N-(4-methyl-3-((1-nicotinoylpiperidin-4-yl)oxy)phenyl)-4-((4-methylpiperazin-1-yl)methyl)-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-(4-methyl-3-((1-nicotinoylpiperidin-4-yl)oxy)phenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide
• 英文别名: N-(4-methyl-3-{[1-(pyridine-3-carbonyl)piperidin-4-yl]oxy}phenyl)-4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)benzamide；4-[(4-Methylpiperazin-1-Yl)methyl]-N-(4-Methyl-3-{[1-(Pyridin-3-Ylcarbonyl)piperidin-4-Yl]oxy}phenyl)-3-(Trifluoromethyl)benzamide；4-[(4-methylpiperazin-1-yl)methyl]-N-[4-methyl-3-[1-(pyridine-3-carbonyl)piperidin-4-yl]oxyphenyl]-3-(trifluoromethyl)benzamide
• 化学式: C₃₂H₃₆F₃N₅O₃
• 分子量: 595.665
• InChiKey: CBLZTDLZCXMNCE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  43
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  78
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  3-(三氟甲基)-4-甲基苯甲酸甲酯 在 盐酸 、 N-溴代丁二酰亚胺(NBS) 、 偶氮二异丁腈 、 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 、 lithium hydroxide 作用下， 以 四氢呋喃 、 四氯化碳 、 水 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 反应 10.0h， 生成 N-(4-methyl-3-((1-nicotinoylpiperidin-4-yl)oxy)phenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide
  参考文献：
  名称：

  一种新型结构的激酶抑制剂

  摘要：

  本发明提供一种新型激酶抑制剂式(I)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物、组合药物或前药。这些化合物单独与至少一种另外的治疗剂联合可用于预防或治疗由酪氨酸激酶活性调节的或者受其影响的或者其中涉及酪氨酸激酶活性的疾病、障碍或病症、自身免疫性疾病，尤其是癌症和其它的细胞增殖性疾病。

  公开号：

  CN104844566B

文献信息

• 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。
• Discovery of 4-Methyl-<i>N</i>-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((1-nicotinoylpiperidin-4-yl)oxy)benzamide (CHMFL-ABL/KIT-155) as a Novel Highly Potent Type II ABL/KIT Dual Kinase Inhibitor with a Distinct Hinge Binding
  作者：Qiang Wang、Feiyang Liu、Beilei Wang、Fengming Zou、Ziping Qi、Cheng Chen、Kailin Yu、Chen Hu、Shuang Qi、Wenchao Wang、Zhenquan Hu、Juan Liu、Wei Wang、Li Wang、Qianmao Liang、Shanchun Zhang、Tao Ren、Qingsong Liu、Jing Liu

  DOI：10.1021/acs.jmedchem.6b01290

  日期：2017.1.12

  The discovery of a novel potent type II ABL/c-KIT dual kinase inhibitor compound. 34 (CHMFL-ABL/KIT-155), which utilized a hydrogen bond formed by NH on the kinase backbone and carbonyl oxygen of 34 as a unique hinge binding, is described. 34 potently inhibited purified ABL (IC50: 46 nM) and c-KIT kinase (IC50: 75 nM) in the biochemical assays and displayed high selectivity (S Score (1) = 0.03) at the concentration of 1 mu M among 468 kinases/mutants in KINOMEscan assay. It exhibited strong antiproliferative activities against BCR-ABL/c-KIT driven CML/GISTs cancer cell lines through blockage of the BCR-ABL/c-KIT mediated signaling pathways, arresting cell cycle progression and induction of apoptosis. 34 possessed a good oral PK property and effectively suppressed the tumor progression in the K562 (CML) and GIST-T1 (GISTs) cells mediated xenograft mouse model. The distinct hinge-binding mode of 34 provided a novel pharmacophore for expanding the chemical structure diversity for the type II kinase inhibitors discovery.
• SELECTIVE C-KIT KINASE INHIBITOR
  申请人：PRECEDO PHARMACEUTICALS CO., LTD

  公开号：US20190084960A1

  公开（公告）日：2019-03-21

  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.
• 一种新型结构的激酶抑制剂
  申请人：合肥中科普瑞昇生物医药科技有限公司

  公开号：CN104844566B

  公开（公告）日：2018-05-18

  本发明提供一种新型激酶抑制剂式(I)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物、组合药物或前药。这些化合物单独与至少一种另外的治疗剂联合可用于预防或治疗由酪氨酸激酶活性调节的或者受其影响的或者其中涉及酪氨酸激酶活性的疾病、障碍或病症、自身免疫性疾病，尤其是癌症和其它的细胞增殖性疾病。