A novel series of benzyl urea analogues based on the structural modification of sorafenib were synthesized.  Their in vitro antitumor activities against MX-1, HepG2, Ketr3 and HT-29 were evaluated using the standard MTT assay.  While several target compounds showed inhibitory activity against multiple cancer cell lines, compound 9 was of particular interest, demonstrating IC₅₀ values (5.69−13.6 µmol·L⁻¹) comparable to those of sorafenib.  Furthermore, compounds 20 and 23 showed more potent inhibitory activity against HT-29 and MX-1 when compared to sorafenib.  In particular, compound 20 bearing the N-3-pyridyl moiety not only exhibited greater inhibitory activity against HT-29 cell line (IC₅₀ 3.82 µmol·L⁻¹), but also had improved solubility at pH 7.2, is worthy of further investigation as a lead to identify novel antitumor agents.