Bromodomain inhibitors

Patent metadata

Field	Value
Publication number	US-9598372-B2
Application number	US-201514789881-A
Country	US
Kind code	B2
Filing date	Jul 1, 2015
Priority date	Oct 18, 2013
Publication date	Mar 21, 2017
Grant date	Mar 21, 2017

Abstract

The present invention relates to substituted heterocyclic derivative compounds, compositions comprising said compounds, and the use of said compounds and compositions for epigenetic regulation by inhibition of bromodomain-mediated recognition of acetyl lysine regions of proteins, such as histones. Said compositions and methods are useful for the treatment of cancer and neoplastic disease.

First claim

I claim:

1. A compound, or a pharmaceutically acceptable salt thereof, of Formula (XXIV)

wherein,
R 13 is —Y—Z; wherein Y is selected from a bond, or —CH 2 —; and Z is selected from —SO 2 R 21 , —N(R 22 )SO 2 R 21 , —SO 2 N(R 22 ) 2 , —N(R 22 )SO 2 N(R 22 ) 2 , —CON(R 22 ) 2 , —N(R 22 )CO 2 R 21 , —N(R 22 )CON(R 22 ) 2 , —N(R 22 )COR 21 , —COR 21 , —OC(O)N(R 22 ) 2 , —OSO 2 N(R 22 ) 2 , —N(R 22 )SO 3 R 21 , or —N(R 22 ) 2 ; and wherein each R 21 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and each R 22 is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;
R 14 is hydrogen, halogen, C 1 -C 3 alkyl, or C 1 -C 3 alkoxy;
R 15 is halogen or U-V, wherein U is a bond, —O—, or —CH 2 —; and V is —CN, alkyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and
R B is

wherein X6 is C—R 7 , wherein R 7 is hydrogen or halogen; X7 is C—R 8 , wherein R 8 is hydrogen or halogen;
or
R B is

wherein X5 is C—R 5 , wherein R 5 is hydrogen or halogen; and R 6 is hydrogen, alkyl, alkoxy, or halogen;
or
R B is

wherein Ring B is an optionally substituted 5-membered heterocyclyl ring containing at least one oxygen or sulfur atom.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is —CH 2 —.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is a bond.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is —SO 2 R 21 , —N(R 22 )SO 2 R 21 , or —N(R 22 ) 2 .

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is —SO 2 R 21 or —N(R 22 )SO 2 R 21 .

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is —N(R 22 )SO 2 R 21 .

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is —SO 2 R 21 .

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 21 is heterocyclyl or heterocyclylalkyl.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 21 is alkyl, cycloalkyl, or cycloalkylalkyl.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 21 is alkyl, and the alkyl is a C 1 -C 4 alkyl.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 22 is alkyl, cycloalkyl, or aralkyl.

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 22 is hydrogen or methyl.

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 14 is hydrogen.

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein U is a bond.

15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein U is —O—.

16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein U is —CH 2 —.

17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein V is alkyl.

18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein V is aryl.

19. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein V is aralkyl.

20. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein V is cycloalkylalkyl.

21. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein V is heterocyclylalkyl.

22. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein V is heteroaryl.

23. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein V is heteroarylalkyl.

24. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein V is alkynyl.

25. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is a bond, Z is —N(R 22 )SO 2 R 21 , U is —O—, and V is aryl, aralkyl or cycloalkylalkyl.

26. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is a bond, Z is —SO 2 R 21 , U is —O—, and V is aryl, aralkyl or cycloalkylalkyl.

27. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R B is

28. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is halogen and R 8 is hydrogen.

29. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is hydrogen and R 8 is halogen.

30. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein both R 7 and R 8 are hydrogen.

31. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

Assignees

• Celgene Quanticel Res Inc

Inventors

• Boloor Amogh

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D217/24 Primary

  Oxygen atoms · CPC title

• C07D241/20

  Nitrogen atoms (nitro radicals C07D241/16) · CPC title

• A61K31/472 Primary

  Non-condensed isoquinolines, e.g. papaverine · CPC title

• C07D413/06

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