We designed a series of 2-methylpyrimidine derivatives as new BCR-ABL inhibitors using scaffold-hopping strategy. These synthetic compounds exhibited significant inhibition against a broad spectrum of Bcr-Abl mutants including the gatekeeper T315I mutant. Compound 7u showed very potent kinase inhibitory activities against Bcr-Abl WT, Bcr-Abl E255K, Bcr-Abl Q252H, Bcr-Abl G250E and Bcr-Abl T315I, with IC50 values of 0.13 nM, 0.17 nM, 0.24 nM, 0.19 nM and 0.65 μM, respectively. This compound also displayed anti-proliferation activity against K562 cell line with an IC50 value of 1.1 nM, thus representing a new lead for further optimization.