Synthesis and Evaluation of 1<i>H</i>-Pyrrolo[2,3-<i>b</i>]pyridine Derivatives as Novel Immunomodulators Targeting Janus Kinase 3

Synthesis and evaluation of novel 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives as potent and orally efficacious immunomodulators targeting JAK3

“…Compound 6 was prepared as previously described 26 and treated with several amines under microwave irradiation to give the desired compounds 7a-d.…”

“…24,25 In our laboratory, a series of 1H-pyrrolo [2,3-b]pyridine-5-carboxamide derivatives was found to exhibit potent and moderately selective JAK3 inhibitory activity, and compound 2 ( Figure 2) was identified as a lead compound. 26 The hydrophobic cycloalkyl ring at the C4-position of these derivatives was important for JAK3 inhibitory activity, due to the interaction with the hydrophobic cavity of JAK3. However, a number of compounds suffered from poor metabolic stability in liver microsomes.…”

Discovery of 3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one derivatives as novel JAK inhibitors

“…9 Compound 3 exhibited weaker JAK3 and JAK1 inhibitory activity than 1. In addition, 3 exhibited higher lipophilicity (C log P = 5.3) than 1 (C log P = 1.8).…”

“…As we previously reported, the pyrrolopyridine scaffold of lead compound 3 was predicted to interact with the hinge region in a manner similar to 1. 9 As compound 3 has a free rotatable bond between the pyrrolopyridine scaffold and cyclohexane ring, the cyclohexane ring was placed at a proper position to access this hydrophobic pocket effectively. While our docking study revealed that Type I cyclization (Fig.…”

“…2). 9 After further optimization, we discovered the tricyclic imidazo-pyrrolopyridinone derivative 19 with potent JAK3 and JAK1 inhibitory activity and favorable metabolic stability. Here, we report the design, synthesis, and structure-activity relationship (SAR) of novel tricyclic JAK inhibitors.…”