Melanoma is the most aggressive form of skin cancer and is the fastest growing type of cancer in the United States. We report here the synthesis of a novel series of quinazolinylmethoxybenzene derivatives 1a-c and their antiproliferative activities against A375 human melanoma cell line. Among them, urea compound 1a (IC50 = 4.8 μM) having 4-chloro-3-trifluoromethylphenyl moiety showed superior antiproliferative activity to Sorafenib (IC50 = 5.5 μM) as a reference compound. These results will helpful for designing structure of a therapeutic agent for the treatment of melanoma.