A series of tepotinib derivatives with two chiral centers was designed, synthesized, and evaluated as anticancer agents. The optimal compound ( R , S )-12a strongly exhibited antiproliferative activity against MHCC97H cell lines with an IC 50 value of 0.002 μM, compared to tepotinib (IC 50 = 0.013 μM). Mechanistic studies revealed that compound ( R, S )-12a significantly inhibited c-Met activation, as well as the downstream AKT signaling pathway, and suppressed wound closure. Moreover, compound ( R, S )-12a induced cellular apoptosis and cell cycle arrest at the G 1 phase in a dose-dependent fashion.