N-(4-(4-(3-(1-(3-aminophenyl)-3-tert-butyl-1H-pyrazol-5-yl)-ureido)phenylamino)quinazolin-6-yl)-3-(4-methylpiperazin-1-yl)propanamide trifluoroacetic acid | 1446981-12-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: N-(4-(4-(3-(1-(3-aminophenyl)-3-tert-butyl-1H-pyrazol-5-yl)-ureido)phenylamino)quinazolin-6-yl)-3-(4-methylpiperazin-1-yl)propanamide trifluoroacetic acid
• CAS: 1446981-12-9
• 化学式: C₂HF₃O₂*C₃₆H₄₃N₁₁O₂
• 分子量: 775.834
• InChiKey: RWFWYHFVIWUVQQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.29
• 重原子数：
  56.0
• 可旋转键数：
  9.0
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  195.66
• 氢给体数：
  6.0
• 氢受体数：
  11.0

反应信息

• 作为产物：
  描述：

  新戊酰基乙腈 在 吗啉 、 盐酸 、 5%-palladium/activated carbon 、 甲酸铵 、 铁粉 、 碳酸氢钠 、 溶剂黄146 、 N,N-二异丙基乙胺 、 sodium hydroxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 N-甲基吡咯烷酮 、 乙醇 、 二氯甲烷 、 水 、 二甲基亚砜 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 反应 68.5h， 生成 N-(4-(4-(3-(1-(3-aminophenyl)-3-tert-butyl-1H-pyrazol-5-yl)-ureido)phenylamino)quinazolin-6-yl)-3-(4-methylpiperazin-1-yl)propanamide trifluoroacetic acid
  参考文献：
  名称：

  Targeting Gain of Function and Resistance Mutations in Abl and KIT by Hybrid Compound Design

  摘要：

  Mutations in the catalytic domain at the gatekeeper position represent the most prominent drug-resistant variants of kinases and significantly impair the efficacy of targeted cancer therapies. Understanding the mechanisms of drug resistance at the molecular and atomic levels will aid in the design and development of inhibitors that have the potential to overcome these resistance mutations. Herein, by introducing adaptive elements into the inhibitor core structure, we undertake the structure-based development of type II hybrid inhibitors to overcome gatekeeper drug-resistant mutations in cSrc-T338M, as well as clinically relevant tyrosine kinase KIT-T6701 and Abl-T315I variants, as essential targets in gastrointestinal stromal tumors (GISTs) and chronic myelogenous leukemia (CML). Using protein X-ray crystallography, we confirm the anticipated binding mode in cSrc, which proved to be essential for overcoming the respective resistances. More importantly, the novel compounds effectively inhibit clinically relevant gatekeeper mutants of KIT and Abl in biochemical and cellular studies.

  DOI：

  10.1021/jm4004076