Discovery Of ((S)-5-(Methoxymethyl)-7-(1-Methyl-1h-Indol-2-Yl)-2-(Trifluoromethyl)-4, 7-Dihydropyrazolo[1,5-A]Pyrimidin-6-Yl)((S)-2-(3-Methylisoxazol-5-Yl)Pyr Rolidin-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 hERG which did not form reactive metabolites. Subsequent optimization for potency and PK properties lead to the discovery of ((S)-5-(methoxymethyl)-7-(1-methyl-1H-indol-2-yl)-2-(trifluoromethyl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)((S)-2-(3-methylisoxazol-5-yl)pyrrolidin-1-yl)methanone (13j), with an acceptable PK profile in preclinical species and potent efficacy in the preclinical rabbit atrial effective refractory period (AERP) model.