N-[4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-3-iodo-4-methyl-benzamide | 1232836-35-9

• 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: N-[4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-3-iodo-4-methyl-benzamide
• 英文别名: N-(4-((4-Ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-iodo-4-methylbenzamide；N-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-iodo-4-methylbenzamide
• CAS: 1232836-35-9
• 化学式: C₂₂H₂₅F₃IN₃O
• 分子量: 531.36
• InChiKey: HACCACJLYCOSKP-UHFFFAOYSA-N

物化性质

• 沸点：
  479.5±45.0 °C(Predicted)
• 密度：
  1.495±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  30
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  35.6
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  3-乙炔咪唑并[1,2-a]吡啶 、 N-[4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-3-iodo-4-methyl-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-[(4-ethylpiperazin-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-乙基哌嗪-1-甲基)-3-三氟甲基苯胺 、 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 N-[4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-3-iodo-4-methyl-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

文献信息

• [EN] PYRROLO[2,3-D]PYRIMIDINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THEIR USE AS KINASE INHIBITORS<br/>[FR] DÉRIVÉS DE 6-AMINO-7-DÉSAZA-PURINE, PROCÉDÉ POUR LES PRÉPARER ET LEUR UTILISATION COMME INHIBITEURS DE KINASES
  申请人：NERVIANO MEDICAL SCIENCES SRL

  公开号：WO2014184069A1

  公开（公告）日：2014-11-20

  The present invention relates to 6-amino-7-deaza-purine derivatives which modulate the activity of protein kinases and are therefore useful in treating diseases caused by dysregulated protein kinase activity, in particular RET family kinases. The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods of treating diseases utilizing pharmaceutical compositions containing these compounds.

  本发明涉及调节蛋白激酶活性的6-氨基-7-去氮嘌呤衍生物，因此在治疗由失调的蛋白激酶活性引起的疾病中特别有用，尤其是RET家族激酶。本发明还提供了制备这些化合物的方法，包括这些化合物的药物组合物，以及利用含有这些化合物的药物组合物治疗疾病的方法。
• Discovery of Type II Inhibitors of TGFβ-Activated Kinase 1 (TAK1) and Mitogen-Activated Protein Kinase Kinase Kinase Kinase 2 (MAP4K2)
  作者：Li Tan、Tyzoon Nomanbhoy、Deepak Gurbani、Matthew Patricelli、John Hunter、Jiefei Geng、Lina Herhaus、Jianming Zhang、Eduardo Pauls、Youngjin Ham、Hwan Geun Choi、Ting Xie、Xianming Deng、Sara J. Buhrlage、Taebo Sim、Philip Cohen、Gopal Sapkota、Kenneth D. Westover、Nathanael S. Gray

  DOI：10.1021/jm500480k

  日期：2015.1.8

  We developed a pharmacophore model for type II inhibitors that was used to guide the construction of a library of kinase inhibitors. Kinome-wide selectivity profiling of the library resulted in the identification of a series of 4-substituted 1H-pyrrolo[2,3-b]pyridines that exhibited potent inhibitory activity against two mitogen-activated protein kinases (MAPKs), TAK1 (MAP3K7) and MAP4K2, as well as

  我们开发了用于指导构建激酶抑制剂库的 II 型抑制剂药效团模型。文库的全激酶组选择性分析导致鉴定出一系列 4 取代的 1 H-吡咯并[2,3 - b ]吡啶，它们对两种丝裂原活化蛋白激酶 (MAPK) TAK1 (MAP3K7) 表现出有效的抑制活性) 和 MAP4K2，以及药理学上研究良好的激酶，如 p38α (MAPK14) 和 ABL。对构效关系 (SAR) 的进一步研究导致鉴定出有效的双重 TAK1 和 MAP4K2 抑制剂，例如1 (NG25) 和2，以及 MAP4K2 选择性抑制剂，例如16和17. 这些抑制剂中的一些具有良好的药代动力学特性，使其能够用于体内药理学研究。TAK1 与1复合的 2.4 Å 共晶结构证实 TAK1 的激活环具有 II 型抑制剂的 DFG-out 构象特征。
• PYRROLO[2,3-D]PYRIMIDINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THEIR USE AS KINASE INHIBITORS
  申请人：NERVIANO MEDICAL SCIENCES S.R.L.

  公开号：US20160166575A1

  公开（公告）日：2016-06-16

  The present invention relates to 6-amino-7-deaza-purine derivatives which modulate the activity of protein kinases and are therefore useful in treating diseases caused by dysregulated protein kinase activity, in particular RET family kinases. The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods of treating diseases utilizing pharmaceutical compositions containing these compounds.

  本发明涉及6-氨基-7-去氮嘌呤衍生物，其调节蛋白激酶的活性，因此在治疗由失调的蛋白激酶活性引起的疾病，特别是RET家族激酶方面非常有用。本发明还提供了制备这些化合物的方法，包括这些化合物的药物组合物，以及利用含有这些化合物的药物组合物治疗疾病的方法。
• SUBSTITUTED PYRIMIDINYL AND PYRIDINYL-PYRROLOPYRIDINONES, PROCESS FOR THEIR PREPARATION AND THEIR USE AS KINASE INHIBITORS
  申请人：NERVIANO MEDICAL SCIENCES S.r.l.

  公开号：US20150299192A1

  公开（公告）日：2015-10-22

  The present invention relates to substituted pyrimidinyl- and pyridinylpyrrolopyridinone compounds which modulate the activity of protein kinases and are therefore useful in treating diseases caused by dysregulated protein kinase activity, in particular RET family kinases. The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods of treating diseases utilizing pharmaceutical compositions containing these compounds.

  本发明涉及取代的嘧啶基和吡啶基吡咯吡啶酮化合物，其调节蛋白激酶活性，因此在治疗由失调的蛋白激酶活性引起的疾病中特别有用，特别是RET家族激酶。本发明还提供了制备这些化合物的方法、包含这些化合物的制药组合物以及利用含有这些化合物的制药组合物治疗疾病的方法。
• Broad spectrum alkynyl inhibitors of T315I Bcr-Abl
  作者：Xianming Deng、Sang Min Lim、Jianming Zhang、Nathanael S. Gray

  DOI：10.1016/j.bmcl.2010.05.043

  日期：2010.7

  A series of alkyne-containing type II inhibitors with potent inhibitory activity of T315I Bcr-Abl has been identified. The most active compound 4 exhibits an EC(50) of less than 1 nM against wild-type Bcr-Abl and an EC50 of 10 nM against T315I mutant but is broadly active against a number of other kinases. (C) 2010 Elsevier Ltd. All rights reserved.