(S)-N-(2-(diethylamino)propyl)-2-(3-hydroxyazetidin-1-yl)-6-(5-(thiophen-2-yl)pyrazolo[1,5-a]pyrimidin-3-yl)isonicotinamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: (S)-N-(2-(diethylamino)propyl)-2-(3-hydroxyazetidin-1-yl)-6-(5-(thiophen-2-yl)pyrazolo[1,5-a]pyrimidin-3-yl)isonicotinamide
• 英文别名: US10100058, Example 145；N-[(2S)-2-(diethylamino)propyl]-2-(3-hydroxyazetidin-1-yl)-6-(5-thiophen-2-ylpyrazolo[1,5-a]pyrimidin-3-yl)pyridine-4-carboxamide
• 化学式: C₂₆H₃₁N₇O₂S
• 分子量: 505.644
• InChiKey: OFBABNCAYHDFSH-KRWDZBQOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  36
• 可旋转键数：
  9
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  127
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  5-氯吡唑并[1,5-a]嘧啶 在 N-溴代丁二酰亚胺(NBS) 、 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 水 、 potassium acetate 、 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 、 N-甲基吡咯烷酮 、 甲醇 、 氯仿 、 水 、 二甲基亚砜 为溶剂， 反应 66.0h， 生成 (S)-N-(2-(diethylamino)propyl)-2-(3-hydroxyazetidin-1-yl)-6-(5-(thiophen-2-yl)pyrazolo[1,5-a]pyrimidin-3-yl)isonicotinamide
  参考文献：
  名称：

  发现钙调蛋白依赖性激酶II（CaMKII）的有效和选择性抑制剂

  摘要：

  我们在此披露了发现的CaMKII抑制剂（7h和7i）在大鼠心室肌细胞中具有强效，对hERG和其他脱靶激酶具有选择性，同时具有良好的CaMKII组织同工型选择性（心脏γ/δ与神经元α/ β）。体外和体内ADME / PK研究证明了这些CaMKII抑制剂对PO（7h大鼠F = 73％）和IV药理学研究的适用性。

  DOI：

  10.1016/j.bmcl.2017.10.040

文献信息

• FUSED HETEROCYCLIC COMPOUNDS AS CAM KINASE INHIBITORS
  申请人：Gilead Sciences, Inc.

  公开号：US20180148457A1

  公开（公告）日：2018-05-31

  The present disclosure relates to compounds that are CaM Kinase inhibitors and to their use in the treatment of various disease states, including atrial fibrillation and myocardial infarction. In particular embodiments, the general structure of the compounds is given by Formula I: wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9 and R 10 are as described herein, to methods for the preparation and use of the compounds and to pharmaceutical compositions containing the same.

  本公开涉及的化合物是CaM激酶抑制剂，用于治疗各种疾病状态，包括心房颤动和心肌梗死。在特定实施例中，化合物的一般结构由公式I给出：其中R1、R2、R3、R4、R5、R6、R9和R10如本文所述，涉及化合物的制备和使用方法以及含有相同化合物的药物组合物。
• Fused heterocyclic compounds as CaM kinase inhibitors
  申请人：Gilead Sciences, Inc.

  公开号：US10100058B2

  公开（公告）日：2018-10-16

  The present disclosure relates to compounds that are CaM Kinase inhibitors and to their use in the treatment of various disease states, including atrial fibrillation and myocardial infarction. In particular embodiments, the general structure of the compounds is given by Formula I: wherein R1, R2, R3, R4, R5, R6, R9 and R10 are as described herein, to methods for the preparation and use of the compounds and to pharmaceutical compositions containing the same.

  本公开涉及作为 CaM 激酶抑制剂的化合物及其在治疗包括心房颤动和心肌梗塞在内的各种疾病状态中的用途。在特定的实施方案中，化合物的一般结构由式 I 给出： 其中 R1、R2、R3、R4、R5、R6、R9 和 R10 如本文所述。
• PYRAZOLOPYRIMIDINE DERIVATIVES AS CAM KINASE INHIBITORS
  申请人：Gilead Sciences, Inc.

  公开号：EP3548495A1

  公开（公告）日：2019-10-09
• [EN] PYRAZOLOPYRIMIDINE DERIVATIVES AS CAM KINASE INHIBITORS<br/>[FR] DÉRIVÉS DE PYRAZOLOPYRIMIDINE EN TANT QU'INHIBITEURS DE KINASE CAM
  申请人：GILEAD SCIENCES INC

  公开号：WO2018102384A1

  公开（公告）日：2018-06-07

  The present disclosure relates to compounds that are CaM Kinase inhibitors and to their use in the treatment of various disease states, including atrial fibrillation and myocardial infarction. In particular embodiments, the general structure of the compounds is given by Formula I: (I) wherein R1, R2, R3, R4, R5, R6, R9 and R10 are as described herein, to methods for the preparation and use of the compounds and to pharmaceutical compositions containing the same.
• Discovery of potent and selective inhibitors of calmodulin-dependent kinase II (CaMKII)
  作者：Dmitry O. Koltun、Eric Q. Parkhill、Rao Kalla、Thao D. Perry、Elfatih Elzein、Xiaofen Li、Scott P. Simonovich、Christopher Ziebenhaus、Timothy R. Hansen、Bruno Marchand、WaiLok K. Hung、Leanna Lagpacan、Magdeleine Hung、Ron G. Aoyama、Bernard P. Murray、Jason K. Perry、John R. Somoza、Armando G. Villaseñor、Nikos Pagratis、Jeff A. Zablocki

  DOI：10.1016/j.bmcl.2017.10.040

  日期：2018.2

  We hereby disclose the discovery of inhibitors of CaMKII (7h and 7i) that are highly potent in rat ventricular myocytes, selective against hERG and other off-target kinases, while possessing good CaMKII tissue isoform selectivity (cardiac γ/δ vs. neuronal α/β). In vitro and in vivo ADME/PK studies demonstrated the suitability of these CaMKII inhibitors for PO (7h rat F = 73%) and IV pharmacological

  我们在此披露了发现的CaMKII抑制剂（7h和7i）在大鼠心室肌细胞中具有强效，对hERG和其他脱靶激酶具有选择性，同时具有良好的CaMKII组织同工型选择性（心脏γ/δ与神经元α/ β）。体外和体内ADME / PK研究证明了这些CaMKII抑制剂对PO（7h大鼠F = 73％）和IV药理学研究的适用性。