Discovery of azaspirocyclic 1H-3,4,5-Trisubstitued pyrazoles as novel G2019S-LRRK2 selective kinase inhibitors.

Mutations in the Leucine Rich Repeat Protein Kinase 2 gene (LRRK2) are genetic predispositions for Parkinson's Disease, of which the G2019S (GS) missense mutation is the most common. GS-LRRK2 has a hyperactive kinase, and although numerous drug discovery programs have targeted the LRRK2 kinase, few have reached clinical trials. We recently reported on the discovery of a novel LRRK2 kinase inhibitor chemotype, 1H-pyrazole biaryl sulfonamides. Although both potent and selective GS-LRRK2 inhibitors, 1H-pyrazole biaryl sulfonamides are incapable of crossing the blood-brain barrier. Retaining the core 1H-pyrazole and focusing our efforts on a phenylsulfonamide bioisosteric replacement, we report the discovery and preliminary development of azaspirocyclic 1H-3,4,5-trisubstituted pyrazoles as potent and selective (>2000-fold) GS-LRRK2 kinase inhibitors capable of entering rodent brain. The compounds disclosed here present an excellent starting point for the development of more brain penetrant compounds.