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.

Synthesis and biological evaluation of 1 ('angular') and 2 ('linear') cycloalkane-annelated 3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidines as novel ligands of the 5-HT6 receptors are disclosed. The new compounds 1 and 2 are highly selective antagonists of the receptor with sub-nanomolar affinities (K-i < 1 nM). In its structure, this new chemotype lacks a basic ionizable side chain, which is considered as the characteristic feature of the 5-HT6 receptor antagonists pharmacophore model. (C) 2010 Elsevier Ltd. All rights reserved.