6-(5-methoxypyridin-3-yl)-2-(3,5-dimethyl-pyrazol-1-yl)-pyrimidin-4-ylamine | 1082056-69-6

• 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: 6-(5-methoxypyridin-3-yl)-2-(3,5-dimethyl-pyrazol-1-yl)-pyrimidin-4-ylamine
• 英文别名: 2-(3,5-Dimethylpyrazol-1-yl)-6-(5-methoxypyridin-3-yl)pyrimidin-4-amine
• CAS: 1082056-69-6
• 化学式: C₁₅H₁₆N₆O
• 分子量: 296.332
• InChiKey: NDTBAOJYPLTXRR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  22
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  91.7
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  6-(5-methoxypyridin-3-yl)-2-(3,5-dimethyl-pyrazol-1-yl)-pyrimidin-4-ylamine 在 吡啶 、 T406石油添加剂 、 氯化亚砜 、 lithium iodide 作用下， 以 二氯甲烷 为溶剂， 反应 25.0h， 生成
  参考文献：
  名称：

  设计和合成三取代嘧啶衍生物作为针对 A2A 腺苷受体和组蛋白脱乙酰酶的双功能肿瘤免疫治疗剂

  摘要：

  A 2A腺苷受体（A 2A AR）作为一种新兴的免疫治疗靶点引起了人们的关注，多种拮抗剂正在临床试验中进行评估。然而，A 2A AR拮抗剂作为单一疗法的疗效有限。在此，我们基于 A 2A AR 拮抗剂PBF-509的核心结构，介绍了一系列新型 A 2A AR/组蛋白脱乙酰酶 (HDAC) 双功能抑制剂的设计和合成。新化合物采用药效团合并策略设计，具有三取代嘧啶核心。测试了所有新化合物对A 2A AR的结合亲和力和对 HDAC 的抑制活性。与 HDAC 抑制剂SAHA和MGCD-0103相比，许多化合物在体外对这两个靶点均表现出纳摩尔或亚纳摩尔活性，其中一些化合物对 MC38、CT26 和 HCT116 结肠癌细胞系表现出同等有效的抗增殖活性。通过分子对接研究预测了化合物5a在 A 2A AR 和 HDAC1 中的结合姿势。总的来说，这些结果表明这些三取代嘧啶衍生物是开发 A 2A AR/HDAC

  DOI：

  10.1016/j.cclet.2023.108136
• 作为产物：
  描述：

  N-[2-(3,5-dimethyl-pyrazol-1-yl)-6-(5-methoxy-pyridin-3-yl)-pyrimidin-4-yl]-acetamide 在 potassium carbonate 作用下， 以 甲醇 为溶剂， 反应 16.0h， 以92%的产率得到6-(5-methoxypyridin-3-yl)-2-(3,5-dimethyl-pyrazol-1-yl)-pyrimidin-4-ylamine
  参考文献：
  名称：

  Lead Optimization of 4-Acetylamino-2-(3,5-dimethylpyrazol-1-yl)-6-pyridylpyrimidines as A_2A Adenosine Receptor Antagonists for the Treatment of Parkinson’s Disease

  摘要：

  4-Acetylamino-2-(3,5-dimethylpyrazol-1-yl)-pyrimidines bearing substituted pyridyl groups as C-6 substituents were prepared as selective adenosine hA(2A) receptor antagonists for the treatment of Parkinson's disease. The 5-methoxy-3-pyridyl derivative 6g (hA(2A) K-i 2.3 nM, hA(1) K-i 190 nM) was orally active at 3 mg/kg in a rat HIC model but exposure was poor in nonrodent species, presumably due to poor aqueous solubility. Follow-on compound 16a (hA(2A) K-i 0.83 nM, hA(1) K-i 130 nM), bearing a 6-(morpholin-4-yl)-2-pyridyl substituent at C-6, had improved solubility and was orally efficacious (3 mg/kg, HIC) but showed time-dependent cytochrome P450 3A4 inhibition, possibly related to morpholine ring metabolism. Compound 16j (hA(2A) K-i 0.44 nM, hA(1) K-i 80 nM), bearing a 6-(4-methoxypiperidin-1-yl)-2-pyridyl substituent at C-6, was sparingly soluble but had good oral exposure in rodent and nonrodent species, had no cytochrome P450 or human ether-a-go-go related gene channel issues, and was orally efficacious at 1 mg/kg in HIC and at 3 mg/kg for potentiation Of L-dopa-induced contralateral rotations in 6-hydroxydopamine-lesioned rats.

  DOI：

  10.1021/jm800851u

文献信息

• Lead Optimization of 4-Acetylamino-2-(3,5-dimethylpyrazol-1-yl)-6-pyridylpyrimidines as A_2A Adenosine Receptor Antagonists for the Treatment of Parkinson’s Disease
  作者：Xiaohu Zhang、John E. Tellew、Zhiyong Luo、Manisha Moorjani、Emily Lin、Marion C. Lanier、Yongsheng Chen、John P. Williams、John Saunders、Sandra M. Lechner、Stacy Markison、Tanya Joswig、Robert Petroski、Jaime Piercey、William Kargo、Siobhan Malany、Mark Santos、Raymond S. Gross、Jenny Wen、Kayvon Jalali、Zhihong O’Brien、Carol E. Stotz、María I. Crespo、José-Luis Díaz、Deborah H. Slee

  DOI：10.1021/jm800851u

  日期：2008.11.27

  4-Acetylamino-2-(3,5-dimethylpyrazol-1-yl)-pyrimidines bearing substituted pyridyl groups as C-6 substituents were prepared as selective adenosine hA(2A) receptor antagonists for the treatment of Parkinson's disease. The 5-methoxy-3-pyridyl derivative 6g (hA(2A) K-i 2.3 nM, hA(1) K-i 190 nM) was orally active at 3 mg/kg in a rat HIC model but exposure was poor in nonrodent species, presumably due to poor aqueous solubility. Follow-on compound 16a (hA(2A) K-i 0.83 nM, hA(1) K-i 130 nM), bearing a 6-(morpholin-4-yl)-2-pyridyl substituent at C-6, had improved solubility and was orally efficacious (3 mg/kg, HIC) but showed time-dependent cytochrome P450 3A4 inhibition, possibly related to morpholine ring metabolism. Compound 16j (hA(2A) K-i 0.44 nM, hA(1) K-i 80 nM), bearing a 6-(4-methoxypiperidin-1-yl)-2-pyridyl substituent at C-6, was sparingly soluble but had good oral exposure in rodent and nonrodent species, had no cytochrome P450 or human ether-a-go-go related gene channel issues, and was orally efficacious at 1 mg/kg in HIC and at 3 mg/kg for potentiation Of L-dopa-induced contralateral rotations in 6-hydroxydopamine-lesioned rats.
• Design and synthesis of tri-substituted pyrimidine derivatives as bifunctional tumor immunotherapeutic agents targeting both A2A adenosine receptors and histone deacetylases
  作者：Ruiquan Liu、Wenwen Duan、Wenzhong Yan、Jinfeng Zhang、Jianjun Cheng

  DOI：10.1016/j.cclet.2023.108136

  日期：2023.1

  The A2A adenosine receptor (A2AAR) has attracted attention as an emerging immunotherapeutic target with several antagonists being evaluated in clinical trials. However, A2AAR antagonists show limited efficacy as monotherapies. Herein, we communicate our design and synthesis of a novel series of A2AAR/histone deacetylase (HDAC) bifunctional inhibitors, based on the core structure of the A2AAR antagonist

  A 2A腺苷受体（A 2A AR）作为一种新兴的免疫治疗靶点引起了人们的关注，多种拮抗剂正在临床试验中进行评估。然而，A 2A AR拮抗剂作为单一疗法的疗效有限。在此，我们基于 A 2A AR 拮抗剂PBF-509的核心结构，介绍了一系列新型 A 2A AR/组蛋白脱乙酰酶 (HDAC) 双功能抑制剂的设计和合成。新化合物采用药效团合并策略设计，具有三取代嘧啶核心。测试了所有新化合物对A 2A AR的结合亲和力和对 HDAC 的抑制活性。与 HDAC 抑制剂SAHA和MGCD-0103相比，许多化合物在体外对这两个靶点均表现出纳摩尔或亚纳摩尔活性，其中一些化合物对 MC38、CT26 和 HCT116 结肠癌细胞系表现出同等有效的抗增殖活性。通过分子对接研究预测了化合物5a在 A 2A AR 和 HDAC1 中的结合姿势。总的来说，这些结果表明这些三取代嘧啶衍生物是开发 A 2A AR/HDAC