Synlett
DOI: 10.1055/s-0043-1775430
letter
Small Molecules in Medicinal Chemistry

A Concise Synthesis of a Key Azabicyclo[2.1.1]hexane Building Block for N-Heteroaryl Indazole LRRK2 Kinase Inhibitors

a   Discovery Chemistry, Merck & Co., Inc., Boston, MA 02115, USA
,
Vladimir Simov
a   Discovery Chemistry, Merck & Co., Inc., Boston, MA 02115, USA
,
Ping Liu
a   Discovery Chemistry, Merck & Co., Inc., Boston, MA 02115, USA
,
Michael J. Ardolino
b   Process Research and Development, Merck & Co., Inc., Boston, MA 02115, USA
,
Theodore Martinot
b   Process Research and Development, Merck & Co., Inc., Boston, MA 02115, USA
,
Thomas Lyons
b   Process Research and Development, Merck & Co., Inc., Boston, MA 02115, USA
,
Ji Qi
c   Process Research and Development, Merck & Co., Inc., Rahway, NJ 07065, USA
,
Jingjun Yin
c   Process Research and Development, Merck & Co., Inc., Rahway, NJ 07065, USA
,
Jinglai Hao
d   WuXi AppTec (Shanghai), No. 1 Building, 288 Fute Zhong Road, WaiGaoQiao Free Trade Zone, Shanghai 200131, P. R. of China
,
Bin Hu
d   WuXi AppTec (Shanghai), No. 1 Building, 288 Fute Zhong Road, WaiGaoQiao Free Trade Zone, Shanghai 200131, P. R. of China
,
Meng Chen
d   WuXi AppTec (Shanghai), No. 1 Building, 288 Fute Zhong Road, WaiGaoQiao Free Trade Zone, Shanghai 200131, P. R. of China
,
Jun Zhang
d   WuXi AppTec (Shanghai), No. 1 Building, 288 Fute Zhong Road, WaiGaoQiao Free Trade Zone, Shanghai 200131, P. R. of China
,
Yu-hong Lam
e   Computational and Structural Chemistry, Merck & Co., Inc., Rahway, NJ 07065, USA
,
Peter H. Fuller
a   Discovery Chemistry, Merck & Co., Inc., Boston, MA 02115, USA
,
J. Michael Ellis
a   Discovery Chemistry, Merck & Co., Inc., Boston, MA 02115, USA
,
Matthew Maddess
b   Process Research and Development, Merck & Co., Inc., Boston, MA 02115, USA
› Author Affiliations


Preview

Abstract

Increasing the fraction of sp3 character in lead compounds has been shown to increase their drug-likeness by improving their potency, selectivity, and physicochemical properties. Azabicyclo[2.1.1]hexanes have recently garnered much interest in the synthetic community as pyrrolidine analogues for their interesting biological properties and stereoelectronic effects. During the course of our optimization of N-heteroaryl LRRK2 inhibitors, we discovered that this unique bicyclic system leads to improvements in solubility and metabolic clearance. Herein, we outline a match-pair analysis showcasing the broad impact of this unique azabicyclo[2.1.1]hexane system on key drug-like properties, as well as a concise and scalable synthesis of this building block, featuring an intramolecular cyclization to forge a strained amide bond.

Supporting Information



Publication History

Received: 08 November 2024

Accepted after revision: 09 December 2024

Article published online:
13 January 2025

© 2025. Thieme. All rights reserved

Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany