Synthesis of BI 894416 and BI 1342561, Two Potent and Selective Spleen Tyrosine Kinase Inhibitors, Labelled with Carbon 14 and with Deuterium.

(R)-4-((R)-1-((6-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-methyl-2H-pyrazolo[3,4-d]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one (BI 894416, 1) and (R)-4-((R)-1-((6-(1-(tert-butyl)-1H-pyrazol-4-yl)-2,3-dimethyl-2H-indazol-4-yl)oxy)ethyl)pyrrolidin-2-one (BI 1342561, 2), are two new potent and selective SYK inhibitors developed to treat severe asthma. Both compounds have similar structures and they differ only in the bicyclic moiety 2-methyl-2H-pyrazolo[4,3-c]pyridine in 1 versus 2,3-dimethyl-2H-indazole in 2. In the carbon 14 synthesis, 1-(1-(tert-butyl)-1H-pyrazol-4-yl)ethan-1-one-1- 14 C ([ 14 C]-8) was prepared from the cyanation of 4-bromopyrazole using zinc [ 14 C]cyanide followed by methyl lithium addition on the nitrile group. The enolate of [ 14 C]-8 was then used to access these two bicyclic moieties via pyrano-pyrazoles [ 14 C]-11 and [ 14 C]-12, which were further transformed in few more steps to [ 14 C]-(1) and [ 14 C]-2. Both inhibitors contain a tert-butyl group. Introducing tert-butyl-d 9 will not only provide internal standards for bioanalytical studies, but it is also expected to slow down the metabolism of these two compounds. Most of the metabolites of compound 1 for example, are the result of tert-butyl oxidation, like alcohol 3, acid 4 and the further N-demethylation of 4 to 5. The detailed preparation of these deuterium labelled metabolites is also described.