Protein degrader targeting OGT and preparation method therefor and use thereof

Abstract

Disclosed are a protein degrader targeting O-GlcNAc Transferase (OGT), and a preparation method therefor and a use thereof. The inventors of the present invention have creatively discovered that a compound recruits MDM2 by means of its interaction with nucleolin (NCL), and through further experiments have found that it can serve as a novel recruiting element for MDM2, which can be used in the preparation of targeted protein degraders and other applications. Using the above findings, the inventors have prepared a novel protein degrader compound targeting OGT, and have found through experimentation that the prepared targeted protein degrader can effectively induce the degradation of OGT, for use in the treatment of diseases mediated by OGT or associated with O-GlcNAc glycosylation (such as neurodegenerative diseases, obesity, tumors, diabetes and complications thereof, cardiovascular diseases, etc.), and will have very promising application prospects in the fields of medicine and health management.

Description

A protein degrader targeting OGT, its preparation method and application Technical Field

[0001] This invention relates to the field of chemical and pharmaceutical technology, specifically to a protein degrading agent targeting O-GlcNAc transferase (OGT), its preparation method, and its application. Background Technology

[0002] OGT (O-Linked N-acetylglucosamine Transferase) is a key enzyme responsible for adding an O-linked N-acetylglucosamine (O-GlcNAc) residue to a serine or threonine residue in a protein; this process is known as O-GlcNAcylation. OGT is widely expressed intracellularly and plays a crucial role in regulating various biological processes, including cell signaling, transcriptional regulation, protein stability, and cellular metabolism. O-GlcNAcylation is considered an important mechanism for cells to respond to changes in nutritional status and environmental stress. Aberrant expression or dysfunction of OGT is closely associated with a variety of diseases, including diabetes, obesity, cardiovascular disease, neurodegenerative diseases, and cancer. Due to its broad regulatory role within cells, OGT holds great potential as a therapeutic target. For example, inhibiting OGT activity may help control hyperglycemia-related metabolic disorders or inhibit cancer cell growth by modulating specific signaling pathways. However, given OGT's critical role in many vital bodily functions, targeted therapeutic strategies require meticulous design to ensure specificity and minimize side effects.

[0003] Targeted protein degradation is a novel and groundbreaking drug development strategy that utilizes inherent intracellular protein degradation pathways to directly degrade pathogenic target proteins. This novel drug form includes various types, such as PROTACs, molecular gels, LYTACs, ATACs, AbTACs, ATTECs, AUTACs, and AUTOTACs. PROTACs (Proteolysis Targeting Chimeras) are bifunctional molecules composed of a target protein ligand, a linker, and an E3 ubiquitin ligase recruitment element. Upon entering the cell, the target protein ligand in a PROTAC specifically binds to the target protein, while the E3 ligase recruitment element at the other end binds to the E3 ligase, forming a target protein-PROTAC-E3 ternary complex. The E3 ubiquitin ligase mediates ubiquitination of the target protein by the ubiquitin-conjugating enzyme E2. The polyubiquitinated target protein is then transported to the proteasome for degradation, thereby reducing the target protein level. In this process, the target protein ligand does not need to occupy the binding site for an extended period. Therefore, PROTACs can cycle multiple times within the cell to exert their effects. Based on the unique mechanism of action of PROTAC, PROTAC drugs have significant advantages in drug development for overcoming drug resistance and untreatable targets. Summary of the Invention

[0004] To overcome the shortcomings of the prior art, the present invention provides a protein degrading agent targeting O-GlcNAc transferase (OGT), its preparation method and application.

[0005] In a first aspect of the invention, a compound (a targeted protein degrader, such as PROTAC) or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound thereof is provided, said compound having the following structure:

[0006] in,

[0007] OGTL is the OGT inhibitor portion, such as the OGT inhibitors or O-GlcNAc transferase inhibitors described in patent applications US15 / 323,206, US17 / 271,793, PCT / US2019 / 048805, CN202210021882.4, CN202211102591.4, and US13 / 375,036;

[0008] ML is the recruitment element portion of the E3 ubiquitin ligase, such as the MDM2 protein recruitment element described in Chinese patent application CN2024114784319 and PCT patent application WO2025 / 087245A1, such as compounds represented by their general formula I, for example, compounds represented by formulas V-1 to V-29, especially the compounds Ori, Ger, CYD, and OriPh described in the examples;

[0009] L is a divalent connector that links OGTL and ML, as described in Chinese patent application CN2024114784319 and PCT patent application WO2025 / 087245A1.

[0010] In some embodiments of the present invention, OGTL is an OGT inhibitor known in the prior art, such as OSMI-1, OSMI-2, OSMI-4, alloxan, etc.

[0011] Specifically, the compound has the following structure:

[0012] in,

[0013] ML is the recruitment element part of the MDM2 protein;

[0014] L is a linking group;

[0015] q is an integer from 1 to 15 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15);

[0016] Z1 and Z2 are independent linking groups;

[0017] Y1 is selected from: -CH(R) P4 )-、-N(R P4 )-, where R P4 Selected from: H, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 Aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic); or, Z2 together with Y and the carbon atom attached to both to form a carbocyclic or heterocyclic ring, wherein the H on the carbocyclic or heterocyclic ring is optionally substituted with a group selected from: H, =O, halogen, cyano, nitro, azide, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic), C1-C10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 alkyl), -O(C) 0-10 alkyl), -S(C 0-10 alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 alkyl), -COO(C 0-10 Alkyl), -OCO(C) 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 Alkyl), -CO(C) 0-10 alkyl);

[0018] Y2 is selected from: -SO2-, -SO-, -C(O)-;

[0019] R P1 R P2 Independently selected from: H, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 heterocyclic); or, R P1 R P2 Together with the nitrogen atom attached thereto, a heterocycle is formed, wherein the alkyl, cycloalkyl, aryl, heterocyclic group, or H on the heterocycle is optionally substituted with a group selected from: H, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 Aryl), -(C0-C6 alkylene)-(4-10 heterocyclic), halogen, cyano, nitro, azide, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 alkyl), -O(C) 0-10 alkyl), -S(C 0-10 alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 alkyl), -COO(C 0-10 Alkyl), -OCO(C) 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 Alkyl), -CO(C) 0-10 alkyl);

[0020] R P3 Selected from: H, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 Aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic); wherein the H on the alkyl, cycloalkyl, aryl, or heterocyclic group is optionally substituted by a group selected from the following groups: H, =O, halogen, cyano, nitro, azide, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic), C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 alkyl), -O(C) 0-10 alkyl), -S(C 0-10 alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 alkyl), -COO(C0-10 Alkyl), -OCO(C) 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 Alkyl), -CO(C) 0-10 alkyl);

[0021] Or, R P3 The benzene ring attached thereto forms a fused carbide ring or heterocycle, wherein the hydrogen atom on the carbide ring or heterocycle is optionally substituted with a group selected from the following: H, =O, halogen, cyano, nitro, azide, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 Aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic); wherein the H on the alkyl, cycloalkyl, aryl, or heterocyclic group is optionally substituted by a group selected from the following: H, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 Aryl), -(C0-C6 alkylene)-(4-10 heterocyclic), halogen, cyano, nitro, azide, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 alkyl), -O(C) 0-10 alkyl), -S(C 0-10 alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 alkyl), -COO(C 0-10 Alkyl), -OCO(C) 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 Alkyl), -CO(C) 0-10 alkyl);

[0022] The MDM2 protein recruitment element is the compound shown in Chinese patent application CN2024114784319 and PCT patent application WO2025 / 087245A1 of formula I, and further, the compound shown in claims 12-16, especially compounds Ori, Ger, CYD, and OriPh.

[0023] In this invention, the compound is a targeted protein degrader using compound I as an MDM2 recruitment element. In vivo, it can bring the target protein and E3 ubiquitin ligase closer, thereby tagging the target protein with ubiquitin, and then degrading it via the ubiquitin-proteasome pathway. Experiments show that the degrader can effectively degrade the target protein (O-GlcNAc transferase (OGT)) and holds promise for the prevention and treatment of diseases related to abnormal expression or dysfunction of OGT (such as diabetes, cardiovascular disease, neurodegenerative diseases, cancer, obesity, etc.).

[0024] In some embodiments of the present invention, q is 1, that is, the compound has the following structure:

[0025] Specifically, R P4 Selected from: H, C1-C6 alkyl; more specifically, R P4 For H.

[0026] In some embodiments of the present invention, Y1 is -NH-. In some embodiments of the present invention, Y1 is -CH2-.

[0027] In some embodiments of the present invention, Y2 is -SO2-.

[0028] In some embodiments of the present invention, the compound has the following structure: (VI-1).

[0029] In some embodiments of the present invention, R P1 It is -(C0-C6 alkylene)-(4-10 membered heterocyclic group), for example -CH2-(4-10 membered heterocyclic group); specifically, R P1 It has the following structure: Among them, ring A is a 4-10 membered heterocyclic ring, and R... P5 One or more independent substituents on ring A, selected from: H, =O, halogen, cyano, nitro, azide, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic), C1-C 10 Haloalkyl, C1-C10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 alkyl), -O(C) 0-10 alkyl), -S(C 0-10 alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 alkyl), -COO(C 0-10 Alkyl), -OCO(C) 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 Alkyl), -CO(C) 0-10 alkyl).

[0030] Specifically, R P5 Selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyalkyl, C1-C6 alkylaminoalkyl, C1-C6 cyanoalkyl. In some embodiments of the present invention, R P5 For H.

[0031] Specifically, ring A can be a 4-6 membered heteroaromatic ring, for example:

[0032] in particular

[0033] In some embodiments of the present invention, R P1 It has the following structure:

[0034] In some embodiments of the present invention, the compound has the following structure:

[0035] In some embodiments of the present invention, R P2 -(C0-C6 alkylene)-Y3-R P6 For example, -CH2-Y3-R P6 Y3 is selected from: single bond, C2-C4 alkylene group, -O-, -S-, -N(C 0-10Alkyl group, -CO group, -CON(C) 0-10 alkyl)-, -N(C 0-10 Alkyl groups) CO-, -SO2-, -SO2N(C 0-10 Alkyl groups, -COO-, -OCO-, -CO-, 3-6 membered cycloalkyl subgroups, 4-6 membered heterocyclic subgroups, R P6 Selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyalkyl, C1-C6 alkylaminoalkyl, C1-C6 cyanoalkyl.

[0036] In some embodiments of the present invention, Y3 is a 4-6 member subheterocyclic group, R P2 It has the following structure: Among them, ring B is a 4-6 membered heteroaromatic ring, such as those defined above regarding ring A, especially Specifically, R P6 It can be H.

[0037] In some embodiments of the present invention, R P2 It has the following structure:

[0038] In some embodiments of the present invention, Y3 is -COO- or -CON(C 0-3 alkyl)-, R P6 Selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxyalkyl.

[0039] In some embodiments of the present invention, R P2 It has the following structure:

[0040] In some embodiments of the present invention, R P1 R P2 Together with the nitrogen atom it is attached to, they form 4-10 membered heterocycles, for example... Some have the following structure: The H on the heterocycle is optionally substituted, with the substituents described above.

[0041] In some embodiments of the invention, Z2 is a substituted or unsubstituted phenylene, heteroaryl (the heteroaryl rings are those defined above with respect to the A ring), or cycloalkylene, particularly phenylene. Further, Z2 has the following structure: For example

[0042] In some embodiments of the present invention, the compound has the following structure: (VI-3), RP7 Selected from: H, halogen (such as F), cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 haloalkyl.

[0043] In some embodiments of the present invention, R P7 For H.

[0044] Specifically, Z1 is -(C0-C6 alkylene)-Z3-(C0-C6 alkylene)-, and Z3 is selected from: single bond, C2-C4 alkylene, C2 alkenyl, C2 alkyneyl, -O-, -S-, -N(C 0-10 Alkyl group, -CO group, -CON(C) 0-10 alkyl)-, -N(C 0-10 Alkyl groups) CO-, -SO2-, -SO2N(C 0-10 Alkyl group, -COO-, -OCO-, -CO-, 3-6 membered cycloalkylene group, 3-6 membered heteroalkylene group. More specifically, Z1 is selected from: -O-, -S-, -NH-.

[0045] In some embodiments of the present invention, Z1 is -O-.

[0046] In some embodiments of the present invention, R P3 Selected from: H, -N(C) 0-6 Alkyl)CO(C 0-6 Alkyl), -CON(C) 0-6 Alkyl)(C 0-6 Alkyl); more specifically, R P3 Selected from:

[0047] In some embodiments of the present invention, R P3 The benzene ring attached to it forms an 8-12 membered fused carbon ring or heterocycle, particularly an 8-10 membered nitrogen-containing heterocycle; specifically, Some have the following structure: Among them, R P8 It is one or more independent substituents on the ring, selected from: H, halogen, C1-C6 alkyl, C1-C6 haloalkyl.

[0048] Specifically, R P8 Selected from: H, halogens (such as F, Cl), methyl, trifluoromethyl.

[0049] In some embodiments of the present invention, the compound has the following structure:

[0050] In some embodiments of the present invention, the aforementioned OGTL or Some have the following structure:

[0051] Furthermore, in addition to the compound shown in CN202411478431.9, other structural analogs have been verified or are under investigation in the prior art, such as patent documents CN105473566A, CN104039796A, CN101139350A, CN101723951A, and CN... 102002051A, CN102295649A, CN102850369A, CN104003998A, CN105524076A, C N106749305A, CN106866695A, CN106883267A, CN108299458A, CN108864132A, CN110627833A, CN113698415A, CN114478566A, CN116621855A, CN114702506A , CN113004241A, CN110950883A, CN110229168A, CN111635395A, CN106749305A Shen QK,Chen ZA, Zhang HJ, Li JL, Liu CF, Gong GH, Quan ZS. Design and synthesis of novel oridonin analogues as potent anticancer agents. J Enzyme Inhib Med Chem. 2018 Dec; 33(1):324-333.; Dai Yi, Zhong Fei. Research progress on structural modification and bioactivity of oridonin [J]. Organic Chemistry, 2017, 37(7):1701-1713. etc., which are incorporated herein by reference in their entirety.

[0052] In some embodiments of the present invention, the ML portion has the following structure:

[0053] in particular

[0054] In some embodiments of the present invention, the ML portion has the following structure:

[0055] in particular

[0056] In some embodiments of the present invention, the ML portion has the following structure:

[0057] In some embodiments of the present invention, the ML portion has the following structure:

[0058] In some embodiments of the present invention, the ML portion has the following structure:

[0059] in particular

[0060] In some embodiments of the present invention, R 12 Selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, C(O)(C 0-6 Alkyl), C(S)(C 0-6 Alkyl), C(S)S(C 0-6 Alkyl), C(O)N(C 0-6 Alkyl)(C 0-6 Alkyl), SO2 (C) 0-6 Alkyl), SO2N(C) 0-6 Alkyl)(C 0-6 Alkyl), P(O)O(C 0-6 Alkyl)(C 0-6 alkyl groups, monosaccharide residues, Among them, R 16 Selected from: halogen, cyano, nitro, azide, C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 alkyl), -O(C) 0-10 alkyl), -S(C 0-10 alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 alkyl), -COO(C 0-10 Alkyl), -OCO(C) 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10Alkyl), -CO(C) 0-10 Alkyl); more specifically, R 12 Selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, C(O)(C 0-6 Alkyl), SO2 (C) 0-6 alkyl), In some embodiments of the present invention, R 12 For H.

[0061] In some embodiments of the present invention, R 16 Selected from: H, halogen, cyano, nitro, azide, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy. In some embodiments of the present invention, R 16 For H.

[0062] In some embodiments of the present invention, R 13 Selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, C(O)(C 0-6 Alkyl), C(S)(C 0-6 Alkyl), C(S)S(C 0-6 Alkyl), C(O)N(C 0-6 Alkyl)(C 0-6 Alkyl), SO2 (C) 0-6 Alkyl), SO2N(C) 0-6 Alkyl)(C 0-6 Alkyl), P(O)O(C 0-6 Alkyl)(C 0-6 alkyl groups, monosaccharide residues, Among them, R 17 Selected from: halogen, cyano, nitro, azide, C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 alkyl), -O(C) 0-10 alkyl), -S(C 0-10 alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C0-10 alkyl), -COO(C 0-10 Alkyl), -OCO(C) 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 Alkyl), -CO(C) 0-10 Alkyl); more specifically, R 13 Selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, C(O)(C 0-6 Alkyl), SO2 (C) 0-6 alkyl), In some embodiments of the present invention, R 13 For H.

[0063] In some embodiments of the present invention, R 17 Selected from: H, halogen, cyano, nitro, azide, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy. In some embodiments of the present invention, R 17 For H.

[0064] In some embodiments of the present invention, R 14 For H.

[0065] In some embodiments of the present invention, R 15 For H.

[0066] In other embodiments of the present invention, R 15 These are monosaccharide residues, such as glucosyl, galactosyl, xylose, and mannose.

[0067] In some embodiments of the present invention, R 23 and R 24 Independently selected from: H, C1-C3 alkyl, phenyl, wherein the H on the phenyl group may optionally be substituted by one or more groups selected from: halogen, hydroxyl, amino, C1-C3 alkoxy; in one embodiment of the invention, R 23 R is methyl; in one embodiment of the invention, R 24 R is methyl; in one embodiment of the invention, R 23 For H, R 24 R is phenyl; in one embodiment of the invention, R 23 For H, R 24 It is 3,4-dimethoxyphenyl.

[0068] In some embodiments of the present invention, R 25 Selected from: H, C1-C6 alkyl, -N(H)(C 0-6 Alkyl), -N(H)CO(C) 0-6Alkyl), -N(H)(C 2-6 alkenyl) (e.g. ), -N(H)(C 3-6 cycloalkyl) (e.g. ), -N(H)(C 0-6 alkylene-4-6-membered nitrogen-containing heterocyclic groups (e.g.) ), 4-8 member nitrogen-containing heterocyclic groups (e.g. ), More specifically, R 25 Selected from: H, methyl, ethyl, amino, In some embodiments of the present invention, R 25 for

[0069] In some embodiments of the present invention, R 25 for R 25a and R 25b Independently selected from: H, C1-C6 alkyl, C1-C6 haloalkyl (e.g. ); or, R 25a and R 25b Together with the nitrogen atom to which it is attached, it forms an optionally substituted 3-6 membered saturated heterocyclic group (e.g. ).

[0070] In some embodiments of the present invention, R 25 It is one or more independent substituents on the ring, selected from: H, C1-C6 alkyl, -O(C 0-6 alkyl), -S(C 0-6 alkyl), -O(C) 2-6 alkenyl) (e.g. ), wherein the H on the alkyl group is optionally substituted with a group selected from the following groups: H, halogen, hydroxyl, azide, amino; or, both R 25 Together with the atoms it is attached to, they form carbon rings or heterocycles (e.g. More specifically, R 25 Selected from: In some embodiments of the present invention, R 25 for

[0071] In some embodiments of the present invention, X is 0. In some embodiments of the present invention, X is S.

[0072] In some embodiments of the present invention, R 26Selected from: H, halogen, cyano, nitro, azide, C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, -COO(C 0-3 alkyl),

[0073] In some embodiments of the present invention, R 26 Selected from: H, halogens, C1-C3 alkyl groups, C3-C6 cycloalkyl groups, The H on the phenyl or heterocyclic group may optionally be substituted by one or more groups selected from the following: halogen, cyano, nitro, azide, hydroxyl, amino, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -N(C 0-3 Alkyl)(C 0-3 alkyl).

[0074] In some embodiments of the present invention, R 31 Selected from: H, halogens, C1-C6 alkyl groups, -O(C 0-6 alkyl), -O(C) 2-12 alkenyl), -N(C) 0-6 Alkyl)(C 0-6 alkyl), -COO(C 0-6 alkyl), -N(C) 0-6 Alkyl)CO(C 0-6 alkyl), -N(C) 0-6 Alkyl)CO(phenyl). In some embodiments of the invention, R 31 For H.

[0075] In some embodiments of the present invention, R 32 and R 33 Independently selected from: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, or R 32 and R 33 Together with the nitrogen atom it is attached to, it forms a 4-8 membered heterocyclic group. More specifically, R 32 and R 33 Independently selected from: H, C1-C6 alkyl groups (such as methyl, ethyl).

[0076] Specifically, L has the following structure: in,

[0077] L1 is a divalent group attached to ML, which can be selected from: single bond, -O-(C0-C6 alkylene)-, -S-(C0-C6 alkylene)-, -N(R L1 )-(C0-C6 alkylene)-, -N(R L2 )C(O)-(C0-C6 alkylene)-、-OP(O)(ORL1 -O-(C0-C6 alkylene)-, -C(O)-(C0-C6 alkylene)-, -C(S)-(C0-C6 alkylene)-, -CON(R) L1 -(C0-C6 alkylene)-, -SO2-(C0-C6 alkylene)-, -SO-(C0-C6 alkylene)-;

[0078] L3 is a divalent group attached to Z1, which can be selected from: single bond, -(C0-C6 alkylene)-O-, -(C0-C6 alkylene)-S-, -(C0-C6 alkylene)-C(O)-, -(C0-C6 alkylene)-C(S)-, -(C0-C6 alkylene)-N(R) L3 )-、-(C0-C6 alkylene)-CON(R L3 )-、-(C0-C6 alkylene)-N(R L3 CO-, -(C0-C6 alkylene)-SO2-, -(C0-C6 alkylene)-SO-, -(C0-C6 alkylene)-(4-10 heterocyclic)-;

[0079] L2 is a C1-C50 hydrocarbon chain (e.g., a C1-C20 alkyl chain) that is saturated or unsaturated with a single bond or divalent valence, consisting of 0-6 methylene units independently substituted with the following: -CY-, -O-, -S-, -SS-, -C(O)-, -C(S)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R) L2 )-、-N(R L2 )C(O)-、-N(R L2 )C(O)O-、-N(R L2 )C(O)N(R L2 )-、-N(R L2 -, -S(O)2-, -S(O)2N(R) L2 )-、-N(R L2 -S(O)2-, -S(O)-, -S(O)N(R) L2 )-、-N(R L2 )S(O)-、-P(O)(OR L 2 -O-, -P(O)-, -P(O)N(R) L2 )-、-P(O)(N(R L2 )2)-、-OP(O)(OR L2 )2N(R L2 )-、-P(O)(OR L2 )2N(R L2 )-、-N(R L2)P(O)(OR L2 )O-、-N(R L2 P(O)-, -Si(R) L2 )2-、-C(=N-CN)-、 Amino acid residues, nucleotide residues, oligonucleotide residues, oligopeptide residues, wherein m2 is selected from an integer selected from 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10), and each -CY- is independently a divalent ring selected from the optionally substituted groups: arylene, cycloalkylene, heterocyclic; the H in the hydrocarbon chain may optionally be substituted by one or more groups selected from the group: halogen, cyano, nitro, azido, -OR L0 -C(O)R L0 -C(S)R L0 -C(O)OR L0 -C(S)SR L0 -OC(O)R L0 -OC(S)R L0 -OC(S)SR L0 -C(O)N(R) L0 )2、-OC(O)N(R L0 )2、-N(R L0 )C(O)OR L0 -N(R) L0 SO2R L0 -SO2N(R) L0 )2、-OSO2N(R L0 )2、-N(R L0 )C(O)R L0 -N(R) L0 )2、-SR L0 -SOR L0 -SO2R L0 -OSO2R L0 C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 Alkyne group, C1-C 10 Haloalkyl, C1-C 10 Haloalkoxy, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic);

[0080] R L0 R L1 R L2and R L3 Independently selected from: H, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic), wherein the C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C0-C6 alkylene, C3-C 10 cycloalkyl, C6-C 10 The hydrogen atoms in the aryl and 4-10 membered heterocyclic groups may optionally be substituted by one or more groups selected from the following: halogen, cyano, nitro, azide, hydroxyl, amino, mercapto, carboxyl, C1-C. 10 Alkyl, C2-C 10 alkenyl, C2-C 10 Alkyne group, C1-C 10 Haloalkyl, C1-C 10 Haloalkoxy, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 Aryl), -(C0-C6 alkylene)-(4-10 heterocyclic).

[0081] Specifically, each -CY- is independently selected from the following optionally substituted divalent rings: phenylene, bicyclic arylene, tricyclic arylene, monocyclic cycloalkylene, bicyclic cycloalkylene, tricyclic cycloalkylene, monocyclic heteroalkylene, bicyclic heteroalkylene, tricyclic heteroalkylene, monocyclic heteroalkylene, bicyclic heteroalkylene, tricyclic heteroalkylene, tricyclic heteroalkylene.

[0082] In some embodiments of the present invention, -CY- is a substituted or unsubstituted phenylene. In some embodiments of the present invention, -CY- is a substituted or unsubstituted 3-12 membered cyclohexene alkylene. In some embodiments of the present invention, -CY- is a substituted or unsubstituted 4-12 membered saturated heterocyclic alkylene.

[0083] In some embodiments of the invention, each -CY- is independently selected from the following:

[0084] Among them, R L4 R L5 Independently selected from: H, OH, halogens, C 1-8 Alkyl, O(C)1-8 Alkyl), S(C) 1-8 Alkyl), NH(C) 1-8 alkyl), N(C) 1-8 Alkyl)2, C 3-11 Cyclic hydrocarbon group, C 3-11 Heterocyclic hydrocarbon groups, O(C) 1-8 cyclic hydrocarbon group), S(C) 1-8 cyclic hydrocarbon group), NH(C) 1-8 cyclic hydrocarbon group), N(C) 1-8 Cyclohydrogen group)(C 1-8 Alkyl groups), OH, NH2, SH, SO2 (C 1-8 Alkyl), P(=O)(OC) 1-8 Alkyl)(C 1-8 Alkyl), P(=O)(OC) 1-8 Alkyl)2, C 1-8 Alkyne group, CH=CH(C 1-8 Alkyl), C(C) 1-8 Alkyl)=CH(C 1-8 Alkyl), C(C) 1-8 Alkyl) = C(C 1-8 Alkyl)2, Si(OH)3, Si(C 1-8 Alkyl)3, Si(OH)(C 1-8 Alkyl)2、C(=O)(C 1-8 Alkyl groups), CO2H, CN, CF3, CHF2, CH2F, NO2, SF5, SO2NH (C 1-8 Alkyl), SO2N(C) 1-8 Alkyl)2, S(=O)N(C 1-8 Alkyl)2、C(=O)NH(C 1-8 Alkyl), C(=O)N(C 1-8 Alkyl)2, N(C) 1-8 alkyl)C(=O)NH(C 1-8 Alkyl), N(C) 1-8 Alkyl)C(=O)N(C 1-8 Alkyl)2, NHC(=O)NH(C 1-8 Alkyl), NHC(=O)N(C 1-8 Alkyl)2, NHC(=O)NH2, N(C) 1-8 alkyl)SO2NH(C 1-8 Alkyl), N(C) 1-8 Alkyl)SO2N(C 1-8 Alkyl)2, NHSO2NH(C 1-8 Alkyl), NHSO2N(C 1-8 Alkyl)2 or NHSO2NH2; or, R L4 RL5 Together with the atoms to which they are attached, they form cycloalkyl or heterocyclic groups.

[0085] More specifically, R L4 R L5 Independently selected from: -CH3, -OH、 Or, R L4 R L5 Together with the atoms they are attached to, they form ternary to hexacyclic alkyl groups (such as... ) or four- to six-membered heterocyclic alkylene compounds (such as ).

[0086] In some embodiments of the present invention, R L1 For H.

[0087] In some embodiments of the present invention, R L3 For H.

[0088] In some embodiments of the present invention, R L4 For H.

[0089] In some embodiments of the present invention, R L4 It is OH.

[0090] In some embodiments of the present invention, R L5 For H.

[0091] In some embodiments of the present invention, R L5 It is OH.

[0092] In one embodiment of the invention, L2 is a C1-C20 straight-chain alkylene group, wherein 0-6 methylene units in the alkylene group are independently substituted by the following groups: -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R L2 )-、-C(O)N(R L2 )-、-N(R L2 C(O)-、 Among them, each R L2 Independently selected from: H, C1-C6 alkyl groups, each R L4 and R L5 Independently selected from: H, OH, C1-C6 alkoxy groups.

[0093] In some specific embodiments of the present invention, L2 is a C1-C20 straight-chain alkylene group, for example:

[0094] In some specific embodiments of the present invention, L2 is a C1-C20 alkylene (e.g., a C1-C12 straight-chain alkylene, a C1-C10 straight-chain alkylene), wherein at least one methylene unit in the alkylene is independently substituted by the following groups: -O-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R) L2 )-、-N(R L2 )C(O)-、-N(R L2 -, -S(O)2-, -S(O)-, Furthermore, L2 is a C1-C6 straight-chain alkylene group, wherein at least one methylene unit in the alkylene group is independently substituted by the following groups: For example

[0095] In some specific embodiments of the present invention, L2 is selected from: Where h is selected from integers between 0 and 10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10), i is selected from integers between 0 and 10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10), and k is selected from integers between 0 and 10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10), as shown below.

[0096] In another embodiment of the invention, L2 is a C1-C20 straight-chain alkylene group, wherein 1-3 methylene units are independently substituted by the following groups: -CY-, Optionally, L2 also contains groups selected from: -O-, -C(O)-, -N(R)-. L2 )-、-C(O)N(R L2 )-、-N(R L2 C(O)-、 Among them, each R L2 Independently selected from: H, C1-C6 alkyl groups, each R L4 Independently selected from: OH, C1-C6 alkoxy groups.

[0097] In some embodiments of the present invention, -CY- is selected from:

[0098] In some embodiments of the invention, L2 is a C1-C20 straight-chain alkylene group, wherein 1-5 methylene units are independently substituted by the following groups: Optionally, L2 also contains groups selected from the following: -O-, -C(O)-, -N(C0-C6 alkyl)-, -C(O)N(C0-C6 alkyl)-, -N(C0-C6 alkyl)C(O)-.

[0099] In some specific embodiments of the present invention, L2 is selected from:

[0100] In some embodiments of the present invention, L1 is -C(O)-. In some embodiments of the present invention, L1 is a single bond.

[0101] In some embodiments of the present invention, L2 is... Where h is 1, 2, 3, 4, 5 or 6, i is 1, 2, 3, 4, 5 or 6, and k is 1, 2, 3, 4, 5 or 6.

[0102] In some embodiments of the present invention, L2 is... Where h is 1, 2, 3, 4, 5 or 6, and i is 1, 2, 3, 4, 5 or 6.

[0103] In one embodiment of the invention, L3 is a single bond. In some embodiments of the invention, L3 is -C(O)-.

[0104] In some embodiments of the present invention, the compound has the following structure:

[0105] More specifically, the compound has the following structure:

[0106] In some embodiments of the present invention, for compounds of formulas VI, VII, and VIII, the ML portion is selected from one of ML-01 to ML-L08, particularly ML-01:

[0107] In some embodiments of the present invention, for compounds of formulas VI, VII, and VIII, the ML portion is selected from one of ML-01-1 to ML-L08-1, particularly ML-01-1:

[0108] In some embodiments of the invention, for the compound shown in Formula A, the E3L portion has one of the structures shown in ML-01-1 to ML-08-1 (especially ML-01-1), and the OGTL portion has one of the structures shown in OGT-L01 to OGT-L12 (especially OGT-L01).

[0109] In some embodiments of the present invention, the compound has the following structure:

[0110] In some embodiments of the present invention, for compounds represented by formulas VI, VII, VIII, and IX, L is selected from the following:

[0111] In some embodiments of the present invention, the compound has the following structure:

[0112] In some embodiments of the present invention, the compound has the following structure:

[0113] In some embodiments of the present invention, the stereoisomers of the compound have the following structures (structures numbered sequentially from DMG001 to DMG015):

[0114] In some embodiments of the present invention, the stereoisomers of the compound have the following structures:

[0115] In a second aspect of the invention, a method for preparing the compound of the first aspect is provided, comprising the step of coupling a small molecule ligand moiety via L and ML.

[0116] In some embodiments of the present invention, the preparation method includes the following steps: first preparing... Then it is linked to the ML reaction; or,

[0117] First, prepare ML-L′-R G Then it is linked to a small molecule ligand; or,

[0118] Prepare ML-L″-R separately G 'and Then the two are coupled;

[0119] Where L', L”, and L”' are arbitrarily chosen suitable linking groups, and R G R G '、R G" " represents any suitable reactive group.

[0120] In some embodiments of the present invention, R G It is a carboxyl group.

[0121] In some embodiments of the present invention, the preparation method further includes preparing... The steps.

[0122] Specifically, if necessary, the preparation method may also include steps of protecting and deprotecting certain groups (such as hydroxyl and amino groups).

[0123] In a third aspect of the invention, a pharmaceutical composition is provided comprising the compound described in the first aspect of the invention or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuterated compound thereof, and one or more pharmaceutically acceptable excipients.

[0124] Specifically, the pharmaceutically acceptable excipients may be selected from one or more of the following: fillers, binders, lubricants, disintegrants, antioxidants, buffers, antibacterial agents, suspending agents, solubilizers, thickeners, stabilizers, and preservatives.

[0125] Specifically, the pharmaceutical composition can be administered via any suitable route of administration, such as gastrointestinal (e.g., oral, sublingual, rectal) or non-gastrointestinal (e.g., intravenous, intramuscular, intranasal, intraocular, intracerebral, intravaginal, intraperitoneal, transdermal, subcutaneous, intradermal, respiratory, etc.). In some embodiments of the invention, the pharmaceutical composition is an injection. In some embodiments of the invention, the pharmaceutical composition is an oral formulation.

[0126] Specifically, the pharmaceutical composition can be prepared into pharmaceutical formulations in the following forms: tablets, capsules, lotions, gels, emulsions, syrups, suspensions, powders, granules, injections, etc.

[0127] Specifically, in the pharmaceutical composition, the content of the compound or its pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuterated compound is from 0.01% to 99.9% (e.g. 0.01%, 0.05%, 0.1%, 0.5%, 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, by mass percentage).

[0128] Specifically, the amount of the active ingredient in a unit dose of the pharmaceutical composition may be varied or adjusted from 0.1 mg to 1000 mg (e.g., 0.1, 1, 5, 10, 20, 40, 50, 100, 200, 400, 500, 1000 mg) depending on the specific application and potency of the active ingredient. If desired, the composition may also contain other suitable therapeutic agents.

[0129] In a fourth aspect of the invention, the use of the compound described in the first aspect or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound thereof in the preparation of a medicament for the prevention and / or treatment of OGT-related diseases or O-GlcNAc glycosylation-related diseases is provided.

[0130] Specifically, the disease is one that can be prevented and / or treated by inhibiting / degrading OGT, such as, but not limited to, neurodegenerative diseases, tumors, metabolic diseases, cardiovascular diseases, autoimmune diseases, and inflammatory diseases.

[0131] Specifically, the neurodegenerative diseases include, but are not limited to: Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), spinocerebellar ataxia (SCA), Pick's disease, etc.

[0132] Specifically, the metabolic diseases include, but are not limited to: obesity, type 1 diabetes, type 2 diabetes, and diabetic complications. Specifically, the diabetic complications include, but are not limited to: insulin resistance, vascular disease, skin ulcers, circulatory system damage, diabetic nephropathy, diabetic retinopathy, diabetic keratopathy, microvascular disease, macrovascular disease, or diabetic neuropathy.

[0133] Specifically, the cardiovascular diseases include, but are not limited to: myocardial ischemia-reperfusion injury, arrhythmia, heart failure, atherosclerosis, and hypertension.

[0134] Specifically, the autoimmune diseases include, but are not limited to: systemic lupus erythematosus, type I diabetes, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, multiple sclerosis, ankylosing spondylitis, psoriasis, ulcerative colitis, Crohn's disease, etc.

[0135] Specifically, the inflammatory diseases include, but are not limited to: gout, inflammatory bowel disease, asthma, allergies, chronic obstructive pulmonary disease (COPD), chronic relapsing multifocal osteomyelitis (CRMO), colitis, conjunctivitis, dry eye syndrome, encephalitis, endocarditis, endometritis, uveitis, etc.

[0136] Specifically, the tumors mentioned are malignant tumors, including but not limited to: head and neck cancer (such as squamous cell carcinoma of the head and neck), liver cancer (such as hepatocellular carcinoma), pancreatic cancer, bile duct cancer, lung cancer (such as small cell lung cancer, non-small cell lung cancer), lung adenocarcinoma (such as invasive adenocarcinoma of the lung), esophageal cancer (such as squamous cell carcinoma of the esophagus), cardia cancer, gastric cancer, gastric adenocarcinoma, intestinal cancer (such as colorectal cancer, colon cancer, rectal cancer, colorectal cancer), breast cancer (such as triple-negative breast cancer, extramammary Paget's disease), cervical cancer (such as squamous cell carcinoma of the cervix), ovarian cancer (such as epithelial ovarian cancer, serous ovarian cancer), uterine cancer (such as endometrial cancer), fallopian tube cancer, prostate cancer, bladder cancer, kidney cancer, and thyroid cancer (such as papillary thyroid carcinoma). Gliomas (such as ependymoma, astrocytoma, neuroblastoma), medulloblastoma, glioma, glioblastoma, osteosarcoma, nasopharyngeal carcinoma, laryngeal carcinoma (such as laryngeal carcinoma, hypopharyngeal carcinoma), retinoblastoma, tongue cancer (such as squamous cell carcinoma of the tongue), oral cancer (such as squamous cell carcinoma of the oral cavity, squamous cell carcinoma of the oropharynx, epidermoid carcinoma of the oral cavity, leukoplakia of the oral cavity, floor of the mouth cancer, buccal mucosa cancer), salivary gland cancer (such as mucoepidermoid carcinoma), adenoid cystic carcinoma, ameloblastoma, skin tumors (such as squamous cell carcinoma of the skin, malignant melanoma, seborrheic keratosis), hematologic malignancies (such as leukemia, lymphoma, multiple myeloma), etc., especially liver cancer, lung cancer, breast cancer, pancreatic cancer, colorectal cancer, gastric cancer, and medulloblastoma.

[0137] Specifically, leukemia can be classified as chronic lymphocytic leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and acute monocytic leukemia.

[0138] Specifically, lymphoma can be B-cell lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, mucosa-associated lymphoid tissue lymphoma (MALT), small lymphocytic lymphoma / chronic lymphocytic leukemia, mantle cell lymphoma (MCL)), or T / NK cell lymphoma.

[0139] In a fifth aspect of the invention, a method for degrading OGT / inhibiting O-GlcNAc glycosylation is provided, comprising the steps of using the compound described in the first aspect of the invention or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuterated compound thereof, or the pharmaceutical composition described in the third aspect of the invention.

[0140] Specifically, the method is performed in vivo or in vitro.

[0141] In a sixth aspect of the invention, a method for preventing and / or treating OGT-related diseases or O-GlcNAc glycosylation-related diseases is provided, comprising administering to a subject in need a compound of the first aspect of the invention or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound thereof, or a pharmaceutical composition of the third aspect of the invention.

[0142] Specifically, the disease is as described in the fourth aspect of the present invention.

[0143] Specifically, the subjects were mammals, particularly humans.

[0144] Specifically, the administration can be carried out via any suitable route of administration, such as gastrointestinal administration (e.g., oral, sublingual, rectal) or non-gastrointestinal administration (e.g., intravenous, intramuscular, intranasal, intraocular, intracerebral, intravaginal, intraperitoneal, transdermal, subcutaneous, intradermal, respiratory, etc.). In some embodiments of the invention, the administration route is injection. In some embodiments of the invention, the administration route is oral.

[0145] In a seventh aspect of the invention, the use of the compound described in the first aspect or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound thereof in the preparation of a medicament for the prevention and / or treatment of obesity is provided.

[0146] In an eighth aspect of the invention, a method for preventing and / or treating obesity is provided, comprising administering to a subject in need a compound described in the first aspect of the invention or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound thereof, or a pharmaceutical composition described in the third aspect of the invention.

[0147] Specifically, the subjects are mammals, particularly humans. Furthermore, the subjects may also have one or more comorbid (or coexisting) conditions selected from the following: prediabetes, impaired oral glucose tolerance, type II diabetes, metabolic syndrome (also known as syndrome X), cardiovascular risk factors, kidney or fatty liver disease (including but not limited to NASH, NAFLD, etc.), sleep apnea, and bulimia.

[0148] Specifically, the administration can be carried out via any suitable route of administration, such as gastrointestinal administration (e.g., oral, sublingual, rectal) or non-gastrointestinal administration (e.g., intravenous, intramuscular, intranasal, intraocular, intracerebral, intravaginal, intraperitoneal, transdermal, subcutaneous, intradermal, respiratory, etc.). In some embodiments of the invention, the administration route is injection. In some embodiments of the invention, the administration route is oral.

[0149] In a ninth aspect of the invention, a weight loss product is provided, comprising the compound described in the first aspect of the invention or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound thereof.

[0150] Furthermore, the product is used for non-therapeutic purposes, such as controlling weight gain, reducing body fat weight, lowering body fat percentage, reducing fat accumulation, improving insulin sensitivity, and improving glucose tolerance, in order to improve physical health, improve body aesthetics, and achieve a more symmetrical physique.

[0151] In a tenth aspect of the invention, a method for fat reduction (reducing body fat weight, lowering body fat percentage) is provided, comprising the step of administering to a subject in need of the compound described in the first aspect of the invention or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuterated compound thereof, or a weight loss product described in the ninth aspect of the invention.

[0152] Specifically, the method is not a treatment for disease, but rather a means to improve the physical health of the subject, enhance body aesthetics, and achieve a more symmetrical physique.

[0153] Specifically, the subjects were mammals, particularly humans.

[0154] In some embodiments of the present invention, the route of administration is injection. In some embodiments of the present invention, the route of administration is oral administration.

[0155] Furthermore, the method may also include providing a low-fat diet, exercise, etc.

[0156] The inventors of this invention have creatively discovered that a compound recruits MDM2 through interaction with nucleolin (NCL). Further experiments revealed that this compound can serve as a novel recruitment element for MDM2, potentially applicable to the preparation of targeted protein degraders. Utilizing this discovery, the inventors prepared a novel protein degrader compound targeting OGT, and experiments showed that the prepared targeted protein degrader effectively induces OGT degradation, making it promising for the treatment of OGT-mediated or O-GlcNAc glycosylation-related diseases, with excellent application prospects in the pharmaceutical field. Attached Figure Description

[0157] Figure 1 shows the results of the experiment described in Example 1, which demonstrates that NCL can bind to MDM2.

[0158] Figure 2 shows the results of the experiment described in Example 2, which indicates that the compound Ori of Formula I recruits MDM2 in dependence on its interaction with NCL; iSN04 can only bind to NCL, but cannot recruit MDM2 in dependence on NCL.

[0159] Figure 3 shows the results of the experiment described in Example 2, which indicates that the compound Ori of Formula I can capture NCL and MDM2; iSN04 can capture NCL, but cannot capture MDM2.

[0160] Figure 4 shows the results of the experiment described in Example 2, which indicates that the compound Ori, represented by Formula I, can capture NCL and MDM2, and silencing NCL can block Ori from recruiting MDM2.

[0161] Figure 5 shows the results of the experiment described in Example 2, which indicates that the compound Ori of Formula I does not affect the interaction between NCL and MDM2, while iSN04 blocks the binding of NCL and MDM2.

[0162] Figure 6 shows a schematic diagram of the interaction mode by which compounds of formula I (such as Ori) recruit MDM2 through their interaction with NCL.

[0163] Figure 7 shows the results of the experiment described in Example 5, which demonstrates that the PROTAC molecule targeting OGT prepared in this invention can degrade OGT.

[0164] Figure 8 shows the results of the experiment described in Example 6, which demonstrates that the PROTAC targeting OGT prepared in this invention can promote OGT ubiquitination.

[0165] Figure 9 shows the results of the experiment described in Example 7, which indicates that the PROTAC targeting OGT prepared in this invention relies on MDM2 and NCL to mediate the degradation of OGT.

[0166] Figure 10 shows the results of the experiment described in Example 8, which demonstrates that the PROTAC targeting OGT prepared in this invention promotes lipolysis in adipocytes.

[0167] Figure 11 shows the results of the experiment described in Example 9, demonstrating the therapeutic effect of the OGT-targeting PROTAC prepared in this invention on obese mice. Figure 11A shows the weight changes of mice in each group; Figure 11B shows photographs of mice in each group after 9 weeks of intervention; Figure 11C shows the fat-free body weight of mice in each group after 9 weeks of intervention (from left to right, the columns represent NCD, PBS, Ori, OSMI-1, Ori+OSMI-1, and DMG002, respectively); Figure 11D shows the fat weight of mice in each group after 9 weeks of intervention (from left to right, the columns represent NCD, PBS, Ori, OSMI-1, Ori+OSMI-1, and DMG002, respectively); Figure 11E shows the ITT test results of mice in the DMG002 and PBS groups; Figure 11F shows the GTT test results of mice in the DMG002 and PBS groups. Detailed Implementation

[0168] Unless otherwise defined, all scientific and technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art.

[0169] All publications, patents, and published patent specifications cited in this article are incorporated herein in their entirety through citation.

[0170] In this invention, the term "aliphatic group" refers to a straight-chain or branched hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a cyclic hydrocarbon group (also referred to herein as "aliphatic ring" or "cycloalkyl") that is fully saturated or contains one or more unsaturated units, connected to other parts of the molecule by a single bond. Suitable aliphatic groups include, but are not limited to, straight-chain or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl, and mixtures thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, (cycloalkyl)alkenyl, etc. Typical aliphatic groups contain 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, preferably 1 to 6 carbon atoms.

[0171] The term "carbon ring" is composed entirely of carbon atoms and can be divided into aliphatic rings and aromatic rings.

[0172] The term "alkyl" refers to a straight-chain or branched hydrocarbon radical that does not contain unsaturated bonds and is connected to the rest of the molecule by a single bond. Typical alkyl groups contain 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, preferably 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, etc. If the alkyl group is substituted with a cycloalkyl group, it is referred to as "cycloalkylalkyl," such as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, etc. If the alkyl group is substituted with an aryl group, it is referred to as "aralkylalkyl," such as benzyl, diphenylmethyl, or phenethyl. If the alkyl group is substituted with a heterocyclic group, it is referred to as "heterocyclicalkyl." In this invention, CO alkyl refers to H, i.e., C 0-10 Alkyl (or C0-C) 10 Alkyl groups include H and C. 1-10 Alkyl (or C1-C) 10 alkyl).

[0173] The term "alkylene" refers to a hydrocarbon group (divalent alkyl) formed by the loss of two hydrogen atoms from an alkane molecule. It can be straight-chain or branched and is connected to the rest of the molecule by a single bond. Typical alkylene groups described herein have 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, preferably 1 to 6 carbon atoms, such as methylene (-CH2-), ethylene, propylene, butylene, etc. In this invention, CO alkylene refers to a single bond, i.e., C...0-10 Alkylene (or C0-C) 10 Alkylenes include single bonds and C bonds. 1-10 Alkylene (or C1-C) 10 (alkylene).

[0174] The term "cycloalkyl" refers to alicyclic hydrocarbons, such as those containing 1 to 4 monocyclic and / or fused rings, containing 3 to 18 carbon atoms, preferably 3 to 10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or adamantyl.

[0175] The term "alkoxy" refers to a substituent formed when the hydrogen in a hydroxyl group is replaced by an alkyl group, such as alkoxy groups containing 1-10 carbon atoms, such as methoxy, ethoxy, propoxy, butoxy, etc.

[0176] The term "alkylamine" refers to a substituent formed when one or two hydrogen atoms of an amino group (-NH2) are replaced by an alkyl group, such as an alkylamine group containing 1-10 carbon atoms, for example...

[0177] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0178] The term "haloalkyl" refers to a group formed by replacing one or more hydrogen atoms in an alkyl group with a halogen atom (such as fluorine, chlorine, bromine or iodine), such as -CHF2, -CH2F, -CF3, -CH2-CF3, -CH2CH2-CF3, -CH2CH2CH2-CF3.

[0179] The term "aryl" refers to a monocyclic or polycyclic free radical, including polycyclic free radicals containing a monoaryl group and / or a fused aryl group (also referred to herein as "aromatic ring"), such as those containing 1-3 monocyclic or fused rings and 6-18 (e.g., 6, 8, 10, 12, 14, 16, 18) carbon ring atoms, C6-C as described in this invention. 12 The aryl group refers to an aryl group containing 6-12 carbon ring atoms, such as phenyl, naphthyl, biphenyl, indene, etc.

[0180] The term "heterocyclic group" refers to a 3- to 18-membered non-aromatic ring group containing 2 to 17 carbon atoms and 1 to 10 heteroatoms. Heterocyclic groups can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, and can include fused, spirocyclic, or bridged ring systems. Heterocyclic groups (also referred to herein as "heterocycles") can be partially saturated (heteroaryl, also referred to herein as "heteroaromatic rings") or fully saturated (heterocyclic alkyl). Suitable heteroaryl groups in the compounds of the present invention contain one, two, or three heteroatoms selected from N, O, S, and P atoms. These heteroaryl groups include, for example, coumarin (including 8-coumarin), quinolinyl (including 8-quinolinyl, isoquinolinyl, pyridinyl, pyrazinyl, pyrazolyl, pyrimidinyl, furanyl, pyrroloyl, thiopheneyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, imidazoleyl, indolyl, isoyndolyl, indazoleyl, inazinyl, phthalazinyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazolidyl, pyridazinyl, triazinyl, cenolinyl, benzimidazolyl, benzofuranyl, benzofuranyl, benzothiopheneyl, benzothiazolyl, benzooxazolyl, quinazolinyl, quinoxolinyl, naphridinyl, and furanopyridinyl. Suitable heterocyclic alkyl groups in the compounds of the present invention contain one, two, or three heteroatoms selected from N, O, or S atoms. These heterocyclic alkyl groups include, for example, pyrrolidinyl, tetrahydrofuranyl, dihydrofuran, tetrahydrothiophenyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, oxothiohexacyclohexyl, piperazine, aziridine, oxothiobutyl, thiohexacyclobutyl, homopiperidinyl, oxopropane, thiopropane, acrylonitrile, oxazinyl, diaziridine, etc. Heptyl, triacetyl, 1,2,3,6-tetrahydropyridyl, 2-pyrrolinyl, 3-pyrrolinyl, dihydroindolyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1,3-dioxapentyl, pyrazolinyl, dithiaalkyl, dithiopentyl, dihydropyranyl, dihydrothiophenyl, pyrazolinyl, imidazolinyl, imidazolinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 3H-indolyl, and quinazinyl. In this invention, for optionally substituted heterocyclic groups, the substituted position can be any suitable carbon atom or heteroatom, for example, for The substitution position of R can be any suitable carbon or nitrogen atom, and it can be, for example...

[0181] In this invention, "D" refers to deuterium; "replaced by deuterium" means replacing one or more hydrogen atoms with a corresponding number of deuterium atoms.

[0182] It should be recognized that, depending on the source of the chemical materials used in the synthesis, there are variations in the natural isotopic abundance in the synthesized compounds. Therefore, the compounds of the present invention will inherently contain small amounts of deuterated isotopes. Despite this variation, the concentrations of these naturally abundant stable hydrogen and carbon isotopes are low and insignificant compared to the degree of stable isotopic substitution in the compounds of the present invention. See, for example, Wada, E et al., Seikagaku, 1994, 66:15; Gannes, LZ et al., Comp Biochem Physiol Mol Integr Physiol, 1998, 119:725.

[0183] In the compounds of this invention, any atom not specifically designated as deuterium is present at its natural isotopic abundance. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen", that position should be understood as having hydrogen according to its natural abundance isotopic composition. Similarly, unless otherwise stated, when a position is specifically designated as "D" or "deuterium", that position should be understood as having deuterium at an abundance at least 3000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 45% deuterium doping).

[0184] The term “isotope enrichment coefficient” used in this article refers to the ratio between the isotopic abundance of a particular isotope and its natural abundance.

[0185] In other embodiments, the compounds of the present invention have an isotopic enrichment factor for each specified deuterium atom of at least 3500 (52.5% deuterium doping at each specified deuterium atom), at least 4000 (60% deuterium doping), at least 4500 (67.5% deuterium doping), at least 5000 (75% deuterium doping), at least 5500 (82.5% deuterium doping), at least 6000 (90% deuterium doping), at least 6333.3 (95% deuterium doping), at least 6466.7 (97% deuterium doping), at least 6600 (99% deuterium doping), or at least 6633.3 (99.5% deuterium doping).

[0186] The term "isotope" refers to a substance whose chemical structure differs from that of a specific compound of the present invention only in terms of its isotopic composition.

[0187] The term "pharmaceutically acceptable salt" includes acid addition salts and base addition salts.

[0188] The term "acid addition salt" includes, but is not limited to, salts derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphonic acid, as well as salts derived from organic acids such as aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkanes, hydroxyalkanes, alkanedioic acids, aromatic acids, and aliphatic and aromatic sulfonic acids. Therefore, these salts include, but are not limited to, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, hydrochlorides, hydrobromates, iodates, acetates, propionates, octanoates, isobutyrates, oxalates, malonates, succinates, octanoates, sebacic acid salts, fumarates, maleates, amygdalinates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, maleates, tartrates, and methanesulfonates, as well as salts of amino acids such as arginine salts, gluconates, and galacturonic acids. Acid addition salts can be prepared by contacting a sufficient amount of the desired acid in a conventional manner to form a salt. The free base can be regenerated by contacting the salt with a base, and the free base can be separated in a conventional manner.

[0189] The term "base addition salt" refers to a salt formed with a metal or amine, such as hydroxides of alkali metals and alkaline earth metals, or with an organic amine. Examples of metals used as cations include, but are not limited to, sodium, potassium, magnesium, and calcium. Suitable amines include, but are not limited to, N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine (ethane-1,2-diamine), N-methylglucosamine, and procaine. Base addition salts can be prepared by contacting the free acid form with a sufficient amount of the desired base in a conventional manner to form the salt. The free acid form can be regenerated by contacting the salt form with an acid, and the free acid can be separated in a conventional manner.

[0190] The term "stereoisomer" includes enantiomers, diastereomers, and geometric isomers. Some compounds of the present invention have cyclic hydrocarbon groups that can be substituted on more than one carbon atom; in this case, all their geometric forms, including cis and trans, and mixtures thereof, are within the scope of the present invention.

[0191] The term "solvent" refers to the physical bond between the compound of this invention and one or more solvent molecules. This physical bond includes various degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, the solvate can be isolated, for example when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Solvents include solution phases and separable solvates. Representative solvates include ethanolides, methanolides, etc.

[0192] The term "prodrug" refers to a Formula I compound that is suitable for administration to patients without excessive toxicity, irritation, or allergic reactions, and is effective for its intended purpose. Prodrugs include acetals, esters, and zwitterionic forms. Prodrugs are converted in the body, such as through hydrolysis in the blood, to yield the parent compound.

[0193] The terms “patient” or “subject”, etc., may be used interchangeably herein to refer to any animal or its cells, whether in vitro or in situ, treated according to the methods described herein. Specifically, the aforementioned animals include mammals, such as rats, mice, guinea pigs, rabbits, dogs, monkeys, or humans, especially humans.

[0194] The term "treatment" refers to the prevention, cure, reversal, reduction, mitigation, minimization, suppression, cessation, and / or cessation of one or more clinical symptoms of a disease after its onset.

[0195] The term "prevention" refers to the treatment taken before a disease develops to avoid, minimize, or prevent the disease from developing or progressing.

[0196] The terms “O-GlcNAc glycosylation-related diseases” and “OGT-related diseases” include, but are not limited to, diseases and conditions with abnormal OGT activity and / or abnormal O-GlcNAc glycosylation levels. Examples of diseases and conditions associated with OGT activity and / or O-GlcNAc glycosylation levels include, but are not limited to, neurodegenerative diseases such as Alzheimer's disease; cancer; obesity; diabetes and its complications; autoimmune diseases; inflammatory diseases; or other OGT-related diseases.

[0197] The term "diabetic complications" is used to refer to diseases associated with diabetes. Non-limiting examples of diabetic complications include microvascular damage, insulin resistance, vascular damage, kidney disease, skin ulcers, circulatory damage, diabetic nephropathy, diabetic retinopathy, macrovascular disease, microvascular disease, cardiac dysfunction, and diabetic neuropathy.

[0198] The term "obesity" refers to a chronic metabolic disease in which excessive or abnormal accumulation of body fat leads to a weight exceeding the normal range. For adults, obesity is defined as a body mass index (BMI) ≥25 (e.g., ≥28, ≥30, ≥34, ≥40), such as BMI = 25-30, 30-35, 30-40.

[0199] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0200] The compound Ori described in the following examples is a compound of formula I and has the following structure: In addition, compound Ger CYD OriPh Similar to Ori, it can also serve as a recruitment element for the MDM2 protein, as described in Chinese patent application CN2024114784319 and PCT patent application WO2025 / 087245A1.

[0201] Example 1: NCL can be combined with MDM2

[0202] 1. Co-immunoprecipitation (Co-IP) is a classic method for studying protein-protein interactions based on the specific interaction between antibodies and antigens. Hep3B liver cancer cells were lysed with IP lysis buffer (Thermo Scientific, catalog number 87788) and incubated overnight at 4°C with an antibody against NCL. Protein A / G magnetic beads (Thermo Scientific, catalog number 88802) were added and incubated at room temperature for 2 hours by rotation. The NCL and its interacting protein complex bound to the magnetic beads were washed with IP lysis buffer (Thermo Scientific, catalog number 87788), and SDS-PAGE protein loading buffer (Beyotime, catalog number P0015) was added. The mixture was heated to 100°C and held for 10 minutes. The magnetic beads were then adsorbed using a magnetic rack, and the supernatant was transferred to a new tube. Western blotting was then performed to detect whether NCL bound MDM2. The immunoblotting procedure was as follows: Protein samples were separated by SDS-PAGE electrophoresis. The separated proteins were transferred to a PVDF membrane and blocked with TBST buffer containing 5% skim milk for 1 hour at room temperature. Then, the membrane was incubated overnight at 4°C with either MDM2 primary antibody (Proteintech, catalog number 27883-1-AP) or NCL primary antibody (Cell Signaling Technology, catalog number 14574S). After washing with TBST, the membrane was incubated with HRP-labeled secondary antibody (Aibotek, catalog number AS014) at room temperature for 1 hour. The protein bands were visualized using an enhanced chemiluminescence detection kit (Aibotek, catalog number RM00021P). Figure 1A shows that NCL can bind to MDM2.

[0203] 2. 2 μg / mL recombinant human NCL (rhNCL, purchased from ACROBiosystems, NUL-H5253) and 2 μg / mL recombinant human MDM2 (rhMDM2, purchased from R&D Systems, E3-202-050) were mixed and incubated at 4°C for 7 hours. Then, the NCL antibody was added and incubated overnight at 4°C. Protein A / G magnetic beads (purchased from Thermo Scientific, catalog number 88802) were added and incubated at room temperature with rotation for 1.5 hours. The magnetic beads were washed three times with TBST buffer, and SDS-PAGE protein loading buffer (purchased from Beyotime, catalog number P0015) was added. The mixture was heated to 100°C and held for 10 minutes. The magnetic beads were adsorbed using a magnetic rack, and the supernatant was transferred to a new tube. An immunoblotting assay was then performed to detect whether NCL bound to MDM2. Figure 1B shows that NCL can bind to MDM2.

[0204] Example 2: Compound Ori recruits MDM2 in a NCL-dependent manner.

[0205] 1. We prepared Ori (Bio-Ori-1), a compound of formula I, with a C-14 hydroxyl group biotinylated. The specific preparation steps are as follows:

[0206] Under nitrogen protection, compound 1 (100 mg, 0.29 mmol) and compound 2 (70 mg, 0.29 mmol) were added to a solution of dimethylformamide (DMF, 2 mL) with EDCI (166 mg, 0.87 mmol) and DMAP (106 mg, 0.87 mmol). The mixture was stirred at room temperature for 16 hours, and the reaction progress was monitored by LCMS. After the reaction was complete, the impure product was purified by Prep-HPLC (Waters 2767 / Qda, Column: SunFire Sunfire C18, 19*250 mm, 10 μm; Mobile Phase A: 0.1% FA / H2O, B: ACN; flow rate: 20 mL / min; gradient: 34%–44%; retention time: 7.6–8.3 min of 17 min). The pure fractions were combined and lyophilized under reduced pressure to give 34 mg of white solid compound Bio-Ori-1, with a yield of 20.17%.

[0207] LCMS: m / z = 591.6 [M+H] + ,t R =8.447min.Purity:100%(254nm).

[0208] 1H NMR(400MHz,DMSO-d6)δ6.38(2s,2H),6.00(s,1H),5.92-5.79(m,3H),5.61(s,1H),4.40(s,1H),4.34-4.26(m,1H) ,4.17-4.02(m,2H),3.83(d,J=10.2Hz,1H),3.53-3.49(m,1H),3.33(s,1H),3.10-3.05(m,1H),2.96(d,J=9.6Hz,1H ),2.84-2.79(m,1H),2.59-2.56(m,1H),2.50-2.43(m,1H),2.18-2.12(m,2H),2.09-2.00(m,7.6Hz,1H),1.86-1.8 1(m,1H),1.77-1.64(m,1H),1.64-1.39(m,7H),1.35-1.17(m,4H),1.12(d,J=6.8Hz,1H),1.00(s,3H),0.99(s,3H).

[0209] 13 C NMR(101MHz,DMSO-d6)δ207.68,172.06,163.19,151.33,119.83,96.20,74.51,73.63,72.04,62.97,62.26,61.49,59.66 ,59.54,55.80,54.31,41.87,40.93,39.37,38.83,34.25,33.81,33.20,30.75,29.81,28.43,28.40,24.56,22.14,20.19.

[0210] 2. We also prepared Ori (Bio-Ori-2), a compound of formula I, with a C-1 hydroxyl group biotinylated. The specific preparation steps are as follows:

[0211] (1)

[0212] A mixture of compound 1 (1 g, 0.27 mmol), 2,2-dimethoxypropane (0.572 g, 5.49 mmol), p-TsOH (3 mg, 0.0137 mmol), and acetone (6 mL) was stirred and refluxed under N2 for 1 hour. The mixture was concentrated to dryness. The residue was diluted with dichloromethane (20 mL), washed with sodium bicarbonate aqueous solution (15 mL x 2), water (10 mL), and brine (15 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography (ethyl acetate in dichloromethane: 0–10%) to give compound 2 (1.0 g, 90.9%) as a white solid.

[0213] LCMS: m / z = 387.2 [M-OH] + ,Rt=1.894min.Purity:92.4%(214nm).

[0214] (2)

[0215] Under N2, EDCI (1.56 g, 8.16 mmol) and DMAP (1 g, 8.16 mmol) were added to a DMF (10 mL) solution of compound 2 (1.1 g, 2.72 mmol) and compound 3 (1 g, 4.08 mmol). The mixture was stirred at room temperature for 16 hours. LCMS showed that the reaction was complete. The reaction solution was purified by preparative HPLC (Welch Xtimate C18 200 × 30 mm × 5 μm water (0.1% FA)-MeCN, 5-95%, 60 mL / min) to give compound 4 (317 mg, 17.84%) as a white solid.

[0216] LCMS: m / z = 613.3 [M-OH] + ,Rt=1.610min.Purity:96.31%(214nm).

[0217] (3)

[0218] A solution of compound 4 (317 mg, 0.5 mmol) in hydrochloric acid (2%, 2 mL) and THF (2 mL) was stirred at room temperature under N2 for 2 hours. LC-MS showed the reaction was complete. The pH was adjusted to 6 with sodium hydroxide (1 M.aq). The reaction solution was purified by preparative HPLC (Welch Ultimate C18 150 × 30 mm × 5 μm, water (0.1% FA)-MeCN, 5-95%, 60 mL / min) to give Bio-Ori-2 (47 mg, 15.83%) as a white solid.

[0219] LCMS:m / z=573.6[M-OH] + ,Rt=8.691min.Purity:100%(214nm).

[0220] 1 H NMR(400MHz,DMSO-d6)δ6.94(s,1H),6.43(s,1H),6.37(s,1H),6.14(s,1H),6.07(d,J=10.4Hz,1H),5.98(s,1H),5.58(s,1H),4.79(s,1H),4.62-4.58(m,1H),4.35–4.26(m,1H),4.23–4.08(m,2H),4.01(d,J=10.4Hz,1H),3.56–3.52(m,1H),3.13–3.04(m,1H),2.95(d,J=9.6Hz,1H),2.85–2.80(m,1H),2.58(d,J=12.4Hz,1H),2.43–2.31(m,1H),2.23(t,J=7.2Hz,2H),2.03–1.89(m,2H),1.64–1.24(m,13H),1.01(s,3H),1.05(s,3H).

[0221] 13 C NMR(101MHz,DMSO-d6)δ208.93,172.31,163.17,152.10,119.99,97.31,75.07,73.44,72.90,62.89,61.62,61.57,59.73,59.65,55.89,51.81,43.06,40.62,40.34,39.36,37.90,34.23,33.66,32.78,30.08,28.51,25.27,24.76,21.96,18.04.

[0222] 3. The procedure for the pull-down assay involves immobilizing a known substance (bait) on a carrier and using it to capture binding proteins (prey) and protein complexes that interact with the binding proteins from a complex mixture. 6 μg / mL of recombinant human NCL (rhNCL) and 6 μg / mL of recombinant human MDM2 (rhMDM2) were mixed and incubated at 4°C for 7 hours. Then, 400 nM of Bio-Ori-1, Bio-Ori-2, biotin-labeled CRO (Bio-CRO: CCTCCTCCTCCTTCTCCTCCTCCTCC, negative control) or iSN04 (Bio-iSN04: AGATTAGGGTGAGGGTGA) was added, and the mixture was incubated at 4°C for 6 hours. Finally, streptavidin agarose gel beads (purchased from Cytiva, catalog number 17511301) were added, and the mixture was incubated overnight at 4°C. The gel beads were washed four times with TBST buffer, and SDS-PAGE protein loading buffer (purchased from Beyotime, catalog number P0015) was added. The mixture was heated to 100°C and held for 10 minutes. After centrifugation, the supernatant was collected. Then, an immunoblotting assay was performed to detect the pull-down products. Figures 2A and 2B show that Ori can bind to NCL but not to MDM2; however, in the presence of NCL, Ori can recruit MDM2 in a NCL-dependent manner. Figure 2C shows that CRO can neither bind to NCL nor recruit MDM2. Figure 2D shows that iSN04 can only bind to NCL but cannot recruit MDM2 in a NCL-dependent manner.

[0223] 4. Hep3B liver cancer cells were lysed with IP lysis buffer (Thermo Scientific, catalog number 87788) and then incubated with different concentrations (0 μM, 200 nM, 500 nM, 1 μM, 5 μM, 10 μM, 20 μM) of Bio-Ori-1, Bio-Ori-2, Bio-CRO or Bio-iSN04 at 4 °C for 6 hours. Then, streptavidin agarose gel beads (Cytiva, catalog number 17511301) were added and incubated overnight at 4 °C. After repeatedly washing the Bio-Ori-1, Bio-Ori-2, Bio-CRO, or Bio-iSN04 bound to the gel beads and the proteins they captured with IP lysis buffer (Thermo Scientific, catalog number 87788), SDS-PAGE protein loading buffer (Beyotime, catalog number P0015) was added, and the mixture was heated to 100°C for 10 minutes. The supernatant, the pull-down product, was collected after centrifugation. The pull-down product was detected using Western blotting. Figures 3A and 3B show that Ori can capture NCL and MDM2; Figure 3C shows that CRO cannot capture NCL and MDM2; Figure 3D shows that iSN04 can capture NCL but not MDM2.

[0224] 5. Hep3B liver cancer cells were incubated with DMSO (Vehicle) or 1 μM Bio-Ori-1 for 12 hours. After cell lysis, the supernatant was incubated overnight at 4°C with streptavidin agarose gel beads (purchased from Cytiva, catalog number 17511301). The Bio-Ori-1 bound to the gel beads and the captured proteins were washed multiple times with IP lysis buffer (purchased from Thermo Scientific, catalog number 87788). SDS-PAGE protein loading buffer (purchased from Beyotime, catalog number P0015) was added, and the mixture was heated to 100°C for 10 minutes. After centrifugation, the supernatant, i.e., the pull-down product, was collected. The pull-down product was detected using Western blotting. The results are shown in Figure 4A; Ori can capture NCL and MDM2.

[0225] 6. Hep3B liver cancer cells were transfected with negative control siRNA (siNC: UUCUCCGAACGUGUCACGUTT) or NCL siRNA (siNCL: GGAUGACGACGACGACGAAGATT). After 48 hours, the cells were incubated with 1 μM Bio-Ori-1 for 12 hours to lyse the cells. The supernatant was then incubated overnight at 4°C with streptavidin agarose gel beads. After washing the Bio-Ori-1 bound to the gel beads and the proteins captured by them multiple times with IP lysis buffer (Thermo Scientific, catalog number 87788), SDS-PAGE protein loading buffer (Beyotime, catalog number P0015) was added, and the mixture was heated to 100°C for 10 minutes. After centrifugation, the supernatant, i.e., the pull-down product, was collected and detected by Western blotting. The results are shown in Figure 4B. Silencing NCL can block Ori recruiting MDM2.

[0226] 7. Hep3B liver cancer cells were lysed with IP lysis buffer (Thermo Scientific, catalog number 87788) and incubated with different concentrations (0 μM, 1 μM, 5 μM, 10 μM, 20 μM) of Ori or iSN04 at 4°C for 6 hours. Then, NCL antibody was added and incubated overnight at 4°C. Protein A / G magnetic beads (Thermo Scientific, catalog number 88802) were added and incubated at room temperature with rotation for 1.5 hours. The NCL bound to the magnetic beads and the captured proteins were washed with IP lysis buffer (Thermo Scientific, catalog number 87788), and SDS-PAGE protein loading buffer (Beyotime, catalog number P0015) was added. The mixture was heated to 100°C for 10 minutes. The magnetic beads were then adsorbed using a magnetic rack, and the supernatant was transferred to a new tube. An immunoblotting assay was then performed to detect whether Ori or iSN04 affected the interaction between NCL and MDM2. The results in Figure 5A show that Ori does not affect the interaction between NCL and MDM2. Similar results were obtained using other Formula I compounds. However, the results in Figure 5B show that iSN04 blocks the binding of NCL to MDM2.

[0227] 8. The above results indicate that compounds of formula I (such as Ori) recruit MDM2 through interaction with NCL, while iSN04, although interacting with NCL, cannot recruit MDM2 through this interaction. Further analysis revealed that compounds of formula I (such as Ori) do not affect the binding of NCL to MDM2, but iSN04 blocks this binding. These data suggest that not all molecules interacting with NCL can be used to recruit MDM2; whether an NCL-interacting molecule can recruit MDM2 depends on whether it affects the formation of the NCL-MDM2 complex. We simulated the three-dimensional structure of the NCL-MDM2 complex using AlphaFold2 and predicted the conformation of the interaction between compounds of formula I (such as Ori) and the NCL-MDM2 complex using HDOCK. The results show that compounds of formula I (such as Ori) do indeed recruit MDM2 through interaction with NCL, and the possible interaction modes are shown in Figure 6. Therefore, we believe that compounds of formula I (such as Ori) can serve as recruitment elements for MDM2 to prepare PROTACs targeting OGT degradation.

[0228] Example 3: Preparation of OGT-targeting PROTAC molecules based on compound I

[0229] In this embodiment, compound Ori of Formula I was used as the recruitment element for the E3 ligase, and the inhibitor OSMI-1 was used as the target protein ligand to prepare PROTAC (hereinafter referred to as DMG001) for degrading OGT.

[0230] The preparation steps are as follows:

[0231] (1) Synthesis of Compound 3:

[0232] Under N2 protection, HATU (351 mg, 0.924 mmol) and DIPEA (298 mg, 2.310 mmol) were added to a DMF (5 mL) solution of compound 1 (300 mg, 0.462 mmol) and compound 2 (140 mg, 0.693 mmol). The mixture was stirred at room temperature for 2 hours. LCMS showed that the reaction was complete. The mixture was diluted with EA (20 mL) and washed with water (20 mL × 3) and brine (20 mL × 3). The combined organic layers were dried over Na2SO4 and filtered. After filtration, the mixture was concentrated under vacuum. The residue was purified by rapid column chromatography (DCM:MeOH = 20:1) to give compound 3 (250 mg, yield: 64.93%) as a yellow oil.

[0233] LCMS: m / z = 834.2 [M+H] + ,Rt=1.49min.Purity:75.68%(214nm)

[0234] (2) Synthesis of Compound 4:

[0235] Under N2 protection, NaOH (1 mL, 5N) was added to a MeOH (5 mL) solution of compound 3 (250 mg, 0.829 mmol). The mixture was stirred at room temperature for 16 hours. LCMS showed that the reaction was complete. The residue was purified by reversed-phase column chromatography (ACN in H2O = 5% to 95% elution) to give compound 4 (150 mg, yield: 61.22%) as a white solid.

[0236] LCMS: m / z = 820.0 [M+H] + ,Rt=1.26min.Purity:72.03%(214nm).

[0237] (3) Synthesis of the target compound DMG001:

[0238] Under N2 protection, DMAP (15 mg, 0.122 mmol) and EDCI (23 mg, 0.120 mmol) were added to a DMF (1 mL) solution of compound 4 (50 mg, 0.061 mmol) and compound 5 (34 mg, 0.092 mmol). The mixture was stirred at room temperature for 16 hours. LCMS showed that the reaction was complete. The crude product was purified by prep-HPLC to give the target compound DMG001 (5.46 mg, yield: 7.69%) as a white solid.

[0239] LCMS: m / z = 1165.0 [MH] - ,Rt=11.724min.Purity:95%(214nm).

[0240] 1 H NMR (400MHz, CD3OD) δ8.55-8.47(m,1H),7.99-7.93(m,1H),7.90-7.83(m,1H),7.82-7.74(m,1H),7.51(s,1H),7.31-7.12(m, 4H),6.93-6.73(m,4H),6.69-6.64(m,1H),6.39-6.20(m,1H),6.12-6.06(m,2H),6.02-5.91(m,2H),5.56(s,1H),4.65-4.54( m,1H),4.46-4.26(m,3H),4.12-4.00(m,2H),3.95-3.76(m,2H),3.69-3.64(m,1H),3.49-3.42(m,1H),3.23-3.04(m,6H),2.5 9(s,1H),2.32-2.13(m,7H),1.98-1.90(m,1H),1.86-1.54(m,12H),1.45-1.39(m,1H),1.34-1.25(m,2H),1.12-1.04(m,6H).

[0241] Example 4: Preparation of OGT-targeting PROTAC molecules based on compound of formula I

[0242] In this embodiment, compound Ori of Formula I was used as the recruitment element for the E3 ligase, and the inhibitor OSMI-1 was used as the target protein ligand to prepare PROTAC (hereinafter referred to as DMG002) that degrades OGT.

[0243] The preparation steps are as follows:

[0244] (1) Synthesis of Compound 7:

[0245] Under N2 protection, HATU (585 mg, 1.539 mmol) and DIPEA (496 mg, 3.845 mmol) were added to a DMF (5 mL) solution of compound 1 (500 mg, 0.770 mmol) and compound 6 (356 mg, 1.155 mmol). The mixture was stirred at room temperature for 2 hours. LCMS showed that the reaction was complete. The mixture was diluted with EA (50 mL) and washed with water (20 mL × 3) and brine (20 mL × 3). The combined organic layers were dried over Na2SO4 and filtered. After filtration, the mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (DCM:MeOH = 20:1) to give compound 7 (600 mg, yield: 83%) as a yellow oil.

[0246] LCMS: m / z = 940.3 [M+H] + ,Rt=1.62min.Purity:67.32%(214nm).

[0247] (2) Synthesis of Compound 8:

[0248] Under N2 protection, 2 mL of NaOH (5N) was added to a MeOH (10 mL) solution of compound 7 (600 mg, 0.829 mmol). The mixture was stirred at room temperature for 16 hours. LC-MS showed that the reaction was complete. The residue was purified by reversed-phase column chromatography (ACN in H2O = 5% to 95% elution) to give compound 8 (400 mg, yield: 67%) as a white solid.

[0249] LCMS: m / z = 463.6 [M / 2 + H] + ,Rt=1.33min.Purity:62.34%(214nm).

[0250] (3) Synthesis of the target compound DMG002:

[0251] Under N2 protection, DMAP (13 mg, 0.106 mmol) and EDCI (21 mg, 0.109 mmol) were added to a DMF (1 mL) solution of compound 8 (50 mg, 0.054 mmol) and compound 5 (29.5 mg, 0.081 mmol). The mixture was stirred at room temperature for 2 hours. LCMS showed that the reaction was complete. The crude product was purified by prep-HPLC (ACN in H2O = 5% to 95% elution) to give the target compound DMG002 (5.10 mg, yield: 7%) as a white solid.

[0252] LCMS: m / z = 637.1 [M / 2 + H]+ ,Rt=10.058min.Purity:100%(214nm).

[0253] 1 H NMR(400MHz,DMSO-d6)δ11.96(s,1H),8.49-8.34(m,1H),7.88-7.81(m,2H),7.66-7.58(m,2H),7.50-7.40(m,1H),7.32-7.28(m,1H),7 .27-7.21(m,1H),7.19-7.13(m,1H),7.12-7.07(m,1H),6.85-6.66(m,4H),6.57-6.52(m,1H),6.50-6.01(m,2H),5.99(s,1H),5.91-5. 82(m,4H),5.61(s,1H),4.57-4.05(m,7H),3.87-3.56(m,4H),3.56-3.49(m,1H),3.38(s,2H),3.24(s,3H),2.98-2.82(m,2H),2.27-1. 97(m,6H),1.92(s,4H),1.85(s,2H),1.72(s,1H),1.64-1.36(m,13H),1.36-1.03(m,5H),1.01(s,3H),0.99(s,3H),0.97-0.93(m,1H).

[0254] Example 5: PROTAC molecules targeting OGT can degrade OGT.

[0255] 1. Preadipocytes (3T3-L1) were incubated with DMG001 at concentrations of 0, 100, 200, 300, 400, and 500 nM. Cell samples were collected after 24 hours, and total protein was extracted using RIPA lysis buffer. Western blotting was used to detect OGT protein degradation. The results are shown in Figure 7A. DMG001 reduced OGT protein levels in a concentration-dependent manner.

[0256] 2. Preadipocytes (3T3-L1) were incubated with 500 nM DMG001. Cell samples were collected at time gradients of 0, 6, 9, 12, and 24 hours for protein extraction and subsequent Western blotting experiments to detect OGT protein degradation. The results are shown in Figure 7B, indicating that DMG001 reduced OGT protein levels in a time-dependent manner.

[0257] 3. Preadipocytes (3T3-L1) were incubated with solvent DMSO (Vehicle) or 500 nM compounds Ori, 500 nM OSMI, 500 nM Ori + 500 nM OSMI-1, or 500 nM DMG001. After 12 hours, cell samples were collected for protein extraction and subsequent Western blotting experiments to detect OGT protein degradation. The results are shown in Figure 7C, indicating that DMG001 can reduce OGT protein levels.

[0258] 4. Preadipocytes (3T3-L1) were incubated with DMG002 at concentrations of 0, 100, 200, 300, 400, and 500 nM. Cell samples were collected after 24 hours, and total protein was extracted using RIPA lysis buffer. Western blotting was used to detect OGT protein degradation. The results are shown in Figure 7D; DMG002 reduced OGT protein levels in a concentration-dependent manner.

[0259] 5. Preadipocytes (3T3-L1) were incubated with 500 nM DMG002. Cell samples were collected at time gradients of 0, 6, 9, 12, 24, and 36 hours for protein extraction and subsequent Western blotting experiments to detect OGT protein degradation. The results are shown in Figure 7E, indicating that DMG002 can reduce OGT protein levels in a time-dependent manner.

[0260] 6. Preadipocytes (3T3-L1) were incubated with solvent DMSO (Vehicle) or 500 nM Ori, 500 nM OSMI, 500 nM Ori + 500 nM OSMI, or 500 nM DMG002. After 24 hours, cell samples were collected for protein extraction and subsequent Western blotting experiments to detect OGT protein degradation. The results are shown in Figure 7F; DMG002 can reduce OGT protein levels.

[0261] Example 6: PROTAC targeting OGT can promote OGT ubiquitination.

[0262] 1. Preadipocytes (3T3-L1) were incubated with DMSO (Vehicle) or 500 nM DMG001 for 12 hours, with 10 μM proteasome inhibitor MG132 added during the last 6 hours of incubation. Cell samples were collected for protein extraction and subsequent Western blotting to detect OGT protein degradation. The results, shown in Figure 8A, indicate that MG132 blocked the degradation of OGT by DMG001, suggesting that DMG001 degradation of OGT depends on the ubiquitin-proteasome pathway.

[0263] 2. Preadipocytes (3T3-L1) were incubated with DMSO (Vehicle) or 500 nM DMG001 for 9 hours. During the last 6 hours of incubation, 10 μM proteasome inhibitor MG132 was added. After cell lysis, the cells were incubated overnight at 4°C with an antibody against OGT. Protein A / G magnetic beads were added and incubated at room temperature for 1.5 hours. After washing the OGT bound to the magnetic beads with IP lysis buffer, SDS-PAGE protein loading buffer was added, and the mixture was heated to 100°C for 10 minutes. The magnetic beads were then adsorbed using a magnetic rack, and the supernatant was transferred to a new tube. Western blotting was then used to detect the ubiquitination level of OGT. The results are shown in Figure 8B; DMG001 promoted OGT ubiquitination.

[0264] 3. Preadipocytes (3T3-L1) were incubated with DMSO (Vehicle) or 500 nM DMG002 for 36 hours, with 10 μM proteasome inhibitor MG132 added during the last 6 hours of incubation. Cell samples were collected for protein extraction and subsequent Western blotting to detect OGT protein degradation. The results, shown in Figure 8C, indicate that MG132 blocked the degradation of OGT by DMG002, suggesting that DMG002-mediated OGT degradation depends on the ubiquitin-proteasome pathway.

[0265] 4. Preadipocytes (3T3-L1) were incubated with DMSO (Vehicle) or 500 nM DMG002 for 18 hours. During the last 6 hours of incubation, 10 μM proteasome inhibitor MG132 was added. After cell lysis, the cells were incubated overnight at 4°C with an antibody against OGT. Protein A / G magnetic beads were added and incubated at room temperature for 1.5 hours. After washing the OGT bound to the magnetic beads with IP lysis buffer, SDS-PAGE protein loading buffer was added, and the mixture was heated to 100°C for 10 minutes. The magnetic beads were then adsorbed using a magnetic rack, and the supernatant was transferred to a new tube. Western blotting was then used to detect the ubiquitination level of OGT. The results are shown in Figure 8D; DMG002 promoted OGT ubiquitination.

[0266] The present invention also prepared other PROTACs targeting OGT, named DMG003 to DMG015 respectively (their structures are shown in the invention description), which can also promote OGT ubiquitination, achieve targeted degradation of OGT, and reduce OGT protein levels. The experimental process is not described in detail here.

[0267] Example 7: PROTAC-dependent MDM2 and NCL-mediated degradation of OGT

[0268] 1. Negative control siRNA (siNC: UUCUCCGAACGUGUCACGUTT) or NCL siRNA (siNCL: GGAUGAAGAUGAUGAGGAATT) were transfected into 3T3-L1 proadipocytes and incubated for 48 hours. During the last 9 hours, DMSO (Vehicle) or 500 nM DMG001 was added. Cell samples were collected for protein extraction and subsequent Western blotting to detect protein degradation. The results are shown in Figure 9A. Silencing NCL reduced the degradation of OGT by DMG001, indicating that DMG001-dependent NCL-mediated OGT degradation.

[0269] 2. Negative control siRNA (siNC: UUCUCCGAACGUGUCACGUTT) or MDM2 siRNA (siMDM2: GCUGCAUUGUUCACGGCAATT) were transfected into 3T3-L1 proadipocytes and incubated for 48 hours. During the last 9 hours, DMSO (Vehicle) or 500 nM DMG001 was added. Cell samples were collected for protein extraction and subsequent Western blotting to detect protein degradation. The results are shown in Figure 9B. Silencing MDM2 reduced the degradation of OGT by DMG001, indicating that DMG001-dependent MDM2-mediated OGT degradation.

[0270] 3. Negative control siRNA (siNC: UUCUCCGAACGUGUCACGUTT) or NCL siRNA (siNCL: GGAUGAAGAUGAUGAGGAATT) were transfected into 3T3-L1 proadipocytes and incubated for 48 hours. During the last 36 hours, DMSO (Vehicle) or 500 nM DMG002 was added. Cell samples were collected for protein extraction and subsequent Western blotting to detect protein degradation. The results are shown in Figure 9C. Silencing NCL reduced the degradation of OGT by DMG002, indicating that DMG002-dependent NCL-mediated OGT degradation.

[0271] 4. Negative control siRNA (siNC: UUCUCCGAACGUGUCACGUTT) or MDM2 siRNA (siMDM2: GCUGCAUUGUUCACGGCAATT) were transfected into 3T3-L1 proadipocytes and incubated for 48 hours. During the last 36 hours, DMSO (Vehicle) or 500 nM DMG002 was added. Cell samples were collected for protein extraction and subsequent Western blotting to detect protein degradation. The results are shown in Figure 9D. Silencing MDM2 reduced the degradation of OGT by DMG002, indicating that DMG002-dependent MDM2-mediated OGT degradation.

[0272] Example 8: PROTAC promotes lipolysis in adipocytes

[0273] Preadipocytes (3T3-L1) were seeded in 6-well cell culture plates. During the experiment, adipogenic differentiation was induced using protogenic medium (Punosay, catalog number PD-031), with DMSO (Vehicle) or 500 nM compounds DMG001 and DMG002 added to the medium every 24 hours. On day 12, the induced adipocytes were stained using an Oil Red O staining kit (Beyotime, catalog number C0157S). Oil Red O staining revealed very clear and distinct lipid droplet staining within the cells. The results are shown in Figure 10. DMG001 and DMG002 reduced intracellular lipid droplet levels.

[0274] Example 9: Therapeutic effect of PROTAC on obese mice

[0275] 1. To evaluate the therapeutic effect of PROTAC on a high-fat diet-induced obese mouse model (DIO), we intervened mice for 9 weeks with PBS, 5 μmol / kg Ori, 5 μmol / kg OSMI-1, 5 μmol / kg Ori + 5 μmol / kg OSMI-1, and 5 μmol / kg DMG002 via intraperitoneal injection three times a week. In addition to the intervention groups, normal-diet mice (NCD) served as controls. During the administration period, we recorded the dynamic changes in mouse body weight and measured body composition using a small animal body composition analyzer after the intervention. The ratio of lean body mass to fat mass was calculated to comprehensively evaluate the drug's regulatory effect on body weight and body composition. The results are shown in Figures 11A-11D. DMG002 reduced the body weight of DIO mice, mainly through reducing fat mass, while having no significant effect on lean body mass.

[0276] 2. Insulin sensitivity test (ITT) and glucose tolerance test (GTT) were performed on DIO mice. In the ITT, mice (week 11) were fasted for 6 hours in the morning, followed by intraperitoneal injection of insulin (0.5 U / kg) (purchased from MCE, catalog number HY-P0035). Tail vein blood was collected at predetermined time points, and blood glucose concentration was quantitatively measured using a VOPET glucometer. The results are shown in Figure 11E. Compared with the PBS control group, the DMS002 treatment group significantly improved insulin sensitivity. In the GTT, mice (week 10) were fasted overnight, followed by intraperitoneal injection of glucose solution (purchased from Pronosex, catalog number PB180418) (dose 1.5 g / kg). Tail vein blood was collected at predetermined time points, and blood glucose concentration was quantitatively measured using a VOPET glucometer. The results are shown in Figure 11F. Compared with the PBS control group, the DMS002 treatment group significantly improved glucose tolerance.

[0277] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

[0278] The foregoing embodiments and methods described in this invention may vary based on the capabilities, experience, and preferences of those skilled in the art.

[0279] The fact that the steps of the method are listed in a certain order in this invention does not constitute any restriction on the order of the method steps.

Claims

1. A compound or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound thereof, characterized in that, The compound has the following structure: in, ML is the recruitment element part of the MDM2 protein; L is a linking group; q is an integer from 1 to 15; Z1 and Z2 are independent linking groups; Y1 is selected from: -CH(R) P4 )-、-N(R P4 )-, where R P4 Selected from: H, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 Aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic); or, Z2 together with Y and the carbon atom attached to both to form a carbocyclic or heterocyclic ring, wherein the H on the carbocyclic or heterocyclic ring is optionally substituted with a group selected from: H, =O, halogen, cyano, nitro, azide, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic), C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 alkyl), -O(C) 0-10 alkyl), -S(C 0-10 alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 alkyl), -COO(C 0-10 Alkyl), -OCO(C) 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 Alkyl), -CO(C) 0-10 alkyl); Y2 is selected from: -SO2-, -SO-, -C(O)-; R P1 R P2 Independently selected from: H, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 heterocyclic); or, R P1 R P2 Together with the nitrogen atom attached thereto, a heterocycle is formed, wherein the alkyl, cycloalkyl, aryl, heterocyclic group, or H on the heterocycle is optionally substituted with a group selected from: H, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 Aryl), -(C0-C6 alkylene)-(4-10 heterocyclic), halogen, cyano, nitro, azide, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 alkyl), -O(C) 0-10 alkyl), -S(C 0-10 alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 alkyl), -COO(C 0-10 Alkyl), -OCO(C) 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 Alkyl), -CO(C) 0-10 alkyl); R P3 Selected from: H, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 Aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic); wherein the H on the alkyl, cycloalkyl, aryl, or heterocyclic group is optionally substituted by a group selected from the following groups: H, =O, halogen, cyano, nitro, azide, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic), C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 alkyl), -O(C) 0-10 alkyl), -S(C 0-10 alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 alkyl), -COO(C 0-10 Alkyl), -OCO(C) 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 Alkyl), -CO(C) 0-10 alkyl); Or, R P3 The benzene ring attached thereto forms a fused carbide ring or heterocycle, wherein the hydrogen atom on the carbide ring or heterocycle is optionally substituted with a group selected from the following: H, =O, halogen, cyano, nitro, azide, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 Aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic); wherein the H on the alkyl, cycloalkyl, aryl, or heterocyclic group is optionally substituted by a group selected from the following: H, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 Aryl), -(C0-C6 alkylene)-(4-10 heterocyclic), halogen, cyano, nitro, azide, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 alkyl), -O(C) 0-10 alkyl), -S(C 0-10 alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 alkyl), -COO(C 0-10 Alkyl), -OCO(C) 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 Alkyl), -CO(C) 0-10 alkyl); The MDM2 protein recruitment element has the following structure: in, Represents a single bond or a double bond. Furthermore, the bonds shown at points a and b are not both double bonds; R1 to R4, R7 to R 11 Independently selected from: H, =O, =C(H)-R A =NN(R) B R C ), hydroxyl, amino, halogen, cyano, nitro, azide, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic), C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, Among them, R A Selected from: H, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 Aryl), -(C0-C6 alkylene)-(4-10 heterocyclic), halogen, cyano, nitro, azide, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 alkyl), -O(C) 0-10 alkyl), -S(C 0-10 alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 alkyl), -COO(C 0-10 Alkyl), -OCO(C) 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 Alkyl), -CO(C) 0-10 alkyl); R B and R C Independently selected from: H, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic); R F Selected from: single bond, C1-C6 alkylene, C2-C6 alkenylene, C2-C6 ynylene, -O-, -S-, -C(O)-, -C(S)-, -C(O)O-, -OC(O)-, -OC(O)O-, -OS(O)2-, -OC(O)N(R) a )-、-C(O)N(R a )-、-N(R a )C(O)-、-N(R a )C(O)O-、-N(R a )C(O)N(R b )-、-N(R a -, -S(O)2-, -S(O)2N(R) a )-、-N(R a -S(O)2-, -S(O)-, -S(O)N(R) a )-、-N(R a )S(O)-、-OP(O)(OR b )O-、-P(O)(OR b -O-, -P(O)-, -OP(O)N(R) a )-、-P(O)N(R a )-、-P(O)(N(R a R b ))-、-OP(O)(OR b )2N(R a )-、-P(O)(OR b )2N(R a )-、-N(R a )P(O)(OR b )O-、-N(R a )P(O)-; where, R a and R b Independently selected from: H, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic); R E Selected from: H, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 Aryl), -(C0-C6 alkylene)-(4-10 heterocyclic), halogen, cyano, nitro, azide, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 alkyl), -O(C) 0-10 alkyl), -S(C 0-10 alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 alkyl), -COO(C 0-10 Alkyl), -OCO(C) 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 Alkyl), -CO(C) 0-10 Alkyl groups, monosaccharide residues, amino acid residues, and nitric oxide (NO) donor residues; Q represents a single bond or C1-C. 20 Alkylene, wherein 0-6 methylene units are independently substituted with the following groups: -Cy-, -O-, -S-, -SS-, -C(O)-, -C(S)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R) c )-、-N(R c )C(O)-、-N(R c )C(O)O-、-N(R c )C(O)N(R d )-、-N(R c -, -S(O)2-, -S(O)2N(R) c )-、-N(R c -S(O)2-, -S(O)-, -S(O)N(R) c )-、-N(R c )S(O)-、-OP(O)(OR d )O-、-P(O)(OR d -O-, -P(O)-, -OP(O)N(R) c )-、-P(O)N(R c )-、-P(O)(N(R c R d ))-、-OP(O)(OR d )2N(R f )-、-P(O)(OR d )2N(R c )-、-N(R c )P(O)(OR d )O-、-N(R c P(O)-、 Where m1 is selected from integers between 1 and 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10), and R c and R d Independently selected from: H, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 Aryl), -(C0-C6 alkylene)-(4-10 heterocyclic); each -Cy- is independently a optionally substituted divalent ring selected from the following: arylene, cycloalkylene, heterocyclic; R5 and R6 are independently selected from: H, hydroxyl, amino, halogen, cyano, nitro, azide, -CF3, -OCF3, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic); The above C0-C6 alkylene groups, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C3-C 10 cycloalkyl, C6-C 10 The H in the aryl or 4-10 membered heterocyclic group may optionally be substituted by one or more groups selected from the following: halogen, cyano, nitro, azide, -OR', -C(O)R', -C(S)R', -C(O)OR', -C(S)SR', -OC(O)R', -OC(S)R', -OC(S)SR', -C(O)NR'R”, -OC(O)NR'R”, -NR'C(O)OR”, -NR'SO2R”, -SO2NR'R”, -OSO2NR'R”, -NR'C(O)R”, -NR'R”, -SR', -SOR', -SO2R', -OSO2R', -SO3H, -PO3H, -OP(O)(OR'), -P(O)(OR')(OR”), -P(O)NR'R”, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 Alkyne group, C1-C 10 Haloalkyl, C1-C 10 Haloalkoxy, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 Aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic group), monosaccharide residues, amino acid residues; Alternatively, R1, R2, R3, R4, R5, R6, R7, R8, and R9 may be selected from one or more of the following schemes: (1) R1 and R2 together with the carbon atoms they are attached to form aliphatic rings, aromatic rings or heterocycles; (2) R2 and R3 together with the carbon atoms they are attached to form aliphatic rings, aromatic rings or heterocycles; (3) R1 and R5 together with the carbon atoms they are attached to form aliphatic rings, aromatic rings or heterocycles; (4) R4 and R5 together with the carbon atoms they are attached to form aliphatic rings, aromatic rings or heterocycles; (5) R4 and R6 together with the carbon atoms they are attached to form aliphatic rings, aromatic rings or heterocycles; (6) R5 and R6 together with the carbon atoms they are attached to form aliphatic rings, aromatic rings or heterocycles; (7) R5 and R7 together with the carbon atoms they are attached to form aliphatic rings, aromatic rings or heterocycles; (8) R8 and R9 together with the carbon atoms they are attached to form aliphatic rings, aromatic rings or heterocycles; The H on the aliphatic ring, aromatic ring, or heterocycle is optionally substituted with one or more groups selected from the following: =O, ... Halogen, cyano, nitro, azide, -OR', -C(O)R', -C(S)R', -C(O)OR', -C(S)SR', -OC(O)R', -OC(S)R', -OC(S)SR', -C(O)NR'R”, -OC(O)NR'R”, -NR'C(O)OR”, -NR'SO2R”, -SO2NR'R”, -OSO2NR'R”, -NR'C(O)R”, -NR'R”, -SR', -SOR', -SO2R', -OSO2R', -SO3H, -PO3H, -OP(O)(OR'), -P(O)(OR')(OR”), -P(O)NR'R”, C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Haloalkoxy, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 Aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic), monosaccharide residues, amino acid residues, nitric oxide (NO) donor residues, wherein the 0-4 methylene units in the C0-C6 alkylene group are independently substituted with the following groups: -Cy-, -O-, -S-, -SS-, -C(O)-, -C(S)-, -C(O)O-, -OC(O)O-, -OC(O)O-, -C(O)N(R) c )-、-N(R e )C(O)-、-N(R e )C(O)O-、-N(R e )C(O)N(R f )-、-N(R e -, -S(O)2-, -S(O)2N(R) e )-、-N(R e -S(O)2-, -S(O)-, -S(O)N(R) e )-、-N(R e )S(O)-、-OP(O)(OR f )O-、-P(O)(OR f -O-, -P(O)-, -OP(O)N(R) f )-、-P(O)N(R f )-、-P(O)(N(R e R f ))-、-OP(O)(OR e )2N(R f )-、-P(O)(OR f )2N(R e )-、-N(R e )P(O)(OR f )O-、-N(R e )P(O)-、 Where n1 is selected from integers between 1 and 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10), and R e and R f Independently selected from: H, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic); wherein the C3-C 10 cycloalkyl, C6-C 10 The hydrogen atom on the aryl or 4-10 membered heterocyclic group is optionally substituted by one or more groups selected from the following: halogen, cyano, nitro, azide, C1-C. 10 Alkyl, C1-C 10 Haloalkyl, -O(C) 0-10 alkyl), -N(C) 0-10 Alkyl)(C 0-10 Alkyl); wherein, R x and R y Independently selected from: H, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic); Each R' and R" is independently selected from: H, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic); wherein the C0-C6 alkylene, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C3-C 10 cycloalkyl, C6-C 10 The hydrogen atoms in aryl and 4-10 membered heterocyclic groups may optionally be substituted by one or more groups selected from the following: halogen, cyano, nitro, azide, C1-C. 10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic), C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 alkyl), -O(C) 0-10 alkyl), -S(C 0-10 alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 alkyl), -COO(C 0-10 Alkyl), -OCO(C) 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 Alkyl), -CO(C) 0-10 alkyl).

2. The compound according to claim 1, characterized in that, The compound has the following structure: in, R P1 It has the following structure: Among them, ring A is a 4-10 membered heterocyclic ring, and R... P5 It is one or more independent substituents on ring A, selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyalkyl, C1-C6 alkylaminoalkyl, C1-C6 cyanoalkyl; R P2 -(C0-C6 alkylene)-Y3-R P6 For example, -CH2-Y3-R P6 Y3 is selected from: single bond, C2-C4 alkylene group, -O-, -S-, -N(C 0-10 Alkyl group, -CO group, -CON(C) 0-10 alkyl)-, -N(C 0-10 Alkyl groups) CO-, -SO2-, -SO2N(C 0-10 Alkyl groups, -COO-, -OCO-, -CO-, 3-6 membered cycloalkyl subgroups, 4-6 membered heterocyclic subgroups, R P6 Selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyalkyl, C1-C6 alkylaminoalkyl, C1-C6 cyanoalkyl; R P3 Selected from: H, -N(C) 0-6 Alkyl)CO(C 0-6 Alkyl), -CON(C) 0-6 Alkyl)(C 0-6 Alkyl); or, R P3 The benzene ring attached to it forms an 8-12 membered fused carbon ring or heterocycle, especially an 8-10 membered nitrogen-containing heterocycle.

3. The compound according to claim 1 or 2, characterized in that, R P1 It has the following structure: R P5 Selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyalkyl, C1-C6 alkylaminoalkyl, C1-C6 cyanoalkyl; Preferably, R P5 For H.

4. The compound according to any one of claims 1-3, characterized in that, R P2 It has the following structure: Ring B is or Y3 is either -COO- or -CON(C) 0-3 alkyl)-, R P6 Selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxyalkyl; More preferably, R P2 It has the following structure: Or, R P2 It has the following structure:

5. The compound according to any one of claims 1-4, characterized in that, R P3 Selected from: H, -N(C) 0-6 Alkyl)CO(C 0-6 Alkyl), -CON(C) 0-6 Alkyl)(C 0-6 Alkyl); preferably from: Some have the following structure: Among them, R P8 It is one or more independent substituents on the ring, selected from: H, halogen, C1-C6 alkyl, C1-C6 haloalkyl.

6. The compound according to any one of claims 1-5, characterized in that, Z2 is a substituted or unsubstituted phenylene; and / or, Z1 is -(C0-C6 alkylene)-Z3-(C0-C6 alkylene)-, where Z3 is selected from: single bond, C2-C4 alkylene, C2 alkenyl, C2 alkyneyl, -O-, -S-, -N(C 0-10 Alkyl group, -CO group, -CON(C) 0-10 alkyl)-, -N(C 0-10 Alkyl groups) CO-, -SO2-, -SO2N(C 0-10 Alkyl group, -COO-, -OCO-, -CO-, 3-6 membered cycloalkyl group, 3-6 membered heteroalkyl group; preferably, Z1 is selected from: -O-, -S-, -NH-, especially -O-.

7. The compound according to claim 1, characterized in that, Some are selected from the following structure:

8. The compound according to any one of claims 1-7, characterized in that, The ML part is selected from one of ML-01 to ML-L08, especially ML-01: in, R 12 Selected from: H, Where Q1 is a single bond or C1-C 10 Alkylene, wherein 0-3 methylene units are independently substituted with the following groups: -Cy-, -O-, -S-, -SS-, -C(O)-, -C(S)-, -C(O)O-, -C(S)S-, -C(O)N(C 0-10 Alkyl)-, -S(O)2-, -S(O)2N(C 0-10 Alkyl group, -PO2-, -P(O)(N(C) 0-10 Alkyl group -, -N(C) 0-10 alkyl)-, -N(C 0-10 Alkyl)C(O)-, -N(C 0-10 Alkyl)S(O)2-, -P(O)-, Where m1 is selected from integers between 0 and 10; R E1 Selected from: H, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(phenyl), -(C0-C6 alkylene)-(4-10 membered heterocyclic), monosaccharide residues, amino acid residues, nitric oxide (NO) donor residues; wherein the C 0-10 Alkyl, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C0-C6 alkylene, C3-C 10 The hydrogen atoms in cycloalkyl, phenyl, and 4-10 membered heterocyclic groups are optionally substituted by one or more groups selected from the following: halogen, cyano, nitro, azide, C1-C. 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 alkyl), -O(C) 0-10 alkyl), -S(C 0-10 alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 alkyl), -COO(C 0-10 Alkyl), -OCO(C) 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 Alkyl), -CO(C) 0-10 alkyl); R 13 Selected from: H, Where Q2 is a single bond or C1-C 10 Alkylene, wherein 0-3 methylene units are independently substituted with the following groups: -Cy-, -O-, -S-, -SS-, -C(O)-, -C(S)-, -C(O)O-, -C(S)S-, -C(O)N(C 0-10 Alkyl)-, -S(O)2-, -S(O)2N(C 0-10 Alkyl group, -PO2-, -P(O)(N(C) 0-10 Alkyl group -, -N(C) 0-10 alkyl)-, -N(C 0-10 Alkyl)C(O)-, -N(C 0-10 Alkyl)S(O)2-, -P(O)-, Where m1 is selected from integers between 0 and 10; R E2 Selected from: H, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(phenyl), -(C0-C6 alkylene)-(4-10 membered heterocyclic), monosaccharide residues, amino acid residues, nitric oxide (NO) donor residues; wherein the C 0-10 Alkyl, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C0-C6 alkylene, C3-C 10 The hydrogen atoms in cycloalkyl, phenyl, and 4-10 membered heterocyclic groups are optionally substituted by one or more groups selected from the following: halogen, cyano, nitro, azide, C1-C. 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 alkyl), -O(C) 0-10 alkyl), -S(C 0-10 alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 alkyl), -COO(C 0-10 Alkyl), -OCO(C) 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 Alkyl), -CO(C) 0-10 alkyl); R 14 and R 15 Independently selected from: H, C1-C 10 Alkyl and monosaccharide residues; R 23 and R 24 Independently selected from: H, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 Aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic); wherein, the C 0-10 The hydrogen atom on the alkyl group may optionally be substituted with one or more groups selected from the following: halogen, cyano, nitro, azide, C1-C. 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 alkyl), -O(C) 0-10 alkyl), -S(C 0-10 alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 alkyl), -COO(C 0-10 Alkyl), -OCO(C) 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 Alkyl), -CO(C) 0-10 alkyl); R 25 Selected from: H, =O, Cl-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 Aryl), -(C0-C6 alkylene)-(4-10 heterocyclic), halogen, cyano, nitro, azide, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 alkyl), -O(C) 0-10 alkyl), -S(C 0-10 alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 alkyl), -COO(C 0-10 Alkyl), -OCO(C) 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 Alkyl), -CO(C) 0-10 alkyl), Wherein, the C 0-10 The hydrogen in the alkyl group may optionally be substituted by one or more groups selected from the following: halogen, cyano, nitro, azide, C1-C. 10 Alkyl, C2-C 10 alkenyl, C2-C 10 Alkyne group, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 alkyl), -O(C) 0-10 alkyl), -S(C 0-10 alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 alkyl), -COO(C 0-10 Alkyl), -OCO(C) 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 Alkyl), -CO(C) 0-10 alkyl); R 31 Selected from: H, halogens, C1-C6 alkyl groups, -O(C 0-6 alkyl), -O(C) 2-12 alkenyl), -N(C) 0-6 Alkyl)(C 0-6 alkyl), -COO(C 0-6 alkyl), -N(C) 0-6 Alkyl)CO(C 0-6 alkyl), -N(C) 0-6 alkyl)CO(phenyl); R 32 and R 33 Independently selected from: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl; Preferably, the ML portion is selected from one of ML-01-1 to ML-L08-1, especially ML-01-1:

9. The compound according to any one of claims 1-8, characterized in that, L has the following structure: in, L1 is a divalent group attached to ML, selected from: single bond, -O-(C0-C6 alkylene)-, -S-(C0-C6 alkylene)-, -N(R L1 )-(C0-C6 alkylene)-, -N(R L2 )C(O)-(C0-C6 alkylene)-、-OP(O)(OR L1 -O-(C0-C6 alkylene)-, -C(O)-(C0-C6 alkylene)-, -C(S)-(C0-C6 alkylene)-, -CON(R) L1 -(C0-C6 alkylene)-, -SO2-(C0-C6 alkylene)-, -SO-(C0-C6 alkylene)-; L3 is a divalent group attached to Z1, selected from: single bond, -(C0-C6 alkylene)-O-, -(C0-C6 alkylene)-S-, -(C0-C6 alkylene)-C(O)-, -(C0-C6 alkylene)-C(S)-, -(C0-C6 alkylene)-N(R) L3 )-、-(C0-C6 alkylene)-CON(R L3 )-、-(C0-C6 alkylene)-N(R L3 CO-, -(C0-C6 alkylene)-SO2-, -(C0-C6 alkylene)-SO-, -(C0-C6 alkylene)-(4-10 heterocyclic)-; L2 is a C1-C50 hydrocarbon chain (e.g., a C1-C20 alkyl chain) that is saturated or unsaturated with a single bond or divalent valence, consisting of 0-6 methylene units independently substituted with the following: -CY-, -O-, -S-, -SS-, -C(O)-, -C(S)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R) L2 )-、-N(R L2 )C(O)-、-N(R L2 )C(O)O-、-N(R L2 )C(O)N(R L2 )-、-N(R L2 -, -S(O)2-, -S(O)2N(R) L2 )-、-N(R L2 -S(O)2-, -S(O)-, -S(O)N(R) L2 )-、-N(R L2 )S(O)-、-P(O)(OR L 2 -O-, -P(O)-, -P(O)N(R) L2 )-、-P(O)(N(R L2 )2)-、-OP(O)(OR L2 )2N(R L2 )-、-P(O)(OR L2 )2N(R L2 )-、-N(R L2 )P(O)(OR L2 )O-、-N(R L2 P(O)-, -Si(R) L2 )2-、-C(=N-CN)-、 Amino acid residues, nucleotide residues, oligonucleotide residues, oligopeptide residues, wherein m2 is selected from an integer selected from 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10), and each -CY- is independently a divalent ring selected from the optionally substituted groups: arylene, cycloalkylene, heterocyclic; the H in the hydrocarbon chain may optionally be substituted by one or more groups selected from the group: halogen, cyano, nitro, azido, -OR L0 -C(O)R L0 -C(S)R L0 -C(O)OR L0 -C(S)SR L0 -OC(O)R L0 -OC(S)R L0 -OC(S)SR L0 -C(O)N(R) L0 )2、-OC(O)N(R L0 )2、-N(R L0 )C(O)OR L0 -N(R) L0 SO2R L0 -SO2N(R) L0 )2、-OSO2N(R L0 )2、-N(R L0 )C(O)R L0 -N(R) L0 )2、-SR L0 -SOR L0 -SO2R L0 -OSO2R L0 C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 Alkyne group, C1-C 10 Haloalkyl, C1-C 10 Haloalkoxy, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic); R L0 R L1 R L2 and R L3 Independently selected from: H, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic), wherein the C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C0-C6 alkylene, C3-C 10 cycloalkyl, C6-C 10 The hydrogen atoms in the aryl and 4-10 membered heterocyclic groups may optionally be substituted by one or more groups selected from the following: halogen, cyano, nitro, azide, hydroxyl, amino, mercapto, carboxyl, C1-C. 10 Alkyl, C2-C 10 alkenyl, C2-C 10 Alkyne group, C1-C 10 Haloalkyl, C1-C 10 Haloalkoxy, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic); Preferably, L1 is -C(O)- or a single bond; Preferably, L3 is a single bond or -C(O)-; Preferably, L2 is a C1-C20 straight-chain alkylene group, or L2 is a C1-C6 straight-chain alkylene group, wherein at least one methylene unit in the alkylene group is independently substituted with the following groups: Alternatively, L2 is selected from: Where h is selected from integers between 0 and 10, i is selected from integers between 0 and 10, and k is selected from integers between 0 and 10; More preferably, L2 is selected from:

10. The compound according to claim 8 or 9, characterized in that, The compound has the following structure: Preferably, the compound has the following structure: Preferably, L is selected from one of the following: Preferably, the stereoisomers of the compound are selected from the following structures:

11. A pharmaceutical composition comprising the compound of any one of claims 1-10 or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuterated compound thereof, and one or more pharmaceutically acceptable excipients.

12. The use of the compound of any one of claims 1-10 or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuterated compound thereof in the preparation of a medicament for the prevention and / or treatment of OGT-related diseases or O-GlcNAc glycosylation-related diseases; Preferably, the disease is selected from: neurodegenerative diseases, tumors, metabolic diseases, cardiovascular diseases, autoimmune diseases, and inflammatory diseases; More preferably, the metabolic disease is selected from: obesity, type 1 diabetes, type 2 diabetes, and diabetic complications.

13. Use of the compound of any one of claims 1-10 or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuterated compound thereof in the preparation of a medicament for the prevention and / or treatment of obesity.

14. A weight loss product comprising the compound of any one of claims 1-10 or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuterated compound thereof.

Images