Imidazo bicyclic iminium compounds as antitumor agents
Compounds of formula I: are disclosed. The compounds are inhibitors of Hedgehog pathway activation and are useful in treating solid tumors. An example of such a compound is:
1. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula II:
wherein:
R 1 is chosen from optionally substituted aryl and optionally substituted heteroaryl;
R 2a is chosen from H and (C 1 -C 4 )alkyl;
R 3a is chosen from optionally substituted aryl and optionally substituted heteroaryl;
A 1 is (a) a fused, saturated ring of 7 members that contains no heteroatoms other than the nitrogen at the point of fusion, said saturated ring optionally substituted with one or two (C 1 -C 4 )alkyl residues or
(b) a fused bicycle, one ring of said fused bicycle being a saturated ring of 7 members that contains no heteroatoms other than the nitrogen at the point of fusion and a second ring of said fused bicycle being a benzene ring, said bicycle optionally substituted with one or two (C 1 -C 4 )alkyl residues; and
X is any counterion.
2. The pharmaceutical composition according to claim 1 wherein II has the formula IIa:
wherein R 4 is one or two (C 1 -C 4 )alkyl residues.
3. The pharmaceutical composition according to claim 1 wherein R 1 is phenyl or optionally substituted phenyl and R 3a is phenyl or optionally substituted phenyl.
4. The pharmaceutical composition according to claim 3 wherein R 1 is phenyl or phenyl substituted with a substituent chosen from halogen, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy, (C 1 -C 2 )alkylenedioxy and phenyl.
5. The pharmaceutical composition according to claim 4 wherein R 2a is H or methyl and R 3a is phenyl or phenyl substituted with a substituent chosen from halogen, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy, (C 1 -C 2 )alkylenedioxy, and phenyl.
6. A compound of formula
wherein
A is (a) a fused, saturated ring of 7 members that contains no heteroatoms other than the nitrogen at the point of fusion, said saturated ring optionally substituted with one or two (C 1 -C 4 )alkyl residues or
(b) a fused bicycle, one ring of said fused bicycle being a saturated ring of 7 members that contains no heteroatoms other than the nitrogen at the point of fusion and a second ring of said fused bicycle being a benzene ring, said bicycle optionally substituted with one or two (C 1 -C 4 )alkyl residues; and
R 6 is one or two substituents chosen independently from the group consisting of halogen, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )acyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, phenyl, benzenesulfonyl, hydroxy, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, oxaalkyl, carboxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkoxycarbonylamino, carboxamido, cyano, acetoxy, nitro, amino, (C 1 -C 6 )alkylamino, (C 1 -C 6 )dialkylamino, mercapto, (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkylsulfoxide, (C 1 -C 6 )alkylsulfonyl, benzyl, heterocyclyl, phenoxy, heteroaryloxy and benzyloxy, and
X is any counterion;
with the proviso that when A is a fused, saturated ring of 7 members and R 6 is bromine or methoxy, R 6 is not in the para position.
7. The compound according to claim 6 of formula:
8. The compound according to claim 7 wherein R 6 is chosen from ethoxy and phenyl.