2-methyl-2-(3-methyl-4-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)propanamide | 1374829-45-4

• 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: 2-methyl-2-(3-methyl-4-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)propanamide
• 英文别名: 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanamide；2-methyl-2-[3-methyl-4-[[4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]pyrazol-1-yl]propanamide
• CAS: 1374829-45-4
• 化学式: C₁₄H₁₈F₃N₇O
• 分子量: 357.338
• InChiKey: FPPNKMUESOMNGR-UHFFFAOYSA-N

物化性质

• 沸点：
  561.0±60.0 °C(Predicted)
• 密度：
  1.45±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  25
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  111
• 氢给体数：
  3
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  2-methyl-2-(3-methyl-4-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)propanamide 在 三氯氧磷 、 ice H2O 、 disodium;carbonate 、 乙酸乙酯 、 氯化钠 、 Sodium sulfate-III 作用下， 以 三氯氧磷 为溶剂， 反应 1.0h， 以to give 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile (100 mg, 42%) as a white solid的产率得到GNE-0877抑制剂
  参考文献：
  名称：

  Pyrazole aminopyrimidine derivatives as LRRK2 modulators

  摘要：

  公式I的化合物或其药学上可接受的盐，其中X，R1，R2，R3，R4和R5的定义如本文所述。还公开了制备该化合物的方法，并将该化合物用于治疗与LRRK2受体相关的疾病，如帕金森病。

  公开号：

  US08815882B2
• 作为产物：
  描述：

  5-溴-2-氯-N-甲基嘧啶-4-胺 在 三氟乙酸 作用下， 以 乙二醇甲醚 为溶剂， 反应 2.0h， 生成 2-methyl-2-(3-methyl-4-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)propanamide
  参考文献：
  名称：

  [EN] PYRAZOLE AMINOPYRIMIDINE DERIVATIVES AS LRRK2 MODULATORS
  [FR] DÉRIVÉS DE PYRAZOLE AMINOPYRIMIDINE EN TANT QUE MODULATEURS DU LRRK2

  摘要：

  化合物的结构式（I）或其药用盐，其中X，R1，R2，R3，R4和R5如本文所定义。还公开了制备这些化合物的方法，并将这些化合物用于治疗与LRRK2受体相关的疾病，如帕金森病。

  公开号：

  WO2012062783A1

文献信息

• [EN] PROCESS FOR THE PREPARATION OF PYRIMIDINYL-4-AMINOPYRAZOLE COMPOUNDS<br/>[FR] PROCÉDÉ DE PRÉPARATION DE COMPOSÉS PYRIMIDINYL-4-AMINOPYRAZOLE
  申请人：DENALI THERAPEUTICS INC

  公开号：WO2019126383A1

  公开（公告）日：2019-06-27

  The present disclosure relates to methods of making LRRK2-inhibiting, pyrimidinyl-4-aminopyrazole compounds and intermediates of formulae I and IV: The compounds are useful as LRRK2 inhibitors in the treatment of LRRK2 mediated diseases, and as intermediates for their manufacture.

  本公开涉及制备抑制LRRK2的嘧啶基-4-氨基吡唑化合物和公式I和IV的中间体的方法：这些化合物在治疗LRRK2介导的疾病中作为LRRK2抑制剂，以及作为其制造的中间体是有用的。
• PYRAZOLE AMINOPYRIMIDINE DERIVATIVES AS LRRK2 MODULATORS
  申请人：Baker-Glenn Charles

  公开号：US20120157427A1

  公开（公告）日：2012-06-21

  Compounds of the formula I: or pharmaceutically acceptable salts thereof, wherein X, R 1 , R 2 , R 3 , R 4 and R 5 are as defined herein. Also disclosed are methods of making the compounds and using the compounds for treatment of diseases associated with LRRK2 receptor, such as Parkinson's disease.

  化合物I的公式为：或其药学上可接受的盐，其中X，R1，R2，R3，R4和R5如本文所定义。还公开了制备该化合物的方法以及使用该化合物治疗与LRRK2受体相关的疾病，如帕金森病的方法。
• Discovery of Highly Potent, Selective, and Brain-Penetrant Aminopyrazole Leucine-Rich Repeat Kinase 2 (LRRK2) Small Molecule Inhibitors
  作者：Anthony A. Estrada、Bryan K. Chan、Charles Baker-Glenn、Alan Beresford、Daniel J. Burdick、Mark Chambers、Huifen Chen、Sara L. Dominguez、Jennafer Dotson、Jason Drummond、Michael Flagella、Reina Fuji、Andrew Gill、Jason Halladay、Seth F. Harris、Timothy P. Heffron、Tracy Kleinheinz、Donna W. Lee、Claire E. Le Pichon、Xingrong Liu、Joseph P. Lyssikatos、Andrew D. Medhurst、John G. Moffat、Kevin Nash、Kimberly Scearce-Levie、Zejuan Sheng、Daniel G. Shore、Susan Wong、Shuo Zhang、Xiaolin Zhang、Haitao Zhu、Zachary K. Sweeney

  DOI：10.1021/jm401654j

  日期：2014.2.13

  Leucine-rich repeat kinase 2 (LRRK2) has drawn significant interest in the neuroscience research community because it is one of the most compelling targets for a potential disease-modifying Parkinson's disease therapy. Herein, we disclose structurally diverse small molecule inhibitors suitable for assessing the implications of sustained in vivo LARK2 inhibition. Using previously reported aminopyrazole 2 as a lead molecule, we were able to engineer structural modifications in the solvent-exposed region of the ATP-binding site that significantly improve human hepatocyte stability, rat free brain exposure, and CYP inhibition and induction liabilities. Disciplined application of established optimal CNS design parameters culminated in the rapid identification of GNE-0877 (11) and GNE-9605 (20) as highly potent and selective LRRK2 inhibitors. The demonstrated metabolic stability, brain penetration across multiple species, and selectivity of these inhibitors support their use in preclinical efficacy and safety studies.
• PROCESS FOR THE PREPARATION OF PYRIMIDINYL-4-AMINOPYRAZOLE COMPOUNDS
  申请人：DENALI THERAPEUTICS INC.

  公开号：US20210009566A1

  公开（公告）日：2021-01-14

  The present disclosure relates to methods of making LRRK2-inhibiting, pyrimidinyl-4-aminopyrazole compounds and intermediates of formulae I and IV: The compounds are useful as LRRK2 inhibitors in the treatment of LRRK2 mediated diseases, and as intermediates for their manufacture.
• US8815882B2
  申请人：——

  公开号：US8815882B2

  公开（公告）日：2014-08-26