Advances in pyrazolo[1,5-a]pyrimidines: synthesis and their role as protein kinase inhibitors in cancer treatment

Abstract

Pyrazolo[1,5-a]pyrimidines are a notable class of heterocyclic compounds with potent protein kinase inhibitor (PKI) activity, playing a critical role in targeted cancer therapy. Protein kinases, key regulators in cellular signalling, are frequently disrupted in cancers, making them important targets for small-molecule inhibitors. This review explores recent advances in pyrazolo[1,5-a]pyrimidine synthesis and their application as PKIs, with emphasis on inhibiting kinases such as CK2, EGFR, B-Raf, MEK, PDE4, BCL6, DRAK1, CDK1 and CDK2, Pim-1, among others. Several synthetic strategies have been developed for the efficient synthesis of pyrazolo[1,5-a]pyrimidines, including cyclization, condensation, three-component reactions, microwave-assisted methods, and green chemistry approaches. Palladium-catalyzed cross-coupling and click chemistry have enabled the introduction of diverse functional groups, enhancing the biological activity and structural diversity of these compounds. Structure–activity relationship (SAR) studies highlight the influence of substituent patterns on their pharmacological properties. Pyrazolo[1,5-a]pyrimidines act as ATP-competitive and allosteric inhibitors of protein kinases, with EGFR-targeting derivatives showing promise in non-small cell lung cancer (NSCLC) treatment. Their inhibitory effects on B-Raf and MEK kinases are particularly relevant in melanoma. Biological evaluations, including in vitro and in vivo studies, have demonstrated their cytotoxicity, kinase selectivity, and antiproliferative effects. Despite these advances, challenges such as drug resistance, off-target effects, and toxicity persist. Future research will focus on optimizing synthetic approaches, improving drug selectivity, and enhancing bioavailability to increase clinical efficacy.