(S)-7-(2-fluoropyridin-3-yl)-3-(tetrahydro-2H-pyran-4-yl)-5'H-spiro[chromeno[2,3-b]pyridin-5,4'-oxazol]-2'-amine | 1215870-26-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡喃
• 英文名称: (S)-7-(2-fluoropyridin-3-yl)-3-(tetrahydro-2H-pyran-4-yl)-5'H-spiro[chromeno[2,3-b]pyridin-5,4'-oxazol]-2'-amine
• 英文别名: (5S)-7-(2-fluoro-3-pyridinyl)-3-(tetrahydro-2H-pyran-4-yl)-spiro[chromeno[2,3-b]pyridine-5,4'-[1,3]oxazol]-2'-amine；(4S)-7'-(2-fluoropyridin-3-yl)-3'-(oxan-4-yl)spiro[5H-1,3-oxazole-4,5'-chromeno[2,3-b]pyridine]-2-amine
• CAS: 1215870-26-0
• 化学式: C₂₄H₂₁FN₄O₃
• 分子量: 432.454
• InChiKey: YAIILFXOQLIACI-DEOSSOPVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  32
• 可旋转键数：
  2
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  91.8
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  3,6-二氢-2H-吡喃-4-硼酸频哪醇酯 在 四(三苯基膦)钯 、 palladium 10% on activated carbon 、 氢气 、 potassium carbonate 、 三乙胺 作用下， 以 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 80.0 ℃ 、101.33 kPa 条件下， 反应 100.83h， 生成 (S)-7-(2-fluoropyridin-3-yl)-3-(tetrahydro-2H-pyran-4-yl)-5'H-spiro[chromeno[2,3-b]pyridin-5,4'-oxazol]-2'-amine
  参考文献：
  名称：

  Inhibitors of β-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1): Identification of (S)-7-(2-Fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (AMG-8718)

  摘要：

  We have previously shown that the aminooxazoline xanthene scaffold can generate potent and orally efficacious BACE1 inhibitors although certain of these compounds exhibited potential hERG liabilities. In this article, we describe 4-aza substitution on the xanthene core as a means to increase BACE1 potency while reducing hERG binding affinity. Further optimization of the P3 and P2' side chains resulted in the identification of 42 (AMG-8718), a compound with a balanced profile of BACE1 potency, hERG binding affinity, and Pgp recognition. This compound produced robust and sustained reductions of CSF and brain A beta levels in a rat pharmacodynamic model and exhibited significantly reduced potential for QTc elongation in a cardiovascular safety model.

  DOI：

  10.1021/jm5012676

文献信息

• SPIRO-TETRACYCLIC RING COMPOUNDS AS BETASECRETASE MODULATORS AND METHODS OF USE
  申请人：Amgen Inc.

  公开号：EP2328903B1

  公开（公告）日：2014-03-05