1-(tert-butyl)-4-chloro-1H-pyrazolo[3,4-d]pyrimidine | 1100365-45-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡唑并嘧啶类
• 英文名称: 1-(tert-butyl)-4-chloro-1H-pyrazolo[3,4-d]pyrimidine
• 英文别名: 1-tert-butyl-4-chloro-1H-pyrazolo[3,4-d]pyrimidine；1-tert-butyl-4-chloropyrazolo[3,4-d]pyrimidine
• CAS: 1100365-45-4
• 化学式: C₉H₁₁ClN₄
• mdl: MFCD11104747
• 分子量: 210.666
• InChiKey: BVJFFNHUTCJYSS-UHFFFAOYSA-N

物化性质

• 沸点：
  311.5±22.0 °C(Predicted)
• 密度：
  1.33±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  14
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.444
• 拓扑面积：
  43.6
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1-(tert-butyl)-4-chloro-1H-pyrazolo[3,4-d]pyrimidine 在 三乙烯二胺 、 tris-(dibenzylideneacetone)dipalladium(0) 、 氯化亚砜 、 水 、 溴 、 sodium hydride 、 cesium fluoride 作用下， 以 N,N-二甲基甲酰胺 、 甲苯 、 乙腈 为溶剂， 反应 0.5h， 生成
  参考文献：
  名称：

  Structure-guided optimization of protein kinase inhibitors reverses aminoglycoside antibiotic resistance

  摘要：

  氨基糖苷磷酸转移酶 APH(3′)-Ia 的活性导致致病性革兰氏阴性菌对氨基糖苷类抗生素产生抗药性，并导致这类抗生素在临床上被淘汰。挽救氨基糖苷类等耐药抗生素的一种策略是用小分子药物靶向产生耐药性的酶。我们以前曾证明，ePK（真核生物蛋白激酶）抑制剂可以抑制 APH 酶，因为这两种酶家族的结构相似。然而，酶-抑制剂复合物的结构信息有限，妨碍了对结果的解释。此外，APHs 和 ePKs 之间化合物的交叉反应也阻碍了它们作为氨基糖苷辅助剂来挽救氨基糖苷类抗生素的活性。在本研究中，我们从结构和功能上描述了蒽吡唑啉酮、4-苯胺基喹唑啉和 PP（吡唑并嘧啶）这三种不同化学支架对 APH（3′）-Ia 的抑制作用，并揭示了与 ePKs 相比，蒽吡唑啉酮和 PP 化合物与 APH（3′）-Ia 的结合模式有所不同。利用这一观察结果，我们确定了 PP 衍生物，它们能选择性地对抗 ePKs，减弱 APH(3′)-Ia 的活性，并挽救氨基糖苷类抗生素对耐药大肠杆菌菌株的活性。本文中描述的结构和抑制研究为基于结构设计化合物提供了一个重要机会，以抑制氨基糖苷磷酸转移酶，从而有可能克服这种形式的抗生素耐药性。

  DOI：

  10.1042/bj20130317
• 作为产物：
  描述：

  5-[(2-tert-butylhydrazono)methyl]-4,6-dichloropyrimidine 以 四氢呋喃 为溶剂， 反应 1.0h， 以98%的产率得到1-(tert-butyl)-4-chloro-1H-pyrazolo[3,4-d]pyrimidine
  参考文献：
  名称：

  Synthesis of 1,4-Disubstituted Pyrazolo[3,4-d]pyrimidines from 4,6-Dichloropyrimidine-5-carboxaldehyde: Insights into Selectivity and Reactivity

  摘要：

  Strategies for carrying out the reaction of 4,6-dichloropyrimidine-5-carboxaldehyde with both aromatic and aliphatic hydrazines to generate 1-substituted 4-chloropyrazolo[3,4-d]pyrimidines in a selective, high-yielding, and operationally simple manner are presented. For aromatic hydrazines, the reaction is performed at a high temperature in the absence of an external base. For aliphatic hydrazines, the reaction proceeds at room temperature in the presence of an external base. The observed selectivity and reactivity trends are rationalized through consideration of the proposed reaction mechanism. The 1-substituted 4-chloropyrazolo[3,4-d]pyrimidine products serve as versatile synthetic intermediates, through further functionalization of the 4-chloride moiety, enabling the rapid generation of a structurally diverse array of 1,4-disubstituted pyrazolo[3,4-d]pyrimidines.

  DOI：

  10.1055/s-0033-1338862

文献信息

• A one step synthesis of 1-alkylpyrazolo[5,4-d]pyrimidines
  作者：Scott Boyd、Leonie Campbell、Wensheng Liao、Qinghong Meng、Zuozhong Peng、Xiaoping Wang、Michael J. Waring

  DOI：10.1016/j.tetlet.2008.10.065

  日期：2008.12

  A new synthesis of 1-alkylpyrazolo[5,4-d]pyrimidines is described. The reaction of 4,6-dichloropyrimidine-5-carbaldehyde with various substituted hydrazines provides such compounds in a single step from commercially available starting materials. This method has advantages over methods currently described in the literature for the construction of such ring systems.

  描述了一种新的1-烷基吡唑并[5,4- d ]嘧啶的合成方法。4，6-二氯嘧啶-5-甲醛与各种取代的肼的反应可从市售原料中一步完成这些化合物。该方法相对于文献中当前描述的用于构造这种环系统的方法具有优势。
• Compounds targeting PRMT5
  申请人：ALIGOS THERAPEUTICS, INC.

  公开号：US11198699B2

  公开（公告）日：2021-12-14

  Provided herein are compounds of Formula (I), or pharmaceutically acceptable salts thereof, pharmaceutical compositions that include a compound described herein (including pharmaceutically acceptable salts of a compound described herein) and methods of synthesizing the same. Also provided herein are methods of treating diseases and/or conditions with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

  本文提供了式(I)化合物或其药学上可接受的盐、包括本文所述化合物的药物组合物（包括本文所述化合物的药学上可接受的盐）以及合成这些化合物的方法。本文还提供了用式（I）化合物或其药学上可接受的盐治疗疾病和/或病症的方法。
• COMPOUNDS TARGETING PRMT5
  申请人：ALIGOS THERAPEUTICS, INC.

  公开号：US20200317686A1

  公开（公告）日：2020-10-08

  Provided herein are compounds of Formula (I), or pharmaceutically acceptable salts thereof, pharmaceutical compositions that include a compound described herein (including pharmaceutically acceptable salts of a compound described herein) and methods of synthesizing the same. Also provided herein are methods of treating diseases and/or conditions with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
• Synthesis of 1,4-Disubstituted Pyrazolo[3,4-d]pyrimidines from 4,6-Dichloropyrimidine-5-carboxaldehyde: Insights into Selectivity and Reactivity
  作者：Christie Morrill、Young-Choon Moon、Suresh Babu、Neil Almstead

  DOI：10.1055/s-0033-1338862

  日期：——

  Strategies for carrying out the reaction of 4,6-dichloropyrimidine-5-carboxaldehyde with both aromatic and aliphatic hydrazines to generate 1-substituted 4-chloropyrazolo[3,4-d]pyrimidines in a selective, high-yielding, and operationally simple manner are presented. For aromatic hydrazines, the reaction is performed at a high temperature in the absence of an external base. For aliphatic hydrazines, the reaction proceeds at room temperature in the presence of an external base. The observed selectivity and reactivity trends are rationalized through consideration of the proposed reaction mechanism. The 1-substituted 4-chloropyrazolo[3,4-d]pyrimidine products serve as versatile synthetic intermediates, through further functionalization of the 4-chloride moiety, enabling the rapid generation of a structurally diverse array of 1,4-disubstituted pyrazolo[3,4-d]pyrimidines.
• Structure-guided optimization of protein kinase inhibitors reverses aminoglycoside antibiotic resistance
  作者：Peter J. Stogios、Peter Spanogiannopoulos、Elena Evdokimova、Olga Egorova、Tushar Shakya、Nick Todorovic、Alfredo Capretta、Gerard D. Wright、Alexei Savchenko

  DOI：10.1042/bj20130317

  日期：2013.9.1

  Activity of the aminoglycoside phosphotransferase APH(3′)-Ia leads to resistance to aminoglycoside antibiotics in pathogenic Gram-negative bacteria, and contributes to the clinical obsolescence of this class of antibiotics. One strategy to rescue compromised antibiotics such as aminoglycosides is targeting the enzymes that confer resistance with small molecules. We demonstrated previously that ePK (eukaryotic protein kinase) inhibitors could inhibit APH enzymes, owing to the structural similarity between these two enzyme families. However, limited structural information of enzyme–inhibitor complexes hindered interpretation of the results. In addition, cross-reactivity of compounds between APHs and ePKs represents an obstacle to their use as aminoglycoside adjuvants to rescue aminoglycoside antibiotic activity. In the present study, we structurally and functionally characterize inhibition of APH(3′)-Ia by three diverse chemical scaffolds, anthrapyrazolone, 4-anilinoquinazoline and PP (pyrazolopyrimidine), and reveal distinctions in the binding mode of anthrapyrazolone and PP compounds to APH(3′)-Ia compared with ePKs. Using this observation, we identify PP derivatives that select against ePKs, attenuate APH(3′)-Ia activity and rescue aminoglycoside antibiotic activity against a resistant Escherichia coli strain. The structures described in the present paper and the inhibition studies provide an important opportunity for structure-based design of compounds to target aminoglycoside phosphotransferases for inhibition, potentially overcoming this form of antibiotic resistance.

  氨基糖苷磷酸转移酶 APH(3′)-Ia 的活性导致致病性革兰氏阴性菌对氨基糖苷类抗生素产生抗药性，并导致这类抗生素在临床上被淘汰。挽救氨基糖苷类等耐药抗生素的一种策略是用小分子药物靶向产生耐药性的酶。我们以前曾证明，ePK（真核生物蛋白激酶）抑制剂可以抑制 APH 酶，因为这两种酶家族的结构相似。然而，酶-抑制剂复合物的结构信息有限，妨碍了对结果的解释。此外，APHs 和 ePKs 之间化合物的交叉反应也阻碍了它们作为氨基糖苷辅助剂来挽救氨基糖苷类抗生素的活性。在本研究中，我们从结构和功能上描述了蒽吡唑啉酮、4-苯胺基喹唑啉和 PP（吡唑并嘧啶）这三种不同化学支架对 APH（3′）-Ia 的抑制作用，并揭示了与 ePKs 相比，蒽吡唑啉酮和 PP 化合物与 APH（3′）-Ia 的结合模式有所不同。利用这一观察结果，我们确定了 PP 衍生物，它们能选择性地对抗 ePKs，减弱 APH(3′)-Ia 的活性，并挽救氨基糖苷类抗生素对耐药大肠杆菌菌株的活性。本文中描述的结构和抑制研究为基于结构设计化合物提供了一个重要机会，以抑制氨基糖苷磷酸转移酶，从而有可能克服这种形式的抗生素耐药性。