1-((3R,4R)-3-(((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)methyl)-4-(hydroxymethyl)pyrrolidin-1-yl)prop-2-en-1-one

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯并嘧啶类
• 英文名称: 1-((3R,4R)-3-(((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)methyl)-4-(hydroxymethyl)pyrrolidin-1-yl)prop-2-en-1-one
• 英文别名: 1-[(3R,4R)-3-[[5-chloro-2-[(1-methylpyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxymethyl]-4-(hydroxymethyl)pyrrolidin-1-yl]prop-2-en-1-one
• 化学式: C₁₉H₂₂ClN₇O₃
• 分子量: 431.882
• InChiKey: BATDFQPFLIRBDO-VXGBXAGGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  30
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  121
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  2,4,5-三氯-7H-吡咯[2,3-D]嘧啶 在 [2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-((2-aminoethyl)phenyl)]palladium(II) chloride 、 potassium 2-methylbutan-2-olate 、 三氟乙酸 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 甲苯 为溶剂， 反应 3.17h， 生成 1-((3R,4R)-3-(((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)methyl)-4-(hydroxymethyl)pyrrolidin-1-yl)prop-2-en-1-one
  参考文献：
  名称：

  Discovery of 1-{(3R,4R)-3-[({5-Chloro-2-[(1-methyl-1H-pyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}oxy)methyl]-4-methoxypyrrolidin-1-yl}prop-2-en-1-one (PF-06459988), a Potent, WT Sparing, Irreversible Inhibitor of T790M-Containing EGFR Mutants

  摘要：

  First generation EGFR TKIs (gefitinib, erlotinib) provide significant clinical benefit for NSCLC cancer patients with oncogenic EGFR mutations. Ultimately, these patients' disease progresses, often driven by a second-site mutation in the EGFR kinase domain (T790M). Another liability of the first generation drugs is severe adverse events driven by inhibition of WT EGFR. As such, our goal was to develop a highly potent irreversible inhibitor with the largest selectivity ratio between the drug-resistant double mutants (L858R/T790M, Del/T790M) and WT EGFR A unique approach to develop covalent inhibitors, optimization of reversible binding affinity, served as a cornerstone of this effort. PF-06459988 was discovered as a novel, third generation irreversible inhibitor, which demonstrates (0 high potency and specificity to the T790M-containing double mutant EGFRs, (ii) minimal intrinsic chemical reactivity of the electrophilic warhead, (iii) greatly reduced proteome reactivity relative to earlier irreversible EGFR inhibitors, and (iv) minimal activity against WT EGFR

  DOI：

  10.1021/acs.jmedchem.5b01633

文献信息

• Discovery of 1-{(3<i>R</i>,4<i>R</i>)-3-[({5-Chloro-2-[(1-methyl-1<i>H</i>-pyrazol-4-yl)amino]-7<i>H</i>-pyrrolo[2,3-<i>d</i>]pyrimidin-4-yl}oxy)methyl]-4-methoxypyrrolidin-1-yl}prop-2-en-1-one (PF-06459988), a Potent, WT Sparing, Irreversible Inhibitor of T790M-Containing EGFR Mutants
  作者：Hengmiao Cheng、Sajiv K. Nair、Brion W. Murray、Chau Almaden、Simon Bailey、Sangita Baxi、Doug Behenna、Sujin Cho-Schultz、Deepak Dalvie、Dac M. Dinh、Martin P. Edwards、Jun Li Feng、Rose Ann Ferre、Ketan S. Gajiwala、Michelle D. Hemkens、Amy Jackson-Fisher、Mehran Jalaie、Ted O. Johnson、Robert S. Kania、Susan Kephart、Jennifer Lafontaine、Beth Lunney、Kevin K.-C. Liu、Zhengyu Liu、Jean Matthews、Asako Nagata、Sherry Niessen、Martha A. Ornelas、Suvi T. M. Orr、Mason Pairish、Simon Planken、Shijian Ren、Daniel Richter、Kevin Ryan、Neal Sach、Hong Shen、Tod Smeal、Jim Solowiej、Scott Sutton、Khanh Tran、Elaine Tseng、William Vernier、Marlena Walls、Shuiwang Wang、Scott L. Weinrich、Shuibo Xin、Haiwei Xu、Min-Jean Yin、Michael Zientek、Ru Zhou、John C. Kath

  DOI：10.1021/acs.jmedchem.5b01633

  日期：2016.3.10

  First generation EGFR TKIs (gefitinib, erlotinib) provide significant clinical benefit for NSCLC cancer patients with oncogenic EGFR mutations. Ultimately, these patients' disease progresses, often driven by a second-site mutation in the EGFR kinase domain (T790M). Another liability of the first generation drugs is severe adverse events driven by inhibition of WT EGFR. As such, our goal was to develop a highly potent irreversible inhibitor with the largest selectivity ratio between the drug-resistant double mutants (L858R/T790M, Del/T790M) and WT EGFR A unique approach to develop covalent inhibitors, optimization of reversible binding affinity, served as a cornerstone of this effort. PF-06459988 was discovered as a novel, third generation irreversible inhibitor, which demonstrates (0 high potency and specificity to the T790M-containing double mutant EGFRs, (ii) minimal intrinsic chemical reactivity of the electrophilic warhead, (iii) greatly reduced proteome reactivity relative to earlier irreversible EGFR inhibitors, and (iv) minimal activity against WT EGFR