New thiazoles and isoindazoles as kinase inhibitors

Abstract

Of the many optimisation goals in the drug discovery process two important parameters are oral bioavailability and genotoxicity. Firstly, poor bioavailability is often caused by a compounds poor aqueous solubility, and this poor solubility is often unknowingly caused by high melting points. Secondly, although aromatic amines are of great synthetic value the genotoxicity attributable to some aromatic amine groups, which can be converted into highly reactive, electrophilic nitrenium-ions, can be prohibitive for long-term treatment against human diseases.<br />The aim of this project was to synthesize novel thiazole and isoindazole systems in order to eliminate the risk of genotoxic impurities and ideally leading to kinase inhibitors with low melting points and thus good aqueous solubility. For this reason the structure/melting point relationship of these compounds was reviewed.