[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-(S)-pyrrolidin-3-yl-amine | 1354692-00-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶并嘧啶类
• 英文名称: [6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-(S)-pyrrolidin-3-yl-amine
• 英文别名: 6-[6-methoxy-5-(trifluoromethyl)pyridin-3-yl]-N-[(3S)-pyrrolidin-3-yl]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-4-amine
• CAS: 1354692-00-4
• 化学式: C₁₈H₂₁F₃N₆O
• 分子量: 394.4
• InChiKey: KLJMPERDUPMWBW-NSHDSACASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  28
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  75.2
• 氢给体数：
  2
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  [6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-(S)-pyrrolidin-3-yl-amine 在 盐酸 、 碳酸氢钠 作用下， 以 二氯甲烷 、 水 、 乙腈 为溶剂， 反应 16.5h， 生成 1-{(S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidin-1-yl}propan-1-one hydrochloride
  参考文献：
  名称：

  [EN] TETRAHYDRO-PYRIDO-PYRIMIDINE DERIVATIVES
  [FR] DÉRIVÉS DE TÉTRAHYDRO-PYRIDO-PYRIMIDINE

  摘要：

  这项发明涉及公式（I）中Y、R1、R2和m所定义的替代四氢吡啶嘧啶衍生物。这些化合物适用于治疗由PI3K酶活性介导的疾病或疾病。

  公开号：

  WO2012004299A1
• 作为产物：
  描述：

  (S)-3-(5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester 在 tris-(dibenzylideneacetone)dipalladium(0) 、 2-二-叔丁基磷-2'-甲基联苯 三氟乙酸 、 sodium t-butanolate 作用下， 以 二氯甲烷 、 叔丁醇 为溶剂， 反应 5.0h， 生成 [6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-(S)-pyrrolidin-3-yl-amine
  参考文献：
  名称：

  [EN] TETRAHYDRO-PYRIDO-PYRIMIDINE DERIVATIVES
  [FR] DÉRIVÉS DE TÉTRAHYDRO-PYRIDO-PYRIMIDINE

  摘要：

  这项发明涉及公式（I）中Y、R1、R2和m所定义的替代四氢吡啶嘧啶衍生物。这些化合物适用于治疗由PI3K酶活性介导的疾病或疾病。

  公开号：

  WO2012004299A1

文献信息

• Discovery of CDZ173 (Leniolisib), Representing a Structurally Novel Class of PI3K Delta-Selective Inhibitors
  作者：Klemens Hoegenauer、Nicolas Soldermann、Frédéric Zécri、Ross S. Strang、Nadege Graveleau、Romain M. Wolf、Nigel G. Cooke、Alexander B. Smith、Gregory J. Hollingworth、Joachim Blanz、Sascha Gutmann、Gabriele Rummel、Amanda Littlewood-Evans、Christoph Burkhart

  DOI：10.1021/acsmedchemlett.7b00293

  日期：2017.9.14

  The predominant expression of phosphoinositide 3-kinase delta (PI3K delta) in leukocytes and its critical role in B and T cell functions led to the hypothesis that selective inhibitors of this isoform would have potential as therapeutics for the treatment of allergic and inflammatory disease. Targeting specifically PI3K delta should avoid potential side effects associated with the ubiquitously expressed PI3K alpha and beta isoforms. We disclose how morphing the heterocyclic core of previously discovered 4,6-diaryl quinazolines to a significantly less lipophilic 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine, followed by replacement of one of the phenyl groups with a pyrrolidine-3-amine, led to a compound series with an optimal on-target profile and good ADME properties. A final lipophilicity adjustment led to the discovery of CDZ173 (leniolisib), a potent PI3K delta selective inhibitor with suitable properties and efficacy for clinical development as an anti-inflammatory therapeutic. In vitro, CDZ173 inhibits a large spectrum of immune cell functions, as demonstrated in B and T cells, neutrophils, monocytes, basophils, plasmocytoid dendritic cells, and mast cells. In vivo, CDZ173 inhibits B cell activation in rats and monkeys in a concentration- and time-dependent manner. After prophylactic or therapeutic dosing, CDZ173 potently inhibited antigen-specific antibody production and reduced disease symptoms in a rat collagen-induced arthritis model. Structurally, CDZ173 differs significantly from the first generation of PI3K delta and PI3K gamma delta-selective clinical compounds. Therefore, CDZ173 could differentiate by a more favorable safety profile. CDZ173 is currently in clinical studies in patients suffering from primary Sjogren's syndrome and in APDS/PASLI, a disease caused by gain of function mutations of PI3K delta.