Inhibitors of leucine-rich repeat kinase 2 (LRRK2) and mutants, such as G2019S, have potential utility in Parkinson's disease treatment. Fragment hit-derived pyrrolo[2,3-<i>d</i>]pyrimidines underwent optimization using X-ray structures of LRRK2 kinase domain surrogates, based on checkpoint kinase 1 (CHK1) and a CHK1 10-point mutant. (2<i>R</i>)-2-Methylpyrrolidin-1-yl derivative <b>18</b> (LRRK2 G2019S c<i>K</i><sub>i</sub> 0.7 nM, LE 0.66) was identified, with increased potency consistent with an X-ray structure of <b>18</b>/CHK1 10-pt. mutant showing the 2-methyl substituent proximal to Ala147 (Ala2016 in LRRK2). Further structure-guided elaboration of <b>18</b> gave the 2-[(1,3-dimethyl-1<i>H</i>-pyrazol-4-yl)amino] derivative <b>32</b>. Optimization of <b>32</b> afforded diastereomeric oxolan-3-yl derivatives <b>44</b> and <b>45</b>, which demonstrated a favorable <i>in vitro</i> PK profile, although they displayed species disconnects in the <i>in vivo</i> PK profile, and a propensity for P-gp- and/or BCRP-mediated efflux in a mouse model. Compounds <b>44</b> and <b>45</b> demonstrated high potency and exquisite selectivity for LRRK2 and utility as chemical probes for the study of LRRK2 inhibition.