IKZF1 degradation agent and preparation method therefor, and application

Abstract

Provided are an IKZF1 degradation agent and a preparation method therefor, and an application, in particular an application in preventing and / or treating IKZF1-related diseases. The degradation agent has the structure as shown in (I), and has very good targeting with respect to IKZF1.

Description

IKZF1 degradation agent, preparation method and application thereof

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to the Chinese patent application filed with the China Patent Office on December 5, 2023, with application number 202311652658.6 and entitled “A IKZF1 degrader, its preparation method and application”, the entire contents of which are incorporated by reference into this application. Technical Field

[0003] The present disclosure relates to the field of chemical medicine technology, and specifically to an IKZF1 degrading agent and a preparation method and application thereof, especially application in preventing and / or treating IKZF1-related diseases. Background Art

[0004] The Ikaros family is a family of zinc-finger transcription factors important for several physiological processes, particularly 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 can produce several protein isoforms through alternative splicing, theoretically allowing the generation of a large number of protein complexes through different combinations of homologs. The distribution of different members of the Ikaros family varies greatly in the body. IKZF1, IKZF2, and IKZF3 are primarily found in lymphoid cells and their corresponding progenitors. IKZF1 has also been detected in the brain, and both IKZF1 and IKZF2 have also been detected in erythrocytes. IKZF4 and IKZF5 are more widely distributed, present in skeletal muscle, liver, brain, and heart. IKZF1 is important for normal lymphocyte development. 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. IKZF1 and IKZF3 are involved in the proliferation of multiple myeloma cells, suggesting a potential role in hematologic malignancies.

[0005] Mutations in the IKZF1 gene have also been found to be associated with the development, proliferation, metastasis, and prognosis of various other malignancies, such as breast cancer, ovarian cancer, liver cancer, skin cancer, lung cancer, and colorectal cancer. They are also associated with the complex phenotype and susceptibility of systemic lupus erythematosus (SLE).

[0006] Molecular glue degraders are a class of small molecules that can induce interactions between E3 ubiquitin ligase substrate receptors and target proteins, leading to target protein degradation. Currently, there are few reports on IKZF1 degraders.

[0007] Overview

[0008] To overcome the deficiencies of the prior art, the present disclosure provides an IKZF1 degrader, a preparation method, and an application thereof. The degrader has excellent targeting properties to IKZF1.

[0009] In a first aspect of the present disclosure, a compound is provided, which has the following structure:

[0010] in,

[0011] V is selected from: -CH2-,

[0012] L has the following structure:

[0013] L1 is selected from: -NH-(C 0-10 Alkylene)-, -O-(C 0-10 alkylene)-;

[0014] L2 is selected from: R3 is selected from: -H, halogen, -CN, -NO2, -CF3, -CHF2, -CH2F, -OH, -OCH3, -OCF3, -OCHF2, -OCH2F, C 1-3 alkyl;

[0015] L3 is selected from: -(C 0-10 Alkylene)-, -(C 0-6 Alkylene)-NH-(C 0-6 Alkylene)-, -(C 0-6 Alkylene)-O-(C 0-6 alkylene)-;

[0016] R1 is One or more independent substituents on the ring, and selected from: =O, halogen, -CN, -NO2, -CF3, -OCF3, 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)SO2(C0-10 Alkyl), -SC 0-10 Alkyl, -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(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)-SO2-(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; R2 is one or more independent substituents on the B ring and is selected from: =O, halogen, -CN, -NO2, -CF3, -OCF3, 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)SO2(C 0-10 Alkyl), -SC0-10 Alkyl, -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(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 Alkylene)-(4-10 membered heterocyclic aromatic group), wherein one or more H in the alkylene, alkyl, cycloalkyl, aryl, heterocycloalkyl, heterocyclic aromatic group is optionally substituted by a group selected from the following: =O, halogen, -CN, -NO2, -CF3, -OCF3, 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)SO2(C 0-10 Alkyl), -SC 0-10 Alkyl, -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(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 alkylene)-(4-10 membered heterocyclic aromatic group).

[0017] In some embodiments of the present disclosure, V is

[0018] In some embodiments of the present disclosure, R3 is halogen, such as F.

[0019] In some embodiments of the present disclosure, L1 is -NH-, -NH-CH2-, -NH-CH2CH2-, -NH-CH2CH2CH2-, -O-, -O-CH2-, -O-CH2CH2-, -O-CH2CH2CH2-.

[0020] In some embodiments of the present disclosure, L3 is -NH-, -CH2-NH-, -CH2CH2-NH-, -CH2CH2CH2-NH-, -O-, -CH2-O-, -CH2CH2-O-, -CH2CH2CH2-O-, a single bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -NH-CH2-, -NH-CH2CH2-, -NH-CH2CH2CH2-, -O-CH2-, -O-CH2CH2-, -O-CH2CH2CH2-.

[0021] In some embodiments of the present disclosure, L has the following structure:

[0022] In some embodiments of the present disclosure, R1 is One or more independent substituents on the ring, selected from: -H, halogen, -CN, -NO2, -CF3, -OCF3, 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)SO2(C 0-10 Alkyl), -SC 0-10 Alkyl, -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(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(C0-10 More specifically, each R1 is selected from: -H, halogen (eg, F), -OH, C 1-6 Alkyl (e.g. -CH3, -CH2CH3), -O(C 1-6 alkyl) (e.g. methoxy, ethoxy), especially -H.

[0023] In some embodiments of the present disclosure, Part of Among them, R 101 、R 102 、R 103 、R 104 、R 105 、R 106 have the definition of R1 respectively; 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. -CH3, -CH2CH3), -O(C 1-6 alkyl) (e.g., methoxy, ethoxy); more specifically, It can be, for example,

[0024] In some embodiments of the present disclosure, Part of Among them, R1' is One or more independent substituents on the ring, selected from: H, halogen, -CN, -NO2, -CF3, -OCF3, 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)SO2(C 0-10 Alkyl), -SC 0-10 Alkyl, -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(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 More specifically, each R1' is selected from: H, halogen, C 1-6 Alkyl, -O(C 0-6 Alkyl), especially H.

[0025] In some embodiments of the present disclosure, the above compound may have the following structure:

[0026] In some embodiments of the present disclosure, 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 disclosure, Ring B is a benzene ring.

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

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

[0031] in particular,

[0032] In some embodiments of the present disclosure, 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

[0033] In some embodiments of the present disclosure, A section can have the following structure:

[0034] Specifically, R2 can be selected from: -H, -F, -Cl, -Br, -I, -CF3, -CHF2, -CH2F, -CH2CF3, -CN, -NO2, -CH3, -OH, -NH2,

[0035] More specifically, R2 can be selected from: -H, -F, -Cl, -Br, -I, -CF3, -CHF2, -CH2F, -CH2CF3, -CN, -NO2, -CH3, -OH, -NH2,

[0036] In some embodiments of the present disclosure, the compound has the following structure:

[0037] wherein A1 is selected from the group consisting of: O, S, NH, CH2;

[0038] A2 is selected from: N, CH;

[0039] A3, A4, A5, A6 are independently selected from: N, CH.

[0040] In some embodiments of the present disclosure, A3, A4, and A5 are all CH.

[0041] In some embodiments of the present disclosure, A6 is N.

[0042] In some embodiments of the present disclosure, A2 is N.

[0043] In some embodiments of the present disclosure, A1 is S.

[0044] In some embodiments of the present disclosure, A1 is O.

[0045] In some embodiments of the present disclosure, A1 is NH.

[0046] In some embodiments of the present disclosure, the compound has the following structure:

[0047] In some embodiments of the present disclosure, The section has the following structure:

[0048] In some embodiments of the present disclosure, the compound has the following structure:

[0049] In a second aspect of the present disclosure, provided are pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds of the compound of the first aspect.

[0050] Specifically, the stereoisomer has the following structure:

[0051] In some embodiments of the present disclosure, the stereoisomer has the following structure:

[0052] In a third aspect of the present disclosure, a pharmaceutical composition is provided, comprising the compound of the first aspect or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound thereof, and one or more pharmaceutically acceptable excipients.

[0053] Specifically, in the pharmaceutical composition, the compound of the first aspect or its pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds can be used alone or in combination with other types of active ingredients.

[0054] 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.

[0055] Specifically, the pharmaceutical composition can be administered by any suitable route, such as enteral administration (e.g., oral, sublingual, rectal) or parenteral administration (e.g., intravenous, intramuscular, intranasal, intraocular, intracerebral, intravaginal, intraperitoneal, transdermal, subcutaneous, intradermal, respiratory tract administration, etc.).

[0056] 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.

[0057] 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.

[0058] Specifically, the pharmaceutical composition is preferably in unit dosage form. In this form, the preparation is subdivided into unit doses containing appropriate amounts of the active ingredient. The unit dosage form can be a capsule, tablet, or any other 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.

[0059] Specifically, the amount of active ingredient in the unit dose formulation can be varied 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 desired, the composition may further comprise other suitable therapeutic agents.

[0060] In a fourth aspect of the present disclosure, 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 IKZF1-related diseases.

[0061] Specifically, the disease is a disease that can be 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, etc.

[0062] Specifically, the tumors include but are 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 disorders (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, urethra cancer, vaginal cancer, vulvar cancer.

[0063] More specifically, the tumor is a hematological malignancy, such as leukemia, lymphoma, or multiple myeloma (MM).

[0064] Particularly, 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. Particularly, the leukemia can be relapsed, refractory or drug-resistant.

[0065] 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 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).

[0066] In some embodiments of the present disclosure, the tumor is acute lymphoblastic leukemia (ALL).

[0067] Specifically, the autoimmune diseases include, but are not limited to, autoimmune diabetes (also known as type I diabetes or insulin-dependent diabetes mellitus), systemic lupus erythematosus, systemic vasculitis, Crohn's disease, 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, Sjogren'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), cicatricial pemphigoid / benign mucous membrane pemphigoid, Colgan'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.

[0068] In some embodiments of the present disclosure, the autoimmune disease is systemic lupus erythematosus (SLE).

[0069] In some embodiments of the present disclosure, the autoimmune disease is type I diabetes or autoimmune thyroid disease.

[0070] 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.

[0071] 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.

[0072] Specifically, the pathogen may be a microorganism, a parasite (protozoa, worm, etc.) or other agent.

[0073] Specifically, the microorganism can be selected from one or more of: viruses, chlamydia, rickettsia, mycoplasma, bacteria, spirochetes, fungi, etc.

[0074] In one embodiment of the present disclosure, the pathogen is a virus, for example, but not limited to, Adenoviridae (such as adenovirus), Herpesviridae (such as HSV1 (oral herpes), HSV2 (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).

[0075] 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.

[0076] Specifically, the xenoimmune disease is a rejection reaction after organ transplantation.

[0077] In a fifth aspect of the present disclosure, a method for preventing and / or treating an IKZF1-related disease is provided, comprising the step of administering to a subject in need thereof an effective amount of the compound of the first aspect or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound thereof, or the pharmaceutical composition of the third aspect.

[0078] Specifically, the disease is as described in the fourth aspect of the present disclosure.

[0079] Specifically, the subject is a mammal, especially a human.

[0080] Detailed description

[0081] Unless otherwise defined, all scientific and technical terms used in the present disclosure have the same meanings as commonly understood by one of ordinary skill in the art to which the present disclosure belongs.

[0082] In the present disclosure, the term "aliphatic group" refers to a straight or branched hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a cyclic hydrocarbon group that is fully saturated or contains one or more unsaturated units (also referred to herein as "carbocycle", "aliphatic ring", "cycloalkyl") that 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, and the like. 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.

[0083] The term "alkyl" refers to a straight or branched hydrocarbon chain radical that does not contain unsaturated bonds, and the hydrocarbon chain radical is connected to the rest of the molecule by a single bond. Typical alkyl 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, 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 disclosure, C0 alkyl refers to H, i.e., C 0-10 Alkyl (or C0-C 10 Alkyl) includes H and C 1-10 Alkyl (or C1-C 10 alkyl).

[0084] 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 disclosure, 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 methylene (-CH2-), ethylene, propylene, butylene, etc. In this disclosure, a C0 alkylene group refers to a single bond, i.e., C 0-10 Alkylene (or C0-C 10 Alkylene) includes single bonds and C 1-10 Alkylene (or C1-C 10 alkylene).

[0085] The term "cycloalkyl" refers to alicyclic hydrocarbons, such as those containing 1 to 4 single rings and / or condensed rings, containing 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.

[0086] The term "alkoxy" refers to a substituent formed by replacing the hydrogen of a hydroxy group with an alkyl group, such as an alkoxy group containing 1 to 10 carbon atoms, such as methoxy, ethoxy, propoxy, butoxy, and the like.

[0087] The term "alkylamino" refers to a substituent formed when one or both hydrogen atoms in an amino group (-NH2) are replaced by an alkyl group, such as an alkylamino group containing 1 to 10 carbon atoms, for example

[0088] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0089] The term "haloalkyl" refers to a group in which one or more hydrogen atoms in an alkyl group are replaced by a halogen atom (e.g., fluorine, chlorine, bromine or iodine), for example, -CHF2, -CH2F, -CF3, -CH2-CF3, -CH2CH2-CF3, -CH2CH2CH2-CF3.

[0090] The term "aryl" refers to a monocyclic or polycyclic radical, including a polycyclic radical containing a monocyclic aromatic group and / or a fused aromatic group, such as a radical containing 1-3 monocyclic or fused rings and 6-18 (e.g., 6, 8, 10, 12, 14, 16, 18) carbon ring atoms. 12 The aryl group refers to an aryl group containing 6 to 12 carbon ring atoms, such as phenyl, naphthyl, biphenyl, indenyl, etc.

[0091] 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. A heterocyclyl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused, spirocyclic, or bridged ring systems. A heterocyclyl group can be partially saturated (heteroaryl) or fully saturated (heterocycloalkyl). Suitable heteroaryl groups in the compounds of the present disclosure contain 1, 2 or 3 heteroatoms selected from N, O, S and P atoms, and include, for example, coumarin, including 8-coumarin, quinolinyl, including 8-quinolinyl, isoquinolinyl, pyridinyl, pyrazinyl, pyrazolyl, pyrimidinyl, furanyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, imidazolyl, indolyl, isoindolyl, indazolyl, indolizinyl, phthalazinyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazolyl, pyridazinyl, triazinyl, cinnolinyl, benzimidazolyl, benzofuranyl, benzofurazolyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl and furopyridinyl. Suitable heterocycloalkyl groups in the compounds of the present disclosure 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, oxathianyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxirane, thiirane, azepine, oxazepine, diazepine, 1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 3H-indolyl and quinolizinyl. In the present disclosure, for optionally substituted heterocyclic groups, the substituted position may be any suitable carbon atom or heteroatom, for example, The substitution position of R can be any suitable carbon atom or nitrogen atom, which can be, for example

[0092] In the present disclosure, "D" refers to deuterium; "substituted with deuterium" refers to replacing one or more hydrogen atoms with a corresponding number of deuterium atoms.

[0093] It will be appreciated that, depending on the source of the chemical materials used in the synthesis, there will be some variation in the natural isotopic abundances of the synthesized compounds. Therefore, the compounds of the present disclosure will inherently contain small amounts of deuterated isotopologues. Despite this variation, the concentrations of these naturally abundant stable hydrogen and carbon isotopes are low and insignificant compared to the degree of stable isotopic substitution in the disclosed compounds. See, for example, Wada, E. et al., Seikagaku, 1994, 66:15; Gannes, L. Z. et al., Comp Biochem Physiol Mol Integr Physiol, 1998, 119:725.

[0094] In the compounds of the present disclosure, any atom not designated as deuterium is present at its natural isotopic abundance. Unless otherwise indicated, when a position is specifically designated as "H" or "hydrogen," the position is understood to have hydrogen at its natural abundance isotopic composition. Similarly, unless otherwise indicated, 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).

[0095] As used herein, the term "isotopic enrichment factor" refers to the ratio between the isotopic abundance and the natural abundance of a particular isotope.

[0096] In other embodiments, the compounds of the present disclosure 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).

[0097] The term "isotopologue" refers to a substance in which the chemical structure differs from a specific compound of the present disclosure only in its isotopic composition.

[0098] The term "pharmaceutically acceptable salts" includes acid addition salts and base addition salts.

[0099] The term "acid addition salt" includes, but is not limited to, salts derived from inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic and phosphonic acids, and salts derived 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. The present invention relates to the preparation of the present invention and the like.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 comprise amino acid whose salt such as arginate, gluconate, galacturonate etc.Acid addition salts can be prepared by making free alkali form contact with sufficient amount of required acid in a conventional manner.Free alkali form can be regenerated by making salt form contact with alkali, and separate this free alkali in a conventional manner.

[0100] The term "base addition salt" refers to salts formed with metals or amines, such as hydroxides of alkali metals and alkaline earth metals, or with organic amines. 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 the 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.

[0101] The term "stereoisomer" includes the presence of enantiomers, diastereomers, and geometric isomers. Some compounds of the present disclosure have cyclic hydrocarbon groups that may be substituted on more than one carbon atom, in which case all geometric forms, including cis- and trans- forms, and mixtures thereof, are within the scope of the present disclosure.

[0102] The term "solvate" refers to a physical association of a compound of the present disclosure with one or more solvent molecules. This physical association includes various degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, a 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 isolatable solvates. Representative solvates include ethanolates, methanolates, and the like.

[0103] The term "prodrug" refers to a form of a compound of Formula I that is suitable for administration to a patient without undue toxicity, irritation, allergic reactions, etc., and is effective for its intended use, including acetal, ester, and zwitterion forms. The prodrug is transformed in vivo, for example, by hydrolysis in the blood, to yield the parent compound.

[0104] The terms "patient" or "subject" and the like are used interchangeably herein to refer to any animal or cell thereof to be treated according to the methods described herein, whether in vitro or in situ. Specifically, the aforementioned animals include mammals, e.g., rats, mice, guinea pigs, rabbits, dogs, monkeys or humans, particularly humans.

[0105] 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.

[0106] The term "prevent" or "prevent" refers to treating a disease before it occurs to avoid, minimize, or make the onset or development of the disease more difficult.

[0107] 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: the degree of cell differentiation (including morphology and function), growth rate, local invasion and metastasis. "Benign tumors" are usually well differentiated, characterized in that they grow slower 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, certain "benign" tumors may later lead to malignant tumors, which may be due to additional genetic changes in a subpopulation of the tumor's neoplastic cells, 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.

[0108] The term "cancer" refers to a malignant tumor (Stedman's Medical Dictionary, 25th ed.; Hensyled.; Williams & Wilkins: Philadelphia, 1990).

[0109] 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.

[0110] The term "inflammation" refers to the body's defensive response to stimuli, manifested by redness, swelling, heat, pain, and functional impairment. It can be infectious inflammation caused by infection or non-infectious inflammation not due to infection, such as inflammation caused by an immune response (such as various types of hypersensitivity reactions and inflammation caused by some autoimmune diseases). The term "inflammatory disease" refers to diseases characterized by inflammation.

[0111] The term "diseases 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.), parasites (protozoa, worms, etc.) or other media, 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), Polypogonadism virus, ... 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).

[0112] The disclosures of various publications, patents, and published patent specifications cited herein are incorporated by reference in their entirety.

[0113] The following will clearly and completely describe the technical solutions of the present disclosure in conjunction with the embodiments of the present disclosure. Obviously, the embodiments described are only a part of the embodiments of the present disclosure, not all of them. All other embodiments obtained by ordinary technicians in this field based on the embodiments of the present disclosure without making any creative efforts shall fall within the scope of protection of the present disclosure.

[0114] Compound Preparation Example:

[0115] Example 1: Preparation of Compound 1

[0116] The synthesis steps are as follows:

[0117] Step 1:

[0118] At room temperature, 01 (5.25 g, 33 mmol) was dissolved in dichloromethane (50 mL). DMF (1d) and (COCl)2 (16.8 g, 132 mmol) were added at 0°C. 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 water (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] +

[0119] Step 2:

[0120] 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 completion of the reaction, the reaction solution was concentrated to obtain a crude product. The crude product was diluted with 30 mL of water and extracted with ethyl acetate (30 mL × 3). The product was washed with saturated brine (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by 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] +

[0121] Step 3:

[0122] At room temperature, BH3 / THF (20 mL) was heated to 40°C, 04 (560 mg, 2.23 mmol) was added, and the mixture was stirred at 40°C for 4 hours. After cooling to room temperature, the reaction solution was quenched with methanol. The quenched reaction solution was concentrated to obtain a crude product, which was purified by column chromatography (dichloromethane:methanol = 20:1) to obtain 05 as a white solid (170 mg, yield: 32.15%). LC-MS: 238.1 [M+H] +

[0123] Step 4:

[0124] 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 in a microwave oven at 100°C for 2 hours. After completion of 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] +

[0125] 1 H NMR (400MHz, DMSO-d6) 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).

[0126] Example 2: Preparation of Compound 2

[0127] The synthesis steps are as follows:

[0128] Step 1:

[0129] At room temperature, 01 (20 g, 125.8 mmol) was dissolved in dichloromethane (200 mL). DMF (5d) and (COCl)2 (31.9 g, 251.5 mmol) were added at 0°C. 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)

[0130] Step 2:

[0131] At room temperature, 02 (18 g, 104 mmol) was dissolved in methanol (200 mL), and LiBH4 (3.4 g, 156 mmol) was added at 0°C. The mixture was allowed to react at room temperature for 1 hour. After completion of the reaction, the reaction solution was quenched with water and extracted with dichloromethane (150 mL × 3). The mixture was washed with saturated brine (100 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by 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] +

[0132] Step 3:

[0133] 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 water (400 mL), extracted with ethyl acetate (400 mL × 3), and washed with saturated brine (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by 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] +

[0134] Step 4:

[0135] 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 allowed to react at room temperature for 30 minutes. After 30 minutes, SOCl2 (2.3 g, 19.4 mmol) was slowly added dropwise. The mixture was stirred at 100°C for 2 hours. After the reaction, the reaction solution was concentrated to obtain the crude product, which was purified by column chromatography (dichloromethane:methanol = 10:1) to obtain 06 (2.4 g, yield: 63.66%) as a yellow solid. LC-MS: 391.1 [M+H] +

[0136] Step 5:

[0137] 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 K2CO3 (5.09 g, 36.92 mmol) was added. The mixture was reacted at 40°C for 16 hours. After completion of 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] +

[0138] 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).

[0139] Example 3: Preparation of Compound 3

[0140] The synthesis steps are as follows:

[0141] Step 1:

[0142] 1 (4.0 g, 10.23 mmol) (prepared in Example 2) was dissolved in dioxane (10 mL) at room temperature, and aqueous ammonia (10 mL) was added. The mixture was allowed to react in a sealed container for 16 hours. The reaction solution was evaporated to dryness and purified by flash silica gel column chromatography (methanol / dichloromethane = 0-20%) to obtain the desired product (2.0 g, yield: 52.61%) as a yellow solid. LC-MS: 371.2 [M+H] + .

[0143] Step 2:

[0144] 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. The reaction mixture was microwaved at 120°C for 2 hours. The mixture was separated by reverse phase preparative liquid chromatography (C18, 5-100% acetonitrile / water as the mobile phase, 0.1% formic acid). The resulting product was lyophilized with dilute hydrochloric acid to give the title compound (450 mg, yield: 13.3%), as a yellow solid. LC-MS: 628.2 [M+H] +

[0145] 1 H 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).

[0146] Example 4: Preparation of Compound 4

[0147] The synthesis steps are as follows:

[0148] Step 1:

[0149] 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). The reaction mixture was microwaved at 120°C for 2 hours. 160 mL of water was added to the reaction solution, and the mixture was 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. The organic phase was then dried over anhydrous sodium sulfate, filtered, and purified by spin column chromatography to afford 02 (313 mg, 9% yield), a yellow oil. LC-MS: 403.0 [M+H] + .

[0150] Step 2:

[0151] 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). The reaction mixture was stirred at 100°C for 2 hours. The reaction solution was dried and then separated by column chromatography to obtain a yellow solid 03 (289 mg, crude product). 100 mg of the yellow crude product was then 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.

[0152] Step 3:

[0153] 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). 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] + .

[0154] 1H 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).

[0155] Example 5: Preparation of Compound 5

[0156] The synthesis steps are as follows:

[0157] Step 1:

[0158] Under ice, 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). The mixture was allowed to react at room temperature for 12 hours. The mixture was quenched with water and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, and spin-dried. The product was purified by column chromatography (ethyl acetate:petroleum ether = 1:2) to afford a colorless oil (1.12 g, yield: 62.6%). LC-MS: 260.3 [M+H] +

[0159] Step 2:

[0160] At room temperature, 02 (300 mg, 1.264 mmol) and CBr4 (503 mg, 1.517 mmol) were added to a DCM (5 mL) solution under argon protection. Triphenylphosphine (398 mg, 1.517 mmol) was added under ice-cooling and the mixture was allowed to react at room temperature for 12 hours. The mixture was quenched with water and 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. The mixture was purified by column chromatography (ethyl acetate:petroleum ether = 1:2) to obtain a white solid (277 mg, yield: 73.3%). LC-MS: 244.1 [M+H] +

[0161] Step 3:

[0162] Sodium borohydride (146.52 mg, 3.873 mmol) was added to a solution of 11 (300 mg, 1.291 mmol) in MeOH (10 mL) at room temperature and allowed to react for 1 hour. The mixture was quenched with saturated ammonium chloride under ice-cooling and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, and spin-dried. The mixture was purified by column chromatography (methanol:dichloromethane = 1:10) to afford a white oily liquid (172 mg, yield: 56.9%). LC-MS: 235.2 [M+H] +

[0163] Step 4:

[0164] Under ice, sodium hydride (42.624 mg, 1.776 mmol) was added to a solution of Intermediate 12 (104 mg, 0.444 mmol) and Intermediate 04 (200 mg, 0.666 mmol) in THF (10 mL) and allowed to react at 40°C for 2 hours. The mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, and spin-dried. The product was purified by column chromatography (ethyl acetate:petroleum ether = 1:1) to afford a yellow solid (133 mg, yield: 66.1%). LC-MS: 454.3 [M+H] +

[0165] Step 5:

[0166] Trifluoroacetic acid (2 mL) was added to a solution of 13 (90 mg, 0.199 mmol) in dichloromethane (2 mL) at room temperature. The mixture was allowed to react for 12 hours, then dried by spun-off and purified by reverse phase chromatography (acetonitrile / water = 35%, 0.3% FA) to afford a purple solid (20 mg, yield: 28.5%). LC-MS: 354.3 [M+H] +

[0167] Step 6:

[0168] To a 100 mL single-necked flask, 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 mixture was purified by HPLC to afford the title compound as a yellow solid (0.91 mg, yield: 2.6%). LC-MS: 610.3 [M+H] +

[0169] 1 H NMR(400MHz,DMSO-d6)δ11.11(s,1H),7.73(s,1H),7.53-7.46(m,1H),7.38(s,1 H),7.27-7.22(m,3H),7.12(s,1H),7.04-6.98(m,2H),6.91(t,J=5.9Hz,2H),5.1 1-5.06(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).

[0170] Example 6: Preparation of Compound 6

[0171] The synthesis steps are as follows:

[0172] Step 1:

[0173] At room temperature, raw material 01 (900 mg, 3.88 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL). 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. The mixture was extracted with water (100 mL) and ethyl acetate (50 mL × 3), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and dried. The residue was purified on a silica gel column (petroleum ether:ethyl acetate = 4:1-3:1) to obtain the desired product as a white solid (800 mg, 57.2%). LC-MS: 365.2 [M+H] + .

[0174] Step 2:

[0175] At room temperature, 03 (800 mg, 2.201 mmol), pinacol diboron (840 mg, 3.307 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (164 mg, 0.224 mmol), and potassium acetate (439 mg, 4.381 mmol) were dissolved in 1,4-dioxane (10 mL). The reaction mixture was stirred at 90°C under argon for 16 hours. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The mixture was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and dried. The residue was purified on a silica gel column (petroleum ether:ethyl acetate = 3:1-2:1) to obtain the desired product as a white solid (450 mg, 58.7%). LC-MS: 343.2 [M+H] + .

[0176] Step 3:

[0177] At room temperature, 04 (450 mg, 1.316 mmol), 05 (468 mg, 1.973 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (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). The reaction mixture was stirred at 90°C under argon for 16 hours. The mixture was extracted with water (50 mL) and ethyl acetate (20 mL × 3), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and dried. The residue was purified on a silica gel column (ethyl acetate:petroleum ether = 33%) to afford the desired product as a brown solid (300 mg, 69.6%). LC-MS: 375.2 [M+H] + .

[0178] Step 4:

[0179] At room temperature, 06 (130 mg, 0.348 mmol) was dissolved in tetrahydrofuran (10 mL). Raney nickel (100 mg) was added at room temperature. The reaction mixture was stirred under a hydrogen balloon at room temperature for 6 hours. Filtered and dried to obtain a colorless viscous liquid as the desired product (80 mg, crude). LC-MS: 379.1 [M+H] + .

[0180] Step 5:

[0181] At room temperature, 07 (75 mg, 0.198 mmol) was dissolved in tetrahydrofuran (10 mL), and wet palladium hydroxide on carbon (100 mg) was added. The hydrogen atmosphere was replaced twice, and the reaction was stirred under a hydrogen balloon at room temperature for 16 hours. The mixture was filtered, the filtrate was dried, and the residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1-2:3) to obtain the desired product as a yellow solid (20 mg, yield: 26.7%). LC-MS: 381.2 [M+H] + .

[0182] Step 6:

[0183] 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 cooling to 20°C, the mixture was isolated using a preparative chromatography (C18, 5-100% acetonitrile / water as the mobile phase, 0.1% formic acid) to afford the title compound as a yellow solid (2.17 mg, yield: 20.9%). LC-MS: 637.4 [M+H] + . 1 HNMR(400MHz,DMSO-d6)δ11.10(s,1H),8.56(d,J=4.3Hz,1H),8.32(d,J=7.9H z,1H),8.03(s,1H),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 ),3.45(s,1H),2.96-2.85(m,1H),2.60(d,J=16.1Hz,2H),2.20-2.01(m,10H).

[0184] Example 7: Preparation of Compound 7

[0185] The synthesis steps are as follows:

[0186] Step 1:

[0187] 01 (719 mg, 2.74 mmol), 02 (550 mg, 2.74 mmol), and N,N-diisopropylethylamine (1.06 g, 8.22 mmol) were dissolved in anhydrous N,N-dimethylformamide (12 mL). (7-Azobenzotriazole)-tetramethyluronium hexafluorophosphate (1.56 g, 4.11 mmol) was added with stirring at room temperature. The reaction mixture was stirred at room temperature for 2 hours. Water (30 mL) was added to the mixture, and the mixture was filtered to obtain a red solid as the desired product (990 mg, yield: 81.2%). LC-MS: 445.1, 447.1 [M+H] +

[0188] Step 2:

[0189] 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 target product (700 mg, yield: 73.6%) was obtained as a purple solid after spin drying. LC-MS: 427.0, 429.0 [M+H] + .

[0190] Step 3:

[0191] 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 a sealed tube. The reaction mixture was stirred at 140°C for 3 hours. The mixture was filtered, and the filtrate was added with water (100 mL). The mixture was extracted with ethyl acetate (20 mL × 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and dried. The residue was slurried (PE:EA = 1:1, 20 mL) to obtain the desired product as a white solid (349 mg, yield: 73.9%). LC-MS: 374.1 [M+H] + .

[0192] Step 4:

[0193] 05 (340 mg, 0.910 mmol) was dissolved in tetrahydrofuran (15 mL), followed by the addition of Raney nickel (100 mg) and 2 drops of aqueous ammonia. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The filtrate was filtered and dried to give the desired product as a red solid (300 mg, yield: 87.3%). LC-MS: 378.1 [M+H] + .

[0194] Step 5:

[0195] 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). The reaction mixture was stirred at 90°C for 2 hours. The mixture was separated by two preparative steps (C18, 5-100% acetonitrile / water as the 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 (400MHz, DMSO-d6) 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) ,2.95-2.85(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).

[0196] Activity test example:

[0197] Example 1: DC50 test of compounds

[0198] 1. Experimental Materials

[0199] 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 Lytic Detection System was purchased from Promega (Cat#N3040), and 96-well plates were purchased from coning (Cat#3610).

[0200] 2. Experimental methods

[0201] The degradation effect of the compound on IKZF1 was determined by measuring the strength of the HiBiT signal in the cells.

[0202] First, collect the cell suspension and centrifuge to discard the supernatant. Resuspend the centrifuged cells in fresh complete culture medium and adjust the cell density to 2.5*10 5 / ml, seed the resuspended cells into an opaque 96-well cell culture plate at 100 μl of cell suspension per well and place in a 37°C cell incubator until ready to use. Add 1 μl of diluted compound at varying concentrations and incubate in the cell incubator for 6 hours. After 6 hours, add 100 μl of Nano Glo HiBiT Lytic Detection System reagent and read the luminescence value on the instrument.

[0203] 3. Data Analysis

[0204] Degradation rate = 100 - (value of the test compound well / average value of the DMSO control well) * 100

[0205] 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.

[0206] 4. Experimental results

[0207] According to the above experimental method, the DC50 of the compounds measured are shown in the following table.

[0208] Table 1 Test results

[0209] The above description is only a preferred embodiment of the present disclosure and is not intended to limit the present disclosure. Any modifications, equivalent substitutions, etc. made within the spirit and principles of the present disclosure should be included in the scope of protection of the present disclosure.

[0210] The foregoing embodiments and methods described in the present disclosure may be varied based on the ability, experience, and preference of those skilled in the art.

[0211] In the present disclosure, merely listing the steps of a 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: -CH2-, L has the following structure: L1 is selected from: -NH-(C 0-10 Alkylene)-, -O-(C 0-10 Alkylene)-; L2 is selected from: R3 is selected from: -H, halogen, -CN, -NO2, -CF3, -CHF2, -CH2F, -OH, -OCH3, -OCF3, -OCHF2, -OCH2F, C 1-3 alkyl; L3 is selected from: -(C 0-10 Alkylene)-, -(C 0-6 Alkylene)-NH-(C 0-6 Alkylene)-, -(C 0-6 Alkylene)-O-(C 0-6 Alkylene)-; R1 is One or more independent substituents on the ring are selected from: =O, halogen, -CN, -NO2, -CF3, -OCF3, 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)SO2(C 0-10 Alkyl), -SC 0-10 Alkyl, -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(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)-SO2-(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; R2 is one or more independent substituents on the B ring and is selected from: =O, halogen, -CN, -NO2, -CF3, -OCF3, 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)SO2(C 0-10 Alkyl), -SC 0-10 Alkyl, -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(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, -NO2, -CF3, -OCF3, 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)SO2(C 0-10 Alkyl), -SC 0-10 Alkyl, -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(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, wherein L1 is selected from: -NH-, -NH-CH2-, -NH-CH2CH2-, -NH-CH2CH2CH2-, -O-, -O-CH2-, -O-CH2CH2-, -O-CH2CH2CH2-.

3. The compound according to any one of claims 1 to 2, wherein L3 is selected from: -NH-, -CH2-NH-, -CH2CH2-NH-, -CH2CH2CH2-NH-, -O-, -CH2-O-, -CH2CH2-O-, -CH2CH2CH2-O-, a single bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -NH-CH2-, -NH-CH2CH2-, -NH-CH2CH2CH2-, -O-CH2-, -O-CH2CH2-, -O-CH2CH2CH2-.

4. The compound according to any one of claims 1 to 3, wherein L is selected from the following structures:

5. The compound according to any one of claims 1 to 4, wherein R1 is selected from: -H, halogen, -OH, C 1-6 Alkyl, -O(C 1-6 alkyl).

6. The compound according to any one of claims 1 to 5, wherein Part of 7. The compound according to any one of claims 1 to 4, wherein The compound has the following structure: Among them, R1' is One or more independent substituents on the ring are selected from: H, halogen, -CN, -NO2, -CF3, -OCF3, 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)SO2(C 0-10 Alkyl), -SC 0-10 Alkyl, -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(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).

8. The compound according to claim 7, wherein The B ring 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.

9. The compound according to claim 8, wherein Ring B is selected from:

10. The compound according to claim 7 or 8, wherein R2 is selected from: -H, -F, -Cl, -Br, -I, -CF3, -CHF2, -CH2F, -CH2CF3, -CN, -NO2, -CH3, 11. The compound according to claim 10, wherein R2 is selected from: -H, -F, -Cl, -Br, -I, -CF3, -CHF2, -CH2F, -CH2CF3, -CN, -NO2, -CH3, -OH, 12. The compound according to claim 7, wherein The part is selected from the following structures:

13. The compound according to claim 1, wherein The compound is selected from the following structures:

14. The compound according to claim 1, wherein The stereoisomers are selected from the following structures:

15. The compound according to claim 14, wherein The stereoisomers are selected from the following structures:

16. A pharmaceutical composition comprising the compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound thereof, and one or more pharmaceutically acceptable excipients.

17. Use of the compound according to any one of claims 1 to 5 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; in, 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.

18. The use according to claim 17, wherein: 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; Wherein, the blood malignancy is selected from: leukemia, lymphoma, multiple myeloma; Wherein, the leukemia is chronic lymphocytic leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, acute myeloid leukemia, acute monocytic leukemia; Wherein, the lymphoma is B cell lymphoma, T cell lymphoma or NK / T cell lymphoma.

19. The use according to claim 17, wherein: 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; Wherein, the autoimmune disease is systemic lupus erythematosus, type I diabetes or autoimmune thyroid disease.

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