5-(3-morpholinophenyl)-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine | 1272354-54-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 恶嗪烷类
• 英文名称: 5-(3-morpholinophenyl)-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine
• 英文别名: 5-(3-morpholin-4-ylphenyl)-N-(pyridin-2-ylmethyl)-2-pyrimidin-5-ylquinazolin-4-amine
• CAS: 1272354-54-7
• 化学式: C₂₈H₂₅N₇O
• 分子量: 475.553
• InChiKey: PWNLJJZHJJJKSC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  36
• 可旋转键数：
  6
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  89
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  3-吗啉苯硼酸 在 bis-triphenylphosphine-palladium(II) chloride 、 四(三苯基膦)钯 、 碳酸氢钠 、 sodium carbonate 、 N,N-二甲基苯胺 、 三乙胺 、 三氯氧磷 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙二醇二甲醚 、 水 为溶剂， 反应 71.0h， 生成 5-(3-morpholinophenyl)-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine
  参考文献：
  名称：

  Selective I_Kur Inhibitors for the Potential Treatment of Atrial Fibrillation: Optimization of the Phenyl Quinazoline Series Leading to Clinical Candidate 5-[5-Phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridine-3-sulfonamide

  摘要：

  We have recently disclosed 5-phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine 1 as a potent I-Kur current blocker with selectivity versus hERG, Na and Ca channels, and an acceptable preclinical PK profile. Upon further characterization in vivo, compound 1 demonstrated an unacceptable level of brain penetration. In an effort to reduce the level of brain penetration while maintaining the overall profile, SAR was developed at the C2' position for a series of close analogues by employing hydrogen bond donors. As a result, 5-[5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridine-3-sulfonamide (25) was identified as the lead compound in this series. Compound 25 showed robust effects in rabbit and canine pharmacodynamic models and an acceptable cross-species pharmacokinetic profile and was advanced as the clinical candidate. Further optimization of 25 to mitigate pH-dependent absorption resulted in identification of the corresponding phosphoramide prodrug (29) with an improved solubility and pharmacokinetic profile.

  DOI：

  10.1021/acs.jmedchem.6b01889

文献信息

• [EN] QUINAZOLINES AS POTASSIUM ION CHANNEL INHIBITORS<br/>[FR] QUINAZOLINES COMME INHIBITEURS DES CANAUX IONIQUES POTASSIQUES
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2011028741A1

  公开（公告）日：2011-03-10

  A compound of formula (I) wherein A, X, Y, Z, R1 and R24 are described herein. The compounds are useful as inhibitors of potassium channel function and in the treatment and prevention of arrhythmia, IKur-associated disorders, and other disorders mediated by ion channel function.

  其中A、X、Y、Z、R1和R24如所述的(I)式化合物。这些化合物作为钾通道功能的抑制剂以及用于治疗和预防心律不齐、IKur相关疾病和其他由离子通道功能介导的疾病是有用的。
• QUINAZOLINES AS POTASSIUM ION CHANNEL INHIBITORS
  申请人：Bristol-Myers Squibb Company

  公开号：US20140031345A1

  公开（公告）日：2014-01-30

  A compound of formula I wherein A, X, Y, Z, R 1 and R 24 are described herein. The compounds are useful as inhibitors of potassium channel function and in the treatment and prevention of arrhythmia, I Kur -associated disorders, and other disorders mediated by ion channel function.

  化合物I的化学式如下，其中A，X，Y，Z，R1和R24的描述在此处。这些化合物可用作钾通道功能的抑制剂，并用于治疗和预防心律失常，IKur相关疾病以及其他离子通道功能介导的疾病。
• Quinazolines as potassium ion channel inhibitors
  申请人：BRISTOL-MYERS SQUIBB COMPANY

  公开号：US10676460B2

  公开（公告）日：2020-06-09

  A compound of formula I wherein A, X, Y, Z, R1 and R24 are described herein. The compounds are useful as inhibitors of potassium channel function and in the treatment and prevention of arrhythmia, IKur-associated disorders, and other disorders mediated by ion channel function.

  式 I 的化合物 其中 A、X、Y、Z、R1 和 R24 如本文所述。这些化合物可作为钾离子通道功能的抑制剂，用于治疗和预防心律失常、IKur 相关性疾病和其他由离子通道功能介导的疾病。
• US8575184B2
  申请人：——

  公开号：US8575184B2

  公开（公告）日：2013-11-05
• US9458114B2
  申请人：——

  公开号：US9458114B2

  公开（公告）日：2016-10-04