Human Severe Acute Respiratory Syndrome (SARS) is a disease caused by SARS coronavirus (SARS CoV). The outbreak of SARS in year 2003 had caused worldwide panic and chaos. Although no cases of SARS have been reported since April 2004, the nature of the unpredictable outbreak of SARS CoV is still a potential threat to the global economy and public health. No effective therapy exists for SARS CoV infection, despite tremendous effort invested in finding anti‐SARS CoV drugs, including targeting SARS‐CoV‐specific main protease or viral attachment, entry, and fusion for intervention. Thus, SARS‐CoV or some variant thereof could easily remerge to cause disease. Previously, we reported on the discovery, synthesis and identification of tylophorine compounds as novel, potent inhibitors of TGEV and SARS CoV in vitro with IC50 values at low nanomolar range. Herein, we further explored new classes of novel benzoisoquinoline compounds for anti‐coronaviruses. Their inhibition in cellular effects is similar to that of phenanthroindolizidine tylophorine compounds. These compounds exerted profound anti‐TGEV replication activity and thereby blocked the TGEV‐induced apoptosis and subsequent cytopathic effect in ST cells.