Discovery of a series of imidazopyrazine small molecule inhibitors of the kinase MAPKAPK5, that show activity using in vitro and in vivo models of rheumatoid arthritis.

MAPKAPK5 has been proposed to play a role in regulation of matrix metalloprotease expression and so to be a potential target for intervention in rheumatoid arthritis. We present here the identification of a series of compounds against this target which are effective in both biochemical and cell assays. The expansion of the series is described, along with early SAR and pharmacokinetics for some representative compounds.

A chemo- and regio-selective three-component dihydropyrimidinone synthesis.

A selective three-component coupling, involving co-condensation of aldehyde pairs with substituted ureas under Lewis acid catalysis, provides rapid access to highly functionalised dihydropyrimidinones; sulfamides react analogously.

Pd(II)-catalyzed intermolecular 1,2-diamination of conjugated dienes.

A Pd(II) chloride precatalyst, in the presence of 1 equiv of benzoquinone, effects highly efficient, regioselective 1,2-diamination of 1,3-dienes using dialkyl ureas under mild conditions. There is no requirement for a large excess of diene.

Stereoselective radical reactions.

For many years, the reputed lack of selectivity in some free-radical reactions has resulted in this class of reaction being overlooked in the stereoselective synthesis of important target molecules. More recently, however, the situation has changed as new and milder methods of radical generation have been developed, which have helped researchers to gain a better understanding of the key factors that influence selectivity in radical transformations. As a consequence, the use of radicals in stereoselective synthesis is increasing and there are a number of important intra- and intermolecular additions, where high levels of stereoselectivity have been achieved in the formation of carbon-carbon bonds.

Manganese(III) acetate-mediated alkylation of beta-keto esters and beta-keto amides: an enantio- and diastereo-selective approach to substituted pyrrolidinones.

beta-Keto esters and beta-keto amides can be efficiently alkylated on reaction with enol ethers and manganese(III) acetate in the presence of copper(II) acetate. These intermolecular radical addition reactions can be used to construct quaternary carbon centres in excellent yield and this method has been utilised in a diastereoselective approach to substituted pyrrolidinones.