(5-Amino-3,4-dimethylthieno[2,3-c]pyridazin-6-yl)-[3-fluoro-3-(3-fluorophenyl)azetidin-1-yl]methanone | 1451996-05-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 氮杂环丁烷
• 英文名称: (5-Amino-3,4-dimethylthieno[2,3-c]pyridazin-6-yl)-[3-fluoro-3-(3-fluorophenyl)azetidin-1-yl]methanone
• 英文别名: (5-amino-3,4-dimethylthieno[2,3-c]pyridazin-6-yl)-[3-fluoro-3-(3-fluorophenyl)azetidin-1-yl]methanone
• CAS: 1451996-05-6
• 化学式: C₁₈H₁₆F₂N₄OS
• 分子量: 374.414
• InChiKey: TYUOZIKLBHKFBG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  26
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  100
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  在 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 、 三氟乙酸 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 生成 (5-Amino-3,4-dimethylthieno[2,3-c]pyridazin-6-yl)-[3-fluoro-3-(3-fluorophenyl)azetidin-1-yl]methanone
  参考文献：
  名称：

  Challenges in the development of an M 4 PAM preclinical candidate: The discovery, SAR, and biological characterization of a series of azetidine-derived tertiary amides

  摘要：

  Herein we describe the continued optimization of M-4 positive allosteric modulators (PAMs) within the 5-amino-thieno[2,3-c] pyridazine series of compounds. In this letter, we disclose our studies on tertiary amides derived from substituted azetidines. This series provided excellent CNS penetration, which had been challenging to consistently achieve in other amide series. Efforts to mitigate high clearance, aided by metabolic softspot analysis, were unsuccessful and precluded this series from further consideration as a preclinical candidate. In the course of this study, we found that potassium tetrafluoroborate salts could be engaged in a tosyl hydrazone reductive cross coupling reaction, a previously unreported transformation, which expands the synthetic utility of the methodology. (C) 2017 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2017.10.053

文献信息

• [EN] SUBSTITUTED 5-AMINOTHIENO[2,3-C]PYRIDAZINE-6-CARBOXAMIDE ANALOGS AS POSITIVE ALLOSTERIC MODULATORS OF THE MUSCARINIC ACETYLCHOLINE RECEPTOR M4<br/>[FR] ANALOGUES DE 5-AMINOTHIÉNO[2,3-C]PYRIDAZINE-6-CARBOXAMIDE SUBSTITUÉS EN TANT QUE MODULATEURS ALLOSTÉRIQUES POSITIFS DU RÉCEPTEUR MUSCARINIQUE DE L'ACÉTYLCHOLINE M4
  申请人：UNIV VANDERBILT

  公开号：WO2013126856A1

  公开（公告）日：2013-08-29

  In one aspect, the invention relates to substituted 5-aminothieno[2,3-c]pyridazine-6- carboxamide analogs, derivatives thereof, and related compounds, which are useful as positive allosteric modulators of the muscarinic acetylcholine receptor M4 (mAChR M4); synthesis methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

  在一个方面，该发明涉及替代的5-氨基噻吩[2,3-c]吡啶嗪-6-羧酰胺类似物，其衍生物和相关化合物，这些化合物可用作肌胆碱受体M4（mAChR M4）的正向变构调节剂；制备这些化合物的合成方法；包括这些化合物的药物组合物；以及使用这些化合物和组合物治疗与肌胆碱受体功能障碍相关的神经和精神疾病的方法。本摘要旨在作为在特定领域进行搜索的扫描工具，并不意味着对本发明的限制。
• SUBSTITUTED 5-AMINOTHIENO[2,3-C]PYRIDAZINE-6-CARBOXAMIDE ANALOGS AS POSITIVE ALLOSTERIC MODULATORS OF THE MUSCARINIC ACETYLCHOLINE RECEPTOR M4
  申请人：Vanderbilt University

  公开号：EP2817295B1

  公开（公告）日：2017-11-01
• US9493481B2
  申请人：——

  公开号：US9493481B2

  公开（公告）日：2016-11-15
• US9868746B2
  申请人：——

  公开号：US9868746B2

  公开（公告）日：2018-01-16
• Challenges in the development of an M 4 PAM preclinical candidate: The discovery, SAR, and biological characterization of a series of azetidine-derived tertiary amides
  作者：James C. Tarr、Michael R. Wood、Meredith J. Noetzel、Bruce J. Melancon、Atin Lamsal、Vincent B. Luscombe、Alice L. Rodriguez、Frank W. Byers、Sichen Chang、Hyekyung P. Cho、Darren W. Engers、Carrie K. Jones、Colleen M. Niswender、Michael W. Wood、Nicholas J. Brandon、Mark E. Duggan、P. Jeffrey Conn、Thomas M. Bridges、Craig W. Lindsley

  DOI：10.1016/j.bmcl.2017.10.053

  日期：2017.12

  Herein we describe the continued optimization of M-4 positive allosteric modulators (PAMs) within the 5-amino-thieno[2,3-c] pyridazine series of compounds. In this letter, we disclose our studies on tertiary amides derived from substituted azetidines. This series provided excellent CNS penetration, which had been challenging to consistently achieve in other amide series. Efforts to mitigate high clearance, aided by metabolic softspot analysis, were unsuccessful and precluded this series from further consideration as a preclinical candidate. In the course of this study, we found that potassium tetrafluoroborate salts could be engaged in a tosyl hydrazone reductive cross coupling reaction, a previously unreported transformation, which expands the synthetic utility of the methodology. (C) 2017 Elsevier Ltd. All rights reserved.