N′,2-Diphenylquinoline-4-carbohydrazide based NK3 receptor antagonists II

Introduction of selected amine containing side chains into the 3-position of N′,2-diphenylquinoline-4-carbohydrazide based NK3 antagonists abolishes unwanted hPXR activation. Introduction of a fluorine at the 8-position is necessary to minimize unwanted hIKr affinity and a piperazine N-tert-butyl group is necessary for metabolic stability. The lead compound (8m) occupies receptors within the CNS following oral dosing (Occ90 7mg/kg po; plasma Occ90 0.4μM) and has good selectivity and excellent PK properties.