Piperazine

Piperazine is one of the most widely incorporated heterocycles in approved pharmaceuticals, present across a broad range of therapeutic areas including oncology, CNS disorders, infectious disease, and cardiovascular medicine. In drug design, the piperazine moiety functions primarily as a basic, hydrophilic group to optimise the physicochemical properties of the final molecule, or as a scaffold to position pharmacophoric groups in the correct geometry for target engagement. The two nitrogen atoms serve as orthogonal synthetic handles, enabling attachment of two distinct pharmacophoric fragments and facilitating modular synthesis strategies, including reductive amination, nucleophilic aromatic substitution, and Buchwald-Hartwig amination, that are well suited to parallel library synthesis and structure-activity relationship campaigns.

Examples of Piperazines in the clinic include Adagrasib (Krazati, Mirati Therapeutics), an FDA-approved, orally bioavailable, irreversible covalent inhibitor of KRAS G12C in which a chiral piperazine is a key structural element, approved in December 2022 for KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer, representing a landmark in the direct targeting of a historically undruggable oncogene. Ciprofloxacin (Cipro, Bayer) is a long-established FDA-approved fluoroquinolone antibiotic containing a piperazine substituent at the C-7 position of the quinolone core, where the ring contributes to Gram-negative antibacterial activity, improved tissue penetration, and favourable oral pharmacokinetics, and remains one of the most prescribed antibacterial agents worldwide.

Our range of Piperazines features novel substitutions and the incorporation of synthetically tractable functional groups such as boronic acids and esters, amines, carboxylic acids, ketones, hydroxyls and halogens to enable expedient synthetic strategies. The full range can be found using the substructure feature of our Search tools.