Aminopeptidase N (APN, CD13), a Zn2+-dependent ecto exoprotease, plays a crucial role in matrix degradation and invasion by tumor cells. Peptide APN inhibitors like bestatin and actinonin have drawbacks for clinical application, such as low bioavailability and proteolytic lability. In this study, we discovered N-phenyl cyclic imide derivatives as nonpeptide APN inhibitors and investigated their structure-activity relationships (SAR). Compounds were prepared via condensation of acid anhydrides with amines, and their APN inhibitory activity was evaluated using human MOLT-4 cells with L-alanine 4-methylcoumaryl-7-amide (Ala-AMC) as substrate; specificity was confirmed by testing dipeptidyl peptidase IV (DPP-IV) inhibition. Changing the cyclic imide from a five-membered (phthalimide) to a six-membered (homophthalimide) ring markedly enhanced APN inhibitory activity. The N-(2,6-diethylphenyl)homophthalimide derivative (28) showed extremely potent activity, surpassing actinonin. Some derivatives exhibited high specificity for APN with no DPP-IV inhibition. These novel nonpeptide APN inhibitors (e.g., 22 and 28) are superior lead compounds for developing low-molecular-weight agents to prevent tumor metastasis, with structural optimization and pharmacological evaluation ongoing.