Conformationally Constrained ortho-Anilino Diaryl Ureas: Discovery of 1-(2-(1′-Neopentylspiro[indoline-3,4′-piperidine]-1-yl)phenyl)-3-(4-(trifluoromethoxy)phenyl)urea, a Potent, Selective, and Bioavailable P2Y1 Antagonist

Preclinical antithromboticefficacy and bleeding models have demonstrated that P2Y1 antagonistsare efficacious as antiplatelet agents and may offer a safety advantage over P2Y12 antagonistsin terms of reduced bleeding liabilities. In this article, we describe the structural modification of the tert-butyl phenoxy portion of lead compound1 and the subsequent discovery of a novel series of conformationally constrained ortho-anilino diaryl ureas. In particular, spiropiperidine indoline-substituted diaryl ureas are described as potent, orally bioavailable small-molecule P2Y1 antagonistswith improved activity in functional assays and improved oral bioavailability in rats. Homology modelingand rat PK/PD studies on benchmark compound 3l will also be presented. Compound 3l was our first P2Y1 antagonistto demonstrate a robust oral antithromboticeffect with mild bleeding liability in the rat thrombosis and hemostasis models.