(R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-2-(dimethylamino)ethanone

• 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: (R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-2-(dimethylamino)ethanone
• 英文别名: Chmfl-flt3-122；1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-2-(dimethylamino)ethanone
• 化学式: C₂₆H₂₉N₇O₂
• 分子量: 471.562
• InChiKey: IZNAFSDUTMZGSF-LJQANCHMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  35
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  102
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  3-碘-4-氨基吡唑并[3,4-d]嘧啶 在 盐酸 、 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 potassium phosphate 、 偶氮二甲酸二异丙酯 、 N,N-二异丙基乙胺 、 三苯基膦 、 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 、 水 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 反应 26.5h， 生成 (R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-2-(dimethylamino)ethanone
  参考文献：
  名称：

  Discovery of (R)-1-(3-(4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-2-(dimethylamino)ethanone (CHMFL-FLT3-122) as a Potent and Orally Available FLT3 Kinase Inhibitor for FLT3-ITD Positive Acute Myeloid Leukemia

  摘要：

  FLT3-ITD mutant has been observed in about 30% of AML patients and extensively studied as a drug discovery target. On the basis of the structure of PCI-32765 (ibrutinib), a BTK kinase inhibitor that was recently reported to bear FLT3 kinase activity through a structure-guided drug design approach, we have discovered compound 18 (CHMFL-FLT3-122), which displayed an IC50 of 40 nM against FLT3 kinase and achieved selectivity over BTK kinase (over 10-fold). It significantly inhibited the proliferation of FLT3-ITD positive AML cancer cell lines MV4-11 (GI(50) = 22 nM), MOLM13/14 (GI(50) = 21 nM/42 nM). More importantly, 18 demonstrated 170-fold selectivity between FLT3 kinase and c-KIT kinase (GI50 = 11 nM versus 1900 nM) in the TEL-fusion isogenic BaF3 cells indicating a potential to avoid the FLT3/c-KIT dual inhibition induced myelosuppression toxicity. In the cellular context it strongly affected FLT3-ITD mediated signaling pathways and induced apoptosis by arresting the cell cycle into the G0/G1 phase. In the in vivo studies 18 demonstrated a good bioavailability (30%) and significantly suppressed the tumor growth in MV4-11 cell inoculated xenograft model (50 mg/kg) without exhibiting obvious toxicity. Compound 18 might be a potential drug candidate for FLT3-ITD positive AML.

  DOI：

  10.1021/acs.jmedchem.5b01611

文献信息

• NOVEL INHIBITOR OF FLT3 KINASE AND USE THEREOF
  申请人：Hefei Institutes of Physical Sicence, Chinese Academy of Sciences

  公开号：EP3248979A1

  公开（公告）日：2017-11-29

  Provided in the present invention is a novel inhibitor of FLT3 kinase, comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, isomer, ester, acid, metabolite or prodrug thereof. Also provided in the present invention are a pharmaceutical composition comprising a compound of formula (I) and a use and method for preventing or treating cell proliferative conditions and/or FLT3-related conditions, in particular for conditions responding to the inhibition of FLT3 kinase (especially FLT3/ITD mutant kinases).

  本发明提供了一种新型FLT3激酶抑制剂，包含式（I）化合物或其药学上可接受的盐、溶液剂、异构体、酯、酸、代谢物或原药。本发明还提供了一种包含式（I）化合物的药物组合物，以及一种用于预防或治疗细胞增殖性病症和/或 FLT3 相关病症，特别是对 FLT3 激酶（尤其是 FLT3/ITD 突变激酶）抑制有反应的病症的用途和方法。
• Inhibitor of FLT3 kinase and use thereof
  申请人：HEFEI INSTITUTES OF PHYSICAL SCIENCE, CHINESE ACADEMY OF SCIENCES

  公开号：US10266535B2

  公开（公告）日：2019-04-23

  Provided in the present invention is a novel inhibitor of FLT3 kinase, comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, isomer, ester, acid, metabolite or prodrug thereof. Also provided in the present invention are a pharmaceutical composition comprising a compound of formula (I) and a use and method for preventing or treating cell proliferative conditions and/or FLT3-related conditions, in particular for conditions responding to the inhibition of FLT3 kinase (especially FLT3/ITD mutant kinases).

  本发明提供了一种新型FLT3激酶抑制剂，包含式（I）化合物或其药学上可接受的盐、溶液剂、异构体、酯、酸、代谢物或原药。本发明还提供了一种包含式（I）化合物的药物组合物，以及一种用于预防或治疗细胞增殖性病症和/或 FLT3 相关病症，特别是对 FLT3 激酶（尤其是 FLT3/ITD 突变激酶）抑制有反应的病症的用途和方法。
• [EN] NOVEL INHIBITOR OF FLT3 KINASE AND USE THEREOF<br/>[FR] NOUVEL INHIBITEUR DE LA KINASE FLT3 ET UTILISATION DE CE DERNIER<br/>[ZH] FLT3激酶的新型抑制剂及其用途
  申请人：HEFEI INST PHYSICAL SCI CAS

  公开号：WO2016115869A1

  公开（公告）日：2016-07-28

  本发明提供了一种新型激酶抑制剂，其包括式(I)的化合物或其药学可接受的盐、溶剂化物、异构体、酯、酸、代谢物、或前药。本发明还提供包括式(I)化合物的药物组合物及其用于预防或治疗细胞增殖性病症和/或FLT3相关病症的用途和方法，特别是响应于FLT3激酶(尤其是FLT3/ITD突变型激酶)抑制的病症。
• Discovery of (<i>R</i>)-1-(3-(4-Amino-3-(4-phenoxyphenyl)-1<i>H</i>-pyrazolo[3,4-<i>d</i>]pyrimidin-1-yl)piperidin-1-yl)-2-(dimethylamino)ethanone (CHMFL-FLT3-122) as a Potent and Orally Available FLT3 Kinase Inhibitor for FLT3-ITD Positive Acute Myeloid Leukemia
  作者：Xixiang Li、Aoli Wang、Kailin Yu、Ziping Qi、Cheng Chen、Wenchao Wang、Chen Hu、Hong Wu、Jiaxin Wu、Zheng Zhao、Juan Liu、Fengming Zou、Li Wang、Beilei Wang、Wei Wang、Shanchun Zhang、Jing Liu、Qingsong Liu

  DOI：10.1021/acs.jmedchem.5b01611

  日期：2015.12.24

  FLT3-ITD mutant has been observed in about 30% of AML patients and extensively studied as a drug discovery target. On the basis of the structure of PCI-32765 (ibrutinib), a BTK kinase inhibitor that was recently reported to bear FLT3 kinase activity through a structure-guided drug design approach, we have discovered compound 18 (CHMFL-FLT3-122), which displayed an IC50 of 40 nM against FLT3 kinase and achieved selectivity over BTK kinase (over 10-fold). It significantly inhibited the proliferation of FLT3-ITD positive AML cancer cell lines MV4-11 (GI(50) = 22 nM), MOLM13/14 (GI(50) = 21 nM/42 nM). More importantly, 18 demonstrated 170-fold selectivity between FLT3 kinase and c-KIT kinase (GI50 = 11 nM versus 1900 nM) in the TEL-fusion isogenic BaF3 cells indicating a potential to avoid the FLT3/c-KIT dual inhibition induced myelosuppression toxicity. In the cellular context it strongly affected FLT3-ITD mediated signaling pathways and induced apoptosis by arresting the cell cycle into the G0/G1 phase. In the in vivo studies 18 demonstrated a good bioavailability (30%) and significantly suppressed the tumor growth in MV4-11 cell inoculated xenograft model (50 mg/kg) without exhibiting obvious toxicity. Compound 18 might be a potential drug candidate for FLT3-ITD positive AML.