We herein report the design and synthesis of benzothiazinones containing a piperidine moiety as new antitubercular agents based on the structure feature of IMB-ZR-1 discovered in our lab. Some of them were found to have good in vitro activity (MIC < 1 μg/mL) against drug-susceptible Mycobacterium tuberculosis H37RV strain. After two set of modifications, compound 2i were found to display comparable in vitro anti-TB activity (MIC < 0.016 μg/mL) to PBTZ169 against drug-sensitive and resistant mycobacterium tuberculosis strains. Compound 2i also showed acceptable PK profiles. Studies to determine PK profiles in lung and in vivo efficacy of 2i are currently under way.