Discovery of Tetrahydropyrazolopyrimidine Carboxamide Derivatives As Potent and Orally Active Antitubercular Agents

Tetrahydropyrazolo­[1,5-<i>a</i>]­pyrimidine scaffold was identified as a hit series from a <i>Mycobacterium tuberculosis</i> (Mtb) whole cell high through-put screening (HTS) campaign. A series of derivatives of this class were synthesized to evaluate their structure–activity relationship (SAR) and structure–property relationship (SPR). Compound <b>9</b> had a promising in vivo DMPK profile in mouse and exhibited potent in vivo activity in a mouse efficacy model, achieving a reduction of 3.5 log CFU of Mtb after oral administration to infected mice once a day at 100 mg/kg for 28 days. Thus, compound <b>9</b> is a potential candidate for inclusion in combination therapies for both drug-sensitive and drug-resistant TB