New recruitment element for ubiquitin ligase and use thereof

Abstract

Disclosed in the present invention are a new recruitment element for a ubiquitin ligase and the use thereof, such as the use thereof in the preparation of a drug for targeted protein degradation, comprising a PROTAC drug. The inventors of the present invention creatively found a compound that recruits, by means of interaction with NCL, a ubiquitin ligase MDM2, and it is found by means of further experiments that the compound can serve as a new recruitment element for MDM2 and can be used in the preparation of a targeted protein degrader and other aspects. According to the above findings, the inventors prepared a targeted protein degrader, and found, by means of experiments, that the prepared targeted protein degrader can effectively mediate the degradation of a target protein by means of the ubiquitin-proteasome pathway, thereby achieving the treatment of target protein-related diseases (such as tumors), which has very good application prospects in the medical field.

Description

A novel recruitment element for ubiquitin ligase and its application Technical Field

[0001] The present invention relates to the field of chemical medicine technology, and in particular to a novel recruitment element for ubiquitin ligase and its application in the preparation of targeted protein degraders such as PROTAC. Background Art

[0002] Targeted protein degradation is a new, groundbreaking drug development strategy that leverages intrinsic protein degradation pathways within the cell to directly degrade pathogenic target proteins. This novel drug modality encompasses a variety of types, including PROTACs, molecular glues, LYTACs, ATACs, AbTACs, ATTECs, AUTACs, and AUTOTACs. PROTAC (Proteolysis Targeting Chimera) is a relatively mature and widely studied type of protein degradation chimera technology, primarily degrading target proteins through the ubiquitin-proteasome pathway. PROTACs are bifunctional molecules composed of a target protein ligand, a linker, and an E3 ubiquitin ligase recruitment element. Upon entry into the cell, the target protein ligand within the PROTAC structure specifically binds to the target protein, while the E3 ubiquitin ligase recruitment element at its other end binds to the E3 ubiquitin 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 target protein levels. In this process, the target protein ligand does not need to occupy the binding site for a long time. Therefore, PROTAC can exert its effects through multiple cycles within the cell. Based on this mechanism of action, PROTAC has attracted widespread attention from academia and industry since its inception. Different from traditional occupancy-driven pharmacology, event-driven PROTAC technology has many advantages, such as high activity, high selectivity, catalytic degradation mode of action, and targeting of undruggable targets.

[0003] Although there are 632 known human E3 ubiquitin ligases, the E3 ubiquitin ligases commonly used in PROTAC technology are very limited, such as CRL4 CRBN 、CRL2 VHL , MDM2 and IAP, among which those entering the clinical stage are mainly limited to CRL4 CRBN and CRL2 VHL. This is a major challenge for the current PROTAC technology. Therefore, there is an urgent need to develop new and efficient E3 ubiquitin ligase recruitment elements to promote the widespread application of PROTAC technology in the development of protein degradation drugs. MDM2, as a classic E3 ubiquitin ligase, has been used in the field of targeted protein degradation for many years, but there has been no breakthrough in clinical trials of MDM2-based PROTAC drugs. At present, the recruitment elements for MDM2 are mainly Nutlin and its derivatives. However, these recruitment elements will produce toxicity during use. The reason may be that the incorrect use of the dose leads to the activation of p53 in the bone marrow and the resulting blood toxicity, including thrombocytopenia and neutropenia. Therefore, it is necessary to find new recruitment elements for MDM2 for the construction of targeted protein degraders (such as PROTAC) and other uses.

[0004] Summary of the Invention

[0005] To overcome the deficiencies of the prior art, the present invention provides a novel recruitment element for the ubiquitin ligase MDM2 and its use in the preparation of targeted protein degraders such as proteolysis targeting chimeras (PROTACs), as well as a novel targeted protein degrader (such as PROTAC) and its preparation method and use.

[0006] In a first aspect of the present invention, a compound or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuterated compound thereof is provided as an E3 ubiquitin ligase recruitment element, for example, for use in preparing targeted protein degraders (TPDs), preparing MDM2 binders or capture agents, or preparing drugs for preventing and / or treating diseases, wherein the compound has the following structure:

[0007] in,

[0008] represents a single bond or a double bond, and a and b are shown Not a double bond at the same time;

[0009] 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, azido, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic group), C1-C10 Halogenated alkyl, C1-C 10 Halogenated alkoxy,

[0010] Among them, R A Selected from: H, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic group), halogen, cyano, nitro, azido, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -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);

[0011] R B and R C Independently selected from: H, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl);

[0012] R F Selected from: single bond, C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, -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 heterocyclyl);

[0013] 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 membered heterocyclic group), halogen, cyano, nitro, azido, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -N(C0-10 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), monosaccharide residues, amino acid residues, nitric oxide (NO) donor residues;

[0014] Q is a single bond or C1-C 20 Alkylene, wherein 0-6 methylene units are independently substituted by -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 c )-、-P(O)(ORd )2N(R c )-、-N(R c )P(O)(OR d )O-、-N(R c )P(O)-、 wherein m1 is selected from an integer between 1 and 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10), wherein 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 membered heterocyclyl); each -Cy- is independently an optionally substituted divalent ring selected from the following: arylene, cycloalkylene, heterocyclyl;

[0015] R5 and R6 are independently selected from the group consisting of: H, hydroxy, amino, halogen, cyano, nitro, azido, -CF3, -OCF3, Cl-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl);

[0016] The above-mentioned C0-C6 alkylene, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C6-C 10The H in the aryl and 4-10 membered heterocyclic groups may be optionally substituted by one or more groups selected from the group consisting of halogen, cyano, nitro, azido, -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'S02R", -SO2NR'R", -OS02NR'R", -NR'C(O)R", -NR'R", -SR', -SOR', -SO2R', -OS02R', -S03H, -PO3H, -OP(O)(OR'), -P(O)(OR')(OR"), -P(O)NR'R", C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Halogenated alkyl, C1-C 10 Halogenated alkoxy, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic group), monosaccharide residue, amino acid residue;

[0017] Alternatively, R1, R2, R3, R4, R5, R6, R7, R8, and R9 are selected from one or more of the following:

[0018] (1) R1 and R2 together with the carbon atoms to which they are attached form an aliphatic ring, an aromatic ring or a heterocyclic ring;

[0019] (2) R2 and R3 together with the carbon atoms to which they are attached form an aliphatic ring, an aromatic ring or a heterocyclic ring;

[0020] (3) R1 and R5 together with the carbon atoms to which they are attached form an aliphatic ring, an aromatic ring or a heterocyclic ring;

[0021] (4) R4 and R5 together with the carbon atoms to which they are attached form an aliphatic ring, an aromatic ring or a heterocyclic ring;

[0022] (5) R4 and R6 together with the carbon atoms to which they are attached form an aliphatic ring, an aromatic ring or a heterocyclic ring;

[0023] (6) R5 and R6 together with the carbon atoms to which they are attached form an aliphatic ring, an aromatic ring or a heterocyclic ring;

[0024] (7) R5 and R7 together with the carbon atoms to which they are attached form an aliphatic ring, an aromatic ring or a heterocyclic ring;

[0025] (8) R8 and R9 together with the carbon atoms to which they are attached form an aliphatic ring, an aromatic ring or a heterocyclic ring;

[0026] wherein the H on the aliphatic ring, aromatic ring or heterocyclic ring is optionally substituted by one or more groups selected from the following: =O, Halogen, cyano, nitro, azido, -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'S02R", -SO2NR'R", -OS02NR'R", -NR'C(O)R", -NR'R", -SR', -SOR', -SO2R', -OS02R', -S03H, -PO3H, -OP(O)(OR'), -P(O)(OR')(OR"), -P(O)NR'R", C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Halogenated alkoxy, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl), monosaccharide residue, amino acid residue, nitric oxide (NO) donor residue, wherein 0-4 methylene units in the C0-C6 alkylene are independently substituted by 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 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 Rf ))-、-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)-、 wherein n1 is selected from an integer between 1 and 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10), wherein 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 group); wherein the C3-C 10 Cycloalkyl, C6-C 10 The H on the aryl group and the 4-10 membered heterocyclic group is optionally substituted by one or more groups selected from the following: halogen, cyano, nitro, azido, 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-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl);

[0027] Each R' and R" is independently selected from: H, Cl-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 group); wherein the C0-C6 alkylene, C1-C10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C6-C 10 The H in the aryl group and the 4-10 membered heterocyclic group may be optionally substituted by one or more groups selected from the following: halogen, cyano, nitro, azido, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic group), C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -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).

[0028] Specifically, the targeted protein degrader is, for example, a targeted protein degrader based on the ubiquitination-proteasome system, endosome-lysosome, or autophagy-lysosome, such as a proteolysis-targeted chimera (PROTAC), a molecular glue, a chaperone-mediated protein degrader (CHAMP), a lysosome-targeted chimera (LYTAC), a GlucTAC, an antibody-PROTAC conjugate (AbTAC), an AUTAC, an AUTOTAC, an ATTEC, an antibody-PROTAC conjugate, an autophagy-targeted degradation chimera (MADTAC), etc. (see, for example, Zhou Luozhu, Sheng Chunquan. Research progress and prospects of targeted protein degradation technology [J]. Pharmaceutical Practice and Service, 2023, 41(06): 341-351+365.; Liu Jinghong, Chen Yimin, Cai Xiaoqing. Emerging technologies and research progress of targeted protein degradation [J]. Acta Pharmaceutica Sinica, 2022, 57(02): 313-320.; Paudel RR, Lu D, Roy Chowdhury S, Monroy EY, Wang J. Targeted Protein Degradation via Lysosomes. Biochemistry. 2023 Feb 7; 62(3): 564-579. etc.), in particular PROTAC, LYTAC, AbTAC, AUTAC, AUTOTAC, antibody-PROTAC conjugates.

[0029] Specifically, the E3 ubiquitin ligase is MDM2.

[0030] Specifically, the recruitment is achieved through the interaction of the compound with nucleolin (NCL).

[0031] In particular, the disease is one for which the recruitment of MDM2 is beneficial for its treatment.

[0032] In some embodiments of the present invention, the disease is, for example, but not limited to, tumors, autoimmune diseases, inflammatory diseases, diseases associated with pathogen infection, neurodegenerative diseases, cardiovascular diseases, metabolic diseases, fibrotic diseases, etc.

[0033] Specifically, each -Cy- can be independently selected from the following:

[0034] Specifically, the monosaccharide residue can be selected from the group consisting of glucosyl, galactosyl, xylosyl and mannosyl.

[0035] Specifically, the nitric oxide (NO) donor residue can be selected from: -ONO2, Among them, RH and R K Independently selected from: H, C1-C 10 Alkyl, C1-C 10 Alkenyl, -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-6 membered heterocyclic group) (e.g. ), or R H and R K Together with the nitrogen atom to which it is attached, it forms a 4-6 membered heterocyclic group (e.g. ).

[0036] In some embodiments of the present invention, R 10 For H.

[0037] In some embodiments of the present invention, R 11 For H.

[0038] In some embodiments of the present invention, R x For H.

[0039] In some embodiments of the present invention, R y is H or phenyl.

[0040] In some embodiments of the present invention, R8 and R9 together with the carbon atoms to which they are attached form an aliphatic ring; more specifically, the compound has the following structure:

[0041] wherein R8′ and R9′ have the same definitions as those for R8 and R9, respectively.

[0042] In some embodiments of the present invention, R8' is =0.

[0043] In some embodiments of the present invention, R9' is selected from the group consisting of: H, =O, Among them, R 31 Selected from: H, halogen, C1-C6 alkyl, -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, or R 32and R 33 Together with the nitrogen atom to which it is attached, it forms a 4-8 membered heterocyclic group.

[0044] In some embodiments of the present invention, R9' is R9" is selected from:

[0045] In some embodiments of the present invention, R9' together with the carbon atom to which it is attached forms a 3-6 membered saturated heterocyclic ring (eg ), wherein the H on the heterocyclic ring is optionally substituted by a group selected from the group consisting of: H, -CO(C 0-6 alkyl), -CO(C 2-6 More specifically, R9' together with the carbon atom to which it is attached forms:

[0046] In some embodiments of the present invention, R9' is selected from:

[0047] In some embodiments of the present invention, R9' is H, ═O, in particular In some embodiments of the present invention, the compound has the following structure:

[0048] In one embodiment of the present invention, R4 and R5 together with the carbon atoms to which they are attached form an aliphatic ring, and R5 and R6 together with the carbon atoms to which they are attached form a heterocyclic ring; more specifically, the compound has the following structure:

[0049] in,

[0050] R 21 Selected from: H, =O, -O(C 0-10 alkyl), -OC(O)(C 0-10 alkyl), -O-monosaccharide residues;

[0051] R 22 Selected from: H, -O(C 0-10 alkyl), -OC(O)(C 0-10 alkyl), -O-monosaccharide residue; or, R 22 and R7 together with the carbon atom to which they are attached form an optionally substituted aliphatic, aromatic or heterocyclic ring.

[0052] In one embodiment of the present invention, the compound has the following structure:

[0053] in,

[0054] R23 and R 24 Independently selected from: H, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic group); wherein the C 0-10 The H on the alkyl group may be optionally substituted by one or more groups selected from the group consisting of halogen, cyano, nitro, azido, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -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).

[0055] In some embodiments of the present invention, R 23 and R 24 are independently selected from: H, C1-C3 alkyl, phenyl, wherein the H on the phenyl group may be optionally substituted by one or more groups selected from the following: halogen, hydroxyl, amino, C1-C3 alkoxy; in one embodiment of the present invention, R 23 and R 24 are all methyl; in one embodiment of the present invention, R 23 H, R 24 is phenyl; in one embodiment of the present invention, R 23 H, R 24 It is 3,4-dimethoxyphenyl.

[0056] In another embodiment of the present invention, R4 and R6 together with the carbon atoms to which they are attached form a heterocyclic ring, and R1 and R5 together with the carbon atoms to which they are attached form a heterocyclic ring; more specifically, the compound has the following structure:

[0057] In another embodiment of the present invention, R5 and R6 together with the carbon atoms to which they are attached form a heterocyclic ring; more specifically, the compound has the following structure:

[0058] In another embodiment of the present invention, R4 and R5 together with the carbon atoms to which they are attached form an aliphatic ring, and R4 and R6 together with the carbon atoms to which they are attached form a heterocyclic ring; more specifically, the compound has the following structure:

[0059] In another embodiment of the present invention, R1 and R2 together with the carbon atoms to which they are attached form a 3-10 membered heterocyclic ring; more specifically, the compound has the following structure:

[0060] in,

[0061] X is O or S;

[0062] R 25 Selected from: H, =O, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic group), halogen, cyano, nitro, azido, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -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(C0-10 alkyl), -CON(C 0-10 Alkyl)(C 0-10 alkyl), -CO(C 0-10 alkyl), Among them, the C 0-10 The H in the alkyl group may be optionally substituted by one or more groups selected from the group consisting of halogen, cyano, nitro, azido, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -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).

[0063] In some embodiments of the present invention, in Formula III-6, R 25 Selected from: H, C1-C6 alkyl, -N(H)(C 0-6 alkyl), -N(H)CO(C 0-6 alkyl), -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 group) (e.g. ), 4-8 membered nitrogen-containing heterocyclic group (e.g. ), More specifically, R 25 Selected from: H, methyl, ethyl, amino,

[0064] In some embodiments of the present invention, in formula III-7 and III-8, 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. ).

[0065] In some embodiments of the present invention, in formula III-9, III-10, and III-11, R 25 is one or more independent substituents on the ring, which are 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 by a group selected from the group consisting of H, halogen, hydroxy, azido, and amino; or, two R 25 Together with the atoms to which it is attached, it forms a carbocyclic or heterocyclic ring (e.g. ). More specifically, R 25 Selected from:

[0066] In another embodiment of the present invention, R8' and R9' together with the carbon atoms to which they are attached form a 3-10 membered heterocyclic ring; more specifically, the compound has the following structure:

[0067] in,

[0068] R 26 Selected from: H, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic group), -(C0-C6 alkenylene)-(C6-C 10 aryl), halogen, cyano, nitro, azido, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C0-10 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 H in the alkyl group may be optionally substituted by one or more groups selected from the group consisting of halogen, cyano, nitro, azido, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -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).

[0069] In some embodiments of the present invention, in formula III-14 and III-15, R 26Selected from: H, halogen, cyano, nitro, azido, C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, -COO(C 0-3 alkyl),

[0070] In some embodiments of the present invention, in III-16 to III-18 and III-20, R 26 Selected from: H, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, Wherein the H on the phenyl group and the heterocyclic group may be optionally substituted by one or more groups selected from the following: halogen, cyano, nitro, azido, hydroxyl, amino, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -N(C 0-3 Alkyl)(C 0-3 alkyl).

[0071] In one embodiment of the present invention, the is a double bond, as shown in b For a single bond.

[0072] In one embodiment of the present invention, the Is a single bond, as shown in b For double bonds.

[0073] In one embodiment of the present invention, the Is a single bond, as shown in b For a single bond.

[0074] In some embodiments of the present invention, the compound has the following structure:

[0075] In some embodiments of the present invention, the compound has the following structure:

[0076] In some embodiments of the present invention, R2 is selected from the group consisting of: H, halogen, ═O, where R J Selected from: H, C1-C6 alkyl, phenyl, C1-C6 alkyl substituted phenyl (eg 4-tert-butylphenyl). In one embodiment of the present invention, R2 is H.

[0077] In some embodiments of the present invention, R3 is selected from the group consisting of: H, halogen, =0, where R J Selected from: H, C1-C6 alkyl, phenyl, C1-C6 alkyl substituted phenyl (eg 4-tert-butylphenyl). In one embodiment of the present invention, R3 is H.

[0078] In some embodiments of the present invention, the compound has the following structure:

[0079] in,

[0080] R 12 Selected from: H, Where Q1 is a single bond or C1-C 10 Alkylene, wherein 0-3 methylene units are independently substituted by: -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)-、-PO2-、-P(O)(N(C 0-10 Alkyl))-、-N(C 0-10 Alkyl)-, -N(C 0-10 Alkyl) C(O)-, -N(C 0-10 Alkyl) S(O)2-、-P(O)-、 Wherein, m1 is selected from an integer 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 heterocyclyl), monosaccharide residue, amino acid residue, nitric oxide (NO) donor residue; 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 H in the cycloalkyl, phenyl, 4-10 membered heterocyclic group is optionally substituted by one or more groups selected from the following: halogen, cyano, nitro, azido, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -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(C0-10 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);

[0081] R 13 Selected from: H, Where Q2 is a single bond or C1-C 10 Alkylene, wherein 0-3 methylene units are independently substituted by: -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)-、-PO2-、-P(O)(N(C 0-10 Alkyl))-、-N(C 0-10 Alkyl)-, -N(C 0-10 Alkyl) C(O)-, -N(C 0-10 Alkyl) S(O)2-、-P(O)-、 Wherein, m1 is selected from an integer 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 heterocyclyl), monosaccharide residue, amino acid residue, nitric oxide (NO) donor residue; 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 H in the cycloalkyl, phenyl, 4-10 membered heterocyclic group is optionally substituted by one or more groups selected from the following: halogen, cyano, nitro, azido, C1-C 10 Alkyl, C1-C 10Halogenated alkyl, C1-C 10 Haloalkoxy, -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);

[0082] R 14 and R 15 Independently selected from: H, C1-C 10 Alkyl, monosaccharide residues.

[0083] 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), monosaccharide residues, Among them, R 16 Selected from: halogen, cyano, nitro, azido, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C0-10 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); more specifically, R 12 Selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, C(O)(C 0-6 alkyl), SO2(C 0-6 alkyl),

[0084] 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), monosaccharide residues, Among them, R 17 Selected from: halogen, cyano, nitro, azido, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C0-10 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); more specifically, R 13 Selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, C(O)(C 0-6 alkyl), SO2(C 0-6 alkyl),

[0085] In some embodiments of the present invention, R 16 Selected from: H, halogen, cyano, nitro, azido, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy.

[0086] In some embodiments of the present invention, R 17 Selected from: H, halogen, cyano, nitro, azido, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy.

[0087] In some embodiments of the present invention, R 14 For H.

[0088] In some embodiments of the present invention, R 15 For H.

[0089] In other embodiments of the present invention, R 15 It is a monosaccharide residue, such as glucosyl, galactosyl, xylosyl, and mannosyl.

[0090] In some embodiments of the present invention, the compounds include, but are not limited to, the following:

[0091] In one embodiment of the present invention, the stereoisomers of the compound have the following structures:

[0092] For example

[0093] In one embodiment of the present invention, the stereoisomers of the compound have the following structures:

[0094] For example

[0095] In addition to the compounds shown in the present invention, there are other structural analogs in the prior art that have been verified or are under study, such as patent documents CN105473566A, CN104039796A, CN101139350A, CN101723951A, CN102002051A, CN102295649A, CN102850369A, CN104003998A, CN105524076A, CN106749305A, CN10686 6695A, CN106883267A, CN108299458A, CN108864132A, CN110627833A, CN113698415A, CN114478566A, CN116 621855A, CN114702506A, CN113004241A, CN110950883A, CN110229168A, CN111635395A, CN106749305AShen 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. Progress in structural modification and biological activity of Rubescensine A [J]. Journal of Organic Chemistry, 2017, 37(7): 1701-1713. etc., which are incorporated herein by reference in their entirety.

[0096] In a second aspect of the present invention, a targeted protein degrader compound or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuterated compound thereof is provided, wherein the compound has the following structure:

[0097] in,

[0098] ML is the MDM2 protein recruitment element portion, which is the structural portion of the compound of the first aspect;

[0099] L is a linking group;

[0100] PI is the ligand portion of the target protein;

[0101] 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).

[0102] In some embodiments of the invention, q is 1.

[0103] In some embodiments of the invention, the ML moiety is selected from the following structures:

[0104] Among them, R1', R2', R3', R7', R 21 '、R 22 '、R 23 '、R 24 '、R 25 '、R 27 '、R 31 '、R 32 ' are R1, R2, R3, R7, R 21 、R 22 、R 23 、R 24 、R 25 、R 27 、R 31 、R 32 A divalent group obtained after a linking reaction (e.g., loss of a leaving group);

[0105] ①, ②, ③, ④, ⑤, ⑥, ⑦, ⑧, ⑨, ⑩ are available linking sites. When they are not used as linking sites, the corresponding R1', R2', R3', R7', R 21 '、R 22 '、R 23 '、R 24 '、R 25 ' or R 27 '、R 31 '、R 32 ' are R1, R2, R3, R7, R 21 、R 22 、R 23 、R 24 、R 25 or R 27 、R 31 、R 32 .

[0106] In some embodiments of the present invention, ① is a linking site.

[0107] In some embodiments of the present invention, ② is a linking site.

[0108] In some embodiments of the present invention, ③ is a linking site.

[0109] In some embodiments of the present invention, ④ is a linking site.

[0110] In some embodiments of the present invention, ⑦ is a linking site.

[0111] In some embodiments of the present invention, R1' is O or OC(O).

[0112] In some embodiments of the present invention, R7' is O or OC(O).

[0113] In some embodiments of the present invention, R 21 ' is O or OC(O).

[0114] In some embodiments of the present invention, R 22 ' is O or OC(O).

[0115] In some embodiments of the present invention, R2' is a single bond.

[0116] In some embodiments of the present invention, R3' is a single bond.

[0117] In some embodiments of the present invention, R 23 ' is a single bond, O or OC(O).

[0118] In some embodiments of the present invention, R 24 ' is a single bond, O or OC(O).

[0119] In some embodiments of the present invention, R 25 ' is a single bond, O or OC(O).

[0120] In some embodiments of the present invention, R 26 ' is a single bond, O or OC(O).

[0121] Further, in some embodiments of the present invention, the ML moiety is selected from the following structures:

[0122] In some embodiments of the present invention, the MDM2 protein recruitment element has the structure shown in formula V-1 to V-29 in the first aspect, especially

[0123] Furthermore, in some embodiments of the present invention, the ML moiety is selected from the following structures:

[0124] In some preferred embodiments of the present invention, only ① serves as the linking site, and the ML portion has the following structure:

[0125] in particular In some embodiments of the present invention, the compound has the following structure:

[0126] In some embodiments of the present invention, the compound has the following structure:

[0127] in particular In some embodiments of the present invention, only ② serves as the linking site, and the ML portion has the following structure:

[0128] in particular

[0129] In some preferred embodiments of the present invention, only ③ serves as the linking site, and the ML portion has the following structure:

[0130] In some preferred embodiments of the present invention, only ④ serves as the linking site, and the ML portion has the following structure:

[0131] In some embodiments of the present invention, only ⑦ serves as the linking site, and the ML portion has the following structure:

[0132] in particular

[0133] Specifically, L has the following structure: in,

[0134] L1 is a divalent group connected to ML, which can be selected from: a single bond, -O-(C0-C6 alkylene)-, -S-(C0-C6 alkylene)-, -C(O)-(C0-C6 alkylene)-, -C(S)-(C0-C6 alkylene)-, -N(R L1 )-(C0-C6 alkylene)-, -CON(R L1 )-(C0-C6 alkylene)-, -N(R L1)CO-(C0-C6 alkylene)-, -SO2-(C0-C6 alkylene)-, -SO-(C0-C6 alkylene)-;

[0135] L3 is a divalent group connected to PI, which can be selected from: a 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 membered heterocyclylene)-;

[0136] L2 is a single bond or a divalent saturated or unsaturated linear or branched C1-C50 hydrocarbon chain, in which 0-6 methylene units are independently substituted by: -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 L2 )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 between 1 and 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10), each -CY- is independently an optionally substituted divalent ring selected from the following: arylene, cycloalkylene, heterocyclylene; H in the hydrocarbon chain may be optionally substituted by one or more groups selected from the following: 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 、-NR 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 Alkynyl, C1-C 10 Halogenated alkyl, C1-C 10 Halogenated alkoxy, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl);

[0137] 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 10Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic group), 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 H in the aryl group and the 4-10 membered heterocyclic group may be optionally substituted by one or more groups selected from the following: halogen, cyano, nitro, azido, hydroxyl, amino, thiol, carboxyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Halogenated alkyl, C1-C 10 Halogenated alkoxy, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl).

[0138] Specifically, each -CY- is independently selected from the following optionally substituted bivalent rings: phenylene, bicyclic arylene, tricyclic arylene, monocyclic cycloalkylene, bicyclic cycloalkylene, tricyclic cycloalkylene, monocyclic heteroarylene, bicyclic heteroarylene, tricyclic heteroarylene, monocyclic heterocycloalkylene, bicyclic heterocycloalkylene, tricyclic heterocycloalkylene.

[0139] In some embodiments of the present invention, -CY- is substituted or unsubstituted phenylene. In some embodiments of the present invention, -CY- is substituted or unsubstituted 3-12 membered cycloalkylene. In some embodiments of the present invention, -CY- is substituted or unsubstituted 4-12 membered saturated heterocycloalkylene.

[0140] In some embodiments of the invention, each -CY- is independently selected from the following:

[0141] Among them, R L4 、R L5 Independently selected from: H, OH, halogen, 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 Cycloalkyl, C3-11 Heterocyclic hydrocarbon, O(C 1-8 Cycloalkyl), S(C 1-8 Cycloalkyl), NH(C 1-8 Cycloalkyl), N(C 1-8 Cycloalkyl) (C 1-8 alkyl), 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 Alkynyl, 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), 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 、R L5 Together with the atoms to which they are attached, they form a cycloalkylene or heterocyclylene group.

[0142] More specifically, R L4 、R L5Independently selected from: -CH3, or, R L4 、R L5 Together with the atoms to which it is attached, it forms a three- to six-membered cycloalkylene group (e.g. ) or a four-membered to six-membered heterocycloalkylene group (such as ).

[0143] In some embodiments of the present invention, R L1 For H.

[0144] In some embodiments of the present invention, R L3 For H.

[0145] In some embodiments of the present invention, R L4 For H.

[0146] In some embodiments of the present invention, R L4 For OH.

[0147] In some embodiments of the present invention, R L5 For H.

[0148] In some embodiments of the present invention, R L5 For OH.

[0149] In one embodiment of the present invention, L2 is a C1-C20 straight chain alkylene, wherein 0-6 methylene units in the alkylene 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, R L2 Independently selected from: H, C1-C6 alkyl, each R L4 and R L5 Independently selected from: H, OH, C1-C6 alkoxy.

[0150] More specifically, L2 can be selected from: C1-C20 straight chain alkylene, -(CH2CH2O) m2 -CH2-, -(CH2CH2O) m2 -CH2CH2-, -CH2-(CH2CH2O) m2 -CH2-, -CH2CH2-(CH2CH2O) m2 -CH2-, -CH2CH2-(CH2CH2O) m2-CH2CH2-、-(C1-C 10 Alkylene)-O-(C1-C 10 Alkylene)-, -(C1-C 10 Alkylene)-NH-(C1-C 10 Alkylene)-, -(C1-C 10 Alkylene)-C(O)NH-(C1-C 10 Alkylene)-, -(C1-C 10 Alkylene)-NHC(O)-(C1-C 10 -(C1-C6 alkylene)-, -(C1-C6 alkylene)-O-(C1-C6 alkylene)-C(O)NH-(C1-C6 alkylene)-, -(C1-C6 alkylene)-O-(C1-C6 alkylene)-NHC(O)-(C1-C6 alkylene)-, wherein m2 is selected from an integer between 1 and 10, g is 0 or 1, h is selected from an integer between 0 and 10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10), and i is selected from an integer between 0 and 10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10).

[0151] In some specific embodiments of the present invention, L2 is selected from: wherein m2 is selected from an integer between 1 and 10, g is 0 or 1, h is selected from an integer between 0 and 10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10), i is selected from an integer between 0 and 10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10), and j is selected from an integer between 1 and 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10).

[0152] In some specific embodiments of the present invention, L2 is selected from:

[0153] In some specific embodiments of the present invention, L2 is selected from:

[0154] In some specific embodiments of the present invention, L2 is selected from:

[0155] In some specific embodiments of the present invention, L2 is selected from:

[0156] In another embodiment of the present 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 further comprises a group selected from the following: -O-, -C(O)-, -N(R L2 )-、-C(O)N(R L2 )-、-N(R L2 )C(O)-、 Among them, R L2 Independently selected from: H, C1-C6 alkyl.

[0157] In some embodiments of the present invention, -CY- is selected from the group consisting of:

[0158] In some specific embodiments of the present invention, L2 is selected from:

[0159] In one embodiment of the present invention, L1 is -C(O)-.

[0160] In one embodiment of the present invention, L1 is a single bond.

[0161] In one embodiment of the present invention, the compound has the following structure:

[0162] In one embodiment of the present invention, the compound has the following structure:

[0163] In some embodiments of the present invention, the compound may have the following structure:

[0164] wherein n is selected from an integer of 1-10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10).

[0165] Specifically, for the PI moiety, the target protein can be, for example, a target protein as shown below:

[0166] In some embodiments of the present invention, the target protein is brominated structural protein 4 (BRD4).

[0167] Specifically, the target protein ligand can be a small molecule compound, oligonucleotide, oligopeptide, polypeptide, protein (such as antibody), etc., especially a small molecule compound.

[0168] Specifically, the BRD4 ligand can be a BRD4 small molecule inhibitor known in the prior art, which is mainly divided into the following categories according to the differences in chemical structure: triazoloazepine derivatives, isoxazole derivatives, pyridine derivatives, tetrahydroquinoline derivatives, triazolopyrazine derivatives, 4-acylpyrrole derivatives, 2-thiazolidinone derivatives, etc. Specific examples include the small molecule inhibitors shown below:

[0169] (For example, Huang Qianhui, Ding Yiyi, Tan Yuwen, et al. Structure and function of bromodomain protein 4 and application of its inhibitors in tumor research [J]. Chinese Journal of Biotechnology, 2023, 39(1): 17.; Feng Lu, Wang Guan, Ouyang Liang. Research progress of small molecule inhibitors of bromodomain protein 4 and its degraders [J]. Advances in Pharmaceutical Sciences, Vol. 44, No. 9, 2020, pp. 656-666, CA, 2020: National Natural Science Foundation of China. etc. as described in existing technical literature).

[0170] In some embodiments of the present invention, the target protein ligand is selected from the group consisting of: JQ1, OTX015, TEN-10, I-BET762, and CPI-0610.

[0171] In one embodiment of the invention, the PI moiety has the following structure:

[0172] In some embodiments of the present invention, L3 is a single bond, -N(H)-, or -C(O)-.

[0173] L3 is a 4-8 membered saturated nitrogen-containing heterocyclic group, such as

[0174] In some embodiments of the present invention, the compound has the following structure:

[0175] In some embodiments of the present invention, the compound has the following structure:

[0176] In some embodiments of the present invention, the compound has the following structure:

[0177] In some embodiments of the present invention, the compound has the following structure:

[0178] In some embodiments of the present invention, the compound has the following structure:

[0179] In some embodiments of the present invention, the compound has the following structure:

[0180] In some embodiments of the present invention, the compound has the following structure:

[0181] In some embodiments of the present invention, the stereoisomers of the compound have the following structures:

[0182] In some embodiments of the present invention, the stereoisomers of the compound have the following structures:

[0183] In some embodiments of the present invention, the stereoisomers of the compound have the following structures:

[0184] In some embodiments of the present invention, the stereoisomers of the compound have the following structures:

[0185] In some embodiments of the present invention, the stereoisomers of the compound have the following structures:

[0186] In some embodiments of the present invention, the stereoisomers of the compound have the following structures:

[0187] In the third aspect of the present invention, a method for preparing the compound of the second aspect is provided, comprising the following steps: first preparing PI-L', and then reacting and connecting it with the compound of the first aspect; or,

[0188] First prepare ML-L', and then react and connect with the target protein ligand compound; or,

[0189] Prepare PI-L3-L2'-N3 and ML-L1-L2"-C≡CH separately, and then connect them through click reaction; or

[0190] PI-L3-L2'-C≡CH and ML-L1-L2"-N3 were prepared separately and then connected by click reaction;

[0191] Wherein, L', L2', and L2" are any suitable linking groups.

[0192] In a fourth aspect of the present invention, a pharmaceutical composition is provided, comprising the compound of the second aspect or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuterated compound thereof, and one or more pharmaceutically acceptable excipients.

[0193] Specifically, the pharmaceutically acceptable excipients may be selected from one or more of fillers, binders, lubricants, disintegrants, antioxidants, buffers, antibacterial agents, suspending agents, solubilizers, thickeners, stabilizers, preservatives, and the like.

[0194] Specifically, the pharmaceutical composition can be administered by any suitable route, such as enteral administration (e.g., oral, sublingual, rectal) or parenteral administration (e.g., intravenous, intramuscular, intranasal, intraocular, intracerebral, intravaginal, intraperitoneal, transdermal, subcutaneous, intradermal, respiratory tract administration, etc.).

[0195] Specifically, the pharmaceutical composition can be prepared into pharmaceutical preparations in the following forms: injection, syrup, elixir, suspension, powder, granule, tablet, capsule, lozenge, cream, ointment, lotion, gel, emulsion, etc.

[0196] When preparing injections, any commonly used carrier in the art can be used, such as water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyethoxylated isostearyl alcohol, and fatty acid esters of polyethylene sorbitan, etc. In addition, commonly used solvents and buffers can also be added.

[0197] Specifically, the pharmaceutical composition is preferably in unit dosage form. In this form, the preparation is subdivided into unit doses containing appropriate amounts of the active ingredient. The unit dosage form can be a capsule, tablet, or any other dosage form; in addition, the unit dosage form can also be a packaged preparation, such as tablets, capsules, and powders packaged in vials or ampoules.

[0198] Specifically, in the pharmaceutical composition, the compound of the second aspect or its pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuterated compound can be used alone or in combination with other types of active ingredients.

[0199] Specifically, the amount of the active ingredient in the unit dose formulation can be varied or adjusted from 0.1 mg to 1000 mg, depending on the specific application and efficacy of the active ingredient. If desired, the composition may further comprise other suitable therapeutic agents.

[0200] In the fifth aspect of the present invention, there is provided the use of the compound of the second aspect or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuterated compound thereof in the preparation of a medicament for preventing and / or treating a disease, wherein the disease is a disease that can be beneficially prevented and / or treated by inhibiting / degrading the target protein.

[0201] Specifically, the target protein is as described in the second aspect of the present invention.

[0202] Specifically, the disease may be, for example, but not limited to, tumors, autoimmune diseases, inflammatory diseases, diseases associated with pathogen infection, neurodegenerative diseases, cardiovascular diseases, metabolic diseases, fibrotic diseases, etc.

[0203] Specifically, the tumors include but are not limited to: lung cancer, malignant melanoma, brain tumors, tumors of the digestive organs, uterine cancer, testicular cancer, palate cancer, pharyngeal cancer, tongue cancer, oral cancer, various sarcomas, osteosarcoma, blood system tumors, nervous system tumors, brain gliomas, glioblastomas, skin cancer, skin appendage cancer and skin metastasis, medulloblastoma, glioma, blastoma, liposarcoma, neuroendocrine tumors, synovial cell sarcoma, gastrinoma, carcinoid tumors, mesothelioma, islet cell carcinoma , schwannoma, meningioma, melanoma, acoustic neuroma, adenocarcinoma, lymphoid malignancies, epithelial squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma, adenocarcinoma lung cancer, peritoneal cancer, squamous cell lung cancer, hepatocellular carcinoma, gastric cancer, intestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, thyroid cancer, bladder cancer, breast cancer, metastatic breast cancer, colon cancer, rectal cancer, prostate cancer, salivary gland cancer, kidney cancer, vulvar cancer, anal cancer, penile cancer, esophageal cancer, biliary tract tumors and head and neck cancer.

[0204] Specifically, the hematological malignancies include leukemia, lymphoma, and multiple myeloma (MM).

[0205] Specifically, the leukemia can be chronic lymphocytic leukemia (CLL) (e.g., B cell CLL, T cell CLL), chronic myeloid leukemia (CML) (e.g., B cell CML, T cell CML), acute lymphocytic leukemia (ALL) (e.g., B cell ALL, T cell ALL), acute myeloid leukemia (AML) (e.g., B cell AML, T cell AML), acute monocytic leukemia, etc.

[0206] Specifically, the lymphoma may be Hodgkin lymphoma (HL) (e.g., B cell HL, T cell HL) and non-Hodgkin lymphoma (NHL) (e.g., B cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodular marginal zone B cell lymphoma, splenic marginal zone B cell lymphoma), primary mediastinal B cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenstrom's macroglobulinemia ( macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B lymphoblastic lymphoma and primary central nervous system (CNS) lymphomas and T-cell NHL, such as precursor T lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary syndrome)), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma and anaplastic large cell lymphoma, NK / T-cell lymphoma, in particular diffuse large B-cell lymphoma (DLBCL).

[0207] Specifically, the autoimmune diseases include but are not limited to organ-specific autoimmune diseases, systemic lupus erythematosus, rheumatoid arthritis, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease, autoimmune hemolytic anemia, thyroid autoimmune disease, ulcerative colitis, etc.

[0208] Specifically, the inflammatory diseases include, but are not limited to, osteoarthritis, acute gout, multiple sclerosis, inflammatory bowel disease (such as Crohn's disease and ulcerative colitis), neuroinflammation, asthma, chronic obstructive airway disease, pneumonia, myositis, eczema, dermatitis, acne, cellulitis, occlusive disease, thrombosis, alopecia, nephritis, vasculitis, retinitis, uveitis, scleritis, sclerosing cholangitis, hypophysitis, thyroiditis, septic shock, systemic inflammatory response syndrome (SIRS), toxic shock syndrome, acute lung injury, ARDS (adult respiratory distress syndrome), acute renal failure, burns, pancreatitis (such as acute pancreatitis), postoperative syndrome, sarcoidosis, Herxheimer reaction, encephalitis, myelitis, meningitis and malaria, etc.

[0209] 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), different types of spinocerebellar ataxia (SCA), Pick's disease, etc.

[0210] Specifically, the pathogen may be a microorganism, a parasite (protozoa, worm, etc.) or other agent.

[0211] Specifically, the microorganism can be selected from one or more of: viruses, chlamydia, rickettsia, mycoplasma, bacteria, spirochetes, fungi, etc.

[0212] In one embodiment of the present invention, the pathogen is a virus, for example, but not limited to, Adenoviridae (such as adenovirus), Herpesviridae (such as HSV1 (oral herpes), HSV2 (genital herpes), VZV (varicella), EBV (Epstein-Barr virus), CMV (cytomegalovirus)), Poxviridae (such as smallpox virus, cowpox virus), Papovaviridae (such as papillomavirus (HPV)), Parvoviridae (such as B19 virus), Hepadnaviridae (such as hepatitis B virus), Polyomaviridae (such as polyoma virus), Reoviridae (such as reovirus, rotavirus), Picornaviridae (such as enterovirus, foot-and-mouth disease virus), Caliciviridae (such as Norwalk virus, hepatitis E virus), Togaviridae (such as rubella virus), Arenaviridae (such as lymphocytic choriomeningitis virus), Retroviridae (HIV-1, HIV-2, HTLV-1), Flaviviridae ( Such as dengue virus, Zika virus, Japanese encephalitis virus, Chikungunya virus, yellow fever virus, hepatitis C virus, West Nile virus, etc.), Orthomyxoviridae (such as influenza virus (such as influenza A virus, influenza B virus, influenza C virus, etc.)), Paramyxoviridae (such as human parainfluenza virus (HPIV) type 1, HPV type 2, HPV type 3, HPV type 4, Sendai virus, mumps virus, measles virus, respiratory syncytial virus, Newcastle disease virus, etc.), Bunyaviridae (such as California encephalitis virus, Hantavirus), Rhabdoviridae (such as rabies virus), Filoviridae (such as Ebola virus, Marburg virus), Coronaviridae (such as HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV, SARS-CoV-2, etc.), Astroviridae (such as astrovirus), Bornaviridae (such as Borna virus).

[0213] Specifically, the diseases related to the pathogen infection include but are not limited to: influenza, SARS, COVID-19, viral hepatitis (such as hepatitis A, hepatitis B, hepatitis C, hepatitis D, etc.), AIDS, rabies, dengue fever, Ebola virus disease, etc.

[0214] Specifically, the cardiovascular diseases include but are not limited to: coronary heart disease, peripheral arterial disease, atherosclerosis, ischemic heart disease, ischemic cardiomyopathy, myocardial infarction, heart failure, angina pectoris, myocarditis, hypercholesterolemia, hypertension, ischemia-reperfusion injury, cerebral ischemia (stroke), embolism (such as pulmonary embolism, renal embolism, hepatic embolism, gastrointestinal embolism or peripheral limb embolism) or myocardial ischemia, etc.

[0215] Specifically, the metabolic diseases include but are not limited to: diabetes (such as type I diabetes, type II diabetes or gestational diabetes), obesity, fatty liver (NASH or others), cachexia, hypercholesterolemia, gout and the like.

[0216] Specifically, the fibrotic diseases include but are not limited to: myocardial fibrosis, pulmonary fibrosis, renal fibrosis, postoperative stenosis, keloid formation, cirrhosis, biliary cirrhosis, scleroderma, etc.

[0217] In one embodiment of the present invention, the target protein is BRD4, and the disease is as described above, particularly hematological tumors (such as acute lymphoblastic leukemia, mixed lineage leukemia, multiple myeloma, Burkitt's lymphoma), hepatocellular carcinoma, triple-negative breast cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer, neuroblastoma, etc.

[0218] In a sixth aspect of the present invention, a method for designing and preparing a PROTAC for a target protein is provided, comprising the steps of using the compound of the first aspect or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuterated compound thereof as an E3 ligase recruitment element and connecting it to a target protein ligand via a linker.

[0219] Specifically, the target protein is as described in the second aspect of the present invention, such as BRD4.

[0220] Specifically, the BRD4 ligands are those described in the second aspect of the present invention, such as JQ1, OTX015, TEN-10, I-BET762, and CPI-0610.

[0221] In the seventh aspect of the present invention, a method for preventing and / or treating a disease mediated by a target protein is provided, comprising the step of administering to a subject in need thereof the compound of the second aspect or its pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuterated compound or the pharmaceutical composition of the fourth aspect.

[0222] Specifically, the target proteins are those described in the second aspect of the present invention.

[0223] Specifically, the disease is a disease that can be beneficially prevented and / or treated by inhibiting / degrading the target protein, such as those described in the fifth aspect of the present invention.

[0224] In one embodiment of the present invention, the target protein is BRD4, and the disease is as described in the fifth aspect of the present invention, in particular, hematological tumors (such as acute lymphoblastic leukemia, mixed lineage leukemia, multiple myeloma, Burkitt's lymphoma), hepatocellular carcinoma, triple-negative breast cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer, neuroblastoma, etc.

[0225] Specifically, the subject is a mammal, especially a human.

[0226] Specifically, the administration can be carried out by any suitable route of administration, such as enteral administration (e.g., oral, sublingual, rectal) or parenteral administration (e.g., intravenous, intramuscular, intranasal, intraocular, intracerebral, intravaginal, intraperitoneal, transdermal, subcutaneous, intradermal, respiratory tract administration, etc.).

[0227] The inventors of the present invention have creatively discovered a compound that recruits MDM2 through interaction with nucleolin (NCL). Further experiments have shown that this compound can serve as a novel recruitment element for MDM2 and can be used in the preparation of PROTACs. The inventors used this discovery to prepare PROTACs, and experimentally found that the prepared PROTACs can effectively mediate the degradation of target proteins through the ubiquitin-proteasome pathway, achieving the treatment of target protein-related diseases (such as tumors), and have very good application prospects in the field of medicine. BRIEF DESCRIPTION OF THE DRAWINGS

[0228] FIG1 shows the results of the experiment described in Example 1, which shows that NCL can bind to MDM2.

[0229] Figure 2 shows the results of the experiment described in Example 2, which shows that the compound of Formula I, Ori, relies on its interaction with NCL to recruit MDM2, and iSN04 can only bind to NCL but cannot rely on NCL to recruit MDM2.

[0230] FIG3 shows the results of the experiment described in Example 2, which shows that the compound of Formula I, Ori, can capture NCL and MDM2, while iSN04 can only capture NCL but not MDM2.

[0231] Figure 4 shows the results of the experiment described in Example 2, which shows that the compound of Formula I, Ori, can capture NCL and MDM2, and silencing NCL can block Ori from recruiting MDM2.

[0232] Figure 5 shows the results of the experiment described in Example 2, which shows that the compound of Formula I, Ori, does not affect the interaction between NCL and MDM2, but iSN04 blocks the binding of NCL to MDM2.

[0233] Figure 6 shows a schematic diagram of the possible mode of action of PROTAC formed by the compound of formula I as a recruitment element for MDM2.

[0234] Figure 7 shows the results of the experiment described in Example 4, which shows that the PROTAC prepared by the present invention can induce the formation of the MDM2-NCL-PROTAC-target protein quaternary complex.

[0235] Figure 8 shows the results of the experiment described in Example 5, which shows that the PROTAC (Ori-JQ1-1) prepared by the present invention can degrade BRD4.

[0236] Figure 9 shows the results of the experiment described in Example 5, which shows that the PROTACs (Ori-JQ1-2, Ori-JQ1-3 and Ori-JQ1-4) prepared by the present invention can degrade BRD4.

[0237] Figure 10 shows the results of the experiment described in Example 5, which shows that the PROTACs prepared by the present invention (Ger-JQ1, Ori-JQ1-5, CYD-JQ1-6, CYD-JQ1-7 and OriPh-JQ1-8) can degrade BRD4.

[0238] Figure 11 shows the results of the experiment described in Example 6, which shows that the PROTAC prepared by the present invention can promote the ubiquitination of BRD4.

[0239] Figure 12 shows the results of the experiment described in Example 7, which shows that the PROTAC prepared by the present invention relies on MDM2 and NCL to mediate the degradation of BRD4.

[0240] Figure 13 shows the results of the experiment described in Example 8, which shows that the PROTAC prepared by the present invention can inhibit the proliferation of liver cancer cells and promote the apoptosis of liver cancer cells.

[0241] Figure 14 shows the results of the experiment described in Example 8, which shows that the PROTAC prepared by the present invention can inhibit the proliferation of lung cancer cells and promote the apoptosis of lung cancer cells.

[0242] Figure 15 shows the results of the experiment described in Example 9, which shows that the PROTAC prepared by the present invention can inhibit tumor cell growth in vivo. DETAILED DESCRIPTION

[0243] Unless otherwise defined, all scientific and technical terms used in the present invention have the same meanings as commonly understood by one of ordinary skill in the art to which the present invention relates.

[0244] In the present invention, the term "aliphatic group" refers to a straight or branched hydrocarbon chain that is completely saturated or contains one or more unsaturated units, or a cyclic hydrocarbon group that is completely saturated or contains one or more unsaturated units (also referred to herein as "aliphatic ring", "cycloalkyl"), which is connected to the rest of the molecule by a single bond. Suitable aliphatic groups include, but are not limited to, straight or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl and mixtures thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, (cycloalkyl)alkenyl and the like. 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.

[0245] The term "alkyl" refers to a straight or branched hydrocarbon chain 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 by a cycloalkyl group, it is correspondingly a "cycloalkylalkyl" group, such as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, etc. If the alkyl group is substituted by an aryl group, it is correspondingly an "aralkyl" group, such as benzyl, diphenylmethyl, or phenethyl. If the alkyl group is substituted by a heterocyclic group, it is correspondingly a "heterocyclylalkyl" group. In the present invention, a C0 alkyl group refers to H, i.e., C 0-10 Alkyl (or C0-C 10 Alkyl) includes H and C 1-10 Alkyl (or C1-C 10 alkyl).

[0246] The term "alkylene" refers to a hydrocarbon group (divalent alkyl) formed by losing two hydrogen atoms from an alkane molecule, which can be a straight chain or branched chain and is connected to the rest of the molecule by a single bond. In this context, a typical alkylene group has 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 the present invention, a C0 alkylene group refers to a single bond, i.e., C 0-10 Alkylene (or C0-C 10 Alkylene) includes single bonds and C 1-10 Alkylene (or C1-C 10 alkylene).

[0247] The term "cycloalkyl" refers to alicyclic hydrocarbons, such as those containing 1 to 4 single rings and / or condensed rings, containing 3-18 carbon atoms, preferably 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantyl, etc.

[0248] The term "alkoxy" refers to a substituent formed by replacing the hydrogen of a hydroxy group with an alkyl group, such as an alkoxy group containing 1 to 10 carbon atoms, such as methoxy, ethoxy, propoxy, butoxy, and the like.

[0249] The term "alkylamino" refers to a substituent formed when one or both hydrogen atoms in an amino group (-NH2) are replaced by an alkyl group, such as an alkylamino group containing 1 to 10 carbon atoms, for example

[0250] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0251] The term "haloalkyl" refers to a group in which one or more hydrogen atoms in an alkyl group are replaced by a halogen atom (e.g., fluorine, chlorine, bromine or iodine), for example, -CHF2, -CH2F, -CF3, -CH2-CF3, -CH2CH2-CF3, -CH2CH2CH2-CF3.

[0252] The term "aryl" refers to a monocyclic or polycyclic free radical, including a polycyclic free radical containing a monocyclic aromatic group and / or a condensed aromatic group, such as a radical containing 1-3 monocyclic or condensed rings and 6-18 (e.g., 6, 8, 10, 12, 14, 16, 18) carbon ring atoms. 12 The aryl group refers to an aryl group containing 6 to 12 carbon ring atoms, such as phenyl, naphthyl, biphenyl, indenyl, etc.

[0253] The term "heterocyclyl" refers to a 3- to 18-membered non-aromatic ring group containing 2 to 17 carbon atoms and 1 to 10 heteroatoms. A heterocyclyl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused, spirocyclic, or bridged ring systems. A heterocyclyl group can be partially saturated (heteroaryl) or fully saturated (heterocycloalkyl). Suitable heteroaryl groups in the compounds of the present invention contain 1, 2 or 3 heteroatoms selected from N, O, S and P atoms, and include, for example, coumarin, including 8-coumarin, quinolyl, including 8-quinolyl, isoquinolyl, pyridinyl, pyrazinyl, pyrazolyl, pyrimidinyl, furanyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, imidazolyl, indolyl, isoindolyl, indazolyl, indolizinyl, phthalazinyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazolyl, pyridazinyl, triazinyl, cinnolinyl, benzimidazolyl, benzofuranyl, benzofurazolyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl and furopyridinyl. Suitable heterocycloalkyl groups in the compounds of the present invention contain 1, 2 or 3 heteroatoms selected from N, O or S atoms, and include, for example, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, oxathianyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxirane, thiirane, azepine, oxazepine, diazepine, Heptyl, triazepine, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, dihydroindole, 2H-pyranyl, 4H-pyranyl, dioxane, 1,3-dioxolane, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothiophenyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 3H-indolyl and quinolizinyl. In the present invention, for the optionally substituted heterocyclic group, the substituted position can be any suitable carbon atom or heteroatom, for example, for The substitution position of R can be any suitable carbon atom or nitrogen atom, which can be, for example

[0254] In the present invention, "D" refers to deuterium; "substituted by deuterium" means replacing one or more hydrogen atoms with a corresponding number of deuterium atoms.

[0255] It will be appreciated that, depending on the source of the chemical materials used in the synthesis, some variation in natural isotopic abundance will exist in the synthesized compounds. Therefore, the compounds of the present invention will inherently contain small amounts of deuterated isotopologues. 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, L.Z. et al., Comp Biochem Physiol Mol Integr Physiol, 1998, 119:725.

[0256] In the compounds of the present invention, any atom not designated as deuterium is present at its natural isotopic abundance. Unless otherwise indicated, when a position is specifically designated as "H" or "hydrogen," the position is understood to have hydrogen at its natural abundance isotopic composition. Similarly, unless otherwise indicated, when a position is specifically designated as "D" or "deuterium," the position is understood to have deuterium at an abundance of at least 3000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 45% deuterium incorporation).

[0257] As used herein, the term "isotopic enrichment factor" refers to the ratio between the isotopic abundance and the natural abundance of a particular isotope.

[0258] In other embodiments, the compounds of the invention have an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[0259] The term "isotopologue" refers to a substance wherein the chemical structure differs from a specific compound of the present invention only in its isotopic composition.

[0260] The term "pharmaceutically acceptable salts" includes acid addition salts and base addition salts.

[0261] The term "acid addition salt" includes, but is not limited to, salts derived from inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic and phosphonic acids, and salts derived from organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids and aliphatic and aromatic sulfonic acids. The present invention relates to the preparation of the present invention and the like.Therefore, these salts include but are not limited to sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, hydrochloride, hydrobromide, iodate, acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate and mesylate, also comprise amino acid whose salt such as arginate, gluconate, galacturonate etc.Acid addition salts can be prepared by making free alkali form contact with sufficient amount of required acid in a conventional manner.Free alkali form can be regenerated by making salt form contact with alkali, and separate this free alkali in a conventional manner.

[0262] The term "base addition salt" refers to salts formed with metals or amines, such as hydroxides of alkali metals and alkaline earth metals, or with organic amines. Examples of metals used as cations include, but are not limited to, sodium, potassium, magnesium, and calcium. Examples of suitable amines include, but are not limited to, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine (ethane-1,2-diamine), N-methylglucamine, 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 isolating the free acid in a conventional manner.

[0263] The term "stereoisomer" includes the presence of enantiomers, diastereomers and geometric isomers. Some compounds of the present invention have cyclic hydrocarbon groups that may be substituted on more than one carbon atom, in which case all geometric forms, including cis and trans forms, and mixtures thereof, are within the scope of the present invention.

[0264] The term "solvate" refers to a physical association of a compound of the invention with one or more solvent molecules. This physical association includes varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, a solvate can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Solvates include solution phases and isolatable solvates. Representative solvates include ethanolates, methanolates, and the like.

[0265] The term "prodrug" refers to a form of a compound of Formula I that is suitable for administration to a patient without undue toxicity, irritation, allergic reactions, etc., and is effective for its intended use, including acetal, ester, and zwitterion forms. The prodrug is transformed in vivo, for example, by hydrolysis in the blood, to yield the parent compound.

[0266] In the present invention, the term "oligonucleotide" is composed of 30 or fewer nucleotides (e.g., 5, 10, 15, 20, 25, 30) (deoxyribonucleotides and / or ribonucleotides), which are single-stranded or double-stranded, particularly single-stranded. The oligonucleotide may include chemical modifications, nucleic acid unit replacements, or linked functional groups; wherein the chemical modification is modification of at least one base, and the chemical modification includes at least one of phosphorylation, methylation, amination, sulfhydrylation, isotopization, phosphorothioate backbone modification, methoxy modification, and fluorination modification; the nucleic acid unit is replaced by at least one nucleic acid unit being replaced by LNA, UNA, or GNA; and the functional group includes at least one of a fluorescent group, a radioactive group, biotin, digoxigenin, a nanoluminescent material, a nucleic acid substance, or an enzyme marker.

[0267] In the present invention, the term "oligopeptide" refers to a peptide composed of 2-10 (e.g., 2, 3, 4, 5, 6, 8, 10) amino acids, "polypeptide" contains 11-50 (e.g., 15, 20, 30, 40, 50) amino acids, and "protein" contains more than 50 amino acids.

[0268] The terms "patient" or "subject" and the like are used interchangeably herein to refer to any animal or cell thereof to be treated according to the methods described herein, whether in vitro or in situ. Specifically, the aforementioned animals include mammals, e.g., rats, mice, guinea pigs, rabbits, dogs, monkeys or humans, particularly humans.

[0269] The term "treating" refers to preventing, curing, reversing, attenuating, alleviating, minimizing, inhibiting, suppressing and / or halting one or more clinical symptoms of a disease after onset of the disease.

[0270] The term "prevent" or "prevent" refers to treating a disease before it occurs to avoid, minimize, or make the onset or development of the disease more difficult.

[0271] The term "BRD4-mediated diseases" mainly refers to diseases associated with abnormal BRD4 activity, especially diseases that can be prevented and / or treated by inhibiting / degrading BRD4.

[0272] The term "tumor" refers to an abnormal mass of tissue, wherein the growth of the mass exceeds the growth of normal tissue and is not coordinated with the growth of normal tissue. Tumors can be "benign" or "malignant", depending on the following characteristics: the degree of cell differentiation (including morphology and function), growth rate, local invasion and metastasis. "Benign tumors" are usually well differentiated, characterized in that they grow slower than malignant tumors and remain confined to the site of origin. In addition, benign tumors do not have the ability to infiltrate, invade or metastasize to distant sites. In some cases, certain "benign" tumors may later lead to malignant tumors, which may be due to additional genetic changes in a subpopulation of the tumor's neoplastic cells, and these tumors are called "precancerous tumors". "Malignant tumors" are usually poorly differentiated (anaplastic) and have a characteristic rapid growth, accompanied by progressive infiltration, invasion and destruction of surrounding tissues. In addition, malignant tumors usually have the ability to metastasize to distant sites.

[0273] The term "cancer" refers to a malignant tumor (Stedman's Medical Dictionary, 25th ed.; Hensyled.; Williams & Wilkins: Philadelphia, 1990).

[0274] The term "autoimmune disease" refers to a disease caused by the body's immune response to its own antigens, resulting in damage to its own tissues.

[0275] The term "inflammation" refers to the body's defensive response to stimuli, manifested by redness, swelling, heat, pain, and functional impairment. It can be infectious inflammation caused by infection or non-infectious inflammation not due to infection, such as inflammation caused by an immune response (such as various types of hypersensitivity reactions and inflammation caused by some autoimmune diseases). The term "inflammatory disease" refers to diseases characterized by inflammation.

[0276] The term "diseases associated with pathogen infection" mainly refers to diseases caused by pathogen infection, which include symptoms of body damage caused by pathogen invasion and manifestations of infection response.

[0277] The term "cardiovascular disease" refers to a group of diseases involving the heart or blood vessels.

[0278] The term "metabolic disease" refers to diseases caused by the accumulation or deficiency of certain metabolic substances such as sugar, fat, protein, purine, calcium and copper when the biochemical processes in the body are disturbed.

[0279] The term "fibrosis" refers to a pathological process in which inflammation leads to necrosis of organ parenchymal cells, abnormal accumulation of extracellular matrix, and excessive deposition of extracellular matrix within the tissue. In severe cases, this can lead to structural destruction of the tissue and the development of organ sclerosis.

[0280] The disclosures of various publications, patents, and published patent specifications cited herein are incorporated by reference in their entirety.

[0281] The following will clearly and completely describe the technical solutions of the present invention in conjunction with the embodiments of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts shall fall within the scope of protection of the present invention.

[0282] The compounds Ori, Ger, CYD, and OriPh described in the following examples are examples of compounds of formula I, each having the following structures:

[0283] Example 1: NCL can bind to MDM2

[0284] Co-immunoprecipitation (Co-IP) is a classic method for studying protein interactions based on the specific interaction between antibodies and antigens.

[0285] 1. Lyse Hep3B liver cancer cells with IP lysis buffer (Thermo Scientific, Catalog No. 87788) and incubate with NCL antibodies overnight at 4°C. Add Protein A / G magnetic beads (Thermo Scientific, Catalog No. 88802) and incubate at room temperature with rotation for 2 hours. Wash NCL and its interacting protein complex bound to the beads with IP lysis buffer (Thermo Scientific, Catalog No. 87788). Add SDS-PAGE protein loading buffer (Beyotime, Catalog No. P0015) and heat to 100°C for 10 minutes. Adsorb the beads with a magnetic stand and transfer the supernatant to a fresh tube. Then, perform a western blot to detect whether NCL binds to MDM2. The immunoblotting protocol was as follows: protein samples were separated by SDS-PAGE electrophoresis and transferred to a PVDF membrane. The membrane was blocked with TBST buffer containing 5% skim milk for 1 hour at room temperature and then incubated overnight at 4°C with a primary antibody against MDM2 (purchased from Proteintech, Catalog No. 27883-1-AP) or a primary antibody against NCL (purchased from Cell Signaling Technology, Catalog No. 14574S). After washing with TBST, the membrane was incubated with an HRP-conjugated secondary antibody (purchased from Abiotech, Catalog No. AS014) at room temperature for 1 hour. Protein bands were visualized using an enhanced chemiluminescence detection kit (purchased from Abiotech, Catalog No. RM00021P). The results in Figure 1A demonstrate that NCL binds to MDM2.

[0286] 2. Mix 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) and incubate at 4°C for 7 hours. Then, add the antibody against NCL and continue incubation at 4°C overnight. Add Protein A / G magnetic beads (purchased from Thermo Scientific, Catalog No. 88802) and incubate at room temperature with rotation for 1.5 hours. Wash the beads three times with TBST buffer, add SDS-PAGE protein loading buffer (purchased from Beyotime, Catalog No. P0015), and heat to 100°C for 10 minutes. Adsorb the beads using a magnetic rack, and remove the supernatant to a fresh tube. Then, perform an immunoblot to detect whether NCL binds to MDM2. The results in Figure 1B demonstrate that NCL binds to MDM2.

[0287] Example 2: Compound Ori recruits MDM2 via interaction with NCL

[0288] 1. We prepared the C-14 hydroxyl group biotinylated compound of formula I Ori (Bio-Ori-1), and the specific preparation steps are as follows:

[0289] Under nitrogen, EDCI (166 mg, 0.87 mmol) and DMAP (106 mg, 0.87 mmol) were added to a solution of compound 1 (100 mg, 0.29 mmol) and compound 2 (70 mg, 0.29 mmol) in dimethylformamide (DMF, 2 ml). The mixture was stirred at room temperature for 16 hours, and the reaction progress was monitored by LCMS. After completion, 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, Phase B: ACN; flow rate: 20 mL / min; gradient: 34%-44%; Retention Time: 7.6-8.3 min of 17 min). Pure fractions were combined and lyophilized under reduced pressure to obtain 34 mg of Bio-Ori-1 as a white solid, with a yield of 20.17%.

[0290] LCMS: m / z=591.6[M+H] + ,t R =8.447min.Purity:100%(254nm).

[0291] 1 H 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).

[0292] 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.

[0293] 2. We also prepared the compound of formula I Ori (Bio-Ori-2) with biotinylated C-1 hydroxyl group. The specific preparation steps are as follows:

[0294] 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 aqueous sodium bicarbonate solution (15 mL*2), water (10 mL), 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 obtain compound 2 (1.0 g, 90.9%) as a white solid.

[0295] LCMS: m / z = 387.2 [M-OH] + ,Rt=1.894min.Purity:92.4%(214nm).

[0296] Under N2, EDCI (1.56 g, 8.16 mmol) and DMAP (1 g, 8.16 mmol) were added to a solution of compound 2 (1.1 g, 2.72 mmol) and compound 3 (1 g, 4.08 mmol) in DMF (10 ml). 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 um water (0.1% FA)-MeCN, 5-95%, 60 mL / min) to obtain compound 4 (317 mg, 17.84%) as a white solid.

[0297] LCMS: m / z = 613.3 [M-OH] +,Rt=1.610min.Purity:96.31%(214nm).

[0298] A solution of compound 4 (317 mg, 0.5 mmol) in hydrochloric acid (2%, 2 mL) and THF (2 mL) was stirred under N2 at room temperature for 2 hours. LCMS showed that 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 Xtimate 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.

[0299] LCMS: m / z = 573.6 [M-OH] + ,Rt=8.691min.Purity:100%(214nm).

[0300] 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).

[0301] 13C 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.

[0302] 3. The process of the pull-down experiment is to fix a substance of known identity (bait) on a carrier and use it to capture the binding protein (prey) and the protein complex that interacts with the binding protein from a complex mixture.

[0303] 6 μg / mL recombinant human NCL (rhNCL) and 6 μg / mL recombinant human MDM2 (rhMDM2) were mixed and incubated at 4°C for 7 hours. Subsequently, 400 nM of Bio-Ori-1, Bio-Ori-2, biotinylated CRO (Bio-CRO: CCTCCTCCTCCTTCTCCTCCTCCC, SEQ ID NO: 4, negative control), or iSN04 (Bio-iSN04: AGATTAGGGTGAGGGTGA, SEQ ID NO: 5) were added and incubated at 4°C for 6 hours. Streptavidin-agarose beads (purchased from Cytiva, Catalog No. 17511301) were added and incubated at 4°C overnight. The beads were washed four times with TBST buffer and SDS-PAGE protein loading buffer (purchased from Beyotime, Catalog No. P0015) was added and heated to 100°C for 10 minutes. The supernatant was collected after centrifugation. The pull-down products were then detected by immunoblotting. The results in Figures 2A and 2B demonstrate that Ori can bind to NCL but not MDM2; however, in the presence of NCL, Ori can recruit MDM2 in a NCL-dependent manner. The results in Figure 2C demonstrate that CRO can neither bind to NCL nor recruit MDM2. The results in Figure 2D demonstrate that iSN04 can only bind to NCL but cannot recruit MDM2 in a NCL-dependent manner.

[0304] 4. Hep3B liver cancer cells were lysed with IP lysis buffer (purchased from Thermo Scientific, cat. no. 87788) and 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. Streptavidin agarose beads (purchased from cytiva, cat. no. 17511301) were then added and incubated at 4°C overnight. After washing the beads with Bio-Ori-1, Bio-Ori-2, Bio-CRO, or Bio-iSN04 and the captured proteins multiple times with IP lysis buffer (Thermo Scientific, Catalog No. 87788), SDS-PAGE protein loading buffer (Beyotime, Catalog No. P0015) was added and heated to 100°C for 10 minutes. After centrifugation, the supernatant was collected, representing the pull-down product. The pull-down product was analyzed by immunoblotting. The results in Figures 3A and 3B demonstrate that Ori can capture NCL and MDM2; Figure 3C demonstrates that CRO cannot capture NCL and MDM2; and Figure 3D demonstrates that iSN04 can capture NCL but not MDM2.

[0305] 5. Hep3B hepatoma cells were incubated with the solvent DMSO (Veh) or 1 μM Bio-Ori-1 for 12 hours. After cell lysis, the supernatant was incubated with streptavidin-agarose beads (purchased from Cytiva, Catalog No. 17511301) at 4°C overnight. Bio-Ori-1 bound to the beads and its captured proteins were washed multiple times with IP lysis buffer (purchased from Thermo Scientific, Catalog No. 87788). SDS-PAGE protein loading buffer (purchased from Beyotime, Catalog No. P0015) was added and heated to 100°C for 10 minutes. After centrifugation, the supernatant was collected, which is the pull-down product. The pull-down product was detected by immunoblotting. As shown in Figure 4A, Ori can capture NCL and MDM2.

[0306] Hep3B hepatoma cells were transfected with negative control siRNA (siNC: UUCUCCGAACGUGUCACGUTT, SEQ ID NO: 1) or NCL siRNA (siNCL: GGAUGACGACGACGACGAAGATT, SEQ ID NO: 2). 48 hours later, the cells were incubated with 1 μM Bio-Ori-1 for 12 hours, lysed, and the supernatant incubated with streptavidin-agarose beads overnight at 4°C. Bio-Ori-1 bound to the beads and its captured proteins were washed multiple times with IP lysis buffer (Thermo Scientific, Cat. No. 87788). SDS-PAGE protein loading buffer (Beyotime, Cat. No. P0015) was added and heated to 100°C for 10 minutes. After centrifugation, the supernatant was collected, representing the pull-down product, and analyzed by immunoblotting. The results, as shown in Figure 4B, show that silencing NCL blocked MDM2 recruitment by Ori.

[0307] 7. Hep3B cancer cells were lysed with IP lysis buffer (Thermo Scientific, Catalog No. 87788) and incubated with different concentrations of Ori or iSN04 (0 μM, 1 μM, 5 μM, 10 μM, and 20 μM) at 4°C for 6 hours. Antibodies against NCL were then added and incubated at 4°C overnight. Protein A / G magnetic beads (Thermo Scientific, Catalog No. 88802) were added and incubated at room temperature with rotation for 1.5 hours. NCL bound to the beads and the captured proteins were washed with IP lysis buffer (Thermo Scientific, Catalog No. 87788). SDS-PAGE protein loading buffer (Beyotime, Catalog No. P0015) was added and heated to 100°C for 10 minutes. The beads were adsorbed using a magnetic rack, and the supernatant was transferred to a fresh tube. Immunoblotting was then performed to examine whether Ori or iSN04 affected the interaction between NCL and MDM2. The results in Figure 5A indicate that Ori does not affect the interaction between NCL and MDM2. The same experiment was performed using other compounds of Formula I, and the results were similar to those of Ori. However, the results in Figure 5B indicate that iSN04 blocks the binding of NCL to MDM2.

[0308] 8. The above results indicate that the compound of Formula I relies on its interaction with NCL to recruit MDM2. Although iSN04 interacts with NCL, it cannot rely on its interaction with NCL to recruit MDM2. Our further analysis found that the compound of Formula I did not affect the binding of NCL to MDM2, but iSN04 blocked the binding of NCL to MDM2. These data tell us that not all molecules that interact with NCL can be used to recruit MDM2. Whether the interacting molecule of NCL can recruit MDM2 depends on whether the molecule affects the formation of a complex between NCL and MDM2. We used AlphaFold2 to simulate the three-dimensional structure of the NCL-MDM2 complex and used HDOCK to predict the conformation of the interaction between the compound of Formula I (such as Ori) and the NCL-MDM2 complex. The results showed that the compound of Formula I does rely on its interaction with NCL to recruit MDM2. The possible mode of action is shown in Figure 6A. Therefore, we believe that the compound of Formula I can form a PROTAC as an MDM2 recruitment element. The possible mode of action is shown in Figure 6B.

[0309] Example 3: Preparation of PROTAC molecules based on compounds of formula I

[0310] Bromodomain-containing protein 4 (BRD4) is a bromodomain-containing protein and a member of the bromodomain and extraterminal domain (BET) protein family. BRD4 typically recognizes acetylated histones and localizes to the promoter or enhancer regions of target genes, initiating and maintaining the expression of tumor-related genes. BRD4 can influence physiological processes such as the cell cycle, proliferation, and apoptosis, playing a crucial role in tumor cell infiltration, metastasis, and malignant progression, making it a potential therapeutic target for various tumors.

[0311] In this example, the compound of formula I was used as the E3 ligase recruitment element and the BRD4 inhibitor JQ1 was used as an example of the target protein ligand to prepare several PROTACs with different structures, as follows:

[0312] 1. Using the compound Ori of formula I as the E3 ligase recruitment element and the BRD4 inhibitor JQ1 as an example of the target protein ligand, a PROTAC for degrading BRD4 (hereinafter referred to as Ori-JQ1-1) was prepared.

[0313] The specific preparation steps are as follows:

[0314] Compound 1 (1 g, 2.19 mmol) was added to a hydrochloric acid / 1,4-dioxane (8 mL) solution and stirred at room temperature for 2 hours while monitoring by LCMS. The mixture was concentrated in vacuo to afford 1.2 g of a yellow solid compound 2 (crude sample), which was used directly in the next reaction without purification.

[0315] LCMS: m / z = 401.2 [M+H] + ,Rt=1.581min,purity:100%(214nm)

[0316] To a solution of compound 2 (500 mg, 1.25 mmol) in dimethylformamide (DMF, 10 ml) were added HATU (713 mg, 1.88 mmol), compound 3 (367 mg, 1.88 mmol), and N,N-diisopropylethylamine (DIEA, 485 mg, 3.75 mmol). The mixture was stirred at room temperature for 2 hours and monitored by LCMS. After the reaction was complete, the mixture was diluted with 10 ml of EA, then washed with water (3 x 10 mL) and brine (3 x 10 mL). The organic layer was dried over Na2SO4 and concentrated and purified by flash column chromatography using dichloromethane / methanol (10:1) as the eluent to afford 550 mg of compound 4 as a yellow solid in a 73% yield.

[0317] LCMS: m / z=542.3[M+H] + ,Rt=1.750min,purity:100%(214nm).

[0318] 1 HNMR (400MHz, DMSO-d6) δ8.16 (t, J = 5.6Hz, 1H), 7.50-7.48 (m, 2H), 7.43-7.41 (m, 2H), 4.52-4.48 (m, 1H), 3.57 (s, 3H), 3.29-3. 15(m,2H),3.14-3.04(m,2H),2.60(s,3H),2.41(s,3H),2.28-2.27(m,2H),1.62(s,3H),1.55-1.37(m,4H),1.31-1.24(m,4H).

[0319] Compound 4 (500 mg, 0.92 mmol) was dissolved in 1,4-dioxane (5 ml) and water (2 ml). LiOH.H2O (110 mg, 4.61 mmol) was added and stirred at room temperature for 2 hours. The reaction was monitored by LCMS until completion. The pH of the mixture was then slowly adjusted to 5 with 1 M HCl at low temperature. The mixture was then extracted with 10 ml of EA (4 times) (10 mL x 4). Finally, the mixture was concentrated in vacuo to obtain 500 mg of a yellow solid, compound 5 (crude), which was used directly in the next reaction without purification.

[0320] LCMS: m / z = 528.2 [M+H] + ,Rt=1.333min,purity:100%(214nm)

[0321] 1 HNMR (400MHz, DMSO-d6) δ11.95(s,1H),8.16(t,J=5.6Hz,1H),7.50-7.48(m,2H),7.43-7.41(m,2H),4.52-4.50(m,1H),3.57(s ,1H),3.29-3.17(m,2H),3.17-3.11(m,2H),2.62(s,3H),2.41(s,3H),2.21-2.17(m,2H),1.62(s,3H),1.51-1.41(m,4H),1.29 -1.26(m,4H).

[0322] Compound 5 (100 mg, 0.19 mmol), EDCI (110 mg, 0.57 mmol), and DMAP (70 mg, 0.57 mmol) were dissolved in DCM (6 ml). Compound 6 (70 mg, 0.19 mmol) was added and stirred at room temperature for 4 hours. The reaction was monitored by LCMS until completion. After concentration and purification by reverse phase chromatography [ACN / water (FA: 0.02%): 5% to 30%], 130 mg of Ori-JQ1-1 as a white solid was obtained in a 78% yield.

[0323] LCMS: m / z=874.6[M+H] + ,Rt=11.048min,purity:100%(214nm)

[0324] 1HNMR(400MHz,DMSO-d6)δ8.16(t,J=5.6Hz,1H),7.50–7.48(m,2H),7.43–7.41(m,2H),5.99 (s,1H),5.88–5.44(m,3H),5.60(s,1H),4.49–4.52(m,1H),4.40(s,1H),4.08–4.06(m,1H), 3.84–3.82(m,1H),3.48-3.56(m,1H),3.31–3.16(m,3H),3.09–3.07(m,2H),2.97–2.94(m,1 H),2.61(s,3H),2.49–2.45(m,1H),2.41(s,3H),2.18–2.09(m,2H),2.09–1.98(m,1H),1.83 -1.88(m,1H),1.77–1.67(m,1H),1.62(s,3H),1.56–1.37(m,7H),1.33–1.18(m,6H),1.12(d,J=6.9Hz,1H),0.99(s,6H).

[0325] 13 C NMR(101MHz,DMSO-d6)δ207.64,172.10,169.77,163.46,155.60,151.34,150.27,137.23,1 35.71,132.73,131.18,130.58,128.94,119.80,96.20,74.51,73.63,72.04,62.96,62.25,5 9.51,54.38,54.34,54.31,41.88,40.93,40.62,40.41,40.20,39.99,39.78,39.57,39.37,38.11,34.41,33.80,33.20,30.75,29.53,28.63,26.58,24.55,22.14,20.19,14.53,13.16.

[0326] 2. Using the compound Ori of formula I as the E3 ligase recruitment element and the BRD4 inhibitor JQ1 as an example of the target protein ligand, another PROTAC that degrades BRD4 (hereinafter referred to as Ori-JQ1-2) was prepared.

[0327] The specific preparation steps are as follows:

[0328] A mixture of compound 1 (1 g, 2.19 mmol) in HCl / dioxane (4 M, 8 mL) was stirred at room temperature for 2 hours. LCMS indicated the reaction was complete. The mixture was concentrated in vacuo to afford compound 2 (1.2 g, crude product) as a yellow solid, which was used in the next step without further purification.

[0329] LCMS: [M+H] + =401.2, Rt=1.581min, purity: 100% (214nm)

[0330] To a solution of compound 2 (500 mg, 1.25 mmol) in DMF (10 mL) was added HATU (713 mg, 1.88 mmol), compound 3 (367 mg, 1.88 mmol) and DIEA (485 mg, 3.75 mmol) at 0°C. The mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS. After completion of the reaction, the mixture was diluted with EA (50 mL), washed with water (3*20 mL) and brine (3*20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography eluting with DCM / MeOH (10:1) to give compound 4 (550 mg, 73% yield) as a yellow solid.

[0331] LCMS: [M+H] + =542.3, Rt=1.750min, purity:100% (214nm).

[0332] 1HNMR(400MHz,DMSO-d6)δ8.16(t,J=5.6Hz,1H),7.50-7.41(m,4H),4.48-4.52(m,1H),3.57(s,3H),3.29–3.15(m,2H ),3.14–3.04(m,2H),2.60(s,3H),2.41(s,3H),2.28-2.27(m,2H),1.62(s,3H),1.55–1.37(m,4H),1.31–1.24(m,4H).

[0333] To a solution of compound 4 (500 mg, 0.92 mmol) in dioxane (5 mL) and water (2 mL) was added LiOH.H2O (110 mg, 4.61 mmol). The mixture was stirred at room temperature for 2 hours. LCMS showed that the reaction was complete. The pH value was slowly adjusted to 5 with HCl (1 M) at low temperature. The mixture was extracted with EA (10 mL × 4). The combined organics were concentrated in vacuo to give compound 5 (500 mg, crude product) as a yellow solid, which was used in the next step without further purification.

[0334] LCMS: [M+H] + =528.2, Rt=1.333min, purity: 100% (214nm)

[0335] 1 HNMR(400MHz,DMSO-d6)δ11.95(s,1H),8.16(t,J=5.6Hz,1H),7.50–7.41(m,4H),4.48–4.50(m,1H),3.57(s,1H),3.29–3.17(m ,2H),3.16–3.04(m,2H),2.62–2.57(m,3H),2.41(s,3H),2.21-2.17(m,2H),1.62(s,3H),1.51–1.41(m,4H),1.27–1.17(m,5H).

[0336] To a solution of compound 5 (200 mg, 0.38 mmol), EDCI (217 mg, 1.14 mmol), and DMAP (139 mg, 1.14 mmol) in DCM (6 mL) was added compound 6 (153 mg, 0.38 mmol), and the mixture was stirred at room temperature for 4 hours. LCMS indicated the reaction was complete. The mixture was concentrated and purified by reverse phase chromatography [acetonitrile / water / FA (0.02%): 60% to 90%] to afford compound 7 (80 mg, 23% yield) as a white solid.

[0337] LCMS: [M+H] + =914.5, Rt = 6.99min, purity: 100% (214nm)

[0338] 1HNMR (400MHz, DMSO-d6) δ8.16 (s, 1H), 7.49–7.40 (m, 4H), 5.99 (s, 1H), 5.72–5.69 (m, 1H), 5.60 (d, J = 7. 2Hz,1H),4.83(s,1H),4.61(s,1H),4.54–4.42(m,1H),4.21–4.20m,1H),3.99–3.97(m,1H),3.61–3.58( m,1H),3.26–3.03(m,6H),2.99–2.97(m,1H),2.59(s,3H),2.41(s,3H),2.20(s,2H),1.92(s,2H),1.62( s,3H),1.55–1.47(m,4H),1.42–1.40(m,5H),1.33(s,4H),1.26(s,4H),1.13(s,3H),1.06–1.05(m,6H).

[0339] To a solution of compound 7 (80 mg, 0.087 mmol) in THF (2 mL) was added hydrochloric acid (0.5 mL, 2%). The mixture was stirred at room temperature for 2 hours. LCMS showed that the reaction was complete. The pH was slowly adjusted to 7-8 with NaHCO3 (saturated aqueous solution) at low temperature. The mixture was extracted with EA (5 mL*4). The organic layer was concentrated, and the residue was purified by reverse phase chromatography [ACN / water / FA (0.02%): 5% to 50%] to give Ori-JQ1-2 (40 mg, 53% yield) as a white solid.

[0340] LCMS: [M+H] + =874.5, Rt = 6.11min, purity: 100% (214nm)

[0341] 1HNMR(400MHz,DMSO-d6)δ8.16(s,1H),7.49–7.41(m,4H),6.93(s,1H),6.11–6.04(m,2H),5.97(s,1H),5. 55(d,J=4.8Hz,1H),4.77(s,1H),4.60–4.58(m,1H),4.50–4.48(m,1H),4.18–4.16(m,1H),4.01–3.98(m, 1H),3.56–3.52(m,1H),3.30–3.00(m,6H),2.94–2.91(m,1H),2.59(s,3H),2.41(s,3H),2.24–2.20(m,2H ),1.95(s,2H),1.62(s,3H),1.52–1.37(m,6H),1.36–1.31(m,3H),1.27-1.25(m,5H),1.06–1.05(m,6H).

[0342] 13 CNMR(101MHz,DMSO-d6)δ208.90,172.40,169.80,163.46,152.07,150.28,137.24,135.72, 131.19,130.57,130.28,130.04,128.91,119.98,97.29,75.05,73.43,72.88,62.86,61.61, 59.76,54.39,51.84,43.04,41.06,40.71,40.30,39.56,39.36,38.85,38.15,37.92,34.32,33.65,32.77,30.04,29.58,28.65,26.49,25.26,24.64,21.94,18.04,14.53,13.16,11.76.

[0343] 3. Using the compound Ori of formula I as the E3 ligase recruitment element and the BRD4 inhibitor JQ1 as an example of the target protein ligand, a PROTAC that degrades BRD4 (hereinafter referred to as Ori-JQ1-3) was prepared.

[0344] The specific preparation steps are as follows:

[0345] To a solution of compound 1 (400 mg, 1 mol) in DMF (5 mL) were added HATU (760 mg, 2 mmol) and compound 2 (554 mg, 2 mmol). DIPEA (388 mg, 3 mmol) was added dropwise to the reaction mixture at 0°C. The reaction was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with EA:PE = 0% to 20% to 50%) to give compound 3 as a yellow solid (500 mg, 75.90% yield).

[0346] LCMS: m / z=661.86[M+H] + , Rt=1.79min, purity: 51.8% (254nm).

[0347] To a solution of compound 3 (240 mg, 0.36 mmol) in MeOH (2.5 mL) and H2O (1.5 mL) was added LiOH (75 mg, 3.6 mmol). The mixture was stirred at 30 ° C. under a nitrogen atmosphere for 6 hours. LCMS showed that the reaction was complete. The mixture was concentrated in vacuo to remove methanol. The pH of the residue was adjusted to 3 with HCl (1 M). The mixture was filtered to obtain compound 4 (200 mg, yield: 91.07%) as a yellow solid.

[0348] LCMS: m / z=604.2[M+H] + , Rt=1.482min, purity:84.51% (254nm).

[0349] To a solution of compound 4 (100 mg, 0.17 mmol) and compound 5 (78 mg, 0.22 mmol) in DMF (1 mL) was added DMAP (21 mg, 0.17 mmol) and EDCI (98 mg, 0.51 mmol). The mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. LCMS showed that the reaction was complete. The mixture was filtered. The residue was purified by prep-HPLC to give Ori-JQ1-3 as a white solid (32 mg, 20.43% yield).

[0350] LCMS: m / z = 950.8 [M+H] + , Rt=10.392min, purity:96.65% (254nm).

[0351] 1H NMR (400MHz, DMSO-d6) δ8.27(t,J=5.5Hz,1H),7.52-7.39(m,4H),6.00(s,1H),5.90-5.82(m,2H),5.80( s,1H),5.61(s,1H),4.54-4.47(m,1H),4.39(d,J=5.1Hz,1H),4.09-4.04(m,1H),3.85-3.81(m,1H),3.6 1-3.41(m,14H),3.29-3.17(m,4H),2.99-2.95(m,1H),2.59(s,3H),2.43-2.34(m,5H),2.07-2.03(m,1H ),1.87-1.83(m,1H),1.73-1.65(m,1H),1.62(s,3H),1.55-1.41(m,3H),1.35-1.09(m,4H),0.99(s,6H).

[0352] 4. Using the compound Ori of formula I as the E3 ligase recruitment element and the BRD4 inhibitor JQ1 as an example of the target protein ligand, a PROTAC that degrades BRD4 (hereinafter referred to as Ori-JQ1-4) was prepared.

[0353] The specific preparation steps are as follows:

[0354] To a mixture of compound 1 (2.0 g, 7.5 mmol) and Cs2CO3 (3.6 g, 11 mmol) in DMF (40 mL) was added CH3I (0.55 mL, 9 mmol) at room temperature. The reaction mixture was stirred at room temperature under nitrogen for 16 hours. LCMS showed that the reaction was complete. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic layer was washed with a saturated aqueous NaCl solution (100 mL x 3). The organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to give crude compound 2 as a brown solid (2.0 g, 98%), which was used in the next step without further purification.

[0355] 1 H NMR (400MHz, DMSO-d6) δ3.59(s,3H),3.28-3.21(m,2H),3.21-3.07(m,3H),2.06-1.97(m,2H),1.94-1.86(m,2H),1.55-1.46(m,2H),1.38(s,9H).

[0356] To a solution of compound 2 (2 g, 7.06 mmol) in dioxane (10 mL) was added a solution of HCl in dioxane (4 M, 10 mL). The mixture was stirred at room temperature for 2 hours. TLC indicated that the reaction was complete. The mixture was concentrated under reduced pressure to give crude compound 3 (1.4 g) as a white solid, which was used in the next step without further purification.

[0357] 1 H NMR(400MHz,DMSO-d6)δ9.03-8.78(m,2H),3.58(s,3H),3.01-2.92(m,2H),2.92-2.8 4(m,2H),2.12-2.02(m,2H),2.01-1.90(m,2H),1.82-1.72(m,2H),1.71-1.61(m,2H).

[0358] To a solution of compound 4 (1.7 g, 3.73 mmol) in DCM (10 mL) was added TFA (10 mL). The mixture was stirred at room temperature for 2 hours. LCMS showed that the reaction was complete. The mixture was concentrated in vacuo to give crude compound 5 (1.45 g), a yellow solid, which was used in the next step without further purification.

[0359] LCMS: m / z = 401.0 [M+H] + ,Rt=1.257min,Purity:74.48%(214nm).

[0360] To a DMF (20 mL) solution of compound 5 (0.5 g, 1.25 mmol) and compound 3 (547.5 mg, 2.5 mmol) was added HATU (950 mg, 2.5 mmol) and DIEA (322.5 mg, 2.5 mmol). The mixture was stirred at room temperature under an Ar atmosphere for 2 hours. LCMS showed that the reaction was complete. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic layer was washed with water (30 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (eluted with MeOH: DCM = 10%) to give compound 6 (yellow solid, 600 mg, 84.99% yield).

[0361] LCMS: m / z=566.2[M+H] + ,Rt=1.360min,Purity:81.35%(214nm).

[0362] To a solution of compound 6 (550 mg, 0.97 mmol) in MeOH (6 mL) and H2O (6 mL) was added LiOH (232.8 mg, 9.7 mmol). The mixture was stirred at room temperature for 2 hours. LCMS showed that the reaction was complete. The mixture was concentrated in vacuo to remove methanol. The pH of the residue was adjusted to 5 with HCl (1 M). The mixture was filtered to obtain crude compound 7 (500 mg) as a yellow solid.

[0363] LCMS: m / z=552.2[M+H] + ,Rt=1.272min,Purity:76.87%(214nm).

[0364] To a DMF (20 mL) solution of compound 7 (0.45 g, 0.82 mmol) and compound 8 (322.54 mg, 1.64 mmol) was added HATU (623.2 mg, 1.64 mmol) and DIEA (211.56 mg, 1.64 mmol). The mixture was stirred at room temperature under an Ar atmosphere for 2 hours. LCMS showed that the reaction was complete. The mixture was diluted with water (40 mL) and extracted with ethyl acetate (50 mL x3). The organic layer was washed with water (40 mL x3), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (eluted with MeOH:DCM=10%) to give compound 9 (yellow solid, 500 mg, 88.25% yield).

[0365] LCMS: m / z = 692.2 [M+H] + ,Rt=1.19min,Purity:65.37%(214nm).

[0366] To a solution of compound 9 (250 mg, 0.362 mmol) in MeOH (6 mL) and H2O (6 mL) was added LiOH (86.88 mg, 3.62 mmol). The mixture was stirred at room temperature for 2 hours. LCMS showed that the reaction was complete. The mixture was concentrated in vacuo to remove MeOH. The pH of the residue was adjusted to 6 with HCl (1 M). The mixture was filtered to obtain crude compound 10 (210 mg) as a yellow solid.

[0367] LCMS: m / z=677.2[M+H] + ,Rt=1.257min,Purity:79.41%(214nm).

[0368] To a solution of compound 10 (100 mg, 0.148 mmol) in DMF (5 mL) were added EDCI (56.74 mg, 0.296 mmol), compound 11 (75.43 mg, 0.207 mmol), and DMAP (36.11 mg, 0.296 mmol). The mixture was stirred at room temperature under an Ar atmosphere for 16 hours. LCMS showed that the reaction was complete. The mixture was filtered. The filtrate was purified by prep-HPLC to obtain Ori-JQ1-4 as a white solid (33.1 mg, 21.86% yield).

[0369] LCMS: m / z = 1023.6 [M+H] + ,Rt=10.853min,Purity:100%(214nm).

[0370] 1 H NMR(400MHz,DMSO-d6)δ7.53-7.46(m,2H),7.46-7.40(m,2H),6.00(s,1H),5.91-5.79(m,3H),5.61(s,1H),4.60-4.52(m,1H), 4.44-4.37(m,1H),4.33-4.22(m,1H),4.13-4.02(m,1H),3.92-3.78(m,1H),3.68-3.40(m,6H),3.39-3.34(m,2H),3.30-3.18(m ,3H),2.99-2.82(m,2H),2.59(s,3H),2.55-2.51(m,3H),2.41(s,3H),2.12-2.07(m,2H),2.07-1.82(m,7H),1.76-1.66(m,2H), 1.63(s,3H),1.61-1.56(m,1H),1.56-1.40(m,5H),1.38-1.27(m,2H),1.27-1.18(m,1H),1.16-1.10(m,1H),1.03-0.97(m,6H).

[0371] 5. Using the compound Ger of formula I as the E3 ligase recruitment element and the BRD4 inhibitor JQ1 as an example of the target protein ligand, a PROTAC that degrades BRD4 (hereinafter referred to as Ger-JQ1) was prepared.

[0372] The specific preparation steps are as follows:

[0373] To a DCM (50 mL) solution of INT-1 (10 g, 21.92 mmol) was added TFA (20 mL). The mixture was then stirred at room temperature under an Ar atmosphere for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to give INT-2 (brown oil, 10 g (crude product)).

[0374] LCMS: m / z = 401.0 [M+H] + ,Rt=1.533min,Purity:52.88%(214nm).

[0375] To a solution of INT-2 (3 g, 7.48 mmol) and N-tert-butyloxycarbonyl-1,3-propanediamine (1.56 g, 8.98 mmol) in DMF (30 mL) were added HATU (3.45 g, 8.98 mmol) and DIEA (2.89 g, 22.44 mmol). The mixture was then stirred at room temperature under an Ar atmosphere for 1 hour. After completion of the reaction, the mixture was diluted with NH4Cl (saturated, 50 mL) and extracted with EA (50 mL*3). The organic layer was washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EA:PE = 50% to obtain INT-3 (white solid, 3 g, 71.94% yield).

[0376] LCMS: m / z=557.1[M+H] + ,Rt=1.683min,Purity:12.55%(214nm).

[0377] To a DCM (10 mL) solution of INT-3 (1 g, 1.79 mmol) was added TFA (2 mL). The mixture was then stirred at room temperature under an Ar atmosphere for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to give INT-4 (yellow oil, 1.5 g (crude product)).

[0378] LCMS: m / z=457.2[M+H] + ,Rt=1.275min,Purity:62.42%(214nm).

[0379] To a solution of INT-5 (2 g, 5.49 mmol) in DCE (25 mL) were added PPTS (690 mg, 2.74 mmol) and INT-6 (7.14 g, 54.88 mmol). The mixture was then stirred overnight at 80 ° C under an Ar atmosphere. After completion of the reaction, the mixture was concentrated in vacuo and purified by reverse phase chromatography [ACN / water): 35% to 40%] to give INT-7 as a white solid (138 mg, 5.26% yield).

[0380] LCMS: m / z=477.4[M+H] + ,Rt=9.193min,Purity:71.40%(214nm).

[0381] To a solution of INT-7 (138 mg, 0.31 mmol) in DMF (3 mL) was added DIEA (80 mg, 0.62 mmol), INT-4 (215 mg, 0.47 mmol) and HATU (236 mg, 0.62 mmol). The mixture was then stirred at room temperature under an Ar atmosphere for 0.5 h. After completion of the reaction, the mixture was concentrated in vacuo and purified by reverse phase chromatography [ACN / water (10 mmol NH4HCO3 / H2O): 52% to 58%] to afford Ger-JQ1 as a white solid (17.31 mg, 6.29% yield).

[0382] LCMS: m / z = 915.9 [M+H] + ,Rt=10.55min,Purity:100%(214nm).

[0383] 1 H NMR (400MHz, DMSO-d6) δ8.19-8.16(m,1H),7.65-7.62(m,1H),7.48(d,J=8.8Hz,2H),7.41(d,J=8.6Hz,2 H),5.99(s,1H),5.66–5.59(m,2H),4.84(s,1H),4.53-4.50(m,1H),4.43(d,J=5.1Hz,1H),4.15-4.12(m ,1H),3.85(d,J=9.8Hz,1H),3.62(m,1H),3.33(s,1H),3.29–2.99(m,7H),2.59(s,3H),2.48–2.37(m,4H ),1.91(d,J=6.4Hz,3H),1.75–1.65(m,2H),1.62(s,3H),1.57–1.21(m,14H),1.15(s,1H),1.04(s,6H).

[0384] 5. Using the compound Ori of formula I as the E3 ligase recruitment element and the BRD4 inhibitor JQ1 as an example of the target protein ligand, a PROTAC that degrades BRD4 (hereinafter referred to as Ori-JQ1-5) was prepared.

[0385] The specific preparation steps are as follows:

[0386] At 0 ° C, NaH (66 mg, 1.64 mmol) was added to a solution of compound 1 (500 mg, 1.37 mmol) in DMF (5 mL). The mixture was stirred at 0 ° C, N2 for 2 hours. To the reaction mixture was added tert-butyl (6-iodohexyl)carbamate (536 mg, 1.64 mmol). The mixture was stirred at 30 ° C for 16 hours. The reaction was quenched with water (20 mL) and extracted with EtOAc (30 mL × 3). The organic phase was concentrated in vacuo. The residue was purified by flash column chromatography (elution: MeOH in DCM = 0% to 10%) to give the product as a yellow solid (240 mg, 31.45% yield).

[0387] LCMS: m / z=564.6[M+H] + ,Rt=2.321min,Purity:2.326%(214nm).

[0388] To a solution of compound 2 (240 mg, 0.43 mmol) in DCM (5 mL) was added TFA (1 mL). The mixture was stirred at room temperature under N2 for 3 hours. LCMS showed that the reaction was complete. The reaction mixture was concentrated (180 mg, crude product) and used directly in the next step without further purification.

[0389] LCMS: m / z=464.6[M+H] + ,Rt=1.836min,Purity:86.55%(214nm).

[0390] To a solution of compound 3 (180 mg, 0.39 mmol) and compound 4 (156 mg, 0.39 mmol) in DMF (5 mL) were added HATU (224 mg, 0.59 mmol) and DIEA (151 mg, 1.17 mmol). The mixture was stirred at room temperature under N2 for 16 hours. The reaction product was filtered. The filtrate was purified by prep-HPLC (0.1% TFA in water / CH3CN) and prep-HPLC (pure water / CH3CN) to give Ori-JQ1-5 as a white solid (11.9 mg, 3.06% yield).

[0391] LCMS: m / z=846.7[M+H] + ,Rt=1.836min,Purity:100.00%(214nm).

[0392] 1 H NMR(400MHz,CD3OD)δ7.48-7.42(m,4H),6.12(s,1H),5.56(s,1H),4.80(s,1H),4.71-4.68(m,1H) ,4.26-4.24(m,1H),4.11-4.09(m,1H),4.04-4.02(m,1H),3.94-3.78(m,2H),3.43-3.41(m,2H),3 .30-3.17(m,2H),2.98-2.96(m,1H),2.74(s,3H),2.54-2.42(m,4H),2.13-1.97(m,1H),1.87-1.7 3(m,2H),1.70(s,3H),1.66-1.50(m,7H),1.45-1.35(m,5H),1.28-1.25(m,2H),1.11-1.08(m,6H).

[0393] 6. Using the compound CYD of formula I as the E3 ligase recruitment element and the BRD4 inhibitor JQ1 as an example of the target protein ligand, a PROTAC for degrading BRD4 (hereinafter referred to as CYD-JQ1-6) was prepared.

[0394] The specific preparation steps are as follows:

[0395] To a solution of compound 6 (5 g, 23.22 mol) in MeOH (25 mL) was added SOCl2 (8.19 g, 69.66 mmol) at 0°C, and the reaction was stirred at 70°C for 3 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to give compound 7 (6 g crude product) as a white solid.

[0396] LCMS: m / z = 230.4 [M+H] + ,Rt=1.414min.

[0397] Compound 7 (0.99 g, 3.74 mmol), HATU (1.90 g, 4.99 mmol) and DIEA (0.97 g, 7.47 mmol) were added to a solution of compound 8 (1 g, 2.49 mol) in DMF (15 mL). The reactants were stirred at room temperature for 2 hours. After completion of the reaction, the mixture was diluted with water (50 mL) and extracted with EA (3×50 mL). The organic layer was washed with a saturated solution of NaCl (50 mL) and dried over anhydrous Na2SO4, filtered, concentrated in vacuo, and purified by silica gel column chromatography eluting with MeOH:DCM=5% to obtain compound 9 as a yellow solid (1 g, 65.79% yield).

[0398] LCMS: m / z=612.4[M+H] + ,Rt=2.231min,Purity:46.04%(214nm).

[0399] To a solution of compound 9 (1 g, 1.63 mol) in THF (9 mL) was added LiOH (1 mol / L, 9 mL) at 0°C, and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was diluted with water and the pH was adjusted to 1-2 with HCl (1 M). The mixture was then extracted with EA (3 × 50 mL), and the organic phase was washed with a saturated NaCl solution (50 mL) and dried over anhydrous Na2SO4. After filtration, the mixture was concentrated under reduced pressure to give compound 5 as a white solid (0.6 g, 61.66%).

[0400] LCMS: m / z=598.3[M+H]+, Rt=1.879min, Purity: 100% (214nm).

[0401] To a solution of compound 1 (5 g, 13.7 mmol) in acetone (100 mL) was added Jones reagent (6 mL) dropwise under an ice-water bath. The resulting mixture was stirred at 0°C for 20 minutes, and isopropanol was added to quench the excess Jones reagent. The mixture was then diluted with water (200 mL) and extracted with dichloromethane (100 mL×3). The DCM phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and evaporated to give a solid crude product. The crude residue was recrystallized in acetone-hexane to give compound 2 as a white solid (4100 mg, 82% yield).

[0402] LCMS: m / z = 345.2 [M-OH] + ,Rt=1.065min,Purity:79.49%(214nm).

[0403] To a solution of compound 2 (2000 mg, 5.4 mmol) in THF (4 mL) was added PyHBr (1760 mg, 5.4 mmol) at room temperature. The reaction mixture was stirred at room temperature for 4 hours, then poured into water (50 mL) and extracted with CH Cl (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na SO, and concentrated in vacuo to give an oily residue. The residue was further purified by silica gel column; eluted with 50% EtOAc in hexane to give the desired product, compound 3, as a colorless amorphous gel (1000 mg, 41.25%).

[0404] LCMS: m / z = 423.2, 425.2 [M-OH] + ,Rt=1.120min,Purity:78.30%(214nm).

[0405] To a solution of compound 3 (200 mg, 0.44 mmol) in ethanol (15 mL) was added 1-allylthiourea (72 mg, 0.64 mmol) at room temperature. The reaction mixture was heated at reflux for 3 hours. After cooling, the mixture was concentrated in vacuo to obtain an oily residue. The residue was purified on a silica gel column; eluted with 50% EtOAc in hexane to obtain the desired product, compound 4, as an amorphous gel (80 mg, 38% yield).

[0406] LCMS: m / z=459.2[M+H] + ,Rt=1.080min,Purity:44.69%(214nm).

[0407] To a solution of compound 5 (80 mg, 0.134 mmol) in DMF (2 mL) was added DMAP (16 mg, 0.13 mmol), EDCI (77 mg, 0.40 mmol) and compound 4 (80 mg, 0.174 mmol). The mixture was then stirred at 25° C. under an Ar atmosphere overnight. After completion of the reaction, the mixture was concentrated in vacuo and purified by reverse phase chromatography [ACN / water (0.1% FA)): 85% to 95%] to afford CYD-JQ1-6 as a white solid (14 mg, 10% yield).

[0408] LCMS: m / z = 1060.9 [M+Na] +,Rt=12.327min,Purity:100%(214nm).

[0409] 1 H NMR(400MHz, DMSO-d6)δ8.15(t,J=5.7Hz,1H),7.52–7.38(m,5H),6.03(s,2H),5.94(s,1H),5.88–5.77(m,1H),5.63(s,1H),5 .43-5.40(m,1H),5.24–5.14(m,1H),5.11–5.04(m,1H),4.53–4.46(m,1H),4.21-4.19(m,1H),3.81–3.66(m,3H),3.64–3.56( m,1H),3.27–3.22(m,1H),3.18–3.01(m,3H),2.93-2.89(m,1H),2.59(s,3H),2.48–2.38(m,5H),2.28-2.24(m,1H),2.15–1.9 0(m,4H),1.89–1.80(m,1H),1.63(s,3H),1.58-1.55(m,1H),1.46-1.40(m,5H),1.30–1.16(m,14H),1.14(s,3H),0.87(s,3H).

[0410] 7. Using the compound CYD of formula I as the E3 ligase recruitment element and the BRD4 inhibitor JQ1 as an example of the target protein ligand, a PROTAC for degrading BRD4 (hereinafter referred to as CYD-JQ1-7) was prepared.

[0411] The specific preparation steps are as follows:

[0412] To a solution of compound 10 (synthesized as described in Section 4) (70 mg, 0.105 mmol) in DMF (5 mL) was added EDCI (40.24 mg, 0.210 mmol), compound 4 (synthesized as described in Section 6) (48.09 mg, 0.105 mmol), and DMAP (24.62 mg, 0.210 mmol). The mixture was stirred at room temperature under an Ar atmosphere for 16 hours. LCMS indicated the reaction was complete. The mixture was filtered. The filtrate was purified by prep-HPLC (Waters 3767 / Qda, column: Sunfire C18, 19×250 mm, 10 μm: mobile phase A: 0.1% FA / H 2 O, B: ACN; flow rate: 20 mL / min; gradient: 67-77%; retention time: 9.1-10.6 min of 16 min) to give CYD-JQ1-7 as a white solid (22.4 mg, 19.07% yield).

[0413] LCMS: m / z = 1139.6 [M+Na] + ,Rt=2.931min,Purity:100%(214nm).

[0414] 1 H NMR (400MHz, DMSO) δ7.57–7.28(m,5H),6.17–6.02(m,2H),5.96(s,1H),5.92–5.75(m,1H),5.66 (s,1H),5.52–5.33(m,1H),5.27–5.14(m,1H),5.13–5.02(m,1H),4.56(s,1H),4.37–4.12(m,2H ),3.85–3.42(m,10H),3.01–2.77(m,2H),2.59(s,3H),2.47–2.44(m,1H),2.41(s,3H),2.30–2. 21(m,1H),2.14–1.80(m,10H),1.79–1.23(m,12H),1.15(s,3H),1.07–0.93(m,2H),0.88(s,3H).

[0415] 8. Using the compound OriPh of formula I as the E3 ligase recruitment element and the BRD4 inhibitor JQ1 as an example of the target protein ligand, a PROTAC that degrades BRD4 (hereinafter referred to as OriPh-JQ1-8) was prepared.

[0416] The specific preparation steps are as follows:

[0417] Under N2, EDCI (768 mg, 4.017 mmol) and DMAP (490 mg, 4.017 mmol) were added to a DCM (10 mL) solution of compound 1 (800 mg, 1.339 mmol) and compound 2 (540 mg, 1.339 mmol). The mixture was stirred at room temperature for 16 hours. LCMS showed that the reaction was complete. The reaction mixture was filtered. The filtrate was concentrated in vacuo. The residue was purified by reverse phase column chromatography to obtain compound 3 (560 mg, 42.49% yield) as a white solid.

[0418] LCMS: m / z = 984.3 [M+H] + ,Rt=1.749min.Purity:39%(214nm).

[0419] To a solution of compound 3 (560 mg, 0.569 mmol) in NMP (10 mL) were added iodobenzene (232 mg, 1.138 mmol), Pd(OAc)2 (26 mg, 0.114 mmol) and DABCO (191 mg, 1.707 mmol) under N2 at 150°C and the mixture was allowed to react for 16 hours. LCMS showed the reaction was complete.

[0420] 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 product was concentrated in vacuo. The residue was purified by reverse phase column chromatography (elution: ACN in H2O = 5% to 95%) to give compound 4 as a white solid (50 mg, 8.33% yield).

[0421] LCMS: m / z = 1060.2 [M+H] + ,Rt=1.680min.Purity:47.4%(214nm).

[0422] To a solution of compound 4 (50 mg, 0.047 mmol) in MeOH (2 mL) and DCM (0.5 mL) was added HCl (0.5 mL, 1 M). The mixture was stirred at room temperature for 1 hour. LCMS showed the reaction was complete. The crude product was purified by reverse phase column chromatography (elution: ACN in H2O = 5% to 95%) to afford OriPh-JQ1-8 as a white solid (11.85 mg, 24.6% yield).

[0423] LCMS: m / z = 1020.5 [M+H] + ,Rt=7.797min.Purity:100%(214nm).

[0424] 1H NMR(400MHz,DMSO-d6)δ8.18-8.13(m,1H),7.59-7.56(m,2H),7.48-7.46(m,4H),7.44-7.41(m,4H),6.90(s,1H),6.34-6.2 9(m,1H),6.10(s,1H),4.89(s,1H),4.64-4.58(m,1H),4.52-4.47(m,1H),4.25-4.21(m,1H),4.05-4.00(m,1H),3.59-3.54 (m,1H),3.29-3.21(m,2H),3.18-3.15(m,1H),3.15-3.11(m,1H),3.08-3.00(m,1H),2.59(s,4H),2.41(s,4H),2.25-2.20( m,2H),2.08-2.01(m,2H),1.62(s,4H),1.47-1.42(m,4H),1.39-1.33(m,4H),1.27-1.21(m,16H),1.06(s,4H),1.02(s,3H).

[0425] Example 4: PROTAC-induced quaternary complex formation

[0426] 1. Incubate Hep3B liver cancer cells with 1 μM Ori or Ori-JQ1-1 (prepared in Example 3) for 2 hours. After cell lysis, incubate with NCL antibody at 4°C overnight. Add Protein A / G magnetic beads (purchased from Thermo Scientific, Product No. 88802) and incubate with rotation at room temperature for 2 hours. Wash the NCL bound to the magnetic beads and the captured proteins with IP lysis buffer (purchased from Thermo Scientific, Product No. 87788), add SDS-PAGE protein loading buffer (purchased from Biyuntian, Product No. P0015), heat to 100°C and hold for 10 minutes. Use a magnetic stand to adsorb the magnetic beads and remove the supernatant to a new tube. Then perform an immunoblotting experiment. The results are shown in Figure 7A. In the presence of Ori-JQ1-1, the NCL antibody can capture NCL, MDM2 and BRD4, indicating that Ori-JQ1-1 can form an MDM2-NCL-PROTAC-BRD4 quaternary complex with NCL, MDM2 and BRD4.

[0427] 2. Incubate Hep3B liver cancer cells with 1 μM Ori or Ori-JQ1-1 for 2 hours. After cell lysis, incubate with MDM2 antibody at 4°C overnight. Add Protein A / G magnetic beads (purchased from Thermo Scientific, Catalog No. 88802) and incubate with rotation at room temperature for 2 hours. Wash the MDM2 bound to the magnetic beads and the captured proteins with IP lysis buffer (purchased from Thermo Scientific, Catalog No. 87788). Add SDS-PAGE protein loading buffer (purchased from Beyotime, Catalog No. P0015) and heat to 100°C for 10 minutes. Use a magnetic stand to adsorb the magnetic beads and remove the supernatant to a new tube. Then perform immunoblotting. The results are shown in Figure 7B. In the presence of Ori-JQ1-1, the MDM2 antibody can capture MDM2, NCL and BRD4, indicating that Ori-JQ1-1 can form an MDM2-NCL-PROTAC-BRD4 quaternary complex with NCL, MDM2 and BRD4.

[0428] 3. Hep3B hepatoma cells were transfected with negative control siRNA (siNC, SEQ ID NO: 1) or NCL siRNA (siNCL, SEQ ID NO: 2) for 48 hours. The cells were then incubated with 1 μM Ori-JQ1-1 for 2 hours. After lysis, the cells were incubated with an MDM2 antibody at 4°C overnight. Protein A / G magnetic beads (Thermo Scientific, Catalog No. 88802) were added and incubated with rotation at room temperature for 2 hours. MDM2 bound to the beads and the captured proteins were washed with IP lysis buffer (Thermo Scientific, Catalog No. 87788). SDS-PAGE protein loading buffer (Beyotime, Catalog No. P0015) was added and heated to 100°C for 10 minutes. The beads were adsorbed using a magnetic rack, and the supernatant was transferred to a fresh tube. Immunoblotting was then performed. The results are shown in Figure 7C . In the presence of Ori-JQ1-1, the antibody against MDM2 could not capture BRD4 after knockdown of NCL, indicating that NCL is intermediate between MDM2 and BRD4 in the quaternary complex induced by Ori-JQ1-1.

[0429] 4. Hep3B hepatoma cells were transfected with negative control siRNA (siNC, SEQ ID NO: 1) or MDM2 siRNA (siMDM2: GCUUGGCCUACAGUCAUCUTT, SEQ ID NO: 3) for 48 hours. The cells were then incubated with 1 μM Ori-JQ1-1 for 2 hours. After lysis, the cells were incubated with an antibody against NCL at 4°C overnight. Protein A / G magnetic beads (Thermo Scientific, Cat. No. 88802) were added and incubated with rotation at room temperature for 2 hours. NCL bound to the beads and the captured proteins were washed with IP lysis buffer (Thermo Scientific, Cat. No. 87788). SDS-PAGE protein loading buffer (Beyotime, Cat. No. P0015) was added and heated to 100°C for 10 minutes. The beads were adsorbed using a magnetic rack, and the supernatant was transferred to a fresh tube. Immunoblotting was then performed. The results are shown in Figure 7D . In the presence of Ori-JQ1-1, the antibody against NCL could still capture NCL and BRD4 after knockdown of MDM2, indicating that NCL is located between MDM2 and BRD4 in the quaternary complex induced by Ori-JQ1-1.

[0430] These results indicate that PROTACs based on Formula I can induce the formation of an MDM2-NCL-PROTAC-target protein quaternary complex, with NCL intervening between MDM2 and the target protein. This mode of action differs from the traditional PROTAC molecule, which induces the formation of an E3-PROTAC-target protein ternary complex.

[0431] Example 5: PROTAC can degrade BRD4

[0432] 1. Hep3B liver cancer cells were incubated with 0, 50, 100, 250, 500, and 1000 nM Ori-JQ1-1 (prepared in Example 3). Cell samples were collected after 12 hours, and total protein was extracted using RIPA lysis buffer (purchased from Beyotime, catalog number: P0013B). The degradation of BRD4 protein was detected by immunoblotting. The process was as follows: protein samples were separated by SDS-PAGE electrophoresis, and the separated proteins were transferred to a PVDF membrane. After blocking with TBST buffer containing 5% skim milk at room temperature for 1 hour, the membrane was incubated with a primary antibody against BRD4 (purchased from Cell Signaling Technology, Catalog No. 13440S) at 4°C overnight. After washing with TBST, the membrane was incubated with an HRP-conjugated secondary antibody (purchased from Abotek, Catalog No. AS014) at room temperature for 1 hour. Protein bands were visualized using an enhanced chemiluminescence detection kit (purchased from Abotek, Catalog No. RM00021P). As shown in Figure 8A, Ori-JQ1-1 can reduce BRD4 protein levels in a concentration-dependent manner.

[0433] 2. Hep3B cancer cells were incubated with 250 nM Ori-JQ1-1. Cell samples were collected at 0, 2, 4, 6, 8, and 12 hours for protein extraction and subsequent immunoblotting to detect BRD4 protein degradation. As shown in Figure 8B, Ori-JQ1-1 reduced BRD4 protein levels in a time-dependent manner.

[0434] 3. Hep3B cancer cells were incubated with the solvent DMSO (Veh) or 250 nM of the compounds Ori, JQ1, Ori+JQ1, Ori-JQ1-1, or dBET1 (positive control, purchased from MCE, Cat. No. HY-101838). Cell samples were collected 12 hours later for protein extraction and subsequent immunoblotting to detect BRD4 protein degradation. As shown in Figure 8C, Ori-JQ1-1 reduced BRD4 protein levels, with a greater effect than dBET1.

[0435] 4. Lung cancer A549 cells were incubated with 0, 200, 400, 600, 800, and 1000 nM Ori-JQ1-1. Cell samples were collected 12 hours later and total protein was extracted using RIPA lysis buffer (purchased from Beyotime, Cat. No. P0013B). BRD4 protein degradation was detected by immunoblotting. As shown in Figure 8D, Ori-JQ1-1 reduced BRD4 protein levels in a concentration-dependent manner.

[0436] Lung cancer A549 cells were incubated with 600 nM Ori-JQ1-1. Cell samples were collected at 0, 2, 4, 6, 8, and 12 hours for protein extraction and subsequent immunoblotting to detect BRD4 protein degradation. As shown in Figure 8E, Ori-JQ1-1 reduced BRD4 protein levels in a time-dependent manner.

[0437] 6. Lung cancer A549 cells were incubated with DMSO or 600 nM of Ori, JQ1, Ori+JQ1, Ori-JQ1-1, or dBET1. Cell samples were collected 12 hours later for protein extraction and subsequent immunoblotting to detect BRD4 protein degradation. As shown in Figure 8F, Ori-JQ1-1 reduced BRD4 protein levels.

[0438] 7. Hep3B liver cancer cells were incubated with 0, 200, 400, 600, 800, and 1000 nM Ori-JQ1-2 (prepared in Example 3). Cell samples were collected 24 hours later and total protein was extracted using RIPA lysis buffer (purchased from Beyotime, Catalog No. P0013B). BRD4 protein degradation was detected by immunoblotting. The results are shown in Figure 9A , which shows that Ori-JQ1-2 can reduce BRD4 protein levels in a concentration-dependent manner.

[0439] 8. Hep3B cancer cells were incubated with 800 nM Ori-JQ1-2. Cell samples were collected at 0, 4, 8, 12, 24, and 36 hours for protein extraction and subsequent immunoblotting to detect BRD4 protein degradation. As shown in Figure 9B, Ori-JQ1-2 reduced BRD4 protein levels in a time-dependent manner.

[0440] 9. Hep3B cancer cells were incubated with DMSO (Veh) or 600 nM of Ori, JQ1, Ori+JQ1, and Ori-JQ1-2. Cell samples were collected 24 hours later for protein extraction and subsequent immunoblotting to detect BRD4 protein degradation. As shown in Figure 9C, Ori-JQ1-2 reduced BRD4 protein levels.

[0441] 10. Hep3B liver cancer cells were incubated with 0, 200, 400, 600, 800, and 1000 nM Ori-JQ1-3 (prepared in Example 3). Cell samples were collected after 12 hours and total protein was extracted using RIPA lysis buffer (purchased from Beyotime, Catalog No. P0013B). BRD4 protein degradation was detected by immunoblotting. The results are shown in Figure 9D , which shows that Ori-JQ1-3 can reduce BRD4 protein levels in a concentration-dependent manner.

[0442] 11. Hep3B liver cancer cells were incubated with 0, 200, 400, 600, 800, and 1000 nM Ori-JQ1-4 (prepared in Example 3). Cell samples were collected 12 hours later and total protein was extracted using RIPA lysis buffer (purchased from Beyotime, Catalog No. P0013B). BRD4 protein degradation was detected by immunoblotting. The results, as shown in Figure 9E, show that Ori-JQ1-4 can reduce BRD4 protein levels in a concentration-dependent manner.

[0443] 12. Hep3B liver cancer cells were incubated with 0, 200, 400, 600, 800, and 1000 nM Ger-JQ1 (prepared in Example 3). Cell samples were collected after 12 hours and total protein was extracted using RIPA lysis buffer (purchased from Beyotime, Catalog No. P0013B). BRD4 protein degradation was detected by immunoblotting. The results are shown in Figure 10A. Ger-JQ1 can reduce BRD4 protein levels in a concentration-dependent manner.

[0444] 13. Hep3B cancer cells were incubated with 800 nM Ger-JQ1. Cell samples were collected at 0, 2, 4, 6, 8, and 12 hours for protein extraction and subsequent immunoblotting to detect BRD4 protein degradation. As shown in Figure 10B, Ger-JQ1 reduced BRD4 protein levels in a time-dependent manner.

[0445] 14. Hep3B hepatoma cells were incubated with 0, 200, 400, 600, and 800 nM Ori-JQ1-5 (prepared in Example 3). Cell samples were collected 12 hours later and total protein was extracted using RIPA lysis buffer (purchased from Beyotime, Catalog No. P0013B). BRD4 protein degradation was detected by immunoblotting. The results, as shown in Figure 10C, show that Ori-JQ1-5 can reduce BRD4 protein levels in a concentration-dependent manner.

[0446] 15. Hep3B cancer cells were incubated with 1000 nM CYD-JQ1-6. Cell samples were collected at 0, 2, 4, 6, 8, and 12 hours for protein extraction and subsequent immunoblotting to detect BRD4 protein degradation. As shown in Figure 10D, CYD-JQ1-6 reduced BRD4 protein levels in a time-dependent manner.

[0447] 16. Hep3B hepatoma cells were incubated with CYD-JQ1-7 (prepared in Example 3) at concentrations of 0, 200, 400, 600, 800, and 1000 nM. Cell samples were collected after 12 hours and total protein was extracted using RIPA lysis buffer (purchased from Beyotime, Catalog No. P0013B). BRD4 protein degradation was detected by immunoblotting. The results, as shown in Figure 10E, show that CYD-JQ1-7 can reduce BRD4 protein levels in a concentration-dependent manner.

[0448] 17. Hep3B hepatoma cells were incubated with 0, 200, 400, 600, 800, and 1000 nM OriPh-JQ1-8 (prepared in Example 3). Cell samples were collected after 12 hours and total protein was extracted using RIPA lysis buffer (purchased from Beyotime, Catalog No. P0013B). BRD4 protein degradation was detected by immunoblotting. The results, as shown in Figure 10F, show that OriPh-JQ1-8 can reduce BRD4 protein levels in a concentration-dependent manner.

[0449] Example 6: PROTAC promotes ubiquitination of BRD4

[0450] Hep3B hepatoma cells were incubated with either DMSO (Veh) or 250 nM Ori-JQ1-1 for 12 hours. During the final 6 hours of incubation, 10 μM of the proteasome inhibitor MG132 was added. Cell samples were collected for protein extraction and immunoblotting to detect BRD4 protein degradation. As shown in Figure 11A, MG132 blocked BRD4 degradation by Ori-JQ1-1, indicating that Ori-JQ1-1's BRD4 degradation is dependent on the ubiquitin-proteasome pathway.

[0451] 2. Hep3B hepatoma cells were incubated with the solvent DMSO (Veh) or 250 nM Ori-JQ1-1 for 12 hours. 10 μM proteasome inhibitor MG132 was added for the last 6 hours of incubation. After lysis, the cells were incubated with an antibody against BRD4 (purchased from Cell Signaling Technology, Catalog No. 13440S) at 4°C overnight. Protein A / G magnetic beads (purchased from Thermo Scientific, Catalog No. 88802) were added and incubated with rotation at room temperature for 2 hours. BRD4 bound to the beads was washed with IP lysis buffer (purchased from Thermo Scientific, Catalog No. 87788), and SDS-PAGE protein loading buffer (purchased from Beyotime, Catalog No. P0015) was added and heated to 100°C for 10 minutes. The beads were adsorbed using a magnetic stand, and the supernatant was transferred to a fresh tube. The ubiquitination level of BRD4 was then detected by immunoblotting. The results are shown in FIG11B , showing that Ori-JQ1-1 promoted the ubiquitination of BRD4.

[0452] Example 7: PROTAC-dependent MDM2 and NCL-mediated degradation of BRD4

[0453] 1. Hep3B hepatoma cells were transfected with negative control siRNA (siNC: UUCUCCGAACGUGUCACGUTT, SEQ ID NO: 1) or NCL siRNA (siNCL: GGAUGACGACGACGACGAAGATT, SEQ ID NO: 2) for 48 hours. The cells were then incubated with DMSO (Veh) or 250 nM Ori-JQ-1 for 12 hours. Cell samples were collected for protein extraction and subsequent immunoblotting to detect protein degradation. As shown in Figure 12A, silencing NCL reduced BRD4 degradation by Ori-JQ1-1, indicating that Ori-JQ1-1 relies on NCL to mediate BRD4 degradation.

[0454] 2. Hep3B hepatoma cells were transfected with negative control siRNA (siNC: UUCUCCGAACGUGUCACGUTT, SEQ ID NO: 1) or MDM2 siRNA (siMDM2: GCUUGGCCUACAGUCAUCUTT, SEQ ID NO: 3) for 48 hours. The cells were then incubated with the solvent DMSO (Veh) or 250 nM Ori-JQ1-1 for 12 hours. The corresponding cell samples were collected for protein extraction and subsequent immunoblotting to detect protein degradation. As shown in Figure 12B, silencing MDM2 reduced the degradation of BRD4 by Ori-JQ1-1, indicating that Ori-JQ1-1 relies on MDM2 to mediate BRD4 degradation.

[0455] Example 8: PROTAC inhibits tumor cell proliferation and promotes apoptosis

[0456] 1. Hep3B hepatoma cells were seeded in 96-well cell culture plates. The culture medium containing the solvent DMSO (Veh) or 250 nM Ori, JQ1, Ori + JQ1, or Ori-JQ1-1 was replaced daily during the experiment. Cell proliferation was assayed using a CCK-8 kit (purchased from MCE, Catalog No. HY-K0301). The absorbance at 450 nm was measured using a microplate reader on the first, second, third, and fourth days. As shown in Figure 13A, Ori-JQ1-1 inhibited Hep3B cell proliferation.

[0457] 2. Hep3B hepatoma cells were seeded in 6-well cell culture plates. The culture medium containing the solvent DMSO (Veh) or 250 nM Ori, JQ1, Ori+JQ1, or Ori-JQ1-1 was replaced every two days during the experiment. Cell colony formation was assessed after 8 days. As shown in Figure 13B, Ori-JQ1-1 inhibited Hep3B cell colony formation.

[0458] 3. Hep3B hepatoma cells were seeded in six-well plates for a cell apoptosis assay. The culture medium containing the solvent DMSO (Veh) or 250 nM Ori, JQ1, Ori+JQ1, or Ori-JQ1-1 was replaced every two days during the experiment. After six days, apoptosis analysis was performed using an Annexin V-FITC and PI double-staining apoptosis detection kit (purchased from Beyotime, Cat. No. C1062L). As shown in Figure 13C, Ori-JQ1-1 promoted apoptosis in Hep3B cells.

[0459] 4. Lung cancer A549 cells were seeded in 96-well cell culture plates. The culture medium containing the solvent DMSO (Veh) or 600 nM Ori, JQ1, Ori + JQ1, or Ori-JQ1-1 was replaced daily during the experiment. Cell proliferation was assayed using a CCK-8 kit (purchased from MCE, Catalog No. HY-K0301). The absorbance at 450 nm was measured using a microplate reader on the first, second, third, and fourth days. The results, as shown in Figure 14A, show that Ori-JQ1-1 inhibited the proliferation of A549 cells.

[0460] 5. Lung cancer A549 cells were seeded into 6-well cell culture plates. The culture medium containing the solvent DMSO (Veh) or 250 nM Ori, JQ1, Ori + JQ1, or Ori-JQ1-1 was replaced every two days during the experiment. Cell colony formation was assessed after 8 days. As shown in Figure 14B, Ori-JQ1-1 inhibited A549 cell colony formation.

[0461] 6. Lung cancer A549 cells were seeded in six-well plates for a cell apoptosis assay. The culture medium containing the solvent DMSO (Veh) or 600 nM Ori, JQ1, Ori+JQ1, or Ori-JQ1-1 was replaced every two days during the experiment. After six days, apoptosis analysis was performed using an Annexin V-FITC and PI double-staining apoptosis detection kit (purchased from Beyotime, Cat. No. C1062L). As shown in Figure 14C, Ori-JQ1-1 promoted apoptosis in A549 cells.

[0462] Example 9: Ori-JQ1-1 inhibits tumor cell growth in vivo

[0463] BALB / c nude mice were subcutaneously inoculated with Hep3B liver cancer cells (5×10 6 / mouse, and the tumor growth was observed every day. After 6 days, the solvent PBS (Veh), Ori, JQ1, Ori+JQ1, Ori-JQ1-1 or the positive control dBET1 (purchased from MCE, product number: HY-101838) was injected into the tail vein at a dose of 3 μmol / kg, and the injection cycle was once every two days. After 14 days of administration, the tumor volume and weight were measured. The results are shown in Figures 15A-15D. The results show that compared with PBS, Ori, JQ1, and Ori+JQ1, Ori-JQ1-1 can significantly inhibit tumor growth, and the effect is better than dBET1.

[0464] 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 in the scope of protection of the present invention.

[0465] The aforementioned embodiments and methods described in the present invention may be varied based on the ability, experience, and preference of those skilled in the art.

[0466] In the present invention, merely listing the steps of the method in a certain order does not constitute any limitation on the order of the method steps.

Claims

1. A compound or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuterated compound thereof, wherein the compound has the following structure: in, ML is the MDM2 protein recruitment component; L is a linking group; PI is the ligand part of the target protein; q is an integer from 1 to 15; The MDM2 protein recruitment element has the following structure: in, represents a single bond or a double bond, and a and b are shown Not a double bond at the same time; 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, azido, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic group), C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, Among them, R A Selected from: H, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic group), halogen, cyano, nitro, azido, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -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-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl); R F Selected from: single bond, C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, -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 heterocyclyl); 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 membered heterocyclic group), halogen, cyano, nitro, azido, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -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), monosaccharide residues, amino acid residues, nitric oxide (NO) donor residues; Q is a single bond or C1-C 20 Alkylene, wherein 0-6 methylene units are independently substituted by -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 c )-、-P(O)(OR d )2N(R c )-、-N(R c )P(O)(OR d )O-、-N(R c )P(O)-、 Wherein, m1 is selected from an integer between 1 and 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10), wherein 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 membered heterocyclyl); each -Cy- is independently an optionally substituted divalent ring selected from the following: arylene, cycloalkylene, heterocyclyl; R5 and R6 are independently selected from: H, hydroxyl, amino, halogen, cyano, nitro, azido, -CF3, -OCF3, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl); The above C0-C6 alkylene, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C6-C 10 The H in the aryl and 4-10 membered heterocyclic groups may be optionally substituted by one or more groups selected from the group consisting of halogen, cyano, nitro, azido, -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'S02R", -SO2NR'R", -OS02NR'R", -NR'C(O)R", -NR'R", -SR', -SOR', -SO2R', -OS02R', -S03H, -PO3H, -OP(O)(OR'), -P(O)(OR')(OR"), -P(O)NR'R", C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic group), monosaccharide residue, amino acid residue; Alternatively, R1, R2, R3, R4, R5, R6, R7, R8, and R9 are selected from one or more of the following: (1) R1 and R2 together with the carbon atoms to which they are attached form an aliphatic ring, an aromatic ring or a heterocyclic ring; (2) R2 and R3 together with the carbon atoms to which they are attached form an aliphatic ring, an aromatic ring or a heterocyclic ring; (3) R1 and R5 together with the carbon atoms to which they are attached form an aliphatic ring, an aromatic ring or a heterocyclic ring; (4) R4 and R5 together with the carbon atoms to which they are attached form an aliphatic ring, an aromatic ring or a heterocyclic ring; (5) R4 and R6 together with the carbon atoms to which they are attached form an aliphatic ring, an aromatic ring or a heterocyclic ring; (6) R5 and R6 together with the carbon atoms to which they are attached form an aliphatic ring, an aromatic ring or a heterocyclic ring; (7) R5 and R7 together with the carbon atoms to which they are attached form an aliphatic ring, an aromatic ring or a heterocyclic ring; (8) R8 and R9 together with the carbon atoms to which they are attached form an aliphatic ring, an aromatic ring or a heterocyclic ring; Wherein the H on the aliphatic ring, aromatic ring or heterocyclic ring is optionally substituted by one or more groups selected from the following: =O, Halogen, cyano, nitro, azido, -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 Halogenated alkyl, C1-C 10 Haloalkoxy, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl), monosaccharide residue, amino acid residue, nitric oxide (NO) donor residue, wherein 0-4 methylene units in the C0-C6 alkylene are independently substituted by 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 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)-、 Wherein, n1 is selected from an integer between 1 and 10, wherein 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 group); wherein the C3-C 10 Cycloalkyl, C6-C 10 The H on the aryl group and the 4-10 membered heterocyclic group is optionally substituted by one or more groups selected from the following: halogen, cyano, nitro, azido, 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-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl); Each R' and R" is independently selected from: H, Cl-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 group); wherein the C0-C6 alkylene, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C6-C 10 The H in the aryl group and the 4-10 membered heterocyclic group may be optionally substituted by one or more groups selected from the following: halogen, cyano, nitro, azido, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic group), C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -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); Preferably, the MDM2 protein recruitment element is selected from the following structures: in, R 21 Selected from: H, =O, -O(C 0-10 Alkyl), -OC(O)(C 0-10 Alkyl), -O-monosaccharide residues; R 22 Selected from: H, -O(C 0-10 Alkyl), -OC(O)(C 0-10 Alkyl), -O-monosaccharide residues; R 23 and R 24 Independently selected from: H, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic group); wherein the C 0-10 The H on the alkyl group may be optionally substituted by one or more groups selected from the following: halogen, cyano, nitro, azido, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -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); X is O or S; R 25 Selected from: H, =O, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic group), halogen, cyano, nitro, azido, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -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), Among them, the C 0-10 The H in the alkyl group may be optionally substituted by one or more groups selected from the following: halogen, cyano, nitro, azido, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -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 26 Selected from: H, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic group), -(C0-C6 alkenylene)-(C6-C 10 aryl), halogen, cyano, nitro, azido, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -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 H in the alkyl group may be optionally substituted by one or more groups selected from the following: halogen, cyano, nitro, azido, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -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, halogen, C1-C6 alkyl, -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 is 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 to which it is attached, it forms a 4-8 membered heterocyclic group; More preferably, the MDM2 protein recruitment element has the following structure: 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 by -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)-、-PO2-、-P(O)(N(C 0-10 Alkyl))-, -N(C 0-10 Alkyl)-, -N(C 0-10 Alkyl)C(O)-, -N(C 0-10 Alkyl) S(O)2-, -P(O)-, Wherein, m1 is selected from an integer 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 heterocyclyl), a monosaccharide residue, an amino acid residue, a nitric oxide (NO) donor residue; 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 H in the cycloalkyl, phenyl, 4-10 membered heterocyclic group is optionally substituted by one or more groups selected from the following: halogen, cyano, nitro, azido, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -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 by -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)-、-PO2-、-P(O)(N(C 0-10 Alkyl))-, -N(C 0-10 Alkyl)-, -N(C 0-10 Alkyl)C(O)-, -N(C 0-10 Alkyl) S(O)2-, -P(O)-, Wherein, m1 is selected from an integer 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 heterocyclyl), a monosaccharide residue, an amino acid residue, a nitric oxide (NO) donor residue; 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 H in the cycloalkyl, phenyl, 4-10 membered heterocyclic group is optionally substituted by one or more groups selected from the following: halogen, cyano, nitro, azido, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -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, monosaccharide residues.

2. The compound according to claim 1, characterized in that The ML portion is selected from the following structures: Among them, R1', R2', R3', R7', R 21 '、R 22 '、R 23 '、R 24 '、R 25 '、R 27 '、R 31 '、R 32 ' are R1, R2, R3, R7, R 21 , R 22 , R 23 , R 24 , R 25 , R 27 , R 31 , R 32 The divalent group obtained after the connection reaction; ①, ②, ③, ④, ⑤, ⑥, ⑦, ⑧, ⑨, ⑩ are available linking sites. When they are not used as linking sites, the corresponding R1', R2', R3', R7', R 21 '、R 22 '、R 23 '、R 24 '、R 25 '、R 27 '、R 31 '、R 32 ' are R1, R2, R3, R7, R 21 , R 22 , R 23 , R 24 , R 25 , R 27 , R 31 , R 32 ; Preferably, the ML portion is selected from the following structures: Preferably, the ML portion is selected from the following structures:

3. The compound according to claim 1 or 2, characterized in that The L has the following structure: in, L1 is a divalent group connected to ML, which is selected from: a single bond, -O-(C0-C6 alkylene)-, -S-(C0-C6 alkylene)-, -C(O)-(C0-C6 alkylene)-, -C(S)-(C0-C6 alkylene)-, -N(R L1 )-(C0-C6 alkylene)-, -CON(R L1 )-(C0-C6 alkylene)-, -N(R L1 )CO-(C0-C6 alkylene)-, -SO2-(C0-C6 alkylene)-, -SO-(C0-C6 alkylene)-; L3 is a divalent group connected to PI, which is selected from: a 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 membered heterocyclylene)-; L2 is a single bond or a divalent saturated or unsaturated straight or branched C1-C50 hydrocarbon chain, in which 0-6 methylene units are independently substituted by: -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 L2 )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 1-10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10), each -CY- is independently an optionally substituted divalent ring selected from the following: arylene, cycloalkylene, heterocyclylene; H in the hydrocarbon chain may be optionally substituted by one or more groups selected from the following: 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 、-NR L0 S02R 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 Alkynyl, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl); 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 group), 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 H in the aryl group and the 4-10 membered heterocyclic group may be optionally substituted by one or more groups selected from the following: halogen, cyano, nitro, azido, hydroxyl, amino, thiol, carboxyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl); Preferably, each -CY- is independently selected from the following: Among them, R L4 , R L5 Independently selected from: H, OH, halogen, 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 Cycloalkyl, C 3-11 Heterocyclic hydrocarbon, O(C 1-8 Cycloalkyl), S(C 1-8 Cyclic hydrocarbon), NH(C 1-8 Cycloalkyl), N(C 1-8 Cycloalkyl) 1-8 alkyl), 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 Alkynyl, 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), 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 , R L5 Together with the atoms to which they are attached, they form a cycloalkylene or heterocyclylene group; More preferably, each -CY- is selected from:

4. The compound according to claim 3, characterized in that 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, R L2 Independently selected from: H, C1-C6 alkyl, each R L4 and R L5 Independently selected from: H, OH, C1-C6 alkoxy; Preferably, L2 is selected from: C1-C20 straight chain alkylene, -(CH2CH2O) m2 -CH2-, -(CH2CH2O) m2 -CH2CH2-, -CH2-(CH2CH2O) m2 -CH2-, -CH2CH2-(CH2CH2O) m2 -CH2-, -CH2CH2-(CH2CH2O) m2 -CH2CH2-、-(C1-C 10 Alkylene)-O-(C1-C 10 Alkylene)-, -(C1-C 10 Alkylene)-NH-(C1-C 10 Alkylene)-, -(C1-C 10 Alkylene)-C(O)NH-(C1-C 10 Alkylene)-, -(C1-C 10 Alkylene)-NHC(O)-(C1-C 10 -(C1-C6 alkylene)-, -(C1-C6 alkylene)-O-(C1-C6 alkylene)-C(O)NH-(C1-C6 alkylene)-, -(C1-C6 alkylene)-O-(C1-C6 alkylene)-NHC(O)-(C1-C6 alkylene)-, wherein m2 is selected from an integer between 1 and 10, g is 0 or 1, h is selected from an integer between 0 and 10, i is selected from an integer between 0 and 10, and j is selected from an integer between 1 and 10; More preferably, L2 is selected from:

5. The compound according to claim 3, characterized in that L2 is a C1-C20 straight chain alkylene group, wherein 1-3 methylene units are independently substituted by the following groups: -CY-, Optionally, L2 further comprises a group selected from the following: -O-, -C(O)-, -N(R L2 )-、-C(O)N(R L2 )-、-N(R L2 )C(O)-、 Among them, R L2 Independently selected from: H, C1-C6 alkyl; Preferably, L2 is selected from:

6. The compound according to any one of claims 3 to 5, characterized in that The compound has the following structure: Preferably, the compound has the following structure: More preferably, the compound may have the following structure: Wherein, n is selected from an integer of 1-10, and m2 is selected from an integer of 1-10.

7. The compound according to any one of claims 1 to 6, characterized in that The target protein is selected from the following: Preferably, the target protein ligand is a small molecule compound, oligonucleotide, oligopeptide, polypeptide or protein; Preferably, the target protein is BRD4, and the target protein ligand is selected from the following: More preferably, the PI moiety has the following structure:

8. The compound according to claim 1, characterized in that The compound has the following structure: More preferably, the stereoisomers of the compound have the following structure:

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuterated compound thereof, and one or more pharmaceutically acceptable excipients.

10. Use of the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuterated compound thereof in the preparation of a medicament for preventing and / or treating a disease, wherein the disease is a disease that can be prevented and / or treated by inhibiting / degrading the target protein; Preferably, the disease is selected from the group consisting of: tumors, autoimmune diseases, inflammatory diseases, diseases associated with pathogen infection, neurodegenerative diseases, cardiovascular diseases, metabolic diseases, and fibrotic diseases; More preferably, the tumor is selected from the group consisting of lung cancer, malignant melanoma, brain tumor, tumor of digestive organs, uterine cancer, testicular cancer, palate cancer, pharyngeal cancer, tongue cancer, oral cancer, various sarcomas, osteosarcoma, blood system tumors, nervous system tumors, brain glioma, glioblastoma, skin cancer, skin appendage cancer and skin metastasis, medulloblastoma, blastoma, liposarcoma, neuroendocrine tumor, synovial cell sarcoma, gastrinoma, carcinoid tumor, mesothelioma, islet cell carcinoma, nerve sheath tumors, meningiomas, melanomas, acoustic neuromas, adenocarcinomas, lymphoid malignancies, epithelial squamous cell carcinomas, small cell lung cancer, non-small cell lung cancer, squamous cell carcinomas, adenocarcinoma lung cancer, peritoneal cancer, squamous cell lung cancer, hepatocellular carcinoma, gastric cancer, intestinal cancer, pancreatic cancer, glioblastomas, cervical cancer, ovarian cancer, liver cancer, thyroid cancer, bladder cancer, breast cancer, metastatic breast cancer, colon cancer, rectal cancer, prostate cancer, salivary gland cancer, kidney cancer, vulvar cancer, anal cancer, penile cancer, esophageal cancer, biliary tract tumors, and head and neck cancer; More preferably, the autoimmune disease is selected from the group consisting of organ-specific autoimmune disease, systemic lupus erythematosus, rheumatoid arthritis, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease, autoimmune hemolytic anemia, thyroid autoimmune disease, and ulcerative colitis; More preferably, the inflammatory disease is selected from the group consisting of osteoarthritis, acute gout, multiple sclerosis, inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis), neuroinflammation, asthma, chronic obstructive airway disease, pneumonia, myositis, eczema, dermatitis, acne, cellulitis, occlusive disease, thrombosis, alopecia, nephritis, vasculitis, retinitis, uveitis, scleritis, sclerosing cholangitis, hypophysitis, thyroiditis, septic shock, systemic inflammatory response syndrome (SIRS), toxic shock syndrome, acute lung injury, ARDS (adult respiratory distress syndrome), acute renal failure, burns, pancreatitis (e.g., acute pancreatitis), postoperative syndrome, sarcoidosis, Herxheimer reaction, encephalitis, myelitis, meningitis, and malaria; More preferably, the neurodegenerative disease is selected from the group consisting of: Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), different types of spinocerebellar ataxia (SCA), Pick's disease; More preferably, the pathogen infection-related disease is selected from: influenza, SARS, COVID-19, viral hepatitis (such as hepatitis A, hepatitis B, hepatitis C, hepatitis D, etc.), AIDS, rabies, dengue fever, Ebola virus disease; More preferably, the cardiovascular disease is selected from the group consisting of coronary heart disease, peripheral arterial disease, atherosclerosis, ischemic heart disease, ischemic cardiomyopathy, myocardial infarction, heart failure, angina pectoris, myocarditis, hypercholesterolemia, hypertension, ischemia-reperfusion injury, cerebrovascular ischemia (stroke), embolism (e.g., pulmonary embolism, renal embolism, hepatic embolism, gastrointestinal embolism or peripheral limb embolism) or myocardial ischemia; More preferably, the metabolic disease is selected from the group consisting of diabetes (such as type I diabetes, type II diabetes or gestational diabetes), obesity, Fatty liver (NASH or other), cachexia, hypercholesterolemia, gout; More preferably, the fibrotic disease is selected from the group consisting of: myocardial fibrosis, pulmonary fibrosis, renal fibrosis, postoperative stenosis, keloid formation, cirrhosis, biliary cirrhosis, scleroderma.

11. The use according to claim 10, characterized in that The target protein is BRD4; Preferably, the disease is a hematological tumor (eg, acute lymphoblastic leukemia, mixed lineage leukemia, multiple myeloma, Burkitt's lymphoma), hepatocellular carcinoma, triple-negative breast cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer, neuroblastoma.

12. A compound or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuterated compound thereof as an E3 ubiquitin ligase recruitment element for preparing a targeted protein degrader, as / preparing an MDM2 binder or capture agent, or preparing a drug for preventing and / or treating a disease, wherein the disease is a disease that is beneficial to its treatment by recruiting MDM2, and the compound has the following structure: in, represents a single bond or a double bond, and a and b are shown Not a double bond at the same time; 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, azido, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic group), C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, Among them, R A Selected from: H, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic group), halogen, cyano, nitro, azido, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -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-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl); R F Selected from: single bond, C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, -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 heterocyclyl); 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 membered heterocyclic group), halogen, cyano, nitro, azido, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -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), monosaccharide residues, amino acid residues, nitric oxide (NO) donor residues; Q is a single bond or C1-C 20 Alkylene, wherein 0-6 methylene units are independently substituted by -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 c )-、-P(O)(OR d )2N(R c )-、-N(R c )P(O)(OR d )O-、-N(R c )P(O)-、 Wherein, m1 is selected from an integer between 1 and 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10), wherein 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 membered heterocyclyl); each -Cy- is independently an optionally substituted divalent ring selected from the following: arylene, cycloalkylene, heterocyclyl; R5 and R6 are independently selected from: H, hydroxyl, amino, halogen, cyano, nitro, azido, -CF3, -OCF3, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl); The above C0-C6 alkylene, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C6-C 10 The H in the aryl and 4-10 membered heterocyclic groups may be optionally substituted by one or more groups selected from the group consisting of halogen, cyano, nitro, azido, -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'S02R", -SO2NR'R", -OS02NR'R", -NR'C(O)R", -NR'R", -SR', -SOR', -SO2R', -OS02R', -S03H, -PO3H, -OP(O)(OR'), -P(O)(OR')(OR"), -P(O)NR'R", C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic group), monosaccharide residue, amino acid residue; Alternatively, R1, R2, R3, R4, R5, R6, R7, R8, and R9 are selected from one or more of the following: (1) R1 and R2 together with the carbon atoms to which they are attached form an aliphatic ring, an aromatic ring or a heterocyclic ring; (2) R2 and R3 together with the carbon atoms to which they are attached form an aliphatic ring, an aromatic ring or a heterocyclic ring; (3) R1 and R5 together with the carbon atoms to which they are attached form an aliphatic ring, an aromatic ring or a heterocyclic ring; (4) R4 and R5 together with the carbon atoms to which they are attached form an aliphatic ring, an aromatic ring or a heterocyclic ring; (5) R4 and R6 together with the carbon atoms to which they are attached form an aliphatic ring, an aromatic ring or a heterocyclic ring; (6) R5 and R6 together with the carbon atoms to which they are attached form an aliphatic ring, an aromatic ring or a heterocyclic ring; (7) R5 and R7 together with the carbon atoms to which they are attached form an aliphatic ring, an aromatic ring or a heterocyclic ring; (8) R8 and R9 together with the carbon atoms to which they are attached form an aliphatic ring, an aromatic ring or a heterocyclic ring; Wherein the H on the aliphatic ring, aromatic ring or heterocyclic ring is optionally substituted by one or more groups selected from the following: =O, Halogen, cyano, nitro, azido, -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 Halogenated alkyl, C1-C 10 Haloalkoxy, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl), monosaccharide residue, amino acid residue, nitric oxide (NO) donor residue, wherein 0-4 methylene units in the C0-C6 alkylene are independently substituted by 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 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)-、 Wherein, n1 is selected from an integer between 1 and 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10), wherein 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 group); wherein the C3-C 10 Cycloalkyl, C6-C 10 The H on the aryl group and the 4-10 membered heterocyclic group is optionally substituted by one or more groups selected from the following: halogen, cyano, nitro, azido, 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-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl); Each R' and R" is independently selected from: H, Cl-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 group); wherein the C0-C6 alkylene, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C6-C 10 The H in the aryl group and the 4-10 membered heterocyclic group may be optionally substituted by one or more groups selected from the following: halogen, cyano, nitro, azido, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic group), C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -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); Preferably, the targeted protein degrader is selected from the group consisting of: PROTAC, molecular glue, CHAMP, LYTAC, GlucTAC, AbTAC, AUTAC, AUTOTAC, ATTEC, antibody-PROTAC conjugate, and MADTAC.

13. The use according to claim 12, characterized in that The compound has the following structure: in, R8' is =0; R9' is selected from: H, =O, Among them, R 31 Selected from: H, halogen, C1-C6 alkyl, -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 is 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 to which it is attached, it forms a 4-8 membered heterocyclic group; Preferably, the compound is selected from the following structures: in, R 21 Selected from: H, =O, -O(C 0-10 Alkyl), -OC(O)(C 0-10 Alkyl), -O-monosaccharide residues; R 22 Selected from: H, -O(C 0-10 Alkyl), -OC(O)(C 0-10 Alkyl), -O-monosaccharide residues; R 23 and R 24 Independently selected from: H, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic group); wherein the C 0-10 The H on the alkyl group may be optionally substituted by one or more groups selected from the following: halogen, cyano, nitro, azido, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -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); X is O or S; R 25 Selected from: H, =O, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic group), halogen, cyano, nitro, azido, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -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), Among them, the C 0-10 The H in the alkyl group may be optionally substituted by one or more groups selected from the following: halogen, cyano, nitro, azido, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -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 26 Selected from: H, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic group), -(C0-C6 alkenylene)-(C6-C 10 aryl), halogen, cyano, nitro, azido, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl Base)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 H in the alkyl group may be optionally substituted by one or more groups selected from the following: halogen, cyano, nitro, azido, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -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); More preferably, the compound has the following structure: 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 by -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)-、-PO2-、-P(O)(N(C 0-10 Alkyl))-, -N(C 0-10 Alkyl)-, -N(C 0-10 Alkyl)C(O)-, -N(C 0-10 Alkyl) S(O)2-, -P(O)-, Wherein, m1 is selected from an integer 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 heterocyclyl), a monosaccharide residue, an amino acid residue, a nitric oxide (NO) donor residue; 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 H in the cycloalkyl, phenyl, 4-10 membered heterocyclic group is optionally substituted by one or more groups selected from the following: halogen, cyano, nitro, azido, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -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 by -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)-、-PO2-、-P(O)(N(C 0-10 Alkyl))-, -N(C 0-10 Alkyl)-, -N(C 0-10 Alkyl)C(O)-, -N(C 0-10 Alkyl) S(O)2-, -P(O)-, Wherein, m1 is selected from an integer 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 heterocyclyl), a monosaccharide residue, an amino acid residue, a nitric oxide (NO) donor residue; 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 H in the cycloalkyl, phenyl, 4-10 membered heterocyclic group is optionally substituted by one or more groups selected from the following: halogen, cyano, nitro, azido, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -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, monosaccharide residues.

14. The use according to claim 13, characterized in that 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), monosaccharide residues, Among them, R 16 Selected from: halogen, cyano, nitro, azido, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -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); Preferably, R 16 Selected from: H, halogen, cyano, nitro, azido, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy.

15. The use according to claim 13, characterized in that 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), monosaccharide residues, Among them, R 17 Selected from: halogen, cyano, nitro, azido, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -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); Preferably, R 17 Selected from: H, halogen, cyano, nitro, azido, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy.

16. The use according to claim 12, characterized in that The compound is selected from the following:

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