Multivalent molecular glue compound, and preparation method therefor and use thereof

Abstract

The present invention relates to a multivalent molecular glue compound, and a preparation method therefor and the use thereof. Specifically, the compound of the present invention has a structure as represented by formula I, wherein the definition of each group and substituent is as described in the description. Further disclosed in the present invention are a method for preparing the compound and the use thereof in the prevention and / or treatment of cancers.

Description

Multivalent molecular glue compounds, preparation and use thereof TECHNICAL FIELD

[0001] The present application relates to the field of medicine, in particular to multivalent molecular glue compounds, preparation and use thereof. BACKGROUND

[0002] Molecular glues are a class of monovalent small molecules that can change the surface structure of E3 ligases, thereby promoting new protein-protein interactions. Compared with PROTAC, molecular glues are more easily absorbed by cells due to their smaller molecular weight, and can work at lower doses. Unlike the way that targeted PROTAC uses flexible linkers to connect two ligands and allows them to twist and turn to form contact points, molecular glue degraders induce an increase in affinity between them by more directly intervening in the protein interface, strengthening the complex formation between E3 ligases and target proteins, ultimately leading to ubiquitination and degradation of target proteins.

[0003] The most widely known molecular glue degraders are thalidomide and its analogues pomalidomide, which are approved immunomodulatory drugs. They can bind to the substrate receptor protein CRBN in CRL4 CRBN E3 ubiquitin ligase, change the properties of the substrate proteins targeted by CRBN, and allow CRL4 CRBN E3 ubiquitin ligase to connect with new substrate proteins and induce the subsequent degradation of the protein. Lenalidomide is the most therapeutically and commercially valuable antitumor small molecule drug in the world, with sales exceeding $6 billion in 2023.

[0004] However, there are many challenges in developing innovative molecular glue degraders. Since the binding pocket of molecular glue is located between the dynamic structures of two molecules, there is no natural pocket for molecular glue to bind compared to traditional drug development and design. Most molecular glue drugs are accidental discoveries, and there is no rational or systematic method to design and develop them. Therefore, it is a great challenge to develop new molecular glue drugs, and an innovative method is needed to break the status quo of accidental discovery of molecular glue drugs. SUMMARY

[0005] The purpose of the present application is to provide a compound of formula I and a preparation method thereof and the use thereof in the prevention and / or treatment of cancer.

[0006] In a first aspect of the present application, a compound of formula I, or an enantiomer, diastereomer thereof, or a pharmaceutically acceptable salt thereof is provided,

[0007] wherein,

[0008] Y is a linking group for connecting m Z;

[0009] Z is -X2-X3-X4, -X3-X4is an E3 ubiquitin ligase binding ligand, X2is used to link Y and -X3-X4;

[0010] m is selected from the group consisting of 2, 3, 4, 5.

[0011] In another preferred embodiment, m is selected from the group consisting of 2, 3, 4.

[0012] In another preferred embodiment, m is 2 or 3.

[0013] In another preferred embodiment, m is 2.

[0014] In another preferred embodiment, the compound is a molecular glue.

[0015] In another preferred embodiment, the compound is a compound of Formula II,

[0016] Z1-Y1-Z2 Formula II

[0017] wherein,

[0018] Y1is

[0019] X1is selected from the group consisting of -CR1R2-, -(C=0)-, O, S, NH;

[0020] R1, R2are each independently selected from the group consisting of H, D, halogen, hydroxyl, C1-C6alkyl, C1-C6alkoxy, halogenated C1-C6alkyl, halogenated C1-C6alkoxy, hydroxyl substituted C1-C6alkyl, hydroxyl substituted C1-C6alkoxy;

[0021] n1, n2are each independently selected from the group consisting of 0, 1, 2, 3, 4;

[0022] R 11 , R 12 are each independently selected from the group consisting of H, D, halogen, C1-C6alkyl, C1-C6alkoxy, halogenated C1-C6alkyl, halogenated C1-C6alkoxy;

[0023] Z1and Z2are the same or different, each independently -X2-X3-X4;

[0024] each X2is the same or different, each independently selected from the group consisting of: -NR3-(C=0)-, -(C=0)-NR3-, -CR4R5-O-, -O-CR4R5-;

[0025] each X3is the same or different, each being independently selected from the group consisting of -CR4R5-O-, null, -O-CR4R5-,

[0026] each X4is the same or different, each being independently selected from the group consisting of:

[0027] each X5, X6is independently selected from the group consisting of N, -CR3-;

[0028] each R3, R4, R5is independently selected from the group consisting of H, D, Ci-C6alkyl, haloCi-C6alkyl.

[0029] In another preferred embodiment, Y1is selected from the group consisting of:

[0030] X1, n1, n2, R 11 , R 12 as defined above.

[0031] In another preferred embodiment, X1is selected from the group consisting of -CR1R2-, -(C=0)-, O, S, NH.

[0032] In another preferred embodiment, R1, R2are each independently selected from the group consisting of H, D, halogen, hydroxyl, Ci-C6alkyl, Ci-C6alkoxy, haloCi-C6alkyl, haloCi-C6alkoxy, hydroxyl substituted Ci-C6alkyl, hydroxyl substituted Ci-C6alkoxy.

[0033] In another preferred embodiment, n1, n2are each independently selected from the group consisting of 0, 1, 2, 3, 4.

[0034] In another preferred embodiment, R 11 , R 12 are each independently selected from the group consisting of H, D, halogen, Ci-C6alkyl, Ci-C6alkoxy, haloCi-C6alkyl, haloCi-C6alkoxy.

[0035] In another preferred embodiment, X1is -CR1R2-;

[0036] R1, R2are each independently selected from the group consisting of H, D, halogen, hydroxyl, Ci-C6alkyl, haloCi-C6alkyl.

[0037] In another preferred embodiment, Z1and Z2are the same and are -X2-X3-X4.

[0038] In another preferred embodiment, X2is selected from the group consisting of: In another preferred embodiment, X2is selected from the group consisting of:

[0039] In another preferred embodiment, X3is selected from the group consisting of -CR4R5-O-, -O-CR4R5-.

[0040] In another preferred embodiment, X4is selected from the group consisting of:

[0041] In another preferred embodiment, each R3, R4, R5is independently selected from the group consisting of H, D, C1-C6alkyl, haloC1-C6alkyl.

[0042] In another preferred embodiment, the compound is a compound of Formula III,

[0043] wherein,

[0044] Y2is

[0045] X7is selected from the group consisting of CR6, N;

[0046] R6is selected from the group consisting of H, D, halogen, hydroxyl, C1-C6alkyl, C1-C6alkoxy, haloC1-C6alkyl, haloC1-C6alkoxy, hydroxyl substituted C1-C6alkyl, hydroxyl substituted C1-C6alkoxy;

[0047] R 21 , R 22 , R 23 are each independently selected from the group consisting of H, D, halogen, C1-C6alkyl, C1-C6alkoxy, haloC1-C6alkyl, haloC1-C6alkoxy;

[0048] n3, n4, n5are each independently selected from the group consisting of 0, 1, 2, 3, 4;

[0049] Z3, Z4and Z5are the same or different, each independently -X2-X3-X4;

[0050] each X2is the same or different, each independently selected from the group consisting of: -NR3-(C=O)-, -(C=O)-NR3-, -CR4R5-O-, -O-CR4R5-;

[0051] each X3is the same or different, each independently selected from the group consisting of -CR4R5-O-, none, -O-CR4R5-,

[0052] each X4is the same or different, each independently selected from the group consisting of:

[0053] each X5, X6is independently selected from the group consisting of N, -CR3-;

[0054] each R3, R4, R5is independently selected from the group consisting of H, D, C1-C6alkyl, haloC1-C6alkyl.

[0055] In another preferred embodiment, Y2is selected from the group consisting of:

[0056] X7, R 21 , R 22 , R 23 , n3, n4, n5are as defined above.

[0057] In another preferred embodiment, X7is selected from the group consisting of CR6, N.

[0058] In another preferred embodiment, X7is CR6.

[0059] In another preferred embodiment, R6is selected from the group consisting of H, D, halogen, hydroxyl, C1-C6alkyl, C1-C6alkoxy, haloC1-C6alkyl, haloC1-C6alkoxy, hydroxyl substituted C1-C6alkyl, hydroxyl substituted C1-C6alkoxy.

[0060] In another preferred embodiment, R6is selected from the group consisting of H, D, halogen, hydroxyl, C1-C6alkyl, C1-C6alkoxy.

[0061] In another preferred embodiment, R 21 , R 22 , R 23 is each independently selected from the group consisting of H, D, halogen, C1-C6alkyl, C1-C6alkoxy, haloC1-C6alkyl, haloC1-C6alkoxy.

[0062] In another preferred embodiment, n3, n4, n5are each independently selected from the group consisting of 0, 1, 2, 3, 4.

[0063] In another preferred embodiment, the compound is selected from the group consisting of:

[0064] In a second aspect of the present application, a method for preparing a compound according to the first aspect of the present application is provided, said method is selected from the group consisting of Method I, Method II, Method III;

[0065] Method I comprises the steps of:

[0066] 1) reacting N3-Y1-N3with in the presence of a base to give

[0067] wherein Y1, X3, X4are as defined above;

[0068] Method two comprises the steps of:

[0069] 1) reacting H2N-Y1-NH2with to give

[0070] wherein Y1, X3, X4are as defined above;

[0071] Method three comprises the steps of:

[0072] 1) reacting H2N-Y1— N3with to give

[0073] 2) converting to

[0074] 3) reacting with to give

[0075] wherein Y1is as defined above;

[0076] X 31 and X 32 are the same or different, each independently selected from the group consisting of -CR4R5-O-, null, -O-CR4R5-,

[0077] each X5, X6is independently selected from the group consisting of N, -CR3-;

[0078] each R3, R4, R5is each independently selected from the group consisting of H, D, C1-C6alkyl, haloC1-C6alkyl;

[0079] X 41 and X 42 are the same or different, each independently selected from the group consisting of:

[0080] In a third aspect of the present application, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a safe and effective amount of a compound according to the first aspect of the present application.

[0081] In a fourth aspect, the present application provides the use of a compound according to the first aspect of the present application for the preparation of a medicament for the prevention and / or treatment of a disease selected from the group consisting of cancer, autoimmune disease, inflammatory disease.

[0082] In another preferred embodiment, the cancer is selected from the group consisting of leukemia, lymphoma, breast cancer, lung cancer, prostate cancer, melanoma.

[0083] In another preferred embodiment, the autoimmune disease is selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, psoriasis, multiple sclerosis.

[0084] In another preferred embodiment, the inflammatory disease is selected from the group consisting of Crohn's disease, ulcerative colitis, rheumatoid arthritis, asthma.

[0085] In another preferred embodiment, the leukemia is selected from the group consisting of myeloid leukemia, lymphocytic leukemia, hairy cell leukemia.

[0086] It should be understood that, within the scope of the present application, each of the technical features described above and each of the technical features described in detail hereinafter (e.g., in the examples) can be combined with each other to form a new or preferred technical solution. Due to the limited space, they will not be listed one by one here. DETAILED DESCRIPTION

[0087] The present inventors have made, through long-term and in-depth research, a molecular glue compound containing multiple E3 ubiquitin ligase binding ligands, which has a novel structure and excellent protein degradation performance, and has great significance for the systematic and successful development of molecular glue compounds. On this basis, the present inventors completed the present application.

[0088] TERMS

[0089] In the present application, the terms used have the general meanings known to those skilled in the art, unless otherwise specified.

[0090] In the present application, the term "halogen" refers to F, Cl, Br or I.

[0091] In the present application, "C1-C6 alkyl" refers to a straight-chain or branched alkyl group comprising 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, tert-pentyl, or the like.

[0092] In the present application, the term "C2-C6 alkenyl" refers to a straight-chain or branched alkenyl group having 2-6 carbon atoms containing one double bond, including, without limitation, ethenyl, propenyl, butenyl, isobutenyl, pentenyl, and hexenyl, etc.

[0093] In the present application, the term "C2-C6alkynyl" refers to a straight or branched chain alkynyl group having 2-6 carbon atoms containing one triple bond, including without limitation ethynyl, propynyl, butynyl, isobutynyl, pentynyl, and hexynyl groups.

[0094] In the present application, the term "C3-C8cycloalkyl" refers to a cyclic alkyl group having 3-8 carbon atoms in the ring, including without limitation cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl groups, and the like.

[0095] In the present application, the term "C1-C6alkoxy" refers to a straight or branched chain alkoxy group having 1-6 carbon atoms, including without limitation methoxy, ethoxy, propoxy, isopropoxy, and butoxy groups, and the like. Preferably, C1-C4alkoxy.

[0096] In the present application, the term "heterocyclyl" refers to a 4-8 membered heterocyclic group containing 1, 2, or 3 heteroatoms selected from N, O, S, including without limitation the following groups:

[0097] In the present application, the terms "aromatic ring" or "aryl" have the same meaning, and preferably "C6-C10aryl". The term "C6-C10aryl" refers to an aromatic ring group having 6-10 carbon atoms in the ring, containing no heteroatoms, such as phenyl, naphthyl, and the like.

[0098] In the present application, the terms "aromatic heterocycle" or "heteroaryl" have the same meaning, and refer to a heteroaromatic group containing one to several heteroatoms. For example, "C3-C10heteroaryl" refers to an aromatic heterocycle containing 1-4 heteroatoms selected from oxygen, sulfur, and nitrogen, and 3-10 carbon atoms. Non-limiting examples include furanyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl ring can be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring that is attached to the parent structure is the heteroaryl ring. The heteroaryl group can be optionally substituted or unsubstituted.

[0099] In the present application, the term "halo" refers to substitution by a halogen.

[0100] In the present application, the term "deutero" refers to substitution by deuterium.

[0101] In the present application, the term "substituted" means that one or more hydrogen atoms on a specified group are replaced with a specified substituent. The specified substituent is a substituent described in the foregoing, or a substituent appearing in each embodiment. Unless otherwise specified, a substituted group can have one substituent selected from a specified group at any substitutable position of the group, which can be the same or different at each position. It will be understood by those skilled in the art that combinations of substituents contemplated by the present application are those combinations that are stable or chemically feasible. The substituents are, for example, but not limited to, halogen, hydroxy, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, aryl, heteroaryl, C1-C8 aldehyde, C2-C10 acyl, C2-C10 ester, amino, C1-C6 alkoxy, C1-C10 sulfonyl, and the like.

[0102] In the present application, the term 1-6 means 1, 2, 3, 4, 5, or 6. Other similar terms each independently have a similar meaning. The term "a plurality" means 2-6, such as 2, 3, 4, 5, or 6.

[0103] It will be understood that when a group is present simultaneously at a plurality of different positions of a compound, the definition thereof at each position is independent of one another, and can be the same or different. That is, the term "selected from the group consisting of" has the same meaning as the term "each independently selected from the group consisting of".

[0104] Compound

[0105] Based on the triazole compound library constructed by the modular click compound library, a series of molecular glue-like compounds are screened. The present application provides a plurality of valent molecular glue-like compounds as potential molecular glue drug candidates.

[0106] Specifically, the present application provides a compound of Formula I, or an enantiomer, diastereomer thereof, or a pharmaceutically acceptable salt thereof,

[0107] wherein,

[0108] Y is a linker group for linking m Zs;

[0109] Z is -X2-X3-X4, -X3-X4 is an E3 ubiquitin ligase binding ligand, and X2 is for linking Y and -X3-X4;

[0110] m is selected from the group consisting of 2, 3, 4, 5.

[0111] More specifically, the present application provides a compound of Formula II, or an enantiomer, diastereomer thereof, or a pharmaceutically acceptable salt thereof,

[0112] Z1-Y1-Z2 Formula II

[0113] wherein,

[0114] Y1is

[0115] Z1and Z2are the same or different, each independently -X2-X3-X4.

[0116] In another preferred embodiment, the compound is one wherein any one of X1, n1, n2, R 11 , R 12 , X2, X3, X4is independently the corresponding group in a specific compound described herein.

[0117] In the present application, Y is a linker group for linking multiple E3 ubiquitin ligase binding ligands. Unlike the prior art monovalent molecular glue, the present compound is a multivalent molecular glue, which contains multiple E3 ubiquitin ligase binding ligands in one molecule. Therefore, the structure of the present compound is very novel and completely different from the prior art molecular glue compounds.

[0118] In addition, the multivalent molecular glue compound of the present application has excellent protein degradation performance, which is even significantly better than the prior art monovalent molecular glue compound, which is very unexpected.

[0119] The structure of the multivalent molecular glue compound in the present application is obviously different from the prior art molecular glue drugs. Compared with the conventional molecular glue drugs discovered by chance, the multivalent binding sites used in the present application can enhance the interaction with target molecules, which may involve different targeting selectivity and action mechanisms. If it can multivalently bind to multiple targets or more efficiently act on a single target, it will undoubtedly enhance the efficacy or reduce side effects.

[0120] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the present application formed with an acid or a base suitable for use as a medicament. The pharmaceutically acceptable salt includes inorganic salts and organic salts. One preferred salt is a salt of a compound of the present application formed with an acid. Suitable acids for salt formation include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, and the like; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, and the like; and amino acids such as proline, phenylalanine, aspartic acid, glutamic acid, and the like.

[0121] Another preferred salt is a salt of a compound of the present application with a base, for example, an alkali metal salt (for example, a sodium or potassium salt), an alkaline earth metal salt (for example, a magnesium or calcium salt), an ammonium salt (for example, a lower alkylammonium salt and other pharmaceutically acceptable amine salts), for example, a methylamine salt, an ethylamine salt, a propylamine salt, a dimethylamine salt, a trimethylamine salt, a diethylamine salt, a triethylamine salt, a t-butylamine salt, an ethylenediamine salt, a hydroxyethylamine salt, a dihydroxyethylamine salt, a trihydroxyethylamine salt, and an amine salt formed by morpholine, piperazine, lysine, respectively.

[0122] The present application provides a method for preparing the compound of formula I. The preparation method of the compound of the present application is described in detail in the following specific examples, but these specific methods do not constitute any limitation to the present application. The compound of the present application can also be conveniently prepared by combining various synthetic methods described in the present specification or known in the art, and such combination can be easily performed by those skilled in the art to which the present application belongs.

[0123] Typically, the starting materials and reagents used in the process flow for preparing the compound of the present application can be purchased through commercial channels, unless otherwise specified.

[0124] Pharmaceutical composition and administration method

[0125] The present application also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a safe and effective amount of the compound of the present application.

[0126] Since the compound of the present application has excellent anti-tumor activity, the compound of the present application and its various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compound of the present application as the main active ingredient can be used for treating, preventing, and alleviating diseases related to tumors.

[0127] The pharmaceutical composition of the present application comprises a safe and effective amount of the compound of the present application or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier. Among them, "a safe and effective amount" means that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Generally, the pharmaceutical composition contains 1-2000 mg of the compound of the present application per dose, more preferably 10-1000 mg of the compound of the present application per dose. Preferably, the "one dose" is one capsule or tablet.

[0128] "Pharmaceutically acceptable carriers" refers to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0129] The pharmaceutical composition is an injection, capsule, tablet, pill, powder, or granule.

[0130] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local administration.

[0131] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0132] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0133] Liquid dosage forms for oral administration include pharmaceutically- acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, dimethylformamide, and the like, or combinations thereof.

[0134] Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0135] Suspensions, in addition to the active compounds, can contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, sodium carbomate, and / or combinations thereof.

[0136] Compositions for parenteral injection can contain physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyol, and suitable mixtures thereof.

[0137] Dosage forms of the compounds of the present application for topical administration include ointments, powders, sprays, and inhalers. The active compound is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as can be required.

[0138] The compounds of the present application can be administered alone or in combination with other pharmaceutically acceptable compounds, such as anti-tumor drugs.

[0139] The therapeutic methods of the present application can be administered alone or in conjunction with other therapeutic procedures or therapeutic agents.

[0140] The pharmaceutical compositions are administered in a therapeutically effective amount to a mammal, such as a human, in need of such treatment. The dose administered to a patient, depending on the subject to be treated, size, and health, the nature of the condition to be treated, and the method of administration, can range from 1 to 2000 mg, preferably 50 to 1000 mg, per day. However, other dosage regimens can be useful. The particular dosage regimen, e.g., size and frequency of dose, and the route of administration, depends on the particular compounds used, the purposes of the dosing regimen, and the condition of the subject to be treated. The skilled practitioner can empirically determine optimum dosages.

[0141] Compared with the prior art, the present application has the following main advantages:

[0142] (1) The present application provides a multivalent molecular glue compound for the first time, which has a very novel structure;

[0143] (2) The multivalent molecular glue compound has excellent degradation performance;

[0144] (3) Compared with monovalent molecular glue, multivalent molecular glue can bind to target molecules or multiple targets through multiple binding sites at the same time, greatly enhancing the affinity to the target. This multi-point binding can significantly reduce the dissociation rate, improve the persistence and efficacy of the drug.

[0145] (4) Through multivalent action, multivalent molecular glue can simultaneously regulate multiple biological pathways or targets, producing a synergistic therapeutic effect. This synergistic effect helps to improve the overall efficacy, especially in the treatment of complex diseases (such as cancer or multiple drug-resistant infections); and due to the enhanced binding force and synergistic effect of multivalent molecular glue, the effective dose required may be lower than that of traditional molecular glue, which can reduce drug toxicity and reduce the treatment burden on patients.

[0146] (5) Multivalent molecular glue, by binding to multiple targets, reduces the risk of single target variation leading to drug resistance. Cells or pathogens are more difficult to escape immune surveillance or drug attack through single gene mutation.

[0147] (6) Multivalent molecular glue, through stable multi-point binding, can prolong its half-life in the body, reduce metabolic degradation, and increase the effective concentration and duration of the drug in the body.

[0148] The present application will be further described in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present application and not to limit the scope of the present application. The experimental methods in the following examples, if not specified, are generally carried out according to the conventional conditions, such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are calculated by weight.

[0149] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as understood by one of ordinary skill in the art. In addition, any method and material similar or equivalent to those described herein can be used in the present application. The preferred methods and materials described herein are only for demonstration.

[0150] Example 1

[0151] Synthesis of Compound 1

[0152] 5,5'-((((methylenebis(3,1-phenylene))bis(1H-1,2,3-triazole-1,4-diyl))bis(methylene))bis(oxy))bis(2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione)

[0153] Into a 50 mL round bottom flask with a magnetic bar, 3,3'-diaminodiphenylmethane (198 mg, 1 mmol, 1 equiv), KHCO3(2.6 mL, 8.0 mmol, 8.0 equiv, 3.0 M aqueous solution) and DMF (6 mL) were added sequentially, after stirring well, FSO2N3(5.0 mL, 2.0 mmol, 2.0 equiv, 0.4 M in MTBE) was added slowly, after 6 hours of reaction, the reaction was detected by LC-MS to be complete. Then 50 mL of ethyl acetate and 50 mL of water were added respectively, and the extraction was separated three times, the organic phase was saturated with brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain a brown oily liquid, which was then purified by column chromatography (eluent: petroleum ether to petroleum ether: dichloromethane = 10:1), and finally a brown oily liquid was obtained, which was directly used for subsequent click.

[0154] Subsequently, the above azide was added to the alkyne precursor 2-(2,6-dioxopiperidin-3-yl)-5-(prop-2-yn-1-yloxy)isoindoline-1,3-dione (624 mg, 2.0 mmol, 2.0 equiv), cuprous bromide (150 mg, 1.0 mmol, 1.0 equiv) and DMF (10 mL), after heating at 60°C for 6 hours, the azide was completely converted by LC-MS monitoring, 500 mL of water was added to the system, and obvious insoluble solid was precipitated, which was separated by filtration to obtain a light green solid. Then reverse phase separation and purification were carried out, the separation system was water (0.1% TFA): acetonitrile, and the separation gradient was water (0.1% TFA): acetonitrile = 95%:5% to acetonitrile 100%, and the separation column type was SW0120, spherical C18, 20-45 μm, Finally, white solid 384 mg was obtained by reduced pressure distillation, with a yield of 44%.

[0155] 1H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 2H), 8.98 (s, 2H), 7.91 (s, 2H), 7.87 (d, J = 8.3 Hz, 2H), 7.75 (d, J = 8.9 Hz, 2H), 7.64 (d, J = 2.2 Hz, 2H), 7.54 (t, J = 7.8 Hz, 2H), 7.51 - 7.42 (m, 4H), 5.47 (s, 4H), 5.13 (dd, J = 12.9, 5.3 Hz, 2H), 4.18 (s, 2H), 2.96 - 2.82 (m, 2H), 2.65 - 2.50 (m, 7H), 2.10 - 2.00 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 172.8, 169.9, 166.8, 166.7, 163.3, 143.0, 142.8, 136.6, 133.3, 130.1, 129.2, 125.3, 123.4, 123.2, 121.1, 120.5, 118.1, 109.3, 62.0, 49.0, 31.0, 30.7, 22.1.

[0156] Example 2

[0157] Synthesis of Compound 2

[0158] 5,5'-(((methylenebis(2-chloro-4,1-phenylene))bis(1H-1,2,3-triazole-1,4-diyl))bis(methylene))bis(oxy))bis(2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione)

[0159] In accordance with the procedure for Example 1 - Synthesis of Compound 1

[0160] 1 H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 2H), 8.98 (s, 2H), 7.91 (s, 2H), 7.87 (d, J = 8.3 Hz, 2H), 7.75 (d, J = 8.9 Hz, 2H), 7.64 (d, J = 2.2 Hz, 2H), 7.54 (t, J = 7.8 Hz, 2H), 7.51 - 7.42 (m, 4H), 5.47 (s, 4H), 5.13 (dd, J = 12.9, 5.3 Hz, 2H), 4.18 (s, 2H), 2.96 - 2.82 (m, 2H), 2.65 - 2.50 (m, 7H), 2.10 - 2.00 (m, 2H). 13C NMR (176 MHz, DMSO-d6) δ 172.8, 169.9, 166.8, 166.7, 163.3, 144.5, 141.9, 133.9, 132.7, 130.5, 128.8, 128.6, 128.5, 127.2, 125.3, 123.4, 121.1, 109.3, 61.8, 48.9, 30.9, 22.1, 22.0. HRMS (ESI) m / z: calcd for C 45 H 31 N 10 O 10 Cl2 + : 941.1602 [M+H] + , found: 941.1578.

[0161] Example 3

[0162] Synthesis of Compound 3

[0163] 5,5'-(((oxybis(3-(trifluoromethyl)-4,1-phenylene))bis(1H-1,2,3-triazole-1,4-diyl))bis(methylene))bis(oxy))bis(2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione)

[0164] In accordance with the synthesis of Example 1 - Step one of Compound 1

[0165] 1 H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 2H), 9.17 (s, 2H), 8.40 (d, J = 2.6 Hz, 2H), 8.28 (dd, J = 9.0, 2.7 Hz, 2H), 7.88 (d, J = 8.3 Hz, 2H), 7.65 (d, J = 2.3 Hz, 2H), 7.53 - 7.45 (m, 4H), 5.51 (s, 4H), 5.13 (dd, J = 13.0, 5.3 Hz, 2H), 2.90 (ddd, J = 17.7, 14.2, 5.5 Hz, 2H), 2.65 - 2.52 (m, 4H), 2.08 - 2.03 (m, 2H). 19 F NMR (377 MHz, DMSO-d6) δ -60.90 (s, 6H). 13C NMR (176 MHz, DMSO-d6) δ 172.7, 169.8, 166.7, 166.7, 163.2, 152.7, 143.2, 133.9, 132.7, 126.5, 125.3, 123.7, 123.5, 122.5 (q, J = 272.8 Hz), 121.2, 121.1, 121.1 (q, J = 32.2 Hz), 119.7, 61.9, 48.9, 30.9, 22.0. HRMS (ESI) m / z: calcd for C 46 H 29 N 10 O 11 F6 + :1011.1921[M+H] + , found:1011.1899.

[0166] Example 4

[0167] Synthesis of Compound 4

[0168] 5,5'-((((thiobis(2,1-phenylene))bis(1H-1,2,3-triazole-1,4-diyl))bis(methylene))bis(oxy))bis(2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione)

[0169] In accordance with the procedure for Example 1 - Step one for the synthesis of Compound 1

[0170] 1 H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 2H), 8.86 (s, 2H), 7.88 (d, J = 8.3 Hz, 2H), 7.68 (d, J = 2.3 Hz, 2H), 7.52 (ddd, J = 8.6, 6.5, 1.9 Hz, 4H), 7.43 (td, J = 7.7, 1.6 Hz, 2H), 7.35 (td, J = 7.6, 1.4 Hz, 2H), 7.27 - 7.19 (m, 4H), 6.82 (td, J = 8.4, 1.4 Hz, 4H), 6.60 (td, J = 7.5, 1.3 Hz, 2H), 5.52 (s, 4H), 5.14 - 5.10 (m, 2H), 2.89 (ddd, J = 17.0, 13.8, 5.4 Hz, 2H), 2.62 - 2.54 (m, 4H), 2.08 - 2.00 (m, 2H). 13C NMR (176 MHz, DMSO-d6) δ 172.8, 169.9, 166.8, 166.7, 163.3, 150., 141.93, 137.3, 134.0, 133.9, 133.8, 131.7, 130.4, 127.0, 126.5, 126.0, 125.3, 123.4, 121.2, 117.0, 115.1, 109.4, 109.3, 62.0, 48.9, 30.9, 22.1, 22.0. HRMS (ESI) m / z: calcd for C 44 H 32 N 10 O 10 NaS + :915.1921[M+Na] + ,found:915.1942.

[0171] Example 5

[0172] Synthesis of compound 5

[0173] 3,3'-(((methylenebis(3,1-phenylene))bis(1H-1,2,3-triazole-1,4-diyl))bis(1- oxoisoindoline-5,2-diyl))bis(piperidine-2,6-dione)

[0174] In accordance with the synthesis of Example 1 - Step one of compound 1

[0175] 1 H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 2H), 9.45 (s, 2H), 8.19 (s, 2H), 8.09 (d, J = 7.9 Hz, 2H), 7.98 (d, J = 2.0 Hz, 2H), 7.88 - 7.79 (m, 4H), 7.61 (t, J = 7.8 Hz, 2H), 7.50 (d, J = 7.7 Hz, 2H), 5.14 (dd, J = 13.2, 5.1 Hz, 2H), 4.61 - 4.38 (m, 4H), 4.25 (s, 2H), 2.93 (ddd, J = 17.8, 13.9, 5.4 Hz, 3H), 2.64 - 2.59 (m, 3H), 2.45 - 2.37 (m, 3H), 2.05 - 1.97 (m, 4H). HRMS (ESI) m / z: calcd for C 43 H 35 N 10 O6 + :787.2736[M+H] + ,found:787.2731.

[0176] Example 6

[0177] Synthesis of compound 6

[0178] 5,5'-(((methylenebis(3,1-phenylene))bis(1H-1,2,3-triazole-1,4-diyl))bis(methylene))bis(piperazine-4,1-diyl))bis(2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione)

[0179] In accordance with the synthesis of Example 1 - Step one of compound 1

[0180] 1 H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 2H), 8.91 (s, 2H), 7.90 (t, J = 1.9 Hz, 2H), 7.76 (dd, J = 9.2, 2.8 Hz, 4H), 7.58 (t, J = 7.9 Hz, 2H), 7.5 - 7.42 (m, 4H), 7.33 (dd, J = 8.6, 2.3 Hz, 2H), 5.09 (dd, J = 12.9, 5.3 Hz, 2H), 4.22 (s, 2H), 3.68 - 3.34 (m, 16H), 2.89 (ddd, J = 17.6, 14.1, 5.5 Hz, 2H), 2.63 - 2.51 (m, 4H), 2.05 - 1.98 (m, 2H). 13 C NMR (176 MHz, DMSO-d6) δ 172.8, 170.0, 167.4, 166.9, 154.2, 142.9, 136.5, 133.8, 130.2, 129.5, 125.0, 120.6, 118.7, 118.3, 108.9, 50.2, 48.8, 44.5, 40.3, 30.9, 22.1, 22.1. HRMS (ESI) m / z: calcd for C 53 H 51 N 14 O8 + : 1011.4009 [M+H] + , found: 1011.4018.

[0181] Example 7

[0182] Synthesis of compound 7

[0183] 4,4'-(((methylenebis(3,1-phenylene))bis(1h-1,2,3-triazole-1,4-diyl))bis(methylene))bis(oxy))bis(2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione)

[0184] In accordance with the synthesis procedure of Example 1 - Compound 1

[0185] 1 H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 2H), 8.96 (s, 2H), 7.91 (s, 2H), 7.85 (t, J = 7.9 Hz, 2H), 7.75 (dd, J = 8.7, 6.0 Hz, 4H), 7.59 - 7.41 (m, 6H), 5.51 (s, 4H), 5.08 (dd, J = 12.7, 5.5 Hz, 2H), 4.18 (s, 2H), 2.88 (ddd, J = 17.6, 13.6, 5.4 Hz, 2H), 2.64 - 2.51 (m, 4H), 2.04 - 1.98 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 172.8, 169.9, 166.7, 165.2, 155.1, 143.0, 142.8, 137.0, 136.6, 133.3, 130.1, 129.30, 123.3, 120.5, 120.3, 118.1, 116.6, 115.8, 62.0, 48.8, 30.9, 21.9. HRMS (ESI) m / z: calcd for C 45 H 35 N 10 O 10 + : 875.2532 [M+H] + , found: 875.2527.

[0186] Example 8

[0187] Synthesis of Compound 8

[0188] 5,5'-((((methylenebis(3,1-phenylene))bis(1h-1,2,3-triazole-1,4-diyl))bis(methylene))bis(oxy)ethyl))bis(2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione)

[0189] In accordance with the synthesis procedure of Example 1 - Compound 1

[0190] 1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 2H), 8.93 (s, 2H), 7.87 (d, J = 1.9 Hz, 2H), 7.82 (d, J = 8.3 Hz, 2H), 7.72 (dt, J = 8.1, 1.5 Hz, 2H), 7.59 (d, J = 2.3 Hz, 2H), 7.51 (t, J = 7.9 Hz, 2H), 7.46 - 7.38 (m, 4H), 6.06 (q, J = 6.4 Hz, 2H), 5.10 (dd, J = 12.8, 5.4 Hz, 2H), 4.15 (s, 2H), 2.88 (ddd, J = 18.2, 13.6, 5.4 Hz, 2H), 2.63 - 2.51 (m, 4H), 2.08 - 2.01 (m, 2H), 1.75 (d, J = 6.4 Hz, 6H). 13 C NMR (101 MHz, DMSO-d6) δ 172.7, 169.9, 166.8, 166.7, 162.6, 148.4, 142.7, 136.6, 133.8, 130.0, 129.1, 125.3, 123.3, 121.8, 121.3, 120.4, 118.0, 110.0, 69.5, 69.1, 48., 30.9, 30.6, 22.0, 20.7. HRMS (ESI) m / z: calcd for C 47 H 39 N 10 O 10 + : 903.2845 [M+H] + , found: 903.2840.

[0191] Example 9

[0192] Synthesis of compound 9

[0193] 5,5'-((((carbonylbis(3,1-phenylene))bis(1H-1,2,3-triazole-1,4-diyl))bis(methylene))bis(oxy))bis(2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione)

[0194] In accordance with the synthesis of Example 1 - Step one of compound 1

[0195] 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 2H), 9.15 (s, 2H), 8.37 - 8.23 (m, 4H), 7.95 - 7.76 (m, 6H), 7.64 (d, J = 2.3 Hz, 2H), 7.48 (dd, J = 8.4, 2.3 Hz, 2H), 5.49 (s, 4H), 5.13 (dd, J = 12.9, 5.3 Hz, 2H), 2.94 - 2.82 (m, 2H), 2.64 - 2.52 (m, 4H), 2.08 - 2.00 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 193.7, 172.7, 169.9, 166.8, 166.7, 163.2, 143.3, 138.0, 136.6, 133.9, 130.5, 129.9, 125.3, 124.3, 123.5, 121.1, 120.7, 109.3, 62.0, 49.0, 30.9, 22.0. HRMS (ESI) m / z: calcd for C 45 H 33 N 10 O 11 + : 889.2330 [M+H] + , found: 889.2352.

[0196] Example 10

[0197] Synthesis of compound 10

[0198] 5,5'-((oxybis(3,l-phenylene))bis(lH-l,2,3-triazole-l,4-diyl))bis(methylene))bis(oxy))bis(2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione)

[0199] In accordance with the synthesis of Example 1 - Step one of compound 1

[0200] 1 H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 2H), 9.05 (s, 2H), 7.91 - 7.58 (m, 11H), 7.47 (d, J = 8.3 Hz, 2H), 7.23 (d, J = 8.3 Hz, 2H), 5.47 (s, 4H), 5.13 (dd, J = 13.1, 5.3 Hz, 2H), 2.95 - 2.82 (m, 2H), 2.65 - 2.53 (m, 4H), 2.06 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 172.8, 169.9, 166.8, 166.7, 163.2, 157.0, 143.1, 137.8, 133.8, 131.7, 125.3, 123.4, 123.3, 121.0, 118.9, 115.4, 110.7, 109.3, 61.9, 49.0, 30.9, 22.0.

[0201] Example 11

[0202] Synthesis of compound 11

[0203] 5,5'-(((((hydroxymethyl)bis(3,1-phenylene))bis(1H-1,2,3-triazole-1,4-diyl))bis(methylene))bis(oxy))bis(2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione)

[0204] In a 50 mL single-necked flask, A3-1 (212 mg, 1 mmol) was added, 5 mL of tetrahydrofuran was added, and the flask was protected by nitrogen. Then, 1.5 mL of zinc borohydride solution (1.5 equiv, 1 M tetrahydrofuran solution) was slowly added under ice bath conditions. The reaction was slowly restored to room temperature and allowed to proceed overnight. LC-MS detection showed that the reaction was complete. The solution was spin-dried to obtain the crude product A3-2 (about 1 mmol). Then, 5 mL of DMF and 4 mL of potassium bicarbonate aqueous solution (3 M aqueous solution) were added. Then, 6 mL of FSO2N3 solution (0.4 M, 2.4 mmol) was added at room temperature. The reaction was allowed to proceed overnight at room temperature. LC-MS detection showed that the reaction was complete. Water was added, and ethyl acetate was used for extraction. The mixture was dried over anhydrous sodium sulfate and purified by column chromatography to obtain 210 mg of A3-3. The two-step yield was 78.9%.

[0205] In a 50 mL single-necked flask, A3-3 150 mg (0.56 mmol) and 352 mg of B1 (1 mmol) were added. Then, 28 mg of copper sulfate pentahydrate and 894 mg of sodium ascorbate were added. Then, 2 mL of water was added, and the reaction was allowed to proceed overnight at room temperature. LC-MS detection showed that the reaction was complete. The product was purified by column chromatography to obtain 240 mg of product, with a yield of 48%.

[0206] 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 2H), 8.99 (s, 2H), 8.04 (d, J = 2.3 Hz, 2H), 7.90-7.84 (m, 2H), 7.76 (dt, J = 6.6, 2.3 Hz, 2H), 7.64 (d, J = 2.3 Hz, 2H), 7.59-7.55 (m, 4H), 7.48 (dd, J = 8.4, 2.3 Hz, 2H), 5.96 (s, 1H), 5.47 (s, 4H), 5.13 (dd, J = 12.9, 5.3 Hz, 2H), 5.05 (d, J = 2.4 Hz, 1H), 2.92-2.84 (m, 2H), 2.65-2.52 (m, 4H), 2.09 - 2.02 (m, 2H). 13 C NMR (176 MHz, DMSO-d6) δ 172.8, 169.9, 169.9, 166.8, 166.7, 163.3, 147.3, 143.0, 136.4, 133.9, 129.9, 126.7, 125.3, 123.4, 123.3, 121.1, 118.8, 117.9, 109.3, 109.2, 73.1, 62.0, 49.0, 48.9, 31.3, 31.2, 30.9, 22.0.

[0207] Example 12

[0208] Synthesis of compound 12

[0209] 5,5'-(((((methylene-d2)bis(3,1-phenylene))bis(1H-1,2,3-triazole-1,4-diyl))bis(methylene))bis(oxy))bis(2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione)

[0210] In a 50 mL three-necked flask, 212 mg of A1-1, 5 ml of anhydrous ether, 800 mg of aluminum chloride was added under ice bath, 230 mg of lithium tetra-deuteride was slowly added, and the reaction was heated to reflux under nitrogen protection. After 8 hours of reaction, 0.25 mL of deuterium water, 0.25 mL of sodium hydroxide (15% aqueous solution), and 0.25 mL of deuterium water were added. After filtration, ethyl acetate extraction, concentration, and purification by column chromatography, 150 mg of product A1-3 was obtained with a two-step yield of 59.5%.

[0211] In a 50 mL single neck flask was added A1-3 150 mg (0.6 mmol), 371.5 mg B1 (1.15 mmol), 38 mg copper sulfate pentahydrate, 1.2 g sodium ascorbate, 2 mL water, and the reaction was allowed to proceed at room temperature overnight. LC-MS indicated the reaction was complete and the product was purified by column chromatography to give 234 mg of product in 44.9% yield.

[0212] 1 H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 2H), 8.97 (s, 2H), 7.92 (t, J = 1.9 Hz, 2H), 7.87 (d, J = 8.3 Hz, 2H), 7.78 - 7.72 (m, 2H), 7.64 (d, J = 2.3 Hz, 2H), 7.54 (t, J = 7.9 Hz, 2H), 7.47 (td, J = 7.5, 6.6, 1.8 Hz, 4H), 5.47 (s, 4H), 5.13 (dd, J = 12.9, 5.4 Hz, 2H), 2.97 - 2.82 (m, 2H), 2.64 - 2.51 (m, 4H), 2.09 - 2.03 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 172.7, 169.9, 166.8, 166.7, 163.3, 143.0, 142.7, 136.6, 133.9, 130.1, 129.5, 125.5, 123.4, 123.2, 121.1, 120.5, 118.1, 109.3, 62.0, 49.0, 30.9, 22.0. HRMS (ESI) m / z: calcd for C 44 H 33 N 10 O 11 + : 877.2663 [M+H] + , found: 877.2667.

[0213] Example 13

[0214] Synthesis of compound 13

[0215] 5,5'-(((((difluoromethylidene)bis(3,1-phenylene))bis(1H-1,2,3-triazole-1,4-diyl))bis(methylene))bis(oxy))bis(2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione)

[0216] In a 50 mL single neck flask, 272 mg of A2-1 was added, and 660 mg of BAST was added under nitrogen protection, and heated to 90 °C in an ice bath, and reacted overnight. TLC detection showed that the reaction was complete. Silica gel was added, and column chromatography was used for purification to obtain 290 mg of A2-2.

[0217] Then A2-2 was added to a 50 mL single neck flask, 10 mL of acetic acid was added, and 0.5 g of reduced iron powder was added under stirring, and reacted overnight at room temperature. TLC detection showed that the reaction was complete. Filtration and rotary evaporation were performed, and the crude product A2-3 (about 1 mmol) was dissolved in 5 mL of DMF, 4 mL of potassium bicarbonate aqueous solution (3M aqueous solution) was added, 6 mL of FSO2N3 solution (0.4M, 2.4 mmol) was added at room temperature, and reacted overnight at room temperature. Ethyl acetate extraction, water washing, and anhydrous sodium sulfate drying were performed, and column chromatography was used for purification to obtain 160 mg of A2-4, with a two-step yield of 56%.

[0218] In a 50 mL single neck flask, 349 mg of B1 (1.1 mmol), 160 mg of A2-4 (0.55 mmol), 5 mL of DMF, and 80 mg of cuprous bromide were added, and heated to 60 °C, and reacted for 4 h. LC-MS detection showed that the reaction was complete. Concentration and column chromatography were used for purification to obtain 234 mg of product, with a yield of 46%.

[0219] 1 H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 2H), 9.13 (s, 2H), 8.21 (s, 2H), 8.12-8.08 (m, 2H), 7.87 (d, J = 8.3 Hz, 2H), 7.77 (d, J = 4.7 Hz, 4H), 7.64 (d, J = 2.3 Hz, 2H), 7.48 (dd, J = 8.3, 2.3 Hz, 2H), 5.49 (s, 4H), 5.13 (dd, J = 13.0, 5.3 Hz, 2H), 2.89 (ddd, J = 17.3, 14.0, 5.4 Hz, 2H), 2.65-2.51 (m, 4H), 2.10-2.01 (m, 2H). 19 F NMR (377 MHz, DMSO-d6) δ -89.14 (s, 2F). 13 C NMR (101 MHz, DMSO-d6) δ 172.7, 169.9, 166.8, 166.7, 163.2, 143.2, 138.3 (t, J = 29.2 Hz), 136.8, 133.9, 130.9, 125.7, 123.6 (t, J = 214.1 Hz), 123.5, 121.1, 116.9, 109.3, 62.0, 49.0, 30.9, 22.0. HRMS (ESI) m / z: calcd for C45 H 33 N 10 O 10 F2 + :911.2349[M+H] + ,found:911.2371.

[0220] Example 14

[0221] Synthesis of compound 14

[0222] 5,5'-(((((fluoromethylene)bis(3,1-phenylene))bis(1H-1,2,3-triazole-1,4-diyl))bis(methylene))bis(oxy))bis(2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione)

[0223] In a 50 mL single-necked flask, A3-1 (212 mg, 1 mmol) was added, 5 mL of tetrahydrofuran was added, and nitrogen protection was performed. A 1.5 mL solution of boron hydride zinc (1.5 equiv, 1M tetrahydrofuran solution) was slowly added under ice bath conditions, and the reaction was slowly restored to room temperature. The reaction was allowed to proceed overnight, and LC-MS detection showed that the reaction was complete. The solution was spin-dried to obtain the crude product A3-2 (about 1 mmol). 5 mL of DMF and 4 mL of an aqueous potassium bicarbonate solution (3M aqueous solution) were added, and 6 mL of FSO2N3 solution (0.4M, 2.4 mmol) was added at room temperature. The reaction was allowed to proceed overnight at room temperature, and LC-MS detection showed that the reaction was complete. Water was added, and ethyl acetate was extracted. Anhydrous sodium sulfate was used for drying, and column chromatography was used for purification to obtain 210 mg of A3-3. The two-step yield was 78.9%.

[0224] Then, in a 50 mL single-necked flask, 210 mg of A3-3 (0.8 mmol) was added, 5 mL of dichloromethane was added, and 350 mg of BAST was slowly added under ice bath conditions. The reaction was slowly restored to room temperature, and the reaction was allowed to proceed overnight. LC-MS detection showed that the reaction was complete. The solution was spin-dried, and column chromatography was used for purification to obtain 190 mg of A3-5.

[0225] In a 50 mL single-necked flask, 190 mg of A3-5 (0.7 mmol) and 442 mg of B1 (1.4 mmol) were added, 5 mL of DMF was added, and 95 mg of cuprous bromide was added. The reaction was allowed to proceed at 60°C for 2 h. LC-MS detection showed that the reaction was complete. Column chromatography was used for purification to obtain 270 mg of the product, with a yield of 42.7%.

[0226] 1H NMR (400 MHz, DMSO-d6) 11.12 (s, 2H), 9.00 (s, 2H), 8.04 (s, 2H), 7.87 (d, J = 8.0 Hz, 2H), 7.77-7.75 (m, 2H), 7.64 (d, J = 8.0 Hz, 2H), 7.59-7.53 (m, 4H), 7.48 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 7.5 Hz, 1H), 5.89 (d, J = 46.4 Hz, 1H), 5.46 (s, 4H), 5.13 (dd, J = 12.9, 5.3 Hz, 2H), 2.95-2.85 (m, 2H), 2.65-2.50 (m, 4H), 2.07-2.00 (m, 2H).

[0227] Example 15

[0228] Synthesis of compound 15

[0229] N,N'-(methylenebis(3,1-phenylene))bis(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)oxy)acetamide)

[0230] In a 100 mL single-neck flask, 2.74 g of A4-1 (10 mmol), 30 mL of DMF, 2.2 g of tert-butyl bromoacetate (11 mmol), 2.12 g of sodium carbonate were added, and the reaction was carried out at room temperature overnight. LC-MS detection showed that the reaction was complete. Column chromatography was used for purification to obtain 3.33 g of A4-2 with a yield of 86%.

[0231] In a 100 mL single-neck flask, 3.33 g of A4-2, 20 mL of 1,4-dioxane, 20 mL of concentrated hydrochloric acid were added, and the reaction was carried out at room temperature overnight. The organic solvent was removed by rotary evaporation, water was added, and a solid was precipitated. Filtration and drying under vacuum gave 2.3 g of A4-3 with a yield of 81%.

[0232] In a 50 mL single-neck flask, 335 mg of A4-3 (1 mmol) was dissolved in 5 mL of DMF, 100 mg of 3,3'-diaminodiphenylmethane (0.5 mmol), 195 mg of DIPEA, and 480 mg of HATU were added, and the reaction was carried out at room temperature overnight. LC-MS detection showed that the reaction was complete. Water was added, and a solid was precipitated. The solid was purified by column chromatography to obtain 310 mg of product with a yield of 74.3%.

[0233] 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 2H), 10.13 (s, 2H), 7.87 (d, J = 8.3 Hz, 2H), 7.51-7.48 (m, 4H), 7.45-7.39 (m, 4H), 7.25 (t, J = 7.8 Hz, 2H), 6.96 (d, J = 7.6 Hz, 2H), 5.12 (dd, J = 12.9, 5.4 Hz, 2H), 4.93 (s, 4H), 3.89 (s, 2H), 2.88 (ddd, J = 17.4, 14.0, 5.4 Hz, 2H), 2.62-2.54 (m, 4H), 2.07-2.01 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 172.8, 169.9, 166.8, 166.7, 165.6, 163.3, 141.7, 138.4, 133.7, 128.9, 125.3, 124.3, 123.5, 120.9, 119.9, 117.5, 109.3, 67.3, 49.0, 41.2, 31.0, 22.1. HRMS (ESI) m / z: calcd for C 43 H 35 N6O 12 + : 827.2313 [M+H] + , found: 827.2320.

[0234] Example 16

[0235] Synthesis of compound 16

[0236] 2-(2,6-dioxopiperidin-3-yl)-5-((1-(3-(3-(4-(((2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)benzyl)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)isoindoline-1,3-dione

[0237] Into a 25 mL round bottom flask with a magnetic bar, 3,3'-diaminodiphenylmethane (198 mg, 1.0 mmol, 1.0 equiv), KHCO3(1.3 mL, 4.0 mmol, 4.0 equiv, 3.0 M in water) and DMF (3 mL) were added in sequence, after stirring well, FSO2N3(2.5 mL, 1.0 mmol, 1.0 equiv, 0.4 M in MTBE) was added slowly, after 6 hours of reaction, the reaction was detected by LC-MS to be complete. Then 50 mL of ethyl acetate and 50 mL of water were added respectively, and the extraction was separated three times, the organic phase was saturated with brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain a brown oily liquid. Then column chromatography was used for separation and purification (eluent: petroleum ether to petroleum ether: dichloromethane = 4: 1), and finally a brown oily liquid was obtained, which was directly used for the subsequent click.

[0238] Then 2-(1-methyl-2,6-dioxopiperidin-3-yl)-5-(prop-2-yn-1-yloxy)isoindoline-1,3-dione (326 mg, 1.0 mmol, 1.0 equiv), cuprous bromide (71 mg, 0.5 mmol, 0.5 equiv) and DMF (5 mL) were added to the above azide, after heating at 60°C for 6 hours, the azide was completely converted after monitoring by LC-MS, 50 mL of water was added to the system, and obvious insoluble solid was precipitated, which was separated by filtration to obtain a light yellow solid. Then reverse phase separation and purification were carried out, the separation system was water (0.1% TFA): acetonitrile, the separation gradient was water (0.1% TFA): acetonitrile = 95%: 5% to acetonitrile 100%, and the separation column type was SW080, spherical C18, 20-45 μm, The final light yellow solid was obtained by reduced pressure distillation, and the yield of the above two steps was 58%. The product obtained above was directly used for the next diazo transfer reaction.

[0239] Then 5-((l-(3-(3-aminobenzyl)phenyl)-lH-l,2,3-triazol-4-yl)methoxy)-2-(l- methyl-2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione prepared in the above step was added into a 25 mL round bottom flask with a magnet, followed by the addition of KHCO3(1.3 mL, 4.0 mmol, 4.0 equiv, 3.0 M aqueous solution) and DMF (5 mL), and then FSO2N3 (2.5 mL, 1.0 mmol, 1.0 equiv, 0.4 M in MTBE) was slowly added after the mixture was stirred uniformly. The reaction was detected by LC-MS after 6 hours. Then 60 mL of ethyl acetate and 60 mL of water were added, and the extraction was separated three times. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then distilled under reduced pressure. The product was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 1: 1 to ethyl acetate), and a brown solid was finally obtained, which was directly used for the subsequent click.

[0240] Finally, 2-(l-methyl-2,6-dioxopiperidin-3-yl)-5-(prop-2-yn-l-yloxy)isoindoline-l,3-dione (326 mg, 1.0 mmol, 1.0 equiv), cuprous bromide (142 mg, 1 mmol, 1 equiv) and DMF (8 mL) were added into the above azide. After the reaction was completed at 60°C for 6 hours, the azide was completely converted by LC-MS monitoring. Then 500 mL of water was added to the system, and a light brown solid was precipitated and separated by filtration. Then the product was purified by reverse phase separation, and the separation system was water (0.1% TFA): acetonitrile, and the separation gradient was water (0.1% TFA): acetonitrile = 95%: 5% to acetonitrile 100%, and the separation column type was SW120, spherical C18, 20-45 μm, A white solid was finally obtained by distillation under reduced pressure, and the total yield of the above four steps was 18%.

[0241] 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.98 (s, 2H), 7.91 (t, J = 2.0 Hz, 2H), 7.87 (dd, J = 8.3, 1.0 Hz, 2H), 7.75 (dd, J = 7.7, 2.2 Hz, 2H), 7.64 (d, J = 2.3 Hz, 2H), 7.54 (t, J = 7.9 Hz, 2H), 7.51 - 7.42 (m, 4H), 5.47 (s, 4H), 5.16 (ddd, J = 26.6, 13.0, 5.4 Hz, 2H), 4.19 (s, 2H), 3.02 (s, 3H), 2.98 - 2.83 (m, 2H), 2.77 (ddd, J = 17.2, 4.6, 2.5 Hz, 1H), 2.63 - 2.52 (m, 3H), 2.10 - 2.01 (m, 2H). 13 C NMR (176 MHz, DMSO-d6) δ 172.8, 171.7, 169.9, 169.7, 166.8, 166.7, 163.3, 163.3, 143.0, 142.8, 136.6, 134.0, 133.9, 130.1, 129.2, 125.4, 125.3, 123.5, 123.4, 123.3, 121.1, 121.1, 120.5, 118.1, 109.3, 109.3, 62.0, 49.5, 49.0, 40.4, 31.1, 30.9, 26.6, 26.6, 22.0, 21.2. HRMS (ESI) m / z: calcd for C 46 H 37 N 10 O 10 + : 889.2694 [M+H] + , found: 889.2705.

[0242] Example 17

[0243] Synthesis of compound 17

[0244] 2-(2,6-dioxopiperidin-3-yl)-5-((1-(3-(3-(4-(1-((2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethyl)-1H-1,2,3-triazol-1-yl)benzyl)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)isoindoline-1,3-dione

[0245] In accordance with the synthesis procedure of Example 16 - Compound 16

[0246] 1 H NMR (400 MHz, DMSO-d6) δ 11.10 (d, J = 6.2 Hz, 2H), 8.97 (s, 1H), 8.94 (s, 1H), 7.92 - 7.85 (m, 3H), 7.82 (d, J = 8.3 Hz, 1H), 7.73 (t, J = 6.9 Hz, 2H), 7.61 (dd, J = 18.5, 2.3 Hz, 2H), 7.53 (td, J = 7.8, 5.2 Hz, 2H), 7.47 (dd, J = 8.2, 2.4 Hz, 1H), 7.43 (dd, J = 8.2, 2.5 Hz, 3H), 6.06 (q, J = 6.4 Hz, 1H), 5.47 (s, 2H), 5.11 (ddd, J = 12.7, 10.4, 5.3 Hz, 2H), 4.17 (s, 2H), 2.88 (ddt, J = 19.7, 12.6, 5.8 Hz, 2H), 2.65 - 2.52 (m, 5H), 2.12 - 1.95 (m, 3H), 1.77 - 1.73 (m, 3H). HRMS (ESI) m / z: calcd for C 46 H 37 N 10 O 10 + : 889.2694 [M+H] + , found: 889.2718.

[0247] Example 18

[0248] Synthesis of compound 18

[0249] 3,3'-(((((Methylenylbis(3,1-phenylene))bis(1H-1,2,3-triazole-1,4-diyl))bis(methylenyl))bis(oxy))bis(1-oxoisoindoline-5,2-diyl))bis(piperidine-2,6-dione)

[0250] In accordance with the synthesis of Example 1 - Step one of compound 1

[0251] 1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 2H), 8.96 (s, 2H), 7.91 (t, J = 1.9 Hz, 2H), 7.75 (dt, J = 8.2, 1.3 Hz, 2H), 7.66 (d, J = 8.4 Hz, 2H), 7.54 (t, J = 7.9 Hz, 2H), 7.45 (d, J = 7.7 Hz, 2H), 7.33 (d, J = 2.2 Hz, 2H), 7.17 (dd, J = 8.4, 2.2 Hz, 2H), 5.34 (s, 4H), 5.08 (dd, J = 13.3, 5.1 Hz, 2H), 4.39 (s, 4H), 2.97 - 2.84 (m, 2H), 2.59 (d, J = 17.6 Hz, 2H), 2.44 - 2.34 (m, 2H), 2.03 - 1.95 (m, 2H). 13 C NMR (176 MHz, DMSO-d6) δ 172.9, 171.4, 171.1, 167.8, 161.1, 144.4, 143.4, 142.8, 136.7, 130.1, 129.9, 129.2, 124.5, 124.4, 123.1, 120.5, 118.1, 115.6, 109.0, 61.4, 51.5, 47.0, 40.4, 31.2, 31.2, 22.5. HRMS (ESI) m / z: calcd for C 45 H 39 N 10 O8 + : 847.2952 [M+H] + , found: 847.2952.

[0252] Example 19

[0253] 5,5'-((((methylenebis(3,1-phenylene))bis(1H-1,2,3-triazole-1,4-diyl))bis(methylene))bis(nitrilo))bis(2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione)

[0254] To a 4 mL vial with a magnetic stir bar was added 3,3'-diaminodiphenylmethane (40 mg, 0.2 mmol, 1 equiv), KHC03(0.52 mL, 1.6 mmol, 8.0 equiv, 3.0 M in water) and DMF (3 mL) sequentially, after stirring well, FSO2N3(1.0 mL, 0.4 mmol, 2.0 equiv, 0.4 M in MTBE) was added slowly, after 6 hours, the reaction was monitored by LC-MS and found to be complete. Then 30 mL ethyl acetate and 30 mL water were added respectively, the organic phase was extracted and separated three times, the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain a brown oily liquid, which was then purified by column chromatography (eluent: petroleum ether to petroleum ether: dichloromethane = 10: 1) to obtain a brown oily liquid, which was directly used for the subsequent click.

[0255] Subsequently, to the above azide, the alkyne precursor 2-(2,6-dioxopiperidin-3-yl)-5-(prop-2-yn-1-ylamino)isoindoline-1,3-dione (125 mg, 0.4 mmol, 2.0 equiv), cuprous bromide (30 mg, 0.2 mmol, 1.0 equiv) and DMF (3 mL) were added, after heating at 60 °C for 6 hours, the azide was completely converted, which was monitored by LC-MS, 200 mL water was added to the system, and obvious insoluble solid was precipitated, which was separated by filtration to obtain a light green solid. Then, reverse phase separation and purification were carried out, the separation system was water (0.1% TFA): acetonitrile, the separation gradient was water (0.1% TFA): acetonitrile = 95%: 5% to acetonitrile 100%, and the separation column type was SW0120, spherical C18, 20-45 μm, The final yellow solid was obtained by distillation under reduced pressure, 139 mg, yield 80%.

[0256] 1 H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 2H), 8.73 (s, 2H), 7.87 (s, 2H), 7.72 (dd, J = 7.8, 2.2 Hz, 2H), 7.59 (d, J = 8.3 Hz, 2H), 7.51 (t, J = 7.8 Hz, 2H), 7.40 (d, J = 7.6 Hz, 2H), 7.10 (s, 2H), 6.98 (dd, J = 8.3, 2.1 Hz, 2H), 5.04 (dd, J = 12.9, 5.3 Hz, 2H), 4.56 (s, 4H), 4.16 (s, 2H), 2.96 - 2.75 (m, 2H), 2.63 - 2.51 (m, 4H), 2.04 - 1.95 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 172.8, 170.1, 167.6, 167.1, 153.9, 145.4, 142.8, 136.7, 134.0, 130.1, 129.0, 125.1, 121.4, 120.3, 117.9, 116.8, 48.68, 38.0, 31.0, 30.7, 22.2. HRMS (ESI) m / z: calcd for C 45 H 37 N 12 O8 + 873.2852 [M+H] + , found: 873.2864.

[0257] Example 20

[0258] 2-(2,6-dioxopiperidin-3-yl)-5-(((1-(3-(3-(4-(((2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)methyl)-1H-1,2,3-triazol-1-yl)benzyl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)amino)isoindoline-1,3-dione

[0259] Into a 25 mL round-bottom flask with a magnetic bar, 3,3'-diaminobenzidine (40 mg, 0.2 mmol, 1.0 equiv), KHCO3(0.27 mL, 0.8 mmol, 4.0 equiv, 3.0 M aqueous solution) and DMF (1 mL) were added in turn, and after stirring uniformly, FSO2N3(0.5 mL, 0.2 mmol, 1.0 equiv, 0.4 M MTBE solution) was slowly added, and the reaction was detected by LC-MS after 6 hours. Then 30 mL of ethyl acetate and 30 mL of water were added respectively, and the extraction was separated three times, and the organic phase was saturated with brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain a brown oily liquid, which was then purified by column chromatography (eluent: petroleum ether to petroleum ether: dichloromethane = 4:1), and finally a brown oily liquid was obtained, which was directly used for subsequent click.

[0260] Subsequently, 2-(2,6-dioxopiperidin-3-yl)-5-(prop-2-yn-1 -ylamino)isoindoline- 1,3-dione (326 mg, 1.0 mmol, 1.0 equiv), cuprous bromide (9 mg, 0.06 mmol, 0.5 equiv) and DMF (8 mL) were added to the above azide. After heating at 60 °C for 6 hours, the azide was completely converted as monitored by LC-MS. 100 mL of water was added to the system, and insoluble solids were precipitated. The light brown solids were separated by filtration. Subsequently, reverse phase separation and purification were performed. The separation system was water (0.1 % TFA): acetonitrile, and the separation gradient was water (0.1 % TFA): acetonitrile = 95%:5% to acetonitrile 100%. The separation column was SW120, spherical C18, 20-45 μm, The final product was obtained as a light yellow solid by vacuum distillation. The product was directly used in the next diazotransfer reaction.

[0261] Subsequently, 2-(2,6-dioxopiperidin-3-yl)-5-(prop-2-yn-1 -ylamino)isoindoline- 1,3-dione (326 mg, 1.0 mmol, 1.0 equiv), cuprous bromide (9 mg, 0.06 mmol, 0.5 equiv) and DMF (8 mL) were added to the above azide. After heating at 60 °C for 6 hours, the azide was completely converted as monitored by LC-MS. 100 mL of water was added to the system, and insoluble solids were precipitated. The light brown solids were separated by filtration. Subsequently, reverse phase separation and purification were performed. The separation system was water (0.1 % TFA): acetonitrile, and the separation gradient was water (0.1 % TFA): acetonitrile = 95%:5% to acetonitrile 100%. The separation column was SW120, spherical C18, 20-45 μm,

[0262] Subsequently, 2-(2,6-dioxopiperidin-3-yl)-5-(prop-2-yn-1 -ylamino)isoindoline- 1,3-dione (326 mg, 1.0 mmol, 1.0 equiv), cuprous bromide (9 mg, 0.06 mmol, 0.5 equiv) and DMF (8 mL) were added to the above azide. After heating at 60 °C for 6 hours, the azide was completely converted as monitored by LC-MS. 100 mL of water was added to the system, and insoluble solids were precipitated. The light brown solids were separated by filtration. Subsequently, reverse phase separation and purification were performed. The separation system was water (0.1 % TFA): acetonitrile, and the separation gradient was water (0.1 % TFA): acetonitrile = 95%:5% to acetonitrile 100%. The separation column was SW120, spherical C18, 20-45 μm, The final product was obtained as a white solid 12 mg by vacuum distillation. The overall yield of the above four steps was 7%.

[0263] 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 2H), 8.73 (s, 2H), 7.87 (s, 2H), 7.72 (dd, J = 7.8, 2.2 Hz, 2H), 7.59 (d, J = 8.3 Hz, 2H), 7.51 (t, J = 7.8 Hz, 2H), 7.40 (d, J = 7.6 Hz, 2H), 7.10 (s, 2H), 6.98 (dd, J = 8.3, 2.1 Hz, 2H), 5.04 (dd, J = 12.9, 5.3 Hz, 2H), 4.56 (s, 4H), 4.16 (s, 2H), 3.03 (s, 3H), 2.92 - 2.81 (m, 2H), 2.73 (ddd, J = 17.2, 4.6, 2.5 Hz, 1H), 2.55 - 2.50 (m, 3H), 2.06 - 1.98 (m, 2H). HRMS (ESI) m / z: calcd for C 46 H 39 N 12 O8 + :886.2936[M+H] + , found:886.2939.

[0264] Effect Examples:

[0265] CCK-8 experimental operation steps (molecular glue pure IC 50 value specific operation)

[0266] Experimental procedure: On the first day, cells were seeded in a 96-well plate at a density of 3000 cells / 90 μL, and on the second day, different concentrations of molecular glue compounds were prepared in an eight-tube with a 3-fold gradient, then 10 μL / well of medium containing drugs was added to the cells. After 3 days of treatment with molecular glue compounds, 10 μl of Cell Counting Kit-8 detection reagent was added to each well, incubated at 37°C for 1-2 hours, and the absorbance was detected at 450 nm.

[0267] IC 50 value calculation method: The final result is calculated according to the cell survival rate formula: cell survival rate = (experimental hole absorbance-blank hole absorbance) / (control hole absorbance-blank hole absorbance) x 100%. Among them, the experimental hole is the cell treated with molecular glue compound, the control hole is the cell treated with DMSO, and the blank hole is the medium without cells. The cell survival rate data is fitted by GraphPad software to obtain the cell survival curve, and the IC 50 value is calculated, and the results are shown in Table 1.

[0268] At this time, the cells included the 293T cell line (human embryonic kidney cells, adherent cells) and the MV411 cell line (human myeloid monocytic leukemia cells, suspension cells).

[0269] Table 1

[0270] illustrate:

[0271] A+++++:IC 50 ≤1nM

[0272] A++++:1nM<IC 50 ≤10nM

[0273] A+++: 10nM < IC 50 ≤100nM

[0274] A++: 100nM < IC 50 ≤1000nM

[0275] A+: 1000nM < IC 50 ≤10000nM

[0276] As can be seen from Table 1:

[0277] 1) The optimal IC50 of multivalent compounds 50 The values ​​reached the pM level, and the antitumor activity of the multivalent compound was significantly improved compared with that of the monovalent compound;

[0278] 2) The antitumor activity is selective for different modified substances.

[0279] Protein degradation experimental procedure (molecular gel pure DC) 50 D max (Specific operation)

[0280] Experimental procedure:

[0281] On the first day, 5×10 5HL-60 cells were plated in 12-well cell culture plates, 1 mL / well; the next day, a concentration gradient of 0, 0.001, 0.01, 0.1, 1, 10, 100 pM of compound was added to the cells, and the cells were treated for 24 hours; on the third day, cell lysate containing protease inhibitors (NP40 buffer + 1% SDS) was added to the cells for lysis, followed by the addition of SDS loading buffer, and boiling at 100°C for 5 minutes. 20 μg of total protein was loaded into the gel wells of a 4-12% SDS-PAGE gel, and the gel was run at 120 volts for 90 minutes. After the electrophoresis was completed, the proteins were transferred to a PVDF membrane by an electroblotting apparatus at 120 volts for 45 minutes. The PVDF membrane was then blocked with 5% nonfat dry milk at room temperature for 1 hour. The membrane was incubated with the primary antibody for GSPT1 protein at 4°C overnight. After the incubation was completed, the membrane was washed with TBST three times for 5 minutes each time. The membrane was then incubated with the secondary antibody labeled with HRP at room temperature for 1 hour. After the incubation was completed, the membrane was washed with TBST three times for 5 minutes each time. The chemiluminescence image was collected by darkroom developing technology.

[0282] Result analysis: The chemiluminescence image was collected by darkroom developing technology to analyze and calculate the DC 50 , D max values, and the results are shown in Table 2.

[0283] Table 2

[0284] From Table 2, it can be seen that:

[0285] 1) The DC 50 values of the multivalent compounds reached the pM level, and the target protein degradation efficiency of the multivalent compounds was significantly improved compared with the monovalent compound thalidomide.

[0286] All the documents mentioned in the present application are cited as references in the present application, as if each document is cited as a reference individually. In addition, it should be understood that, after reading the above teaching of the present application, those skilled in the art can make various modifications or changes to the present application, and these equivalent forms also fall within the scope defined by the claims attached to the present application.

Claims

1. A compound of Formula I, or an enantiomer, diastereomer thereof, or a pharmaceutically acceptable salt thereof, wherein, Y is a linker for linking m Z; Z is -X2-X3-X4, -X3-X4 is an E3 ubiquitin ligase binding ligand, and X2 is for linking Y and -X3-X4; m is selected from the group consisting of 2, 3, 4, 5.

2. The compound of claim 1, wherein m is selected from the group consisting of 2, 3, 4.

3. The compound of claim 1, wherein The compound is a compound of Formula II, Z1-Y1-Z2 Formula II wherein, Y1 is X1 is selected from the group consisting of -CR1R2-, -(C=O)-, O, S, NH; R1, R2 are each independently selected from the group consisting of H, D, halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxyl substituted C1-C6 alkyl, hydroxyl substituted C1-C6 alkoxy; n1, n2 are each independently selected from the group consisting of 0, 1, 2, 3, 4; R 11 , R 12 are each independently selected from the group consisting of H, D, halogen, C1-C6alkyl, C1-C6alkoxy, haloC1-C6alkyl, haloC1-C6alkoxy; Z1 and Z2 are the same or different, each independently -X2-X3-X4; each X2is the same or different, each being independently selected from the group consisting of: -NR3-(C=O)-, -(C=O)-NR3-, -CR4R5-O-, -O-CR4R5-; each X3is the same or different, each being independently selected from the group consisting of -CR4R5-O-, null, -O-CR4R5-, each X4is the same or different, each being independently selected from the group consisting of: each X5, X6 is independently selected from the group consisting of N, -CR3-; each R3, R4, R5 is each independently selected from the group consisting of H, D, C1-C6 alkyl, halogenated C1-C6 alkyl.

4. The compound of claim 3, wherein, Y1is selected from the group consisting of: X1, n1, n2, R 11 , R 12 As defined in claim 3.

5. The compound of claim 3, wherein X1 is selected from the group consisting of -CR1R2-, -(C=O)-, O, S, NH.

6. The compound of claim 3, wherein R1, R2 are each independently selected from the group consisting of H, D, halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxyl substituted C1-C6 alkyl, hydroxyl substituted C1-C6 alkoxy.

7. The compound of claim 3, wherein n1, n2 are each independently selected from the group consisting of 0, 1, 2, 3, 4.

8. The compound of claim 3, wherein R 11 , R 12 are each independently selected from the group consisting of H, D, halogen, C1-C6alkyl, C1-C6alkoxy, haloC1-C6alkyl, haloC1-C6alkoxy.

9. The compound of claim 3, wherein X1 is -CR1R2-; R1, R2 are each independently selected from the group consisting of H, D, halogen, hydroxyl, C1-C6 alkyl, halogenated C1-C6 alkyl.

10. The compound of claim 3, wherein Z1 and Z2 are the same and -X2-X3-X4.

11. The compound of claim 3, wherein X2is selected from the group consisting of:

12. The compound of claim 3, wherein X3 is selected from the group consisting of -CR4R5-O-, -O-CR4R5-.

13. The compound of claim 3, wherein X4is selected from the group consisting of:

14. The compound of claim 1, wherein The compound is a compound of formula III, wherein, Y2 is X7 is selected from the group consisting of CR6, N; R6 is selected from the group consisting of H, D, halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxyl substituted C1-C6 alkyl, hydroxyl substituted C1-C6 alkoxy; R 21 , R 22 , R 23 are each independently selected from the group consisting of H, D, halogen, C1-C6alkyl, C1-C6alkoxy, haloC1-C6alkyl, haloC1-C6alkoxy; n3, n4, n5 are each independently selected from the group consisting of 0, 1, 2, 3, 4; Z3, Z4 and Z5 are the same or different, each independently -X2-X3-X4; each X2is the same or different, each being independently selected from the group consisting of: -NR3-(C=O)-, -(C=O)-NR3-, -CR4R5-O-, -O-CR4R5-; each X3is the same or different, each being independently selected from the group consisting of -CR4R5-O-, null, -O-CR4R5-, each X4is the same or different, each being independently selected from the group consisting of: each X5, X6 is independently selected from the group consisting of N, -CR3-; each R3, R4, R5 is each independently selected from the group consisting of H, D, C1-C6 alkyl, halogenated C1-C6 alkyl.

15. The compound of claim 14, wherein, Y2is selected from the group consisting of: X7, R 21 , R 22 , R 23 , n3, n4, n5 are as defined in claim 14.

16. The compound of claim 14, wherein X7 is CR6.

17. The compound of claim 14, wherein R6is selected from the group consisting of H, D, halogen, hydroxyl, C1-C6alkyl, C1-C6alkoxy, haloC1-C6alkyl, haloC1-C6alkoxy, hydroxyl substituted C1-C6alkyl, hydroxyl substituted C1-C6alkoxy.

18. The compound of claim 14, wherein R 21 , R 22 , R 23 are each independently selected from the group consisting of H, D, halogen, Ci-C6-alkyl, Ci-C6-alkoxy, halogen-Ci-C6-alkyl, halogen-Ci-C6-alkoxy; n3, n4, n5 are each independently selected from the group consisting of 0, 1, 2, 3, 4.

19. The compound of claim 1, wherein The compound is selected from the group consisting of:

20. A process for the preparation of a compound of claim 3, wherein, the method is selected from the group consisting of Method 1, Method 2, Method 3; Method one includes the steps of: 1) N3— Y1— N3 with to give wherein Y1, X3, X4are as defined in claim 3; Method two comprises the steps of: 1) reacting H2N— Y1— NH2 with The reaction gives wherein Y1, X3, X4are as defined in claim 3; Method three comprises the steps of: 1) reacting H2N— Y1— N3 with The reaction gives 2) will be converted to 3) will be With The reaction gives wherein Y1is as defined in claim 3; X 31 and X 32 are identical or different, each independently selected from the group consisting of -CR4R5-O-, none, -O-CR4R5-, each X5, X6is independently selected from the group consisting of N, -CR3-; each R3, R4, R5is independently selected from the group consisting of H, D, Ci-C6alkyl, haloCi-C6alkyl; X 41 and X 42 the same or different, each independently selected from the group consisting of:

21. A pharmaceutical composition comprising, a pharmaceutically acceptable carrier and a safe and effective amount of a compound of claim 1.

22. Use of a compound according to claim 1, characterized in that, for the preparation of a medicament for the prevention and / or treatment of a disease selected from the group consisting of cancer, autoimmune diseases, inflammatory diseases.

Images