Discovery of 3(S)-thiomethyl pyrrolidine ERK inhibitors for oncology

Compound 5 (SCH772984) was identified as a potent inhibitor of ERK1/2 with excellent selectivity against a panel of kinases (0/231 kinases tested @ 100?nM) and good cell proliferation activity, but suffered from poor PK (rat AUC PK @10?mpk?=?0?μM?h; F%?=?0) which precluded further development. In an effort to identify novel ERK inhibitors with improved PK properties with respect to 5, a systematic exploration of sterics and composition at the 3-position of the pyrrolidine led to the discovery of a novel 3(S)-thiomethyl pyrrolidine analog 28 with vastly improved PK (rat AUC PK @10?mpk?=?26?μM?h; F%?=?70).