The starting enamine derivatives 1a,c were allowed to react with different substituted benzylidenemalononitrile derivatives 2a,b to afford the corresponding tetrahydroquinoline-o-aminocarbonitrile derivatives 4a-d. The treatment of 4a-d with conc. H2SO4 at room temperature led to formation of hexahydroquinoline-oaminocarboxamide derivatives 5a-d, while complete hydrolysis had been occurred upon their refluxing with conc. H2SO4 to get the acid analogues 6a-d. Condensation reaction of the derivatives 4a-d with various acid chlorides in pyridine afforded the corresponding hexahydroquinoline-acetamide/benzamide derivatives 7a-d & 8a-d. Furthermore, the compounds 4a-d were fused with urea, thiourea, formamide and acetic anhydride to gain the novel hexa(tetra)hydropyrimido[4,5-b]quinolin derivatives 9a-d, 10a-d, 11a-d and 12a-d, respectively. Some of the newly synthesized analogues were chosen to evaluate their in-vitro cytotoxic activity against human liver carcinoma cell lines (HEPG2). The obtained data revealed that the tested derivatives produced significant activity in comparison with the used reference drug Doxorubicin.