The appearance of the new SARS coronavirus 2 (SARS-CoV-2) in 2019 has triggered a continued global pandemic of serious disease similar to pneumonia designated as coronavirus disease 2019 (COVID-19) 1. The development of a vaccine is likely to require at least 12-18 months, and the typical deadline for the approval of a new antiviral treatment may exceed 10 years. So, reuse of known drugs could significantly accelerate the deployment of new therapies for COVID-19. To this end, we profile a library of known drugs that covers approximately 12,000 small molecules in clinical stage or approved by the FDA. We report the identification of 100 molecules that inhibit viral replication, included 21 known drugs that exhibit dose response relationships. Of these, thirteen were found to harbor effective concentrations likely proportional to achievable therapeutic doses in patients, including the PIKfyve kinase apilimod inhibitor 2-4and cysteine protease inhibitors MDL-28170, Z LVG CHN2, VBY-825 and ONO 5334. In particular,, MDL-28170 was found to be, Ono 5334 and apilimod antagonize viral replication in cells similar to human iPSC-derived pneocytes, and the PIKfyve inhibitor also demonstrated antiviral efficacy in a primary model of human lung exthoon. Since most of the molecules identified in this study have already advanced in the clinic, the well-known pharmacological and human safety profiles of these compounds will allow an accelerated clinical and preclinical evaluation of these medicines for the treatment of COVID-19.