Cellular Potency Optimization of Novel Heme-Binding Imidazo[5,1-<i>b</i>]thiazoles, Imidazo[1,5-<i>a</i>]pyridines and Pyrazines as Potent IDO1 Inhibitors Devoid of Cytochrome P450 Inhibition

Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2) are key enzymes in the kynurenine pathway of the catabolism of the essential amino acid tryptophan. Both enzymes actively contribute to the immunosuppressive microenvironment in many types of cancer. Selective or dual inhibition of these enzymes could, therefore, be beneficial in combination with other immunotherapies such as immune-checkpoint therapy. In a fragment-based approach, we optimized fragment <b>3</b> into a series of potent imidazo[5,1-<i>b</i>]thiazole, imidazo[1,5-<i>a</i>]pyridine and pyrazine IDO1 inhibitors. The introduction of the triazole side chain resulted in a reduced enzyme-to-cell potency shift for IDO1 inhibition, albeit at the expense of TDO2 potency, and allowed the discovery of potent and cellular active IDO1 inhibitors. Moreover, despite the propensity of the imidazole motif to inhibit cytochrome P450 enzymes (CYP), we were able to discover potent IDO1 inhibitors devoid of CYP inhibition. Imidazo[1,5-<i>a</i>]pyrazine <b>(<i>R</i>)-100</b> has an overall suitable profile, which warrants further investigation.