Heterocyclic compound, and pharmaceutical composition comprising same and use thereof

Abstract

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

Description

Heterocyclic compounds, pharmaceutical compositions thereof and their uses

[0001] This application is based on and claims priority to CN application number 202411733199.9 filed on November 29, 2024, the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0002] This application belongs to the pharmaceutical field, specifically relating to a heterocyclic compound, its pharmaceutical composition and uses, which can be used as a VAV1 degrading agent. Background Technology

[0003] 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.

[0004] 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, functioning as an adaptor protein and regulating T-cell and B-cell receptor activation signal transduction.

[0005] VAV1 is a key component of the T-cell and B-cell antigen receptor signaling complex. In T cells, the 76 kDa leukocyte protein (SLP76) containing a Src homology (SH)2 domain is recruited to the transmembrane connective tissue (LAT) via its SH2 domain, thereby activating T cells. The LAT / SLP76 complex is a key scaffold for other proteins in the proximal TCR signaling complex, including VAV1. VAV1 interacts with other proteins via its SH2 and proline-rich / SH3 domains. In B cells, VAV1 interacts with a signaling complex comprising a SLP76 homology scaffold protein, SLP65 (also known as a B-cell connective protein), Bruton's tyrosine kinase (BTK), Grb2, and phospholipase-γ (PLCγ)2. The assembly of these protein complexes activates downstream events, including phosphorylation of PLCγ1 / 2; Ca 2+ VAV1 is involved in the activation of signaling pathways mediated by protein kinase C (PKC) and p38 mitogen-activated protein kinase (MAPK); and the regulation of transcription factors, including activated T cell nuclear factor (NFAT), nuclear factor κB (NF-κB), and activator protein-1 (AP-1). VAV1 does not rely on the "scaffolding" function of guanine nucleotide exchange factor (GEF) but appears to depend on its involvement in these antigen receptor-proximal signaling complexes. The primary GEF-dependent function of VAV1 is the activation of Rac / Rho family GTPases. In T cells and B cells, co-stimulation by CD28 and CD19 is crucial for optimal phosphorylation of VAV1 and activation of downstream signaling pathways. The exact mechanism of VAV1 co-receptor activation remains to be fully determined. While the precise role of VAV1 in human diseases awaits clinical validation, multiple pieces of evidence suggest its association with autoimmune and chronic inflammatory diseases, supporting its potential as a therapeutic target.

[0006] 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-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

[0007] This application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0008] in:

[0009] X is CR x Or N;

[0010] Ring A is selected from phenyl, 5-10 membered heterocyclic groups, and 5-10 membered heteroaryl groups;

[0011] Ring B is selected from phenyl, 5-10 membered cycloalkyl, 5-20 membered heterocyclic and 5-20 membered heteroaryl;

[0012] R x Selected from H, halogen, hydroxyl, cyano, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0013] Each R 1 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 3-6 cycloalkyl groups and 3-6 membered heterocyclic groups;

[0014] Or R x And one of the R 1 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, oxo groups, and C-membered groups. 1-6 One or more substituents in the alkyl group are substituted;

[0015] R 2 Selected from C 1-6 alkoxy, 5-20 membered heterocyclic, 5-20 membered heteroaryl or -TR 5 The 5-20 membered heterocyclic group and the 5-20 membered heteroaryl group are optionally surrounded by one or more R g replace;

[0016] T is selected from C 1-6 Alkylene, -OC 1-6 Alkylene, C(O)-C 1-6 Alkylene and -NR T1 -C 1-6 Alkylene, the C 1- 6-alkylene groups are optionally selected from halogens, hydroxyl groups, C64, hydroxyl groups, and C64. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 The substance is substituted by one or more substituents selected from hydroxyalkyl, cyano, and amino groups.

[0017] R 5 It is a 5-10 membered heteroaryl or a 5-10 membered heterocyclic group, wherein the 5-10 membered heterocyclic group and the 5-10 membered heteroaryl group are optionally surrounded by one or more R g replace;

[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, oxo, C 3-6 cycloalkyl groups and 3-6 membered heterocyclic groups;

[0019] Or one of the R 1And one of the R 3 The atoms bonded to it form C 5-10 Cycloalkyl or 5-10 membered heterocyclic group, wherein the C 5-10 Cycloalkyl groups and 5-10-membered heterocyclic groups are optionally selected from halogens, hydroxyl groups, oxo groups, and C-membered groups. 1-6 One or more substituents in the alkyl group are substituted;

[0020] R g Selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, hydroxyl, cyano, amino, oxo, C 3-6 cycloalkyl groups and 3-6 membered heterocyclic groups;

[0021] n is 0, 1, 2, 3, 4, 5, or 6;

[0022] m can be 0, 1, 2, 3, or 4;

[0023] The condition is that when both ring A and ring B are phenyl, one or more of the following conditions must be met:

[0024] (1) X is N;

[0025] (2) X is CR x R x And one of the R 1 The atoms bonded to it form C 3-8 cycloalkyl or 3-8 membered heterocyclic groups;

[0026] (3) An R 1 And an R 3 The atoms bonded to it form C 5-10 Cycloalkyl or 5-10 membered heterocyclic groups;

[0027] (4)R 2 It is an 11-20 membered heterocyclic group or an 11-20 membered heteroaryl group.

[0028] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from 5-20 membered heterocyclic groups, 5-20 membered heteroaryl groups, or -TR 5 The 5-20 membered heterocyclic group and the 5-20 membered heteroaryl group are optionally surrounded by one or more R g Replacement; T, R 5 and R g As defined by compound (I).

[0029] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (I) is the compound represented by formula (II):

[0030] Among them, rings A and R 1 R 2 R 3 X, m, and n are defined above, provided that when ring A is phenyl, one or more of the following conditions are satisfied:

[0031] (1) X is N;

[0032] (2) X is CR x R x And one of the R 1 The atoms bonded to it form C 3-8 cycloalkyl or 3-8 membered heterocyclic groups;

[0033] (3) An R 1 And an R 3 The atoms bonded to it form C 5-10 Cycloalkyl or 5-10 membered heterocyclic groups;

[0034] (4)R 2 It is an 11-20 membered heterocyclic group or an 11-20 membered heteroaryl group.

[0035] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein Selected from

[0036] Y 1 Y 3 Y 4 and Y 5 Whether the two are the same or different, and each is an independent CR 1 Or N;

[0037] Y 2 Selected from O, S, NR 1 and C(R) 1 )2;

[0038] Y 6 Y 7 Y 8 and Y 9 Whether the two are the same or different, and each is an independent CR 1 Or N;

[0039] G 1 and G 2 They are the same or different, and each is independently C or N;

[0040] It can be a single bond or a double bond;

[0041] Ring D is a 5-6 membered heterocyclic group or a 5-6 membered heteroaryl group;

[0042] R 1a R 1b R 1c R 1d and R 4 They may be the same or different, and each is independently selected from chemical bonds, H, halogens, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, hydroxyl, cyano, amino, C 3-6 cycloalkyl groups and 3-6 membered heterocyclic groups;

[0043] p is 0, 1, 2 or 3;

[0044] The condition is that when Y 6 Y 7 Y 8 and Y 9 All are CR 1 At that time, one or more of the following conditions are met:

[0045] (1) X is N;

[0046] (2) X is CR x R x And one of the R 1 The atoms connected to it form a ring;

[0047] (3) An R 1 And an R 3 The atoms connected to it form a ring;

[0048] (4)R 2 It is an 11-20 membered heterocyclic group or an 11-20 membered heteroaryl group.

[0049] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein Selected from R 4 It can replace the H on NH;

[0050] R 1 R 1a R 1b R 1c R 1d and R 4 They may be the same or different, and each is independently selected from H, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C1-6 Hydroxyalkyl, hydroxyl, cyano, amino, C 3-6 cycloalkyl groups and 3-6 membered heterocyclic groups;

[0051] s can be 0, 1, 2, or 3;

[0052] p is 0, 1, 2 or 3;

[0053] The condition is that when for At that time, one or more of the following conditions are met:

[0054] (1) X is N;

[0055] (2) X is CR x R x And one of the R 1 The atoms connected to it form a ring;

[0056] (3) An R 1 And an R 3 The atoms connected to it form a ring;

[0057] (4)R 2 It is an 11-20 membered heterocyclic group or an 11-20 membered heteroaryl group.

[0058] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (I) is a compound represented by formulas (III), (IV), (V) and (VI):

[0059] in,

[0060] R 3 and R 4a 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 3-6 cycloalkyl groups and 3-6 membered heterocyclic groups;

[0061] Or, R 3 and R 4a The atoms bonded to it form C 5-10 Cycloalkyl or 5-10 membered heterocyclic group, wherein the C 5-10 Cycloalkyl groups and 5-10-membered heterocyclic groups are optionally selected from halogens, hydroxyl groups, oxo groups, and C-membered groups. 1-6 One or more substituents in the alkyl group are substituted;

[0062] q is 0, 1, or 2;

[0063] R 1a R 1b R 1c R 1d R 2 Ring B, G 1 G 2 , ring D, R 4 X, m, and p are defined as above.

[0064] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein Selected from:

[0065] R 2 R 3 And m are as defined above.

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

[0067] R 2 R 3 And m are as defined above.

[0068] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (I) is a compound represented by formula (V-1), formula (VII), or formula (VIII):

[0069] in,

[0070] L 1 Selected from C 1-6 Alkylene, aOC 1-6 Alkylene, aC 1-6 Alkylene-O-, a-NR L -C 1-6 Alkylene, aC 1-6 Alkylene-NR L -、aC(O)NR L -C 1-6 Alkylene and aC 1-6 Alkylene-NR L C(O)-, the a-terminus is connected to CR 3d On adjacent carbon atoms, the C 1-6 Alkylenes are optionally selected from halogens, hydroxyl groups, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6The substance is substituted by one or more substituents selected from hydroxyalkyl, cyano, and amino groups;

[0071] L 2 Selected from C 1-6 Alkylene, bOC 1-6 Alkylene, bC 1-6 Alkylene-O-, b-NR L -C 1-6 Alkylene and bC 1-6 Alkylene-NR L -,b end is attached to the carbon atom adjacent to C(O), wherein C 1-6 Alkylenes are optionally selected from halogens, hydroxyl groups, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 The substance is substituted by one or more substituents selected from hydroxyalkyl, cyano, and amino groups.

[0072] R L Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-6 cycloalkyl groups and 3-6 membered heterocyclic groups;

[0073] R 3a R 3b R 3c and R 3d They may be the same or different, and each is independently selected from H, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, hydroxyl, cyano, amino, oxo, C 3-6 cycloalkyl groups and 3-6 membered heterocyclic groups;

[0074] R 1a R 1b R 1c R 1d R 2 G 1 G 2 , ring D, R 4 X and q are defined as above.

[0075] In some embodiments, the compound represented by formula (V-1), formula (VII), or formula (VIII), or a pharmaceutically acceptable salt thereof, wherein L 1Selected from -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, aO-CH2-, a-CH2-O-, aO-CH2CH2-, a-CH2CH2-O-, a-NH-CH2CH2-, a-CH2CH2-NH-, a-NH-CH2-, a-CH2-NH-, aC(O)NH-CH2CH2-, aC(O)N(CH3)-CH2CH2-, a-CH2CH2-NHC(O) and a-CH2CH2-N(CH3)C(O), with the a-terminus connected to CR. 3d On adjacent carbon atoms;

[0076] L 2 Selected from -CH2CH2-, -CH2CH2CH2-, aO-CH2-, a-CH2-O-, aO-CH2CH2-, a-CH2CH2-O-, a-NH-CH2CH2-, a-CH2CH2-NH-, a-NH-CH2-, and a-CH2-NH-, with the a-terminus connected to CR. 3d On adjacent carbon atoms.

[0077] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (I) is a compound represented by formula (IX):

[0078] Wherein, the ring C is a 5-10 membered cycloalkyl group or a 5-20 membered heterocyclic group;

[0079] R 1a R 1b R 1c R 1d R 2 R 3 X and m are defined as above.

[0080] In some embodiments, the compound represented by formula (IX) or a pharmaceutically acceptable salt thereof, wherein Selected from R 2 R 3 And m are as defined above.

[0081] In some embodiments, the compound represented by formula (IX) or a pharmaceutically acceptable salt thereof, wherein Selected from R 2 R 3 And m are as defined above.

[0082] In some embodiments, the compound represented by formula (IX) or a pharmaceutically acceptable salt thereof, wherein for R 2 R 3 And m are as defined above.

[0083] In some embodiments, the compound represented by formula (IX) or a pharmaceutically acceptable salt thereof, wherein for R 2 R 3 And m are as defined above.

[0084] In some embodiments, the compound represented by formula (I), formula (II), formula (III), formula (IV), formula (V), formula (V-1), formula (VI), formula (VII), formula (VIII) or formula (IX), or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from:

[0085] C 1-6 Alkoxy,

[0086] R g Selected from H, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 1-6 Hydroxyalkyl;

[0087] q can be 0, 1, or 2.

[0088] In some embodiments, the compound represented by formula (I), formula (II), formula (III), formula (IV), formula (V), formula (V-1), formula (VI), formula (VII), formula (VIII) or formula (IX), or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from:

[0089] R g Selected from H, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 1-6 Hydroxyalkyl;

[0090] q can be 0, 1, or 2.

[0091] In some embodiments, the compounds represented by formula (I) and formula (IX), or pharmaceutically acceptable salts thereof, wherein R 2 Selected from:

[0092] C 1-3 Alkoxy,

[0093] R g Selected from H and C 1-3 alkyl;

[0094] q can be 0, 1, or 2.

[0095] In some embodiments, the compounds represented by formula (I) and formula (IX), or pharmaceutically acceptable salts thereof, wherein R 2 Selected from:

[0096] -OCH3、

[0097] In some embodiments, the compounds represented by formulas (I), (II), and (III), or pharmaceutically acceptable salts thereof, wherein R 2 Selected from:

[0098] R g Selected from H and C 1-3 alkyl;

[0099] q can be 0, 1, or 2.

[0100] In some embodiments, the compounds represented by formulas (I), (II), and (III), or pharmaceutically acceptable salts thereof, wherein R 2 Selected from:

[0101] In some embodiments, the compound represented by formula (I), formula (II), formula (III), formula (IV), formula (V), formula (V-1), formula (VI), formula (VII), formula (VIII) or formula (IX), or a pharmaceutically acceptable salt thereof, wherein X is a CR x ;R x As defined above.

[0102] In some embodiments, the compound represented by formula (I), formula (II), formula (III), formula (IV), formula (V), formula (V-1), formula (VI), formula (VII), formula (VIII) or formula (IX) or a pharmaceutically acceptable salt thereof, wherein X is CH.

[0103] In some embodiments, the compound represented by formula (I), formula (II), formula (III), formula (IV), formula (V), formula (V-1), formula (VI), formula (VII), formula (VIII) or formula (IX), or a pharmaceutically acceptable salt thereof, wherein R 1 R 1a R 1b R 1c R 1d and R 4They may be the same or different, and each is independently selected from H, halogens, and C. 1-6 alkyl.

[0104] In some embodiments, the compound represented by formula (I), formula (II), formula (III), formula (IV), formula (V), formula (V-1), formula (VI), formula (VII), formula (VIII) or formula (IX), or a pharmaceutically acceptable salt thereof, wherein R 1 R 1a R 1b R 1c R 1d and R 4 They may be the same or different, and each is independently selected from H, chlorine and methyl.

[0105] In some embodiments, the compound represented by formula (IX) or a pharmaceutically acceptable salt thereof, wherein R 1a For chlorine, R 1b R 1c R 1d For H.

[0106] In some embodiments, the compound represented by formula (I), formula (II), formula (III), formula (IV), formula (V), formula (V-1), formula (VI), formula (VII), formula (VIII) or formula (IX), or a pharmaceutically acceptable salt thereof, wherein R 3 R 3a R 3b R 3c and R 3d They may be the same or different, and each is independently selected from H, halogens, and C. 1-6 alkyl.

[0107] In some embodiments, the compound represented by formula (I), formula (II), formula (III), formula (IV), formula (V), formula (V-1), formula (VI), formula (VII), formula (VIII) or formula (IX), or a pharmaceutically acceptable salt thereof, wherein R 3 R 3a R 3b R 3c and R 3d All are H.

[0108] Exemplary specific compounds shown in this application include, but are not limited to, the structures in Table A below:

[0109] Table A

[0110] Exemplary specific compounds shown in this application include, but are not limited to, the structures in Table B below:

[0111] Table B

[0112] In some embodiments, the compounds in Form A of this application include for

[0113] In some embodiments, the compounds in Form B of this application include for

[0114] In another aspect, this application provides isotope labels for compounds shown in Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (V-1), Formula (VII), Formula (VIII) or Formula (IX), and those shown in Table A or Table B, wherein the isotope label is preferably deuterium (D or 2 H) replaces hydrogen ( 1 H).

[0115] 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.

[0116] In another aspect, this application provides an E3 ligase-molecular glue binary complex, wherein the molecular glue is the aforementioned compound or a pharmaceutically acceptable salt thereof.

[0117] In another aspect, this application provides an E3 ligase-molecular glue-VAV1 protein ternary complex, wherein the molecular glue is the aforementioned compound or a pharmaceutically acceptable salt thereof.

[0118] In another aspect, this application also provides the use of compounds of formula (I), (II), (III), (IV), (V), (VI), (V-1), (VII), (VIII) or (IX), shown in Table A or Table B, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, in the preparation of a medicament for degrading VAV1 protein.

[0119] In another aspect, this application also provides the use of compounds of formula (I), (II), (III), (IV), (V), (VI), (V-1), (VII), (VIII) or (IX), shown in Table A or Table B, 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 compound interacts with E3 ligase prior to the interaction between VAV1 protein and E3 ligase.

[0120] In another aspect, this application also provides the use of compounds of formula (I), (II), (III), (IV), (V), (VI), (V-1), (VII), (VIII) or (IX), shown in Table A or Table B, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, in the preparation of a medicament for contacting an E3 ligase to allow the contacted E3 ligase to interact with VAV1 and thereby degrade VAV1.

[0121] In another aspect, this application also provides the use of compounds of formula (I), (II), (III), (IV), (V), (VI), (V-1), (VII), (VIII) or (IX), compounds shown in Table A or Table B, or pharmaceutically acceptable salts thereof or pharmaceutical compositions containing the same, 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.

[0122] In this application, the lymphocytes may be T cells.

[0123] In this application, the lymphocytes may be B cells.

[0124] This application also provides the use of compounds of formula (I), (II), (III), (IV), (V), (VI), (V-1), (VII), (VIII) or (IX), compounds shown in Table A or Table B, 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.

[0125] 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, and hepatitis.

[0126] 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), (II), (III), (IV), (V), (VI), (V-1), (VII), (VIII), or (IX), a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a aforementioned isotopic label thereof, or a pharmaceutical composition comprising the aforementioned, or the aforementioned E3 ligase-molecular glue binary complex.

[0127] 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), (II), (III), (IV), (V), (VI), (V-1), (VII), (VIII), or (IX), a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a aforementioned isotopic label thereof, or a pharmaceutical composition comprising the aforementioned, or the aforementioned E3 ligase-molecular glue binary complex, wherein the compound mediates the interaction between VAV1 protein and E3 ligase, thereby increasing the degradation of VAV1 protein.

[0128] 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), (II), (III), (IV), (V), (VI), (V-1), (VII), (VIII), or (IX), a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a aforementioned isotopic label thereof, or a pharmaceutical composition comprising the aforementioned, or the aforementioned E3 ligase-molecular glue binary complex, wherein the compound interacts with the E3 ligase prior to the interaction of the VAV1 protein with the E3 ligase.

[0129] 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), (II), (III), (IV), (V), (VI), (V-1), (VII), (VIII), or (IX), a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a aforementioned isotope label thereof, or a aforementioned pharmaceutical composition comprising the thereof, wherein the compound (i) is contacted with an E3 ligase, and (ii) the contacted E3 ligase interacts with VAV1, thereby degrading the VAV1 protein.

[0130] 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), (II), (III), (IV), (V), (VI), (V-1), (VII), (VIII), or (IX), a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a aforementioned isotopic label thereof, or a pharmaceutical composition comprising the aforementioned, or the aforementioned E3 ligase-molecular glue binary complex.

[0131] 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 (I-1), or formula (I-2), shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the aforementioned compound, or the aforementioned E3 ligase-molecular glue binary complex.

[0132] This application also provides a compound of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (V-1), formula (VII), formula (VIII) or formula (IX), a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition or the aforementioned E3 ligase-molecular glue binary complex, for use as a medicine.

[0133] This application also provides a compound of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (V-1), formula (VII), formula (VIII) or formula (IX), a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition or the aforementioned E3 ligase-molecular glue binary complex, which is used as a VAV1 degrading agent.

[0134] This application also provides a compound of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (V-1), formula (VII), formula (VIII) or formula (IX), a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the aforementioned compound, or an E3 ligase-molecular glue binary complex thereof, for use as a medicament for the prevention and / or treatment of diseases or conditions caused by or related to lymphocyte developmental or activity disorders.

[0135] This application also provides a compound of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (V-1), formula (VII), formula (VIII) or formula (IX), a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the aforementioned compound, or an E3 ligase-molecular glue binary complex thereof, for use 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.

[0136] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0137] 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.

[0138] 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.

[0139] 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.

[0140] 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.

[0141] 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.

[0142] 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.

[0143] 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.

[0144] 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.

[0145] In the chemical structure of the compound described in this application, the bond... This indicates that no configuration has been specified. Indicates absolute configuration, that is, if chiral isomers exist in the chemical structure, the bonds... It can be Or simultaneously include Two configurations, This indicates the presence of axial chirality.

[0146] key This indicates that the configuration is not specified, including cis (E) or trans (Z) configurations.

[0147] 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.

[0148] 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.

[0149] 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.

[0150] 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.

[0151] "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.

[0152] 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. Beneficial effects

[0153] This application provides a small molecule compound that can be used as a VAV1 degrader. Such compounds or pharmaceutical compositions have a superior degradation effect on VAV1 and can be used to effectively treat or prevent autoimmune diseases, inflammatory diseases, metabolic diseases, cardiovascular diseases, kidney diseases, central nervous system diseases or cancer.

[0154] Terminology Definitions and Explanations

[0155] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0156] 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.

[0157] The term "alkoxy" refers to -O- (alkyl), where alkyl is defined as described herein. Preferably, it is C-. 1-6 Alkoxy groups (i.e., those containing 1, 2, 3, 4, 5, or 6 carbon atoms). Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups can be substituted or unsubstituted.

[0158] 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, and more preferably C atoms. 1-6 Alkylenes (i.e., including 1, 2, 3, 4, 5, and 6 carbon atoms). Non-limiting examples include methylene (-CH2-), ethylene (-CH2CH2-), etc. The alkylenes may be substituted or unsubstituted.

[0159] 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...). 2-6 alkenyl), 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.

[0160] 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.

[0161] 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.

[0162] 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:

[0163] 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:

[0164] 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:

[0165] 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 can be a cycloalkyl ring or an aryl ring, and non-limiting examples include... etc.; preferred The cycloalkyl group may be substituted or unsubstituted.

[0166] 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 may be considered as 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.

[0167] 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:

[0168] 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:

[0169] 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:

[0170] 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: The heterocyclic group may be substituted or unsubstituted.

[0171] 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 may be substituted or unsubstituted.

[0172] 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: Etc. Heteroaryl groups can be substituted or unsubstituted.

[0173] 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.

[0174] 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".

[0175] The term “cycloalkyloxy” refers to cycloalkyl-O-, where the cycloalkyl group is as defined herein.

[0176] The term “heterocyclic oxy group” refers to a heterocyclic group -O-, wherein the heterocyclic group is as defined herein.

[0177] 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.

[0178] The term “haloalkoxy” refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group is as defined herein.

[0179] The term “deuterated alkyl” refers to an alkyl group that is substituted with one or more deuterium atoms, wherein the alkyl group is as defined herein.

[0180] The term “deuterated alkoxy” refers to an alkoxy group that is substituted with one or more deuterium groups, wherein the alkoxy group is as defined herein.

[0181] The term "hydroxyalkyl" refers to an alkyl group that is substituted with one or more hydroxyl groups, wherein the alkyl group and the hydroxyl group are as defined herein.

[0182] The term "cyanoalkyl" refers to an alkyl group that is substituted with one or more cyano groups, wherein the alkyl and cyano groups are as defined herein.

[0183] The term "aminoalkyl" refers to an alkyl group that is substituted with one or more amino groups, wherein the alkyl and amino groups are as defined herein.

[0184] The term "halogen" refers to F, Cl, Br, or I.

[0185] The term "hydroxyl group" refers to -OH.

[0186] The term "amino" refers to -NH2.

[0187] The term "cyano" refers to -CN.

[0188] The term "nitro" refers to -NO2.

[0189] The term "oxo" or "oxo" refers to "=O" when it substitutes on C, and "=O" when it substitutes on N.

[0190] The term "carbonyl" refers to C=O.

[0191] The term "carboxyl group" refers to -C(O)OH.

[0192] 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.

[0193] "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.

[0194] "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).

[0195] 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

[0196] 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.

[0197] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0198] 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.

[0199] HPLC determinations were performed using a Shimadzu HPLC-2010C high-performance liquid chromatograph (XBRIDGE 2.1*50mm, 3.5um column).

[0200] Chiral HPLC analysis was performed using THARSFC X5.

[0201] 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.

[0202] Column chromatography typically uses Qingdao marine silica gel 200-300 mesh as the carrier.

[0203] High-performance liquid chromatography (HPLC) was performed using Waters 2767, Waters 2545, and the innovative Hengtong LC3000 preparative chromatograph.

[0204] Chiral preparative column chromatography was performed using Shimadzu LC-20AP and THARSFC PREP 80.

[0205] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0206] The pressurized hydrogenation reaction uses a Beijing Jiawei Kechuang Technology GCD-500G hydrogen generator.

[0207] The microwave reaction uses a Biotage initiator+ type microwave reactor.

[0208] Unless otherwise specified in the experimental examples, the reactions were carried out under an argon or nitrogen atmosphere.

[0209] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of about 1 liter.

[0210] A hydrogen atmosphere refers to a reaction vessel connected to a hydrogen balloon with a volume of approximately 1 liter.

[0211] Unless otherwise specified in the experimental examples, the reaction temperature is room temperature, ranging from 20℃ to 30℃.

[0212] 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.

[0213] Example 1 (Compound 15)

[0214] Step 1: Synthesis of compound 15c

[0215] Compound 15a (p-diiodobenzene) (100 mg, 0.45 mmol) and compound 15b ((1-methyl-1H-pyrazol-3-yl)methanol) (50.46 mg, 0.45 mmol) were dissolved in tetrahydrofuran (5 mL) under ice bath conditions. Triphenylphosphine (141.64 mg, 0.54 mmol) and diethyl azodicarbonate (109.19 mg, 0.54 mmol) were added sequentially. The reaction mixture was brought to room temperature and stirred for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by thin-layer chromatography on silica gel (dichloromethane) to give compound 15c (170 mg). MS m / z (ESI): 314.9 [M+1] + .

[0216] Step 2: Synthesis of compound 15f

[0217] Under nitrogen atmosphere at room temperature, compound 15d (4-bromoindole-1-carboxylic acid tert-butyl ester) (500 mg, 1.69 mmol) was dissolved in 1,4-dioxane (8 mL), followed by compound 15e (2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)pyridine) (705.25 mg, 1.69 mmol), potassium phosphate (1.07 g, 5.07 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (247.31 mg, 0.34 mmol). The reaction mixture was heated to 90 °C and stirred for 16 hours under nitrogen protection. 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 (ethyl acetate / petroleum ether = 0-100%) to give compound 15f (702 mg). MS m / z (ESI): 507.2 [M+1] + .

[0218] Step 3: Synthesis of 15g of compound

[0219] Compound 15f (600 mg, 1.18 mmol) was dissolved in methanol (10 mL) under hydrogen atmosphere at room temperature. Pd / C (59.02 mg, 0.55 mmol) and palladium hydroxide (59.65 mg, 0.42 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 1 day, followed by the addition of Pd / C (80 mg, 0.75 mmol), and the mixture was stirred at room temperature for 4 days. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, and the filter cake was washed with methanol (10 mL × 3), followed by washing with dichloromethane (10 mL × 3). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-5%) to give 15 g (157 mg) of compound. MS m / z (ESI): 275.0 [M-55] + .

[0220] Step 4: Synthesis of compound 15h

[0221] 15 g (157 mg, 0.48 mmol) of the compound was dissolved in 2.5 mL of hydrochloric acid-dioxane solution under ice bath conditions, and the reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-40%) to give compound 15h (100 mg). MS m / z (ESI): 231.1 [M+1] + .

[0222] Step 5: Synthesis of Compound 15

[0223] Compound 15h (40 mg, 0.17 mmol) was dissolved in 1,4-dioxane (1 mL), followed by the addition of compound 15c (66.75 mg, 0.17 mmol), cesium carbonate (166.17 mg, 0.51 mmol), 2-dicyclohexylphospho-2',6'-diisopropoxy-1,1'-biphenyl (15.87 mg, 0.03 mmol), and methanesulfonic acid (2-dicyclohexylphospho-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (28.44 mg, 0.03 mmol). The reaction mixture was heated to 90 °C and stirred for 16 hours under nitrogen protection. 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 = 0-5%) to obtain the crude product, which was then purified by a Combi-Flash rapid reagent (C18 reversed-phase column, mobile phase: acetonitrile-water; gradient: 0-60%) to obtain compound 15 (1.74 mg). MS m / z (ESI): 417.2 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.85 (s, 1H), 7.66 (s, 1H), 7.18 (d, J = 8.0Hz, 2H), 7. 02(d,J=8.0Hz,2H),6.96(t,J=8.0Hz,1H),6.74(d,J=8.0Hz,1H),6.47(d,J= 8.0Hz,1H),6.30(s,1H),4.96(s,2H),3.87–3.83(m,6H),3.03–2.95(m,2H), 2.75–2.66(m,1H),2.53–2.51(m,1H),2.22–2.14(m,1H),2.03–1.99(m,1H).

[0224] Example 2 (Compound 16)

[0225] Step 1: Synthesis of compound 16b

[0226] Compound 16a (3-iodophenol) (100 mg, 0.45 mmol) and compound 15b (50.46 mg, 0.45 mmol) were dissolved in tetrahydrofuran (2 mL) under ice bath conditions. Triphenylphosphine (141.64 mg, 0.54 mmol) and diethyl azodicarbonate (94.04 mg, 0.54 mmol) were added sequentially. The reaction mixture was brought to room temperature and stirred for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 80-90%) to give compound 16b (200 mg). MS m / z (ESI): 314.9 [M+1]+

[0227] Step 2: Synthesis of Compound 16

[0228] Compound 15h (synthesized as described in step 4 of Example 1) (40 mg, 0.17 mmol) was dissolved in 1,4-dioxane (1 mL), followed by the addition of compound 16b (76.29 mg, 0.17 mmol), cesium carbonate (166.17 mg, 0.51 mmol), 2-dicyclohexylphospho-2',6'-diisopropoxy-1,1'-biphenyl (15.87 mg, 0.03 mmol), and methanesulfonic acid (2-dicyclohexylphospho-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (28.44 mg, 0.03 mmol). The reaction mixture was heated to 90 °C and stirred for 16 hours under nitrogen protection. 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 = 0-5%) to obtain the crude product, which was then purified by thin-layer chromatography on silica gel plates (methanol / dichloromethane = 8%), and finally purified by silica gel column chromatography (methanol / dichloromethane = 0-5%) to obtain compound 16 (5.11 mg). MS m / z (ESI): 417.2 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.86 (s, 1H), 7.67 (d, J = 4.0Hz, 1H), 7.25–7.21 (m, 1H), 7.04–6.97(m,2H),6.82–6.80(m,2H),6.66–6.60(m,1H),6.55(d,J=8.0Hz,1H),6 .31(d,J=4.0Hz,1H),5.01(s,2H),3.93–3.87(m,3H),3.83(s,3H),3.07–2.96(m, 2H),2.76–2.67(m,1H),2.55–2.53(m,1H),2.24–2.14(m,1H),2.05–1.99(m,1H).

[0229] Example 3 (Compound 86)

[0230] Step 1: Synthesis of compound 86c

[0231] At -5 °C, triisopropylsilane (2.81 g, 17.84 mmol) was added to a solution of compounds 86a (1 g, 8.92 mmol) and 86b (1.39 g, 8.92 mmol) in acetonitrile (50 mL). The mixture was stirred at -5 °C for 0.5 hours, followed by the addition of trimethylsilyl trifluoromethanesulfonate (2.02 g, 8.92 mmol). The reaction mixture was stirred at -5 °C for another 1.5 hours. After the reaction was complete, the reaction solution was quenched with saturated sodium bicarbonate solution (20 mL), extracted with ethyl acetate (30 mL × 2), and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-5%) to give compound 86c (500 mg). MS m / z (ESI): 253.15 [M+1] + .

[0232] Step 2: Synthesis of compound 86d

[0233] Compound 86c (0.25 g, 0.99 mmol) was added to a mixture of acetone (5 mL) and dilute hydrochloric acid (2.0 N, 5 mL), and the reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the pH of the reaction solution was adjusted to 8 with saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane (20 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 0-5%) to give compound 86d (200 mg). MS m / z (ESI): 209.1 [M+1] + .

[0234] Step 3: Synthesis of compound 86e

[0235] At -78 °C, bis(trimethylsilylaminolithium) (1.0 M, 0.79 mL, 0.79 mmol) was added to a tetrahydrofuran (6 mL) solution of compound 86d (150 mg, 0.72 mmol) and N-phenylbis(trifluoromethanesulfonyl)imide (283 mg, 0.79 mmol). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was quenched with saturated ammonium chloride solution (10 mL), extracted with ethyl acetate (20 mL × 2), and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 0-1%) to give compound 86e (120.0 mg). MS m / z (ESI): 341.05 [M+1] + .

[0236] Step 4: Synthesis of Compound 86

[0237] Under nitrogen protection, compound 86e (35.0 mg, 0.10 mmol) was dissolved in a mixed solution of 1,4-dioxane and water (4.0 mL / 0.4 mL). Compound 86f (35.9 mg, 0.10 mmol), potassium phosphate (71.0 mg, 0.31 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium(II) chloride (7.5 mg, 0.010 mmol) were added sequentially to the mixture. The reaction mixture was stirred at 90 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini 5μm C18 150*21.2mm, 5μm; mobile phase: acetonitrile:water (0.1% formic acid); gradient: 30-70%; column temperature: 25℃; flow rate: 20mL / min; wavelength: 214nm) to obtain compound 86 (8.8mg). MS m / z (ESI): 414.2 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ10.90(s,1H),7.66(s,1H),7.38(s,1H),7.29–7.19(m,2H ),7.12(dd,J=7.2,2.0Hz,1H),5.59–5.39(m,1H),4.49–4.34(m,2H),4.26(dd,J=1 2.0,4.8Hz,1H),3.80(s,3H),3.74–3.64(m,1H),2.82–2.70(m,1H),2.56–2.52(m ,1H),2.41–2.19(m,4H),2.14–2.04(m,1H),2.03–1.92(m,2H),1.74–1.60(m,1H).

[0238] The following compounds can be synthesized using the methods described in the examples above.

[0239] Biological evaluation

[0240] Test Example 1. Evaluation of VAV1 degradation in Jurkat cells

[0241] 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 represents 1 nM < DC50 ≤ 1000 nM. The results are shown in Table 1.

[0242] Table 1

[0243] 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, in: X is CR x Or N; Ring A is selected from phenyl, 5-10 membered heterocyclic groups, and 5-10 membered heteroaryl groups; Ring B is selected from 5-10 membered cycloalkyl, phenyl, 5-20 membered heterocyclic and 5-20 membered heteroaryl; R x Selected from H, halogen, hydroxyl, cyano, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 1 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 3-6 cycloalkyl groups and 3-6 membered heterocyclic groups; Or R x And one of the R 1 The atoms bonded to it form C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, wherein the C 3- The 8-cyclic alkyl group and the 3-8-membered heterocyclic group are optionally selected from halogens, hydroxyl groups, oxo groups, and C-membered groups. 1-6 One or more substituents in the alkyl group are substituted; R 2 Selected from C 1-6 alkoxy, 5-20 membered heterocyclic, 5-20 membered heteroaryl or -TR 5 The 5-20 membered heterocyclic group and the 5-20 membered heteroaryl group are optionally surrounded by one or more R g replace; T is selected from C 1-6 Alkylene, -OC 1-6 Alkylene, C(O)-C 1-6 Alkylene and -NR T1 -C 1-6 Alkylene, the C 1-6 Alkylenes are optionally selected from halogens, hydroxyl groups, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 The substance is substituted by one or more substituents selected from hydroxyalkyl, cyano, and amino groups. R 5 It is a 5-10 membered heteroaryl or a 5-10 membered heterocyclic group, wherein the 5-10 membered heterocyclic group and the 5-10 membered heteroaryl group are optionally surrounded by one or more R g replace; 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, oxo, C 3-6 cycloalkyl groups and 3-6 membered heterocyclic groups; Or one of the R 1 And one of the R 3 The atoms bonded to it form C 5-10 Cycloalkyl or 5-10 membered heterocyclic group, wherein the C 5-10 Cycloalkyl groups and 5-10-membered heterocyclic groups are optionally selected from halogens, hydroxyl groups, oxo groups, and C-membered groups. 1-6 One or more substituents in the alkyl group are substituted; R g Selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, hydroxyl, cyano, amino, oxo, C 3-6 cycloalkyl groups and 3-6 membered heterocyclic groups; n is 0, 1, 2, 3, 4, 5, or 6; m can be 0, 1, 2, 3, or 4; The condition is that when both ring A and ring B are phenyl, one or more of the following conditions must be met: (1) X is N; (2) X is CR x R x And one of the R 1 The atoms bonded to it form C 3-8 cycloalkyl or 3-8 membered heterocyclic groups; (3) An R 1 And an R 3 The atoms bonded to it form C 5-10 Cycloalkyl or 5-10 membered heterocyclic groups; (4)R 2 It is an 11-20 membered heterocyclic group or an 11-20 membered heteroaryl group.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from 5-20 membered heterocyclic groups, 5-20 membered heteroaryl groups, or -TR 5 The 5-20 membered heterocyclic group and the 5-20 membered heteroaryl group are optionally surrounded by one or more R g Replacement; T, R 5 and R g As defined in claim 1.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is the compound of formula (IX): in, The ring C is a 5-10 membered cycloalkyl group or a 5-20 membered heterocyclic group; R 1a R 1b R 1c R 1d They may be the same or different, and each is independently selected from chemical bonds, H, halogens, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, hydroxyl, cyano, amino, C 3-6 cycloalkyl groups and 3-6 membered heterocyclic groups; R 2 R 3 X and m are as defined in claim 1 or 2; Preferably, Selected from For single or double bonds, R 2 R 3 And m 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 the compound of formula (I) is the compound of formula (II): in, Rings A and R 1 R 2 R 3 X, m, and n are as defined in claim 1, provided that when ring A is phenyl, one or more of the following conditions are satisfied: (1) X is N; (2) X is CR x R x And one of the R 1 The atoms bonded to it form C 3-8 cycloalkyl or 3-8 membered heterocyclic groups; (3) An R 1 And an R 3 The atoms bonded to it form C 5-10 Cycloalkyl or 5-10 membered heterocyclic groups; (4)R 2 It is an 11-20 membered heterocyclic group or an 11-20 membered heteroaryl group.

5. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein... Selected from Y 1 Y 3 Y 4 and Y 5 Whether the two are the same or different, and each is an independent CR 1 Or N; Y 2 Selected from O, S, NR 1 and C(R) 1 )2; Y 6 Y 7 Y 8 and Y 9 Whether the two are the same or different, and each is an independent CR 1 Or N; G 1 and G 2 They are the same or different, and each is independently C or N; It can be a single bond or a double bond; Ring D is a 5-6 membered heterocyclic group or a 5-6 membered heteroaryl group; R 1a R 1b R 1c R 1d and R 4 They may be the same or different, and each is independently selected from chemical bonds, H, halogens, and C. 1-6 Alkyl, C 1- 6-Hydroalkyl, C 1-6 Hydroxyalkyl, hydroxyl, cyano, amino, C 3-6 cycloalkyl groups and 3-6 membered heterocyclic groups; p is 0, 1, 2 or 3; The condition is that when Y 6 Y 7 Y 8 and Y 9 All are CR 1 At that time, one or more of the following conditions are met: (1) X is N; (2) X is CR x R x And one of the R 1 The atoms connected to it form a ring; (3) An R 1 And an R 3 The atoms connected to it form a ring; (4)R 2 It is an 11-20 membered heterocyclic group or an 11-20 membered heteroaryl group; Preferably, Selected from R 4 It can replace the H on NH; R 1 R 1a R 1b R 1c R 1d and R 4 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 3-6 cycloalkyl groups and 3-6 membered heterocyclic groups; s can be 0, 1, 2, or 3; p is 0, 1, 2 or 3; The condition is that when for At that time, one or more of the following conditions are met: (1) X is N; (2) X is CR x R x And one of the R 1 The atoms connected to it form a ring; (3) An R 1 And an R 3 The atoms connected to it form a ring; (4)R 2 It is an 11-20 membered heterocyclic group or an 11-20 membered heteroaryl group.

6. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (I) is a compound represented by formula (III), (IV), (V) and (VI): in, R 3 and R 4a 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 3-6 cycloalkyl groups and 3-6 membered heterocyclic groups; Or, R 3 and R 4a The atoms bonded to it form C 5-10 Cycloalkyl or 5-10 membered heterocyclic group, wherein the C 5-10 Cycloalkyl groups and 5-10-membered heterocyclic groups are optionally selected from halogens, hydroxyl groups, oxo groups, and C-membered groups. 1-6 One or more substituents in the alkyl group are substituted; q is 0, 1, or 2; R 1a R 1b R 1c R 1d R 2 Ring B, G 1 G 2 , ring D, R 4 X, m, and p are as defined in any one of claims 1-4.

7. The compound according to any one of claims 1, 2, 5 or 6, or a pharmaceutically acceptable salt thereof, wherein... Selected from: R 2 R 3 And m as defined in any one of claims 1, 2, 5 or 6.

8. The compound according to any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (I) is a compound represented by formula (V-1), formula (VII), or formula (VIII): in, L 1 Selected from C 1-6 Alkylene, aOC 1-6 Alkylene, aC 1-6 Alkylene-O-, a-NR L -C 1-6 Alkylene, aC 1-6 Alkylene-NR L -、aC(O)NR L -C 1-6 Alkylene and aC 1-6 Alkylene-NR L C(O)-, the a-terminus is connected to CR 3d On adjacent carbon atoms, the C 1-6 Alkylenes are optionally selected from halogens, hydroxyl groups, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 The substance is substituted by one or more substituents selected from hydroxyalkyl, cyano, and amino groups. L 2 Selected from C 1-6 Alkylene, bOC 1-6 Alkylene, bC 1-6 Alkylene-O-, b-NR L -C 1-6 Alkylene and bC 1-6 Alkylene-NR L -,b end is attached to the carbon atom adjacent to C(O), wherein C 1-6 Alkylenes are optionally selected from halogens, hydroxyl groups, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 The substance is substituted by one or more substituents selected from hydroxyalkyl, cyano, and amino groups. R L Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-6 cycloalkyl groups and 3-6 membered heterocyclic groups; R 3a R 3b R 3c and R 3d They may be the same or different, and each is independently selected from H, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, hydroxyl, cyano, amino, oxo, C 3-6 cycloalkyl groups and 3-6 membered heterocyclic groups; R 1a R 1b R 1c R 1d R 2 G 1 G 2 , ring D, R 4 X and q are as defined in any one of claims 1-7.

9. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein L 1 Selected from -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, aO-CH2-, a-CH2-O-, aO-CH2CH2-, a-CH2CH2-O-, a-NH-CH2CH2-, a-CH2CH2-NH-, a-NH-CH2-, a-CH2-NH-, aC(O)NH-CH2CH2-, aC(O)N(CH3)-CH2CH2-, a-CH2CH2-NHC(O) and a-CH2CH2-N(CH3)C(O), with the a-terminus connected to CR. 3d On adjacent carbon atoms; L 2 Selected from -CH2CH2-, -CH2CH2CH2-, aO-CH2-, a-CH2-O-, aO-CH2CH2-, a-CH2CH2-O-, a-NH-CH2CH2-, a-CH2CH2-NH-, a-NH-CH2-, and a-CH2-NH-, with the a-terminus connected to CR. 3d On adjacent carbon atoms.

10. The compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from: C 1-6 Alkoxy, R g Selected from H, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 1-6 Hydroxyalkyl; q can be 0, 1, or 2.

11. The compound according to any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein X is a CR x ;R x As defined in claim 1.

12. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-11, wherein: R 1 R 1a R 1b R 1c R 1d and R 4 They may be the same or different, and each is independently selected from H, halogens, and C. 1-6 alkyl.

13. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-12, wherein, R 3 R 3a R 3b R 3c and R 3d They may be the same or different, and each is independently selected from H, halogens, and C. 1-6 alkyl.

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

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

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

17. Use of the compound of any one of claims 1-15 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 16 in the preparation of a medicament for degrading VAV1 protein.

18. Use of the compound of any one of claims 1-15 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 16 in the preparation 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.

19. Use of the compound of any one of claims 1-15, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 16 in the preparation of a medicament for the prevention and / or treatment of diseases or conditions caused by or related to dysregulation of lymphocyte development or activity, preferably, said lymphocytes being T cells.

20. Use of the compound of any one of claims 1-15, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 16 in the preparation of 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; preferably, the autoimmune diseases 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, 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, and hepatitis.

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