tert-butyl 3-(4-(cyclopropylcarbamoyl)phenyl)-6-(1,1,1-trifluoro-2-methylpropan-2-ylamino)imidazo[1,2-b]pyridazin-8-yl((tetrahydro-2H-pyran-4-yl)methyl)carbamate | 1263425-68-8

• 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 3-(4-(cyclopropylcarbamoyl)phenyl)-6-(1,1,1-trifluoro-2-methylpropan-2-ylamino)imidazo[1,2-b]pyridazin-8-yl((tetrahydro-2H-pyran-4-yl)methyl)carbamate
• 英文别名: tert-butyl N-[3-[4-(cyclopropylcarbamoyl)phenyl]-6-[(1,1,1-trifluoro-2-methylpropan-2-yl)amino]imidazo[1,2-b]pyridazin-8-yl]-N-(oxan-4-ylmethyl)carbamate
• CAS: 1263425-68-8
• 化学式: C₃₁H₃₉F₃N₆O₄
• 分子量: 616.684
• InChiKey: WPTRVXFUAKBXSQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  44
• 可旋转键数：
  10
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  110
• 氢给体数：
  2
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  tert-butyl 3-(4-(cyclopropylcarbamoyl)phenyl)-6-(1,1,1-trifluoro-2-methylpropan-2-ylamino)imidazo[1,2-b]pyridazin-8-yl((tetrahydro-2H-pyran-4-yl)methyl)carbamate 在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 15.0h， 以78%的产率得到N-cyclopropyl-4-(8-((tetrahydro-2H-pyran-4-yl)methylamino)-6-(1,1,1-trifluoro-2-methylpropan-2-ylamino)imidazo[1,2-b]pyridazin-3-yl)benzamide
  参考文献：
  名称：

  Discovery of Imidazo[1,2-b]pyridazine Derivatives: Selective and Orally Available Mps1 (TTK) Kinase Inhibitors Exhibiting Remarkable Antiproliferative Activity

  摘要：

  Monopolar spindle 1 (Mps1) is an attractive oncology target due to its high expression level in cancer cells as well as the correlation of its expression levels with histological grades of cancers. An imidazo[1,2-a]pyrazine 10a was identified during an HTS campaign. Although 10a exhibited good biochemical activity, its moderate cellular as well as antiproliferative activities needed to be improved. The cocrystal structure of an analogue of 10a guided our lead optimization to introduce substituents at the 6-position of the scaffold, giving the 6-aryl substituted 21b which had improved cellular activity but no oral bioavailability in rat. Property-based optimization at the 6-position and a scaffold change led to the discovery of the imidazo[1,2-b]pyridazine-based 27f, an extremely potent (cellular Mps1 IC50 = 0.70 nM, A549 IC50 = 6.0 nM), selective Mps1 inhibitor over 192 kinases, which could be orally administered and was active in vivo. This 27f demonstrated remarkable antiproliferative activity in the nanomolar range against various tissue cancer cell lines.

  DOI：

  10.1021/jm501599u
• 作为产物：
  描述：

  4-氨甲基四氢吡喃 在 4-二甲氨基吡啶 、 tris-(dibenzylideneacetone)dipalladium(0) 、 N-碘代丁二酰亚胺 、 [1,1'-二(二叔丁基膦)二茂铁]合二氯钯(II) 、 sodium carbonate 、 N,N-二异丙基乙胺 、 sodium t-butanolate 、 2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 40.0h， 生成 tert-butyl 3-(4-(cyclopropylcarbamoyl)phenyl)-6-(1,1,1-trifluoro-2-methylpropan-2-ylamino)imidazo[1,2-b]pyridazin-8-yl((tetrahydro-2H-pyran-4-yl)methyl)carbamate
  参考文献：
  名称：

  Discovery of Imidazo[1,2-b]pyridazine Derivatives: Selective and Orally Available Mps1 (TTK) Kinase Inhibitors Exhibiting Remarkable Antiproliferative Activity

  摘要：

  Monopolar spindle 1 (Mps1) is an attractive oncology target due to its high expression level in cancer cells as well as the correlation of its expression levels with histological grades of cancers. An imidazo[1,2-a]pyrazine 10a was identified during an HTS campaign. Although 10a exhibited good biochemical activity, its moderate cellular as well as antiproliferative activities needed to be improved. The cocrystal structure of an analogue of 10a guided our lead optimization to introduce substituents at the 6-position of the scaffold, giving the 6-aryl substituted 21b which had improved cellular activity but no oral bioavailability in rat. Property-based optimization at the 6-position and a scaffold change led to the discovery of the imidazo[1,2-b]pyridazine-based 27f, an extremely potent (cellular Mps1 IC50 = 0.70 nM, A549 IC50 = 6.0 nM), selective Mps1 inhibitor over 192 kinases, which could be orally administered and was active in vivo. This 27f demonstrated remarkable antiproliferative activity in the nanomolar range against various tissue cancer cell lines.

  DOI：

  10.1021/jm501599u

文献信息

• [EN] FUSED IMIDAZOLE DERIVATIVE HAVING TTK INHIBITORY ACTION<br/>[FR] DÉRIVÉ D'IMIDAZOLE CONDENSÉ PRÉSENTANT UNE ACTIVITÉ INHIBITRICE ENVERS TTK
  申请人：ONCOTHERAPY SCIENCE INC

  公开号：WO2011013729A1

  公开（公告）日：2011-02-03

  　本発明は、下記一般式で示されるＴＴＫ阻害作用を有する化合物及び当該化合物を含有する医薬品に関する。　式（Ｉ）中、（Ｘ、Ｙ、Ｖ、Ｗ）は、（－Ｎ＝、＝ＣＲ１－、＝Ｎ－、－ＣＲ７＝）、（－ＣＲ２＝、＝Ｎ－、＝Ｎ－、－ＣＲ７＝）等、Ａは置換もしくは非置換の芳香族炭化水素環等、Ｌは単結合、－Ｃ（＝Ｏ）－ＮＲＡ－等、Ｚは式：－ＮＲ３Ｒ４で示される基または式：－ＯＲ５で示される基であり、Ｒ１～Ｒ３，Ｒ６，Ｒ７は水素等、Ｒ４およびＲ５は、置換もしくは非置換のアルキル等、Ｒ８は置換もしくは非置換のシクロアルキル等である。