(S)-5-fluoro-N4-(1-(5-fluoropyridin-2-yl)ethyl)-N2-(5-methyl-1H-pyrazol-3-yl)-6-(4-(methylsulfonyl)piperazin-1-yl)pyrimidine-2,4-diamine | 1075758-07-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: (S)-5-fluoro-N4-(1-(5-fluoropyridin-2-yl)ethyl)-N2-(5-methyl-1H-pyrazol-3-yl)-6-(4-(methylsulfonyl)piperazin-1-yl)pyrimidine-2,4-diamine
• 英文别名: 5-fluoro-4-N-[(1S)-1-(5-fluoropyridin-2-yl)ethyl]-2-N-(5-methyl-1H-pyrazol-3-yl)-6-(4-methylsulfonylpiperazin-1-yl)pyrimidine-2,4-diamine
• CAS: 1075758-07-4
• 化学式: C₂₀H₂₅F₂N₉O₂S
• 分子量: 493.54
• InChiKey: OEQWYBMMCJIJKN-ZDUSSCGKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  34
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  140
• 氢给体数：
  3
• 氢受体数：
  12

反应信息

• 作为产物：
  描述：

  2,4-dichloro-5-fluoro-6-(4-(methylsulfonyl)piperazin-1-yl)pyrimidine 在 tris-(dibenzylideneacetone)dipalladium(0) 、 caesium carbonate 、 R-(+)-1,1'-联萘-2,2'-双二苯膦 、 N,N-二异丙基乙胺 作用下， 以 正丁醇 为溶剂， 生成 (S)-5-fluoro-N4-(1-(5-fluoropyridin-2-yl)ethyl)-N2-(5-methyl-1H-pyrazol-3-yl)-6-(4-(methylsulfonyl)piperazin-1-yl)pyrimidine-2,4-diamine
  参考文献：
  名称：

  Discovery of novel Jak2–Stat pathway inhibitors with extended residence time on target

  摘要：

  The discovery of the activating mutation V617F in the JH2 domain of Jak2 and the modulation of oncogenic Stat3 by Jak2 inhibitors have spurred a great interest in the inhibition of the Jak2/Stat pathway in oncology. In this Letter, we communicate the discovery of novel inhibitors of the Jak2/Stat5 axis, the N-(1H-pyrazol-3-yl)pyrimidin-2-amino derivatives. The rationale, synthesis and biological evaluation of these derivatives are reported. Two lead analogs from this series, 6 and 9, displayed prolonged residence time on Jak2, at enzymatic level. Although 6 and 9 exhibited moderate selectivity in a selected kinase panel, we chose to test these inhibitors in vivo as a consequence to their long residence time. However, extended inhibition of Jak2 due to the long residence time, in the form of inhibiting phosphorylation of downstream Stat5, was not recapitulated in an in vivo setting. (c) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.02.111

文献信息

• [EN] PYRAZOLYL-AMINO-SUBSTITUTED PYRIMIDINES AND THEIR USE FOR THE TREATMENT OF CANCER<br/>[FR] PYRIMIDINES SUBSTITUÉS PAR PYRAZOLYLE-AMINO ET LEUR UTILISATION DANS LE TRAITEMENT DU CANCER
  申请人：ASTRAZENECA AB

  公开号：WO2008132502A1

  公开（公告）日：2008-11-06

  [EN] The present invention relates to compounds of Formula (I) and to their pharmaceutical compositions, and to their methods of use. These compounds provide a treatment for myeloproliferative disorders and cancer.
  [FR] La présente invention porte sur des composés de Formule (I) et sur leurs compositions pharmaceutiques, ainsi que sur leurs procédés d'utilisation. Ces composés fournissent un traitement pour des troubles myéloprolifératifs et le cancer.
• Discovery of novel Jak2–Stat pathway inhibitors with extended residence time on target
  作者：Huiping Guan、Michelle L. Lamb、Bo Peng、Shan Huang、Nancy DeGrace、Jon Read、Syeed Hussain、Jiaquan Wu、Caroline Rivard、Marat Alimzhanov、Geraldine Bebernitz、Kirsten Bell、Minwei Ye、Michael Zinda、Stephanos Ioannidis

  DOI：10.1016/j.bmcl.2013.02.111

  日期：2013.5

  The discovery of the activating mutation V617F in the JH2 domain of Jak2 and the modulation of oncogenic Stat3 by Jak2 inhibitors have spurred a great interest in the inhibition of the Jak2/Stat pathway in oncology. In this Letter, we communicate the discovery of novel inhibitors of the Jak2/Stat5 axis, the N-(1H-pyrazol-3-yl)pyrimidin-2-amino derivatives. The rationale, synthesis and biological evaluation of these derivatives are reported. Two lead analogs from this series, 6 and 9, displayed prolonged residence time on Jak2, at enzymatic level. Although 6 and 9 exhibited moderate selectivity in a selected kinase panel, we chose to test these inhibitors in vivo as a consequence to their long residence time. However, extended inhibition of Jak2 due to the long residence time, in the form of inhibiting phosphorylation of downstream Stat5, was not recapitulated in an in vivo setting. (c) 2013 Elsevier Ltd. All rights reserved.