3-iodo-4-methyl-N-(4-((4-methyl-1,4-diazepan-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide | 1232836-34-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 3-iodo-4-methyl-N-(4-((4-methyl-1,4-diazepan-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide
• CAS: 1232836-34-8
• 化学式: C₂₂H₂₅F₃IN₃O
• 分子量: 531.36
• InChiKey: TXQKISWSLKQZQK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.01
• 重原子数：
  30.0
• 可旋转键数：
  4.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  35.58
• 氢给体数：
  1.0
• 氢受体数：
  3.0

反应信息

• 作为反应物：
  描述：

  3-乙炔咪唑并[1,2-a]吡啶 、 3-iodo-4-methyl-N-(4-((4-methyl-1,4-diazepan-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide 在 copper(l) iodide 、 四(三苯基膦)钯 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 16.0h， 生成 N-{4-[(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)methyl]-3-(trifluoromethyl)phenyl}-3-[2-(imidazo[1,2-a]pyridin-3-yl)ethynyl]-4-methylbenzamide
  参考文献：
  名称：

  Discovery of 3-[2-(Imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide (AP24534), a Potent, Orally Active Pan-Inhibitor of Breakpoint Cluster Region-Abelson (BCR-ABL) Kinase Including the T315I Gatekeeper Mutant

  摘要：

  In the treatment of chronic myeloid leukemia (CML) with BCR-ABL kinase inhibitors, the T315I gatekeeper mutant has emerged as resistant to all currently approved agents. This report describes the structure-guided design of a novel series of potent pan-inhibitors of BCR-ABL, including the T315I mutation. A key structural feature is the carbon-carbon triple bond linker which skirts the increased bulk of I1e315 side chain. Extensive SAR studies led to the discovery of development candidate 20g (AP24534), which inhibited the kinase activity of both native BCR-ABL and the T315I mutant with low nM IC(50)s, and potently inhibited proliferation of corresponding Ba/F3-derived cell lines. Daily oral administration of 20g significantly prolonged survival of mice injected intravenously with BCR-ABL(T315I) expressing Ba/F3 cells. These data, coupled with a favorable ADME profile, support the potential of 20g to be an effective treatment for CM L, including patients refractory to all currently approved therapies.

  DOI：

  10.1021/jm100395q
• 作为产物：
  描述：

  4-(4-methyl-[1,4]diazepan-1-yl methyl)-3-trifluoromethyl-phenylamine 、 3-碘-4-甲基苯甲酰氯 在 4-二甲氨基吡啶 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 2.0h， 生成 3-iodo-4-methyl-N-(4-((4-methyl-1,4-diazepan-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide
  参考文献：
  名称：

  Discovery of 3-[2-(Imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide (AP24534), a Potent, Orally Active Pan-Inhibitor of Breakpoint Cluster Region-Abelson (BCR-ABL) Kinase Including the T315I Gatekeeper Mutant

  摘要：

  In the treatment of chronic myeloid leukemia (CML) with BCR-ABL kinase inhibitors, the T315I gatekeeper mutant has emerged as resistant to all currently approved agents. This report describes the structure-guided design of a novel series of potent pan-inhibitors of BCR-ABL, including the T315I mutation. A key structural feature is the carbon-carbon triple bond linker which skirts the increased bulk of I1e315 side chain. Extensive SAR studies led to the discovery of development candidate 20g (AP24534), which inhibited the kinase activity of both native BCR-ABL and the T315I mutant with low nM IC(50)s, and potently inhibited proliferation of corresponding Ba/F3-derived cell lines. Daily oral administration of 20g significantly prolonged survival of mice injected intravenously with BCR-ABL(T315I) expressing Ba/F3 cells. These data, coupled with a favorable ADME profile, support the potential of 20g to be an effective treatment for CM L, including patients refractory to all currently approved therapies.

  DOI：

  10.1021/jm100395q