5-(6-Aminopyridin-3-yl)-1,3-thiazol-2-amine | 1444302-81-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 5-(6-Aminopyridin-3-yl)-1,3-thiazol-2-amine
• 英文别名: 5-(6-aminopyridin-3-yl)-1,3-thiazol-2-amine
• CAS: 1444302-81-1
• 化学式: C₈H₈N₄S
• 分子量: 192.244
• InChiKey: RVOACERNJMERPH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  13
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  106
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  5-(6-Aminopyridin-3-yl)-1,3-thiazol-2-amine 在 sodium hydride 作用下， 以 四氢呋喃 、 吡啶 为溶剂， 生成
  参考文献：
  名称：

  Discovery of Conformational Control Inhibitors Switching off the Activated c-KIT and Targeting a Broad Range of Clinically Relevant c-KIT Mutants

  摘要：

  Drug resistance due to acquired mutations that constitutively activate c-KIT is a significant challenge in the treatment of patients with gastrointestinal stromal tumors (GISTs). Herein, we identified 1-(5-ethyl-isoxazol-3-yl)-3-(4-{2-[6-(4-ethylpiperazin-1-yl)pyrimidin-4-ylamino]-thiazol-5-yl}phenyl)urea (10a) as a potent inhibitor against unactivated and activated c-KIT. The binding of 10a induced rearrangements of the DFG motif, alpha C-helix, juxtamembrane domain, and the activation loop to switch the activated c-KIT back to its structurally inactive state. To the best of our knowledge, it is the first structural evidence demonstrating how a compound can inhibit the activated c-KIT by switching back to its inactive state through a sequence of conformational changes. Moreover, 10a can effectively inhibit various c-KIT mutants and the proliferation of several GIST cell lines. The distinct binding features and superior inhibitory potency of 10a, together with its excellent efficacy in the xenograft model, establish 10a as worthy of further clinical evaluation in the advanced GISTs.

  DOI：

  10.1021/acs.jmedchem.8b01845
• 作为产物：
  描述：

  tert-butyl N-[5-(6-aminopyridin-3-yl)-1,3-thiazol-2-yl]carbamate 在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 1.5h， 以100%的产率得到5-(6-Aminopyridin-3-yl)-1,3-thiazol-2-amine
  参考文献：
  名称：

  Design, synthesis and biological evaluation of novel aminothiazoles as antiviral compounds acting against human rhinovirus

  摘要：

  We describe here the design, synthesis and biological evaluation of antiviral compounds acting against human rhinovirus (HRV). A series of aminothiazoles demonstrated pan-activity against the HRV genotypes screened and productive structure-activity relationships. A comprehensive investigational library was designed and performed allowing the identification of potent compounds with lower molecular weight and improved ADME profile. 31d-1, 31d-2, 31f showed good exposures in CD-1 mice. The mechanism of action was discovered to be a host target: the lipid kinase phosphatidylinositol 4-kinase III beta (PI4KIII beta). The identification of the pan-HRV active compound 31f combined with a structurally distinct literature compound T-00127-HEV1 allowed the assessment of target related tolerability of inhibiting this kinase for a short period of time in order to prevent HRV replication. (c) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.04.077

文献信息

• Design, synthesis and biological evaluation of novel aminothiazoles as antiviral compounds acting against human rhinovirus
  作者：Anne Décor、Chantal Grand-Maître、Oliver Hucke、Jeff O’Meara、Cyrille Kuhn、Léa Constantineau -Forget、Christian Brochu、Eric Malenfant、Mégan Bertrand-Laperle、Josée Bordeleau、Elise Ghiro、Marc Pesant、Gulrez Fazal、Vida Gorys、Michael Little、Colette Boucher、Sylvain Bordeleau、Pascal Turcotte、Tim Guo、Michel Garneau、Catherine Spickler、Annick Gauthier

  DOI：10.1016/j.bmcl.2013.04.077

  日期：2013.7

  We describe here the design, synthesis and biological evaluation of antiviral compounds acting against human rhinovirus (HRV). A series of aminothiazoles demonstrated pan-activity against the HRV genotypes screened and productive structure-activity relationships. A comprehensive investigational library was designed and performed allowing the identification of potent compounds with lower molecular weight and improved ADME profile. 31d-1, 31d-2, 31f showed good exposures in CD-1 mice. The mechanism of action was discovered to be a host target: the lipid kinase phosphatidylinositol 4-kinase III beta (PI4KIII beta). The identification of the pan-HRV active compound 31f combined with a structurally distinct literature compound T-00127-HEV1 allowed the assessment of target related tolerability of inhibiting this kinase for a short period of time in order to prevent HRV replication. (c) 2013 Elsevier Ltd. All rights reserved.
• Discovery of Conformational Control Inhibitors Switching off the Activated c-KIT and Targeting a Broad Range of Clinically Relevant c-KIT Mutants
  作者：Tsung-Sheng Wu、Wen-Hsing Lin、Hui-Jen Tsai、Ching-Cheng Hsueh、Tsu Hsu、Pei-Chen Wang、Hui-You Lin、Yi-Hui Peng、Cheng-Tai Lu、Lung-Chun Lee、Chih-Hsiang Tu、Fang-Chun Kung、Hui-Yi Shiao、Teng-Kuang Yeh、Jen-Shin Song、Jia-Yu Chang、Yu-Chieh Su、Li-Tzong Chen、Chiung-Tong Chen、Weir-Torn Jiaang、Su-Ying Wu

  DOI：10.1021/acs.jmedchem.8b01845

  日期：2019.4.25

  Drug resistance due to acquired mutations that constitutively activate c-KIT is a significant challenge in the treatment of patients with gastrointestinal stromal tumors (GISTs). Herein, we identified 1-(5-ethyl-isoxazol-3-yl)-3-(4-2-[6-(4-ethylpiperazin-1-yl)pyrimidin-4-ylamino]-thiazol-5-yl}phenyl)urea (10a) as a potent inhibitor against unactivated and activated c-KIT. The binding of 10a induced rearrangements of the DFG motif, alpha C-helix, juxtamembrane domain, and the activation loop to switch the activated c-KIT back to its structurally inactive state. To the best of our knowledge, it is the first structural evidence demonstrating how a compound can inhibit the activated c-KIT by switching back to its inactive state through a sequence of conformational changes. Moreover, 10a can effectively inhibit various c-KIT mutants and the proliferation of several GIST cell lines. The distinct binding features and superior inhibitory potency of 10a, together with its excellent efficacy in the xenograft model, establish 10a as worthy of further clinical evaluation in the advanced GISTs.