The bone morphogenetic protein (BMP) pathway is a promising new target for the design of therapeutic agents for the treatment of low bone mass. This study optimized the structure of the anti-osteoporosis compound 38 by balancing its lipophilicity and improving its stability. Twenty derivatives which were not reported in the literature were designed and synthesized. The ovariectomized rat model of osteoporosis was selected to evaluate the therapeutic effects. Compound 125 showed better therapeutic efficacy than that of 38. We verified the anti-osteoporosis activity and BMP-2 protein upregulation after treatment with 125 in a zebrafish osteoporosis model. We found that 125 improved the ADME properties, therapeutic efficacy, and pharmacokinetics of the drug. Overall, we evaluated the anti-osteoporosis effects of the compounds of this type, preliminarily determined the target patient population, verified the mechanism of action, clarified the level of toxicity, and provided preliminary ADME data. We believe that these compounds can both correct bone loss that is already occurring in patients and have broad clinical applicability.