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Imidazo-[1, 2- a ]pyrazine 1 is a potent inhibitor of Aurora A and B kinase in vitro and is effective in in vivo tumor models, but has poor oral bioavailbility and is unsuitable for oral dosing. We describe herein our effort to improve oral exposure in this class, resulting ultimately in the identification of a potent Aurora inhibitor 16 , which exhibited good drug exposure levels across species upon oral dosing, and showed excellent in vivo efficacy in a mouse xenograft tumor model when dosed orally. [ABSTRACT FROM AUTHOR]

Abstract: Our continued effort toward the development of the imidazo[1,2-a]pyrazine scaffold as Aurora kinase inhibitors is described. Bioisosteric approach was applied to optimize the 8-position of the core. Several new potent Aurora A/B dual inhibitors, such as 25k and 25l, were identified. [Copyright &y& Elsevier]

[Display omitted] • Tertiary amino nucleoside via tethered aminohydroxylation. • Diastereospecificity. • Nucleosides bearing ethynyl/amino at the C2′ position. Syntheses of both 2′-amino-2′-ethynyl guanosine and uridine, using an intramolecular aminohydroxylation reaction as the key step, are described. The corresponding 5′- O -triphosphates of the aforementioned nucleosides were obtained and the inhibitory activity was subsequently evaluated against the hepatitis C virus NS5B polymerase. [ABSTRACT FROM AUTHOR]