Heterocyclic-substituted indazolone compounds, preparation method therefor, pharmaceutical composition and use thereof

Abstract

Disclosed in the present invention are heterocyclic-substituted indazolone compounds, a preparation method therefor, a pharmaceutical composition and the use thereof. Specifically, provided are compounds of formula (I), or pharmaceutically acceptable salts, tautomers, stereoisomers, isotope compounds, pharmaceutically acceptable salts, esters, prodrugs or hydrates thereof, a preparation method therefor, a pharmaceutical composition and the use thereof. The compounds disclosed by the present invention serving as CRL4CRBN E3 ubiquitin ligase regulators have good anti-tumor activity, and thus can be used for preparing drugs for treating CRL4CRBN E3 ubiquitin ligase related diseases.

Description

Heterocyclic substituted indazolone compounds, preparation methods, pharmaceutical compositions and applications thereof Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and in particular to a class of heterocyclic-substituted indazolone compound derivatives as targeted protein degradation agents, as well as preparation methods, pharmaceutical compositions and applications thereof. Background Art

[0002] Targeted protein degradation is a promising area for the discovery and development of innovative therapeutics. Targeted protein degradation technology transcends the mode of action of traditional small molecule inhibitors and can directly induce substrate proteins through the ubiquitin-proteasome protein degradation (UPS) pathway in vivo. Currently, targeted protein degradation technologies based on the ubiquitin-proteasome system (UPS) primarily include proteolysis targeting chimeras (PROTACs) and molecular glues.

[0003] Molecular glues are small molecules that induce protein-protein interactions and can exert precise temporal control over various biological processes. Molecular glues are small molecules that act on protein interfaces and form novel protein-protein interactions. Molecular glues mediate proximity-induced protein degradation and possess intrinsic advantages over heterobifunctional proteolysis-targeting chimeras, including unprecedented mechanisms, unique bioactivities, and favorable physicochemical properties. However, the paucity of serendipitously discovered molecular glues has hindered their development as reagents for bioassays and disease treatment. Therefore, rational discovery and design strategies are essential for the development of molecular glue-based drugs.

[0004] Currently, CRBN-based molecular glue degraders are mainly immunomodulatory drugs (IMiDs), such as thalidomide, lenalidomide, and pomalidomide. Because CRBN ligands and immunomodulatory imide drugs (IMiDs) have good drug-like properties, targeting CRBN is the main mode of action of molecular glue degraders. However, IMiDs are inherently unstable and easily hydrolyzed in body fluids. For example, thalidomide undergoes racemization and hydrolysis in body fluids, and the rate accelerates with increasing pH. Therefore, at pH 7, 7.4, and 8, the hydrolysis half-life of thalidomide is 11, 5, and 1.25 hours, respectively. Therefore, the development of small molecules with good pharmaceutical properties targeting CRBN is an important direction for the design of molecular glue degraders.

[0005] Lenalidomide is currently mainly used to treat multiple myeloma and myelodysplastic syndrome, but its efficacy in other indications is not very ideal; therefore, the development of a novel class of indazolone molecular glue degraders can improve the therapeutic effect on tumors and expand new indications, which can be used to further address unmet clinical needs. CRBN New ligands and new molecular glues for E3 ubiquitin ligases have important research value and practical significance in the development of new drugs.

[0006] Summary of the Invention

[0007] The present inventors have found through literature research that indazolones and their derivatives have unique biological activities and good metabolic stability. CRBN The crystal structure analysis of E3 ubiquitin ligase binding, molecular docking and computational simulation showed that the derivative of the new skeleton (3-(3-oxo-1,3-dihydro-2H-indazol-2-yl)piperidine-2,6-dione) obtained by combining indazolone and glutarimide ring can better bind to CRL4. CRBN The pocket in the E3 ubiquitin ligase is bound to reduce the steric repulsion with the carbonyl group on the nearby polypeptide chain in the bound protein, which can serve as a kind of favorable binding to CRL4. CRBN Therefore, based on the good bioavailability and drug metabolism properties of indazolone structures, we designed a new skeleton by combining indazolone and glutarimide rings. This indazolone-derived glutarimide structure can bind well to CRL4. CRBN E3 ubiquitin ligase binding; various novel CRL4 structures can be obtained through structural modification CRBN E3 ubiquitin ligase molecular glue degrader.

[0008] The purpose of the present invention is to provide a novel indazolone skeleton structure CRL4 CRBN E3 ubiquitin ligase molecular glue degraders have improved tumor treatment effects and can broaden the indications of molecular glue degraders, and provide CRL4 with better physicochemical properties for the design and development of degraders of related pathogenic proteins. CRBN Ligand for E3 ubiquitin ligase.

[0009] One aspect of the present invention is to provide a compound represented by general formula (I), its enantiomers, diastereomers, racemates, isotopic compounds, metabolic precursors, metabolites, pharmaceutically acceptable salts, esters, prodrugs or hydrates thereof.

[0010] Another aspect of the present invention is to provide a method for preparing the compound represented by general formula (I), an important intermediate for preparing the compound and a preparation method thereof.

[0011] Another aspect of the present invention is to provide a compound as shown in the general formula (I) and its tautomers, enantiomers, diastereomers, racemates, metabolites, metabolic precursors, isotopic compounds, pharmaceutically acceptable salts, esters, prodrugs or hydrates thereof, characterized in that the compound is used to prepare a method for preventing or treating CRL4. CRBN Drugs or diagnostic reagents for diseases related to E3 ubiquitin ligase; preferably, the CRBN Diseases associated with E3 ubiquitin ligases include cancer, pain, central nervous system diseases, and immune system diseases.

[0012] In order to achieve the above-mentioned object, the first aspect of the present invention provides a compound represented by the following general formula (I), or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotope compound, pharmaceutically acceptable salt, ester, prodrug or hydrate thereof:

[0013] Wherein, R1 is hydrogen or C 1-3 alkyl;

[0014] R2 is hydrogen or halogen;

[0015] R3 is hydrogen, deuterium or halogen;

[0016] X does not exist;

[0017] A1 is a substituted or unsubstituted 4-6 membered heterocyclyl, wherein the substituted or unsubstituted 4-6 membered heterocyclyl is optionally substituted by one or more groups selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, hydroxy, carboxyl, aminocarbonyl, 4-10 membered heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, C2-C6 alkenyl, C3-C8 heterocyclyloxy, and C3-C8 cycloalkyloxy;

[0018] L is none, -CH2- or -CH2-CH2-; wherein said -CH2- or -CH2-CH2- is optionally substituted by 1-2 groups selected from the group consisting of halogen, C1-C3 alkyl or halogenated C1-C3 alkyl;

[0019] A2 is selected from: none, C1-C6 alkyl, C 2-6 Alkynyl, C6-10 aryl, C3-C10 cycloalkyl, 4-6 membered heterocyclic group, 5-6 membered heteroaryl, benzo 5-6 membered heteroaryl; wherein, the C1-C6 alkyl, C 2-6Alkynyl, C6-10 aryl, C4-C10 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, benzo 5-6 membered heteroaryl are optionally substituted by one or more groups selected from the following: hydrogen, deuterium, halogen, cyano, nitro, hydroxyl, carboxyl, aminocarbonyl, 4-10 membered heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, halogen substituted C1-C6 alkyl, halogen substituted C1-C6 alkoxy, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, C2-C6 alkenyl, C 2-6 Alkynyl, C3-C8 heterocyclyloxy, C3-C8 cycloalkyloxy, hydroxy-substituted C1-C6 alkoxy, C1-C6 alkoxy substituted C1-C6 alkoxy; wherein the substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl are optionally substituted by one or more groups selected from the following: hydrogen, halogen, cyano, nitro, hydroxy, carboxyl, 4-10 membered heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, C2-C6 alkenyl, C 2-6 alkynyl, C3-C8 heterocyclyloxy, C3-C8 cycloalkyloxy, hydroxy-substituted C1-C6 alkoxy, and C1-C6 alkoxy-substituted C1-C6 alkoxy.

[0020] In another preferred embodiment, the compound has a structure shown in formula (I-1-1):

[0021] Wherein, R1 is hydrogen, methyl or ethyl;

[0022] R2 is hydrogen or fluorine;

[0023] R3 is hydrogen, deuterium or fluorine;

[0024] Y is -CH- or N;

[0025] n1 is 0, 1, or 2;

[0026] a1 and a2 are each independently 0 or 1;

[0027] Or A2 is selected from: phenyl, 4-6 membered heterocyclic group, 5-6 membered heteroaryl, phenyl and 5-6 membered heteroaryl or C 2-6 Alkynyl, wherein the phenyl, 4-6 membered heterocyclic, 5-6 membered heteroaryl, phenyl and 5-6 membered heteroaryl or C 2-6The alkynyl group is optionally substituted by one or more groups selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, hydroxy, carboxyl, aminocarbonyl, 4-10 membered heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 heterocyclyloxy, C3-C8 cycloalkyloxy, hydroxy-substituted C1-C6 alkoxy, and C1-C6 alkoxy-substituted C1-C6 alkoxy.

[0028] In another preferred embodiment, A2 is selected from: phenyl, pyridyl; wherein the phenyl and pyridyl are optionally substituted by one or more groups selected from the following: hydrogen, deuterium, halogen, cyano, 4-10 membered heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, C3-C8 heterocyclyloxy, C3-C8 cycloalkyloxy, hydroxy-substituted C1-C6 alkoxy, C1-C6 alkoxy-substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, substituted or unsubstituted 5-6 membered heteroaryl.

[0029] In another preferred embodiment, L is none or CH2; wherein the -CH2- or -CH2-CH2- is optionally substituted by 1-2 groups selected from the following groups: halogen, C1-C3 alkyl or halogenated C1-C3 alkyl; preferably, L is CH2.

[0030] In another preferred embodiment, A2 is a substituted or unsubstituted C2-C6 alkynyl group (such as ethynyl or propynyl), wherein the substituted alkynyl group may be optionally substituted by a C1-C3 alkyl group, a C6-10 aryl group, or a 5-6 membered heteroaryl group; wherein the aryl or heteroaryl group is optionally substituted by one or more groups selected from the following: hydrogen, halogen, cyano, and nitro.

[0031] In another preferred embodiment, the compound has a structure shown by formula (I-27)-(I-28):

[0032] Wherein, R1 is hydrogen, methyl or ethyl;

[0033] R2 is hydrogen or fluorine;

[0034] R3 is hydrogen, deuterium or fluorine;

[0035] A2 is selected from: phenyl, pyridyl; wherein the phenyl, pyridyl is optionally substituted by one or more groups selected from the following: hydrogen, deuterium, halogen, cyano, 4-10 membered heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, C3-C8 heterocyclyloxy, C3-C8 cycloalkyloxy, hydroxy-substituted C1-C6 alkoxy, C1-C6 alkoxy substituted by C1-C6 alkoxy.

[0036] In another preferred embodiment, Selected from:

[0037] In another preferred embodiment, the compound represented by general formula (I) is one of the following compounds:

[0038] The compound, or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotope compound, pharmaceutically acceptable salt, ester, prodrug or hydrate thereof.

[0039] Another aspect of the present invention provides a method for preparing the compound represented by general formula (I), which is selected from one of the following methods:

[0040] The synthesis of compound 6F is based on Organic Letters, 2020, 22(16): 6277-6282.

[0041] Synthesis method 1:

[0042] Step 1-1: Compound 6A and compound 6B are reacted by coupling reaction to obtain compound 6C;

[0043] Step 1-2: Compound 6C is hydrolyzed in the presence of lithium hydroxide to obtain compound 6D;

[0044] Step 1-3: Compound 6D and 1G are condensed to obtain compound 6E;

[0045] Step 1-4: Compound 6E reacts with tetrahydroxydiboron and sodium hydroxide to obtain compound 6F;

[0046] Step 1-5: Compound 6F is hydrogenated at normal pressure to give 6G;

[0047] Step 1-6: Compound 6G is cyclized with potassium tert-butoxide to give compound 6H;

[0048] Step 1-7: Compound 6H is deprotected with hydrochloric acid to obtain compound 6I;

[0049] Step 1-8: Compound 6I is subjected to reductive amination with an aldehyde to give 6J;

[0050] R2 is as defined in the first aspect of the present invention.

[0051] Another aspect of the present invention provides the use of the compounds of general formula (I) and their tautomers, enantiomers, diastereomers, racemates, metabolites, metabolic precursors, isotopic compounds, pharmaceutically acceptable salts, esters, prodrugs, hydrates, crystalline hydrates and solvates for the preparation of drugs or diagnostic reagents for preventing or treating diseases associated with CRL4 CRBN E3 ubiquitin ligase.

[0052] Another aspect of the present invention provides the use of compounds as represented by general formula (I) and their tautomers, enantiomers, diastereomers, racemates, metabolites, metabolic precursors, isotopic compounds, pharmaceutically acceptable salts, esters, prodrugs, hydrates thereof, crystalline hydrates, and solvates in the preparation of drugs for treating or preventing diseases, disorders, or conditions associated with abnormal production or regulation of TNF-α activity, production or regulation of IL-2 activity, or production or regulation of IFNγ activity.

[0053] Another aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective dose of a compound as represented by general formula (I) and its tautomers, enantiomers, diastereomers, racemates, metabolites, metabolic precursors, isotopic compounds, pharmaceutically acceptable salts, esters, prodrugs, hydrates, crystalline hydrates, solvates and other pharmaceutically acceptable carriers.

[0054] Another aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective dose of a compound represented by general formula (I) and its tautomers, enantiomers, diastereomers, racemates, metabolites, metabolic precursors, isotopic compounds, pharmaceutically acceptable salts, esters, prodrugs, hydrates, crystalline hydrates, solvates, and one or more other ingredients having pharmaceutical therapeutic activity.

[0055] The compounds of the present invention as represented by general formula (I) and their tautomers, enantiomers, diastereomers, racemates, metabolites, metabolic precursors, isotopic compounds, pharmaceutically acceptable salts, esters, prodrugs, hydrates, crystalline hydrates, and solvates can produce a synergistic effect with one or more other ingredients having pharmaceutical therapeutic activity in the prevention or treatment of specific diseases or functional disorders.

[0056] The compounds of the present invention as represented by general formula (I) and their tautomers, enantiomers, diastereomers, racemates, metabolites, metabolic precursors, isotopic compounds, pharmaceutically acceptable salts, esters, prodrugs, hydrates, crystalline hydrates and solvates can also reduce or eliminate the toxic and side effects produced by one or more other pharmaceutically active ingredients in the prevention or treatment of specific diseases or functional disorders, and vice versa.

[0057] Another aspect of the present invention provides a pharmaceutical composition, wherein the additional one or more ingredients having pharmaceutical therapeutic activity as described above include macromolecular compounds, such as proteins, polysaccharides and nucleic acids; small molecule compounds such as inorganic compounds, organometallic compounds, organic small molecule compounds of synthetic or natural origin, etc.

[0058] Another aspect of the present invention provides a pharmaceutical composition, which is characterized in that the pharmaceutical composition further comprises other therapeutic agents, and the other therapeutic agents are dexamethasone, rituximab, trastuzumab, PD-1 inhibitors, PDL-1 inhibitors, pemetrexed, topotecan, doxorubicin, bortezomib, gemcitabine, dacarbazine, clarithromycin, vincristine, cytarabine, prednisone, docetaxel, clofarabine injection, HDAC inhibitors, androgen receptor inhibitors, androgen biosynthesis inhibitors, BTK inhibitors, erythrocyte growth hormone, minocycline, Elotuzumab, Palbociclib, Nivolumab, Pembrolizumab, Panobinostat, Ublituximab, Romidepsin, Eltrombopag, CAR-T and one or more of melphalan, azacitidine, and BCL2 inhibitors.

[0059] Another aspect of the present invention is to provide a compound as shown in the general formula (I) for use in the preparation of a treatment or prevention of a disease associated with CRL4CRBN E3 ubiquitin ligase, including but not limited to cancer, pain, nervous system diseases and immune system diseases. It is characterized in that the disease is a blood tumor or a solid tumor, preferably, the blood tumor is selected from: myelodysplastic syndrome, myeloid leukemia, non-Hodgkin's lymphoma, chronic lymphocytic leukemia, chronic myelomonocytic leukemia, myelofibrosis, Burkitt's lymphoma, Hodgkin's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, ciliary body and chronic melanoma, iris melanoma, recurrent interocular melanoma, T cell lymphoma, erythroid lymphoma, monocytic and monocytic leukemia, central nervous system lymphoma, multiple myeloma, mantle cell lymphoma; the solid tumor is selected from: brain Meningioma, spinal cord tumor, lung cancer, ovarian cancer, skin cancer, renal cell carcinoma, astrocytoma, amyloidosis, complex regional pain syndrome type I, malignant melanoma, radiculopathy, glioblastoma, sarcoma, malignant glioma, refractory plasmacytoma, melanoma with extraocular extension, thyroid cancer, breast cancer, prostate cancer, hepatocellular carcinoma or primary macroglobulinemia, adrenocortical carcinoma, bile duct cancer, bladder cancer, bone cancer, brain cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, gallbladder cancer, stomach cancer, head and neck cancer, kidney cancer, liver cancer, uterine cancer, rhabdoid tumor, neuroblastoma, pancreatic cancer, testicular cancer, glioma.

[0060] Another aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by formula (I), and one or more of its stereoisomers, pharmaceutically acceptable salts, prodrugs, solvates, hydrates, and crystalline forms, and at least one excipient, diluent, or carrier. A typical formulation is prepared by mixing the compound represented by formula (I) of the present invention with a carrier, diluent, or excipient. Suitable carriers, diluents, or excipients are well known to those skilled in the art and include substances such as carbohydrates, waxes, water-soluble and / or swellable polymers, hydrophilic or hydrophobic substances, gelatin, oils, solvents, and water. The specific carrier, diluent, or excipient used will depend on the intended use and purpose of the compound of the present invention. Solvents are generally selected based on solvents deemed safe and effective for administration to mammals by those skilled in the art. Generally, safe solvents are non-toxic aqueous solvents such as water, as well as other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include one or more of water, ethanol, propylene glycol, polyethylene glycol (such as PEG400, PEG300), etc. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, flavorings, flavorings or other known additives to enable the drug to be manufactured or used in an acceptable form.

[0061] When the compound of formula (I) of the present invention is used in combination with at least one other drug, the two or more drugs can be used separately or in combination, preferably administered in the form of a pharmaceutical composition. The compound of formula (I) or pharmaceutical composition of the present invention can be administered to a subject separately or together in any known oral, intravenous, rectal, vaginal, transdermal, or other topical or systemic administration form.

[0062] These pharmaceutical compositions may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, flavorings, flavorings or other known additives so that the pharmaceutical compositions can be manufactured or used in an acceptable form.

[0063] The medicament of the present invention is preferably administered orally. Solid dosage forms for oral administration may include capsules, tablets, powders, or granular formulations. In a solid dosage form, the compound or pharmaceutical composition of the present invention is mixed with at least one inert excipient, diluent, or carrier. Suitable excipients, diluents, or carriers include substances such as sodium citrate or dicalcium phosphate, or starch, lactose, sucrose, mannitol, silicic acid, etc.; binders such as carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, gum arabic, etc.; humectants such as glycerol, etc.; disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, specific complex silicates, sodium carbonate, etc.; solution retardants such as paraffin, etc.; absorption enhancers such as quaternary ammonium compounds, etc.; adsorbents such as kaolin, bentonite, etc.; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, etc. In the case of capsules and tablets, the dosage form may also include a buffer. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using, for example, lactose and high molecular weight polyethylene glycols as excipients.

[0064] The liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the compound of the present invention or its composition, the liquid dosage form may contain an inert diluent commonly used in the art, such as water or other solvents; solubilizers and emulsifiers such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide; oils (such as cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, sesame oil, etc.); glycerol; tetrahydrofurfuryl alcohol; fatty acid esters of polyethylene glycol and sorbitan; or mixtures of several of these substances.

[0065] In addition to these inert diluents, the composition may also include excipients such as one or more of a wetting agent, an emulsifier, a suspending agent, a sweetener, a flavoring agent, and a fragrance. In the case of a suspension, in addition to the compound or combination of the present invention, it may further contain a carrier such as a suspending agent, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, and tragacanth, or a mixture of several of these substances.

[0066] Compositions for rectal or vaginal administration are preferably suppositories and can be prepared by mixing the compound or combination of the present invention with suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at room temperature but liquid at body temperature and melt in the rectum or vagina to release the active compound.

[0067] The compounds or pharmaceutical compositions of the present invention may be administered in other topical dosage forms, including creams, powders, sprays, and inhalants. The drug may be mixed under sterile conditions with a pharmaceutically acceptable excipient, diluent, or carrier, and any desired preservatives, buffers, or propellants. Ophthalmic formulations, ophthalmic ointments, powders, and solutions are also intended to be encompassed within the scope of this invention.

[0068] The present invention also provides compounds represented by the general formula (I) and their tautomers, enantiomers, diastereomers, racemates, metabolic precursors, metabolites, isotopic compounds, pharmaceutically acceptable salts, esters, prodrugs or hydrates, solvates or crystal forms thereof as CRL4 CRBN Use of selective modulators of E3 ubiquitin ligases to regulate CUL4 CRBN E3 ubiquitin ligase activity.

[0069] The present invention also provides a compound as shown in the general formula (I) and its tautomers, enantiomers, diastereomers, racemates, metabolic precursors, metabolites, isotopic compounds, pharmaceutically acceptable salts, esters, prodrugs or hydrates, solvates or crystal forms thereof, which can be used in the preparation of a compound for treating or preventing CRL4. CRBN Use of drugs for diseases related to E3 ubiquitin ligase involvement. CRBN Diseases related to E3 ubiquitin ligase involvement include (but are not limited to) tumors, central nervous system diseases, and immune diseases.

[0070] In a preferred embodiment, the present invention relates to a method for treating or preventing a disease, disorder or condition associated with TNF-α production or regulation of TNF-α activity, IL-2 production or dysregulation of IL-2 activity, wherein the method comprises administering to a subject an effective amount of an isoindoline derivative represented by general formula (I), a pharmaceutically acceptable salt, solvate, stereoisomer, isotope compound, metabolite and prodrug thereof. According to the method of the present invention, examples of such diseases, disorders and conditions to be treated or prevented include, but are not limited to, cancer, including solid tumors, TNF-α-related disorders, undesirable angiogenesis-related diseases and disorders, pain, macular degeneration (MD)-related syndromes, skin diseases, keratosis, respiratory diseases (e.g., lung diseases), immunodeficiency diseases, central nervous system (CNS) diseases, autoimmune diseases, atherosclerosis, genetic diseases, allergies, viruses, sleep disorders and related syndromes, inflammatory diseases, PDE-4-related diseases or IL-2-related diseases. Examples of such diseases, disorders or conditions that are well known in the art include, but are not limited to, those described in PCT Patent Publications WO2012015986 and WO2006018182, and US Patent Publication US20100204227, some of which are hereby incorporated by reference in their entirety.

[0071] The compounds represented by the general formula (I) of the present invention, and their stereoisomers, pharmaceutically acceptable salts, prodrugs, solvates, hydrates or crystalline forms can be used in monotherapy or combination therapy. When used in combination therapy, the compounds of formula (I), their enantiomers, diastereomers, racemates and mixtures thereof, as well as their pharmaceutically acceptable salts, crystalline hydrates and solvates, are included in a therapeutically effective dose, and one or more other ingredients with pharmaceutical therapeutic activity. The one or more other ingredients with pharmaceutical therapeutic activity include macromolecular compounds, such as proteins (antibodies or polypeptides), polysaccharides and nucleic acids (DNA or RNA), etc.; and small molecule compounds, such as inorganic compounds, organometallic compounds, synthetic or naturally derived organic small molecule compounds, etc.; in addition, radiation, surgery, cell therapy, hormone therapy or cytokine therapy, etc. are also included. The compounds of formula (I) of the present invention, their prodrugs, enantiomers, diastereomers, racemates, and mixtures thereof, as well as their pharmaceutically acceptable salts, crystalline hydrates, and solvates, can produce a synergistic effect with one or more other ingredients having pharmaceutical therapeutic activity in the prevention or treatment of specific diseases or functional disorders. The compounds of formula (I) of the present invention, their prodrugs, enantiomers, diastereomers, racemates, and mixtures thereof, as well as their pharmaceutically acceptable salts, crystalline hydrates, and solvates, can also reduce or eliminate the toxic side effects produced by one or more other ingredients having pharmaceutical therapeutic activity in the prevention or treatment of specific diseases or functional disorders, and vice versa.

[0072] In another preferred embodiment, the disease or functional disorder includes, but is not limited to: cancer, diseases or functional disorders related to angiogenesis, pain (including but not limited to complex regional pain syndrome), macular degeneration and related functional disorders, skin diseases, lung functional disorders, immunodeficiency diseases, damage and functional disorders of the central nervous system, and TNFα-related diseases or functional disorders.

[0073] The pain is nociceptive pain, neuropathic pain, visceral pain, migraine, headache, or postoperative pain; the central nervous system disease is amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, or Tourette syndrome; the neuropathic pain is complex regional pain syndrome, dystrophy, or diabetic neuropathy.

[0074] In another preferred embodiment, the cancer includes, but is not limited to, skin cancer (such as melanoma), lymphatic system cancer, breast cancer, cervical cancer, uterine cancer, digestive tract cancer, lung cancer, ovarian cancer, prostate cancer, colon cancer, rectal cancer, oral cancer, brain tumor, head and neck cancer, pharyngeal cancer, testicular cancer, kidney cancer, pancreatic cancer, spleen cancer, liver cancer, bladder cancer, laryngeal cancer, and cancers associated with AIDS. The compounds provided by the present invention are also effective for hematologic malignancies and myelomas, such as multiple myeloma and acute and chronic leukemia. The compounds provided by the present invention can be used to prevent or treat primary tumors and metastatic tumors.

[0075] The compounds represented by the general formula (I) may contain one or more asymmetric or chiral centers and may therefore exist in different stereoisomeric forms. The compounds of the present invention include all stereoisomeric forms, including but not limited to diastereomers, enantiomers and atropisomers and mixtures thereof (such as racemic mixtures), metabolic precursors, metabolites, isotopic compounds, pharmaceutically acceptable salts, esters, prodrugs or hydrates thereof. The compounds represented by the general formula (I) may also exist in different tautomeric forms, all of which are included within the scope of the present invention.

[0076] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. The above description is not intended to limit the aspects of the present invention in any form. DETAILED DESCRIPTION

[0077] After extensive and in-depth research, the present inventors have provided a class of CRL4 with novel structure and excellent anti-tumor activity through a large number of screening and testing. CRBN E3 ubiquitin ligase modulator compounds. The inventors of the present invention have studied CRL4 CRBN The following important information was obtained by analyzing the crystal structure of the complex between E3 ubiquitin ligase and small molecules (PDB ID: 4CI2, 5HXB): CRL4 CRBN E3 ubiquitin ligases have multiple binding pockets for small molecules, so it is possible to develop small molecules with complex structures and multiple binding sites to achieve CRL4 CRBN E3 ubiquitin ligase effectively binds to small molecules. Molecular dynamics simulation methods are used to analyze the structural dynamics and binding site of the model molecule and E3 ubiquitin ligase interface. Combined with molecular docking and complex-based pharmacophore matching strategies, the binding mode and interaction of the compound at the E3 ubiquitin ligase active site are evaluated through scoring functions, and computational simulation and optimization of structural design are performed to obtain a new specific CRL4 CRBN Small molecule modulators of E3 ubiquitin ligases.

[0078] Based on this information, the inventors designed and synthesized a series of CRL4 with novel indazolone skeleton structure described in this application. CRBN Small molecule modulators of E3 ubiquitin ligases were tested for their CRBN binding and IKZF2 degradation activity in acute myeloid leukemia (Molm-13) cells. CRBN / DDB1 inhibition assays demonstrated that most of the compounds described in the present invention exhibited strong inhibitory activity against CRBN / DDB1 binding, with most exhibiting comparable inhibitory activity to lenalidomide and DKY-709. Representative compounds also demonstrated high IKZF2 degradation rates in acute myeloid leukemia (Molm-13) cells, comparable to the existing isoindoline-based CRBN modulator, DKY-70, currently under clinical investigation, and some exhibited superior activity to DKY-709. Therefore, the indazolone compounds developed in this application, upon application to an organism, can modulate the degradation of substrate proteins or the degradation of new pathogenic proteins by regulating the ubiquitin-proteasome-mediated protein degradation pathway, thereby achieving effective CRBN-targeted disease treatment. This invention was completed on this basis.

[0079] the term

[0080] When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents that would result if the formula were written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0081] Those skilled in the art will understand that the combinations of substituents contemplated by the present invention are those that are stable or chemically feasible. References to substitutions in the relevant structures herein include both substitution and non-substitution, such as "optionally" or "optionally" substituted with a substituent, to including both substitution and non-substitution.

[0082] The term "when the number of substituents is greater than 1, the R substituents may be the same or different substituents" mentioned in the present invention means that when there are multiple substituents in a certain structure, the substituent combination of R may be selected from a variety of different types of substituents.

[0083] The term "substituted" only applies to sites that can be substituted by substituents, and does not include substitutions that cannot be achieved based on existing chemical knowledge. The term "substituted" refers to the replacement of one or more hydrogen atoms on a specific group by a specific substituent. The specific substituents are the substituents described above, or the substituents that appear in the examples. Unless otherwise specified, an arbitrarily substituted group may have a substituent selected from a specific group at any substitutable site of the group, and the substituents may be the same or different at each position. A cyclic substituent, such as a heterocycloalkyl, may be connected to another ring, such as a cycloalkyl, to form a spirobicyclic system, for example, where the two rings share one carbon atom. Unless otherwise specified, substitution may refer to a group being substituted by one or more groups selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, carboxyl, 4-10 membered heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, C2-C6 alkenyl, C3-C8 heterocyclyloxy, C3-C8 cycloalkyloxy, hydroxy-substituted C1-C6 alkoxy, and C1-C6 alkoxy-substituted C1-C6 alkoxy.

[0084] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0085] The term "plurality" refers to two or more, such as 2, 3, 4, 5 or 6.

[0086] The term "C1-C6 alkyl" refers to a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms in the chain, such as an alkyl group containing 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl group used in this article or as part of another group has 1 to 6 carbon atoms (i.e., C1-C6 alkyl), or 1 to 3 carbon atoms (i.e., C1-3 alkyl), including but not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like.

[0087] The term "C2-C6 alkenyl" refers to an unsaturated straight or branched hydrocarbon radical having 2 to 6 carbon atoms and including one or more double bonds, such as an alkenyl radical comprising 2, 3, 4, 5 or 6 carbon atoms. Examples of alkynyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, and 3-butynyl. The alkynyl groups of the present invention may be substituted or unsubstituted.

[0088] The term "C2-C6 alkynyl" refers to an unsaturated straight or branched hydrocarbon radical having 2 to 6 carbon atoms and comprising one or more triple bonds, such as an alkynyl radical comprising 2, 3, 4, 5 or 6 carbon atoms. Examples of alkynyl radicals include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, isobutynyl, sec-butynyl, butadiynyl, 1-pentynyl, 2-pentynyl, isopentenyl, 1,3-pentadiynyl, 1,4-pentadiynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadiynyl, 1,4-hexadiynyl, 1,5-hexadiynyl, 2,4-hexadiynyl or 1,3,5-hexatriynyl. The alkynyl radicals of the present invention may be substituted or unsubstituted.

[0089] The term "C1-C6 alkoxy" refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like.

[0090] The term "aryl" refers to a 6-14 membered all-carbon monocyclic or fused polycyclic group having a conjugated p-electron system, preferably a 6- to 10-membered ring (i.e., C6-C10 aryl), more preferably phenyl and naphthyl, and most preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is the aryl ring.

[0091] The term "halogen-substituted C1-C6 alkoxy" refers to a linear or branched C1-C6 alkoxy group substituted by a single or multiple halogens, including but not limited to -OCH2F, -OCHF2, and -OCF3.

[0092] The term "halogen-substituted C1-C6 alkyl" refers to a straight-chain or branched C1-C6 alkyl group substituted by a single or multiple halogens, including but not limited to 2-bromoethyl, 2-bromopropyl, and the like.

[0093] The term "C3-C10 cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent. The C3-C10 cycloalkyl is preferably a C4-C7 cycloalkyl or a C5-C6 cycloalkyl. Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentenyl, and cyclohexyl. Polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls.

[0094] The term "4-10 membered heterocyclyl" refers to a group containing one or more saturated and / or partially saturated rings, which includes 4 to 10 ring atoms, wherein one or more (e.g., 2, 3) ring atoms are selected from nitrogen, oxygen, sulfur or S(O)m (wherein m is an integer from 0 to 2) heteroatoms, and the remaining ring atoms are carbon. The 4-10 membered heterocyclyl is preferably a 4-6 membered heterocyclyl, for example, propylene oxide, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl.

[0095] The term "C2-C6 alkenyl" means a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing at least one double bond, having 2 to 6 carbon atoms and connected to the rest of the molecule by one or more single bonds, such as, but not limited to, ethenyl, propenyl, butenyl, styryl, and phenylpropenyl.

[0096] The term "heteroaryl" refers to a 5-14 membered aromatic group having 1 to 4 (e.g., 2 or 3) heteroatoms as ring atoms, with the remaining ring atoms being carbon, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen, preferably 5-10 members, more preferably 5 or 6 members, such as thienyl, furyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like.

[0097] The term "benzo 5-6 membered heteroaryl" refers to a bicyclic ring structure formed by a phenyl group and a heteroaryl group having 5-6 ring atoms as defined above, wherein the atom attached to the rest of the molecule is located on the phenyl ring, such as quinolyl, isoquinolyl, indolyl, benzofuranyl, etc.

[0098] "Hydrate" refers to a compound containing water.

[0099] "Pharmaceutically acceptable salts" refer to salts formed between the drug molecule and the corresponding organic or inorganic acid or organic or inorganic base. Inorganic acids from which salts can be derived include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, trifluoroacetic acid, succinic acid, mesylate, and the like. By way of example only, salts derived from inorganic bases include sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, such as alkylamines (i.e., NH2(alkyl)), dialkylamines (i.e., HN(alkyl)2), trialkylamines (i.e., N(alkyl)3), substituted alkylamines (i.e., NH2(substituted alkyl)), di(substituted alkyl)amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl)amines (i.e., N(substituted alkyl)3), etc. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0100] In the present invention, unless otherwise specified, the terms used have the general meanings known to those skilled in the art. In the present invention, the definitions of different general formulas or multiple identical groups in the same general formula are independent of each other.

[0101] Active ingredient

[0102] As used herein, "compound of the present invention" or "active ingredient" refers to the compound represented by Formula I, and also includes pharmaceutically acceptable salts, tautomers, stereoisomers, and prodrugs thereof.

[0103] The compound represented by formula (I) may also exist in different tautomeric forms, all of which are included within the scope of the present invention.

[0104] The term "tautomer" refers to constitutional isomers of different energies that are interconvertible via a low energy barrier, the reaction typically resulting in the formal migration of a hydrogen atom or proton accompanied by conversion of a single bond and an adjacent double bond.

[0105] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. All such compounds contemplated by the present invention, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, racemates, and other mixtures, are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and their mixtures are encompassed by the present invention.

[0106] The compounds of formula (I) may contain one or more asymmetric or chiral centers and may therefore exist in different stereoisomeric forms. The compounds of the present invention include all stereoisomeric forms, including but not limited to diastereomers, enantiomers and atropisomers and mixtures thereof (e.g., racemates), which are all included within the scope of the present invention.

[0107] Unless otherwise indicated, the term "enantiomer" refers to stereoisomers that are mirror images of one another.

[0108] Unless otherwise indicated, the term "diastereomer" refers to stereoisomers that have two or more chiral centers and that are not mirror images of each other.

[0109] "Racemate" refers to two stereoisomers that are mirror images of each other, with opposite optical rotations that cancel each other out.

[0110] There are chiral centers in the general formula and example compounds of the present invention. Therefore, the single configuration or racemate of the compound of the present invention is also within the scope of this application. In addition, there is corresponding evidence in the prior art that compounds with an amine structure, their R configuration, S configuration, and racemate will all be converted into a 1:1 racemate on cells in in vitro cell experiments and enter the body. Therefore, those skilled in the art can expect that the technical solutions corresponding to the enantiomers or racemates of the compound of the present invention can achieve comparable technical effects. If it is necessary to obtain an example compound of a single configuration in the present invention, the example compound of a single configuration can be obtained through the intermediate 1B of a single configuration and the synthetic method 1 in the compound preparation method, thereby obtaining an enantiomer. In addition, the example compound of a diastereoisomer can be obtained by preparing the intermediate 1B of a single configuration, so diastereoisomers can also be obtained in the present invention. These different isomeric forms are all stereoisomers.

[0111] The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more atoms comprising the compound. For example, the compound may be labeled with radioactive isotopes, such as deuterium (D), tritium (T), 12C, 13C, and 14C. For another example, deuterated drugs may be formed by replacing hydrogen with heavy hydrogen. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared to non-deuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced therapeutic efficacy, and extended drug biological half-life. All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0112] As used herein and unless otherwise specified, the term "prodrug" refers to a derivative of a compound that contains a bioreactive functional group such that the bioreactive functional group can be cleaved from the compound or otherwise reacted under biological conditions (in vitro or in vivo) to provide the compound. Typically, the prodrug is inactive, or at least less active than the compound itself, such that its activity is not exerted until the compound is cleaved from the bioreactive functional group. The bioreactive functional group can be hydrolyzed or oxidized under biological conditions to provide the compound. For example, a prodrug may contain a biohydrolyzable group. Examples of biohydrolyzable groups include, but are not limited to, biohydrolyzable phosphates, biohydrolyzable esters, biohydrolyzable amides, biohydrolyzable carbonates, biohydrolyzable carbamates, and biohydrolyzable ureides. When the compounds of the present invention contain basic groups, they can be prepared as pharmaceutically acceptable salts, including inorganic and organic acid salts. Suitable acids for forming salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, toluenesulfonic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.

[0113] The present invention also encompasses any novel intermediates disclosed herein.

[0114] Pharmaceutical compositions and methods of administration

[0115] As used herein, a "pharmaceutical composition" refers to a formulation of a compound of the present invention and a medium generally accepted in the art for delivering a biologically active compound to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate administration to an organism, thereby facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0116] The compounds of formula (I) can be used in combination with other drugs known to treat or improve similar conditions. When administered in combination, the original drug's route of administration and dosage can remain unchanged, while the compound of formula I is taken simultaneously or subsequently. When the compound of formula I is taken simultaneously with one or more other drugs, a pharmaceutical composition containing one or more known drugs and the compound of formula I can be preferably used. Drug combinations also include taking the compound of formula I and one or more other known drugs during overlapping time periods. When the compound of formula I is used in combination with one or more other drugs, the dosage of the compound of formula I or the known drug may be lower than the dosage of each drug taken alone.

[0117] As used herein, the term "pharmaceutically acceptable" refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, that is, the substance can be administered to a subject without causing an adverse biological response or interacting in an adverse manner with any components contained in the composition.

[0118] In this application, "pharmaceutically acceptable carrier" includes but is not limited to any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavoring, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the relevant governmental regulatory authorities as acceptable for human or livestock use.

[0119] Drugs or active ingredients that can be used in combination with the compound of general formula (I) include but are not limited to one or more of dexamethasone, rituximab, trastuzumab, PD-1 inhibitors, PDL-1 inhibitors, pemetrexed, topotecan, doxorubicin, bortezomib, gemcitabine, dacarbazine, clarithromycin, vincristine, cytarabine, prednisone, docetaxel, clofarabine injection, HDAC inhibitors, kinase targeted inhibitors, androgen receptor inhibitors, androgen biosynthesis inhibitors, erythrocyte growth hormone, minocycline, elotuzumab, palbociclib, nivolumab, pembrolizumab, panobinostat, ublizumab, romidepsin, eltrombopag, CAR-T and melphalan.

[0120] A typical formulation is prepared by mixing a compound represented by the general formula (I) of the present invention and a carrier, diluent or excipient. Suitable carriers, diluents or excipients are well known to those skilled in the art and include substances such as carbohydrates, waxes, water-soluble and / or swellable polymers, hydrophilic or hydrophobic substances, gelatin, oils, solvents, water, etc. The specific carrier, diluent or excipient used will depend on the mode of use and purpose of the compound of the present invention. Solvents are generally selected based on solvents that are considered safe and effective for administration to mammals by those skilled in the art. In general, safe solvents are non-toxic aqueous solvents such as pharmaceutical water, and other non-toxic solvents that are soluble in water or miscible with water. Suitable aqueous solvents include one or more of water, ethanol, propylene glycol, polyethylene glycol (such as PEG400, PEG300), etc. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, flavorings, flavorings or other known additives to enable the compound represented by formula (I) to be manufactured or used in an acceptable form.

[0121] When the compound of formula (I) of the present invention is used in combination with at least one other drug, the two or more drugs can be used separately or in combination, preferably administered in the form of a pharmaceutical composition. The compound of formula (I) or pharmaceutical composition of the present invention can be administered to a subject separately or together in any known oral, intravenous, rectal, vaginal, transdermal, or other topical or systemic administration form.

[0122] These pharmaceutical compositions may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, flavorings, flavorings or other known additives so that the pharmaceutical compositions can be manufactured or used in an acceptable form.

[0123] The medicament of the present invention is preferably administered orally. Solid dosage forms for oral administration may include capsules, tablets, powders, or granular formulations. In a solid dosage form, the compound or pharmaceutical composition of the present invention is mixed with at least one inert excipient, diluent, or carrier. Suitable excipients, diluents, or carriers include substances such as sodium citrate or dicalcium phosphate, or starch, lactose, sucrose, mannitol, silicic acid, etc.; binders such as carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, gum arabic, etc.; humectants such as glycerol, etc.; disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, specific complex silicates, sodium carbonate, etc.; solution retardants such as paraffin, etc.; absorption enhancers such as quaternary ammonium compounds, etc.; adsorbents such as kaolin, bentonite, etc.; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, etc. In the case of capsules and tablets, the dosage form may also include a buffer. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using, for example, lactose and high molecular weight polyethylene glycols as excipients.

[0124] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the compound of the present invention or its composition, the liquid dosage form may contain an inert diluent commonly used in the art, such as water or other solvents; solubilizers and emulsifiers such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide; oils (such as cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, sesame oil, etc.); glycerol; tetrahydrofurfuryl alcohol; fatty acid esters of polyethylene glycol and sorbitan; or mixtures of several of these substances.

[0125] In addition to these inert diluents, the composition may also include excipients such as one or more of wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, and perfuming agents.

[0126] In the case of suspensions, in addition to the compound or combination of the present invention, it may further contain a carrier such as a suspending agent, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, or a mixture of several of these substances.

[0127] Compositions for rectal or vaginal administration are preferably suppositories and can be prepared by mixing the compound or combination of the present invention with suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at room temperature but liquid at body temperature and melt in the rectum or vagina to release the active compound.

[0128] The compounds or pharmaceutical compositions of the present invention may be administered in other topical dosage forms, including creams, powders, sprays, and inhalants. The drug may be mixed under sterile conditions with a pharmaceutically acceptable excipient, diluent, or carrier, and any desired preservatives, buffers, or propellants. Ophthalmic formulations, ophthalmic ointments, powders, and solutions are also intended to be encompassed within the scope of this invention.

[0129] As used herein, the terms "administer," "administer," "administer," and the like refer to methods by which a compound or composition can be delivered to the desired site for biological action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injections or infusions), topical administration, and rectal administration. Those skilled in the art are familiar with administration techniques that can be used for the compounds and methods described herein, such as those discussed in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. In preferred embodiments, the compounds and compositions discussed herein are administered orally.

[0130] As used herein, the terms "pharmaceutical combination," "drug combination," "combination therapy," "administration of another therapy," "administration of another therapeutic agent," and the like refer to a pharmaceutical therapy obtained by mixing or combining more than one active ingredient, and include both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that at least one compound described herein and at least one synergistic agent are administered to a patient simultaneously as a single entity or single dosage form. The term "non-fixed combination" means that at least one compound described herein and at least one synergistic agent are administered to a patient simultaneously, in combination, or sequentially at variable intervals as separate entities. This also applies to cocktail therapies, e.g., administration of three or more active ingredients.

[0131] The pharmaceutical composition of the present invention comprises a safe and effective amount of a compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 10-1000 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0132] The compound or pharmaceutical composition of the present invention can be used to prepare a drug for treating or preventing diseases in which CRL4CRBNE3 ubiquitin ligase participates. The diseases related to CRL4CRBNE3 ubiquitin ligase participates described in the present invention include, but are not limited to, tumors, central nervous system diseases, and immune diseases.

[0133] In a preferred embodiment, the disease includes but is not limited to: cancer, pain (including but not limited to complex regional pain syndrome), skin diseases, immunodeficiency diseases, central nervous system damage and dysfunction.

[0134] In another preferred embodiment, the cancer includes (but is not limited to): skin cancer (such as melanoma), lymphatic system cancer, breast cancer, cervical cancer, uterine cancer, digestive tract cancer, lung cancer, ovarian cancer, prostate cancer, colon cancer, rectal cancer, oral cancer, brain tumor, head and neck cancer, pharyngeal cancer, testicular cancer, kidney cancer, pancreatic cancer, spleen cancer, liver cancer, bladder cancer, laryngeal cancer and cancer related to AIDS. The compounds provided by the present invention are also effective for hematological tumors and myeloma, such as multiple myeloma, lymphoma and acute and chronic leukemia. The compounds provided by the present invention can also be used to prevent or treat primary tumors and metastatic tumors.

[0135] The use of the drug molecules of the present invention includes but is not limited to the diseases selected from the group consisting of myelodysplastic syndrome, multiple myeloma, mantle cell lymphoma, non-Hodgkin's lymphoma, chronic lymphocytic leukemia, chronic myelomonocytic leukemia, myelofibrosis, Burkitt's lymphoma, Hodgkin's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, ciliary body and chronic melanoma, iris melanoma, recurrent interocular melanoma, T cell lymphoma, erythroid lymphoma, monoblastic leukemia, Myeloid and monocytic leukemia, myeloid leukemia, central nervous system lymphoma, meningioma, spinal cord tumor, non-small cell lung cancer, ovarian cancer, skin cancer, renal cell carcinoma, astrocytoma, amyloidosis, complex regional pain syndrome type I, malignant melanoma, radiculopathy, glioblastoma, gliosarcoma, malignant glioma, refractory plasmacytoma, melanoma with extraocular extension, papillary and follicular thyroid cancer, breast cancer, prostate cancer, hepatocellular carcinoma, or essential macroglobulinemia.

[0136] The main advantages of the present invention include:

[0137] 1. The present invention provides a novel indazolone skeleton structure CRL4 CRBN E3 ubiquitin ligase molecular glue degraders have improved tumor treatment effects and can broaden the indications of molecular glue degraders, and provide CRL4 with better physicochemical properties for the design and development of degraders of related pathogenic proteins. CRBN Ligand for E3 ubiquitin ligase.

[0138] 2. Based on the structural instability of existing CRBN ligands and immunomodulatory imide drugs (IMiDs), which are easily hydrolyzed in body fluids, this invention optimizes their structure and develops a molecular glue-like degradation agent with an indazolone skeleton (Formula I) through skeleton transition. This skeleton has good chemical stability.

[0139] 3. The compounds with indazolone skeleton structure of the present invention have good drug metabolism properties and have better bioavailability and drug metabolism properties compared with other positive compounds.

[0140] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0141] In all embodiments, 1H NMR spectra were measured using 400 MHz Bruker and 500 MHz Bruker nuclear magnetic resonance instruments, with chemical shifts expressed in δ (ppm). Mass spectra were determined using MS UPLC-MS (ESI). The UPLC model was Waters HPLC H-CLASS, and the MS (ESI) model was Waters SQ Detector 2. Anhydrous tetrahydrofuran was prepared by reflux drying and deoxygenation of benzophenone / sodium metal, and anhydrous toluene and anhydrous dichloromethane were prepared by reflux drying of calcium chloride. Solvents used for column chromatography mobile phases, such as petroleum ether, ethyl acetate, and dichloromethane, were purchased from Sinopharm Chemical Reagent Co., Ltd. The thin layer chromatography silica gel plates (HSGF254) used in reaction detection were from Sinopharm Chemical Reagent Co., Ltd. Compound separation used 200-300 mesh silica gel from Sinopharm Chemical Reagent Co., Ltd. The raw materials in the present invention can be obtained from commercial sources, such as the main reagents purchased from Sinopharm Chemical Reagent Co., Ltd., or prepared by methods known in the art, or prepared according to the methods described in the present invention.

[0142] Example 1: 3-(6-(1-benzylpiperidin-4-yl)-3-oxo-1,3-dihydro-2H-indazol-2-yl)piperidine-2,6-dione (Z1)

[0143] Synthesis route:

[0144] Step 1:

[0145] Methyl 4-chloro-2-nitrobenzoate (1 g, 4.63 mmol), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (1.43 g, 4.63 mmol), potassium carbonate (1.2 g, 9.26 mmol), and tetrakistriphenylphosphine palladium (268 mg, 0.232 mmol) were added to a mixed solvent of 1,4-dioxane (20 mL) and water (5 mL). The reaction system was purged with nitrogen and heated to 90°C under nitrogen protection overnight. The 1,4-dioxane was removed by concentration under reduced pressure, and the residue was extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent removed under reduced pressure. The resulting residue was separated by silica gel column chromatography to obtain 1.5 g of the product as a yellow oil in an 89% yield.

[0146] Step 2:

[0147] The compound tert-butyl 4-(4-(methoxycarbonyl)-3-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (1 g, 2.76 mmol) was added to tetrahydrofuran (10 mL), and an aqueous solution (10 mL) of lithium hydroxide monohydrate (174 mg, 4.14 mmol) was added. The reaction was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure and dried to obtain 977 mg of the product, which was used directly in the next reaction without purification.

[0148] Step 3:

[0149] The compound 4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-nitrobenzoic acid lithium salt (977 mg, 2.76 mmol), (S)-tert-butyl 4,5-diamino-5-oxopentanoate monohydrochloride (659 mg, 2.76 mmol), and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (1.05 g, 2.76 mmol) were added to N,N-dimethylformamide (15 mL). N,N-diisopropylethylamine (1.4 mL, 8.28 mmol) was added dropwise and reacted at room temperature for 12 hours. The reaction solution was diluted with ethyl acetate, washed with water, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain 1.28 g of the product as a yellow oil in an 87% yield. The theoretical value of UPLC-MS (ESI) is C 26 H 36 N4O8[M+H] + :533.59, the measured value is: 553.62.

[0150] Step 4:

[0151] Compound 4-(4-((1-amino-5-(tert-butoxy)-1,5-dioxolane-2-yl)carbamoyl)-3-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1.78 g, 3.35 mmol) was added to methanol (20 mL), tetrahydroxydiboron (1.5 g, 16.76 mmol) was added at 0°C, and then a methanol solution of sodium hydroxide (1.34 g, 33.5 mmol) (20 mL) was added. The mixture was reacted at 0°C for 10 minutes, then the temperature was raised to 40°C and the reaction was allowed to proceed overnight. After TLC monitoring, the reaction was quenched by adding saturated ammonium chloride solution, extracted with ethyl acetate, and separated. The organic phase was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to column chromatography to obtain 1.1 g of the product, 66%. The theoretical value of UPLC-MS (ESI) was C 26 H 36 N4O6[M+H] + :501.60, measured value: 501.35.

[0152] Step 5:

[0153] Compound 4-(2-(1-amino-5-(tert-butoxy)-1,5-dioxolane-2-yl)-3-oxo-2,3-dihydro-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (100 mg, 0.2 mmol) and 10% Pd / C (10 ng) were added to methanol (10 mL). The resulting mixture was vigorously stirred under hydrogen conditions and reacted overnight. After the reaction was completed, the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 73 mg of the product with a yield of 73%. The theoretical value of UPLC-MS (ESI) was C 26 H 38 N4O6[M+H] + :503.61, measured value: 503.47.

[0154] Step 6:

[0155] tert-Butyl 4-(2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-3-oxo-2,3-dihydro-1H-indazol-6-yl)piperidine-1-carboxylate (100 mg, 0.2 mmol) and p-toluenesulfonic acid monohydrate (228 mg, 1.2 mmol) were added to acetonitrile (3 mL) and reacted at 80°C overnight. The reaction solution was concentrated and the crude product was used for the next step.

[0156] Step 7:

[0157] The compound 3-(3-oxo-6-(piperidin-4-yl)-1,3-dihydro-2H-indazol-2-yl)piperidine-2,6-dione 4-methylbenzenesulfonate (100 mg, 0.2 mmol) was dissolved in a mixed solution of N,N-dimethylformamide (1 mL) and dichloromethane (1 mL), and benzaldehyde (0.025 mL, 0.25 mmol) and sodium triacetoxyborohydride (127 mg, 0.6 mmol) were added. The reaction system was allowed to react overnight at room temperature. After the reaction was completed, the mixture was diluted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The resulting residue was separated by silica gel column chromatography to obtain 30 mg of the product with a yield of 35%. The theoretical value of UPLC-MS (ESI) was C 24 H 26 N4O3[M+H] + :419.50, measured value: 419.62. 1H NMR(500MHz,Methanol-d4)δ7.71(d,J=8.2Hz,1H),7.43(m,5H),7.16(s,1H), 7.11(d,J=8.2Hz,1H),5.38(dd,J=13.2,5.2Hz,1H),3.98(s,2H),2.92(ddd,J= 18.6,13.6,5.4Hz,1H),2.86–2.75(m,2H),2.67(td,J=11.7,4.6Hz,2H),2.51( qd,J=13.2,4.6Hz,1H),2.24(ddd,J=10.3,5.1,2.8Hz,1H),2.00–1.90(m,6H).

[0158] Example 2: 3-(6-(1-(4-chlorobenzyl)piperidin-4-yl)-3-oxo-1,3-dihydro-2H-indazol-2-yl)piperidine-2,6-dione (Z2)

[0159] The synthesis method was similar to that in Example 1 to obtain compound Z2. 1 H NMR(500MHz,DMSO)δ11.03(s,1H),9.94(s,1H),7.64(t,J=7.1Hz,1H),7.61–7.55(m,4H) ,7.01(d,J=8.7Hz,2H),5.33(dd,J=13.2,5.1Hz,1H),4.36(d,J=4.8Hz,2H),3.48(d,J=12 .2Hz,2H),3.07(d,J=11.9Hz,2H),2.98–2.88(m,2H),2.62(d,J=12.9Hz,1H),2.37(dt,J=21.5,11.0Hz,1H),2.05(dd,J=17.9,10.5Hz,3H),1.96–1.85(m,2H). UPLC-MS (ESI) theoretical value is C 24 H 26 ClN4O3[M+H] + :453.16, measured value 453.30.

[0160] Example 3: 3-(6-(1-(4-fluorobenzyl)piperidin-4-yl)-3-oxo-1,3-dihydro-2H-indazol-2-yl)piperidine-2,6-dione (Z3)

[0161] The synthetic method was similar to that of Example 45 to obtain compound D47. 1H NMR (500MHz, DMSO) δ11.03(s,1H),9.93(s,1H),7.65(d,J=8.5Hz,1H),7.60(dd,J=8.6,5.5H z,2H),7.36(t,J=8.8Hz,2H),7.01(d,J=8.2Hz,2H),5.33(dd,J=13.2,5.2Hz,1H),4.36(d,J =4.9Hz,2H),3.48(d,J=11.7Hz,2H),3.12–3.01(m,2H),2.97–2.87(m,2H),2.66–2.59(m,1H),2.42–2.33(m,1H),2.10–2.00(m,3H),1.87(dd,J=23.4,12.7Hz,2H). UPLC-MS (ESI) theoretical value is C 24 H 26 FN4O3[M+H] + :437.19, measured value 437.33.

[0162] Example 4: (S)-3-(3-oxo-6-(1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-1,3-dihydro-2H-indazol-2-yl)piperidine-2,6-dione (Z4)

[0163] The synthesis method was similar to that in Example 1 to obtain compound Z4. 1 H NMR (500MHz, DMSO) δ11.03(s,1H),9.93(s,1H),7.91(d,J=8.1Hz,2H),7.79(d,J=8.0Hz,2H),7. 65(d,J=8.5Hz,1H),7.02(d,J=8.2Hz,2H),5.33(dd,J=13.1,5.2Hz,1H),4.47(d,J=4.6Hz,2H),3 .50(d,J=12.3Hz,2H),3.17–3.07(m,2H),2.97–2.88(m,2H),2.62(d,J=13.2Hz,1H),2.39–2.33(m,1H),2.11–1.99(m,3H),1.90(dd,J=23.4,12.9Hz,2H).UPLC-MS(ESI)theorized for C25H26F3N4O3[M+H] + :487.19, measured value 487.39.

[0164] Example 5: 3-(3-oxo-6-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,3-dihydro-2H-indazol-2-yl)piperidine-2,6-dione (Z5)

[0165] The synthesis method was similar to that in Example 1 to obtain compound Z5. 1 H NMR (500MHz, DMSO) δ11.02(s,1H),9.93(s,1H),7.69(d,J=8.6Hz,2H),7.65(d,J=8.1Hz,1H),7 .52(d,J=8.1Hz,2H),7.02(d,J=8.7Hz,2H),5.32(dd,J=13.1,5.2Hz,1H),4.40(d,J=4.2Hz,2H ), 3.50(d,J=11.6Hz,2H),3.13–3.05(m,2H),2.97–2.89(m,2H),2.65–2.60(m,1H),2.37(dd,J=13.1,4.3Hz,1H),2.04(d,J=13.0Hz,3H),1.89(dd,J=23.5,12.6Hz,2H). UPLC-MS (ESI) theoretical value was C 25 H 26 F3N4O4[M+H] + :503.18, measured value 503.40.

[0166] Example 6: 3-(6-(1-(4-methylbenzyl)piperidin-4-yl)-3-oxo-1,3-dihydro-2H-indazol-2-yl)piperidine-2,6-dione (Z6)

[0167] The synthesis method was similar to that in Example 1 to obtain compound Z6. 1 H NMR (500MHz, DMSO) δ11.03(s,1H),9.93(s,1H),7.42(d,J=8.0Hz,2H),7.31(t,J=5.5Hz ,3H),7.01(d,J=8.6Hz,2H),5.33(dd,J=13.2,5.2Hz,1H),4.31(d,J=4.8Hz,2H),3.47( d, J = 11.1 Hz, 2H), 3.09–3.00 (m, 2H), 2.93 (ddd, J = 13.9, 12.5, 5.5 Hz, 2H), 2.65–2.59 (m, 1H), 2.37-2.32 (m, 4H), 2.05 (dd, J = 19.7, 9.4 Hz, 3H), 1.92 (s, 2H). UPLC-MS (ESI) theoretical value was C 25 H 29 N4O3[M+H] + :433.22, measured value 433.37.

[0168] Example 7: 4-((4-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-indazol-6-yl)piperidin-1-yl)methyl)benzonitrile (Z7)

[0169] The synthesis method was similar to that in Example 1 to obtain compound Z7. 1 H NMR (500 MHz, DMSO-d6) δ 11.01 (s, 1H), 10.07 (s, 1H), 8.01–7.81 (m, 4H), 7.63 (d, J = 8.1 Hz, 1H), 7.08–7.00 (m, 2H), 5.31 (dd, J = 13.1, 5.2 Hz, 1H), 4.46 (s, 2H), 3.43 (s, 2H), 3.05 (d, J = 2.8 Hz, 2H), 2.98–2.88 (m, 2H), 2.67–2.60 (m, 1H), 2.44–2.35 (m, 1H), 2.18 (s, 2H), 2.10–2.03 (m, 1H), 1.96 (s, 2H). UPLC-MS (ESI) requires C 25 H 26 N5O3[M+H] + :444.20, measured value 444.37.

[0170] Example 8: 3-(3-oxo-6-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-1,3-dihydro-2H-indazol-2-yl)piperidine-2,6-dione (Z8)

[0171] The synthesis method was similar to that in Example 1 to obtain compound Z8. 1 H NMR(500MHz,DMSO)δ11.02(s,1H),9.92(s,1H),8.78–8.68(m,2H),7.65(d,J=8.3Hz,1 H),7.59(d,J=5.4Hz,2H),7.02(d,J=8.4Hz,2H),5.33(dd,J=13.1,5.2Hz,1H),4.41(s ,2H),3.50(d,J=10.7Hz,2H),3.11(s,2H),2.97–2.89(m,2H),2.63(dd,J=7.4,5.6Hz,1H),2.35(t,J=7.8Hz,1H),2.08–2.00(m,3H),1.95–1.85(m,2H). UPLC-MS (ESI) theoretical value was C 23 H 26 N5O3[M+H] +:420.20, measured value 420.41.

[0172] Example 9: 3-(6-(1-(3-chloro-2-fluorobenzyl)piperidin-4-yl)-3-oxo-1,3-dihydro-2H-indazol-2-yl)piperidine-2,6-dione (Z9)

[0173] The synthesis method was similar to that in Example 1 to obtain compound Z9. 1 H NMR(500MHz,DMSO)δ11.02(s,1H),9.93(s,1H),7.77(s,1H),7.67–7.59(m,2H),7.40(d,J =7.9Hz,1H),7.02(s,2H),5.32(dd,J=13.1,5.2Hz,1H),4.46(s,2H),3.55(d,J=11.0Hz,2 H), 3.19 (d, J = 10.1 Hz, 2H), 2.93 (ddd, J = 18.9, 13.6, 5.3 Hz, 2H), 2.63 (dd, J = 9.8, 6.1 Hz, 1H), 2.36 (d, J = 4.6 Hz, 1H), 2.10–1.99 (m, 3H), 1.91 (d, J = 11.5 Hz, 2H). UPLC-MS (ESI) theoretical value is C 24 H 25 ClFN4O3[M+H] + :471.15, measured value 471.33.

[0174] Example 10: 3-(6-(1-(3-chlorobenzyl)piperidin-4-yl)-3-oxo-1,3-dihydro-2H-indazol-2-yl)piperidine-2,6-dione (Z10)

[0175] The synthesis method was similar to that in Example 1 to obtain compound Z10. 1H NMR (500MHz, DMSO) δ11.02(s,1H),9.92(s,1H),7.68(s,1H),7.65(d,J=8.2Hz,1H),7.60–7.50( m,3H),7.02(d,J=8.4Hz,2H),5.32(dd,J=13.2,5.2Hz,1H),4.38(d,J=4.8Hz,2H),3.49(d,J=11. 7Hz,2H),3.09(dd,J=22.4,10.8Hz,2H),2.93(s,2H),2.63(dd,J=9.6,5.9Hz,1H),2.37(dd,J=12.9,4.4Hz,1H),2.06(dd,J=17.5,7.3Hz,3H),1.90(dd,J=23.5,12.6Hz,2H). UPLC-MS (ESI) theoretical value is C 24 H 26 ClN4O3[M+H] + :453.16, measured value 453.64.

[0176] Example 11: 3-((4-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-indazol-6-yl)piperidin-1-yl)methyl)benzonitrile (Z11)

[0177] The synthesis method was similar to that in Example 1 to obtain compound Z11. 1 H NMR (400MHz, DMSO) δ11.02 (s, 1H), 9.93 (s, 1H), 8.07 (s, 1H), 7.99 (d, J = 7.7Hz, 1H), 7.92(d,J=7.8Hz,1H),7.78–7.62(m,3H),7.04(s,1H),5.38–5.31(m,1H),4.43(s,2 H), 3.51 (d, J = 12.2 Hz, 2H), 3.11 (d, J = 11.3 Hz, 2H), 2.94 (m, 2H), 2.44–2.31 (m, 1H), 2.07 (d, J = 8.2 Hz, 3H), 1.95 (t, J = 12.6 Hz, 2H). UPLC-MS (ESI) requires C25H26N5O3 [M+H] + :444.20, measured value 444.35.

[0178] Example 12: 3-(3-oxo-6-(1-(3-(trifluoromethyl)benzyl)piperidin-4-yl)-1,3-dihydro-2H-indazol-2-yl)piperidine-2,6-dione (Z12)

[0179] The synthesis method was similar to that in Example 1 to obtain compound Z12. 1 H NMR (500MHz, DMSO-d6) δ11.03(s,1H),9.93(s,1H),7.99(s,1H),7.88(t,J=8.3Hz,2H),7.76(t,J=7.7H z,1H),7.66(d,J=8.1Hz,1H),7.03(d,J=7.9Hz,2H),5.33(dd,J=13.2,5.3Hz,1H),4.49(d,J=5.0Hz,2H ), 3.12(q,J=11.6Hz,2H),2.94(ddd,J=13.6,11.8,6.8Hz,2H),2.64(d,J=16.8Hz,2H),2.43–2.32(m,2H),2.07(ddd,J=12.8,9.0,6.3Hz,3H),1.90(q,J=13.1Hz,2H). UPLC-MS(ESI)theorized for C25H26F3N4O3[M+H] + :487.19, measured value 487.27.

[0180] Example 13: 3-(6-(1-(2-chlorobenzyl)piperidin-4-yl)-3-oxo-1,3-dihydro-2H-indazol-2-yl)piperidine-2,6-dione (Z13)

[0181] The synthesis method was similar to that in Example 1 to obtain compound Z13. 1 H NMR(500MHz,DMSO-d6)δ11.03(s,1H),9.94(s,1H),7.76(dd,J=7.2,2.2Hz,1H),7.68– 7.62(m,2H),7.58–7.49(m,2H),7.02(d,J=8.1Hz,2H),5.33(dd,J=13.1,5.2Hz,1H),4 .52 (d, J = 5.0 Hz, 2H), 3.30 (dd, J = 25.5, 13.8 Hz, 3H), 3.00–2.90 (m, 2H), 2.63 (d, J = 16.3 Hz, 1H), 2.46–2.29 (m, 2H), 2.10–2.01 (m, 3H), 1.99–1.90 (m, 2H). UPLC-MS (ESI) theoretical value was C 24 H 26 ClN4O3[M+H] + :453.16, measured value 453.30.

[0182] Example 14: (S)-2-((4-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-indazol-6-yl)piperidin-1-yl)methyl)benzonitrile (Z14)

[0183] The synthesis method was similar to that in Example 1 to obtain compound Z14. 1 H NMR (400MHz, DMSO-d6) δ11.02(s,1H),9.98(s,1H),8.02(d,J=7.7Hz,1H),7.8 8(d,J=4.2Hz,2H),7.77–7.70(m,1H),7.70–7.62(m,1H),7.03(d,J=10.1Hz,2 H),5.33(dd,J=13.1,5.2Hz,1H),4.54(s,2H),3.60–3.50(m,2H),3.28(d,J=1 2.2Hz,2H),3.05–2.87(m,2H),2.64(dt,J=17.0,3.6Hz,1H),2.39(qd,J=13.1, 4.4 Hz, 1H), 2.11–1.92 (m, 5H). UPLC-MS (ESI) theoretical value is C 25 H 26 N5O3[M+H] + :444.20, measured value 444.36.

[0184] Example 15: 3-(3-oxo-6-(1-(2-(trifluoromethyl)benzyl)piperidin-4-yl)-1,3-dihydro-2H-indazol-2-yl)piperidine-2,6-dione (Z15)

[0185] The synthesis method was similar to that in Example 1 to obtain compound Z15. 1 H NMR (500 MHz, DMSO-d6) δ 11.03 (s, 1H), 9.94 (s, 1H), 7.98 (d, J = 7.8 Hz, 1H), 7.89 (q, J = 7.7 Hz, 2H), 7.73 (t, J = 7.6 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.04 (s, 2H), 5.33 (dd, J = 13.1, 5.2 Hz, 1H), 4.59–4.51 (m, 2H), 3.30 (s, 2H), 3.07–2.82 (m, 3H), 2.69–2.58 (m, 2H), 2.40 (d, J = 4.6 Hz, 1H), 2.03 (s, 5H). UPLC-MS (ESI) requires C 25 H 26 F3N4O3[M+H]+ :487.19, measured value 487.35.

[0186] Example 16: 3-(6-(1-(2,4-difluorobenzyl)piperidin-4-yl)-3-oxo-1,3-dihydro-2H-indazol-2-yl)piperidine-2,6-dione (Z16)

[0187] The synthesis method was similar to that in Example 1 to obtain compound Z16. 1 H NMR(500MHz,DMSO-d6)δ11.04(s,1H),9.93(s,1H),7.74–7.70(m,1H),7.65(d,J=8.3Hz,1H), 7.47(td,J=9.7,2.6Hz,1H),7.29(td,J=8.5,2.6Hz,1H),7.01(d,J=7.9Hz,2H),5.33(dd,J=13 .1,5.2Hz,1H),4.40(d,J=4.4Hz,2H),3.15(t,J=11.4Hz,2H),2.96–2.88(m,2H),2.63(d,J=16.8Hz,2H),2.43–2.32(m,2H),2.09–2.00(m,3H),1.90(d,J=12.7Hz,2H). UPLC-MS (ESI) theoretical value was C 24 H 25 F2N4O3[M+H] + :455.18, measured value 455.31.

[0188] Example 17: 3-(6-(1-(2,4-dichlorobenzyl)piperidin-4-yl)-3-oxo-1,3-dihydro-2H-indazol-2-yl)piperidine-2,6-dione (Z17)

[0189] The synthesis method was similar to that in Example 1 to obtain compound Z17. 1H NMR (500MHz, DMSO-d6) δ11.04(s,1H),9.94(s,1H),7.85(d,J=2.1Hz,1H),7.77(d,J=8 .3Hz,1H),7.68–7.63(m,2H),7.02(s,2H),5.33(dd,J=13.2,5.2Hz,1H),4.50(s,2H), 3.54 (d, J = 11.8 Hz, 2H), 3.26 (d, J = 11.9 Hz, 2H), 3.05–2.85 (m, 3H), 2.63 (d, J = 17.1 Hz, 1H), 2.43–2.31 (m, 2H), 2.09–2.01 (m, 3H), 1.92 (d, J = 12.2 Hz, 2H). UPLC-MS (ESI) theoretical value was C 24 H 25 Cl2N4O3[M+H] + :487.12, measured value 487.27.

[0190] Example 18: 3-(6-(1-(4-chloro-2-fluorobenzyl)piperidin-4-yl)-3-oxo-1,3-dihydro-2H-indazol-2-yl)piperidine-2,6-dione (Z18)

[0191] The synthesis method was similar to that in Example 1 to obtain compound Z18. 1 H NMR(500MHz,DMSO-d6)δ11.04(s,1H),9.94(s,1H),7.75–7.66(m,2H),7.66–7.64(m,1H),7.5 0(dd,J=8.3,2.2Hz,1H),7.02(s,2H),5.34(dd,J=13.1,5.2Hz,1H),4.42(d,J=4.2Hz,2H),3. 53 (d, J = 11.6 Hz, 2H), 3.16 (q, J = 11.5 Hz, 2H), 2.93 (ddt, J = 16.4, 10.3, 3.9 Hz, 2H), 2.62 (d, J = 3.5 Hz, 1H), 2.38 (s, 1H), 2.10–2.02 (m, 3H), 1.91 (td, J = 13.3, 3.7 Hz, 2H). UPLC-MS (ESI) theoretical value was C 24 H 25 ClFN4O3[M+H] + :471.15, measured value 471.29.

[0192] Example 19: 3-(6-(1-(2-chloro-4-fluorobenzyl)piperidin-4-yl)-3-oxo-1,3-dihydro-2H-indazol-2-yl)piperidine-2,6-dione (Z19)

[0193] The synthesis method was similar to that in Example 1 to obtain compound Z19. 1 H NMR(500MHz,DMSO-d6)δ11.04(s,1H),9.94(s,1H),7.83–7.80(m,1H),7.67(dd,J=11.5,8.6H z,2H),7.44(dd,J=8.5,2.7Hz,1H),7.02(d,J=7.7Hz,2H),5.36–5.32(m,1H),4.49(d,J=4.9Hz ,2H),3.25(s,1H),2.97(d,J=5.5Hz,1H),2.92(dt,J=16.7,3.8Hz,2H),2.63(d,J=15.8Hz,2H),2.41–2.32(m,2H),2.06(dd,J=20.7,8.5Hz,3H),1.95(t,J=12.5Hz,2H). UPLC-MS (ESI) theoretical value was C 24 H 25 ClFN4O3[M+H] + :471.15, measured value 471.33.

[0194] Example 20: 4-((4-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-indazol-6-yl)piperidin-1-yl)methyl)-3-fluorobenzonitrile (Z20)

[0195] The synthesis method was similar to that in Example 1 to obtain compound Z20. 1 H NMR (500 MHz, DMSO-d6) δ 11.04 (s, 1H), 9.74 (s, 1H), 8.17 (s, 1H), 8.08 (d, J = 9.5 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.47 (s, 1H), 7.32 (dd, J = 8.1, 1.4 Hz, 1H), 7.01 (d, J = 8.2 Hz, 1H), 5.36–5.30 (m, 1H), 4.50 (s, 2H), 3.23–3.18 (m, 2H), 2.77–2.69 (m, 2H), 2.65–2.58 (m, 2H), 2.07–1.96 (m, 5H). UPLC-MS (ESI) required C 25 H 25 FN5O3[M+H]+ :462.19, measured value 462.20.

[0196] Example 21: 3-(3-oxo-6-(1-(prop-2-yn-1-yl)piperidin-4-yl)-1,3-dihydro-2H-indazol-2-yl)piperidine-2,6-dione (Z21)

[0197] The synthesis method was similar to that in Example 1 to obtain compound Z21. 1 H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 9.95 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.05 (d, J = 12.1 Hz, 2H), 5.33 (dd, J = 13.1, 5.2 Hz, 1H), 4.14 (s, 2H), 2.94 (ddd, J = 16.8, 13.5, 5.3 Hz, 2H), 2.64 (d, J = 17.4 Hz, 2H), 2.40 (td, J = 13.1, 4.5 Hz, 2H), 1.95–1.85 (m, 2H), 1.24 (s, 1H). UPLC-MS (ESI) requires C 20 H 23 N4O3[M+H] + :367.17, measured value 367.32.

[0198] Example 22: 3-(3-oxo-6-(1-(quinolin-5-ylmethyl)piperidin-4-yl)-1,3-dihydro-2H-indazol-2-yl)piperidine-2,6-dione (Z22)

[0199] The synthesis method was similar to that in Example 1 to obtain compound Z22.

[0200] Example 23: 3-(3-oxo-6-(1-(4-(thiazol-2-yl)benzyl)piperidin-4-yl)-1,3-dihydro-2H-indazol-2-yl)piperidine-2,6-dione (Z23)

[0201] The synthesis method was similar to that in Example 1 to obtain compound Z23.

[0202] Example 24: 3-(6-(1-(4-ethynylbenzyl)piperidin-4-yl)-3-oxo-1,3-dihydro-2H-indazol-2-yl)piperidine-2,6-dione (Z24)

[0203] The synthesis method was similar to that of Example 45 to obtain compound D68. 1H NMR (400MHz, DMSO) δ11.02 (s, 1H), 9.93 (s, 1H), 7.67–7.60 (m, 3H), 7.56 (d, J = 8.3Hz, 2H), 7. 03(s,2H),5.33(dd,J=13.1,5.1Hz,1H),4.39(d,J=4.7Hz,2H),4.34(s,1H),3.49(d,J=11.9H z, 2H), 3.09 (q, J = 11.4 Hz, 2H), 3.00–2.92 (m, 1H), 2.90 (d, J = 3.4 Hz, 1H), 2.64 (d, J = 17.1 Hz, 1H), 2.39 (td, J = 13.2, 4.4 Hz, 1H), 2.11–2.00 (m, 3H), 1.96–1.83 (m, 2H). UPLC-MS (ESI) theoretical value is C 26 H 27 N4O3[M+H] + :443.20, measured value 443.35.

[0204] Example 25: (S)-3-(6-(1-(4-chloro-2-methylbenzyl)piperidin-4-yl)-3-oxo-1,3-dihydro-2H-indazol-2-yl)piperidine-2,6-dione (Z25)

[0205] The synthesis method was similar to that in Example 1 to obtain compound Z25.

[0206] Example 26: 3-(6-(4-Benzylpiperazin-1-yl)-3-oxo-1,3-dihydro-2H-indazol-2-yl)piperidine-2,6-dione (Z26)

[0207] The synthesis method was similar to that in Example 1 to obtain compound Z26. 1 H NMR (400 MHz, DMSO) δ 7.81 (s, 1H), 7.74 (d, J = 2.2 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.54–7.50 (m, 5H), 7.40 (s, 1H), 7.11 (dd, J = 8.9, 2.2 Hz, 1H), 5.04 (dd, J = 5.3, 3.0 Hz, 1H), 4.42 (s, 2H), 4.01 (s, 2H), 3.45 (s, 2H), 3.15 (s, 4H), 2.75–2.66 (m, 1H), 2.57 (dt, J = 11.2, 5.5 Hz, 1H), 2.45–2.38 (m, 1H), 2.36–2.30 (m, 1H). UPLC-MS (ESI) requires C 23 H 24N5O3[M+H] + :420.20, measured value 420.35.

[0208] 2. Experimental Examples

[0209] 1. In vitro cell degradation data of compounds

[0210] Western blot analysis

[0211] Molm-13 cells in logarithmically growing phase were seeded at 5×105 cells / well in 12-well plates. Compounds were added at various concentrations diluted in complete medium to a final volume of 1 mL. After 16 hours of culture, cells were harvested into 2 mL EP tubes, centrifuged, and lysed in 100 μL of 1× Loading Buffer on ice for 30 minutes. The cells were then boiled in a metal bath at 95°C for 15 minutes. After cooling, the samples were subjected to SDS-PAGE electrophoresis, transferred to nitrocellulose membranes, and blocked with 5% skim milk powder at room temperature for 1.5 hours. Primary antibodies against IKZF2 and β-actin were added and incubated overnight at 4°C. After washing three times for 10 minutes, the corresponding secondary antibodies (1:10,000) were added and incubated at room temperature for 1 hour. After washing three times for 10 minutes, ECL developer was added and the gel was exposed on a gel imaging system. Bands were processed and analyzed using Image Lab software. The grayscale value of the band represents the signal intensity; lower grayscale values ​​indicate lower signal intensity. The relative multiple normalized to the internal reference protein was used as the protein expression level of each group (Int). The degradation rate of the target protein in each group was calculated as the ratio of the target protein expression level in the compound group (Int_target) to the target protein expression level in the negative control group (Int_DMSO). The calculation formula is as follows: Protein degradation = (1-Int_target / Int_DMSO) × 100%

[0212] The degradation rates of IKZF2 by the example compounds at a concentration of 1 μM are shown in Table 1. In Table 1, A indicates that the degradation rate of IKZF2 is greater than 70%, B indicates that the degradation rate of IKZF2 is 40% or less than 70%, and C indicates that the degradation rate of IKZF2 is less than 40%.

[0213] Based on the test results of the degradation rate of IKF2 in acute myeloid leukemia cells (Molm-13) of some of the above example compounds, it was found that most of the example compounds of the present invention had a high degradation rate of IKZF2 in acute leukemia cells (Molm-13) at a concentration of 1 μM, and most of them were better than or equivalent to the positive compound DKY-709 currently under clinical research. Therefore, the compounds of the present invention can be used to prevent, treat and regulate CRBN (CRL4 CRBNDiseases associated with E3 ubiquitin ligase) activity, such as acute myeloid leukemia or, without limitation, other potential tumor diseases, pain, neurological diseases, and immune system diseases.

[0214] 2.CRBN / DDB1 binding TR-FRET assay

[0215] 1. Experimental steps

[0216] 1. Take 0.1 μL of reference solution and place it in a 384-well reaction plate. The final detection concentration is 100 μM. Dilute 3 times and plate 10 points.

[0217] 2. Add 2.5 μL of CRBN / DDB1 to the 384-well reaction plate and centrifuge at 1000 rpm for 1 minute.

[0218] 3. Add 2.5 μL of Thalidomide-BODIPY to the 384-well reaction plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 15 minutes.

[0219] 4. Add 5 μL of His-Tb to the 384 reaction plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 60 minutes.

[0220] 5. Read the TR-FRET signal using BMG (ratio 520 / 490 nm).

[0221] The inhibition rates of the compounds on CRBN / DDB1 binding are shown in Table 3 below: A indicates an inhibition rate > 70%, B indicates an inhibition rate of 50% < 70%, and C indicates an inhibition rate < 50%.

[0222] Table 2. Inhibition rate of compounds on CRBN / DDB1 binding

[0223] Based on the results of the inhibition rate test of some of the above-mentioned example compounds on CRBN / DDB1 binding at a concentration of 1 micromolar, it was found that most of the example compounds of the present invention have excellent inhibitory activity against CRBN / DDB1 binding, and most of the compounds have inhibitory activities superior to or equivalent to those of lenalidomide and DKY-709. Therefore, the compounds of the present invention can effectively bind to CRBN and promote the degradation of substrates through the CRBN ubiquitin ligase system, thereby achieving better therapeutic effects on diseases.

[0224] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotope compound, pharmaceutically acceptable salt, ester, prodrug or hydrate thereof: in, R1 is hydrogen or C 1-3 alkyl; R2 is hydrogen or halogen; R3 is hydrogen, deuterium or halogen; X does not exist; A1 is a substituted or unsubstituted 4-6 membered heterocyclic group, wherein the substituted or unsubstituted 4-6 membered heterocyclic group is optionally substituted by one or more groups selected from the following: hydrogen, deuterium, halogen, cyano, nitro, hydroxyl, carboxyl, aminocarbonyl, 4-10 membered heterocyclic group, C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, C2-C6 alkenyl, C3-C8 heterocyclyloxy and C3-C8 cycloalkyloxy; L is none, -CH2- or -CH2-CH2-; wherein said -CH2- or -CH2-CH2- is optionally substituted by 1-2 groups selected from the group consisting of halogen, C1-C3 alkyl or halogenated C1-C3 alkyl; A2 is selected from: none, C1-C6 alkyl, C 2-6 Alkynyl, C6-10 aryl, C3-C10 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, benzo 5-6 membered heteroaryl; wherein the C1-C6 alkyl, C 2-6 The alkynyl, C6-10 aryl, C4-C10 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, benzo 5-6 membered heteroaryl are optionally substituted by one or more groups selected from the following: hydrogen, deuterium, halogen, cyano, nitro, hydroxyl, carboxyl, aminocarbonyl, 4-10 membered heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, halogen substituted C1-C6 alkyl, halogen substituted C1-C6 alkoxy, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, C2-C6 alkenyl, C 2-6 wherein the substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl are optionally substituted by one or more groups selected from the following: hydrogen, halogen, cyano, nitro, hydroxyl, carboxyl, 4-10 membered heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, halogen substituted C1-C6 alkyl, halogen substituted C1-C6 alkoxy, C2-C6 alkenyl, C 2-6 Alkynyl, C3-C8 heterocyclyloxy, C3-C8 cycloalkyloxy, hydroxy-substituted C1-C6 alkoxy, and C1-C6 alkoxy-substituted C1-C6 alkoxy.

2. The compound according to claim 1, its pharmaceutically acceptable salt, tautomer, stereoisomer, isotope compound, pharmaceutically acceptable salt, ester, prodrug or hydrate thereof, characterized in that: The compound has a structure shown in formula (I-1-1): Wherein, R1 is hydrogen, methyl or ethyl; R2 is hydrogen or fluorine; R3 is hydrogen, deuterium or fluorine; Y is -CH- or N; n1 is 0, 1 or 2; a1 and a2 are independently 0 or 1; or A2 is selected from: phenyl, 4-6 membered heterocyclic group, 5-6 membered heteroaryl, phenyl and 5-6 membered heteroaryl or C 2-6 Alkynyl, wherein the phenyl, 4-6 membered heterocyclic, 5-6 membered heteroaryl, phenyl and 5-6 membered heteroaryl or C 2-6 The alkynyl group is optionally substituted by one or more groups selected from the following: hydrogen, deuterium, halogen, cyano, nitro, hydroxyl, carboxyl, aminocarbonyl, 4-10 membered heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 heterocyclyloxy, C3-C8 cycloalkyloxy, hydroxy-substituted C1-C6 alkoxy, C1-C6 alkoxy substituted by C1-C6 alkoxy.

3. The compound according to claim 2, its pharmaceutically acceptable salt, tautomer, stereoisomer, isotope compound, pharmaceutically acceptable salt, ester, prodrug or hydrate thereof, characterized in that: A2 is selected from: phenyl, pyridyl; wherein the phenyl, pyridyl is optionally substituted by one or more groups selected from the following: hydrogen, deuterium, halogen, cyano, 4-10 membered heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, C3-C8 heterocyclyloxy, C3-C8 cycloalkyloxy, hydroxy-substituted C1-C6 alkoxy, C1-C6 alkoxy substituted by C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, substituted or unsubstituted 5-6 membered heteroaryl.

4. The compound according to claim 1, its pharmaceutically acceptable salt, tautomer, stereoisomer, isotope compound, pharmaceutically acceptable salt, ester, prodrug or hydrate thereof, characterized in that: L is none or CH2; wherein the -CH2- or -CH2-CH2- is optionally substituted by 1-2 groups selected from the group consisting of halogen, C1-C3 alkyl or halogenated C1-C3 alkyl; preferably, L is CH2.

5. The compound according to any one of claims 1, its pharmaceutically acceptable salt, tautomer, stereoisomer, isotope compound, pharmaceutically acceptable salt, ester, prodrug or hydrate thereof, characterized in that: The compounds have structures shown in formula (I-27)-(I-28): Wherein, R1 is hydrogen, methyl or ethyl; R2 is hydrogen or fluorine; R3 is hydrogen, deuterium or fluorine; A2 is selected from: phenyl, pyridyl; wherein the phenyl, pyridyl is optionally substituted by one or more groups selected from the following: hydrogen, deuterium, halogen, cyano, 4-10 membered heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, C3-C8 heterocyclyloxy, C3-C8 cycloalkyloxy, hydroxy-substituted C1-C6 alkoxy, C1-C6 alkoxy substituted by C1-C6 alkoxy.

6. The compound according to claim 1, its pharmaceutically acceptable salt, tautomer, stereoisomer, isotope compound, pharmaceutically acceptable salt, ester, prodrug or hydrate thereof, characterized in that: Selected from:

7. The compound according to claim 1, its pharmaceutically acceptable salt, tautomer, stereoisomer, isotope compound, pharmaceutically acceptable salt, ester, prodrug or hydrate thereof, characterized in that: The compounds are the following compounds:

8. A method for preparing the compound of claim 1, wherein the method is selected from one of the following methods: Synthesis method 1: Step 1-1: Compound 6A and compound 6B are reacted by coupling reaction to obtain compound 6C; Step 1-2: Compound 6C is hydrolyzed in the presence of lithium hydroxide to obtain compound 6D; Step 1-3: Compound 6D and 1G are subjected to condensation reaction to obtain compound 6E; Step 1-4: Compound 6E reacts with tetrahydroxydiboron and sodium hydroxide to obtain compound 6F; Step 1-5: Compound 6F is hydrogenated at normal pressure to obtain 6G; Step 1-6: Compound 6G is cyclized by potassium tert-butoxide to obtain compound 6H; Step 1-7: Compound 6H is deprotected by hydrochloric acid to obtain compound 6I; Step 1-8: Compound 6I is subjected to reductive amination with an aldehyde to give 6J; R2 has the same meaning as defined in claim 1.

9. A pharmaceutical composition comprising a therapeutically effective dose of a compound according to any one of claims 1 to 5, its tautomers, enantiomers, diastereomers, racemates, isotopic compounds, pharmaceutically acceptable salts, esters, prodrugs or hydrates thereof and other pharmaceutically acceptable carriers.

10. The pharmaceutical composition according to claim 9, further comprising one or more selected from dexamethasone, rituximab, trastuzumab, PD-1 inhibitor, PDL-1 inhibitor, pemetrexed, topotecan, doxorubicin, bortezomib, gemcitabine, dacarbazine, clarithromycin, vincristine, cytarabine, prednisone, docetaxel, clofarabine injection, HDAC inhibitor, androgen receptor inhibitor, androgen biosynthesis inhibitor, BTK inhibitor, erythrocyte growth hormone, minocycline, Elotuzumab, Palbociclib, Nivolumab, Pembrolizumab, Panobinostat, Ublituximab, Romidepsin, Eltrombopag, CAR-T and melphalan, azacitidine, BCL2 inhibitor.

11. Use of the compound according to claim 1, its tautomer, enantiomer, diastereomer, racemate, isotope compound, pharmaceutically acceptable salt, ester, prodrug or hydrate thereof in the preparation of a medicament for preventing or treating a disease associated with CRL4 CRBN E3 ubiquitin ligase.

12. The use according to claim 11, wherein The use of the invention in diseases associated with CRL4 CRBN E3 ubiquitin ligase is preferably cancer, pain, central nervous system diseases and immune system diseases.

13. The use according to claim 11, characterized in that The disease is a blood tumor or a solid tumor. Preferably, the blood tumor is selected from the group consisting of myelodysplastic syndrome, myeloid leukemia, non-Hodgkin's lymphoma, chronic lymphocytic leukemia, chronic myelomonocytic leukemia, myelofibrosis, Burkitt's lymphoma, Hodgkin's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, ciliary body and chronic melanoma, iris melanoma, recurrent interocular melanoma, T-cell lymphoma, erythroid lymphoma, monocytic and monocytic leukemia, central nervous system lymphoma, multiple myeloma, and mantle cell lymphoma; the solid tumor is selected from the group consisting of meningioma, Spinal cord tumors, lung cancer, ovarian cancer, skin cancer, renal cell carcinoma, astrocytoma, amyloidosis, complex regional pain syndrome type I, malignant melanoma, radiculopathy, glioblastoma, sarcoma, malignant glioma, refractory plasmacytoma, extraocular extension of melanoma, thyroid cancer, breast cancer, prostate cancer, hepatocellular carcinoma or primary macroglobulinemia, adrenocortical carcinoma, bile duct cancer, bladder cancer, bone cancer, brain cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, gallbladder cancer, stomach cancer, head and neck cancer, kidney cancer, liver cancer, uterine cancer, rhabdoid, neuroblastoma, pancreatic cancer, testicular cancer, brain glioma.

14. The use of claim 12, wherein the pain is nociceptive pain, neuropathic pain, visceral pain, migraine, headache or postoperative pain; and the central nervous system disease is amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis or Tourette syndrome.

15. The use of claim 14, wherein the neuropathic pain is complex regional pain syndrome, dystrophy or diabetic neuropathy.

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