Optimization of Versatile Oxindoles as Selective PI3Kδ Inhibitors

Abstract

The 3,3-disubstituted oxindole moiety is a versatile and rigid three-dimensionally shaped scaffold. When engineered with a purine hinge-binding core, exceptionally selective PI3Kδ kinase inhibitors were discovered by exploiting small differences in isoform selectivity pockets. Crystal structures of early lead <b>2f</b> bound to PI3Kδ and PI3Kα helped rationalize the high selectivity observed with <b>2f</b>. By attenuating the lypophilicity and metabolic liabilities of an oxindole moiety, we improved the preclinical species PK and solubility and reduced adenosine uptake activity. The excellent potency and kinome selectivity of 7-azaoxindole <b>4d</b> and spirooxindole <b>5d</b>, together with a low plasma clearance and good half-life in rat and dog, supported a low once-daily predicted human dose.