Multivalent molecular glue compound as well as preparation and application thereof

Abstract

The invention relates to multivalent molecular glue compounds as well as preparation and application thereof. Specifically, the compound disclosed by the invention has a structure as shown in a formula I, and the definitions of all groups and substituent groups are described in the specification. The invention also discloses a preparation method of the compound and application of the compound in prevention and / or treatment of cancers.

Description

TECHNICAL FIELD

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

[0002] Molecular glue is a kind of monovalent small molecule, which can change the surface structure of E3 ligase, thereby promoting new protein-protein interaction. Compared with PROTAC, molecular glue is more easily absorbed by cells due to its smaller molecular weight, and can play a role at a lower dose. Unlike the way of targeting PROTAC which uses flexible linker to connect two ligands and allows them to twist and turn to form contact points, molecular glue degraders intervene the protein interface more directly, strengthen the complex formation between E3 ligase and target protein, thereby inducing the increase of affinity between them, ultimately leading to ubiquitination and degradation of target protein.

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

[0004] However, there are many challenges in developing innovative molecular glue degraders. Since the binding pocket of molecular glue is located in the dynamic structure of two molecules, there is no natural pocket for molecular glue to bind compared to traditional drug development and design. Most of the current molecular glue drugs are accidental discoveries, and there is no reasonable or systematic method to design and develop them, so 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]

[0008] wherein,

[0009] Y is a linking group for connecting m Z;

[0010] Z is -X2-X3-X4, -X3-X4 is an E3 ubiquitin ligase binding ligand, X2 is for linking Y and -X3-X4;

[0011] m is selected from the group consisting of 2, 3, 4, 5.

[0012] In another preferred embodiment, m is selected from the group consisting of 2, 3, 4.

[0013] In another preferred embodiment, m is 2 or 3.

[0014] In another preferred embodiment, m is 2.

[0015] In another preferred embodiment, the compound is a molecular glue.

[0016] In another preferred embodiment, the compound is a compound of Formula II,

[0017] Z1-Y1-Z2 Formula II

[0018] wherein,

[0019] Y1 is

[0020] X1 is selected from the group consisting of -CR1R2-, -(C=0)-, O, S, NH;

[0021] R1, R2 are each independently selected from the group consisting of H, D, halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, halo C1-C6 alkoxy, hydroxyl substituted C1-C6 alkyl, hydroxyl substituted C1-C6 alkoxy;

[0022] n1, n2 are each independently selected from the group consisting of 0, 1, 2, 3, 4;

[0023] R 11 , R 12 are each independently selected from the group consisting of H, D, halogen, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, halo C1-C6 alkoxy;

[0024] Z1 and Z2 are the same or different, each independently -X2-X3-X4;

[0025] each X2 is the same or different, each independently selected from the group consisting of: -NR3-(C=0)-, -(C=0)-NR3-, -CR4R5-O-, -O-CR4R5-;

[0026] each X3 is the same or different, each independently selected from the group consisting of -CR4R5-O-, none, -O-CR4R5-,

[0027] each X4is the same or different, each being independently selected from the group consisting of:

[0028]

[0029] each X5, X6is independently selected from the group consisting of N, -CR3-;

[0030] each R3, R4, R5is each independently selected from the group consisting of H, D, C1-C6alkyl, halogenated C1-C6alkyl.

[0031] In another preferred embodiment, Y1is selected from the group consisting of:

[0032] X1, n1, n2, R 11 , R 12 as defined above.

[0033] In another preferred embodiment, X1is selected from the group consisting of -CR1R2-, -(C=0)-, O, S, NH.

[0034] In another preferred embodiment, 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.

[0035] In another preferred embodiment, n1, n2are each independently selected from the group consisting of 0, 1, 2, 3, 4.

[0036] In another preferred embodiment, 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.

[0037] In another preferred embodiment, X1is -CR1R2-;

[0038] R1, R2are each independently selected from the group consisting of H, D, halogen, hydroxyl, C1-C6alkyl, halogenated C1-C6alkyl.

[0039] In another preferred embodiment, Z1and Z2are the same and are -X2-X3-X4.

[0040] In another preferred embodiment, X2is selected from the group consisting of:

[0041] In another preferred embodiment, X3is selected from the group consisting of -CR4R5-O-, -O-CR4R5-.

[0042] In another preferred embodiment, X4is selected from the group consisting of:

[0043] In another preferred embodiment, each R3, R4, R5is independently selected from the group consisting of H, D, C1-C6alkyl, haloC1-C6alkyl.

[0044] In another preferred embodiment, the compound is a compound of Formula III,

[0045]

[0046] wherein,

[0047] Y2is

[0048] X7is selected from the group consisting of CR6, N;

[0049] 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;

[0050] 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;

[0051] n3, n4, n5are each independently selected from the group consisting of 0, 1, 2, 3, 4;

[0052] Z3, Z4and Z5are the same or different, each independently -X2-X3-X4;

[0053] each X2is the same or different, each independently selected from the group consisting of: -NR3-(C=O)-, -(C=O)-NR3-, -CR4R5-O-, -O-CR4R5-;

[0054] each X3is the same or different, each independently selected from the group consisting of -CR4R5-O-, none, -O-CR4R5-,

[0055]

[0056] each X4is the same or different, each independently selected from the group consisting of:

[0057]

[0058]

[0059] each X5, X6is independently selected from the group consisting of N, -CR3-;

[0060] each R3, R4, R5is independently selected from the group consisting of H, D, Ci-C6alkyl, haloCi-C6alkyl.

[0061] In another preferred embodiment, Y2is selected from the group consisting of:

[0062]

[0063] X7, R 21 , R 22 , R 23 , n3, n4, n5are as defined above.

[0064] In another preferred embodiment, X7is selected from the group consisting of CR6, N.

[0065] In another preferred embodiment, X7is CR6.

[0066] In another preferred embodiment, R6is 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.

[0067] In another preferred embodiment, R6is selected from the group consisting of H, D, halogen, hydroxyl, Ci-C6alkyl, Ci-C6alkoxy.

[0068] In another preferred embodiment, R 21 , R 22 , R 23 are each independently selected from the group consisting of H, D, halogen, Ci-C6alkyl, Ci-C6alkoxy, haloCi-C6alkyl, haloCi-C6alkoxy.

[0069] In another preferred embodiment, n3, n4, n5are each independently selected from the group consisting of 0, 1, 2, 3, 4.

[0070] In another preferred embodiment, the compound is selected from the group consisting of:

[0071]

[0072]

[0073]

[0074] In a second aspect, the present application provides a method for preparing a compound according to the first aspect of the present application, said method is selected from the group consisting of Method I, Method II, Method III;

[0075] Method I comprises the steps of:

[0076]

[0077] 1) reacting N3-Y1-N3 with to obtain

[0078] wherein Y1, X3, X4 are as defined above;

[0079] Method II comprises the steps of:

[0080]

[0081] 1) reacting H2N-Y1-NH2 with to obtain

[0082] wherein Y1, X3, X4 are as defined above;

[0083] Method III comprises the steps of:

[0084]

[0085] 1) reacting H2N-Y1-N3 with to obtain

[0086] 2) converting to

[0087] 3) reacting with to obtain

[0088] wherein Y1 is as defined above;

[0089] X 31 and X 32 are the same or different, each independently selected from the group consisting of -CR4R5-O-, null, -O-CR4R5-,

[0090] each X5, X6 is independently selected from the group consisting of N, -CR3-;

[0091] each R3, R4, R5 is independently selected from the group consisting of H, D, C1-C6 alkyl, haloC1-C6 alkyl; X 41 and X42 each independently of one another, is selected from the group consisting of:

[0092]

[0093]

[0094] 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 the compound according to the first aspect of the present application.

[0095] In a fourth aspect of the present application, there is provided the use of the compound according to the first aspect of the present application for the manufacture of a medicament for the prevention and / or treatment of a disease selected from the group consisting of: cancer, autoimmune disease, inflammatory disease.

[0096] In another preferred embodiment, the cancer is selected from the group consisting of: leukemia, lymphoma, breast cancer, lung cancer, prostate cancer, melanoma.

[0097] In another preferred embodiment, the autoimmune disease is selected from the group consisting of: rheumatoid arthritis, systemic lupus erythematosus, psoriasis, multiple sclerosis.

[0098] In another preferred embodiment, the inflammatory disease is selected from the group consisting of: Crohn's disease, ulcerative colitis, rheumatoid arthritis, asthma.

[0099] In another preferred embodiment, the leukemia is selected from the group consisting of: myeloid leukemia, lymphocytic leukemia, hairy cell leukemia.

[0100] It should be understood that, within the scope of the present application, each of the technical features described above and in the following (e.g., in the examples) can be combined with each other to form new or preferred technical solutions. Due to the limited space, they are not listed one by one here. DETAILED DESCRIPTION

[0101] The present inventors, through long-term and in-depth research, have unexpectedly prepared a molecular glue compound comprising 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.

[0102] TERMS

[0103] In the present application, the terms used have the general meanings known to those skilled in the art, unless otherwise specified.

[0104] In the present application, the term "halogen" refers to F, Cl, Br or I.

[0105] In the present application, the term "C1-C6alkyl" refers to straight or branched chain alkyl groups including 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, neopentyl, tert-pentyl, or the like.

[0106] In the present application, the term "C2-C6alkenyl" refers to straight or branched chain alkenyl groups containing one double bond, including 2 to 6 carbon atoms, such as ethenyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl, and the like.

[0107] In the present application, the term "C2-C6alkynyl" refers to straight or branched chain alkynyl groups containing one triple bond, including 2 to 6 carbon atoms, such as ethynyl, propynyl, butynyl, isobutynyl, pentynyl, hexynyl, and the like.

[0108] In the present application, the term "C3-C8cycloalkyl" refers to cyclic alkyl groups having 3 to 8 carbon atoms in the ring, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

[0109] In the present application, the term "C1-C6alkoxy" refers to straight or branched chain alkoxy groups having 1 to 6 carbon atoms, including, but not limited to, methoxy, ethoxy, propoxy, isopropoxy, and butoxy, and the like. Preferably, C1-C4alkoxy.

[0110] In the present application, the term "heterocyclyl" refers to 4-8 membered heterocyclic groups containing 1, 2, or 3 heteroatoms selected from N, O, S, including, but not limited to, the following groups:

[0111] In the present application, the terms "aromatic ring" or "aryl" have the same meaning, and are preferably "C6-C10aryl". The term "C6-C10aryl" refers to aromatic ring groups having 6 to 10 carbon atoms in the ring, not containing heteroatoms, such as phenyl, naphthyl, and the like.

[0112] In the present application, the terms "aromatic heterocycle" or "heteroaryl" have the same meaning, and refer to heteroaromatic groups containing one to several heteroatoms. For example, "C3-C10heteroaryl" refers to aromatic heterocycles containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen, and 3 to 10 carbon atoms. Non-limiting examples include furanyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkyl pyrrolyl, 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.

[0113] In the present application, the term "halo" refers to substitution by a halogen.

[0114] In the present application, the term "deuterated" refers to substitution by deuterium.

[0115] In the present application, the term "substituted" refers to substitution of one or more hydrogen atoms on a specified group by 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. Those skilled in the art will appreciate that combinations of substituents contemplated by the present application are those that are stable or chemically feasible. The substituents are, for example, but not limited to, halogen, hydroxyl, 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.

[0116] In the present application, the term 1-6 refers to 1, 2, 3, 4, 5, or 6. Other similar terms each independently have a similar meaning. The term "a plurality" refers to 2-6, such as 2, 3, 4, 5, or 6.

[0117] It should be understood that when a group is present simultaneously in 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".

[0118] Compound

[0119] 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 multivalent molecular glue-like compounds as potential molecular glue drug candidates.

[0120] Specifically, the present application provides a compound of formula I, or an enantiomer, diastereomer thereof, or a pharmaceutically acceptable salt thereof,

[0121]

[0122] wherein,

[0123] Y is a linker group for connecting m Zs;

[0124] Z is -X2-X3-X4, -X3-X4 is an E3 ubiquitin ligase binding ligand, and X2 is for connecting Y and -X3-X4;

[0125] m is selected from the group consisting of 2, 3, 4, 5.

[0126] More specifically, the present application provides a compound of Formula II, or an enantiomer, diastereomer thereof, or a pharmaceutically acceptable salt thereof,

[0127] Z1-Y1-Z2 Formula II

[0128] wherein,

[0129] Y1 is

[0130] Z1 and Z2 are the same or different, each independently -X2-X3-X4.

[0131] In another preferred embodiment, any one of X1, n1, n2, R 11 , R 12 , X2, X3, X4 in the compound is independently the corresponding group in the specific compound described in the present application.

[0132] In the present application, Y is a linker group for connecting multiple E3 ubiquitin ligase binding ligands. Unlike the existing monovalent molecular glue, the compound of the present application is a multivalent molecular glue, which contains multiple E3 ubiquitin ligase binding ligands in one molecule. Therefore, the structure of the compound of the present application is very novel and completely different from the existing molecular glue compounds.

[0133] In addition, the multivalent molecular glue compound of the present application has excellent protein degradation performance, which is even significantly better than the existing monovalent molecular glue compound, which is very unexpected.

[0134] The structure of the multivalent molecular glue compound in the present application is obviously different from the molecular glue drugs of the past. Compared with the conventional molecular glue drugs which are obtained by chance, the multivalent binding sites are used in the examples of the present application to enhance the interaction with target molecules, which can involve different targeting selectivity and action mechanisms from the past. 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.

[0135] 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 salt and organic salt. 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, benzene sulfonic acid, naphthalene sulfonic acid, and the like; and amino acids such as proline, phenylalanine, aspartic acid, glutamic acid, and the like.

[0136] 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.

[0137] The present application further provides a method for preparing the compound of the present application. 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 limit 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 pertains.

[0138] Typically, the starting materials and reagents used in the preparation process of the compound of the present application can be purchased through commercial channels, unless otherwise specified.

[0139] Pharmaceutical composition and administration method

[0140] The present application further provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a safe and effective amount of the compound of the present application.

[0141] Since the compound of the present application has excellent anti-tumor activity, the compound of the present application and various crystal forms thereof, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compound of the present application as a main active ingredient can be used for treating, preventing, and alleviating diseases related to tumors.

[0142] 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.

[0143] "Pharmaceutically acceptable carrier" means one or more compatible solid or liquid filler or gel materials, which are suitable for human use, and which are nontoxic to the subject. "Compatible" means that the composition including the carrier, excipient, and / or vehicle is tolerated by the subject and does not significantly reduce the efficacy of the compound of the application. Examples of pharmaceutically acceptable carriers are water, salt solutions, alcohols, gum arabic, glucose, carbohydrates, starch, calcium phosphate, various types of lubeilizers, stabilizers, binders, excipients, and the like. Examples of such carriers include, but are not limited to, saline, buffered saline, sodium acetate, polyethylene glycol, gelatin, dextrose, lactose, sucrose, calcium phosphate, magnesium stearate, sodium lauryl sulfate, acacia, gelatin, talc, salicylic acid, and other such carriers. Examples of other suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E.W. Martin. The pharmaceutical compositions of this application can be administered in a manner appropriate to the application, for example, orally in the form of tablets, capsules, granules, powders or syrup; rectally in the form of suppositories; parenterally, e.g., intravenously, intramuscularly, subcutaneously, or intrasternally, in the form of a solution, suspension or emulsion; or topically in the form of a cream, ointment or gel.

[0144] The pharmaceutical composition can be in the form of an injection, a capsule, a tablet, a pill, a powder or a granule.

[0145] The pharmaceutical composition can be in the form of an injection, a capsule, a tablet, a pill, a powder or a granule.

[0146] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert excipient (or carrier) such as sodium citrate or dicalcium phosphate, or with such other ingredients as binders, (a) fillers or extenders, e.g., starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) humectants, e.g., hydroxymethylcellulose, alginic acid, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) moisturizing agents, e.g., glycerol; (d) disintegrating agents, e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solution retarders, e.g., paraffin; (f) absoφtion accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, e.g., cetyl alcohol and glyceryl monostearate; (h) adsorbents, e.g., kaolin and bentonite; and (i) lubricants, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage form can also comprise buffering agents.

[0147] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings and shells known in the art. They can contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions that can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.​

[0148] 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.

[0149] Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0150] 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, and agar-agar, as well as mixtures thereof, and the like.

[0151] The 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.

[0152] 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.

[0153] The compounds of the present application can be administered alone or in combination with other pharmaceutically acceptable compounds, such as anti-tumor drugs.

[0154] The therapeutic methods of the present application can be administered alone or in conjunction with other therapeutic procedures or therapeutic agents.

[0155] The pharmaceutical compositions are administered in a safe and effective amount, which is a quantity of the compounds of the present application suitable for administration to a mammal (e.g., human) in need of treatment, wherein the dosage is administered in an amount pharmaceutically considered effective for administration, and for a 60 kg body weight human, the daily administration dosage is usually 1-2000 mg, preferably 50-1000 mg. Of course, the specific dosage should also consider the administration route, patient health condition, and the like, which are within the skill of a skilled physician.

[0156] Compared with the prior art, the present application has the following main advantages:

[0157] (1) The present application first provides a polyvalent molecular glue compound, which has a very novel structure;

[0158] (2) The multivalent molecular glue compound has excellent degradation performance;

[0159] (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.

[0160] (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.

[0161] (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.

[0162] (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.

[0163] 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.

[0164] 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.

[0165] Example 1

[0166] Synthesis of Compound 1

[0167]

[0168] 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)

[0169]

[0170] 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 washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain a brown oily liquid. Then column chromatography separation and purification (eluent: petroleum ether to petroleum ether: dichloromethane = 10:1) was performed, and finally a brown oily liquid was obtained, which was directly used for subsequent click.

[0171] Subsequently, the azide above 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 after monitoring by LC-MS, 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 was 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%, and the separation column type was SW0120, spherical C18, 20-45 μm, Finally, white solid 384 mg was obtained by distillation under reduced pressure, with a yield of 44%.

[0172] 1H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 2H), 8.98 (s, 2H), 7.91 (s, 2H), 7.87 (d, J = 8.0 Hz, 2H), 7.75 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 2.2 Hz, 2H), 7.54 (t, J = 8.0 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, 4H), 2.10 - 2.00 (m, 2H).

[0173] Example 2

[0174] Synthesis of Compound 2

[0175]

[0176] 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)

[0177]

[0178] In accordance with the procedure for Example 1 - Step one for the synthesis of Compound 1

[0179] 1 H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 2H), 8.98 (s, 2H), 7.91 (s, 2H), 7.87 (d, J = 8.0 Hz, 2H), 7.54 (d, J = 8.0 Hz, 2H), 7.51 - 7.42 (m, 4H), 7.16 (d, J = 8.0 Hz, 2H), 5.47 (s, 4H), 5.13 (dd, J = 12.9, 5.3 Hz, 2H), 4.01 (s, 2H), 2.96 - 2.82 (m, 2H), 2.65 - 2.50 (m, 4H), 2.10 - 2.00 (m, 2H).

[0180] Example 3

[0181] Synthesis of Compound 3

[0182]

[0183] 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)

[0184]

[0185] In accordance with the procedure for Example 1 - Synthesis of Compound 1, Step one

[0186] 1 H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 2H), 8.98 (s, 2H), 7.91 (s, 2H), 7.87 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 5.47 (s, 4H), 5.13 (dd, J = 12.9, 5.3 Hz, 2H), 2.96 - 2.82 (m, 2H), 2.65 - 2.50 (m, 4H), 2.10 - 2.00 (m, 2H).

[0187] Example 4

[0188] Synthesis of Compound 4

[0189]

[0190] 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)

[0191]

[0192] In accordance with the procedure for Example 1 - Synthesis of Compound 1, Step one

[0193] 1 H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 2H), 8.98 (s, 2H), 7.91 (s, 2H), 7.87 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 5.47 (s, 4H), 5.13 (dd, J = 12.9, 5.3 Hz, 2H), 2.96 - 2.82 (m, 2H), 2.65 - 2.50 (m, 4H), 2.10 - 2.00 (m, 2H).

[0194] Example 5

[0195] Synthesis of compound 5

[0196]

[0197] 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)

[0198]

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

[0200] 1 H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 2H), 9.47 (s, 2H), 8.19 (s, 2H), 8.09 (d, J = 8.0 Hz, 2H), 7.99 (s, 2H), 7.87 - 7.81 (m, 4H), 7.61 (t, J = 8.0 Hz, 2H), 7.50 (d, J = 8.0 Hz, 2H), 5.15 (dd, J = 12.9, 5.3 Hz, 2H), 4.48 (dd, J = 12.0 Hz, 4H), 4.25 (s, 2H), 2.96 - 2.82 (m, 2H), 2.65 - 2.50 (m, 4H), 2.10 - 2.00 (m, 2H).

[0201] Example 6

[0202] Synthesis of compound 6

[0203]

[0204] 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)

[0205]

[0206] In accordance with the synthesis steps of Example 1 - compound 1

[0207] 1H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 2H), 8.98 (s, 2H), 7.93 (s, 2H), 7.76 (d, J = 8.0 Hz, 2H), 7.67 (d, J = 8.0 Hz, 2H), 7.51 (t, J = 8.0 Hz, 2H), 7.41 (d, J = 2.2 Hz, 2H), 7.33 (s, 2H), 7.25 (d, J = 2.2 Hz, 2H), 5.06 (dd, J = 12.9, 5.3 Hz, 2H), 4.17 (s, 2H), 3.61 (s, 4H), 3.19 (t, J = 7.1 Hz, 4H), 3.02 (t, J = 7.1 Hz, 4H), 2.96 - 2.82 (m, 2H), 2.65 - 2.50 (m, 4H), 2.10 - 2.00 (m, 2H).

[0208] Example 7

[0209] Synthesis of Compound 7

[0210]

[0211] 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)

[0212]

[0213] In accordance with the synthesis of Example 1 - Step one of Compound 1

[0214] 1 H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 2H), 8.97 (s, 2H), 7.92 (s, 2H), 7.85 (t, J = 8.0 Hz, 2H), 7.80 - 7.72 (m, 4H), 7.54 (t, J = 8.0 Hz, 2H), 7.49 (d, J = 2.2 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 5.51 (s, 4H), 5.08 (dd, J = 12.9, 5.3 Hz, 2H), 4.18 (s, 2H), 2.96 - 2.82 (m, 2H), 2.65 - 2.50 (m, 4H), 2.10 - 2.00 (m, 2H).

[0215] Example 8

[0216] Synthesis of Compound 8

[0217]

[0218] 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)

[0219]

[0220] In accordance with the synthesis steps of Example 1 - Compound 1

[0221] 1 H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 2H), 8.95 (s, 2H), 7.88 (s, 2H), 7.82 (d, J = 8.0 Hz, 2H), 7.72 (d, J = 8.0 Hz, 2H), 7.59 (s, 2H), 7.51 (t, J = 8.0 Hz, 2H), 7.42 (td, J = 8.0, 2.2 Hz, 4H), 6.06 (q, J = 6.4 Hz, 2H), 5.13 (dd, J = 13.0, 5.3 Hz, 2H), 4.15 (s, 2H), 2.96 - 2.82 (m, 2H), 2.65 - 2.50 (m, 4H), 2.10 - 2.00 (m, 2H), 1.75 (d, J = 6.4 Hz, 6H).

[0222] Example 9

[0223] Synthesis of Compound 9

[0224]

[0225] 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)

[0226]

[0227] In accordance with the synthesis steps of Example 1 - Compound 1

[0228] 1H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 2H), 8.98 (s, 2H), 7.91 (s, 2H), 7.87 (d, J = 8.0 Hz, 2H), 7.75 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 2.2 Hz, 2H), 7.54 (t, J = 8.0 Hz, 2H), 7.51 - 7.42 (m, 4H), 5.47 (s, 4H), 5.13 (dd, J = 12.9, 5.3 Hz, 2H), 2.96 - 2.82 (m, 2H), 2.65 - 2.50 (m, 4H), 2.10 - 2.00 (m, 2H).

[0229] Example 10

[0230] Synthesis of Compound 10

[0231]

[0232] 5,5'-((oxybis(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)

[0233]

[0234] In accordance with the procedure for Example 1 - Synthesis of Compound 1, Step one

[0235] 1 H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 2H), 8.98 (s, 2H), 7.91 (s, 2H), 7.87 (d, J = 8.0 Hz, 2H), 7.75 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 2.2 Hz, 2H), 7.54 (t, J = 8.0 Hz, 2H), 7.51 - 7.42 (m, 4H), 5.47 (s, 4H), 5.13 (dd, J = 12.9, 5.3 Hz, 2H), 2.96 - 2.82 (m, 2H), 2.65 - 2.50 (m, 4H), 2.10 - 2.00 (m, 2H).

[0236] Example 11

[0237] Synthesis of Compound 11

[0238]

[0239] 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)

[0240]

[0241] In a 50 mL single neck flask, A3-1 (212 mg, 1 mmol) was added, 5 mL tetrahydrofuran was added, nitrogen protection, 1.5 mL zinc borohydride solution (1.5 equiv, 1 M tetrahydrofuran solution) was slowly added under ice bath condition, slowly recovered to room temperature, reacted overnight, LC-MS detected that the reaction was complete, the solution was rotary dried to obtain the crude product A3-2 (about 1 mmol), 5 mL DMF, 4 mL potassium bicarbonate aqueous solution (3 M aqueous solution) were added, 6 mL FSO2N3 solution (0.4 M, 2.4 mmol) was added at room temperature, and the reaction was carried out at room temperature overnight. LC-MS detected that the reaction was complete, water was added, ethyl acetate was extracted, anhydrous sodium sulfate was dried, and column chromatography was used for purification to obtain 210 mg of A3-3. The two-step yield was 78.9%.

[0242] In a 50 mL single neck flask, A3-3 150 mg (0.56 mmol) was added, 352 mg B1 (1 mmol), 28 mg copper sulfate pentahydrate, 894 mg sodium ascorbate, 2 mL water were added, and the reaction was carried out at room temperature overnight. LC-MS detected that the reaction was complete, and column chromatography was used for purification to obtain 240 mg of product, with a yield of 48%.

[0243] 1 H 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), 5.95 (d, J = 7.5 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).

[0244] Example 12

[0245] Synthesis of compound 12

[0246]

[0247] 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)

[0248]

[0249] 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 yield of 59.5% for two steps.

[0250] In a 50 mL single-necked flask, 150 mg of A1-3 (0.6 mmol), 371.5 mg of B1 (1.15 mmol), 38 mg of copper sulfate pentahydrate, 1.2 g of sodium ascorbate, and 2 mL of water were added. After reaction at room temperature overnight, the reaction was detected by LC-MS, and 234 mg of product was obtained by column chromatography with a yield of 44.9%.

[0251] 1 H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 2H), 8.98 (s, 2H), 8.04 (s, 2H), 7.86-7.92 (m, 4H), 7.74 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 8.0 Hz, 2H), 7.45-7.56 (m, 6H), 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).

[0252] Example 13

[0253] Synthesis of compound 13

[0254]

[0255] 5,5'-(((((difluoromethyl)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)

[0256]

[0257] In a 50 mL single neck flask, 272 mg of A2-1 was added, under nitrogen protection, 660 mg of BAST was added under ice bath, heated to 90 °C under nitrogen protection overnight, TLC detection reaction complete, silica gel was added, column chromatography purification to obtain 290 mg of A2-2.

[0258] Then A2-2 was added to a 50 mL single neck flask, 10 mL of acetic acid was added, 0.5 g of reduced iron powder was added under stirring, room temperature reaction overnight, TLC detection reaction complete, filtration and rotary evaporation, 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 the reaction was carried out at room temperature overnight. Ethyl acetate extraction, water washing, anhydrous sodium sulfate drying, column chromatography purification to obtain 160 mg of A2-4, two-step yield 56%.

[0259] In a 50 mL single neck flask, 349 mg of B1 (1.1 mmol) was added, 160 mg of A2-4 (0.55 mmol) was added, 5 mL of DMF was added, 80 mg of cuprous bromide was added, heated to 60 °C, reacted for 4 h, LC-MS detection reaction complete, concentrated, purified by column chromatography to obtain 234 mg of product, yield 46%.

[0260] 1 H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 2H), 8.98 (s, 2H), 7.91 (s, 2H), 7.87 (d, J = 8.0 Hz, 2H), 7.75 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 2.2 Hz, 2H), 7.54 (t, J = 8.0 Hz, 2H), 7.51 - 7.42 (m, 4H), 5.47 (s, 4H), 5.13 (dd, J = 12.9, 5.3 Hz, 2H), 2.96 - 2.82 (m, 2H), 2.65 - 2.50 (m, 4H), 2.10 - 2.00 (m, 2H).

[0261] Example 14

[0262] Synthesis of compound 14

[0263]

[0264] 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)

[0265]

[0266] In a 50 mL single-neck flask, 210 mg of A3-3 (0.8 mmol) was added, 5 mL of dichloromethane, 350 mg of BAST was slowly added under ice bath, slowly returned to room temperature, reacted overnight, LC-MS detected that the reaction was complete, rotary evaporation, column chromatography purification to obtain 190 mg of A3-5.

[0267] In a 50 mL single-neck flask, 210 mg of A3-3 (0.8 mmol) was added, 5 mL of dichloromethane, 350 mg of BAST was slowly added under ice bath, slowly returned to room temperature, reacted overnight, LC-MS detected that the reaction was complete, rotary evaporation, column chromatography purification to obtain 190 mg of A3-5.

[0268] In a 50 mL single-neck flask, 190 mg of A3-5 (0.7 mmol) was added, 442 mg of B1 (1.4 mmol), 5 mL of DMF, 95 mg of cuprous bromide, 60°C for 2h, LC-MS detected that the reaction was complete, column chromatography purification to obtain 270 mg of product, yield 42.7%

[0269] 1 H 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).

[0270] Example 15

[0271] Synthesis of compound 15

[0272]

[0273] N,N'-(Methylenebis(3,1-phenylene))bis(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetamide)

[0274]

[0275] 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%.

[0276] 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 suction gave 2.3 g of A4-3 with a yield of 81%.

[0277] 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%.

[0278] 1 H NMR (400 MHz, DMSO-d6) 11.12 (s, 2H), 10.13 (s, 2H), 7.87 (d, J = 8.0 Hz, 2H), 7.50-7.40 (m, 8H), 7.25 (t, J = 8.0 Hz, 2H), 6.96 (d, J = 8.0 Hz, 2H), 5.12 (dd, J = 12.9, 5.3 Hz, 2H), 4.93 (s, 4H), 3.90 (s, 2H), 2.95-2.85 (m, 2H), 2.65-2.50 (m, 4H), 2.07-2.00 (m, 2H).

[0279] Example 16

[0280] Synthesis of compound 16

[0281]

[0282] 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

[0283]

[0284] 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 completed. Then 50 mL of ethyl acetate and 50 mL of water were added respectively, and the organic phase was extracted and separated three times, and then saturated brine was washed, 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.

[0285] 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, and after 6 hours of reaction at 60°C, the azide was completely converted after monitoring by LC-MS. 50 mL of water was added to the system, and obvious insoluble solids were precipitated. After filtration and separation, a light yellow solid was obtained. Then reverse phase separation and purification were carried out, 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 SW080, spherical C18, 20-45 μm, The light yellow solid was finally obtained by distillation under reduced pressure, and the yield of the above two steps was 58%. The product obtained above was directly used for the next diazo transfer reaction.

[0286] 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 previous 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), which was stirred uniformly, then FSO2N3(2.5 mL, 1.0 mmol, 1.0 equiv, 0.4 M in MTBE) was slowly added, and 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 organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then column chromatography was used for separation and purification (eluent: petroleum ether: ethyl acetate = 1:1 to ethyl acetate), and finally a brown solid was obtained, which was directly used for the subsequent click.

[0287] 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, 500 mL of water was added to the system, and a light brown solid was precipitated. After filtration, the 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 SW120, spherical C18, 20-45 μm, Finally, a white solid was obtained by vacuum distillation, and the total yield of the above four steps was 18%.

[0288] 1 H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 8.98 (s, 2H), 7.92 (s, 2H), 7.87 (d, J = 8.0 Hz, 2H), 7.75 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 2.4 Hz, 2H), 7.54 (t, J = 8.0 Hz, 2H), 7.52 - 7.42 (m, 4H), 5.47 (s, 4H), 5.16 (ddd, J = 26.0, 13.0, 5.2 Hz, 2H), 4.18 (s, 2H), 3.02 (s, 3H), 2.98 - 2.83 (m, 2H), 2.64 - 2.51 (m, 4H), 2.11 - 2.02 (m, 2H).

[0289] Example 17

[0290] Synthesis of compound 17

[0291]

[0292] 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

[0293]

[0294] In accordance with the synthesis of Example 16 - compound 16, step one

[0295] 1 H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 8.98 (s, 2H), 7.92 (s, 2H), 7.87 (d, J = 8.0 Hz, 2H), 7.75 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 2.4 Hz, 2H), 7.54 (t, J = 8.0 Hz, 2H), 7.52 - 7.42 (m, 4H), 5.47 (s, 2H), 5.28 (q, J = 6.8 Hz, 1H), 5.16 (ddd, J = 26.0, 13.0, 5.2 Hz, 2H), 4.18 (s, 2H), 3.02 (s, 3H), 2.98 - 2.83 (m, 2H), 2.64 - 2.51 (m, 4H), 2.11 - 2.02 (m, 2H), 1.83 (d, J = 6.8 Hz, 1H).

[0296] Example 18

[0297] Synthesis of compound 18

[0298]

[0299] 3,3'-(((((methylenebis(3,1-phenylene))bis(1H-1,2,3-triazole-1,4-diyl))bis(methylene))bis(oxy))bis(1-oxoisoindoline-5,2-diyl))dipiperidine-2,6-dione

[0300]

[0301] In accordance with the synthesis of Example 1 - compound 1, step one

[0302] 1H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 2H), 8.98 (s, 2H), 7.91 (s, 2H), 7.87 (d, J = 8.0 Hz, 2H), 7.75 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 2.2 Hz, 2H), 7.54 (t, J = 8.0 Hz, 2H), 7.51 - 7.42 (m, 4H), 5.47 (s, 4H), 5.13 (dd, J = 12.9, 5.3 Hz, 2H), 4.48 (dd, J = 12.0 Hz, 4H), 4.18 (s, 2H), 2.96 - 2.82 (m, 2H), 2.65 - 2.50 (m, 4H), 2.10 - 2.00 (m, 2H).

[0303] Effect Examples:

[0304] CCK-8 experimental operation steps (molecular glue pure product IC 50 value specific operation)

[0305] 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.

[0306] IC 50 value calculation method: the final result is calculated according to the cell survival rate formula: cell survival rate = (experimental hole absorption value-blank hole absorption value) / (control hole absorption value-blank hole absorption value) x 100%. Among them, the experimental hole is the cell treated with molecular glue compound, the control hole is the cell treated with DMSO. The blank hole is the medium without cells. The cell survival rate data is fitted into the cell survival curve by GraphPad software, and the IC 50 value is calculated, and the results are shown in Table 1.

[0307] At this time, the cells include 293T cell line (human embryonic kidney cells, adherent cells), MV411 cell line (human myelomonocytic leukemia cells, suspended cells).

[0308] Table 1

[0309]

[0310]

[0311] Explanation:

[0312] A+++++: IC 50 ≤ 1 nM

[0313] A+++: 1 nM < IC 50 ≤ 10 nM

[0314] A++: 10 nM < IC 50 ≤ 100 nM

[0315] A+: 100 nM < IC 50 ≤ 1000 nM

[0316] A+: 1000 nM < IC 50 ≤ 10000 nM

[0317] From Table 1, we can know that:

[0318] 1) The IC50value of the optimal multivalent compound reaches the pM level, and the antitumor activity of the multivalent compound is significantly improved compared with the monovalent compound;

[0319] 2) The antitumor activity is selective for different modifications.

[0320] Protein degradation experiment operation steps (molecular glue pure DC 50 , D max value specific operation)

[0321] Experimental operation:

[0322] On the first day, 5x10 5 HL-60 cells were plated into a 12-well cell culture plate, 1 mL / well; on the second day, 0, 0.001, 0.01, 0.1, 1, 10, 100 pM concentration gradient of compound was added to the cells, and the drug treatment was 24 hours; on the third day, cell lysate containing protease inhibitor (NP40 buffer + 1% SDS) was added to the cells for lysis, and then SDS loading buffer was added, and boiled at 100°C for 5 minutes. 20 μg of total protein was loaded into a 4-12% SDS-PAGE gel well, and electrophoresis was performed at 120 volts for 90 minutes. After electrophoresis, the protein was transferred to a PVDF membrane by an electroblotting instrument at 120 volts for 45 minutes. Then the PVDF membrane was blocked with 5% skim milk powder at room temperature for 1 hour. The membrane was incubated with GSPT1 protein primary antibody at 4°C overnight. After incubation, the membrane was washed with TBST for 3 times, 5 minutes each time. Then the membrane was incubated with HRP-labeled secondary antibody at room temperature for 1 hour. After incubation, the membrane was washed with TBST for 3 times, 5 minutes each time. The chemiluminescence image was collected by darkroom development technology.

[0323] Result analysis: collect chemiluminescence image by darkroom developing technique to analyze and calculate DC 50 , D max Numerical values, results are shown in Table 2.

[0324] Table 2

[0325] Compound No. DC 50 ]] D max (%)]] 1 2 pM 100 9 <2 pM 100 10 <2 pM 100 Thalidomide > 30 μM 0

[0326] From Table 2, it can be seen that:

[0327] 1) The DC50value of the multivalent compound reaches the pM level, and compared with the monovalent compound thalidomide, the target protein degradation efficiency of the multivalent compound is significantly improved.

[0328] 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 amendments 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 its enantiomers, diastereomers, or pharmaceutically acceptable salts thereof, in, Y is a linking group used to link m Z groups; Z stands for -X2-X3-X4, where -X3-X4 is the E3 ubiquitin ligase-binding ligand, and X2 is used to link Y and -X3-X4. m is selected from the following groups: 2, 3, 4, 5.

2. The compound according to claim 1, characterized in that, The compound is a compound of formula II. Type II Z1-Y1-Z2 in, Y1 is X1 is selected from the following group: -CR1R2-, -(C=O)-, O, S, NH; R1 and R2 are each independently selected from the following group: H, D, halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, hydroxyl-substituted C1-C6 alkyl, hydroxyl-substituted C1-C6 alkoxy. n1 and n2 are each independently selected from the following groups: 0, 1, 2, 3, 4; R 11 R 12 Each is independently selected from the following group: H, D, halogen, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy; Z1 and Z2 may be the same or different, and each is independently -X2-X3-X4; Each x2 may be the same or different, and each x2 may be independently selected from the following groups: -NR3-(C=O)-, -(C=O)-NR3-, -CR4R5-O-, -O-CR4R5-; Each X3 may be the same or different, and each is independently selected from the following groups: -CR4R5-O-, None, -O-CR4R5-, Each x4 may be the same or different, and each x4 may be independently selected from the following groups: Each X5 and X6 is independently selected from the following group: N, -CR3-; Each of R3, R4, and R5 is independently selected from the following group: H, D, C1-C6 alkyl, and halogenated C1-C6 alkyl.

3. The compound according to claim 2, characterized in that, Y1 is selected from the following group: X1, n1, n2, R 11 R 12 As defined in claim 2.

4. The compound according to claim 2, characterized in that, X1 is -CR1R2-; R1 and R2 are each independently selected from the following group: H, D, halogen, hydroxyl, C1-C6 alkyl, and halogenated C1-C6 alkyl.

5. The compound according to claim 1, characterized in that, The compound is a compound of formula III. in, Y2 is X7 is selected from the following group: CR6, N; R6 is selected from the following group: H, D, halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, hydroxyl-substituted C1-C6 alkyl, hydroxyl-substituted C1-C6 alkoxy. R 21 R 22 R 23 Each is independently selected from the following group: H, D, halogen, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy; n3, n4, and n5 are each independently selected from the following groups: 0, 1, 2, 3, and 4; Z3, Z4 and Z5 may be the same or different, and each is independently -X2-X3-X4; Each x2 may be the same or different, and each x2 may be independently selected from the following groups: -NR3-(C=O)-, -(C=O)-NR3-, -CR4R5-O-, -O-CR4R5-; Each X3 may be the same or different, and each is independently selected from the following groups: -CR4R5-O-, None, -O-CR4R5-, Each x4 may be the same or different, and each x4 may be independently selected from the following groups: Each X5 and X6 is independently selected from the following group: N, -CR3-; Each of R3, R4, and R5 is independently selected from the following group: H, D, C1-C6 alkyl, and halogenated C1-C6 alkyl.

6. The compound according to claim 5, characterized in that, Y2 is selected from the following group: X7, R 21 R 22 R 23 n3, n4, and n5 are as defined in claim 5.

7. The compound according to claim 1, characterized in that, The compounds are selected from the group consisting of:

8. A method for preparing the compound according to claim 2, characterized in that, The method is selected from the following group: Method 1, Method 2, and Method 3; Method 1 includes the following steps: 1) Mix N3-Y1—N3 with The reaction yields Wherein, Y1, X3, and X4 are as defined in claim 2; Method 2 includes the following steps: 1) Mix H2N-Y1-NH2 with The reaction yielded Wherein, Y1, X3, and X4 are as defined in claim 2; Method 3 includes the following steps: 1) Mix H2N--Y1-N3 with The reaction yielded 2) Convert to 3) and The reaction yielded Wherein, Y1 is defined as in claim 2; X 31 and X 32 Whether identical or different, each is independently selected from the following groups: -CR4R5-O-, None, -O-CR4R5-, Each X5 and X6 is independently selected from the following group: N, -CR3-; Each of R3, R4, and R5 is independently selected from the following group: H, D, C1-C6 alkyl, halo-C1-C6 alkyl; X 41 and X 42 Whether they are the same or different, each should be selected independently from the following groups:

9. A pharmaceutical composition, characterized in that, The compound comprising a pharmaceutically acceptable carrier and a safe and effective amount as claimed in claim 1.

10. Use of the compound according to claim 1, characterized in that, Used to prepare a medicine for the prevention and / or treatment of diseases selected from the group consisting of: cancer, autoimmune diseases, and inflammatory diseases.

Images