A series of non-sulfonamide/non-sulfone derived potent 5-HT6 receptor inverse agonists has been disclosed. Representative compound 9 (Ki = 14 nm) displayed selectivity against a set of family members as well as brain permeability 6 h post-oral administration. In addition, the separated enantiomers of compound 9 displayed difference in activity indicating the influence of chirality on potency.
Based on ‘HTS-hit’ compound 1a (Ki = 5.73 μm against h5-HT6), compound 9 (Ki = 14 nm) was developed. Enantiomers of 9 (Ki of 7 nm versus 38 nm) displayed effect of chirality on potency.