Dihydroquinolinones for medical treatment

Patent metadata

Field	Value
Publication number	US-11401256-B2
Application number	US-202016809345-A
Country	US
Kind code	B2
Filing date	Mar 4, 2020
Priority date	Sep 4, 2017
Publication date	Aug 2, 2022
Grant date	Aug 2, 2022

Abstract

The present invention provides dihydroquinolinone compounds which bind to the ubiquitously expressed E3 ligase protein cereblon (CRBN) and alter the substrate specificity of the CRBN E3 ubiquitin ligase complex, resulting in breakdown of intrinsic downstream proteins. The disclosed compounds are useful for the treatment of cancer.

First claim

We claim:

1. A compound of the formula:

or a pharmaceutically acceptable salt thereof
wherein
X 1 is N or CH;
X 3 is N or CH;
and if one of X 1 or X 3 is nitrogen, the other one is CH;
R 3 is selected from: —(CH 2 ) 0-1 -aryl substituted by 1-2 substituents selected from R 4 , —(CH 2 ) 0-2 —N(R 3c )C(═O)—C 3-7 cycloalkyl, amino-C 1-6 alkyl, —C(═O)N(R 3a ,R 3b ) C(═O)O—C 1-6 alkyl, C 1-6 alkyl, and —C 3-7 cycloalkyl;
wherein one of the R 3 substituents is selected from —C(═O)N(R 3a ,R 3b ) and C(═O)O—C 1-6 alkyl;
R 3a is selected from hydrogen and C 1-6 alkyl;
R 3b is selected hydrogen and C 1-6 alkyl;
or R 3a and R 3b form together with the nitrogen to which they are attached form a heterocycloalkyl;
R 3c is hydrogen; and
R 4 is selected from amino, —C(═O)N(R 3a ,R 3b ), C 1-6 alkoxy, C 1-6 alkyl, halo-C 1-6 alkyl, and hydroxy-C 1-6 alkyl.

2. The compound of claim 1 , wherein X 1 is N.

3. The compound of claim 1 , wherein X 3 is N.

4. The compound of claim 1 , wherein R 3 is aryl substituted by 1-2 substituents selected from R 4 , wherein R 4 is selected from —C(═O)N(R 3a ,R 3b ), C 1-6 alkyl, and C 1-6 alkoxy.

5. The compound of claim 1 , wherein R 3 is aryl substituted by 1-2 substituents selected from R 4 , wherein R 4 is selected from C 1-6 alkoxy, C 1-6 alkyl, halo-C 1-6 alkyl, and hydroxy-C 1-6 alkyl.

6. The compound of claim 1 , wherein R 3 is —C(═O)N(R 3a ,R 3b ).

7. The compound of claim 6 , wherein R 3a is hydrogen and R 3b is C 1-6 alkyl.

8. The compound of claim 7 , wherein R 3b is methyl.

9. The compound of claim 1 of the formula:

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1 of the formula:

or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1 of the formula:

or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1 of the formula:

or a pharmaceutically acceptable salt thereof.

13. A compound of the formula:

or a pharmaceutically acceptable salt thereof
wherein
X 1 is N or CH;
X 3 is N or CH;
and if one of X 1 or X 3 is nitrogen, the other one is CH;
R 3 is selected from: —C(═O)N(R 3a ,R 3b ), C(═O)O—C 1-6 alkyl, unsubstituted heteroaryl, and heteroaryl substituted by 1-2 substituents selected from R 4 ;
wherein one of the R 3 substituents is selected from —C(═O)N(R 3a ,R 3b ) and C(═O)O—C 1-6 alkyl;
R 3a is selected from hydrogen and C 1-6 alkyl;
R 3b is selected hydrogen and C 1-6 alkyl;
R 3c is hydrogen;
R 4 is selected from amino, —(CH 2 ) 0-2 —N(R 3c )C(═O)—C 1-6 alkyl, —C(═O)—C 1-6 alkyl, —C(═O)N(R 3a ,R 3b ), C 1-6 alkoxy, C 1-6 alkyl, halo-C 1-6 alkyl, heteroaryl substituted by 1-2 substituents selected from R 5 , and hydroxy-C 1-6 alkyl; and
R 5 is C 1-6 alkyl.

14. The compound of claim 13 , wherein X 1 is N.

15. The compound of claim 13 , wherein X 3 is N.

16. The compound of claim 13 , wherein R 3 is heteroaryl substituted by 1 or 2 substituents selected from R 4 wherein R 4 is selected from —C(═O)N(R 3a ,R 3b ), C 1-6 alkyl, and C 1-6 alkoxy.

17. The compound of claim 13 , wherein R 3 is unsubstituted heteroaryl.

18. The compound of claim 13 , wherein R 3 is —C(═O)N(R 3a ,R 3b ).

19. The compound of claim 18 , wherein R 3a is hydrogen and R 3b is C 1-6 alkyl.

20. The compound of claim 19 , wherein R 3b is methyl.

21. The compound of claim 13 of the formula:

or a pharmaceutically acceptable salt thereof.

22. The compound of claim 13 of the formula:

or a pharmaceutically acceptable salt thereof.

23. The compound of claim 13 of the formula:

or a pharmaceutically acceptable salt thereof.

24. The compound of claim 13 of the formula:

or a pharmaceutically acceptable salt thereof.

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

26. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof of claim 13 optionally in a pharmaceutically acceptable carrier.

Assignees

• C4 Therapeutics Inc

Inventors

• Norcross Roger
• Britschgi Adrian
• Dey Fabian
• Goergler Annick
• Kusznir Eric Andre
• Wichert Moreno Attilio

Classifications

• 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

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/4704

  2-Quinolinones, e.g. carbostyril · CPC title

• A61K47/55

  the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug · CPC title

• C07D401/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title