Phosphodiesterase-9 (PDE9) is a promising target for the treatment of Alzheimer's disease (AD). To discover efficient PDE9 inhibitors with good metabolic stability and solubility, a series of novel pyrazolopyrimidinone derivatives have been designed with the assistance of molecular docking and dynamics simulations. All the fourteen synthesized compounds gave excellent inhibition ratio against PDE9 at 10 nM. Compound 1k with the IC<sub>50</sub> of 2.0 nM against PDE9, showed good metabolic stability (t<sub>1/2</sub> of 57 min) in the RLM as well as good solubility (195 mg/L). The analysis on binding modes of targeted compounds may provide insight for further structural modification.