t-butyl 5-(bromomethyl)pyrazine-2-carboxylate | 1151655-03-6

• 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: t-butyl 5-(bromomethyl)pyrazine-2-carboxylate
• 英文别名: Tert-butyl 5-(bromomethyl)pyrazine-2-carboxylate
• CAS: 1151655-03-6
• 化学式: C₁₀H₁₃BrN₂O₂
• 分子量: 273.129
• InChiKey: MBAOYMKCYGUTFC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  15
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  52.1
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  t-butyl 5-(bromomethyl)pyrazine-2-carboxylate 在 三乙胺 、 三氟乙酸 作用下， 以 氯仿 、 乙腈 为溶剂， 反应 9.0h， 生成 5-(acetoxymethyl)pyrazine-2-carboxylic acid
  参考文献：
  名称：

  Orally bioavailable HCV NS5A inhibitors of unsymmetrical structural class

  摘要：

  A novel unsymmetrical structural class of orally bioavailable hepatitis C virus (HCV) nonstructural 5A protein (NS5A) inhibitors has been generated by improving both the solubility and membrane permeability of the lead compound found in our previous work. The representative compound 14, with a 5-hydroxymethylpyrazine group and a 3-t-butylpropargyl group on each side of the molecule, exhibited the best oral bioavailability in this study, inhibiting not only the HCV genotype 1a, 1b, 2a, and 3a replicons with EC50 values in the picomolar range, but also inhibited 1a Q30 mutants induced by launched symmetrical inhibitors with EC50 values in the low nanomolar range.

  DOI：

  10.1016/j.bmcl.2020.127361
• 作为产物：
  描述：

  t-butyl 5-methylpyrazine-2-carboxylate 在 N-溴代丁二酰亚胺(NBS) 、 过氧化苯甲酰 、 碳酸氢钠 作用下， 以 1,2-二氯乙烷 、 DCM 、 DCE 、 水 为溶剂， 反应 24.0h， 以64%的产率得到t-butyl 5-(bromomethyl)pyrazine-2-carboxylate
  参考文献：
  名称：

  [EN] 3,4,6,7-TETRAHYDRO-1H-PYRROLO[3,4-D]PYRIMIDINE-2,5-DIONES AND THEIR THERAPEUTIC USE
  [FR] 3,4,6,7-TÉTRAHYDRO-1H-PYRROLO[3,4-D]PYRIMIDINE-2,5-DIONES ET LEUR UTILISATION THÉRAPEUTIQUE

  摘要：

  含有两个取代的3,4,6,7-四氢-1H-吡咯[3,4-d]嘧啶-2,5-二酮分子的化合物，通过一个含有甜菜碱或带电离子基团的连接基团共价连接在一起，是人类中性粒细胞弹性蛋白酶活性的抑制剂，用于治疗呼吸道疾病，尤其是通过吸入途径。

  公开号：

  WO2009060206A1

文献信息

• Novel Inhibitors of the MDM2-p53 Interaction Featuring Hydrogen Bond Acceptors as Carboxylic Acid Isosteres
  作者：Ana Z. Gonzalez、Zhihong Li、Hilary P. Beck、Jude Canon、Ada Chen、David Chow、Jason Duquette、John Eksterowicz、Brian M. Fox、Jiasheng Fu、Xin Huang、Jonathan Houze、Lixia Jin、Yihong Li、Yun Ling、Mei-Chu Lo、Alexander M. Long、Lawrence R. McGee、Joel McIntosh、Jonathan D. Oliner、Tao Osgood、Yosup Rew、Anne Y. Saiki、Paul Shaffer、Sarah Wortman、Peter Yakowec、Xuelei Yan、Qiuping Ye、Dongyin Yu、Xiaoning Zhao、Jing Zhou、Steven H. Olson、Daqing Sun、Julio C. Medina

  DOI：10.1021/jm401911v

  日期：2014.4.10

  We previously reported the discovery of potent and selective morpholinone and piperidinone inhibitors of the MDM2-p53 interaction. These inhibitors have in common a carboxylic acid moiety that engages in an electrostatic interaction with MDM2-His96. Our continued search for potent and diverse inhibitors led to the discovery of novel replacements for these acids uncovering new interactions with the MDM2 protein. In particular, using pyridine or thiazole as isosteres of the carboxylic acid moiety resulted in very potent analogues. From these, AM-6761 (4) emerged as a potent inhibitor with remarkable biochemical (HTRF IC50 = 0.1 nM) and cellular potency (SJSA-1 EdU IC50 = 16 nM), as well as favorable pharmacokinetic properties. Compound 4 also shows excellent antitumor activity in the SJSA-1 osteosarcoma xenograft model with an ED50 of 11 mg/kg. Optimization efforts toward the discovery of these inhibitors as well as the new interactions observed with the MDM2 protein are described herein.