A transition-metal-free sp3 C-H amination reaction has been established for imidazo[1,5-a]pyridine synthesis employing molecular iodine from 2-pyridyl ketones and alkylamines. In the presence of sodium acetate (NaOAc), the I2-mediated oxidative annulations of readily available substrates produced a variety of imidazo[1,5-a]pyridine derivatives efficiently in a one-pot manner. The present synthetic approach is operationally simple and can be conveniently carried out on a gram scale. Moreover, under the optimal reaction conditions a series of 1-(2-pyridyl)imidazo[1,5-a]pyridine cysteine protease inhibitors were easily prepared from the corresponding di-2-pyridyl ketones and substituted benzylamines in satisfactory yields.