N-(2-methyl-5-((4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide | 1086422-83-4

• 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-(2-methyl-5-((4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide
• 英文别名: N-(2-methyl-5-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenylcarbamoyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide；N-[3-(Trifluoromethyl)-4-[(4-methyl-1-piperazinyl)methyl]phenyl]-3-[[[1H-pyrrolo[2,3-b]pyridine-5-yl]carbonyl]amino]-4-methylbenzamide；N-[2-methyl-5-[[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]carbamoyl]phenyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxamide
• CAS: 1086422-83-4
• 化学式: C₂₉H₂₉F₃N₆O₂
• 分子量: 550.583
• InChiKey: XMTCFSFHPPARKV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  40
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  93.4
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  4-甲基-3-硝基苯甲酸 在 palladium 10% on activated carbon 、 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 氢气 、 三乙胺 、 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 四氢呋喃 、 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 29.0h， 生成 N-(2-methyl-5-((4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide
  参考文献：
  名称：

  Identification and Optimization of New Dual Inhibitors of B-Raf and Epidermal Growth Factor Receptor Kinases for Overcoming Resistance against Vemurafenib

  摘要：

  Epidermal growth factor receptor (EGFR) amplification has been demonstrated to be critical for the inherent and/or acquired resistance against current B-Raf(V600E) inhibitor therapy for melanoma and colorectal cancer patients. We describe the discovery and structure-activity relationship study of a series of 1H-pyrazolo[3,4-b]pyridine-5-carboxamide analogues as novel dual inhibitors of EGFR and B-Raf(V600E) mutant. One of the most promising compounds, 6a, potently inhibited both of the kinases with IC50 values of 8.0 and 51 nM, respectively. The compound also strongly suppressed the proliferation of a panel of intrinsic and acquired resistant melanoma and/or colorectal cancer cells harboring overexpressed EGFR with submicromolar IC50 values. Further mechanism investigation revealed that 6a could sustainably inhibit the activation of the MAPK path way in the resistant SK-MEL-28 PR30 melanoma cancer cells and WiDr colorectal cancer cells with EGFR amplification. Our results support the hypothesis that the EGFR/B-Raf(V600E) dual inhibition might be a tractable strategy to overcome the intrinsic and acquired resistance of melanoma and/or colorectal cancers against the current B-Raf(V600E) inhibitor therapy.

  DOI：

  10.1021/jm500007h

文献信息

• [EN] PROTEIN KINASE INHIBITORS AND METHODS FOR USING THEREOF<br/>[FR] INHIBITEURS DE LA PROTÉINE KINASE ET PROCÉDÉ D'UTILISATION DE CEUX-CI
  申请人：IRM LLC

  公开号：WO2008144253A1

  公开（公告）日：2008-11-27

  [EN] The invention provides compounds of formula (l) and pharmaceutical compositions thereof, which are useful as protein kinase inhibitors, and methods for using such compounds to treat, ameliorate or prevent a condition associated with abnormal or deregulated kinase activity. In some embodiments, the invention provides methods for using such compounds to treat, ameliorate or prevent diseases or disorders that involve abnormal activation of AIk, AbI, Aurora-A, B-Raf, C-Raf, Bcr-Abl, BRK, BIk, Bmx, BTK, c-Kit, c-RAF, CSK, c-SRC, EphBl, EphB2, EphB4, FLTl, Fms, Flt3, Fyn, FRK3, JAK2, KDR, Lck, Lyn, PDGFRalpha, PDGFRbeta, PKCalpha, SAPK2alpha, Src, SIK, Syk, Tie2 and TrkB kinases.
  [FR] L'invention concerne des composés représentés par la formule (l) et des compositions pharmaceutiques de ceux-ci qui sont utiles en tant qu'inhibiteurs de la protéine kinase, et des procédés destinés à utiliser de tels composés pour traiter, améliorer ou prévenir un état pathologique associé à une activité kinase anormale ou dérégulée. Dans certains modes de réalisation, l'invention propose des procédés destinés à utiliser de tels composés afin de traiter, d'améliorer ou de prévenir des maladies ou des troubles qui impliquent une activation anormale des kinases AIk, AbI, Aurora-A, B-Raf, C-Raf, Bcr-Abl, BRK, BIk, Bmx, BTK, c-Kit, c-RAF, CSK, c-SRC, EphBl, EphB2, EphB4, FLTl, Fms, Flt3, Fyn, FRK3, JAK2, KDR, Lck, Lyn, PDGFRalpha, PDGFRbeta, PKCalpha, SAPK2alpha, Src, SIK, Syk, Tie2 et TrkB.
• Identification and Optimization of New Dual Inhibitors of B-Raf and Epidermal Growth Factor Receptor Kinases for Overcoming Resistance against Vemurafenib
  作者：Huimin Cheng、Yu Chang、Lianwen Zhang、Jinfeng Luo、Zhengchao Tu、Xiaoyun Lu、Qingwen Zhang、Jibu Lu、Xiaomei Ren、Ke Ding

  DOI：10.1021/jm500007h

  日期：2014.3.27

  Epidermal growth factor receptor (EGFR) amplification has been demonstrated to be critical for the inherent and/or acquired resistance against current B-Raf(V600E) inhibitor therapy for melanoma and colorectal cancer patients. We describe the discovery and structure-activity relationship study of a series of 1H-pyrazolo[3,4-b]pyridine-5-carboxamide analogues as novel dual inhibitors of EGFR and B-Raf(V600E) mutant. One of the most promising compounds, 6a, potently inhibited both of the kinases with IC50 values of 8.0 and 51 nM, respectively. The compound also strongly suppressed the proliferation of a panel of intrinsic and acquired resistant melanoma and/or colorectal cancer cells harboring overexpressed EGFR with submicromolar IC50 values. Further mechanism investigation revealed that 6a could sustainably inhibit the activation of the MAPK path way in the resistant SK-MEL-28 PR30 melanoma cancer cells and WiDr colorectal cancer cells with EGFR amplification. Our results support the hypothesis that the EGFR/B-Raf(V600E) dual inhibition might be a tractable strategy to overcome the intrinsic and acquired resistance of melanoma and/or colorectal cancers against the current B-Raf(V600E) inhibitor therapy.