cis-2,6-dimethyl-4-(4-(5-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-3-yl)pyridin-2-yl)morpholine

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡唑类
• 英文名称: cis-2,6-dimethyl-4-(4-(5-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-3-yl)pyridin-2-yl)morpholine
• 英文别名: (2R,6S)-2,6-dimethyl-4-[4-[5-(1-methylpyrazol-4-yl)-1H-indazol-3-yl]pyridin-2-yl]morpholine
• 化学式: C₂₂H₂₄N₆O
• 分子量: 388.472
• InChiKey: HBXHVLCJHPPPMZ-GASCZTMLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  29
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  71.9
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  3-(2-chloropyridin-4-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-trityl-1H-indazole 、 cis-2,6-dimethylmorpholine 在 tris-(dibenzylideneacetone)dipalladium(0) 、 sodium t-butanolate 、 1,3-双-(2,6-二异丙基苯基)咪唑鎓氯化物 、 三氟乙酸 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 水 为溶剂， 以50 %的产率得到cis-2,6-dimethyl-4-(4-(5-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-3-yl)pyridin-2-yl)morpholine
  参考文献：
  名称：

  用于治疗帕金森病的强效、选择性和脑渗透性 1-Heteroaryl-1H-Indazole LRRK2 激酶抑制剂的发现和优化

  摘要：

  抑制富含亮氨酸重复激酶 2 (LRRK2) 激酶活性代表了一种治疗帕金森病的遗传支持、化学易处理和潜在的疾病缓解机制。在此，我们描述了一系列新型强效选择性中枢神经系统 (CNS) 渗透剂 1-杂芳基-1 H-吲唑 I 型（ATP 竞争性）LRRK2 抑制剂的优化。I 型 ATP 竞争性激酶物理化学特性通过基于结构的药物设计与 sp 3 –sp 2交叉偶联技术实现的平行药物化学相结合，与 CNS 类药物特性相结合。这导致发现了一个独特的 sp 3- 丰富的螺腈基序赋予非凡的效力、药代动力学和有利的 CNS 药物样特性。先导化合物25在人外周血单核细胞中表现出卓越的靶向效力、出色的脱靶激酶选择性和大鼠的良好脑暴露，最终实现低预计人体剂量和临床前安全性，值得进步对临床前候选启用研究。

  DOI：

  10.1021/acs.jmedchem.2c01605

文献信息

• COMPOUNDS INHIBITING LEUCINE-RICH REPEAT KINASE ENZYME ACTIVITY
  申请人：MERCK SHARP & DOHME CORP.

  公开号：US20160009682A1

  公开（公告）日：2016-01-14

  The present invention is directed to indazole compounds which are potent inhibitors of LRRK2 kinase and useful in the treatment or prevention of diseases in which the LRRK2 kinase is involved, such as Parkinson's Disease. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which LRRK-2 kinase is involved.

  本发明涉及一种indazole化合物，该化合物是LRRK2激酶的有效抑制剂，并可用于治疗或预防LRRK2激酶参与的疾病，如帕金森病。本发明还涉及包含这些化合物的药物组合物以及在预防或治疗LRRK-2激酶参与的这些疾病中使用这些化合物和组合物。
• PHOSPHO-RAB ANTIBODIES, ASSAYS AND METHODS OF USE THEREOF
  申请人：Denali Therapeutics Inc.

  公开号：US20210147573A1

  公开（公告）日：2021-05-20

  In one aspect, antibodies that specifically bind to a phosphorylated Rab protein are provided. In some embodiments, the antibody is a monoclonal antibody that specifically binds to a phosphorylated human Rab10 protein and recognizes an epitope within or comprising the sequence AGQERFH(pT)ITTSYYR. In some embodiments, the antibody is a monoclonal antibody that specifically binds to a phosphorylated human Rab8a protein and recognizes an epitope within or comprising the sequence QERFR(pT)ITTAY. Methods and materials for detecting LRRK2 and Rab protein are also provided.
• US9440952B2
  申请人：——

  公开号：US9440952B2

  公开（公告）日：2016-09-13
• [EN] COMPOUNDS INHIBITING LEUCINE-RICH REPEAT KINASE ENZYME ACTIVITY<br/>[FR] COMPOSÉS INHIBANT L'ACTIVITÉ ENZYMATIQUE DE LA KINASE À RÉPÉTITION RICHE EN LEUCINE
  申请人：MERCK SHARP & DOHME

  公开号：WO2014137728A1

  公开（公告）日：2014-09-12

  The present invention is directed to indazole compounds which are potent inhibitors of LRRK2 kinase and useful in the treatment or prevention of diseases in which the LRRK2 kinase is involved, such as Parkinson's Disease. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which LRRK-2 kinase is involved.
• Discovery and Optimization of Potent, Selective, and Brain-Penetrant 1-Heteroaryl-1<i>H</i>-Indazole LRRK2 Kinase Inhibitors for the Treatment of Parkinson’s Disease
  作者：David A. Candito、Vladimir Simov、Anmol Gulati、Solomon Kattar、Ryan W. Chau、Blair T. Lapointe、Joey L. Methot、Duane E. DeMong、Thomas H. Graham、Ravi Kurukulasuriya、Mitchell H. Keylor、Ling Tong、Gregori J. Morriello、John J. Acton、Barbara Pio、Weiguo Liu、Jack D. Scott、Michael J. Ardolino、Theodore A. Martinot、Matthew L. Maddess、Xin Yan、Hakan Gunaydin、Rachel L. Palte、Spencer E. McMinn、Lisa Nogle、Hongshi Yu、Ellen C. Minnihan、Charles A. Lesburg、Ping Liu、Jing Su、Laxminarayan G. Hegde、Lily Y. Moy、Janice D. Woodhouse、Robert Faltus、Tina Xiong、Paul Ciaccio、Jennifer A. Piesvaux、Karin M. Otte、Matthew E. Kennedy、David Jonathan Bennett、Erin F. DiMauro、Matthew J. Fell、Santhosh Neelamkavil、Harold B. Wood、Peter H. Fuller、J. Michael Ellis

  DOI：10.1021/acs.jmedchem.2c01605

  日期：2022.12.22

  activity represents a genetically supported, chemically tractable, and potentially disease-modifying mechanism to treat Parkinson’s disease. Herein, we describe the optimization of a novel series of potent, selective, central nervous system (CNS)-penetrant 1-heteroaryl-1H-indazole type I (ATP competitive) LRRK2 inhibitors. Type I ATP-competitive kinase physicochemical properties were integrated with

  抑制富含亮氨酸重复激酶 2 (LRRK2) 激酶活性代表了一种治疗帕金森病的遗传支持、化学易处理和潜在的疾病缓解机制。在此，我们描述了一系列新型强效选择性中枢神经系统 (CNS) 渗透剂 1-杂芳基-1 H-吲唑 I 型（ATP 竞争性）LRRK2 抑制剂的优化。I 型 ATP 竞争性激酶物理化学特性通过基于结构的药物设计与 sp 3 –sp 2交叉偶联技术实现的平行药物化学相结合，与 CNS 类药物特性相结合。这导致发现了一个独特的 sp 3- 丰富的螺腈基序赋予非凡的效力、药代动力学和有利的 CNS 药物样特性。先导化合物25在人外周血单核细胞中表现出卓越的靶向效力、出色的脱靶激酶选择性和大鼠的良好脑暴露，最终实现低预计人体剂量和临床前安全性，值得进步对临床前候选启用研究。