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The gene amplification of human epidermal growth factor receptor 2 (HER2) plays an essential role in the proliferation and progression of several cancers. However, HER2 inhibitors such as lapatinib strongly suppress wild-type EGFR, resulting in severe adverse effects. Therefore, there is an unmet need for highly selective HER2 inhibitors. In this study, we describe the design and synthesis of novel quinazoline derivatives that exhibit enhanced selectivity for HER2 over wild-type EGFR. Structure-activity relationship analysis indicated t