# US 11,299,460 B2 · MDM2 inhibitor, preparation method therefor, pharmaceutical composition thereof and use thereof

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- Number: US 11,299,460 B2
- Document ID: US11299460B2
- Status: Granted
- Kind: B2
- Application number: 17/281,368
- Filed: 2019-09-30
- Published: 2022-01-06
- Granted: 2022-04-12
- Earliest claimed: 2018-09-30
- Assignees: Shanghai Longwood Biopharmaceuticals Co., Ltd.
- Applicants: Shanghai Longwood Biopharmaceuticals Co., Ltd.
- Inventors: Zhe Wang; Zhihong Zeng; Rongzhen Jiang
- Web page: https://patentgrep.com/patent/US11299460B2

## CPC

- C07D 211/74: Oxygen atoms
- C07D 211/76: attached in position 2 or 6
- A61P 35/00: Antineoplastic agents
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to an MDM2 inhabitor, a preparation method therefor, a pharmaceutical composition thereof, and the use thereof specifically, the present invention relates to a compound represented by formula I. The compound has excellent MDM2 inhibitory activities, and can be used for preparing a pharmaceutical composition for treating cancers and other diseases related to MDM2 activities, particularly p53 wild-type cancer.

## Claims

### Claim 1

A compound according to Formula I:
or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts, hydrates or solvates thereof,
wherein,
is selected from the group consisting of 5, 6 or 7 membered heterocyclic with 1-3 N and 0-2 heteroatoms selected from S and O;
X is independently C═O or S═(O)2;
n is 1, 2, 3 or 4;
each R is selected independently from the group consisting of H, Cyano, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-10 membered heteroaryl with 1-3 heteroatoms selected from N, S and O;
Z1 is selected from the group consisting of H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl(including single, fused or bridged ring form), substituted or unsubstituted C6-C10 aryl;
Q is selected from the group consisting of
M and p are selected independently from the group consisting of 1, 2, 3 or 4;
Each Z2 and Z3 is selected independently from the group consisting of none, substituted or unsubstituted C1-C7 alkylidene, NR1, O, S, C═O, S═(O)2;
Z4 is selected
wherein, R1 is selected from the group consisting of H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C10 aryl, CN, —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 and Re are selected independently from the group consisting of H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C6-C10 aryl; the Rd and Re herein form a 4-10 membered heterocyclic with adjacent N, and the heterocyclic contains 1-2 N and 0-2 S or O;
R2 is selected from the group consisting of substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-10 membered heteroaryl with 1-3 heteroatoms selected from N, S and O;
Unless otherwise specified, “substituted” refers to being substituted by one or more (for example, 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, —NH2, carboxy, unsubstituted or substituted group selected from the group consisting of C6-C10 aryl, halogenated C6-C10 aryl, 5-10 membered heteroaryl with 1-3 heteroatoms selected from N, S and O; halogenated 5-10 membered heteroaryl with 1-3 heteroatoms selected from N, S and O; and the substituted is substituted by substituents selected from the group consisting of halogen, C1-C6 alkoxy;
with the proviso that when Z4 is
R, then Q is

### Claim 2 (depends on 1)

The compound of claim 1, stereoisomers or tautomers thereof, or pharmaceutically acceptable salts, hydrates or solvates thereof, wherein the compound has a structure according to Formula II:

### Claim 3 (depends on 1)

The compound of claim 1, wherein the compound has a structure according to Formula III:
wherein, Ra and Rb are independently selected from substituted or unsubstituted C6-C10 aryl and 5-10 membered heteroaryl with 1-3 heteroatoms selected from N, S and O;
Re is selected from the group consisting of H, CN, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy;
the remaining groups are defined as in claim 1.

### Claim 4 (depends on 1)

The compound of claim 1, wherein the compound has a structure according to formula IV:

### Claim 5 (depends on 1)

The compound of claim 1, wherein the compound has a structure selected from the following table:
number
structure
001
002
003
004
005
006
007
008
009
010
011
012
013
014
015
016
017
018
019
020
021
022
023
024
025
028A
028B
029
030
031
034
035
039
040
041
042
043
045
046
047
048
049
050
051
052
053
054

### Claim 6 (depends on 1)

A method of preparing the compound of Formula I of claim 1, wherein the method comprises, or is through step 1, step 2 or step 3:
Step 1:
wherein, each group is defined as described in claim 1.

### Claim 7 (depends on 1)

A pharmaceutical composition, comprising (1) the compound as of claim 1 or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts, hydrates or solvates thereof; (2) a pharmaceutically acceptable carrier.

### Claim 8 (depends on 7)

A method of treating diseases related to the activity or expression of MDM2 in a subject in need thereof, wherein the diseases related to the activity or expression of MDM2 is 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, esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, prostate cancer and skin cancer, squamous cell carcinoma; lymphatic lineage hematopoietic system tumors, leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non Hodgkin's lymphoma, hair cell lymphoma and Burkitt's lymphoma, bone marrow lineage hematopoietic system tumors, acute and chronic myeloid leukemia, myelodysplastic syndrome and promyelocytic leukemia; mesenchymal neoplasms, fibrosarcoma and rhabdomyosarcoma and other sarcomas, soft tissue sarcoma and osteosarcoma; central and peripheral nervous system tumors, astrocytoma, neuroblastoma, glioma and neurosarcoma; other tumors, melanoma, seminoma, teratoma, osteosarcoma, xerodermapigmentosum, keratoacanthoma, follicular thyroid cancer and Kaposi's sarcoma, endometrial cancer, head and neck cancer, glioblastoma, malignant ascites, hematopoietic system cancer, thyroid hyperplasia, 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 septicemia, the method comprising administering to the subject an effective amount of the pharmaceutical composition of claim 7.

### Claim 9 (depends on 1)

An MDM2 inhibitor, wherein the inhibitor comprises the compound of claim 1, or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts, hydrates or solvates thereof.

### Claim 10 (depends on 1)

A method of inhibiting MDM2 activity and expression in vitro comprising contacting the compound of claim 1, or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts, hydrates or solvates thereof with MDM2 protein.