Design and Synthesis of Bicyclic Pyrimidinones as Potent and Orally Bioavailable HIV-1 Integrase Inhibitors

HIV integrase is one of the three enzymes encoded by HIV genome and is essential for viral replication, but integrase inhibitors as marketed drugs have just very recently started to emerge. In this study, we show the evolution from the N-methylpyrimidinone structure to bicyclic pyrimidinones. Introduction of a suitably substituted amino moiety modulated the physical−chemical properties of the molecules and conferred nanomolar activity in the inhibition of spread of HIV-1 infection in cell culture. An extensive SAR study led to sulfamide (R)-22b, which inhibited the strand transfer with an IC₅₀ of 7 nM and HIV infection in MT4 cells with a CIC₉₅ of 44 nM, and ketoamide (S)-28c that inhibited strand transfer with an IC₅₀ of 12 nM and the HIV infection in MT4 cells with a CIC₉₅ of 13 nM and exhibited a good pharmacokinetic profile when dosed orally to preclinical species.