Endocyclic Trisubstituted Hydroxylamine Isosteres of Basic Amines for ADME Modulation and Reduction of hERG Activity

The attachment of solvent-exposed basic amines to kinase inhibitors via an aliphatic chain is a strategy commonly employed to increase aqueous solubility but one that is often complicated by increased human ether-a-go-go (hERG) activity and reduced metabolic stability. Extrapolating from previous work on the replacement of the solubilizing morphilinoalkyl and N-methyl piperazinoalkyl chains in the tyrosine kinase inhibitors gefitinib and bosutinib by isosteric hydroxylamines with concomitant reduction in hERG activity without loss of potency against the target kinases, using the PAK1 kinase inhibitor FRAX1036 as model, we describe our exploration of endo- and exocyclic hydroxylamine units as replacements of solubilizing N-methyl-4-piperidinylalkyl chains. These studies culminate with the development of the 5N-methyl-1,2,5-oxadiazepan-5-yl moiety as an isosteric replacement of the parent N-methyl-4-piperidinylalkyl group without loss of potency as a PAK1 inhibitor, a 2-fold increase in selectivity over hERG inhibition, parent-like rates of metabolism by human liver microsomes and MDCKII and Caco-2 efflux ratios.