N-(4-(3-(2-aminopyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-(5-methylpyridin-2-yl)phthalazin-1-amine

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: N-(4-(3-(2-aminopyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-(5-methylpyridin-2-yl)phthalazin-1-amine
• 英文别名: N-(4-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-(5-methyl-2-pyridinyl)-1-phthalazinamine；N-[4-[3-(2-aminopyrimidin-4-yl)pyridin-2-yl]oxyphenyl]-4-(5-methylpyridin-2-yl)phthalazin-1-amine
• 化学式: C₂₉H₂₂N₈O
• 分子量: 498.547
• InChiKey: AJZHFGIIOVOHLB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  38
• 可旋转键数：
  6
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.03
• 拓扑面积：
  125
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  2-溴-5-甲基吡啶 在 肼 、 三氯氧磷 作用下， 以 乙醇 、 仲丁醇 为溶剂， 反应 24.0h， 生成 N-(4-(3-(2-aminopyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-(5-methylpyridin-2-yl)phthalazin-1-amine
  参考文献：
  名称：

  Discovery of N-(4-(3-(2-Aminopyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-(4-methylthiophen-2-yl)phthalazin-1-amine (AMG 900), A Highly Selective, Orally Bioavailable Inhibitor of Aurora Kinases with Activity against Multidrug-Resistant Cancer Cell Lines

  摘要：

  Efforts to improve upon the physical properties and metabolic stability of Aurora kinase inhibitor 14a revealed that potency against multidrug-resistant cell lines was compromised by increased polarity. Despite its high in vitro metabolic intrinsic clearance, 23r (AMG 900) showed acceptable pharmacokinetic properties and robust pharmacodynamic activity. Projecting from in vitro data to in vivo target coverage was not practical due to disjunctions between enzyme and cell data, complex and apparently contradictory indicators of binding kinetics, and unmeasurable free fraction in plasma. In contrast, it was straightforward to relate pharmacokinetics to pharmacodynamics and efficacy by following the time above a threshold concentration. On the basis of its oral route of administration, a selectivity profile that favors Aurora-driven pharmacology and its activity against multidrug-resistant cell lines, 23r was identified as a potential best-in-class Aurora kinase inhibitor. In phase 1 dose expansion studies with G-CSF support, 23r has shown promising single agent activity.

  DOI：

  10.1021/acs.jmedchem.5b00183

文献信息

• Aurora Kinase Modulators and Method of Use
  申请人：CEE Victor J.

  公开号：US20110263530A1

  公开（公告）日：2011-10-27

  The present invention relates to chemical compounds having a general formula I wherein A 1 , A 2 , C 1 , C 2 , D, L 1 , L 2 , Z and R 3 , R 4 , R 6 , R 7 and R 8 are defined herein, which are capable of modulating Aurora kinase protein activity, thereby influencing various disease states and conditions related to the activities of Aurora kinase proteins. For example, the compounds are capable of influencing the process of cell cycle and cell proliferation to treat cancer and cancer-related diseases. The invention also includes pharmaceutical compositions, processes of preparing compounds of the invention, synthetic intermediates and methods of treatment of conditions related to the activity of Aurora kinase.

  本发明涉及具有一般式I的化合物，其中定义了A1、A2、C1、C2、D、L1、L2、Z和R3、R4、R6、R7和R8，这些化合物能够调节极化激酶蛋白活性，从而影响与极化激酶蛋白活性相关的各种疾病状态和情况。例如，这些化合物能够影响细胞周期和细胞增殖的过程，以治疗癌症和与癌症相关的疾病。本发明还包括制备本发明化合物的药物组合物、合成中间体和治疗与极化激酶活性相关疾病的方法。
• AURORA KINASE MODULATORS AND METHOD OF USE
  申请人：Amgen Inc.

  公开号：US20140066430A1

  公开（公告）日：2014-03-06

  The present invention relates to chemical compounds having a general formula I wherein A 1 , A 2 , C 1 , C 2 , D, L 1 , L 2 , Z and R 3 , R 4 , R 6 , R 7 and R 8 are defined herein, which are capable of modulating Aurora kinase protein activity, thereby influencing various disease states and conditions related to the activities of Aurora kinase proteins. For example, the compounds are capable of influencing the process of cell cycle and cell proliferation to treat cancer and cancer-related diseases. The invention also includes pharmaceutical compositions, processes of preparing compounds of the invention, synthetic intermediates and methods of treatment of conditions related to the activity of Aurora kinase.

  本发明涉及具有一般式I的化合物，其中A1，A2，C1，C2，D，L1，L2，Z和R3，R4，R6，R7和R8在此定义，这些化合物能够调节极化激酶蛋白活性，从而影响与极化激酶蛋白活动相关的各种疾病状态和病情。例如，这些化合物能够影响细胞周期和细胞增殖过程，以治疗癌症和癌症相关疾病。本发明还包括制备本发明化合物的药物组合物、合成中间体和治疗与极化激酶活性相关疾病的方法。
• Aurora kinase modulators and method of use
  申请人：Cee Victor J.

  公开号：US20090163501A1

  公开（公告）日：2009-06-25

  The present invention relates to chemical compounds having a general formula I wherein A 1 , A 2 , C 1 , C 2 , D, L 1 , L 2 , Z and R 3 , R 4 , R 6 , R 7 and R 8 are defined herein, which are capable of modulating Aurora kinase protein activity, thereby influencing various disease states and conditions related to the activities of Aurora kinase proteins. For example, the compounds are capable of influencing the process of cell cycle and cell proliferation to treat cancer and cancer-related diseases. The invention also includes pharmaceutical compositions, processes of preparing compounds of the invention, synthetic intermediates and methods of treatment of conditions related to the activity of Aurora kinase.

  本发明涉及具有一般式I的化合物，其中A1、A2、C1、C2、D、L1、L2、Z和R3、R4、R6、R7和R8在此被定义，这些化合物能够调节极化激酶蛋白的活性，从而影响与极化激酶蛋白的活动相关的各种疾病状态和条件。例如，这些化合物能够影响细胞周期和细胞增殖的过程，以治疗癌症和癌症相关疾病。本发明还包括制药组合物、制备本发明化合物的过程、合成中间体和治疗与极化激酶活性相关的疾病的方法。
• US7560551B2
  申请人：——

  公开号：US7560551B2

  公开（公告）日：2009-07-14
• US8022221B2
  申请人：——

  公开号：US8022221B2

  公开（公告）日：2011-09-20