Development of indazole mineralocorticoid receptor antagonists and investigation into their selective late-stage functionalization

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:29

Article

Liu, Kun¹  Kurukulasuriya, Ravi¹  Dykstra, Kevin¹  DiMichelle, Lisa¹  Liu, Jinchu¹  Vachal, Petr¹  Ogawa, Anthony¹  DeVita, Robert J.¹  Shen, Dong-Ming¹  Tan, Qiang¹  Chen, Yili¹  Gauthier, Don¹  Verras, Andreas¹  Crespo, Alejandro¹  Zamlynny, Beata¹  Madwed, Jeffrey¹  Hoek, Maarten¹  Bateman, Thomas¹  Yang, Yun-Fang²  Houk, K. N.²  Krska, Shane¹  Cernak, Tim^1,3 

[1] Merck & Co Inc, Rahway, NJ 07065 USA

[2] Univ Calif Los Angeles, Dept Chem & Biochem, Los Angeles, CA 90095 USA

[3] Univ Michigan, Dept Med Chem, Ann Arbor, MI 48109 USA

关键词: Late-stage functionalization;    Mineralocorticoid receptor antagonists;    C-H functionalization;    C-H borylation;    High-throughput experimentation;   

DOI  :  10.1016/j.bmcl.2019.04.024

来源: Elsevier

【 摘 要 】

The derivatization of pharmaceuticals is a core activity in the discovery and development of new medicines. Late-stage functionalization via modern C-H functionalization chemistry has emerged as a powerful technique with which to diversify advanced pharmaceutical intermediates. We report herein a case study in late-stage functionalization towards the development of a new class of indazole-based mineralocorticoid receptor antagonists (MRA). An effort to modify the electronics of the core indazole heterocycle inspired the use of modern C-H borylation chemistry. New reactivity patterns were revealed and studied computationally. Ultimately, a de novo synthesis delivered a key 6-fluoroindazole compound 26, a potent MRA with excellent metabolic stability.

【 授权许可】

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