Methyl 1-(5,6-dimethylthieno[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 噻吩并嘧啶酮衍生物
• 英文名称: Methyl 1-(5,6-dimethylthieno[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylate
• 化学式: C₁₅H₁₉N₃O₂S
• 分子量: 305.401
• InChiKey: JLCWWXKPUHFBGI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  21
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  83.6
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  Methyl 1-(5,6-dimethylthieno[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylate 在 氨 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 、 lithium hydroxide 作用下， 以 甲醇 、 水 、 1,2-二氯乙烷 、 N,N-二甲基甲酰胺 为溶剂， 生成 1-(5,6-Dimethylthieno[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide
  参考文献：
  名称：

  Discovery and optimization of a novel series of highly CNS penetrant M 4 PAMs based on a 5,6-dimethyl-4-(piperidin-1-yl)thieno[2,3- d ]pyrimidine core

  摘要：

  This Letter describes the chemical optimization of a novel series of M-4 positive allosteric modulators (PAMs) based on a 5,6-dimethyl-4-(piperidin-1-yl) thieno[2,3-d]pyrimidine core, identified from an MLPCN functional high-throughput screen. The HTS hit was potent and selective, but not CNS penetrant. Potency was maintained, while CNS penetration was improved (rat brain: plasma K-p = 0.74), within the original core after several rounds of optimization; however, the thieno[2,3-d]pyrimidine core was subject to extensive oxidative metabolism. Ultimately, we identified a 6-fluoroquinazoline core replacement that afforded good M-4 PAM potency, muscarinic receptor subtype selectivity and CNS penetration (rat brain:plasma K-p > 10). Moreover, this campaign provided fundamentally distinct M-4 PAM chemotypes, greatly expanding the available structural diversity for this exciting CNS target. (C) 2016 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2016.05.010
• 作为产物：
  描述：

  4-哌啶甲酸甲酯 、 4-氯-5,6-二甲基噻吩[2,3-D]嘧啶 在 N-甲基吡咯烷酮 、 N,N-二异丙基乙胺 作用下， 反应 0.25h， 以90%的产率得到Methyl 1-(5,6-dimethylthieno[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylate
  参考文献：
  名称：

  Discovery and optimization of a novel series of highly CNS penetrant M 4 PAMs based on a 5,6-dimethyl-4-(piperidin-1-yl)thieno[2,3- d ]pyrimidine core

  摘要：

  This Letter describes the chemical optimization of a novel series of M-4 positive allosteric modulators (PAMs) based on a 5,6-dimethyl-4-(piperidin-1-yl) thieno[2,3-d]pyrimidine core, identified from an MLPCN functional high-throughput screen. The HTS hit was potent and selective, but not CNS penetrant. Potency was maintained, while CNS penetration was improved (rat brain: plasma K-p = 0.74), within the original core after several rounds of optimization; however, the thieno[2,3-d]pyrimidine core was subject to extensive oxidative metabolism. Ultimately, we identified a 6-fluoroquinazoline core replacement that afforded good M-4 PAM potency, muscarinic receptor subtype selectivity and CNS penetration (rat brain:plasma K-p > 10). Moreover, this campaign provided fundamentally distinct M-4 PAM chemotypes, greatly expanding the available structural diversity for this exciting CNS target. (C) 2016 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2016.05.010