Human epidermal growth factor receptor 2 (HER2) is a critical therapeutic target for HER2-positive or HER2-dependent cancers. While several HER2 kinase inhibitors have been identified, achieving high selectivity for HER2 over EGFR remains a significant challenge. In this study, we aimed to develop HER2-selective inhibitors with enhanced cellular activity. To improve the limited cellular activity of derivatives with a quinoline moiety against HER2, we synthesized a novel series of derivatives by bioisosteric replacement. These derivatives demonstrated significantly improved selectivity for HER2 over EGFR, with a 7- to 12-fold enhancement compared to lapatinib in kinase assays. Furthermore, they exhibited enhanced cellular activity, leading to improved anti-proliferative effects against HER2-dependent SKBR3 cells. Notably, the representative compound 14f demonstrated more potent inhibition of HER2 phosphorylation at the cellular level compared to lapatinib. Additionally, compound 14f exhibited high HER2 selectivity, significantly inhibited colony formation in SKBR3 cells, and displayed good metabolic stability. These findings suggest the potential of these compounds as novel therapeutic candidates for HER2-positive cancers.