In summary, we have discovered a novel class of small molecule inhibitors against the human D-amino Acid Oxidase (DAO). Different from the earlier lead compounds, this chemical class features a non-acidic dihydropyrazine dione head moiety. Starting from hit compound 12, SAR work in the linker region led to the discovery of thioether linker analogs which showed enhanced DAO potency with desirable PK and brain penetration properties. With tool compound 37, we were able to demonstrate PK/PD in an in vivo mouse model at drug exposure levels devoid of any adverse events. Continued SAR work has led to compounds with significant improvement in both DAO biochemical and cellular potency.