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 method for inhibiting a histone demethylase enzyme comprising contacting a histone demethylase enzyme with a compound of Formula (XXIV)
wherein the compound of Formula (XXIV) includes a pharmaceutically acceptable salt thereof, and wherein:
R 13 is —Y—Z; wherein
Y is 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 , 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, and
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
wherein
Ring B is optionally substituted 5-membered heterocyclyl ring containing at least one oxygen or sulfur atom.
2. The method of claim 1 , wherein Z is —SO 2 R 21 , —N(R 22 )SO 2 R 21 , —SO 2 R 21 , or —N(R 22 ) 2 .
3. The method of claim 1 , wherein R 21 is heterocyclyl or heterocyclylalkyl.
4. The method of claim 1 , wherein R 21 is alkyl, cycloalkyl, or cycloalkylalkyl.
5. The method of claim 1 , wherein R 21 is alkyl, and the alkyl is C 1 -C 4 alkyl.
6. The method of claim 1 , wherein R 22 is alkyl, cycloalkyl, or aralkyl.
7. The method of claim 1 , wherein R 22 is hydrogen or methyl.
8. The method of claim 1 , wherein V is alkyl, aryl, aralkyl, cycloalkylalkyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, or alkynyl.
9. The method of claim 1 , wherein Y is a bond; Z is —N(R 22 )SO 2 R 21 ; U is —O—; and V is aryl, aralkyl, or cycloalkylalkyl.
10. The method of claim 1 , wherein Y is a bond; Z is —SO 2 R 21 ; U is —O—; and V is aryl, aralkyl, or cycloalkylalkyl.
11. The method of claim 1 , wherein R B is
wherein X6 is C—R 7 , wherein R 7 is hydrogen or halogen, and X7 is C—R 8 , wherein R 8 is hydrogen or halogen.
12. The method of claim 11 , wherein R 7 is halogen and R 8 is hydrogen.
13. The method of claim 11 , wherein R 7 is hydrogen and R 8 is halogen.
14. The method of claim 11 , wherein both R 7 and R 8 are hydrogen.
15. A method of treating a histone demethylase-associated cancer wherein the cancer is selected from Burkitt lymphoma, promyelocytic leukemia, non-small cell lung cancer, NUT midline carcinoma, or breast cancer in a subject comprising administering a therapeutically effective dose of a compound of Formula (XXIV)
wherein the compound of Formula (XXIV) includes a pharmaceutically acceptable salt thereof, and 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, and
X7 is C—R 5 , 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.
16. The method of claim 15 , wherein Z is —SO 2 R 21 , —N(R 22 )SO 2 R 21 , or —N(R 22 ) 2 .
17. The method of claim 15 , wherein R 21 is heterocyclyl or heterocyclylalkyl.
18. The method of claim 15 , wherein R 21 is alkyl, cycloalkyl, or cycloalkylalkyl.
19. The method of claim 15 , wherein R 21 is alkyl, and the alkyl is C 1 -C 4 alkyl.
20. The method of claim 15 , wherein R 22 is alkyl, cycloalkyl, or aralkyl.
21. The method of claim 15 , wherein R 22 is hydrogen or methyl.
22. The method of claim 15 , wherein R 14 is hydrogen.
23. The method of claim 15 , wherein V is alkyl, aryl, aralkyl, cycloalkylalkyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, or alkynyl.
24. The method of claim 15 , wherein Y is a bond; Z is —N(R 22 )SO 2 R 21 ; U is —O—; and V is aryl, aralkyl, or cycloalkylalkyl.
25. The method of claim 15 , wherein Y is a bond; Z is —SO 2 R 21 ; U is —O—; and V is aryl, aralkyl, or cycloalkylalkyl.
26. The method of claim 15 , wherein R B is
wherein X6 is C—R 7 , wherein R 7 is hydrogen or halogen;
and X7 is C—R 8 , wherein R 8 is hydrogen or halogen.
27. The method of claim 26 , wherein R 7 is halogen and R 8 is hydrogen.