(3-Phenylsulfonylcycloalkano[e and d]pyrazolo[1,5-a]pyrimidin-2-yl)amines: Potent and Selective Antagonists of the Serotonin 5-HT6 Receptor

5-HT6 receptors are exclusively localized in the CNS and have high affinity with many psychotropic agents. Though the role of this receptor in many CNS diseases is widely anticipated, lack of definite progress in the development of 5-HT6 receptor-oriented drugs indicates a need for further discoveries of novel chemotypes with high potency and high selectivity to the receptor. Here we present preparations and biological evaluation of a series of (3-phenylsulfonylcycloalkano[e and d]pyrazolo[1,5-a]pyrimidin-2-yl)amines. Phenylsulfonylcyclopentapyrazolopyrimidine 7 was found to be a highly selective 5-HT6 receptor antagonist with high affinity (low picomolar range) and potency. 7 and a few of its analogues were further tested for biological effect on 5-HT2B receptors and hERG potassium channels, potential liability targets. Such liability appears to be minimal, based on the in vitro data.