In this study, we investigated the design and synthesis of three series of molecules acting as kinase inhibitors. The first two series are rigidified analogues of the multikinase inhibitor, sorafenib, which is usually used for treatment of hepatocellular carcinoma (HCC) among others but suffers from lack of selectivity. The first series was completed and tested against three HCC cell lines. It was found that compound 6h exerted superior antiproliferative potency against all the three tested HCC cell lines compared to sorafenib. Based on these preliminary results, compound 6h was selected for further biological and in silico investigations. Up to 30 μM, compound 6h did not inhibit 50% of the proliferation of WI-38 normal cells, which indicated promising selectivity. In addition, compound 6h exerted superior kinase selectivity than sorafenib. It is relatively selective for Vascular Endothelial Growth Factor Receptor (VEGFR)2 and VEGFR3 angiogenesis-related kinases. Western blotting confirmed the ability of 6h to pass through cell membrane and inhibit VEGFR2 inside HepG2 cell line in dose dependent matter. Caspase-3/7 and lactate dehydrogenase (LDH) tests were performed and confirmed compound 6h induces apoptosis and necrosis, respectively. Compound 6h is also estimated to be devoid of potential cardiotoxicity due to its weak potency against Human Ether-à-go-go-Related Gene (hERG). The second series has been initiated, and preliminary results showed promising activity of compounds 7h, 7l, 7n, and 7p. In the third series possessing imidazo[2.1-b]thiazole nucleus, a novel first-in-class, and the only Human Epidermal growth factor Receptor (HER)4 selective inhibitor so far was discovered. Compound 19k was tested against 60 National Cancer Institute (NCI) cell lines and a panel of kinases. It showed promising antiproliferative activity. It is selective towards cancer cell lines than normal cells. Its ability to penetrate T-47D cell membrane and inhibit ErbB4 kinase inside the cells has been confirmed. 19k w