Piperidinedione derivatives, processes for their preparation and uses thereof

Abstract

The present application relates to a kind of piperidinedione derivatives, its preparation method and the medical use of pharmaceutical composition containing the derivative. Specifically, the present application relates to a kind of piperidinedione derivatives shown in general formula (I), its preparation method and its pharmaceutically acceptable salt, and their purposes as therapeutic agent, especially as VAV1 degradation agent, wherein the definition of each substituent in general formula (I) is the same as the definition in the specification.

Description

Technical Field

[0001] This invention relates to a piperidine derivative, its preparation method, pharmaceutical compositions containing the derivative, and its use as a therapeutic agent, particularly as a VAV1 degrading agent. Background Technology

[0002] The VAV family, a group of signal transduction proteins, consists of phosphorylation-dependent GDP / GTP guanine nucleotide exchange factors (GEFs) and adaptor molecules of Rho subfamily GTPases. In vertebrates, this family comprises 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. Family members VAV2 and VAV3 are more widely expressed.

[0003] Studies have shown that VAV1 plays a crucial role in TCR-mediated activation and T cell effector function. VAV1 functions as a scaffold protein in the GEF-independent pathway. Lymph node T cells isolated from GEF-inactivated mice exhibited normal TCR-mediated calcium release and NFAT pathway activation in vitro. Conversely, transfection of human VAV1-deficient J.Vav1 T cells with a GEF-retaining N-terminal truncated mutant resulted in incomplete calcium release and NFAT pathway activation in vitro due to the inability to interact with phospholipase C-γ (PLCγ)1. 2+ VAV1 releases, binds to calmodulin, and activates the NFAT pathway. It regulates various cellular functions and signaling pathways in hematopoietic-derived cells (such as T cells and B cells, natural killer cells, and osteoclasts) by activating certain GTPases. Its functions include actin remodeling, F-actin polymerization, TCR aggregation, integrin-mediated cell adhesion activation, immune synapse formation between T cells and antigen-presenting cells (APCs), and chemokine-mediated cell migration. VAV1 also regulates cytoskeleton remodeling in B cells.

[0004] Inflammation is a physiological response of the immune system to damage and infection. In this process, the immune system signals and activates immune cells to repair damaged tissue and protect against infections from viruses, bacteria, and other pathogens. However, inappropriate activation can also lead to disease. Chronic inflammation is a major cause of several diseases, including rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and psoriasis. Although the rise of immunotherapy in recent years has made progress in treating these diseases, significant unmet medical needs remain.

[0005] Currently, treatment options for autoimmune diseases and chronic inflammatory diseases remain limited. Many drugs work by blocking single proteins (e.g., drugs targeting TNF or IL-17A) or signaling pathways (e.g., JAK inhibitors), but their efficacy is insufficient and they have certain side effects. Numerous pieces of evidence suggest that VAV1 is associated with autoimmune and chronic inflammatory diseases, supporting its potential as a therapeutic target.

[0006] Targeting VAV1 expression or function offers various therapeutic approaches. One approach, based on azathioprine activity, involves designing more specific thiopurine analogs to provide a new avenue for VAV1 / Rac1 pathway blockade, but this has not yet been tested in clinical trials. Another emerging approach utilizes the in vivo ubiquitin-proteasome system to target VAV1 protein degradation. PROTAC degraders need to be able to simultaneously bind to both the target protein and the E3 ubiquitin ligase via different binding pockets, leading to the ubiquitination of the target protein and its subsequent removal from the cell. While effective, this approach presents a challenge for VAV1, a protein lacking a clearly defined binding pocket. Molecular glue degraders can bind to the surface of the E3 ligase complex to promote polyubiquitination of novel protein substrates involved in disease development and ultimately proteasome degradation. Studies have shown that targeting VAV1 protein degradation using molecular glue technology can modulate T-cell and B-cell receptor-mediated activity, significantly reducing cytokine secretion both in vivo and in vitro. Cytokines are essential proteins for maintaining autoimmune diseases.

[0007] No new drugs targeting VAV1 that degrade molecular adhesives have been launched on the market. Currently, only one company is developing such drugs: Monte Rosa Therapeutics' MRT-6160, which is in Phase I clinical trials. Given its unique mechanism of action, it possesses strong innovation and practicality. Overall, this target has enormous market potential and a differentiated advantage, and there is still significant room for further research into the VAV1 target. Summary of the Invention

[0008] To address the aforementioned technical problems, the present invention provides a compound of general formula (I) or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically usable salts thereof:

[0009]

[0010] in:

[0011] L1 is selected from -C(=O)-, -C 0-4 Alkylene-, -O(C) 0-4 alkylene)-, -NR a (C 0-4 alkylene)-, -NR a C(=O)(C0-4 alkylene)- or -(C 0-4 alkylene C(=O)-, wherein the C 0-4 The alkylene group is optionally surrounded by one or more atoms selected from deuterium, halogen, hydroxyl, cyano, C. 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Substituents of haloalkyl groups;

[0012] R a Each is independently selected from hydrogen atoms or C atoms. 1-6 alkyl;

[0013] X and Y are each independently selected from CR b Or N;

[0014] R b Each is independently selected from hydrogen atom, halogen, hydroxyl group, cyano group, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 Alkoxy groups may optionally be further divided by one or more groups selected from halogen, hydroxyl, cyano, or C. 1-6 Substituents of alkoxy groups;

[0015] R 1 The group is selected from 3-12-membered heterocyclic groups, 5-10-membered heteroaryl groups, or 8-10-membered fused rings, wherein the 3-12-membered heterocyclic group, 5-10-membered heteroaryl group, or 8-10-membered fused ring is optionally further selected from one or more groups selected from =O, halogen, hydroxyl, cyano, C 1-6 Alkyl or C 1-6 Substituents of alkoxy groups;

[0016] R 6a and R 6b Each is independently selected from hydrogen atom, deuterium atom, hydroxyl group, halogen, nitro group, cyano group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-10 Aryl, 5-6 quinone heteroaryl, -SF5, wherein the C 2-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-10 aryl, 5-6 heteroaryl, optionally further selected by one or more groups selected from hydroxyl, halogen, nitro, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-10 Substituted by aryl or 5-6 heteroaryl substituents;

[0017] R 7 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkyl groups;

[0018] W is selected from:

[0019] 1) 3-12 heterocyclic group, C 3-8 Cycloalkyl, 5-10-membered heteroaryl, or 8-10-membered bicyclic fused ring, wherein the 8-10-membered bicyclic fused ring is preferably a fused ring of aryl or heteroaryl with a monocyclic heterocyclic group or a monocyclic cycloalkyl group, wherein the 3-12-membered heterocyclic group, C 3-8 Cycloalkyl, 5-10-membered heteroaryl, or 8-10-membered fused ring optionally further selected from one or more of =O, deuterium, halogen, hydroxyl, cyano, SF5, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Substituents of haloalkyl groups;

[0020] 2) Where “-*” indicates that the group is related to the general formula (I) Connection sites;

[0021] This indicates that the group is related to the general formula (I). Connection sites;

[0022] L2 is selected from -O(C 0-4 alkylene)-, -NR j (C 0-4 alkylene)-, -NR j C(=O)(C 0-4 alkylene)- or -(C 0-4 alkylene C(=O)-, wherein the C 0-4 The alkylene group is optionally surrounded by one or more atoms selected from deuterium, halogen, hydroxyl, cyano, C. 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Substituents of haloalkyl groups;

[0023] R j Each is independently selected from hydrogen atoms or C atoms. 1-6 alkyl;

[0024] R 2Selected from hydrogen atom, deuterium atom, hydroxyl group, halogen, cyano group, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 Alkoxy groups may optionally be further divided by one or more groups selected from halogen, hydroxyl, cyano, or C. 1-6 Substituents of alkoxy groups;

[0025] R 3 R 4 and R 5 Each is independently selected from hydrogen atom, deuterium atom, hydroxyl group, cyano group, C 1-6 Alkyl or C 1-6 Alkoxy;

[0026] 3) Where “-*” indicates that the group is related to the general formula (I) Connection sites; This indicates that the group is related to the general formula (I). Connection sites;

[0027] R 8 Selected from hydrogen atom, deuterium atom, hydroxyl group, halogen, cyano group, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 Alkoxy groups may optionally be further divided by one or more groups selected from halogen, hydroxyl, cyano, or C. 1-6 Substituents of alkoxy groups;

[0028] R 9 R 10 and R 11 Each is independently selected from hydrogen atom, deuterium atom, hydroxyl group, cyano group, C 1-6 Alkyl or C 1-6 Alkoxy;

[0029] And / or, R 9 and R 7 R 8 and R 6a R 11 and R 6b Each of the atoms independently forms a 5-12 membered heterocyclic group or a 5-6 membered heteroaryl group with the atoms to which it is attached, wherein the 5-12 membered heterocyclic group or the 5-6 membered heteroaryl group is optionally further composed of one or more atoms selected from =O, deuterium, halogen, hydroxyl, cyano, SF5, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Substituents of haloalkyl groups;

[0030] The condition is that when W is At that time, R 9 and R 7 R 8 and R 6a R 11 and R 6b At least one of the three groups, together with the atoms it is attached to, forms a 5-12 membered heterocyclic group or a 5-6 membered heteroaryl group, wherein the 5-12 membered heterocyclic group or the 5-6 membered heteroaryl group is optionally further composed of one or more atoms selected from =O, deuterium, halogen, hydroxyl, cyano, SF5, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 The alkyl halogroup is substituted by a substituent.

[0031] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer, deuterated product or a pharmaceutically acceptable salt thereof, wherein the compound of general formula (II) or a stereoisomer, tautomer, deuterated product or a pharmaceutically acceptable salt thereof is:

[0032]

[0033] Among them, ring A is selected from 3-12 membered heterocyclic groups, C 3-8 Cycloalkyl, 5-10-membered heteroaryl or 8-10-membered bicyclic fused ring; wherein the bicyclic fused ring is preferably a fused ring of aryl or heteroaryl with monocyclic heterocyclic or monocyclic cycloalkyl;

[0034] R e Whether the groups are the same or different, they are each independently selected from deuterium atoms, halogens, hydroxyl groups, cyano groups, SF5, and C. 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkyl groups;

[0035] And / or, two Rs e It forms a -C (=O) with the same carbon atom it is attached to;

[0036] m can be 0, 1, 2, 3, or 4;

[0037] L1, R 1 R 6a R 6b R 7 The definitions of X or Y are as described in general formula (I).

[0038] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer, deuterated product or a pharmaceutically acceptable salt thereof, wherein the compound of general formula (III) or a stereoisomer, tautomer, deuterated product or a pharmaceutically acceptable salt thereof is:

[0039]

[0040] L2 is selected from -O- or -NR. j -;

[0041] R j Selected from hydrogen atoms or C 1-6 alkyl;

[0042] R 2 Selected from hydrogen atom, deuterium atom, hydroxyl group, halogen, cyano group, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 Alkoxy groups may optionally be further divided by one or more groups selected from halogen, hydroxyl, cyano, or C. 1-6 Substituents of alkoxy groups;

[0043] R 3 R 4 and R 5 Each is independently selected from hydrogen atom, deuterium atom, hydroxyl group, cyano group, C 1-6 Alkyl or C 1-6 Alkoxy;

[0044] L1, R 1 R 6a R 6b R 7 The definitions of X or Y are as described in general formula (I).

[0045] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein the compound is of general formula (IV-1), (IV-2) or (IV-3) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof:

[0046]

[0047] Among them, ring B, ring C and ring D are each independently selected from 5-12 membered heterocyclic groups or 5-6 membered heteroaryl groups;

[0048] R f R g and R h Each is independently selected from halogen, hydroxyl, cyano, SF5, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkyl groups;

[0049] And / or, two Rs f It forms a -C (=O) with the same carbon atom it is attached to;

[0050] And / or, two Rs g It forms a -C (=O) with the same carbon atom it is attached to;

[0051] And / or, two Rs h It forms a -C (=O) with the same carbon atom it is attached to;

[0052] n is 0, 1, 2, 3 or 4;

[0053] p is 0, 1, 2, 3 or 4;

[0054] q can be 0, 1, 2, 3, or 4;

[0055] R 8 Selected from hydrogen atom, deuterium atom, hydroxyl group, halogen, cyano group, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 Alkoxy groups may optionally be further divided by one or more groups selected from halogen, hydroxyl, cyano, or C. 1-6 Substituents of alkoxy groups;

[0056] R 9 R 10 and R 11 Each is independently selected from hydrogen atom, deuterium atom, hydroxyl group, cyano group, C 1-6 Alkyl or C 1-6 Alkoxy;

[0057] L1, R 1 R 6a R 6b R 7 The definitions of X or Y are as described in general formula (I).

[0058] A preferred embodiment of the present invention is a compound of general formula (I) or (II) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein ring A is selected from 3-8 membered heterocyclic groups, C 3-6 Cycloalkyl, 5-10-membered heteroaryl or 8-10-membered bicyclic fused ring, wherein the 8-10-membered bicyclic fused ring is preferably a fused ring of aryl and monocyclic heterocyclic group;

[0059] R e Whether the groups are the same or different, they are each independently selected from deuterium, halogen, hydroxyl, cyano, SF5, methyl, methoxy or trifluoromethoxy;

[0060] And / or, two Rs e It forms a -C (=O) with the same carbon atom it is attached to;

[0061] m can be 0, 1, 2, 3, or 4.

[0062] A preferred embodiment of the present invention is a compound of formula (I) or (II) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein... Selected from the following groups:

[0063]

[0064] X1 is selected from halogens, preferably chlorine.

[0065] A preferred embodiment of the present invention is a compound of general formula (I) or (III) or a stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt thereof, wherein L2 is selected from -O- or -NH-.

[0066] A preferred embodiment of the present invention is a compound of formula (IV-1), (IV-2) or (IV-3) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein ring B is selected from 5-8 membered heterocyclic groups, and R... f Selected from halogens, hydroxyl groups, cyano groups, SF5, methyl groups, methoxy groups, or trifluoromethoxy groups;

[0067] And / or, two Rs f It forms a -C (=O) with the same carbon atom it is attached to.

[0068] A preferred embodiment of the present invention is a compound of formula (IV-1), (IV-2) or (IV-3) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein ring C is selected from 6-8 membered heterocyclic groups, and R... g Selected from halogens, hydroxyl groups, cyano groups, SF5, methyl groups, methoxy groups, or trifluoromethoxy groups;

[0069] And / or, two Rs g It forms a -C (=O) with the same carbon atom it is attached to.

[0070] A preferred embodiment of the present invention is a compound of formula (IV-1), (IV-2) or (IV-3) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein ring D is selected from 6-8 membered heterocyclic groups, and R... h Selected from halogens, hydroxyl groups, cyano groups, SF5, methyl groups, methoxy groups, or trifluoromethoxy groups;

[0071] And / or, two Rs h It forms a -C (=O) with the same carbon atom it is attached to.

[0072] A preferred embodiment of the present invention is a compound of formula (I) or (III) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein R2 Selected from halogens, preferably chlorine.

[0073] A preferred embodiment of the present invention is a compound of formula (I) or (III) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein R 3 R 4 and R 5 It is a hydrogen atom.

[0074] A preferred embodiment of the present invention is a compound of formula (I), (IV-1), (IV-2) or (IV-3) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein R 8 Selected from halogens, preferably chlorine.

[0075] A preferred embodiment of the present invention is a compound of formula (I), (IV-1), (IV-2) or (IV-3) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein R 9 R 10 and R 11 It is a hydrogen atom.

[0076] A preferred embodiment of the present invention is a compound of formula (I), (II), (III), (IV-1), (IV-2) or (IV-3) or a stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt thereof, wherein L1 is selected from the bond.

[0077] A preferred embodiment of the present invention is a compound of formula (I), (II), (III), (IV-1), (IV-2) or (IV-3) or a stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt thereof, wherein R 1 The group is selected from 3-12-membered heterocyclic groups, wherein the 3-12-membered heterocyclic group is optionally further substituted by one or more substituents selected from =O, halogen, hydroxyl, cyano, methyl or methoxy.

[0078] A preferred embodiment of the present invention is a compound of formula (I), (II), (III), (IV-1), (IV-2) or (IV-3) or a stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt thereof, wherein R 1 for

[0079] In a preferred embodiment of the present invention, the compounds of the general formula are selected from:

[0080]

[0081]

[0082] Or its stereoisomers, tautomers, deuterated derivatives, or medicinal salts thereof.

[0083] Note: If there is a difference between the drawn structure and the given name of the structure, the drawn structure will be given greater weight.

[0084] Furthermore, the present invention provides a pharmaceutical composition comprising an effective dose of a compound of general formula (I) or (II) or a stereoisomer, tautomer, deuterated compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or combination thereof.

[0085] The present invention provides the use of a compound of general formula (I), (II), (III), (IV-1), (IV-2) or (IV-3) or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a VAV1 degrading agent.

[0086] The present invention also provides the use of a compound of formula (I), (II), (III), (IV-1), (IV-2) or (IV-3) or a stereoisomer, tautomer, deuterated product or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating VAV1-mediated diseases; preferably, wherein the VAV1-mediated disease is an autoimmune disease or an inflammatory disease; more preferably, the autoimmune disease or inflammatory disease is selected from multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, and idiopathic dermatitis. Hashimoto's thyroiditis, myasthenia gravis, type I or II diabetes and related diseases, vasculitis, pernicious anemia, Sjögren's syndrome, uveitis, psoriasis, Graves' ophthalmopathy, alopecia areata, allergic asthma, atopic dermatitis, allergic rhinitis, conjunctivitis, allergic contact dermatitis, inflammatory bowel disease, Crohn's disease or ulcerative colitis, endogenous asthma, inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury, atherosclerosis, osteoarthritis, irritant contact dermatitis, eczematous dermatitis, seborrheic dermatitis, inflammatory eye disease, keratoconjunctivitis, myocarditis or hepatitis.

[0087] The present invention also provides the use of compounds of general formula (I), (II), (III), (IV-1), (IV-2) or (IV-3) or their stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of treatments for autoimmune diseases or inflammatory diseases; preferably, wherein the autoimmune diseases or inflammatory diseases are selected from multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, idiopathic dermatitis, Hashimoto's thyroiditis, myasthenia gravis, type I thyroiditis, etc. Or type II diabetes and related diseases, vasculitis, pernicious anemia, Sjögren's syndrome, uveitis, psoriasis, Graves' ophthalmopathy, alopecia areata, allergic asthma, atopic dermatitis, allergic rhinitis, conjunctivitis, allergic contact dermatitis, inflammatory bowel disease, Crohn's disease or ulcerative colitis, endogenous asthma, inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury, atherosclerosis, osteoarthritis, irritant contact dermatitis, eczematous dermatitis, seborrheic dermatitis, inflammatory eye disease, keratoconjunctivitis, myocarditis or hepatitis.

[0088] Detailed description of the invention

[0089] Unless otherwise stated, some terms used in this specification and claims are defined as follows:

[0090] When "alkyl" is used as a group or part of a group, it refers to a group consisting of C1-C2. 20 Straight-chain or branched aliphatic hydrocarbon groups. Preferably C1-C. 10 Alkyl groups, more preferably C1-C6 alkyl groups. Examples of alkyl groups include, but are not limited to, 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, etc. The alkyl group may be substituted or unsubstituted.

[0091] “C α-β "Alkylene" refers to an aliphatic hydrocarbon group containing a minimum of α and a maximum of β carbon atoms in a branched or linear relationship. It has two residues derived from the same carbon atom or two different carbon atoms of the parent alkane by removing two hydrogen atoms, where α and β represent integers. The designation of C0 alkylene indicates a direct bond. 1-6Examples of alkylene compounds include, but are not limited to, methylene, 1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1,2-propylene, 1,3-propylene, 1,4-butylene, etc. α-β Alkylenes can be substituted or unsubstituted.

[0092] "Alkenyl" refers to an alkyl group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond. Representative examples include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl. C2-C4 alkenyl groups are preferred. Alkenyl groups may be optionally substituted or unsubstituted.

[0093] "Alkyne group" refers to an aliphatic hydrocarbon group containing a single carbon-carbon triple bond, which can be straight-chain or branched. C2-C is preferred. 10 The alkynyl group is preferred, more preferably C2-C6 alkynyl, and most preferably C2-C4 alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl. The alkynyl group may be substituted or unsubstituted.

[0094] "Cycloalkyl" refers to a non-aromatic cyclic alkyl group in which one or more cyclic atoms are carbon atoms and the ring contains 0, 1 or more double bonds, including monocyclic, polycyclic, fused ring, bridged ring and spirocyclic, preferably having a 3 to 7 member monocyclic or a 5 to 18 member bicyclic or tricyclic.

[0095] Examples of "monocycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,

[0096] Monocyclic alkyl groups can be substituted or unsubstituted.

[0097] "Spirocycloalkyl" refers to a polycyclic group consisting of 5 to 18 quintiles, two or more cyclic structures, where the monocyclic rings share a carbon atom (called a spiro atom) with each other, containing 0, 1, or more double bonds within the rings, but without any ring having fully conjugated π electrons. Preferably, it is a 6 to 14 quintile group, more preferably a 7 to 10 quintile group. Based on the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified as monospiro, bispiro, or polyspirocycloalkyl groups, preferably monospiro and bispirocycloalkyl groups, and preferably 4 / 5, 4 / 4, 4 / 6, 3 / 6, 5 / 5, or 5 / 6 quintile groups. Non-limiting examples of "spirocycloalkyl" include, but are not limited to: spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[2.4]heptyl, Spirocycloalkyl groups can be substituted or unsubstituted.

[0098] "Fused cycloalkyl" refers to a 5- to 18-membered, all-carbon polycyclic group containing two or more cyclic structures sharing a pair of carbon atoms. One or more rings may contain 0, 1, or more double bonds, but none of the rings has fully conjugated π electrons. It is preferably a 6- to 14-membered aromatic system, more preferably a 6- to 10-membered system. 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-membered / 5-membered, 5-membered / 5-membered, or 5-membered / 6-membered bicyclic fused cycloalkyl. Non-limiting examples of "fused cycloalkyl" include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, decahydronaphthyl, tetradecahydrophenanthrene, etc. The fused cycloalkyl group can be substituted or unsubstituted.

[0099] "Bridged cycloalkyl" refers to an aromatic system with 5 to 18 members, containing two or more cyclic structures, sharing two non-directly connected carbon atoms, and one or more rings may contain 0, 1, or more double bonds, but none of the rings has fully conjugated π electrons. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to: (1s,4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-bicyclo[3.3.1]nonyl, bicyclo[2.2.2]octyl, (1r,5r)-bicyclo[3.3.2]decyl,

[0100] Bridged cycloalkyl groups can be substituted or unsubstituted.

[0101] The terms “heterocyclic group,” “heterocyclic alkyl group,” “heterocyclic,” or “heterocyclic” are used interchangeably in this application and all refer to a non-aromatic heterocyclic group in which one or more cyclic atoms are selected from nitrogen, oxygen, or S(O). r (where r is selected from 0, 1 or 2) heteroatoms, containing 0, 1 or more double bonds in the ring, including monocyclic, polycyclic, fused ring, bridged ring and spirocyclic, preferably having 3 to 8-membered monocyclic or 5 to 18-membered bicyclic or tricyclic, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and / or sulfur.

[0102] The heterocyclic group can be substituted or unsubstituted.

[0103] Examples of "monocyclic heterocyclic groups" include, but are not limited to, morpholino, oxetane, azabolane, thiomorpholino, tetrahydrofurano, tetrahydropyrano, 1,1-dioxo-thiomorpholino, piperidino, 2-oxo-piperidino, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazine-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperazine, hexahydropyrimidine,

[0104]

[0105] "Spirocyclone" refers to a polycyclic aromatic group with 5 to 18 members, two or more ring structures, in which the monocyclic rings share an atom with each other, and contains 0, 1 or more double bonds within the rings, but none of the rings has fully conjugated π electrons. One or more ring atoms are selected from nitrogen, oxygen or S(O). r (where r is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. Preferably, it is 6 to 14 membered, more preferably 7 to 10 membered. Spirocycloalkyl groups are classified into monospirocycloalkyl, bispirocycloalkyl or polyspirocycloalkyl groups according to the number of shared spiroatoms between rings, preferably monospirocycloalkyl and bispirocycloalkyl. More preferably, it is 3 / 6 membered, 4 / 4 membered, 4 / 5 membered, 4 / 6 membered, 5 / 5 membered, 5 / 6 membered or 6 / 6 membered monospirocycloalkyl. Non-limiting examples of "spirocycloalkyl" include, but are not limited to: 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[3.5]nonyl, 5-oxaspiro[2.4]heptyl,

[0106] "Densely fused cyclic groups" refer to polycyclic groups containing two or more ring structures that share a pair of atoms with each other. One or more rings may contain 0, 1, or more double bonds, but none of the rings have fully conjugated π electrons. One or more ring atoms are selected from nitrogen, oxygen, or S(O). r (where r is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting embodiments of "fused heterocyclic group" include, but are not limited to: octahydropyrrolo[3,4-c]pyrrol, octahydro-1H-isoindolyl, 3-azabicyclo[3.1.0]hexyl, octahydrobenzo[b][1,4]dioxin,

[0107] "Bridged heterocyclic group" refers to a polycyclic group with 5 to 18 members, containing two or more ring structures that share two atoms that are not directly connected. One or more rings may contain 0, 1 or more double bonds, but none of the rings have fully conjugated π electrons. One or more ring atoms are selected from nitrogen, oxygen or S(O). r (where r is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. Preferably, it is 6 to 14-membered, more preferably 7 to 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, and more preferably bicyclic or tricyclic. Non-limiting embodiments of "bridged heterocyclic groups" include, but are not limited to: 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl, 2-azabicyclo[3.3.2]decyl.

[0108] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be linked together in a fused manner. The term "aryl" includes monocyclic or bicyclic aryl groups, such as phenyl, naphthyl, and tetrahydronaphthyl aromatic groups. Preferably, the aryl group is C6-C. 10 Aryl, more preferably phenyl and naphthyl, most preferably naphthyl. The aryl group can be substituted or unsubstituted.

[0109] "Heteroaryl" refers to an aromatic 5- to 6-membered monocyclic or 8- to 10-membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and / or sulfur. Examples of "heteroaryl" compounds include, but are not limited to, furanyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiopheneyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrroleyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzo[m]dioxacyclopentenyl, benzo[thiophene], benzimidazolyl, indoleyl, isoyindolyl, 1,3-dioxo-isoindolyl, quinolinyl, indoleyl, benzo[isothiazolyl], benzo[oxazolyl], benzo[isothiazolyl], isothiazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, pyridyl, pyridine- 2(1H)-keto, pyrimidinyl, pyrazin-2(1H)-keto, pyrimidin-4(3H)-keto, pyrimidin-2(1H)-keto, pyridazin-3(2H)-keto, 1H-indolyl, 1H-benzo[d]imidazolyl, 1H-pyrrolo[2,3-c]pyridyl, 3H-imidazo[4,5-c]pyridyl, isoquinolinyl, quinazolinyl, 2H-isoindolyl, furan[3,2-b]pyridyl, furan[2,3-c]pyridyl, thieno[2,3-c]pyridyl, benzofuranyl, benzo[b]thienoyl, 1H-pyrrolo[3,2-b]pyridyl, 2H-pyrrolo[3,4-c]pyridyl

[0110] The heteroaryl group can be substituted or unsubstituted.

[0111] A "fused ring" refers to a polycyclic group in which two or more ring structures share a pair of atoms, wherein at least one ring has a fully conjugated π electron aromatic system, and one or more rings may contain 0, 1 or more double bonds, but at least one ring does not have a fully conjugated π electron aromatic system, wherein the ring atoms are selected from 0, 1 or more nitrogen, oxygen or S(O). r (where r is selected from 0, 1, or 2) heteroatoms, and the remaining ring atoms are carbon. The fused ring preferably comprises a bicyclic or tricyclic fused ring, wherein the bicyclic fused ring is preferably a fused ring of an aryl or heteroaryl group with a monocyclic heterocyclic group or a monocyclic cycloalkyl group. Preferably, it is 6 to 14 quinary, more preferably 8 to 10 quinary. Examples of "fused rings" include, but are not limited to:

[0112]

[0113] "Alkoxy" refers to an (alkyl-O-) group. Alkyl groups are defined in the relevant section of this document. C1-C6 alkoxy groups are preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, etc.

[0114] "Alkylthio" refers to a (alkyl-S-) group. Alkyl groups are defined in the relevant section of this document. C1-C6 alkylthio groups are preferred. Examples include, but are not limited to: methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-butylthio, etc.

[0115] "Nitro" refers to the -NO2 group.

[0116] "Hydroxy" refers to the -OH group.

[0117] "Halogens" refer to fluorine, chlorine, bromine, and iodine.

[0118] "Amino" refers to -NH2.

[0119] "Hydroxyamino group" refers to -NHOH.

[0120] “Cyano” refers to -CN.

[0121] "Benzyl" refers to -CH2-phenyl.

[0122] "Carboxyl group" refers to -C(=O)OH.

[0123] "Carboxylic acid ester group" refers to -C(=O)O-alkyl or -C(=O)O-cycloalkyl, where the definitions of alkyl and cycloalkyl are as described above.

[0124] “Hydroxyalkyl” refers to an alkyl group substituted with a hydroxyl group, where the definition of alkyl is as described above.

[0125] "Aminoalkyl" refers to an amino-substituted alkyl group, where the definition of alkyl is as described above.

[0126] "Halogenated alkyl" refers to halogen-substituted alkyl groups, where the definition of alkyl is as described above.

[0127] "Haloalkoxy" refers to halogen-substituted alkoxy groups, where the definition of alkoxy groups is as described above.

[0128] "DMSO" refers to dimethyl sulfoxide.

[0129] “BOC” refers to tert-butoxycarbonyl.

[0130] “Bn” refers to benzyl.

[0131] "THP" refers to 2-tetrahydropyranyl.

[0132] "TFA" refers to trifluoroacetic acid.

[0133] “Ts” refers to p-toluenesulfonyl group.

[0134] “Bn” refers to benzyl.

[0135] “SEM” refers to (trimethylsilyl)ethoxymethyl.

[0136] "Formyl group" refers to

[0137] A "leaving group," or simply a group, is an atom or functional group that breaks off from a larger molecule in a chemical reaction. It's a term used in nucleophilic substitution and elimination reactions. In a nucleophilic substitution reaction, the reactant attacked by the nucleophile is called the substrate, and the atom or group of atoms that breaks off with a pair of electrons from the substrate molecule is called the leaving group. Groups that readily accept electrons and have a strong ability to accept negative charges are desirable leaving groups. The smaller the pKa of the conjugate acid of the leaving group, the easier it is for the leaving group to break off from other molecules. This is because a smaller pKa means the leaving group doesn't need to bond with other atoms and has a stronger tendency to exist as an anion (or an electrically neutral leaving group). Common leaving groups include, but are not limited to, halogens, methanesulfonyl groups, -OTs, or -OH.

[0138] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, and more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0139] Unless otherwise specified, the terms "substitution" or "substituted" in this specification refer to the substitution of a group by one or more groups selected from the following: deuterium, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, haloalkoxy, hydroxyalkyl, carboxyl, carboxylic acid ester, SF5, =O, -OR 5 -C(=O)R 5 -C(=O)OR 5 -N(R) 6 )C(=O)R 7 -N(R) 6 )C(=O)OR 7 -NR 6 R 7 -C(=O)NR 6 R 7 -CH2NHC(=O)OR 5 -CH2NR 6 R 7 -S (=O) r NR 6 R 7 or -S(O) r R 5 The substituents are replaced;

[0140] R 5 Each is independently selected from alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally further selected from one or more of deuterium, hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR9 R 10 or -N(R) 9 )C(=O)R 10 The substituents are replaced;

[0141] R 6 and R 7 Each is independently selected from hydrogen atom, hydroxyl, alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl may optionally be further selected from one or more of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR 9 R 10 or -N(R) 9 )C(=O)R 10 The substituents are replaced;

[0142] Or, R 6 and R 7 The atoms bonded to them together form a structure containing one or more N, O, or S (=O). r The 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group is optionally further selected by one or more groups selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R 8 -C(=O)OR 8 -OC(=O)R 8 -NR 9 R 10 -C(=O)NR 9 R 10 -S(=O)2NR 9 R 10 or -N(R) 9 )C(=O)R 10 The substituents are replaced;

[0143] R 8 R 9 and R 10Each is independently selected from hydrogen atoms, alkyl, amino, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl may optionally be further substituted by one or more substituents selected from hydroxyl, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, carboxyl or carboxylic ester group;

[0144] r can be 0, 1, or 2 independently.

[0145] The compounds of this invention may contain asymmetric or chiral centers, and thus exist in different stereoisomer forms. It is contemplated that all stereoisomer forms of the compounds of this invention, including but not limited to diastereomers, enantiomers, atropisomers, and geometric (conformal) isomers, and mixtures thereof, such as racemic mixtures, are within the scope of this invention.

[0146] Unless otherwise stated, the structures described in this invention also include all isomers of this structure (e.g., diastereomers, enantiomers, and trans-isomers, and geometric (conformal) isomers; for example, R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers). Therefore, individual stereoisomers of the compounds of this invention, as well as mixtures of enantiomers, mixtures of diastereomers, and mixtures of geometric (conformal) isomers, are all within the scope of this invention.

[0147] "Medicinal salts" refer to certain salts of the above-mentioned compounds that retain their original biological activity and are suitable for medicinal use. Medicinal salts of compounds represented by general formula (I) can be metal salts or amine salts formed with suitable acids.

[0148] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs, along with other chemical components, such as physiologically pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and its biological activity. Detailed Implementation

[0149] The following embodiments are used to further describe the present invention, but these embodiments are not intended to limit the scope of the present invention.

[0150] Example

[0151] The examples provide preparation and structural identification data for representative compounds represented by formula (I). It must be noted that the following examples are illustrative of the invention and not intended to limit it. 1The 1H NMR spectra were obtained using a Bruker instrument (400 MHz), and chemical shifts are expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. 1 H NMR representation: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of doublet, dt = doublet of triplet. If the coupling constant is provided, the unit is Hz.

[0152] Mass spectrometry is performed using an LC / MS instrument, and the ionization method can be ESI or APCI.

[0153] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. 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.

[0154] Column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0155] In the following examples, all temperatures are in Celsius unless otherwise specified. Unless otherwise specified, all starting materials and reagents are commercially available or synthesized according to known methods. Commercially available materials and reagents are used directly without further purification. Unless otherwise specified, they are purchased from manufacturers including but not limited to Aldrich Chemical Company, ABCR GmbH & Co. KG, Acros Organics, Guangzan Chemical Technology Co., Ltd., and Jingyan Chemical Technology Co., Ltd.

[0156] CD3OD: Deuterated methanol.

[0157] CDCl3: Deuterated chloroform.

[0158] DMSO-d6: Deuterated dimethyl sulfoxide.

[0159] Argon atmosphere refers to a reaction flask connected to an argon gas balloon with a volume of approximately 1L.

[0160] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0161] The compounds were purified using silica gel column chromatography and reversed-phase column chromatography. The eluent system was selected from: A: petroleum ether and ethyl acetate; B: dichloromethane and methanol; C: dichloromethane: ethyl acetate; D: trifluoroacetic acid aqueous solution and acetonitrile. The volume ratio of the solvent varied depending on the polarity of the compound and could be adjusted by adding small amounts of acidic or basic reagents, such as acetic acid or triethylamine.

[0162] Example 1

[0163] 3-((2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)amino)piperidine-2,6-dione

[0164]

[0165] first step

[0166] 1-(3'-bromo-2'-chloro-[1,1'-biphenyl]-4-yl)pyridin-2(1H)-one

[0167] At room temperature, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (137.19 mg, 184.95 μmol) and potassium carbonate (765.68 mg, 5.55 mmol) were added sequentially to a solution of 1,3-dibromo-2-chlorobenzene 1a (500 mg, 1.85 mmol, commercially available) and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)pyridin-2(1H)-one 1b (824.37 mg, 2.77 mmol, commercially available) in 1,4-dioxane (5 mL) and water (0.5 mL). The reaction mixture was stirred at 80 °C for 16 hours under nitrogen protection. After the reaction was completed, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: system A) to obtain 1c (310 mg) of 1-(3'-bromo-2'-chloro-[1,1'-biphenyl]-4-yl)pyridin-2(1H)-one, with a yield of 46.5%.

[0168] MS m / z(ESI): 360.0 [M+1]

[0169] Step 2

[0170] 3-((2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)amino)piperidine-2,6-dione

[0171] Cesium carbonate (135.52 mg, 415.94 μmol) and (SP-4-1)-[1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylylene]dichloro(3-chloropyridine-KN)palladium (13.49 mg, 13.86 μmol) were added to a solution of 1,4-dioxane 1c (50 mg, 138.65 μmol) and 3-aminopiperidine-2,6-dione 1d (35.53 mg, 277.29 μmol) in 1,4-dioxane (2 mL). After the reaction was completed, the mixture was filtered, concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (Waters 3767 / Qda column: SunFire C18, 19*250mm, 10µm; mobile phase A: 0.1% FA / H2O, B: ACN; flow rate: 20ml / min; gradient: 35-45%; retention time: 8.8-9.8 min, 16 min) to obtain 3-((2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)amino)piperidin-2,6-dione 1 (3.64mg), yield 6.4%.

[0172] MS m / z(ESI): 408.2 [M+1]

[0173] 1 H NMR (400MHz, DMSO) δ10.95 (s, 1H), 7.73 (dd, J = 6.8, 1.6Hz, 1H), 7.56–7.46 (m ,5H),7.24(t,J=8.0Hz,1H),6.90(d,J=7.6Hz,1H),6.69(dd,J=7.6,1.2Hz,1 H),6.51(d,J=9.2Hz,1H),6.34(td,J=6.8,1.2Hz,1H),5.72(d,J=7.2Hz,1H) ,4.60–4.45(m,1H),2.91–2.78(m,1H),2.69–2.55(m,1H),2.22–2.02(m,2H).

[0174] Example 2

[0175] 3-(5-(4-(2-oxopiperidin-1-yl)phenyl)furan-2-yl)piperidine-2,6-dione

[0176]

[0177] first step

[0178] 1-(4-(furan-2-yl)phenyl)piperidin-2-one

[0179] 1-(4-iodophenyl)piperidin-2-one 2b (2 g, 6.64 mmol, commercially available) and 2-furanboronic acid 2a (1.11 g, 9.96 mmol, commercially available) were added to 1,4-dioxane (20 mL) and water (2 mL), followed by the addition of potassium carbonate (2.75 g, 19.93 mmol) and 1,1-di-tert-butylphosphinoferrocene dichloropalladium (434.21 mg, 664.18 μmol). The reaction mixture was heated to 90 °C under nitrogen protection and reacted for 16 hours. After the reaction was complete, the reaction solution was directly concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give 1-(4-(furan-2-yl)phenyl)piperidin-2-one 2c (1.3 g), with a yield of 81.1%.

[0180] MS m / z(ESI): 242.2 [M+1]

[0181] Step 2

[0182] 1-(4-(5-bromofuran-2-yl)phenyl)piperidin-2-one

[0183] 1-(4-(furan-2-yl)phenyl)piperidin-2-one 2c (1.0 g, 4.14 mmol) was added to N,N-dimethylformamide (6 mL), followed by N-bromosuccinimide (885.16 mg, 4.97 mmol). The reaction mixture was reacted at room temperature under nitrogen protection for 16 hours. After the reaction was complete, the reaction solution was quenched with an aqueous sodium sulfite solution (50 mL), extracted with dichloromethane (30 mL × 3), and the combined organic phases were washed with saturated sodium chloride (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to give 1-(4-(5-bromofuran-2-yl)phenyl)piperidin-2-one 2d (520 mg), yield 39.2%.

[0184] MS m / z(ESI): 320.1 [M+1]

[0185] Step 3

[0186] 1-(4-(5-(2,6-bis(benzyloxy)pyridin-3-yl)furan-2-yl)phenyl)piperidin-2-one

[0187] 1-(4-(5-bromofuran-2-yl)phenyl)piperidin-2-one 2d (500 mg, 1.56 mmol) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridine 2e (977.50 mg, 2.34 mmol) were dissolved in 1,4-dioxane (5 mL) and water (0.5 mL), followed by the addition of potassium carbonate (647.49 mg, 4.68 mmol) and 1,1-di-tert-butylphosphine-ferrocene-palladium chloride (102.09 mg, 156.16 μmol). Under nitrogen protection, the reaction mixture was heated to 90 °C and the reaction was continued for 16 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, quenched with water (30 mL), extracted with ethyl acetate (30 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system B) to give 1-(4-(5-(2,6-bis(benzyloxy)pyridin-3-yl)furan-2-yl)phenyl)piperidin-2-one 2f (510 mg), yield 61.6%.

[0188] MS m / z(ESI): 531.2 [M+1]

[0189] Step 4

[0190] 3-(5-(4-(2-oxopiperidin-1-yl)phenyl)furan-2-yl)piperidine-2,6-dione

[0191] Palladium on carbon (100 mg, 10%) was added to a 5 mL solution of 1-(4-(5-(2,6-bis(benzyloxy)pyridin-3-yl)furan-2-yl)phenyl)piperidin-2-one 2f (100 mg, 0.19 mmol). The reaction mixture was stirred at room temperature under a hydrogen atmosphere (30 psi) for 1.5 h. After the reaction was complete, palladium on carbon was filtered, the filter cake was washed with dichloromethane, the filtrates were combined and concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (Waters 3767 / QDA column: SunFire Sunfire C18, 19*250mm, 10µm; mobile phase A: 10mmol / L; A: 0.1% FA / H2O; B: acetonitrile; flow rate: 20mL / min; gradient: 55-65%; retention time: 9min, 17min) to give 3-(5-(4-(2-oxopiridin-1-yl)phenyl)furan-2-yl)piperidin-2,6-dione 2 (10.29mg, yield 15.5%).

[0192] MS m / z(ESI): 353.1 [M+1]

[0193] 1H NMR (400MHz, DMSO) δ10.92(s,1H),7.64(d,J=8.0Hz,2H),7.32(d,J=8.0Hz,2H),6.88(d,J=4.0Hz,1H),6.43(d,J=4.0Hz,1H),4.1 3-4.09(m,1H),3.63-3.60(m,2H),2.72-2.65(m,1H),2.59-2.54(m,1H),2.41-2.38(m,2H),2.34–2.13(m,2H),1.86-1.83(m,4H).

[0194] Example 3

[0195] 3-(5-(4-(2-oxopiperidin-1-yl)phenyl)thiophen-2-yl)piperidine-2,6-dione

[0196]

[0197]

[0198] first step

[0199] 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidin-2-one

[0200] 1-(4-iodophenyl)piperidin-2-one 3a (2 g, 6.64 mmol, commercially available) was added to 1,4-dioxane (20 mL), followed by 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborane) (4.64 g, 9.96 mmol, commercially available), potassium acetate (1.95 g, 19.93 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (492.68 mg, 664.18 μmol). The reaction mixture was heated to 90 °C under nitrogen protection and the reaction was continued for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, quenched with water (50 mL), extracted with ethyl acetate (50 mL × 3), and the combined organic phases were washed with saturated sodium chloride (80 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)piperidin-2-one 3b (1.1 g), yield 55.0%.

[0201] MS m / z(ESI): 302.0 [M+1]

[0202] Step 2

[0203] 1-(4-(thiophen-2-yl)phenyl)piperidin-2-one

[0204] 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)piperidin-2-one 3b (886.74 mg, 2.94 mmol) and 2-bromothiophene 3c (400 mg, 2.45 mmol) were dissolved in 1,4-dioxane (5 mL) and water (0.5 mL), followed by the addition of potassium carbonate (1.02 g, 7.36 mmol) and 1,1-di-tert-butylphosphine-ferrocene-palladium chloride (159.90 mg, 245.35 μmol). The reaction mixture was heated to 90 °C under nitrogen protection and the reaction was continued for 16 hours. After the reaction was complete, the mixture was cooled to room temperature. The reaction mixture was quenched with water (20 mL), extracted with ethyl acetate (30 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to give 1-(4-(thiophene-2-yl)phenyl)piperidin-2-one 3d (480 mg), yield 76.0%. MS m / z (ESI): 258.1 [M+1]

[0205] Step 3

[0206] 1-(4-(5-bromothiophen-2-yl)phenyl)piperidin-2-one

[0207] 1-(4-(thiophen-2-yl)phenyl)piperidin-2-one 3d (550 mg, 2.14 mmol) was added to tetrahydrofuran (15 mL), followed by the addition of N-bromosuccinimide (418.41 mg, 2.35 mmol). The reaction mixture was stirred at room temperature under nitrogen protection for 4 hours. After the reaction was complete, the reaction mixture was quenched with an aqueous sodium sulfite solution, extracted with dichloromethane (30 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to give 1-(4-(5-bromothiophen-2-yl)phenyl)piperidin-2-one 3e (480 mg), yield 66.8%.

[0208] MS m / z(ESI): 336.0 [M+1]

[0209] Step 4

[0210] 1-(4-(5-(2,6-bis(benzyloxy)pyridin-3-yl)thiophen-2-yl)phenyl)piperidin-2-one

[0211] 1-(4-(5-bromothiophene-2-yl)phenyl)piperidin-2-one 3e (300 mg, 892.20 μmol) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridine 2e (446.78 mg, 1.07 mmol) were dissolved in 1,4-dioxane (3 mL) and water (0.3 mL), followed by the addition of potassium carbonate (369.92 mg, 2.68 mmol) and 1,1-di-tert-butylphosphine-ferrocene-palladium chloride (58.15 mg, 89.22 μmol). The reaction mixture was heated to 90 °C under nitrogen protection and the reaction was continued for 16 hours. After the reaction was complete, the mixture was cooled to room temperature. The reaction mixture was quenched with water (20 mL), extracted with ethyl acetate (30 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system B) to give 1-(4-(5-(2,6-bis(benzyloxy)pyridin-3-yl)thiophen-2-yl)phenyl)piperidin-2-one 3f (180 mg), yield 36.9%.

[0212] MS m / z (ESI): 547.0 [M+1]

[0213] Step 5

[0214] 3-(5-(4-(2-oxopiperidin-1-yl)phenyl)thiophen-2-yl)piperidine-2,6-dione

[0215] 1-(4-(5-(2,6-bis(benzyloxy)pyridin-3-yl)thiophen-2-yl)phenyl)piperidin-2-one 3f (70 mg, 128.05 μmol) was added to methanol (1 mL) and tetrahydrofuran (1 mL), followed by the addition of palladium on carbon (108.86 mg, 896.32 μmol). The reaction mixture was heated to 40 °C under a hydrogen atmosphere (30 psi) and the reaction was continued for 24 hours. After the reaction was complete, the reaction mixture was filtered, the filter cake was washed with methanol, the filtrates were combined and concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (Waters 2767 / QDA column: SunFire Sunfire C18, 19*250mm, 10µm; mobile phase A: 0.1% FA / H2O, B: ACN; flow rate: 20ml / min; slope: 33-43%; retention time: 8.3-9.2min, 16min) to obtain 3-(5-(4-(2-oxopiridin-1-yl)phenyl)thiophene-2-yl)piperidin-2,6-dione 3 (2mg), yield 4.2%.

[0216] MS m / z(ESI): 369.2 [M+1]

[0217] 1H NMR (400MHz, DMSO) δ10.93(s,1H),7.62(t,J=8.0Hz,2H),7.37(d,J=3.6Hz,1H),7.32(d,J=8.0Hz,2H),7.00(d,J=3.6Hz,1H),4.24–4 .17(m,1H),3.63(t,J=5.6Hz,2H),2.73–2.66(m,1H),2.61–2.57(m,1H),2.41(t,J=6.0Hz,2H),2.32–2.19(m,2H),1.90–1.82(m,4H).

[0218] Biological evaluation

[0219] Test Example 1: Determination of VAV1 protein degradation by the compounds of the present invention

[0220] The following methods were used to determine the activity of the compounds of this invention against VAV1 protein degradation. Jurkat (Clone E6-1) cells were purchased from the Cell Resource Center of the Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and cultured in RPMI 1640 medium containing 10% fetal bovine serum, 100U penicillin, and 100μg / mL streptomycin. The Jurkat VAV1 Hibit stable cell line was constructed internally by Hisun Pharmaceuticals using Nano- The HiBiT Lytic Detection System (Promega, catalog number N3030) detects HiBiT signals to quantify VAV1 protein.

[0221] The experimental method was performed according to the kit instructions, and is briefly described below: The test compound was first dissolved in DMSO to prepare a 10 mM stock solution, which was then diluted with culture medium to prepare the test sample. The final concentration range of the compound was 10000 nM-1.52 nM. Cells in the logarithmic growth phase were seeded at a density of 30,000 cells per well into 96-well cell culture plates and cultured overnight at 37°C in an air incubator. The test compound was then added, and the cells were cultured for another 24 hours. After the culture was completed, 50 μL of Nano-120 solution was added to each well. HiBiT Lytic Reagent (using Nano- according to the kit instructions) HiBiT Lytic Buffer dilutes LGBiT Protein and Nano- The sample was prepared using HiBiT LyticSubstrate, shaken for 5 minutes, and then allowed to stand for 10 minutes. The luminescence values ​​of each well were then read using a microplate reader in Luminescence mode. The percentage inhibition rate of the compound at each concentration was calculated by comparing it with the control group (0.1% DMSO). Nonlinear regression analysis was then performed in GraphPad Prism 9 software using the logarithm of compound concentration versus inhibition rate to obtain the DC value of the compound in degrading VAV1 protein. 50 value.

[0222] Conclusion: The compounds of this invention are effective against DC degradation by VAV1 protein. 50 <100nM, exhibiting good degradation activity.

Claims

1. A compound of general formula (I) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof: in: L1 is selected from -C(=O)-, -C 0-4 Alkylene-, -O(C) 0-4 alkylene)-, -NR a (C 0-4 alkylene)-, -NR a C(=O)(C 0-4 alkylene)- or -(C 0-4 alkylene C(=O)-, wherein the C 0-4 The alkylene group is optionally surrounded by one or more atoms selected from deuterium, halogen, hydroxyl, cyano, C. 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Substituents of haloalkyl groups; R a Each is independently selected from hydrogen atoms or C atoms. 1-6 alkyl; X and Y are each independently selected from CR b Or N; R b Each is independently selected from hydrogen atom, halogen, hydroxyl group, cyano group, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 Alkoxy groups may optionally be further divided by one or more groups selected from halogen, hydroxyl, cyano, or C. 1-6 Substituents of alkoxy groups; R 1 The group is selected from 3-12-membered heterocyclic groups, 5-10-membered heteroaryl groups, or 8-10-membered fused rings, wherein the 3-12-membered heterocyclic group, 5-10-membered heteroaryl group, or 8-10-membered fused ring is optionally further selected from one or more groups selected from =O, halogen, hydroxyl, cyano, C 1-6 Alkyl or C 1-6 Substituents of alkoxy groups; R 6a and R 6b Each is independently selected from hydrogen atom, deuterium atom, hydroxyl group, halogen, nitro group, cyano group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-10 Aryl, 5-6 quinone heteroaryl, -SF5, wherein the C 2-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-10 aryl, 5-6 heteroaryl, optionally further selected by one or more groups selected from hydroxyl, halogen, nitro, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-10 Substituted by aryl or 5-6 heteroaryl substituents; R 7 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkyl groups; W is selected from: 1) 3-12 heterocyclic group, C 3-8 Cycloalkyl, 5-10-membered heteroaryl, or 8-10-membered bicyclic fused ring, wherein the 8-10-membered bicyclic fused ring is preferably a fused ring of aryl or heteroaryl with a monocyclic heterocyclic group or a monocyclic cycloalkyl group, wherein the 3-12-membered heterocyclic group, C 3-8 Cycloalkyl, 5-10-membered heteroaryl, or 8-10-membered fused ring optionally further selected from one or more of =O, deuterium, halogen, hydroxyl, cyano, SF5, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Substituents of haloalkyl groups; 2) Where "-*" indicates that the group is related to the general formula (I) Connection sites; This indicates that the group is related to the general formula (I). Connection sites; L2 is selected from -O(C 0-4 alkylene)-, -NR j (C 0-4 alkylene)-, -NR j C(=O)(C 0-4 alkylene)- or -(C 0-4 alkylene C(=O)-, wherein the C 0-4 The alkylene group is optionally surrounded by one or more atoms selected from deuterium, halogen, hydroxyl, cyano, C. 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Substituents of haloalkyl groups; R j Each is independently selected from hydrogen atoms or C atoms. 1-6 alkyl; R 2 Selected from hydrogen atom, deuterium atom, hydroxyl group, halogen, cyano group, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 Alkoxy groups may optionally be further divided by one or more groups selected from halogen, hydroxyl, cyano, or C. 1-6 Substituents of alkoxy groups; R 3 R 4 and R 5 Each is independently selected from hydrogen atom, deuterium atom, hydroxyl group, cyano group, C 1-6 Alkyl or C 1-6 Alkoxy; 3) Where "-*" indicates that the group is related to the general formula (I) Connection sites; This indicates that the group is related to the general formula (I). Connection sites; R 8 Selected from hydrogen atom, deuterium atom, hydroxyl group, halogen, cyano group, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 Alkoxy groups may optionally be further divided by one or more groups selected from halogen, hydroxyl, cyano, or C. 1-6 Substituents of alkoxy groups; R 9 R 10 and R 11 Each is independently selected from hydrogen atom, deuterium atom, hydroxyl group, cyano group, C 1-6 Alkyl or C 1-6 Alkoxy; And / or, R 9 and R 7 R 8 and R 6a R 11 and R 6b Each of the atoms independently forms a 5-12 membered heterocyclic group or a 5-6 membered heteroaryl group with the atoms to which it is attached, wherein the 5-12 membered heterocyclic group or the 5-6 membered heteroaryl group is optionally further composed of one or more atoms selected from =O, deuterium, halogen, hydroxyl, cyano, SF5, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Substituents of haloalkyl groups; The condition is that when W is At that time, R 9 and R 7 R 8 and R 6a R 11 and R 6b At least one of the three groups, together with the atoms it is attached to, forms a 5-12 membered heterocyclic group or a 5-6 membered heteroaryl group, wherein the 5-12 membered heterocyclic group or the 5-6 membered heteroaryl group is optionally further composed of one or more atoms selected from =O, deuterium, halogen, hydroxyl, cyano, SF5, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 The alkyl halogroup is substituted by a substituent.

2. The compound according to claim 1, or its stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, wherein it is the compound according to general formula (II), or its stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof: in, Ring A is selected from 3-12 membered heterocyclic groups, C 3-8 Cycloalkyl, 5-10-membered heteroaryl or 8-10-membered bicyclic fused ring; wherein the bicyclic fused ring is preferably a fused ring of aryl or heteroaryl with monocyclic heterocyclic or monocyclic cycloalkyl; R e Whether the groups are the same or different, they are each independently selected from deuterium atoms, halogens, hydroxyl groups, cyano groups, SF5, and C. 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkyl groups; And / or, two Rs e It forms a -C (=O) with the same carbon atom it is attached to; m can be 0, 1, 2, 3, or 4; L1, R 1 R 6a R 6b R 7 The definitions of X or Y are as described in claim 1.

3. The compound according to claim 1, or its stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, wherein it is the compound according to general formula (III), or its stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof: in, L2 is selected from -O- or -NR j -; R j Selected from hydrogen atoms or C 1-6 alkyl; R 2 Selected from hydrogen atom, deuterium atom, hydroxyl group, halogen, cyano group, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 Alkoxy groups may optionally be further divided by one or more groups selected from halogen, hydroxyl, cyano, or C. 1-6 Substituents of alkoxy groups; R 3 R 4 and R 5 Each is independently selected from hydrogen atom, deuterium atom, hydroxyl group, cyano group, C 1-6 Alkyl or C 1-6 Alkoxy; L1, R 1 R 6a R 6b R 7 The definitions of X or Y are as described in claim 1.

4. The compound according to claim 1, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein the compound is a compound of general formula (IV-1), (IV-2), or (IV-3), or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof: in, Rings B, C, and D are each independently selected from 5-12 membered heterocyclic groups or 5-6 membered heteroaryl groups; R f R g and R h Each is independently selected from halogen, hydroxyl, cyano, SF5, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkyl groups; And / or, two Rs f It forms a -C (=O) with the same carbon atom it is attached to; And / or, two Rs g It forms a -C (=O) with the same carbon atom it is attached to; And / or, two Rs h It forms a -C (=O) with the same carbon atom it is attached to; n is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; q can be 0, 1, 2, 3, or 4; R 8 Selected from hydrogen atom, deuterium atom, hydroxyl group, halogen, cyano group, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 Alkoxy groups may optionally be further divided by one or more groups selected from halogen, hydroxyl, cyano, or C. 1-6 Substituents of alkoxy groups; R 9 R 10 and R 11 Each is independently selected from hydrogen atom, deuterium atom, hydroxyl group, cyano group, C 1-6 Alkyl or C 1-6 Alkoxy; L1, R 1 R 6a R 6b R 7 The definitions of X or Y are as described in claim 1.

5. The compound according to claim 2, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein ring A is selected from 3-8 membered heterocyclic groups, C 3-6 Cycloalkyl, 5-10-membered heteroaryl or 8-10-membered bicyclic fused ring, wherein the 8-10-membered bicyclic fused ring is preferably a fused ring of aryl and monocyclic heterocyclic group; R e Whether the groups are the same or different, they are each independently selected from deuterium, halogen, hydroxyl, cyano, SF5, methyl, methoxy or trifluoromethoxy; And / or, two Rs e It forms a -C (=O) with the same carbon atom it is attached to; m can be 0, 1, 2, 3, or 4.

6. The compound according to claim 2 or 5, or a stereoisomer, tautomer, deuterated product, or pharmaceutically acceptable salt thereof, wherein... Selected from the following groups: X1 is selected from halogens, preferably chlorine.

7. The compound according to claim 3, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein, L2 is selected from -O- or -NH-.

8. The compound according to claim 4, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein, Ring B is selected from 5-8 membered heterocyclic groups, R f Selected from halogens, hydroxyl groups, cyano groups, SF5, methyl groups, methoxy groups, or trifluoromethoxy groups; And / or, two Rs f It forms a -C (=O) with the same carbon atom it is attached to.

9. The compound according to claim 4, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein, Cycle C is selected from 6-8 membered heterocyclic groups, R g Selected from halogens, hydroxyl groups, cyano groups, SF5, methyl groups, methoxy groups, or trifluoromethoxy groups; And / or, two Rs g It forms a -C (=O) with the same carbon atom it is attached to.

10. The compound according to claim 4, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein, Ring D is selected from 6-8 membered heterocyclic groups, R h Selected from halogens, hydroxyl groups, cyano groups, SF5, methyl groups, methoxy groups, or trifluoromethoxy groups; And / or, two Rs h It forms a -C (=O) with the same carbon atom it is attached to.

11. The compound according to claim 1 or 3, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein, R 2 Selected from halogens, preferably chlorine.

12. The compound according to claim 1 or 3, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein, R 3 R 4 and R 5 It is a hydrogen atom.

13. The compound according to claim 1 or 4, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein, R 8 Selected from halogens, preferably chlorine.

14. The compound according to claim 1 or 4, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein, R 9 R 10 and R 11 It is a hydrogen atom.

15. The compound according to any one of claims 1-14, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein, L1 is selected from the key.

16. The compound according to any one of claims 1-15, or a stereoisomer, tautomer, deuterated product, or pharmaceutically acceptable salt thereof, wherein, R 1 The group is selected from 3-12-membered heterocyclic groups, wherein the 3-12-membered heterocyclic group is optionally further substituted by one or more substituents selected from =O, halogen, hydroxyl, cyano, methyl or methoxy.

17. The compound according to any one of claims 1-16, or a stereoisomer, tautomer, deuterated product, or pharmaceutically acceptable salt thereof, wherein, R 1 for 18. The compound according to any one of claims 1-17, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, wherein the compound is:

19. A pharmaceutical composition comprising an effective dose of the compound according to any one of claims 1-18 or its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, excipient or combination thereof.

20. Use of the compound or its stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, according to any one of claims 1-18, or the pharmaceutical composition according to claim 19, in the preparation of a VAV1 degrading agent.

21. Use of the compound or its stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, according to any one of claims 1-18, or the pharmaceutical composition according to claim 19, in the preparation of a medicament for treating VAV1-mediated diseases; preferably, wherein the VAV1-mediated disease is an autoimmune disease or an inflammatory disease; more preferably, the autoimmune disease or inflammatory disease is selected from multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, idiopathic dermatitis, Hashimoto's thyroiditis, severe thyroiditis, etc. Myasthenia gravis, type I or II diabetes and related diseases, vasculitis, pernicious anemia, Sjögren's syndrome, uveitis, psoriasis, Graves' ophthalmopathy, alopecia areata, allergic asthma, atopic dermatitis, allergic rhinitis, conjunctivitis, allergic contact dermatitis, inflammatory bowel disease, Crohn's disease or ulcerative colitis, endogenous asthma, inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury, atherosclerosis, osteoarthritis, irritant contact dermatitis, eczematous dermatitis, seborrheic dermatitis, inflammatory eye disease, keratoconjunctivitis, myocarditis or hepatitis.

22. The use of the compound or its stereoisomer, tautomer, deuterated form or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 19, in the preparation of a treatment for an autoimmune disease or inflammatory disease; preferably, wherein the autoimmune disease or inflammatory disease is selected from multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, idiopathic dermatitis, Hashimoto's thyroiditis, myasthenia gravis, type I or type II diabetes and related diseases, vasculitis, pernicious anemia, Sjögren's syndrome, uveitis, psoriasis, Graves' ophthalmopathy, alopecia areata, allergic asthma, atopic dermatitis, allergic rhinitis, conjunctivitis, allergic contact dermatitis, inflammatory bowel disease, Crohn's disease or ulcerative colitis, endogenous asthma, inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury, atherosclerosis, osteoarthritis, irritant contact dermatitis, eczematous dermatitis, seborrheic dermatitis, inflammatory eye disease, keratoconjunctivitis, myocarditis or hepatitis.

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