N⁴-methyl-N²-(5-methyl-1-(oxetan-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine | 1374825-28-1

• 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: N⁴-methyl-N²-(5-methyl-1-(oxetan-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine
• 英文别名: 4-N-methyl-2-N-[5-methyl-1-(oxetan-3-yl)pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine
• CAS: 1374825-28-1
• 化学式: C₁₃H₁₅F₃N₆O
• 分子量: 328.297
• InChiKey: LKBKYMMKFJAHFT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  23
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  76.9
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  2-氯-N-甲基-5-(三氟甲基)嘧啶-4-胺 、 5-methyl-1-(oxetan-3-yl)-1H-pyrazol-4-amine 在 tris-(dibenzylideneacetone)dipalladium(0) 、 3-methyl-1-(oxetan-3-yl)-1H-pyrazol-4-amine 、 caesium carbonate 、 2-二环己基磷-2,4,6-三异丙基联苯 作用下， 以 1,4-二氧六环 为溶剂， 反应 0.5h， 以4.9%的产率得到N⁴-methyl-N²-(5-methyl-1-(oxetan-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine
  参考文献：
  名称：

  Discovery of Highly Potent, Selective, and Brain-Penetrant Aminopyrazole Leucine-Rich Repeat Kinase 2 (LRRK2) Small Molecule Inhibitors

  摘要：

  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.

  DOI：

  10.1021/jm401654j

文献信息

• [EN] PYRAZOLE AMINOPYRIMIDINE DERIVATIVES AS LRRK2 MODULATORS<br/>[FR] DÉRIVÉS DE PYRAZOLE AMINOPYRIMIDINE EN TANT QUE MODULATEURS DU LRRK2
  申请人：HOFFMANN LA ROCHE

  公开号：WO2012062783A1

  公开（公告）日：2012-05-18

  Compounds of the formula (I), or pharmaceutically acceptable salts thereof, wherein X, R1, R2, R3, R4 and R5 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。
• 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。
• ASSAYS AND BIOMARKERS FOR LRRK2
  申请人：Genentech, Inc.

  公开号：EP2646819A1

  公开（公告）日：2013-10-09
• US8815882B2
  申请人：——

  公开号：US8815882B2

  公开（公告）日：2014-08-26
• [EN] ASSAYS AND BIOMARKERS FOR LRRK2<br/>[FR] TESTS ET BIOMARQUEURS DESTINÉS AU LRRK2
  申请人：GENENTECH INC

  公开号：WO2012075046A1

  公开（公告）日：2012-06-07

  Biomarkers for screening subjects for Parkinson's disease and providing companion diagnostic tools for therapies using LRRK2 modulators, and assays for screening compounds and compositions for modulation of LRRK2 activity.