Discovery of ((<i>S</i>)-5-(Methoxymethyl)-7-(1-methyl-1<i>H</i>-indol-2-yl)-2-(trifluoromethyl)-4,7-dihydropyrazolo[1,5-<i>a</i>]pyrimidin-6-yl)((<i>S</i>)-2-(3-methylisoxazol-5-yl)pyrrolidin-1-yl)methanone As a Potent and Selective I_Kur Inhibitor

Previously disclosed dihydropyrazolopyrimidines are potent and selective blockers of I_Kur current. A potential liability with this chemotype is the formation of a reactive metabolite which demonstrated covalent binding to protein in vitro. When substituted at the 2 or 3 position, this template yielded potent I_Kur inhibitors, with selectivity over <i>h</i>ERG which did not form reactive metabolites. Subsequent optimization for potency and PK properties lead to the discovery of ((<i>S</i>)-5-(methoxymethyl)-7-(1-methyl-1<i>H</i>-indol-2-yl)-2-(trifluoromethyl)-4,7-dihydropyrazolo­[1,5-<i>a</i>]­pyrimidin-6-yl)­((<i>S</i>)-2-(3-methylisoxazol-5-yl)­pyrrolidin-1-yl)­methanone (<b>13j</b>), with an acceptable PK profile in preclinical species and potent efficacy in the preclinical rabbit atrial effective refractory period (AERP) model