A series of novel Nâarylâ5âarylâ6,7,8,9âtetrahydropyrimido[4,5âb]quinolinâ4âamines 4aâ4l was synthesized as potential anticancer agents through Dimroth rearrangement reaction of intermediates 3aâ3c. Pyrimido[4,5âb]quinolines 4aâ4l showed promising activity against the Michigan Cancer Foundationâ7 (MCFâ7) cell line, compared with lapatinib as the reference drug. Compounds 4d, 4h, 4i, and 4l demonstrated higher cytotoxic activity than lapatinib, with IC50 values of 2.67, 6.82, 4.31, and 1.62â”M, respectively. Compounds 4d, 4i, and 4l showed promising epidermal growth factor receptor (EGFR) inhibition with IC50 values of 0.065, 0.116, and 0.052â”M, respectively. These compounds were subjected to human epidermal growth factor receptor 2 (HER2) inhibition and showed IC50 values of 0.09, 0.164, and 0.055â”M, respectively. Compounds 4d, 4i, and 4l are good candidates as dual EGFR/HER2 inhibitors. The most active compound, 4l, was subjected to cellâcycle analysis and induced cellâcycle arrest at the S phase. Compound 4l induced apoptosis 60âfold compared with control untreated MCFâ7 cells. 4l can inhibit cancer metastasis. It reduced MCFâ7 cell infiltration and metastasis by 45% compared with control untreated cells.