The JAK-STAT pathway mediates signaling by cytokines, which control survival, proliferation, and differentiation of a variety of cells. In recent years, a single point mutation (V617F) in the tyrosine kinase JAK2 was found to be present with a high incidence in myeloproliferative disorders (MPDs). This mutation led to hyperactivation of JAK2, cytokine-independent signaling, and subsequent activation of downstream signaling networks. The genetic, biological, and physiological evidence suggests that JAK2 inhibitors could be effective in treating MPDs. De novo design efforts of new scaffolds identified 1-amino-5H-pyrido[4,3-b]indol-4-carboxamides as a new viable lead series. Subsequent optimization of cell potency, metabolic stability, and off-target activities of the leads led to the discovery of 7-(2-aminopyrimidin-5-yl)-1-{[(1R)-1-cyclopropyl-2,2,2-trifluoroethyl]amino}-5H-pyrido[4,3-b]indole-4-carboxamide (65). Compound 65 is a potent, orally active inhibitor of JAK2 with excellent selectivity, PK profile, and in vivo efficacy in animal models.

中文翻译：

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发现Janus激酶2（JAK2）的1-氨基-5 H-吡啶并[4,3 - b ]吲哚-4-羧酰胺抑制剂可治疗骨髓增生异常。

JAK-STAT途径通过细胞因子介导信号传导，该细胞因子控制各种细胞的存活，增殖和分化。近年来，发现在酪氨酸激酶JAK2中存在单点突变（V617F），在骨髓增生性疾病（MPD）中发病率很高。此突变导致JAK2过度激活，细胞因子非依赖性信号传导以及下游信号传导网络的后续激活。遗传，生物学和生理学证据表明，JAK2抑制剂可有效治疗MPD。从头开始设计新的支架，确定了1-amino-5 H -pyrido [4,3- b] indol-4-carboxamides作为一种新的可行的铅系列。随后优化了细胞效力，代谢稳定性和靶标的脱靶活性，导致发现7-（2-氨基嘧啶-5-基）-1-{[（（1 R）-1-环丙基-2,2 ，2-三氟乙基]氨基} -5 H-吡啶并[4,3 - b ]吲哚-4-羧酰胺（65）。化合物65是有效的，口服活性的JAK2抑制剂，在动物模型中具有出色的选择性，PK曲线和体内功效。