methyl (5-(6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamate | 1494684-28-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯并三嗪类
• 英文名称: methyl (5-(6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamate
• 英文别名: CYH33；Risovalisib；methyl N-[5-[6-[(4-methylsulfonylpiperazin-1-yl)methyl]-4-morpholin-4-ylpyrrolo[2,1-f][1,2,4]triazin-2-yl]-4-(trifluoromethyl)pyridin-2-yl]carbamate
• CAS: 1494684-28-4
• 化学式: C₂₄H₂₉F₃N₈O₅S
• 分子量: 598.606
• InChiKey: KTLQDDGRBDLKMN-UHFFFAOYSA-N

物化性质

• 密度：
  1.57±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  41
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  143
• 氢给体数：
  1
• 氢受体数：
  14

反应信息

• 作为反应物：
  描述：

  甲烷磺酸 、 methyl (5-(6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamate 以 四氢呋喃 为溶剂， 反应 5.0h， 以100%的产率得到methyl (5-(6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamate mesylate
  参考文献：
  名称：

  PYRROLO[2,1-F][1,2,4]TRIAZINE COMPOUND, AND PREPARATION METHOD AND APPLICATION THEREOF

  摘要：

  本发明涉及一种吡咯并[2,1-f][1,2,4]三嗪化合物，其异构体或药学上可接受的盐、酯或水合物，以及其制备方法和应用。吡咯并[2,1-f][1,2,4]三嗪化合物具有一般式(I)表示的结构。一般式(I)表示的吡咯并[2,1-f][1,2,4]三嗪化合物可以抑制磷脂酰肌醇-3激酶（PI3K）信号通路，因此可用于制备用于治疗磷脂酰肌醇-3激酶相关疾病如癌症的药物。

  公开号：

  US20150141644A1
• 作为产物：
  描述：

  methyl 1-amino-5-carbamoyl-1H-pyrrole-3-carboxylate 在 4-二甲氨基吡啶 、 copper(II) choride dihydrate 、 dimethyl sulfide borane 、 potassium carbonate 、 三乙胺 、 三氯氧磷 作用下， 以 四氢呋喃 、 乙醇 、 氯仿 、 二甲基亚砜 、 N,N-二甲基甲酰胺 为溶剂， 反应 123.5h， 生成 methyl (5-(6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamate
  参考文献：
  名称：

  Identification of methyl (5-(6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamate (CYH33) as an orally bioavailable, highly potent, PI3K alpha inhibitor for the treatment of advanced solid tumors

  摘要：

  In various human cancers, PI3Ks pathway is ubiquitously dysregulated and thus become a promising anti-cancer target. To discover new potent and selective PI3K inhibitors as potential anticancer drugs, new pyrrolo[2,1-f][1,2,4]triazines were designed, leading to the discovery of compound 37 (CYH33), a selective PI3Kα inhibitor (IC₅₀ = 5.9 nM, β/α, δ/α,γ/α = 101-, 13-, 38-fold). Western blot analysis confirmed that compound 37 could inhibit phosphorylation of AKT in human cancer cells to modulate the cellular PI3K/AKT/mTOR pathway. And further evaluation in vivo against SKOV-3 xenograft models demonstrated that a dose-dependent antitumor efficacy was achieved.

  DOI：

  10.1016/j.ejmech.2020.112913

文献信息

• 7-SITE SUBSTITUTED PYRROLE TRIAZINE COMPOUNDS OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF, AND PREPARATION METHOD THEREFOR AND USES THEREOF
  申请人：Shanghai Institute of Materia Medica, Chinese Academy of Sciences

  公开号：EP3643717A1

  公开（公告）日：2020-04-29

  The present disclosure relates to 7-substituted pyrrolo[2,1-f][1,2,4]triazine compounds or pharmaceutically acceptable salts thereof, and preparation methods and uses thereof. These compounds show good PI3K inhibitory activity, can effectively inhibit the activity of PI3K kinase, and has significant enhancement and improvement of pharmacokinetic properties, such as bioavailability, due to the introduction of the 7-position group; furthermore, the compounds of the present disclosure exhibit an unpredictable high selectivity and strong inhibitory activity on PI3Kδ, and thus these compounds can be used for treating diseases related to PI3K pathway, especially for anti-cancer or for the treatment of tumors, leukemias and autoimmune diseases. After further optimizing and screening, the compounds are expected to be developed into a new type of anti-tumor drugs.

  本公开涉及7-取代吡咯并[2,1-f][1,2,4]三嗪化合物或其药学上可接受的盐及其制备方法和用途。这些化合物显示出良好的 PI3K 抑制活性，能有效抑制 PI3K 激酶的活性，并且由于引入了 7 位基团，药代动力学特性（如生物利用度）得到显著增强和改善；此外，本公开的化合物对PI3Kδ具有难以预测的高选择性和强抑制活性，因此这些化合物可用于治疗与PI3K通路相关的疾病，特别是抗癌或治疗肿瘤、白血病和自身免疫性疾病。经过进一步优化和筛选，这些化合物有望开发成新型抗肿瘤药物。
• 7-site substituted pyrrole triazine compounds or pharmaceutically acceptable salts thereof, and preparation method thereof and uses thereof
  申请人：SHANGHAI INSTITUTE OF MATERIA MEDICA, CHINESE ACADEMY OF SCIENCES

  公开号：US11214572B2

  公开（公告）日：2022-01-04

  The present disclosure relates to 7-substituted pyrrolo[2,1-f][1,2,4]triazine compounds or pharmaceutically acceptable salts thereof, and preparation methods and uses thereof. These compounds show good PI3K inhibitory activity, can effectively inhibit the activity of PI3K kinase, and has significant enhancement and improvement of pharmacokinetic properties, such as bioavailability, due to the introduction of the 7-position group; furthermore, the compounds of the present disclosure exhibit an unpredictable high selectivity and strong inhibitory activity on PI3Kδ, and thus these compounds can be used for treating diseases related to PI3K pathway, especially for anti-cancer or for the treatment of tumors, leukemias and autoimmune diseases. After further optimizing and screening, the compounds are expected to be developed into a new type of anti-tumor drugs.

  本公开涉及7-取代吡咯并[2,1-f][1,2,4]三嗪化合物或其药学上可接受的盐及其制备方法和用途。这些化合物显示出良好的 PI3K 抑制活性，能有效抑制 PI3K 激酶的活性，并且由于引入了 7 位基团，药代动力学特性（如生物利用度）得到显著增强和改善；此外，本公开的化合物对PI3Kδ具有难以预测的高选择性和强抑制活性，因此这些化合物可用于治疗与PI3K通路相关的疾病，特别是抗癌或治疗肿瘤、白血病和自身免疫性疾病。经过进一步优化和筛选，这些化合物有望开发成新型抗肿瘤药物。
• 7-SUBSTITUTED PYRROLE TRIAZINE COMPOUNDS OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF, AND PREPARATION METHOD THEREFOR AND USES THEREOF
  申请人：Shanghai Institute of Materia Medica, Chinese Academy of Sciences

  公开号：EP3643717B1

  公开（公告）日：2021-06-02
• PYRROLO[2,1-F[1,2,4]TRIAZINE COMPOUNDS, PREPARATION METHODS AND APPLICATIONS THEREOF
  申请人：Shanghai Institute of Materia Medica, Chinese Academy of Sciences

  公开号：US20170000800A1

  公开（公告）日：2017-01-05

  The present invention relates to a pyrrolo[2,1-f][1,2,4]triazine compound, an isomer thereof or a pharmaceutically acceptable salt, ester or hydrate thereof, and a preparation method and application thereof. The pyrrolo[2,1-f][1,2,4]triazine compound has a structure expressed in general formula (I). The pyrrolo[2,1-f][1,2,4]triazine compound expressed in general formula (I) can inhibit a phosphatidylinositol-3 kinase (PI3K) signal pathway, thereby being used to prepare medicine for treating phosphatidylinositol-3 kinase related diseases such as cancer.
• 7-SITE SUBSTITUTED PYRROLE TRIAZINE COMPOUNDS OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF, AND PREPARATION METHOD THEREOF AND USES THEREOF
  申请人：SHANGHAI INSTITUTE OF MATERIA MEDICA, CHINESE ACADEMY OF SCIENCES

  公开号：US20200157110A1

  公开（公告）日：2020-05-21

  The present disclosure relates to 7-substituted pyrrolo[2,1-f][1,2,4]triazine compounds or pharmaceutically acceptable salts thereof, and preparation methods and uses thereof. These compounds show good PI3K inhibitory activity, can effectively inhibit the activity of PI3K kinase, and has significant enhancement and improvement of pharmacokinetic properties, such as bioavailability, due to the introduction of the 7-position group; furthermore, the compounds of the present disclosure exhibit an unpredictable high selectivity and strong inhibitory activity on PI3Kδ, and thus these compounds can be used for treating diseases related to PI3K pathway, especially for anti-cancer or for the treatment of tumors, leukemias and autoimmune diseases. After further optimizing and screening, the compounds are expected to be developed into a new type of anti-tumor drugs.