Abstract: Objective To synthesize compounds based on imidazo-fused heterocycles and evaluate their anti-tumor activity against breast cancer. Methods The compounds 1a-1e, 2a and 2b were synthesized by aerobic copper-catalyzed halocyclization of methyl N-heteroaromatics with aliphatic amines; 3a and 3b were generated by sonogashira reaction and Suzuki reaction, respectively; the compounds 4a-4c were obtained by Buchwald-Hartwig reaction of the corresponding amines and 1e. The effects of these compounds against breast cancer cells and their nephrotoxicity were determined using MTT assay. Annexin VFITC/ PI apoptosis detection kit was used to assess the apoptosis-inducing effects of these compounds in breast cancer cells. With normal saline as the control, the safety and anti-tumor activity of the compound 2a (daily dose of 10 mg/kg for 14 days) was tested in a mouse model bearing human breast cancer xenografts. Results The compounds 2a, 4a, 4b and 4c all showed obvious anti-tumor activities. Among these compounds, 2a showed the most potent anti-tumor effect against breast cancer cells with an IC50 of 9.77 ± 2.32 μmol/L, similar to that of cisplatin (IC50=8.96 ± 2.35 μmol/L); 2a also showed a slightly lower nephrotoxicity than cisplatin, and their CC50 was 10.79±0.87 μmol/L and 8.45±0.68 μmol/L, respectively. 2a obviously promoted apoptosis of breast cancer cells in vitro and caused a moderate suppression of the breast cancer growth in the tumor-bearing mouse models without producing serious adverse effects. Conclusion Four compounds synthesized based on imidazo-fused heterocycles have anti-tumor activities against breast cancer. The compound 2a is capable of dose-dependently promoting apoptosis of breast cancer cells in vitro and has a good safety and a moderate efficacy for suppressing tumor growth in mouse models bearing human breast cancer xenografts.