9-(9H-purin-6-yl)-1,9-diazaspiro[5.5]undecane-3-carboxylic acid | 1452809-08-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并嘧啶类
• 英文名称: 9-(9H-purin-6-yl)-1,9-diazaspiro[5.5]undecane-3-carboxylic acid
• 英文别名: 9-(7H-purin-6-yl)-1,9-diazaspiro[5.5]undecane-3-carboxylic acid
• CAS: 1452809-08-3
• 化学式: C₁₅H₂₀N₆O₂
• 分子量: 316.363
• InChiKey: DKDRBYGOIPHLMM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.8
• 重原子数：
  23
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  107
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  methyl 1,9-dibenzyl-1,9-diazaspiro[5.5]undec-3-ene-3-carboxylate 在 盐酸 、 palladium 10% on activated carbon 、 氢气 、 三乙胺 、 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 水 、 正丁醇 为溶剂， 20.0~100.0 ℃ 、101.33 kPa 条件下， 反应 36.0h， 生成 9-(9H-purin-6-yl)-1,9-diazaspiro[5.5]undecane-3-carboxylic acid
  参考文献：
  名称：

  Synthesis and evaluation of heteroaryl substituted diazaspirocycles as scaffolds to probe the ATP-binding site of protein kinases

  摘要：

  With the success of protein. kinase inhibitors as drugs to target cancer, there is a continued need for new kinase inhibitor scaffolds. We have investigated the synthesis and kinase inhibition of new heteroaryl-substituted diazaspirocyclic compounds that mimic ATP. Versatile syntheses of substituted diazaspirocycles through ring-closing metathesis were demonstrated. Diazaspirocycles directly linked to heteroaromatic hinge binder groups provided ligand efficient inhibitors of multiple kinases, suitable as starting points for further optimization. The binding modes of representative diazaspirocyclic motifs were confirmed by protein crystallography. Selectivity profiles were influenced by the hinge binder group and the interactions of basic nitrogen atoms in the scaffold with acidic side-chains of residues in the ATP pocket. The introduction of more complex substitution to the diazaspirocycles increased potency and varied the selectivity profiles of these initial hits through engagement of the P-loop and changes to the spirocycle conformation, demonstrating the potential of these core scaffolds for future application to kinase inhibitor discovery. (C) 2013 The Authors. Published by Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2013.07.021

文献信息

• Synthesis and evaluation of heteroaryl substituted diazaspirocycles as scaffolds to probe the ATP-binding site of protein kinases
  作者：Charlotte E. Allen、Chiau L. Chow、John J. Caldwell、Isaac M. Westwood、Rob L. M. van Montfort、Ian Collins

  DOI：10.1016/j.bmc.2013.07.021

  日期：2013.9

  With the success of protein. kinase inhibitors as drugs to target cancer, there is a continued need for new kinase inhibitor scaffolds. We have investigated the synthesis and kinase inhibition of new heteroaryl-substituted diazaspirocyclic compounds that mimic ATP. Versatile syntheses of substituted diazaspirocycles through ring-closing metathesis were demonstrated. Diazaspirocycles directly linked to heteroaromatic hinge binder groups provided ligand efficient inhibitors of multiple kinases, suitable as starting points for further optimization. The binding modes of representative diazaspirocyclic motifs were confirmed by protein crystallography. Selectivity profiles were influenced by the hinge binder group and the interactions of basic nitrogen atoms in the scaffold with acidic side-chains of residues in the ATP pocket. The introduction of more complex substitution to the diazaspirocycles increased potency and varied the selectivity profiles of these initial hits through engagement of the P-loop and changes to the spirocycle conformation, demonstrating the potential of these core scaffolds for future application to kinase inhibitor discovery. (C) 2013 The Authors. Published by Elsevier Ltd. All rights reserved.