5-bromo-2-chloro-N-(4-methoxyphenyl)pyrimidin-4-amine

• 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: 5-bromo-2-chloro-N-(4-methoxyphenyl)pyrimidin-4-amine
• 化学式: C₁₁H₉BrClN₃O
• 分子量: 314.569
• InChiKey: GUBXCKFSVIECIH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  17
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.09
• 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：

  5-bromo-2-chloro-N-(4-methoxyphenyl)pyrimidin-4-amine 在 potassium fluoride 、 对甲苯磺酸 、 4,7,13,16,21,24-六氧-1,10-二氮双环[8.8.8]二十六烷 作用下， 以 1,4-二氧六环 、 乙腈 为溶剂， 反应 4.25h， 生成 5-bromo-N²-(4-(2-(2-fluoroethoxy)ethoxy)phenyl)-N⁴-(4-methoxyphenyl)pyrimidine-2,4-diamine
  参考文献：
  名称：

  Synthesis, biological evaluation, and molecular dynamics (MD) simulation studies of three novel F-18 labeled and focal adhesion kinase (FAK) targeted 5-bromo pyrimidines as radiotracers for tumor

  摘要：

  Focal adhesion lcinase (FAK) is considered as an attractive target for oncology. A series of F-18 labeled 5bromo-N-2-(4-(2-fluoro-pegylated (FPEG))-3,5-dimethoxyphenyl)-N-4-(4-methoxyphenyl)pyrimidine2,4-diamine derivatives were prepared and evaluated as the FAK targeted radiotracers for the early diagnoses of tumor. For the study of the FAK targeted drug molecules, this was the first attempt to develop the tumor diagnostic imaging agents on the radiopharmaceutical level. They inhibited the activity of FAK with IC50 in the range of 91.4-425.7 nM, and among which the result of the [F-19]2 was relatively good and had a modest IC50 of 91.4 nM. The [F-19]2 was also profiled in vitro against some other kinds of cancer related kinases (including two kinds of non-receptor tyrosine kinase: PYK2 and JAK2, and three kinds of receptor tyrosine kinase: IGF-1R, EGFR and PDGFR(3). It displayed 25.2 folds selectivity against PYK2, 35.1 folds selectivity against EGFR, and more than 100 folds selectivity against IGF-1R, JAK2 and PDGFRO. For the biodistribution in 5180 bearing mice, the corresponding [F-18]2 were also relatively good, with modest tumor uptake of 5.47 +/- 0.19 and 5.80 +/- 0.06 %ID/g at 15 and 30 min post-injection, respectively. Furthermore, its tumor/muscle, tumor/bone and tumor/blood ratio at 15 min post-injection were 3.16, 2.53 and 4.52, respectively. And its tumor/muscle, tumor/bone and tumor/blood ratio at 30 min post injection were 3.14, 2.76 and 4.43, respectively. In addition, coronal micro-PET/CT images of a mouse bearing 5180 tumor clearly confirmed that [F-18]2 could be accumulated in tumor, especially at 30 min post-injection. Besides, for the jI8F12, both the biodistribution data and the micro-PET/CT imaging study showed significantly reduced uptake of the radiotracer in the tumor tissue at 30 min post-injection in mice that received PF-562,271 (one of the reported best selective FAK inhibitor which was developed by Pfitzer Inc. and inhibited the activity of FAK with IC50 value of 1.5 nM) at 1 h before the injection of radiotracer. In combination with the above kinase profiling assay, it could be indicated that the uptake of [F-18]2 in tumor of the mouse model was due to FAK expression, and that [F-18]2 might be a kind of selectively FAK targeted tumor imaging agents. What's more, the results of the MD (molecular dynamics) simulations were in agreement with the changing trends of the interaction between the different F-19 standards and the FAK (expressed as the in vitro inhibitory abilities of enzymatic activities of FAK in this article), which was also in agreement with and had great effect on the changing trends of the uptake of the corresponding F-18 labeled tracers in tumor and some of theirs target/non-target ratios. (C) 2017 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2017.01.015
• 作为产物：
  描述：

  5-溴-2,4-二氯嘧啶 、 甲氧苯胺 在 potassium carbonate 作用下， 以 异丙醇 、 水 为溶剂， 以51.4%的产率得到5-bromo-2-chloro-N-(4-methoxyphenyl)pyrimidin-4-amine
  参考文献：
  名称：

  新型F-18标记的嘧啶衍生物的合成和评估：潜在的FAK抑制剂和PET成像剂可用于癌症检测†

  摘要：

  基于计算机辅助药物设计，成功合成了一系列新型嘧啶衍生物，并通过1 H NMR，13 C HNMR和MS光谱进行了表征。评估了所有新化合物对粘着斑激酶的活性，并显示出与对照药物相比较低的IC 50值。特别地，对于化合物8i，其IC 50值为0.060μM，表明其作为粘着斑激酶抑制剂的优点。为了评估这些化合物作为PET显像剂在癌症检测中的潜力，将化合物8a，8c，8h和8i依次标记为18F.四种18 F标记的嘧啶衍生物在生理盐水和小鼠血浆中显示适当的log  P值和高稳定性。值得注意的是，化合物[ 18 F] - 8A与在苯环的4-甲氧基表现出良好的体内小鼠轴承S180肿瘤，促进化合物[的另一微PET成像研究生物分布数据18 - F] 8A。在注射后60分钟时将S 18肿瘤小鼠的[ 18 F- 8a ]的microPET图像显示出S180肿瘤的摄取很明显。这些结果表明化合物[ 18 F] -8a

  DOI：

  10.1039/c6ra28851k

文献信息

• [EN] HETEROBICYCLIC INHIBITORS OF MAT2A AND METHODS OF USE FOR TREATING CANCER<br/>[FR] INHIBITEURS HÉTÉROBICYCLIQUES DE MAT2A ET PROCÉDÉS D'UTILISATION POUR LE TRAITEMENT DU CANCER
  申请人：AGIOS PHARMACEUTICALS INC

  公开号：WO2020243376A1

  公开（公告）日：2020-12-03

  The present disclosure provides for compounds according to Formula I, Formula II, and their pharmaceutically acceptable salts, tautomers, and/or isotopologues as described in the disclosure. The compounds are inhibitors of methionine adenosyltransferase isoform 2A (MAT2A). Also provided are pharmaceutical compositions and methods of using the compounds for treating cancers, including some cancers in which the gene encoding methylthioadenosine phosphorylase (MTAP) is deleted.

  本公开提供了根据公式I、公式II以及其在公开描述中所述的药用可接受盐、互变异构体和/或同位素体的化合物。这些化合物是蛋氨酸腺苷转移酶同种型2A（MAT2A）的抑制剂。还提供了药物组合物和使用这些化合物治疗癌症的方法，包括一些编码甲硫腺苷磷酸化酶（MTAP）的基因被删除的癌症。
• Synthesis and evaluation of novel F-18-labeled pyrimidine derivatives: potential FAK inhibitors and PET imaging agents for cancer detection
  作者：Dawei Wang、Yu Fang、Hang Wang、Xingyu Xu、Jianping Liu、Huabei Zhang

  DOI：10.1039/c6ra28851k

  日期：——

  low IC50 values in comparison with control drugs. In particular, for compound 8i, its IC50 value was 0.060 μM, suggesting its advantage as a focal adhesion kinase inhibitor. To evaluate the potentiality of these compounds as PET imaging agents in cancer detection, compounds 8a, 8c, 8h, and 8i were successively labeled with 18F. The four 18F-labeled pyrimidine derivatives showed appropriate log P values

  基于计算机辅助药物设计，成功合成了一系列新型嘧啶衍生物，并通过1 H NMR，13 C HNMR和MS光谱进行了表征。评估了所有新化合物对粘着斑激酶的活性，并显示出与对照药物相比较低的IC 50值。特别地，对于化合物8i，其IC 50值为0.060μM，表明其作为粘着斑激酶抑制剂的优点。为了评估这些化合物作为PET显像剂在癌症检测中的潜力，将化合物8a，8c，8h和8i依次标记为18F.四种18 F标记的嘧啶衍生物在生理盐水和小鼠血浆中显示适当的log  P值和高稳定性。值得注意的是，化合物[ 18 F] - 8A与在苯环的4-甲氧基表现出良好的体内小鼠轴承S180肿瘤，促进化合物[的另一微PET成像研究生物分布数据18 - F] 8A。在注射后60分钟时将S 18肿瘤小鼠的[ 18 F- 8a ]的microPET图像显示出S180肿瘤的摄取很明显。这些结果表明化合物[ 18 F] -8a
• Synthesis, biological evaluation, and molecular dynamics (MD) simulation studies of three novel F-18 labeled and focal adhesion kinase (FAK) targeted 5-bromo pyrimidines as radiotracers for tumor
  作者：Yu Fang、Dawei Wang、Xingyu Xu、Jianping Liu、Aiqin Wu、Xiang Li、Qianqian Xue、Huan Wang、Hang Wang、Huabei Zhang

  DOI：10.1016/j.ejmech.2017.01.015

  日期：2017.2

  Focal adhesion lcinase (FAK) is considered as an attractive target for oncology. A series of F-18 labeled 5bromo-N-2-(4-(2-fluoro-pegylated (FPEG))-3,5-dimethoxyphenyl)-N-4-(4-methoxyphenyl)pyrimidine2,4-diamine derivatives were prepared and evaluated as the FAK targeted radiotracers for the early diagnoses of tumor. For the study of the FAK targeted drug molecules, this was the first attempt to develop the tumor diagnostic imaging agents on the radiopharmaceutical level. They inhibited the activity of FAK with IC50 in the range of 91.4-425.7 nM, and among which the result of the [F-19]2 was relatively good and had a modest IC50 of 91.4 nM. The [F-19]2 was also profiled in vitro against some other kinds of cancer related kinases (including two kinds of non-receptor tyrosine kinase: PYK2 and JAK2, and three kinds of receptor tyrosine kinase: IGF-1R, EGFR and PDGFR(3). It displayed 25.2 folds selectivity against PYK2, 35.1 folds selectivity against EGFR, and more than 100 folds selectivity against IGF-1R, JAK2 and PDGFRO. For the biodistribution in 5180 bearing mice, the corresponding [F-18]2 were also relatively good, with modest tumor uptake of 5.47 +/- 0.19 and 5.80 +/- 0.06 %ID/g at 15 and 30 min post-injection, respectively. Furthermore, its tumor/muscle, tumor/bone and tumor/blood ratio at 15 min post-injection were 3.16, 2.53 and 4.52, respectively. And its tumor/muscle, tumor/bone and tumor/blood ratio at 30 min post injection were 3.14, 2.76 and 4.43, respectively. In addition, coronal micro-PET/CT images of a mouse bearing 5180 tumor clearly confirmed that [F-18]2 could be accumulated in tumor, especially at 30 min post-injection. Besides, for the jI8F12, both the biodistribution data and the micro-PET/CT imaging study showed significantly reduced uptake of the radiotracer in the tumor tissue at 30 min post-injection in mice that received PF-562,271 (one of the reported best selective FAK inhibitor which was developed by Pfitzer Inc. and inhibited the activity of FAK with IC50 value of 1.5 nM) at 1 h before the injection of radiotracer. In combination with the above kinase profiling assay, it could be indicated that the uptake of [F-18]2 in tumor of the mouse model was due to FAK expression, and that [F-18]2 might be a kind of selectively FAK targeted tumor imaging agents. What's more, the results of the MD (molecular dynamics) simulations were in agreement with the changing trends of the interaction between the different F-19 standards and the FAK (expressed as the in vitro inhibitory abilities of enzymatic activities of FAK in this article), which was also in agreement with and had great effect on the changing trends of the uptake of the corresponding F-18 labeled tracers in tumor and some of theirs target/non-target ratios. (C) 2017 Elsevier Masson SAS. All rights reserved.
• Preparation, <i>in vitro</i> and <i>in vivo</i> evaluation, and molecular dynamics (MD) simulation studies of novel F-18 labeled tumor imaging agents targeting focal adhesion kinase (FAK)
  作者：Yu Fang、Dawei Wang、Xingyu Xu、Gila Dava、Jianping Liu、Xiang Li、Qianqian Xue、Huan Wang、Jiangshan Zhang、Huabei Zhang

  DOI：10.1039/c8ra00652k

  日期：——

  Finally, in order to further increase the uptake of the F-18 labeled tracer in tumor, the following points should arouse attention, which could also be considered as the new findings and contributions of this study to the field of the tumor imaging agents: (1) the F-18 labeled tumor radiotracers which have closer interaction with the FAK, should be further designed, via building of models such as 3D-QSAR

  粘着斑激酶（FAK）已被确定为肿瘤早期诊断和治疗的有希望的靶点。在这项工作中，我们获得并评估了另外两种新型的基于嘧啶的 F-18 标记的靶向 FAK 的肿瘤显像剂。其中，相应的 F-19 标准品 [ 19 F] 2显示出对 FAK 的抑制作用，IC 50值为 57.1 nM（优于我们发表的工作中的结果），并对其他一些与癌症相关的癌症表现出良好的选择性。激酶。[ 18 F] 2在体内也有较好的效果在 S180 荷瘤小鼠中的生物分布，在注射后 15 分钟和 30 分钟，肿瘤摄取量分别为 5.40 ± 0.12 和 5.96 ± 0.09 % ID/g。更重要的是，在注射后30分钟，[ 18 F] 2可以在肿瘤中积累，这可以从携带S180肿瘤的小鼠的冠状显微PET图像中观察到。此外，[ 18 F] 2与 PF-562271（众所周知的最佳选择性 FAK 抑制剂之一）的阻断研究显示，在小鼠注射后 30