Our previous efforts have proved that modifications targeting the 150-cavity of influenza neuraminidase can achieve more potent and more selective inhibitors. In this work, four subseries of C5-NH<sub>2</sub> modified oseltamivir derivatives were designed and synthesized to explore every region inside the 150-cavity. Among them, compound <b>23d</b> was exceptionally potent against the whole panel of Group-1 NAs with IC<sub>50</sub> values ranging from 0.26 to 0.73 nM, being 15-53 times better than oseltamivir carboxylate (OSC) and 7-11 times better than zanamivir. In cellular assays, <b>23d</b> showed more potent or equipotent antiviral activities against corresponding virus strains compared to OSC with no cytotoxicity. Furthermore, <b>23d</b> exhibited high metabolic stability in human liver microsomes (HLM) and low inhibitory effect on main cytochrome P450 enzymes. Notably, <b>23d</b> displayed favorable druggability in vivo and potent antiviral efficacy in the embryonated egg model and mice model. Overall, <b>23d</b> appears to be a promising candidate for the treatment of influenza virus infection.