N-(3-((2-((1-methyl-1H-pyrazol-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)acrylamide | 1428774-66-6

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: N-(3-((2-((1-methyl-1H-pyrazol-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)acrylamide
• 英文别名: N-[3-[[2-[(1-methylpyrazol-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]phenyl]prop-2-enamide
• CAS: 1428774-66-6
• 化学式: C₁₉H₁₇N₇O₂
• 分子量: 375.39
• InChiKey: ZOLXJDSFGCNIAL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  28
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.05
• 拓扑面积：
  110
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  2,4-二氯-7H吡咯[2,3-D]嘧啶 在 盐酸 、 tris-(dibenzylideneacetone)dipalladium(0) 、 potassium carbonate 、 caesium carbonate 、 4,5-双二苯基膦-9,9-二甲基氧杂蒽 、 三氟乙酸 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 乙腈 为溶剂， 反应 9.75h， 生成 N-(3-((2-((1-methyl-1H-pyrazol-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)acrylamide
  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

• PYRROLOPYRIMIDINE AND PURINE DERIVATIVES
  申请人：Cheng Hengmiao

  公开号：US20130079324A1

  公开（公告）日：2013-03-28

  The present invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein Q, T, V, W, X, Y, Z, ring A, R 1 , R 2 , R 3 , R 4 , R 5 , R 5a , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and m are defined herein. There novel pyrrolopyrimidine and purine derivatives are useful in the treatment of abnormal cell growth, such as cancer, in mammals. Additional embodiments relate to pharmaceutical compositions containing the compounds and to methods of using the compounds and compositions in the treatment of abnormal cell growth in mammals.

  本发明涉及式（I）的化合物或其药学上可接受的盐，其中Q、T、V、W、X、Y、Z、环A、R1、R2、R3、R4、R5、R5a、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17和m在此定义。这些新颖的吡咯嘧啶和嘌呤衍生物在哺乳动物中治疗异常细胞生长，如癌症方面具有用处。另外，本发明还涉及含有这些化合物的药物组合物，以及在哺乳动物中治疗异常细胞生长的方法。
• US9040547B2
  申请人：——

  公开号：US9040547B2

  公开（公告）日：2015-05-26
• 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