A series of novel, potent 4-aminothienopyridine B-Raf kinase inhibitors was designed and synthesized using knowledge-based design. Compounds 5f, and 6k exhibited not only excellent potency in both enzyme assay (IC50= 5.1, 16.6 nM) and cellular assay (IC50= 0.2, 0.2 μM), but also had an outstanding selectivity profile against other kinases.