CN114853731A

CN114853731A - Difunctional MDM2 protein degrading agent, and preparation method, pharmaceutical composition and application thereof

Info

Publication number: CN114853731A
Application number: CN202110157172.XA
Authority: CN
Inventors: 王喆; 曾志宏; 江荣珍; 赖满庆
Original assignee: Shanghai Longwood Biopharmaceuticals Co Ltd
Current assignee: Shanghai Longwood Biopharmaceuticals Co Ltd
Priority date: 2021-02-04
Filing date: 2021-02-04
Publication date: 2022-08-05
Also published as: WO2022166970A1

Abstract

The invention provides a protein degradation targeting chimera, and a preparation method, a pharmaceutical composition and application thereof. Specifically, the protein degradation targeting chimera comprises the following structure: MDM2 target protein inhibitor-C (O) NH-L ² ‑Y ¹ ‑B ¹ Wherein, the definition of each group is described in the specification. The compounds are useful for treating conditions or disorders (e.g., cancer) that respond to the degradation of MDM2 protein.

Description

Difunctional MDM2 protein degrading agent, and preparation method, pharmaceutical composition and application thereof

Technical Field

The invention relates to the field of small molecule drugs, and particularly provides an MDM2 protein degrading agent, and a preparation method, a pharmaceutical composition and application thereof.

Background

The p53 gene is the cancer suppressor gene with the highest relevance to human tumors, and has the functions of maintaining genome stability and inhibiting or preventing cell transformation, thereby inhibiting tumor occurrence. Research on novel anti-tumor drugs targeting p53 has become a hotspot in the field, and research results show that MDM2 (krine double minute 2) is a key negative regulator of p53, p53 activates MDM2 transcription, and MDM2 in turn inhibits p53 activity, so that the MDM 53 and the MDM2 form an autoregulation feedback loop to keep both p53 and MDM2 at a low level under normal conditions. The abnormal expression of MDM2 in tumor cells leads to the rapid degradation of P53 and the inactivation of the P53 pathway, thereby affecting the inhibition level of the P3832 on the tumor, so that P53 is released from the control of MDM2, the P53 pathway is activated, and the effects of inhibiting the growth of tumor cells and inducing the apoptosis of the tumor cells can be expected. Unlike normal cellular P53 activation due to uncommon causes, tumor cells are under sustained cellular stress with various insults including hypoxia and pro-apoptotic oncogene activation. Thus, inactivation of the p53 pathway in tumors has a strong selective advantage, and researchers suggest that abrogation of p53 function may be a prerequisite for tumor survival. To support this, three investigational groups have used mouse models to demonstrate that loss of p53 function is a continuing requirement for tumor maintenance. When researchers restored p53 function to p53 inactivated tumors, the tumors regressed.

In 50% of solid tumors and 10% of liquid tumors, p53 was inactivated by mutation and/or deletion. In cancer, the other major members of the p53 pathway are also genetically or epigenetically altered. MDM2 is an oncoprotein that inhibits p53 function, and MDM2 has been reported to be activated by gene amplification at an incidence of up to 10%. MDM2 is in turn inhibited by another tumor suppressor, p14 ARF. Alterations downstream of p53 are thought to be responsible for at least partially inactivating the p53 pathway in p53 wild-type. To support this concept, some p53 wild-type tumors appear to show a decrease in apoptotic function, but their ability to undergo cell cycle arrest remains intact. One cancer treatment strategy involves the use of small molecules that bind MDM2 and counteract its interaction with p 53. MDM2 inhibits p53 activity by three mechanisms: 1) used as E3 ubiquitin ligase to facilitate p53 degradation; 2) binds to the p53 transcriptional activation domain and blocks the p53 transcriptional activation domain; and 3) export p53 from the nucleus to the cytoplasm. All three of these mechanisms will block by counteracting the MDM2-p53 interaction. This therapeutic strategy can be applied specifically to p53 wild-type tumors, and studies have shown promise in reducing tumor growth in vitro and in vivo using small molecule MDM2 protein-degrading agents. Further, in patients with p 53-inactivated tumors, it is possible to selectively protect normal tissues from damage due to stabilization of wild-type p53 in normal tissues after inhibition of MDM 2.

Protein degradation targeting chimera (PROTAC) is a technology derived from the Nobel chemical prize, and the technical principle of the PROTAC is that a target protein is linked with intracellular E3 ligase by using a bifunctional small molecule to ubiquitinate the target protein, so that the target protein is recognized by proteasomes to cause the target protein to be degraded. There is a constant effort to maintain appropriate protein levels in eukaryotic cells, which are producing and degrading thousands of proteins at each time. The key factor in maintaining protein balance is a small protein molecule called Ubiquitin (Ubiquitin). When it is linked to proteins, these proteins are transported to the proteasome for degradation. The bifunctional protein degrading agent comprises a target protein inhibitor, a linker group (linker) and a ligand of E3 ubiquitin protein ligase protein.

In view of the above, there is a need in the art to develop novel bifunctional MDM2 protein degrading agents.

Disclosure of Invention

The invention aims to provide a novel MDM2 protein degradation agent.

In a first aspect of the invention, there is provided a protein degradation targeting chimera comprising:

MDM2 target protein inhibitor-C (O) NH-L ² -Y ¹ -B ¹

Wherein,

-L ² -Y ¹ is a linking group, wherein L ² Is- (Y) ² ) _r -，Y ² Selected from the group consisting of: -CH ₂ -、-O-、-N(R ^2b )-；

And r is 0, 1,2,3, 4, 5,6,7 or 8;

Y ¹ selected from the group consisting of: -C ≡ C-, -CH ═ CH-, -CH ≡ C-, -CH-, -C ≡ C-, -CH-, -C ≡ C-, -CH-, -C ≡ C-, -CH-, -C-, -CH-, -C ≡ C-, -CH-, -C ≡ C-, -CH-, -C-, -CH-, -C-, -CH-, -C-, -CH-, -C-, -CH-, -C-, -CH-, -C-, -CH-, -C-, -CH-, -C-, -CH-, -C-, - ₂ -、-O-、-N(R ^2b )-、-C(＝O)N(R ^2c )-、-N(R ^2d )C(＝O)CH ₂ O-and-N (R) ^2e )C(＝O)CH ₂ N(R ^2f ) -a group of compositions; or Y ¹ Is absent;

wherein, -N (R) ^2d )C(＝O)CH ₂ O-and-N (R) ^2e )C(＝O)CH ₂ N(R ^2f ) Carboxamide nitrogen atom of and-C (═ O) N (R) ^2e ) Carbon atom of (A) with L ² Connecting;

R ^2b 、R ^2c 、R ^2d 、R ^2e and R ^2f Each independently selected from the group consisting of hydrogen and C1-4 alkyl;

B ¹ selected from the group consisting of:

the MDM2 target protein inhibitor is a structural fragment formed by covalent bonds of a compound shown as a formula I and a connecting group;

wherein,

is a 5-, 6-or 7-membered heterocyclic group; wherein said heterocyclic group includes 1 to 3N atoms, and 0 to 2 hetero atoms selected from the group consisting of S and O;

x is C ═ O or S ═ O ₂ ；

n is 1,2,3 or 4;

each R is independently selected from the group consisting of: H. cyano, halogen, substituted or unsubstituted C ₁ -C ₆ Alkyl, substituted or unsubstituted C ₁ -C ₆ Alkoxy, substituted or unsubstituted C ₃ -C ₈ Cycloalkyl, substituted or unsubstituted C ₆ -C ₁₀ Aryl, or substituted or unsubstituted 5-to 10-membered heteroaryl having 1 to 3 heteroatoms selected from the group consisting of N, S and O;

Z ₁ selected from the group consisting of: H. substituted or unsubstituted C ₁ -C ₆ Alkyl of (2)Substituted or unsubstituted C ₁ -C ₆ Alkoxy, substituted or unsubstituted C ₃ -C ₈ Cycloalkyl (including monocyclic, fused or bridged ring forms), substituted or unsubstituted C ₆ -C ₁₀ An aryl group;

q is selected from the group consisting of:

m, p are each independently 1,2,3 or 4;

each Z ₂ Or Z ₃ Each independently selected from the group consisting of: free, substituted or unsubstituted C ₁ -C ₇ Alkylene, NR ₁ 、O、S、C＝O、S＝(O) ₂ ；

Z ₄ Is selected from

Wherein, R is ₁ Selected from the group consisting of: H. substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C ₆ -C ₁₀ Aryl, cyano, -C (═ O) -NRdRe, -C (═ O) -substituted or unsubstituted C1-C6 alkoxy, -C (═ O) -substituted or unsubstituted C1-C6 alkyl, -C (═ O) -substituted or unsubstituted C3-C10 cycloalkyl, -C (═ O) -substituted or unsubstituted C2-C6 alkenyl, -C (═ O) -substituted or unsubstituted C2-C6 alkynyl;

rd, Re are each independently selected from the group consisting of: H. substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C ₆ -C ₁₀ An aryl group; or said Rd and Re form with the adjacent N atom a 4-10 membered heterocyclic ring containing 1-2 nitrogen atoms and 0-2S or O atoms;

R ₂ selected from the group consisting of: substituted or unsubstituted C ₁ -C ₆ Alkyl, substituted or unsubstituted C ₃ -C ₈ Cycloalkyl, substituted or unsubstituted C ₆ -C ₁₀ Aryl, or substituted or unsubstituted 5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O;

unless otherwise specified, "substituted" means substituted with one or more (e.g., 2,3, 4, etc.) substituents selected from the group consisting of: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, oxo, -CN, hydroxy, amino, carboxy, a group selected from the group consisting of unsubstituted or substituted by one or more substituents selected from the group consisting of: C6-C10 aryl, halogenated C6-C10 aryl, 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O, halogenated 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O; the substituents are selected from the following group: halogen, C1-C6 alkoxy;

with the proviso that when Z ₄ Is composed of

When Q is

In another preferred embodiment, the

Selected from the group consisting of:

in another preferred embodiment, the compound of formula I has the structure as described in formula II below:

in another preferred embodiment, n is 3.

In another preferred embodiment, R is selected from the group consisting of: substituted or unsubstituted C ₁ -C ₆ Alkyl, substituted or unsubstituted C ₆ -C ₁₀ And (4) an aryl group.

In another preferred embodiment, the compound of formula I has the structure as described in formula III below:

wherein Ra and Rb are each independently substituted or unsubstituted C ₆ -C ₁₀ Aryl, or substituted or unsubstituted 5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O;

rc and Rd are each independently selected from the group consisting of: H. cyano, halogen, substituted or unsubstituted C ₁ -C ₆ Alkyl, substituted or unsubstituted C ₁ -C ₆ Alkoxy group of (a);

the definition of each group is as described above.

In another preferred embodiment, Ra and Rb are each independently substituted or unsubstituted phenyl.

In another preferred embodiment, the compound of formula I has the structure as described in formula IV below:

in another preferred embodiment, Z is ¹ Selected from the group consisting of: substituted or unsubstituted C ₃ -C ₈ Cycloalkyl (including monocyclic, fused or bridged ring forms), substituted or unsubstituted C ₆ -C ₁₀ And (4) an aryl group.

In another preferred embodiment, the proteolytic degradation targeting chimera has a structure as described in formula V below:

wherein Z is ₅ Is composed of L ² -Y ¹ -B ¹ The constituent groups.

In another preferred embodiment, the group-L ² -Y ¹ Is a linking group, wherein L ² Is- (Y) ² ) _r -，Y ² Selected from the group consisting of: -CH ₂ -、-O-；

And r is 0, 1,2,3, 4, 5,6,7 or 8;

Y ¹ selected from the group consisting of: -C ≡ C-, -CH ═ CH-, -CH ≡ C-, -CH-, -C ≡ C-, -CH-, -C ≡ C-, -CH-, -C ≡ C-, -CH-, -C-, -CH-, -C ≡ C-, -CH-, -C ≡ C-, -CH-, -C-, -CH-, -C-, -CH-, -C-, -CH-, -C-, -CH-, -C-, -CH-, -C-, -CH-, -C-, -CH-, -C-, -CH-, -C-, - ₂ -、-O-、-N(R ^2b )-、-C(＝O)N(R ^2c )-。

In a second aspect of the invention, there is provided a pharmaceutical composition comprising (1) a proteolytic degradation targeting chimera according to the first aspect of the invention, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof; (2) a pharmaceutically acceptable carrier.

In a third aspect of the invention, there is provided the use of a proteolytic targeting chimera according to the first aspect of the invention, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to the second aspect of the invention, for the preparation of a pharmaceutical composition for the prevention and/or treatment of a disease associated with the activity or amount of expression of MDM 2.

In a fourth aspect of the invention, there is provided a MDM2 protein degrading agent, the inhibitor comprising a proteolytic degradation targeting chimera according to the first aspect of the invention, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

In another preferred embodiment, the pharmaceutical composition is used for treating a disease selected from the group consisting of: bladder, breast, colon, rectal, kidney, liver, lung (small cell lung and non-small cell lung), esophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin (including squamous cell carcinoma); lymphoid lineage hematopoietic system tumors (including leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, hodgkin's lymphoma, non-hodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma); hematopoietic tumors of myeloid lineage (including acute and chronic myelogenous leukemias, myelodysplastic syndrome, and promyelocytic leukemia); tumors of mesenchymal origin (including fibrosarcomas and rhabdomyosarcomas, as well as other sarcomas, such as soft tissue sarcomas and osteosarcomas); tumors of the central and peripheral nervous system (including astrocytomas, neuroblastomas, gliomas, and schwannomas); and other tumors (including melanoma, seminoma, teratoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma (keratedothrombosum), follicular carcinoma of the thyroid, and kaposi's sarcoma), endometrial carcinoma, head and neck cancer, glioblastoma, malignant ascites, hematopoietic cancers, thyroid hyperplasia (especially Grave's disease), cyst, asthma, Chronic Obstructive Pulmonary Disease (COPD), emphysema, psoriasis, contact dermatitis, conjunctivitis, allergic rhinitis, Systemic Lupus Erythematosus (SLE), ulcerative colitis, Crohn's disease, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Alzheimer's disease, atherosclerosis, Huntington's disease, inflammatory disease, hypoxia, ulcer, viral infection, bacterial infection, and bacterial sepsis.

In another preferred embodiment, the disease is p53 wild type cancer.

In another preferred embodiment, the cancer is p53 wild type and CDKN2A mutant cancer.

In another aspect, the invention provides a diagnostic for determining which patients should be administered a compound of the invention.

In another preferred embodiment, there is provided a method of inhibiting the activity or expression of MDM2 in vitro, the method comprising the steps of: contacting a proteolytic targeting chimera according to the first aspect of the invention, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, with MDM2 protein.

It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.

Detailed Description

The present inventors have extensively and intensively studied to find a class of MDM2 protein degrading agents having an excellent inhibitory effect. On this basis, the inventors have completed the present invention.

Definition of

As used herein, the term "alkyl" includes straight or branched chain alkyl groups. E.g. C ₁ -C ₈ Alkyl represents a straight or branched chain alkyl group having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and the like.

As used herein, the term "alkenyl" includes straight or branched chain alkenyl groups. E.g. C ₂ -C ₆ Alkenyl means a straight or branched alkenyl group having 2 to 6 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, or the like.

As used herein, the term "alkynyl" includes straight or branched chain alkynyl groups. E.g. C ₂ -C ₆ Alkynyl means straight or branched chain alkynyl having 2 to 6 carbon atoms, such as ethynyl, propynyl, butynyl, or the like.

As used herein, the term "C ₃ -C ₁₀ Cycloalkyl "refers to cycloalkyl groups having 3 to 10 carbon atoms. It may be a monocyclic ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or the like. It may also be in the form of a double ring, for example a bridged or spiro ring.

As used herein, the term "C ₁ -C ₈ Alkylamino "is defined as being substituted by C ₁ -C ₈ The amino group substituted by the alkyl can be mono-substituted or di-substituted; for example, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, di-tert-butylamino and the like.

As used herein, the term "C ₁ -C ₈ Alkoxy "means a straight or branched chain alkoxy group having 1 to 8 carbon atoms; for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy and the like.

As used herein, the term "3-10 membered heterocycloalkyl having 1-3 heteroatoms selected from the group consisting of N, S and O" refers to a saturated or partially saturated cyclic group having 3-10 atoms and wherein 1-3 atoms are heteroatoms selected from the group consisting of N, S and O. It may be monocyclic or may be in the form of a double ring, for example a bridged or spiro ring. Specific examples may be oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl, and the like.

As used herein, the term "C ₆ -C ₁₀ Aryl "means an aryl group having 6 to 10 carbon atoms, for example, phenyl or naphthyl and the like.

As used herein, the term "5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O" refers to a cyclic aromatic group having 5-10 atoms and wherein 1-3 atoms are heteroatoms selected from the group consisting of N, S and O. It may be a single ring or a condensed ring form. Specific examples may be pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3) -triazolyl, and (1,2,4) -triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, and the like.

Unless specifically stated to be "substituted or unsubstituted", the groups of the present invention may be substituted with a substituent selected from the group consisting of: halogen, nitrile group, nitro group, hydroxyl group, amino group, C ₁ -C ₆ Alkyl-amino, C ₁ -C ₆ Alkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, halo C ₁ -C ₆ Alkyl, halo C ₂ -C ₆ Alkenyl, halo C ₂ -C ₆ Alkynyl, halo C ₁ -C ₆ Alkoxy, allyl, benzyl, C ₆ -C ₁₂ Aryl radical, C ₁ -C ₆ alkoxy-C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Alkoxy-carbonyl, phenoxycarbonyl, C ₂ -C ₆ Alkynyl-carbonyl, C ₂ -C ₆ Alkenyl-carbonyl, C ₃ -C ₆ Cycloalkyl-carbonyl, C ₁ -C ₆ Alkyl-sulfonyl radicalAnd the like.

As used herein, "halogen" or "halogen atom" refers to F, Cl, Br, and I. More preferably, the halogen or halogen atom is selected from F, Cl and Br. "halogenated" means substituted with an atom selected from F, Cl, Br, and I.

Unless otherwise specified, the structural formulae depicted herein are intended to include all isomeric forms (e.g., enantiomers, diastereomers and geometric isomers (or conformational isomers)): such as R, S configuration containing an asymmetric center, (Z), (E) isomers of double bonds, and the like. Thus, individual stereochemical isomers of the compounds of the present invention or mixtures of enantiomers, diastereomers or geometric isomers (or conformers) thereof are within the scope of the present invention.

As used herein, the term "tautomer" means that structural isomers having different energies may exceed the low energy barrier, thereby converting with each other. For example, proton tautomers (i.e., proton transmutations) include interconversion by proton shift, such as 1H-indazoles and 2H-indazoles. Valence tautomers include interconversion by recombination of some of the bonding electrons.

As used herein, the term "solvate" refers to a complex of a compound of the present invention coordinated to solvent molecules in a specific ratio.

As used herein, the term "hydrate" refers to a complex formed by the coordination of a compound of the present invention with water.

MDM2 protein degrading agent

As used herein, "compound of the invention" refers to a compound of formula I, and also includes and various crystalline forms, pharmaceutically acceptable salts, hydrates, or solvates of the compound of formula I:

wherein,

is 5-membered, 6-membered orA 7-membered heterocyclic group; wherein said heterocyclic group includes 1 to 3N atoms, and 0 to 2 hetero atoms selected from the group consisting of S and O;

x is C ═ O or S ═ O ₂ ；

n is 1,2,3 or 4;

each R is independently selected from the group consisting of: H. cyano, halogen, substituted or unsubstituted C ₁ -C ₆ Alkyl, substituted or unsubstituted C ₁ -C ₆ Alkoxy, substituted or unsubstituted C ₃ -C ₈ Cycloalkyl, substituted or unsubstituted C ₆ -C ₁₀ Aryl, or substituted or unsubstituted 5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O;

Z ₁ selected from the group consisting of: H. substituted or unsubstituted C ₁ -C ₆ Alkyl, substituted or unsubstituted C ₁ -C ₆ Alkoxy, substituted or unsubstituted C ₃ -C ₈ Cycloalkyl (including monocyclic, fused or bridged ring forms), substituted or unsubstituted C ₆ -C ₁₀ An aryl group;

q is selected from the group consisting of:

m, p are each independently 1,2,3 or 4;

each Z ₂ Or Z ₃ Each independently selected from the group consisting of: substituted or unsubstituted C ₁ -C ₇ Alkylene, NR ₁ 、O、S、C＝O、S＝(O) ₂ ；

Z ₄ Is selected from

Wherein, R is ₁ Selected from the group consisting of: H. substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C ₆ -C ₁₀ Aryl, cyano, -C (═ O) -NRdRe, -C (═ O) -substituted or unsubstituted C1-C6 alkoxy, -C (═ O) -substituted or unsubstituted C1-C6 alkyl, -C (═ O) -substituted or unsubstituted C3-C10 cycloalkyl, -C (═ O) -substituted or unsubstituted C2-C6 alkenylUnsubstituted C2-C6 alkynyl;

rd, Re are each independently selected from the group consisting of: H. substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C ₆ -C ₁₀ An aryl group; or said Rd and Re form with the adjacent N atom a 4-8 membered heterocyclic ring containing 1-2 nitrogen atoms and 0-1S or O atoms;

unless otherwise specified, "substituted" means substituted with one or more (e.g., 2,3, 4, etc.) substituents selected from the group consisting of: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, oxo, -CN, hydroxy, amino, carboxy, a group selected from the group consisting of unsubstituted or substituted with one or more substituents selected from the group consisting of: C6-C10 aryl, halogenated C6-C10 aryl, 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O, halogenated 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O; the substituents are selected from the following group: halogen, C1-C6 alkoxy;

with the proviso that when Z ₄ Is composed of

When Q is

As used herein, "pharmaceutically acceptable salt" refers to a salt formed by a compound of the present invention with an acid or base that is suitable for use as a pharmaceutical. Pharmaceutically acceptable salts include inorganic and organic salts. One preferred class of salts is that formed by reacting a compound of the present invention with an acid. Suitable acids for forming the salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, etc., organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, phenylmethanesulfonic acid, benzenesulfonic acid, etc.; and acidic amino acids such as aspartic acid and glutamic acid. Suitable cations for salt formation include: cations of alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.

In another preferred embodiment, the

m、n、p、Z ₁ 、Z ₂ 、Z ₃ 、Z ₄ Q, R are each independently a group corresponding to each of the compounds in table 1.

Preferred MDM2 protein degrading agents are the compounds shown below:

bifunctional protein degradation targeting chimeras as MDM2 protein degradation agents

The invention also provides a bifunctional protein degradation targeting chimera serving as an MDM2 protein degradation agent, and the targeting chimera has a structure shown as the following formula:

MDM2 target protein inhibitor-C (O) NH-L ² -Y ¹ -B ¹

Wherein,

And r is 0, 1,2,3, 4, 5,6,7 or 8;

Y ¹ selected from the group consisting of: -C ≡ C-, -CH ═ CH-, -CH ₂ -、-O-、-N(R ^2b )-、-C(＝O)N(R ^2c )-、-N(R ^2d )C(＝O)CH ₂ O-and-N (R) ^2e )C(＝O)CH ₂ N(R ^2f ) -a group of compositions; or Y ¹ Is absent;

B ¹ selected from the group consisting of:

the MDM2 target protein inhibitor is a compound of formula I as described above.

Pharmaceutical compositions and methods of administration

Since the compound of the present invention has excellent inhibitory activity against MDM2, the compound of the present invention and various crystalline forms thereof, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof, and pharmaceutical compositions containing the compound of the present invention as a main active ingredient can be used for treating (stabilizing, alleviating or curing) cancer. Cancers that may be treated with the compounds of the present invention include, without limitation, cancers such as bladder, breast, colon, rectal, kidney, liver, lung (small cell lung and non-small cell lung), esophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin (including squamous cell carcinoma); tumors of lymphoid lineage (including leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma and Burkitt's lymphoma (Burkett's lymphoma); tumors of myeloid lineage (including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia), tumors of mesenchymal origin (including fibrosarcoma and rhabdomyosarcoma and other sarcomas such as soft tissue sarcoma and osteosarcoma), tumors of central and peripheral nervous system (including astrocytoma, neuroblastoma, glioma and schwannoma), and other tumors (including melanoma, seminoma, teratoma, osteosarcoma, xeroderma pigmentosum), Keratoacanthoma (keratocothroma), thyroid follicular carcinoma, and kaposi's sarcoma). Other cancers that may be treated with the compounds of the present invention include endometrial cancer, head and neck cancer, glioblastoma, malignant ascites, and cancers of the hematopoietic system.

Specific cancers that may be treated with the compounds of the present invention include soft tissue sarcomas, bone cancers (e.g., osteosarcoma), breast tumors, bladder cancers, Li-Fraumeni syndrome, brain tumors, rhabdomyosarcoma, adrenocortical carcinoma, colorectal cancer, non-small cell lung cancer, and Acute Myelogenous Leukemia (AML).

The pharmaceutical compositions of the present invention comprise a safe and effective amount of a compound of the present invention in combination with a pharmaceutically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000mg of a compound of the invention per dose, more preferably, 10-200mg of a compound of the invention per dose. Preferably, said "dose" is a capsule or tablet.

"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of intermixing with and with the compounds of the present invention without significantly diminishing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g. sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g. stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g. soybean oil, sesame oil, peanut oil, olive oil)Etc.), polyol (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), and the like

) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.

The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, parenteral (intravenous, intramuscular or subcutaneous).

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like.

In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.

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

The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds, such as chemical anti-cancer drugs.

When administered in combination, the pharmaceutical composition further comprises one or more (2, 3, 4, or more) other pharmaceutically acceptable compounds (e.g., chemical anti-cancer drugs). One or more (2, 3, 4, or more) of the other pharmaceutically acceptable compounds (e.g., chemical anti-cancer drugs) can be used simultaneously, separately or sequentially with a compound of the invention for the treatment of cancer or a related disease.

When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) to be treated, wherein the administration dose is a pharmaceutically-considered effective administration dose, and for a human body with a weight of 60kg, the daily administration dose is usually 1 to 2000mg, preferably 20 to 500 mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.

The main advantages of the invention include:

(1) the compounds of the invention are novel in structure and have excellent MDM2 inhibitory action. In the application, the existing sulfone compounds are transformed into sulfimide compounds, so that the activity or expression quantity of MDM2 can be kept, the binding rate of plasma proteins is reduced, free drugs are increased, and the compounds are easy to pass through membranes and are transported to organ tissues to play a role.

(2) The compounds of the invention are very low toxic to normal cells and can therefore be applied to the subject over a wide dosage range.

(3) The compound has good drug forming property, has better solubility compared with the prior compound, and shows good bioavailability in vivo experiments.

(4) The compounds of the present invention and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient are useful for the treatment of cancer-related diseases.

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.

The individual compounds presented in the examples were prepared by the following route:

example 1

Synthesis of 2- ((3R,5R,6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-1- ((2S) -3-methyl-1- (propyl-2-sulfonimidoyl) butyl-2-) -2-oxopiperidin-3-yl) acetic acid

Step 1: 4- (3-chlorophenyl) -5- (4-chlorophenyl) -5-hydroxy-2-methylpentanoic acid methyl ester

Dissolving 4- (3-chlorophenyl) -5- (4-chlorophenyl) -2-methyl-5-oxopentanoic acid methyl ester (36.5g) in ethanol (300ml), cooling to 0-5 ℃, and adding NaBH in portions ₄ (2.85g), reacting at 0-10 ℃ for 2 hours, tracking the reaction by TLC until the reaction is almost complete, dropwise adding acetic acid (8 ml) until no hydrogen is released, concentrating the solvent, adding 300ml of ethyl acetate, washing with water and saturated sodium bicarbonate in this order, drying over anhydrous magnesium sulfate, and concentrating to obtain 37g of methyl 4- (3-chlorophenyl) -5- (4-chlorophenyl) -5-hydroxy-2-methylpentanoate.

Step 2: 4- (3-chlorophenyl) -5- (4-chlorophenyl) -5-hydroxy-2-methylpentanoic acid

37g of methyl 4- (3-chlorophenyl) -5- (4-chlorophenyl) -5-hydroxy-2-methylpentanoate was dissolved in ethanol (300ml), and LiOH ₂ O (8.4g) in 100ml of an aqueous solution, at 20 ℃ for 18 hours, followed by TLC for substantial completion of the reaction, and 4N hydrochloric acid was added dropwise to the resulting solution to pH<1, the solvent was concentrated, and 250ml × 2 was extracted with toluene at 50 ℃ and washed with water to obtain a toluene solution of 4- (3-chlorophenyl) -5- (4-chlorophenyl) -5-hydroxy-2-methylpentanoic acid, which was directly subjected to the next reaction.

And step 3: 5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyltetrahydro-2H-pyran-2-one

Reacting 4- (3-chlorophenyl) -5- (4-chlorobenzeneToluene solution of the base) -5-hydroxy-2-methylpentanoic acid, TsOH ₂ And O (1.0g), heating for water-splitting reflux reaction for 2 hours, tracking the reaction by TLC to be almost complete, washing by using saturated sodium bicarbonate aqueous solution after cooling, drying by anhydrous magnesium sulfate, concentrating the toluene solution to obtain a crude product of 37.7g, and separating by column chromatography to obtain the 5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyltetrahydro-2H-pyran-2-one.

And 4, step 4: (±) (3S,5R,6R) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyltetrahydro-2H-pyran-2-one

Dissolving 5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyltetrahydro-2H-pyran-2-one (6.7g) and bromopropene (7.26g) in THF (25ml), cooling to-50 ℃, dropwise adding LiHMDS (26ml of 1M in THF) solution, stirring for 1 hour after the dropwise adding is finished and the temperature is 0 ℃, tracking the disappearance of raw materials by TLC, adding saturated ammonium chloride solution, extracting by ethyl acetate, separating by column chromatography to obtain 6.0g of product, difficult for the isomer to be purified by passing through a column, adding 6.0g of product into 50ml of n-heptane/toluene (10: 1), heating for reflux dissolving, slowly cooling to room temperature, and precipitating 2.8g of solid which is (+/-) (3S,5R,6R) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyltetrahydro-2H-pyridine Pyran-2-ones.

¹ HNMR(CDCl ₃ ,400MHz)：7.22～7.11(m,4H),6.873(d,1H,J＝1.9Hz),6.745(d,1H,J＝7.8Hz),6.58～6.54(m,2H),5.804(m,1H),5.677(d,1H,J＝5.1Hz),5.157(d,1H,J＝10.2Hz),5.125(dd,1H,J＝1.6,15.3Hz),3.787(dt,1H,J＝4.5,12.2Hz),2.598(dd,1H,J＝7.9,14.1Hz),2.488(dd,1H,J＝7.1,13.7Hz),1.954(t,1H,J＝14.0Hz),1.897(dd,1H,J＝4.5,14.0Hz),1.389(s,3H).

And 5: 2- ((2R,3R) -2- (3-chlorophenyl) -3- (4-chlorophenyl) -3-hydroxypropyl) -N- ((S) -1-hydroxy-3-methylbutyl-2) -2-methylpentene-4-amide

(+ -) -3S, 5R,6R) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyltetrahydro-2H-pyran-2-one (1.0g) was dissolved in toluene (1ml), L-valinol (0.825g) was added, and the mixture was heated to 100 ℃ for 5 hours, TLC tracing reaction is almost complete, ethyl acetate is added after cooling, 1N hydrochloric acid and saturated sodium bicarbonate are used for washing in sequence, after anhydrous magnesium sulfate is dried, concentration gave 1.48g of 2- ((2R,3R) -2- (3-chlorophenyl) -3- (4-chlorophenyl) -3-hydroxypropyl) -N- ((S) -1-hydroxy-3-methylbutyl-2) -2-methylpentene-4-amide.

Step 6: trifluoromethanesulfonic acid (3S,5S,6R,8S) -8-allyl-6- (3-chlorophenyl) -5- (4-chlorophenyl) -3-isopropyl-8-methyl-2, 3,5,6,7, 8-hexahydrooxazolo [3,2-a ] o-4-pyridinium salt

2- ((2R,3R) -2- (3-chlorophenyl) -3- (4-chlorophenyl) -3-hydroxypropyl) -N- ((S) -1-hydroxy-3-methylbutyl-2) -2-methylpentene-4-amide (63.6g) was dissolved in DCM (640ml), 2,6-lutidine (57g) was added, cooled to-78 deg.C and Tf was added dropwise ₂ O (97.6g), was allowed to warm to rt overnight after dropwise addition, washed with 0.5m tfoh solution (200ml), extracted with ethyl acetate (500ml × 2), the organic phase was concentrated and dissolved in DCM (400ml) and separated by column chromatography under the conditions:

silica gel: 120g of

The sample loading amount at each time is as follows: 10g

Mobile phase: a is n-heptane, B is acetone

Time (min)	Flow phase ratio
		0-5	25％
5-15	25％-35％
		15-30	35％
30-35	25％

The less polar isomer (27.4g, 34.8%) was obtained as trifluoromethanesulfonic acid (3S,5S,6R,8S) -8-allyl-6- (3-chlorophenyl) -5- (4-chlorophenyl) -3-isopropyl-8-methyl-2, 3,5,6,7, 8-hexahydrooxazole [3,2-a ] o-4-pyridinium salt:

¹ HNMR(d6-DMSO,400MHz):8.15～7.10(m,8H),5.812(m,1H),5.346(dd,1H,J＝1.2,16.8Hz),5.238(dd,1H,J＝1.5,10.1Hz),5.173(d,1H,J＝11.3Hz),5.003(dd,1H,J＝5.5,10.2Hz),4.870(t,1H,J＝10.2Hz),4.323(m,1H),4.057(ddd,1H,3.1,13.7,10.6Hz),2.812(dd,1H,J＝7.1,13.7Hz),2.717(dd,1H,J＝7.4,13.7Hz),2.316(t,1H,13.7Hz),1.993(dd,1H,J＝13.7,3.5Hz),1.303(s,3H),0.579(d,3H,J＝6.7Hz),0.524(d,3H,J＝7.0Hz),0.428(m,1H).

and the polar large isomer (22.8g, 28.9%) was trifluoromethanesulfonic acid (3S,5R,6S,8R) -8-allyl-6- (3-chlorophenyl) -5- (4-chlorophenyl) -3-isopropyl-8-methyl-2, 3,5,6,7, 8-hexahydrooxazole [3,2-a ] o-4-pyridinium salt:

¹ HNMR(d6-DMSO,400MHz):7.50～7.05(m,8H),5.902(m,1H),5.290(dd,1H,J＝1.6,17.2Hz),5.230(dd,1H,J＝2.4,10.2Hz),5.140(d,1H,J＝10.2Hz),5.084(dd,1H,J＝3.9,10.2Hz),4.927(t,1H,J＝10.2Hz),3.878(m,1H),3.423(m,1H),2.733(dd,1H,J＝8.3,14.1Hz),2.657(dd,1H,J＝6.7,13.7Hz),2.334(t,1H,13.7Hz),2.005(dd,1H,J＝13.7,2.7Hz),1.334(s,3H),0.884(d,3H,J＝6.6Hz),0.662(d,3H,J＝6.6Hz).

and 7: (3S,5R,6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- ((S) -1- (isopropylmercapto) -3-methylbutyl-2) -3-methylpiperidin-2-one

Under the protection of nitrogen, isopropylmercaptan (10.4g) was added dropwise to a solution of potassium tert-butoxide (82.2ml of 1M THF), the mixture was appropriately cooled to a temperature not exceeding 30 ℃ and stirred for 10min, a DMF solution (80ml) of trifluoromethanesulfonic acid (3S,5S,6R,8S) -8-allyl-6- (3-chlorophenyl) -5- (4-chlorophenyl) -3-isopropyl-8-methyl-2, 3,5,6,7, 8-hexahydrooxazolo [3,2-a ] and-4-pyridinium (17.8g) was added, the mixture was heated to 50 ℃ for 3 hours, TLC-traced, and the mixture was poured into 600ml of water, extracted with ethyl acetate (200 ml. times.3), washed with water, concentrated and then separated by column chromatography to give 13.5g of an oily product (3S,5R,6S) -3-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- ((S) -1- (isopropylmercapto) -3-methylbutyl-2) -3-methylpiperidin-2-one.

And 8: (3S,5R,6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- ((S) -1- (isopropylsulfoxido) -3-methylbutyl-2) -3-methylpiperidin-2-one

Dissolving (3S,5R,6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- ((S) -1- (isopropylmercapto) -3-methylbutyl-2) -3-methylpiperidine-2-one (2.03g) in methanol (25ml), adding 0.60ml of 30% hydrogen peroxide, reacting at 20-25 ℃ for 2 days, adding a sodium thiosulfate solution to terminate the reaction, extracting with ethyl acetate, drying over anhydrous magnesium sulfate, filtering, concentrating, and performing column chromatography to obtain 1.99g of (3S,5R,6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- ((S) -1- (isopropylsulfoxide) -3-methylbutyl-2) -3-methyl Piperidin-2-one, a mixture of the two isomers, was obtained in 95% yield.

¹ HNMR(CDCl ₃ ,400MHz):7.27～7.00(m,7H),6.978(d,1H,J＝6.8Hz),5.898(m,1H),5.260(d,1H,J＝16.8Hz),5.180(dd,1H,J＝1.2,10.0Hz),4.860(d,1H,J＝8.4Hz),3.620(t,1H,J＝10.5Hz),3.541(ddd,1H,J＝2.3,11.0,13.3Hz),3.017(m,2H),2.860(dd,1H,J＝2.7,12.9Hz),2.741(dd,1H,J＝8.2,14.1Hz),2.716(dd,1H,J＝2.8,13.3Hz),2.585(dd,1H,J＝6.7,13.7Hz),2.188(m,1H),2.101(t,1H,J＝13.7Hz),1.922(dd,1H,J＝2.8,13.7Hz),1.343(d,3H,J＝7.0Hz),1.277(d,3H,J＝7.0Hz),1.199(s,3H),0.863(t,1H,J＝6.6Hz),0.675(d,3H,J＝6.7Hz),0.481(d,3H,J＝7.0Hz).

And step 9: 2,2, 2-trifluoroacetyl N- (((S) -2- ((3S,5R,6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-1-yl) -3-methylbutyl) (isopropyl) (oxy) -l 6-sulphonamidinamine)

(3S,5R,6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- ((S) -1- (isopropylsulfoxido) -3-methylbutyl-2) -3-methylpiperidin-2-one (336mg) and trifluoroacetamide (142.4mg) were dissolved in DCM (4ml), followed by addition of MgO (126.5mg) and Rh ₂ (OAc) ₄ (6.9mg) and finally PhI (OAc) ₂ (303.7mg) was stirred at rt overnight, filtered, the solid was washed with DCM, the solution was concentrated and passed through the column with the eluent n-heptane/ethyl acetate 2: 1, 58mg of the product 2,2, 2-trifluoroacetyl N- (((S) -2- ((3S,5R,6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-1-yl) -3-methylbutyl) (isopropyl) (oxy) -l 6-sulphonamidinamine) are obtained as a mixture of the two isomers in 14% yield.

¹ HNMR(CDCl ₃ ,400MHz):7.3～7.1(m,6H),6.932(s,1H),6.860(t,1H,J＝3.2Hz),5.904(m,1H),5.239(m,2H),4.959(d,1H,J＝10.8Hz),4.450(dd,1H,J＝7.6,15.2Hz),4.135(m,1H),3.368(m,2H),3.186(ddd,1H,J＝1.6,7.6,9.2Hz),2.658(m,2H),2.390(m,1H),2.229(t,1H,J＝13.6Hz),1.898(dd,1H,J＝3.2,14.0Hz),1.522(d,3H,J＝7.0Hz),1.484(d,3H,J＝7.0Hz),1.282(t,1H,J＝7.2Hz),1.256(s,3H),0.684(d,3H,J＝6.8Hz),0.620(d,3H,J＝7.2Hz).

Step 10: 2- ((3R,5R,6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-1- ((2S) -3-methyl-1- (N- (2,2, 2-trifluoroacetyl) -2-propylsulfonamidino) butyl-2-) -2-oxopiperidin-3-yl) acetic acid

2,2, 2-trifluoroacetyl N- (((S) -2- ((3S,5R,6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-1-yl) -3-methylbutyl) (isopropyl) (oxy) -l 6-sulfoneamidilamine) (150mg) and ruthenium trichloride (7.3mg) were dissolved in DCM/water (5ml/5ml), followed by addition of tetrabutylammonium hydrogen sulfate (15.8mg) and sodium periodate (300mg) and stirring overnight at room temperature, filtration, extraction with DCM, drying and concentration of the solution, passage through a column, eluent N-heptane/ethyl acetate 1: 1, 120mg of the product 2- ((3R,5R,6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-1- ((2S) -3-methyl-1- (N- (2,2, 2-trifluoroacetyl) -2-propylsulfonamidino) butyl-2-) -2-oxopiperidin-3-yl) acetic acid are obtained as a mixture of two isomers in 77.6% yield.

¹ H NMR(400MHz,Methanol-d4)δ7.27(br,4H),7.19–6.89(m,4H),5.00(dd,1H,J＝20.4,11.0Hz),4.44(ddd,1H,J＝28.6,15.1,9.2Hz),4.08(m,1H),3.71–3.48(m,2H),3.39–3.17(m,2H),3.05–2.92(m,1H),2.67–2.55(m,1H),2.34–1.93(m,4H),1.51(d,3H,J＝7.1Hz),1.47(d,3H,J＝7.1Hz),1.46(s,3H),1.35(d,3H,J＝3.2Hz),0.47(d,3H,J＝7.0Hz).

Step 11: 2- ((3R,5R,6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-1- ((2S) -3-methyl-1- (2-propylsulfoneamidino) butyl-2-) -2-oxopiperidin-3-yl) acetic acid

2- ((3R,5R,6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-1- ((2S) -3-methyl-1- (N- (2,2, 2-trifluoroacetyl) -2-propylsulfonamidino) butyl-2-) -2-oxopiperidin-3-yl) acetic acid (100mg) was dissolved in methanol (2.0ml), followed by addition of potassium carbonate (417mg) and stirring at room temperature for 2 hours, addition of water and ethyl acetate, pH adjustment to 6 with 3NHCl, liquid separation, drying and concentration of the solution, column passage, eluent N-heptane/ethyl acetate ═ 1: 1 to 0: 1, obtaining two isomer products, wherein the polarity is large and small is 31mg, the polarity is small and is 18mg, and the total yield is 57%. Culturing single crystal with low-polarity compound, and obtaining the configuration of the compound through single crystal X-ray diffraction experiment

Compound 12 with Rs large polarity: ¹ H NMR(400MHz,Chloroform-d)δ7.22(br,4H),7.10–6.91(m,3H),6.84(dd,1H,J＝5.4,3.3Hz),5.38(d,1H,J＝11.0Hz),4.12–3.97(m,1H),3.40–3.20(m,2H),3.13(m,1H),2.94–2.72(m,2H),2.37(t,1H,J＝13.7Hz),2.19(m,1H),1.91(dd,1H,J＝13.8,3.0Hz),1.57(d,1H,J＝6.8Hz),1.41(s,3H),1.37(d,3H,J＝7.1Hz),1.35(d,3H,J＝7.1Hz),1.30–1.13(m,3H),0.61(d,2H,J＝6.6Hz),0.44(d,2H,J＝6.8Hz).

compound 13 with less Ss polarity: ¹ H NMR(400MHz,Chloroform-d)δ7.24(br,4H),7.09–6.95(m,3H),6.86(dd,1H,J＝5.4,3.1Hz),5.30(d,1H,J＝11.0Hz),3.99(dd,1H,J＝13.6,10.4Hz),3.46(t,1H,J＝8.6Hz),3.30(ddd,1H,J＝14.0,10.9,3.1Hz),3.13(m,1H),2.99–2.76(m,3H),2.37(t,1H,J＝13.7Hz),2.12(dt,1H,J＝14.9,6.9Hz),1.90(dd,1H,J＝13.8,3.0Hz),1.43–1.34(m,6H),0.61(d,3H,J＝6.6Hz),0.42(d,3H,J＝6.9Hz).

example 2

The compound 4- (2- ((3R,5R,6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-1- ((S) -2-propylsulfoneamidin) but-2-yl) -2-oxopiperidin-3-yl) acetamido) benzoic acid

Step 1: synthesis of methyl 4- (2- ((3R,5R,6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-1- ((2S) -3-methyl-1- (N- (2,2, 2-trifluoroacetyl) -2-propylsulfonamidino) butyl-2-) -2-oxopiperidin-3-yl) acetamido) benzoate

2- ((3R,5R,6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-1- ((2S) -3-methyl-1- (N- (2,2, 2-trifluoroacetyl) -2-propylsulfonamidino) butyl-2-) -2-oxopiperidin-3-yl) acetic acid (800mg), methyl p-aminobenzoate (219mg), DMAP (324mg) and EDC.HCl (508.4mg) were successively added to a DCM (16ml) solution at 0 ℃ under nitrogen, and stirred overnight at room temperature. The reaction was complete by TLC. Adding water into the reaction solution under ice bath to quench the reaction, adjusting the pH value to 2 with cold 1N HCl solution, separating the solution, washing the organic phase with 1N HCl again, washing with water, washing with saturated salt water, drying with anhydrous magnesium sulfate, concentrating, and separating the residue by column chromatography to obtain 600mg of white foamy solid with the yield of 62.6%. ¹ H NMR(400MHz,CDCl ₃ )δ8.84(s,1H),8.07(d,J＝8.7Hz,2H),7.71(d,J＝8.7Hz,2H),7.27–7.06(m,6H),6.97(s,1H),6.91(t,J＝3.6Hz,1H),4.97(d,J＝10.9Hz,1H),4.56(dd,J＝13.9,10.6Hz,1H),4.14(q,J＝7.2Hz,1H),3.94(s,3H),3.39(dd,J＝16.4,11.7Hz,3H),2.89(q,J＝14.4Hz,2H),2.38(t,J＝13.8Hz,1H),2.15–1.92(m,2H),1.58(d,J＝6.8Hz,3H),1.53(d,J＝6.9Hz,3H),1.46(s,3H),0.75(d,J＝6.7Hz,3H),0.36(d,J＝7.0Hz,3H).

Step 2: synthesis of 4- (2- ((3R,5R,6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-1- ((S) -2-propylsulfoneamidin) but-2-yl) -2-oxopiperidin-3-yl) acetamido) benzoic acid

Methyl 4- (2- ((3R,5R,6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-1- ((2S) -3-methyl-1- (N- (2,2, 2-trifluoroacetyl) -2-propylsulfonamidino) butyl-2-) -2-oxopiperidin-3-yl) acetamido) benzoate (600mg) and LiOH ₂ O (127mg) was added to MeOH/H ₂ To a solution of O/THF (2.4ml/1.2ml/1.2ml), stirring was performed at room temperature. The reaction was complete by TLC. Concentrating to remove solvent, adding water 10ml and ethyl acetate 20ml into residue, adjusting pH to 2 with cold 1N HCl solution, separating, extracting water layer with ethyl acetate, mixing organic phases, washing with water, washing with saturated salt water, and drying with anhydrous magnesium sulfateConcentrating, separating the residue, and freeze-drying to obtain white solid 250mg with yield 48.4%. 1H NMR (400MHz, Methanol-d4) δ 8.05(d, J ═ 7.5Hz,2H),7.81(d, J ═ 8.7Hz,2H),7.20(M,6H),6.86(d, J ═ 19.2Hz,2H),5.13(s,1H),5.01(s,1H),4.43(s,1H),3.57(M,3H),3.08(d, J ═ 13.6Hz,1H),2.67(d, J ═ 13.9Hz,1H), 2.48-2.06 (M,3H),1.47(d, J ═ 38.1Hz,9H),0.77(s,3H),0.59(s,3H), LC-MS: M +1 ═ 686.2 ═ LC-MS ═ 686.2 ═ M +1 ═ 686.2 ═ M,3H

By the same experimental procedure, the conversion of methyl p-aminobenzoate to methyl 2-methoxy-4-aminobenzoate gave 4- (2- ((3R,5R,6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-1- ((2S) -3-methyl-1- (propan-2-ylsulfamidino) butan-2-yl) -2-oxopiperidin-3-yl) acetamido) -2-methoxybenzoic acid.

Example 3

Synthesis of 4- (2- ((3R,5R,6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-1- ((2S) -3-methyl-1- (propan-2-ylthioamidino) butan-2-yl) -2-oxopiperidin-3-yl) acetamido) -N- (5- (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-4-yl) pent-4-yn-1-yl) -2-methoxybenzamide

Step 1:

methyl 3-bromo-2-bromomethyl-benzoate (5.00g, 16.2mmol) and 3-amino-piperidine-2, 6-dione hydrochloride (2.94g, 17.9mmol) were added to acetonitrile (50ml) followed by triethylamine (8.21g, 81.1mmol), heated to reflux overnight, the reaction turned dark purple, cooled to room temperature and filtered, the solid washed with water (20ml) and MTBE (20ml) to give 2.70g of a solid after vacuum drying in 52% yield. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.03(s,1H),7.88(d,J＝7.9Hz,1H),7.78(d,J＝7.5Hz,1H),7.52(t,J＝7.7Hz,1H),5.16(dd,J＝13.3,5.1Hz,1H),4.43(d,J＝17.6Hz,1H),4.27(d,J＝17.6Hz,1H),2.92(ddd,J＝18.1,13.6,5.4Hz,1H),2.65–2.51(m,1H),2.45(dd,J＝13.3,4.3Hz,1H),2.02(ddd,J＝13.0,6.1,3.3Hz,1H).

Step 2:

the compound 3- (4-bromo-1-oxoisoindol-2-yl) piperidine-2, 6-dione (1.00g, 3.09mmol) and the compound t-butyl pent-4-yn-1-ylcarbamate (680mg, 3.71mmol) were added to anhydrous DMF (10ml), and after nitrogen substitution, CuI (59mg, 0.31mmol) and Pd (PPh) were added ₃ ) ₂ Cl ₂ (217mg, 0.31mmol), reacting at 80 ℃ overnight under nitrogen protection, cooling to room temperature, adding ethyl acetate and water, extracting for layering, drying the organic phase, concentrating, and separating by column chromatography to obtain 1.12g of compound (5- (2- (2, 6-dioxopiperidin-3-yl) -1-oxoiso-4-yl) pent-4-yn-1-yl) carbamic acid tert-butyl ester with a yield of 85%. LC-MS, positive ion [ M +1]＝426。

And step 3:

the compound tert-butyl 5- (2- (2, 6-dioxopiperidin-3-yl) -1-oxoiso-4-yl) pent-4-yn-1-yl) carbamate (1.10g, 2.59mmol) was added to a 4M HCl/dioxane solution (15ml), stirred overnight at room temperature and concentrated to give 650mg of the compound 5- (2- (2, 6-dioxopiperidin-3-yl) -1-oxoiso-4-yl) pent-4-yn-1-yl) amine hydrochloride in 69% yield. LC-MS, positive ion [ M +1] ═ 326.

And 4, step 4:

the compound 4- (2- ((3R,5R,6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-1- ((2S) -3-methyl-1- (propan-2-ylthioamidino) butan-2-yl) -2-oxopiperidin-3-yl) acetamido) -2-methoxybenzoic acid (71.6mg, 0.1mmol) and the compound 5- (2- (2, 6-dioxopiperidin-3-yl) -1-oxoiso-4-yl) pent-4-yn-1-yl amine hydrochloride (43.4mg, 0.12mmol) was added to anhydrous DMF (2.0ml), stirred at room temperature for 5min then HATU (45.6mg, 0.12mmol) added followed by DIPEA (51.7mg, 0.4mmol), stirred at room temperature overnight, preparative HPLC isolated as 20mg of a solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.00(s,1H),10.43(s,1H),8.17(t,J＝5.8Hz,1H),7.77(d,J＝8.5Hz,1H),7.71(d,J＝7.3Hz,1H),7.63(dd,J＝7.7,1.1Hz,1H),7.58–7.47(m,2H),7.36(s,3H),7.32–7.11(m,3H),6.98(d,J＝7.7Hz,1H),6.94(s,1H),5.29(d,J＝10.9Hz,1H),5.15(dd,J＝13.3,5.0Hz,1H),4.55–4.45(m,1H),4.35(d,J＝17.9Hz,1H),3.95(s,1H),3.85(s,3H),3.45(q,J＝6.7Hz,2H),3.18(s,1H),3.08(d,J＝13.5Hz,1H),2.93(t,J＝15.2Hz,1H),2.68–2.52(m,5H),2.18–2.06(m,3H),2.01(d,J＝11.7Hz,1H),1.84(q,J＝6.9Hz,2H),1.35(d,J＝3.7Hz,3H),1.33(d,J＝3.7Hz,3H),1.28(s,3H),0.59(d,J＝6.6Hz,3H),0.41(d,J＝6.9Hz,3H).

Example 4

4- (2- ((3R,5R,6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-1- ((2S) -3-methyl-1- (propan-2-ylthioamidino) butan-2-yl) -2-oxopiperidin-3-yl) acetamido) -N- (5- (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-4-yl) pentyl) -2-methoxybenzamide

Step 1:

the hydrochloride salt of the compound 5- (2- (2, 6-dioxopiperidin-3-yl) -1-oxoiso-4-yl) pent-4-yn-1-yl) amine (79mg) was added to methanol (10ml), and after nitrogen substitution, 10% Pd/C (75mg) was added, followed by hydrogen substitution, and after 3 days at room temperature under normal pressure, LC-MS showed completion of the reaction, after nitrogen substitution, filtration and concentration of the filtrate gave 68mg of a solid.

Step 2:

the compound 4- (2- ((3R,5R,6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-1- ((2S) -3-methyl-1- (propan-2-ylthioamidino) butan-2-yl) -2-oxopiperidin-3-yl) acetamido) -2-methoxybenzoic acid (98mg) and the compound 5- (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-4-yl) pent-1-ylamine hydrochloride (60mg) were added to anhydrous DMF (2.0ml), stirred at room temperature for 5min, after the solid had dissolved, HATU (62.4mg) was added, DIPEA (70.8mg, N) was then added, stirred overnight at room temperature and isolated by preparative HPLC as a 20mg solid.

Example 5

4- (2- ((3R,5R,6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-1- ((2S) -3-methyl-1- (propan-2-ylthioamidino) butan-2-yl) -2-oxopiperidin-3-yl) acetamido) -N- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-4-yl) amino) butyl) -2-methoxybenzamide

Step 1:

tert-butyl (4-oxobutyl) carbamate (774mg, 4.14mmol) and 3- (4-amino-1-oxoisoindol-2-yl) piperidine-2, 6-dione (1.18g, 4.55mmol) were dissolved in DMF (8.0ml), sodium triacetoxyborohydride (1.75g, 8.28mmol) was added thereto at room temperature, and the mixture was stirred overnight, and the reaction mixture was diluted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, concentrated to give a crude product, and separated by column chromatography to give 530mg of a solid.

Step 2

Step 3 in reference example 3

Step 3

Refer to step 4 in example 3.

Example 6

Step 1:

refer to step 4 in example 3. Step 2:

step 3 in reference example 3

And step 3:

refer to step 4 in example 3.

Characterization data for each compound are shown in the table below.

Bioassay example 1 homogeneous phase time-resolved fluorescence assay (HTRF assay)

The standard assay conditions for the in vitro HTRF assay consist of: total reaction volumes of 50ul of 1mM DTT, 0.1% BSA, 2.5nM GST-hMDM2(aa1-188), 5nM biotinylated-p 53(aa1-83), 1.8nM SA-XEnvironment (Cisbio; Bedford, Mass.), 0.6nM anti-GST-cryptate (cryptate) monoclonal antibody (Cisbio; Bedford, Mass.) and 200mM KF in black 384-well Costar polypropylene plates at 1XPBS buffer pH 7.4. Amino acid residues 1-188 of human MDM2 are expressed in E.coli as an amino-terminal glutathione-S-transferase (GST) fusion protein (GST-hMDM 2). Residues 1-83 of human p53 were expressed as amino-terminal AviTag < TM > -TrxA-6xHis fusion protein (biotinylated p53) in E.coli. Each protein was isolated from the cell homogenate by affinity chromatography.

Specifically, 10uLGST-hMDM2 was incubated with 10ul of diluted compounds in 10% DMSO (various concentrations, serial dilutions) for 20 minutes at room temperature. 20uL of biotinylated-p 53 was added to the GST-hMDM2+ compound mixture, followed by incubation at room temperature for 60 min. 10uL of detection buffer consisting of SA-XLent, anti-GST cryptate antibody and KF was added to GST-hMDM2, biotinylated-p 53 and the compound reaction and left at room temperature to reach and maintain equilibrium for >4 hr. The final concentration of DMSO in the reaction was 2%. Time resolved fluorescence readings were measured on a microplate multi-label reader. Percent inhibition was calculated relative to nutlin-3.

When the titer of MDM2 protein degrading agent increased, a modified HTRF assay (HTRF2 assay) was performed. All assay conditions were identical to those described above except for the following changes in reagent concentration: 0.2nM GST-hMDM2(1-188), 0.5nM biotinylation-p 53(1-83), 0.18nM SA-XLent, and 100mM KF.

The results are given in the table below. + is 10nm, + is 10-100 nm, and +++ is 100nm

TABLE 1 HTRF assay

Numbering	IC ₅₀
		055	+
056	+
		057	+
058	+
		059	+
060	+
		061	+
062	+
		063	+

Biological test example 2p21 assay

Inhibition of the interaction between hmmd 2 and p53 results in activation of the p53 pathway via stabilization and accumulation of p 53. p53 activates transcription of many genes, one of which is p21< WAF1/CIP1 >. To assess the potency of hMDM2 protein degrading agents, p21 transcript levels in compound-associated cells relative to Dimethylsulfoxide (DMSO) -treated control cells were measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR).

On day 1, SJSA-1cells were washed at 3X10 ⁴ The density of individual cells/well was seeded in 100ul growth medium (RPMI 1640; 10mM HEPES; 1mM sodium pyruvate; 1X penicillin-streptomycin-glutamine (PSQ); and 10% fetal bovine serum (all reagents from Invitrogen; Carlsbad, CA)) in 96-well cell culture plates. The cells were incubated at 37 ℃ and 5% CO ₂ Incubate overnight.

On day 2, hMDM2 protein degradants were serially diluted in DMSO (Sigma-Aldrich; St. Louis, Mo.). 5ul of each compound dilution was added to 245ul of filtered assay medium (RPMI1640, 10mM HEPES, 1mM sodium pyruvate, and 1XPSQ) containing 10% FBS. Alternatively, the assay is also performed in the presence of 10% human serum or 10% mouse serum, or in the absence of any serum. Growth medium was removed from seeded SJSA-1cells and replaced with 100 ul/well of assay medium. Then 100ul of medium containing diluted inhibitor was added to each well to a final volume of 200 ul. Dose titration of this compound yielded final concentrations ranging from 0.049uM to 50uM, plus DMSO control. The cells are incubated at 37 ℃ and 5% CO in the presence of an inhibitor ₂ The mixture was incubated for 7 hours. At the end of the incubation, the medium was removed from the cells and the plate was stored at-80 ℃.

On day 3, total RNA was purified from inhibitor-and DMSO-treated SJSA-1cells using Qiagen BioRobot Universal works according to the RNeasy96BioRobot8000 kit protocol from the manufacturer (Qiagen; Valencia, Calif.).

To measure the level of p21 transcript present, qRT-PCR was used. Levels of p21 and housekeeping gene, glyceraldehyde 3-phosphate dehydrogenase (GAPDH) were determined in technical replicates from total RNA from each inhibitor-or DMSO-treated well. qRT-ion was determined using the relative quantitation (Δ Δ Ct) method on an Applied biosystems prism7900HT instrument using the following cycling conditionsAnd (3) PCR reaction: 48 ℃, 30 minutes, followed by 95 ℃, 10 minutes, then 40 cycles consisting of 95 ℃, 15 seconds, and 60 ℃,1 minute. Data were analyzed using Applied biosystems sdss 2.2 software with GAPDH as an endogenous control and DMSO-treated samples as a calibrator. The SDS2.2 software calculated for each treated sample Relative Quantification (RQ) or fold increase of p21 levels relative to DMSO control. The maximum (100%) fold induction of p21 was defined by the maximum value of the fitted curve for the reference compound. Fold induction of p21 at each inhibitor dose tested was converted to a value representing the percentage of the maximum. Dose response curves were generated using XLFit software (IDBusinesssolutions, Alameda, Calif.) to calculate the IC of each inhibitor tested ₅₀ Transition value (transitvalue). + is expressed as<1 μ M, wherein ++ represents 1-10 μ M, and +++ represents>10μM

TABLE 2 Cell assay (SJSA-1cells)

Numbering	IC ₅₀
		055	+
056	+
		057	++
058	++
		059	++
060	++
		061	++
062	++
		063	++

All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims

1. A protein degradation targeting chimera, comprising:

MDM2 target protein inhibitor-C (O) NH-L ² -Y ¹ -B ¹

Wherein,

And r is 0, 1,2,3, 4, 5,6,7 or 8;

B ¹ selected from the group consisting of:

wherein,

x is C ═ O or S ═ O ₂ ；

n is 1,2,3 or 4;

q is selected from the group consisting of:

m, p are each independently 1,2,3 or 4;

Z ₄ Is selected from

unless otherwise specified, "substituted" means substituted with one or more (e.g., 2,3, 4, etc.) substituents selected from the group consisting of: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, oxo, -CN, hydroxy, amino, carboxy, a group selected from the group consisting of unsubstituted or substituted with one or more substituents selected from the group consisting of: C6-C10 aryl, halogenated C6-C10 aryl, 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O, halogenated 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O; the substituent is selected from the following group: halogen, C1-C6 alkoxy;

with the proviso that when Z ₄ Is composed of

When Q is

2. The proteolytic targeting chimera of claim 1, wherein the compound of formula I has the structure of formula II:

3. the proteolytic targeting chimera of claim 1, wherein the compound of formula I has the structure of formula III:

rc and Rd are each independently selected from the group consisting of: H. cyano, halogenElement, substituted or unsubstituted C ₁ -C ₆ Alkyl, substituted or unsubstituted C ₁ -C ₆ Alkoxy group of (a);

the radicals are as defined in claim 1.

4. The proteolytic targeting chimera of claim 1, wherein the compound of formula I has the structure shown in formula IV below:

5. the proteolytic targeting chimera of claim 1, wherein Z is ¹ Selected from the group consisting of: substituted or unsubstituted C ₃ -C ₈ Cycloalkyl (including monocyclic, fused or bridged ring forms), substituted or unsubstituted C ₆ -C ₁₀ And (4) an aryl group.

6. The proteolytic targeting chimera of claim 1, wherein the proteolytic targeting chimera has a structure according to formula V below:

wherein Z is ₅ Is composed of L ² -Y ¹ -B ¹ The constituent groups.

7. The proteolytic targeting chimera of claim 1, wherein-L ² -Y ¹ Is a linking group, wherein L ² Is- (Y) ² ) _r -，Y ² Selected from the group consisting of: -CH ₂ -、-O-；

And r is 0, 1,2,3, 4, 5,6,7 or 8;

8. A pharmaceutical composition comprising (1) the proteolytic targeting chimera of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate thereof; (2) a pharmaceutically acceptable carrier.

9. Use of the proteolytic targeting chimera according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to claim 7, for the preparation of a pharmaceutical composition for the prevention and/or treatment of diseases associated with the activity or expression of MDM 2.

10. An MDM2 protein degrading agent, wherein the inhibitor comprises the protein degradation targeting chimera of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof.