Nitrogen-containing heterocycles are highly valuable scaffolds in medicinal chemistry, as reflected by their prevalence in marketed drugs.1 While some N-heterocyclic frameworks have been exhaustively studied, others remain neglected, often due to synthetic challenges. One such underexplored class of N-heterocycles is the pyrrolodiazines. An example within this class is the pyrrolo[1,2-c]pyrimidine motif, which is found in natural products such as variolin B. While these systems show promising therapeutic potential as protein kinase inhibitors,2 they lack flexible synthetic routes that enable access to highly functionalised derivatives.
Building upon the Morris group total synthesis of variolin B,3,4 we sought to explore the therapeutic potential of this scaffold which required the development of novel and modular synthetic pathways. In addition, an alternate synthesis of the parent pyrrolopyrimidine scaffold employing a cyclodehydration strategy was developed, enabling rapid generation of pendant-ring derivatives. These compounds were shown to possess nanomolar potency towards members of the CLK/DYRK and DRAK kinase families. Importantly, the kinase selectivity profile can be tuned by varying the substitution pattern, highlighting the utility of these compact heterocyclic systems.