(S)-1-((6-(5-(3-methoxy-5-methylphenyl)-1-methyl-1H-pyrazol-4-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)propan-2-ol

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: (S)-1-((6-(5-(3-methoxy-5-methylphenyl)-1-methyl-1H-pyrazol-4-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)propan-2-ol
• 英文别名: (2S)-1-[[6-[5-(3-methoxy-5-methylphenyl)-1-methylpyrazol-4-yl]-2-pyridin-3-ylpyrimidin-4-yl]amino]propan-2-ol
• 化学式: C₂₄H₂₆N₆O₂
• 分子量: 430.509
• InChiKey: GUZKLQHABRPUPO-INIZCTEOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  32
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  98
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (S)-1-((6-(5-(3-methoxy-5-methylphenyl)-1-methyl-1H-pyrazol-4-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)propan-2-ol 在 三氟二甲基硫醚络合物 作用下， 以 二氯甲烷 为溶剂， 以57%的产率得到(S)-3-(4-(6-((2-hydroxypropyl)amino)-2-(pyridin-3-yl)pyrimidin-4-yl)-1-methyl-1H-pyrazol-5-yl)-5-methylphenol
  参考文献：
  名称：

  Structure-based optimization and biological evaluation of trisubstituted pyrazole as a core structure of potent ROS1 kinase inhibitors

  摘要：

  Recently inhibition of ROS1 kinase has proven to be a promising strategy for several indications such as glioblastoma, non-small cell lung cancer (NSCLC), and cholangiocarcinoma. Our team reported trisubstituted pyrazole-based ROS1 inhibitors by which two inhibitors showed good IC₅₀ values in enzyme-based screening. To develop more advanced ROS1 inhibitors through SAR this trisubstituted pyrazole-based scaffold has been built. Consequently, 16 compounds have been designed, synthesized and shown potent IC₅₀ values in the enzymatic assay, which are from 13.6 to 283 nM. Molecular modeling studies explain how these ROS1 kinase inhibitors revealed effectively the key interactions with ROS1 ATP binding site. Among these compounds, compound 9a (IC₅₀=13.6 nM) has exerted 5 fold potency than crizotinib and exhibited high degree of selectivity (selectivity score value=0.028) representing the number of non-mutant kinases with biological activity over 90% at 10 μM.

  DOI：

  10.1016/j.bmc.2014.06.020
• 作为产物：
  描述：

  2,4-二氯-6-甲基嘧啶 在 potassium carbonate 、 N,N-二异丙基乙胺 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 45.0h， 生成 (S)-1-((6-(5-(3-methoxy-5-methylphenyl)-1-methyl-1H-pyrazol-4-yl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)propan-2-ol
  参考文献：
  名称：

  Structure-based optimization and biological evaluation of trisubstituted pyrazole as a core structure of potent ROS1 kinase inhibitors

  摘要：

  Recently inhibition of ROS1 kinase has proven to be a promising strategy for several indications such as glioblastoma, non-small cell lung cancer (NSCLC), and cholangiocarcinoma. Our team reported trisubstituted pyrazole-based ROS1 inhibitors by which two inhibitors showed good IC₅₀ values in enzyme-based screening. To develop more advanced ROS1 inhibitors through SAR this trisubstituted pyrazole-based scaffold has been built. Consequently, 16 compounds have been designed, synthesized and shown potent IC₅₀ values in the enzymatic assay, which are from 13.6 to 283 nM. Molecular modeling studies explain how these ROS1 kinase inhibitors revealed effectively the key interactions with ROS1 ATP binding site. Among these compounds, compound 9a (IC₅₀=13.6 nM) has exerted 5 fold potency than crizotinib and exhibited high degree of selectivity (selectivity score value=0.028) representing the number of non-mutant kinases with biological activity over 90% at 10 μM.

  DOI：

  10.1016/j.bmc.2014.06.020

文献信息

• Structure-based optimization and biological evaluation of trisubstituted pyrazole as a core structure of potent ROS1 kinase inhibitors
  作者：Byung Sun Park、Mohammad M. Al-Sanea、Ahmed Z. Abdelazem、Hye Mi Park、Eun Joo Roh、Hyun-Mee Park、Kyung Ho Yoo、Taebo Sim、Jin Sung Tae、So Ha Lee

  DOI：10.1016/j.bmc.2014.06.020

  日期：2014.8

  Recently inhibition of ROS1 kinase has proven to be a promising strategy for several indications such as glioblastoma, non-small cell lung cancer (NSCLC), and cholangiocarcinoma. Our team reported trisubstituted pyrazole-based ROS1 inhibitors by which two inhibitors showed good IC₅₀ values in enzyme-based screening. To develop more advanced ROS1 inhibitors through SAR this trisubstituted pyrazole-based scaffold has been built. Consequently, 16 compounds have been designed, synthesized and shown potent IC₅₀ values in the enzymatic assay, which are from 13.6 to 283 nM. Molecular modeling studies explain how these ROS1 kinase inhibitors revealed effectively the key interactions with ROS1 ATP binding site. Among these compounds, compound 9a (IC₅₀=13.6 nM) has exerted 5 fold potency than crizotinib and exhibited high degree of selectivity (selectivity score value=0.028) representing the number of non-mutant kinases with biological activity over 90% at 10 μM.