RAF (Ras activating factor) kinases are important and attractive targets for cancer therapy. With the aim of discovering RAF inhibitors that bind to DFG-out inactive conformation created by the movement of Asp-Phe-Gly (DFG), we conducted structure-based drug design using the X-ray cocrystal structures of BRAF (v-raf murine sarcoma viral oncogene homolog B1), starting from bisarylurea derivative based on 1-pyrazolo[3,4-]pyrimidine scaffold . Most of the synthesized compounds showed good to excellent inhibitory activities against BRAF kinase, possessed moderate to potent anti-proliferative activities against four tumor cell lines (A375, HT-29, PC-3 and A549) and good selectivity towards cancer cells rather normal cells (Madin-Darby canine kidney, MDCK). The most promising compound, , exhibited potent inhibitory activity against not only BRAF (half maximal inhibitory concentration, IC = 23.6 nM) but also wild-type BRAF (IC = 51.5 nM) and C-RAF (IC = 8.5 nM), and effective cellular anti-proliferative activities against A375, HT-29, PC-3 and A549 cell lines as well as a very good selectivity profile. Moreover, compound mainly arrested the A375 cell line in the G0/G1 stage, and showed significant suppression of MEK (mitogen-activated protein kinase kinase) phosphorylation in A375 and HT-29 cell lines. Taken together, the optimal compound showed excellent in vitro potency as a pan-RAF inhibitor. In addition, the promise of compound was further confirmed by molecular dynamics simulation and binding free energy calculations.