Janus kinases (JAKs) regulate various inflammatory and immune responses and are targets for the treatment of inflammatory and immune diseases. As a novel class of immunomodulators targeting JAK3, 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives are promising candidates for treating such diseases. In chemical modification of lead compound 2, the substitution of a cycloalkyl ring for an N-cyanopyridylpiperidine in C4-position was effective for increasing JAK3 inhibitory activity. In addition, modulation of physical properties such as molecular lipophilicity and basicity was important for reducing human ether-a-go-go-related gene (hERG) inhibitory activity. Our optimization study gave compound 31, which exhibited potent JAK3 inhibitory activity as well as weak hERG inhibitory activity. In cellular assay, 31 exhibited potent immunomodulating effect on IL-2-stimulated T cell proliferation. In a pharmacokinetic study, good metabolic stability and oral bioavailability of 31 were achieved in rats, dogs, and monkeys. Further, 31 prolonged graft survival in an in vivo rat heterotopic cardiac transplant model.

Janus激酶（JAKs）调节各种炎症和免疫反应，是治疗炎症和免疫疾病的靶标。作为靶向JAK3的新型免疫调节剂，1 H-吡咯并[2，3 - b ]吡啶-5-甲酰胺衍生物是有望治疗此类疾病的候选物。在铅化合物2的化学修饰中，在C 4位上用环烷基环取代N-氰基吡啶基哌啶对提高JAK3抑制活性是有效的。另外，调节诸如分子亲脂性和碱性的物理性质对于降低人与人有关的基因（hERG）的抑制活性也很重要。我们的优化研究得出了化合物31，其表现出有效的JAK3抑制活性以及弱hERG抑制活性。在细胞分析中，有31种对IL-2刺激的T细胞增殖表现出强力的免疫调节作用。在药代动力学研究中，在大鼠，狗和猴子中获得了31种良好的代谢稳定性和口服生物利用度。此外，在体内大鼠异位心脏移植模型中31延长了移植物存活。