Development of a Concise Multikilogram Synthesis of LPA‑1 Antagonist BMS-986020 via a Tandem Borylation–Suzuki Procedure

The process development for the synthesis of BMS-986020 (<b>1</b>) via a palladium catalyzed tandem borylation/Suzuki reaction is described. Evaluation of conditions culminated in an efficient borylation procedure using tetrahydroxydiboron followed by a tandem Suzuki reaction employing the same commercially available palladium catalyst for both steps. This methodology addressed shortcomings of early synthetic routes and was ultimately used for the multikilogram scale synthesis of the active pharmaceutical ingredient <b>1</b>. Further evaluation of the borylation reaction showed useful reactivity with a range of substituted aryl bromides and iodides as coupling partners. These findings represent a practical, efficient, mild, and scalable method for borylation

Discovery of Potent and Orally Bioavailable Dihydropyrazole GPR40 Agonists

G protein-coupled receptor 40 (GPR40) has become an attractive target for the treatment of diabetes since it was shown clinically to promote glucose-stimulated insulin secretion. Herein, we report our efforts to develop highly selective and potent GPR40 agonists with a dual mechanism of action, promoting both glucose-dependent insulin and incretin secretion. Employing strategies to increase polarity and the ratio of sp³/sp² character of the chemotype, we identified BMS-986118 (compound <b>4</b>), which showed potent and selective GPR40 agonist activity <i>in vitro</i>. <i>In vivo</i>, compound <b>4</b> demonstrated insulinotropic efficacy and GLP-1 secretory effects resulting in improved glucose control in acute animal models