9-ethyl-8-(4-((4-hydroxypiperidin-4-yl)methyl)piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

• 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: 9-ethyl-8-(4-((4-hydroxypiperidin-4-yl)methyl)piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
• 英文别名: 9-ethyl-8-[4-[(4-hydroxypiperidin-4-yl)methyl]piperazin-1-yl]-6,6-dimethyl-11-oxo-5H-benzo[b]carbazole-3-carbonitrile
• 化学式: C₃₁H₃₇N₅O₂
• 分子量: 511.667
• InChiKey: BTNNIEZIMHCWOV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  38
• 可旋转键数：
  4
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  95.4
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  、 1-噁-6-氮杂螺[2.5]辛烷-6-羧酸-1,1-二甲基乙酯 在 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 乙醇 、 二氯甲烷 为溶剂， 以70%的产率得到9-ethyl-8-(4-((4-hydroxypiperidin-4-yl)methyl)piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
  参考文献：
  名称：

  Metabolism-based structure optimization: Discovery of a potent and orally available tyrosine kinase ALK inhibitor bearing the tetracyclic benzo[b]carbazolone core

  摘要：

  A metabolism-based fine-tuning structure-optimization was conducted to address the oxidative metabolism and hERG blockade of our early ALK inhibitor. Compound 8 was identified showing high potency against both ALK wild type and gatekeeper mutant. In addition to the optimal PK properties and significant cell antiproliferative effects, 8 showed complete tumor growth inhibition at doses of 50 or 10 mg/kg once daily in the Karpas299 xenograft model. All these results encouraged the further development of 8 as a potent and orally bioavailable ALK inhibitor. (C) 2016 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2016.10.039