A Mitsunobu response of amino alcohol and bromo chloro hydroxypyridine afforded pyridine . Boronate ester , prepared from its corresponding bromoindazole, was coupled with inside a Suzuki coupling reaction to provide . A second Suzuki coupling to install the phenyl ring in the position of your pyridine core was carried out beneath microwave irradiation ailments, furnishing in really good yield. The ultimate de safety in the BOC group afforded the preferred tri substituted pyridine derivative . Several different analogs that has a array of C substituents had been prepared by this route. A Stille or Negishi coupling response was also put to use in case the corresponding organo tin or organo zinc reagents had been available. Within the scenarios of n and o, a Sonogashira response was applied as previously described. The representative analogs are listed in Table . As proven in Scheme , the phenyl group inside the amino aryl side chain was also replaced by a substituted indole ring, which was launched by way of Larock?s indole synthesis as the crucial phase, beginning from substituted bromoanilines and silylated alkynes.
Commercially available chiral amino acid was decreased with LiAlH to afford alcohol , which was coupled with hydroxypyridine below Mitsunobu response situations to afford compound . The TMS group was launched onto the terminal alkyne to provide , which was i thought about this coupled with boronate ester under microwave assisted Suzuki response problems to afford in very good yield. Treatment method of compound with substituted bromoanilines followed by a 2nd Suzuki coupling with furanyl boronic acid had been carried out in a single pot underneath microwave irradiation at C. TFA deprotection on the Boc group gave the target molecules . Added azaindole analogs were prepared within a similar manner from compound and unique regioisomers of ortho aminobromo pyridines.
Consistent with our hypothesis that substitution in the position in the core pyridine would diminish ROCK inhibition, a fold improvement in selectivity in excess of ROCK was accomplished when evaluating compound a and compound a . Furthermore, compound a demonstrated virtually fold larger AKT potency, whilst compound a was observed for being approximately equipotent against ROCK and selleck chemicals rho kinase inhibitor AKT. Table shows the SAR preferences in the substitution at C in the pyridine core. Aside from phenyl, ortho phenol of b was also tolerated, providing excellent selectivity against ROCK. The halogenated ortho phenol analogs had been observed as getting potent and selective, notably compound h, which demonstrated single digit nanomolar potency against AKT and higher than , fold selectivity in excess of ROCK. Nonetheless, the meta and para phenol derivatives were less potent AKT inhibitors.
Likewise, the ortho anisole e, demonstrated lowered potency towards AKT. Incorporation of 5 membered heterocycles at C place was also investigated. The furanyl derivative j was observed to get considerably more potent and selective than the furanyl regio iso mer i.