| Summary: | 2,3,4-trisubstituted thiazoles <b>3a</b>–<b>i</b>, having a methyl group in position four, were synthesized by the reaction of 1,4-disubstituted thiosemicarbazides with chloroacetone in ethyl acetate/Et<sub>3</sub>N at room temperature or in ethanol under reflux. The structures of new compounds were determined using NMR spectroscopy, mass spectrometry, and elemental analyses. Moreover, the structure of compound <b>3a</b> was unambiguously confirmed with X-ray analysis. The cell viability assay of <b>3a</b>–<b>i</b> at 50 µM was greater than 87%, and none of the tested substances were cytotoxic. Compounds <b>3a</b>–<b>i</b> demonstrated good antiproliferative activity, with GI<sub>50</sub> values ranging from 37 to 86 nM against the four tested human cancer cell lines, compared to the reference erlotinib, which had a GI<sub>50</sub> value of 33 nM. The most potent derivatives were found to be compounds <b>3a</b>, <b>3c</b>, <b>3d</b>, and <b>3f</b>, with GI<sub>50</sub> values ranging from 37 nM to 54 nM. The EGFR-TK and BRAF<sup>V600E</sup> inhibitory assays’ results matched the antiproliferative assay’s results, with the most potent derivatives, as antiproliferative agents, also being the most potent EGFR and BRAF<sup>V600E</sup> inhibitors. The docking computations were employed to investigate the docking modes and scores of compounds <b>3a</b>, <b>3c</b>, <b>3d</b>, and <b>3f</b> toward BRAF<sup>V600E</sup> and EGFR. Docking computations demonstrated the good affinity of compound <b>3f</b> against BRAF<sup>V600E</sup> and EGFR, with values of −8.7 and −8.5 kcal/mol, respectively.
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