Novel recruitment element of ubiquitin ligase and application of novel recruitment element

Abstract

The invention discloses a novel recruitment element of ubiquitin ligase and application of the recruitment element, such as application in preparation of targeted protein degradation drugs, including PROTAC drugs. The inventor creatively discovers that the compound recruits ubiquitin ligase MDM2 through interaction with NCL, and further experiments discover that the compound can be used as a novel recruitment element of MDM2 and can be used in the aspects of preparation of targeted protein degradation agents and the like. The inventor prepares the targeted protein degradation agent by utilizing the discovery, and the experiment finds that the prepared targeted protein degradation agent can effectively mediate the degradation of the target protein through a ubiquitin-proteasome way, realizes the treatment of target protein related diseases (such as tumors), and has a very good application prospect in the field of medicines.

Description

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 breakthrough drug development strategy that uses the intrinsic protein degradation pathway in cells to directly degrade pathogenic target proteins. This new drug form includes many types, such as PROTAC, molecular glue, LYTAC, ATAC, AbTAC, ATTEC, AUTAC, AUTOTAC, etc. PROTAC (Proteolysis Targeting Chimera), namely protein degradation targeted chimera technology, is a relatively mature and most studied type, mainly degrading target proteins through the ubiquitin-proteasome pathway. PROTAC is a bifunctional molecule composed of three parts: target protein ligand, linker and E3 ubiquitin ligase recruitment element. After PROTAC enters the cell, the target protein ligand in its structure specifically binds to the target protein, and the E3 ubiquitin ligase recruitment element at the other end binds to the E3 ubiquitin ligase, thereby forming a target protein-PROTAC-E3 ternary complex. The E3 ubiquitin ligase mediates the ubiquitin conjugation enzyme E2 to ubiquitinate the target protein, and the target protein marked by polyubiquitination will be transported to the proteasome for degradation, thereby reducing the level of the target protein. In the above process, the target protein ligand does not need to occupy the binding site for a long time. Therefore, PROTAC can work multiple times in the cell. Based on the mechanism of action of PROTAC, this technology has received widespread attention from academia and industry since its inception. Different from the traditional occupancy-driven pharmacology principle, 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 of PROTAC technology at present. Therefore, it is urgent 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. As a classic E3 ubiquitin ligase, MDM2 has been used in the field of protein targeted 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 improper use of dosage 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. Summary of the invention

[0004] 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.

[0005] 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, and preparing drugs for preventing and / or treating diseases, wherein the compound has the following structure:

[0006]

[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 Haloalkoxy,

[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: 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);

[0016] The above 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 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;

[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'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 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-C 10Alkyl, 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, 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), AUTAC, AUTOTAC, 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 of targeted protein degradation and their research progress [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 which would be amenable to treatment through recruitment of MDM2.

[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: glucosyl, galactosyl, xylosyl, and mannosyl.

[0035] Specifically, the above 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]

[0042] wherein R8′ and R9′ have the same definitions as above for R8 and R9, respectively.

[0043] In some embodiments of the present invention, R8' is =0.

[0044] In some embodiments of the present invention, 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 33is 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.

[0045] In some embodiments of the present invention, R9' is R9" is selected from:

[0046]

[0047] 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:

[0048] In some embodiments of the present invention, R9' is selected from:

[0049] 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:

[0050]

[0051] 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:

[0052]

[0053] in,

[0054] R 21 Selected from: H, =O, -O(C 0-10 Alkyl), -OC(O)(C 0-10 Alkyl), -O-monosaccharide residues;

[0055] R 22 Selected from: H, -O(C 0-10 Alkyl), -OC(O)(C 0-10 alkyl), -O-monosaccharide residue; or, R 22and R7 together with the carbon atom to which they are attached form an optionally substituted aliphatic, aromatic or heterocyclic ring.

[0056] In one embodiment of the present invention, the compound has the following structure:

[0057]

[0058] in,

[0059] 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).

[0060] 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: halogen, hydroxyl, amino, C1-C3 alkoxy; in one embodiment of the present invention, R23 and R 24 are all methyl groups; in one embodiment of the present invention, R 23 For H, R 24 is phenyl; in one embodiment of the present invention, R 23 For H, R 24 It is 3,4-dimethoxyphenyl.

[0061] 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:

[0062]

[0063] 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:

[0064]

[0065] 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:

[0066]

[0067] 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:

[0068]

[0069]

[0070] in,

[0071] X is O or S;

[0072] 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 0-10Alkyl), -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).

[0073] In some embodiments of the present invention, in Formula III-6, R 25Selected 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,

[0074] 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. ).

[0075] In some embodiments of the present invention, in formula III-9, III-10, 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, hydroxyl, azido, 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:

[0076] 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:

[0077]

[0078] in,

[0079] 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 0-10Alkyl), -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).

[0080] In some embodiments of the present invention, in formula III-14 and III-15, R 26 Selected from: H, halogen, cyano, nitro, azido, C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, -COO(C 0-3 alkyl),

[0081] 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).

[0082] In one embodiment of the present invention, is a double bond, as shown in b For a single key.

[0083] In one embodiment of the present invention, is a single bond, as shown in b For double bonds.

[0084] In one embodiment of the present invention, is a single bond, as shown in b For a single key.

[0085] In some embodiments of the present invention, the compound has the following structure:

[0086]

[0087] In some embodiments of the present invention, the compound has the following structure:

[0088]

[0089]

[0090] In some embodiments of the present invention, R2 is selected from: 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.

[0091] In some embodiments of the present invention, R3 is selected from: 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, R3 is H.

[0092] In some embodiments of the present invention, the compound has the following structure:

[0093]

[0094]

[0095]

[0096] in,

[0097] 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 10cycloalkyl), -(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);

[0098] 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 0-10Alkyl) 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);

[0099] R 14 and R 15 Independently selected from: H, C1-C 10 Alkyl, monosaccharide residues.

[0100] In some embodiments of the present invention, R 12Selected 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); more specifically, R 12 Selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, C(O)(C 0-6 alkyl), SO2(C 0-6 alkyl),

[0101] 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 0-6alkyl), 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,

[0102] 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); more specifically, R 13 Selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, C(O)(C 0-6 alkyl), SO2(C 0-6 alkyl),

[0103] 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.

[0104] 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.

[0105] In some embodiments of the present invention, R 14 For H.

[0106] In some embodiments of the present invention, R 15 For H.

[0107] In other embodiments of the present invention, R 15 It is a monosaccharide residue, such as glucosyl, galactosyl, xylosyl, and mannosyl.

[0108] In some embodiments of the present invention, the compounds include, but are not limited to, the following:

[0109]

[0110]

[0111]

[0112]

[0113]

[0114] In one embodiment of the present invention, the stereoisomers of the compound have the following structures:

[0115] For example

[0116] In one embodiment of the present invention, the stereoisomers of the compound have the following structures:

[0117] For example

[0118] 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 being studied, 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 MedChem. 2018 Dec; 33(1): 324-333.; Dai Yi, Zhong Fei. Research progress on the structural modification and biological activity of Rubescensine A[J]. Organic Chemistry, 2017, 37(7): 1701-1713., etc., which are incorporated herein by reference in their entirety.

[0119] 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:

[0120]

[0121] in,

[0122] ML is the MDM2 protein recruitment element portion, which is the structural portion of the compound described in the first aspect;

[0123] L is a linking group;

[0124] PI is the ligand part of the target protein;

[0125] 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).

[0126] In some embodiments of the invention, q is 1.

[0127] In some embodiments of the invention, the ML moiety is selected from the following structures:

[0128]

[0129]

[0130] 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 connection reaction (e.g., loss of a leaving group);

[0131] ①, ②, ③, ④, ⑤, ⑥, ⑦, ⑧, ⑨, ⑩ are available connection sites. When they are not used as connection 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 .

[0132] In some embodiments of the present invention, ① is a linking site.

[0133] In some embodiments of the present invention, ② is a connection site.

[0134] In some embodiments of the present invention, ③ is a connection site.

[0135] In some embodiments of the present invention, ④ is a linking site.

[0136] In some embodiments of the present invention, ⑦ is a linking site.

[0137] In some embodiments of the present invention, R1' is O or OC(O).

[0138] In some embodiments of the present invention, R7' is O or OC(O).

[0139] In some embodiments of the present invention, R 21 ' is O or OC(O).

[0140] In some embodiments of the present invention, R 22 ' is O or OC(O).

[0141] In some embodiments of the present invention, R2' is a single bond.

[0142] In some embodiments of the present invention, R3' is a single bond.

[0143] In some embodiments of the present invention, R 23 ' is a single bond, O or OC(O).

[0144] In some embodiments of the present invention, R 24 ' is a single bond, O or OC(O).

[0145] In some embodiments of the present invention, R 25 ' is a single bond, O or OC(O).

[0146] In some embodiments of the present invention, R 26 ' is a single bond, O or OC(O).

[0147] Further, in some embodiments of the present invention, the ML moiety is selected from the following structures:

[0148]

[0149]

[0150] 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

[0151] Furthermore, in some embodiments of the present invention, the ML moiety is selected from the following structures:

[0152]

[0153]

[0154]

[0155] In some preferred embodiments of the present invention, only ① is used as the connection site, and the ML part has the following structure:

[0156]

[0157]

[0158] in particular In some embodiments of the present invention, the compound has the following structure:

[0159]

[0160] In some embodiments of the present invention, the compound has the following structure:

[0161]

[0162] in particular In some embodiments of the present invention, only ② is used as the connection site, and the ML part has the following structure:

[0163]

[0164]

[0165] in particular In some preferred embodiments of the present invention, only ③ is used as the connection site, and the ML part has the following structure:

[0166]

[0167]

[0168] In some preferred embodiments of the present invention, only ④ is used as the connection site, and the ML part has the following structure:

[0169]

[0170]

[0171] In some embodiments of the present invention, only ⑦ is used as the connection site, and the ML part has the following structure:

[0172] in particular Specifically, L has the following structure: in,

[0173] 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)-;

[0174] 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)-;

[0175] 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 10aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl);

[0176] 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 heterocyclic group).

[0177] 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.

[0178] 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.

[0179] In some embodiments of the invention, each -CY- is independently selected from the following:

[0180]

[0181]

[0182]

[0183] 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 1-8alkyl)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 it is attached, it forms a cycloalkylene or heterocyclylene.

[0184] More specifically, R L4 , R L5 Independently selected from: -CH3, or, R L4 , R L5 Together with the atoms to which they are attached, they form a three-membered to six-membered cycloalkylene group (e.g. ) or a four-membered to six-membered heterocycloalkylene group (such as ).

[0185] In some embodiments of the present invention, R L1 For H.

[0186] In some embodiments of the present invention, R L3 For H.

[0187] In some embodiments of the present invention, R L4 For H.

[0188] In some embodiments of the present invention, R L4 For OH.

[0189] In some embodiments of the present invention, R L5 For H.

[0190] In some embodiments of the present invention, R L5 For OH.

[0191] In one embodiment of the present invention, L2 is a C1-C20 straight chain alkylene group, wherein 0-6 methylene units in the alkylene group are independently substituted by the following groups: -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R L2 )-、-C(O)N(R L2 )-、-N(R L2 )C(O)-、 Among them, R L2Independently selected from: H, C1-C6 alkyl, each R L4 and R L5 Independently selected from: H, OH, C1-C6 alkoxy.

[0192] 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).

[0193] In some specific embodiments of the present invention, L2 is selected from:

[0194]

[0195] 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).

[0196] In some specific embodiments of the present invention, L2 is selected from:

[0197] In some specific embodiments of the present invention, L2 is selected from:

[0198] In some specific embodiments of the present invention, L2 is selected from:

[0199] In some specific embodiments of the present invention, L2 is selected from:

[0200]

[0201]

[0202] 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.

[0203] In some embodiments of the invention, -CY- is selected from:

[0204]

[0205] In some specific embodiments of the present invention, L2 is selected from:

[0206] In one embodiment of the present invention, L1 is -C(O)-.

[0207] In one embodiment of the present invention, L1 is a single bond.

[0208] In one embodiment of the present invention, the compound has the following structure:

[0209]

[0210]

[0211] In one embodiment of the present invention, the compound has the following structure:

[0212]

[0213] In some embodiments of the present invention, the compound may have the following structure:

[0215]

[0216] wherein n is selected from an integer of 1-10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10).

[0217] Specifically, for the PI part, the target protein can be, for example, a target protein as shown below:

[0218] FAK USP7 GPX4 PI3K JAK MetAP-2 ER AR BET IKAROS RTK ALC EGFR HER2 TRK BTK STAT IRAK4 BCL-XL TBK1 FRS2 STAT3 HDAC6 PDEδ MAFF Tau GSK-3 α-syn mxD TDP-43 FUS SOD NS3 / 4A RIPK2 BCR-ABL PCAF / GCN5 SHP2 Bcl-2 PD-L1 NAMPT EGFR-L858R NA STING FKBP12 TK BRDT FAP Hsp70 NLRP3 cGAS FLT3-ITD c-Met ALK Akt CK2 FLT3 Sirt2 Pirin SMAD3 ARNT CDK2 CDK4 CDK6 CDK9 ERK1 BRD2 BRD4 BRD6 BRD9 ERK2 IKZF1 IKZF3 RAR Bcr / Abl c-Abl DAPK1 PSD-95 TRIM24 CRABP-I CRABP-II TACC3 AHR FKBP12 ERRα X protein Huntingtin DHODH Halo Tags NQO1 GSTP1 CDK12 PARP1 p53 HMGCR LqCy VEGFR-2 SMARCA4 EED SMARCA2 SGK3 EGFR / PARP ERK5 KRAS EZH2 MEK ER / GPER XPO1

[0219] In some embodiments of the invention, the target protein is brominated structural protein 4 (BRD4).

[0220] Specifically, the target protein ligand can be a small molecule compound, an oligonucleotide, an oligopeptide, a polypeptide, a protein (such as an antibody), etc., especially a small molecule compound.

[0221] 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 difference in chemical structure: triazoloazepine derivatives, isoxazole derivatives, pyridine derivatives, tetrahydroquinoline derivatives, triazolopyrazine derivatives, 4-acylpyrrole derivatives, 2-thiazolidinone derivatives, etc., and specific examples are small molecule inhibitors as shown below:

[0222]

[0223]

[0224] (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]. Progress in Pharmaceutical Sciences, Vol. 44, No. 9, 2020, pp. 656-666, CA, 2020: National Natural Science Foundation of China. and other prior art literature).

[0225] In some embodiments of the present invention, the target protein ligand is selected from: JQ1, OTX015, TEN-10, I-BET762, CPI-0610.

[0226] In one embodiment of the invention, the PI moiety has the following structure:

[0227]

[0228] In some embodiments of the present invention, L3 is a single bond, -N(H)- or -C(O)-.

[0229] L3 is a 4-8 membered saturated nitrogen-containing heterocyclic group, such as

[0230] In some embodiments of the present invention, the compound has the following structure:

[0231]

[0232]

[0233] In some embodiments of the present invention, the compound has the following structure:

[0234]

[0235]

[0236]

[0237]

[0238]

[0239]

[0240] In some embodiments of the present invention, the compound has the following structure:

[0241]

[0242]

[0243] In some embodiments of the present invention, the compound has the following structure:

[0244] In some embodiments of the present invention, the compound has the following structure:

[0245]

[0246]

[0247]

[0248] In some embodiments of the present invention, the compound has the following structure:

[0249]

[0250]

[0251]

[0252] In some embodiments of the present invention, the compound has the following structure:

[0253]

[0254]

[0255]

[0256] In some embodiments of the present invention, the stereoisomers of the compound have the following structures:

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264] In some embodiments of the present invention, the stereoisomers of the compound have the following structures:

[0265]

[0266] In some embodiments of the present invention, the stereoisomers of the compound have the following structures:

[0267] In some embodiments of the present invention, the stereoisomers of the compound have the following structures:

[0268]

[0269]

[0270] In some embodiments of the present invention, the stereoisomers of the compound have the following structures:

[0271]

[0272]

[0273]

[0274] In some embodiments of the present invention, the stereoisomers of the compound have the following structures:

[0275]

[0276]

[0277]

[0278] In the third aspect of the present invention, a method for preparing the compound of the second aspect is provided, which comprises the following steps: first preparing PI-L', and then reacting and connecting it with the compound of the first aspect; or,

[0279] First prepare ML-L', and then react and connect with the target protein ligand compound; or,

[0280] Prepare PI-L3-L2'-N3 and ML-L1-L2"-C≡CH separately, and then connect them by click reaction; or

[0281] PI-L3-L2'-C≡CH and ML-L1-L2"-N3 were prepared respectively and then connected by click reaction;

[0282] Wherein, L', L2', and L2" are any suitable connecting groups.

[0283] In the fourth aspect of the present invention, a pharmaceutical composition is provided, comprising the compound described in the second aspect or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuterated compound thereof, and one or more pharmaceutically acceptable excipients.

[0284] 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.

[0285] Specifically, the pharmaceutical composition can be administered by any suitable route, such as gastrointestinal administration (e.g., oral, sublingual, rectal administration) or parenteral administration (e.g., intravenous, intramuscular, intranasal, intraocular, intracerebral, intravaginal, intraperitoneal, transdermal, subcutaneous, intradermal, respiratory tract administration, etc.).

[0286] 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.

[0287] 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.

[0288] Specifically, the pharmaceutical composition is preferably in unit dosage form. In this form, the preparation is subdivided into unit doses containing appropriate amounts of active ingredients. The unit dosage form can be a capsule, tablet or any 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.

[0289] Specifically, in the pharmaceutical composition, the compound described in 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.

[0290] Specifically, the amount of the active ingredient in the unit dose preparation can be changed or adjusted from 0.1 mg to 1000 mg, depending on the specific application and efficacy of the active ingredient. If necessary, the composition may also contain other suitable therapeutic agents.

[0291] In the fifth aspect of the present invention, there is provided the use of the compound of the second aspect or its pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuterated compound 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.

[0292] Specifically, the target protein is as described in the second aspect of the present invention.

[0293] 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, and the like.

[0294] Specifically, the tumor includes but is not limited to: lung cancer, malignant melanoma, brain tumor, tumor of digestive organ, uterine cancer, testicular cancer, palate cancer, pharyngeal cancer, tongue cancer, oral cancer, various sarcomas, osteosarcoma, blood system tumor, nervous system tumor, brain glioma, glioblastoma, skin cancer, skin appendage cancer and skin metastasis, medulloblastoma, glioma, blastoma, liposarcoma, neuroendocrine tumor, synovial cell sarcoma, gastrinoma, carcinoid tumor, 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 carcinoma, 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.

[0295] Specifically, the hematological malignancies include leukemia, lymphoma, and multiple myeloma (MM).

[0296] 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.

[0297] 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's 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).

[0298] 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.

[0299] 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.

[0300] 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.

[0301] Specifically, the pathogen may be a microorganism, a parasite (protozoa, worms, etc.) or other agents.

[0302] Specifically, the microorganism can be selected from one or more of: viruses, chlamydia, rickettsia, mycoplasma, bacteria, spirochetes, fungi and the like.

[0303] 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 (external genital herpes), VZV (varicella), EBV (Epstein-Barr virus), CMV (cytomegalovirus)), Poxviridae (such as smallpox virus, vaccinia virus), Papovaviridae (such as papillomavirus (HPV)), Parvoviridae (such as B19 virus), Hepadnaviridae (such as hepatitis B virus), Polyomaviridae (such as polyomavirus), 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).

[0304] 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.

[0305] Specifically, the cardiovascular disease includes, but is 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, cerebrovascular ischemia (stroke), embolism (such as pulmonary embolism, renal embolism, hepatic embolism, gastrointestinal embolism or peripheral limb embolism) or myocardial ischemia, etc.

[0306] 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.

[0307] Specifically, the fibrotic diseases include, but are not limited to, myocardial fibrosis, pulmonary fibrosis, renal fibrosis, postoperative stenosis, keloid formation, cirrhosis, biliary cirrhosis, scleroderma, and the like.

[0308] In one embodiment of the present invention, the target protein is BRD4, and the disease is as described above, particularly hematological tumors (e.g., 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.

[0309] In the sixth aspect of the present invention, a method for designing and preparing a PROTAC for a target protein is provided, comprising the step of using the compound described in 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.

[0310] Specifically, the target protein is as described in the second aspect of the present invention, such as BRD4.

[0311] 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.

[0312] 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.

[0313] Specifically, the target proteins are those described in the second aspect of the present invention.

[0314] 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.

[0315] 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.

[0316] Specifically, the subject is a mammal, especially a human.

[0317] Specifically, the administration can be 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.).

[0318] The inventors of the present invention creatively discovered a compound that recruits MDM2 by interacting with nucleolin (NCL), and further experiments found that it can be used as a new recruitment element for MDM2, which can be used in PROTAC preparation and other aspects. The inventors prepared PROTAC using the above findings, and found through experiments that the prepared PROTAC 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 has very good application prospects in the field of medicine. BRIEF DESCRIPTION OF THE DRAWINGS

[0319] Figure 1 Shown are the results of the experiment described in Example 1, which demonstrates that NCL can bind to MDM2.

[0320] Figure 2 The results of the experiment described in Example 2 are shown, which show that the compound of Formula I Ori relies on the interaction with NCL to recruit MDM2, and iSN04 can only bind to NCL but cannot rely on NCL to recruit MDM2.

[0321] Figure 3 The results of the experiment described in Example 2 are shown, which show that the compound of Formula I, Ori, can capture NCL and MDM2, and iSN04 can only capture NCL but not MDM2.

[0322] Figure 4 Shown are the results of the experiment described in Example 2, which show that the compound of Formula I, Ori, can capture NCL and MDM2, and silencing NCL can block Ori from recruiting MDM2.

[0323] Figure 5 Shown are the results of the experiment described in Example 2, which show 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.

[0324] Figure 6 Shown is a schematic diagram of the possible mode of action of PROTAC formed by the compound of formula I as a recruitment element of MDM2.

[0325] Figure 7Shown are the results of the experiment described in Example 4, which show that the PROTAC prepared by the present invention can induce the formation of an MDM2-NCL-PROTAC-target protein quaternary complex.

[0326] Figure 8 Shown are the results of the experiment described in Example 5, which show that the PROTAC (Ori-JQ1-1) prepared by the present invention can degrade BRD4.

[0327] Fig. 9 Shown are the results of the experiment described in Example 5, which show that the PROTACs (Ori-JQ1-2, Ori-JQ1-3 and Ori-JQ1-4) prepared by the present invention can degrade BRD4.

[0328] Fig.10 Shown are the results of the experiment described in Example 5, which show that the PROTACs (Ger-JQ1, Ori-JQ1-5, CYD-JQ1-6, CYD-JQ1-7 and OriPh-JQ1-8) prepared by the present invention can degrade BRD4.

[0329] Fig.11 Shown are the results of the experiment described in Example 6, which show that the PROTAC prepared by the present invention can promote the ubiquitination of BRD4.

[0330] Fig.12 Shown are the results of the experiment described in Example 7, which show that the PROTAC prepared by the present invention relies on MDM2 and NCL to mediate the degradation of BRD4.

[0331] Fig.13 The results of the experiment described in Example 8 are shown, which show that the PROTAC prepared by the present invention can inhibit the proliferation of liver cancer cells and promote the apoptosis of liver cancer cells.

[0332] Fig.14 The results of the experiment described in Example 8 are shown, which show that the PROTAC prepared by the present invention can inhibit the proliferation of lung cancer cells and promote the apoptosis of lung cancer cells.

[0333] Fig.15 Shown are the results of the experiment described in Example 9, which show that the PROTAC prepared by the present invention can inhibit tumor cell growth in vivo. DETAILED DESCRIPTION

[0334] 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.

[0335] 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, etc. Typical aliphatic groups contain 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, preferably 1 to 6 carbon atoms.

[0336] The term "alkyl" refers to a straight or branched hydrocarbon chain radical that does not contain an unsaturated bond, and the hydrocarbon chain radical 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 "heterocyclic alkyl group". In the present invention, a C0 alkyl group refers to H, i.e., C0 0-10 Alkyl (or C0-C 10 Alkyl) includes H and C 1-10 Alkyl (or C1-C 10 alkyl).

[0337] 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 a 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 a single bond and C 1-10 Alkylene (or C1-C 10 alkylene).

[0338] The term "cycloalkyl" refers to alicyclic hydrocarbons, such as those containing 1 to 4 single rings and / or condensed rings, 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.

[0339] The term "alkoxy" refers to a substituent formed by replacing the hydrogen in a hydroxy group with an alkyl group, such as an alkoxy group containing 1 to 10 carbon atoms, for example, methoxy, ethoxy, propoxy, butoxy, and the like.

[0340] The term "alkylamino" refers to a substituent formed by replacing one or both hydrogen atoms in an amino group (-NH2) with an alkyl group, such as an alkylamino group containing 1 to 10 carbon atoms, for example

[0341] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0342] The term "haloalkyl" refers to a group formed by replacing one or more hydrogen atoms in an alkyl group with a halogen atom (e.g., fluorine, chlorine, bromine or iodine), for example, -CHF2, -CH2F, -CF3, -CH2-CF3, -CH2CH2-CF3, -CH2CH2CH2-CF3.

[0343] 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 free 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 and the like.

[0344] 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. The heterocyclyl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can contain fused, spirocyclic or bridged ring systems. The 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, furazanyl, pyridazinyl, triazinyl, cinnolinyl, benzimidazolyl, benzofuranyl, benzofurazanyl, 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, oxathiolanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxirane, thiirane, azepine, oxazepine, diazepine, In the present invention, for the optionally substituted heterocyclic group, the substituted position can be any suitable carbon atom or heteroatom, for example, The substitution position of R can be on any suitable carbon atom or nitrogen atom, which can be, for example

[0345] 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.

[0346] It should be recognized that, depending on the source of the chemical materials used in the synthesis, there is some variation in the natural isotopic abundance in the synthesized compounds. Therefore, the compounds of the present invention will inherently contain small amounts of deuterated isotopologues. Despite this variation, the concentration of such naturally abundant stable hydrogen and carbon isotopes is still very low and insignificant compared to the degree of stable isotopic substitution of the compounds of the present invention. See, for example, Wada, E et al., Seikagaku, 1994, 66: 15; Gannes, LZ et al., Comp Biochem Physiol Mol Integr Physiol, 1998, 119: 725.

[0347] In the compounds of the present invention, any atom not designated as deuterium is present at its natural isotopic abundance. Unless otherwise specified, when a position is specifically designated as "H" or "hydrogen", the position is understood to have hydrogen according to its natural abundance isotopic composition. Similarly, unless otherwise specified, 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).

[0348] As used herein, the term "isotopic enrichment factor" refers to the ratio between the isotopic abundance and the natural abundance of a particular isotope.

[0349] 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).

[0350] The term "isotopologue" refers to species wherein the chemical structure differs from a specific compound of the present invention only in its isotopic composition.

[0351] The term "pharmaceutically acceptable salts" includes acid addition salts and base addition salts.

[0352] The term "acid addition salt" includes, but is not limited to, salts from inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic and phosphonic acids, and salts 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. 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 comprising amino acid salts such as arginate, gluconate, galacturonate etc. Acid addition salts can be prepared by contacting the free alkali form with a sufficient amount of the required acid to form a salt in a conventional manner. The free alkali form can be regenerated by contacting the salt form with an alkali, and the free alkali is separated in a conventional manner.

[0353] The term "base addition salt" refers to a salt formed with a metal or amine, such as an alkali metal and alkaline earth metal hydroxide, or with an organic amine. 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 a 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.

[0354] The term "stereoisomer" includes the presence of enantiomers, diastereomers and geometric isomers. Some compounds of the present invention have cyclic hydrocarbon groups that can be substituted on more than one carbon atom, in which case all geometric forms, including cis and trans, and mixtures thereof, are within the scope of the present invention.

[0355] The term "solvate" refers to a physical association of a compound of the invention with one or more solvent molecules. The physical association includes various degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, the solvate can be isolated, for example when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Solvates include solution phases and separable solvates. Representative solvates include ethanolates, methanolates, and the like.

[0356] The term "prodrug" refers to a form of the compound of formula I which is suitable for administration to patients without undue toxicity, irritation, allergic response, etc. and is effective for its intended use, including acetal, ester and zwitterion forms. The prodrug is transformed in vivo, such as by hydrolysis in the blood, to yield the parent compound.

[0357] In the present invention, the term "oligonucleotide" is composed of 30 or less (e.g., 5, 10, 15, 20, 25, 30) nucleotides (deoxyribonucleotides and / or ribonucleotides), which are single-stranded or double-stranded, especially single-stranded. The oligonucleotide may include chemical modification, nucleic acid unit replacement or connection functional groups; wherein the chemical modification is that at least one base is modified, and the chemical modification includes at least one of phosphorylation, methylation, amination, sulfhydrylation, isotopization, thiophosphate backbone modification, methoxy modification, and fluorination modification; the nucleic acid unit is replaced by at least one nucleic acid unit replaced by LNA, UNA or GNA; the functional group includes at least one of a fluorescent group, a radioactive group, biotin, digoxin, a nanoluminescent material, a nucleic acid substance or an enzyme marker.

[0358] 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.

[0359] The term "patient" or "subject" and the like are used interchangeably herein and refer to any animal or cell thereof treated according to the methods described herein, whether in vitro or in situ. Specifically, the aforementioned animal includes mammals, e.g., rats, mice, guinea pigs, rabbits, dogs, monkeys or humans, particularly humans.

[0360] 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.

[0361] The term "prevent" refers to avoiding, minimizing or making the onset or development of a disease difficult by treating it before it occurs.

[0362] The term "BRD4-mediated disease" mainly refers to diseases associated with abnormal BRD4 activity, especially diseases that can be beneficially prevented and / or treated by inhibiting / degrading BRD4.

[0363] 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: degree of cell differentiation (including morphology and function), growth rate, local invasion and metastasis. "Benign tumors" are usually well-differentiated, characterized by slower growth 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, some "benign" tumors may later lead to malignant tumors, which may be caused by additional genetic changes in a subpopulation of the neoplastic cells of the tumor, 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.

[0364] The term "cancer" refers to a malignant tumor (Stedman's Medical Dictionary, 25th ed.; Hensyled.; Williams & Wilkins: Philadelphia, 1990).

[0365] 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.

[0366] The term "inflammation" is the body's defense response to stimulation, manifested as redness, swelling, heat, pain, and dysfunction, etc. It can be infectious inflammation caused by infection, or non-infectious inflammation not caused by infection, such as inflammation caused by immune response (such as various types of hypersensitivity reactions, inflammation caused by some autoimmune diseases). The term "inflammatory disease" refers to a disease with inflammation.

[0367] The term "diseases associated with pathogen infection" mainly refers to diseases caused by pathogen infection, which include symptoms of body damage and infection response caused by pathogen invasion.

[0368] The term "cardiovascular disease" refers to a group of diseases involving the heart or blood vessels.

[0369] 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.

[0370] The term "fibrosis" refers to the pathological process in which inflammation leads to necrosis of organ parenchymal cells, abnormal increase and excessive deposition of extracellular matrix in tissues. In severe cases, it causes destruction of tissue structure and organ sclerosis.

[0371]

[00136] Various publications, patents, and published patent specifications are cited herein, the disclosures of which are incorporated by reference in their entireties.

[0372] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments 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 creative work are within the scope of protection of the present invention.

[0373] The compounds Ori, Ger, CYD, and OriPh described in the following examples are examples of compounds of formula I, and have the following structures respectively:

[0374]

[0375] Example 1: NCL can bind to MDM2

[0376] Co-immunoprecipitation (Co-IP) is a classic method for studying protein interactions based on the specific interaction between antibodies and antigens.

[0377] 1. Lyse the liver cancer cells Hep3B with IP lysis buffer (purchased from Thermo Scientific, catalog number 87788) and incubate with NCL antibody at 4°C overnight. Add Protein A / G magnetic beads (purchased from Thermo Scientific, catalog number 88802) and rotate and incubate at room temperature for 2 hours. Wash the NCL and its interacting protein complex bound to the magnetic beads with IP lysis buffer (purchased from Thermo Scientific, catalog number 87788), add SDS-PAGE protein loading buffer (purchased from Beyotime, catalog number P0015), heat to 100°C and continue for 10 minutes. Use a magnetic stand to adsorb the magnetic beads and take the supernatant to a new tube. Then perform an immunoblot experiment (western blot) to detect whether NCL binds to MDM2. The steps of the immunoblotting experiment are as follows: the 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 the primary antibody of MDM2 (purchased from proteintech, catalog number 27883-1-AP) or the primary antibody of NCL (purchased from Cell Signaling Technology, catalog number 14574S) at 4°C overnight, and then washed with TBST. The membrane was incubated with HRP-labeled secondary antibody (purchased from Abotek, catalog number AS014) at room temperature for 1 hour, and the protein band blot was visualized using an enhanced chemiluminescence detection kit (purchased from Abotek, catalog number RM00021P). Figure 1 The results of A indicate that NCL can bind to MDM2.

[0378] 2. Mix 2μg / mL recombinant human NCL (rhNCL, purchased from ACROBiosystems, NUL-H5253) and 2μg / mL recombinant human MDM2 (rhMDM2, purchased from R&D Systems, E3-202-050) and incubate at 4°C for 7 hours, then add NCL antibody and continue incubation at 4°C overnight. Add Protein A / G magnetic beads (purchased from Thermo Scientific, catalog number 88802) and incubate at room temperature for 1.5 hours. Wash the magnetic beads three times with TBST buffer, add SDS-PAGE protein loading buffer (purchased from Biyuntian, catalog number P0015), heat to 100°C and continue for 10 minutes. Use a magnetic stand to adsorb the magnetic beads and take the supernatant to a new tube. Then perform an immunoblotting experiment to detect whether NCL binds to MDM2. Figure 1 The results in B indicate that NCL can bind to MDM2.

[0379] Example 2: Compound Ori recruits MDM2 via interaction with NCL

[0380] 1. We prepared the compound of formula I Ori (Bio-Ori-1) with biotinylation of the hydroxyl group at the C-14 position. The specific preparation steps are as follows:

[0381]

[0382] Under nitrogen protection, 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), stirred at room temperature for 16 hours, and the reaction progress was monitored by LCMS. After the reaction was completed, the impure product was purified by Prep-HPLC (Waters 2767 / Qda, Column: SunFire Sunfire C18, 19*250 mm, 10 um; Mobile Phase A: 0.1% FA / H2O, B: ACN; flow rate: 20 mL / min; gradient: 34% to 44%; Retention Time: 7.6-8.3 min of 17 min). The pure fractions were combined and freeze-dried under reduced pressure to obtain 34 mg of a white solid compound Bio-Ori-1 with a yield of 20.17%.

[0383] LCMS: m / z = 591.6 [M+H] + ,t R =8.447min.Purity:100%(254nm).

[0384] 1H NMR(400MHz,DMSO-d6)δ6.38(2s,2H),6.00(s,1H),5.92-5.79(m,3H),5.61(s,1H),4.40(s,1H),4.34-4.26(m,1H) ,4.17-4.02(m,2H),3.83(d,J=10.2Hz,1H),3.53-3.49(m,1H),3.33(s,1H),3.10-3.05(m,1H),2.96(d,J=9.6Hz,1H ),2.84-2.79(m,1H),2.59-2.56(m,1H),2.50-2.43(m,1H),2.18-2.12(m,2H),2.09-2.00(m,7.6Hz,1H),1.86-1.8 1(m,1H),1.77-1.64(m,1H),1.64-1.39(m,7H),1.35-1.17(m,4H),1.12(d,J=6.8Hz,1H),1.00(s,3H),0.99(s,3H).

[0385] 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.

[0386] 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: (1)

[0388]

[0389] 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 give compound 2 (1.0 g, 90.9%) as a white solid.

[0390] LCMS: m / z = 387.2 [M-OH] + ,Rt=1.894min.Purity:92.4%(214nm). (2)

[0392]

[0393] Under N2, EDCI (1.56 g, 8.16 mmol) and DMAP (1 g, 8.16 mmol) were added to a DMF (10 ml) solution of compound 2 (1.1 g, 2.72 mmol) and compound 3 (1 g, 4.08 mmol). The mixture was stirred at room temperature for 16 hours. LCMS showed that the reaction was complete. The reaction solution was purified by preparative HPLC (Welch Xtimate C18 200×30 mm×5 um water (0.1% FA)-MeCN, 5-95%, 60 mL / min) to obtain compound 4 (317 mg, 17.84%) as a white solid.

[0394] LCMS: m / z = 613.3 [M-OH] + ,Rt=1.610min.Purity:96.31%(214nm). (3)

[0396]

[0397] 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 um water (0.1% FA)-MeCN, 5-95%, 60 mL / min) to give Bio-Ori-2 (47 mg, 15.83%) as a white solid.

[0398] LCMS: m / z = 573.6 [M-OH] + ,Rt=8.691min.Purity:100%(214nm).

[0399] 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).

[0400] 13 C NMR(101MHz,DMSO-d6)δ208.93,172.31,163.17,152.10,119.99,97.31,75.07,73.44,72.90,62.89,61.62,61.57,59.73 ,59.65,55.89,51.81,43.06,40.62,40.34,39.36,37.90,34.23,33.66,32.78,30.08,28.51,25.27,24.76,21.96,18.04.

[0401] 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.

[0402] 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, followed by the addition of 400 nM Bio-Ori-1, Bio-Ori-2, biotinylated CRO (Bio-CRO: CCTCCTCCTCTCTCTCCTCCTCCC, SEQ ID NO: 4, negative control) or iSN04 (Bio-iSN04: AGATTAGGGTGAGGGTGA, SEQ ID NO: 5), incubated at 4°C for 6 hours, and then added with streptavidin agarose beads (purchased from cytiva, catalog number 17511301) and continued to incubate at 4°C overnight. The beads were washed 4 times with TBST buffer, and SDS-PAGE protein loading buffer (purchased from Beyotime, catalog number P0015) was added and heated to 100°C for 10 minutes. The supernatant was collected after centrifugation. Then, immunoblotting was performed to detect the pull-down products. Figure 2 The results of A and 2B indicate that Ori can bind to NCL but not to MDM2; however, in the presence of NCL, Ori can rely on NCL to recruit MDM2. Figure 2 The results of C indicate that CRO can neither bind to NCL nor recruit MDM2. Figure 2 The results in D indicate that iSN04 can only bind to NCL but cannot rely on NCL to recruit MDM2.

[0403] 4. Hep3B liver cancer cells were lysed with IP lysis buffer (purchased from Thermo Scientific, catalog number 87788), and then incubated with different concentrations (0 μM, 200 nM, 500 nM, 1 μM, 5 μM, 10 μM, 20 μM) of Bio-Ori-1, Bio-Ori-2, Bio-CRO or Bio-iSN04 at 4°C for 6 hours, followed by the addition of streptavidin agarose beads (purchased from cytiva, catalog number 17511301) and continued incubation at 4°C overnight. After washing the Bio-Ori-1, Bio-Ori-2, Bio-CRO or Bio-iSN04 bound to the gel beads and the captured proteins 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 taken, which was the pull-down product. The pull-down product was detected by immunoblotting. Figure 3Results from A and 3B indicate that Ori can capture NCL and MDM2; Figure 3 The results of C showed that CRO could not capture NCL and MDM2; Figure 3 The results in D indicate that iSN04 can capture NCL but not MDM2.

[0404] 5. Incubate the liver cancer cells Hep3B with solvent DMSO (Veh) or 1μM Bio-Ori-1 for 12 hours. After the cells are lysed, incubate the supernatant with streptavidin agarose gel beads (purchased from cytiva, product number 17511301) at 4°C overnight. After washing the Bio-Ori-1 bound to the gel beads and the captured proteins with IP lysis buffer (purchased from Thermo Scientific, product number 87788) several times, add SDS-PAGE protein loading buffer (purchased from Beyotime, product number P0015), heat to 100°C and continue for 10 minutes. After centrifugation, take the supernatant, which is the pull-down product. The pull-down product was detected by immunoblotting. The results are as follows. Figure 4 As shown in A, Ori can capture NCL and MDM2.

[0405] 6. Negative control siRNA (siNC: UUCUCCGAACGUGUCACGUTT, SEQID NO: 1) or NCL siRNA (siNCL: GGAUGACGACGACGACGAAGATT, SEQ ID NO: 2) was transfected into liver cancer cells Hep3B. After 48 hours, the cells were incubated with 1 μM Bio-Ori-1 for 12 hours, the cells were lysed, and the supernatant was incubated with streptavidin agarose gel beads at 4°C overnight. After washing the Bio-Ori-1 bound to the gel beads and the captured proteins with IP lysis buffer (purchased from Thermo Scientific, catalog number 87788) several times, SDS-PAGE protein loading buffer (purchased from Bio-Time, catalog number P0015) was added and heated to 100°C for 10 minutes. After centrifugation, the supernatant, i.e. the pull-down product, was taken and the pull-down product was detected by immunoblotting. The results are as follows. Figure 4 B, Silencing of NCL blocks the recruitment of MDM2 by Ori.

[0406] 7. Hep3B liver cancer cells were lysed with IP lysis buffer (purchased from Thermo Scientific, catalog number 87788), and then incubated with different concentrations (0μM, 1μM, 5μM, 10μM, 20μM) of Ori or iSN04 at 4°C for 6 hours, followed by the addition of NCL antibody and continued incubation at 4°C overnight. Protein A / G magnetic beads (purchased from Thermo Scientific, catalog number 88802) were added and rotated and incubated at room temperature for 1.5 hours. NCL bound to the magnetic beads and the captured proteins were washed with IP lysis buffer (purchased from Thermo Scientific, catalog number 87788), and SDS-PAGE protein loading buffer (purchased from Beyotime, catalog number P0015) was added and heated to 100°C for 10 minutes. The magnetic beads were adsorbed with a magnetic stand and the supernatant was taken to a new tube. Then, an immunoblotting experiment was performed to detect whether Ori or iSN04 affects the interaction between NCL and MDM2. Figure 5 The results of A showed that Ori did not affect the interaction between NCL and MDM2. The same experiment was performed using other compounds of formula I, and the experimental results were similar to those of compound Ori. However, Figure 5 The results in B indicate that iSN04 blocks the binding of NCL to MDM2.

[0407] 8. The above results show that the compound of formula I relies on the interaction with NCL to recruit MDM2. Although iSN04 interacts with NCL, it cannot rely on the interaction with NCL to recruit MDM2. Our further analysis found that the compound of formula I does not affect the binding of NCL and MDM2, but iSN04 blocks the binding of NCL and MDM2. These data tell us that not all molecules that interact with NCL can be used to recruit MDM2. Whether the interacting molecules 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 show that the compound of formula I does rely on the interaction with NCL to recruit MDM2. The possible mode of action is as follows. Figure 6 As shown in A. Therefore, we believe that the compound of formula I can serve as a recruitment element for MDM2 to form PROTAC, and the possible mode of action is as follows Figure 6 As shown in B.

[0408] Example 3: Preparation of PROTAC molecules based on compounds of formula I

[0409] Bromodomain-containing protein 4 (BRD4) is a bromodomain-containing protein and a member of the bromodomain and extraterminal domain (BET) protein family. BRD4 usually recognizes acetylated histones and localizes to the promoter or enhancer region of the target gene to initiate and maintain the expression of tumor-related genes. BRD4 can affect physiological processes such as cell cycle, proliferation and apoptosis, plays an important role in the infiltration and metastasis of tumor cells and the malignant development of tumors, and is a potential target for the treatment of various tumors.

[0410] 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:

[0411] 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.

[0412] The specific preparation steps are as follows: (1)

[0414]

[0415] Compound 1 (1 g, 2.19 mmol) was added to a hydrochloric acid / 1,4-dioxane (8 mL) solution, stirred at room temperature for 2 hours, and monitored by LCMS. The mixture was concentrated in vacuo to obtain 1.2 g of yellow solid compound 2 (crude sample), which was directly used in the next step without purification.

[0416] LCMS: m / z = 401.2 [M+H] + ,Rt=1.581min,purity:100%(214nm) (2)

[0418]

[0419] HATU (713 mg, 1.88 mmol), compound 3 (367 mg, 1.88 mmol) and N,N-diisopropylethylamine (DIEA, 485 mg, 3.75 mmol) were added to a solution of compound 2 (500 mg, 1.25 mmol) in dimethylformamide (DMF, 10 ml), stirred at room temperature for 2 hours, and monitored by LCMS. After the reaction was completed, the mixture was diluted with 10 ml EA, then washed with water (3*10 mL) and brine (3*10 mL). The organic layer was dried over Na2SO4, concentrated and purified by flash column chromatography and eluted with dichloromethane / methanol (10:1) to obtain 550 mg of yellow solid compound 4 with a yield of 73%.

[0420] LCMS: m / z = 542.3 [M+H] + ,Rt=1.750min,purity:100%(214nm).

[0421] 1 HNMR (400MHz, DMSO-d6) δ8.16 (t, J = 5.6 Hz, 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). (3)

[0423]

[0424] Compound 4 (500 mg, 0.92 mmol) was dissolved in 1,4-dioxane (5 ml) and water (2 ml) solution, LiOH.H2O (110 mg, 4.61 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS until completion. Then, the pH value of the mixture was slowly adjusted to 5 with HCl (1 M) at low temperature. Next, the mixture was extracted with 10 ml EA (4 times) (10 mL*4). Finally, 500 mg of yellow solid compound 5 (crude sample) was obtained by vacuum concentration, which can be directly used in the next step without purification.

[0425] LCMS: m / z = 528.2 [M+H] + ,Rt=1.333min,purity:100%(214nm)

[0426] 1HNMR(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). (4)

[0428]

[0429] 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), and 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 white solid Ori-JQ1-1 was finally obtained with a yield of 78%.

[0430] LCMS: m / z = 874.6 [M+H] + ,Rt=11.048min,purity:100%(214nm)

[0431] 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).

[0432] 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.

[0433] 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.

[0434] The specific preparation steps are as follows: (1)

[0436]

[0437] 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 showed that the reaction was complete. The mixture was concentrated in vacuo to give compound 2 (1.2 g, crude product) as a yellow solid, which was used in the next step without further purification.

[0438] LCMS: [M+H] + =401.2, Rt=1.581min, purity: 100% (214nm) (2)

[0440]

[0441] 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 the reaction was completed, the mixture was diluted with EA (50 mL), washed with water (3*20 mL), brine (3*20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography, eluted with DCM / MeOH (10:1) to give compound 4 (550 mg, 73% yield) as a yellow solid.

[0442] LCMS: [M+H] + =542.3, Rt=1.750min, purity:100% (214nm).

[0443] 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). (3)

[0445]

[0446] 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), a yellow solid, which was used in the next step without further purification.

[0447] LCMS: [M+H] + =528.2, Rt=1.333min, purity: 100% (214nm)

[0448] 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). (4)

[0450]

[0451] Compound 6 (153 mg, 0.38 mmol) was added 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), and the mixture was stirred at room temperature for 4 hours. LCMS showed that the reaction was complete. The mixture was concentrated and purified by reverse phase chromatography [acetonitrile / water / FA (0.02%): 60% to 90%] to give compound 7 (80 mg, 23% yield) as a white solid.

[0452] LCMS: [M+H] + =914.5, Rt = 6.99min, purity: 100% (214nm)

[0453] 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). (5)

[0455]

[0456] 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 value 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%~50%] to give Ori-JQ1-2 (40 mg, 53% yield) as a white solid.

[0457] LCMS: [M+H] + =874.5, Rt = 6.11min, purity: 100% (214nm)

[0458] 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).

[0459] 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.

[0460] 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.

[0461] The specific preparation steps are as follows: (1)

[0463]

[0464] HATU (760 mg, 2 mmol) and compound 2 (554 mg, 2 mmol) were added to a solution of compound 1 (400 mg, 1 mol) in DMF (5 mL). 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 (eluted with EA: PE = 0% to 20% to 50%) to give compound 3 as a yellow solid (500 mg, 75.90% yield).

[0465] LCMS: m / z = 661.86 [M+H] + , Rt=1.79min, purity: 51.8% (254nm). (2)

[0467]

[0468] 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 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 give compound 4 (200 mg, yield: 91.07%) as a yellow solid.

[0469] LCMS: m / z=604.2[M+H] + , Rt=1.482min, purity:84.51% (254nm). (3)

[0471]

[0472] 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 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).

[0473] LCMS: m / z = 950.8 [M+H] + , Rt=10.392min, purity:96.65% (254nm).

[0474] 1 H 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).

[0475] 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.

[0476] The specific preparation steps are as follows: (1)

[0478]

[0479] 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 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, a brown solid (2.0 g, 98%), which was used in the next step without further purification.

[0480] 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). (2)

[0482]

[0483] 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 showed 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.

[0484] 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). (3)

[0486]

[0487] 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) as a yellow solid, which was used in the next step without further purification.

[0488] LCMS: m / z = 401.0 [M+H] + ,Rt=1.257min,Purity:74.48%(214nm). (4)

[0490]

[0491] HATU (950 mg, 2.5 mmol) and DIEA (322.5 mg, 2.5 mmol) were added to a DMF (20 mL) solution of compound 5 (0.5 g, 1.25 mmol) and compound 3 (547.5 mg, 2.5 mmol). The mixture was stirred at room temperature under 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 x3). 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).

[0492] LCMS: m / z = 566.2 [M+H] + ,Rt=1.360min,Purity:81.35%(214nm). (5)

[0494]

[0495] 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 give crude compound 7 (500 mg) as a yellow solid.

[0496] LCMS: m / z=552.2[M+H] + ,Rt=1.272min,Purity:76.87%(214nm). (6)

[0498]

[0499] HATU (623.2 mg, 1.64 mmol) and DIEA (211.56 mg, 1.64 mmol) were added to a DMF (20 mL) solution of compound 7 (0.45 g, 0.82 mmol) and compound 8 (322.54 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).

[0500] LCMS: m / z = 692.2 [M+H] + ,Rt=1.19min,Purity:65.37%(214nm). (7)

[0502]

[0503] 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 give crude compound 10 (210 mg) as a yellow solid.

[0504] LCMS: m / z=677.2[M+H] + ,Rt=1.257min,Purity:79.41%(214nm). (8)

[0506]

[0507] To a solution of compound 10 (100 mg, 0.148 mmol) in DMF (5 mL) was 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 Ar atmosphere for 16 hours. LCMS showed that the reaction was complete. The mixture was filtered. The filtrate was purified by prep-HPLC to give Ori-JQ1-4 as a white solid (33.1 mg, 21.86% yield).

[0508] LCMS: m / z = 1023.6 [M+H] + ,Rt=10.853min,Purity:100%(214nm).

[0509] 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).

[0510] 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.

[0511] The specific preparation steps are as follows: (1)

[0513]

[0514] TFA (20 mL) was added to a DCM (50 mL) solution of INT-1 (10 g, 21.92 mmol). The mixture was then stirred at room temperature under an Ar atmosphere for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to give INT-2 (brown oil, 10 g (crude product)).

[0515] LCMS: m / z = 401.0 [M+H] + ,Rt=1.533min,Purity:52.88%(214nm). (2)

[0517]

[0518] HATU (3.45 g, 8.98 mmol) and DIEA (2.89 g, 22.44 mmol) were added to a DMF (30 mL) solution of INT-2 (3 g, 7.48 mmol) and N-tert-butyloxycarbonyl-1,3-propylenediamine (1.56 g, 8.98 mmol). The mixture was then stirred at room temperature under Ar atmosphere for 1 hour. After the reaction was completed, 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 and eluted with EA:PE=50% to give INT-3 (white solid, 3 g, 71.94% yield).

[0519] LCMS: m / z=557.1[M+H] + ,Rt=1.683min,Purity:12.55%(214nm). (3)

[0521]

[0522] TFA (2 mL) was added to a DCM (10 mL) solution of INT-3 (1 g, 1.79 mmol). 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)).

[0523] LCMS: m / z = 457.2 [M+H] + ,Rt=1.275min,Purity:62.42%(214nm). (4)

[0525]

[0526] PPTS (690 mg, 2.74 mmol) and INT-6 (7.14 g, 54.88 mmol) were added to a solution of INT-5 (2 g, 5.49 mmol) in DCE (25 mL). The mixture was then stirred overnight at 80 ° C under an Ar atmosphere. After the reaction was completed, 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).

[0527] LCMS: m / z = 477.4 [M+H] +,Rt=9.193min,Purity:71.40%(214nm). (5)

[0529]

[0530] DIEA (80 mg, 0.62 mmol), INT-4 (215 mg, 0.47 mmol) and HATU (236 mg, 0.62 mmol) were added to a solution of INT-7 (138 mg, 0.31 mmol) in DMF (3 mL). The mixture was then stirred at room temperature under Ar atmosphere for 0.5 h. After the reaction was complete, the mixture was concentrated in vacuo and purified by reverse phase chromatography [ACN / water (10 mmol NH4HCO3 / H2O): 52% to 58%] to give Ger-JQ1 as a white solid (17.31 mg, 6.29% yield).

[0531] LCMS: m / z = 915.9 [M+H] + ,Rt=10.55min,Purity:100%(214nm).

[0532] 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).

[0533] 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.

[0534] The specific preparation steps are as follows: (1)

[0536]

[0537] At 0°C, NaH (66 mg, 1.64 mmol) was added to a DMF (5 mL) solution of compound 1 (500 mg, 1.37 mmol). 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).

[0538] LCMS: m / z = 564.6 [M+H] + ,Rt=2.321min,Purity:2.326%(214nm). (2)

[0540]

[0541] 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.

[0542] LCMS: m / z = 464.6 [M+H] + ,Rt=1.836min,Purity:86.55%(214nm). (3)

[0544]

[0545] HATU (224 mg, 0.59 mmol) and DIEA (151 mg, 1.17 mmol) were added to a DMF (5 mL) solution of compound 3 (180 mg, 0.39 mmol) and compound 4 (156 mg, 0.39 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).

[0546] LCMS: m / z = 846.7 [M+H] +,Rt=1.836min,Purity:100.00%(214nm).

[0547] 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).

[0548] 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.

[0549] The specific preparation steps are as follows: (1)

[0551]

[0552] 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.

[0553] LCMS: m / z = 230.4 [M+H] + ,Rt=1.414min. (2)

[0555]

[0556] 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 reactant was stirred at room temperature for 2 hours. After the reaction was completed, 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, eluted with MeOH:DCM=5%, to give compound 9 as a yellow solid (1 g, 65.79% yield).

[0557] LCMS: m / z=612.4 [M+H] + ,Rt=2.231min,Purity:46.04%(214nm). (3)

[0559]

[0560] At 0°C, LiOH (1 mol / L, 9 mL) was added to a solution of compound 9 (1 g, 1.63 mol) in THF (9 mL), and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, 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), the organic phase was washed with a saturated solution of NaCl (50 mL), and dried over anhydrous Na2SO4. After filtration, the mixture was concentrated under reduced pressure to obtain compound 5 as a white solid (0.6 g, 61.66%).

[0561] LCMS: m / z=598.3[M+H]+, Rt=1.879min, Purity: 100% (214nm). (4)

[0563]

[0564] Jones reagent (6 mL) was added dropwise to a solution of compound 1 (5 g, 13.7 mmol) in acetone (100 mL) 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).

[0565] LCMS: m / z = 345.2 [M-OH] + ,Rt=1.065min,Purity:79.49%(214nm). (5)

[0567]

[0568] PyHBr3 (1760 mg, 5.4 mmol) was added to a solution of compound 2 (2000 mg, 5.4 mmol) in THF (4 mL) at room temperature. The reaction mixture was stirred at room temperature for 4 hours, then poured into water (50 mL) and extracted with CH2Cl2 (50 mL×3). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, 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%).

[0569] LCMS: m / z = 423.2, 425.2 [M-OH] + ,Rt=1.120min,Purity:78.30%(214nm). (6)

[0571]

[0572] 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 to reflux for 3 hours. After cooling, the mixture was concentrated in vacuo to give an oily residue. The residue was purified by silica gel column; eluted with 50% EtOAc in hexane to give the desired product compound 4 as an amorphous gel (80 mg, 38% yield).

[0573] LCMS: m / z = 459.2 [M+H] + ,Rt=1.080min,Purity:44.69%(214nm). (7)

[0575]

[0576] DMAP (16 mg, 0.13 mmol), EDCI (77 mg, 0.40 mmol) and compound 4 (80 mg, 0.174 mmol) were added to a solution of compound 5 (80 mg, 0.134 mmol) in DMF (2 mL). The mixture was then stirred overnight at 25 ° C. under Ar atmosphere. After the reaction was completed, the mixture was concentrated in vacuo and purified by reverse phase chromatography [ACN / water (0.1% FA)): 85% to 95%] to give CYD-JQ1-6 as a white solid (14 mg, 10% yield).

[0577] LCMS: m / z = 1060.9 [M + Na] + ,Rt=12.327min,Purity:100%(214nm).

[0578] 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).

[0579] 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.

[0580] The specific preparation steps are as follows:

[0581]

[0582] EDCI (40.24 mg, 0.210 mmol), compound 4 (synthesized by the relevant method in Part 6) (48.09 mg, 0.105 mmol) and DMAP (24.62 mg, 0.210 mmol) were added to a DMF (5 mL) solution of compound 10 (synthesized by the relevant method in Part 4) (70 mg, 0.105 mmol). The mixture was stirred at room temperature under Ar atmosphere for 16 hours. LCMS showed that 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 / H2O, 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).

[0583] LCMS: m / z = 1139.6 [M + Na] + ,Rt=2.931min,Purity:100%(214nm).

[0584] 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).

[0585] 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.

[0586] The specific preparation steps are as follows: (1)

[0588]

[0589] 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.

[0590] LCMS: m / z = 984.3 [M+H] + ,Rt=1.749min.Purity:39%(214nm). (2)

[0592]

[0593] 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) at N2 150°C and reacted for 16 hours. LCMS showed that the reaction was complete.

[0594] The mixture was diluted with EA (50 mL), washed with water (20 mL×3), brine (20 mL×3). The combined organic layer was dried over Na2SO4 and filtered. After filtration, it 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).

[0595] LCMS: m / z = 1060.2 [M+H] + ,Rt=1.680min.Purity:47.4%(214nm). (3)

[0597]

[0598] 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 that the reaction was complete. The crude product was purified by reverse phase column chromatography (elution: ACN in H2O = 5% to 95%) to give OriPh-JQ1-8 as a white solid (11.85 mg, 24.6% yield).

[0599] LCMS: m / z = 1020.5 [M+H] + ,Rt=7.797min.Purity:100%(214nm).

[0600] 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).

[0601] Example 4: PROTAC induces the formation of a quaternary complex

[0602] 1. Incubate the liver cancer cells Hep3B with 1 μM Ori or Ori-JQ1-1 (prepared in Example 3) for 2 hours. After the cells are lysed, incubate with the NCL antibody at 4°C overnight. Add Protein A / G magnetic beads (purchased from Thermo Scientific, item number 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, item number 87788), add SDS-PAGE protein loading buffer (purchased from Biyuntian, item number P0015), heat to 100°C and continue for 10 minutes. Use a magnetic stand to adsorb the magnetic beads and take the supernatant to a new tube. Then perform an immunoblotting experiment. The results are as follows. Figure 7 As shown in A, in the presence of Ori-JQ1-1, the antibody of NCL 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.

[0603] 2. Incubate the liver cancer cells Hep3B with 1μM Ori or Ori-JQ1-1 for 2 hours. After the cells are lysed, incubate with the MDM2 antibody at 4°C overnight. Add Protein A / G magnetic beads (purchased from Thermo Scientific, catalog number 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 number 87788), add SDS-PAGE protein loading buffer (purchased from Beyotime, catalog number P0015), heat to 100°C and continue for 10 minutes. Use a magnetic stand to adsorb the magnetic beads and take the supernatant to a new tube. Then perform an immunoblotting experiment. The results are as follows. Figure 7 As shown in B, in the presence of Ori-JQ1-1, the antibody of MDM2 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.

[0604] 3. Transfect the negative control siRNA (siNC, SEQ ID NO: 1) or NCL siRNA (siNCL, SEQ ID NO: 2) into the liver cancer cells Hep3B for 48 hours, and then incubate the cells with 1 μM 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), heat to 100°C and continue for 10 minutes. Use a magnetic stand to adsorb the magnetic beads and take the supernatant to a new tube. Then perform an immunoblotting experiment. The results are as follows. Figure 7 As shown in C, 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.

[0605] 4. Transfect the liver cancer cells Hep3B with negative control siRNA (siNC, SEQ ID NO: 1) or MDM2 siRNA (siMDM2: GCUUGGCCUACAGUCAUCUTT, SEQ ID NO: 3) for 48 hours, and then incubate the cells with 1 μM Ori-JQ1-1 for 2 hours. After cell lysis, incubate with NCL antibody at 4°C overnight. Add Protein A / G magnetic beads (purchased from ThermoScientific, catalog number 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, catalog number 87788), add SDS-PAGE protein loading buffer (purchased from Biyuntian, catalog number P0015), heat to 100°C and continue for 10 minutes. Use a magnetic stand to adsorb the magnetic beads and take the supernatant to a new tube. Then perform an immunoblotting experiment. The results are as follows. Figure 7 As shown in D, in the presence of Ori-JQ1-1, the antibody against NCL can still capture NCL and BRD4 after knocking down MDM2, indicating that NCL is between MDM2 and BRD4 in the quaternary complex induced by Ori-JQ1-1.

[0606] The above results show that PROTAC based on the compound of formula I can induce the formation of MDM2-NCL-PROTAC-target protein quaternary complex, and NCL is between MDM2 and target protein in the quaternary complex. This mode of action is different from the traditional PROTAC molecule inducing the formation of E3-PROTAC-target protein ternary complex.

[0607] Example 5: PROTAC can degrade BRD4

[0608] 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 is as follows: the protein samples were separated by SDS-PAGE electrophoresis, and the separated proteins were transferred to PVDF membranes. After blocking with TBST buffer containing 5% skim milk at room temperature for 1 hour, the primary antibody of BRD4 (purchased from Cell Signaling Technology, catalog number 13440S) was incubated overnight at 4°C, and then washed with TBST. The membrane was incubated with HRP-labeled secondary antibody (purchased from: Abotek, catalog number: AS014) at room temperature for 1 hour, and the protein bands were visualized using an enhanced chemiluminescence detection kit (purchased from: Abotek, catalog number: RM00021P). The results are as follows. Figure 8 As shown in A, Ori-JQ1-1 can reduce the protein level of BRD4 in a concentration-dependent manner.

[0609] 2. Hep3B liver cancer cells were incubated with 250 nM Ori-JQ1-1, and the corresponding cell samples were collected at 0, 2, 4, 6, 8, and 12 hours for protein extraction and subsequent immunoblotting experiments to detect the degradation of BRD4 protein. Figure 8 As shown in B, Ori-JQ1-1 can reduce the protein level of BRD4 in a time-dependent manner.

[0610] 3. Hep3B hepatoma cells were incubated with solvent DMSO (Veh) or 250 nM compounds Ori, JQ1, Ori+JQ1, Ori-JQ1-1 or dBET1 (positive control, purchased from MCE, catalog number HY-101838). Cell samples were collected 12 hours later for protein extraction and subsequent immunoblotting experiments to detect the degradation of BRD4 protein. The results are shown in Figure 8 As shown in C, Ori-JQ1-1 can reduce the protein level of BRD4, and the effect is better than dBET1.

[0611] 4. Lung cancer A549 cells were incubated with 0, 200, 400, 600, 800, and 1000 nM Ori-JQ1-1. Cell samples were collected after 12 hours, and total protein was extracted using RIPA lysis buffer (purchased from: Biotech, catalog number: P0013B). Western blotting was used to detect the degradation of BRD4 protein. The results are shown in Figure 8 As shown in D, Ori-JQ1-1 can reduce the protein level of BRD4 in a concentration-dependent manner.

[0612] 5. Lung cancer cells A549 were incubated with 600 nM Ori-JQ1-1, and the corresponding cell samples were collected at 0, 2, 4, 6, 8, and 12 hours for protein extraction and subsequent immunoblotting experiments to detect the degradation of BRD4 protein. Figure 8 As shown in E, Ori-JQ1-1 can reduce the protein level of BRD4 in a time-dependent manner.

[0613] 6. Lung cancer A549 cells were incubated with solvent DMSO or 600 nM compound 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. Figure 8 As shown in F, Ori-JQ1-1 can reduce the protein level of BRD4.

[0614] 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 after 24 hours, and total protein was extracted using RIPA lysis buffer (purchased from: Bio-Tech, catalog number: P0013B). The degradation of BRD4 protein was detected by immunoblotting. The results are shown in Fig. 9 As shown in A, Ori-JQ1-2 can reduce the protein level of BRD4 in a concentration-dependent manner.

[0615] 8. Hep3B liver cancer cells were incubated with 800 nM Ori-JQ1-2, and the corresponding cell samples were collected at 0, 4, 8, 12, 24, and 36 hours for protein extraction and subsequent immunoblotting experiments to detect the degradation of BRD4 protein. Fig. 9 As shown in B, Ori-JQ1-2 can reduce the protein level of BRD4 in a time-dependent manner.

[0616] 9. Hep3B hepatoma cells were incubated with solvent DMSO (Veh) or 600 nM compounds Ori, JQ1, Ori+JQ1, Ori-JQ1-2. Cell samples were collected 24 hours later for protein extraction and subsequent immunoblotting to detect BRD4 protein degradation. Fig. 9As shown in C, Ori-JQ1-2 can reduce the protein level of BRD4.

[0617] 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: Bio-Tech, catalog number: P0013B). The degradation of BRD4 protein was detected by immunoblotting. The results are shown in Fig. 9 As shown in D, Ori-JQ1-3 can reduce the protein level of BRD4 in a concentration-dependent manner.

[0618] 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 after 12 hours, and total protein was extracted using RIPA lysis buffer (purchased from: Bio-Tech, catalog number: P0013B). The degradation of BRD4 protein was detected by immunoblotting. The results are shown in Fig. 9 As shown in E, Ori-JQ1-4 can reduce the protein level of BRD4 in a concentration-dependent manner.

[0619] 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: Bio-Tech, catalog number: P0013B). The degradation of BRD4 protein was detected by immunoblotting. The results are shown in Table 1. Fig.10 As shown in A, Ger-JQ1 can reduce the protein level of BRD4 in a concentration-dependent manner.

[0620] 13. Hep3B liver cancer cells were incubated with 800 nM Ger-JQ1, and the corresponding cell samples were collected at 0, 2, 4, 6, 8, and 12 hours for protein extraction and subsequent immunoblotting experiments to detect the degradation of BRD4 protein. The results are shown in Fig.10 As shown in B, Ger-JQ1 can reduce the protein level of BRD4 in a time-dependent manner.

[0621] 14. Hep3B liver cancer cells were incubated with 0, 200, 400, 600, and 800 nM Ori-JQ1-5 (prepared in Example 3). Cell samples were collected after 12 hours, and total protein was extracted using RIPA lysis buffer (purchased from: Bio-Tech, catalog number: P0013B). The degradation of BRD4 protein was detected by immunoblotting. The results are shown in Fig.10 As shown in C, Ori-JQ1-5 can reduce the protein level of BRD4 in a concentration-dependent manner.

[0622] 15. Hep3B hepatoma cells were incubated with 1000 nM CYD-JQ1-6, and the corresponding cell samples were collected at 0, 2, 4, 6, 8, and 12 hours for protein extraction and subsequent immunoblotting experiments to detect the degradation of BRD4 protein. The results are as follows Fig.10 As shown in D, CYD-JQ1-6 can reduce the protein level of BRD4 in a time-dependent manner.

[0623] 16. Hep3B liver cancer cells were incubated with 0, 200, 400, 600, 800, and 1000 nM CYD-JQ1-7 (prepared in Example 3). Cell samples were collected after 12 hours, and total protein was extracted using RIPA lysis buffer (purchased from: Bio-Tech, catalog number: P0013B). The degradation of BRD4 protein was detected by immunoblotting. The results are shown in Fig.10 As shown in F, CYD-JQ1-7 can reduce the protein level of BRD4 in a concentration-dependent manner.

[0624] 17. Hep3B liver cancer 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: Bio-Tech, catalog number: P0013B). The degradation of BRD4 protein was detected by immunoblotting. The results are shown in Table 1. Fig.10 As shown in F, OriPh-JQ1-8 can reduce the protein level of BRD4 in a concentration-dependent manner.

[0625] Example 6: PROTAC promotes ubiquitination of BRD4

[0626] 1. Hep3B cancer cells were incubated with solvent DMSO (Veh) or 250nM Ori-JQ1-1 for 12 hours, and 10μM proteasome inhibitor MG132 was added in the last 6 hours of incubation. The corresponding cell samples were collected for protein extraction and subsequent immunoblotting experiments to detect BRD4 protein degradation. The results are shown in Fig.11 As shown in A, MG132 can block the degradation of BRD4 by Ori-JQ1-1, indicating that the degradation of BRD4 by Ori-JQ1-1 depends on the ubiquitin-proteasome pathway.

[0627] 2. Incubate the liver cancer cells Hep3B with solvent DMSO (Veh) or 250nM Ori-JQ1-1 for 12 hours, and add 10μM proteasome inhibitor MG132 in the last 6 hours of incubation. After cell lysis, incubate with BRD4 antibody (purchased from Cell Signaling Technology, catalog number 13440S) at 4°C overnight. Add Protein A / G magnetic beads (purchased from Thermo Scientific, catalog number 88802) and incubate with rotation at room temperature for 2 hours. After washing the BRD4 bound to the magnetic beads with IP lysis buffer (purchased from Thermo Scientific, catalog number 87788), add SDS-PAGE protein loading buffer (purchased from Beyotime, catalog number P0015), heat to 100°C and continue for 10 minutes. Use a magnetic stand to adsorb the magnetic beads and take the supernatant to a new tube. Then use an immunoblotting experiment to detect the ubiquitination level of BRD4. The results are as follows Fig.11 As shown in B, Ori-JQ1-1 promoted the ubiquitination of BRD4.

[0628] Example 7: PROTAC relies on MDM2 and NCL to mediate degradation of BRD4

[0629] 1. Negative control siRNA (siNC: UUCUCCGAACGUGUCACGUTT, SEQ ID NO: 1) or NCL siRNA (siNCL: GGAUGACGACGACGACGAAGATT, SEQ ID NO: 2) was transfected into Hep3B hepatoma cells for 48 hours, and then the cells were incubated with solvent DMSO (Veh) or 250nM Ori-JQ-1 for 12 hours. The corresponding cell samples were collected for protein extraction and subsequent immunoblotting experiments to detect protein degradation. The results are shown in Fig.12 As shown in A, silencing NCL can reduce the degradation of BRD4 by Ori-JQ1-1, indicating that Ori-JQ1-1 depends on NCL to mediate the degradation of BRD4.

[0630] 2. Negative control siRNA (siNC: UUCUCCGAACGUGUCACGUTT, SEQ ID NO: 1) or MDM2 siRNA (siMDM2: GCUUGGCCUACAGUCAUCUTT, SEQ ID NO: 3) was transfected into Hep3B hepatoma cells for 48 hours, and then the cells were incubated with solvent DMSO (Veh) or 250nM Ori-JQ1-1 for 12 hours. The corresponding cell samples were collected for protein extraction and subsequent immunoblotting experiments to detect protein degradation. The results are shown in Fig.12As shown in B, silencing MDM2 can reduce the degradation of BRD4 by Ori-JQ1-1, indicating that Ori-JQ1-1 depends on MDM2 to mediate the degradation of BRD4.

[0631] Example 8: PROTAC inhibits tumor cell proliferation and promotes apoptosis

[0632] 1. Hep3B hepatoma cells were inoculated into 96-well cell culture plates. During the experiment, the culture medium containing solvent DMSO (Veh) or 250nM Ori, JQ1, Ori+JQ1 or Ori-JQ1-1 was replaced every day. The cell proliferation experiment was performed using a CCK-8 kit (purchased from MCE, item number HY-K0301). The absorbance at 450nm was measured using an ELISA reader on the first, second, third and fourth days. The results are shown in Table 1. Fig.13 As shown in A, Ori-JQ1-1 can inhibit the proliferation of Hep3B cells.

[0633] 2. Hep3B hepatoma cells were inoculated into 6-well cell culture plates. During the experiment, the culture medium containing solvent DMSO (Veh) or 250nM Ori, JQ1, Ori+JQ1 or Ori-JQ1-1 was replaced every two days. Cell colony formation was detected after 8 days. The results are shown in Fig.13 As shown in B, Ori-JQ1-1 can inhibit the colony formation of Hep3B cells.

[0634] 3. Hep3B hepatoma cells were inoculated into six-well plates for apoptosis experiments. During the experiment, the culture medium containing solvent DMSO (Veh) or 250nM Ori, JQ1, Ori+JQ1 or Ori-JQ1-1 was replaced every two days. After 6 days, the cell apoptosis analysis was performed using the AnnexinV-FITC and PI double staining cell apoptosis detection kit (purchased from Beyotime, catalog number C1062L). The results are shown in Figure 2. Fig.13 As shown in C, Ori-JQ1-1 can promote the apoptosis of Hep3B cells.

[0635] 4. Lung cancer A549 cells were inoculated into 96-well cell culture plates. During the experiment, the culture medium containing solvent DMSO (Veh) or 600nM Ori, JQ1, Ori+JQ1 or Ori-JQ1-1 was replaced every day. The cell proliferation experiment was performed using a CCK-8 kit (purchased from MCE, item number HY-K0301). The absorbance at 450nm was detected using an ELISA reader on the first, second, third and fourth days. The results are shown in Table 1. Fig.14 As shown in A, Ori-JQ1-1 can inhibit the proliferation of A549 cells.

[0636] 5. Lung cancer A549 cells were inoculated into 6-well cell culture plates. During the experiment, the culture medium containing solvent DMSO (Veh) or 250nM Ori, JQ1, Ori+JQ1 or Ori-JQ1-1 was replaced every two days. Cell colony formation was detected after 8 days. The results are shown in Fig.14 As shown in B, Ori-JQ1-1 can inhibit the colony formation of A549 cells.

[0637] 6. Lung cancer A549 cells were inoculated in six-well plates for apoptosis experiments. During the experiment, the culture medium containing solvent DMSO (Veh) or 600nM Ori, JQ1, Ori+JQ1 or Ori-JQ1-1 was replaced every two days. After 6 days, the AnnexinV-FITC and PI double staining apoptosis detection kit (purchased from Beyotime, catalog number C1062L) was used for apoptosis analysis. The results are shown in Figure 2. Fig.14 As shown in C, Ori-JQ1-1 can promote the apoptosis of A549 cells.

[0638] Example 9: Ori-JQ1-1 inhibits tumor cell growth in vivo

[0639] BALB / c nude mice were subcutaneously inoculated with Hep3B liver cancer cells, with a cell number of 5×10 6 / mouse, and the tumor growth was observed every day. After 6 days, the tail vein was injected with solvent PBS (Veh), Ori, JQ1, Ori+JQ1, Ori-JQ1-1 or positive control dBET1 (purchased from MCE, catalog number: HY-101838), the injection dose was 3μmol / 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 Fig.15 The results showed that compared with PBS, Ori, JQ1, and Ori+JQ1, Ori-JQ1-1 could significantly inhibit tumor growth, and the effect was better than dBET1.

[0640] 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 principle of the present invention should be included in the protection scope of the present invention.

[0641] 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.

[0642] 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)-O-(C1-C6 alkylene) -(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, an oligonucleotide, an oligopeptide, a polypeptide or a 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:

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 others), 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, 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, in, 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)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:

Images