Synthesis of Diazaspirocycles for MRCK Inhibitors as Anti-cancer Agents

In the quest for new therapeutics targeting the metastatic spread of cancer, the synthesis of novel inhibitors for underexplored kinases is at the forefront. Recently, potent and selective inhibitors for a new cancer therapy target in the myotonic dystrophy-related Cdc42-binding kinases (MRCK) have been discovered for the treatment of aggressive cancers. The inhibitors feature a diazaspirocycle that significantly influences potency. While spirocycles are privileged scaffolds in medicinal chemistry, synthetic methods for their construction are limited, and asymmetric methods are in demand to access single enantiomers for biological applications. This work highlights the design and synthesis of diazaspirocycles for MRCK inhibition, focusing on the development of efficient asymmetric methods. Substituted α-amino nitriles are employed as key building blocks to expand the parent heterocycle into the desired bicyclic structure through haloalkylation, reductive cyclization, or direct reductive amination. Chiral directing groups, including naturally occurring menthol and amino alcohols, are assessed for their ability to access the desired enantiomer necessary for MRCK inhibition. The synthetic pathway designed can be applied to a wide range of substrates to create novel spirocyclic inhibitors in the future. As a result, the asymmetric construction of innovative spirocycles for MRCK inhibition opens the door for the discovery of modern therapeutics targeting the spread of aggressive cancers.