tert-butyl 6-(2-chloro-4-(oxazol-5-yl)phenylamino)-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylate | 1400284-88-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: tert-butyl 6-(2-chloro-4-(oxazol-5-yl)phenylamino)-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylate
• 英文别名: Tert-butyl 6-[2-chloro-4-(1,3-oxazol-5-yl)anilino]-2-(1-methylpyrazol-4-yl)pyrrolo[3,2-c]pyridine-1-carboxylate；tert-butyl 6-[2-chloro-4-(1,3-oxazol-5-yl)anilino]-2-(1-methylpyrazol-4-yl)pyrrolo[3,2-c]pyridine-1-carboxylate
• CAS: 1400284-88-9
• 化学式: C₂₅H₂₃ClN₆O₃
• 分子量: 490.949
• InChiKey: OYORONOSHXMKGA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  35
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  100
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  6-bromo-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine 在 4-二甲氨基吡啶 、 tris-(dibenzylideneacetone)dipalladium(0) 、 caesium carbonate 、 三乙胺 、 4,5-双二苯基膦-9,9-二甲基氧杂蒽 作用下， 以 N,N-二甲基乙酰胺 、 乙酸乙酯 为溶剂， 反应 1.92h， 生成 tert-butyl 6-(2-chloro-4-(oxazol-5-yl)phenylamino)-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylate
  参考文献：
  名称：

  Structure-Based Design of Orally Bioavailable 1H-Pyrrolo[3,2-c]pyridine Inhibitors of Mitotic Kinase Monopolar Spindle 1 (MPS1)

  摘要：

  The protein kinase MPS1 is a crucial component of the spindle assembly checkpoint signal and is aberrantly over-expressed in many human cancers. MPS1 is one of the top 25 genes overexpressed in tumors with chromosomal instability and aneuploidy. PTEN-deficient breast tumor cells are particularly dependent upon MPS1 for their survival, making it a target of significant interest in oncology. We report the discovery and optimization of potent and selective MPS1 inhibitors based on the 1H-pyrrolo[3,2-c]pyridine scaffold, guided by structure-based design and cellular characterization of MPS1 inhibition, leading to 65 (CCT251455). This potent and selective chemical tool stabilizes an inactive conformation of MPS1 with the activation loop ordered in a manner incompatible with ATP and substrate-peptide binding; it displays a favorable oral pharmacokinetic profile, shows dose-dependent inhibition of MPS1 in an HCT116 human tumor xenograft model, and is an attractive tool compound to elucidate further the therapeutic potential of MPS1 inhibition.

  DOI：

  10.1021/jm401395s

文献信息

• PYRROLOPYRIDINEAMINO DERIVATIVES AS MPS1 INHIBITORS
  申请人：Cancer Research Technology Ltd

  公开号：EP2686318B1

  公开（公告）日：2016-03-09
• US9371319B2
  申请人：——

  公开号：US9371319B2

  公开（公告）日：2016-06-21
• Structure-Based Design of Orally Bioavailable 1<i>H</i>-Pyrrolo[3,2-<i>c</i>]pyridine Inhibitors of Mitotic Kinase Monopolar Spindle 1 (MPS1)
  作者：Sébastien Naud、Isaac M. Westwood、Amir Faisal、Peter Sheldrake、Vassilios Bavetsias、Butrus Atrash、Kwai-Ming J. Cheung、Manjuan Liu、Angela Hayes、Jessica Schmitt、Amy Wood、Vanessa Choi、Kathy Boxall、Grace Mak、Mark Gurden、Melanie Valenti、Alexis de Haven Brandon、Alan Henley、Ross Baker、Craig McAndrew、Berry Matijssen、Rosemary Burke、Swen Hoelder、Suzanne A. Eccles、Florence I. Raynaud、Spiros Linardopoulos、Rob L. M. van Montfort、Julian Blagg

  DOI：10.1021/jm401395s

  日期：2013.12.27

  The protein kinase MPS1 is a crucial component of the spindle assembly checkpoint signal and is aberrantly over-expressed in many human cancers. MPS1 is one of the top 25 genes overexpressed in tumors with chromosomal instability and aneuploidy. PTEN-deficient breast tumor cells are particularly dependent upon MPS1 for their survival, making it a target of significant interest in oncology. We report the discovery and optimization of potent and selective MPS1 inhibitors based on the 1H-pyrrolo[3,2-c]pyridine scaffold, guided by structure-based design and cellular characterization of MPS1 inhibition, leading to 65 (CCT251455). This potent and selective chemical tool stabilizes an inactive conformation of MPS1 with the activation loop ordered in a manner incompatible with ATP and substrate-peptide binding; it displays a favorable oral pharmacokinetic profile, shows dose-dependent inhibition of MPS1 in an HCT116 human tumor xenograft model, and is an attractive tool compound to elucidate further the therapeutic potential of MPS1 inhibition.