Resistant viruses containing mutant neuraminidases (NAs) with diminished drug affinity continue to emerge, and new anti-influenza agents are urgently required. Several potent inhibitors targeting the hydrophobic 150-cavity of viral NAs have been developed by modifying the antiviral drugs, oseltamivir carboxylate (OSC) and zanamivir, with hydrophobic groups. Here, we describe a different strategy for exploring novel and efficient NA inhibitors by targeting the charged amino acid residues around the entrance to the 150-cavity. We synthesized a C5-substituted OSC derivative (1e) with a 4′-phenyl-1,2,3-triazolyl group capable of entering the 150-cavity, and solved the crystal structure of 1e in complex with influenza A virus N5 NA. Using the resulting structural information, we next designed and synthesized two series of OSC derivatives carrying various polar substituents at the triazolyl group of 1e and 2e, with 2e being a 5′-phenyl-1,2,3-triazole regioisomer of 1e. The NA inhibition assays demonstrated that the 2 series (2e–n) generally had superior activity compared with the 1 series (1e–n). Compound 2j, bearing a 3-phenylamino group on the triazole ring, was the most potent inhibitor of all tested NAs including an N2 NA containing the E119V OSC-resistant mutation. Moreover, 2j potently inhibited viral replication in vitro, and molecular docking studies revealed that its phenylamino group can form an additional strong hydrogen bond with residue D151 near the entrance of the 150-cavity. The design method described in this study provides useful insights into the development of novel NA inhibitors. Compound 2j warrants further structural optimization to obtain a candidate for clinical use.