Bicyclic inhibitors of CBX chromodomains
A genus of bicyclic inhibitors of CBX chromodomains is disclosed. The compounds are of the following genus: in which A, E, and G represent carbon or nitrogen such that the compounds are indoles or benzimidazoles. A particular subgenus of 1,3-disubstituted-1,3-dihydro-2H-benzo[d]imidazol-2-imines is of the general formula: The compounds inhibit CBX proteins.
1 . A compound of formula (I):
wherein:
represents a single bond;
A is N;
E is C═NR 3 ;
wherein:
R 3 is H
G is N;
X 1 is selected from H, halogen, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkyl, (C 1 -C 4 )perfluoroalkyl, hydroxy, (C 1 -C 4 )perfluoroalkoxy, and amino;
R 1 is —CR 5 R 6 —R 9 ;
wherein:
R 5 and R 6 are H;
R 9 is a substituted nitrogen-containing 5-membered ring heteroaryl;
wherein:
said substituted nitrogen-containing 5-membered ring heteroaryl includes a substituent —(CR 10 R 11 ) n2 —R 14 ;
wherein:
R 10 and R 11 are independently selected from H and (C 1 -C 3 )alkyl;
n2 is 0 or 1; and
R 14 is optionally substituted phenyl, wherein said optionally substituted phenyl optionally includes one, two, or three substituents selected from (C 1 -C 3 )alkyl, halogen, (C 1 -C 3 )alkoxy, (C 1 -C 3 )haloalkoxy, and (C 1 -C 3 )haloalkyl; and
R 2 is —(CR 15 R 16 )—CH(OH)—R 19 ;
wherein:
R 15 and R 16 are H; and
R 19 is optionally substituted phenyl, wherein one to three optional substituents of the phenyl ring are selected from halogen, (C 1 -C 4 )alkyl, and (C 1 -C 4 )haloalkyl.
2 . A compound according to claim 1 of formula (II):
3 . A compound according to claim 1 , wherein X 1 is selected from H, halogen, and (C 1 -C 4 )alkoxy.
4 . A compound according to claim 1 , wherein R 15 and R 16 are H.
5 . A compound according to claim 1 , wherein said optionally substituted phenyl is substituted with halogen.
6 . A compound according to claim 1 , wherein:
X 1 is H, halogen, or methoxy;
R 1 is —CH 2 -R 9 , wherein R 9 is
wherein:
R 24 is selected from:
wherein:
R 25 is selected from H, methyl, halogen, and methoxy;
R 26 is selected from H, methyl, halogen, and methoxy;
R 27 is selected from H, methyl, halogen, and methoxy; and
n5 is 0 or 1 and
R 2 is —CH2-CH(OH)—R 19 ;
wherein:
R 19 is
7 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to claim 1 .