(2S)-1-((4-[3-(6-amino-5-methoxypyridin-3-yl)-1-isopropyl-1H-pyrazol-4-yl]pyrimidin-2-yl)amino)propan-2-ol | 1111637-21-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: (2S)-1-((4-[3-(6-amino-5-methoxypyridin-3-yl)-1-isopropyl-1H-pyrazol-4-yl]pyrimidin-2-yl)amino)propan-2-ol
• 英文别名: (2S)-1-[[4-[3-(6-amino-5-methoxypyridin-3-yl)-1-propan-2-ylpyrazol-4-yl]pyrimidin-2-yl]amino]propan-2-ol
• CAS: 1111637-21-8
• 化学式: C₁₉H₂₅N₇O₂
• 分子量: 383.453
• InChiKey: OKBGAVWELCPKEG-LBPRGKRZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  28
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  124
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (2S)-1-((4-[3-(6-amino-5-methoxypyridin-3-yl)-1-isopropyl-1H-pyrazol-4-yl]pyrimidin-2-yl)amino)propan-2-ol 在 戴斯-马丁氧化剂 、 三溴化硼 作用下， 生成
  参考文献：
  名称：

  Structural modifications of a 3-methoxy-2-aminopyridine compound to reduce potential for mutagenicity and time-dependent drug–drug interaction

  摘要：

  (S)-1-((4-(3-(6-Amino-5-methoxypyridin-3-yl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)propan-2-ol, 1, was recently identified as a potent inhibitor of the oncogenic kinase bRAF. Compounds containing 3-methoxy-2-aminopyridine, as in 1, comprised a promising lead series because of their high ligand efficiency and excellent ADME profile. However, following metabolic oxidation, compounds in this series also demonstrated two significant safety risks: mutagenic potential and time-dependent drug-drug interaction (TDI). Metabolite identification studies revealed formation of a reactive metabolite. We hypothesized that minimizing or blocking the formation of such a metabolite would mitigate the safety liabilities. Our investigation demonstrated that structural modifications which either reduced the electron density of the 3-methoxy-2-aminopyridine ring or blocked the reactive site following metabolic oxidation were successful in reducing TDI and AMES mutagenicity. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2012.10.011

文献信息

• PYRAZOLE COMPOUNDS
  申请人：Cui Jingrong Jean

  公开号：US20090221608A1

  公开（公告）日：2009-09-03

  The present invention is directed to compounds of Formula (I), and to pharmaceutically acceptable salts thereof, their synthesis, and their use as Raf inhibitors.

  本发明涉及式（I）化合物及其药学上可接受的盐，其合成以及作为Raf抑制剂的用途。
• PYRAZOLE COMPOUNDS AND THEIR USE AS RAF INHIBITORS
  申请人：Pfizer Inc.

  公开号：EP2183243A2

  公开（公告）日：2010-05-12
• ピラゾール化合物およびＲａｆ阻害剤としてのその使用
  申请人：ファイザー・インク

  公开号：JP4792126B2

  公开（公告）日：2010-11-18
• US7772246B2
  申请人：——

  公开号：US7772246B2

  公开（公告）日：2010-08-10
• [EN] PYRAZOLE COMPOUNDS<br/>[FR] COMPOSÉS PYRAZOLES
  申请人：PFIZER

  公开号：WO2009016460A2

  公开（公告）日：2009-02-05

  The present invention is directed to compounds of Formula (I) and to pharmaceutically acceptable salts thereof, their synthesis, and their use as Raf inhibitors.