Substituted aromatic derivative, and preparation method therefor and use thereof

Abstract

The present invention relates to a substituted aromatic derivative, a preparation method therefor and the use of a pharmaceutical composition comprising the derivative in medicine. Specifically, the present invention relates to a substituted aromatic derivative represented by general formula (I), a preparation method therefor and a pharmaceutically acceptable salt thereof, and the use thereof as therapeutic agents, particularly as VAV1 degraders, wherein the definitions of the substituents in general formula (I) are the same as those defined in the description.

Description

Substituted aromatic derivatives, their preparation methods and uses

[0001] Cross-reference of related applications

[0002] This application claims priority to two patent applications filed with the China National Intellectual Property Administration on February 26, 2025, entitled "Substituted Aromatic Derivatives and Their Preparation Methods and Uses" (application number CN202510218953.3) and October 22, 2025, entitled "Substituted Aromatic Derivatives and Their Preparation Methods and Uses" (application number CN202511516470.8), the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention relates to a substituted aromatic derivative, its preparation method, a pharmaceutical composition containing the derivative, and its use as a therapeutic agent, particularly as a VAV1 degrading agent. Background Technology

[0004] 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.

[0005] 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.

[0006] 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.

[0007] 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.

[0008] 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.

[0009] There are currently no effective marketed drugs targeting VAV1 molecular adhesive degradation agents. Only one company is in development: Monte Rosa Therapeutics' MRT-6160, which is in Phase I clinical trials. There is a significant unmet clinical need for effective VAV1 degradation agents. Summary of the Invention

[0010] 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:

[0011] in Selected from those containing Fragment of 5-12 membered heterocyclic groups;

[0012] The condition is that, Not selected

[0013] R 7 Each element independently selects from deuterium, halogens, hydroxyl groups, cyano groups, SF5, and C. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0014] And / or, two Rs 7 It forms a -C (=O) with the same carbon atom it is attached to;

[0015] m is selected from 0, 1, 2, 3, and 4;

[0016] X and Y are each independently selected from CR A and N;

[0017] R A Each is independently selected from hydrogen atom, halogen, hydroxyl group, cyano group, C 1-6 Alkyl and C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 Alkoxy groups may optionally be further selected from halogens, hydroxyl groups, cyano groups, and C. 1-6 The alkoxy group is substituted; preferably, R A It is a hydrogen atom;

[0018] R 2 Selected from hydrogen atom, deuterium atom, hydroxyl group, halogen, cyano group, C 1-6 Alkyl and C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 Alkoxy groups may optionally be further selected from halogens, hydroxyl groups, cyano groups, and C. 1-6 Substituents of alkoxy groups;

[0019] R 3 R 4 and R 5 Each is independently selected from hydrogen atom, deuterium atom, hydroxyl group, cyano group, C 1-6 Alkyl and C 1-6 Alkyl groups;

[0020] R 6 Each is independently selected from halogen, hydroxyl, cyano, C 1-6 Alkyl and C 1-6 Alkoxy, wherein the C1-6 Alkyl or C 1-6 Alkoxy groups may optionally be further selected from halogens, hydroxyl groups, cyano groups, and C. 1-6 Substituents of alkoxy groups;

[0021] n is selected from 0, 1, and 2;

[0022] L1 is selected from the key, -C 1-4 Alkylene-, -O(C) 0-4 alkylene)-, -NR a (C 0-4 alkylene)-, -NR a C(=O)(C 0-4 alkylene)- and -(C 0-4 Alkylene C(=O)-, wherein the alkylene group is optionally composed of one or more atoms selected from deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkyl groups;

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

[0024] R 1 The group is selected from 3-12-membered heterocyclic groups, 5-10-membered heteroaryl groups, and 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 halogen, hydroxyl, cyano, C 1-6 Alkyl and C 1-6 The alkoxy group is replaced by a substituent.

[0025] 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... Selected from those containing The 7-12 member bicyclic heterocyclic group of the fragment and

[0026] 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... Selected from the following groups:

[0027] 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 L1 is selected from a bond (covalent bond).

[0028] 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 R 1 The group is selected from 3-12-membered heterocyclic groups and 5-10-membered heteroaryl groups, wherein the 3-12-membered heterocyclic group or the 5-10-membered heteroaryl group is optionally further substituted by one or more substituents selected from halogen, hydroxyl, cyano, methyl and methoxy groups.

[0029] 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 R 1 for

[0030] 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 R 2 Selected from halogens, preferably chlorine.

[0031] 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 R 3 R 4 R 5 It is a hydrogen atom.

[0032] In a preferred embodiment of the present invention, the compounds of the general formula are selected from:

[0033] Or its stereoisomers, tautomers, deuterated derivatives, or medicinal salts thereof.

[0034] Note: If there is a discrepancy between the drawn structure and the given name of the structure, the drawn structure shall prevail.

[0035] Furthermore, the present invention provides a pharmaceutical composition comprising a compound of general formula (I) or a stereoisomer, tautomer, deuterated compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0036] The present invention provides the use of a compound of general formula (I) or its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of a VAV1 degrading agent.

[0037] The present invention also provides the use of a compound of general formula (I) or its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of a medicament for treating or preventing VAV1-mediated diseases; preferably, wherein the VAV1-mediated diseases are autoimmune diseases and / or inflammatory diseases; more preferably, the autoimmune diseases or inflammatory diseases are selected from multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, idiopathic dermatitis, Hashimoto's thyroiditis, and 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 diseases, keratoconjunctivitis, myocarditis, and hepatitis.

[0038] Accordingly, this application provides a method for treating or preventing VAV1-mediated diseases, comprising administering to a subject in need a compound of general formula (I) or a stereoisomer, tautomer, deuterated form or pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in this application. Preferably, the VAV1-mediated disease is an autoimmune disease and / 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, 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, and hepatitis.

[0039] The present invention also provides the use of a compound of general formula (I) or its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of a medicament for treating or preventing autoimmune diseases and / or inflammatory diseases; 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 and hepatitis.

[0040] Accordingly, this application provides a method for treating or preventing autoimmune diseases and / or inflammatory diseases, comprising administering to a subject in need a compound of general formula (I) of this application or a stereoisomer, tautomer, deuterated compound or pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in this application. Preferably, the autoimmune disease or inflammatory disease mentioned therein 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, and hepatitis.

[0041] Detailed description of the invention

[0042] Unless otherwise stated, some terms used in this specification and claims are defined as follows:

[0043] 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. 10Alkyl groups, more preferably C1-C6 and C1-C4 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.

[0044] “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. 1-6 Examples 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.

[0045] "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.

[0046] "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.

[0047] "Cycloalkyl" refers to a non-aromatic cyclic alkyl group in which one or more of the cyclic atoms are carbon atoms, and the ring contains 0, 1 or more double bonds, including monocyclic, polycyclic, fused, bridged and spirocyclic, preferably having a 3 to 7 member monocyclic or a 5 to 18 member bicyclic or tricyclic.

[0048] Examples of "monocycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,

[0049] Monocyclic alkyl groups can be substituted or unsubstituted.

[0050] "Spirocycloalkyl" refers to a polycyclic group with 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 none of the rings having fully conjugated π electrons, preferably 6 to 14 quintiles, more preferably 7 to 10 quintiles. Based on the number of spiro atoms shared between the rings, spirocycloalkyl is classified into monospiro, bispiro, or polyspirocycloalkyl, preferably monospiro and bispirocycloalkyl, preferably 4 / 5, 4 / 4, 4 / 6, 3 / 6, 5 / 5, or 5 / 6 quintiles. 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.

[0051] "Fused cycloalkyl" refers to a 5- to 18-membered polycyclic aromatic hydrocarbon group containing two or more ring 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 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.

[0052] "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, Bridged cycloalkyl groups can be substituted or unsubstituted.

[0053] 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 sulfur.

[0054] The heterocyclic group can be substituted or unsubstituted.

[0055] 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, etc.

[0056] "Spirocycloheterocyclic group" refers to a polycyclic 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, and 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 groups. 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,

[0057] "Fused heterocyclic group" refers to a polycyclic group containing two or more ring structures that share a pair of atoms. 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,

[0058] "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 a bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic group, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting embodiments of the "bridged heterocyclic group" include, but are not limited to: 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl, 2-azabicyclo[3.3.2]decyl,

[0059] "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.

[0060] "Heteroaryl" refers to an aromatic 5- to 6-membered monocyclic or 8- to 10-membered bicyclic ring, which may contain 1 to 4, for example 1, 2, 3, or 4 atoms selected from nitrogen, oxygen, or sulfur. Preferred heteroaryl groups are 5- to 10-membered heteroaryl groups, such as 5- to 6-membered heteroaryl groups; the heteroaryl group may contain 1, 2, 3, or 4 heteroatoms selected from nitrogen, oxygen, and 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], benzo[imidazolyl], 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, pyridine Pyridyl, 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

[0061] The heteroaryl group can be substituted or unsubstituted.

[0062] 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, and 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:

[0063] "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.

[0064] "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.

[0065] "Nitro" refers to the -NO2 group.

[0066] "Hydroxy" refers to the -OH group.

[0067] "Halogens" refer to fluorine, chlorine, bromine, and iodine.

[0068] "Amino" refers to -NH2.

[0069] "Hydroxyamino group" refers to -NHOH.

[0070] “Cyano” refers to -CN.

[0071] "Benzyl" refers to -CH2-phenyl.

[0072] "Carboxyl group" refers to -C(=O)OH.

[0073] "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.

[0074] “Hydroxyalkyl” refers to an alkyl group substituted with a hydroxyl group, where the definition of alkyl is as described above.

[0075] "Aminoalkyl" refers to an amino-substituted alkyl group, where the definition of alkyl is as described above.

[0076] "Halogenated alkyl" refers to halogen-substituted alkyl groups, where the definition of alkyl is as described above.

[0077] "Haloalkoxy" refers to halogen-substituted alkoxy groups, where the definition of alkoxy groups is as described above.

[0078] "DMSO" refers to dimethyl sulfoxide.

[0079] “BOC” refers to tert-butoxycarbonyl.

[0080] “Bn” refers to benzyl.

[0081] "THP" refers to 2-tetrahydropyranyl.

[0082] "TFA" refers to trifluoroacetic acid.

[0083] “Ts” refers to p-toluenesulfonyl group.

[0084] “Bn” refers to benzyl.

[0085] “SEM” refers to (trimethylsilyl)ethoxymethyl.

[0086] "Formyl group" refers to

[0087] 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.

[0088] "Substituted" refers to a group in which one or more hydrogen atoms, preferably up to five, and more preferably one to three hydrogen atoms, 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 (through 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).

[0089] In this application, "one or more" means one or more, such as one, two, three, four or five or more.

[0090] Unless otherwise specified, the terms "substituted" or "substituted" in this specification refer to the substitution of a group by one or more (e.g., 1, 2, or 3) groups selected from the following: deuterium, alkyl, alkenyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocyclic alkoxy, cycloalkylthio, heterocyclic alkylthio, 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)R7 -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;

[0091] R 5 Each is independently selected from alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally further selected by one, two, or three groups from 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)2NR 9 R 10 and -N(R) 9 )C(=O)R 10 The substituents are replaced;

[0092] R 6 and R 7 Each is independently selected from hydrogen atom, hydroxyl, alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally further selected by one, two, or three groups 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 and -N(R) 9 )C(=O)R10 The substituents are replaced;

[0093] Or, R 6 and R 7 The atoms bonded to them together form a structure containing one or more N, O, or S atoms (=O). r The 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group is optionally further selected by one, two or three of the following groups: 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 and -N(R) 9 )C(=O)R 10 The substituents are replaced;

[0094] R 8 R 9 and R 10 Each is independently selected from hydrogen atoms, alkyl, amino, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally further substituted by one, two or three substituents selected from hydroxyl, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, carboxyl and carboxylic ester groups;

[0095] r is independently selected from 0, 1, and 2.

[0096] 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.

[0097] 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.

[0098] "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.

[0099] "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 a physiologically pharmaceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity. Detailed Implementation

[0100] 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.

[0101] Example

[0102] 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. 1 The 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.

[0103] Mass spectrometry is performed using an LC / MS instrument, and the ionization method can be ESI or APCI.

[0104] 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.

[0105] Column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0106] 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.

[0107] CD3OD: Deuterated methanol.

[0108] CDCl3: Deuterated chloroform.

[0109] DMSO-d6: Deuterated dimethyl sulfoxide.

[0110] Argon atmosphere refers to a reaction flask connected to an argon gas balloon with a volume of approximately 1L.

[0111] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0112] 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.

[0113] Example 1

[0114] 2-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)-2,7-diazaspiro[4.5]decane-6,8-dione

[0115] 2-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)-2,7-diazaspiro[4.5]decane-6,8-dione

[0116] first step

[0117] 1-(3'-bromo-2'-chloro-[1,1'-biphenyl]-4-yl)pyridin-2(1H)-one

[0118] 1-(3'-bromo-2'-chloro-[1,1'-biphenyl]-4-yl)pyridin-2(1H)-one

[0119] 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 complete, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (evolving solvent: system A) to give 1c (310 mg) of 1-(3'-bromo-2'-chloro-[1,1'-biphenyl]-4-yl)pyridin-2(1H)-one, in a yield of 46.5%. MS m / z (ESI): 360.0 [M+1]

[0120] Step 2

[0121] 2-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)-2,7-diazaspiro[4.5]decane-6,8-dione

[0122] 2-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)-2,7-diazaspiro[4.5]decane-6,8-dione

[0123] To a solution of 1,4-dioxane (1 mL) of 1-(3'-bromo-2'-chloro-[1,1'-biphenyl]-4-yl)pyridin-2(1H)-one 1c (29.80 mg, 82.63 μmol) and 2,7-diazaspiro[4.5]decane-6,8-dione hydrochloride 1d (20.85 mg, 123.95 μmol), (SP-4-1)-[1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylylene]dichloro(3-chloropyridin-KN)palladium (8.04 mg, 8.26 μmol) and cesium carbonate (134.61 mg, 413.15 μmol) were added. The reaction mixture was stirred at 90 °C under nitrogen protection for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (Waters 2767 / QDA) column purification: Pursuit XRs 10C18, 21.2*250mm, 10µm; mobile phase A: 0.1% FA in H2O solution; B: ACN; flow rate: 20ml / min; gradient: 44-44%; retention time: 9.2-10.4 min-17 min) to obtain 2-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)-2,7-diazaspiro[4.5]decane-6,8-dione 1 (5.47mg), yield 14.8%.

[0124] MS m / z(ESI): 448.2 [M+1]

[0125] 1 H NMR (400MHz, DMSO-d6) δ10.76 (s, 1H), 7.73 (dd, J = 6.8, 1.6Hz, 1H), 7.56-7.45 ( m,5H),7.31(t,J=8.0Hz,1H),7.10(d,J=7.2Hz,1H),6.94(dd,J=7.6,1.2Hz,1H ),6.51(d,J=8.8Hz,1H),6.36-6.31(m,1H),3.63-3.57(m,1H),3.55-3.46(m,2 H),3.45-3.37(m,1H),2.64-2.56(m,2H),2.41-2.31(m,1H),2.11-1.92(m,3H).

[0126] Example 2

[0127] 7-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)-2,7-diazaspiro[4.4]nonane-1,3-dione

[0128] 7-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)-2,7-diazaspiro[4.4]nonane-1,3-dione

[0129] To a solution of 1,4-dioxane (1 mL) of 1-(3'-bromo-2'-chloro-[1,1'-biphenyl]-4-yl)pyridin-2(1H)-one 1c (30 mg, 83.19 μmol) and 2,7-diazaspiro[4.4]nonane-1,3-dione hydrochloride 2a (19.24 mg, 124.78 μmol), (SP-4-1)-[1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylylene]dichloro(3-chloropyridin-KN)palladium (8.09 mg, 8.32 μmol) and cesium carbonate (135.52 mg, 415.94 μmol) were added. The reaction mixture was stirred at 90 °C under nitrogen protection for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered, and concentrated. 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: 40-50%; retention time: 17 min - 8.5 min) to obtain 7-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)-2,7-diazaspiro[4.4]nonane-1,3-dione 2 (1.03mg), yield 2.9%.

[0130] MS m / z(ESI): 434.1 [M+1]

[0131] 1H NMR(400MHz,DMSO-d6)δ11.29(s,1H),7.76-7.69(m,1H),7.56-7.45(m,5H),7 .30(t,J=8.0Hz,1H),7.07(d,J=7.2Hz,1H),6.92(d,J=7.6Hz,1H),6.51(d,J= 9.6Hz,1H),6.34(t,J=6.0Hz,1H),3.75-3.60(m,2H),3.47(d,J=9.6Hz,1H),3 .41-3.37(m,1H),2.77(d,J=2.8Hz,2H),2.31-2.22(m,1H),2.15-2.04(m,1H).

[0132] Example 3

[0133] 7-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)-5-azaspiro[2.5]octane-4,6-dione

[0134] first step

[0135] methyl 1-(bromomethyl)cyclopropane-1-carboxylate

[0136] 1-(bromomethyl)cyclopropane-1-carboxylic acid methyl ester

[0137] 1-(hydroxymethyl)cyclopropane-1-carboxylic acid methyl ester 3a (2 g, 15.37 mmol, commercially available) was added to a solution of dichloromethane (20 mL), and the mixture was cooled to 0 °C. Triphenylphosphine (4.83 g, 18.44 mmol) and carbon tetrabromide (7.65 g, 23.05 mmol) were then added. The reaction mixture was allowed to rise to room temperature and reacted for 1 hour. After the reaction was complete, the mixture was quenched with water (30 mL), extracted with dichloromethane (50 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate. 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 give 1-(bromomethyl)cyclopropane-1-carboxylic acid methyl ester 3b (2.2 g), with a yield of 74.2%. 1H NMR (400MHz, CDCl3) δ3.73 (s, 3H), 3.61 (s, 2H), 1.54 (q, J = 4.4Hz, 2H), 1.03 (q, J = 4.4Hz, 2H).

[0138] Step 2

[0139] methyl 1-(2-(3-bromo-2-chlorophenyl)-2-cyanoethyl)cyclopropane-1-carboxylate

[0140] 1-(2-(3-bromo-2-chlorophenyl)-2-cyanoethyl)cyclopropane-1-carboxylic acid methyl ester

[0141] Under nitrogen protection, 2-(3-bromo-2-chlorophenyl)acetonitrile 3c (200 mg, 867.72 μmol, commercially available) was dissolved in tetrahydrofuran (3 mL). The reaction mixture was cooled to 0 °C, and sodium hydrogen (41.65 mg, 1.74 mmol, 60%) and methyl 1-(bromomethyl)cyclopropane-1-carboxylic acid ester 3b (167.50 mg, 867.72 μmol) were added sequentially. The reaction mixture was then heated to room temperature and the reaction continued for 2 hours. After the reaction was completed, saturated ammonium chloride solution (20 mL) was added to quench the reaction, followed by extraction with dichloromethane (30 mL × 3). The combined organic phases were washed with saturated sodium chloride (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 (developing solvent: system A) to give methyl 1-(2-(3-bromo-2-chlorophenyl)-2-cyanoethyl)cyclopropane-1-carboxylic acid ester 3d (200 mg), with a yield of 67.3%.

[0142] 1H NMR (400MHz, DMSO) δ7.81(dd,J=8.0,1.6Hz,1H),7.60(dd,J=8.0,1.6Hz,1H),7.38(t,J=8.0Hz,1H),4.88-4.83(m,1H),3.5 8(s,3H),2.32-2.26(m,1H),2.10-2.03(m,1H),1.25-1.20(m,1H),1.16-1.10(m,1H),1.09-1.03(m,1H),0.78-0.72(m,1H).

[0143] Step 3

[0144] 7-(3-bromo-2-chlorophenyl)-5-azaspiro[2.5]octane-4,6-dione

[0145] 7-(3-bromo-2-chlorophenyl)-5-azaspiro[2.5]octane-4,6-dione

[0146] Methyl 1-(2-(3-bromo-2-chlorophenyl)-2-cyanoethyl)cyclopropane-1-carboxylic acid ester 3d (100 mg, 291.87 μmol) was dissolved in acetic acid (6 mL) and concentrated sulfuric acid (1 mL). The reaction mixture was heated to 90 °C under nitrogen protection and reacted for 3 hours. After the reaction was completed, it was cooled to room temperature. The pH of the reaction mixture was adjusted to 8-9 by slowly adding saturated sodium bicarbonate aqueous solution, and then extracted with ethyl acetate (30 mL × 3). 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 (developing solvent: system A) to give 7-(3-bromo-2-chlorophenyl)-5-azaspiro[2.5]octane-4,6-dione 3e (40 mg), yield 41.7%.

[0147] MS m / z(ESI): 327.9 [M+1]

[0148] Step 4

[0149] 7-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)-5-azaspiro[2.5]octane-4,6-dione

[0150] 7-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)-5-azaspiro[2.5]octane-4,6-dione

[0151] 7-(3-bromo-2-chlorophenyl)-5-azaspiro[2.5]octane-4,6-dione 3e (10 mg, 30.43 μmol) and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)pyridin-2(1H)-one 1b (9.04 mg, 30.43 μmol) were added to 1,4-dioxane (1 mL) and water (0.1 mL). Then, potassium carbonate (4.21 mg, 30.43 μmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (22.57 mg, 30.43 μmol) were added to the system. 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 (10 mL), extracted with ethyl acetate (10 mL × 3), and the combined organic phases were washed with saturated ammonium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (Waters 2767 / Qda column: SunFire Sunfire C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA / H2O, B: ACN; flow rate: 20 mL / min; gradient: 40-50%; retention time: 7.9-8.8 min, 16 min) to give 7-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)-5-azaspiro[2.5]octane-4,6-dione 3 (4.27 mg), yield 33.5%.

[0152] MS m / z(ESI): 419.1 [M+1]

[0153] 1H NMR (400MHz, DMSO) δ11.05(s,1H),7.74(dd,J=6.8,1.6Hz,1H),7.57-7.50(m,5H),7.47-7.42(m,2H),7.40-7.36(m,1H),6.52(d,J=9.2Hz,1H) ,6.37-6.31(m,1H),4.49-4.41(m,1H),2.76(t,J=12.8Hz,1H),1.67-1. 61(m,1H),1.43–1.37(m,1H),1.02(t,J=8.0Hz,2H),0.84-0.78(m,1H).

[0154] Example 4

[0155] 3-(2-chloro-4-(2-oxopyridin-1(2H)-yl)-[1,1-biphenyl]-3-yl)pyrrolidine-2,5-dione

[0156] 3-(2-chloro-4-(2-oxopyridin-1(2H)-yl)-biphenyl-3-yl)pyrrolidine-2,5-dione

[0157] first step

[0158] 3-(3-bromo-2-chlorophenyl)pyrrolidine-2,5-dione

[0159] 3-(3-bromo-2-chlorophenyl)pyrrolidine-2,5-dione

[0160] At room temperature, (3-bromo-2-chlorophenyl)boronic acid 4a (250 mg, 1.06 mmol), pyrrole-2,5-dione (150 mg, 1.54 mmol), (1,5-cyclooctadiene) rhodium chloride (I) dimer (30 mg, 0.06 mmol), potassium hydroxide (60 mg, 1.07 mmol), water (1.0 mL), and 1,4-dioxane (5.0 mL) were sequentially added to a 10 mL microwave-safe tube. After purging with nitrogen three times, the mixture was stirred at 100 °C for 20 minutes. LC-MS analysis confirmed complete reaction of the starting materials. The reaction solution was directly evaporated to dryness and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to obtain 3-(3-bromo-2-chlorophenyl)pyrrole-2,5-dione 4b (180 mg) in yield 58.8% MS m / z (ESI): 288.0 [M+1]

[0161] Step 2

[0162] 3-(2-chloro-4-(2-oxopyridin-1(2H)-yl)-[1,1-biphenyl]-3-yl)pyrrolidine-2,5-dione

[0163] 3-(2-chloro-4-(2-oxopyridin-1(2H)-yl)-biphenyl-3-yl)pyrrolidine-2,5-dione

[0164] At room temperature, 3-(3-bromo-2-chlorophenyl)pyrrolidine-2,5-dione 4b (100 mg, 0.34 mmol), 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)pyridin-2(1H)-one 1b (150 mg, 0.50 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (25 mg, 0.03 mmol), sodium bicarbonate (60 mg, 0.71 mmol), 1,4-dioxane (6 mL), and water (1.0 mL) were sequentially added to a 50 mL single-necked flask. The mixture was purged with nitrogen three times and stirred at 85°C for 3 hours. The reaction proceeded to completion as determined by LC-MS. The reaction solution was purified by reverse-phase column chromatography (evolving solvent: system D) to give 3-(2-chloro-4-(2-oxopyridin-1(2H)-yl)-biphenyl-3-yl)pyrrolidine-2,5-dione 4 (10 mg), yield 7.6%.

[0165] MS m / z(ESI): 379.1 [M+1]

[0166] 1 H NMR (400MHz, DMSO-d6) δ11.44(s,1H),7.72(dd,J=7.0,2.1Hz,1H),7.59-7.48(m,5H),7.47-7.37(m,3H),6.51(d,J=9 .1Hz,1H),6.34(td,J=6.7,1.4Hz,1H),4.62-4.58(m,1H),3.17(dd,J=18.0,9.8Hz,1H),2.76(dd,J=18.0,6.0Hz,1H).

[0167] Example 5

[0168] 1-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)-3-azabicyclo[3.1.0]hexane-2,4-dione

[0169] 1-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)-3-azabicyclo[3.1.0]hexane-2,4-dione

[0170] first step

[0171] 2-bromo-2-(3-bromo-2-chloro-phenyl)acetate

[0172] 2-Bromo-2-(3-Bromo-2-chlorophenyl)acetic acid ester

[0173] Methyl 2-(3-bromo-2-chlorophenyl)acetate 5a (4.1 g, 15.56 mmol) was added to a carbon tetrachloride (40 mL) solution, followed by benzoyl peroxide (376.88 mg, 1.56 mmol) and N-bromosuccinimide (2.77 g, 15.56 mmol). The reaction mixture was heated to 70 °C under nitrogen protection and reacted for 16 hours. After the reaction was complete, the reaction solution was cooled to room temperature, quenched with water (30 mL), extracted with dichloromethane (50 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: system A) to give 2-bromo-2-(3-bromo-2-chlorophenyl)acetate 5b (4.2 g), yield 78.8%.

[0174] MS m / z (ESI): 341.3 [M+1]

[0175] Step 2

[0176] dimethyl 1-(3-bromo-2-chloro-phenyl)cyclopropane-1,2-dicarboxylate

[0177] 1-(3-bromo-2-chlorophenyl)cyclopropane-1,2-dicarboxylic acid dimethyl ester

[0178] 2-Bromo-2-(3-bromo-2-chlorophenyl)acetate 5b (2 g, 5.84 mmol) was added to anhydrous toluene (20 mL) solution, followed by potassium methoxide (491.55 mg, 7.01 mmol). The reaction mixture was cooled to -5 °C under nitrogen protection, and then methyl propylene glycol (754.26 mg, 8.76 mmol) was added. After the addition was complete, the reaction mixture was stirred at -5 °C for 16 hours. After the reaction was complete, the pH was adjusted to 6–7 with 1 M hydrochloric acid solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase separation (evolving solvent: system D) to give 1-(3-bromo-2-chlorophenyl)cyclopropane-1,2-dicarboxylic acid dimethyl ester 5c (821 mg), yield 20.2%.

[0179] MS m / z (ESI): 347.0 [M+1]

[0180] Step 3

[0181] 1-(3-bromo-2-chloro-phenyl)cyclopropane-1,2-dicarboxylic acid

[0182] 1-(3-bromo-2-chlorophenyl)cyclopropane-1,2-dicarboxylic acid

[0183] At room temperature, 5c (821 mg, 2.36 mmol) of 1-(3-bromo-2-chlorophenyl)cyclopropane-1,2-dicarboxylic acid dimethyl ester was dissolved in tetrahydrofuran (5 mL) and water (5 mL), and potassium hydroxide (397.59 mg, 7.09 mmol) was added to react the mixture. The reaction mixture was heated to 70 °C under nitrogen protection and reacted for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and the pH was adjusted to 6–7 with 2 M hydrochloric acid solution. The mixture was extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase separation (evolving solvent: system D) to give 5d (230 mg) of 1-(3-bromo-2-chlorophenyl)cyclopropane-1,2-dicarboxylic acid, with a yield of 30.5%.

[0184] MS m / z (ESI): 316.8 [M-1]

[0185] Step 4

[0186] 1-(3-bromo-2-chloro-phenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione

[0187] 1-(3-bromo-2-chlorophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione

[0188] 1-(3-bromo-2-chlorophenyl)cyclopropane-1,2-dicarboxylic acid 5d (200 mg, 625.91 μmol) was added to a 25 mL solution of p-xylene, followed by the addition of urea (187.96 mg, 3.13 mmol). The reaction mixture was heated to 150 °C and reacted for 48 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase separation (eluent: system D) to give 1-(3-bromo-2-chlorophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione 5e (100 mg), with a yield of 53.2%.

[0189] MS m / z (ESI): 299.8 [M+1]

[0190] Step 5

[0191] 1-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)-3-azabicyclo[3.1.0]hexane-2,4-dione

[0192] 1-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)-3-azabicyclo[3.1.0]hexane-2,4-dione contains 1-(3-bromo-2-chlorophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione 5e (40 mg, 133.10 μmol) and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)phenyl) Pyridine-2(1H)-one 1b (47.46 mg, 159.71 μmol) was added to 1,4-dioxane (0.5 mL) and water (0.05 mL). Then, potassium carbonate (55.18 mg, 399.29 μmol) and [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (8.67 mg, 13.31 μmol) were added to the system. The reaction mixture was heated to 90 °C under nitrogen protection and the reaction was continued for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature, quenched with water (5 mL), extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters 3767 / Qda column: SunFire Sunfire C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA / H2O, B: ACN; flow rate: 20 mL / min; gradient: 8-18%; retention time: 8 min, 17 min) to give 1-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)-3-azabicyclo[3.1.0]hexane-2,4-dione 5 (2.74 mg), yield 5.3%.

[0193] MS m / z(ESI): 391.2 [M+1]

[0194] 1 H NMR (400MHz, DMSO) δ10.82 (s, 1H), 7.73 (d, J = 7.2Hz, 1H), 7.60-7.47 (m, 8H), 6.5 1(d,J=9.2Hz,1H),6.35(t,J=6.8Hz,1H),2.79-2.76(m,1H),2.17-2.09(m,2H).

[0195] Example 6

[0196] 1-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)dihydropyrimidine-2,4(1H,3H)-dion

[0197] e1-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)dihydropyrimidin-2,4(1H,3H)-dione

[0198] first step

[0199] 1-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0200] 1-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)dihydropyrimidin-2,4(1H,3H)-dione

[0201] At room temperature, 1,4-dioxane (5 mL) of 1-(3'-bromo-2'-chloro-[1,1'-biphenyl]-4-yl)pyridin-2(1H)-one 1c (200 mg, 554.58 μmol) and hexahydropyrimidine-2,4-dione (126.56 mg, 1.11 mmol) was added to the system, followed by the addition of cesium carbonate (542.08 mg, 1.66 mmol) and (2'-methylamino-1,1'-biphenyl-2-yl)palladium. EPhos-Pd-G4 (2.55 mg, 2.77 μmol) and bicyclohexyl(3-isopropoxy-2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphonane Ephos (59.34 mg, 110.92 μmol) were reacted under nitrogen protection at 100 °C for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, quenched with 20 mL of water, and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters). 3767 / Qda column: XBridge C18, 19*250mm, 10µm; mobile phase A: 0.1% FA / H2O, B: ACN; flow rate: 20ml / min; gradient: 30-40%; retention time: 8.4 min, 17 min), yielded 1-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 6 (2.42 mg), yield 1.11%.

[0202] MS m / z(ESI): 394.1 [M+1]

[0203] 1H NMR (400MHz, DMSO) δ10.50 (s, 1H), 7.74 (dd, J = 6.8, 1.6Hz, 1H), 7.60-7.50 (m, 7H), 7.48-7.40 (m, 1H), 6.5 2(d,J=9.2Hz,1H),6.34(dd,J=9.6,4.0Hz,1H),3.82-3.74(m,1H),3.71-3.64(m,1H),2.80-2.73(m,2H).

[0204] Biological evaluation

[0205] Test Example 1: Determination of VAV1 protein degradation by the compounds of the present invention

[0206] 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, 100 U penicillin, and 100 μg / mL streptomycin. The Jurkat VAV1 Hibit stable cell line was constructed internally by Hisun Pharmaceuticals and used... The HiBiT Lytic Detection System (Promega, catalog number N3030) detects HiBiT signals to quantify VAV1 protein.

[0207] 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 complete, 50 μL of the solution was added to each well. HiBiT Lytic Reagent (use according to the kit instructions) HiBiT Lytic Buffer dilutes LgBiT Protein and The sample was prepared using HiBiT Lytic Substrate, 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 Values. The results are shown in Table 1.

[0208] Table 1. Degradation activity of the compounds of the present invention on VAV1 protein

[0209] 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 Selected from those containing Fragment of 5-12 membered heterocyclic groups; The condition is that, Not selected R 7 Each element independently selects from deuterium, halogens, hydroxyl groups, cyano groups, SF5, and C. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups; And / or, two Rs 7 It forms a -C (=O) with the same carbon atom it is attached to; m is selected from 0, 1, 2, 3, and 4; X and Y are each independently selected from CR A and N; R A Each is independently selected from hydrogen atom, halogen, hydroxyl group, cyano group, C 1-6 Alkyl and C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 Alkoxy groups may optionally be further selected from halogens, hydroxyl groups, cyano groups, and C. 1-6 The alkoxy group is substituted; preferably, R A It is a hydrogen atom; R 2 Selected from hydrogen atom, deuterium atom, hydroxyl group, halogen, cyano group, C 1-6 Alkyl and C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 Alkoxy groups may optionally be further selected from halogens, hydroxyl groups, cyano groups, and 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 and C 1-6 Alkyl groups; R 6 Each is independently selected from halogen, hydroxyl, cyano, C 1-6 Alkyl and C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 Alkoxy groups may optionally be further selected from halogens, hydroxyl groups, cyano groups, and C. 1-6 Substituents of alkoxy groups; n is selected from 0, 1, and 2; L1 is selected from the key, -C 1-4 Alkylene-, -O(C) 0-4 alkylene)-, -NR a (C 0-4 alkylene)-, -NR a C(=O)(C 0-4 alkylene)- and -(C 0-4 Alkylene C(=O)-, wherein the alkylene group is optionally composed of one or more atoms selected from deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkyl groups; R a Each is independently selected from hydrogen atoms and C atoms. 1-6 alkyl; R 1 The group is selected from 3-12-membered heterocyclic groups, 5-10-membered heteroaryl groups, and 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 halogen, hydroxyl, cyano, C 1-6 Alkyl and C 1-6 The alkoxy group is replaced by a substituent.

2. The compound according to claim 1, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein... Selected from those containing The 7-12 member bicyclic heterocyclic group of the fragment and 3. The compound according to claim 1, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein... Selected from the following groups:

4. The compound according to any one of claims 1-3, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein, L1 is selected from the key.

5. The compound according to any one of claims 1-4, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein, R 1 The group is selected from 3-12-membered heterocyclic groups and 5-10-membered heteroaryl groups, wherein the 3-12-membered heterocyclic group or the 5-10-membered heteroaryl group is optionally further substituted by one or more substituents selected from halogen, hydroxyl, cyano, methyl and methoxy groups.

6. The compound according to any one of claims 1-5, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein, R 1 for 7. The compound according to any one of claims 1-6, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein, R 2 Selected from halogens, preferably chlorine.

8. The compound according to any one of claims 1-7, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein, R 3 R 4 R 5 It is a hydrogen atom.

9. The compound according to any one of claims 1-8, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, wherein the compound is selected from:

10. A pharmaceutical composition comprising a compound according to any one of claims 1-9, or a stereoisomer, tautomer, deuterated compound or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

11. Use of the compound or stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 10, in the preparation of a VAV1 degrading agent.

12. Use of the compound or stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 1-9, in the preparation of a medicament for treating or preventing VAV1-mediated diseases; preferably, wherein the VAV1-mediated diseases are autoimmune diseases and / or inflammatory diseases; more preferably, the autoimmune diseases or inflammatory diseases are selected from multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, idiopathic dermatitis, and 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, and hepatitis.

13. The use of the compound or its stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, according to any one of claims 1-9, or the pharmaceutical composition according to claim 10, in the preparation of a medicament for treating or preventing autoimmune diseases and / or inflammatory diseases; preferably, wherein the said 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 mellitus. 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 diseases, keratoconjunctivitis, myocarditis, and hepatitis.

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