(R)-N-(3-(1-amino-3-methyl-3,4-dihydropyrrolo[1,2-a]pyrazin-3-yl)-4-fluorophenyl)-5-cyanopicolinamide | 1398112-69-0

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (R)-N-(3-(1-amino-3-methyl-3,4-dihydropyrrolo[1,2-a]pyrazin-3-yl)-4-fluorophenyl)-5-cyanopicolinamide
• 英文别名: (R)-5-cyano-pyridine-2-carboxylic acid [3-(1-methyl-3,4-dihydro-pyrrolo[1,2-a]pyrazin-3-yl)-4-fluoro-phenyl]-amide；N-{3-[(3R)-1-amino-3-methyl-3,4-dihydropyrrolo[1,2-a]pyrazin-3-yl]-4-fluorophenyl}-5-cyanopyridine-2-carboxamide；N-[3-[(3R)-1-amino-3-methyl-4H-pyrrolo[1,2-a]pyrazin-3-yl]-4-fluorophenyl]-5-cyanopyridine-2-carboxamide
• CAS: 1398112-69-0
• 化学式: C₂₁H₁₇FN₆O
• 分子量: 388.404
• InChiKey: FZFJUKOAGOAQFB-NRFANRHFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  29
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  109
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  (R)-3-(5-bromo-2-fluorophenyl)-1-methoxy-3-methyl-3,4-dihydropyrrolo[1,2-a]pyrazine 在 tris-(dibenzylideneacetone)dipalladium(0) 、 R-(+)-1,1'-联萘-2,2'-双二苯膦 二苯甲酮亚胺 、 氨 、 氯化铵 、 4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐 、 sodium t-butanolate 作用下， 以 甲醇 、 乙醇 、 甲苯 为溶剂， 反应 128.08h， 生成 (R)-N-(3-(1-amino-3-methyl-3,4-dihydropyrrolo[1,2-a]pyrazin-3-yl)-4-fluorophenyl)-5-cyanopicolinamide
  参考文献：
  名称：

  [EN] 3,4-DIHYDRO-PYRROLO[1,2-a]PYRAZIN-1-YLAMINE DERIVATIVES USEFUL AS INHIBITORS OF BETA-SECRETASE (BACE)
  [FR] DÉRIVÉS DE 3,4-DIHYDRO-PYRAZOLO[1,2-A]PYRAZIN-1-YLAMINE UTILES EN TANT QU'INHIBITEURS DE BÊTA-SÉCRÉTASE (BACE)

  摘要：

  本发明涉及作为β-分泌酶抑制剂的新型3,4-二氢吡咯并[l,2-a]吡嗪-1-胺衍生物，该酶也被称为β-位点淀粉样蛋白裂解酶、BACE、BACE1、Asp2或memapsin2。该发明还涉及包含这些化合物的药物组合物，用于制备这些化合物和组合物的方法，以及将这些化合物和组合物用于预防和治疗涉及β-分泌酶的疾病，如阿尔茨海默病（AD）、轻度认知障碍、老年痴呆、带有Lewy小体的痴呆、唐氏综合征、与中风相关的痴呆、与帕金森病相关的痴呆或与β-淀粉样蛋白相关的痴呆。

  公开号：

  WO2012120023A1

文献信息

• [EN] 3,4-DIHYDRO-PYRROLO[1,2-a]PYRAZIN-1-YLAMINE DERIVATIVES USEFUL AS INHIBITORS OF BETA-SECRETASE (BACE)<br/>[FR] DÉRIVÉS DE 3,4-DIHYDRO-PYRAZOLO[1,2-A]PYRAZIN-1-YLAMINE UTILES EN TANT QU'INHIBITEURS DE BÊTA-SÉCRÉTASE (BACE)
  申请人：JANSSEN PHARMACEUTICA NV

  公开号：WO2012120023A1

  公开（公告）日：2012-09-13

  The present invention relates to novel 3,4-dihydro-pyrrolo[l,2-a]pyrazin-1-ylamine derivatives as inhibitors of beta-secretase, also known as beta-site amyloid cleaving enzyme, BACE, BACE1, Asp2, or memapsin2. The invention is also directed to pharmaceutical compositions comprising such compounds, to processes for preparing such compounds and compositions, and to the use of such compounds and compositions for the prevention and treatment of disorders in which beta-secretase is involved, such as Alzheimer's disease (AD), mild cognitive impairment, senility, dementia, dementia with Lewy bodies, Down's syndrome, dementia associated with stroke, dementia associated with Parkinson's disease or dementia associated with beta-amyloid.

  本发明涉及作为β-分泌酶抑制剂的新型3,4-二氢吡咯并[l,2-a]吡嗪-1-胺衍生物，该酶也被称为β-位点淀粉样蛋白裂解酶、BACE、BACE1、Asp2或memapsin2。该发明还涉及包含这些化合物的药物组合物，用于制备这些化合物和组合物的方法，以及将这些化合物和组合物用于预防和治疗涉及β-分泌酶的疾病，如阿尔茨海默病（AD）、轻度认知障碍、老年痴呆、带有Lewy小体的痴呆、唐氏综合征、与中风相关的痴呆、与帕金森病相关的痴呆或与β-淀粉样蛋白相关的痴呆。
• 4-AMINO-6-PHENYL-5,6-DIHYDROIMIDAZO[1,5-A]PYRAZINE DERIVATIVES AS INHIBITORS OF BETA-SECRETASE (BACE)
  申请人：JANSSEN PHARMACEUTICA NV

  公开号：US20160115170A1

  公开（公告）日：2016-04-28

  The present invention relates to novel 5,6-dihydroimidazo[1,5-a]pyrazinyl derivatives as inhibitors of beta-secretase, also known as beta-site amyloid cleaving enzyme, BACE, in particular BACE1 and/or BACE2 (wherein BACE1, is also known as Asp2, or memapsin2 and BACE2 is also known as Asp1, Memapsin 1 or DRAP). The invention is also directed to pharmaceutical compositions comprising such compounds, to processes for preparing such compounds and compositions, and to the use of such compounds and compositions for the prevention and treatment of disorders in which beta-secretase is involved, such as Alzheimer's disease (AD), mild cognitive impairment, senility, dementia, dementia with Lewy bodies, Down's syndrome, dementia associated with stroke, dementia associated with Parkinson's disease, dementia of the Alzheimer's type, dementia associated with beta-amyloid, age-related macular degeneration, type 2 diabetes and other metabolic disorders.

  本发明涉及一种新型的5,6-二氢咪唑[1,5-a]吡嗪衍生物，作为β-分泌酶抑制剂，也称为β-淀粉样蛋白分解酶，BACE，特别是BACE1和/或BACE2（其中BACE1也称为Asp2或memapsin2，BACE2也称为Asp1、Memapsin 1或DRAP）。本发明还涉及包含这些化合物的制药组合物、制备这些化合物和组合物的方法，以及利用这些化合物和组合物预防和治疗与β-分泌酶有关的疾病，如阿尔茨海默病（AD）、轻度认知障碍、老年痴呆、帕金森病相关痴呆、Down综合症、中风相关痴呆、β-淀粉样蛋白相关的痴呆、年龄相关性黄斑变性、2型糖尿病和其他代谢性疾病。
• US9580433B2
  申请人：——

  公开号：US9580433B2

  公开（公告）日：2017-02-28
• Evaluation of a Series of β-Secretase 1 Inhibitors Containing Novel Heteroaryl-Fused-Piperazine Amidine Warheads
  作者：Daniel Oehlrich、Aldo Peschiulli、Gary Tresadern、Michiel Van Gool、Juan Antonio Vega、Ana Isabel De Lucas、Sergio A. Alonso de Diego、Hana Prokopcova、Nigel Austin、Sven Van Brandt、Michel Surkyn、Michel De Cleyn、Ann Vos、Frederik J. R. Rombouts、Gregor Macdonald、Dieder Moechars、Harrie J. M. Gijsen、Andrés A. Trabanco

  DOI：10.1021/acsmedchemlett.9b00181

  日期：2019.8.8

  Despite several years of research, only a handful of beta-secretase (BACE) 1 inhibitors have entered clinical trials as potential therapeutics against Alzheimers disease. The intrinsic basic nature of low molecular weight, amidine-containing BACE 1 inhibitors makes them far from optimal as central nervous system drugs. Herein we present a set of novel heteroaryl-fused piperazine amidine inhibitors designed to lower the basicity of the key, enzyme binding, amidine functionality. This study resulted in the identification of highly potent (IC50 <= 10 nM), permeable lead compounds with a reduced propensity to suffer from P-glycoprotein-mediated efflux.