Atropisomerism is a dynamic type of axial chirality that is ubiquitous in medicinal chemistry. Majority of drugs (83% of FDA-approved kinase inhibitors) possess an unstable atropisomeric axis, allowing these compounds to access the majority of dihedral conformations around the bond axis. While they engage their targeted protein within a narrow range of these conformations, the remaining available conformations can interact with other proteins leading to off-target inhibition causing unwanted side-effects. The Gustafson lab hypothesized that the selectivity of an atropisomerically unstable, promiscuous inhibitor could be increased by preorganizing it into the conformation preferred by oncogenic targets and preventing bond rotation to bind off-target proteins. Chapter 1 reviews examples of atropisomerism in drug discovery including my colleague’s proof-of-concept paper on leveraging atropisomerism to increase selectivity of pyrrolopyrimidine-based inhibitors (PPYs). My PhD research begins in Chapter 2 where we optimized the atropisomeric PPYs for potency and selectivity, resulting in a therapeutically relevant inhibitor towards RET and mutant EGFR kinases. Along the way, we discovered the increases in inhibitor selectivity was due to the narrowing of accessible low-energy conformations. This led to the development of conformational binding maps that were used to predict a kinase’s preferred binding conformation and guide the design of new covalent inhibitors for BTK kinase (Chapter 3). During this work we encountered unintended structural perturbations when incorporating an atropisomeric locking substituent, which led to the design of a stereochemically unstable, yet conformationally-tuned, selective BTK inhibitor. Chapter 4 presents other PPY preorganization strategies to target unique ligand binding regions as well as the development of conformational binding maps for pyridones and diaryl amines drug scaffolds. Chapter 5 discusses various catalytic atropisomeric methodologies to access enantiopure inhibitor scaffolds of PPYs, diaryl ethers and diaryl amines. Together, restricting accessible conformational space via stable atropisomerism or other tuning methods has catalyzed the development of novel, selective therapeutics and should serve as a long-standing strategy in drug design.