-methyl-1H-pyrazol-3-yl)methanol) (1 g, 8.92 mmol) was dissolved in tetrahydrofuran (20 mL) under ice bath conditions. Carbon tetrabromide (3.55 g, 10.7 mmol) and triphenylphosphine (3.51 g, 13.38 mmol) were then added in portions. The reaction mixture was slowly heated to room temperature and stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (methanol / dichloromethane = 0-10%) to give compound 11b (1.1 g). MS m / z (ESI): 175.0 [M+1] + .

[0291] Step 2: Synthesis of compound 11d

[0292] Compound 11c (4-bromopyridin-2(1H)-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 conditions. The reaction mixture was then stirred at room temperature for 12 hours. After the reaction was complete, the reaction mixture was extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated brine (30 mL × 1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1-1 / 1) to give 11d (196 mg). MS m / z (ESI): 267.9 [M+1] + .

[0293] Step 3: Synthesis of Compound 11

[0294] Compound 11d (40 mg, 0.15 mmol) was dissolved in 1,4-dioxane (2 mL), followed by the addition of compound 39a (52 mg, 0.15 mmol), potassium phosphate (96 mg, 0.45 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (11 mg, 0.015 mmol). Under nitrogen protection, the reaction mixture was heated to 100 °C and stirred for 16 hours. After the reaction was complete, the 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 give compound 11 (20 mg). MS m / z (ESI): 411.0 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.93(s,1H),7.73(d,J=7.0Hz,1H),7.64(d,J=2.1Hz,1H), 7.41(d,J=4.7Hz,2H),7.33(t,J=4.7Hz,1H),6.37(d,J=1.8Hz,1H),6.27(dd,J=7.0 ,2.0Hz,1H),6.20(d,J=2.2Hz,1H),5.06(s,2H),4.34(dd,J=12.3,4.9Hz,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).

[0295] Example 6 (compound 1)

[0296]

[0297] Step 1: Synthesis of Compound 1

[0298] Compound 1a (4-pyridineboronic acid) (10 mg, 0.081 mmol) was dissolved in 1,4-dioxane (1 mL), followed by the sequential addition of compound 1b (24.51 mg, 0.081 mmol) (synthetic method referred to page 184 of patent WO2024151547A1, Synthesis of Intermediate AA-1), potassium phosphate (51.58 mg, 0.24 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (11.85 mg, 0.016 mmol). Under nitrogen protection, the reaction mixture was heated to 80 °C and stirred for 2 days. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-3%) to give compound 1 (3.20 mg). MS m / z (ESI): 301.0 [M+1] + .1 H NMR(400MHz,DMSO-d6)δ10.94(s,1H),8.68(s,2H),7.46–7.44(m,4H),7.37–7.35(m,1H),4.36(dd ,J=4.0,12.0Hz,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).

[0299] The following compounds can be synthesized using the preparation methods described in the above examples.

[0300]

[0301]

[0302]

[0303] Biological evaluation

[0304] Test Example 1. Evaluation of VAV1 degradation in Jurkat cells

[0305] Jurkat cells (ATCC#TIB-152) were cultured in 90% RPMI 1640 basal medium (Gibco#22400-089), 10% FBS (Gibco#10099-141C), and 1% penicillin-streptomycin mixture (Gibco#15140-122) at a density of 1 x 10⁻⁶ cells / mL. ^6The cells were seeded at a density suitable for each well in a 12-well plate. After incubating in a CO2 incubator (37°C, 5% CO2) for 1 hour, 6 μL of DMSO (final concentration 0.4%) and 100 nM, 10 nM, and 1 nM of the test compound were added, respectively. After incubation for another 24 hours, the cells were centrifuged, and the culture supernatant was discarded. The cells were washed once with PBS, and 50 μL of RIPA lysis buffer (Beyotime #P0013B) was added. The plates were placed on ice with gentle pipetting or shaking for 15 minutes, followed by centrifugation at 15,000 rpm for 10 minutes. Total protein was quantified using a BCA kit (Beyotime #P0010). Protein electrophoresis was performed on a 4-15% gradient gel (BIO-RAD#458086). Transfer was performed using a pre-prepared transfer kit (BIO-RAD#1704156) on a turbo (Bio-Rad#1704150) plate. Blocking buffer (LI-COR#927-60000) was used for 15 minutes. VAV1 antibody (CST#2502S) and GAPDH (CST#2118S) were incubated overnight at 4°C. After incubation at room temperature for 2 hours with IRDye800CW-labeled goat anti-rabbit secondary antibody (LI-COR#926-32211), fluorescence signals were captured by imaging on a Li-Cor Odyssey DLX instrument, thus obtaining VAV1 and GAPDH blot images. The integrated band intensity of the blot images was then analyzed using ImageStudio software, and normalization was performed using the internal control protein GAPDH to calculate the degradation rate of VAV1. For degradation rate, A indicates degradation rate ≥ 75%, B indicates 25% ≤ degradation rate < 75%, and C indicates degradation rate < 25%. The results are shown in Table 1.

[0306] Table 1

[0307]

[0308]

[0309] Test Example 2. Evaluation of VAV1 degradation in Jurkat cells

[0310] Jurkat cells (ATCC#TIB-152) were cultured in 90% RPMI 1640 basal medium (Gibco#22400-089), 10% FBS (Gibco#10099-141C), and a 1% penicillin-streptomycin mixture (Gibco#15140-122) at a density of 2 x 10⁻⁶ cells / year. ^5Cells were seeded at a density of 0.1 μg / ml poly-L-lysine (Sangon Biotech #E607014) in 96-well plates (Greiner #655090). Cells were incubated in a CO2 incubator (37°C, 5% CO2) for 2 hours to allow cell adhesion. Then, 10 μL of 0.22% DMSO and the test compounds at concentrations of 1000 nM, 200 nM, 40 nM, 8 nM, 1.6 nM, 0.32 nM, and 0.06 nM were added, and the cells were incubated for another 24 hours. After centrifuging the cell culture plate, fix the cells with 4% paraformaldehyde (Beyotime-P0099-500ml) for 20 minutes, permeabilize with 0.1% Triton X-100 (Sigma#T8787-500ml) for 20 minutes, block with blocking buffer (LI-COR#927-60000) at room temperature for 1.5 hours, and incubate overnight at 4°C with VAV1 antibody (CST#2502S, 1:100). IRDye800CW-labeled goat anti-rabbit secondary antibody (LI-COR#926-32211, 1:1500) and CellTag... TM After incubation at room temperature for 2 hours with 700 μL Stain (Li-Cor #926-41090), the emission signal was captured by imaging detection on a Li-Cor Odyssey DLX instrument, thereby obtaining VAV1 and CellTag. TM 700 Stain fluorescence images. Subsequently, Image Studio software was used to analyze the fluorescence signal intensity of each cell in each well of each cell plate. After subtracting the background signal, the internal control CellTag was used. TM The 700 Stain signal was normalized, and the compound concentration representing 50% degradation of VAV1, i.e., DC50, was calculated. A indicates DC50 ≤ 50 nM, B indicates 50 nM < DC50 ≤ 500 nM, and C indicates DC50 > 500 nM. The results are shown in Table 2.

[0311] Table 2

[0312] Example Compound DC50 (nM) 3 47 B 4 40 B 5 11 A

[0313] The embodiments of the technical solution of the present invention have been described above by way of example. It should be understood that the protection scope of the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made by those skilled in the art within the spirit and principles of the present invention should be included within the protection scope of the claims of this application.

Claims

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein: Formula (I) 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein T is selected from: 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. Ring A and Ring B are the same or different, each independently a 5-12 membered heterocyclyl or a 5-12 membered heteroaryl; wherein: n is 0, 1, 2, 3, or 4; 5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (II), Formula (III), or Formula (IV): 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. wherein, and n are defined as in claims 1-5.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, 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 12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein 13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein 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. The compound has the following structure: 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 with one or more C 1-6 alkyl; R is selected from the group consisting of H, C 7 alkylene-pyrazolyl, 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 for C 1-6 alkylene, wherein 1, 2 or 3 CH2in the alkylene group are optionally and each independently replaced with a substituent selected from the group consisting of -0-, -S-, -NR 1-6 -; C(O); C L1 alkylene is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano and C 3-8 alkyl; and wherein the ring alkyl or 3-8 membered heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano and C 1-6 alkyl; and wherein the ring alkyl or 3-8 membered heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano and C 1-6 alkyl; and wherein the ring alkyl or 3-8 membered heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano and C 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.

15. A pharmaceutical composition comprising at least one therapeutically effective amount of a compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. R 8 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 molecular glue is a compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof. The molecular glue is a compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof.

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

17. An E3 ligase-molecular glue-VAV1 protein ternary complex, wherein, 19. Use of a compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of 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, the compound interacts with E3 ligase prior to the interaction of VAV1 protein with E3 ligase.

20. Use of a compound of any one of claims 1-14, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 15, or the E3 ligase-molecular glue binary complex of 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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