Modularized molecular gel compound library as well as construction method and application thereof

Abstract

The invention relates to a modularized molecular gel compound library as well as a construction method 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 and the like.

Description

Technical Field

[0001] This invention relates to the pharmaceutical field, specifically to a modular molecular glue compound library, its construction method, and its applications. Background Technology

[0002] Molecular glues are a class of compounds or molecules that play a crucial role in binding and stabilizing protein-protein interactions in biological systems. These molecules act as "glue" by enhancing the affinity between proteins, ultimately influencing various cellular processes. Molecular glue compounds have attracted widespread attention in drug discovery, chemical biology, and basic research due to their potential to regulate protein interactions, thereby affecting various cellular pathways.

[0003] Since their initial discovery in the early 1990s, molecular glues have gradually become a hot research area in the scientific and pharmaceutical industries. They are a class of monovalent small molecules that achieve targeted protein degradation by altering the shape of specific degrading enzymes, promoting the binding of these enzymes to proteins that are typically difficult to target. Compared to protein-degrading chimeras (PROTACs), molecular glues are more easily absorbed by cells due to their smaller molecular weight and can exert their effects at lower doses. Unlike targeted PROTACs, which use flexible linkers to connect two ligands and allow them to twist and rotate to form contact points, molecular glue degraders intervene more directly at the protein interface, enhancing the formation of the complex between the E3 ligase and the target protein, thereby inducing increased affinity between them, ultimately leading to ubiquitination and degradation of the target protein. These properties are particularly valuable in the treatment of oncology and rare diseases, as many disease-related proteins have not yet been effectively targeted by traditional small molecule drugs or antibody therapies.

[0004] Currently, the most popular molecular weight gel drugs on the market are approved immunomodulatory drugs (IMiDs) such as thalidomide and its analogues pomalidomide, which can interact with CRL4. CRBN E3 ubiquitin ligase binds to the substrate receptor protein cereblon (CRBN), altering the properties of the substrate protein targeted by CRBN, thereby enabling CRL4 to... CRBN E3 ubiquitin ligases can link to novel substrate proteins and induce their subsequent degradation. Lenalidomide is one of the world's most valuable and commercially viable small-molecule anti-tumor drugs, with sales exceeding $6 billion in 2023.

[0005] Although these drugs are currently used to treat certain types of blood cancers and some autoimmune diseases, their potential applications in other indications highlight the broad prospects of molecular glue technology in the medical field. A search of the Synapse database using the keyword "molecular glue" revealed 76 molecular glue-related drugs in development or on the market, covering 247 indications, 38 targets, and 2124 clinical trials, of which three resulted in drug transactions (lenalidomide, thalidomide, and pomalidomide).

[0006] However, developing innovative molecular glue degraders faces numerous challenges. First, because the binding pocket of molecular glues is located within the dynamic structure of two molecules, unlike traditional drug development and design, molecular glues lack natural binding pockets. Second, initial screening of molecular glue degraders must be conducted in a cellular environment, which not only increases costs and time consumption but also requires extensive post-screening validation. The human body contains over 600 E3 ligases, and selecting ligases suitable for degrading specific target proteins is quite challenging, especially considering that scientists have a relatively deep biological understanding of only 20-30 of these ligases, further complicating the discovery of new molecular glues. Furthermore, the probability of finding small molecules that can facilitate interaction between E3 ligases and target proteins is low, and our current understanding of the general chemical properties of molecular glues is still limited; these factors all increase the complexity of compound library screening.

[0007] Currently, most molecular glue drugs are discovered by chance, and there is no reasonable or systematic method for their design and development. There is an urgent need for an innovative method to break the status quo of accidental discovery of molecular glue drugs. Summary of the Invention

[0008] The purpose of this invention is to provide a compound of Formula I, a method for its preparation, and its use in the prevention and / or treatment of cancer.

[0009] In a first aspect, the present invention provides a molecular gel compound of Formula I, or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof.

[0010] YZ type I

[0011] in,

[0012] Y is selected from the following group of subgroups, whether substituted or unsubstituted: C1-C6 alkyl, -(CH2) m -Saturated or partially unsaturated C3-C12 cycloalkyl groups, -(CH2) m - Contains 1-3 heteroatoms selected from N, O, or S, consisting of 3-8 membered heterocyclic alkyl groups, -(CH2) m - Contains 1-3 heteroatoms selected from N, O, or S, consisting of 5-10 heteroaryl groups, -(CH2) m -C6-C10 aryl,

[0013]

[0014] The substitution independently refers to substitution by 1, 2, 3, or 4 substituents selected from the group consisting of: halogen, hydroxyl, -N3, -CN, =O, amino, -COORc, Ra-substituted or unsubstituted C1-C6 alkyl, Ra-substituted or unsubstituted C2-C6 alkenyl, Ra-substituted or unsubstituted C2-C6 alkynyl, Ra-substituted or unsubstituted C1-C6 alkoxy, Ra-substituted or unsubstituted C1-C6 alkyl-S-, C3-C8 cycloalkyl, C3-C8 cycloalkyl-S-, -(C=O)-Ra-substituted or unsubstituted C1-C6 alkyl, -NH-(C=O)-Ra-substituted or unsubstituted C1-C6 alkyl, -NH-(C=O)-O-(CH2). m -C6-C10 aryl, -NH-(CH2) m -C6-C10 aryl, -(C=O)-NH-(CH2) m -Ra substituted or unsubstituted C6-C10 aryl groups, -(CH2) m -NH-(C=O)-O-Ra substituted or unsubstituted C1-C6 alkyl groups, -N(C1-C6 alkyl)-(C=O)-O-C1-C6 alkyl groups, -(CH2) m -Ra substituted or unsubstituted C6-C10 aryl groups, -O-(CH2) m -Ra substituted or unsubstituted C6-C10 aryl groups, -O-(CH2) m -Ra substituted or unsubstituted 5-10 membered heteroaryl groups containing 1-3 heteroatoms selected from N, O or S; -S-(CH2) m -Ra substituted or unsubstituted C6-C10 aryl groups, -(C=O)-NRcRd, -(C=O)-NH-(CH2) m -(C=O)-NH-Ra substituted or unsubstituted C1-C6 alkyl groups, -(CH2) m -NRcRd, -X1-C3-C8 cycloalkyl, -(CH2) m-Ra-substituted or unsubstituted 3-8 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O, or S; -O-Ra-substituted or unsubstituted 3-8 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O, or S; -(C=O)-Ra-substituted or unsubstituted 3-8 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O, or S; -NH-S(=O)2-Ra-substituted or unsubstituted C1-C6 alkyl groups; -S(=O)2-Ra-substituted or unsubstituted C1-C6 alkyl groups; -NH-S(=O)2-Ra-substituted or unsubstituted C6-C10 aryl groups; -S(=O)2-Ra-substituted or unsubstituted C6-C10 aryl groups. -B-(OH)2、-(CH2) m -(C=O)-O-C1-C6 alkyl, -(C=O)-Ra-substituted or unsubstituted 3-8 membered heterocyclic alkylene group containing 1-3 heteroatoms selected from N, O or S -COORc, -(C=O)-Ra-substituted or unsubstituted C6-C10 aryl, -S(=O)2-NRc-Ra-substituted or unsubstituted C6-C10 aryl, -NH-Ra-substituted or unsubstituted 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, Ra-substituted or unsubstituted 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S,

[0015]

[0016] -P-(C6-C10 aryl)2,

[0017] Each X1 is independently selected from the following groups: O, S, -CRcRd-, -NH-, -O-(CH2). m -、-S(=O)2-;

[0018] Each Ra is independently selected from the group consisting of: halogen, hydroxyl, amino, CN, Rb-substituted or unsubstituted C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, Rb-substituted or unsubstituted C1-C6 alkoxy, -COORc, -N3, Rb substituted or unsubstituted C6-C10 aryl, 5-10 heteroaryl containing 1-3 heteroatoms selected from N, O or S, -NH-(C=O)-O-C1-C6 alkyl, =O, -NH-C6-C10 aryl;

[0019] Each Rc and Rd is independently selected from the following group: H, Rb substituted or unsubstituted C1-C6 alkyl, Rb substituted or unsubstituted C2-C6 alkenyl, Rb substituted or unsubstituted C2-C6 alkynyl, Re substituted or unsubstituted C6-C10 aryl, Re substituted or unsubstituted 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, C3-C8 cycloalkyl;

[0020] Each Rb is independently selected from the following group: halogen, C6-C10 aryl, hydroxyl, -COOH, -COO-C1-C6 alkyl, C1-C6 alkyl-S-, C1-C6 alkoxy, amino, -N3;

[0021] Each Re is independently selected from the following groups: 5-10 membered heteroaryl groups containing 1-3 heteroatoms selected from N, O or S;

[0022] Each m is independently selected from the following group: 0, 1, 2, 3, 4, 5, 6;

[0023] Each n is independently selected from the following groups: 0, 1, 2, 3;

[0024] Z is -X2-X3-X4;

[0025] X2 is selected from the following group: -NR3-(C=O)-, -(C=O)-NR3-, -CR4R5-O-, -O-CR4R5-;

[0026] X3 is selected from the following group: -CR4R5-O-, -CR4R5-NH-, None, -O-CR4R5-

[0027]

[0028] X4 is selected from the following group:

[0029]

[0030]

[0031] Each X5 and X6 is independently selected from the following group: N, -CR3-;

[0032] Each of R3, R4, and R5 is independently selected from the following group: H, D, C1-C6 alkyl, and halogenated C1-C6 alkyl.

[0033] In another preferred embodiment, Y is selected from the following group of substituted or unsubstituted groups: C1-C6 alkyl, -(CH2). m -Saturated or partially unsaturated C3-C12 cycloalkyl groups, -(CH2)m - Contains 1-3 heteroatoms selected from N, O, or S, consisting of 3-8 membered heterocyclic alkyl groups, -(CH2) m - Contains 1-3 heteroatoms selected from N, O, or S, consisting of 5-10 heteroaryl groups, -(CH2) m -C6-C10 aryl,

[0034] The substitution independently refers to substitution by 1, 2, 3, or 4 substituents selected from the group consisting of: halogen, hydroxyl, -N3, -CN, =O, amino, -COORc, Ra-substituted or unsubstituted C1-C6 alkyl, Ra-substituted or unsubstituted C2-C6 alkenyl, Ra-substituted or unsubstituted C2-C6 alkynyl, Ra-substituted or unsubstituted C1-C6 alkoxy, Ra-substituted or unsubstituted C1-C6 alkyl-S-, C3-C8 cycloalkyl, C3-C8 cycloalkyl-S-, -(C=O)-Ra-substituted or unsubstituted C1-C6 alkyl, -NH-(C=O)-Ra-substituted or unsubstituted C1-C6 alkyl, -NH-(C=O)-O-(CH2). m -C6-C10 aryl, -NH-(CH2) m -C6-C10 aryl, -(C=O)-NH-(CH2) m -Ra substituted or unsubstituted C6-C10 aryl groups, -(CH2) m -NH-(C=O)-O-Ra substituted or unsubstituted C1-C6 alkyl groups, -N(C1-C6 alkyl)-(C=O)-O-C1-C6 alkyl groups, -(CH2) m -Ra substituted or unsubstituted C6-C10 aryl groups, -O-(CH2) m -Ra substituted or unsubstituted C6-C10 aryl groups, -O-(CH2) m -Ra substituted or unsubstituted 5-10 membered heteroaryl groups containing 1-3 heteroatoms selected from N, O or S; -S-(CH2) m -Ra substituted or unsubstituted C6-C10 aryl groups, -(C=O)-NRcRd, -(C=O)-NH-(CH2) m -(C=O)-NH-Ra substituted or unsubstituted C1-C6 alkyl groups, -(CH2) m -NRcRd, -X1-C3-C8 cycloalkyl, -(CH2) m-Ra-substituted or unsubstituted 3-8 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O, or S; -O-Ra-substituted or unsubstituted 3-8 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O, or S; -(C=O)-Ra-substituted or unsubstituted 3-8 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O, or S; -NH-S(=O)2-Ra-substituted or unsubstituted C1-C6 alkyl groups; -S(=O)2-Ra-substituted or unsubstituted C1-C6 alkyl groups; -NH-S(=O)2-Ra-substituted or unsubstituted C6-C10 aryl groups; -S(=O)2-Ra-substituted or unsubstituted C6-C10 aryl groups. -B-(OH)2、-(CH2) m -(C=O)-O-C1-C6 alkyl, -(C=O)-Ra-substituted or unsubstituted 3-8 membered heterocyclic alkylene group containing 1-3 heteroatoms selected from N, O or S -COORc, -(C=O)-Ra-substituted or unsubstituted C6-C10 aryl, -S(=O)2-NRc-Ra-substituted or unsubstituted C6-C10 aryl, -NH-Ra-substituted or unsubstituted 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, Ra-substituted or unsubstituted 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S,

[0035]

[0036] -P-(C6-C10 aryl)2,

[0037] Each X1 is independently selected from the following groups: O, S, -CRcRd-, -NH-, -O-(CH2). m -、-S(=O)2-;

[0038] Each Ra is independently selected from the group consisting of: halogen, hydroxyl, amino, CN, Rb-substituted or unsubstituted C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, Rb-substituted or unsubstituted C1-C6 alkoxy, -COORc, -N3, Rb substituted or unsubstituted C6-C10 aryl, 5-10 heteroaryl containing 1-3 heteroatoms selected from N, O or S, -NH-(C=O)-O-C1-C6 alkyl, =O, -NH-C6-C10 aryl;

[0039] Each Rc and Rd is independently selected from the following group: H, Rb substituted or unsubstituted C1-C6 alkyl, Rb substituted or unsubstituted C2-C6 alkenyl, Rb substituted or unsubstituted C2-C6 alkynyl, Re substituted or unsubstituted C6-C10 aryl, Re substituted or unsubstituted 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, C3-C8 cycloalkyl;

[0040] Each Rb is independently selected from the following group: halogen, C6-C10 aryl, hydroxyl, -COOH, -COO-C1-C6 alkyl, C1-C6 alkyl-S-, C1-C6 alkoxy, amino, -N3;

[0041] Each Re is independently selected from the following groups: 5-10 membered heteroaryl groups containing 1-3 heteroatoms selected from N, O or S;

[0042] Each m is independently selected from the following group: 0, 1, 2, 3, 4, 5, 6;

[0043] Each n is independently selected from the following groups: 0, 1, 2, 3.

[0044] In another preferred example, X2 is selected from the following group: -NR3-(C=O)-, -(C=O)-NR3-, -CR4R5-O-, -O-CR4R5-.

[0045] In another preferred embodiment, X2 is

[0046] In another preferred embodiment, X3 is selected from the group consisting of: -CR4R5-O-, -CR4R5-NH-, none, -O-CR4R5-,

[0047] In another preferred embodiment, X3 is -CR4R5-O-;

[0048] R4 and R5 are each independently selected from the following group: H, C1-C6 alkyl.

[0049] In another preferred embodiment, X4 is selected from the following group:

[0050]

[0051] In another preferred embodiment, X4 is selected from the following group:

[0052]

[0053] In another preferred embodiment, X4 is

[0054] In another preferred embodiment, Y is selected from the group consisting of substituted or unsubstituted groups: -(CH2). m -Saturated or partially unsaturated C3-C12 cycloalkyl groups, -(CH2) m - Contains 1-3 heteroatoms selected from N, O, or S, consisting of 3-8 membered heterocyclic alkyl groups, -(CH2) m - Contains 1-3 heteroatoms selected from N, O, or S, consisting of 5-10 heteroaryl groups, -(CH2) m -C6-C10 aryl;

[0055] The replacement is as defined above.

[0056] In another preferred embodiment, in Y, the substitution independently refers to substitution by 1, 2, 3, or 4 substituents selected from the group consisting of halogens, -CF3, Ra-substituted or unsubstituted C1-C6 alkyl-S-, -(CH2). m -Ra substituted or unsubstituted C6-C10 aryl groups, -NH-(CH2) m -C6-C10 aryl, -NH-S(=O)2-Ra substituted or unsubstituted C1-C6 alkyl, -S(=O)2-Ra substituted or unsubstituted C1-C6 alkyl, -NH-S(=O)2-Ra substituted or unsubstituted C6-C10 aryl, -S(=O)2-Ra substituted or unsubstituted C6-C10 aryl, -O-(CH2) m -Ra substituted or unsubstituted C6-C10 aryl groups, -O-(CH2) m -Ra-substituted or unsubstituted 5-10-membered heteroaryl groups containing 1-3 heteroatoms selected from N, O or S; Ra-substituted or unsubstituted 5-10-membered heteroaryl groups containing 1-3 heteroatoms selected from N, O or S;

[0057] Ra is defined as above.

[0058] In another preferred embodiment, each Ra is independently selected from the group consisting of: halogen, amino, -OH, -CF3, Rb-substituted or unsubstituted C1-C6 alkyl, Rb-substituted or unsubstituted C6-C10 aryl;

[0059] Rb is -NH2.

[0060] In another preferred embodiment, the compounds are selected from the group consisting of: compounds shown in Table 1, compounds shown in Table 2, compounds shown in Table 3, compounds shown in Table 4, compounds shown in Table 5, compound 11, compound 12, compound 13, compound 14, and compound 15.

[0061] A second aspect of the present invention provides a method for preparing the compound described in the first aspect of the present invention, or its enantiomers, diastereomers, or pharmaceutically acceptable salts thereof, comprising the steps of:

[0062]

[0063] Y-N3 and The reaction yields

[0064] Wherein, Y, X3, and X4 are as defined in the first aspect of this invention.

[0065] A third aspect of the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a safe and effective amount of the compound of the first aspect of the present invention, or an enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof.

[0066] A fourth aspect of the invention provides the use of the compound described in the first aspect of the invention, or its enantiomers, diastereomers, or pharmaceutically acceptable salts thereof, for the preparation of a medicament for the prevention and / or treatment of diseases selected from the group consisting of: cancer, autoimmune diseases, and inflammatory diseases.

[0067] In another preferred embodiment, the cancer is selected from the group consisting of leukemia, lymphoma, breast cancer, lung cancer, prostate cancer, and melanoma.

[0068] In another preferred embodiment, the autoimmune disease is selected from the group consisting of: rheumatoid arthritis, systemic lupus erythematosus, psoriasis, and multiple sclerosis.

[0069] In another preferred embodiment, the inflammatory disease is selected from the group consisting of Crohn's disease, ulcerative colitis, rheumatoid arthritis, and asthma.

[0070] In another preferred embodiment, the leukemia is selected from the group consisting of myeloid leukemia, lymphocytic leukemia, and hairy cell leukemia.

[0071] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0072] Through long-term and in-depth research, the inventors unexpectedly prepared a molecular adhesive compound with excellent protein degradation properties. Based on this, the inventors completed this invention.

[0073] the term

[0074] In this invention, unless otherwise specified, the terms used have the general meanings known to those skilled in the art.

[0075] In this invention, the term "halogen" refers to F, Cl, Br, or I.

[0076] In this invention, "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, pterpentyl, or similar groups.

[0077] In this invention, the term "C2-C6 alkenyl" refers to a straight-chain or branched alkenyl group having 2-6 carbon atoms and containing a double bond, and includes, without limitation, vinyl, propenyl, butenyl, isobutenyl, pentenyl, and hexenyl groups.

[0078] In this invention, the term "C2-C6 ynyl" refers to a straight-chain or branched ynyl group having 2-6 carbon atoms and containing a triple bond, and includes, without limitation, ethynyl, propynyl, butynyl, isobutynyl, pentylyl, and hexynyl.

[0079] In this invention, the term "C3-C8 cycloalkyl" refers to a cyclic alkyl group having 3-8 carbon atoms on a ring, and includes, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. The term "C3-C12 cycloalkyl" has a similar meaning.

[0080] In this invention, the term "C1-C6 alkoxy" refers to a straight-chain or branched alkoxy group having 1-6 carbon atoms, and includes, without limitation, methoxy, ethoxy, propoxy, isopropoxy, and butoxy. Preferably, it is a C1-C4 alkoxy group.

[0081] In this invention, the term "heterocyclic alkyl" refers to a 4-8 membered heterocyclic group containing 1, 2, or 3 heteroatoms selected from N, O, and S, including (but not limited to) the following groups:

[0082] In this invention, the terms "aromatic ring" or "aryl" have the same meaning, and are preferably "C6-C10 aryl". The term "C6-C10 aryl" refers to an aromatic cyclic group with 6-10 carbon atoms that does not contain heteroatoms on the ring, such as phenyl, naphthyl, etc.

[0083] In this invention, the terms "aromatic heterocycle" or "heteroaryl" have the same meaning, referring to a heteroaromatic group containing one or more heteroatoms. For example, "C3-C10 heteroaryl" refers to an aromatic heterocycle containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen, and 3 to 10 carbon atoms. Non-limiting examples include: furanyl, thiophene, pyridinyl, pyrazolyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is the heteroaryl ring. The heteroaryl group may be optionally substituted or unsubstituted.

[0084] In this invention, the term "halogenated" refers to being replaced by a halogen.

[0085] In this invention, the term "deuterium substitution" refers to being replaced by deuterium.

[0086] In this invention, the term "substitution" refers to the substitution of one or more hydrogen atoms on a specific group by a specific substituent. The specific substituent is the substituent described accordingly above, or the substituent appearing in the various embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substituted site of that group, and the substituents may be the same or different at each position. Those skilled in the art will understand that the combinations of substituents contemplated in this invention are stable or chemically feasible combinations. Such substituents include, but are not limited to: halogens, hydroxyl groups, carboxyl groups (-COOH), C1-C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C3-C8 cycloalkyl groups, 3- to 12-membered heterocyclic groups, aryl groups, heteroaryl groups, C1-C8 aldehyde groups, C2-C10 acyl groups, C2-C10 ester groups, amino groups, C1-C6 alkoxy groups, C1-C10 sulfonyl groups, etc.

[0087] In this invention, the terms 1-6 refer to 1, 2, 3, 4, 5, or 6. Other similar terms each have a similar meaning independently. The term "multiple" refers to 2-6, such as 2, 3, 4, 5, or 6.

[0088] It should be understood that when a group exists simultaneously at multiple different positions in a compound, its definition at each position is independent and can be the same or different. That is, the term "selected from the following group:" and the term "each independently selected from the following group:" have the same meaning.

[0089] compound

[0090] Our research group developed a "modular clicker compound library" method that can construct large compound libraries containing triazole skeletons, which is expected to improve the screening efficiency of colloid drugs. Therefore, based on currently well-studied colloid degraders, we synthesized colloid precursors containing alkyne groups and synthesized small colloid libraries by in-situ CuAAC reactions with 4596 azides in 96-well plates. Subsequently, we collaborated with Professor Min Lu's research group at Ruijin Hospital, Shanghai Jiao Tong University, to explore phenotypic screening and animal experiments. Currently, based on the synthesized alkyne precursors, we have established 7 triazole libraries, totaling 31092 compounds, of which several thousand are colloids.

[0091] The present invention aims to break the current status quo of accidental discovery of molecular glue drugs by constructing a large triazole compound library through a modular click compound library method to improve the possibility of molecular glue drug screening.

[0092] This invention provides compounds of formula I, or their enantiomers, diastereomers, or pharmaceutically acceptable salts thereof.

[0093] YZ type I

[0094] The groups are defined as described above.

[0095] In another preferred embodiment, in the compound, each of the groups is independently the group corresponding to the specific compound of the present invention.

[0096] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by the compounds of the present invention with an acid or base that is suitable for use as a medicine. Pharmaceutically acceptable salts include both inorganic and organic salts. A preferred class of salts are those formed by the compounds of the present invention with an acid. Suitable acids for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, 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, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid.

[0097] Another preferred class of salts are salts formed by the compounds of the present invention with a base, such as alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., magnesium or calcium salts), ammonium salts (such as lower alkanol ammonium salts and other pharmaceutically acceptable amine salts), such as methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tert-butylamine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0098] The embodiments of this invention specifically describe the preparation method of the compound of formula I, but these specific methods do not constitute any limitation on the invention. The compounds of this invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, such combinations being readily performed by those skilled in the art.

[0099] Typically, the raw materials and reagents used in the preparation process of the compounds of the present invention can be purchased commercially unless otherwise specified.

[0100] Pharmaceutical Compositions and Administration

[0101] The present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a safe and effective amount of the compound, or an enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof.

[0102] Because the compounds of the present invention have excellent antitumor activity, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to treat, prevent and alleviate tumor-related diseases.

[0103] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, the compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably, 10-1000 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0104] "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.

[0105] The pharmaceutical composition is an injection, capsule, tablet, pill, powder, or granule.

[0106] 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.

[0107] 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 the dosage forms of capsules, tablets, and pills.

[0108] 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.

[0109] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0110] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0111] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0112] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0113] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0114] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as antitumor drugs).

[0115] The treatment method of the present invention can be used alone or in combination with other treatment methods or drugs.

[0116] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) requiring treatment. The dosage administered is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–2000 mg, preferably 50–1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skills of a skilled physician.

[0117] Compared with the prior art, the present invention has the following main advantages:

[0118] (1) The molecular gel compound of the present invention has excellent protein degradation activity;

[0119] (2) Unlike the traditional approach of accidentally discovering molecular glue drugs, this invention uses click chemistry to discover hundreds of potential molecular glue drugs with excellent protein degradation activity.

[0120] (3) The hundreds of potential molecular gel drugs obtained by the click chemistry method of this invention may bind to different targets, which is expected to lead to the discovery of new targets.

[0121] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions as described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0122] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0123] Preparation Examples

[0124] Synthetic methods of acetylene precursors

[0125] Acetylene precursor 1 ((2-(2,6-dioxopiperidin-3-yl)-5-(prop-2-yn-1-yloxy)isoindoline-1,3-dione))

[0126]

[0127] Synthesis of acetylene precursor 1

[0128]

[0129] 11 g (40 mmol) of 4-hydroxythalidomide and 120 mL of DMF were added to a 250 mL round-bottom flask, followed by 4.2 mL (48 mmol, 1.2 equiv) of propargyl bromide. Finally, 8.5 g (80 mmol) of powdered Na2CO3 was added with stirring. The reaction was carried out at 40 °C for 24 hours (monitored by LC-MS). At this time, a large amount of white insoluble solid was clearly visible in the reaction system.

[0130] After reacting for 24 hours, the reaction solution was cooled to room temperature, and 150 mL of ethyl acetate was added and stirred for 1 hour. Most of the inorganic salts were separated by diatomaceous earth filtration, resulting in a dark brown filtrate. Most of the solvent was then removed by vacuum distillation. The solution was subsequently extracted three times with 150 mL of ethyl acetate and 150 mL of water (a small amount of saturated brine could be added to promote phase separation). The combined organic phases were washed five times with 5 M LiCl aqueous solution, followed by washing with saturated brine, drying over anhydrous sodium sulfate, and removing the solvent by vacuum distillation to obtain a brownish-yellow solid. This solid was then slurried with ethyl acetate:acetone in a 1:1 ratio (150 mL + 150 mL) for one hour, and filtered to obtain 8.4 g of a creamy-white solid with an LC-MS purity of 95% and a yield of approximately 67%.

[0131] 1 H NMR (500MHz, DMSO-d6) δ11.12(s,1H),7.88(d,J=8.3Hz,1H),7.52(d,J=2.3Hz,1H),7.40(dd,J=8.3,2.3Hz,1H),5.13(dd,J=12.9,5 .4Hz,1H),5.06(d,J=2.4Hz,2H),3.69(t,J=2.3Hz,1H),2.89(ddd,J=16.9,13.8,5.4Hz,1H),2.64–2.53(m,2H),2.09–2.02(m,1H).

[0132] MS(ESI,m / z): Calculated value C 16 H 12 N₂O₅: 312.0746 [M+H] + Measured value: 312.0749.

[0133] Acetylene precursor 2((5-(but-3-yn-2-yloxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione))

[0134]

[0135] Synthesis of acetylene precursor 2

[0136]

[0137] 5.5 g (20 mmol) of 4-hydroxythalidomide and 60 mL of DMF were added to a 250 mL round-bottom flask, followed by 5.4 g (24 mmol, 1.2 equiv) of p-toluenesulfonic acid (1-butyn-3-yl) ester. Finally, 4.3 g (40 mmol) of powdered Na2CO3 was added with stirring. The reaction was carried out at 80 °C for 24 hours (monitored by LC-MS). At this time, a large amount of white insoluble solid was clearly visible in the reaction system.

[0138] After reacting for 24 hours, the reaction solution was cooled to room temperature, and 60 mL of ethyl acetate was added and stirred for 1 hour. Most of the inorganic salts were separated by diatomaceous earth filtration, resulting in a dark brown filtrate. Most of the solvent was then removed by vacuum distillation. The filtrate was subsequently extracted three times with 60 mL of ethyl acetate and 60 mL of water (a small amount of saturated brine could be added to promote phase separation). The combined organic phases were washed five times with 5 M LiCl aqueous solution, followed by washing with saturated brine. The solution was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation to obtain a pale yellow solid. Finally, column chromatography was used for purification (eluent: petroleum ether: ethyl acetate = 4:1 to 1:1), yielding 3.2 g of a white solid, with a yield of approximately 50%.

[0139] 1 H NMR (400MHz, DMSO-d6) δ11.12(s,1H),7.87(d,J=8.3Hz,1H),7.51(s,1H),7.40(dd,J=8.3,2.3Hz,1H),5.43(qd,J=6.5,2.0Hz,1H),5.13(dd,J= 12.9,5.3Hz,1H),3.66(dd,J=2.2,1.0Hz,1H),2.89(ddd,J=17.9,14.0,5.2Hz,1H),2.67–2.45(m,3H),2.13–1.97(m,1H),1.61(d,J=6.5Hz,3H).

[0140] MS(ESI,m / z): Calculated value C 17 H 14 N₂O₅: 326.09O₃[M+H] + Measured value: 326.0905.

[0141] Acetylene precursor 3((2-(2,6-dioxopiperidin-3-yl)-5-(4-(prop-2-yn-1-yl)piperazin-1-yl)isoindoline-1,3-dione))

[0142]

[0143] Synthesis of acetylene precursor 3

[0144]

[0145] 1.38 g (5 mmol) of 4-fluthalidomide [2-(2,6-dioxo-3-piperidinyl)-4-fluoro-1H-isoindole-1,3(2H)-dione] and 20 mL of DMF were added to a 50 mL reaction flask. Then, 1.08 g (5.5 mmol) of N-propargylpiperazine dihydrochloride was added, followed by 3.5 mL (2.5 g, 25 mmol) of triethylamine. The mixture was stirred at 60 °C for 6 hours (LC / MS monitoring reaction).

[0146] After the reaction was complete, the reaction solution was poured into 200 mL of saturated brine, extracted with 50 mL x 3 ethyl acetate, and the combined organic phases were washed with 100 mL x 4 saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a dark yellow solid. Finally, column chromatography was used for purification (eluent: dichloromethane / methanol = 100:0 to 10:1), yielding 914 mg of a yellow foamy solid, with a yield of approximately 48%.

[0147] 1H NMR (400MHz, DMSO-d6) δ11.08(s,1H),7.72(m,1H),7.68(d,J=8.5Hz,1H),7.26(dd,J=8.6,2.3Hz,1H),5.16(dd,J=12.8,5.4 Hz,1H),3.47(t,J=5.1Hz,4H),3.35(d,J=2.5Hz,2H),3.20–3.17(m,1H),2.96–2.79(m,1H),2.66–2.52(m,6H),2.04(m,1H).

[0148] The acetylene precursor 4 ((3-(2-propyn-1-ylamino)-2,6-piperidinedione)) is a commercially available reagent.

[0149]

[0150] The acetylene precursor 5((3-(5-ethynyl-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-2,6-piperidindione))

[0151]

[0152] Synthesis of acetylene precursor 5

[0153]

[0154] In a 100 mL single-necked flask, 2.0 g of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 2.4 g of trimethylsilyne, 20 mL of triethylamine, and 30 mL of N,N-dimethylformamide were added. Under nitrogen protection, 59 mg of cuprous iodide and 218 mg of bis(triphenylphosphine)palladium dichloride were added. The reaction was carried out overnight in an oil bath at 70 °C. After the reaction was completed by TLC, water was added, and a solid precipitated. The solid was filtered, washed with water, and an intermediate product was obtained. The intermediate product was added to a 500 mL single-necked flask, 150 mL of dichloromethane was added, and 7.5 mL of tetrabutylammonium fluoride (1 M in THF) was added in an ice bath. The mixture was slowly heated to room temperature. After the reaction was completed by TLC, the product was washed with water, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain 1.3 g of product. The two-step yield was 78%.

[0155] 1H NMR (400MHz, DMSO-d6) δ11.00(s,1H),7.73(d,J=8.2Hz,2H),7.60(dd,J=7.8,1.4Hz,1H),5.12(dd,J=13.3,5.1Hz,1H),4.53–4 .29(m,3H),2.91(ddd,J=17.4,13.6,5.4Hz,1H),2.60(ddd,J=17.3,4.6,2.3Hz,1H),2.39(qd,J=13.2,4.5Hz,1H),2.01(m,1H).

[0156] Synthesis of fluorosulfonyl azide

[0157] Fluorosulfonyl azide

[0158]

[0159] Synthesis of fluorosulfonyl azide (methyl tert-butyl ether solution)

[0160]

[0161] Add sodium azide (1.96 g, 30 mmol, 1 equiv), distilled water (60 mL), and MTBE (60 mL) to a 250 mL polytetrafluoroethylene flask and stir rapidly in an ice bath. Dissolve 1-(fluorosulfonyl)-2,3-dimethyl-1H-imidazolium trifluoromethanesulfonate (11.1 g, 36 mL, 1.2 equiv) completely in MeCN (4 mL). Quickly add the resulting viscous solution to the vigorously stirred mixture and stir vigorously in an ice bath for 10 minutes. Then pour the mixture into a 200 mL separatory funnel and perform phase separation at room temperature. Collect the organic phase containing the product in a plastic bottle and place it in a cool reagent cabinet for 12 hours. Remove the red droplets formed during the settling period using a plastic pipette to obtain a colorless organic phase, i.e., an MTBE solution of FSO₂N₃. 19 It can be used directly after the concentration is determined by F NMR.

[0162] 19 F NMR (400MHz) δ 61.53ppm

[0163] Triazole compound library construction process

[0164] A triazole compound library I (containing a total of 4596 triazole products) was established based on acetylene precursor 1.

[0165]

[0166] First, prepare a 25 mM DMSO solution of acetylene precursor 1, a 250 mM sodium ascorbate aqueous solution, a 5 mM copper sulfate aqueous solution, and a 5 mM MTPTA ligand aqueous solution. Then, mix 50 mL of the 5 mM copper sulfate aqueous solution with 50 mL of the 5 mM ligand aqueous solution to prepare a 100 mL 2.5 mM CuSO4 / ligand aqueous solution.

[0167] To a 96-well plate containing 10 μL of the corresponding azide, 10 μL of 25 mM sodium ascorbate aqueous solution, 20 μL of 25 mM DMSO solution of acetylene precursor 1, and finally 10 μL of 2.5 mM CuSO4 / ligand aqueous solution were added sequentially. After sealing the plate, the reaction mixture was heated to 40 °C at 900 rpm for 24 hours. After 24 hours, random samples were taken for LC-MS monitoring, and the results showed that the azide was almost completely converted. Then, another 50 μL of DMSO was added to the 96-well plate and mixed well. Finally, 50 μL of the reaction solution from 48 of the 96-well plates was transferred to a 384-well plate for phenotypic screening.

[0168] The final screening results were as follows: 961 potential molecular gels with degradation toxicity were screened for the MV411 cell line (human myeloid monocytic leukemia cells); 113 potential molecular gels with degradation toxicity were screened for the U937 cell line (human histiocytic lymphoma cells); and 28 potential molecular gels with degradation toxicity were screened for the 293T cell line (human embryonic kidney cells).

[0169] A triazole compound library II (containing a total of 4608 triazole products) was established based on acetylene precursor 2.

[0170]

[0171] First, prepare a 25 mM DMSO solution of acetylene precursor 2, a 250 mM sodium ascorbate aqueous solution, a 5 mM copper sulfate aqueous solution, and a 5 mM MTPTA ligand aqueous solution. Then, mix 50 mL of the 5 mM copper sulfate aqueous solution with 50 mL of the 5 mM ligand aqueous solution to prepare a 100 mL 2.5 mM CuSO4 / ligand aqueous solution.

[0172] To a 96-well plate containing 10 μL of the corresponding azide, 20 μL of 25 mM DMSO solution of acetylene precursor 2, 10 μL of 2.5 mM CuSO4 / ligand aqueous solution, and finally 10 μL of 25 mM sodium ascorbate aqueous solution were added sequentially. After sealing the plate, the reaction mixture was heated to 40 °C at 900 rpm for 24 hours. After 24 hours, random samples were taken for LC-MS monitoring, and the results showed that the azide was almost completely converted. Then, another 50 μL of DMSO was added to the 96-well plate and mixed well. Finally, 50 μL of the reaction solution from 48 of the 96-well plates was transferred to a 384-well plate for phenotypic screening.

[0173] The final screening results were as follows: 117 potential molecular gels with degradation toxicity were screened for the MV411 cell line (human myeloid monocytic leukemia cells); and 42 potential molecular gels with degradation toxicity were screened for the U937 cell line (human histiocytic lymphoma cells).

[0174] A triazole compound library III (containing a total of 4608 triazole products) was established based on acetylene precursor 3.

[0175] The specific operating procedure is consistent with that of the triazole compound library II established based on acetylene precursor 2.

[0176]

[0177] The final screening results were as follows: 16 potential molecular gels with degradation toxicity were screened for the MV411 cell line (human myeloid monocytic leukemia cells); and 17 potential molecular gels with degradation toxicity were screened for the U937 cell line (human histiocytic lymphoma cells).

[0178] A triazole compound library IV (containing a total of 4032 triazole products) was established based on acetylene precursor 4.

[0179] The specific operating procedure is consistent with that of the triazole compound library II established based on acetylene precursor 2.

[0180]

[0181] The final screening results were as follows: 8 potential molecular gels with degradation toxicity were screened for the MV411 cell line (human myeloid monocytic leukemia cells); and 9 potential molecular gels with degradation toxicity were screened for the U937 cell line (human histiocytic lymphoma cells).

[0182] A triazole compound library V (containing a total of 4032 triazole products) was established based on acetylene precursor 5.

[0183] The specific operating procedure is consistent with that of the triazole compound library II established based on acetylene precursor 2.

[0184] The final screening results were as follows: 758 potential molecular gels with degradation toxicity were screened for the MV411 cell line (human myeloid monocytic leukemia cells); and 96 potential molecular gels with degradation toxicity were screened for the U937 cell line (human histiocytic lymphoma cells).

[0185] Synthesis methods of molecular adhesive examples

[0186] Example 1 - Synthesis of Compound 1 (i.e., Compounds 1-68, 1-236, 1-320)

[0187]

[0188]

[0189] 5-((1-(3-(3-aminobenzyl)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0190]

[0191] 3,3'-Diaminodiphenylmethane (198 mg, 1 mmol, 1 equivalent), KHCO3 (1.3 mL, 4 mmol, 4 equivalent, 3.0 M aqueous solution), and DMF (3 mL) were added sequentially to a 25 mL round-bottom flask equipped with a magnetic stir bar. After stirring thoroughly, FSO2N3 (2.5 mL, 1.0 mmol, 1.0 equivalent, 0.4 M MTBE solution) was slowly added. After reacting for 4 hours, the reaction was confirmed to be complete by LC-MS. Then, 25 mL of ethyl acetate and 25 mL of water were added respectively for extraction and separation three times. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain a brown oily liquid. This was then purified by column chromatography (eluent: petroleum ether to petroleum ether: dichloromethane = 4:1) to obtain the final brown oily liquid, which was directly used for subsequent clicks.

[0192] Subsequently, acetylene precursor 1 (312 mg, 1 mmol, 1 equiv), cuprous bromide (30 mg, 0.2 mmol, 0.2 equiv), and DMF (5 mL) were added to the azide. After heating to 60 °C for 6 hours, LC-MS was used to monitor complete azide conversion. Then, 50 mL of water was added to the system, resulting in the precipitation of an insoluble solid. Filtration yielded a light green solid. Reverse-phase purification was then performed using a water (0.1% TFA):acetonitrile separation system with a separation gradient of water (0.1% TFA):acetonitrile = 95%:5% to 100% acetonitrile. The separation column was an SW080 spherical C18 column, 20-45 μm. Vacuum distillation eventually yielded 250 mg of a white solid, with a yield of 48%.

[0193] 1H NMR (400MHz, DMSO-d6) δ11.12(s,1H),8.97(s,1H),7.87(d,J=8.3Hz,1H),7.78(s, 1H),7.71(d,J=8.2Hz,1H),7.64(s,1H),7.54–7.45(m,2H),7.33(d,J=7.6Hz,1H), 6.97–6.88(m,1H),6.47–6.35(m,3H),5.47(s,2H),5.13(dd,J=12.9,5.4Hz,1H),4 .98(s,2H),3.88(s,2H),2.93–2.84(m,1H),2.62–2.52(m,2H),2.07–2.04(m,1H).

[0194] Example 2 - Synthesis of Compound 2 (i.e., Compounds 1-60, 1-220, and 1-323)

[0195]

[0196] N-((1R,2R)-2-(4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)-1,2-diphenylethyl)-4-methylbenzenesulfonamide

[0197]

[0198] The synthesis steps are consistent with those of Compound 1 in Example 1.

[0199] 1H NMR (500MHz, DMSO-d6) δ11.14(s,1H),8.62(s,1H),8.58(d,J=9.8Hz,1H),7.86(d,J=8.3Hz,1H),7.61(s,1H),7.45(d d,J=8.3,2.3Hz,1H),7.36(d,J=7.0Hz,2H),7.22(d,J=8.1Hz,2H),7.16–7.09(m,3H),7.06(dt,J=7.4,4.3Hz,2H),7. 00(d,J=8.0Hz,2H),6.95–6.88(m,3H),5.94(d,J=11.2Hz,1H),5.46(t,J=10.5Hz,1H),5.36(q,J=12.2Hz,2H),5.14( dd,J=12.8,5.4Hz,1H),2.89(ddd,J=17.8,13.6,5.3Hz,1H),2.64–2.54(m,2H),2.21(s,3H),2.05(d,J=13.3Hz,1H).

[0200] Example 3 - Synthesis of Compound 3 (i.e., Compounds 1-245)

[0201]

[0202] 2-(2,6-dioxopiperidin-3-yl)-5-((1-(4-(quinoline-2-ylmethoxy)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)isoindoline-1,3-dione

[0203]

[0204] The synthesis steps are consistent with those of Compound 1 in Example 1.

[0205] 1 H NMR (400MHz, DMSO-d6) δ11.12(s,1H),8.89(s,1H),8.44(d,J=8.4Hz,1H),8.02( t,J=9.1Hz,2H),7.90–7.76(m,4H),7.71(d,J=8.5Hz,1H),7.65–7.61(m,2H),7.4 8(dd,J=8.5,2.3Hz,1H),7.29(d,J=9.2Hz,2H),5.46(d,J=5.3Hz,4H),5.13(dd,J =12.8,5.3Hz,1H),2.89(t,J=14.5Hz,1H),2.66–2.52(m,2H),2.08–2.03(m,1H).

[0206] Example 4 - Synthesis of Compound 4 (i.e., Compounds 1-235, 1-319)

[0207]

[0208] 5-((1-((10,11-dihydro-5H-dibenzo[a,d][7]cycloen-5-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0209]

[0210] The synthesis steps are consistent with those of Compound 1 in Example 1.

[0211] 1 H NMR(500MHz,DMSO-d6)δ11.14(s,1H),8.06(s,1H),7.83(d,J=8.3Hz,1H),7.51(d, J=2.3Hz,1H),7.37(dd,J=8.3,2.3Hz,1H),7.12(dt,J=14.5,7.5Hz,4H),7.01–6.95 (m,4H),5.30(s,2H),5.14(dd,J=12.8,5.4Hz,1H),4.99(s,2H),3.35(s,1H),2.90 (ddd,J=16.8,13.8,5.4Hz,3H),2.65–2.51(m,2H),2.08(s,4H),2.07–2.04(m,1H).

[0212] Example 5 - Synthesis of Compound 5 (i.e., Compounds 1-242, 1-327)

[0213]

[0214] 2-(2,6-dioxopiperidin-3-yl)-5-((1-(2-(o-tolyloxy)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)isoindoline-1,3-dione

[0215]

[0216] The synthesis steps are consistent with those of Compound 1 in Example 1.

[0217] 1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),8.72(s,1H),7.84–7.72(m,2H),7.59(s,1H) ),7.51–7.40(m,2H),7.32–7.23(m,2H),7.17(q,J=7.0,6.5Hz,1H),7.08(t,J=7. 4Hz,1H),6.91(d,J=8.0Hz,1H),6.83(d,J=8.3Hz,1H),5.43(s,2H),5.10(dd,J=1 2.8,5.3Hz,1H),2.85(s,1H),2.61–2.49(m,2H),2.07(s,3H),2.03–2.01(m,1H).

[0218] Example 6 - Synthesis of Compound 6 (i.e., Compounds 1-105 and 1-288)

[0219]

[0220] 5-((1-(2-(benzylamino)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0221]

[0222] The synthesis steps are consistent with those of Compound 1 in Example 1.

[0223] 1 H NMR (400MHz, DMSO-d6) δ11.12(s,1H),8.65(s,1H),7.85(d,J=8.3Hz,1H),7.65(s ,1H),7.48(dd,J=8.4,2.3Hz,1H),7.31–7.26(m,4H),7.19(t,J=7.7,6.7Hz,3H),6 .68-6.65(m,2H),6.12(t,J=6.1Hz,1H),5.45(s,2H),5.11(dd,J=12.9,5.4Hz,1H ),4.33(d,J=5.9Hz,2H),2.93–2.79(m,1H),2.61–2.49(m,2H),2.04–2.01(m,1H).

[0224] Example 7 - Synthesis of Compound 7 (i.e., Compounds 1-35, 1-256)

[0225]

[0226] 5-((1-(2-(cyclohexylthio)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0227]

[0228] The synthesis steps are consistent with those of Compound 1 in Example 1.

[0229] 1 H NMR (400MHz, DMSO-d6) δ11.14(s,1H),8.63(s,1H),7.87(d,J=8.3Hz,1H),7.71(d ,J=7.9Hz,1H),7.66(s,1H),7.60–7.44(m,4H),5.50(s,2H),5.20–5.07(m,1H),3. 09(s,1H),2.90(t,J=15.0Hz,1H),2.60(d,J=17.1Hz,1H),2.04(d,J=12.3Hz,1H) ,1.73(d,J=12.3Hz,2H),1.55–1.48(m,3H),1.23–1.17(m,3H),1.13-1.07(m,3H).

[0230] Example 8 - Synthesis of Compound 8 (i.e., Compounds 1-163)

[0231]

[0232] 2-(2,6-dioxopiperidin-3-yl)-5-((1-(2-(2-(hydroxymethyl)phenyl)thio)benzyl)-1H-1,2,3-triazol-4-yl)methoxy)isoindoline-1,3-dione

[0233]

[0234] The synthesis steps are consistent with those of Compound 1 in Example 1.

[0235] 1H NMR (400MHz, DMSO-d6) δ11.14(s,1H),8.25(s,1H),7.85(d,J=8.3Hz,1H),7.59(d,J=2. 3Hz,1H),7.56(d,J=7.0Hz,1H),7.44(dd,J=8.4,2.3Hz,1H),7.40–7.30(m,3H),7.24–7. 17(m,2H),7.13–7.08(m,1H),7.06–7.00(m,1H),5.73(s,2H),5.36(s,2H),5.13(dd,J= 12.9,5.3Hz,1H),4.54(s,2H),2.95–2.83(m,1H),2.65–2.51(m,2H),2.06–2.03(m,1H).

[0236] Example 9 - Synthesis of Compound 9 (i.e., Compounds 1-244)

[0237]

[0238] 2-(2,6-dioxopiperidin-3-yl)-5-((1-(2,2-diphenylethyl)-1H-1,2,3-triazol-4-yl)methoxy)isoindoline-1,3-dione

[0239]

[0240] The synthesis steps are consistent with those of Compound 1 in Example 1.

[0241] 1 H NMR (400MHz, DMSO-d6) δ11.13(s,1H),8.11(s,1H),7.82(d,J=8.3Hz,1H),7.50(s,1H),7.36(d,J=7.5Hz,5H),7.25(t,J= 7.5Hz,4H),7.16(t,J=7.0Hz,2H),5.29(s,2H),5.18–5.06(m,3H),4.72(t,J=8.3Hz,1H),2.89(s,1H),2.65–2.52(m,2H).

[0242] Example 10 - Synthesis of Compound 10 (i.e., Compounds 1-193, 1-287)

[0243]

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

[0245]

[0246] The synthesis steps are consistent with those of Compound 1 in Example 1.

[0247] 1 H NMR (400MHz, DMSO-d6) δ11.15(s,1H),8.69(s,1H),7.86(d,J=8.3Hz,1H),7.70–7.59(m,2H),7.53(t,J=7.9Hz,1H),7.46(dd,J=8.4,2.3Hz,1H),7.44 –7.24(m,6H),7.16(t,J=7.5Hz,1H),5.46(s,2H),5.24(s,2H),5.14(dd,J= 13.0,5.3Hz,1H),2.94–2.86(m,1H),2.66–2.51(m,2H),2.08-2.03(m,1H).

[0248] Example 11 - Synthesis of Compound 11

[0249]

[0250] 5-((1-(4-(4,6-bis(4-aminophenyl)-1,3,5-triazin-2-yl)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0251]

[0252] The synthesis steps are consistent with those of Compound 1 in Example 1.

[0253] 1 H NMR (400MHz, DMSO-d6) δ11.13(s,1H),8.87(s,1H),7.95(d,J=7.5Hz,1H),7.90(d,J=7.5Hz,4H),7.85–7.77(m,5H),7.36(d,J=7.5Hz,1H),6 .70(d,J=7.5Hz,4H),5.52(s,2H),5.24(s,4H),5.13(dd,J=12.9,5.3Hz,1H),2.89(t,J=12.9Hz,1H),2.65–2.51(m,2H),2.10–2.00(m,1H).

[0254] Example 12 - Synthesis of Compound 12

[0255]

[0256] 5-((1-(4-(4-amino-2-(trifluoromethyl)phenoxy)-3-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0257]

[0258] The synthesis steps are consistent with those of Compound 1 in Example 1.

[0259] 1 H NMR (400MHz, DMSO-d6) δ11.13(s,1H),8.80(s,1H),7.95(d,J=7.2Hz,1H),7.91 (s,1H),7.8(s,1H),7.57(d,J=7.3Hz,1H),7.36(d,J=7.2Hz,1H),7.14(s,1H),6 .93(d,J=7.3Hz,1H),6.78–6.74(m,2H),5.52(s,2H),5.28(s,2H),5.13(dd,J= 12.9,5.3Hz,1H),2.89(t,J=12.9Hz,1H),2.65–2.51(m,2H),2.10–2.00(m,1H).

[0260] Example 13 - Synthesis of Compound 13

[0261]

[0262] 5-((1-(7-amino-5,5-dioxodibenzo[b,d]thiophene-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0263]

[0264] The synthesis steps are consistent with those of Compound 1 in Example 1.

[0265] 1H NMR (400MHz, DMSO-d6) δ11.13(s,1H),8.87(s,1H),8.16(s,1H),7.96–7.93(m,2H),7.83–7.78(m,3H),7.36(d,J=7.2Hz,1H),7.33(s,1H),7 .58(d,J=7.2Hz,1H),5.52(s,2H),5.28(s,2H),5.13(dd,J=12.9,5.3Hz,1H),2.89(t,J=12.9Hz,1H),2.65–2.51(m,2H),2.10–2.00(m,1H).

[0266] Example 14 - Synthesis of Compound 14

[0267]

[0268] 5-((1-(2-((2-aminophenyl)thio)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0269]

[0270] The synthesis steps are consistent with those of Compound 1 in Example 1.

[0271] 1 H NMR (400MHz, DMSO-d6) δ11.13(s,1H),8.87(s,1H),7.88(d,J=7.6Hz,1H),7.68( s,1H),7.57–7.48(m,2H),7.43(t,J=7.8Hz,1H),7.35(t,J=7.5Hz,1H),7.28–7.1 7(m,2H),6.81(dd,J=9.0,7.3Hz,2H),6.59(t,J=7.4Hz,1H),5.52(s,2H),5.13( dd,J=12.9,5.3Hz,1H),2.96–2.82(m,2H),2.65–2.51(m,2H),2.10–2.00(m,1H).

[0272] Example 15 - Synthesis of Compound 15

[0273]

[0274] 5-((1-(2-chloro-4-(3-chloro-4-methylbenzyl)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0275]

[0276] The synthesis steps are consistent with those of Compound 1 in Example 1.

[0277] 1 H NMR (400MHz, DMSO-d6) δ11.13(s,1H),8.87(s,1H),7.95(d,J=7.3Hz,1H),7.83 (s,1H),7.54(d,J=7.2Hz,1H),7.38–7.35(m,2H),7.31(s,1H),7.10–7.05(m,2 H),7.01(d,J=7.2Hz,1H),5.52(s,2H),5.13(dd,J=12.9,5.3Hz,1H),3.99(s,2 H),2.89(t,J=12.9Hz,1H),2.65–2.51(m,2H),2.16(s,3H),2.10–2.00(m,1H).

[0278] Example 16 Preparation of other compounds (Tables 1-5)

[0279] Referring to Examples 1-15, the difference lies in the use of corresponding raw materials to obtain the other compounds listed in Tables 1-5.

[0280] Example of effect:

[0281] Experimental procedures for sieving drugs using a 384-well plate

[0282] Experimental materials: Chemiluminescence cell viability assay kit (Promega, catalog number G7572), MuIti-Drop automated cell separator (Thermo Scientific), Cell Explorer high-throughput screening workstation (PerkinElmer), CulturPlate-384 cell culture plate (PerkinElmer)

[0283] Experimental procedure: On the first day, cells (MV411, U937, or 293T) were seeded into cell culture plates using an automated separatory funnel at 1500 cells / well, with 50 μL of culture medium containing cells per well. On the second day, 20 384 plates containing the compound were added one by one to the cell culture plates (0.1 μL / well) to achieve a final compound concentration of 10 μM. The treatment lasted for 72 hours. On the fifth day, 10 μL of luminescent cell viability assay reagent was added to each well, and the mixture was shaken for 1 minute to mix before measuring the luminescence intensity.

[0284] Results analysis: The normalized activity value was obtained by dividing the emission signal value of the experimental well in each plate by the average emission signal value of the DMSO well in each plate.

[0285] An activity value of 1 indicates that the cell viability in the experimental wells is consistent with that in the DMSO wells.

[0286] An activity value less than 1 indicates that the cell viability in the experimental wells is lower than that in the DMSO wells.

[0287] An activity value greater than 1 indicates that the cell viability in the experimental wells is higher than that in the DMSO wells.

[0288] At this point, compounds with a standardized activity value of less than 0.5 are considered effective compounds. When the value is less than 0.5, it means that the number of cells in the experimental wells is reduced by more than half compared to the DMSO wells, and it is defined as an effective compound (i.e. a compound with degradation toxicity).

[0289] Using the drug screening method of the present invention, when the molecular gel is the existing molecular gel compound thalidomide, the standardized activity values ​​obtained are 1.08 in 293T cells, 0.94 in MV411 cells, and 0.91 in U937 cells.

[0290] Table 1 shows the molecular glue compounds (Formula IA) prepared based on acetylene precursor 1.

[0291] Table 2 shows the molecular glue compounds (Formula IB) prepared based on acetylene precursor 2.

[0292] Table 3 shows the molecular glue compounds (Formula IC) prepared based on acetylene precursor 3.

[0293] Table 4 shows the molecular glue compounds (Formula ID) prepared based on acetylene precursor 4.

[0294] Table 5 shows the molecular gel compounds (Formula IE) prepared based on acetylene precursor 5.

[0295] illustrate:

[0296] A+++++: Standardized activity value ≤ 0.01

[0297] A++++: 0.01 < standardized activity value ≤ 0.03

[0298] A+++: 0.03 < standardized activity value ≤ 0.05

[0299] A++: 0.05 < standardized activity value ≤ 0.1

[0300] A+: 0.1 < standardized activity value ≤ 0.3

[0301] A: 0.3 < standardized activity value ≤ 0.5

[0302]

[0303] Table 1

[0304]

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333] Table 2

[0334]

[0335]

[0336]

[0337]

[0338]

[0339]

[0340]

[0341]

[0342]

[0343]

[0344]

[0345]

[0346]

[0347]

[0348]

[0349] Table 3

[0350]

[0351]

[0352]

[0353]

[0354]

[0355] Table 4

[0356]

[0357]

[0358]

[0359] Table 5

[0360]

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369]

[0370]

[0371]

[0372]

[0373]

[0374]

[0375]

[0376]

[0377]

[0378]

[0379]

[0380]

[0381]

[0382]

[0383]

[0384]

[0385] CCK-8 Experimental Procedure (Specific Operation for IC50 Value of Pure Molecular Gel)

[0386] Experimental Procedure: On day 1, cells (MV411 or 293T) were seeded at a density of 3000 cells / 90 μL in 96-well plates. On day 2, different concentrations of the molecular gel compound were prepared in 8-tube sets at a 3-fold gradient. Then, 10 μL of the drug-containing culture medium was added to each well. After 3 days of treatment with the molecular gel compound, 10 μL of Cell Counting Kit-8 assay reagent was added to each well, and the cells were incubated at 37°C for 1-2 hours. The absorbance was measured at 450 nm.

[0387] IC50 value calculation method: The final result is calculated according to the cell viability formula: Cell viability = (Absorbance value of experimental wells - Absorbance value of blank wells) / (Absorbance value of control wells - Absorbance value of blank wells) × 100%. Where, experimental wells contain cells treated with a molecular gel compound, control wells contain cells treated with DMSO, and blank wells contain cell-free culture medium. Cell viability data are used to fit cell viability curves using GraphPad software, and the IC50 value is calculated.

[0388] 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).

[0389] Table 6

[0390] Compound numbering MV411 IC50(nM) 293T IC50(nM) 1 (i.e., compounds 1-68, 1-236, and 1-320) A+++ A++ 2 (i.e., compounds 1-60, 1-220, and 1-323) A++++ A++ 3 (i.e., compounds 1-245) A++++ A++ 4 (i.e., compounds 1-235 and 1-319) A++++ A+++ 5 (i.e., compounds 1-242 and 1-327) A+++ A++ 6 (i.e., compounds 1-105 and 1-288) A++++ A++ 7 (i.e., compounds 1-35 and 1-256) A++++ A+++ 8 (i.e., compounds 1-163) A++++ A++ 9 (i.e., compounds 1-244) A+++ A+ 10 (i.e., compounds 1-193 and 1-287) A++++ A++ 11 A+++++ A++++ 12 A++ 13 A+++ 14 A++++ 15 A++ Thalidomide >30000 >30000

[0391] illustrate:

[0392] A+++++:IC50≤1nM

[0393] A++++:1nM<IC50≤10nM

[0394] A+++: 10nM < IC50 ≤ 100nM

[0395] A++: 100nM < IC50 ≤ 1000nM

[0396] A+: 1000nM < IC50 ≤ 10000nM

[0397] As shown in Table 6, based on the drug screening activity results, 15 compounds were selected from the top 50 for synthesis and verification. It was found that these compounds had significantly improved antitumor activity compared with the unmodified thalidomide. The IC50 of these compounds all reached the nM level, which is consistent with the drug screening results.

[0398] Protein degradation experiment procedure (specific operation of DC50 and Dmax values ​​of pure molecular gel).

[0399] Experimental procedure:

[0400] 1. For compounds 1, 4, 8-15, and thalidomide: On day 1, administer 5 × 10 5 MV4-11 cells were seeded into 12-well cell culture plates, 1 mL / well. On the second day, compounds with concentration gradients of 0, 0.01, 0.1, and 1 μM were added to the cells, and treatment lasted 24 hours. On the third day, cell lysis buffer (NP40 buffer + 1% SDS) containing protease inhibitors 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 wells of a 4-12% SDS-PAGE gel and run at 120 V for 90 minutes. After electrophoresis, the protein was transferred to a PVDF membrane using an electroblotting instrument at 120 V for 45 minutes. The PVDF membrane was then blocked with 5% skim milk at room temperature for 1 hour. The membrane was incubated overnight at 4°C with GSPT1 protein primary antibody. After incubation, the membrane was washed three times with TBST for 5 minutes each time. The membrane was then incubated with HRP-labeled secondary antibody at room temperature for 1 hour. After incubation, the membrane was washed three times with TBST for 5 minutes each time. Chemiluminescence images were acquired using darkroom development technology.

[0401] 2. For compounds 3, 5, 6, and 7: On the first day, use 5 × 10 5293T cells were seeded into 12-well cell culture plates, 1 mL / well. On the second day, compounds with concentration gradients of 0, 0.1, 0.3, 1, 3, 10, and 30 μM were added to the cells, and treatment lasted 24 hours. On the third day, cell lysis buffer (NP40 buffer + 1% SDS) containing protease inhibitors 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 wells of a 4-12% SDS-PAGE gel and run at 120 V for 90 minutes. After electrophoresis, the protein was transferred to a PVDF membrane using an electroblotting instrument at 120 V for 45 minutes. The PVDF membrane was then blocked with 5% skim milk at room temperature for 1 hour. Compound 3 was incubated with KPNA2 protein primary antibody, compound 5 with PLK1 protein primary antibody, compound 7 with NFYB protein primary antibody, and compound 8 with CDC20 protein primary antibody overnight at 4°C. After incubation, the membrane was washed three times with TBST for 5 minutes each time. It was then incubated with HRP-labeled secondary antibody at room temperature for 1 hour. After incubation, the membrane was washed three times with TBST for 5 minutes each time. Chemiluminescence images were acquired using darkroom development techniques.

[0402] 3. For compound 2: On the first day, 5 × 10 5 1 THP-1 cells were seeded into 12-well cell culture plates, 1 mL / well. On the second day, compounds with concentration gradients of 0, 0.1, 0.3, 1, 3, 10, and 30 μM were added to the cells, and treatment lasted 24 hours. On the third day, cell lysis buffer (NP40 buffer + 1% SDS) containing protease inhibitors 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 wells of a 4-12% SDS-PAGE gel and run at 120 V for 90 minutes. After electrophoresis, the protein was transferred to a PVDF membrane using an electroblotting instrument at 120 V for 45 minutes. The PVDF membrane was then blocked with 5% skim milk at room temperature for 1 hour. The membrane was incubated overnight at 4°C with MYB protein primary antibody. After incubation, the membrane was washed three times with TBST for 5 minutes each time. The membrane was then incubated with HRP-labeled secondary antibody at room temperature for 1 hour. After incubation, the membrane was washed three times with TBST for 5 minutes each time. Chemiluminescence images were acquired using darkroom development technology.

[0403] Results Analysis: DC was calculated by analyzing chemiluminescence images acquired using darkroom development technology. 50 And the Dmax value.

[0404] Table 7

[0405] Compound numbering <![CDATA[DC 50 (nM)]]> Dmax(%) 1 (i.e., compounds 1-68, 1-236, and 1-320) A++++ A+++++ 2 (i.e., compounds 1-60, 1-220, and 1-323) A+++ A+++++ 3 (i.e., compounds 1-245) A++ A++++ 4 (i.e., compounds 1-235 and 1-319) A+++++ A+++++ 5 (i.e., compounds 1-242 and 1-327) A+++ A++++ 6 (i.e., compounds 1-105 and 1-288) A++ A+++ 7 (i.e., compounds 1-35 and 1-256) A++ A++++ 8 (i.e., compounds 1-163) A+++++ A+++++ 9 (i.e., compounds 1-244) A+++++ A+++++ 10 (i.e., compounds 1-193 and 1-287) A+++++ A+++++ 11 A+++++ A+++++ 12 A++++ A+++++ 13 A+++++ A+++++ 14 A++++ A+++++ 15 A++++ A+++++ Thalidomide >30μM 0

[0406] illustrate:

[0407] A+++++:DC 50 ≤10nM

[0408] A++++:10nM<DC 50 ≤100nM

[0409] A+++: 100nM < DC 50 ≤1000nM

[0410] A++: 1000nM < DC 50 ≤10000nM

[0411] A+++++: 90%<Dmax≤100%

[0412] A++++: 70% < Dmax ≤ 90%

[0413] A+++: 50% ≤ Dmax ≤ 70%

[0414] As shown in Table 7, different compounds exhibit differences in the selection of degradation targets and the efficiency of target degradation, indicating that the degradation of different targets is selective for the linkage of amine precursors.

[0415] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A molecular gel compound of Formula I, or its enantiomers, diastereomers, or pharmaceutically acceptable salts thereof. YZ Formula I in, Y is selected from the following group of subgroups, whether substituted or unsubstituted: C1-C6 alkyl, -(CH2) m -Saturated or partially unsaturated C3-C12 cycloalkyl groups, -(CH2) m - Contains 1-3 heteroatoms selected from N, O, or S, consisting of 3-8 membered heterocyclic alkyl groups, -(CH2) m - Contains 1-3 heteroatoms selected from N, O, or S, consisting of 5-10 heteroaryl groups, -(CH2) m -C6-C10 aryl, The substitution independently refers to substitution by 1, 2, 3, or 4 substituents selected from the group consisting of: halogen, hydroxyl, -N3, -CN, =O, amino, -COORc, Ra-substituted or unsubstituted C1-C6 alkyl, Ra-substituted or unsubstituted C2-C6 alkenyl, Ra-substituted or unsubstituted C2-C6 alkynyl, Ra-substituted or unsubstituted C1-C6 alkoxy, Ra-substituted or unsubstituted C1-C6 alkyl-S-, C3-C8 cycloalkyl, C3-C8 cycloalkyl-S-, -(C=O)-Ra-substituted or unsubstituted C1-C6 alkyl, -NH-(C=O)-Ra-substituted or unsubstituted C1-C6 alkyl, -NH-(C=O)-O-(CH2). m -C6-C10 aryl, -NH-(CH2) m -C6-C10 aryl, -(C=O)-NH-(CH2) m -Ra substituted or unsubstituted C6-C10 aryl groups, -(CH2) m -NH-(C=O)-O-Ra substituted or unsubstituted C1-C6 alkyl groups, -N(C1-C6 alkyl)-(C=O)-O-C1-C6 alkyl groups, -(CH2) m -Ra substituted or unsubstituted C6-C10 aryl groups, -O-(CH2) m -Ra substituted or unsubstituted C6-C10 aryl groups, -O-(CH2) m -Ra substituted or unsubstituted 5-10 membered heteroaryl groups containing 1-3 heteroatoms selected from N, O or S; -S-(CH2) m -Ra substituted or unsubstituted C6-C10 aryl groups, -(C=O)-NRcRd, -(C=O)-NH-(CH2) m -(C=O)-NH-Ra substituted or unsubstituted C1-C6 alkyl groups, -(CH2) m -NRcRd, -X1-C3-C8 cycloalkyl, -(CH2) m -Ra-substituted or unsubstituted 3-8 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O, or S; -O-Ra-substituted or unsubstituted 3-8 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O, or S; -(C=O)-Ra-substituted or unsubstituted 3-8 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O, or S; -NH-S(=O)2-Ra-substituted or unsubstituted C1-C6 alkyl groups; -S(=O)2-Ra-substituted or unsubstituted C1-C6 alkyl groups; -NH-S(=O)2-Ra-substituted or unsubstituted C6-C10 aryl groups; -S(=O)2-Ra-substituted or unsubstituted C6-C10 aryl groups. -B-(OH)2、-(CH2) m -(C=O)-O-C1-C6 alkyl, -(C=O)-Ra-substituted or unsubstituted 3-8 membered heterocyclic alkylene group containing 1-3 heteroatoms selected from N, O or S -COORc, -(C=O)-Ra-substituted or unsubstituted C6-C10 aryl, -S(=O)2-NRc-Ra-substituted or unsubstituted C6-C10 aryl, -NH-Ra-substituted or unsubstituted 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, Ra-substituted or unsubstituted 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, Each X1 is independently selected from the following groups: O, S, -CRcRd-, -NH-, -O-(CH2). m -、-S(=O)2-; Each Ra is independently selected from the group consisting of: halogen, hydroxyl, amino, CN, Rb-substituted or unsubstituted C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, Rb-substituted or unsubstituted C1-C6 alkoxy, -COORc, -N3, Rb substituted or unsubstituted C6-C10 aryl, 5-10 heteroaryl containing 1-3 heteroatoms selected from N, O or S, -NH-(C=O)-O-C1-C6 alkyl, =O, -NH-C6-C10 aryl; Each Rc and Rd is independently selected from the following group: H, Rb substituted or unsubstituted C1-C6 alkyl, Rb substituted or unsubstituted C2-C6 alkenyl, Rb substituted or unsubstituted C2-C6 alkynyl, Re substituted or unsubstituted C6-C10 aryl, Re substituted or unsubstituted 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, C3-C8 cycloalkyl; Each Rb is independently selected from the following group: halogen, C6-C10 aryl, hydroxyl, -COOH, -COO-C1-C6 alkyl, C1-C6 alkyl-S-, C1-C6 alkoxy, amino, -N3; Each Re is independently selected from the following groups: 5-10 membered heteroaryl groups containing 1-3 heteroatoms selected from N, O or S; Each m is independently selected from the following group: 0, 1, 2, 3, 4, 5, 6; Each n is independently selected from the following groups: 0, 1, 2, 3; Z is -X2-X3-X4; X2 is selected from the following group: -NR3-(C=O)-, -(C=O)-NR3-, -CR4R5-O-, -O-CR4R5-; X3 is selected from the following group: -CR4R5-O-, -CR4R5-NH-, None, -O-CR4R5- X4 is selected from the following group: 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.

2. The compound according to claim 1, characterized in that, X2 is 3. The compound according to claim 1, characterized in that, X3 is -CR4R5-O-; R4 and R5 are each independently selected from the following group: H, C1-C6 alkyl.

4. The compound according to claim 1, characterized in that, Y is selected from the following group, either substituted or unsubstituted: -(CH2) m -Saturated or partially unsaturated C3-C12 cycloalkyl groups, -(CH2) m - Contains 1-3 heteroatoms selected from N, O, or S, consisting of 3-8 membered heterocyclic alkyl groups, -(CH2) m - Contains 1-3 heteroatoms selected from N, O, or S, consisting of 5-10 heteroaryl groups, -(CH2) m -C6-C10 aryl; The substitution is as defined in claim 1.

5. The compound according to claim 1, characterized in that, In Y, the substitution independently refers to substitution by 1, 2, 3, or 4 substituents selected from the group consisting of halogens, -CF3, Ra-substituted or unsubstituted C1-C6 alkyl groups -S-, -(CH2). m -Ra substituted or unsubstituted C6-C10 aryl groups, -NH-(CH2) m -C6-C10 aryl, -NH-S(=O)2-Ra substituted or unsubstituted C1-C6 alkyl, -S(=O)2-Ra substituted or unsubstituted C1-C6 alkyl, -NH-S(=O)2-Ra substituted or unsubstituted C6-C10 aryl, -S(=O)2-Ra substituted or unsubstituted C6-C10 aryl, -O-(CH2) m -Ra substituted or unsubstituted C6-C10 aryl groups, -O-(CH2) m -Ra-substituted or unsubstituted 5-10-membered heteroaryl groups containing 1-3 heteroatoms selected from N, O or S; Ra-substituted or unsubstituted 5-10-membered heteroaryl groups containing 1-3 heteroatoms selected from N, O or S; Ra is as defined in claim 1.

6. The compound according to claim 1, characterized in that, Each Ra is independently selected from the following group: halogen, amino, -OH, -CF3, Rb-substituted or unsubstituted C1-C6 alkyl, Rb-substituted or unsubstituted C6-C10 aryl; Rb is -NH2.

7. The compound according to claim 1, characterized in that, The compounds are selected from the following group: compounds shown in Table 1, compounds shown in Table 2, compounds shown in Table 3, compounds shown in Table 4, compounds shown in Table 5, compound 11, compound 12, compound 13, compound 14, and compound 15.

8. A method for preparing the compound of claim 2, or its enantiomers, diastereomers, or pharmaceutically acceptable salts thereof, characterized in that, Including the following steps: will with The reaction yields Wherein, Y, X3, and X4 are as defined in claim 1.

9. A pharmaceutical composition, characterized in that, The compound of claim 1, or its enantiomers, diastereomers, or pharmaceutically acceptable salts thereof, comprising a pharmaceutically acceptable carrier and a safe and effective amount thereof.

10. Use of the compound of claim 1, or its enantiomers, diastereomers, or pharmaceutically acceptable salts thereof, 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.

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