Abstract <p><b>Objective:</b> This study reports the efficient catalysis of a three-component reaction involving 5-(substituted phenyl)-1,3,4-thiadiazol-2-amine (<b>IIIa–IIIq</b>), quinoline-2-carbaldehyde, and triethyl phosphite, using zirconium oxychloride (ZrOCl₂) as a catalyst in ethanol under reflux conditions. The reaction yields α-aminophosphonates in good to excellent yields. Notably, the catalyst can be recovered and reused multiple times without significant loss of activity. <b>Methods:</b> A series of diethyl (((5-(substituted phenyl)-1,3,4-thiadiazol-2-yl)amino)(quinolin-2-yl)methyl)phosphonate derivatives (<b>VIa–VIq</b>) was synthesized and evaluated for <i>in vitro</i> anticancer activity against the HCC827 and H1975 human non-small cell lung cancer cell lines using the MTT assay. <b>Results and Discussion:</b> The structure–activity relationship (SAR) analysis revealed that electron-withdrawing groups on the phenyl ring enhance anticancer activity, while electron-donating groups, the presence of an alkyl chain between the thiadiazole and phenyl rings, and increased steric bulk on the phenyl ring are detrimental to activity. Additionally, due to their low selectivity towards wild-type EGFR (WT-EGFR), the synthesized compounds may exhibit reduced toxicity associated with WT-EGFR inhibition. Compounds (<b>VIe</b>) and (<b>VIf</b>) showed selective cytotoxicity toward cancer cells and did not display toxicity against normal cells at concentrations up to IC₅₀ &gt;20 μM. <b>Conclusions:</b> These findings provide valuable leads that merit further optimization for the development of improved cancer therapeutics.</p>