BRAF, a serine/threonine kinase, plays a key role in the development of certain types of cancer, particularly melanoma. 2-(3,4,5-Trimethoxyphenylamino)-6-(3-acetamidophenyl)-pyrazine, 1, was identified as a low micromolar (IC 50 = 3.5 microM) BRAF inhibitor from a high-throughput screen of a library of 23000 compounds. This compound was chosen as the starting point of a program aimed at developing inhibitors of mutant (V600E)BRAF. We have already reported on the optimization of the trimethoxyphenylamino moiety of 1. In this paper, we describe the synthesis of a series of compounds derived from 1 with the purpose of optimization of the pyrazine central core and the phenylacetamido moiety in order to increase the potency against (V600E)BRAF compared to CRAF. The biological activity of the new inhibitors was assessed against mutant (V600E)BRAF in vitro. Several compounds were identified with IC 50s of 300-500 nM for (V600E)BRAF, and all compounds that were assessed showed selectivity for (V600E)BRAF compared to CRAF by 5-->86-fold.