Refinement of imidazo[2,1-a]pyrimidines in pursuit of potential drug candidates against group 2 influenza A viruses

We discovered a series of imidazo[1,2-a]pyrimidines as potent, group 2 selective inhibitors of influenza A viruses (IAVs) that target the hemagglutinin-mediated viral entry process. Preliminary hit-to-lead optimization efforts afforded promising IAV inhibitors with improved activity against infectious H7N7 and H3N2 viruses. We now report a more comprehensive cycle of structure-activity relationship studies and optimization of metabolic stability, and overall druglike properties of this series of imidazo[1,2-a]pyrimidines, which allowed in the identification of two lead compounds that show promise as preclinical candidates. Compounds 10 and 12 inhibited pseudotyped H7N1 with EC₅₀ values of 0.09 and 0.47 μM, respectively. They were among the most potent compounds in the viral replication assay when tested against infectious H3N2 IAV, and they also demonstrated remarkable activity against avian influenza viruses; these data designated these imidazo[1,2-a]pyrimidines as potent broad-spectrum group 2 IAV inhibitors. Compounds 10 and 12 exhibit dissimilar but desirable drug metabolism and pharmacokinetics (DMPK) profiles, and therefore they offer different options for specific and effective patient treatment.