2,5-dichloro-N-((tetrahydrofuran-2-yl)methyl)pyrimidin-4-amine

• 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: 2,5-dichloro-N-((tetrahydrofuran-2-yl)methyl)pyrimidin-4-amine
• 英文别名: 2,5-dichloro-N-(oxolan-2-ylmethyl)pyrimidin-4-amine
• 化学式: C₉H₁₁Cl₂N₃O
• 分子量: 248.112
• InChiKey: DKRPRBXWBGAPAG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  15
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  47
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2,5-dichloro-N-((tetrahydrofuran-2-yl)methyl)pyrimidin-4-amine 在 盐酸 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 20.0h， 生成 3-(4-(5-chloro-4-((tetrahydrofuran-2-yl)methylamino)pyrimidin-2-ylamino)phenyl)-N-(2-(dimethylamino)ethyl)propanamide hydrochloride
  参考文献：
  名称：

  [EN] INHIBITORS OF ACK1/TNK2 TYROSINE KINASE
  [FR] INHIBITEURS DE LA TYROSINE KINASE ACK1/TNK2

  摘要：

  描述了癌症治疗和抗癌化合物。特别是，披露了Ack1酪氨酸激酶的抑制剂及其在癌症治疗中的应用。还披露了筛选新的Ack1酪氨酸激酶抑制剂的方法。在具体示例中，披露了具有I至IV式的化合物。

  公开号：

  WO2015021149A1
• 作为产物：
  描述：

  2-四氢糠胺 、 2,4,5-三氯嘧啶 在 三乙胺 作用下， 以 甲醇 为溶剂， 反应 1.0h， 以93%的产率得到2,5-dichloro-N-((tetrahydrofuran-2-yl)methyl)pyrimidin-4-amine
  参考文献：
  名称：

  [EN] INHIBITORS OF ACK1/TNK2 TYROSINE KINASE
  [FR] INHIBITEURS DE LA TYROSINE KINASE ACK1/TNK2

  摘要：

  描述了癌症治疗和抗癌化合物。特别是，披露了Ack1酪氨酸激酶的抑制剂及其在癌症治疗中的应用。还披露了筛选新的Ack1酪氨酸激酶抑制剂的方法。在具体示例中，披露了具有I至IV式的化合物。

  公开号：

  WO2015021149A1

文献信息

• MULTI-SUBSTITUTED PYRIMIDINE DERIVATIVES WITH EXCELLENT KINASE INHIBITORY ACTIVITIES
  申请人：KOREA INSTITUTE OF SCIENCE AND TECHNOLOGY

  公开号：US20190315726A1

  公开（公告）日：2019-10-17

  Disclosed are a novel pyrimidine derivative compound, a pharmaceutically acceptable salt thereof, a method for preparing the compound and a pharmaceutical use of the compound as an anticancer agent or a therapeutic agent for degenerative brain diseases. Specifically, the novel pyrimidine derivative compound has excellent inhibitory activities against kinase enzymes such as ARK5/NUAK1, ACK1, FLT3, JAK1, JAK2 and JAK2 (V617F) and thus is useful for treating and preventing leukemia, ovarian cancer, breast cancer, non-small cell carcinoma, colorectal cancer, glioma, and brain protein abnormalities such as Alzheimer's disease, progressive supranuclear palsy and frontotemporal dementia, that is, degenerative diseases caused by Tau deposition.

  本文披露了一种新型嘧啶衍生物化合物，其药用盐，制备该化合物的方法以及将该化合物用作抗癌剂或治疗退行性脑疾病的药用。具体来说，这种新型嘧啶衍生物化合物对激酶酶类如ARK5/NUAK1、ACK1、FLT3、JAK1、JAK2和JAK2(V617F)具有出色的抑制活性，因此可用于治疗和预防白血病、卵巢癌、乳腺癌、非小细胞癌、结直肠癌、胶质瘤以及脑蛋白异常疾病，如阿尔茨海默病、进行性核上性麻痹和颞叶痴呆等由Tau沉积引起的退行性疾病。
• INHIBITORS OF ACK1/TNK2 TYROSINE KINASE
  申请人：H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE, INC.

  公开号：US20160176826A1

  公开（公告）日：2016-06-23

  Described are cancer therapies and anti-cancer compounds. In particular, disclosed are inhibitors of Ack1 tyrosine kinase and their use in the treatment of cancer. Methods of screening for new Ack1 tyrosine kinase inhibitors are also disclosed. In specific example, compound having Formula I through IV are disclosed.

  本文描述了癌症治疗和抗癌化合物。特别地，揭示了Ack1酪氨酸激酶抑制剂及其在癌症治疗中的应用。还披露了筛选新的Ack1酪氨酸激酶抑制剂的方法。具体例子中，揭示了具有I至IV式的化合物。
• Inhibitors of ACK1/TNK2 tyrosine kinase
  申请人：H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE, INC.

  公开号：US10017478B2

  公开（公告）日：2018-07-10

  Described are cancer therapies and anti-cancer compounds. In particular, disclosed are inhibitors of Ack1 tyrosine kinase and their use in the treatment of cancer. Methods of screening for new Ack1 tyrosine kinase inhibitors are also disclosed. In specific example, compound having Formula I through IV are disclosed.

  所述的是癌症疗法和抗癌化合物。 特别是公开了 Ack1 酪氨酸激酶的抑制剂及其在治疗癌症中的用途。 还公开了筛选新的Ack1酪氨酸激酶抑制剂的方法。 在具体实例中，公开了具有式I至式IV的化合物。
• Multi-substituted pyrimidine derivatives with excellent kinase inhibitory activities
  申请人：KOREA INSTITUTE OF SCIENCE AND TECHNOLOGY

  公开号：US10683282B2

  公开（公告）日：2020-06-16

  Disclosed are a novel pyrimidine derivative compound, a pharmaceutically acceptable salt thereof, a method for preparing the compound and a pharmaceutical use of the compound as an anticancer agent or a therapeutic agent for degenerative brain diseases. Specifically, the novel pyrimidine derivative compound has excellent inhibitory activities against kinase enzymes such as ARK5/NUAK1, ACK1, FLT3, JAK1, JAK2 and JAK2 (V617F) and thus is useful for treating and preventing leukemia, ovarian cancer, breast cancer, non-small cell carcinoma, colorectal cancer, glioma, and brain protein abnormalities such as Alzheimer's disease, progressive supranuclear palsy and frontotemporal dementia, that is, degenerative diseases caused by Tau deposition.

  本发明公开了一种新型嘧啶衍生物化合物、其药学上可接受的盐、制备该化合物的方法以及该化合物作为抗癌剂或退行性脑疾病治疗剂的药物用途。具体地说，该新型嘧啶衍生物化合物对激酶如 ARK5/NUAK1、ACK1、FLT3、JAK1、JAK2 和 JAK2 (V617F)具有极好的抑制活性，因此可用于治疗和预防白血病、卵巢癌、乳腺癌、非小细胞癌、乳腺癌、非小细胞肺癌、非小细胞肺癌、非小细胞肺癌、非小细胞肺癌、非小细胞肺癌、非小细胞肺癌和非小细胞肺癌、乳腺癌、非小细胞癌、结直肠癌、胶质瘤，以及阿尔茨海默病、进行性核上性麻痹和额颞叶痴呆等脑蛋白异常，即由 Tau 沉积引起的退行性疾病。
• Development of Novel ACK1/TNK2 Inhibitors Using a Fragment-Based Approach
  作者：Harshani R. Lawrence、Kiran Mahajan、Yunting Luo、Daniel Zhang、Nathan Tindall、Miles Huseyin、Harsukh Gevariya、Sakib Kazi、Sevil Ozcan、Nupam P. Mahajan、Nicholas J. Lawrence

  DOI：10.1021/jm501929n

  日期：2015.3.26

  The tyrosine kinase ACK1, a critical signal transducer regulating survival of hormone-refractory cancers, is an important therapeutic target, for which there are no selective inhibitors in clinical trials to date. This work reports the discovery of novel and potent inhibitors for ACK1 tyrosine kinase (also known as TNK2) using an innovative fragment-based approach. Focused libraries were designed and synthesized by selecting fragments from reported ACK inhibitors to create hybrid structures in a mix and match process. The hybrid library was screened by enzyme-linked immunosorbent assay-based kinase inhibition and P-33 HotSpot assays. Systematic structure-activity relationship studies led to the identification of compound (R)-9b, which shows potent in vitro (IC50 = 56 nM, n = 3, P-33 HotSpot assay) and in vivo (IC50 < 2 mu M, human cancer cell lines) ACK1 inhibition. Both (R)-9b and (S)-9b were stable in human plasma and displayed a long half-life (t(1/2) > 6 h).