2,4-dichloro-5,8-dihydro-6H-pyrano[3,4-d]pyrimidine | 1269461-25-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡喃嘧啶类
• 英文名称: 2,4-dichloro-5,8-dihydro-6H-pyrano[3,4-d]pyrimidine
• 英文别名: 2,4-dichloro-6,8-dihydro-5H-pyrano[3,4-d]pyrimidine
• CAS: 1269461-25-7
• 化学式: C₇H₆Cl₂N₂O
• 分子量: 205.043
• InChiKey: BDNFHGOSDKHGLO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  12
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  35
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  2,4-dichloro-5,8-dihydro-6H-pyrano[3,4-d]pyrimidine 在 tris-(dibenzylideneacetone)dipalladium(0) 、 palladium diacetate 、 caesium carbonate 、 三苯基膦 、 2-二环己基磷-2,4,6-三异丙基联苯 作用下， 以 1,4-二氧六环 、 乙醇 、 乙腈 为溶剂， 生成 1-(4-(benzylamino)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide
  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
• 作为产物：
  描述：

  methyl 5-amino-3,6-dihydro-2H-pyran-4-carboxylate 在 三氯氧磷 作用下， 以 N,N-二甲基苯胺 、 乙腈 为溶剂， 生成 2,4-dichloro-5,8-dihydro-6H-pyrano[3,4-d]pyrimidine
  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

• 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。
• FUSED PYRIMIDINES AND SUBSTITUTED QUINAZOLINES AS INHIBITORS OF P97
  申请人：Zhou Han-Jie

  公开号：US20140024661A1

  公开（公告）日：2014-01-23

  A group of fused two ring pyrimidine compounds having a heterocycles substituent at the 2 position and a substituted amine at the 4 position as well as optional aliphatic, functional and/or aromatic components substituted at other positions of the pyrimidine and other ring are disclosed. In addition a group of quinazoline compounds having similar substituents at the 2 and 4 positions as well as at other positions 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.
• FUSED PYRIMIDINES AS INHIBITORS OF P97 COMPLEX
  申请人：CLEAVE BIOSCIENCES, INC.

  公开号：US20160332990A1

  公开（公告）日：2016-11-17

  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.
• US9062026B2
  申请人：——

  公开号：US9062026B2

  公开（公告）日：2015-06-23
• US9828363B2
  申请人：——

  公开号：US9828363B2

  公开（公告）日：2017-11-28