4-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-2-((6-methoxy-3-pyridinyl)amino)imidazo[1,2-a]pyridin-6-yl)-N,N-dimethyl-1-piperazinecarboxamide | 1256036-41-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: 4-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-2-((6-methoxy-3-pyridinyl)amino)imidazo[1,2-a]pyridin-6-yl)-N,N-dimethyl-1-piperazinecarboxamide
• 英文别名: 4-[3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-2-[(6-methoxypyridin-3-yl)amino]imidazo[1,2-a]pyridin-6-yl]-N,N-dimethylpiperazine-1-carboxamide
• CAS: 1256036-41-5
• 化学式: C₂₄H₂₉N₁₁O₂
• 分子量: 503.567
• InChiKey: WXJHQJVEUDYPFR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  37
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  143
• 氢给体数：
  2
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  6-溴-2-氯咪唑并[1,2-a]吡啶 在 tris-(dibenzylideneacetone)dipalladium(0) 、 三氟甲磺酸 、 Brettphos palladacycle 、 palladium diacetate 、 caesium carbonate 、 R-(+)-1,1'-联萘-2,2'-双二苯膦 、 三乙胺 、 三苯基膦 、 三氟乙酸 、 sodium t-butanolate 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 甲苯 为溶剂， 反应 19.5h， 生成 4-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-2-((6-methoxy-3-pyridinyl)amino)imidazo[1,2-a]pyridin-6-yl)-N,N-dimethyl-1-piperazinecarboxamide
  参考文献：
  名称：

  The imidazo[1,2-a]pyridine ring system as a scaffold for potent dual phosphoinositide-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitors

  摘要：

  Based on lead compound 1, which was discovered from a high-throughput screen, a series of PI3K alpha/mTOR inhibitors were evaluated that contained an imidazo[1,2-a] pyridine as a core replacement for the benzimidazole contained in 1. By exploring various ring systems that occupy the affinity pocket, two fragments containing a methoxypyridine were identified that gave <100 nM potency toward PI3K alpha in enzyme and cellular assays with moderate stability in rat and human liver microsomes. With the two methoxypyridine groups selected to occupy the affinity pocket, analogs were prepared with various fragments intended to occupy the ribose pocket of PI3K alpha and mTOR. From these analogs, tertiary alcohol 18 was chosen for in vivo pharmacodynamic evaluation based on its potency in the PI3K alpha cellular assay, microsomal stability, and in vivo pharmacokinetic properties. In a mouse liver pharmacodynamic assay, compound 18 showed 56% inhibition of HFG-induced AKT (Ser473) phosphorylation at a 30 mg/kg dose. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2015.08.016

文献信息

• [EN] HETEROARYL COMPOUNDS AS PIKK INHIBITORS<br/>[FR] COMPOSÉS HÉTÉROARYLE EN TANT QU'INHIBITEURS DES PIKK
  申请人：AMGEN INC

  公开号：WO2010132598A1

  公开（公告）日：2010-11-18

  The present invention provides compounds that are PIKK inhibitors, more specifically, mTOR and/or PI3Kα kinase inhibitors and are therefore useful for the treatment of diseases treatable by inhibition of kinases, specifically PI3 kinases, more specifically, mTOR and/or PI3Kα, such as cancer. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.

  本发明提供了一种PIKK抑制剂化合物，更具体地说，是mTOR和/或PI3Kα激酶抑制剂，因此适用于治疗通过抑制激酶可治疗的疾病，具体而言是PI3激酶，更具体地说是mTOR和/或PI3Kα，如癌症。还提供了含有这种化合物的药物组合物和制备这种化合物的方法。
• Heteroaryl Compounds as PIKK Inhibitors
  申请人：Bode Christiane

  公开号：US20120190666A1

  公开（公告）日：2012-07-26

  The present invention provides compounds that are PIKK inhibitors, more specifically, mTOR and/or PI3Kα kinase inhibitors and are therefore useful for the treatment of diseases treatable by inhibition of kinases, specifically PI3 kinases, more specifically, mTOR and/or PI3Kα, such as cancer. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.

  本发明提供了一些可用于抑制激酶治疗可被抑制激酶疾病的化合物，更具体地说，是mTOR和/或PI3Kα激酶抑制剂，例如癌症。同时还提供了含有这些化合物的制药组合物和制备这些化合物的方法。
• HETEROARYL COMPOUNDS AS PIKK INHIBITORS
  申请人：Amgen, Inc

  公开号：EP2430013A1

  公开（公告）日：2012-03-21
• The imidazo[1,2-a]pyridine ring system as a scaffold for potent dual phosphoinositide-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitors
  作者：Markian M. Stec、Kristin L. Andrews、Yunxin Bo、Sean Caenepeel、Hongyu Liao、John McCarter、Erin L. Mullady、Tisha San Miguel、Raju Subramanian、Nuria Tamayo、Douglas A. Whittington、Ling Wang、Tian Wu、Leeanne P. Zalameda、Nancy Zhang、Paul E. Hughes、Mark H. Norman

  DOI：10.1016/j.bmcl.2015.08.016

  日期：2015.10

  Based on lead compound 1, which was discovered from a high-throughput screen, a series of PI3K alpha/mTOR inhibitors were evaluated that contained an imidazo[1,2-a] pyridine as a core replacement for the benzimidazole contained in 1. By exploring various ring systems that occupy the affinity pocket, two fragments containing a methoxypyridine were identified that gave <100 nM potency toward PI3K alpha in enzyme and cellular assays with moderate stability in rat and human liver microsomes. With the two methoxypyridine groups selected to occupy the affinity pocket, analogs were prepared with various fragments intended to occupy the ribose pocket of PI3K alpha and mTOR. From these analogs, tertiary alcohol 18 was chosen for in vivo pharmacodynamic evaluation based on its potency in the PI3K alpha cellular assay, microsomal stability, and in vivo pharmacokinetic properties. In a mouse liver pharmacodynamic assay, compound 18 showed 56% inhibition of HFG-induced AKT (Ser473) phosphorylation at a 30 mg/kg dose. (C) 2015 Elsevier Ltd. All rights reserved.