No abstract

JAK2 kinase inhibitors are a promising new class of agents for the treatment of myeloproliferative neoplasms and have potential for the treatment of other diseases possessing a deregulated JAK2-STAT pathway. X-ray structure and ADME guided refinement of C-4 heterocycles to address metabolic liability present in dialkylthiazole 1 led to the discovery of a clinical candidate, BMS-911543 (11), with excellent kinome selectivity, in vivo PD activity, and safety profile.

Unnatural amino acids play an important role in peptide based drug discovery. Herein, we report a class of differentially protected azatryptophan derivatives synthesized from N-tosyl-3-haloazaindoles 1 and Fmoc-protected tert-butyl iodoalanine 2 via a Negishi coupling. Through ligand screening, Pd2(dba)3/XPhos was found to be a superior catalyst for the coupling of 1 with the zinc derivative of 2 to give tert-butyl ( S )-2-((((9H-fluoren-9-yl)­methoxy)­carbonyl)­amino)-3-(1-tosyl-1H-pyrrolo­[2,3-b]­pyridin-3-yl)­propanoate derivatives 3 in 69–91% isolated yields. In addition, we have demonstrated that the protecting groups, namely, Ts, Fmoc, and t Bu, can be easily removed selectively.