WO2022166970A1

WO2022166970A1 - Bifunctional mdm2 protein degrader, and preparation method therefor and pharmaceutical composition and use thereof

Info

Publication number: WO2022166970A1
Application number: PCT/CN2022/075420
Authority: WO
Inventors: 王喆; 曾志宏; 江荣珍; 赖满庆
Original assignee: 上海长森药业有限公司
Priority date: 2021-02-04
Filing date: 2022-02-07
Publication date: 2022-08-11
Also published as: CN114853731A

Abstract

Provided in the present invention are a proteolysis targeting chimera, and a preparation method therefor and a pharmaceutical composition and the use thereof. Specifically, the proteolysis targeting chimera comprises the following structure: an MDM2 target protein inhibitor-C(O)NH-L2-Y1-B1, wherein each group is as defined in the description. The compound is used for the treatment of conditions or disorders (such as cancers) which are responsive to the degradation of the MDM2 protein.

Description

A kind of bifunctional MDM2 protein degrading agent, its preparation method, pharmaceutical composition and application

technical field

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

Background technique

The p53 gene is the most tumor suppressor gene related to human tumors. It has the functions of maintaining genome stability and inhibiting or preventing cell transformation, thereby inhibiting the occurrence of tumors. The research on new anti-tumor drugs targeting p53 has become a hot spot in this field. The research results show that MDM2 (murine double minute 2) is a key negative regulator of p53, p53 activates the transcription of MDM2, and MDM2 in turn inhibits the activity of p53. The two form an autoregulatory feedback loop to keep both p53 and MDM2 at low levels under normal circumstances. The abnormal expression of MDM2 in tumor cells leads to the rapid degradation of p53 and the inactivation of the p53 pathway, which affects its inhibitory level on tumors. Therefore, the release of p53 from the control of MDM2 and the activation of the p53 pathway are expected to inhibit tumor cell growth. and induction of apoptosis. Unlike normal cellular p53 activation due to uncommon causes, tumor cells are under constant cellular stress with various impairments including hypoxia and activation of pro-apoptotic oncogenes. Therefore, the inactivation of the p53 pathway in tumors has a strong selective advantage, and some researchers have proposed that the elimination of p53 function may be a prerequisite for tumor survival. In support of this idea, three investigative research groups have used mouse models to demonstrate that loss of p53 function is an ongoing requirement for tumor maintenance. When the researchers restored p53 function in p53-inactivated tumors, the tumors regressed.

In 50% of solid tumors and 10% of liquid tumors, p53 is inactivated by mutation and/or deletion. In cancer, other key members of the p53 pathway are also genetically or epigenetically altered. MDM2, an oncoprotein that inhibits p53 function, has been reported to be activated by gene amplification with an incidence of up to 10%. MDM2 is in turn inhibited by another tumor suppressor, p14ARF. Changes downstream of p53 are thought to be likely responsible for at least partial inactivation of the p53 pathway in p53 wild-type. In support of this concept, some p53 wild-type tumors appear to show reduced 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 p53. MDM2 inhibits p53 activity through three mechanisms: 1) acts as an E3 ubiquitin ligase to promote p53 degradation; 2) binds to and blocks the p53 transcriptional activation domain; and 3) exports p53 from the nucleus to the cytoplasm . All three mechanisms will be blocked by counteracting the MDM2-p53 interaction. This therapeutic strategy can be targeted to p53 wild-type tumors, and studies have shown promise in reducing tumor growth in vitro and in vivo using small-molecule MDM2 protein degraders. Further, in patients with p53-inactivated tumors, the stabilization of wild-type p53 in normal tissues after MDM2 inhibition may selectively protect normal tissues from damage.

Protein degradation targeting chimera (PROTAC) is a technology derived from the Nobel Prize in Chemistry. The principle of PROTAC technology is to use bifunctional small molecules to link the target protein and the intracellular E3 ligase to ubiquitinate the target protein. Thus, it is recognized by the proteasome and leads to the degradation of the target protein. Eukaryotic cells are constantly struggling to maintain proper protein levels, producing and degrading thousands of proteins at every moment. A key factor in maintaining protein balance is a small protein molecule called ubiquitin. When it is linked to proteins, it causes those proteins to be transported to the proteasome for degradation. The bifunctional protein degrader comprises a target protein inhibitor, a linker and a ligand for the E3 ubiquitin protein ligase protein.

In conclusion, there is a need in the art to develop novel bifunctional MDM2 protein degraders.

SUMMARY OF THE INVENTION

The purpose of the present invention is to provide a novel MDM2 protein degrading agent.

A first aspect of the present invention provides a protein degradation targeting chimera, the protein degradation targeting chimera comprising:

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

in,

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

and r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

Y ¹ is selected from the group consisting of -C≡C-, -CH=CH-, -CH ₂ -, -O-, -N(R ^2b )-, -C(=O)N(R ^2c )-, - The group consisting of N(R ^2d )C(=O)CH ₂ O- and -N(R ^2e )C(=O)CH ₂ N(R ^2f )-; or Y ¹ is absent;

And when Y ¹ does not exist, r is not 0;

Among them, the carboxamide nitrogen atom of -N(R ^2d )C(=O)CH ₂ O- and -N(R ^2e )C(=O)CH ₂ N(R ^2f )- and -C(=O)N The carbon atom of (R ^2e )- is connected to L ² ;

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

B ¹ is selected from the following group:

The MDM2 target protein inhibitor is a structural fragment formed by a compound shown in the following formula I and a linking group through a covalent bond;

in,

is a 5-membered, 6-membered or 7-membered heterocyclic group; wherein, the heterocyclic group includes 1-3 N atoms, and 0-2 heteroatoms selected from the following groups 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 _C1 - _C6 alkyl, substituted or unsubstituted _C1 - _C6 alkoxy, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted C ₆ -C ₁₀ aryl, or substituted or unsubstituted 5- with 1-3 heteroatoms selected from the group N, S and O 10-membered heteroaryl;

Z ₁ is 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 ring Alkyl (including monocyclic, paracyclic or bridged forms), substituted or unsubstituted _C6 - _C10 aryl;

Q is selected from the following group:

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

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

Z ₄ is selected from

Wherein, described R ₁ is selected from the following group: 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;

Z ₆ is selected from the group consisting of CH ₂ , C(O) or N;

Rd and 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 _C6 - _C10 aryl; or Described Rd and Re and adjacent N atom form 4-10 membered heterocycle, and described heterocycle contains 1-2 nitrogen atom and 0-2 S or O atom;

R ₂ is 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 following groups N, S and O;

Unless otherwise specified, the "substituted" refers to being substituted by one or more (eg, 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, hydroxyl, amino, Carboxyl, unsubstituted or substituted with one or more substituents selected from the group consisting of: C6-C10 aryl, halogenated C6-C10 aryl, with 1-3 selected from N , 5-10-membered heteroaryl groups of heteroatoms of S and O, halogenated 5-10-membered heteroaryl groups with 1-3 heteroatoms selected from N, S and O; the substituents are selected from The next group: halogen, C1-C6 alkoxy;

The additional condition is that when _Z4 is

, Q is

In another preferred embodiment, the

Choose from the following group:

In another preferred embodiment, the compound of formula I has the structure described in the following formula II:

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 groups, and substituted or unsubstituted C ₆ -C ₁₀ aryl groups.

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

Wherein, Ra and Rb are each independently a substituted or unsubstituted C ₆ -C ₁₀ aryl group, or a substituted or unsubstituted 5-10-membered heteroatom having 1-3 heteroatoms selected from the following groups of N, S and O Heteroaryl;

Rc and Rd are each independently selected from the group consisting of H, cyano, halogen, substituted or unsubstituted _C1 - _C6 alkyl, substituted or unsubstituted _C1 - _C6 alkoxy;

The definitions of each group are as described above.

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

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

In another preferred embodiment, the Z ¹ is selected from the following group: substituted or unsubstituted C ₃ -C ₈ cycloalkyl (including monocyclic, parallel or bridged forms), substituted or unsubstituted C ₆ -C ₁₀ aryl.

In another preferred embodiment, the protein degradation targeting chimera has the structure described in the following formula V:

Wherein, Z ₅ is a group consisting of L ² -Y ¹ -B ¹ .

In another preferred example, the -L ² -Y ¹ - is a linking group, wherein, L ² is -(Y ² ) _r -, and Y ² is selected from the following group: -CH ₂ -, -O- ;

and r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

Y ¹ is selected from the group consisting of -C≡C-, -CH=CH-, -CH ₂ -, -O-, -N(R ^2b )-, -C(=O)N(R ^2c )-.

In another preferred embodiment, the protein degradation targeting chimera has the structure described in the following formula VI:

In another preferred embodiment, described Z ₅ is selected from the following group:

In another preferred embodiment, Z ₆ is CH.

In another preferred example, the Z ₅ is

In another preferred embodiment, the protein degradation targeting chimera is compound 055, 056, 057, 058, 059, 060, 061, 062, or 063 as shown in the Examples.

The second aspect of the present invention provides a pharmaceutical composition, comprising (1) the protein degradation targeting chimera according to the first aspect of the present invention, or a stereoisomer or tautomer thereof, or A pharmaceutically acceptable salt, hydrate or solvate; (2) a pharmaceutically acceptable carrier.

The third aspect of the present invention provides a protein degradation targeting chimera according to the first aspect of the present invention, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrated Use of the compound or solvate or the pharmaceutical composition according to the second aspect of the present invention for preparing a pharmaceutical composition for preventing and/or treating diseases related to the activity or expression level of MDM2.

The fourth aspect of the present invention provides an MDM2 protein degrading agent, the inhibitor comprising the protein degradation targeting chimera according to the first aspect of the present 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 to treat diseases selected from the group consisting of bladder cancer, breast cancer, colon cancer, rectal cancer, kidney cancer, liver cancer, lung cancer (small cell lung cancer and non-small cell lung cancer) Lung cancer), esophagus, gallbladder, ovarian, pancreatic, gastric, cervical, thyroid, prostate and skin cancers (including squamous cell carcinoma); lymphoid lineage hematopoietic tumors (including leukemia, acute lymphoblastic leukemia) , chronic myeloid leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma, and Burkitt lymphoma 's lymphoma); myeloid lineage hematopoietic tumors (including acute and chronic myeloid leukemia, myelodysplastic syndromes, and promyelocytic leukemia); tumors of mesenchymal origin (including fibrosarcoma and rhabdomyosarcoma and 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 Fetal tumor, osteosarcoma, xeroderma pigmentosum (xenodromapigmentosum), keratoctanthoma, follicular thyroid carcinoma and Kaposi's sarcoma), endometrial cancer, head and neck cancer, glioblastoma Cytoma, malignant ascites, hematopoietic cancer, thyroid hyperplasia (especially Grave's disease), cysts, asthma, chronic obstructive pulmonary disease (COPD), emphysema, psoriasis, contact dermatitis, conjunctivitis, allergies Rhinitis, Systemic Lupus Erythematosus (SLE), Ulcerative Colitis, Crohn's Disease, Multiple Sclerosis, Rheumatoid Arthritis, Inflammatory Bowel Disease, Alzheimer's Disease disease), atherosclerosis, Huntington's disease, inflammatory diseases, hypoxia, ulcers, viral infections, bacterial infections, 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 present invention provides diagnostics for determining which patients should be administered a compound of the present invention.

In another preferred embodiment, a method for inhibiting the activity or expression level of MDM2 in vitro is provided, the method comprising the steps of: targeting the protein degradation of the first aspect of the present invention to a chimera, or a stereoisomer thereof or The tautomer, or a pharmaceutically acceptable salt, hydrate or solvate thereof, is contacted with the MDM2 protein.

It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (eg, the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, it is not repeated here.

Detailed ways

After extensive and in-depth research, the present inventors found a class of MDM2 protein degraders with excellent inhibitory effect. On this basis, the inventors have completed the present invention.

definition

As used herein, the term "alkyl" includes straight or branched chain alkyl groups. For example C ₁ -C ₈ alkyl means straight or branched chain alkyl having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl Wait.

As used herein, the term "alkenyl" includes straight or branched chain alkenyl groups. For example C ₂ -C ₆ alkenyl refers to straight or branched alkenyl having 2-6 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2 -butenyl, or similar groups.

As used herein, the term "alkynyl" includes straight or branched chain alkynyl groups. For example, C2 _- _C6alkynyl refers to a straight or branched chain alkynyl group having 2 to 6 carbon atoms, such as ethynyl, propynyl, butynyl, or the like.

As used herein, the term "C3 _- _C10 cycloalkyl" refers to a cycloalkyl group having 3-10 carbon atoms. It may be a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or the like. Bicyclic forms, such as bridged or spiro forms, are also possible.

As used herein, the term "C ₁ -C ₈ alkylamino" refers to an amine group substituted with a C ₁ -C ₈ alkyl group, which may be mono- or di-substituted; for example, methylamino, ethylamino, Propylamine, isopropylamine, butylamine, isobutylamine, tert-butylamine, dimethylamine, diethylamine, dipropylamine, diisopropylamine, dibutylamine, diisobutylamine, diisobutylamine tert-Butylamine, etc.

As used herein, the term "C ₁ -C ₈ alkoxy" refers to a straight or branched alkoxy group having 1-8 carbon atoms; eg, methoxy, ethoxy, propoxy, iso Propoxy, butoxy, isobutoxy, tert-butoxy, etc.

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 heterocycloalkyl having 3-10 atoms and wherein 1-3 atoms are A saturated or partially saturated cyclic group of heteroatoms selected from the following groups N, S and O. It may be monocyclic or bicyclic, eg bridged or spirocyclic. Specific examples may be oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl, and the like.

As used herein, the term " _C6 - _C10 aryl" refers to an aryl group having 6-10 carbon atoms, eg, phenyl or naphthyl and the like.

As used herein, the term "5-10 membered heteroaryl having 1-3 heteroatoms selected from the following groups N, S and O" refers to having 5-10 atoms and wherein 1-3 atoms are selected from Cyclic aromatic groups of heteroatoms of the following groups N, S and O. It may be a single ring or a fused 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 that the group described in the present invention is "substituted or unsubstituted", the group of the present invention can be substituted by a substituent selected from the following group: halogen, nitrile, nitro, hydroxyl, amino , C ₁ -C ₆ alkyl-amino, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, halogenated C ₁ - C ₆ alkyl, halogenated C ₂ -C ₆ alkenyl, halogenated C ₂ -C ₆ alkynyl, halogenated C ₁ -C ₆ alkoxy, allyl, benzyl, C ₆ -C ₁₂ aryl , C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl, 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, etc.

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. "Halo" means substituted with an atom selected from F, Cl, Br, and I.

Unless otherwise specified, the structural formulas described herein are intended to include all isomeric forms (such as enantiomers, diastereomers and geometric isomers (or conformational isomers)): for example, those containing asymmetric R, S configuration of the center, (Z), (E) isomer of double bond, etc. Accordingly, individual stereochemical isomers or mixtures of enantiomers, diastereomers or geometric isomers (or conformational isomers) of the compounds of the present invention are within the scope of the present invention.

As used herein, the term "tautomer" means that structural isomers having different energies can exceed a low energy barrier, thereby interconverting. For example, proton tautomers (ie, protonation) include interconversion by migration of protons, such as 1H-indazole and 2H-indazole. Valence tautomers include interconversion by some bonding electron recombination.

As used herein, the term "solvate" refers to a complex in which a compound of the present invention coordinates with solvent molecules to form a complex in specified proportions.

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 degrader

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

in,

X is C=O or S=(O) ₂ ;

n is 1, 2, 3 or 4;

Q is selected from the following group:

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

Each Z ₂ or Z ₃ is 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

Rd and 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 _C6 - _C10 aryl; or The Rd and Re and the adjacent N atoms form a 4-8 membered heterocycle, and the heterocycle contains 1-2 nitrogen atoms and 0-1 S or O atoms;

The additional condition is that when _Z4 is

, Q is

As used herein, "pharmaceutically acceptable salts" refer to salts of compounds of the present invention with acids or bases that are suitable for use as pharmaceuticals. Pharmaceutically acceptable salts include inorganic and organic salts. A preferred class of salts are the salts of the compounds of the present invention with acids. Acids suitable for forming salts include, but are not limited to, inorganic acids such as hydrochloric, hydrobromic, hydrofluoric, sulfuric, nitric, phosphoric, formic, acetic, propionic, oxalic, malonic, succinic, fumaric, Maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenemethanesulfonic acid, benzenesulfonic acid and other organic acids; and acidic amino acids such as aspartic acid and glutamic acid. Suitable salt-forming cations include alkali and alkaline earth metal cations, such as sodium, lithium, potassium, calcium, magnesium, etc., and non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to Ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc.

In another preferred embodiment, the

m, n, p, Z ₁ , Z ₂ , Z ₃ , Z ₄ , Q and R are each independently a group corresponding to each compound in Table 1.

Preferred MDM2 protein degraders are the compounds shown below:

Bifunctional protein degradation targeting chimeras as MDM2 protein degraders

In the present invention, a bifunctional protein degradation targeting chimera as an MDM2 protein degrading agent is also provided, and the targeting chimera has the structure shown in the following formula:

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

in,

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

B ¹ is selected from the following group:

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

Pharmaceutical compositions and methods of administration

Since the compound of the present invention has excellent MDM2 inhibitory activity, the compound of the present invention and its various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and compounds containing the compound of the present invention as the main active ingredient Pharmaceutical compositions can be used to treat (stabilize, alleviate or cure) cancer. Cancers that can be treated with the compounds of the present invention include, but are not limited to, cancers such as bladder, breast, colon, rectal, kidney, liver, lung (small cell and non-small cell), esophagus, gallbladder, Ovarian, pancreatic, gastric, cervical, thyroid, prostate, and skin cancers (including squamous cell carcinoma); lymphoid lineage hematopoietic tumors (including leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, acute lymphoblastic Cellular leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, and Burkett's lymphoma; myeloid lineage hematopoietic tumors ( including acute and chronic myeloid leukemia, myelodysplastic syndromes, and promyelocytic leukemia); tumors of mesenchymal origin (including fibrosarcoma and rhabdomyosarcoma and other sarcomas such as soft tissue sarcoma and osteosarcoma); central and peripheral nervous system tumors (including astrocytoma, neuroblastoma, glioma, and schwannoma); and other tumors (including melanoma, seminoma, teratoma, osteosarcoma, xeroderma pigmentosum ( xenodromapigmentosum), keratoctanthoma, follicular thyroid carcinoma and Kaposi's sarcoma). Other cancers that may be treated with the compounds of the invention include endometrial cancer, head and neck cancer, glioblastoma, Malignant ascites, and hematopoietic cancer.

Specific cancers that can be treated with the compounds of the present invention include soft tissue sarcomas, bone cancers (eg, osteosarcoma), breast tumors, bladder cancer, Li-Fraumeni syndrome, brain tumors, rhabdomyosarcoma, adrenocortical cancer, colorectal cancer, non-small cell lung cancer , and acute myeloid leukemia (AML).

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

"Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid filler or gel substances which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity. "Compatibility" as used herein means that the components of the composition are capable of admixture with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid) , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as

), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

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 (a) fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators such as quaternary amine compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, hard Calcium fatty acid, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shell materials, 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 in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes. 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 compound, liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, and the like.

Besides 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 such as 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 non-aqueous carriers, diluents, solvents or excipients 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 (eg, chemical anticancer drugs).

When administered in combination, the pharmaceutical composition also includes one or more (2, 3, 4, or more) other pharmaceutically acceptable compounds (eg, chemical anticancer drugs). One or more (2, 3, 4, or more) of the other pharmaceutically acceptable compounds (eg, chemical anticancer drugs) can be used simultaneously, separately or sequentially with the compounds of the present invention for the treatment of cancer or related diseases.

When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) in need of treatment, and the dose is the effective dose considered pharmaceutically, for a 60kg body weight, the daily dose is The administration dose is usually 1 to 2000 mg, preferably 20 to 500 mg. Of course, the specific dosage should also take into account the route of administration, the patient's health and other factors, which are all within the skill of the skilled physician.

The main advantages of the present invention include:

(1) The compounds of the present invention have novel structures and excellent MDM2 inhibitory effects. In the present application, the existing sulfone compounds are transformed into sulfimide compounds, which can keep the activity or expression amount of MDM2 inhibiting, reduce the plasma protein binding rate, increase the free drugs, and be easily transported to the organs across the membrane Organization works.

(2) The compound of the present invention has very low toxicity to normal cells, so it can be applied to the treatment object in a wide dosage range.

(3) The compound of the present invention has good druggability. Compared with the existing compounds, the compound of the present invention has better solubility and exhibits good bioavailability in in vivo experiments. Compared with the existing compounds, the compounds of the present invention can be easily formed into pharmaceutically acceptable salts, thus facilitating further formulation.

(4) The compound of the present invention and the pharmaceutical composition containing the compound of the present invention as the main active ingredient can be used for the treatment of cancer-related diseases.

The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. In the following examples, the experimental methods without specific conditions are usually in accordance with conventional conditions, or in accordance with the conditions suggested by the manufacturer. Percentages and parts are by weight unless otherwise indicated.

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

Example 1

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

Step 1: Methyl 4-(3-chlorophenyl)-5-(4-chlorophenyl)-5-hydroxy-2-methylpentanoate

4-(3-Chlorophenyl)-5-(4-chlorophenyl)-2-methyl-5-oxopentanoic acid methyl ester (36.5g) was dissolved in ethanol (300ml), cooled to 0～ 5°C, add NaBH ₄ (2.85g) in batches, react at 0～10°C for 2 hours, TLC tracking reaction is basically complete, add acetic acid (～8ml) dropwise until no hydrogen is released, concentrate the solvent, add 300ml of ethyl acetate, followed by Washed with water and saturated sodium bicarbonate, dried over anhydrous magnesium sulfate, and concentrated to obtain 37 g 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), LiOH.H ₂ O (8.4 g) in an aqueous solution of 100ml, react at 20°C for 18 hours, the TLC tracking reaction is basically complete, dropwise add 4N hydrochloric acid to pH<1, concentrate the solvent, add toluene at 50°C to extract 250ml×2, wash with water to obtain 4-(3-chlorobenzene) base)-5-(4-chlorophenyl)-5-hydroxy-2-methylvaleric acid in toluene solution directly to the next step.

Step 3: 5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahydro-2H-pyran-2-one

The toluene solution of 4-(3-chlorophenyl)-5-(4-chlorophenyl)-5-hydroxy-2-methylpentanoic acid was added with TsOH.H ₂ O (1.0 g), heated to separate water and refluxed Reaction for 2 hours, TLC tracking reaction was basically complete, washed with saturated aqueous sodium bicarbonate solution after cooling, dried over anhydrous magnesium sulfate, concentrated toluene solution to obtain 37.7g of crude product, separated by column chromatography to obtain 5-(3-chlorophenyl)- 6-(4-Chlorophenyl)-3-methyltetrahydro-2H-pyran-2-one.

Step 4: (±)(3S,5R,6R)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahydro-2H-pyridine furan-2-one

5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahydro-2H-pyran-2-one (6.7g) and bromopropene (7.26g) were dissolved in THF (25ml), cooled to -50°C, added dropwise LiHMDS (26ml 1M in THF) solution, raised to 0°C and stirred for 1 hour, TLC tracked the disappearance of raw materials, added saturated ammonium chloride solution, extracted with ethyl acetate, column Chromatographic separation to obtain 6.0g of product, the isomer was difficult to purify through column, 6.0g of product was added to 50ml of n-heptane/toluene (10:1), heated and refluxed to dissolve, slowly cooled to room temperature, 2.8g of solid was precipitated, is (±)(3S,5R,6R)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahydro-2H-pyran- 2-keto.

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).

Step 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-ketone (1.0g) was dissolved in toluene (1ml), L-Valinol (0.825g) was added, heated to 100°C and reacted for 5 hours, TLC tracking reaction was basically complete, after cooling, ethyl acetate was added, followed by 1N Washed with hydrochloric acid and saturated sodium bicarbonate, dried over anhydrous magnesium sulfate, and concentrated to obtain 2-((2R,3R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-3-hydroxypropane base)-N-((S)-1-hydroxy-3-methylbutyl-2)-2-methylpentene-4-amide 1.48 g.

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-hexahydrooxazol[3,2-a]-4-pyridine 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°C, Tf ₂ was added dropwise O (97.6g), warmed to room temperature and reacted overnight, washed with 0.5MTfOH solution (200ml), extracted with ethyl acetate (500ml×2), the organic phase was concentrated and dissolved in DCM (400ml), separated by column chromatography, and the conditions for:

Silicone: 120g

Amount of each sample: 10g

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

时间(min)Time (min)	流动相比例mobile phase ratio
0-50-5	25％25%
5-155-15	25％-35％25%-35%
15-3015-30	35％35%
30-3530-35	25％25%

The less polar isomer (27.4 g, 34.8%) was obtained as (3S,5S,6R,8S)-8-allyl-6-(3-chlorophenyl)-5-(trifluoromethanesulfonic acid) 4-Chlorophenyl)-3-isopropyl-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]o-4-pyridine 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 more polar isomer (22.8 g, 28.9%) as trifluoromethanesulfonic acid (3S,5R,6S,8R)-8-allyl-6-(3-chlorophenyl)-5-( 4-Chlorophenyl)-3-isopropyl-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]o-4-pyridine 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).

Step 7: (3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropyl) Mercapto)-3-methylbutyl-2)-3-methylpiperidin-2-one

Under nitrogen protection, isopropyl mercaptan (10.4g) was added dropwise to the (82.2ml 1M THF) solution of potassium tert-butoxide, cooled properly so that the temperature did not exceed 30°C, stirred for 10min after dropping, and 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]-4-pyridine salt (17.8g) in DMF solution (80ml) was raised to 50°C and reacted for 3 hours, followed by TLC after the reaction was completed, poured Into 600ml of water, extracted with ethyl acetate (200ml×3), washed with water, concentrated and separated by column chromatography to obtain 13.5g of oily product (3S,5R,6S)-3-allyl-5-(3-chlorophenyl) -6-(4-Chlorophenyl)-1-((S)-1-(isopropylmercapto)-3-methylbutyl-2)-3-methylpiperidin-2-one.

Step 8: (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropyl) Sulfoxide)-3-methylbutyl-2)-3-methylpiperidin-2-one

(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylmercapto) -3-Methylbutyl-2)-3-methylpiperidin-2-one (2.03g) was dissolved in methanol (25ml), 0.60ml of 30% hydrogen peroxide was added, the reaction was carried out at 20-25°C for 2 days, and thiosulfuric acid was added. The reaction was terminated with sodium solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated, and separated by column chromatography to obtain 1.99g (3S,5R,6S)-3-allyl-5-(3-chlorophenyl) -6-(4-Chlorophenyl)-1-((S)-1-(isopropylsulfoxide)-3-methylbutyl-2)-3-methylpiperidin-2-one, As a mixture of two isomers, the yield is 95%.

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, 13.3 Hz), 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).

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)-16-sulfonamidinoamine)

(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfoxide) yl)-3-methylbutyl-2)-3-methylpiperidin-2-one (336 mg) and trifluoroacetamide (142.4 mg) were dissolved in DCM (4 ml), followed by the addition of MgO (126.5 mg) and Rh ₂ (OAc) ₄ (6.9 mg), finally PhI(OAc) ₂ (303.7 mg) was added and stirred at room temperature overnight, filtered, the solid was washed with DCM, the solution was concentrated, passed through a column, the eluent was n-heptane/ethyl acetate Ester=2:1, 58 mg of product 2,2,2-trifluoroacetyl N-(((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorobenzene) yl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-3-methylbutyl)(isopropyl)(oxy)-16-sulfoneamidine amine) as a mixture of two isomers in 14% yield.

¹ H NMR (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-propylsulfoneamidino)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)-16-sulfonamidinoamine) (150mg) and tris Ruthenium chloride (7.3mg) was dissolved in DCM/water (5ml/5ml), then tetrabutylammonium hydrogen sulfate (15.8mg) and sodium periodate (300mg) were added and stirred at room temperature overnight, filtered, extracted with DCM, the solution After drying and concentration, it was passed through a column, and the eluent was n-heptane/ethyl acetate = 1:1 to obtain 120 mg 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-propylsulfoneamidino) Butyl-2-)-2-oxopiperidin-3-yl)acetic acid, a mixture of two isomers, 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=3.2 Hz),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-Propylsulfonamidino)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-propylsulfoneamidino)butyl-2-)-2-oxopiperidin-3-yl)acetic acid (100 mg) dissolved in methanol (2.0ml), then potassium carbonate (417mg) was added and stirred at room temperature for 2 hours, water and ethyl acetate were added, the pH was adjusted to 6 with 3N HCl, the solution was separated, the solution was dried and concentrated, passed through the column, and the eluent was n-heptane/ Ethyl acetate = 1:1 to 0:1, two isomer products are obtained, the more polar product is 31 mg, the less polar product is 18 mg, and the total yield is 57%. Compounds with small polarity are grown in single crystals, and the configuration of the compounds is obtained by single crystal X-ray diffraction experiments.

Compound 12 with high Rs 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 small 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

Compound 4-(2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-3-methyl yl-1-((S)-2-propylsulfonamidino)butan-2-yl)-2-oxopiperidin-3-yl)acetamido)benzoic acid

Step 1: 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)acetamide Synthesis of methyl) 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 the DCM (16ml) solution and stirred at room temperature overnight. The reaction was complete as detected by TLC. Water was added dropwise to the reaction solution under ice bath to quench the reaction, the cold 1N HCl solution was adjusted to pH=2, the layers were separated, the organic phase was washed once more with 1N HCl, washed with water, washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated, and the residue was 600 mg of white foamy solid was obtained by column chromatography with a yield of 62.6%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.84 (s, 1H), 8.07 (d, J=8.7 Hz, 2H), 7.71 (d, J=8.7 Hz, 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=6.7 Hz,3H),0.36 (d,J＝7.0Hz,3H).

Step 2: 4-(2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-3 - Synthesis of methyl-1-((S)-2-propylsulfonamidino)butan-2-yl)-2-oxopiperidin-3-yl)acetamido)benzoic acid

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)ethyl Amido)methyl benzoate (600 mg) and LiOH.H ₂ O (127 mg) were added to a solution of MeOH/H ₂ O/THF (2.4 ml/1.2 ml/1.2 ml) and stirred at room temperature. The reaction was complete as detected by TLC. Concentrate off the solvent, add 10 ml of water, 20 ml of ethyl acetate to the residue, adjust pH=2 with cold 1N HCl solution, separate the layers, extract the aqueous layer once more with ethyl acetate, combine the organic phases, wash with water, wash with saturated brine, anhydrous magnesium sulfate After drying, concentration, the residue was prepared, separated and lyophilized to obtain 250 mg of white solid with a yield of 48.4%. 1H NMR(400MHz,Methanol-d4)δ8.05(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

According to the same experimental method, 4-(2-((3R,5R,6S)-5-(3-chloro) can be obtained by replacing methyl p-aminobenzoate with methyl 2-methoxy-4-aminobenzoate Phenyl)-6-(4-chlorophenyl)-3-methyl-1-((2S)-3-methyl-1-(propan-2-ylthiamidinyl)butan-2-yl) -2-Oxopiperidin-3-yl)acetamido)-2-methoxybenzoic acid.

Example 3

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

step 1:

3-Bromo-2-bromomethyl-benzoic acid methyl ester (5.00 g, 16.2 mmol) and 3-amino-piperidine-2,6-dione hydrochloride (2.94 g, 17.9 mmol) were added to acetonitrile (50 ml) ), then added triethylamine (8.21g, 81.1mmol), heated to reflux overnight, the reaction solution turned dark purple, cooled to room temperature and filtered, the solid was washed with water (20ml) and MTBE (20ml), and dried in vacuo to give 2.70 g solid, 52% yield. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.03 (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:

Compound 3-(4-bromo-1-oxoisoindol-2-yl)piperidine-2,6-dione (1.00 g, 3.09 mmol) and compound pent-4-yn-1-ylcarbamic acid Tert-butyl ester (680 mg, 3.71 mmol) was added to anhydrous DMF (10 ml), after nitrogen replacement, CuI (59 mg, 0.31 mmol) and Pd(PPh ₃ ) ₂ Cl ₂ (217 mg, 0.31 mmol) were added, under nitrogen protection for 80 ℃ reacted overnight, cooled to room temperature, added ethyl acetate and water, extracted and separated, the organic phase was dried, concentrated and separated by column chromatography to obtain 1.12 g of compound (5-(2-(2,6-dioxopiperidine). -3-yl)-1-oxoiso-4-yl)pent-4-yn-1-yl)carbamate tert-butyl ester, 85% yield. LC-MS, positive ion [M+1]=426.

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 4M HCl/dioxane solution (15ml), stirred at room temperature overnight, and concentrated to obtain 650mg of compound 5-(2-(2,6-dioxopiperidin-3-yl)- 1-oxoiso-4-yl)pent-4-yn-1-yl)amine hydrochloride, 69% yield. LC-MS, positive ion [M+1]=326.

Step 4:

Compound 4-(2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((2S)-3- Methyl-1-(propan-2-ylthiamidino)butan-2-yl)-2-oxopiperidin-3-yl)acetamido)-2-methoxybenzoic acid (71.6 mg, 0.1 mmol) and compound 5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoiso-4-yl)pent-4-yn-1-yl)amine hydrochloride (43.4 mg, 0.12 mmol) was added to anhydrous DMF (2.0 ml), stirred at room temperature for 5 min, added HATU (45.6 mg, 0.12 mmol), then added DIPEA (51.7 mg, 0.4 mmol), stirred overnight at room temperature, and separated by preparative HPLC 20 mg of solid were obtained. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.00 (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＝11.7 Hz,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-ylthiamidinyl)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:

Compound 5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoiso-4-yl)pent-4-yn-1-yl)amine hydrochloride (79 mg) Methanol (10ml) was added, 10% Pd/C (75mg) was added after nitrogen replacement, and then replaced with hydrogen. After 3 days of reaction at room temperature and normal pressure, LC-MS showed that the reaction was complete, after nitrogen replacement, filtration, and the filtrate was concentrated to obtain 68mg solid.

Step 2:

Compound 4-(2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((2S)-3- Methyl-1-(propan-2-ylthiamidino)butan-2-yl)-2-oxopiperidin-3-yl)acetamido)-2-methoxybenzoic acid (98 mg) and Compound 5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)pentan-1-amine hydrochloride (60 mg) was added to anhydrous DMF ( 2.0ml), stirred at room temperature for 5min, after the solid was dissolved, HATU (62.4mg) was added, then DIPEA (70.8mg) was added, stirred at room temperature overnight, and 20mg of solid was obtained by preparative HPLC separation.

Example 5

4-(2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((2S)-3-methyl -1-(Propan-2-ylthiamidino)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 (774 mg, 4.14 mmol) and 3-(4-amino-1-oxoisoindol-2-yl)piperidine-2,6-dione (1.18 g, 4.55 mmol) was added to DMF (8.0 ml) to dissolve, then sodium triacetoxyborohydride (1.75 g, 8.28 mmol) was added at room temperature and stirred overnight, the reaction solution was diluted with ethyl acetate, and washed with saturated brine. , dried over anhydrous sodium sulfate, concentrated to obtain the crude product, and separated by column chromatography to obtain 530 mg of solid.

Step 2

Refer to step 3 in Example 3

Step 3

Refer to step 4 in Example 3.

Example 6

step 1:

Refer to step 4 in Example 3.

Step 2:

Refer to step 3 in Example 3

Step 3:

Refer to step 4 in Example 3.

According to the methods in the above examples, the following compounds were prepared, and their characterization data are shown in the following table.

Biological test example 1 Homogeneous time-resolved fluorescence assay (HTRF assay)

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

Specifically, 10 u of LGST-hMDM2 was incubated with 10 ul of diluted compounds (various concentrations, serial dilutions) in 10% DMSO for 20 minutes at room temperature. 20 uL of biotinylated-p53 was added to the GST-hMDM2+ compound mixture followed by incubation at room temperature for 60 min. Add 10 uL of detection buffer consisting of SA-XLent, anti-GST cryptate antibody, and KF to the GST-hMDM2, biotinylated-p53, and compound reactions and place at room temperature to equilibrate and maintain > 4hr. The final concentration of DMSO in this reaction was 2%. Time-resolved fluorescence readings were measured on a microplate multi-label reader. Percent inhibition was calculated relative to nutlin-3.

A modified HTRF assay (HTRF2 assay) was performed when the titer of the MDM2 protein degrader increased. All assay conditions were the same as above except for the following reagent concentration changes: 0.2 nM GST-hMDM2 (1-188), 0.5 nM biotinylated-p53 (1-83), 0.18 nM SA-XLent, and 100 mM KF.

The results are given in the table below. + means <10nm, ++ means 10～100nm, +++ means >100nm

Table 1 HTRF assay

编号Numbering	IC ₅₀ _IC50
055055	++
056056	++
057057	++
058058	++
059059	++
060060	++
061061	++
062062	++
063063	++

Biological test example 2 p21 determination

Inhibition of the interaction between hMDM2 and p53 leads to activation of the p53 pathway via stabilization and accumulation of p53. p53 activates the transcription of many genes, one of which is p21<WAF1/CIP1>. To assess the potency of hMDM2 protein degraders, quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to measure p21 transcript levels in compound-associated cells relative to dimethyl sulfoxide (DMSO)-treated control cells .

On day 1, SJSA- ¹ cells were seeded at a density of 3x10 cells/well in 100 ul growth medium (RPMI1640; 10 mM HEPES; 1 mM sodium pyruvate; 1X penicillin-streptomycin) in 96-well cell culture plates - Glutamine (PSQ); and 10% fetal bovine serum (all reagents from Invitrogen; Carlsbad, CA)). The cells were incubated overnight at 37°C and 5% _CO2 .

On day 2, hMDM2 protein degraders were serially diluted in DMSO (Sigma-Aldrich; St. Louis, MO). 5ul of each compound dilution was added to 245ul of filtered assay medium (RPMI1640, 10 mM HEPES, 1 mM sodium pyruvate, and 1XPSQ) containing 10% FBS. Alternatively, the assay was 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 the seeded SJSA-1 cells and replaced with 100 ul/well of assay medium. 100 ul of medium containing the diluted inhibitor was then added to each well to a final volume of 200 ul. Dose titration of this compound yielded final concentrations ranging from 0.049uM–50uM, plus a DMSO control. The cells were incubated in the presence of inhibitors for 7 hours at 37°C and 5% _CO2 . At the end of the incubation, the medium was removed from the cells and the plate was stored at -80°C.

On day 3, total RNA was purified from inhibitor- and DMSO-treated SJSA-1 cells using the Qiagen BioRobot Universal workstation following the RNeasy96 BioRobot8000 kit protocol from the manufacturer (Qiagen; Valencia, CA).

To measure the level of p21 transcript present, qRT-PCR was used. Levels of p21 and the housekeeping gene, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), were determined in technical replicates from total RNA from each inhibitor- or DMSO-treated well. qRT-PCR reactions were determined using the relative quantification (ΔΔCt) method on an Applied Biosystems Prism 7900HT instrument using the following cycling conditions: 48°C, 30 min, followed by 95°C, 10 min, then 40 cycles of 95°C, 15 sec and 60°C, 1 minute cycle. Data were analyzed using Applied Biosystems SDS 2.2 software with GAPDH as an endogenous control and DMSO-treated samples as a calibrator. The relative quantification (RQ) or fold increase of p21 levels relative to the DMSO control was calculated by the SDS 2.2 software for each treated sample. The maximum (100%) fold of p21 induction was defined by the maximum of the fitted curve for the reference compound. The fold induction of p21 at each inhibitor dose tested was converted to a value representing a percentage of the maximum. Dose-response curves were generated using XLFit software (ID Business Solutions, Alameda, CA) to calculate _IC50 transition values for each inhibitor tested. + is indicated as <1 μM, ++ is indicated as 1-10 μM, and +++ is indicated as >10 μM

Table 2 Cell assay (SJSA-1 cells)

编号Numbering	IC ₅₀ _IC50
055055	++
056056	++
057057	++++
058058	++++
059059	++++
060060	++++
061061	++++
062062	++++
063063	++++

All documents mentioned herein are incorporated by reference in this application as if each document were individually incorporated by reference. In addition, it should be understood that after reading the above-mentioned teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims

A protein degradation targeting chimera, characterized in that the protein degradation targeting chimera comprises:

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

in,

-L 2 -Y 1 - is a linking group, wherein, L 2 is -(Y 2 ) r -, and Y 2 is selected from the group of: -CH 2 -, -O-, -N(R 2b )-;

and r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

Y 1 is selected from the group consisting of -C≡C-, -CH=CH-, -CH 2 -, -O-, -N(R 2b )-, -C(=O)N(R 2c )-, - The group consisting of N(R 2d )C(=O)CH 2 O- and -N(R 2e )C(=O)CH 2 N(R 2f )-; or Y 1 is absent;

And when Y 1 does not exist, r is not 0;

Among them, the carboxamide nitrogen atom of -N(R 2d )C(=O)CH 2 O- and -N(R 2e )C(=O)CH 2 N(R 2f )- and -C(=O)N The carbon atom of (R 2e )- is connected to L 2 ;

R 2b , R 2c , R 2d , R 2e and R 2f are each independently selected from the group consisting of hydrogen and C1-4 alkyl;

B 1 is selected from the following group:

The MDM2 target protein inhibitor is a structural fragment formed by a compound shown in the following formula I and a linking group through a covalent bond;

in,

is a 5-membered, 6-membered or 7-membered heterocyclic group; wherein, the heterocyclic group includes 1-3 N atoms, and 0-2 heteroatoms selected from the following groups 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 C1 - C6 alkyl, substituted or unsubstituted C1 - C6 alkoxy, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 6 -C 10 aryl, or substituted or unsubstituted 5- with 1-3 heteroatoms selected from the group N, S and O 10-membered heteroaryl;

Z 1 is 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 ring Alkyl (including monocyclic, paracyclic or bridged forms), substituted or unsubstituted C6 - C10 aryl;

Q is selected from the following group:

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

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

Z 4 is selected from
Wherein, described R 1 is selected from the following group: 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;

Z 6 is selected from the group consisting of CH 2 , C(O) or N;

Rd and 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 C6 - C10 aryl; or Described Rd and Re and adjacent N atom form 4-10 membered heterocycle, and described heterocycle contains 1-2 nitrogen atom and 0-2 S or O atom;

R 2 is 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 following groups N, S and O;

Unless otherwise specified, the "substituted" refers to being substituted by one or more (eg, 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, hydroxyl, amino, Carboxyl, unsubstituted or substituted with one or more substituents selected from the group consisting of: C6-C10 aryl, halogenated C6-C10 aryl, with 1-3 selected from N , 5-10-membered heteroaryl groups of heteroatoms of S and O, halogenated 5-10-membered heteroaryl groups with 1-3 heteroatoms selected from N, S and O; the substituents are selected from The next group: halogen, C1-C6 alkoxy;

The additional condition is that when Z4 is
, Q is
The protein degradation targeting chimera of claim 1, wherein the compound of the formula I has the structure of the following formula II:
The protein degradation targeting chimera of claim 1, wherein the compound of formula I has the structure of the following formula III:

Wherein, Ra and Rb are each independently a substituted or unsubstituted C 6 -C 10 aryl group, or a substituted or unsubstituted 5-10-membered heteroatom having 1-3 heteroatoms selected from the following groups of N, S and O Heteroaryl;

Rc and Rd are each independently selected from the group consisting of H, cyano, halogen, substituted or unsubstituted C1 - C6 alkyl, substituted or unsubstituted C1 - C6 alkoxy;

The definition of each group is as described in claim 1 .
The protein degradation targeting chimera of claim 1, wherein the compound of formula I has the structure described in the following formula IV:
The protein degradation targeting chimera of claim 1, wherein said Z 1 is selected from the group consisting of substituted or unsubstituted C 3 -C 8 cycloalkyl (including monocyclic, cyclic or bridged ring form), substituted or unsubstituted C6 - C10 aryl.
The protein degradation targeting chimera of claim 1, wherein the protein degradation targeting chimera has the structure of the following formula V:

Wherein, Z 5 is a group consisting of L 2 -Y 1 -B 1 .
The protein degradation targeting chimera of claim 1, wherein the -L 2 -Y 1 - is a linking group, wherein L 2 is -(Y 2 ) r -, and Y 2 is selected from Lower group: -CH 2 -, -O-;

and r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

Y 1 is selected from the group consisting of -C≡C-, -CH=CH-, -CH 2 -, -O-, -N(R 2b )-, -C(=O)N(R 2c )-.
The protein degradation targeting chimera of claim 1, wherein the protein degradation targeting chimera has the structure described in the following formula VI:
The protein degradation targeting chimera of claim 1, wherein the Z 5 is selected from the group consisting of:
The protein degradation targeting chimera of claim 1, wherein Z 6 is CH.
The protein degradation targeting chimera of claim 1, wherein the Z 5 is
The protein degradation targeting chimera of claim 1, wherein the protein degradation targeting chimera is selected from the group consisting of:
A pharmaceutical composition, characterized in that, comprising (1) the protein degradation targeting chimera as claimed in claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, hydrate or solvate; (2) a pharmaceutically acceptable carrier.
The protein degradation targeting chimera of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or the drug of claim 13 The use of the composition is characterized in that it is used to prepare a pharmaceutical composition for preventing and/or treating diseases related to the activity or expression level of MDM2.
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 thereof , hydrate or solvate.