N-(6-(4-aminophenoxy)pyrimidin-4-yl)acetamide

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: N-(6-(4-aminophenoxy)pyrimidin-4-yl)acetamide
• 英文别名: N-[6-(4-aminophenoxy)pyrimidin-4-yl]acetamide
• 化学式: C₁₂H₁₂N₄O₂
• 分子量: 244.253
• InChiKey: URJDEWWRFTWILY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  18
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  90.1
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  1-萘乙酸 、 N-(6-(4-aminophenoxy)pyrimidin-4-yl)acetamide 在 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 为溶剂， 反应 14.0h， 以78%的产率得到N-[4-(6-acetylaminopyrimidin-4-yloxy)phenyl]-2-naphthalen-1-yl-acetamide
  参考文献：
  名称：

  Discovery of N-(4-(6-Acetamidopyrimidin-4-yloxy)phenyl)-2-(2-(trifluoromethyl)phenyl)acetamide (CHMFL-FLT3-335) as a Potent FMS-like Tyrosine Kinase 3 Internal Tandem Duplication (FLT3-ITD) Mutant Selective Inhibitor for Acute Myeloid Leukemia

  摘要：

  Most of the current FMS-like tyrosine kinase 3 (FLT3) inhibitors lack selectivity between FLT3 kinase and cKIT kinase as well as the FLT3 wt and internal tandem duplication (ITD) mutants. We report a new compound 27, which displays GI(50) values of 30-80 nM against different ITD mutants and achieves selectivity over both FLT3 wt (8-fold) and cKIT kinase in the transformed BaF3 cells (>300-fold). 27 potently inhibits the proliferation of the FLT3-ITD-positive acute myeloid leukemia cancer lines through suppression of the phosphorylation of FLT3 kinase and downstream signaling pathways, induction of apoptosis, and arresting the cell cycle into the G0/G1 phase. 27 also displays potent antiproliferative effect against FLT3-ITD-positive patient primary cells, whereas it does not apparently affect FLT3 wt primary cells. In addition, it also exhibits a good therapeutic window to PBMC compared to PKC412. In the in vivo studies, 27 demonstrates favorable PK profiles and suppresses the tumor growth in the MV4-11 cell inoculated mouse xenograft model.

  DOI：

  10.1021/acs.jmedchem.8b01594
• 作为产物：
  描述：

  N-(6-chloropyrimidin-4-yl)acetamide 在 盐酸 、 caesium carbonate 作用下， 以 甲醇 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 反应 25.0h， 生成 N-(6-(4-aminophenoxy)pyrimidin-4-yl)acetamide
  参考文献：
  名称：

  一类嘧啶类衍生物激酶抑制剂

  摘要：

  本发明涉及一种激酶抑制剂，其包括式I的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药。本发明还涉及包括该激酶抑制剂的药物组合物，以及使用这些化合物和组合物来抑制细胞或受试者的野生型FLT3、突变型FLT3‑ITD、PDGFRα和/或PDGFRβ激酶活性、以及在受试者中预防或治疗激酶相关病症的用途和方法。

  公开号：

  CN108368060B

文献信息

• Process for the preparation of 4-phenoxy quinoline derivatives
  申请人：Eisai R&D Management Co., Ltd.

  公开号：EP1777218A1

  公开（公告）日：2007-04-25

  The present invention concerns a process for preparing a compound represented by the following general formula (a-11): or a pharmacologically acceptable salt or hydrate thereof, which comprises reacting a compound represented by the following general formula (a-12): with a compound represented by the following general formula (a-4) : wherein the residues R1, R2, Rsa1 - Rsa3, R300, R301 and Z are as defined in the claims.

  本发明涉及一种制备由以下通式（a-11）代表的化合物的工艺： 或其药理学上可接受的盐或水合物的制备工艺，该工艺包括使下式通式（a-12）所代表的化合物反应： 与下式通式（a-4）所代表的化合物反应： 其中残基 R1、R2、Rsa1-Rsa3、R300、R301 和 Z 如权利要求中所定义。
• CLASS OF PYRIMIDINE DERIVATIVE KINASE INHIBITORS
  申请人：Hefei Institutes of Physical Science, Chinese Academy of Sciences

  公开号：EP3730483A1

  公开（公告）日：2020-10-28

  The present invention relates to a kinase inhibitor, comprising a compound of Formula I or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof. The present invention also relates to a pharmaceutical composition comprising the kinase inhibitor, and to uses and methods for using these compounds and compositions to inhibit the activity of wild-type FLT3, mutant FLT3-ITD, PDGFRα and/or PDGFRβ kinase in a cell or a subject, as well as uses and methods of these compounds and compositions to preventing or treating kinase-associated conditions in a subject.

  本发明涉及一种激酶抑制剂，包括式I化合物或其药学上可接受的盐、溶液剂、酯、酸、代谢物或原药。本发明还涉及一种包含激酶抑制剂的药物组合物，以及使用这些化合物和组合物抑制细胞或受试者体内野生型FLT3、突变型FLT3-ITD、PDGFRα和/或PDGFRβ激酶活性的用途和方法，以及这些化合物和组合物预防或治疗受试者体内激酶相关疾病的用途和方法。
• PYRIMIDINE DERIVATIVE KINASE INHIBITORS
  申请人：HEFEI INSTITUTES OF PHYSICAL SCIENCE, CHINESE ACADEMY OF SCIENCES

  公开号：US20200323850A1

  公开（公告）日：2020-10-15

  The present invention relates to a kinase inhibitor, comprising a compound of Formula I or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof. The present invention also relates to a pharmaceutical composition comprising the kinase inhibitor, and to uses and methods for using these compounds and compositions to inhibit the activity of wild-type FLT3, mutant FLT3-ITD, PDGFRα and/or PDGFRβ kinase in a cell or a subject, as well as uses and methods of these compounds and compositions to preventing or treating kinase-associated conditions in a subject.
• Discovery of <i>N</i>-(4-(6-Acetamidopyrimidin-4-yloxy)phenyl)-2-(2-(trifluoromethyl)phenyl)acetamide (CHMFL-FLT3-335) as a Potent FMS-like Tyrosine Kinase 3 Internal Tandem Duplication (FLT3-ITD) Mutant Selective Inhibitor for Acute Myeloid Leukemia
  作者：Xiaofei Liang、Beilei Wang、Cheng Chen、Aoli Wang、Chen Hu、Fengming Zou、Kailin Yu、Qingwang Liu、Feng Li、Zhenquan Hu、Tingting Lu、Junjie Wang、Li Wang、Ellen L. Weisberg、Lili Li、Ruixiang Xia、Wenchao Wang、Tao Ren、Jian Ge、Jing Liu、Qingsong Liu

  DOI：10.1021/acs.jmedchem.8b01594

  日期：2019.1.24

  Most of the current FMS-like tyrosine kinase 3 (FLT3) inhibitors lack selectivity between FLT3 kinase and cKIT kinase as well as the FLT3 wt and internal tandem duplication (ITD) mutants. We report a new compound 27, which displays GI(50) values of 30-80 nM against different ITD mutants and achieves selectivity over both FLT3 wt (8-fold) and cKIT kinase in the transformed BaF3 cells (>300-fold). 27 potently inhibits the proliferation of the FLT3-ITD-positive acute myeloid leukemia cancer lines through suppression of the phosphorylation of FLT3 kinase and downstream signaling pathways, induction of apoptosis, and arresting the cell cycle into the G0/G1 phase. 27 also displays potent antiproliferative effect against FLT3-ITD-positive patient primary cells, whereas it does not apparently affect FLT3 wt primary cells. In addition, it also exhibits a good therapeutic window to PBMC compared to PKC412. In the in vivo studies, 27 demonstrates favorable PK profiles and suppresses the tumor growth in the MV4-11 cell inoculated mouse xenograft model.
• 一类嘧啶类衍生物激酶抑制剂
  申请人：中国科学院合肥物质科学研究院

  公开号：CN108368060B

  公开（公告）日：2020-09-15

  本发明涉及一种激酶抑制剂，其包括式I的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药。本发明还涉及包括该激酶抑制剂的药物组合物，以及使用这些化合物和组合物来抑制细胞或受试者的野生型FLT3、突变型FLT3‑ITD、PDGFRα和/或PDGFRβ激酶活性、以及在受试者中预防或治疗激酶相关病症的用途和方法。