4-(3-(6-fluoro-1-oxoisoindolin-2-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide

• 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-(3-(6-fluoro-1-oxoisoindolin-2-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
• 化学式: C₃₁H₂₆FN₃O₃
• 分子量: 507.564
• InChiKey: VVJGEJVGPIRMKO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.92
• 重原子数：
  38.0
• 可旋转键数：
  4.0
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.16
• 拓扑面积：
  99.42
• 氢给体数：
  3.0
• 氢受体数：
  3.0

反应信息

• 作为产物：
  描述：

  3-羟基苯甲酸乙酯 在 ammonium hydroxide 、 potassium phosphate 、 四(三苯基膦)钯 、 Rh/Al₂O₃ 、 氢气 、 1-羟基苯并三唑 、 戴斯-马丁氧化剂 、 1,2-二氯乙烷 、 2,3-二氯-5,6-二氰基-1,4-苯醌 作用下， 以 四氢呋喃 、 乙醇 、 正己烷 、 二氯甲烷 、 水 、 溶剂黄146 、 甲苯 为溶剂， 反应 14.0h， 生成 4-(3-(6-fluoro-1-oxoisoindolin-2-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
  参考文献：
  名称：

  Small Molecule Reversible Inhibitors of Bruton’s Tyrosine Kinase (BTK): Structure–Activity Relationships Leading to the Identification of 7-(2-Hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl]-9H-carbazole-1-carboxamide (BMS-935177)

  摘要：

  Bruton's tyrosine,kinase (BTK) belongs to the TEC family of nonreceptor tyrosine kinases and plays a critical role in multiple cell types responsible for numerous auto-immune diseases. This article will detail the structure-activity relationships (SARs) leading to a novel second generation series of potent and, selective reversible carbazole inhibitors of BTK. With an excellent pharmacokinetic profile as well as demonstrated in vivo activity and an acceptable safety profile, 7-(2-hydroxypropan-2-yl)-4-[2-methyl-3-(4-oXo-3,4-dihydroquinazdlin-3-yl)phenyl]-9H-carbazole-1-carboxarnide 6 (BMS-935177) was selected:to advance into clinical development.

  DOI：

  10.1021/acs.jmedchem.6b00722

文献信息

• US8084620B2
  申请人：——

  公开号：US8084620B2

  公开（公告）日：2011-12-27
• Small Molecule Reversible Inhibitors of Bruton’s Tyrosine Kinase (BTK): Structure–Activity Relationships Leading to the Identification of 7-(2-Hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl]-9<i>H</i>-carbazole-1-carboxamide (BMS-935177)
  作者：George V. De Lucca、Qing Shi、Qingjie Liu、Douglas G. Batt、Myra Beaudoin Bertrand、Rick Rampulla、Arvind Mathur、Lorell Discenza、Celia D’Arienzo、Jun Dai、Mary Obermeier、Rodney Vickery、Yingru Zhang、Zheng Yang、Punit Marathe、Andrew J. Tebben、Jodi K. Muckelbauer、ChiehYing J. Chang、Huiping Zhang、Kathleen Gillooly、Tracy Taylor、Mark A. Pattoli、Stacey Skala、Daniel W. Kukral、Kim W. McIntyre、Luisa Salter-Cid、Aberra Fura、James R. Burke、Joel C. Barrish、Percy H. Carter、Joseph A. Tino

  DOI：10.1021/acs.jmedchem.6b00722

  日期：2016.9.8

  Bruton's tyrosine,kinase (BTK) belongs to the TEC family of nonreceptor tyrosine kinases and plays a critical role in multiple cell types responsible for numerous auto-immune diseases. This article will detail the structure-activity relationships (SARs) leading to a novel second generation series of potent and, selective reversible carbazole inhibitors of BTK. With an excellent pharmacokinetic profile as well as demonstrated in vivo activity and an acceptable safety profile, 7-(2-hydroxypropan-2-yl)-4-[2-methyl-3-(4-oXo-3,4-dihydroquinazdlin-3-yl)phenyl]-9H-carbazole-1-carboxarnide 6 (BMS-935177) was selected:to advance into clinical development.