Substituted pyrrolo[3,4-d]imidazoles as MDM2-p53 inhibitors

Patent metadata

Field	Value
Publication number	US-11639355-B2
Application number	US-201916979202-A
Country	US
Kind code	B2
Filing date	Mar 12, 2019
Priority date	Mar 12, 2018
Publication date	May 2, 2023
Grant date	May 2, 2023

Abstract

Disclosed is a novel class of MDM2-p53 inhibitor compounds having an imidaxopyrolone structure, and specifically disclosed are compounds represented by formulas (I-1) and (I-2) and pharmaceutically acceptable salts thereof.

First claim

What is claimed is:

1. A compound represented by formula (I-1):

or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:

 is:

X 3 is CH or CR 10 ;
X 4 is CH or CR 11 ;
X 5 is CH or CR 12 ;
R 1 is H or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2, or 3 independently selected R a substituents;
R 2 is phenyl, wherein the phenyl is optionally substituted with 1, 2, or 3 independently selected R e substituents;
R 3 is H, halogen, CN, C 1-3 alkyl, C 1-3 heteroalkyl, NH 2 , or OH, wherein the C 1-3 heteroalkyl comprises 1, 2, or 3 heteroatoms or heteroatomic groups independently selected from the group consisting of —C(O)—, —C(O)O—, —C(S)—, N, —NH—, —O—, —S—, —S(O)—, and —S(O) 2 —, and further wherein the C 1-3 alkyl or C 1-3 heteroalkyl is optionally substituted with 1, 2, or 3 independently selected R c substituents;
R 4 is H, halogen, CN, C 1-3 alkyl, C 1-3 heteroalkyl, NH 2 , or OH, wherein the C 1-3 heteroalkyl comprises 1, 2, or 3 heteroatoms or heteroatomic groups independently selected from the group consisting of —C(O)—, —C(O)O—, —C(S)—, N, —NH—, —O—, —S—, —S(O)—, and —S(O) 2 —, and further wherein the C 1-3 alkyl or C 1-3 heteroalkyl is optionally substituted with 1, 2, or 3 independently selected R c substituents;
R 6 is CH(CH 3 ) 2 ;
R 7 is OC 1-3 alkyl, wherein the OC 1-3 alkyl is optionally substituted with 1, 2, or 3 independently selected halogen substituents;
R 8 is OC 1-3 alkyl, wherein the OC 1-3 alkyl is optionally substituted with 1, 2, or 3 independently selected halogen substituents;
R 10 is halogen, CN, C 1-3 alkyl, C 1-3 heteroalkyl, NH 2 , or OH, wherein the C 1-3 heteroalkyl comprises 1, 2, or 3 heteroatoms or heteroatomic groups independently selected from the group consisting of —C(O)—, —C(O)O—, —C(S)—, N, —NH—, —O—, —S—, —S(O)—, and —S(O) 2 —, and further wherein the C 1-3 alkyl or C 1-3 heteroalkyl is optionally substituted with 1, 2, or 3 independently selected R d substituents;
R 11 is halogen, CN, C 1-3 alkyl, C 1-3 heteroalkyl, NH 2 , or OH, wherein the C 1-3 heteroalkyl comprises 1, 2, or 3 heteroatoms or heteroatomic groups independently selected from the group consisting of —C(O)—, —C(O)O—, —C(S)—, N, —NH—, —O—, —S—, —S(O)—, and —S(O) 2 —, and further wherein the C 1-3 alkyl or C 1-3 heteroalkyl is optionally substituted with 1, 2, or 3 independently selected R d substituents;
R 12 is halogen, CN, C 1-3 alkyl, C 1-3 heteroalkyl, NH 2 , or OH, wherein the C 1-3 heteroalkyl comprises 1, 2, or 3 heteroatoms or heteroatomic groups independently selected from the group consisting of —C(O)—, —C(O)O—, —C(S)—, N, —NH—, —O—, —S—, —S(O)—, and —S(O) 2 —, and further wherein the C 1-3 alkyl or C 1-3 heteroalkyl is optionally substituted with 1, 2, or 3 independently selected R d substituents;
each R a is independently halogen, CN, C 1-3 alkyl, C 1-3 heteroalkyl, NH 2 , OH, or C 3-5 cycloalkyl, wherein each C 1-3 heteroalkyl independently comprises 1, 2, or 3 heteroatoms or heteroatomic groups independently selected from the group consisting of —C(O)—, —C(O)O—, —C(S)—, N, —NH—, —O—, —S—, —S(O)—, and —S(O) 2 —, and further wherein each C 1-3 alkyl, C 1-3 heteroalkyl, or C 3-5 cycloalkyl is optionally and independently substituted with 1, 2, or 3 independently selected R substituents;
each R b is independently halogen, CN, C 1-3 alkyl, C 1-3 heteroalkyl, NH 2 , OH, or C 3-5 cycloalkyl, wherein each C 1-3 heteroalkyl independently comprises 1, 2, or 3 heteroatoms or heteroatomic groups independently selected from the group consisting of —C(O)—, —C(O)O—, —C(S)—, N, —NH—, —O—, —S—, —S(O)—, and —S(O) 2 —, and further wherein each C 1-3 alkyl, C 1-3 heteroalkyl, or C 3-5 cycloalkyl is optionally and independently substituted with 1, 2, or 3 independently selected R substituents;
each R c is independently halogen, CN, C 1-3 alkyl, C 1-3 heteroalkyl, NH 2 , OH, or C 3-5 cycloalkyl, wherein each C 1-3 heteroalkyl independently comprises 1, 2, or 3 heteroatoms or heteroatomic groups independently selected from the group consisting of —C(O)—, —C(O)O—, —C(S)—, N, —NH—, —O—, —S—, —S(O)—, and —S(O) 2 —, and further wherein each C 1-3 alkyl, C 1-3 heteroalkyl, or C 3-5 cycloalkyl is optionally and independently substituted with 1, 2, or 3 independently selected R substituents;
each R d is independently halogen, CN, C 1-3 alkyl, C 1-3 heteroalkyl, NH 2 , OH, or C 3-5 cycloalkyl, wherein each C 1-3 heteroalkyl independently comprises 1, 2, or 3 heteroatoms or heteroatomic groups independently selected from the group consisting of —C(O)—, —C(O)O—, —C(S)—, N, —NH—, —O—, —S—, —S(O)—, and —S(O) 2 —, and further wherein each C 1-3 alkyl, C 1-3 heteroalkyl, or C 3-5 cycloalkyl is optionally and independently substituted with 1, 2, or 3 independently selected R substituents; and
each R is independently F, Cl, Br, I, CN, CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , NH 2 , NO 2 , OH, or OCH 3 .

2. The compound as defined in claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein

is:

3. The compound as defined in claim 2 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein

is:

4. The compound as defined in claim 3 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein

is:

5. The compound as defined in claim 1 , wherein the compound is of formula (I-3):

or a pharmaceutically acceptable salt or stereoisomer thereof.

6. The compound as defined in claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
(i) R 1 is H, CH 3 , CH 2 CH 3 , or CH(CH 3 ) 2 ; or
(ii) R 2 is phenyl, wherein the phenyl is optionally substituted with 1 or 2 independently selected R e substituents; or
(iii) each R a is independently F, Cl, Br, I, CN, CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , NH 2 , OH, OCH 3 , or cyclopropyl;
each R b is independently F, Cl, Br, I, CN, CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , NH 2 , OH, OCH 3 , or cyclopropyl;
each R c is independently F, Cl, Br, I, CN, CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , NH 2 , OH, OCH 3 , or cyclopropyl; and
each R d is independently F, Cl, Br, I, CN, CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , NH 2 , OH, OCH 3 , or cyclopropyl.

7. The compound as defined in claim 6 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2 is phenyl, 4-chlorophenyl, or 4-cyclopropylphenyl.

8. The comp

Assignees

• Luoxin Pharmaceutical Shanghai Co Ltd
• Shandong Luoxin Pharmacy Stock
• Medshine Discovery Inc

Inventors

• Chen Kevin X
• Yan Xiaobing
• Huang Jianglei
• Nie Yuekun
• Hu Guoping
• Li Jian
• Chen Shuhui
• Dong Jiaqiang
• Wang Tie-Lin

Classifications

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• A61P31/12

  Antivirals · CPC title

• A61P35/02 Primary

  specific for leukemia · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title