Pyrazolo[3,4-b]pyridine kinase inhibitors: a patent review (2008 – present)

Abstract

Introduction: Numerous heterocycles occur as recurring motifs in the design of kinase inhibitors. Pyrazolo[3,4-b]pyridine has proved particularly versatile due to its ability to interact with kinases via multiple binding modes. As such, this scaffold has been claimed for kinase inhibition in many patents originating from several companies and universities, and these cover a broad range of kinase targets.Areas covered: Patents from 2008 to the present in which pyrazolo[3,4-b] pyridine is utilized as a key element for inhibitor binding are included. This scaffold typically binds to the hinge region of the kinase, but examples in which other key interactions are formed are included in this review. Articles published in peer-reviewed journals that supplement information provided in the patent literature are highlighted.Expert opinion: Several bicyclic heterocycles are capable of forming a hydrogen bond donor–acceptor pair. This interaction is common among kinase inhibitors, particularly at the hinge region. These heterocycles are elaborated to form additional interactions in the kinase pocket which provide potency and selectivity, and thus serve as key scaffolds in kinase inhibitor design. Pyrazolo[3,4-b]pyridine can be viewed as having elements of both pyrrolo[2,3-b]pyridine and indazole and can therefore achieve multiple kinase binding modes. This scaffold is often encountered in kinase inhibitors as a result. Examination of the patent literature suggests that in some cases this group is simply one of several hinge binders examined for a particular series. In other cases, the pyrazolo[3,4-b]pyridine appears to provide an advantage, either in terms of intellectual property, inhibitor activity, physical properties or synthetic flexibility.