3-iodo-6-(1-methyl-1H-pyrazol-4-yl)-5-nitro-1H-indazole | 1351813-06-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡唑类
• 英文名称: 3-iodo-6-(1-methyl-1H-pyrazol-4-yl)-5-nitro-1H-indazole
• 英文别名: 3-iodo-6-(1-methylpyrazol-4-yl)-5-nitro-2H-indazole
• CAS: 1351813-06-3
• 化学式: C₁₁H₈IN₅O₂
• 分子量: 369.121
• InChiKey: UOEXWMARBBAVCD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  19
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.09
• 拓扑面积：
  92.3
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3-iodo-6-(1-methyl-1H-pyrazol-4-yl)-5-nitro-1H-indazole 在 乙醇 、 四丁基氟化铵 、 三乙酰氧基硼氢化钠 、 铁粉 、 sodium hydride 、 氯化铵 、 溶剂黄146 、 乙二胺 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 31.42h， 生成 3-[5-(cyclohexylamino)-6-(1-methylpyrazol-4-yl)-1H-indazol-3-yl]benzenesulfonamide
  参考文献：
  名称：

  Indazole-Based Potent and Cell-Active Mps1 Kinase Inhibitors: Rational Design from Pan-Kinase Inhibitor Anthrapyrazolone (SP600125)

  摘要：

  Monopolar spindle 1 (Mps1) is essential for centrosome duplication, the spindle assembly check point, and the maintenance of chromosomal instability. Mps1 is highly expressed in cancer cells, and its expression levels correlate with the histological grades of cancers. Thus, selective Mps1 inhibitors offer an attractive opportunity for the development of novel cancer therapies. To design novel Mps1 inhibitors, we utilized the pan-kinase inhibitor anthrapyrazolone (4, SP600125) and its crystal structure bound to JNK1. Our design efforts led to the identification of indazole-based lead 6 with an Mps1 IC50 value of 498 nM. Optimization of the 3- and 6-positions on the indazole core of 6 resulted in 23c with improved Mps1 activity (IC50 = 3.06 nM). Finally, application of structure-based design using the X-ray structure of 23d bound to Mps1 culminated in the discovery of 32a and 32b with improved potency for cellular Mps1 and A549 lung cancer cells. Moreover, 32a and 32b exhibited reasonable selectivities over 120 and 166 kinases, respectively.

  DOI：

  10.1021/jm4000215
• 作为产物：
  描述：

  6-溴-5-硝基-1H-吲唑 在 dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) 、 四丁基氟化铵 、 碘 、 sodium hydride 、 potassium carbonate 、 乙二胺 、 potassium hydroxide 作用下， 以 四氢呋喃 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 14.17h， 生成 3-iodo-6-(1-methyl-1H-pyrazol-4-yl)-5-nitro-1H-indazole
  参考文献：
  名称：

  Indazole-Based Potent and Cell-Active Mps1 Kinase Inhibitors: Rational Design from Pan-Kinase Inhibitor Anthrapyrazolone (SP600125)

  摘要：

  Monopolar spindle 1 (Mps1) is essential for centrosome duplication, the spindle assembly check point, and the maintenance of chromosomal instability. Mps1 is highly expressed in cancer cells, and its expression levels correlate with the histological grades of cancers. Thus, selective Mps1 inhibitors offer an attractive opportunity for the development of novel cancer therapies. To design novel Mps1 inhibitors, we utilized the pan-kinase inhibitor anthrapyrazolone (4, SP600125) and its crystal structure bound to JNK1. Our design efforts led to the identification of indazole-based lead 6 with an Mps1 IC50 value of 498 nM. Optimization of the 3- and 6-positions on the indazole core of 6 resulted in 23c with improved Mps1 activity (IC50 = 3.06 nM). Finally, application of structure-based design using the X-ray structure of 23d bound to Mps1 culminated in the discovery of 32a and 32b with improved potency for cellular Mps1 and A549 lung cancer cells. Moreover, 32a and 32b exhibited reasonable selectivities over 120 and 166 kinases, respectively.

  DOI：

  10.1021/jm4000215