3-amino-5-(2-(methylamino)pyrimidin-4-yl)pyridin-2(1H)-one | 1276634-71-9

• 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: 3-amino-5-(2-(methylamino)pyrimidin-4-yl)pyridin-2(1H)-one
• 英文别名: 3-amino-5-(2-(methylamino)pyrimidin-4-yl)-(1H)-pyridin-2-one；3-amino-5-[2-(methylamino)pyrimidin-4-yl]-1H-pyridin-2-one
• CAS: 1276634-71-9
• 化学式: C₁₀H₁₁N₅O
• 分子量: 217.23
• InChiKey: KHPWXBBPXQOMHZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.5
• 重原子数：
  16
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  92.9
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  4-哌嗪苯甲酸 、 3-amino-5-(2-(methylamino)pyrimidin-4-yl)pyridin-2(1H)-one 在 三氯氧磷 作用下， 以 乙腈 为溶剂， 反应 6.0h， 以55%的产率得到3-(4-(piperidin-1-yl)benzoylamino)-5-(2-(methylamino)pyrimidin-4-yl)-(1H)-pyridin-2-one
  参考文献：
  名称：

  Discovery and Structure−Activity Relationship of 3-Aminopyrid-2-ones as Potent and Selective Interleukin-2 Inducible T-Cell Kinase (Itk) Inhibitors

  摘要：

  Interleukin-2 inducible T-cell kinase (Itk) plays a role in T-cell functions, and its inhibition potentially represents an attractive intervention point to treat autoimmune and allergic diseases. Herein we describe the discovery of a series of potent and selective novel inhibitors of Itk. These inhibitors were identified by structure-based design, starting from a fragment generated de novo, the 3-aminopyrid-2-one motif. Functionalization of the 3-amino group enabled rapid enhancement of the inhibitory activity against Itk, while introduction of a substituted heteroaromatic ring in position 5 of the pyridone fragment was key to achieving optimal selectivity over related kinases. A careful analysis of the hydration patterns in the kinase active. site was necessary to fully explain the observed selectivity profile. The best molecule prepared in this optimization campaign, 7v, inhibits Itk with a K-i of 7 nM and has a good selectivity profile across kinases.

  DOI：

  10.1021/jm101499u
• 作为产物：
  描述：

  3-氨基-5-溴-2-甲氧基吡啶 在 四(三苯基膦)钯 、 三甲基氯硅烷 、 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 potassium acetate 、 sodium carbonate 、 sodium iodide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙醇 、 水 、 甲苯 、 乙腈 为溶剂， 反应 44.0h， 生成 3-amino-5-(2-(methylamino)pyrimidin-4-yl)pyridin-2(1H)-one
  参考文献：
  名称：

  Synthesis and profiling of a 3-aminopyridin-2-one-based kinase targeted fragment library: Identification of 3-amino-5-(pyridin-4-yl)pyridin-2(1H)-one scaffold for monopolar spindle 1 (MPS1) and Aurora kinases inhibition

  摘要：

  Screening a 3-aminopyridin-2-one based fragment library against a 26-kinase panel representative of the human kinome identified 3-amino 5 (1-methyl-1H-pyrazol-4-yl)pyridin-2(1H)-one (2) and 3-amino-5(pyridin-4-yl)pyridin-2(1H)-one (3) as ligand efficient inhibitors of the mitotic kinase Monopolar Spindle 1 (MPS1) and the Aurora kinase family. These kinases are well recognised as attractive targets for therapeutic intervention for treating cancer. Elucidation of the binding mode of these fragments and their analogues has been carried out by X-ray crystallography. Structural studies have identified key interactions with a conserved lysine residue and have highlighted potential regions of MPS1 which could be targeted to improve activity and selectivity. (C) 2018 The Authors. Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmc.2018.04.033

文献信息

• US4514400A
  申请人：——

  公开号：US4514400A

  公开（公告）日：1985-04-30
• Synthesis and profiling of a 3-aminopyridin-2-one-based kinase targeted fragment library: Identification of 3-amino-5-(pyridin-4-yl)pyridin-2(1H)-one scaffold for monopolar spindle 1 (MPS1) and Aurora kinases inhibition
  作者：Daren Fearon、Isaac M. Westwood、Rob L.M. van Montfort、Richard Bayliss、Keith Jones、Vassilios Bavetsias

  DOI：10.1016/j.bmc.2018.04.033

  日期：2018.7

  Screening a 3-aminopyridin-2-one based fragment library against a 26-kinase panel representative of the human kinome identified 3-amino 5 (1-methyl-1H-pyrazol-4-yl)pyridin-2(1H)-one (2) and 3-amino-5(pyridin-4-yl)pyridin-2(1H)-one (3) as ligand efficient inhibitors of the mitotic kinase Monopolar Spindle 1 (MPS1) and the Aurora kinase family. These kinases are well recognised as attractive targets for therapeutic intervention for treating cancer. Elucidation of the binding mode of these fragments and their analogues has been carried out by X-ray crystallography. Structural studies have identified key interactions with a conserved lysine residue and have highlighted potential regions of MPS1 which could be targeted to improve activity and selectivity. (C) 2018 The Authors. Published by Elsevier Ltd.
• Discovery and Structure−Activity Relationship of 3-Aminopyrid-2-ones as Potent and Selective Interleukin-2 Inducible T-Cell Kinase (Itk) Inhibitors
  作者：Jean-Damien Charrier、Andrew Miller、David P. Kay、Guy Brenchley、Heather C. Twin、Philip N. Collier、Sharn Ramaya、Shazia B. Keily、Steven J. Durrant、Ronald M. A. Knegtel、Adam J. Tanner、Kieron Brown、Adam P. Curnock、Juan-Miguel Jimenez

  DOI：10.1021/jm101499u

  日期：2011.4.14

  Interleukin-2 inducible T-cell kinase (Itk) plays a role in T-cell functions, and its inhibition potentially represents an attractive intervention point to treat autoimmune and allergic diseases. Herein we describe the discovery of a series of potent and selective novel inhibitors of Itk. These inhibitors were identified by structure-based design, starting from a fragment generated de novo, the 3-aminopyrid-2-one motif. Functionalization of the 3-amino group enabled rapid enhancement of the inhibitory activity against Itk, while introduction of a substituted heteroaromatic ring in position 5 of the pyridone fragment was key to achieving optimal selectivity over related kinases. A careful analysis of the hydration patterns in the kinase active. site was necessary to fully explain the observed selectivity profile. The best molecule prepared in this optimization campaign, 7v, inhibits Itk with a K-i of 7 nM and has a good selectivity profile across kinases.