Indazolone compound as well as preparation method, pharmaceutical composition and application thereof

Abstract

The invention discloses an indazolone compound as well as a preparation method, a pharmaceutical composition and application thereof. Specifically, provided are a compound of formula (I), or a pharmaceutically acceptable salt, a tautomer, a stereoisomer, an isotope compound, a pharmaceutically acceptable salt, an ester, a prodrug or a hydrate thereof, a preparation method, a pharmaceutical composition and an application thereof. As a CRL4CRBNE3 ubiquitin ligase regulator, the compound disclosed by the invention has good anti-tumor activity, and can be used for preparing medicines for treating diseases related to CRL4CRBNE3 ubiquitin ligase. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, and in particular to a class of indazolone compound derivatives, preparation methods, pharmaceutical compositions and applications thereof. Background Art

[0002] Targeted protein degradation is a promising field for the discovery and development of innovative therapies. Targeted protein degradation technology breaks through 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. At present, targeted protein degradation technology based on the ubiquitination proteasome system (UPS) mainly includes proteolysis targeting chimera (PROTAC) and molecular glue (Molecular Glue).

[0003] Molecular glues are small molecules that induce protein-protein interactions and can provide precise temporal control over various biological processes. Molecular glues are small molecules that act on protein interfaces and form new protein-protein interactions. Molecular glues mediate proximity-induced protein degradation and have intrinsic advantages over heterobifunctional proteolysis-targeting chimeras, including unprecedented mechanisms, unique bioactivities, and favorable physicochemical properties. However, the lack of molecular glues discovered by chance has hampered their development into reagents for bioassays and disease treatment. Therefore, rational discovery and design strategies are necessary for the development of molecular glue drugs.

[0004] At present, the molecular glue degraders based on CRBN are mainly immunomodulatory drugs (IMiDs), such as thalidomide, lenalidomide and pomalidomide. Since CRBN ligands and immunomodulatory imide drugs (IMiDs) have good drug-like properties, targeting CRBN is the main mode of action of molecular degraders. However, IMiDs are inherently unstable and easily hydrolyzed in body fluids. For example, thalidomide will undergo racemization and hydrolysis in body fluids, and the rate increases 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 class of novel molecular glue degraders can improve the therapeutic effect on tumors and expand new indications, which can be used to further address unmet clinical needs. CRBNNew ligands and new molecular glues for E3 ubiquitin ligases have important research value and practical significance in the development of new drugs. Summary of the invention

[0006] The inventors have found through literature research that indazolone and its derivatives have unique biological activity and good metabolic stability. CRBN Based on the crystal structure analysis of E3 ubiquitin ligase binding, we found through molecular docking and computational simulation 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 rings 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, thus, it 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 type of 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.

[0007] The purpose of the present invention is to provide a novel indazolone skeleton structure CRL4 CRBN E3 ubiquitin ligase molecular glue degraders, which 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 Ligands for E3 ubiquitin ligases.

[0008] One aspect of the present invention is to provide a compound represented by the general formula (I), its enantiomer, diastereomer, racemate, isotope compound, metabolic precursor, metabolite, pharmaceutically acceptable salt, ester, prodrug or hydrate thereof.

[0009] Another aspect of the present invention is to provide a method for preparing the compound represented by the general formula (I), and an important intermediate for preparing the compound and a method for preparing the compound.

[0010] Another aspect of the present invention is to provide compounds as shown in the general formula (I) and their tautomerisms

[0011] isomer, enantiomer, diastereomer, racemate, metabolite, metabolic precursor, isotope compound, pharmaceutically acceptable salt, ester, prodrug or hydrate thereof, characterized in that the compound is used to prepare a drug for preventing or treating CRL4 CRBN Drugs or diagnostic agents for diseases related to E3 ubiquitin ligases; 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 object, 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]

[0014] Among them, R 1 is hydrogen, methyl or ethyl;

[0015] R 2 is hydrogen or fluorine;

[0016] R 3 is hydrogen, deuterium or fluorine;

[0017] L is none, -CH 2 -、S、-CO-、-CH(CH 3 )-;

[0018] XA 1 The combination is -(CH 2 ) n -O-CH 2 -A 1 、-(CH 2 ) n -NHCONH-A 1 、-(CH 2 ) n -NHCOCF 2 -A 1 、-CONH-(CH 2 ) n -A 1 、-CONH-CO-A 1 、-CONHCH(CH 3 )-A 1 、-CONHCH(CF 3 )-A 1 ;

[0019] n is 0 or 1;

[0020] When XA 1 The combination is -(CH2 ) n -O-CH 2 -A 1 Or, L is none, -CH 2 -、S、-CO-、-CH(CH 3 )-;

[0021] A 1 Selected from: halogen-substituted and unsubstituted phenyl, halogen-substituted and unsubstituted pyridyl, and five-membered heteroaryl containing N, O, and S;

[0022] A 2 Selected from: phenyl, pyridyl, piperazinyl, piperidinyl, morpholinyl, azetidinyl; wherein the phenyl, pyridyl, piperazinyl, piperidinyl, morpholinyl 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, C 1 -C 6 Alkoxy, halogen substituted C 1 -C 6 Alkyl, halogen substituted C 1 -C 6 substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, C3-C8 heterocyclyloxy, C3-C8 cycloalkyloxy, hydroxy substituted C 1 -C 6 Alkoxy, C 1 -C 6 Alkoxy substituted C 1 -C 6 wherein the substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl is optionally substituted by one or more groups selected from the following: hydrogen, halogen, cyano, 4-10 membered heterocyclic group, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halogen substituted C 1 -C 6 Alkyl, halogen substituted C 1 -C 6 Alkoxyl groups;

[0023] When XA 1 The combination is -(CH 2 ) n -NHCONH-A 1 or -(CH 2 ) n -NHCOCF 2 -A 1 When L and A 2 At the same time, it is none;

[0024] A 1 Selected from: phenyl, the aforementioned phenyl is substituted by one or more groups selected from the following: hydrogen, halogen, cyano, C1-C6 alkyl;

[0025] When XA 1 The combination is -CONHCH(CH 3 )-A 1 、-CONH-(CH 2 ) n -A 1 、-CONH-CO-A 1 or -CONHCH(CF 3 )-A 1 When L and A 2 At the same time, it does not exist;

[0026] A 1 Selected from: phenyl, pyridyl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 4-6 membered heterocyclyl, 4-6 membered heterocyclyl phenyl, C 1 -C 6 Alkyl; the aforementioned C6-10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 4-6 membered heterocyclic group, C 1 -C 6 The alkyl group is substituted by one or more groups selected from the following: hydrogen, deuterium, halogen, cyano, 4-10 membered heterocyclic group, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halogen substituted C 1 -C 6 Alkyl, halogen substituted C 1 -C 6 of alkoxy.

[0027] In another preferred embodiment, R 1 is hydrogen, methyl or ethyl;

[0028] R 2 is hydrogen or fluorine;

[0029] R 3 is hydrogen, deuterium or fluorine;

[0030] L is none, -CH 2 -、S、-CO-、-CH(CH 3 )-;

[0031] XA 1 The combination is -(CH 2 ) n -O-CH 2 -A 1 、-(CH2 ) n -NHCONH-A 1 、-(CH 2 ) n -NHCOCF 2 -A 1 、-(CH 2 ) n -NHCH 2 -A 1 、-CONH-(CH 2 ) n -A 1 、-CONHCH(CH 3 )-A 1 、-CONHCH(CF 3 )-A 1 , or X does not exist;

[0032] n is 0 or 1;

[0033] When XA 1 The combination is -(CH 2 ) n -O-CH 2 -A 1 Or, L is none, -CH 2 -、S、-CO-、-CH(CH 3 )-;

[0034] A 1 Selected from: halogen-substituted and unsubstituted phenyl, halogen-substituted and unsubstituted pyridyl, and five-membered heteroaryl containing N, O, and S;

[0035] A 2 The invention is selected from the group consisting of phenyl, pyridyl, piperazinyl, piperidinyl and morpholinyl; wherein the phenyl, pyridyl, piperazinyl, piperidinyl and morpholinyl are optionally substituted by one or more groups selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, hydroxyl, carboxyl, aminocarbonyl, 4-10 membered heterocyclyl, C1-C6 alkyl, C 1 -C 6 Alkoxy, halogen substituted C 1 -C 6 Alkyl, halogen substituted C 1 -C 6 substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, C3-C8 heterocyclyloxy, C3-C8 cycloalkyloxy, hydroxy substituted C 1 -C 6 Alkoxy, C 1 -C 6 Alkoxy substituted C 1 -C 6wherein the substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl is optionally substituted by one or more groups selected from the following: hydrogen, halogen, cyano, 4-10 membered heterocyclic group, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halogen substituted C 1 -C 6 Alkyl, halogen substituted C 1 -C 6 Alkoxyl groups;

[0036] When XA 1 The combination is -(CH 2 ) n -NHCONH-A 1 or -(CH 2 ) n -NHCOCF 2 -A 1 When L and A 2 At the same time, it is none;

[0037] A 1 Selected from: phenyl, the aforementioned phenyl is substituted by one or more groups selected from the following: hydrogen, halogen, cyano, C1-C6 alkyl;

[0038] When XA 1 The combination is -CONHCH(CH 3 )-A 1 、-CONH-(CH 2 ) n -A 1 or -CONHCH(CF 3 )-A 1 When L and A 2 At the same time, it does not exist;

[0039] A 1 Selected from: phenyl, pyridyl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 4-6 membered heterocyclic group, C 1 -C 6 Alkyl; the aforementioned C6-10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 4-6 membered heterocyclic group, C 1 -C 6 The alkyl group is substituted by one or more groups selected from the following: hydrogen, deuterium, halogen, cyano, 4-10 membered heterocyclic group, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halogen substituted C 1 -C 6 Alkyl, halogen substituted C1 -C 6 of alkoxy.

[0040] In another preferred embodiment, the compound has a structure shown by formula (I-1)-(I-11):

[0041]

[0042] Among them, R 1 is hydrogen, methyl or ethyl;

[0043] R 2 is hydrogen or fluorine;

[0044] R 3 is hydrogen, deuterium or fluorine;

[0045] R 4 is H or halogen;

[0046] n = 0 or 1;

[0047] R 5 is selected from phenyl, pyridyl or morpholinyl, wherein the phenyl, pyridyl or morpholinyl is optionally substituted by one or more groups selected from the following: hydrogen, halogen, cyano, 4-10 membered heterocyclic group, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halogen substituted C 1 -C 6 Alkyl, halogen substituted C 1 -C 6 Alkoxyl groups;

[0048] A 2 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 heterocyclic group, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halogen substituted C 1 -C 6 Alkyl, halogen substituted C 1 -C 6 Alkoxy, C3-C8 heterocyclyloxy, C3-C8 cycloalkyloxy, hydroxy substituted C 1 -C 6 Alkoxy, C 1 -C 6 Alkoxy substituted C 1 -C 6 Alkoxy.

[0049] In another preferred embodiment, the compound has a structure shown by formula (I-29)-(I-30):

[0050]

[0051] Among them, R 1 is hydrogen, methyl or ethyl;

[0052] R 2 is hydrogen or fluorine;

[0053] R 3 is hydrogen, deuterium or fluorine;

[0054] R 11 is hydrogen or methyl;

[0055] Each q is independently 0 or 1;

[0056] Z is N or -CH-;

[0057] R 5 is selected from phenyl, pyridyl or morpholinyl, wherein the phenyl, pyridyl or morpholinyl is optionally substituted by one or more groups selected from the following: hydrogen, halogen, cyano, 4-10 membered heterocyclic group, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halogen substituted C 1 -C 6 Alkyl, halogen substituted C 1 -C 6 Alkoxyl groups;

[0058] A 2 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 heterocyclic group, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halogen substituted C 1 -C 6 Alkyl, halogen substituted C 1 -C 6 Alkoxy, C3-C8 heterocyclyloxy, C3-C8 cycloalkyloxy, hydroxy substituted C 1 -C 6 Alkoxy, C 1 -C 6 Alkoxy substituted C 1 -C 6 Alkoxy.

[0059] In another preferred embodiment, R 1 For hydrogen.

[0060] In another preferred embodiment, R 3 is hydrogen or deuterium;

[0061] In another preferred embodiment, L is CH 2 .

[0062] In another preferred embodiment, XA 1 The combination is -(CH 2 ) n -O-CH 2 -A 1 .

[0063] In another preferred embodiment, n is 0.

[0064] In another preferred embodiment, A 1 is halogen substituted and unsubstituted phenyl.

[0065] In another preferred embodiment, R 5 is phenyl, wherein the phenyl is optionally substituted by one or more groups selected from the following: hydrogen, halogen, cyano, C 1 -C 6 Alkyl and halogen substituted C 1 -C 6 of alkyl.

[0066] In another preferred embodiment, the compound has a structure shown by formula (I-12)-(I-13):

[0067]

[0068] Among them, R 1 is hydrogen, methyl or ethyl;

[0069] R 2 is hydrogen or fluorine;

[0070] R 3 is hydrogen, deuterium or fluorine;

[0071] n is 0 or 1;

[0072] R 6 Each is independently selected from: hydrogen, halogen, cyano, C 1 -C 6 alkyl;

[0073] m is 0, 1, 2, 3, 4 or 5.

[0074] In another preferred embodiment, the compound has a structure shown in formula (I-31)-(I-32):

[0075]

[0076] Among them, R 1 is hydrogen, methyl or ethyl;

[0077] R 2 is hydrogen or fluorine;

[0078] R 3 is hydrogen, deuterium or fluorine;

[0079] R 6 Each is independently selected from: hydrogen, halogen, cyano, C 1 -C 6 alkyl;

[0080] m is 0, 1, 2, 3, 4 or 5.

[0081] In another preferred embodiment, the compound has a structure shown by formula (I-20)-(I-26):

[0082]

[0083] Among them, R 1 is hydrogen, methyl or ethyl;

[0084] R 2 is hydrogen or fluorine;

[0085] R 3 is hydrogen, deuterium or fluorine;

[0086] R 9 Each is independently selected from: hydrogen, halogen, cyano, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halogen substituted C 1 -C 6 Alkyl, halogen substituted C 1 -C 6 Alkoxyl groups;

[0087] p is 0, 1, 2, 3, 4 or 5;

[0088] A 1 Selected from: phenyl, pyridyl, substituted or unsubstituted C3-C10 cycloalkyl, 4-6 membered heterocyclic group, C 1 -C 6 Alkyl; the aforementioned phenyl, pyridyl, substituted or unsubstituted C3-C10 cycloalkyl, 4-6 membered heterocyclic group, C 1 -C 6 The alkyl group is substituted by one or more groups selected from the following: hydrogen, deuterium, halogen, cyano, 4-10 membered heterocyclic group, C 1 -C 6 Alkyl, C 1 -C6 Alkoxy, halogen substituted C 1 -C 6 Alkyl, halogen substituted C 1 -C 6 alkoxy, C3-C8 heterocyclyloxy, C3-C8 cycloalkyloxy.

[0089] In another preferred embodiment, Selected from:

[0090]

[0091] In another preferred embodiment, Selected from:

[0092]

[0093]

[0094] In another preferred embodiment, the compound represented by general formula (I) is one of the following compounds:

[0095]

[0096]

[0097]

[0098] The compound, or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotope compound, pharmaceutically acceptable salt, ester, prodrug or hydrate thereof.

[0099] One aspect of the present invention provides a method for preparing a compound represented by general formula (I), wherein the method is selected from one of the following methods:

[0101] Synthesis references of compounds 1I and 3E: Organic Letters, 2020, 22(16): 6277-6282, Nature communications, 2020, 11(1): 1-13, Bioorg Med Chem Lett, 2013, 23(10): 2936-40.

[0102] Synthesis method 1:

[0103]

[0104] Step 1-1: Compound 1A and compound 1B undergo nucleophilic substitution reaction to obtain compound 1C;

[0105] Step 1-2: Compound 1C and compound 1D undergo nucleophilic substitution reaction to obtain compound 1E;

[0106] Step 1-3: Compound 1E is hydrolyzed with alkaline to obtain compound 1F;

[0107] Step 1-4: Compound 1F and 1G are subjected to condensation reaction to obtain compound 1H;

[0108] Step 1-5: Compound 1H reacts with tetrahydroxydiboron and sodium hydroxide to obtain compound 1I

[0109] Step 1-6: Compound 1I is subjected to a p-toluenesulfonic acid reflux reaction to obtain compound 1J.

[0110] R 5 As defined above;

[0111] Synthesis method 2:

[0112]

[0113] Step 2-1: Compound 2A reacts with compound 2B in the presence of N,N'-carbonyldiimidazole and triethylamine to obtain compound 2C;

[0114] Step 2-2: Compound 2A and compound 2D are reacted in the presence of HATU and N,N-diisopropylethylamine to obtain compound 2E.

[0115] R 2 , R 3 , R 6 , m is as defined above;

[0116] Synthesis method three:

[0117]

[0118] Step 3-1: Compound 3A and R 8 -NH 2 Compound 3B was obtained through condensation reaction;

[0119] Step 3-2: Compound 3B is hydrolyzed in the presence of lithium hydroxide to obtain compound 3C;

[0120] Step 3-3: Compound 3C and 1G are subjected to condensation reaction to obtain compound 3D;

[0121] Step 3-4: Compound 3D reacts with tetrahydroxydiboron and sodium hydroxide to obtain compound 3E;

[0122] Step 3-5: Compound 3E is subjected to p-toluenesulfonic acid reflux reaction to obtain compound 3F;

[0123] R 8 -NH 2 Selected from:

[0124] R 9 As defined above.

[0125] 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 preparing drugs or diagnostic reagents for preventing or treating diseases associated with CRL4 CRBN E3 ubiquitin ligase.

[0126] 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, solvates thereof 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, production or regulation of IFNγ activity.

[0127] Another aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective dose of a compound as represented by the general formula (I) and their tautomers, enantiomers, diastereomers, racemates, metabolites, metabolic precursors, isotopic compounds, pharmaceutically acceptable salts, esters, prodrugs, hydrates, crystalline hydrates, solvates and other pharmaceutically acceptable carriers.

[0128] Another aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective dose of a compound represented by the general formula (I) and their tautomers, enantiomers, diastereomers, racemates, metabolites, metabolic precursors, isotopic compounds, pharmaceutically acceptable salts, esters, prodrugs, hydrates, crystalline hydrates, solvates thereof, and one or more other ingredients having pharmaceutical therapeutic activity.

[0129] The compounds of the present invention as shown in general formula (I) and their tautomers, enantiomers, diastereomers, racemates, metabolites, metabolic precursors, isotopic compounds, pharmaceutically acceptable salts, esters, prodrugs, hydrates, crystalline hydrates, solvates can produce synergistic effects with one or more other ingredients with pharmaceutical therapeutic activity in the prevention or treatment of specific diseases or functional disorders.

[0130] The compounds of the present invention as shown in the 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 process of preventing or treating specific diseases or functional disorders, and vice versa.

[0131] Another aspect of the present invention provides a pharmaceutical composition, wherein the other one or more ingredients having pharmaceutical therapeutic activity as described above include macromolecular compounds, such as proteins, polysaccharides and nucleic acids, etc.; small molecule compounds such as inorganic compounds, organometallic compounds, organic small molecule compounds of synthetic or natural origin, etc.

[0132] Another aspect of the present invention provides a pharmaceutical composition, wherein the preferred embodiment is characterized in that the pharmaceutical composition further comprises other therapeutic agents, and the other therapeutic agents are one or more of 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.

[0133] Another aspect of the present invention is to provide a compound as shown in the general formula (I) for the preparation of a method for treating or preventing 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, disorder or condition includes: myelodysplastic syndrome, multiple myeloma, mantle cell lymphoma, non-Hodgkin's lymphoma, chronic lymphocytic leukemia, chronic myelomonocytic leukemia, myelofibrosis, Burkitt's lymphoma, Hodgkin's lymphoma, large cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, ciliary body and chronic melanoma, iris melanoma, recurrent interocular melanoma, T-cell lymphoma, erythroid lymphoma, monoblastic and monocytic leukemia. , myeloid leukemia, central nervous system lymphoma, brain tumor, meningioma, spinal cord tumor, thyroid cancer, non-small cell lung cancer, ovarian cancer, skin cancer, renal cell carcinoma, astrocytoma, amyloidosis, complex regional pain syndrome type I, malignant melanoma, radiculopathy, myelofibrosis, glioblastoma, gliosarcoma, malignant glioma, refractory plasmacytoma, melanoma with extraocular extension, solid tumors, papillary and follicular thyroid cancer, breast cancer, prostate cancer, hepatocellular carcinoma, or primary macroglobulinemia.

[0134] Another aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by the general 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 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, including 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 and purpose of use of the compound of the present invention. The solvent is generally selected based on solvents that are considered by those skilled in the art to be safe and effective for administration to mammals. In general, safe solvents are non-toxic aqueous solvents such as 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, flavoring agents, flavoring agents or other known additives to make the drug in an acceptable form for manufacture or use.

[0135] When the compound of the general formula (I) of the present invention is used in combination with at least one other drug, the two drugs or multiple drugs can be used separately or in combination, preferably in the form of a pharmaceutical composition. The compound of the general formula (I) or the 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 local or systemic administration forms.

[0136] 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, flavoring agents, flavoring agents or other known additives so that the pharmaceutical compositions can be manufactured or used in an acceptable form.

[0137] The drug of the present invention is preferably administered orally. Solid dosage forms for oral administration may include capsules, tablets, powders or granular preparations. In the 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.; wetting agents 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 promoters 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 lactose or other excipients such as high molecular weight polyethylene glycols.

[0138] The above-mentioned 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 dehydrated sorbitan; or a mixture of several of these substances, etc.

[0139] 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. For suspensions, in addition to the compound or combination of the present invention, it may further contain a carrier such as a suspending agent, such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, or a mixture of several of these substances.

[0140] 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.

[0141] 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 preservative, buffer or propellant. Ophthalmic formulations, ophthalmic ointments, powders and solutions are also intended to be included within the scope of the present invention.

[0142] 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 their hydrates, solvates or crystal forms as CRL4 CRBN Use of selective modulators of E3 ubiquitin ligases to regulate CUL4 CRBN E3 ubiquitin ligase activity.

[0143] 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, 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 the involvement of E3 ubiquitin ligases include (but are not limited to) tumors, central nervous system diseases and immune diseases.

[0144] 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 TNF-α activity regulation, IL-2 production or IL-2 activity abnormal regulation, wherein the method is to treat or prevent an effective amount of an isoindoline derivative represented by general formula (I), its pharmaceutically acceptable salt, solvate, stereoisomer, isotope compound, metabolite and prodrug. 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, allergic, viral, 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.

[0145] The compounds represented by the general formula (I) of the present invention, and their stereoisomers, pharmaceutically acceptable salts, prodrugs, solvates, hydrates or crystal forms can be used in monotherapy or combined therapy. When used in combined therapy, a therapeutically effective dose of the compound of formula (I), its enantiomers, diastereomers, racemates and mixtures thereof, and pharmaceutically acceptable salts, crystalline hydrates and solvates thereof, and one or more other ingredients with pharmaceutical therapeutic activity are included. 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 natural 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, and their pharmaceutically acceptable salts, crystalline hydrates and solvates can produce synergistic effects with one or more other ingredients with pharmaceutical therapeutic activity in the process of preventing or treating specific diseases or functional disorders. The compounds of formula (I) of the present invention, their prodrugs, enantiomers, diastereomers, racemates and mixtures thereof, and their pharmaceutically acceptable salts, crystalline hydrates and solvates can also reduce or eliminate the toxic and side effects produced by one or more other ingredients with pharmaceutical therapeutic activity in the process of preventing or treating specific diseases or functional disorders, and vice versa.

[0146] 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.

[0147] 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 compound provided by the present invention is also effective for hematological tumors and myeloma, such as multiple myeloma and acute and chronic leukemia. The compound provided by the present invention can be used to prevent or treat primary tumors and metastatic tumors.

[0148] The compound shown in the general formula (I) may contain one or more asymmetric or chiral centers, and therefore may 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, and the compounds shown in the general formula (I) may also exist in different tautomeric forms, all of which are included within the scope of the present invention.

[0149] 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 embodiments) can be combined with each other to form new or preferred technical solutions. The above description does not mean to limit the aspects of the present invention in any form. DETAILED DESCRIPTION

[0150] After extensive and in-depth research, the 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 of E3 ubiquitin ligase and small molecule (PDB ID: 4CI2, 5HXB): CRL4 CRBN E3 ubiquitin ligases have multiple binding pockets for small molecules, so small molecules with complex structures and multiple binding sites can be developed to achieve CRL4 CRBNEffective combination of E3 ubiquitin ligase and small molecules. At the same time, molecular dynamics simulation methods were 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 active site of E3 ubiquitin ligase were evaluated through scoring functions, and computational simulation and optimization of structural design were performed to obtain a new specific CRL4 CRBN Small molecule modulators of E3 ubiquitin ligases.

[0151] 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 regulators of E3 ubiquitin ligases were developed, and the activity of the compounds was tested. The test results of representative compounds in multiple myeloma cell lines (MM.1S), mantle cell lymphoma cell lines (Mino), and acute myeloid leukemia cell lines (MV-4-11) showed that the new small molecule regulators have very high cell growth inhibitory activity. However, the original CRBN regulators with isoindoline structures, that is, IMiDs that have been on the market or are under clinical research, do not have good cell growth inhibitory activity in mantle cell lymphoma cell lines (Mino) or acute myeloid leukemia cell lines (MV-4-11). Therefore, after the indazolone compounds developed in this application act on the organism, they can regulate the degradation of substrate proteins or regulate new pathogenic degradation by regulating the ubiquitin-proteasome-mediated protein degradation pathway in the organism, thereby achieving effective disease treatment based on the CRBN target. The present invention was completed on this basis.

[0152] the term

[0153] When substituents are described by conventional chemical formulas written from left to right, the substituents also include chemically equivalent substituents that would result if the formula were written from right to left. 2 O- is equivalent to -OCH 2 -.

[0154] Those skilled in the art will appreciate that the combinations of substituents contemplated by the present invention are those that are stable or chemically feasible. The substitutions on the relevant structures in the present invention include substitution and non-substitution, such as "optionally" or "optionally" substituted with a certain substituent, which means including the meaning of being substituted or non-substituted with a certain substituent.

[0155] 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.

[0156] 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 substituent is a substituent described in the previous text or a substituent appearing in the embodiments. 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 substituent 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, two rings share one carbon atom. If not otherwise specified, substitution may refer to a group being replaced by one or more groups selected from the following: hydrogen, halogen, cyano, nitro, hydroxy, carboxyl, 4-10 membered heterocyclyl, C1-C6 alkyl, C 1 -C 6 Alkoxy, halogen substituted C 1 -C 6 Alkyl, halogen substituted C 1 -C 6 Alkoxy, C 2 -C 6 alkenyl, C3-C8 heterocyclyloxy, C3-C8 cycloalkyloxy, hydroxy substituted C 1 -C 6 Alkoxy, and C 1 -C 6 Alkoxy substituted C 1 -C 6 Alkoxy.

[0157] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0158] The term "plurality" refers to two or more, such as 2, 3, 4, 5 or 6.

[0159] The term "C 1 -C 6 "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 other groups 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.

[0160] The term "C 1 -C 6 The term "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.

[0161] The term "aryl" refers to a 6-14-membered all-carbon monocyclic or fused polycyclic group with a conjugated p-electron system, preferably a 6- to 10-membered ring (i.e., C6-C10 aryl), more preferably phenyl and naphthyl, most preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is the aryl ring.

[0162] The term "halogen-substituted C 1 -C 6 "Alkoxy" refers to a straight or branched chain C 1 -C 6 Alkoxy, including but not limited to -OCH 2 F, -OCHF 2 、-OCF 3 .

[0163] The term "halogen-substituted C 1 -C 6 "Alkyl" refers to a straight chain or branched chain C substituted by one or more halogens. 1 -C 6 Alkyl groups include, but are not limited to, 2-bromoethyl, 2-bromopropyl, and the like.

[0164] The term "C3-C10 cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic 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, and polycyclic cycloalkyls include spirocyclic, condensed, and bridged cycloalkyls.

[0165] The term "4-10 membered heterocyclyl" refers to a group containing one or more saturated and / or partially saturated rings, which include 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.

[0166] The term "C 2 -C 6 "Alkenyl" means a straight or branched hydrocarbon chain group consisting only 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, phenylpropenyl.

[0167] 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, furanyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl and the like.

[0168] "Hydrate" refers to a compound containing water.

[0169] "Pharmaceutically acceptable salts" refer to the corresponding salts formed by the drug molecule and the corresponding organic acid, inorganic acid or organic base, inorganic base. Inorganic acids from which salts can be derived include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. 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, etc. By way of example only, salts derived from inorganic bases include sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, 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. By way of example only, specific examples of suitable amines include isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0170] 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 formulae or multiple identical groups in the same general formulae are independent of each other.

[0171] Active ingredients

[0172] 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.

[0173] 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.

[0174] 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.

[0175] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. All such compounds contemplated by the present invention include cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers and racemates and other mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may exist in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present invention.

[0176] The compound shown in formula (I) may contain one or more asymmetric or chiral centers and therefore may 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 racemates), which are all included within the scope of the present invention.

[0177] Unless otherwise indicated, the term "enantiomer" refers to stereoisomers that are mirror images of one another.

[0178] 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.

[0179] "Racemate" refers to two stereoisomers that are mirror images of each other, with opposite optical rotations that cancel each other out.

[0180] There are chiral centers in the general formula and embodiment compounds of the present invention, therefore, the single configuration or racemate of the compounds of the present invention is also within the scope of the present application. In addition, there is corresponding evidence in the prior art that compounds with amine structures, their R configuration, S configuration, and racemate will be converted into 1:1 racemates 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 compounds of the present invention can achieve equivalent technical effects. In the present invention, if it is necessary to obtain an embodiment compound of a single configuration, the embodiment 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 can be used to obtain the embodiment compound of a single configuration, therefore, enantiomers can be obtained. In addition, the embodiment compound of diastereomers can be obtained by preparing the intermediate 1B of a single configuration, therefore, diastereomers can also be obtained in the present invention. These different isomeric forms all belong to stereoisomers.

[0181] The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more atoms constituting 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 between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending the biological half-life of drugs. All isotopic composition changes of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.

[0182] As used herein and unless otherwise specified, the term "prodrug" refers to a derivative of a compound containing a bioreactive functional group, such that under biological conditions (in vitro or in vivo), the bioreactive functional group can be cleaved from the compound or otherwise reacted to provide the compound. Typically, the prodrug is inactive, or at least less active than the compound itself, so that its activity can only be exerted after 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, the 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 into pharmaceutically acceptable salts, including inorganic acid salts and organic acid salts. Acids suitable for forming salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, 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, benzenesulfonic acid, benzenesulfonic acid, and the like; and acidic amino acids such as aspartic acid and glutamic acid.

[0183] The present invention also encompasses any novel intermediates disclosed herein.

[0184] Pharmaceutical compositions and methods of administration

[0185] In this application, "pharmaceutical composition" refers to a preparation of the compound of the present invention and a medium generally accepted in the art for delivering the biologically active compound to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote administration of the organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0186] 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 administration method and dosage of the original drug can remain unchanged, and the compound of formula I can be taken simultaneously or subsequently. When the compound of formula I is taken simultaneously with one or more other drugs, it is preferred to use a pharmaceutical composition containing one or more known drugs and the compound of formula I. Drug combination also includes taking the compound of formula I and one or more other known drugs in 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 them taken alone.

[0187] The term "pharmaceutically acceptable" as used herein 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 adverse biological reactions or interacting in an adverse manner with any components contained in the composition.

[0188] In this application, "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, 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.

[0189] 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, ublidomide, romidepsin, eltrombopag, CAR-T and melphalan.

[0190] 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, and the like. 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), and the like. 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, flavoring agents, flavoring agents or other known additives to enable the compound represented by formula (I) to be manufactured or used in an acceptable form.

[0191] When the compound of formula (I) of the present invention is used in combination with at least one other drug, the two drugs or multiple drugs can be used separately or in combination, preferably 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 forms.

[0192] 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, flavoring agents, flavoring agents or other known additives so that the pharmaceutical compositions can be manufactured or used in an acceptable form.

[0193] The drug of the present invention is preferably administered orally. Solid dosage forms for oral administration may include capsules, tablets, powders or granular preparations. In the 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.; wetting agents 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 promoters 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 lactose or other excipients such as high molecular weight polyethylene glycols.

[0194] 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 dehydrated sorbitan; or a mixture of several of these substances, etc.

[0195] In addition to these inert diluents, the composition may also include excipients such as one or more of wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, and perfuming agents.

[0196] 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.

[0197] 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.

[0198] 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 preservative, buffer or propellant. Ophthalmic formulations, ophthalmic ointments, powders and solutions are also intended to be included within the scope of the present invention.

[0199] The terms "administering", "administering", "administering", etc. used in the present invention refer to methods that can deliver a compound or composition 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 injection or infusion), 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.

[0200] As used herein, the terms "drug combination", "drug combination", "combination therapy", "administration of other treatments", "administration of other therapeutic agents" and the like refer to drug treatments obtained by mixing or combining more than one active ingredient, including fixed and non-fixed combinations of the active ingredients. The term "fixed combination" refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient in the form of a single entity or a single dosage form. The term "non-fixed combination" refers to the simultaneous administration, combined administration or sequential administration at variable intervals of at least one compound described herein and at least one synergistic agent to a patient in the form of separate entities. These also apply to cocktail therapy, for example the administration of three or more active ingredients.

[0201] The pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, and more preferably, contains 10-1000 mg of the compound of the present invention per dose. Preferably, the "one dose" is a capsule or tablet.

[0202] The compound or pharmaceutical composition of the present invention can be used to prepare drugs 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.

[0203] 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, damage and dysfunction of the central nervous system.

[0204] 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 being able to be used to treat 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.

[0205] The use of the drug molecules of the present invention includes but is not limited to the diseases selected from: 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, 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 leukemia, central nervous system lymphoma, meningioma, spinal cord tumors, 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 primary macroglobulinemia.

[0206] The main advantages of the present invention include:

[0207] 1. The present invention provides a novel indazolone skeleton structure CRL4 CRBN E3 ubiquitin ligase molecular glue degraders, which 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 Ligands for E3 ubiquitin ligases.

[0208] 2. Based on the instability of the existing CRBN ligands and immunomodulatory imide drugs IMiDs, which are easily hydrolyzed in body fluids, the present invention optimizes their structures and develops a molecular glue degradation agent with an indazolone skeleton as shown in Formula I through skeleton transition, which has good chemical stability.

[0209] The present invention can quickly and efficiently construct the indazolone molecular glue skeleton shown in formula I through light-induced cyclization of primary amine and o-nitrobenzyl alcohol (PANAC reaction).

[0210] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0211] In all embodiments, 1 H NMR spectrum test instruments are 400MHz Bruker and 500MHz Bruker nuclear magnetic resonance instruments, and chemical shifts are expressed in δ (ppm); mass spectra are measured by MS mass spectrometry UPLC-MS (ESI); wherein the UPLC model is WatersHPLC H-CLASS, and the MS (ESI) model is Waters SQ Detector 2; anhydrous tetrahydrofuran is prepared by benzophenone / metallic sodium reflux drying and deoxygenation, and anhydrous toluene and anhydrous dichloromethane are prepared by calcium chloride reflux drying; petroleum ether, ethyl acetate, dichloromethane and other solvents used for column chromatography mobile phase are all purchased from Sinopharm Chemical Reagent Co., Ltd.; the thin layer chromatography silica gel plate (HSGF254) used in reaction detection comes from Sinopharm Chemical Reagent Co., Ltd.; and the 200-300 mesh silica gel of Sinopharm Chemical Reagent Co., Ltd. is selected for compound separation. 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 the method inhibited in the art, or prepared according to the method described in the present invention.

[0212] Example 1: (S)-3-(7-((4-(morpholinomethyl)benzyl)oxy)-3-oxo-1,3-dihydro-2H-indazol-2-yl)piperidine-2,6-dione (D1)

[0213] Synthesis route:

[0214]

[0215] Step 1: Heat a suspension of compound 1.1 (500 mg, 2.54 mmol), compound 1.2 (2.0 g, 7.60 mmol) and potassium carbonate (351 mg, 2.54 mmol) in acetonitrile to 50 °C for overnight reaction. After the reaction was complete as monitored by TLC, cool to room temperature, filter, concentrate under reduced pressure, and obtain 910 mg of a white solid by column chromatography. The yield was 94%. 1 H NMR (500MHz, CDCl3) δ7.61 (dd, J=7.9, 1.1Hz, 1H), 7.47–7.39 (m, 3H), 7.34 (d, J= 8.2Hz,2H),7.24(dd,J=8.4,1.0Hz,1H),5.20(s,2H),4.48(s,2H),3.90(s,3H).

[0216] Step 2: A suspension of compound 1.3 (350 mg, 0.9 mmol), morpholine (86 μL, 1.01 mmol) and potassium carbonate (191 mg, 1.38 mmol) in acetonitrile was stirred at room temperature overnight. After the reaction was completed as monitored by TLC, the mixture was filtered and concentrated under reduced pressure. 351 mg of a white solid was obtained by column chromatography. The yield was 99%.

[0217] Step 3: Dissolve compound 1.4 (393 mg, 1.0 mmol) in 10 mL of anhydrous tetrahydrofuran, add 5 mL of lithium hydroxide (63 mg, 1.5 mmol) aqueous solution, stir at room temperature for 2 hours, and after the reaction is complete as monitored by TLC, concentrate under reduced pressure and dry in vacuum for direct use in the next step.

[0218] Step 4: Compound 1.5 (201 mg, 0.52 mmol), (S)-4,5-diamino-5-oxopentanoic acid tert-butyl ester (124 mg, 0.52 mmol), and HATU (198 mg, 0.52 mmol) were dissolved in 10 mL of anhydrous DMF, and DIPEA (258 μL, 1.56 mmol) was added at room temperature. The reaction system was reacted overnight at room temperature. After the TLC reaction was complete, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed several times with a saturated sodium chloride solution, dried, filtered, concentrated, and column chromatography was performed to obtain 210 mg of a gray solid with a yield of 73%. The theoretical value of UPLC-MS (ESI) was C 28 H 36 N 4 O 8 [M+H] + :557.62, the measured value is: 557.62.

[0219] Step 5: Compound 1.6 (202 mg, 0.36 mmol) was dissolved in methanol (5 mL), tetrahydroxydiboron (161 mg, 1.8 mmol) was added at 0°C, and then a methanol solution (5 mL) of sodium hydroxide (144 mg, 3.6 mmol) was added. After reacting at the same temperature for 10 minutes, the temperature was raised to 40°C and reacted overnight. After TLC monitoring, a saturated ammonium chloride solution was added to quench the reaction, and ethyl acetate was added for extraction. The organic phase was washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography to obtain 160 mg of the product with a yield of 85%. The theoretical value of UPLC-MS (ESI) was C 28 H 36 N 4 O 6 [M+H] + :525.62, the measured value is: 525.53. 1 H NMR (500MHz, DMSO) δ9.75 (s, 1H), 7.48 (t, J = 9.4Hz, 3H), 7.34 (d, J = 7.9Hz, 2H), 7. 30(s,1H),7.23(d,J=7.8Hz,1H),7.18(d,J=7.9Hz,1H),7.05(t,J=7.8Hz,1H),5.2 2(s,2H),4.87(dd,J=9.7,6.0Hz,1H),3.63–3.51(m,4H),3.47(s,2H),2.94(d,J= 29.3Hz,2H),2.34(s,4H),2.20(d,J=14.5Hz,2H),2.12–1.97(m,2H),1.35(s,9H).

[0220] Step 6: Dissolve compound 1.7 (75 mg, 0.14 mmol) and p-toluenesulfonic acid monohydrate (160 mg, 0.14 mmol) in acetonitrile (6 mL) and react at 80°C overnight. The reaction solution was concentrated and purified by HPLC to obtain 60 mg of the product with a yield of 95%. The theoretical value of UPLC-MS (ESI) was C 24 H 26 N 4 O 5 [M+H] + :451.50, the measured value is: 451.53. 1H NMR (500MHz, DMSO) δ10.98(s,1H),10.09(s,1H),7.49(d,J=8.0Hz,2H),7.34(d,J=8.0 Hz,2H),7.25(d,J=7.7Hz,1H),7.20(d,J=7.8Hz,1H),7.05(t,J=7.8Hz,1H),5.30(dd, J=13.1,5.2Hz,1H),5.22(s,2H),3.60–3.53(m,4H),3.47(s,2H),2.92(ddd,J=17.2,1 3.8,5.4Hz,1H),2.65–2.58(m,1H),2.57–2.51(m,1H),2.34(s,4H),2.10–2.03(m,1H). 13 C NMR (126 MHz, DMSO) δ 172.78, 169.63, 165.05, 145.19, 137.75, 135.21, 132.16, 129.00, 127.91, 121.77, 118.55, 116.66, 114.81, 112.95, 69.48, 66.20, 62.14, 53.87, 53.16, 48.61, 30.94, 22.36. Example 2: (S)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-indazol-7-yl)oxy)methyl))benzyl)piperazin-1-yl)-3-fluorobenzonitrile (D2)

[0221] Synthesis route:

[0222]

[0223] Step 1: Dissolve the compound 3-((4-(bromomethyl)benzyl)oxy)-2-nitrobenzoic acid methyl ester (321 mg, 0.844 mmol), 3-fluoro-4-piperazinylbenzonitrile (191 mg, 0.93 mmol) and potassium carbonate (175 mg, 1.27 mmol) in acetonitrile (15 mL) and react at room temperature overnight. After TLC monitoring, the reaction was completed and filtered, the filtrate was concentrated, and the product was obtained by column chromatography (308 mg) as a white solid with a yield of 72%. The theoretical value of UPLC-MS (ESI) was C 27 H 25 FN 4 O 5 [M+H] + :505.52, the measured value is: 505.57.

[0224] Step 2: Dissolve the compound 3-((4-((4-(4-cyano-2-fluorophenyl)piperazin-1-yl)methyl)benzyl)oxy)-2-nitrobenzoic acid methyl ester (345 mg, 0.68 mmol) in tetrahydrofuran (8 mL), add lithium hydroxide monohydrate (43 mg, 1.03 mmol) in water (8 mL), stir at room temperature to react overnight, concentrate the reaction solution under reduced pressure, and dry to obtain 315 mg of the product, which is directly used in the next step without purification.

[0225] Step 3: Add compound 3-((4-((4-(4-cyano-2-fluorophenyl)piperazine-1-yl)methyl)benzyl)oxy)-2-nitrobenzoic acid lithium salt (315 mg, 0.68 mmol), (S)-4,5-diamino-5-oxopentanoic acid tert-butyl ester monohydrochloride (162 mg, 0.68 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl)uronium hexafluorophosphate (259 mg, 0.68 mmol) to N,N-dimethylformamide (10 mL), add N,N-diisopropylethylamine (0.332 mL, 2.04 mmol) dropwise, and react 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 residue was subjected to column chromatography to obtain 423 mg of the product as a yellow oil with a yield of 98%. The theoretical value of UPLC-MS (ESI) is C 35 H 39 FN 6 O 7 [M+H] + :675.73, the measured value is: 675.61.

[0226] Step 4: Compound (S)-5-amino-4-(3-((4-((4-(4-cyano-2-fluorophenyl)piperazin-1-yl)methyl)benzyl)oxy)-2-nitrobenzamido)-5-oxopentanoic acid tert-butyl ester (421 mg, 0.62 mmol) was added to methanol (10 mL), tetrahydroxydiboron (278 mg, 3.1 mmol) was added at 0°C, and then a methanol solution (10 mL) of sodium hydroxide (248 mg, 6.2 mmol) was added, and the mixture was reacted at 0°C for 10 minutes, and then the temperature was raised to 40°C for overnight reaction. After the reaction was complete as monitored by TLC, a saturated ammonium chloride solution was added to quench the reaction, and ethyl acetate was added for extraction, and the organic phase was separated. The organic phase was washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography to obtain 265 mg of the product as a colorless oil with a yield of 66%.

[0227] Step 5: Add compound (S)-5-amino-4-(7-((4-((4-(4-cyano-2-fluorophenyl)piperazin-1-yl)methyl)benzyl)oxy)-3-oxo-1,3-dihydro-2H-indazol-2-yl)-5-oxopentanoic acid tert-butyl ester (265 mg, 0.41 mmol) and p-toluenesulfonic acid monohydrate (471 mg, 2.47 mmol) to acetonitrile (8 mL) and react at 80°C overnight. The reaction solution was concentrated and purified by HPLC to obtain 47 mg of the product with a yield of 20%. The theoretical value of UPLC-MS (ESI) was C 31 H 29 FN 6 O 4 [M+H] + :569.61, the measured value is: 569.55. 1 H NMR (600 MHz, DMSO-d 6 )δ10.97(s,1H),10.10(s,1H),7.68(dd,J=13.3,1.5Hz,1H),7.56(dd,J=8.5,1.6Hz,1H),7.50 (d,J=7.7Hz,2H),7.37(d,J=7.6Hz,2H),7.25(d,J=7.8Hz,1H),7.20(d,J=7.8Hz,1H),7.11(s,1 H),7.06(t,J=7.8Hz,1H),5.30(dd,J=13.1,5.2Hz,1H),5.23(s,2H),3.55(s,2H),3.18(s,4H) ,2.92(ddd,J=17.3,13.8,5.4Hz,1H),2.64–2.58(m,1H),2.56–2.50(m,5H),2.10–2.03(m,1H). 13 C NMR (151 MHz, DMSO-d 6 )δ172.66,169.51,162.67,153.05(d,J=246.6Hz),145.07,143.75,137.65,135.16,129.80,128.93,127.84,121.69 ,119.67,119.50,119.31,118.46,118.30,114.71,112.86,102.11,69.37,61.49,53.75,52.13,49.13,30.82,22.24.

[0228] Example 3: (S)-4-(4-((5-(((2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-indazol-7-yl)oxy)methyl)pyridin-2-yl)thio)piperidin-1-yl)-3-fluorobenzonitrile (D3)

[0229] Synthesis route:

[0230]

[0231] Step 1: Dissolve N-Boc-4-mercaptopiperidine (1.05 g, 4.83 mmol), 2-fluoropyridine-5-carboxaldehyde (664 mg, 5.31 mmol) and potassium carbonate (1.67 g, 12.08 mmol) in N, N-dimethylformamide (10 mL). Heat the reaction solution to 80 ° C and stir for 1 hour. Remove the solvent from the reaction solution under reduced pressure, add water to dilute, extract with ethyl acetate, combine the organic phases, wash with saturated sodium chloride solution, dry with anhydrous sodium sulfate, filter, remove the solvent under reduced pressure, and separate the residue by silica gel column chromatography to obtain 1.5 g of product with a yield of 96%. UPLC-MS (ESI) theoretical value is C 16 H 22 N 2 O 3 S[M+H] + :323.42, measured value: 323.53.

[0232] 1 H NMR (500MHz, DMSO-d6) δ10.00(s,1H),8.92(dd,J=2.2,0.8Hz,1H),8.02(dd,J=8.4,2.3Hz,1H),7.48(d,J=8.4Hz,1H),4.10( tt,J=10.4,3.9Hz,1H),3.85–3.77(m,2H),3.08(s,2H),2.07–1.98(m,2H),1.53(dtd,J=13.1,10.5,4.1Hz,2H),1.41(s,9H).

[0233] Step 2: Dissolve the compound 4-((5-formylpyridin-2-yl)thio)piperidine-1-carboxylic acid tert-butyl ester (1.5 g) in dichloromethane (10 mL), add trifluoroacetic acid (3 mL) dropwise under ice bath, react for 1 hour, concentrate the reaction solution, and dry to obtain 1.5 g of the product. The crude product is used directly in the next step without purification. The theoretical value of UPLC-MS (ESI) is C 11 H 14 N 2 OS[M+H] + :223.31, measured value: 223.14

[0234] Step 3: Dissolve the compound 6-(piperidin-4-thio)nicotinaldehyde trifluoroacetate (1.5 g, 4.46 mmol), 3,4-difluorobenzonitrile (1.24 g, 8.92 mmol) and potassium carbonate (1.85 g, 13.38 mmol) in N,N-dimethylformamide (15 mL). Stir the reaction solution at 80°C overnight. Concentrate the reaction solution under reduced pressure, add water to dilute, extract with ethyl acetate, combine the organic phases, wash with saturated sodium chloride solution, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is column chromatographed to obtain 1.33 g of the product with a yield of 87%. The theoretical value of UPLC-MS (ESI) is C 18 H 16 FN 3 OS[M+H] + :342.40, measured value: 342.29. 1 HNMR(500MHz,Chloroform-d)δ10.00(s,1H),8.83(dd,J=2.2,0.9Hz,1H),7.93( dd,J=8.4,2.2Hz,1H),7.37(ddd,J=8.4,1.9,0.8Hz,1H),7.30–7.27(m,2H),6.9 5(t,J=8.5Hz,1H),4.21(tt,J=10.1,4.1Hz,1H),3.60–3.54(m,2H),3.11(ddd,J =12.7,10.1,2.9Hz,2H),2.32–2.22(m,2H),1.95(dtd,J=13.7,10.1,3.7Hz,2H). 13 C NMR (126MHz, Chloroform-d) δ 189.95, 166.26, 154.00 (d, J = 248.6Hz), 152.58, 144.28, 134.62, 129.42 (d, J = 3. 4Hz),128.03,122.59,119.74(d,J=25.0Hz),119.01(d,J=3.8Hz),118.44,103.61,49.71,49.68,40.10,31.91.

[0235] Step 4: Add the compound 3-fluoro-4-(4-((5-formylpyridin-2-yl)thio)piperidin-1-yl)benzonitrile (1.33 g, 3.90 mmol) to tetrahydrofuran (20 mL) under ice bath conditions, slowly add sodium borohydride (294 mg, 7.79 mmol), react for 1 hour, quench the reaction solution with water, then extract with ethyl acetate and combine the organic phases, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate the filtrate under reduced pressure. The residue is subjected to column chromatography to obtain 1.24 g of the product with a yield of 93%. The theoretical value of UPLC-MS (ESI) is C 18 H 18 FN 3 OS[M+H] + :344.42, measured value: 344.30. 1 H NMR(500MHz,Chloroform-d)δ8.41(d,J=2.2Hz,1H),7.54(dd,J=8.2,2.3Hz,1H),7.3 5(dd,J=8.5,1.9Hz,1H),7.29–7.23(m,1H),7.19(d,J=8.2Hz,1H),6.93(t,J=8.5Hz, 1H),4.66(s,2H),4.09–4.02(m,1H),3.55(dt,J=11.8,4.3Hz,2H),3.07(ddd,J=12.7 ,9.9,2.9Hz,2H),2.23(dq,J=12.8,3.9Hz,2H),1.90(dtd,J=13.5,10.0,3.6Hz,2H).

[0236] Step 5: Add the compound 3-fluoro-4-(4-((5-(hydroxymethyl)pyridin-2-yl)thio)piperidin-1-yl)benzonitrile (376 mg, 1.1 mmol), methyl 2-nitro-3-hydroxybenzoate (180 mg, 0.91 mmol) and triphenylphosphine (287 mg, 1.1 mmol) to dry tetrahydrofuran (5 mL), slowly add diisopropyl azodicarboxylate (221 mg, 1.1 mmol) dropwise at 0°C, stir overnight, and concentrate the reaction solution under reduced pressure. The obtained residue is subjected to column chromatography to obtain 458 mg of the product with a yield of 96%. The theoretical value of UPLC-MS (ESI) is C 26 H 23 FN 4 O 5 S[M+H] + :523.55, measured value: 523.33. 1H NMR(500MHz,Chloroform-d)δ8.45–8.41(m,1H),7.64(dd,J=7.9,1.1Hz,1H),7.53(dd,J=8.3,2.3Hz,1H ),7.50(t,J=8.2Hz,1H),7.35(ddd,J=8.5,2.1,0.8Hz,1H),7.31(dd,J=8.4,1.2Hz,1H),7.27(dd,J=12.6 ,2.0Hz,1H),7.20(dd,J=8.2,0.9Hz,1H),5.14(s,2H),4.08(tt,J=9.9,4.0Hz,1H),3.91(s,3H),3.59–3 .52(m,2H),3.09(ddd,J=12.7,10.1,2.9Hz,2H),2.28–2.21(m,2H),1.91(dtd,J=13.6,10.0,3.7Hz,2H).

[0237] Step 6: Add compound 3-((6-((1-(4-cyano-2-fluorophenyl)piperidin-4-yl)thio)pyridin-3-yl)methoxy)-2-nitrobenzoic acid methyl ester (458 mg, 0.87 mmol) to tetrahydrofuran (10 mL), add lithium hydroxide monohydrate (37 mg, 0.87 mmol) in water (3 mL), stir at room temperature to react overnight, concentrate the reaction solution under reduced pressure, and dry to obtain 450 mg of the product, which is directly used in the next step without purification.

[0238] Step 7: Add compound 3-((6-((1-(4-cyano-2-fluorophenyl)piperidin-4-yl)thio)pyridin-3-yl)methoxy)-2-nitrobenzoic acid lithium salt (450 mg, 0.87 mmol), (S)-4,5-diamino-5-oxopentanoic acid tert-butyl ester monohydrochloride (208 mg, 0.87 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl)urea hexafluorophosphate (332 mg, 0.87 mmol) to N,N-dimethylformamide (10 mL), add N,N-diisopropylethylamine (0.457 mL, 2.62 mmol) dropwise, and react 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, and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography to obtain 550 mg of the product with a yield of 91%. The theoretical value of UPLC-MS (ESI) is C 34 H 37 FN 6 O 7 S[M+H] + :693.76, measured value: 693.43. 1H NMR(500MHz,Chloroform-d)δ8.44(d,J=2.3Hz,1H),7.57–7.44(m,3H),7.35(dd,J=8.5,1.9Hz,1H),7.26–7.17(m,3 H),6.94(t,J=8.5Hz,1H),5.14(s,2H),4.59(td,J=8.1,7.7,4.7Hz,1H),4.07(dq,J=9.5,4.8,4.2Hz,1H),3.72(tt,J =6.3,3.0Hz,1H),3.55(dt,J=12.6,4.3Hz,2H),3.17(dt,J=11.8,5.7Hz,1H),3.12–3.05(m,2H),2.67–2.51(m,1H), 2.40(dt,J=16.9,6.5Hz,1H),2.29–2.13(m,3H),2.04(q,J=7.5Hz,1H),1.95–1.86(m,2H),1.79(s,1H),1.44(s,9H).

[0239] Step 8: Add the compound 5-amino-4-(3-((6-((1-(4-cyano-2-fluorophenyl)piperidin-4-yl)thio)pyridin-3-yl)methoxy)-2-nitrobenzamide)-5-oxopentanoic acid tert-butyl ester (550 mg, 0.79 mmol) to methanol (7 mL), add tetrahydroxydiboron (355 mg, 3.97 mmol) at 0°C, and then add a methanol solution (8 mL) of sodium hydroxide (317 mg, 7.94 mmol), react at 0°C for 10 minutes, and then heat to 40°C to react overnight. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, washed with water, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The residue was column chromatographed to obtain 443 mg of the product with a yield of 84%. The theoretical value of UPLC-MS (ESI) is C 34 H 37 FN 6 O 5 S[M+H] + :661.77, measured value: 661.46.

[0240] Step 9: Add the compound 5-amino-4-(7-((6-((1-(4-cyano-2-fluorophenyl)piperidin-4-yl)thio)pyridin-3-yl)methoxy)-3-oxo-1,3-dihydro-2H-indazol-2-yl)-5-oxopentanoic acid tert-butyl ester (150 mg, 0.23 mmol) and p-toluenesulfonic acid monohydrate (259 mg, 1.36 mmol) to acetonitrile (3 mL) and react at 80°C overnight. The reaction solution was concentrated and purified by HPLC to obtain 35 mg of the product with a yield of 26%. The theoretical value of UPLC-MS (ESI) was C 30 H 27 FN 6 O 4 S[M+H] + :587.64, measured value: 587.33. 1 H NMR (500MHz, DMSO-d6) δ10.99(s,1H),10.08(s,1H),8.65(d,J=2.2Hz,1H),7.81(dd,J=8.3,2.3Hz,1H),7.69(dd,J=13.3,2.0Hz,1H),7.56(dd, J=8.4,2.0Hz,1H),7.36(d,J=8.2Hz,1H),7.27(d,J=7.8Hz,1H),7.23(d,J=7.8Hz,1H),7.16(t,J=8.8Hz,1H),7.08(t,J=7.8Hz,1H),5.32(dd,J =13.1,5.3Hz,1H),5.24(s,2H),4.03(tt,J=10.2,4.0Hz,1H),3.52(dt,J=12.8,4.1Hz,2H),3.08(ddd,J=12.9,10.3,2.7Hz,2H),2.93(ddd,J=1 7.2,13.7,5.4Hz,1H),2.65–2.51(m,2H),2.16(dq,J=12.1,3.6Hz,2H), 2.07(dtd,J=12.9,5.4,2.4Hz,1H), 1.76(dtd,J=13.7,10.3,3.6Hz,2H). 13CNMR(126MHz,DMSO-d6)δ172.76,169.62,162.75,157.46,153.14(d,J=246.1Hz),149.18,144.89,143.98,137.75,136.68,129.90,128.28,12 2.09,121.80,119.82,119.67,119.62,118.58,118.44,115.07,113.03 ,102.07(d,J=9.9Hz),66.99,53.87,49.20,49.16,31.71,30.93,22.37.

[0241] Example 4: 4-(4-((5-(((2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-indazol-7-yl)oxy)methyl)pyridin-2-yl)thio)piperidin-1-yl)-3-fluorobenzonitrile (D4)

[0242]

[0243] The synthesis method is as described in Example 1 to obtain compound D4. 1 H NMR (500 MHz, DMSO-d 6 )δ11.00(s,1H),10.14(s,1H),7.74(dd,J=13.2,2.0Hz,1H),7.63(d,J=7.9Hz,2H),7.60(dd,J=8 .4,1.9Hz,1H),7.52–7.46(m,2H),7.27(d,J=7.8Hz,1H),7.21(d,J=7.8Hz,1H),7.16(t,J=8.7Hz ,1H),7.07(t,J=7.8Hz,1H),5.36–5.29(m,3H),3.78(s,2H),3.57–3.40(m,2H),3.29–3.14(m,4H),2.93(ddd,J=17.2,13.8,5.5Hz,1H),2.66–2.54(m,2H),2.12–2.00(m,1H). UPLC-MS(ESI)theoretical value is C 31 H 28 FN 6 O 5 [M+H] + : Calculated value 583.21, measured value 583.38.

[0244] Example 5: 3-(7-((4-(4-(2-fluoro-4-methylphenyl)piperazine-1-carbonyl)benzyl)oxy)-3-oxo-1,3-dihydro-2H-indazol-2-yl)piperidine-2,6-dione (D5)

[0245]

[0246] The synthesis method is as described in Example 1 to obtain compound D5. 1 H NMR (500 MHz, DMSO-d 6 )δ11.00(s,1H),10.14(s,1H),7.62(d,J=7.9Hz,2H),7.48(d,J=8.1Hz,2H),7.27(d,J=7.8Hz,1H),7.21(d,J=7.8Hz,1H),7.07(t,J=7.8Hz,1H),7.00–6.89(m,3H),5.35–5.28(m,3H),3.77(s,2H),3.49(s,2H),3.07–2.86(m,5H),2.65–2.53(m,2H),2.24(s,3H),2.11–2.04(m,1H). UPLC-MS(ESI)theoretical value is C 31 H 31 FN 5 O 5 [M+H] + : Calculated value 572.23, measured value 572.32.

[0247] Example 6: 3-(7-((4-(((2S,6R)-2,6-dimethylmorpholino)methyl)benzyl)oxy)-3-oxo-1,3-dihydro-2H-indazol-2-yl)piperidine-2,6-dione (D6)

[0248]

[0249] The synthesis method is as described in Example 1 to obtain compound D6. 1 H NMR (500 MHz, DMSO-d 6)δ11.00(s,1H),10.11(s,1H),7.65(d,J=7.9Hz,2H),7.56(d,J=8.0Hz,2H),7.28(d,J=7.7Hz,1H), 7.21(d,J=7.8Hz,1H),7.07(t,J=7.8Hz,1H),5.39–5.27(m,3H),4.34(s,2H),3.82(tdd,J=12.4,6. 1,1.9Hz,3H),3.27(s,1H),2.94(ddd,J=17.1,13.8,5.4Hz,1H),2.69(t,J=11.5Hz,2H),2.63(dt,J=17.7,3.2Hz,1H),2.58–2.52(m,1H),2.13–2.03(m,1H),1.12(d,J=6.3Hz,6H). UPLC-MS(ESI)theoretical value is C 26 H 31 N 4 O 5 [M+H] + : Calculated value 479.22, measured value 479.45.

[0250] Example 7: 3-(7-((4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)benzyl)oxy)-3-oxo-1,3-dihydro-2H-indazol-2-yl)piperidine-2,6-dione (D7)

[0251]

[0252] The synthesis method is as described in Example 1 to obtain compound D7. 1 H NMR (500MHz, DMSO) δ10.98(s,1H),10.11(s,1H),7.50(d,J=7.6Hz,2H),7.37(d,J=7.6Hz,2 H),7.25(d,J=7.8Hz,1H),7.23–7.15(m,2H),7.06(td,J=8.7,5.7Hz,2H),6.99(t,J=5.3Hz, 1H), 5.31 (dd, J = 13.1, 5.1 Hz, 1H), 5.23 (s, 2H), 3.54 (s, 2H), 3.35 (s, 4H), 2.96 (s, 4H), 2.93–2.87 (m, 1H), 2.66–2.57 (m, 1H), 2.54–2.51 (m, 1H), 2.11–2.02 (m, 1H). UPLC-MS (ESI) theoretical value is C 30 H 29 F 2 N 5 O4 [M+H] + : Calculated value 562.22, measured value 562.37.

[0253] Example 8: 3-(7-((4-((4-(3-chlorophenyl)piperazin-1-yl)methyl)benzyl)oxy)-3-oxo-1,3-dihydro-2H-indazol-2-yl)piperidine-2,6-dione (D8)

[0254]

[0255] The synthesis method was similar to that of Example 1 to obtain compound D8. 1 H NMR (500MHz, DMSO) δ10.98(s,1H),10.10(s,1H),7.51(d,J=7.5Hz,2H),7.38(d,J=7.7Hz,2H),7.26 (d,J=7.9Hz,1H),7.21(d,J=8.0Hz,2H),7.07(t,J=7.8Hz,1H),6.92(s,1H),6.88(d,J=8.6Hz,1H),6 .78 (d, J = 7.8 Hz, 1H), 5.31 (dd, J = 13.1, 5.1 Hz, 1H), 5.24 (s, 2H), 3.54 (s, 2H), 3.34-3.29 (m, 4H), 3.17 (s, 4H), 2.98-2.87 (m, 1H), 2.63 (d, 1H), 2.54-2.51 (m, 1H), 2.10-2.04 (m, 1H). UPLC-MS (ESI) theoretical value is C 30 H 31 C1N 5 O 4 [M+H] + : Calculated value 560.20, measured value 560.28.

[0256] Example 9: 3-(7-((4-((4-(4-chlorophenyl)piperazin-1-yl)methyl)benzyl)oxy)-3-oxo-1,3-dihydro-2H-indazol-2-yl)piperidine-2,6-dione (D9)

[0257]

[0258] The synthesis method was similar to that of Example 1 to obtain compound D9. 1 H NMR (500MHz, DMSO) δ10.98(s,1H),10.10(s,1H),7.51(d,J=7.7Hz,2H),7.37(d,J=7.6Hz,2H),7.26(d,J=7.8Hz,1H),7.23–

[0259] 7.19(m,3H),7.07(t,J=7.8Hz,1H),6.96–6.90(m,2H),5.31(dd,J=13.1,5.2Hz,1H),5.23(s ,2H),3.56–3.52(m,2H),3.34-3.29(m,4H),3.13(t,J=5.0Hz,4H),2.98–2.87(m,1H),2.66–

[0260] 2.58 (m, 1H), 2.54-2.51 (m, 1H), 2.10–2.04 (m, 1H). UPLC-MS (ESI) theoretical value is C 30 H 31 C1N 5 O 4 [M+H] + : Calculated value 560.20, measured value 560.32.

[0261] Example 10: 3-(7-((4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)benzyl)oxy)-3-oxo-1,3-dihydro-2H-indazol-2-yl)piperidine-2,6-dione (D10)

[0262]

[0263] The synthesis method was similar to that of Example 1 to obtain compound D10. 1 H NMR (500MHz, DMSO) δ10.98(s,1H),10.10(s,1H),7.51(d,J=7.7Hz,2H),7.38(d,J=7.7Hz,2H),7.2 6(d,J=7.8Hz,1H),7.21(d,J=7.8Hz,1H),7.08(d,J=7.8Hz,1H),7.06–7.01(m,2H),6.95–6.91(m,2 H), 5.31 (dd, J = 13.1, 5.2 Hz, 1H), 5.23 (s, 2H), 3.54 (d, J = 2.6 Hz, 2H), 3.34-3.29 (m, 4H), 3.07 (s, 4H), 2.98–2.87 (m, 1H), 2.64–2.57 (m, 1H), 2.55–2.52 (m, 1H), 2.10–2.04 (m, 1H). UPLC-MS (ESI) theoretical value is C 30 H 31 FN 5 O 4 [M+H] + : Calculated value 544.23, measured value 544.32.

[0264] Example 11: 3-(3-oxo-7-((4-((4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)methyl)benzyl)oxy)-1,3-dihydro-2H-indazol-2-yl)piperidine-2,6-dione (D11)

[0265]

[0266] The synthesis method was similar to that of Example 1 to obtain compound D11. 1 H NMR (500MHz, DMSO) δ11.00(s,1H),10.18(s,1H),7.63(q,J=8.2Hz,2H),7.55(d,J=8.4Hz,1H ),7.42(s,2H),7.32(s,2H),7.26(d,J=8.1Hz,1H),7.22(d,J=7.1Hz,2H),7.09(dd,J=13.6,8 .1Hz,1H),5.32(dd,J=12.9,5.1Hz,1H),5.28(s,2H),4.22(s,2H),3.57(s,2H),3.51(s,2H),3.49(s,3H),3.47(s,2H),2.89(m,1H),2.67–2.55(m,1H),2.08(m,1H). UPLC-MS(ESI)theoretical value is C 30 H 31 F 3 N 5 O 4 [M+H] + : Calculated value 594.22, measured value 594.34.

[0267] Example 12: 3-(7-((4-((4-(2,4-dichlorophenyl)piperazin-1-yl)methyl)benzyl)oxy)-3-oxo-1,3-dihydro-2H-indazol-2-yl)piperidine-2,6-dione (D12)

[0268]

[0269] The synthesis method was similar to that of Example 1 to obtain compound D12. 1H NMR(500MHz,DMSO)δ11.01(s,1H),10.12(s,1H),7.70–7.64(m,2H),7.64–7.56(m,3H),7.42 (dd,J=8.7,2.5Hz,1H),7.30–7.22(m,2H),7.21(d,J=7.8Hz,1H),7.07(t,J=7.8Hz,1H),5.3 4 (d, J = 5.2 Hz, 1H), 5.31 (s, 2H), 4.45 (s, 2H), 3.57 (t, J = 5.5 Hz, 4H), 3.25 (s, 2H), 3.08–2.97 (m, 2H), 2.97–2.88 (m, 1H), 2.62 (m, 1H), 2.54-2.51 (m, 1H), 2.09 (m, 1H). UPLC-MS (ESI) theoretical value is C 30 H 30 Cl 2 N 5 O 4 [M+H] + : Calculated value 594.16, measured value 594.25.

[0270] Example 13: 3-(7-((4-((3-morpholinoazetidin-1-yl)methyl)benzyl)oxy)-3-oxo-1,3-dihydro-2H-indazol-2-yl)piperidine-2,6-dione (D13)

[0271]

[0272] The synthesis method was similar to that of Example 1 to obtain compound D13. 1 H NMR(500MHz,DMSO)δ11.00(s,1H),7.62(d,J=8.0Hz,2H),7.52(d,J=8.0Hz,2H),7.27 (d,J=7.8Hz,1H),7.20(d,J=7.7Hz,1H),7.07(t,J=7.8Hz,1H),5.32(dd,J=13.2,5.2 Hz,1H),5.29(s,2H),4.45(s,2H),4.20(s,4H),3.73(s,5H),3.42(s,1H),2.99–2.88 (m,1H),2.78–2.68(m,3H),2.65–2.60(m,1H),2.54-2.51(m,1H),2.13–2.05(m,1H).

[0273] The theoretical value of UPLC-MS (ESI) is C 27 H 32 N 5 O5 [M+H] + : Calculated value 506.23, measured value 506.34.

[0274] Example 14: 4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-5-fluoro-3-oxo-2,3-dihydro-1H-indazol-7-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile (D14)

[0275]

[0276] The synthesis method was similar to that of Example 1 to obtain compound D14. 1 H NMR (400MHz, DMSO) δ11.00(s,1H),10.11(s,1H),7.78(dd,J=13.1,1.9Hz,1H),7.67–7.61(m,3H), 7.57(d,J=7.9Hz,2H),7.22(dd,J=10.3,7.2Hz,2H),7.04(dd,J=7.6,2.2Hz,1H),5.31(d,J=12.8H z, 3H), 4.42 (s, 2H), 3.72 (d, J = 13.0 Hz, 2H), 3.41 (s, 2H), 3.25 (s, 2H), 3.16 (d, J = 12.6 Hz, 2H), 2.98–2.90 (m, 1H), 2.61 (d, J = 16.8 Hz, 1H), 2.54–2.51 (m, 1H), 2.13–2.03 (m, 1H). UPLC-MS (ESI) theoretical value is C 31 H 29 F 2 N 6 O 4 [M+H] + : Calculated value 587.21, measured value 587.62.

[0277] Example 15: 3-(7-((4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)benzyl)oxy)-5-fluoro-3-oxo-1,3-dihydro-2H-indazol-2-yl)piperidine-2,6-dione (D15)

[0278]

[0279] The synthesis method was similar to that of Example 1 to obtain compound D15. 1H NMR (500MHz, DMSO) δ11.02 (s, 1H), 10.14 (s, 1H), 7.66 (d, J = 7.7Hz, 2H), 7.59 ( d,J=7.8Hz,2H),7.32–7.20(m,2H),7.15(td,J=9.5,5.8Hz,1H),7.05(dd,J=7 .5,2.5Hz,2H),5.34(s,3H),4.44(s,2H),4.2(s,2H),3.44(s,4H),3.26(s,2H ),2.95–2.89(m,1H),2.66–2.58(m,1H),2.54–2.51(m,1H),2.14–2.06(m,1H).

[0280] The theoretical value of UPLC-MS (ESI) is C 31 H 29 F 2 N 6 O 4 [M+H] + : Calculated value 580.21, measured value 580.63.

[0281] Example 16: 3-(7-((4-((4-(2,4-dichlorophenyl)piperazin-1-yl)methyl)benzyl)oxy)-5-fluoro-3-oxo-1,3-dihydro-2H-indazol-2-yl)piperidine-2,6-dione (D16)

[0282]

[0283] The synthesis method was similar to that of Example 1 to obtain compound D16. 1 H NMR(500MHz,DMSO)δ11.00(s,1H),10.15(s,1H),7.56–7.48(m,3H),7.41–7.36(m,3 H),7.26–7.20(m,1H),7.17(d,J=8.7Hz,1H),7.03(dd,J=7.5,2.3Hz,1H),5.32(dd,J =13.0,5.1Hz,1H),5.25(s,2H),3.57(s,2H),3.35(s,4H),2.97(s,4H),2.93–2.88(m,1H),2.62–2.58(m,1H),2.54–2.51(m,1H),2.10–2.04(m,1H). UPLC-MS(ESI)theoretical value is C 30 H 29 C l2 FN 5 O 4[M+H]+: calculated value 612.15, found value 612.30.

[0284] Example 17: 3-(5-fluoro-3-oxo-7-((4-((4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)methyl)benzyl)oxy)-1,3-dihydro-2H-indazol-2-yl)piperidine-2,6-dione (D17)

[0285]

[0286] The synthesis method was similar to that of Example 1 to obtain compound D17. 1 H NMR (500MHz, DMSO) δ11.01(s,1H),10.15(s,1H),7.51(t,J=8.0Hz,4H),7.40(d,J=7.7H z,2H),7.23(dd,J=11.3,2.3Hz,1H),7.05(dd,J=8.1,5.6Hz,3H),5.32(dd,J=13.2,5.2H z, 1H), 5.26 (s, 2H), 3.55 (d, J = 8.5 Hz, 2H), 3.35 (s, 4H), 3.28 (t, J = 5.0 Hz, 4H), 2.98–2.87 (m, 1H), 2.65–2.57 (m, 1H), 2.54–2.51 (m, 1H), 2.12–2.03 (m, 1H). UPLC-MS (ESI) theoretical value is C 31 H 30 F 4 N 5 O 4 [M+H]+: calculated value 612.22, found value 612.36.

[0287] Example 18: 3-(7-((4-((4-(4-chlorophenyl)piperazin-1-yl)methyl)benzyl)oxy)-5-fluoro-3-oxo-1,3-dihydro-2H-indazol-2-yl)piperidine-2,6-dione (D18)

[0288]

[0289] The synthesis method was similar to that of Example 1 to obtain compound D18. 1H NMR (500MHz, DMSO) δ11.01(s,1H),10.15(s,1H),7.51(d,J=7.7Hz,2H),7.39(d,J=7.7Hz,2H ),7.23(dd,J=9.5,2.9Hz,3H),7.04(dd,J=7.6,2.2Hz,1H),6.96–6.90(m,2H),5.32(dd,J=1 3.1,5.2Hz,1H),5.25(s,2H),3.54(d,J=4.3Hz,2H),3.35(s,4H),3.13(t,J=4.9Hz,4H),2.98–2.87(m,1H),2.65–2.58(m,1H),2.54–2.51(m,1H),2.08–2.05(m,1H). UPLC-MS(ESI)theoretical value is C 30 H 30 CIF 5 O4[M+H] + : Calculated value 578.19, measured value 578.36.

[0290] Example 19: 3-(5-fluoro-7-((4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)benzyl)oxy)-3-oxo-1,3-dihydro-2H-indazol-2-yl)piperidine-2,6-dione (D19)

[0291]

[0292] The synthesis method was similar to that of Example 1 to obtain compound D19. 1 H NMR (500MHz, DMSO) δ11.01(s,1H),10.15(s,1H),7.51(d,J=7.7Hz,2H),7.39(d,J=7.7Hz, 2H),7.23(dd,J=11.2,2.2Hz,1H),7.08–7.00(m,3H),6.97–6.89(m,2H),5.32(dd,J=13.2, 5.2Hz,1H),5.25(s,2H),3.54(d,J=6.3Hz,2H),3.35(s,4H),3.07(d,J=5.8Hz,4H),2.97–2.87(m,1H),2.64–2.57(m,1H),2.54–2.51(m,1H),2.11–2.03(m,1H). UPLC-MS(ESI)theoretical value is C 30 H 30 F 2 N 5 O 4 [M+H] +: Calculated value 562.22, measured value 562.33.

[0293] Example 20: 3-(5-fluoro-7-((4-((3-morpholinoazetidin-1-yl)methyl)benzyl)oxy)-3-oxo-1,3-dihydro-2H-indazol-2-yl)piperidine-2,6-dione (D20)

[0294]

[0295] The synthesis method was similar to that of Example 1 to obtain compound D20. 1 H NMR (500MHz, DMSO) δ11.01(s,1H),10.15(s,1H),7.48(d,J=7.8Hz,2H),7.34(d,J=8.0H z,2H),7.21(dd,J=11.2,2.3Hz,1H),7.03(dd,J=7.6,2.2Hz,1H),5.32(dd,J=13.2,5.2H z, 1H), 5.24 (s, 2H), 3.67 (s, 2H), 3.60–3.51 (m, 5H), 3.42 (s, 1H), 2.98–2.86 (m, 4H), 2.65–2.56 (m, 1H), 2.54–2.51 (m, 1H), 2.23 (s, 4H), 2.11–2.03 (m, 1H). UPLC-MS (ESI) theoretical value is C 27 H 31 FN 5 O 5 [M+H] + : Calculated value 524.22, measured value 524.47.

[0296] Example 21: 3-(7-((4-((4-(4-chloro-2-fluorophenyl)piperazin-1-yl)methyl)benzyl)oxy)-5-fluoro-3-oxo-1,3-dihydro-2H-indazol-2-yl)piperidine-2,6-dione (D21)

[0297]

[0298] The synthesis method was similar to that of Example 1 to obtain compound D21. 1H NMR (500MHz, DMSO) δ11.02(s,1H),10.17(s,1H),7.66(d,J=8.0Hz,2H),7.59(d,J=8.1Hz,2H),7 .42(dd,J=12.2,2.4Hz,1H),7.26–7.20(m,2H),7.12(t,J=9.1Hz,1H),7.05(dd,J=7.6,2.2Hz,1 H), 5.37–5.30 (m, 3H), 4.45 (s, 2H), 3.55–3.48 (m, 2H), 3.42 (s, 2H), 3.25 (s, 2H), 3.05 (s, 2H), 2.99–2.88 (m, 1H), 2.66–2.58 (m, 1H), 2.54–2.51 (m, 1H), 2.14–2.05 (m, 1H). UPLC-MS (ESI) theoretical value is C 30 H 29 CIF 2 N 5 O 4 [M+H] + :596.18, measured value 596.27.

[0299] Example 22: 3-(1-methyl-7-((4-morpholinomethyl)benzyl)oxy)-3-oxo-1,3-dihydro-2H-indazol-2-yl)piperidine-2,6-dione (D22)

[0300]

[0301] The synthesis method was similar to that of Example 1 to obtain compound D22. 1 H NMR (500MHz, DMSO) δ11.03(s,1H),7.61(d,J=7.7Hz,2H),7.57(d,J=6.9Hz,2H),7.33(d, J=8.0Hz,1H),7.29(d,J=7.8Hz,1H),7.20(dd,J=8.8,6.8Hz,1H),5.35(s,2H),5.10–5.0 4 (m, 1H), 4.37 (s, 2H), 3.97 (d, J = 12.9 Hz, 4H), 3.65 (d, J = 12.3 Hz, 4H), 2.81 (t, J = 14.6 Hz, 1H), 2.72–2.58 (m, 2H), 2.04 (d, J = 11.9 Hz, 1H), 1.27–1.19 (m, 3H). UPLC-MS (ESI) theoretical value is C 25 H 29 N 4 O 5 [M+H] +:465.52, measured value 465.37.

[0302] Example 23: 3-(1-ethyl-7-((4-morpholinomethyl)benzyl)oxy)-3-oxo-1,3-dihydro-2H-indazol-2-yl)piperidine-2,6-dione (D23)

[0303]

[0304] The synthesis method was similar to that of Example 1 to obtain compound D23. 1 H NMR (500MHz, DMSO) δ11.03(s,1H),7.61(d,J=8.0Hz,2H),7.57(d,J=7.9Hz,2H),7.33(d,J=7.9Hz,1 H),7.28(d,J=7.6Hz,1H),7.20(t,J=7.8Hz,1H),5.35(s,2H),5.07(dd,J=12.6,5.3Hz,1H),4.37(s ,2H),4.11(dq,J=13.8,6.7Hz,2H),3.97(d,J=12.9Hz,4H),3.64(t,J=12.2Hz,4H),3.27(d,J=12.8Hz,2H),2.87–2.76(m,1H),2.72–2.57(m,2H),2.07–1.99(m,1H),1.23(s,3H). UPLC-MS(ESI)theoretical value is C 26 H 31 N 4 O 5 [M+H] + :479.55, measured value 479.86.

[0305] Example 24: 4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-methyl-3-oxo-2,3-dihydro-1H-indazol-7-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile (D24)

[0306]

[0307] The synthesis method was similar to that of Example 1 to obtain compound D24. 1H NMR (500MHz, DMSO) δ11.05(s,1H),7.83–7.76(m,1H),7.64(d,J=10.5Hz,3H),7.59(d,J=7.8Hz,2H ),7.34(dd,J=7.9,1.0Hz,1H),7.30(dd,J=7.8,0.9Hz,1H),7.22(td,J=8.2,2.7Hz,2H),5.35(s,2 H), 5.14 (dd, J = 12.6, 5.3 Hz, 1H), 4.44 (s, 2H), 3.73 (d, J = 13.1 Hz, 3H), 3.26 (s, 3H), 3.19 (d, J = 12.6 Hz, 2H), 2.87–2.78 (m, 1H), 2.73–2.58 (m, 2H), 2.10–2.04 (m, 1H), 1.24 (s, 3H) UPLC-MS (ESI) theoretical value is C 32 H 32 FN 6 O 4 [M+H] + :583.64, measured value 583.49.

[0308] Example 25: 4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-methyl-3-oxo-2,3-dihydro-1H-indazol-7-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile (D25)

[0309]

[0310] The synthesis method was similar to that of Example 1 to obtain compound D25. 1 H NMR(500MHz,DMSO)δ11.04(s,1H),7.79(dd,J=13.1,1.9Hz,1H),7.64–7.58(m,5H),7.36– 7.27(m,2H),7.23–7.17(m,2H),5.35(s,2H),5.07(dd,J=12.5,5.3Hz,1H),4.43(s,2H),4 .12 (dq, J = 14.0, 6.9 Hz, 1H), 3.79 (dd, J = 15.0, 7.1 Hz, 2H), 3.44 (d, J = 12.2 Hz, 4H), 2.87–2.76 (m, 1H), 2.71–2.58 (m, 2H), 2.07–2.01 (m, 1H), 1.30–1.22 (m, 3H). UPLC-MS (ESI) theoretical value is C 33 H 34 FN 6 O 4 [M+H]+ :597.66, measured value 597.35.

[0311] Example 26: (S)-3-(3-oxo-7-((2-(4-(trifluoromethoxy)phenyl)oxazol-5-yl)methoxy)-1,3-dihydro-2H-indazol-2-yl)piperidine-2,6-dione (D26)

[0312] Synthesis route:

[0313]

[0314] Step 1:

[0315] Compound 4-trifluoromethoxyphenylboronic acid (1g, 4.89mmol), ethyl 2-iodooxazole-5-carboxylate (1g, 3.25mmol), sodium carbonate (795mg, 7.5mmol) and tetrakistriphenylphosphine palladium (433mg, 0.375mmol) were added to a mixed solvent of 1,4-dioxane (15mL) and water (3mL), the reaction system was replaced with nitrogen, and the temperature was raised to 90°C under nitrogen protection to react overnight. 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 was removed under reduced pressure. The residue was separated by silica gel column chromatography to obtain 661mg of the product, a yellow oil, with a yield of 59%. The theoretical value of UPLC-MS (ESI) is C 13 H 10 F 3 NO 4 [M+H] + :302.22, measured value: 302.17.

[0316] Step 2:

[0317] The compound 2-(4-(trifluoromethoxy)phenyl)oxazole-5-carboxylic acid ethyl ester (611mg, 2mmol) was dissolved in ethanol (15mL), and calcium chloride (1.3g, 12mmol) was added. The reaction system was cooled to 0°C, and sodium borohydride (227mg, 6mmol) was slowly added. The temperature was raised to room temperature and the reaction was allowed to react overnight. Saturated ammonium chloride solution (5mL) was added to the reaction system to quench the reaction, and the mixture was diluted with water and extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was separated by silica gel column chromatography to obtain 311mg of the product as a white solid with a yield of 59%. The theoretical value of UPLC-MS (ESI) was C 11 H 8 F 3 NO 3 [M+H] +:260.18, measured value: 260.26.

[0318] Step 3:

[0319] Compound (2-(4-(trifluoromethoxy)phenyl)oxazol-5-yl)methanol (200 mg, 1 mmol), methyl 2-nitro-3-hydroxybenzoate (315 mg, 1.2 mmol) and triphenylphosphine (315 mg, 1.2 mmol) were added to dry tetrahydrofuran (8 mL), and diisopropyl azodicarboxylate (0.236 mL) was slowly added dropwise at 0°C, stirred overnight, and the reaction solution was concentrated under reduced pressure. The residue was subjected to column chromatography to obtain 400 mg of the product as a yellow oil with a yield of 89%. The theoretical value of UPLC-MS (ESI) was C 19 H 13 F 3 N 2 O 7

[0320] [M+H] + :439.32, measured value: 439.40.

[0321] Step 4:

[0322] The compound 2-nitro-3-((2-(4-(trifluoromethoxy)phenyl)oxazol-5-yl)methoxy)benzoic acid methyl ester (440 mg, 1 mmol) was added to tetrahydrofuran (8 mL), and an aqueous solution (4 mL) of lithium hydroxide monohydrate (63 mg, 1.5 mmol) was added. The reaction was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure and dried to obtain 430 mg of the product, which was directly used in the next step without purification.

[0323] Step 5:

[0324] The compound 2-nitro-3-((2-(4-(trifluoromethoxy)phenyl)oxazol-5-yl)methoxy)benzoic acid lithium salt (431mg, 1mool), (S)-4,5-diamino-5-oxopentanoic acid tert-butyl ester monohydrochloride (239mg, 1mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl)uronium hexafluorophosphate (381mg, 1mmol) were added to N,N-dimethylformamide (10mL), and N,N-diisopropylethylamine (0.523mL, 3mmol) was added dropwise, and the reaction was carried out 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 residue was subjected to column chromatography to obtain 530mg of the product with a yield of 87%. The theoretical value of UPLC-MS (ESI) was C 27 H 27 F 3 N 4 O9 [M+H] + :609.53, measured value: 609.50.

[0325] Step 6:

[0326] Compound (S)-5-amino-4-(2-nitro-3-((2-(4-(trifluoromethoxy)phenyl)oxazol-5-yl)methoxy)benzamide)-5-oxopentanoic acid tert-butyl ester (420 mg, 0.69 mmol) was added to methanol (7 mL), tetrahydroxydiboron (309 mg, 3.45 mmol) was added at 0°C, and then a methanol solution (9 mL) of sodium hydroxide (276 mg, 6.9 mmol) was added, and the mixture was reacted at 0°C for 10 minutes, and then the mixture was heated to 40°C and reacted overnight. After the reaction was completed by TLC monitoring, a saturated ammonium chloride solution was added to quench the reaction, and ethyl acetate was added for extraction, and the organic phase was separated, washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography to obtain 123 mg of the product as a yellow oil with a yield of 31%. The theoretical value of UPLC-MS (ESI) was C 27 H 27 F 3 N 4 O 7 [M+H] + :577.53, the measured value is 577.56:

[0327] Step 7:

[0328] Compound (S)-5-amino-5-oxo-4-(3-oxo-7-((2-(4-(trifluoromethoxy)phenyl)oxazol-5-yl)methoxy)-1,3-dihydro-2H-indazol-2-yl)pentanoic acid tert-butyl ester (123 mg, 0.21 mmol) and p-toluenesulfonic acid monohydrate (240 mg, 1.26 mol) were added to acetonitrile (6 mL) and reacted at 80°C overnight. The reaction solution was concentrated and purified by HPLC to obtain 35 mg of the product with a yield of 33%. The theoretical value of UPLC-MS (ESI) was C 23 H 17 F 3 N 4 O 6 [M+H] + :503.41, measured value:503.31. 1H NMR(500MHz,DMSO-d6)δ11.04(s,1H),10.72(s,1H),7.76(d,J=8.9Hz,2H),7 .47(d,J=8.2Hz,2H),7.14–7.11(m,1H),7.08(t,J=7.6Hz,1H),7.05(s,1H), 7.03–7.00(m,1H),5.37(d,J=16.3Hz,1H),5.17(dd,J=12.4,5.1Hz,1H),5.0 9(d,J=16.4Hz,1H),2.91–2.81(m,1H),2.76–2.64(m,2H),2.28–2.21(m,1H).

[0329] Example 27: (S)-3-(7-((2-(4-chlorophenyl)oxazol-5-yl)methoxy)-3-oxo-1,3-dihydro-2H-indazol-2-yl)piperidine-2,6-dione (D27)

[0330]

[0331] The synthesis method was similar to Example 26 to obtain Compound ID 27. 1 H NMR (500 MHz, DMSO) δ 11.02 (s, 1H), 10.59 (s, 1H), 7.61–7.55 (m, 2H), 7.15–7.05 (m, 3H), 7.05–6.97 (m, 3H), 5.40–5.31 (m, 2H), 5.17 (dd, J = 12.5, 5.2 Hz, 1H), 2.71 (dd, J = 17.2, 4.5 Hz, 2H), 2.27 (d, J = 21.1 Hz, 2H). UPLC-MS (ESI) theoretical value is C 22 H 18 C1N 4 O 5 [M+H] + :453.85, measured value:453.23.

[0332] Example 28: 3-(7-((2-(4-methoxyphenyl)oxazol-5-yl)methoxy)-3-oxo-1,3-dihydro-2H-indazol-2-yl)piperidine-2,6-dione (D28)

[0333]

[0334] The synthetic method was similar to that of Example 26 to obtain compound D28. 1H NMR (500 MHz, DMSO) δ 11.04 (s, 1H), 10.69 (s, 1H), 7.61–7.55 (m, 2H), 7.15–7.05 (m, 3H), 7.05–6.97 (m, 3H), 6.96 (s, 1H), 5.40–5.31 (m, 2H), 5.03 (s, 1H), 3.80 (s, 3H), 2.26 (d, J = 11.0 Hz, 1H), 2.00 (dd, J = 16.0, 8.0 Hz, 2H). UPLC-MS (ESI) theoretical value is C 23 H 21 N 4 O 6 [M+H] + :449.14, measured value:449.35.

[0335] Example 29: N-(4-chlorobenzyl)-2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-indazole-6-carboxamide (D29)

[0336]

[0337] Compound 29-1 (1 g, 4.44 mmol) was placed in a round-bottom flask, dissolved in 20 mL DMF, added with compound 29-2 (1.57 g, 6.67 mmol) and HATU (5 g, 13.32 mmol), stirred for 3 minutes, and then added with DIPEA (5.0, 22.2 mmol), stirred at room temperature for 4 hours. After the reaction, it was dissolved in ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, evaporated under reduced pressure, and purified by column chromatography to obtain 1.71 g of product 29-3 with a yield of 94%.

[0338] Synthesis of compound 29-4:

[0339] Compound 29-3 (1.71 g, 4.1 mmol) was placed in a round-bottom flask and dissolved in 10 ml of tetrahydrofuran. LiOH hydrate (0.984 g, 24.6 mmol) dissolved in water (10 ml) was added and stirred for 1 hour. After the reaction was completed, the solvent was evaporated under reduced pressure. The yield was 100%.

[0340] Synthesis of compound 29-5:

[0341] Compound 29-4 (2.76 g, 6.74 mmol) was placed in a round-bottom flask, stirred and dissolved in methanol, and tetrahydroxydiboron (3.025 g, 33.75 mmol) was added after ice bath at 0°C, and sodium hydroxide (2.7 g, 67.5, mmol) dissolved in methanol was added. After 10 minutes, the mixture was heated at 40°C for 4 hours. After the reaction was completed, the mixture was extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure and then column chromatography was performed to obtain 2.4 g of the product with a yield of 98%.

[0342] Synthesis of compound 29-8:

[0343] Take compound 29-5 and compound 29-6, the equivalent and operation steps are the same as compound 3.

[0344] Synthesis of compound 29-9:

[0345] Compound 29-8 (50 mg, 0.10 mmol) was placed in a round-bottom flask, 5 mg of acetonitrile was stirred and dissolved, and p-toluenesulfonic acid hydrate (16 mg, 0.61 mmol) was added. The mixture was heated under reflux at 90 °C for 4 hours. After the reaction, the solvent was evaporated under reduced pressure and purified by high performance liquid chromatography to obtain 10 mg of compound 29 as a white solid with a yield of 23%. 1 H NMR (500 MHz, DMSO-d 6 )δ9.43(t,J=6.0Hz,1H),8.75(s,1H),7.96(d,J=8.1Hz,1H),7.91(d,J=8.7Hz,2H),7.49(s,1H),7.43–7.33(m,4H),5.13(dd,J=5.4,3.0Hz,1H),4.50(d,J=5.9Hz,2H),2.78(dt,J=17.6,3.8Hz,1H),2.62(ddd,J=17.7,12.6,5.7Hz,1H),2.47(dd,J=8.8,3.9Hz,1H),2.39(ddq,J=14.0,6.0,2.8Hz,1H). UPLC-MS(ESI)theoretical value is C 20 H 18 C1N 4 O 4 [M+H] + :413.09, measured value:413.25.

[0346] Example 30: N-((S)-1-(4-chlorophenyl)ethyl)-2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-indazole-6-carboxamide (D30)

[0347]

[0348] The synthetic method was similar to Example 29 to obtain compound D30. 1 H NMR (500 MHz, DMSO-d 6 )δ11.06(s,1H),10.25(s,1H),9.01(d,J=7.8Hz,1H),7.78(d,J=8.1Hz,1H),7.70(s,1H),7.62(dd,J=8.1,1.4Hz,1H),7.41(q,J=8.7Hz,4H),5.39(dd,J=13.1,5.2Hz,1H),5.16(p,J=7.2Hz,1H),2.98–2.92(m,1H),2.69–2.64(m,1H),2.46–2.38(m,1H),2.14–2.09(m,1H),1.48(d,J=7.1Hz,3H). UPLC-MS(ESI)theoretical value is C 21 H 20 C1N 4 O 4 [M+H] + :427.11, measured value:427.26.

[0349] Example 31: N-((S)-1-(4-chlorophenyl)ethyl)-2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-indazole-6-carboxamide (D31)

[0350]

[0351] The synthetic method was similar to Example 29 to obtain compound D31. 1 H NMR (500 MHz, DMSO-d 6 )δ11.06(s,1H),8.94(d,J=8.0Hz,1H),7.77(d,J=8.1Hz,1H),7.70(s,1H),7.64–7.55(m,1H), 7.29(d,J=7.9Hz,2H),7.16–7.10(m,2H),5.39(dd,J=13.1,5.2Hz,1H),5.13(h,J=8.1,7.6Hz,1 H), 3.70 (s, 3H), 2.95 (ddd, J = 17.3, 13.6, 5.4 Hz, 1H), 2.69–2.62 (m, 1H), 2.49–2.37 (m, 2H), 2.28 (s, 3H), 2.12 (dtt, J = 12.8, 5.4, 3.3 Hz, 1H), 1.46 (dd, J = 11.6, 7.0 Hz, 3H). UPLC-MS (ESI) theoretical value is C22 H 23 N 4 O 4 [M+H] + :407.16, measured value:407.33.

[0352] Example 32: 2-(2,6-dioxopiperidin-3-yl)-3-oxo-N-((R)-1-phenylethyl)-2,3-dihydro-1H-indazole-6-carboxamide (D32)

[0353]

[0354] The synthetic method was similar to that of Example 29 to obtain compound D32. 1 H NMR (500 MHz, DMSO-d 6 )δ11.07(s,1H),8.99(d,J=8.0Hz,1H),7.78(d,J=8.1Hz,1H),7.71(t,J=1.0Hz,1H),7.62(dd,J=8. 1,1.4Hz,1H),7.44–7.36(m,2H),7.36–7.29(m,2H),7.27–7.19(m,1H),5.39(dd,J=13.1,5.2Hz,1H) ,5.18(p,J=7.3Hz,1H),2.95(ddd,J=17.2,13.7,5.4Hz,1H),2.65(dt,J=17.1,3.9Hz,1H),2.43(qd,J=13.3,4.6Hz,1H),2.12(dtd,J=12.9,5.4,2.5Hz,1H),1.50(d,J=7.1Hz,3H). UPLC-MS(ESI)theoretical value is C 21 H 21 N 4 O 4 [M+H] + :393.15, measured value:393.32

[0355] Example 33: 2-(2,6-dioxopiperidin-3-yl)-3-oxo-N-((S)-1-phenylethyl)-2,3-dihydro-1H-indazole-6-carboxamide (D33)

[0356]

[0357] The synthetic method was similar to that of Example 29 to obtain compound D33. 1 H NMR (500 MHz, DMSO-d 6)δ11.06(s,1H),10.24(s,1H),8.99(d,J=8.0Hz,1H),7.77(dd,J=8.1,0.7Hz,1H),7.71(t,J= 1.1Hz,1H),7.62(dd,J=8.2,1.4Hz,1H),7.44–7.38(m,2H),7.37–7.31(m,2H),7.27–7.20(m, 1H), 5.39 (dd, J = 13.2, 5.2 Hz, 1H), 5.18 (p, J = 7.2 Hz, 1H), 2.95 (ddd, J = 17.1, 13.6, 5.4 Hz, 1H), 2.69–2.62 (m, 1H), 2.43 (qd, J = 13.2, 4.5 Hz, 1H), 1.50 (d, J = 7.1 Hz, 3H). UPLC-MS (ESI) theoretical value is C 21 H 21 N 4 O 4 [M+H] + :393.15, measured value:393.32

[0358] Example 34: N-((R)-1-(4-chlorophenyl)ethyl)-2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-indazole-6-carboxamide (D34)

[0359]

[0360] The synthetic method was similar to Example 29 to obtain compound D34. 1 H NMR (500 MHz, DMSO-d 6 )δ11.07(s,1H),10.25(s,1H),9.01(d,J=7.9Hz,1H),7.89–7.58(m,3H),7.41(qd,J=8.5,1.5Hz,4H),5.39(dd,J=13.1,5.2Hz,1H),5.17(pd,J=7.2,3.0Hz,1H),2.95(ddd,J=17.3,13.7,5.4Hz,1H),2.71–2.61(m,1H),2.41(td,J=13.3,4.6Hz,1H),1.48(d,J=7.1Hz,3H). UPLC-MS(ESI)theoretical value is C 21 H 20 C1N 4 O 4 [M+H] + :427.11, measured value:427.37

[0361] Example 35: 2-(2,6-dioxopiperidin-3-yl)-3-oxo-N-((S)-2,2,2-trifluoro-1-phenylethyl)-2,3-dihydro-1H-indazole-6-carboxamide (D35)

[0362]

[0363] The synthesis method was referred to Example 29 to obtain compound D35. The theoretical value of UPLC-MS (ESI) was C 21 H 20 C1N 4 O 4 [M+H] + :447.12, measured value:447.30.

[0364] Example 36: 2-(2,6-dioxopiperidin-3-yl)-N-(4-methylbenzyl)-3-oxo-2,3-dihydro-1H-indazole-6-carboxamide (D36)

[0365]

[0366] The synthetic method was similar to that of Example 29 to obtain compound D36. 1 H NMR (500 MHz, DMSO-d 6 )δ9.34(t,J=6.0Hz,1H),8.77–8.72(m,1H),7.95(d,J=8.1Hz,1H),7.90(dd,J=8.2,1 .4Hz,1H),7.87(s,1H),7.53–7.45(m,1H),7.25–7.20(m,2H),7.18–7.10(m,2H),5.12 (dd, J = 5.4, 3.0 Hz, 1H), 4.47 (d, J = 6.0 Hz, 2H), 2.89 (s, 1H), 2.78 (dt, J = 17.5, 3.9 Hz, 1H), 2.65–2.59 (m, 1H), 2.40 (dt, J = 6.1, 2.8 Hz, 1H), 2.28 (s, 3H). UPLC-MS (ESI) theoretical value is C 21 H 21 N 4 O 4 [M+H] + :393.15, measured value:393.15.

[0367] Example 37: 2-(2,6-dioxopiperidin-3-yl)-3-oxo-N-((R)-2,2,2-trifluoro-1-phenylethyl)-2,3-dihydro-1H-indazole-6-carboxamide (D37)

[0368]

[0369] The synthetic method was similar to Example 29 to obtain compound D37. 1 H NMR (500 MHz, DMSO-d 6 )δ11.07(s,1H),10.32(s,1H),9.71(s,1H),7.71(d,J=7.2Hz,4H),7.45(q,J=7.8,6.8Hz,6H),6.07(s,1H),5.41(s,1H),3.69(s,5H),2.95(s,2H),2.13(s,2H). UPLC-MS(ESI)theoretical value is C 21 H 18 F 3 N 4 O 4 [M+H] + :447.12, measured value:447.34.

[0370] Example 38: N-((S)-1-(2,4-difluorophenyl)ethyl)-2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-indazole-6-carboxamide (D38)

[0371]

[0372] The synthetic method was similar to that of Example 29 to obtain compound D38. 1 H NMR (500 MHz, DMSO-d 6 )δ9.25(dd,J=12.4,7.5Hz,1H),8.70(dd,J=3.8,1.2Hz,1H),8.01–7.85(m,2H),7.62– 7.43(m,2H),7.22(dddd,J=15.4,12.3,6.2,2.5Hz,1H),7.09(tt,J=8.7,2.7Hz,1H),5 .43–5.29 (m, 2H), 2.88 (dt, J = 17.0, 5.1 Hz, 1H), 2.76 (ddd, J = 17.3, 10.3, 4.5 Hz, 1H), 2.66–2.58 (m, 1H), 2.41–2.36 (m, 1H), 1.50 (dd, J = 7.1, 3.8 Hz, 3H). UPLC-MS (ESI) theoretical value is C 21 H 19 F 2 N 4 O 4 [M+H] + :429.13, measured value:429.31.

[0373] Example 39: N-((S)-1-(3-chlorophenyl)ethyl)-2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-indazole-6-carboxamide (D39)

[0374]

[0375] The synthetic method was similar to that of Example 29 to obtain compound D39. 1 H NMR (500 MHz, DMSO-d 6 )δ9.20(d,J=7.8Hz,1H),8.71(s,1H),7.97(d,J=8.1Hz,1H),7.91(dd,J=8.1,1.4Hz,1H),7.8 7(s,1H),7.48(d,J=4.6Hz,2H),7.38(d,J=4.8Hz,2H),7.32(qd,J=4.2,2.0Hz,1H),5.19(p,J =7.2Hz,1H),5.13(dd,J=5.5,2.9Hz,1H),3.06(s,1H),2.78(dt,J=17.4,3.8Hz,1H),2.62(dd,J=11.4,6.4Hz,1H),2.40(dt,J=6.9,3.5Hz,1H),1.50(d,J=7.0Hz,3H). UPLC-MS(ESI)theoretical value is C 21 H 20 C1N 4 O 4 [M+H] + :427.11, measured value:427.33.

[0376] Example 40: N-(tert-butyl)-2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-indazole-6-carboxamide (D40)

[0377]

[0378] The synthetic method was similar to Example 29 to obtain compound D40. 1 H NMR (500 MHz, DMSO-d 6)δ10.33(s,1H),8.63–8.56(m,1H),8.13(d,J=13.6Hz,1H),7.95–7.87(m,1H),7.90–7.81(m,1H),5.31(t,J=5.4Hz,1H),2.77(q,J=5.7Hz,1H),2.69–2.58(m,1H),2.41–2.30(m,1H),2.29–2.16(m,1H),1.43–1.34(m,9H). UPLC-MS(ESI)theoretical value is C 17 H 21 N 4 O 4 [M+H] + :345.15, measured value:345.38.

[0379] Example 41: N-((R)-6-chlorochroman-4-yl)-2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-indazole-6-carboxamide (D41)

[0380]

[0381] The synthetic method was similar to Example 29 to obtain compound D41. 1 H NMR (500 MHz, DMSO-d 6 )δ10.87(s,1H),9.28(dd,J=12.8,8.0Hz,1H),8.77(t,J=1.7Hz,1H),8.03–7.80(m ,2H),7.38–7.11(m,2H),6.94–6.71(m,1H),5.31(q,J=8.4,7.5Hz,1H),4.30(qdd,J =10.7,6.8,3.3Hz,2H),2.89(dt,J=17.0,5.1Hz,1H),2.77(ddd,J=12.5,9.1,4.6Hz,1H),2.70–2.56(m,1H),2.43–2.34(m,1H),2.18–2.06(m,2H). UPLC-MS (ESI) theoretical value is C 22 H 20 C1N 4 O 5 [M+H] + :455.10, measured value:455.29.

[0382] Example 42: 2-(2,6-dioxopiperidin-3-yl)-N-((R)-8-methylchroman-4-yl)-3-oxo-2,3-dihydro-1H-indazole-6-carboxamide (D42)

[0383]

[0384] The synthetic method was similar to Example 29 to obtain compound D42. 1 H NMR (500 MHz, DMSO-d 6 )δ9.24(dd,J=12.0,8.1Hz,1H),8.76(s,1H),8.01–7.84(m,2H),7.09–6.98(m,2H),6.79 (dd,J=8.0,6.3Hz,1H),5.30(q,J=6.8Hz,1H),5.13(dd,J=5.4,2.9Hz,1H),4.33(dddd,J =33.2,10.7,7.3,3.3Hz,2H),2.92–2.83(m,1H),2.77(dt,J=17.4,4.3Hz,1H),2.61(dd,J=11.3,6.5Hz,1H),2.40(dt,J=6.2,3.0Hz,1H),2.18–2.05(m,5H). UPLC-MS (ESI) theoretical value is C 23 H 23 N 4 O 5 [M+H] + :435.16, measured value:435.29.

[0385] Example 43: N-butyl-2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-indazole-6-carboxamide (D43)

[0386]

[0387] The synthetic method was similar to that of Example 29 to obtain compound D43. 1 H NMR (500 MHz, DMSO-d 6 )δ8.77(t,J=5.7Hz,1H),8.69(t,J=1.0Hz,1H),7.95–7.91(m,1H),7.90–7.83(m,2H),7.49(s,1H),5.12(dd,J=5.4,3.0Hz,1H),3.31–3.28(m,2H),2.78(dd,J=17.4,4.0Hz,1H),2.65–2.59(m,1H),2.49–2.43(m,1H),2.41–2.36(m,1H),1.54(tt,J=7.8,6.3Hz,3H),1.39–1.28(m,3H),0.92(t,J=7.3Hz,4H). UPLC-MS(ESI)theoretical value is C17 H 21 N 4 O 4 [M+H] + :345.15, measured value:345.41.

[0388] Example 44: (S)-2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-indazol-6-yl)methyl)-2,2-difluoroacetamide (D44)

[0389]

[0390] Step 1:

[0391] Add 4-((bis(tert-butoxycarbonyl)amino)methyl)-2-nitrobenzoic acid methyl ester (300 mg, 0.73 mmol) to dichloromethane (2 mL), slowly add 4 mol / L hydrochloric acid 1,4-dioxane solution (6 mL), and react at room temperature for 12 hours. After the reaction is complete, concentrate and directly proceed to the next step.

[0392] Step 2:

[0393] 4-(Aminomethyl)-2-nitrobenzoic acid methyl ester hydrochloride (246mg, 1mmol), 2-(4-chlorophenyl)-2,2-difluoroacetic acid (227mg, 1.1mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl) urea hexafluorophosphate (418mg, 1.1mmol) were added to N,N-dimethylformamide (10mL), and N,N-diisopropylethylamine (1.39mL, 8mmol) was added, and the reaction was carried out 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 residue was subjected to column chromatography to obtain 100mg of the product, and the yield of the colorless oil was 25%. The theoretical value of UPLC-MS (ESI) was C 17 H 13 CIF 2 N 2 O 5 [M+H] + :399.75, the measured value is: 399.66.

[0394] Step 3:

[0395] The compound 4-((2-(4-chlorophenyl)-2,2-difluoroacetylamino)methyl)-2-nitrobenzoic acid methyl ester (100 mg, 0.25 mmol) was added to tetrahydrofuran (3 mL), and an aqueous solution (3 mL) of lithium hydroxide monohydrate (16 mg, 0.376 mmol) was added. The reaction was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure and dried to obtain 97 mg of the product, which was directly used in the next step without purification.

[0396] Step 4:

[0397] Compound 4-((2-(4-chlorophenyl)-2,2-difluoroacetylamino)methyl)-2-nitrobenzoic acid lithium salt (97 mg), (S)-4,5-diamino-5-oxopentanoic acid tert-butyl ester monohydrochloride (60 mg, 0.25 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl)uronium hexafluorophosphate (95 mg, 0.25 mmol) were added to N,N-dimethylformamide (3 mL), and N,N-diisopropylethylamine (0.131 mL, 0.75 mmol) was added dropwise. The reaction was allowed to react 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 residue was subjected to column chromatography to obtain 126 mg of the product with a yield of 89%. The theoretical value of UPLC-MS (ESI) was C 25 H 27 CIF 2 N 4 O 7 [M+H] + :568.96, the measured value is: 568.91.

[0398] Step 5:

[0399] The compound (S)-5-amino-4-(4-((2-(4-chlorophenyl)-2,2-difluoroacetylamino)methyl)-2-nitrobenzamide)-5-oxopentanoic acid tert-butyl ester (30 mg, 0.0.053 mmol) was dissolved in methanol (3 mL), tetrahydroxydiboron (24 mg, 0.264 mmol) was added at 0°C, and then a methanol solution (3 mL) of sodium hydroxide (20 mg, 0.5 mmol) was added, and the mixture was reacted at 0°C for 10 minutes, and then the temperature was raised to 40°C for overnight reaction. After the reaction was completed by TLC monitoring, a saturated ammonium chloride solution was added to quench the reaction, and ethyl acetate was added for extraction, and the liquids were separated. The organic phase was washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography to obtain 19 mg of the product with a yield of 67%. The theoretical value of UPLC-MS (ESI) was C 25 H 27 CIF 2 N 4 O5 [M+H] + :537.96, the measured value is: 537.88.

[0400] Step 6:

[0401] Compound (S)-5-amino-4-(6-((2-(4-chlorophenyl)-2,2-difluoroacetylamino)methyl)-3-oxo-1,3-dihydro-2H-indazol-2-yl)-5-oxopentanoic acid tert-butyl ester (19 mg, 0.035 mmol) and p-toluenesulfonic acid monohydrate (40 mg, 0.212 mmol) were added to acetonitrile (2 mL) and reacted at 80° C. overnight. The reaction solution was concentrated and purified by HPLC to obtain 7 mg of the product with a yield of 42%. The theoretical value of UPLC-MS (ESI) was C 21 H 17 CIF 2 N 4 O 4 [M+H] + :463.84, the measured value is: 463.36. 1 HNMR(500MHz,DMSO)δ10.76(s,1H),9.78(s,1H),9.43(s,1H),8.18(s,1H),7.84(s,1H),7.79(d,J=7.9Hz,1H),7.61(s,2H),7.45(s,1H ),7.30(d,J=9.1Hz,1H),5.08(d,J=2.9Hz,1H),4.49(d,J=6.1Hz,2H),2.74(d,J=17.7Hz,1H),2.64–2.57(m,2H),2.36(d,J=1.9Hz,1H).

[0402] Example 45: (S)-1-(3-chloro-4-methylphenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-indazol-6-yl)methyl)urea (D45)

[0403]

[0404] Step 1:

[0405] 4-(Aminomethyl)-2-nitrobenzoic acid methyl ester hydrochloride (180mg, 0.73mmol) and 3-chloro-4-methylphenyl isocyanate (135mg, 0.80mmol) were added to acetonitrile (8mL), and triethylamine (0.507mL, 3.65mmol) was added. The reaction system was heated to 40°C for 6 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, diluted with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography to obtain 247mg of the product as a white solid with a yield of 89%. The theoretical value of UPLC-MS (ESI) was C 16 H 14 C1N 3 O 5 [M+H] + :364.75, the measured value is: 364.77.

[0406] Step 2:

[0407] The compound (247 mg, 0.65 mmol) was added to tetrahydrofuran (3 mL), and an aqueous solution (2 mL) of lithium hydroxide monohydrate (41 mg, 0.98 mmol) was added. The mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure and dried to obtain 241 mg of the product, which was used directly in the next step without purification.

[0408] Compound 4-((3-(3-chloro-4-methylphenyl)ureido)methyl)-2-nitrobenzoic acid lithium salt (241 mg), (S)-4,5-diamino-5-oxopentanoic acid tert-butyl ester monohydrochloride (171 mg, 0.72 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl)urea hexafluorophosphate (274 mg, 0.72 mmol) were added to N,N-dimethylformamide (10 mL), and N,N-diisopropylethylamine (0.34 mL, 1.95 mmol) was added dropwise, and the reaction was carried out 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 residue was subjected to column chromatography to obtain 322 mg of the product with a yield of 90%. The theoretical value of UPLC-MS (ESI) was C 24 H 28 C1N 5 O 7 [M+H] + :534.97, the measured value is: 534.89.

[0409] Step 3:

[0410] Compound (S)-5-amino-4-(4-((3-(3-chloro-4-methylphenyl)ureido)methyl)-2-nitrobenzamide)-5-oxopentanoic acid tert-butyl ester (358 mg, 0.67 mmol) was added to methanol (5 mL), tetrahydroxydiboron (300 mg, 3.35 mmol) was added at 0°C, and then a methanol solution (5 mL) of sodium hydroxide (268 mg, 6.7 mmol) was added, and the mixture was reacted at 0°C for 10 minutes, and then the mixture was heated to 40°C and reacted overnight. After the reaction was completed by TLC monitoring, a saturated ammonium chloride solution was added to quench the reaction, and ethyl acetate was added for extraction, and the organic phase was separated, washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography to obtain 272 mg of the product, 81%. The theoretical value of UPLC-MS (ESI) was C 25 H 30 C1N 5 O 5 [M+H] + :517.00, the measured value is: 517.03.

[0411] Step 4:

[0412] Compound (S)-5-amino-4-(6-((3-(3-chloro-4-methylphenyl)ureido)methyl)-3-oxo-1,3-dihydro-2H-indazol-2-yl)-5-oxopentanoic acid tert-butyl ester (272 mg, 0.53 mmol) and p-toluenesulfonic acid monohydrate (601 mg, 3.16 mmol) were added to acetonitrile (mL) and reacted at 80°C overnight. The reaction solution was concentrated and purified by HPLC to obtain 60 mg of the product with a yield of 26%. The theoretical value of UPLC-MS (ESI) was C 21 H 20 C1N 5 O 4 [M+H] + :442.87, the actual value is: 442.91.

[0413] Example 46: N-Benzyl-2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-indazole-6-carboxamide (D46)

[0414]

[0415] The synthetic method was similar to Example 29 to obtain compound D46. 1H NMR (500MHz, DMSO) δ11.06(s,1H),10.26(s,1H),9.21(t,J=5.9Hz,1H),7.77(d,J=8.1Hz, 1H),7.72(s,1H),7.62(d,J=8.2Hz,1H),7.33(d,J=4.7Hz,4H),7.25(dd,J=8.8,4.4Hz,1H ),5.39(dd,J=13.1,5.1Hz,1H),4.50(d,J=5.9Hz,2H),2.93(dd,J=22.3,8.7Hz,1H),2.65(d,J=12.5Hz,1H),2.40(dd,J=19.8,15.6Hz,1H),2.14–2.06(m,1H). UPLC-MS(ESI)theoretical value is C 20 H 19 N 4 O 4 [M+H] + :379.13, measured value:379.25.

[0416] Example 47: 2-(2,6-dioxopiperidin-3-yl)-N-((S)-1-(4-ethylphenyl)ethyl)-3-oxo-2,3-dihydro-1H-indazole-6-carboxamide (D47)

[0417]

[0418] The synthetic method was similar to Example 29 to obtain compound D47. 1 H NMR (500MHz, DMSO) δ11.06(s,1H),10.22(s,1H),8.93(d,J=8.0Hz,1H),7.76(d,J=8.2Hz,1H),7.69(s ,1H),7.61(d,J=8.2Hz,1H),7.30(d,J=8.1Hz,2H),7.16(d,J=8.1Hz,2H),5.38(dd,J=13.1,5.2Hz,1H) ,5.14(p,J=7.1Hz,1H),2.99–2.89(m,1H),2.64(d,J=16.6Hz,1H),2.57(q,J=7.6Hz,2H),2.41(qd,J=13.3,4.5Hz,1H),2.15–2.05(m,1H),1.47(d,J=7.1Hz,3H),1.16(t,J=7.6Hz,3H). UPLC-MS(ESI)theoretical value is C 23 H 25 N 4 O 4 [M+H]+ :421.18, measured value:421.16. 2. Experimental Example

[0419] The present invention also tests the activity of the polysubstituted isoindoline compounds of the embodiment compounds on three major types of blood tumor cell lines, representative of which are: multiple myeloma cell line (MM.1S), mantle cell lymphoma cell line (Mino), and acute myeloid leukemia cell line (MV-4-11). The cell proliferation inhibition activity of these three representative cell lines was tested. The experimental materials required for the pharmacological experiments were purchased commercially unless otherwise specified.

[0420] 1. Effects of compounds on MM.1S cell proliferation

[0421] MM.1S cells were cultured with 1640 plus 10% fetal bovine serum and collected. The cell concentration was diluted according to the 7-day action time. 180ul of cell suspension was added to each well of a 96-well cell plate to make the cell number 20,000. 20ul of DMSO with a final concentration of 0.2% was added to the control cell wells. The compound was diluted 5 times from the 10mM stock solution and 20ul was also added to the compound cell wells (DMSO final concentration was 0.2%). The cells were placed at 37°C and 5% CO 2 Incubate in a culture incubator for 7 days. Prepare the reaction solution according to the MTS kit (Promega, G5430) and add 20 μL to each well in a 37°C, 5% CO 2 Incubate in the incubator for 3-4 hours. Read the absorbance at 490nm using an ELISA plate, and use the absorbance at 690nm as the background value, with OD490-OD690 as the final raw data. The inhibitory rate of the compound is calculated as follows: Inhibition rate = (OD DMSO -OD 化合物 ) / (OD DMSO -O 空白 )×100%. The IC50 of the proliferation inhibition of the compound was fitted by Graph PadPrism 5.0. The experiment was repeated three times, and the average and standard deviation were calculated using three parallel experiments each time.

[0422] The results of the cell activity test are shown in Table 1 below: A represents cell activity IC 50 <200nM, B indicates cell viability 200nM <IC 50 <1μM, C indicates cell viability 1μM <IC 50 <10μM, D represents cell activity IC 50 >10μM.

[0423] Table 1. Inhibitory activity of compounds on MM.1S cell proliferation

[0424]

[0425]

[0426] Based on the test results of the above compound cell growth inhibition activity, some of the embodiment compounds of the present invention have good inhibitory activity on the growth of multiple myeloma MM.1S cells, and the activity of some compounds is better than that of the marketed drugs lenalidomide or pomalidomide. On the other hand, the development of these structurally diverse compounds provides more optional material bases and new structures for obtaining more active drug molecules and molecules with better pharmaceutical properties. Therefore, the compounds of the present invention can be used to prevent, treat and regulate CRBN (CRL4 CRBN Diseases associated with decreased E3 ubiquitin ligase (E3 ubiquitin ligase) activity, such as multiple myeloma or, without limitation, other potential tumor diseases, pain, neurological diseases, and immune system diseases.

[0427] 2. Inhibitory activity of compounds on Mino cell proliferation

[0428] Mino cells were cultured with 1640 plus 15% fetal bovine serum and collected. The cell concentration was diluted according to the 3-day action time. 90 μl of cell suspension was added to each well of the 96-well cell plate to make the cell number 8,000. 10 ul of DMSO with a final concentration of 0.2% was added to the control cell wells. The compound was diluted 5 times from the 10 mM stock solution and 10 ul was also added to the compound cell wells (DMSO final concentration was 0.2%). The cells were placed at 37°C and 5% CO 2 Incubate in the incubator for 3 days. Prepare the reaction solution according to the MTS kit (Promega, G5430) and add 20 μL to each well in a 37°C, 5% CO 2 Incubate in incubator for 3-4 hours.

[0429] The absorbance value at 490 nm was read using an ELISA plate, and the absorbance value at 690 nm was used as the background value, and OD490-OD690 was used as the final raw data. The inhibition rate of the compound was calculated as follows: Inhibition rate = (OD DMSO -OD 化合物 ) / (OD DMSO -O 空白 )×100%. IC of the compound for proliferation inhibition 50 The data were fitted by Graph Pad Prism 5.0. The experiment was repeated three times, and the mean and standard deviation were calculated using three parallel experiments each time.

[0430] The results of the cell activity test are shown in Table 2 below: A represents cell activity IC 50 <200nM, B indicates cell viability 200nM <IC 50 <1μM, C indicates cell viability 1μM <IC50 <10μM, D represents cell activity IC 50 >10μM.

[0431] Table 2. Inhibitory activity of compounds on Mino cell proliferation

[0432]

[0433]

[0434] Based on the test results of the cell growth inhibitory activity of some of the above-mentioned example compounds, it was found that some example compounds of the present invention have good inhibitory activity on the growth of mantle cell lymphoma Mino cells, and the activity of most of the compounds is better than that of the marketed drugs lenalidomide or pomalidomide. On the other hand, the development of these structurally diverse compounds provides an optional material basis and molecular source for obtaining more active drug molecules and molecules with better pharmaceutical properties. Therefore, the compounds of the present invention broaden the scope of application of amide drugs in the treatment of hematological tumor diseases, and can be used to expand to other indications of hematological tumors, such as as active molecules for mantle cell lymphoma diseases, and as a drug or diagnostic reagent for the prevention or treatment of such diseases. Therefore, the compounds of the present invention can be used as a powerful new CRBN modulator for the prevention, treatment and regulation of CRBN (CRL4 CRBN Diseases associated with E3 ubiquitin ligase) activity, such as multiple myeloma, mantle cell lymphoma or, without limitation, other potential tumor diseases, pain, neurological diseases and immune system diseases.

[0435] 3. Inhibitory activity of compounds on MV-411 cell proliferation

[0436] MV-4-11 cells were cultured with IMDM plus 10% fetal bovine serum and collected. The cell concentration was diluted according to the 7-day action time. 180ul of cell suspension was added to each well of a 96-well cell plate to make the cell number 2000. 20ul of DMSO with a final concentration of 0.2% was added to the control cell wells. The compound was diluted 5 times from the 10mM stock solution and 20ul was also added to the compound cell wells (DMSO final concentration was 0.2%). The cells were placed at 37°C and 5% CO 2 Incubate in a culture incubator for 7 days. Prepare the reaction solution according to the MTS kit (Promega, G5430) and add 20 μL to each well in a 37°C, 5% CO 2 Incubate in the incubator for 3-4 hours. Read the absorbance at 490nm using an ELISA plate, and use the absorbance at 690nm as the background value, with OD490-OD690 as the final raw data. The inhibitory rate of the compound is calculated as follows: Inhibition rate = (OD DMSO -OD 化合物 ) / (ODDMSO -O 空白 )×100%. The IC50 of the proliferation inhibition of the compound was fitted by GraphPad Prism 5.0. The experiment was repeated three times, and the mean and standard deviation were calculated using three parallel experiments each time.

[0437] The results of the cell activity test are shown in Table 3 below: A represents cell activity IC 50 <200nM, B indicates cell activity 200nM <IC 50 <1μM, C indicates cell activity 1μM≤IC 50 ≤20μM, D represents cell activity IC 50 >20μM.

[0438] Table 3. Inhibitory activity of compounds on MV-4-11 cell proliferation

[0439] serial number MV-411 serial number MV-411 D1 D D25 C D2 A D26 C D3 B D27 D D4 C D28 D D5 C D29 D D7 A D30 C D8 A D31 D D9 A D32 D D10 A D33 D D11 A D34 D D12 A D35 D D13 B D36 D D14 A D37 D D15 A D38 D D16 A D39 D D17 A D40 D D18 A D41 D D19 A D42 D D20 B D44 C D21 A D46 D D22 D D47 B D23 D Lenalidomide D D24 D

[0440] Based on the test results of the cell growth inhibition activity of some of the above-mentioned compounds in the acute myeloid leukemia cell line (MV-4-11), it was found that some of the compounds in the embodiments of the present invention have very good inhibitory activity against acute leukemia cells MV-4-11 cells. IC of some compounds 50 At the nanomolar level, the best IC of the compounds tested in the table 50 Can reach <

[0441] 100nM; however, the cell inhibitory activity (IC 50 ) are all greater than 20μΜ.

[0442] Therefore, for the compounds of the present invention, we transformed the amine nucleus into an indazolone nucleus, and obtained unexpected effects on the cells of the acute myeloid leukemia cell line (MV-4-11), which was far superior to the marketed drugs and the drugs under clinical development in terms of cell activity.

[0443] 4.CRBN / DDB1 binding TR-FRET assay

[0444] 1. Experimental steps

[0445] 1. Take 0.1 μL of reference solution in a 384 reaction plate, the final detection concentration is 100 μM, diluted 3 times, 10 points.

[0446] 2. Add 2.5 μL CRBN / DDB1 to the 384 reaction plate and centrifuge at 1000 rpm for 1 minute.

[0447] 3. Add 2.5 μL Thalidomide-BODIPY to the 384 reaction plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 15 minutes.

[0448] 4. Add 5 μL His-Tb to the 384 reaction plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 60 minutes.

[0449] 5. Use BMG to read the TR-FRET signal (ratio 520 / 490 nm).

[0450] The inhibition rate of the compounds on CRBN / DDB1 binding is shown in Table 4 below: A indicates an inhibition rate > 90%, B indicates an inhibition rate of 50% < 90%, and C indicates an inhibition rate < 50%.

[0451] Table 4. Inhibition rate of compounds on CRBN / DDB1 binding

[0452]

[0453] Based on the test results of the inhibition rate of CRBN / DDB1 binding of some of the above example compounds at a concentration of 10 micromolar, it was found that most of the example compounds of the present invention have good inhibitory activity on CRBN / DDB1 binding, and most of the compounds are better than or equivalent to lenalidomide in inhibitory activity.

[0454] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

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, methyl or ethyl; R2 is hydrogen or fluorine; R3 is hydrogen, deuterium or fluorine; L is none, -CH2-, S, -CO-, -CH(CH3)-; X-A1 combination is -(CH2) n -O-CH2-A1, -(CH2) n -NHCONH-A1, -(CH2) n -NHCOCF2-A1, -CONH-(CH2) n -A1, -CONH-CO-A1, -CONHCH(CH3)-A1, -CONHCH(CF3)-A1; n is 0 or 1; When X-A1 is combined with -(CH2) n -O-CH2-A1 or, L is none, -CH2-, S, -CO-, -CH(CH3)-; A1 is selected from: halogen-substituted and unsubstituted phenyl, halogen-substituted and unsubstituted pyridyl, and five-membered heteroaryl containing N, O, and S; A2 is selected from: phenyl, pyridyl, piperazinyl, piperidinyl, morpholinyl, azetidinyl; wherein the phenyl, pyridyl, piperazinyl, piperidinyl, morpholinyl 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 pyridyl, C3-C8 heterocyclyloxy, C3-C8 cycloalkyloxy, hydroxy-substituted C1-C6 alkoxy, C1-C6 alkoxy substituted by C1-C6 alkoxy; wherein the substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl is optionally substituted by one or more groups selected from the following: hydrogen, halogen, cyano, 4-10 membered heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy; When X-A1 is combined with -(CH2) n -NHCONH-A1 or -(CH2) n -NHCOCF2-A1, L and A2 are both absent; A1 is selected from: phenyl, wherein the phenyl is substituted by one or more groups selected from the following: hydrogen, halogen, cyano, C1-C6 alkyl; When the X-A1 combination is -CONHCH(CH3)-A1, -CONH-(CH2) n When -A1, -CONH-CO-A1 or -CONHCH(CF3)-A1, L and A2 are not present at the same time; A1 is selected from: phenyl, pyridyl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 4-6 membered heterocyclyl, 4-6 membered heterocyclylphenyl, C1-C6 alkyl; the aforementioned C6-10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 4-6 membered heterocyclyl, C1-C6 alkyl is 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.

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 compounds have structures shown in formulas (I-1) to (I-11): Wherein, R1 is hydrogen, methyl or ethyl; R2 is hydrogen or fluorine; R3 is hydrogen, deuterium or fluorine; R4 is H or halogen; n = 0 or 1; R5 is selected from phenyl, pyridyl or morpholinyl, wherein the phenyl, pyridyl or morpholinyl is optionally substituted by one or more groups selected from the following: hydrogen, halogen, cyano, 4-10 membered heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, halogen substituted C1-C6 alkyl, halogen substituted C1-C6 alkoxy; 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.

3. 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 have structures shown in formula (I-29)-(I-30): Wherein, R1 is hydrogen, methyl or ethyl; R2 is hydrogen or fluorine; R3 is hydrogen, deuterium or fluorine; R 11 is hydrogen or methyl; Each q is independently 0 or 1; Z is N or -CH-; R5 is selected from phenyl, pyridyl or morpholinyl, wherein the phenyl, pyridyl or morpholinyl is optionally substituted by one or more groups selected from the following: hydrogen, halogen, cyano, 4-10 membered heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, halogen substituted C1-C6 alkyl, halogen substituted C1-C6 alkoxy; 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.

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: The compounds have structures shown in formula (I-12)-(I-13): Wherein, R1 is hydrogen, methyl or ethyl; R2 is hydrogen or fluorine; R3 is hydrogen, deuterium or fluorine; n is 0 or 1; R6 are each independently selected from: hydrogen, halogen, cyano, C1-C6 alkyl; m is 0, 1, 2, 3, 4 or 5.

5. 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 have structures shown in formula (I-31)-(I-32): Wherein, R1 is hydrogen, methyl or ethyl; R2 is hydrogen or fluorine; R3 is hydrogen, deuterium or fluorine; R6 are each independently selected from: hydrogen, halogen, cyano, C1-C6 alkyl; m is 0, 1, 2, 3, 4 or 5.

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: The compounds have structures shown in formula (I-20)-(I-26): Wherein, R1 is hydrogen, methyl or ethyl; R2 is hydrogen or fluorine; R3 is hydrogen, deuterium or fluorine; R9 are each independently selected from: hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy; p is 0, 1, 2, 3, 4 or 5; A1 is selected from: phenyl, pyridyl, substituted or unsubstituted C3-C10 cycloalkyl, 4-6 membered heterocyclyl, C1-C6 alkyl; the aforementioned phenyl, pyridyl, substituted or unsubstituted C3-C10 cycloalkyl, 4-6 membered heterocyclyl, C1-C6 alkyl is 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.

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: Selected from: Selected from:

8. 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:

9. 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 1A and compound 1B undergo nucleophilic substitution reaction to obtain compound 1C; Step 1-2: Compound 1C and compound 1D undergo nucleophilic substitution reaction to obtain compound 1E; Step 1-3: Compound 1E is hydrolyzed with alkaline to obtain compound 1F; Step 1-4: Compound 1F and 1G are subjected to condensation reaction to obtain compound 1H; Step 1-5: Compound 1H reacts with tetrahydroxydiboron and sodium hydroxide to obtain compound 1I Step 1-6: Compound 1I is subjected to p-toluenesulfonic acid reflux reaction to obtain compound 1J; R5 is the same as defined in claim 2; Synthesis method 2: Step 2-1: Compound 2A reacts with compound 2B in the presence of N,N'-carbonyldiimidazole and triethylamine to obtain compound 2C; Step 2-2: Compound 2A and compound 2D are reacted in the presence of HATU and N,N-diisopropylethylamine to obtain compound 2E; R2, R3, R6, and m are the same as those defined in claim 4; Synthesis method three: Step 3-1: Compound 3A and R8-NH2 undergo condensation reaction to obtain compound 3B; Step 3-2: Compound 3B is hydrolyzed in the presence of lithium hydroxide to obtain compound 3C; Step 3-3: Compound 3C and 1G are subjected to condensation reaction to obtain compound 3D; Step 3-4: Compound 3D reacts with tetrahydroxydiboron and sodium hydroxide to obtain compound 3E; Step 3-5: Compound 3E is subjected to p-toluenesulfonic acid reflux reaction to obtain compound 3F; R8-NH2 is selected from: R9 has the same meaning as defined in claim 6.

10. A pharmaceutical composition comprising a therapeutically effective dose of the compound of claim 1, its tautomers, enantiomers, diastereomers, racemates, isotopic compounds, pharmaceutically acceptable salts, esters, prodrugs or hydrates thereof and other pharmaceutically acceptable carriers.

11. The pharmaceutical composition according to claim 10, further comprising one or more selected from the group consisting of 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.

12. 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.

13. The use according to claim 12, wherein The diseases associated with CRL4 CRBN E3 ubiquitin ligase are cancer, pain, central nervous system diseases and immune system diseases.

14. The use according to claim 11, wherein The disease is a hematological tumor or a solid tumor.

15. The use according to claim 14, wherein The disease is 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, monocytic and monocytic leukemia, acute myeloid leukemia, central nervous system disease, Systemic 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, extraocular extension of melanoma, papillary and follicular thyroid cancer, breast cancer, prostate cancer, hepatocellular carcinoma or primary macroglobulinemia, large cell lymphoma, myeloid leukemia, brain tumor, thyroid cancer.

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