Aromatase inhibition remains a key therapeutic strategy for hormone-dependent breast cancer (HDBC). Among non-steroidal aromatase inhibitors (NSAIs), letrozole and anastrozole are well-established treatments. To further probe structure–function relationships within the human aromatase active site, we synthesized a library of 42 novel azole derivatives. Several compounds displayed nanomolar inhibitory activity, with potencies approaching that of letrozole in vivo, while maintaining favorable selectivity against other steroidogenic enzymes. Notably, benzoselenazolinone 75 emerged as the most promising candidate, exhibiting potency comparable to letrozole with improved in vitro selectivity, thereby justifying further evaluation in vivo.