Discovery of Clinical Candidate (1R,4r)‑4-((R)‑2-((S)‑6-Fluoro‑5H‑imidazo[5,1‑a]isoindol-5-yl)-1-hydroxyethyl)cyclohexan-1-ol (Navoximod), a Potent and Selective Inhibitor of Indoleamine 2,3-Dioxygenase 1

A novel class of 5-substituted 5H-imidazo­[5,1-a]­isoindoles are described as potent inhibitors of indoleamine 2,3-dioxygenase 1 (IDO1). A structure-based drug design approach was used to elaborate the 5H-imidazo­[5,1-a]­isoindole core and to improve potency and pharmacological properties. Suitably placed hydrophobic and polar functional groups in the lead molecule allowed improvement of IDO1 inhibitory activity while minimizing off-target liabilities. Structure–activity relationship studies focused on optimizing IDO1 inhibition potency and a pharmacokinetic profile amenable to oral dosing while controlling CYP450 and hERG inhibitory properties.