N-(3-(1-isonicotinoylpiperidin-4-yloxy)-4-methylphenyl)-3-(trifluoromethyl)benzamide

• 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-(3-(1-isonicotinoylpiperidin-4-yloxy)-4-methylphenyl)-3-(trifluoromethyl)benzamide
• 英文别名: (N-(4-methyl-3-(1-isonicotinoylpiperid-4-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide；Chmfl-kit-110；N-[4-methyl-3-[1-(pyridine-4-carbonyl)piperidin-4-yl]oxyphenyl]-3-(trifluoromethyl)benzamide
• 化学式: C₂₆H₂₄F₃N₃O₃
• 分子量: 483.49
• InChiKey: XFHUWXYRCAAZHK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  35
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  71.5
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  1-Boc-4-甲烷磺酰氧基哌啶 在 盐酸 、 5%-palladium/activated carbon 、 氢气 、 potassium carbonate 、 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 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 反应 10.0h， 生成 N-(3-(1-isonicotinoylpiperidin-4-yloxy)-4-methylphenyl)-3-(trifluoromethyl)benzamide
  参考文献：
  名称：

  Discovery of N-(3-((1-Isonicotinoylpiperidin-4-yl)oxy)-4-methylphenyl)-3-(trifluoromethyl)benzamide (CHMFL-KIT-110) as a Selective, Potent, and Orally Available Type II c-KIT Kinase Inhibitor for Gastrointestinal Stromal Tumors (GISTs)

  摘要：

  c-KIT kinase is a validated drug discovery target for gastrointestinal stromal tumors (GISTs). Clinically used c-KIT kinase inhibitors, i.e., Imatinib and Sunitinib, bear other important targets such as ABL or FLT3 kinases. Here we report our discovery of a more selective c-KIT inhibitor, compound 13 (CHMFL-KIT-110), which completely abolished ABL and FLT3 kinase activity. KinomeScan selectivity profiling (468 kinases) of 13 exhibited a high selectivity (S score (1) = 0.01). 13 displayed great antiproliferative efficacy against GISTs cell lines GIST-T1 and GIST-882 (GI50: 0.021 and 0.043 mu M, respectively). In the cellular context, it effectively affected c-KIT-mediated signaling pathways and induced apoptosis as well as cell cycle arrest. In addition, 13 possessed acceptable bioavailability (36%) and effectively suppressed the tumor growth in GIST-T1 cell inoculated xenograft model without apparent toxicity. 13 currently is undergoing extensive preclinical evaluation and might be a potential drug candidate for GISTs.

  DOI：

  10.1021/acs.jmedchem.6b00200

文献信息

• SELECTIVE C-KIT KINASE INHIBITOR
  申请人：Precedo Pharmaceuticals Co., Ltd.

  公开号：EP3438094A1

  公开（公告）日：2019-02-06

  The present invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt, a solvate, an ester, an acid, a metabolite or a prodrug thereof. The compound itself in the present invention or in combination with at least one therapeutic agent can be used for preventing or treating diseases, disorders or symptoms caused by the adjustment of the activity of tyrosine kinase C-KIT, or affected by the activity of the tyrosine kinase C-KIT or involving in the activity of the tyrosine kinase C-KIT, especially cancers or other cell proliferation diseases.

  本发明提供了一种由式（I）代表的化合物，或其药学上可接受的盐、溶液剂、酯、酸、代谢物或原药。本发明中的化合物本身或与至少一种治疗剂组合可用于预防或治疗由酪氨酸激酶C-KIT活性调整引起的、或受酪氨酸激酶C-KIT活性影响的、或涉及酪氨酸激酶C-KIT活性的疾病、失调或症状，特别是癌症或其他细胞增殖疾病。
• Selective C-KIT kinase inhibitor
  申请人：PRECEDO PHARMACEUTICALS CO., LTD

  公开号：US10793543B2

  公开（公告）日：2020-10-06

  The present invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt, a solvate, an ester, an acid, a metabolite or a prodrug thereof. The compound itself in the present invention or in combination with at least one therapeutic agent can be used for preventing or treating diseases, disorders or symptoms caused by the adjustment of the activity of tyrosine kinase C-KIT, or affected by the activity of the tyrosine kinase C-KIT or involving in the activity of the tyrosine kinase C-KIT, especially cancers or other cell proliferation diseases.

  本发明提供了一种由式（I）代表的化合物，或其药学上可接受的盐、溶液剂、酯、酸、代谢物或原药。本发明中的化合物本身或与至少一种治疗剂组合可用于预防或治疗由酪氨酸激酶C-KIT活性调整引起的、或受酪氨酸激酶C-KIT活性影响的、或涉及酪氨酸激酶C-KIT活性的疾病、失调或症状，特别是癌症或其他细胞增殖疾病。
• EP3438094
  申请人：——

  公开号：——

  公开（公告）日：——
• Discovery of <i>N</i>-(3-((1-Isonicotinoylpiperidin-4-yl)oxy)-4-methylphenyl)-3-(trifluoromethyl)benzamide (CHMFL-KIT-110) as a Selective, Potent, and Orally Available Type II c-KIT Kinase Inhibitor for Gastrointestinal Stromal Tumors (GISTs)
  作者：Qiang Wang、Feiyang Liu、Beilei Wang、Fengming Zou、Cheng Chen、Xiaochuan Liu、Aoli Wang、Shuang Qi、Wenchao Wang、Ziping Qi、Zheng Zhao、Zhenquan Hu、Wei Wang、Li Wang、Shanchun Zhang、Yuexiang Wang、Jing Liu、Qingsong Liu

  DOI：10.1021/acs.jmedchem.6b00200

  日期：2016.4.28

  c-KIT kinase is a validated drug discovery target for gastrointestinal stromal tumors (GISTs). Clinically used c-KIT kinase inhibitors, i.e., Imatinib and Sunitinib, bear other important targets such as ABL or FLT3 kinases. Here we report our discovery of a more selective c-KIT inhibitor, compound 13 (CHMFL-KIT-110), which completely abolished ABL and FLT3 kinase activity. KinomeScan selectivity profiling (468 kinases) of 13 exhibited a high selectivity (S score (1) = 0.01). 13 displayed great antiproliferative efficacy against GISTs cell lines GIST-T1 and GIST-882 (GI50: 0.021 and 0.043 mu M, respectively). In the cellular context, it effectively affected c-KIT-mediated signaling pathways and induced apoptosis as well as cell cycle arrest. In addition, 13 possessed acceptable bioavailability (36%) and effectively suppressed the tumor growth in GIST-T1 cell inoculated xenograft model without apparent toxicity. 13 currently is undergoing extensive preclinical evaluation and might be a potential drug candidate for GISTs.