Bromodomain inhibitors
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.
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.