Discovery of 7‑Oxo-2,4,5,7-tetrahydro‑6<i>H</i>‑pyrazolo[3,4‑<i>c</i>]pyridine Derivatives as Potent, Orally Available, and Brain-Penetrating Receptor Interacting Protein 1 (RIP1) Kinase Inhibitors: Analysis of Structure–Kinetic Relationships

We report the discovery of 7-oxo-2,4,5,7-tetrahydro-6<i>H</i>-pyrazolo­[3,4-<i>c</i>]­pyridine derivatives as a novel class of receptor interacting protein 1 (RIP1) kinase inhibitors. On the basis of the overlay study between HTS hit <b>10</b> and GSK2982772 (<b>6</b>) in RIP1 kinase, we designed and synthesized a novel class of RIP1 kinase inhibitor <b>11</b> possessing moderate RIP1 kinase inhibitory activity and P-gp mediated efflux. The optimization of the core structure and the exploration of appropriate substituents utilizing SBDD approach led to the discovery of <b>22</b>, a highly potent, orally available, and brain-penetrating RIP1 kinase inhibitor with excellent PK profiles. Compound <b>22</b> significantly suppressed necroptotic cell death both in mouse and human cells. Oral administration of <b>22</b> (10 mg/kg, bid) attenuated disease progression in the mouse experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). Moreover, analysis of structure–kinetic relationship (SKR) for our novel chemical series was also discussed