N-[2-(3,5-dimethylpyrazol-1-yl)-6-((R)-2-methoxymethyl-5-methylpyrrolidin-1-yl)pyrimidin-4-yl]acetamide | 1101846-39-2

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: N-[2-(3,5-dimethylpyrazol-1-yl)-6-((R)-2-methoxymethyl-5-methylpyrrolidin-1-yl)pyrimidin-4-yl]acetamide
• 英文别名: N-[2-(3,5-dimethylpyrazol-1-yl)-6-[(2R)-2-(methoxymethyl)-5-methylpyrrolidin-1-yl]pyrimidin-4-yl]acetamide
• CAS: 1101846-39-2
• 化学式: C₁₈H₂₆N₆O₂
• 分子量: 358.443
• InChiKey: VFZQDRIKYWPIDY-WPZCJLIBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  26
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  85.2
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  N-[6-chloro-2-(3,5-dimethylpyrazol-1-yl)pyrimidin-4-yl]acetamide 、 (2R)-2-(methoxymethyl)-5-methylpyrrolidine 以 1,4-二氧六环 为溶剂， 反应 2.0h， 生成 N-[2-(3,5-dimethylpyrazol-1-yl)-6-((R)-2-methoxymethyl-5-methylpyrrolidin-1-yl)pyrimidin-4-yl]acetamide
  参考文献：
  名称：

  N-[6-Amino-2-(heteroaryl)pyrimidin-4-yl]acetamides as A_2A Receptor Antagonists with Improved Drug Like Properties and in Vivo Efficacy

  摘要：

  In the present article, we report on a strategy to improve the physical properties of a series of small molecule human adenosine 2A (hA(2A)) antagonists. One of the aromatic rings typical of this series of antagonists is replaced with a series of aliphatic groups, with the aim of disrupting crystal packing of the molecule to lower the melting point and in turn to improve the solubility. Herein, we describe the SAR of a new series of water-soluble 2,4,6-trisubstituted pyrimidines where R-1 is an aromatic heterocycle, R-2 is a short-chain alkyl amide, and the typical R-3 aromatic heterocyclic substituent is replaced with an aliphatic amino substituent. This approach significantly enhanced aqueous solubility and lowered the log P of the system to provide molecules without significant hERG or CYP liabilities and robust in vivo efficacy.

  DOI：

  10.1021/jm800908d

文献信息

• <i>N</i>-[6-Amino-2-(heteroaryl)pyrimidin-4-yl]acetamides as A_2A Receptor Antagonists with Improved Drug Like Properties and in Vivo Efficacy
  作者：Marion C. Lanier、Manisha Moorjani、Zhiyong Luo、Yongsheng Chen、Emily Lin、John E. Tellew、Xiaohu Zhang、John P. Williams、Raymond S. Gross、Sandra M. Lechner、Stacy Markison、Tanya Joswig、William Kargo、Jaime Piercey、Mark Santos、Siobhan Malany、Marilyn Zhao、Robert Petroski、María I. Crespo、José-Luis Díaz、John Saunders、Jenny Wen、Zhihong O’Brien、Kayvon Jalali、Ajay Madan、Deborah H. Slee

  DOI：10.1021/jm800908d

  日期：2009.2.12

  In the present article, we report on a strategy to improve the physical properties of a series of small molecule human adenosine 2A (hA(2A)) antagonists. One of the aromatic rings typical of this series of antagonists is replaced with a series of aliphatic groups, with the aim of disrupting crystal packing of the molecule to lower the melting point and in turn to improve the solubility. Herein, we describe the SAR of a new series of water-soluble 2,4,6-trisubstituted pyrimidines where R-1 is an aromatic heterocycle, R-2 is a short-chain alkyl amide, and the typical R-3 aromatic heterocyclic substituent is replaced with an aliphatic amino substituent. This approach significantly enhanced aqueous solubility and lowered the log P of the system to provide molecules without significant hERG or CYP liabilities and robust in vivo efficacy.