IKZF1 degradation agent as well as preparation method and application thereof

Abstract

The invention discloses an IKZF1 degradation agent as well as a preparation method and application thereof, and particularly relates to application in prevention and / or treatment of IKZF1 related diseases. The degradation agent has the following structure, and has very good targeting property on IKZF1. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the technical field of chemical medicine, and in particular to an IKZF1 degradation agent and a preparation method and application thereof, in particular to an application in preventing and / or treating IKZF1-related diseases. Background Art

[0002] The Ikaros family is a series of zinc finger protein transcription factors that are important for certain physiological processes, especially lymphocyte development. Ikaros (IKZF1) was first discovered in 1992, and in the following two decades, four additional homologs have been identified: Helios (IKZF2), Aiolos (IKZF3), Eos (IKZF4), and Pegasus (IKZF5). Each homolog gene can produce several protein isoforms through alternative splicing, theoretically allowing a large number of protein complexes to be produced through different combinations of various homologs. The distribution of different members of the Ikaros family varies greatly in the body. IKZF1, IKZF2, and IKZF3 are mainly found in lymphoid cells and their corresponding progenitor cells. In addition, IKZF1 has also been detected in the brain, and IKZF1 and IKZF2 have also been detected in erythrocytes. IKZF4 and IKZF5 are more widely distributed and are present in skeletal muscle, liver, brain, and heart. IKZF1 is important for the normal development of lymphocytes, and deletion of the exons encoding the first three N-terminal zinc fingers results in mice lacking T cells, B cells, natural killer (NK) cells, and their progenitors. Genetic alterations in IKZF1 are associated with poor outcomes in acute lymphoblastic leukemia (ALL) treatment, and IKZF1 and IKZF3 are involved in the proliferation of multiple myeloma cells, suggesting a potential role in hematological malignancies.

[0003] It has also been found that mutations in the IKZF1 gene are associated with the occurrence, development, proliferation, metastasis, and prognosis of a variety of other malignant tumors (such as breast cancer, ovarian cancer, liver cancer, skin cancer, lung cancer, and colorectal cancer). It is also associated with the complex phenotype and susceptibility of systemic lupus erythematosus (SLE).

[0004] Molecular glue degraders are a class of small molecules that can induce the interaction between E3 ubiquitin ligase substrate receptors and target proteins, leading to the degradation of target proteins. Currently, there are few reports on degraders targeting IKZF1. Summary of the invention

[0005] In order to overcome the deficiencies of the prior art, the present invention provides an IKZF1 degrading agent and a preparation method and application thereof, wherein the degrading agent has very good targeting to IKZF1.

[0006] In a first aspect of the present invention, a compound is provided, which has the following structure:

[0007]

[0008] in,

[0009] V is selected from: -CH 2 -、

[0010] L has the following structure:

[0011] L 1 Selected from: -NH-(C 0-10 Alkylene)-, -O-(C 0-10 Alkylene)-;

[0012] L 2 Selected from: R 3 Selected from: -H, halogen, -CN, -NO 2 , -CF 3 , -CHF 2 、-CH 2 F, -OH, -OCH 3 、-OCF 3 、-OCHF 2 、-OCH 2 F.C 1-3 alkyl;

[0013] L 3 Selected from: -(C 0-10 Alkylene)-, -(C 0-6 Alkylene)-NH-(C 0-6 Alkylene)-, -(C 0-6 Alkylene)-O-(C 0-6 Alkylene)-;

[0014] R 1 for One or more independent substituents on the ring are selected from: =O, halogen, -CN, -NO 2 , -CF 3 、-OCF 3 , C 0-10 Alkyl, -O(C 0-10 Alkyl), -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO 2 (C 0-10 Alkyl), -SC0-10 Alkyl, -SO(C 0-10 Alkyl), -SO 2 (C 0-10 Alkyl), -SO 2 N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(C 0-10 Alkyl), -CO(C 0-10 alkyl), L' is selected from: a single bond, -(C 0-10 Alkylene)-, -(C 0-10 Alkylene)-NR L1 -(C 0-10 Alkylene)-, -(C 0-10 Alkylene)-O-(C 0-10 Alkylene)-, -(C 0-10 Alkylene)-S-(C 0-10 Alkylene)-, -(C 0-10 Alkylene)-NR L1 CO-(C 0-10 Alkylene)-, -(C 0-10 Alkylene)-CONR L1 -(C 0-10 Alkylene)-, -(C 0-10 Alkylene)-CO-(C 0-10 Alkylene)-, -(C 0-10 Alkylene)-SO 2 -(C 0-10 Alkylene)-, -(C 0-10 Alkylene)-SO-(C 0-10 Alkylene)-; R L1 Selected from: H, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-10 membered heterocycloalkyl; R 2 is one or more independent substituents on the B ring and is selected from: =O, halogen, -CN, -NO 2 , -CF 3 、-OCF 3 , C 0-10 Alkyl, -O(C 0-10 Alkyl), -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C0-10 Alkyl), -N(C 0-10 alkyl)SO 2 (C 0-10 Alkyl), -SC 0-10 Alkyl, -SO(C 0-10 Alkyl), -SO 2 (C 0-10 Alkyl), -SO 2 N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(C 0-10 Alkyl), -CO(C 0-10 Alkyl), -(C 0-10 Alkylene)-(C 3-6 Cycloalkyl), -(C 0-10 Alkylene)-(C 6-10 Aryl), -(C 0-10 alkylene)-(4-10 membered heterocycloalkyl),-(C 0-10 wherein one or more H in the alkylene, alkyl, cycloalkyl, aryl, heterocycloalkyl, heteroaromatic group is optionally substituted by a group selected from the following: =O, halogen, -CN, -NO 2 , -CF 3 、-OCF 3 , C 0-10 Alkyl, -O(C 0-10 Alkyl), -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO 2 (C 0-10 Alkyl), -SC 0-10 Alkyl, -SO(C 0-10 Alkyl), -SO 2 (C 0-10 Alkyl), -SO 2 N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(C 0-10Alkyl), -CO(C 0-10 Alkyl), -(C 0-10 Alkylene)-(C 3-6 Cycloalkyl), -(C 0-10 Alkylene)-(C 6-10 Aryl), -(C 0-10 alkylene)-(4-10 membered heterocycloalkyl),-(C 0-10 (4-10 membered heterocyclic aromatic group).

[0015] In some embodiments of the present invention, V is

[0016] In some embodiments of the present invention, R 3 is a halogen, such as F.

[0017] In some embodiments of the present invention, L 1 -NH-, -NH-CH 2 -、-NH-CH 2 CH 2 -、-NH-CH 2 CH 2 CH 2 -、-O-、-O-CH 2 -、-O-CH 2 CH 2 -、-O-CH 2 CH 2 CH 2 -.

[0018] In some embodiments of the present invention, L 3 -NH-, -CH 2 -NH-, -CH 2 CH 2 -NH-, -CH 2 CH 2 CH 2 -NH-, -O-, -CH 2 -O-, -CH 2 CH 2 -O-, -CH 2 CH 2 CH 2 -O-, single bond, -CH 2 -、-CH 2 CH 2 -、-CH 2 CH 2 CH 2 -、-NH-CH 2 -、-NH-CH 2 CH 2-、-NH-CH 2 CH 2 CH 2 -、-O-CH 2 -、-O-CH 2 CH 2 -、-O-CH 2 CH 2 CH 2 -.

[0019] In some embodiments of the present invention, L has the following structure:

[0020]

[0021] In some embodiments of the present invention, R 1 for One or more independent substituents on the ring are selected from: -H, halogen, -CN, -NO 2 , -CF 3 、-OCF 3 , C 1-10 Alkyl, -O(C 0-10 Alkyl), -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO 2 (C 0-10 Alkyl), -SC 0-10 Alkyl, -SO(C 0-10 Alkyl), -SO 2 (C 0-10 Alkyl), -SO 2 N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(C 0-10 Alkyl), -CO(C 0-10 alkyl); more specifically, each R 1 Selected from: -H, halogen (such as F), -OH, C 1-6 Alkyl (e.g. -CH 3 、-CH 2 CH 3 )、-O(C 1-6 alkyl) (e.g. methoxy, ethoxy), especially -H.

[0022] In some embodiments of the present invention, Part of Among them, R 101 , R 102 , R 103 , R 104 , R 105 , R 106 R 1 definition; specifically, R 103 , R 104 , R 105 , R 106 Can be H (ie for ); specifically, R 101 , R 102 Independently selected from: -H, halogen (such as F), -OH, C 1-6 Alkyl (e.g. -CH 3 、-CH 2 CH 3 )、-O(C 1-6 alkyl) (e.g., methoxy, ethoxy); more specifically, It can be, for example,

[0023] In some embodiments of the present invention, Part of Among them, R 1 'for One or more independent substituents on the ring are selected from: H, halogen, -CN, -NO 2 , -CF 3 、-OCF 3 , C 1-10 Alkyl, -O(C 0-10 Alkyl), -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO 2 (C 0-10 Alkyl), -SC 0-10 Alkyl, -SO(C 0-10 Alkyl), -SO 2 (C 0-10 Alkyl), -SO 2 N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(C 0-10 Alkyl), -CO(C 0-10 alkyl); more specifically, each R 1 'Selected from: H, halogen, C 1-6 Alkyl, -O(C 0-6 Alkyl), especially H.

[0024] In some embodiments of the present invention, the above compound may have the following structure:

[0025]

[0026] In some embodiments of the present invention, L' is a single bond.

[0027] Specifically, the B ring can be an aromatic ring or a heteroaromatic ring, such as a benzene ring, a bicyclic aromatic ring, a tricyclic aromatic ring, a monocyclic heteroaromatic ring, a bicyclic heteroaromatic ring, or a tricyclic heteroaromatic ring.

[0028] In some embodiments of the present invention, Ring B is a benzene ring.

[0029] In some embodiments of the invention, Ring B is a monocyclic heteroaromatic ring, such as

[0030] In some embodiments of the present invention, Ring B is a bicyclic heteroaromatic ring, such as a 5,5-fused or 6,5-fused heteroaromatic ring, specifically

[0031]

[0032] in particular,

[0033] In some embodiments of the present invention, Ring B is a tricyclic heteroaromatic ring, such as a 5,6,5-fused, 6,5,5-fused or 5,6,6-fused heteroaromatic ring, specifically

[0034] In some embodiments of the present invention, A section can have the following structure:

[0035]

[0036]

[0037]

[0038] Specifically, R 2 Can be selected from: -H, -F, -Cl, -Br, -I, -CF 3 , -CHF 2 、-CH 2 F, -CH 2 CF 3 、-CN、-NO 2 、-CH 3 ,

[0039]

[0040]

[0041]

[0042] More specifically, R 2 Can be selected from: -H, -F, -Cl, -Br, -I, -CF 3 , -CHF 2 、-CH 2 F, -CH 2 CF 3 、-CN、-NO 2 、-CH 3 , -OH, -NH 2 ,

[0043] In some embodiments of the present invention, the compound has the following structure:

[0044]

[0045] Among them, A 1 Selected from: O, S, NH, CH 2 ;

[0046] A 2 Selected from: N, CH;

[0047] A 3 , A 4 , A 5 , A 6 Independently selected from: N, CH.

[0048] In some embodiments of the present invention, A 3 , A 4 , A 5 All are CH.

[0049] In some embodiments of the present invention, A 6 is N.

[0050] In some embodiments of the present invention, A 2 is N.

[0051] In some embodiments of the present invention, A 1 For S.

[0052] In some embodiments of the present invention, A 1 is O.

[0053] In some embodiments of the present invention, A 1 For NH.

[0054] In some embodiments of the present invention, the compound has the following structure:

[0055]

[0056] In some embodiments of the present invention, The section has the following structure:

[0057]

[0058]

[0059]

[0060]

[0061] In some embodiments of the present invention, the compound has the following structure:

[0062]

[0063]

[0064] In a second aspect of the present invention, provided are pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds of the compound of the first aspect.

[0065] Specifically, the stereoisomer has the following structure:

[0066]

[0067] In some embodiments of the present invention, the stereoisomer has the following structure:

[0068]

[0069] In the third aspect of the present invention, a pharmaceutical composition is provided, comprising the compound described in the first aspect or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound thereof, and one or more pharmaceutically acceptable excipients.

[0070] Specifically, in the pharmaceutical composition, the compound of the first aspect or its pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound can be used alone or in combination with other types of active ingredients.

[0071] Specifically, the pharmaceutically acceptable excipients may be selected from one or more of fillers, binders, lubricants, disintegrants, antioxidants, buffers, antibacterial agents, suspending agents, solubilizers, thickeners, stabilizers, preservatives, and the like.

[0072] Specifically, the pharmaceutical composition can be administered by any suitable route, such as gastrointestinal administration (e.g., oral, sublingual, rectal administration) or parenteral administration (e.g., intravenous, intramuscular, intranasal, intraocular, intracerebral, intravaginal, intraperitoneal, transdermal, subcutaneous, intradermal, respiratory tract administration, etc.).

[0073] Specifically, the pharmaceutical composition can be prepared into pharmaceutical preparations in the following forms: injection, syrup, elixir, suspension, powder, granule, tablet, capsule, lozenge, cream, ointment, lotion, gel, emulsion, etc.

[0074] When preparing injections, any commonly used carrier in the art can be used, such as water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyethoxylated isostearyl alcohol, and fatty acid esters of polyethylene sorbitan, etc. In addition, commonly used solvents and buffers can also be added.

[0075] Specifically, the pharmaceutical composition is preferably in unit dosage form. In this form, the preparation is subdivided into unit doses containing appropriate amounts of active ingredients. The unit dosage form can be a capsule, tablet or any dosage form; in addition, the unit dosage form can also be a packaged preparation, such as tablets, capsules and powders packaged in vials or ampoules.

[0076] Specifically, the amount of active ingredient in the unit dose formulation can be changed or adjusted from 0.1 mg to 1000 mg (e.g., 0.1, 1, 5, 10, 20, 40, 50, 100, 200, 400, 500, 1000 mg), depending on the specific application and efficacy of the active ingredient. If necessary, the composition may also include other suitable therapeutic agents.

[0077] In a fourth aspect of the present invention, there is provided use of the compound of the first aspect or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound thereof in the preparation of a medicament for preventing and / or treating an IKZF1-related disease.

[0078] Specifically, the disease is a disease that can be beneficially prevented and / or treated by degrading IKZF1, such as, but not limited to, tumors, autoimmune diseases, inflammatory diseases, diseases associated with pathogen infection, neurodegenerative diseases, heteroimmune diseases, and the like.

[0079] Specifically, the tumor includes but is not limited to: adrenal cancer, anal cancer, angiosarcoma, appendix cancer, bile duct cancer, bladder cancer, breast cancer, brain cancer, bronchial cancer, carcinoid tumor, cervical cancer, choriocarcinoma, chordoma, craniopharyngioma, colorectal cancer, connective tissue cancer, epithelial cancer, ependymoma, endothelial sarcoma, endometrial cancer, esophageal cancer, Ewing's sarcoma, eye cancer, gallbladder cancer, gastric cancer, gastrointestinal stromal tumor (GIST), germ cell cancer, head and neck cancer, hematological malignancies, hemangioblastoma, hypopharyngeal cancer, inflammatory myofibroblastic tumor , immune cell amyloidosis, kidney cancer, liver cancer, lung cancer, leiomyosarcoma (LMS), muscle cancer, mesothelioma, myeloproliferative disease (MPD), neuroblastoma, neurofibroma, neuroendocrine cancer, osteosarcoma, ovarian cancer, papillary adenocarcinoma, pancreatic cancer, penile cancer, pineal tumor, primitive neuroectodermal tumor (PNT), prostate cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer, small intestine cancer, soft tissue sarcoma, sebaceous gland cancer, sweat gland cancer, synovioma, testicular cancer, thyroid cancer, urethral cancer, vaginal cancer, vulvar cancer.

[0080] More specifically, the tumor is a hematological malignancy, such as leukemia, lymphoma, multiple myeloma (MM).

[0081] Specifically, the leukemia can be chronic lymphocytic leukemia (CLL) (e.g., B cell CLL, T cell CLL), chronic myeloid leukemia (CML) (e.g., B cell CML, T cell CML), acute lymphocytic leukemia (ALL) (e.g., B cell ALL, T cell ALL), acute myeloid leukemia (AML) (e.g., B cell AML, T cell AML), acute monocytic leukemia, particularly acute myeloid leukemia. Specifically, the leukemia can be relapsed, refractory or drug-resistant.

[0082] Specifically, the lymphoma may be Hodgkin lymphoma (HL) (e.g., B cell HL, T cell HL) and non-Hodgkin lymphoma (NHL) (e.g., B cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodular marginal zone B cell lymphoma, splenic marginal zone B cell lymphoma), primary mediastinal B cell lymphoma, Burkitt's lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenstrom's macroglobulinemia ( macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B lymphoblastic lymphoma and primary central nervous system (CNS) lymphomas and T-cell NHL, such as precursor T lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary syndrome)), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma and anaplastic large cell lymphoma, NK / T-cell lymphoma, in particular diffuse large B-cell lymphoma (DLBCL).

[0083] In some embodiments of the invention, the tumor is acute lymphoblastic leukemia (ALL).

[0084] Specifically, the autoimmune diseases include, but are not limited to, autoimmune diabetes (also known as type I diabetes or insulin-dependent diabetes), systemic lupus erythematosus, systemic vasculitis, regional enteritis, cardiomyopathy, hemolytic anemia, fibromyalgia, Graves' disease, ulcerative colitis, Crohn's disease, multiple sclerosis, myasthenia gravis, myositis, neutropenia, psoriasis, chronic fatigue syndrome, juvenile arthritis, juvenile diabetes, scleroderma, psoriatic arthritis, Sjögren's syndrome, rheumatic fever, rheumatoid arthritis, Arthritis, idiopathic thrombocytopenic purpura (ITP), Hashimoto's disease, mixed connective tissue disease, interstitial cystitis, pernicious anemia, leukoencephalitis, alopecia areata, ankylosing spondylitis, primary biliary cirrhosis, anti-GBM nephritis, anti-TBM nephritis, antiphospholipid syndrome, polymyalgia rheumatica, polymyositis, autoimmune Addison's disease, chronic active hepatitis, vitiligo, psoriasis, autoimmune hyperlipidemia, autoimmune myocarditis, temporal arteritis, autoimmune thyroid disease, axonal and neuronal neuropathy, Behcet's disease, bullous pemphigoid, allergy Asthma, osteoarthritis, Chagas' disease, uveitis, chronic inflammatory demyelinating polyneuropathy (CIDP), scar pemphigoid / benign mucous membrane pemphigoid, Kogan's syndrome, congenital heart block, coxsackievirus myocarditis, demyelinating neuropathy, dermatomyositis, discoid lupus, lens antigen uveitis, polyarteritis nodosa, Dressler's syndrome, essential mixed cryoglobulinemia, Evans syndrome, Goodpasture's syndrome, allergic rhinitis, infectious neuronitis, hypogammaglobulinemia, inclusion body myositis, bullous Herpes (vesiculobullous) skin disease, Wegener's granulomatosis, Meniere's disease, Lambert-Eaton syndrome, Moren's ulcer, atypical celiac disease, ocular cicatricial pemphigoid, pemphigus vulgaris, perivenous encephalomyelitis, postpericardiotomy syndrome, scleritis, sperm testicular autoimmunity, stiff-man syndrome, subacute bacterial endocarditis (SBE), sympathetic ophthalmia, transverse myelitis and necrotizing myelopathy, autoimmune polyglandular syndrome type I, autoimmune polyglandular syndrome type II, pernicious anemia and endometriosis, etc.

[0085] In some embodiments of the invention, the autoimmune disease is systemic lupus erythematosus (SLE).

[0086] In some embodiments of the invention, the autoimmune disease is type I diabetes or autoimmune thyroid disease.

[0087] Specifically, the inflammatory diseases include, but are not limited to, osteoarthritis, acute gout, multiple sclerosis, inflammatory bowel disease (such as Crohn's disease and ulcerative colitis), neuroinflammation, asthma, chronic obstructive airway disease, pneumonia, myositis, eczema, dermatitis, acne, cellulitis, occlusive disease, thrombosis, alopecia, nephritis, vasculitis, retinitis, uveitis, scleritis, sclerosing cholangitis, hypophysitis, thyroiditis, septic shock, systemic inflammatory response syndrome (SIRS), toxic shock syndrome, acute lung injury, ARDS (adult respiratory distress syndrome), acute renal failure, burns, pancreatitis (such as acute pancreatitis), postoperative syndrome, sarcoidosis, Herxheimer reaction, encephalitis, myelitis, meningitis and malaria, etc.

[0088] Specifically, the neurodegenerative diseases include, but are not limited to, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), different types of spinocerebellar ataxia (SCA), Pick's disease, etc.

[0089] Specifically, the pathogen may be a microorganism, a parasite (protozoa, worms, etc.) or other agents.

[0090] Specifically, the microorganism can be selected from one or more of: viruses, chlamydia, rickettsia, mycoplasma, bacteria, spirochetes, fungi and the like.

[0091] In one embodiment of the present invention, the pathogen is a virus, for example, but not limited to, Adenoviridae (such as adenovirus), Herpesviridae (such as HSV1 (oral herpes), HSV2 (external genital herpes), VZV (varicella), EBV (Epstein-Barr virus), CMV (cytomegalovirus)), Poxviridae (such as smallpox virus, vaccinia virus), Papovaviridae (such as papillomavirus (HPV)), Parvoviridae (such as B19 virus), Hepadnaviridae (such as hepatitis B virus), Polyomaviridae (such as polyomavirus), Reoviridae (such as reovirus, rotavirus), Picornaviridae (such as enterovirus, foot-and-mouth disease virus), Caliciviridae (such as Norwalk virus, hepatitis E virus), Togaviridae (such as rubella virus), Arenaviridae (such as lymphocytic choriomeningitis virus), Retroviridae (HIV-1, HIV-2, HTLV-1), Flaviviridae ( Such as dengue virus, Zika virus, Japanese encephalitis virus, Chikungunya virus, yellow fever virus, hepatitis C virus, West Nile virus, etc.), Orthomyxoviridae (such as influenza virus (such as influenza A virus, influenza B virus, influenza C virus, etc.)), Paramyxoviridae (such as human parainfluenza virus (HPIV) type 1, HPV type 2, HPV type 3, HPV type 4, Sendai virus, mumps virus, measles virus, respiratory syncytial virus, Newcastle disease virus, etc.), Bunyaviridae (such as California encephalitis virus, Hantavirus), Rhabdoviridae (such as rabies virus), Filoviridae (such as Ebola virus, Marburg virus), Coronaviridae (such as HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV, SARS-CoV-2, etc.), Astroviridae (such as astrovirus), Bornaviridae (such as Borna virus).

[0092] Specifically, the diseases related to the pathogen infection include but are not limited to: influenza, SARS, COVID-19, viral hepatitis (such as hepatitis A, hepatitis B, hepatitis C, hepatitis D, etc.), AIDS, rabies, dengue fever, Ebola virus disease, etc.

[0093] Specifically, the xenoimmune disease is a rejection reaction after organ transplantation.

[0094] In the fifth aspect of the present invention, a method for preventing and / or treating IKZF1-related diseases is provided, comprising the step of administering to a subject in need thereof an effective amount of the compound of the first aspect or its pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound, or the pharmaceutical composition of the third aspect.

[0095] Specifically, the disease is as described in the fourth aspect of the present invention.

[0096] Specifically, the subject is a mammal, especially a human. DETAILED DESCRIPTION

[0097] Unless otherwise defined, all scientific and technical terms used in the present invention have the same meanings as commonly understood by one of ordinary skill in the art to which the present invention relates.

[0098] In the present invention, the term "aliphatic group" refers to a straight or branched hydrocarbon chain that is completely saturated or contains one or more unsaturated units, or a cyclic hydrocarbon group that is completely saturated or contains one or more unsaturated units (also referred to herein as "carbocycle", "aliphatic ring", "cycloalkyl"), which is connected to the rest of the molecule by a single bond. Suitable aliphatic groups include, but are not limited to, straight or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl and mixtures thereof, such as (cycloalkyl) alkyl, (cycloalkenyl) alkyl, (cycloalkyl) alkenyl, etc. Typical aliphatic groups contain 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, preferably 1 to 6 carbon atoms.

[0099] The term "alkyl" refers to a straight or branched hydrocarbon chain radical that does not contain an unsaturated bond, and the hydrocarbon chain radical is connected to the rest of the molecule by a single bond. A typical alkyl group contains 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, preferably 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, etc. In the present invention, C 0 Alkyl refers to H, i.e. C 0-10 Alkyl (or C 0 -C 10 Alkyl) includes H and C 1-10 Alkyl (or C 1 -C 10 alkyl).

[0100] The term "alkylene" refers to a hydrocarbon group (divalent alkyl) formed by losing two hydrogen atoms from an alkane molecule, which can be a straight chain or branched chain and is connected to the rest of the molecule by a single bond. In this context, a typical alkylene group has 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, preferably 1 to 6 carbon atoms, such as a methylene group (-CH 2 -), ethylene, propylene, butylene, etc. In the present invention, C 0 Alkylene refers to a single bond, i.e. C 0-10 Alkylene (or C 0 -C 10 Alkylene) includes a single bond and C 1-10 Alkylene (or C 1 -C10 alkylene).

[0101] The term "cycloalkyl" refers to alicyclic hydrocarbons, such as those containing 1 to 4 single rings and / or condensed rings, 3-18 carbon atoms, preferably 3-10 (e.g. 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantyl, etc.

[0102] The term "alkoxy" refers to a substituent formed by replacing the hydrogen in a hydroxy group with an alkyl group, such as an alkoxy group containing 1 to 10 carbon atoms, for example, methoxy, ethoxy, propoxy, butoxy, and the like.

[0103] The term "alkylamino" refers to an amino group (-NH 2 ) is replaced by an alkyl group, such as an alkylamino group containing 1 to 10 carbon atoms, for example

[0104] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0105] The term "haloalkyl" refers to a group formed by replacing one or more hydrogen atoms in an alkyl group with a halogen atom (such as fluorine, chlorine, bromine or iodine), such as -CHF 2 、-CH 2 F, -CF 3 、-CH 2 -CF 3 、-CH 2 CH 2 -CF 3 、-CH 2 CH 2 CH 2 -CF 3 .

[0106] The term "aryl" refers to a monocyclic or polycyclic free radical, including a polycyclic free radical containing a monocyclic aromatic group and / or a condensed aromatic group, such as a free radical containing 1-3 monocyclic or condensed rings and 6-18 (e.g., 6, 8, 10, 12, 14, 16, 18) carbon ring atoms. 6 -C 12 The aryl group refers to an aryl group containing 6 to 12 carbon ring atoms, such as phenyl, naphthyl, biphenyl, indenyl and the like.

[0107] The term "heterocyclyl" refers to a 3- to 18-membered non-aromatic ring group containing 2 to 17 carbon atoms and 1 to 10 heteroatoms. The heterocyclyl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can contain fused, spirocyclic or bridged ring systems. The heterocyclyl group can be partially saturated (heteroaryl) or fully saturated (heterocycloalkyl). Suitable heteroaryl groups in the compounds of the present invention contain 1, 2 or 3 heteroatoms selected from N, O, S and P atoms, and include, for example, coumarin, including 8-coumarin, quinolyl, including 8-quinolyl, isoquinolyl, pyridinyl, pyrazinyl, pyrazolyl, pyrimidinyl, furanyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, imidazolyl, indolyl, isoindolyl, indazolyl, indolizinyl, phthalazinyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, pyridazinyl, triazinyl, cinnolinyl, benzimidazolyl, benzofuranyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl and furopyridinyl. Suitable heterocycloalkyl groups in the compounds of the present invention contain 1, 2 or 3 heteroatoms selected from N, O or S atoms, and include, for example, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, oxathiolanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxirane, thiirane, azepine, oxazepine, diazepine, In the present invention, for the optionally substituted heterocyclic group, the substituted position can be any suitable carbon atom or heteroatom, for example, The substitution position of R can be on any suitable carbon atom or nitrogen atom, which can be, for example

[0108] In the present invention, "D" refers to deuterium; "substituted by deuterium" means replacing one or more hydrogen atoms with a corresponding number of deuterium atoms.

[0109] It should be recognized that, depending on the source of the chemical materials used in the synthesis, there is some variation in the natural isotopic abundance in the synthesized compounds. Therefore, the compounds of the present invention will inherently contain small amounts of deuterated isotopologues. Despite this variation, the concentration of such naturally abundant stable hydrogen and carbon isotopes is still very low and insignificant compared to the degree of stable isotopic substitution of the compounds of the present invention. See, for example, Wada, E et al., Seikagaku, 1994, 66: 15; Gannes, LZ et al., Comp Biochem Physiol Mol Integr Physiol, 1998, 119: 725.

[0110] In the compounds of the present invention, any atom not designated as deuterium is present at its natural isotopic abundance. Unless otherwise specified, when a position is specifically designated as "H" or "hydrogen", the position is understood to have hydrogen according to its natural abundance isotopic composition. Similarly, unless otherwise specified, when a position is specifically designated as "D" or "deuterium", the position is understood to have deuterium at an abundance of at least 3000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 45% deuterium incorporation).

[0111] As used herein, the term "isotopic enrichment factor" refers to the ratio between the isotopic abundance and the natural abundance of a particular isotope.

[0112] In other embodiments, the compounds of the invention have an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[0113] The term "isotopologue" refers to species wherein the chemical structure differs from a specific compound of the present invention only in its isotopic composition.

[0114] The term "pharmaceutically acceptable salts" includes acid addition salts and base addition salts.

[0115] The term "acid addition salt" includes, but is not limited to, salts from inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic and phosphonic acids, and salts from organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids and aliphatic and aromatic sulfonic acids. Therefore, these salts include but are not limited to sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, hydrochloride, hydrobromide, iodate, acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate and mesylate, also comprising amino acid salts such as arginate, gluconate, galacturonate etc. Acid addition salts can be prepared by contacting the free alkali form with a sufficient amount of the required acid to form a salt in a conventional manner. The free alkali form can be regenerated by contacting the salt form with an alkali, and the free alkali is separated in a conventional manner.

[0116] The term "base addition salt" refers to a salt formed with a metal or amine, such as an alkali metal and alkaline earth metal hydroxide, or with an organic amine. Examples of metals used as cations include, but are not limited to, sodium, potassium, magnesium, and calcium. Examples of suitable amines include, but are not limited to, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine (ethane-1,2-diamine), N-methylglucamine, and procaine. Base addition salts can be prepared by contacting the free acid form with a sufficient amount of the desired base in a conventional manner to form a salt. The free acid form can be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner.

[0117] The term "stereoisomer" includes the presence of enantiomers, diastereomers and geometric isomers. Some compounds of the present invention have cyclic hydrocarbon groups that can be substituted on more than one carbon atom, in which case all geometric forms, including cis and trans, and mixtures thereof, are within the scope of the present invention.

[0118] The term "solvate" refers to a physical association of a compound of the invention with one or more solvent molecules. The physical association includes various degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, the solvate can be isolated, for example when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Solvates include solution phases and separable solvates. Representative solvates include ethanolates, methanolates, and the like.

[0119] The term "prodrug" refers to a form of the compound of formula I which is suitable for administration to patients without undue toxicity, irritation, allergic response, etc. and is effective for its intended use, including acetal, ester and zwitterion forms. The prodrug is transformed in vivo, such as by hydrolysis in the blood, to yield the parent compound.

[0120] The term "patient" or "subject" and the like are used interchangeably herein and refer to any animal or cell thereof treated according to the methods described herein, whether in vitro or in situ. Specifically, the aforementioned animal includes mammals, e.g., rats, mice, guinea pigs, rabbits, dogs, monkeys or humans, particularly humans.

[0121] The term "treating" refers to preventing, curing, reversing, attenuating, alleviating, minimizing, inhibiting, suppressing and / or halting one or more clinical symptoms of a disease after onset of the disease.

[0122] The term "prevent" refers to avoiding, minimizing or making the onset or development of a disease difficult by treating it before it occurs.

[0123] The term "tumor" refers to an abnormal mass of tissue, wherein the growth of the mass exceeds the growth of normal tissue and is not coordinated with the growth of normal tissue. Tumors can be "benign" or "malignant", depending on the following characteristics: degree of cell differentiation (including morphology and function), growth rate, local invasion and metastasis. "Benign tumors" are usually well-differentiated, characterized by slower growth than malignant tumors, and remain confined to the site of origin. In addition, benign tumors do not have the ability to infiltrate, invade or metastasize to distant sites. In some cases, some "benign" tumors may later lead to malignant tumors, which may be caused by additional genetic changes in a subpopulation of the neoplastic cells of the tumor, and these tumors are called "precancerous tumors". "Malignant tumors" are usually poorly differentiated (anaplastic) and have a characteristic rapid growth, accompanied by progressive infiltration, invasion and destruction of surrounding tissues. In addition, malignant tumors usually have the ability to metastasize to distant sites.

[0124] The term "cancer" refers to a malignant tumor (Stedman's Medical Dictionary, 25th ed.; Hensyled.; Williams & Wilkins: Philadelphia, 1990).

[0125] The term "autoimmune disease" refers to a disease caused by the body's immune response to its own antigens, resulting in damage to its own tissues.

[0126] The term "inflammation" is the body's defense response to stimulation, manifested as redness, swelling, heat, pain, and dysfunction, etc. It can be infectious inflammation caused by infection, or non-infectious inflammation not caused by infection, such as inflammation caused by immune response (such as various types of hypersensitivity reactions, inflammation caused by some autoimmune diseases). The term "inflammatory disease" refers to a disease with inflammation.

[0127] The term "disease associated with pathogen infection" mainly refers to diseases caused by pathogen infection, including symptoms of body damage caused by pathogen invasion and manifestations of infection response. The pathogen can be a microorganism (such as virus, chlamydia, rickettsia, mycoplasma, bacteria, spirochetes, fungi, etc.), a parasite (protozoa, worms, etc.) or other vectors. In particular, the pathogen is a virus, for example, but not limited to, adenoviridae (such as adenovirus), herpesviridae (such as HSV1 (oral herpes), HSV2 (external genital herpes), VZV (varicella), EBV (Epstein-Barr virus), CMV (cytomegalovirus)), poxviridae (such as smallpox virus, cowpox virus), papovarus, leukoencephalitis, leukemia ... Viridae (such as papillomavirus (HPV)), Parvoviridae (such as B19 virus), Hepadnaviridae (such as hepatitis B virus), Polyomaviridae (such as polyomavirus), Reoviridae (such as reovirus, rotavirus), Picornaviridae (such as enterovirus, foot-and-mouth disease virus), Caliciviridae (such as Norwalk virus, hepatitis E virus), Togaviridae (such as rubella virus), Arenaviridae (such as lymphocytic choriomeningitis virus), Retroviridae (such as HIV), -1, HIV-2, HTLV-1), Flaviviridae (such as dengue virus, Zika virus, Japanese encephalitis virus, Chikungunya virus, yellow fever virus, hepatitis C virus, West Nile virus, etc.), Orthomyxoviridae (such as influenza virus (such as influenza A virus, influenza B virus, influenza C virus, etc.)), Paramyxoviridae (such as human parainfluenza virus type 1 (HPIV), HPV type 2, HPV type 3, HPV type 4, Sendai virus, mumps virus, measles virus, respiratory syncytial virus, Newcastle disease virus, etc.), Bunyaviridae (such as California encephalitis virus, Hantavirus), Rhabdoviridae (such as rabies virus), Filoviridae (such as Ebola virus, Marburg virus), Coronaviridae (such as HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV, SARS-CoV-2, etc.), Astroviridae (such as Astrovirus), Bornaviridae (such as Borna virus).

[0128]

[00136] Various publications, patents, and published patent specifications are cited herein, the disclosures of which are incorporated by reference in their entireties.

[0129] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0130] Compound Preparation Example:

[0131] Example 1: Preparation of Compound 1

[0132]

[0133] The synthesis steps are as follows:

[0134] Step 1:

[0135]

[0136] At room temperature, 01 (5.25 g, 33 mmol) was dissolved in dichloromethane (50 mL), and DMF (1d) was added at 0°C. (COCl) 2 (16.8 g, 132 mmol). The mixture was stirred at room temperature for 10 minutes. After 10 minutes, the reaction solution was concentrated to obtain a crude product, which was dissolved in dichloromethane (40 mL) and ammonia (10 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated to obtain a crude product, which was purified by column chromatography (petroleum ether: ethyl acetate = 1:20) to obtain a yellow solid 02 (4.85 g, yield: 93.09%). LC-MS: 156.8 [MH] +

[0137] Step 2:

[0138]

[0139] At room temperature, 02 (1 g, 6.3 mmol) was dissolved in acetonitrile (15 mL), and DIEA (2.45 g, 19.0 mmol) and 03 (1.43 g, 12.7 mmol) were added. The mixture was reacted at 70 ° C for 16 hours. After the reaction, the reaction solution was concentrated to obtain a crude product, 30 mL of water was added to the crude product for dilution, ethyl acetate (30 mL × 3) was extracted, and saturated brine (20 mL × 3) was washed, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was subjected to column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain a light yellow solid 04 (600 mg, yield: 37.74%). LC-MS: 252.2.0 [M+H] +

[0140] Step 3:

[0141]

[0142] At room temperature, BH 3 / THF (20mL) was heated to 40°C, 04 (560mg, 2.23mmol) was added, and the mixture was stirred at 40°C for 4 hours. After cooling to room temperature, methanol was added to the reaction solution to quench it, and the quenched reaction solution was concentrated to obtain a crude product, which was purified by column chromatography (dichloromethane: methanol = 20: 1) to obtain a white solid 05 (170mg, yield: 32.15%). LC-MS: 238.1 [M+H] +

[0143] Step 4:

[0144]

[0145] At room temperature, 05 (150 mg, 0.6 mmol) and 06 (350 mg, 1.3 mmol) were dissolved in DMSO (2 mL), and DIEA (345 mg, 1.9 mmol) was added. The mixture was reacted at 100 ° C in a microwave for 2 hours. After the reaction, the crude product was purified by reverse phase chromatography to obtain the title compound as a yellow-green solid (18.5 mg, yield: 6%). LC-MS: 494.1 [M+H] +

[0146] 1 H NMR (400 MHz, DMSO-d 6 )δ11.09(s,1H),7.69(d,J=5.1Hz,1H),7.54(t,J=8.0Hz,1H),7.17-7.10(m,1H),7.06(d, J=7.2Hz,1H),6.96(d,J=8.5Hz,1H),6.65-6.55(m,1H),6.40(t,J=4.8Hz,1H),5.07(dd,J =12.9,5.4Hz,1H),4.57(d,J=6.6Hz,2H),3.16(t,J=6.3Hz,2H),2.95-2.82(m,1H),2.70- 2.55(m,2H),2.10-2.00(m,1H),1.75-1.55(m,6H),1.20-1.08(m,3H),0.95-0.82(m,2H).

[0147] Example 2: Preparation of Compound 2

[0148]

[0149] The synthesis steps are as follows:

[0150] Step 1:

[0151]

[0152] At room temperature, 01 (20 g, 125.8 mmol) was dissolved in dichloromethane (200 mL). DMF (5 d) was added at 0 °C. (COCl) was added. 2 (31.9 g, 251.5 mmol). The mixture was stirred at room temperature for 1 hour. After 1 hour, the reaction solution was concentrated to obtain a crude product, which was dissolved in methanol (200 mL). The mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated to obtain a crude product, which was purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain a white solid 02 (18 g, yield: 82.9%). TLC (PE: EA = 5:1)

[0153] Step 2:

[0154]

[0155] At room temperature, 02 (18 g, 104 mmol) was dissolved in methanol (200 mL), and LiBH was added at 0 °C. 4 (3.4 g, 156 mmol). The mixture was reacted at room temperature for 1 hour. After the reaction was completed, the reaction solution was quenched with water, extracted with dichloromethane (150 mL × 3), washed with saturated brine (100 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was subjected to column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain a white solid 03 (11 g, yield: 73.33%). LC-MS: 313.0 [2M + Na] +

[0156] Step 3:

[0157]

[0158] At room temperature, 04 (8 g, 32.4 mmol) and 03 (5.6 g, 38.9 mmol) were dissolved in DMSO (40 mL), and DIEA (20.9 g, 162 mmol) was added. The mixture was stirred in a microwave at 150 ° C for 2 hours. After cooling to room temperature, the reaction solution was diluted with (400 mL) of water, extracted with ethyl acetate (400 mL × 3), washed with saturated brine (100 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was subjected to column chromatography (petroleum ether: ethyl acetate = 2:3) to obtain a white solid 05 (3.6 g, yield: 30.0%). LC-MS: 373.0 [M + H] +

[0159] Step 4:

[0160]

[0161] At room temperature, 05 (3.6 g, 9.68 mmol) was dissolved in dichloromethane (10 mL) and toluene (20 mL), and pyridine (306 mg, 3.9 mmol) was added. The mixture was reacted at room temperature for 30 minutes. After 30 minutes, SOCl was slowly added dropwise. 2 (2.3 g, 19.4 mmol). The mixture was stirred at 100°C for 2 hours. After the reaction, the reaction solution was concentrated to obtain a crude product, which was purified by column chromatography (dichloromethane: methanol = 10:1) to obtain a yellow solid 06 (2.4 g, yield: 63.66%). LC-MS: 391.1 [M+H] +

[0162] Step 5:

[0163]

[0164] At room temperature, 06 (2.4 g, 6.15 mmol) and 07 (2.4 g, 9.23 mmol) were dissolved in DMF (10 mL), and K 2 CO 3 (5.09 g, 36.92 mmol). The mixture was reacted at 40°C for 16 hours. After the reaction, the crude product was purified by reverse phase chromatography to obtain the title compound as a white solid (640.36 mg, yield: 17.3%). LC-MS: 615.0 [M+H] +

[0165] 1 H NMR (400MHz, DMSO-d6) δ10.96(s,1H),8.56(dd,J=4.6,1.5Hz,1H),8.32(dd,J=8.2,1.5Hz,1H),7.82(d,J=5.1Hz,1H),7 .56–7.49(m,2H),7.35(t,J=7.3Hz,2H),6.80(s,1H),6.64(t,J=4.8Hz,1H),5.28(s,2H),5.11(dd,J=13.3,5.0Hz,1H), 4.35(dd,J=65.2,17.5Hz,2H),3.15–3.8(m,2H),2.94–2.88(m,1H),2.68–2.66(m,1H),2.60–2.54(m,1H),2.46–2.40(m ,1H),2.33–2.30(m,1H),2.24–2.18(m,2H),2.02–1.96(m,1H),1.95–1.90(m,2H),1.61–1.52(m,2H),1.21–1.13(m,2H).

[0166] Example 3: Preparation of Compound 3

[0167]

[0168] The synthesis steps are as follows:

[0169] Step 1:

[0170]

[0171] 1 (4.0 g, 10.23 mmol) (prepared in Example 2) was dissolved in dioxane (10 mL) at room temperature, and then ammonia water (10 mL) was added. The mixture was reacted for 16 hours in a sealed container. The reaction solution was dried by rotary evaporation and purified by a rapid silica gel column (methanol / dichloromethane = 0-20%) to obtain a yellow solid as the target product (2.0 g, yield: 52.61%). LC-MS: 371.2 [M+H] + .

[0172] Step 2:

[0173]

[0174] 2 (2.0 g, 5.38 mmol), 3 (2.23 g, 8.08 mmol) and N,N-diisopropylethylamine (2.8 g, 21.52 mmol) were dissolved in anhydrous dimethyl sulfoxide (10 mL) at room temperature, and the reaction mixture was subjected to microwave reaction at 120°C for 2 hours. The mixture was separated by reverse phase liquid phase preparation (C18, 5-100% acetonitrile / water as mobile phase, 0.1% formic acid), and the obtained product was lyophilized with dilute hydrochloric acid to obtain the title compound (450 mg, yield: 13.3%, yellow solid). LC-MS: 628.2 [M+H] + ,

[0175] 1H NMR (400MHz, DMSO-d6) δ11.11(s,1H),8.57(d,J=4.4Hz,1H),8.32(d,J=8.1Hz,1H),7.71(d,J=5.9H z,1H),7.56(dd,J=11.4,5.6Hz,2H),7.36–7.20(m,1H),7.09(d,J=7.1Hz,1H),6.98(d,J=8.6Hz,1H ),6.61(dd,J=7.6,5.5Hz,1H),5.09(dd,J=12.7,5.3Hz,1H),4.69–4.64(m,2H),3.36–3.26(m,3H), 3.19–3.08(m,1H),2.98–2.84(m,1H),2.62–2.54(m,2H),2.22–2.19(m,2H),2.09–2.02(m,1H),2.00 -1.90(m,2H),1.83–1.66(m,1H),1.67–1.50(m,2H),1.34–1.12(m,2H).

[0176] Example 4: Preparation of Compound 4

[0177]

[0178] The synthesis steps are as follows:

[0179] Step 1:

[0180]

[0181] At room temperature, 01 (1.25 g, 8.62 mmol), 05 (2 g, 7.22 mmol), and N-ethyldiisopropylamine (12.6 mL, 72.47 mmol) were mixed in dimethyl sulfoxide (20 mL), and the reaction mixture was subjected to microwave reaction at 120°C for 2 hours. 160 mL of water was added to the reaction solution and extracted three times with 50 mL of dichloromethane. The organic phase was washed twice with 30 mL of water and once with 30 mL of brine, and then the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain yellow oil 02 (313 mg, yield 9%). LC-MS: 403.0 [M+H] + .

[0182] Step 2:

[0183]

[0184] At room temperature, 02 (434 mg, 1.08 mmol), thionyl chloride (0.16 mL, 2.2 mmol) and pyridine (35 uL, 0.43 mmol) were mixed in anhydrous toluene (5 mL), and the reaction mixture was stirred at 100 ° C for 2 hours. The reaction solution was spin-dried and separated by column chromatography to obtain a yellow solid 03 (289 mg, crude product). Then 100 mg of the yellow crude product was purified by thin layer chromatography to obtain a yellow oil 03 (70 mg) LC-MS: 421.0 [M+H] + , TLC: petroleum ether:ethyl acetate=5:1, Rf=0.3.

[0185] Step 3:

[0186]

[0187] At room temperature, 03 (70 mg, 0.167 mmol), 04 (65 mg, 0.25 mmol) and potassium carbonate (138 mg, 0.998 mmol) were mixed in anhydrous N,N-dimethylformamide (0.5 mL), and the reaction mixture was stirred at 40 ° C for 16 hours. The title compound was obtained by reverse preparation as a white solid (2.04 mg, yield: 2%). LC-MS: 645.3 [M+H] + .

[0188] 1 H NMR (400MHz, DMSO-d6) δ10.97(s,1H),8.46(s,1H),8.23(d,J=8.8Hz,1H),7.78(d,J=5.1Hz,1H),7.51(t,J=7 .8Hz,1H),7.35(dd,J=11.6,7.8Hz,2H),6.96(d,J=8.8Hz,1H),6.82–6.75(m,1H),6.63(t,J=4.9Hz,1H),5.2 7(s,2H),5.10(dd,J=13.2,4.9Hz,1H),4.35(dd,J=64.4,17.6Hz,2H),3.93(s,3H),3.60–3.50(m,2H),3.31– 3.28(m,2H),3.04–2.87(m,2H),2.64–2.57(m,1H),2.06–1.85(m,4H),1.69–1.61(m,2H),1.53–1.40(m,2H).

[0189] Example 5: Preparation of Compound 5

[0190]

[0191] The synthesis steps are as follows:

[0192] Step 1:

[0193]

[0194] Under ice bath, sodium borohydride (1.99 g, 52.5 mmol) was added to a solution of 01 (1 g, 7.51 mmol), anhydrous nickel chloride (973 mg, 7.51 mmol) and di-tert-butyl dicarbonate (3.278 g, 15.02 mmol) in MeOH (48 mL) and THF (32 mL), and the mixture was reacted at room temperature for 12 hours. The mixture was quenched with water, extracted with ethyl acetate (50 mL × 3), the organic phases were combined, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, and dried by spin drying. A colorless oily liquid (1.12 g, yield: 62.6%) was obtained by column chromatography (ethyl acetate: petroleum ether = 1:2). LC-MS: 260.3 [M + H] +

[0195] Step 2:

[0196]

[0197] 02 (300 mg, 1.264 mmol) and CBr were added at room temperature. 4 (503mg, 1.517mmol) was added to a DCM (5mL) solution, and triphenylphosphine (398mg, 1.517mmol) was added under argon protection in an ice bath, and the mixture was reacted at room temperature for 12 hours. The mixture was quenched with water, extracted with ethyl acetate (50mL×3), and the organic phases were combined, washed with saturated brine (50mL×2), dried over anhydrous sodium sulfate, and dried by spin drying. The mixture was purified by column chromatography (ethyl acetate: petroleum ether=1:2) to obtain a white solid (277mg, yield: 73.3%). LC-MS: 244.1[M+H] +

[0198] Step 3:

[0199]

[0200] Sodium borohydride (146.52 mg, 3.873 mmol) was added to a MeOH (10 mL) solution of 11 (300 mg, 1.291 mmol) at room temperature and reacted at room temperature for 1 hour. Saturated ammonium chloride was added to quench the mixture under ice bath, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, and dried by spin drying. The mixture was purified by column chromatography (methanol: dichloromethane = 1:10) to obtain a white oily liquid (172 mg, yield: 56.9%). LC-MS: 235.2 [M+H] +

[0201] Step 4:

[0202]

[0203] Under ice bath, sodium hydride (42.624 mg, 1.776 mmol) was added to THF (10 mL) of intermediate 12 (104 mg, 0.444 mmol) and intermediate 04 (200 mg, 0.666 mmol), and the mixture was reacted at 40°C for 2 hours. The mixture was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, and dried by spin drying. The mixture was purified by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain a yellow solid (133 mg, yield: 66.1%). LC-MS: 454.3 [M + H] +

[0204] Step 5:

[0205]

[0206] Trifluoroacetic acid (2 mL) was added to 13 (90 mg, 0.199 mmol) in dichloromethane (2 ml) at room temperature, and the mixture was reacted at room temperature for 12 hours, dried by rotation, and purified by reverse phase (acetonitrile / water = 35%, 0.3% FA) to obtain a purple solid (20 mg, yield: 28.5%). LC-MS: 354.3 [M+H] +

[0207] Step 6:

[0208]

[0209] In a 100 mL single-mouth bottle, 14 (20 mg, 0.0566 mmol), 15 (15.634 mg, 0.0566 mmol), N,N-diisopropylethylamine (21.94 mg, 0.1698 mmol) and dimethyl sulfoxide (1 mL) were added and reacted at 120°C for 12 hours. The reaction solution was purified by HPLC to obtain the title compound as a yellow solid (0.91 mg, yield: 2.6%). LC-MS: 610.3 [M+H] +

[0210] 1 H NMR (400 MHz, DMSO-d 6)δ11.11(s,1H),7.73(s,1H),7.53–7.46(m,1H),7.38(s,1H),7.27–7.22(m ,3H),7.12(s,1H),7.04–6.98(m,2H),6.91(t,J=5.9Hz,2H),5.11–5.06(m, 1H),4.52(d,J=5.9Hz,2H),4.38(s,2H),2.88(d,J=11.6Hz,2H),2.59(d,J= 22.9Hz, 4H), 2.01 (dd, J=14.8, 7.1Hz, 4H), 1.82–1.72 (m, 2H), 1.46 (s, 2H).

[0211] Example 6: Preparation of Compound 6

[0212]

[0213] The synthesis steps are as follows:

[0214] Step 1:

[0215]

[0216] At room temperature, the raw material 01 (900 mg, 3.88 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and lithium bis(trimethylsilyl)amide (5.81 mL, 5.81 mmol, 1 M tetrahydrofuran solution) was added dropwise at -70 ° C. The reaction mixture was stirred at -70 ° C for 0.5 hours, and 02 (2.07 g, 5.79 mmol) was added. The reaction mixture was stirred at room temperature for 16.5 hours. Water (100 mL) and ethyl acetate (50 mL × 3) were added for extraction, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and dried. The residue was purified by silica gel column (petroleum ether: ethyl acetate = 4: 1-3: 1) to obtain a white solid as the target product (800 mg, 57.2%). LC-MS: 365.2 [M + H] + .

[0217] Step 2:

[0218]

[0219] At room temperature, 03 (800 mg, 2.201 mmol), biboronic acid pinacol ester (840 mg, 3.307 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (164 mg, 0.224 mmol) and potassium acetate (439 mg, 4.381 mmol) were dissolved in 1,4-dioxane (10 mL), and the reaction mixture was stirred at 90 ° C under argon protection for 16 hours. Water (100 mL) was added, extracted with ethyl acetate (50 mL × 3), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and dried. The residue was purified by silica gel column (petroleum ether: ethyl acetate = 3: 1-2: 1) to obtain a white solid as the target product (450 mg, 58.7%). LC-MS: 343.2 [M + H] + .

[0220] Step 3:

[0221]

[0222] At room temperature, 04 (450 mg, 1.316 mmol), 05 (468 mg, 1.973 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (97 mg, 0.131 mmol) and potassium carbonate (362 mg, 2.630 mmol) were dissolved in 1,4-dioxane (4 mL) and water (1 mL), and the reaction mixture was stirred at 90 ° C under argon protection for 16 hours. Water (50 mL) and ethyl acetate (20 mL × 3) were added to extract, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and dried. The residue was purified by silica gel column (ethyl acetate: petroleum ether = 33%) to obtain a brown solid as the target product (300 mg, 69.6%). LC-MS: 375.2 [M + H] + .

[0223] Step 4:

[0224]

[0225] At room temperature, 06 (130 mg, 0.348 mmol) was dissolved in tetrahydrofuran (10 mL), and Raney nickel (100 mg) was added at room temperature. The reaction mixture was stirred under a hydrogen balloon at room temperature for 6 hours. Filter and spin dry to obtain a colorless viscous liquid as the target product (80 mg, crude product). LC-MS: 379.1 [M+H] + .

[0226] Step 5:

[0227]

[0228] At room temperature, 07 (75 mg, 0.198 mmol) was dissolved in tetrahydrofuran (10 mL), wet palladium hydroxide on carbon (100 mg) was added, and the hydrogen was replaced twice, and the mixture was stirred under a hydrogen balloon at room temperature for 16 hours. The mixture was filtered and the filtrate was dried by rotary evaporation. The residue was separated by silica gel column (petroleum ether: ethyl acetate = 1:1-2:3) to obtain a yellow solid as the target product (20 mg, yield: 26.7%). LC-MS: 381.2 [M+H] + .

[0229] Step 6:

[0230]

[0231] At room temperature, 08 (15 mg, 0.0395 mmol), 09 (15 mg, 0.0543 mmol) and N,N-diisopropylethylamine (15 mg, 0.116 mmol) were mixed in dimethyl sulfoxide (1 mL). The reaction mixture was stirred at 120°C for 2 hours. After the mixture was cooled to 20°C, it was separated by preparative chromatography (C18, 5-100% acetonitrile / water as mobile phase, 0.1% formic acid) to obtain the title compound as a yellow solid (2.17 mg, yield: 20.9%). LC-MS: 637.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.10(s,1H),8.56(d,J=4.3Hz,1H),8.32(d,J=7.9Hz,1H),8.03(s,1 H),7.90(d,J=8.4Hz,1H),7.56–7.46(m,3H),7.33(s,1H),7.00(dd,J=18 .0,7.8Hz,2H),5.08(dd,J=12.5,5.1Hz,1H),4.69(d,J=5.7Hz,2H),3.4 5(s,1H),2.96–2.85(m,1H),2.60(d,J=16.1Hz,2H),2.20–2.01(m,10H).

[0232] Example 7: Preparation of Compound 7

[0233]

[0234] The synthesis steps are as follows:

[0235] Step 1:

[0236]

[0237] Dissolve 01 (719 mg, 2.74 mmol), 02 (550 mg, 2.74 mmol) and N,N-diisopropylethylamine (1.06 g, 8.22 mmol) in anhydrous N,N-dimethylformamide (12 mL), add (7-azobenzotriazole)-tetramethyluronium hexafluorophosphate (1.56 g, 4.11 mmol) under stirring at room temperature, and stir the reaction mixture at room temperature for 2 hours. Add water (30 mL) to the mixture, and filter to obtain a red solid as the target product (990 mg, yield: 81.2%). LC-MS: 445.1, 447.1 [M+H] +

[0238] Step 2:

[0239]

[0240] 03 (990 mg, 2.22 mmol) was dissolved in acetic acid (10 mL), and the reaction mixture was stirred at 70°C for 1 hour. The purple solid was obtained by spin drying as the target product (700 mg, yield: 73.6%). LC-MS: 427.0, 429.0 [M+H] + .

[0241] Step 3:

[0242]

[0243] At room temperature, 04 (540 mg, 1.26 mmol), zinc cyanide (296 mg, 2.52 mmol), zinc powder (16.5 mg, 0.252 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (204 mg, 0.252 mmol), tetrakis(triphenylphosphine)palladium (291 mg, 0.252 mmol) and anhydrous N-methylpyrrolidone (20 mL) were added to the sealed tube, and the reaction mixture was stirred at 140 ° C for 3 hours. Filter, add water (100 mL) to the filtrate, extract with ethyl acetate (20 mL × 3), wash with saturated brine (50 mL), dry with anhydrous sodium sulfate, filter, spin dry, and the residue is slurried (PE: EA = 1: 1, 20 mL) to obtain a white solid as the target product (349 mg, yield: 73.9%). LC-MS: 374.1 [M + H] + Step 4:

[0244]

[0245] Dissolve 05 (340 mg, 0.910 mmol) in tetrahydrofuran (15 mL), then add Raney nickel (100 mg) and drop 2 drops of ammonia water. The reaction mixture is stirred at room temperature under a hydrogen atmosphere for 3 hours. Filter and spin dry the filtrate to obtain a red solid as the target product (300 mg, yield: 87.3%). LC-MS: 378.1 [M+H] + .

[0246] Step 5:

[0247]

[0248] 06 (170 mg, 0.450 mmol), 07 (124 mg, 0.450 mmol) and N,N-diisopropylethylamine (174 mg, 1.35 mmol) were dissolved in anhydrous dimethyl sulfoxide (4 mL), and the reaction mixture was stirred at 90°C for 2 hours. The mixture was prepared twice (C18, 5-100% acetonitrile / water as mobile phase, 0.03% trifluoroacetic acid) to obtain the title compound as a yellow-green solid (48.35 mg, yield: 16.9%). LC-MS: 634.3 [M+H] + , 1 H NMR (400 MHz, DMSO-d 6 )δ11.11(s,1H),8.60(dd,J=4.6,1.3Hz,1H),8.36(dd,J=8.2,1.3Hz,1H),7.96(s,1H),7.77(dd,J=8.4,1.8Hz ,1H),7.63–7.56(m,2H),7.53–7.47(m,1H),7.37(t,J=5.8Hz,1H),7.04(d,J=7.1Hz,1H),7.01(d,J=8.6Hz,1H ),5.08(dd,J=12.9,5.4Hz,1H),4.75(d,J=5.9Hz,2H),4.00(s,3H),3.55–3.47(m,1H),3.34–3.27(m,1H),2.9 5–2.85(m,1H),2.64–2.52(m,2H),2.40–2.31(m,2H),2.28–2.19(m,2H),2.09–2.01(m,1H),1.96–1.82(m,4H).

[0249] Activity test example:

[0250] Example 1: DC50 test of compounds

[0251] 1. Experimental Materials

[0252] The IKZF1 / Jurkat HiBiT cell line was constructed by Shanghai Runnuo Biotechnology Co., Ltd., RPMI-1640 medium was purchased from Gibco (Cat#C11875500BT), FBS was purchased from Gibco (Cat#10091148), Nano Glo HiBiT LyticDetection System was purchased from Promega (Cat#N3040), and 96-well plates were purchased from coning (Cat#3610).

[0253] 2. Experimental methods

[0254] The degradation effect of the compound on IKZF1 was determined by measuring the strength of the HiBiT signal in the cells.

[0255] First, collect the cell suspension and centrifuge to discard the supernatant. Resuspend the centrifuged cells in fresh complete medium and adjust the cell density to 2.5*10 5 / ml, inoculate the resuspended cells into an opaque 96-well cell culture plate, 100ul / well cell suspension, and place in a 37-degree cell culture incubator for later use. Add 1ul of diluted compounds of different concentrations and place in the cell culture incubator for 6 hours. After 6 hours, add 100ul of Nano Glo HiBiT Lytic Detection System reagent and read the luminescence value on the instrument.

[0256] 3. Data Analysis

[0257] Degradation rate = 100-(value of the test compound well / average value of the DMSO control well)*100

[0258] According to the degradation rate and concentration corresponding to each gradient concentration well, the gradient curve of the degradation rate was fitted using GraphPad software, and the DC50 of the compound was calculated.

[0259] 4. Experimental results

[0260] According to the above experimental method, the DC50 of the compounds measured is shown in the following table.

[0261] Table 1 Test results

[0262]

[0263]

[0264] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

[0265] The aforementioned embodiments and methods described in the present invention may be varied based on the ability, experience and preference of those skilled in the art.

[0266] In the present invention, merely listing the steps of the method in a certain order does not constitute any limitation on the order of the method steps.

Claims

1. A compound, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound thereof, wherein the compound has the following structure: in, V is selected from: -CH 2 -、 L has the following structure: L 1 Selected from: -NH-(C 0-10 Alkylene)-, -O-(C 0-10 Alkylene)-; L 2 Selected from: R 3 Selected from: -H, halogen, -CN, -NO 2 , -CF 3 , -CHF 2 、-CH 2 F, -OH, -OCH 3 、-OCF 3 、-OCHF 2 、-OCH 2 F.C 1-3 alkyl; L 3 Selected from: -(C 0-10 Alkylene)-, -(C 0-6 Alkylene)-NH-(C 0-6 Alkylene)-, -(C 0-6 Alkylene)-O-(C 0-6 Alkylene)-; R 1 for One or more independent substituents on the ring are selected from: =O, halogen, -CN, -NO 2 , -CF 3 、-OCF 3 , C 0-10 Alkyl, -O(C 0-10 Alkyl), -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO 2 (C 0-10 Alkyl), -SC 0-10 Alkyl, -SO(C 0-10 Alkyl), -SO 2 (C 0-10 Alkyl), -SO 2 N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(C 0-10 Alkyl), -CO(C 0-10 alkyl), L' is selected from: a single bond, -(C 0-10 Alkylene)-, -(C 0-10 Alkylene)-NR L1 -(C 0-10 Alkylene)-, -(C 0-10 Alkylene)-O-(C 0-10 Alkylene)-, -(C 0-10 Alkylene)-S-(C 0-10 Alkylene)-, -(C 0-10 Alkylene)-NR L1 CO-(C 0-10 Alkylene)-, -(C 0-10 Alkylene)-CONR L1 -(C 0-10 Alkylene)-, -(C 0-10 Alkylene)-CO-(C 0-10 Alkylene)-, -(C 0-10 Alkylene)-SO 2 -(C 0-10 Alkylene)-, -(C 0-10 Alkylene)-SO-(C 0-10 Alkylene)-; R L1 Selected from: H, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-10 membered heterocycloalkyl; R 2 is one or more independent substituents on the B ring and is selected from: =O, halogen, -CN, -NO 2 , -CF 3 、-OCF 3 , C 0-10 Alkyl, -O(C 0-10 Alkyl), -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO 2 (C 0-10 Alkyl), -SC 0-10 Alkyl, -SO(C 0-10 Alkyl), -SO 2 (C 0-10 Alkyl), -SO 2 N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(C 0-10 Alkyl), -CO(C 0-10 Alkyl), -(C 0-10 Alkylene)-(C 3-6 Cycloalkyl), -(C 0-10 Alkylene)-(C 6-10 Aryl), -(C 0-10 alkylene)-(4-10 membered heterocycloalkyl),-(C 0-10 wherein one or more H in the alkylene, alkyl, cycloalkyl, aryl, heterocycloalkyl, heteroaromatic group is optionally substituted by a group selected from the following: =O, halogen, -CN, -NO 2 , -CF 3 、-OCF 3 , C 0-10 Alkyl, -O(C 0-10 Alkyl), -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO 2 (C 0-10 Alkyl), -SC 0-10 Alkyl, -SO(C 0-10 Alkyl), -SO 2 (C 0-10 Alkyl), -SO 2 N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(C 0-10 Alkyl), -CO(C 0-10 Alkyl), -(C 0-10 Alkylene)-(C 3-6 Cycloalkyl), -(C 0-10 Alkylene)-(C 6-10 Aryl), -(C 0-10 alkylene)-(4-10 membered heterocycloalkyl),-(C 0-10 (4-10 membered heterocyclic aromatic group).

2. The compound according to claim 1, It is characterized in that L 1 Selected from: -NH-, -NH-CH 2 -, -NH-CH 2 CH 2 -, -NH-CH 2 CH 2 CH 2 -, -O-, -O-CH 2 -, -O-CH 2 CH 2 -, -O-CH 2 CH 2 CH 2 -.

3. A compound according to any one of claims 1 to 2, It is characterized in that L 3 Selected from: -NH-, -CH 2 -NH-, -CH 2 CH 2 -NH-, -CH 2 CH 2 CH 2 -NH-, -O-, -CH 2 -O-, -CH 2 CH 2 -O-, -CH 2 CH 2 CH 2 -O-, single bond, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -NH-CH 2 -, -NH-CH 2 CH 2 -, -NH-CH 2 CH 2 CH 2 -, -O-CH 2 -, -O-CH 2 CH 2 -, -O-CH 2 CH 2 CH 2 -.

4. A compound according to any one of claims 1 to 3, It is characterized in that L is selected from the following structures:

5. The compound according to any one of claims 1 to 4, It is characterized in that R 1 Selected from: -H, halogen, -OH, C 1-6 Alkyl, -O(C 1-6 alkyl); Preferably, Part of 6. The compound according to any one of claims 1 to 4, It is characterized in that The compound has the following structure: Among them, R 1 'for One or more independent substituents on the ring are selected from: H, halogen, -CN, -NO 2 , -CF 3 、-OCF 3 , C 1-10 Alkyl, -O(C 0-10 Alkyl), -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO 2 (C 0-10 Alkyl), -SC 0-10 Alkyl, -SO(C 0-10 Alkyl), -SO 2 (C 0-10 Alkyl), -SO 2 N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(C 0-10 Alkyl), -CO(C 0-10 alkyl); Preferably, R 1 'Selected from: H, halogen, C 1-6 Alkyl, -O(C 0-6 alkyl), especially H; Preferably, L' is a single bond.

7. The compound according to claim 6, It is characterized in that Ring B is a benzene ring, a bicyclic aromatic ring, a tricyclic aromatic ring, a monocyclic heteroaromatic ring, a bicyclic heteroaromatic ring, or a tricyclic heteroaromatic ring; Preferably, the B ring is selected from:

8. The compound according to claim 6 or 7, It is characterized in that R 2 Selected from: -H、-F、-Cl、-Br、-I、-CF 3 、-CHF 2 、-CH 2 F、-CH 2 CF 3 、-CN、-NO 2 、-CH 3 、 -OH、 -NH 2 、 Preferably, R 2 Selected from: -H, -F, -Cl, -Br, -I, -CF 3 , -CHF 2 、-CH 2 F, -CH 2 CF 3 、-CN、-NO 2 、-CH 3 , -OH, -NH 2 , 9. The compound according to claim 6, It is characterized in that The part is selected from the following structures:

10. The compound according to claim 1, It is characterized in that The compound is selected from the following structures:

11. The compound according to claim 1, It is characterized in that The stereoisomers are selected from the following structures: Preferably, the stereoisomer is selected from the following structures:

12. A pharmaceutical composition comprising the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound thereof, and one or more pharmaceutically acceptable excipients.

13. Use of the compound according to any one of claims 1 to 11 or its pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound in the preparation of a medicament for preventing and / or treating IKZF1-related diseases; Preferably, the disease is selected from the group consisting of: tumors, autoimmune diseases, inflammatory diseases, diseases associated with pathogen infection, neurodegenerative diseases, and heterologous immune diseases.

14. The use according to claim 13, It is characterized in that The tumor is selected from the group consisting of adrenal cancer, anal cancer, angiosarcoma, appendix cancer, bile duct cancer, bladder cancer, breast cancer, brain cancer, bronchial cancer, carcinoid tumor, cervical cancer, choriocarcinoma, chordoma, craniopharyngioma, colorectal cancer, connective tissue cancer, epithelial cancer, ependymoma, endothelial sarcoma, endometrial cancer, esophageal cancer, Ewing's sarcoma, eye cancer, gallbladder cancer, gastric cancer, gastrointestinal stromal tumor (GIST), germ cell cancer, head and neck cancer, hematological malignancies, hemangioblastoma, hypopharyngeal cancer, inflammatory myofibroblastic tumor, immune cell carcinoma, Cellular amyloidosis, renal cancer, liver cancer, lung cancer, leiomyosarcoma (LMS), muscle cancer, mesothelioma, myeloproliferative disease (MPD), neuroblastoma, neurofibroma, neuroendocrine cancer, osteosarcoma, ovarian cancer, papillary adenocarcinoma, pancreatic cancer, penile cancer, pineal tumor, primitive neuroectodermal tumor (PNT), prostate cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer, small intestine cancer, soft tissue sarcoma, sebaceous gland cancer, sweat gland cancer, synovioma, testicular cancer, thyroid cancer, urethral cancer, vaginal cancer, vulvar cancer; Preferably, the hematological malignancy is selected from: leukemia, lymphoma, multiple myeloma; Preferably, the leukemia is chronic lymphocytic leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, acute myeloid leukemia, acute monocytic leukemia, especially acute myeloid leukemia; Preferably, the lymphoma is B-cell lymphoma, T-cell lymphoma or NK / T-cell lymphoma, in particular diffuse large B-cell lymphoma.

15. The use according to claim 13, It is characterized in that The autoimmune disease is selected from the group consisting of type I diabetes, systemic lupus erythematosus, systemic vasculitis, regional enteritis, cardiomyopathy, hemolytic anemia, fibromyalgia, Graves' disease, ulcerative colitis, Crohn's disease, multiple sclerosis, myasthenia gravis, myositis, neutropenia, psoriasis, chronic fatigue syndrome, juvenile arthritis, juvenile diabetes, scleroderma, psoriatic arthritis, Sjögren's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, idiopathic thrombocytopenic purpura (ITP), Hashimoto's disease, mixed connective tissue disease, interstitial cystitis, pernicious anemia, leukoencephalitis, alopecia areata, ankylosing spondylitis, primary biliary cirrhosis, anti-GBM nephritis, anti-TBM nephritis, antiphospholipid syndrome, polymyalgia rheumatica, polymyositis, autoimmune Addison's disease, chronic active hepatitis, vitiligo, psoriasis, autoimmune hyperlipidemia, autoimmune myocarditis, temporal arteritis, autoimmune thyroid disease, axonal and neuronal neuropathy, Behcet's disease, bullous pemphigoid, allergic asthma, osteoarthritis, Chagas' disease, Uveitis, chronic inflammatory demyelinating polyneuropathy (CIDP), scarring pemphigoid / benign mucous membrane pemphigoid, Kogan's syndrome, congenital heart block, coxsackievirus myocarditis, demyelinating neuropathy, dermatomyositis, discoid lupus, lens antigenic uveitis, polyarteritis nodosa, Dressler's syndrome, essential mixed cryoglobulinemia, Evans syndrome, Goodpasture's syndrome, allergic rhinitis, infectious neuronitis, hypogammaglobulinemia, inclusion body myositis, vesiculobullous eruption (vesiculobullous eruption culobullous) skin disease, Wegener's granulomatosis, Meniere's disease, Lambert-Eaton syndrome, Moren's ulcer, atypical celiac disease, ocular cicatricial pemphigoid, pemphigus vulgaris, perivenous encephalomyelitis, postpericardiotomy syndrome, scleritis, sperm-testicular autoimmunity, stiff-man syndrome, subacute bacterial endocarditis (SBE), sympathetic ophthalmia, transverse myelitis and necrotizing myelopathy, autoimmune polyglandular syndrome type I, autoimmune polyglandular syndrome type II, pernicious anemia, and endometriosis; Preferably, the autoimmune disease is systemic lupus erythematosus, type I diabetes or autoimmune thyroid disease.

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