3,3-Disubstituted oxetanes have been utilized as bioisosteres for gem-dimethyl and cyclobutane functionalities. Wereport the discovery of a novel class of oxetane indole-amine 2,3-dioxygenase (IDO1) inhibitors suitable for Q3W (once every 3weeks) oral and parenteral dosing. A diamide class of IDO inhibitors was discovered through an automated ligand identificationsystem (ALIS). Installation of an oxetane andfluorophenyl dramatically improved the potency. Identification of a biaryl moiety as anunconventional amide isostere addressed the metabolic liability of amide hydrolysis. Metabolism identification (Met-ID)-guidedtarget design and the introduction of polarity resulted in the discovery of potent IDO inhibitors with excellent pharmacokinetic (PK)profiles in multiple species. To enable rapid synthesis of the key oxetane intermediate, a novel oxetane ring cyclization was alsodeveloped, as well as optimization of a literature route on kg scale. These IDO inhibitors may enable unambiguous proof-of-concepttesting for the IDO1 inhibition mechanism for oncology.
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