N-benzyl-2-chloro-5,6,7,8-tetrahydroquinazolin-4-amine | 1454256-90-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: N-benzyl-2-chloro-5,6,7,8-tetrahydroquinazolin-4-amine
• CAS: 1454256-90-6
• 化学式: C₁₅H₁₆ClN₃
• 分子量: 273.765
• InChiKey: ZKGXJLHTIYLMIJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  19
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  37.8
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  N-benzyl-2-chloro-5,6,7,8-tetrahydroquinazolin-4-amine 在 tris-(dibenzylideneacetone)dipalladium(0) 、 caesium carbonate 、 lithium hydroxide 、 2-二环己基磷-2,4,6-三异丙基联苯 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 水 为溶剂， 反应 7.0h， 生成 1-(4-(benzylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-2-methyl-1H-indole-4-carboxylic acid
  参考文献：
  名称：

  发现不可逆的p97抑制剂。

  摘要：

  由于人类p97的抑制剂在癌症和其他疾病中的潜在治疗应用，因此人们一直在积极寻求抑制剂。然而，共价和不可逆的p97抑制剂尚未得到很好的研究。本文中，我们报告了p97的共价和不可逆抑制剂的设计，合成和生物学评估。在我们合成的一个酰胺和一个反向酰胺系列中，我们已经鉴定出一种p97抑制剂，其功能不可逆性已在体外和细胞中建立。同样重要的是，质谱分析揭示了该化合物标记的三个潜在的半胱氨酸残基，并且诱变和计算机建模表明，Cys522是主要位点，经修饰可能会损害p97的功能。在一起

  DOI：

  10.1021/acs.jmedchem.9b00144
• 作为产物：
  描述：

  2-环己酮甲酸乙酯 在 盐酸 、 三氯氧磷 作用下， 以 乙醇 、 乙腈 为溶剂， 反应 2.0h， 生成 N-benzyl-2-chloro-5,6,7,8-tetrahydroquinazolin-4-amine
  参考文献：
  名称：

  Discovery of a First-in-Class, Potent, Selective, and Orally Bioavailable Inhibitor of the p97 AAA ATPase (CB-5083)

  摘要：

  The AAA-ATPase p97 plays vital roles in mechanisms of protein homeostasis, including ubiquitin proteasome system (ups) mediated protein degradation, endoplasmic reticulum-associated degradation (BRAD), and autophagy. Herein we describe our lead optimization efforts focused on in vitro potency, ADME, and pharmaceutical properties that led to the discovery of a potent, ATP-competitive, D2-selective, and orally bioavailable p97 inhibitor 71, CB-6083. Treatment of tumor cells with 71 leads to significant accumulation of markers associated with inhibition of UPS and ERAD functions, which induces irresolvable proteotoxic stress and cell, death. In tumor bearing mice, oral administration of 71 causes rapid accumulation Of markers of the unfolded protein response (UPR) and subsequently induces apoptosis leading to Sustained antitumor activity in in vivo, xenograft models of both solid and hematological tumors. 71 has been taken into phase I clinical trials in patients with multiple myeloma and solid tumors.

  DOI：

  10.1021/acs.jmedchem.5b01346

文献信息

• [EN] MONO AND BICYCLIC RING BORONIC ACID, ESTER AND SALT COMPOUNDS AS INHIBITORS OF P97 COMPLEX<br/>[FR] COMPOSÉS D'ESTER, DE SEL ET D'ACIDE BORONIQUE À NOYAU MONOCYCLIQUE ET BICYCLIQUE EN TANT QU'INHIBITEURS DE COMPLEXE P97
  申请人：CLEAVE BIOSCIENCES INC

  公开号：WO2016200840A1

  公开（公告）日：2016-12-15

  Monocyclic or bicyclic ring boronic acid or ester compounds having an arylalkyi amine substituent at the 4 position and a substituted 5:6 bicyclic group at the 2 position of the mono or bicyclic ring boronic acid or ester as well as optional aliphatic, functional and/or aromatic components substituted at other positions of the mono or bicyclic boronic acid or ester compounds are disclosed. These compounds are inhibitors of the AAA proteasome complex containing p97 and are effective medicinal agents for treatment of diseases associated with the Valosin containing protein and p97 bioactivity such as cancer. Formula (I).

  单环或双环硼酸或硼酸酯化合物，在4位具有芳烷基胺取代基，在单环或双环硼酸或硼酸酯的2位具有取代的5:6双环基团，以及在单环或双环硼酸或硼酸酯化合物的其他位置可选地取代有脂肪族、功能性和/或芳香族组分。这些化合物是含有p97的AAA蛋白酶体的抑制剂，并且是治疗与含有Valosin蛋白和p97生物活性相关的疾病的有效药物，如癌症。公式(I)。
• [EN] FUSED PYRIMIDINES AS INHIBITORS OF p97 COMPLEX<br/>[FR] PYRIMIDINES FUSIONNÉES EN TANT QU'INHIBITEURS DU COMPLEXE P97
  申请人：ZHOU HAN-JIE

  公开号：WO2014015291A1

  公开（公告）日：2014-01-23

  Fused pyrimidine compounds having a saturated, unsaturated or aromatic A ring fused to a pyrimidine ring and having a complex substituents at the 2 position and a substituted amine at the 4 position of the pyrimidine ring as well as optional aliphatic, functional and/or aromatic components substituted at other positions of the pyrimidine ring and A ring are disclosed. These compounds are inhibitors of the AAA proteasome complex containing p97 and are effective medicinal agents for treatment of diseases associated with p97 bioactivity such as cancer.

  本发明揭示了一种融合嘧啶化合物，其具有饱和、不饱和或芳香性A环与嘧啶环融合，并在嘧啶环的2位具有复杂的取代基，在4位具有取代胺基，以及在其他位置可选地具有取代的脂肪族、功能性和/或芳香性组分的嘧啶环和A环。这些化合物是包含p97的AAA蛋白酶复合物的抑制剂，是治疗与p97生物活性相关的疾病如癌症的有效药物。
• FUSED PYRIMIDINES AS INHIBITORS OF P97 COMPLEX
  申请人：Cleave Biosciences, Inc.

  公开号：US20170258795A1

  公开（公告）日：2017-09-14

  Fused pyrimidine compounds having a saturated, unsaturated or aromatic A ring fused to a pyrimidine ring and having a complex substituents at the 2 position and a substituted amine at the 4 position of the pyrimidine ring as well as optional aliphatic, functional and/or aromatic components substituted at other positions of the pyrimidine ring and A ring are disclosed. These compounds are inhibitors of the AAA proteasome complex containing p97 and are effective medicinal agents for treatment of diseases associated with p97 bioactivity such as cancer.

  本发明公开了一种融合嘧啶化合物，其具有饱和，不饱和或芳香性A环融合到嘧啶环上，并在嘧啶环的2位位置具有复杂的取代基和取代胺在嘧啶环的4位位置，以及可选的脂肪烷基，功能性和/或芳香基组分取代在嘧啶环和A环的其他位置。这些化合物是AAA蛋白酶复合物的抑制剂，包含p97，并且是用于治疗与p97生物活性相关的疾病的有效药物，例如癌症。
• Fused pyrimidines as inhibitors of P97 complex
  申请人：Cleave Biosciences, Inc.

  公开号：US10010554B2

  公开（公告）日：2018-07-03

  Fused pyrimidine compounds having a saturated, unsaturated or aromatic A ring fused to a pyrimidine ring and having a complex substituents at the 2 position and a substituted amine at the 4 position of the pyrimidine ring as well as optional aliphatic, functional and/or aromatic components substituted at other positions of the pyrimidine ring and A ring are disclosed. These compounds are inhibitors of the AAA proteasome complex containing p97 and are effective medicinal agents for treatment of diseases associated with p97 bioactivity such as cancer.

  本发明公开了具有与嘧啶环融合的饱和、不饱和或芳香 A 环的融合嘧啶化合物，该化合物在嘧啶环的 2 位具有复合取代基，在 4 位具有取代胺，并在嘧啶环和 A 环的其他位置具有任选取代的脂肪族、官能团和/或芳香族成分。这些化合物是含有 p97 的 AAA 蛋白酶体复合物的抑制剂，是治疗与 p97 生物活性有关的疾病（如癌症）的有效药物。
• Fused pyrimidines as inhibitors of p97 complex
  申请人：Cleave Biosciences, Inc.

  公开号：US10174005B2

  公开（公告）日：2019-01-08

  The present invention is directed to certain fused pyrimidines having a homo or hetero cyclopentyl, cyclohexyl or cycloheptyl ring as the pyrimidine fusion partner; having an amino benzyl or substituted amino benzyl group at the 4 position of the pyrimidine ring; and a 5:6 heterobicyclo ring with at least one N, O or S at the 2 position of the pyrimidine ring. These compounds are useful for treatment of cancer by inhibition of the p97 complex.

  本发明涉及某些融合嘧啶，其嘧啶融合伙伴为同族或杂族环戊基、环己基或环庚基环；在嘧啶环的 4 位上具有氨基苄基或取代氨基苄基；以及在嘧啶环的 2 位上具有至少一个 N、O 或 S 的 5:6 杂双环。这些化合物通过抑制 p97 复合物可用于治疗癌症。