Benzimidazole derivatives: preparation and pharmaceutical applications
The present invention relates to hydroxamate compounds which are inhibitors of histone deacetylase. More particularly, the present invention relates to benzimidazole containing compounds and methods for their preparation. These compounds may be useful as medicaments for the treatment of proliferative disorders as well as other diseases involving, relating to or associated with dysregulation of histone deacetylase (HDAC).
1. A compound of the formula:
wherein
R 1 is selected from the group consisting of: H and unsubstituted or substituted C 1 -C 10 alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, C 4 -C 9 heterocycloalkylalkyl, arylalkyl, and heteroarylalkyl, each of which may be unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen, ═O, ═S, —CN, —NO 2 , alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylamino, acylamino, aminoalkyl, phenoxy, benzyloxy, alkylsulfonyl, arylsulfonyl, aminosulfonyl, —COOH, —C(O)OR 5 , —SH, and acyl;
R 2 is selected from the group consisting of: H, halogen, and unsubstituted or substituted C 1 -C 10 alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, C 4 -C 9 heterocycloalkylalkyl, arylalkyl, and heteroarylalkyl, each of which may be unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen, ═O, ═S, —CN, —NO 2 , alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, phenoxy, benzyloxy, alkylamino, acylamino, aminoalkyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, —COOH, —C(O)OR 5 , —SH, and acyl;
R 3 is selected from the group consisting of H, C 1 -C 6 alkyl, and acyl;
X and Y are the same or different and are independently selected from the group consisting of: H, halogen, —CN, —NO 2 , —CF 3 , C 1 -C 4 alkyl, —COR 5 , —SR 6 , —OR 6 , and —NR 7 R 8 ;
R 5 is C 1 -C 4 alkyl;
R 6 is C 1 -C 4 alkyl;
R 7 and R 8 are each independently selected from the group consisting of: H, C 1 -C 4 alkyl, C 4 -C 9 cycloalkyl, C 4 -C 9 heterocycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl;
or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 wherein R 3 =H.
3. A compound according to claim 1 wherein X and Y=H.
4. A compound according to claim 1 wherein R 1 is selected from the group consisting of: H and unsubstituted or substituted hydroxyalkyl, C 1 -C 10 alkyl, heteroalkyl, arylalkyl, heteroarylalkyl, and heterocycloalkyl, each of which may be unsubstituted or substituted as defined in claim 1 .
5. The compound according to claim 1 wherein R 1 is selected from the group consisting of: H, methyl; (pyridin-3-yl)methyl; 2-hydroxy-ethyl; 2,3-di-hydroxy-propyl; and 3-hydroxy-propyl.
6. A compound according to claim 1 wherein R 2 is selected from the group consisting of H, and unsubstituted or substituted C 1 -C 10 alkyl, arylalkyl, aryl, heteroaryl, heteroalkyl, and cycloalkyl, each of which may be unsubstituted or substituted as defined in claim 1 .
7. A compound according to claim 1 wherein R 2 is selected from the group consisting of 2-phenyl-propyl, 2-phenyl-ethyl, 4-methoxy-phenyl, 4-benzyloxy-3-methoxy-phenyl, pyridin-2-yl, and pyridin-4-yl.
8. The compound of claim 1 wherein the compound is selected from compounds, and their pharmaceutically acceptable salts, selected from the group consisting of
9. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable diluent, excipient or carrier.
10. The compound of claim 1 wherein the compound is selected from compounds, and their pharmaceutically acceptable salts, selected from the group consisting of
11. The compound according to claim 1 wherein R 1 is selected from the group consisting of: 2-(piperidin-1-yl)-ethyl; 2-(pyrrolidin-1-yl )-ethyl; 2-diethylamino-ethyl; and 3-dimethylamino-2,2-dimethyl-propyl.