Aryl-substituted imidazoles

Patent metadata

Field	Value
Publication number	US-10647702-B2
Application number	US-201715812605-A
Country	US
Kind code	B2
Filing date	Nov 14, 2017
Priority date	Sep 30, 2010
Publication date	May 12, 2020
Grant date	May 12, 2020

Abstract

The compounds of the invention are antagonists of MDM2 and MDMX, with excellent specificity for MDM2 and MDMX over other proteins, and with selective binding affinity to MDMX over MDM2. The compounds can therefore regulate p53 activity and treat a variety of cancers. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

First claim

What is claimed is:

1. A compound having the formula:

wherein Ar 1 and Ar 2 are independently:

wherein Ar 1 and Ar 2 are different and have a cis relationship;
wherein R 1 is hydrogen;
wherein R 2 and R 3 are independently selected from halogen, methoxy, ethoxy, n-propoxyl, i-propoxyl, n-butoxyl, i-butoxyl, and t-butoxyl;
wherein R 4a -R 4e are independently selected from hydrogen and halogen
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , having the formula:

3. A pharmaceutical composition comprising, in a pharmaceutically acceptable carrier, a compound of claim 1
or a pharmaceutically acceptable salt thereof.

4. The pharmaceutical composition of claim 3 , wherein the compound has the formula:

5. The compound of claim 1 , wherein R 2 and R 3 are independently selected from halogen, methoxy, and i-propoxyl.

6. The compound of claim 1 , wherein R 4a -R 4e are independently selected from hydrogen, chloro, and bromo.

7. The compound of claim 1 , wherein R 2 and R 3 are independently selected from halogen, methoxy, and i-propoxyl; and wherein R 4a -R 4e are independently selected from hydrogen, chloro, and bromo.

8. The compound of claim 1 , wherein R 3 is methoxy or chloro.

9. The compound of claim 1 , wherein R 2 is i-propoxyl.

10. The compound of claim 1 , wherein Ar e is 4-chlorophenyl.

11. The compound of claim 1 , wherein AO is 4-bromophenyl.

12. The compound of claim 1 , wherein AO is 3-chlorophenyl.

13. The compound of claim 1 , wherein R 3 is methoxy, wherein R 2 is i-propoxyl, wherein Ar 2 is 4-chlorophenyl, and wherein Ar 1 is 4-bromophenyl.

14. The compound of claim 1 , R 3 is chloro, wherein R 2 is i-propoxyl, Ar 2 is 4-chlorophenyl, and wherein Ar 1 is 3-chlorophenyl.

15. The pharmaceutical composition of claim 3 , wherein R 2 and R 3 are independently selected from halogen, methoxy, and i-propoxyl.

16. The pharmaceutical composition of claim 3 , wherein R 4a -R 4e are independently selected from hydrogen, chloro, and bromo.

17. The pharmaceutical composition of claim 3 , wherein R 2 and R 3 are independently selected from halogen, methoxy, and i-propoxyl; and wherein R 4a -R 4e are independently selected from hydrogen, chloro, and bromo.

18. The pharmaceutical composition of claim 3 , wherein R 3 is methoxy or chloro.

19. The pharmaceutical composition of claim 3 , wherein R 2 is i-propoxyl.

20. The pharmaceutical composition of claim 3 , wherein Ar 2 is 4-chlorophenyl.

21. The pharmaceutical composition of claim 3 , wherein AO is 4-bromophenyl.

22. The pharmaceutical composition of claim 3 , wherein AO is 3-chlorophenyl.

23. The pharmaceutical composition of claim 3 , wherein R 3 is methoxy, wherein R 2 is i-propoxyl, wherein Ar 2 is 4-chlorophenyl, and wherein Ar 1 is 4-bromophenyl.

24. The pharmaceutical composition of claim 3 , R 3 is chloro, wherein R 2 is i-propoxyl, Ar 2 is 4-chlorophenyl, and wherein Ar 1 is 3-chlorophenyl.

Assignees

• St Jude Childrens Res Hospital

Inventors

• Guy R Kiplin
• Zhang Yiqun
• Young Brandon
• Dyer Michael
• Finch Kristin
• Bashford Donald
• Bharatham Nagakumar
• Kriwacki Richard
• Royappa Grace
• Min Lie
• Min Jaeki
• Ferreira Antonio

Classifications

• C07D233/22

  Radicals substituted by oxygen atoms · CPC title

• C07D403/14

  containing three or more hetero rings · CPC title

• C07D403/06 Primary

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• A61P35/00

  Antineoplastic agents · CPC title