Isoquinoline Kelch-like ECH-Associated Protein 1‑Nuclear Factor (Erythroid-Derived 2)-like 2 (KEAP1-NRF2) Inhibitors with High Metabolic Stability

Pharmacological activation of NRF2 (nuclear factor erythroid
2-related
factor 2) arises from blocking the interaction of NRF2 with its negative
regulator, KEAP1 (Kelch-like ECH-associated protein 1). We previously
reported an isoquinoline-based NRF2 activator, but this compound showed
negative logD7.4 and a −2 charge at physiological
pH, which may have limited its membrane permeability. In this work,
we report potent, metabolically stable analogs that result from replacing
a carboxymethyl group at the 4-position with a fluoroalkyl group.