Design, synthesis and evaluation of substituted N-methyl-N-(pyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amines as JAK1-selective inhibitors for the treatment of rheumatoid arthritis

Abstract

Based on (R)-N-methyl-N-(5-azaspiro[2.4]heptan-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a core scaffold, we identified (R)-3-(7-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5-azaspiro[2.4]heptan-5-yl)-3-oxopropanenitrile [(R)-6c] as a JAK1 selective inhibitor. The structural design was based on the combination of tofacitinibs 7-deazapurine and 5-azaspiro[2.4]heptan-7-amine. Compound (R)-6c exhibited 8.5 nM IC50 on JAK1 with a selectivity index of 48 over JAK2. To optimize (R)-6c as a lead compound, we performed cell-based functional assays, human whole blood tests, in vitro ADME, hERG, kinase profiling, and pharmacokinetic tests. Rat in vivo studies verified that (R)-6c exhibited desired efficacies on CIA and AIA models.