Modular molecular glue compound library, construction method therefor and use thereof

Abstract

The present invention relates to a modular molecular glue compound library, a construction method therefor and the use thereof. Specifically, a compound of the present invention has a structure represented by formula I, the definitions of each group and substituent being as described in the description. Also disclosed in the present invention are a preparation method for the compound and the use thereof in preventing and / or treating cancers and the like.

Description

A modular library of molecular glue compounds, and methods of construction and use thereof TECHNICAL FIELD

[0001] The present application relates to the field of medicine, in particular to a modular library of molecular glue compounds, and methods of construction and use thereof. BACKGROUND

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

[0003] Since the first discovery in the early 1990s, molecular glue has gradually become a research hotspot in the scientific community and the pharmaceutical industry. It is a class of monovalent small molecules that promote the binding of specific degrading enzymes to proteins that are usually difficult to target by changing the shape of the degrading enzyme, thereby achieving targeted protein degradation. Compared with PROTAC, molecular glue is easier to be absorbed by cells due to its smaller molecular weight and can function at lower doses. Unlike PROTAC, which uses a flexible linker to connect two ligands and allows them to twist and rotate to form contact points, molecular glue degraders intervene more directly in the protein interface, strengthening the complex formation between E3 ligase and target proteins, thereby inducing an increase in their affinity, ultimately leading to ubiquitination and degradation of the target protein. These characteristics are particularly valuable in the fields of oncology and rare disease treatment, as many disease-related proteins have not been effectively targeted by traditional small molecule drugs or antibody therapies.

[0004] The most popular molecular glue drug on the market is thalidomide and its analogs, such as pomalidomide, which are approved immunomodulatory drugs (IMiDs). They can bind to the substrate receptor protein cereblon (CRBN) in the CRL4 CRBN E3 ubiquitin ligase, change the properties of the substrate proteins targeted by CRBN, and allow CRL4 CRBN E3 ubiquitin ligase to connect with new substrate proteins and induce the subsequent degradation of the proteins. Among them, lenalidomide is the most valuable and commercially valuable anti-tumor small molecule drug in the world, with sales exceeding $6 billion in 2023.

[0005] Although these drugs are currently used to treat certain types of blood cancer 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" found that there are a total of 76 drugs related to molecular glue in development or on the market, involving 247 indications, 38 targets, and 2124 clinical trials, of which 3 have resulted in drug transactions (lenalidomide, thalidomide, and pomalidomide, respectively).

[0006] However, there are many challenges in developing innovative molecular glue degraders. First, since the binding pocket of molecular glue is located between the dynamic structures of two molecules, there is no natural pocket for molecular glue to bind compared to traditional drug development design. Second, the preliminary screening of molecular glue degraders must be done in a cellular environment, which not only increases costs and time consumption, but also requires a lot of post-validation work. There are more than 600 E3 ligases in the human body, and it is challenging to select ligases suitable for degrading specific target proteins, especially considering that scientists have a deeper biological understanding of only 20-30 of these ligases, which makes it more difficult to discover new molecular glues. In addition, the probability of finding small molecules that can promote the interaction between E3 ligases and target proteins is low, and the current understanding of the general chemical properties of molecular glues is shallow, which all increase the complexity of compound library screening.

[0007] Most molecular glue drugs are discovered accidentally, and there is no reasonable or systematic method to design and develop them, so an innovative method is needed to break the status quo of accidental discovery of molecular glue drugs. SUMMARY

[0008] The purpose of the present application is to provide a compound represented by Formula I and a preparation method thereof and the use thereof in the prevention and / or treatment of cancer and the like.

[0009] In a first aspect of the present application, a molecular glue compound represented by Formula I, or an enantiomer, diastereomer thereof, or a pharmaceutically acceptable salt thereof is provided, Y-Z Formula I

[0010] wherein,

[0011] Y is selected from the following group of substituted or unsubstituted groups: C1-C6 alkyl, -(CH2) m -saturated or partially unsaturated C3-C12 cycloalkyl, -(CH2) m -3-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S, -(CH2) m -5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, -(CH2) m -C6-C10 aryl, said substitution independently means substitution with 1, 2, 3 or 4 substituents selected from the group consisting of halogen, hydroxy, -N3, -CN, =0, amino, -COORc, R3substituted or unsubstituted C1-C6alkyl, R3substituted or unsubstituted C2-C6alkenyl, R3substituted or unsubstituted C2-C6alkynyl, R3substituted or unsubstituted C1-C6alkoxy, R3substituted or unsubstituted C1-C6alkyl-S-, C3-C8cycloalkyl, C3-C8cycloalkyl-S-, -(C=0)-R3substituted or unsubstituted C1-C6alkyl, -NH-(C=0)-R3substituted or unsubstituted C1-C6alkyl, -NH-(C=0)-0-(CH2) m -C6-C10aryl, -NH-(CH2) m -C6-C10aryl, -(C=0)-NH-(CH2) m -R3substituted or unsubstituted C6-C10aryl, -(CH2) m -NH-(C=0)-0-R3substituted or unsubstituted C1-C6alkyl, -N(C1-C6alkyl)-(C=0)-0-C1-C6alkyl, -(CH2) m -R3substituted or unsubstituted C6-C10aryl, -0-(CH2) m -R3substituted or unsubstituted C6-C10aryl, -0-(CH2) m -R3substituted or unsubstituted 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, -S-(CH2) m -R3substituted or unsubstituted C6-C10aryl, -(C=0)-NRcRd, -(C=0)-NH-(CH2) m -(C=0)-NH-R3substituted or unsubstituted C1-C6alkyl, -(CH2) m -NRcRd, -X1-C3-C8cycloalkyl, -(CH2) m -R3substituted or unsubstituted 3-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S, -0-R3substituted or unsubstituted 3-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S, -(C=0)-R3substituted or unsubstituted 3-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S, -NH-S(=0)2-R3substituted or unsubstituted C1-C6alkyl, -S(=0)2-R3substituted or unsubstituted C1-C6alkyl, -NH-S(=0)2-R3substituted or unsubstituted C6-C10aryl, -S(=0)2-R3substituted or unsubstituted C6-C10aryl, -B-(OH)2, -(CH2)m -(C=0)-0-Ci-C6alkyl, -(C=0)-Ra-substituted or unsubstituted 3-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O, or S, - (C=0)-Rc, -(C=0)-Ra-substituted or unsubstituted C6-Cio aryl, -S(=0)2-NRc-Ra- substituted or unsubstituted C6-Cio aryl, -NH-Ra-substituted or unsubstituted 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O, or S, Ra- substituted or unsubstituted 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O, or S, -P-(C6-Cio aryl)2,

[0012] each X1is independently selected from the group consisting of O, S, -CRcRd-, -NH-, -0-(CH2) m -,-S(=0)2-;

[0013] each Ra is independently selected from the group consisting of halogen, hydroxyl, amino, CN, Rb-substituted or unsubstituted Ci-C6alkyl, C2-C6alkenyl, C3-C8cycloalkyl, Rb-substituted or unsubstituted Ci-C6alkoxy, -COORc, -N3, Rb-substituted or unsubstituted C6-Cio aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O, or S, -NH-(C=0)-0-Ci-C6alkyl, =0, -NH-C6-Cio aryl;

[0014] each Rc, Rd is each independently selected from the group consisting of H, Rb-substituted or unsubstituted Ci-C6alkyl, Rb-substituted or unsubstituted C2-C6alkenyl, Rb-substituted or unsubstituted C2-C6alkynyl, Re-substituted or unsubstituted C6-Cio aryl, Re-substituted or unsubstituted 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O, or S, C3-C8cycloalkyl;

[0015] each Rb is independently selected from the group consisting of halogen, C6-Cio aryl, hydroxyl, -COOH, -COO-Ci-C6alkyl, Ci-C6alkyl-S-, Ci-C6alkoxy, amino, -N3;

[0016] each Re is independently selected from the group consisting of: 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O, or S;

[0017] each m is independently selected from the group consisting of 0, 1, 2, 3, 4, 5, 6;

[0018] each n is independently selected from the group consisting of 0, 1, 2, 3;

[0019] Z is -X2-X3-X4;

[0020] X2is selected from the group consisting of: -NR3-(C=0)-, -(C=0)-NR3-, -CR4R5-0-, -0-CR4R5-;

[0021] X3is selected from the group consisting of: -CR4R5-0-, -CR4R5-NH-, null, -0-CR4R5-,

[0022] X4is selected from the group consisting of:

[0023] each X5, X6is independently selected from the group consisting of: N, -CR3-;

[0024] each R3, R4, R5is independently selected from the group consisting of: H, D, C1-C6alkyl, haloC1-C6alkyl.

[0025] In another preferred embodiment, Y is selected from the group consisting of substituted or unsubstituted: C1-C6alkyl, -(CH2) m -saturated or partially unsaturated C3-C12cycloalkyl, -(CH2) m -3-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from the group consisting of N, O, or S, -(CH2) m -5-10 membered heteroaryl containing 1-3 heteroatoms selected from the group consisting of N, O, or S, -(CH2) m -C6-C10aryl, said substitution is independently substitution with 1, 2, 3, or 4 substituents selected from the group consisting of: halogen, hydroxyl, -N3, -CN, =0, amino, -COORc, Ra-substituted or unsubstituted C1-C6alkyl, Ra-substituted or unsubstituted C2-C6alkenyl, Ra-substituted or unsubstituted C2-C6alkynyl, Ra-substituted or unsubstituted C1-C6alkoxy, Ra-substituted or unsubstituted C1-C6alkyl-S-, C3-C8cycloalkyl, C3-C8cycloalkyl-S-, -(C=0)-Ra-substituted or unsubstituted C1-C6alkyl, -NH-(C=0)-Ra-substituted or unsubstituted C1-C6alkyl, -NH-(C=0)-O-(CH2) m -C6-C10aryl, -NH-(CH2) m -C6-C10aryl, -(C=0)-NH-(CH2) m -Ra-substituted or unsubstituted C6-C10aryl, -(CH2)m -NH-(C=O)-O-Ra-substituted or unsubstituted C1-C6alkyl, -N(C1-C6alkyl)-(C=O)-O-C1-C6alkyl, -(CH2) m -Ra-substituted or unsubstituted C6-C10aryl, -O-(CH2) m -Ra-substituted or unsubstituted C6-C10aryl, -O-(CH2) m -Ra-substituted or unsubstituted 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O, or S, -S-(CH2) m -Ra-substituted or unsubstituted C6-C10aryl, -(C=O)-NRcRd, -(C=O)-NH-(CH2) m -(C=O)-NH-Ra-substituted or unsubstituted C1-C6alkyl, -(CH2) m -NRcRd, -X1-C3-C8cycloalkyl, -(CH2) m -Ra-substituted or unsubstituted 3-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O, or S, -O-Ra-substituted or unsubstituted 3-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O, or S, -(C=O)-Ra-substituted or unsubstituted 3-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O, or S, -NH-S(=O)2-Ra-substituted or unsubstituted C1-C6alkyl, -S(=O)2-Ra-substituted or unsubstituted C1-C6alkyl, -NH-S(=O)2-Ra-substituted or unsubstituted C6-C10aryl, -S(=O)2-Ra-substituted or unsubstituted C6-C10aryl, -B-(OH)2, -(CH2) m -(C=O)-O-C1-C6alkyl, -(C=O)-Ra-substituted or unsubstituted 3-8 membered heterocycloalkylene containing 1-3 heteroatoms selected from N, O, or S, -COORc, -(C=O)-Ra-substituted or unsubstituted C6-C10aryl, -S(=O)2-NRc-Ra-substituted or unsubstituted C6-C10aryl, -NH-Ra-substituted or unsubstituted 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O, or S, Ra-substituted or unsubstituted 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O, or S, -P-(C6-C10aryl)2,

[0026] each X1is independently selected from the group consisting of O, S, -CRcRd-, -NH-, -O-(CH2) m -, -S(=O)2-;

[0027] each Ra is independently selected from the group consisting of halogen, hydroxyl, amino, CN, Rb-substituted or non-substituted C1-C6alkyl, C2-C6alkenyl, C3-C8cycloalkyl, Rb-substituted or non-substituted C1-C6alkoxy, -COORc, -N3, Rb-substituted or non-substituted C6-C10aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, -NH-(C=O)-O-C1-C6alkyl, =O, -NH-C6-C10aryl;

[0028] each Rc, Rd is independently selected from the group consisting of H, Rb-substituted or non-substituted C1-C6alkyl, Rb-substituted or non-substituted C2-C6alkenyl, Rb-substituted or non-substituted C2-C6alkynyl, Re-substituted or non-substituted C6-C10aryl, Re-substituted or non-substituted 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, C3-C8cycloalkyl;

[0029] each Rb is independently selected from the group consisting of halogen, C6-C10aryl, hydroxyl, -COOH, -COO-C1-C6alkyl, C1-C6alkyl-S-, C1-C6alkoxy, amino, -N3;

[0030] each Re is independently selected from the group consisting of: 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S;

[0031] each m is independently selected from the group consisting of 0, 1, 2, 3, 4, 5, 6;

[0032] each n is independently selected from the group consisting of 0, 1, 2, 3.

[0033] In another preferred embodiment, X2 is selected from the group consisting of: -NR3-(C=O)-, -(C=O)-NR3-, -CR4R5-O-, -O-CR4R5-.

[0034] In another preferred embodiment, X2 is

[0035] In another preferred embodiment, X3 is selected from the group consisting of -CR4R5-O-, -CR4R5-NH-, null, -O-CR4R5-,

[0036] In another preferred embodiment, X3 is -CR4R5-O-;

[0037] R4, R5 are each independently selected from the group consisting of H, C1-C6alkyl.

[0038] In another preferred embodiment, X4 is selected from the group consisting of:

[0039] In another preferred embodiment, X4is selected from the group consisting of:

[0040] In another preferred embodiment, X4is

[0041] In another preferred embodiment, Y is selected from the group consisting of substituted or unsubstituted -(CH2) m - saturated or partially unsaturated C3-C12cycloalkyl, -(CH2) m - 3-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O, or S, -(CH2) m - 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O, or S, -(CH2) m - C6-C10aryl;

[0042] said substituents are as defined above.

[0043] In another preferred embodiment, in Y, said substituents independently mean 1, 2, 3, or 4 substituents selected from the group consisting of halogen, -CF3, Ra-substituted or unsubstituted C1-C6alkyl-S-, -(CH2) m - Ra-substituted or unsubstituted C6-C10aryl, -NH-(CH2) m - C6-C10aryl, -NH-S(=O)2-Ra-substituted or unsubstituted C1-C6alkyl, -S(=O)2-Ra-substituted or unsubstituted C1-C6alkyl, -NH-S(=O)2-Ra-substituted or unsubstituted C6-C10aryl, -S(=O)2-Ra-substituted or unsubstituted C6-C10aryl, -O-(CH2) m - Ra-substituted or unsubstituted C6-C10aryl, -O-(CH2) m - Ra-substituted or unsubstituted C6-C10aryl, -O-(CH2)

[0044] Ra is as defined above.

[0045] In another preferred embodiment, each Ra is independently selected from the group consisting of halogen, amino, -OH, -CF3, Rb-substituted or unsubstituted C1-C6alkyl, Rb-substituted or unsubstituted C6-C10aryl;

[0046] Rb is -NH2.

[0047] In another preferred embodiment, the compound is selected from the group consisting of the compounds shown in Table 1, the compounds shown in Table 2, the compounds shown in Table 3, the compounds shown in Table 4, the compounds shown in Table 5, compound 11, compound 12, compound 13, compound 14, compound 15, compound 16, and compound 17.

[0048] In a second aspect of the present application, there is provided a method for preparing a compound of the first aspect of the present application, or an enantiomer, a diastereomer thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

[0049] reacting Y-N3 with to obtain

[0050] wherein Y, X3, and X4are as defined in the first aspect of the present application.

[0051] In a third aspect of the present application, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a safe and effective amount of a compound of the first aspect of the present application, or an enantiomer, a diastereomer thereof, or a pharmaceutically acceptable salt thereof.

[0052] In a fourth aspect of the present application, there is provided a use of a compound of the first aspect of the present application, or an enantiomer, a diastereomer thereof, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the prevention and / or treatment of a disease selected from the group consisting of cancer, autoimmune disease, and inflammatory disease.

[0053] In another preferred embodiment, the cancer is selected from the group consisting of leukemia, lymphoma, breast cancer, lung cancer, prostate cancer, and melanoma.

[0054] In another preferred embodiment, the autoimmune disease is selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, psoriasis, and multiple sclerosis.

[0055] In another preferred embodiment, the inflammatory disease is selected from the group consisting of Crohn's disease, ulcerative colitis, rheumatoid arthritis, and asthma.

[0056] In another preferred embodiment, the leukemia is selected from the group consisting of myeloid leukemia, lymphocytic leukemia, and hairy cell leukemia.

[0057] It should be understood that, within the scope of the present application, all combinations between the above-mentioned technical features of the present application and the technical features specifically described hereinafter (e.g., in the examples) can be combined with each other to form new or preferred technical solutions. Due to the limited space, they will not be listed one by one here. DETAILED DESCRIPTION

[0058] The present inventors have made a molecular glue compound having excellent protein degradation performance through long-term and in-depth research. On this basis, the present inventors have completed the present application.

[0059] The terms

[0060] In the present application, the terms used have the general meanings well known to those skilled in the art, unless otherwise specified.

[0061] In the present application, the term "halogen" means F, Cl, Br or I.

[0062] In the present application, "C1-C6 alkyl" means a straight chain or branched alkyl group including 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, tert-pentyl, or the like.

[0063] In the present application, the term "C2-C6 alkenyl" means a straight chain or branched alkenyl group having 2-6 carbon atoms containing one double bond, including, without limitation, ethenyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl, and the like.

[0064] In the present application, the term "C2-C6 alkynyl" means a straight chain or branched alkynyl group having 2-6 carbon atoms containing one triple bond, including, without limitation, ethynyl, propynyl, butynyl, isobutynyl, pentynyl, hexynyl, and the like.

[0065] In the present application, the term "C3-C8 cycloalkyl" means a cyclic alkyl group having 3-8 carbon atoms in the ring, including, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. The term "C3-C12 cycloalkyl" has a similar meaning.

[0066] In the present application, the term "C1-C6 alkoxy" means a straight chain or branched alkoxy group having 1-6 carbon atoms, including, without limitation, methoxy, ethoxy, propoxy, isopropoxy, and butoxy, and the like. Preferably, C1-C4 alkoxy.

[0067] In the present application, the term "heterocycloalkyl" is a 4-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O, S, including, without limitation, the following groups:

[0068] In the present application, the terms "aromatic ring" or "aryl" have the same meaning, and preferably "C6-C10 aryl". The term "C6-C10 aryl" means an aromatic ring group having 6-10 carbon atoms in the ring not containing heteroatoms, such as phenyl, naphthyl, and the like.

[0069] In the present application, the terms "aromatic heterocycle" or "heteroaryl" have the same meaning and refer to a heteroaromatic group containing one to several heteroatoms. For example, "C3-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, 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.

[0070] In the present application, the term "halo" refers to substitution by a halogen.

[0071] In the present application, the term "deutero" refers to substitution by deuterium.

[0072] 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 as described in the foregoing or as it appears in each embodiment. Unless otherwise specifically indicated, a substituted group can have one substituent selected from a specified group at any substitutable position on the group, and the substituent at each position can be the same or different. It will be understood by one skilled in the art that combinations of substituents contemplated by the present application are those combinations that result in stable or chemically feasible compounds. The substituents are, for example, but not limited to, halogen, hydroxy, carboxy (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, aryl, heteroaryl, C1-C8 aldehydo, C2-C10 acyl, C2-C10 ester, amino, C1-C6 alkoxy, C1-C10 sulfonyl, and the like.

[0073] In the present application, the terms 1-6 mean 1, 2, 3, 4, 5, or 6. Other similar terms each independently have a similar meaning. The term "a plurality" means 2-6, such as 2, 3, 4, 5, or 6.

[0074] It will be understood that when a group occurs more than once in a compound, its definition at each occurrence is independent of its definition at every other occurrence. 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".

[0075] Compounds

[0076] The modular click compound library method developed by our research group can construct a large compound library containing triazole skeleton, which is expected to improve the screening efficiency of molecular glue drugs. Therefore, based on the molecular glue degrading agent which is currently studied more, a molecular glue precursor containing alkyne group is synthesized, and in-situ CuAAC reaction is carried out with 4608 azides in a 96-well plate to synthesize a small molecular glue library. Subsequently, in cooperation with the research group of Professor Lu Min of Ruijin Hospital of Shanghai Jiaotong University, phenotype screening, animal experiments and other explorations are carried out. At present, based on the synthesized alkyne precursor, a total of 7 triazole libraries are established, with a total of 31092 compounds, of which the number of molecular glue can reach several thousand.

[0077] The present application breaks the current status of accidental discovery of molecular glue drugs, and constructs a large triazole compound library by the method of modular click compound library to improve the possibility of screening of molecular glue drugs.

[0078] The present application provides a compound of formula I, or an enantiomer, diastereomer thereof, or a pharmaceutically acceptable salt thereof, Y-Z Formula I

[0079] Wherein each group is as defined above.

[0080] In another preferred embodiment, each of the groups in the compound is independently the corresponding group in the specific compound described in the present application.

[0081] 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 drug. Pharmaceutically acceptable salts include inorganic salts and organic salts. One preferred class of salts is a salt of a compound of the present application with an acid. Suitable acids for salt formation include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, and the like; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, and the like; and amino acids such as proline, phenylalanine, aspartic acid, glutamic acid, and the like.

[0082] Another preferred class of salts is a salt of a compound of the present application with a base, such as an alkali metal salt (e.g., sodium or potassium salt), an alkaline earth metal salt (e.g., magnesium or calcium salt), an ammonium salt (e.g., lower alkanolammonium salt and other pharmaceutically acceptable amine salt), such as methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, t-butylamine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, trihydroxyethylamine salt, and amine salt formed with morpholine, piperazine, lysine, respectively.

[0083] The present application specifically describes the preparation of the compounds of the present application of Formula I, but these specific methods do not limit the present application in any way. The compounds of the present application can also be readily prepared by combining various synthetic methods described in the present specification or known in the art, such combinations being readily made by one skilled in the art to which the present application pertains.

[0084] Typically, the starting materials and reagents used in the preparation of the compounds of the present application are commercially available, unless otherwise specified.

[0085] Pharmaceutical compositions and methods of administration

[0086] The present application also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a safe and effective amount of the compound, or an enantiomeric, diastereomeric isomer thereof, or a pharmaceutically acceptable salt thereof.

[0087] Because the compounds of the present application have excellent anti-tumor activity, the compounds of the present application and various crystal forms thereof, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof, and pharmaceutical compositions containing the compounds of the present application as the main active ingredient can be used to treat, prevent, and alleviate diseases associated with tumors.

[0088] 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, "safe and effective amount" refers to the amount of the compound 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 "dose" is a capsule or tablet.

[0089] "Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid filler or gel materials that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatible" here means that the components of the composition can be mixed with the compound of the present application and among themselves without significantly reducing the efficacy of the compound. Examples of part of the pharmaceutically acceptable carrier are 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, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium dodecyl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0090] The pharmaceutical composition is an injection, a capsule, a tablet, a pill, a powder or a granule.

[0091] The mode of administration of the compounds or pharmaceutical compositions of the present application is not narrowly critical and representative modes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0092] 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 excipients as (a) fillers or extenders, e.g., starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, e.g., hydroxymethylcellulose, alginic acid, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, 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) absorption accelerators, e.g., quaternary ammonium compounds; (g) moisturizing agents, e.g., glycerol and sorbitol; (h) respiration accelerators, e.g., high molecular weight polyethylene glycols; 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 forms can also comprise buffering agents.

[0093] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, e.g., enteric coatings and other materials well 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.

[0094] 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, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and the like, as well as mixtures thereof.

[0095] Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0096] In addition to the active compounds, the suspensions can contain suspending agents, e.g., ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, agar-agar, or mixtures of these substances, and the like.

[0097] The compositions for parenteral injection can contain physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.

[0098] Dosage forms for topical administration of a compound of this application include ointments, powders, sprays, and inhalers. The active component is admixed with a carrier, which can be a sterile powder, a sterile non-fluid, or a sterile fluid.

[0099] The compounds of the present application can be administered alone, or in combination with other pharmaceutically acceptable compounds, such as anti-tumor drugs.

[0100] The therapeutic methods of the present application can be used alone, or in combination with other therapeutic modalities or therapeutic agents.

[0101] The pharmaceutical compositions are used in a safe and effective amount of the compounds of the present application for a mammal (e.g., a human) in need of treatment, wherein the amount is administered in a dosage pharmaceutically considered effective, and for a 60 kg body weight human, the daily dosage is usually 1-2000 mg, preferably 50-1000 mg. Of course, the specific dosage will take into account a variety of factors, such as the means of administration, the health of the patient, and the like, all of which is within the skill of the skilled practitioner.

[0102] Compared with the prior art, the present application has the following main advantages:

[0103] (1) The molecular glue compounds of the present application have excellent protein degradation activity;

[0104] (2) Unlike the traditional accidental discovery of molecular glue drugs, the present application applies the click chemistry method to discover hundreds of potential molecular glue drugs with excellent protein degradation activity;

[0105] (3) The hundreds of potential molecular glue drugs obtained by the click chemistry method of the present application can bind to different target points, and are expected to realize the discovery of new target points.

[0106] The application will be further described in conjunction with specific examples. It should be understood that these examples are intended to illustrate the application and are not intended to limit the scope of the application. The experimental procedures in the following examples, unless otherwise specified, were generally performed according to routine conditions, such as those 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 indicated, percentages and parts are by weight.

[0107] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Also, any method and material similar or equivalent to those described herein can be used in the practice of the present application. The description herein of any particular methods and materials is primarily intended to provide examples.

[0108] Preparation Examples

[0109] Synthesis of alkyne precursor

[0110] Alkyne precursor 1 ((2-(2,6-dioxopiperidin-3-yl)-5-(prop-2-yn-1-yloxy)isoindoline-1,3-dione))

[0111] Synthesis of alkyne precursor 1

[0112] Into a 250 mL round bottom flask, 11 g (40 mmol) of starting material 4-hydroxysalidomide was added, followed by 120 mL of DMF, then 4.2 mL (48 mmol, 1.2 equiv) of propargyl bromide, and finally 8.5 g (80 mmol) of powdered Na2CO3, and stirred at 40 °C for 24 hours (LC-MS monitoring), at which time there was a significant amount of white insoluble solid in the reaction system.

[0113] After 24 hours of reaction, the reaction solution was cooled to room temperature, 150 mL of ethyl acetate was added, and stirred for 1 hour, then most of the inorganic salts were separated by filtration with diatomite, and finally a dark brown filtrate was obtained, and most of the solvent was removed by distillation under reduced pressure. Then the filtrate was extracted with 150 mL of ethyl acetate / 150 mL of water three times (at this time a small amount of saturated brine can be added to promote phase separation), and the organic phase was washed with 5M LiCl aqueous solution 5 times, and then washed with saturated brine, dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure to obtain a brownish yellow solid. At this time, the solid was slurried with ethyl acetate: acetone = 1:1 (150 mL + 150 mL) for 1 hour, and then filtered to obtain a milky white solid 8.4 g, with a LC-MS purity of 95%, and a yield of about 67%.

[0114] 1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 7.87 (d, J = 8.3 Hz, 1H), 7.51 (d, J = 2.3 Hz, 1H), 7.40 (dd, J = 8.3, 2.4 Hz, 1H), 5.13 (dd, J = 12.9, 5.3 Hz, 1H), 5.05 (d, J = 2.5 Hz, 2H), 3.67 (t, J = 2.4 Hz, 1H), 2.97 - 2.81 (m, 1H), 2.66 - 2.51 (m, 2H), 2.10 - 2.03 (m, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 172.8, 172.7, 169.9, 166.8, 166.7, 162.4, 133.8, 125.3, 123.8, 121.4, 109.3, 79.3, 78.3, 56.5, 49.0, 31.0, 22.0. HRMS (ESI) m / z: calcd for C 16 H 12 N2O5 + : 312.0746 [M+H] + , found: 312.0749.

[0115] Alkyne precursor 2 ((5-(but-3-yn-2-yloxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione)

[0116] Synthesis of alkyne precursor 2

[0117] In a 250 mL round bottom flask, 5.5 g (20 mmol) of starting material 4-hydroxysalidomide was added to 60 mL of DMF, followed by 5.4 g (24 mmol, 1.2 equiv) of p-toluenesulfonic acid (1-butyn-3-yl) ester, and finally 4.3 g (40 mmol) of powdered Na2CO3 was added with stirring, and reacted at 80 °C for 24 hours (LC-MS monitoring), at which time there was a significant amount of white insoluble solid in the reaction system.

[0118] After the reaction was cooled to room temperature, 60 mL of ethyl acetate was added and stirred for 1 hour. Most of the inorganic salts were separated by celite filtration. The dark brown filtrate was obtained and most of the solvent was removed by distillation under reduced pressure. Then, 60 mL of ethyl acetate / 60 mL of water was used to extract three times (at this time, a small amount of saturated brine was added to promote phase separation). The organic phase was combined and washed with 5M LiCl aqueous solution for 5 times, and then washed with saturated brine. Anhydrous sodium sulfate was used for drying, and the solvent was removed by distillation under reduced pressure to obtain a light yellow solid. Finally, column chromatography was used for separation and purification (eluent: petroleum ether: ethyl acetate = 4:1 to 1:1). Finally, 3.2 g of white solid was obtained with a yield of about 50%.

[0119] 1 H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 7.86 (d, J = 8.3 Hz, 1H), 7.51 (s, 1H), 7.40 (dd, J = 8.3, 2.3 Hz, 1H), 5.42 (q, J = 5.5, 4.6 Hz, 1H), 5.13 (dd, J = 12.9, 5.3 Hz, 1H), 3.64 (d, J = 1.9 Hz, 1H), 2.89 (ddd, J = 18.1, 13.9, 5.2 Hz, 1H), 2.66 - 2.50 (m, 2H), 2.11 - 2.01 (m, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 172.8, 169.9, 166.8, 166.7, 162.1, 133.7, 125.3, 123.7, 121.9, 109.8, 82.1, 77.7, 64.0, 49.0, 31.0, 22.0, 21.6. HRMS (ESI) m / z: calcd for C 17 H 14 N2O5 + : 326.0903 [M+H] + , found: 326.0905.

[0120] Alkyne precursor 3 ((2-(2,6-dioxopiperidin-3-yl)-5-(4-(prop-2-yn-1-yl)piperazin-1-yl)isoindoline-1,3-dione))

[0121] Synthesis of alkyne precursor 3

[0122] Into a 50 mL reaction flask was added 1.38 g (5 mmol) of starting material 4-fluorosalidomide [2-(2,6-dioxo-3-piperidinyl)-4-fluoro-1H-isoindole-1,3(2H)-dione], 20 ml of DMF, followed by 1.08 g (5.5 mmol) of starting material N- propargylpiperazine dihydrochloride, and finally 3.5 mL (2.5 g, 25 mmol) of triethylamine. The reaction was stirred at 60 °C for 6 hours (LC / MS tracking of the reaction).

[0123] After the reaction was complete, the reaction was poured into 200 mL of saturated brine, and 50 mL of ethyl acetate was extracted three times. The combined organic phase was washed with 100 mL of saturated brine four times, dried over anhydrous sodium sulfate, and the organic phase was concentrated to give a dark yellow solid. Finally, column chromatography purification (eluent: dichloromethane / methanol = 100:0 to 10:1) gave 914 mg of a yellow foam solid with a yield of about 48%.

[0124] 1 H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 7.35 (d, J = 2.3 Hz, 1H), 7.26 (dd, J = 8.6, 2.4 Hz, 1H), 5.07 (dd, J = 12.9, 5.4 Hz, 1H), 3.47 (t, J = 5.0 Hz, 4H), 3.34 (d, J = 2.5 Hz, 2H), 3.18 (t, J = 2.4 Hz, 1H), 2.94 - 2.82 (m, 2H), 2.73 (s, 1H), 2.61 - 2.54 (m, 5H), 2.05 - 1.99 (m, 1H). 13 C NMR (176 MHz, DMSO-d6) δ 172.8, 170.1, 167.5, 167.0, 162.3, 155.2, 133.9, 124.9, 118.4, 117.9, 108.2, 79.4, 76.0, 50.6, 48.8, 46.8, 45.9, 35.8, 31.0, 22.2. HRMS (ESI) m / z: calcd for C 15 H 12 N2O3Na + : 403.1382 [M+Na] + , found: 403.1380.

[0125] Alkyne precursor 4 ((3-(2-propyn-1-ylamino)-2,6-piperidinedione)) was a commercially available reagent

[0126] Alkyne precursor 5 ((3-(5-ethynyl-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-2,6- piperidinedione))

[0127] Synthesis of alkyne precursor 5

[0128] Into a 100 mL single neck flask was added 3-(5-bromo-l-oxoisoindolin-2-yl)piperidine-2,6-dione (2.0 g), trimethylsilylacetylene (2.4 g), triethylamine (20 mL), N,N-dimethylformamide (30 mL), cuprous iodide (59 mg), bis(triphenylphosphine)palladium dichloride (218 mg) under nitrogen protection, 70 degree Celsius oil bath, reaction overnight, TLC track reaction end, add water, precipitate solid, filter, water wash, get intermediate product, add intermediate product to 500 mL single neck flask, add 150 mL dichloromethane, add tetrabutylammonium fluoride (7.5 mL, 1M in THF) under ice bath, slowly rise to room temperature, TLC track reaction end, add water wash, organic phase dried with anhydrous sodium sulfate, column chromatography purification, get 1.3 g product, two step yield 78%.

[0129] 1 H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 7.73 (d, J = 8.1 Hz, 2H), 7.60 (d, J = 7.8 Hz, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.40 (q, J = 17.3 Hz, 2H), 4.42 (s, 1H), 2.91 (ddd, J = 17.3, 13.7, 5.4 Hz, 1H), 2.66 - 2.56 (m, 1H), 2.39 (qd, J = 13.3, 4.5 Hz, 1H), 2.04 - 1.98 (m, 1H). 13 C NMR (176 MHz, DMSO-d6) δ 172.9, 170.9, 167.3, 142.4, 131.9, 131.6, 126.9, 124.8, 123.3, 83.0, 82.9, 51.7, 47.1, 31.3, 31.2, 22.4. HRMS (ESI) m / z: calcd for C 15 H 12 N2O3Na + : 291.0746 [M+Na] + , found: 291.0746.

[0130] Synthesis of fluorosulfonyl azide

[0131] Fluorosulfonyl azide

[0132] Synthesis of fluorosulfonyl azide (methyl tert-butyl ether solution)

[0133] Into a 250 mL polytetrafluoroethene flask, sodium azide (1.96 g, 30 mmol, 1 equiv), distilled water (60 mL) and MTBE (60 mL) were added, and an ice bath was used for rapid stirring. 1-(fluorosulfonyl)-2,3-dimethyl-1H-imidazole trifluoromethanesulfonate (11.1 g, 36 mL, 1.2 equiv) was completely dissolved in MeCN (4 mL), and the resulting viscous solution was quickly added to the vigorously stirred mixture, which was stirred vigorously for 10 min under an ice water bath, and then the mixture was poured into a 200 mL separatory funnel, and the organic phase containing the product was left in a plastic bottle and placed in a cool reagent cabinet for 12 h. The red droplets generated during the standing period were removed with a plastic pipette to obtain a colorless organic phase, which was the MTBE solution of FSO2N3. The concentration of FSO2N3 was determined by1H NMR, and the solution was directly used. 19 The F NMR was used for determining the concentration.

[0134] 19 F NMR (400 MHz) δ 61.53 ppm

[0135] Library construction process of a library of triazole compounds

[0136] Library of triazole compounds I (a total of 4608 triazole products) established based on alkyne precursor 1

[0137] First, 25 mM DMSO solution of alkyne precursor 1, 250 mM aqueous solution of sodium ascorbate, 5 mM aqueous solution of copper sulfate, and 5 mM aqueous solution of THPTA ligand were prepared. Then, 50 mL of 5 mM aqueous solution of copper sulfate and 50 mL of 5 mM aqueous solution of ligand were mixed to prepare 100 mL of 2.5 mM CuSO4 / ligand aqueous solution.

[0138] Into a 96-well plate containing 10 μL of the corresponding azide, 10 μL of 25 mM aqueous solution of sodium ascorbate, 20 μL of 25 mM DMSO solution of alkyne precursor 1 were sequentially added, and finally 10 μL of 2.5 mM CuSO4 / ligand aqueous solution was added. After sealing the plate, the shaker was heated at 40°C for 24 hours, and the rotation speed was 900 rpm at this time. After 24 hours, random sampling was performed for LC-MS monitoring, and the results showed that the azide was almost completely converted. Then, 50 μL of DMSO was further added to the 96-well plate and shaken, and finally 50 μL of the reaction solution in the 48 96-well plates was transferred to a 384-well plate for phenotype screening.

[0139] The final screening results are: 961 potential molecular glues with degradation toxicity are screened for the MV411 cell line (human myelomonocytic leukemia cells); 113 potential molecular glues with degradation toxicity are screened for the U937 cell line (human histiocytic lymphoma cells); and 28 potential molecular glues with degradation toxicity are screened for the 293T cell line (human embryonic kidney cells).

[0140] Triazole compound library II (a total of 4608 triazole products) established based on alkyne precursor 2

[0141] First, 25 mM alkyne precursor 2 DMSO solution, 250 mM sodium ascorbate aqueous solution, 5 mM copper sulfate aqueous solution, and 5 mM THPTA ligand aqueous solution are prepared. Then, 50 mL of 5 mM copper sulfate aqueous solution and 50 mL of 5 mM ligand aqueous solution are mixed to prepare 100 mL of 2.5 mM CuSO4 / ligand aqueous solution.

[0142] To the 96-well plate containing 10 μL of the corresponding azide, 20 μL of 25 mM alkyne precursor 2 DMSO solution, 10 μL of 2.5 mM CuSO4 / ligand aqueous solution are sequentially added, and finally 10 μL of 25 mM sodium ascorbate aqueous solution is added. After sealing the plate, the oscillator is heated at 40°C for 24 hours, at which time the rotation speed is 900 rpm. After 24 hours, random sampling LC-MS monitoring shows that the azide is almost completely converted. Then, 50 μL of DMSO is further added to the 96-well plate and shaken, and finally 50 μL of the reaction solution in the 48 96-well plates is transferred to the 384-well plate for phenotype screening.

[0143] The final screening results are: 117 potential molecular glues with degradation toxicity are screened for the MV411 cell line (human myelomonocytic leukemia cells); and 42 potential molecular glues with degradation toxicity are screened for the U937 cell line (human histiocytic lymphoma cells).

[0144] Triazole compound library III (a total of 4608 triazole products) established based on alkyne precursor 3

[0145] The specific operation method is consistent with that of the triazole compound library II established based on alkyne precursor 2

[0146] The final screening results are: 16 potential molecular glues with degradation toxicity are screened for the MV411 cell line (human myelomonocytic leukemia cells); and 17 potential molecular glues with degradation toxicity are screened for the U937 cell line (human histiocytic lymphoma cells).

[0147] Triazoles compound library IV (4032 triazoles in total) was established based on alkyne precursor 4

[0148] The specific operation method is consistent with that of triazoles compound library II established based on alkyne precursor 2

[0149] The final screening results are: 8 potential molecular glue with degradation toxicity are screened for MV411 cell line (human myelomonocytic leukemia cells); 9 potential molecular glue with degradation toxicity are screened for U937 cell line (human histiocytic lymphoma cells).

[0150] Triazoles compound library V (4032 triazoles in total) was established based on alkyne precursor 5

[0151] The specific operation method is consistent with that of triazoles compound library II established based on alkyne precursor 2

[0152] The final screening results are: 758 potential molecular glue with degradation toxicity are screened for MV411 cell line (human myelomonocytic leukemia cells); 96 potential molecular glue with degradation toxicity are screened for U937 cell line (human histiocytic lymphoma cells).

[0153] Synthesis method of molecular glue examples

[0154] Example 1 - Synthesis of compound 1 (i.e. compound 1-68, 1-236, 1-320)

[0155] 5-((1-(3-(3-aminobenzyl)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0156] Into a 25 mL round-bottom flask with a magnetic bar, 3,3'-diaminodiphenylmethane (198 mg, 1 mmol, 1 equiv), KHCO3 (1.3 mL, 4 mmol, 4 equiv, 3.0 M aqueous solution) and DMF (3 mL) were sequentially added, and after stirring, FSO2N3 (2.5 mL, 1.0 mmol, 1.0 equiv, 0.4 M MTBE solution) was slowly added. After 4 hours of reaction, the reaction was detected by LC-MS to be complete. Then 25 mL of ethyl acetate and 25 mL of water were added, and the organic phase was extracted and separated three times, and then saturated brine was added for washing, 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 subsequent click.

[0157] Subsequently, the azide above was charged with alkyne precursor 1 (312 mg, 1 mmol, 1 equiv), cuprous bromide (30 mg, 0.2 mmol, 0.2 equiv) and DMF (5 mL), after heating at 60 °C for 6 hours, LC-MS monitoring the complete conversion of the azide, 50 mL of water was added to the system, a significant amount of insoluble solid precipitated, which was separated by filtration to obtain a light green solid. Subsequently, reverse phase separation purification was performed, the separation system was water (0.1% TFA): acetonitrile, the separation gradient was water (0.1% TFA): acetonitrile = 95%:5% to acetonitrile 100%, the separation column model was SW080, spherical C18, 20-45 pm, Vacuum distillation finally obtained 250 mg of white solid, yield 48%.

[0158] 1 H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.98 (s, 1H), 7.87 (d, J = 8.2 Hz, 1H), 7.83 (s, 1H), 7.74 (dd, J = 7.9, 2.2 Hz, 1H), 7.64 (s, 1H), 7.53 (t, J = 7.8 Hz, 1H), 7.48 (dd, J = 8.3, 2.3 Hz, 1H), 7.37 (d, J = 7.7 Hz, 1H), 7.27 (t, J = 7.7 Hz, 1H), 7.05 (d, J = 7.6 Hz, 1H), 6.97 - 6.88 (m, 2H), 5.47 (s, 2H), 5.13 (dd, J = 12.9, 5.3 Hz, 1H), 2.96 - 2.82 (m, 1H), 2.65 - 2.51 (m, 2H), 2.13 - 1.98 (m, 1H). 13 C NMR (176 MHz, DMSO-d6) δ 172.8, 170.0, 166.9, 166.8, 163.3, 143.1, 143.1, 142.2, 136.6, 133.9, 130.1, 129.7, 129.3, 125.4, 123.5, 123.3, 121.1, 120.5, 118.0, 118.0, 109.4, 62.0, 49.0, 40.5, 31.0, 22.1. HRMS (ESI) m / z: calcd for C 29 H 25 N6O5 + : 537.1886 [M+H] + , found: 537.1874.

[0159] Example 2 - Synthesis of compound 2 (i.e. compounds 1-60, 1-220, 1-323)

[0160] 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

[0161] In accordance with the synthesis of Example 1 - Step one of compound 1

[0162] 1 H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.61 (s, 1H), 8.55 (d, J = 9.7 Hz, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.61 (s, 1H), 7.45 (dd, J = 8.3, 2.3 Hz, 1H), 7.35 (d, J = 5.1 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 7.16 - 7.08 (m, 3H), 7.08 - 7.03 (m, 2H), 7.00 (d, J = 8.0 Hz, 2H), 6.94 - 6.90 (m, 3H), 5.94 (d, J = 11.2 Hz, 1H), 5.45 (t, J = 10.5 Hz, 1H), 5.41 - 5.30 (m, 2H), 5.13 (dd, J = 12.9, 5.4 Hz, 1H), 2.89 (ddd, J = 17.5, 14.0, 5.5 Hz, 1H), 2.65 - 2.51 (m, 2H), 2.22 (s, 3H), 2.11 - 1.96 (m, 1H). 13 C NMR (176 MHz, DMSO-d6) δ 172.8, 170.0, 166.9, 166.8, 163.4, 141.8, 141.7, 138.3, 137.4, 136.0, 133.9, 128.8, 128.3, 128.3, 127.7, 127.7, 127.0, 126.1, 125.3, 124.1, 123.4, 121.1, 109.3, 68.3, 62.2, 60.3, 49.0, 31.0, 22.1, 20.8. HRMS (ESI) m / z: calcd for C 37 H 33 N6O7S + : 705.2131 [M+H] + , found: 705.2137.

[0163] Example 3 - Synthesis of compound 3 (i.e. compound 1-245)

[0164] 2-(2,6-dioxopiperidin-3-yl)-5-((1-(4-(quinolin-2-ylmethoxy)phenyl)-1H-1,2,3- triazol-4-yl)methoxy)isoindoline-1,3-dione

[0165] In accordance with the synthesis of Example 1 - Step one of compound 1

[0166] 1 H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.88 (s, 1H), 8.47 (d, J = 8.5 Hz, 1H), 8.03 (t, J = 8.9 Hz, 2H), 7.90 - 7.78 (m, 4H), 7.72 (d, J = 8.5 Hz, 1H), 7.67 - 7.61 (m, 2H), 7.47 (dd, J = 8.3, 2.3 Hz, 1H), 7.32 - 7.25 (m, 2H), 5.47 (d, J = 9.0 Hz, 4H), 5.13 (dd, J = 12.9, 5.4 Hz, 1H), 2.89 (ddd, J = 17.5, 14.1, 5.4 Hz, 1H), 2.65 - 2.52 (m, 2H), 2.11 - 1.98 (m, 1H). 13 C NMR (176 MHz, DMSO-d6) δ 172.8, 169.9, 166.8, 166.8, 163.3, 158.2, 157.1, 146.7, 142.8, 137.5, 133.9, 130.3, 130.1, 128.3, 128.0, 127.3, 126.8, 125.3, 123.4, 123.2, 122.0, 121.1, 119.7, 115.9, 109.3, 71.0, 62.0, 49.0, 31.0, 22.0. HRMS (ESI) m / z: calcd for C 32 H 25 N6O6 + : 589.1836 [M+H] + , found: 589.1831.

[0167] Example 4 - Synthesis of compound 4 (i.e. compounds 1-235, 1-319)

[0168] 5-((1-((10,11-dihydro-5H-dibenzo[a,d][7]cyclohepten-5-yl)methyl)-1H-1,2,3-triazol-4- yl)methoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

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

[0170] 1 H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.05 (s, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.51 (d, J = 2.2 Hz, 1H), 7.37 (dd, J = 8.3, 2.3 Hz, 1H), 7.18 - 7.06 (m, 4H), 7.06 - 6.90 (m, 4H), 5.30 (s, 2H), 5.13 (dd, J = 13.0, 5.3 Hz, 1H), 4.99 (d, J = 8.4 Hz, 2H), 3.42 - 3.34 (m, 2H), 3.07 - 2.82 (m, 3H), 2.63 - 2.53 (m, 2H), 2.12 - 1.92 (m, 1H). 13 C NMR (176 MHz, DMSO-d6) δ 172.8, 170.0, 166.8, 166.8, 163.2, 141.4, 139.7, 133.8, 130.3, 127.2, 126.0, 125.2, 125.1, 123.3, 121.2, 109.3, 61.9, 49.0, 32.5, 31.0, 22.1, 22.0. HRMS (ESI) m / z: calcd for C 32 H 28 N5O5 + : 562.2085 [M+H] + , found: 562.2079.

[0171] Example 5 - Synthesis of Compound 5 (i.e. Compound 1-242, 1-327)

[0172] 2-(2,6-dioxopiperidin-3-yl)-5-((1-(2-(o-tolyloxy)phenyl)-1H-1,2,3-triazol-4- yl)methoxy)isoindoline-1,3-dione

[0173] In accordance with the procedure for Example 1 - Step one for the synthesis of Compound 1

[0174] 1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.75 (s, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.80 (dd, J = 7.9, 1.7 Hz, 1H), 7.62 (d, J = 2.3 Hz, 1H), 7.50 (td, J = 7.9, 1.7 Hz, 1H), 7.46 (dd, J = 8.3, 2.3 Hz, 1H), 7.35 - 7.26 (m, 2H), 7.21 (t, J = 7.7 Hz, 1H), 7.11 (t, J = 7.4 Hz, 1H), 6.94 (d, J = 8.1 Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H), 5.47 (s, 2H), 5.13 (dd, J = 12.9, 5.4 Hz, 1H), 2.90 (ddd, J = 17.5, 14.2, 5.4 Hz, 1H), 2.65 - 2.51 (m, 2H), 2.10 (s, 3H), 2.09 - 1.99 (m, 1H). 13 C NMR (176 MHz, DMSO-d6) δ 172.8, 169.9, 166.8, 166.8, 163.3, 152.8, 149.6, 142.0, 133.9, 131.6, 131.1, 129.1, 127.6, 126.9, 126.9, 126.6, 125.3, 124.9, 123.4, 123.4, 121.1, 119.3, 117.4, 109.3, 61.8, 49.0, 40.0, 30.9, 22.1, 15.6. HRMS (ESI) m / z: calcd for C 29 H 24 N5O6 + 538.1727 [M+H] + found: 538.1714.

[0175] Example 6 - Synthesis of compound 6 (i.e. compounds 1-105, 1-288)

[0176] 5-((1-(2-(Benzylamino)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0177] In accordance with the procedure of Example 1 - Synthesis of compound 1

[0178] 1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.67 (s, 1H), 7.88 (d, J = 8.3 Hz, 1H), 7.68 (d, J = 2.3 Hz, 1H), 7.51 (dd, J = 8.3, 2.3 Hz, 1H), 7.34 - 7.29 (m, 4H), 7.28 - 7.19 (m, 3H), 6.71 (t, J = 7.9 Hz, 2H), 5.49 (s, 2H), 5.14 (dd, J = 13.0, 5.3 Hz, 1H), 4.36 (s, 2H), 2.90 (ddd, J = 17.6, 14.0, 5.4 Hz, 1H), 2.66 - 2.52 (m, 2H), 2.14 - 1.99 (m, 1H). 13 C NMR (176 MHz, DMSO-d6) δ 172.8, 170.0, 166.9, 166.8, 163.4, 142.2, 142.1, 139.5, 134.0, 130.5, 128.4, 126.8, 126.7, 126.5, 126.1, 125.4, 123.4, 122.4, 121.1, 115.8, 112.5, 109.4, 62.1, 49.0, 45.9 30.4, 22.1, 22.1. HRMS (ESI) m / z: calcd for C 29 H 25 N6O5 + : 537.1886 [M+H] + , found: 537.1880.

[0179] Example 7 - Synthesis of compound 7 (i.e. compounds 1-35, 1-256)

[0180] 5-((1-(2-(Cyclohexylthio)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0181] In accordance with the procedure of Example 1 - Synthesis of compound 1

[0182] 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.62 (s, 1H), 7.87 (d, J = 8.3 Hz, 1H), 7.71 (d, J = 6.7 Hz, 1H), 7.65 (d, J = 2.3 Hz, 1H), 7.61 - 7.42 (m, 4H), 5.50 (s, 2H), 5.13 (dd, J = 13.0, 5.3 Hz, 1H), 3.12 - 3.05 (m, 1H), 2.94 - 2.85 (m, 1H), 2.65 - 2.52 (m, 2H), 2.08 - 2.01 (m, 1H), 1.78 - 1.66 (m, 2H), 1.60 - 1.54 (m, 2H), 1.51 - 1.46 (m, 1H), 1.26 - 1.15 (m, 2H), 1.13 - 1.04 (m, 3H). 13 C NMR (176 MHz, DMSO-d6) δ 172.8, 169.9, 166.8, 166.8, 163.3, 141.7, 136.9, 133.9, 132.0, 131.8, 130.6, 127.4, 127.3, 127.2, 125.3, 123.4, 121.2, 109.5, 61.8, 49.0, 45.2, 32.4, 31.0, 25.2, 25.1, 22.1. HRMS (ESI) m / z: calcd for C 28 H 28 N5O5S + : 546.1811 [M+H] + , found: 546.1811.

[0183] Example 8 - Synthesis of compound 8 (i.e. compound 1-163)

[0184] 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

[0185] In accordance with the procedure of Example 1 - Synthesis of compound 1, step one

[0186] 1H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 8.25 (s, 1H), 7.84 (d, J = 8.3 Hz, 1H), 7.62 - 7.54 (m, 2H), 7.44 (dd, J = 8.4, 2.3 Hz, 1H), 7.39 - 7.28 (m, 3H), 7.25 - 7.16 (m, 2H), 7.14 - 7.08 (m, 1H), 7.03 (d, J = 7.7 Hz, 1H), 5.73 (s, 2H), 5.37 (s, 2H), 5.13 (dd, J = 12.9, 5.3 Hz, 1H), 4.56 (s, 2H), 2.97 - 2.83 (m, 1H), 2.65 - 2.52 (m, 2H), 2.09 - 2.02 (m, 1H). 13 CNMR (101 MHz, DMSO-d6) δ 172.8, 169.9, 166.8, 166.8, 163.3, 142.8, 141.9, 135.8, 134.0, 133.8, 131.9, 131.5, 131.1, 129.8, 129.5, 128.0, 127.8, 127.85, 127.4, 125.4, 125.3, 123.3, 121.1, 109.3, 62.0, 60.8, 51.1, 49.0, 34.4, 31.0, 22.1. HRMS (ESI) m / z: calcd for C 30 H 26 N5O6S + :584.1598[M+H] + , found:584.1591.

[0187] Example 9 - Synthesis of compound 9 (i.e. compound 1-244)

[0188] 2-(2,6-dioxopiperidin-3-yl)-5-((1-(2,2-diphenylethyl)-1H-1,2,3-triazol-4-yl)methoxy)isoindoline-1,3-dione

[0189] In accordance with the procedure of Example 1 - Synthesis of compound 1, step one

[0190] 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.09 (s, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.49 (d, J = 2.2 Hz, 1H), 7.35 (d, J = 7.9 Hz, 5H), 7.24 (t, J = 7.5 Hz, 4H), 7.15 (t, J = 7.3 Hz, 2H), 5.29 (s, 2H), 5.16 - 5.06 (m, 3H), 4.71 (t, J = 8.3 Hz, 1H), 2.89 (ddd, J = 17.6, 14.2, 5.4 Hz, 1H), 2.64 - 2.51 (m, 2H), 2.10 - 1.99 (m, 1H). 13 C NMR (176 MHz, DMSO-d6) δ 172.7, 169.9, 166.8, 166.7, 163.1, 141.3, 141.2, 133.8, 128.5, 127.7, 126.7, 125.2, 124.9, 123.3, 121.1, 109.2, 61.9, 52.8, 50.8, 48.9, 39.8, 30.9, 22.0. HRMS (ESI) m / z: calcd for C 30 H 26 N5O5 + : 536.1934 [M+H] + , found: 536.1932.

[0191] Example 10 - Synthesis of compound 10 (i.e. compounds 1-193, 1-287)

[0192] 5-((1-(2-(BENZYLOXY)PHENYL)-1H-1,2,3-TRIAZOL-4-YL)METHOXY)-2-(2,6-DIOXOPIPERIDIN-3-YL)ISOINDOLE-1,3-DIONE

[0193] In accordance with the procedure of Example 1 - Synthesis of compound 1, step one

[0194] 1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.68 (s, 1H), 7.86 (d, J = 8.3 Hz, 1H), 7.66 (dd, J = 7.9, 1.7 Hz, 1H), 7.63 (d, J = 2.3 Hz, 1H), 7.53 (td, J = 7.9, 1.7 Hz, 1H), 7.46 (dd, J = 8.3, 2.3 Hz, 1H), 7.40 (d, J = 8.5 Hz, 1H), 7.38 - 7.29 (m, 5H), 7.17 (t, J = 7.6 Hz, 1H), 5.46 (s, 2H), 5.24 (s, 2H), 5.13 (dd, J = 12.9, 5.3 Hz, 1H), 2.90 (ddd, J = 17.3, 14.1, 5.4 Hz, 1H), 2.65 - 2.53 (m, 2H), 2.07 - 1.98 (m, 1H). 13 C NMR (176 MHz, DMSO-d6) δ 172.7, 169.9, 166.8, 166.7, 163.3, 150.7, 141.7, 136.2, 133.9, 130.8, 128.4, 127.9, 127.2, 127.0, 126.0, 125.9, 125.3, 123.3, 121.2, 121.0, 114.4, 109.3, 70.0, 61.9, 48.9, 30.9, 22.1, 22.0. HRMS (ESI) m / z: calcd for C 29 H 24 N5O6 + 538.1727 [M+H] + , found: 538.1721.

[0195] Example 11 - Synthesis of Compound 11

[0196] 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

[0197] In accordance with the procedure for Example 1 - Synthesis of Compound 1, Step one

[0198] 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 7.87 (d, J = 8.3 Hz, 1H), 7.51 (d, J = 2.3 Hz, 1H), 7.40 (dd, J = 8.3, 2.3 Hz, 1H), 5.12 (dd, J = 12.9, 5.3 Hz, 1H), 5.05 (d, J = 2.4 Hz, 2H), 3.68 (t, J = 2.3 Hz, 1H), 2.95 - 2.82 (m, 1H), 2.65 - 2.52 (m, 2H), 2.12 - 1.98 (m, 1H). 13 C NMR (176 MHz, DMSO-d6) δ 172.7, 169.8, 166.7, 166.6, 162.3, 162.2, 133.7, 125.2, 123.7, 121.3, 109.2, 79.3, 78.2, 56.4, 48.9, 30.9, 22.0, 22.0. HRMS (ESI) m / z: calcd for C 37 H 29 N 10 O5 + : 693.2322 [M+H] + , found: 693.2330.

[0199] Example 12 - Synthesis of compound 12

[0200] 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

[0201] In accordance with the steps of Example 1 - Synthesis of compound 1

[0202] 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.07 (s, 1H), 8.25 (d, J = 2.7 Hz, 1H), 8.12 (dd, J = 9.0, 2.7 Hz, 1H), 7.87 (d, J = 8.3 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 7.48 (dd, J = 8.3, 2.3 Hz, 1H), 7.09 - 6.98 (m, 2H), 6.92 (dd, J = 8.8, 2.7 Hz, 1H), 5.48 (s, 2H), 5.13 (dd, J = 12.9, 5.4 Hz, 1H), 2.89 (ddd, J = 17.5, 14.1, 5.5 Hz, 1H), 2.67 - 2.52 (m, 2H), 2.08 - 1.96 (m, 1H). 19 F NMR (377 MHz, DMSO-d6) δ -60.73 (s, 3F), -61.01 (s, 3F). 13 C NMR (176 MHz, DMSO-d6) δ 172.7, 169.9, 166.8, 166.7, 163.2, 155.8, 143.1, 133.9, 130.8, 126.4, 125.3, 122.0, 121.8 (q, J = 29.9 Hz), 123.5, 123.9, 123.7, 123.5, 119.6 (q, J = 5.3 Hz), 119.0, 118.7 (q, J = 140.8 Hz), 117.4, 111.4, 109.3, 62.0, 49.0, 30.9, 22.0. HRMS (ESI) m / z: calcd for C 30 H 21 N6O6F6 + : 675.1427 [M+H] + , found: 675.1426.

[0203] Example 13 - Synthesis of Compound 13

[0204] 5-((1-(7-amino-5,5-dioxodibenzo[b,d]thiophen-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)-2- (2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0205] In accordance with the procedure for Example 1 - Synthesis of Compound 1, Step one

[0206] 1H NMR (400 MHz, DMSO-d6) δ 11.13 (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 = 7.2 Hz, 1H), 7.33 (s, 1H), 7.58 (d, J = 7.2 Hz, 1H), 5.52 (s, 2H), 5.28 (s, 2H), 5.13 (dd, J = 12.9, 5.3 Hz, 1H), 2.89 (t, J = 12.9 Hz, 1H), 2.65 - 2.51 (m, 2H), 2.10 - 2.00 (m, 1H).

[0207] Example 14 - Synthesis of Compound 14

[0208] 5-((1-(2-((2-aminophenyl)sulfanyl)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione

[0209] In accordance with the procedures of Example 1 - Synthesis of Compound 1

[0210] 1 H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.55 (s, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.63 - 7.57 (m, 2H), 7.56 - 7.51 (m, 2H), 7.46 (dd, J = 8.3, 2.3 Hz, 1H), 7.38 - 7.32 (m, 1H), 5.43 (s, 2H), 5.12 (dd, J = 12.8, 5.4 Hz, 1H), 2.89 (ddd, J = 16.7, 13.7, 5.4 Hz, 1H), 2.66 - 2.51 (m, 2H), 2.07 - 1.96 (m, 1H). 13 C NMR (176 MHz, DMSO-d6) δ 172.8, 169.9, 166.8, 166.7, 163.3, 141.8, 136.9, 133.8, 133.5, 131.0, 130.8, 129.2, 127.2, 126.7, 125.3, 123.4, 121.0, 109.3, 61.8, 48.9, 30.9, 22.1, 22.0. HRMS (ESI) m / z: calcd for C 28 H 23 N6O5S + : 555.1451 [M+H] +, found: 555.1453.

[0211] Example 15 - Synthesis of compound 15

[0212] 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

[0213] In accordance with the procedure for Example 1 - Synthesis of compound 1

[0214] 1 H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.71 (s, 1H), 7.87 (d, J = 8.3 Hz, 1H), 7.67 - 7.58 (m, 3H), 7.49 (dd, J = 8.3, 2.3 Hz, 1H), 7.41 (dd, J = 8.1, 1.9 Hz, 1H), 7.18 (d, J = 2.0 Hz, 1H), 6.98 (dd, J = 8.2, 2.0 Hz, 1H), 6.77 (d, J = 8.2 Hz, 1H), 5.48 (s, 2H), 5.13 (dd, J = 12.9, 5.3 Hz, 2H), 3.90 (s, 2H), 2.89 (ddd, J = 17.4, 14.1, 5.4 Hz, 1H), 2.65 - 2.51 (m, 2H), 2.08 - 2.04 (m, 1H). 13 C NMR (176 MHz, DMSO-d6) δ 172.8, 169.9, 166.8, 166.7, 163.3, 146.2, 141.9, 133.9, 132.2, 130.1, 129.1, 128.4, 128.3, 128.3, 128.2, 127.2, 125.3, 123.4, 121.1, 117.4, 116.0, 109.3, 61.8, 48.9, 38.8, 30.9, 22.1, 22.0. HRMS (ESI) m / z: calcd for C 29 H 23 N6O5Cl2 + : 605.1107 [M+H] + , found: 605.1111.

[0215] Example 16 - Synthesis of compound 16

[0216] 5-((1-(3-(3-azidobenzyl)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0217] Into a 25 mL round bottom flask with a magnetic bar, 3-(3-azidobenzyl)aniline (112 mg, 0.5 mmol, 1.0 equiv), 2-(1-methyl-2,6-dioxopiperidin-3-yl)-5-(prop-2-yn-1-yloxy)isoindoline-1,3-dione (156 mg, 0.5 mmol, 1.0 equiv), cuprous bromide (36 mg, 0.25 mmol, 0.5 equiv) and DMF (4 mL) were added sequentially. After heating at 60 °C for 6 hours, the reaction was monitored by LC-MS until the azide was completely converted. Then 50 mL of distilled water was added to the reaction mixture, and a significant amount of solid precipitated. The crude product was isolated by filtration as a light yellow solid. Subsequently, FSO2N3 (1.25 mL, 0.5 mmol, 1.0 equiv, 0.4 M in MTBE) and KHCO3 (670 μL, 2.0 mmol, 4.0 equiv, 3.0 M in water) were added directly to the crude product, along with DMF (5 mL). The reaction progress was monitored by LC-MS. After the reaction was complete, the reaction mixture was cooled to room temperature. Then 50 mL of distilled water was added to the reaction mixture, and a significant amount of solid precipitated. The solid was isolated by filtration and dried in an infrared oven. The product was purified by reverse phase column chromatography. The separation system was water (0.1% TFA): acetonitrile, with a separation gradient of water (0.1% TFA): acetonitrile = 95%:5% to acetonitrile 100%, and the separation column was SW220, spherical C18, 20-45 μm, Finally, 29 mg of white solid was obtained by lyophilization, with a yield of 10%.

[0218] 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.97 (s, 1H), 7.90-7.83 (m, 2H), 7.73 (dd, J = 7.7, 2.2 Hz, 1H), 7.64 (d, J = 2.2 Hz, 1H), 7.52 (t, J = 7.8 Hz, 1H), 7.48 (dd, J = 8.3, 2.3 Hz, 1H), 7.40 (d, J = 7.7 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.13 (d, J = 7.6 Hz, 1H), 7.08 (s, 1H), 6.97 (dd, J = 8.0, 2.3 Hz, 1H), 5.47 (s, 2H), 5.13 (dd, J = 12.9, 5.3 Hz, 1H), 4.07 (s, 2H), 2.89 (ddd, J = 17.4, 14.1, 5.4 Hz, 1H), 2.58 (td, J = 13.9, 4.1 Hz, 2H), 2.14-1.99 (m, 1H). 13 C NMR (176 MHz, DMSO-d6) δ 172.7, 169.8, 166.7, 166.7, 163.2, 142.9, 142.8, 139.4, 136.5, 133.8, 130.1, 130.0, 129.1, 125.6, 125.3, 123.4, 123.2, 121.0, 120.4, 119.3, 118.0, 116.9, 109.3, 61.9, 48.9, 30.9, 22.1, 22.0. HRMS (ESI) m / z: calcd for C 29 H 22 N8O5Na + :585.1611[M+Na] + , found:585.1603.

[0219] Example 17 - Synthesis of Compound 17

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

[0221] Into a 25 mL round bottom flask with a magnetic bar was added 3-(3- azidobenzyl)aniline (112 mg, 0.5 mmol, 1.0 equiv), 2-(2,6-dioxopiperidin-3-yl)-5- (prop-2-yn-1 -ylamino)isoindoline-1,3-dione (156 mg, 0.5 mmol, 1.0 equiv), cuprous bromide (36 mg, 0.25 mmol, 0.5 equiv) and DMF (4 mL) sequentially. After heating at 60 °C for 6 h, LC-MS monitoring showed complete conversion of azide. 100 mL water was added to the system, and a significant amount of insoluble solid was precipitated. The crude product was isolated by filtration as a light yellow solid. Reverse phase separation purification was then performed using a separation system of water (0.1% TFA): acetonitrile with a separation gradient of water (0.1% TFA): acetonitrile = 95%:5% to acetonitrile 100%, and a separation column model of SW080, spherical C18, 20-45 μm, Finally, 195 mg of white solid was obtained by lyophilization, with a yield of 73%.

[0222] 1 H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.87 (s, 1H), 7.91 - 7.82 (m, 2H), 7.73 (dd, J = 8.0, 2.2 Hz, 1H), 7.66 (d, J = 2.2 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.48 (dd, J = 8.0, 2.2 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.34 (t, J = 8.0 Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H), 7.08 (s, 1H), 6.97 (dd, J = 8.0, 2.3 Hz, 1H), 6.28 (s, 1H), 5.28 (s, 2H), 5.10 (dd, J = 12.9, 5.3 Hz, 1H), 4.07 (s, 2H), 2.89 (ddd, J = 17.4, 14.1, 5.4 Hz, 1H), 2.56 (td, J = 13.9, 4.1 Hz, 2H), 2.12 - 1.99 (m, 1H). HRMS (ESI) m / z: calcd for C 29 H 26 N7O4 + : 535.1968 [M+H] + , found: 535.1966.

[0223] Preparation of other compounds of Tables 1-5

[0224] Reference is made to Examples 1-17, except that the corresponding starting materials are used, to prepare other compounds of Tables 1-5.

[0225] Effect Examples:

[0226] 384-well plate corresponding to the experimental operation steps of the drug screening

[0227] Experimental materials: CellTiter-Glo Luminescent Cell Viability Assay Kit (manufacturer Promega, item number G7572), Multi-Drop Combi Reagent Dispenser (Thermo Scientific), Cell Explorer High Throughput Screening Workstation (PerkinElmer), CulturPlate-384 Cell Culture Plate (PerkinElmer)

[0228] Experimental operation: On the first day, use the automatic reagent dispenser to spread the cells (MV411, U937 or 293T) into the cell culture plate, 1500 cells per well, 50 μL of cell culture medium per well; on the second day, add 20 384-plate containing compounds to the cell plate one by one (0.1 μL per well), so that the final compound concentration is 10 μM; add drug treatment for 72 hours, on the fifth day, add 10 μL of CellTiter-Glo Luminescent Cell Viability Assay Kit to each well, shake for 1 minute to mix, and then detect the luminescence intensity.

[0229] Result analysis: Divide the luminescence signal value of each experimental well in each plate by the average luminescence signal value of the DMSO well in each plate to obtain the normalized activity value.

[0230] The activity value is equal to 1, indicating that the cell survival rate of the experimental well is consistent with that of the DMSO well.

[0231] The activity value is less than 1, indicating that the cell survival rate of the experimental well is lower than that of the DMSO well.

[0232] The activity value is greater than 1, indicating that the cell survival rate of the experimental well is higher than that of the DMSO well.

[0233] At this time, the compound with a normalized activity value less than 0.5 is considered to be an effective compound, and when the value is less than 0.5, it means that the cells in the experimental well are more than half less than the DMSO well, which is defined as an effective compound (i.e. a compound with degradation toxicity).

[0234] When the molecular glue is the existing molecular glue compound thalidomide, the normalized activity value obtained by using the drug screening method of the present application is 1.08 in 293T cells, 0.94 in MV411 cells, and 0.91 in U937 cells.

[0235] Table 1 is a molecular glue compound (Formula IA) prepared based on alkyne precursor 1.

[0236] Table 2 is a molecular glue compound (Formula IB) prepared based on alkyne precursor 2.

[0237] Table 3 is a molecular glue compound (Formula IC) prepared based on alkyne precursor 3.

[0238] Table 4 is a molecular glue compound (Formula ID) prepared based on alkyne precursor 4.

[0239] Table 5 is a molecular glue compound (Formula IE) prepared based on alkyne precursor 5.

[0240] Description:

[0241] A+++++: Normalized activity value < 0.01

[0242] A+++: 0.01 < Normalized activity value < 0.03

[0243] A++: 0.03 < Normalized activity value < 0.05

[0244] A+: 0.05 < Normalized activity value < 0.1

[0245] A+: 0.1 < Normalized activity value < 0.3

[0246] A: 0.3 < Normalized activity value < 0.5

[0247] Table 1

[0248] Table 2

[0249] Table 3

[0250] Table 4

[0251] Table 5

[0252] CCK-8 experimental operation steps (molecular glue pure product IC 50 Value specific operation)

[0253] Experimental steps: On the first day, cells (MV411 or 293T) 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 molecular glue compound treatment, 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.

[0254] IC 50Value 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 culture 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.

[0255] At this time, the cells include 293T cell line (human embryonic kidney cells, adherent cells), MV411 cell line (human myelomonocytic leukemia cells, suspended cells) respectively.

[0256] Table 6

[0257] Explanation:

[0258] A+++++: IC 50 ≤1nM

[0259] A+++: 1nM < IC 50 ≤10nM

[0260] A++: 10nM < IC 50 ≤100nM

[0261] A+: 100nM < IC 50 ≤1000nM

[0262] A+: 1000nM < IC 50 ≤10000nM

[0263] From table 6, according to the screening activity results, 17 compounds are selected from the top 50 to synthesize pure products for verification, and it is found that compared with the thalidomide before modification, the anti-tumor activity of these compounds is significantly improved, and the IC 50 of these compounds reaches the nM level, which is consistent with the screening results.

[0264] Protein degradation experiment operation steps (molecular glue pure product DC 50 , D max Value specific operation)

[0265] Experimental operation:

[0266] 1. For compounds 1, 4, 8-15, thalidomide: on the first day, 5x10 5MV4-11 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.

[0267] 2. For compounds 3, 5, 6, and 7: On the first day, 5 × 10 5 293T 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.

[0268] 3. For compound 2: On the first day, 5 × 10 5THP-1 cells were plated in 12-well cell culture plates at 1 mL / well; the next day, a concentration gradient of 0, 0.1, 0.3, 1, 3, 10, 30 μΜ compound was added to the cells, and the cells were treated for 24 hours. On the third day, cell lysate containing protease inhibitors (NP40 buffer + 1% SDS) was added to the cells for lysis, followed by the addition of SDS loading buffer, which was boiled at 100°C for 5 minutes. 20 μg of total protein was loaded into the wells of a 4-12% SDS-PAGE gel, and the gel was run at 120 volts for 90 minutes. After the electrophoresis was complete, the proteins were transferred to a PVDF membrane by electroblotting apparatus at 120 volts for 45 minutes. The PVDF membrane was then blocked with 5% nonfat dry milk at room temperature for 1 hour. The membrane was incubated with MYB protein primary antibody at 4°C overnight. After the incubation was complete, the membrane was washed with TBST three times for 5 minutes each time. The membrane was then incubated with HRP-labeled secondary antibody at room temperature for 1 hour. After the incubation was complete, the membrane was washed with TBST three times for 5 minutes each time. Chemiluminescence images were collected by darkroom development techniques.

[0269] Result analysis: Chemiluminescence images were collected by darkroom development techniques to analyze and calculate DC 50 and D max Numerical values.

[0270] Table 7

[0271] Explanation:

[0272] A +++++: DC 50 ≤ 10 nM

[0273] A + + + + : 10 nM < DC 50 ≤ 100 nM

[0274] A + + + : 100 nM < DC 50 ≤ 1000 nM

[0275] A + + : 1000 nM < DC 50 ≤ 10000 nM

[0276] A + + + + + : 90% < D max ≤ 100%

[0277] A + + + + : 70% < D max ≤ 90%

[0278] A + + + : 50% ≤ D max ≤ 70%

[0279] From Table 7, it can be seen that different compounds have differences in the selection of target degradation and the efficiency of target degradation, indicating that the degradation of different targets has selectivity for the connection of amine precursors.

[0280] All documents referred to in the present application are incorporated herein by reference as if each individual document were incorporated by reference. In addition, it is to be understood that the application can be carried out by specifically different embodiments and that each disclosed embodiment can be implemented with or without the corresponding use of the other embodiments. Other embodiments will occur to readers of the application from the teaching- presented herein.

Claims

1. A molecular glue compound of Formula I, or an enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof, Y-Z Formula I wherein, Y is selected from the group consisting of substituted or unsubstituted: C1-C6alkyl, -(CH2) m - saturated or partially unsaturated C3-C12cycloalkyl, -(CH2) m - 3-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O, or S, -(CH2) m - 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O, or S, -(CH2) m - C6-C10aryl, said substitution independently means substitution with 1, 2, 3 or 4 substituents selected from the group consisting of halogen, hydroxy, -N3, -CN, =0, amino, -COORc, R a substituted or non-substituted C1-C6 alkyl, R a substituted or non-substituted C2-C6 alkenyl, R a substituted or non-substituted C2-C6 alkynyl, R a substituted or non-substituted C1-C6 alkoxy, R a substituted or non-substituted C1-C6 alkyl-S-, C3-C8 cycloalkyl, C3-C8 cycloalkyl-S-, -(C=0)-R a substituted or non-substituted C1-C6 alkyl, -NH-(C=0)-R a substituted or non-substituted C1-C6 alkyl, -NH-(C=0)-0-(CH2) m -C6-C10 aryl, -NH-(CH2) m -C6-C10 aryl, -(C=0)-NH-(CH2) m -R a substituted or non-substituted C6-C10 aryl, -(CH2) m -NH-(C=0)-0-R a substituted or non-substituted C1-C6 alkyl, -N(C1-C6 alkyl)-(C=0)-0-C1-C6 alkyl, -(CH2) m -R a substituted or non-substituted C6-C10 aryl, -0-(CH2) m -R a substituted or non-substituted C6-C10 aryl, -0-(CH2) m -R a substituted or non-substituted 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, -S-(CH2) m -R a substituted or non-substituted C6-C10 aryl, -(C=0)-NRcRd, -(C=0)-NH-(CH2) m -(C=0)-NH-R a substituted or non-substituted C1-C6 alkyl, -(CH2) m -NRcRd, -X1-C3-C8 cycloalkyl, -(CH2) m -R a substituted or non-substituted 3-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S, -0-R a substituted or non-substituted 3-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S, -(C=0)-R a substituted or non-substituted 3-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S, -NH-S(=0)2-R a substituted or non-substituted C1-C6 alkyl, -S(=0)2-R a substituted or non-substituted C1-C6 alkyl, -NH-S(=0)2-R a substituted or non-substituted C6-C10 aryl, -S(=0)2-R a substituted or non-substituted C6-C10 aryl, -B-(OH)2, -(CH2) m -(C=O)-O-C1-C6alkyl, -(C=O)-Ra-substituted or unsubstituted 3-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O, or S, -COORc, -(C=O)-Ra-substituted or unsubstituted C6-C10aryl, -S(=O)2-NRc-Ra-substituted or unsubstituted C6-C10aryl, -NH-Ra-substituted or unsubstituted 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O, or S, Ra-substituted or unsubstituted 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O, or S, -P-(C6-C10aryl)2, each X1is independently selected from the group consisting of 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-C6alkyl, C2-C6alkenyl, C3-C8cycloalkyl, Rb-substituted or unsubstituted C1-C6alkoxy, -COORc, -N3, Rb-substituted or unsubstituted C6-C10 aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O, or S, -NH-(C=0)-0-Ci-C6 alkyl, =0, -NH-C6-C10 aryl; each Rc, Rd is independently selected from the group consisting of H, Rb-substituted or unsubstituted Ci-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 group consisting of halogen, C6-C10 aryl, hydroxyl, -COOH, -COO-Ci-C6 alkyl, Ci-C6 alkyl-S-, Ci-C6 alkoxy, amino, -N3; each Reis independently selected from the group consisting of: 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O, or S; each m is independently selected from the group consisting of 0, 1, 2, 3, 4, 5, 6; each n is independently selected from the group consisting of 0, 1, 2, 3; Z is -X2-X3-X4; X2is selected from the group consisting of: -NR3-(C=0)-, -(C=0)-NR3-, -CR4R5-O-, -0-CR4R5-; X3is selected from the group consisting of -CR4R5-O-, -CR4R5-NH-, null, -O-CR4R5-, X4is selected from the group consisting of: each X5, X6 is independently selected from the group consisting of N, -CR3-; each R3, R4, R5 is independently selected from the group consisting of H, D, Ci-C6 alkyl, haloCi-C6 alkyl.

2. The compound of claim 1, wherein Y is selected from the group consisting of substituted or unsubstituted: C1-C6alkyl, -(CH2) m - saturated or partially unsaturated C3-C12cycloalkyl, -(CH2) m - 3-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S, -(CH2) m - 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, -(CH2) m - C6-C10aryl, said substitution is independently substitution with 1, 2, 3 or 4 substituents selected from the group consisting of: halogen, hydroxyl, -N3, -CN, =0, amino, -COORc, Ra-substituted or unsubstituted C1-C6alkyl, Ra-substituted or unsubstituted C2-C6alkenyl, Ra-substituted or unsubstituted C2-C6alkynyl, Ra-substituted or unsubstituted C1-C6alkoxy, Ra-substituted or unsubstituted C1-C6alkyl-S-, C3-C8cycloalkyl, C3-C8cycloalkyl-S-, -(C=0)-Ra-substituted or unsubstituted C1-C6alkyl, -NH-(C=0)-Ra-substituted or unsubstituted C1-C6alkyl, -NH-(C=0)-0-(CH2) m - C6-C10aryl, -NH-(CH2) m - C6-C10aryl, -(C=0)-NH-(CH2) m - Ra-substituted or unsubstituted C6-C10aryl, -(CH2) m - NH-(C=0)-0-Ra-substituted or unsubstituted C1-C6alkyl, -N(C1-C6alkyl)-(C=0)-0-C1-C6alkyl, -(CH2) m - Ra-substituted or unsubstituted C6-C10aryl, -0-(CH2) m - Ra-substituted or unsubstituted C6-C10aryl, -0-(CH2) m - Ra-substituted or unsubstituted 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, -S-(CH2) m - Ra-substituted or unsubstituted C6-C10aryl, -(C=0)-NRcRd, -(C=0)-NH-(CH2) m - (C=0)-NH-Ra-substituted or unsubstituted C1-C6alkyl, -(CH2) m - NRcRd, -X1-C3-C8cycloalkyl, -(CH2) m - 3-8 membered heterocycloalkyl substituted or not by Ra, - 3-8 membered heterocycloalkyl substituted or not by -O-Ra, - 3-8 membered heterocycloalkyl substituted or not by -(C=O)-Ra, - C1-C6 alkyl substituted or not by -NH-S(=O)2-Ra, - C1-C6 alkyl substituted or not by -S(=O)2-Ra, - C6-C10 aryl substituted or not by -NH-S(=O)2-Ra, - C6-C10 aryl substituted or not by -S(=O)2-Ra, - 5-10 membered heteroaryl substituted or not by Ra, - 5-10 membered heteroaryl substituted or not by -NH-Ra, - 5-10 membered heteroaryl substituted or not by Ra, - B-(OH)2, -(CH2) m - (C=O)-O-C1-C6 alkyl, - (C=O)-Ra substituted or not by 3-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S, -COORc, - (C=O)-Ra substituted or not by C6-C10 aryl, - S(=O)2-NRc-Ra substituted or not by C6-C10 aryl, - NH-Ra substituted or not by 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, - Ra substituted or not by 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, - P-(C6-C10 aryl)2, each X1is independently selected from the group consisting of 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-C6alkyl, C2-C6alkenyl, C3-C8cycloalkyl, Rb-substituted or unsubstituted C1-C6alkoxy, -COORc, -N3, Rb-substituted or unsubstituted C6-C10 aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O, or S, -NH-(C=0)-0-Ci-C6 alkyl, =0, -NH-C6-C10 aryl; each Rc, Rd is independently selected from the group consisting of H, Rb-substituted or unsubstituted Ci-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 group consisting of halogen, C6-C10 aryl, hydroxyl, -COOH, -COO-Ci-C6 alkyl, Ci-C6 alkyl-S-, Ci-C6 alkoxy, amino, -N3; each Reis independently selected from the group consisting of: 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O, or S; each m is independently selected from the group consisting of 0, 1, 2, 3, 4, 5, 6; each n is independently selected from the group consisting of 0, 1, 2, 3.

3. The compound of claim 1, wherein X2is selected from the group consisting of: -NR3-(C=0)-, -(C=0)-NR3-, -CR4R5-O-, -0-CR4R5-.

4. The compound of claim 1, wherein X2 is 5. The compound of claim 1, wherein X3is selected from the group consisting of -CR4R5-O-, -CR4R5-NH-, null, -O-CR4R5-, 6. The compound of claim 1, wherein X3 is -CR4R5-O-; R4, R5 is independently selected from the group consisting of H, Ci-C6 alkyl.

7. The compound of claim 1, wherein X4is selected from the group consisting of:

8. The compound of claim 1, wherein X4is selected from the group consisting of:

9. The compound of claim 1, wherein X4 is 10. The compound of claim 1, wherein Y is selected from the group consisting of substituted or unsubstituted -(CH2) m - saturated or partially unsaturated C3-C12cycloalkyl, -(CH2) m - 3-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O, or S, -(CH2) m - 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O, or S, -(CH2) m - C6-C10aryl; said substituents are as defined in claim 1.

11. The compound of claim 1, wherein Y, said substitution is independently a substitution with 1, 2, 3, or 4 substituents selected from the group consisting of: halo, -CF3, Ra-substituted or unsubstituted C1-C6alkyl-S-, -(CH2) m -Ra-substituted or unsubstituted C6-C10aryl, -NH-(CH2) m -C6-C10aryl, -NH-S(=O)2-Ra-substituted or unsubstituted C1-C6alkyl, -S(=O)2-Ra-substituted or unsubstituted C1-C6alkyl, -NH-S(=O)2-Ra-substituted or unsubstituted C6-C10aryl, -S(=O)2-Ra-substituted or unsubstituted C6-C10aryl, -O-(CH2) m -Ra-substituted or unsubstituted C6-C10aryl, -O-(CH2) m -Ra-substituted or unsubstituted 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O, or S, Ra-substituted or unsubstituted 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O, or S; Ra is as defined in claim 1. Rb is as defined in claim 1.

12. The compound of claim 1, wherein 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; Rb is -NH2.

13. The compound of claim 1, wherein The compound is selected from the group consisting of the compounds shown in Table 1, the compounds shown in Table 2, the compounds shown in Table 3, the compounds shown in Table 4, the compounds shown in Table 5, compound 11, compound 12, compound 13, compound 14, compound 15, compound 16, and compound 17.

14. A process for preparing a compound of claim 4, or an enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof, wherein, comprising the steps of: Y-N3 and to give wherein Y, X3, and X4 are as defined in claim 1.

15. A pharmaceutical composition comprising, A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a safe and effective amount of a compound of claim 1, or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof.

16. Use of a compound of claim 1, or an enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof, wherein, A medicament for preventing and / or treating a disease selected from the group consisting of cancer, autoimmune diseases, and inflammatory diseases. A medicament for preventing and / or treating a disease selected from the group consisting of cancer, autoimmune diseases, and inflammatory diseases.

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