Synthesis of Atropsiomerically Stable Pyrrolopyrimidine Analogues for Increased Selectivity for Kinase Inhibitor

Many biologically active compounds consist of interconverting atropisomeric mixtures. While one of the atropisomers inhibits the target, the other may lead to off-target effects. In this work, we employed atropisomerism to improve kinase selectivity by synthesizing atropisomerically stable pyrrolopyrimidines. The different atropisomers were separated by chiral stationary phase HPLC and were profiled on a panel of 18 tyrosine kinases of interest. Differential selectivity patterns amongst the atropisomers were observed and increased selectivity as compared to the parent non-atropisomerically preorganized molecule. We then further studied the observed effects by computational docking studies. These provided insights into the structure-based origins of these effects. This work is one of the first to preorganize a promiscuous medicinal scaffold for increased target selectivity. The work provides fundamental insight on the utility of this methodology to apply to other atropisomeric target scaffolds.