4-bromo-8-fluoro-N-methyl-5H-pyrido[4,3-b]indol-1-amine | 1132094-19-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 4-bromo-8-fluoro-N-methyl-5H-pyrido[4,3-b]indol-1-amine
• CAS: 1132094-19-9
• 化学式: C₁₂H₉BrFN₃
• 分子量: 294.126
• InChiKey: DYKAZKPUYKYDSN-UHFFFAOYSA-N

物化性质

• 沸点：
  480.0±45.0 °C(predicted)
• 密度：
  1.739±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  17
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  40.7
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  4-bromo-8-fluoro-N-methyl-5H-pyrido[4,3-b]indol-1-amine 在 双氧水 、 potassium carbonate 作用下， 以 N-甲基吡咯烷酮 、 水 、 二甲基亚砜 为溶剂， 生成 8-fluoro-1-(methylamino)-5H-pyrido[4,3-b]indole-4-carboxamide
  参考文献：
  名称：

  Discovery of 1-Amino-5H-pyrido[4,3-b]indol-4-carboxamide Inhibitors of Janus Kinase 2 (JAK2) for the Treatment of Myeloproliferative Disorders

  摘要：

  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 JAK.2, 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.

  DOI：

  10.1021/jm200909u
• 作为产物：
  描述：

  8-fluoro-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one 在 N-溴代丁二酰亚胺(NBS) 、 三氯氧磷 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 49.25h， 生成 4-bromo-8-fluoro-N-methyl-5H-pyrido[4,3-b]indol-1-amine
  参考文献：
  名称：

  Discovery of 1-Amino-5H-pyrido[4,3-b]indol-4-carboxamide Inhibitors of Janus Kinase 2 (JAK2) for the Treatment of Myeloproliferative Disorders

  摘要：

  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 JAK.2, 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.

  DOI：

  10.1021/jm200909u

文献信息

• Tricyclic Compounds Useful as Inhibitors of Kinases
  申请人：Truchon Jean-Francois

  公开号：US20100048551A1

  公开（公告）日：2010-02-25

  The present invention provides inhibitors of kinases, specifically IκB kinases, JAK1, JAK2, JAK3 and TYK2. The invention also provides for compositions comprising such inhibitory compounds and methods of inhibiting said kinase activity by administering the compound to a patient in need of treatment for myeloproliferative disorders, cancer or NF-κB-mediated diseases.

  本发明提供了激酶抑制剂，特别是IκB激酶、JAK1、JAK2、JAK3和TYK2的抑制剂。本发明还提供了包含这种抑制性化合物的组合物，并通过将该化合物用于需要治疗骨髓增生性疾病、癌症或NF-κB介导疾病的患者来抑制该激酶活性的方法。
• Tricyclic compounds useful as inhibitors of kinases
  申请人：Truchon Jean-Francois

  公开号：US08518964B2

  公开（公告）日：2013-08-27

  The present invention provides inhibitors of kinases, specifically IκB kinases, JAK1, JAK2, JAK3 and TYK2. The invention also provides for compositions comprising such inhibitory compounds and methods of inhibiting said kinase activity by administering the compound to a patient in need of treatment for myeloproliferative disorders, cancer or NF-κB-mediated diseases.

  本发明提供了激酶抑制剂，特别是IκB激酶、JAK1、JAK2、JAK3和TYK2的抑制剂。本发明还提供了包含这些抑制剂化合物的组合物，以及通过向需要治疗骨髓增殖性疾病、癌症或NF-κB介导疾病的患者施用该化合物来抑制该激酶活性的方法。
• WO2007/61764
  申请人：——

  公开号：——

  公开（公告）日：——
• TRICYCLIC COMPOUNDS USEFUL AS INHIBITORS OF KINASES
  申请人：Merck Sharp & Dohme Corp.

  公开号：EP1954290B1

  公开（公告）日：2012-07-25
• US8518964B2
  申请人：——

  公开号：US8518964B2

  公开（公告）日：2013-08-27