3-chloro-5-[(3,5-dichloro-1H-indazol-4-yl)oxy]benzonitrile | 1034708-74-1

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 3-chloro-5-[(3,5-dichloro-1H-indazol-4-yl)oxy]benzonitrile
• 英文别名: 3-chloro-5-[(3,5-dichloro-2H-indazol-4-yl)oxy]benzonitrile
• CAS: 1034708-74-1
• 化学式: C₁₄H₆Cl₃N₃O
• 分子量: 338.58
• InChiKey: ZTMDEBDROOTYQY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  61.7
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  3-chloro-5-[(3,5-dichloro-1H-indazol-4-yl)oxy]benzonitrile 在 caesium carbonate 、 三氟乙酸 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 0.17h， 生成 3-chloro-5-{[3,5-dichloro-1-(1H-pyrazolo[3,4-b]pyridin-3-ylmethyl)-1H-indazol-4-yl]oxy}benzonitrile
  参考文献：
  名称：

  Design and Synthesis of Conformationally Constrained Inhibitors of Non-Nucleoside Reverse Transcriptase

  摘要：

  Highly active antiretroviral therapy (HAART) significantly reduces human immunodeficiency virus (HIV) viral load and has led to a dramatic decrease in acquired immunodeficiency syndrome (AIDS) related mortality. Despite this success, there remains a critical need for new HIV therapies to address the emergence of drug resistant viral strains. Next generation NNRTIs are sought that are effective against these mutant forms of the HIV virus. The bound conformations of our lead inhibitors, MK-1107 (1) and MK-4965 (2), were divergent about the oxymethylene linker, and each of these conformations was rigidified using two isomeric cyclic constraints. The constraint derived from the bioactive conformation of 2 provided novel, highly potent NNRTIs that possess broad spectrum antiviral activity and good pharmacokinetic profiles. Systematic SAR led to the identification of indazole as the optimal conformational constraint to provide MK-6186 (3) and MK-7445 (6). Despite their reduced flexibility, these compounds had potency comparable to that of the corresponding acyclic ethers in both recombinant enzyme and cell based assays against both the wild-type and the clinically relevant mutant strains.

  DOI：

  10.1021/jm2010173
• 作为产物：
  描述：

  2-氯-5-氟苯酚 在 N-氯代丁二酰亚胺 、 四(三苯基膦)钯 、 potassium tert-butylate 、 potassium carbonate 、 一水合肼 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 N-甲基吡咯烷酮 、 乙醇 、 正己烷 、 乙基苯 、 N,N-二甲基甲酰胺 为溶剂， 反应 97.67h， 生成 3-chloro-5-[(3,5-dichloro-1H-indazol-4-yl)oxy]benzonitrile
  参考文献：
  名称：

  Design and Synthesis of Conformationally Constrained Inhibitors of Non-Nucleoside Reverse Transcriptase

  摘要：

  Highly active antiretroviral therapy (HAART) significantly reduces human immunodeficiency virus (HIV) viral load and has led to a dramatic decrease in acquired immunodeficiency syndrome (AIDS) related mortality. Despite this success, there remains a critical need for new HIV therapies to address the emergence of drug resistant viral strains. Next generation NNRTIs are sought that are effective against these mutant forms of the HIV virus. The bound conformations of our lead inhibitors, MK-1107 (1) and MK-4965 (2), were divergent about the oxymethylene linker, and each of these conformations was rigidified using two isomeric cyclic constraints. The constraint derived from the bioactive conformation of 2 provided novel, highly potent NNRTIs that possess broad spectrum antiviral activity and good pharmacokinetic profiles. Systematic SAR led to the identification of indazole as the optimal conformational constraint to provide MK-6186 (3) and MK-7445 (6). Despite their reduced flexibility, these compounds had potency comparable to that of the corresponding acyclic ethers in both recombinant enzyme and cell based assays against both the wild-type and the clinically relevant mutant strains.

  DOI：

  10.1021/jm2010173

文献信息

• Non-nucleoside reverse transcriptase inhibitors
  申请人：Anthony Neville J.

  公开号：US20080275097A1

  公开（公告）日：2008-11-06

  Compounds of Formula I: are HIV reverse transcriptase inhibitors, wherein V, W, X, Y, Z, R 1 , R 2 , R 4 , R 5 , R 6 , ring A, ring B, j and k are defined herein. The compounds of Formula I, and the pharmaceutically acceptable salts and prodrugs thereof, are useful in the inhibition of HIV reverse transcriptase, the prophylaxis and treatment of infection by HIV and in the prophylaxis, delay in the onset or progression, and treatment of AIDS. The compounds and their salts can be employed as ingredients in pharmaceutical compositions, optionally in combination with other antivirals, immunomodulators, antibiotics or vaccines.

  化合物I的公式是HIV反转录酶抑制剂，其中V、W、X、Y、Z、R1、R2、R4、R5、R6、环A、环B、j和k在此定义。化合物I及其医药上可接受的盐和前药在抑制HIV反转录酶、预防和治疗HIV感染以及预防、延迟发病或进展和治疗艾滋病方面具有用途。这些化合物及其盐可以与其他抗病毒药物、免疫调节剂、抗生素或疫苗组合使用作为药物组成部分。
• NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
  申请人：Anthony Neville J.

  公开号：US20100286192A1

  公开（公告）日：2010-11-11

  Compounds of Formula I: are HIV reverse transcriptase inhibitors, wherein V, W, X, Y, Z, R 1 , R 2 , R 4 , R 5 , R 6 , ring A, ring B, j and k are defined herein. The compounds of Formula I, and the pharmaceutically acceptable salts and prodrugs thereof, are useful in the inhibition of HIV reverse transcriptase, the prophylaxis and treatment of infection by HIV and in the prophylaxis, delay in the onset or progression, and treatment of AIDS. The compounds and their salts can be employed as ingredients in pharmaceutical compositions, optionally in combination with other antivirals, immunomodulators, antibiotics or vaccines.

  化学式为I的化合物：是HIV反转录酶抑制剂，其中V、W、X、Y、Z、R1、R2、R4、R5、R6、环A、环B、j和k在此定义。化合物I的药物可接受的盐和前药，在抑制HIV反转录酶、预防和治疗HIV感染以及预防、延缓或治疗艾滋病方面有用。这些化合物及其盐可作为药物组成部分，可以与其他抗病毒药物、免疫调节剂、抗生素或疫苗组合使用。
• US7781454B2
  申请人：——

  公开号：US7781454B2

  公开（公告）日：2010-08-24
• [EN] NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS<br/>[FR] INHIBITEURS NON-NUCLÉOSIDIQUES DE LA TRANSCRIPTASE INVERSE
  申请人：MERCK & CO INC

  公开号：WO2008076225A2

  公开（公告）日：2008-06-26

  [EN] Compounds of Formula I are HIV reverse transcriptase inhibitors, wherein V, W, X, Y, Z, R¹, R², R⁴, R⁵, R⁶, ring A, ring B, j and k are defined herein. The compounds of Formula I, and the pharmaceutically acceptable salts and prodrugs thereof, are useful in the inhibition of HIV reverse transcriptase, the prophylaxis and treatment of infection by HIV and in the prophylaxis, delay in the onset or progression, and treatment of AIDS. The compounds and their salts can be employed as ingredients in pharmaceutical compositions, optionally in combination with other antivirals, immunomodulators, antibiotics or vaccines.
  [FR] L'invention concerne des composés de formule I qui consistent en des inhibiteurs de la transcriptase inverse du VIH, V, W, X, Y, Z, R¹, R², R⁴, R⁵, R⁶, cycle A, cycle B, j et k étant définis dans le présent document. Les composés de formule I, et les sels et promédicaments de ceux-ci acceptables sur le plan pharmaceutique, sont utiles dans l'inhibition de la transcriptase inverse du VIH, dans la prophylaxie et le traitement d'infection par le VIH et dans la prophylaxie, le retardement de l'apparition ou de la progression, et le traitement du SIDA. Les composés et leurs sels peuvent être utilisés comme ingrédients dans des compositions pharmaceutiques, facultativement combinés à d'autres antiviraux, immunomodulateurs, antibiotiques ou vaccins.
• Design and Synthesis of Conformationally Constrained Inhibitors of Non-Nucleoside Reverse Transcriptase
  作者：Robert Gomez、Samson J. Jolly、Theresa Williams、Joseph P. Vacca、Maricel Torrent、Georgia McGaughey、Ming-Tain Lai、Peter Felock、Vandna Munshi、Daniel DiStefano、Jessica Flynn、Mike Miller、Youwei Yan、John Reid、Rosa Sanchez、Yuexia Liang、Brenda Paton、Bang-Lin Wan、Neville Anthony

  DOI：10.1021/jm2010173

  日期：2011.11.24

  Highly active antiretroviral therapy (HAART) significantly reduces human immunodeficiency virus (HIV) viral load and has led to a dramatic decrease in acquired immunodeficiency syndrome (AIDS) related mortality. Despite this success, there remains a critical need for new HIV therapies to address the emergence of drug resistant viral strains. Next generation NNRTIs are sought that are effective against these mutant forms of the HIV virus. The bound conformations of our lead inhibitors, MK-1107 (1) and MK-4965 (2), were divergent about the oxymethylene linker, and each of these conformations was rigidified using two isomeric cyclic constraints. The constraint derived from the bioactive conformation of 2 provided novel, highly potent NNRTIs that possess broad spectrum antiviral activity and good pharmacokinetic profiles. Systematic SAR led to the identification of indazole as the optimal conformational constraint to provide MK-6186 (3) and MK-7445 (6). Despite their reduced flexibility, these compounds had potency comparable to that of the corresponding acyclic ethers in both recombinant enzyme and cell based assays against both the wild-type and the clinically relevant mutant strains.