Sobhana Babu Boga

Selective functionalization of complex heterocycles via an automated strong base screening platform

Knochel–Hauser bases, derived from 2,2,6,6-tetramethylpiperidinyl (TMP) metal amides, offer exceptional selectivity and functional group tolerance in the regioselective metalation of arenes and heteroarenes. The selectivity, stability and yield of these reactions are highly dependent on the nature of the base, additive and deprotonation temperature. We have developed and validated an automated micro-scale high throughput experimentation (HTE) approach to rapidly optimize base and temperature matrices. We describe the application of this approach to the regioselective functionalization of a variety of complex heterocycles and extension to the preparation of organometallic reagents for transition metal catalyzed cross-coupling screens.

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 @ 100u202fnM) and good cell proliferation activity, but suffered from poor PK (rat AUC PK @10u202fmpku202f=u202f0u202fμMu202fh; F%u202f=u202f0) 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 @10u202fmpku202f=u202f26u202fμMu202fh; F%u202f=u202f70).

MK-8353: Discovery of an Orally Bioavailable Dual Mechanism ERK Inhibitor for Oncology

The emergence and evolution of new immunological cancer therapies has sparked a rapidly growing interest in discovering novel pathways to treat cancer. Toward this aim, a novel series of pyrrolidine derivatives (compound 5) were identified as potent inhibitors of ERK1/2 with excellent kinase selectivity and dual mechanism of action but suffered from poor pharmacokinetics (PK). The challenge of PK was overcome by the discovery of a novel 3(S)-thiomethyl pyrrolidine analog 7. Lead optimization through focused structure-activity relationship led to the discovery of a clinical candidate MK-8353 suitable for twice daily oral dosing as a potential new cancer therapeutic.

Discovery of 3-morpholino-imidazole[1,5-a]pyrazine BTK inhibitors for rheumatoid arthritis ☆

8-Amino-imidazo[1,5-a]pyrazine-based Brutons tyrosine kinase (BTK) inhibitors, such as 6, exhibited potent inhibition of BTK but required improvements in both kinase and hERG selectivity (Liu et al., 2016; Gao et al., 2017). In an effort to maintain the inhibitory activity of these analogs and improve their selectivity profiles, we carried out SAR exploration of groups at the 3-position of pyrazine compound 6. This effort led to the discovery of the morpholine group as an optimized pharmacophore. Compounds 13, 23 and 38 displayed excellent BTK potencies, kinase and hERG selectivities, and pharmacokinetic profiles.