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Pyrazolo[1,5-<i>a</i>]pyrimidines have been reported as potent inhibitors of mycobacterial ATP synthase for the treatment of <i>Mycobacterium tuberculosis</i> (<i>M.tb</i>). In this work, we report the design and synthesis of approximately 70 novel 3,5-diphenyl-<i>N</i>-(pyridin-2-ylmethyl)pyrazolo[1,5-<i>a</i>]pyrimidin-7-amines and their comprehensive structure–activity relationship studies. The most effective pyrazolo[1,5-<i>a</i>]pyrimidin-7-amine analogues contained a 3-(4-fluoro)phenyl group, together with a variety of 5-alkyl, 5-aryl and 5-heteroaryl substituents. A range of substituted 7-(2-pyridylmethylamine) derivatives were also active. Some of these compounds exhibited potent in vitro <i>M.tb</i> growth inhibition, low hERG liability and good mouse/human liver microsomal stabilities, highlighting their potential as inhibitors of <i>M.tb</i>.