Invasive fungal infections (IFIs) are fatal infections, but treatment options are limited. The clinical efficacies of existing drugs are unsatisfactory because of side effects, drug-drug interaction, unfavorable pharmacokinetic profiles, and emerging drug-resistant fungi. Therefore, the development of antifungal drugs with a new mechanism is an urgent issue. Herein, we report novel aryl guanidine antifungal agents, which inhibit a novel target enzyme in the ergosterol biosynthesis pathway. Structure-activity relationship development and property optimization by reducing lipophilicity led to the discovery of <b>6h</b>, which showed potent antifungal activity against <i>Aspergillus fumigatus</i> in the presence of serum, improved metabolic stability, and PK properties. In the murine systemic <i>A. fumigatus</i> infection model, <b>6h</b> exhibited antifungal efficacy equivalent to voriconazole (<b>1e</b>). Furthermore, owing to the inhibition of a novel target in the ergosterol biosynthesis pathway, <b>6h</b> showed antifungal activity against azole-resistant <i>A. fumigatus</i>.