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Piperazine-piperidine compounds as hepatitis C virus inhibitors

A technology of compounds and therapeutic agents, applied in the field of piperazine-piperidine compounds as hepatitis C virus inhibitors, capable of solving unmet problems

Inactive Publication Date: 2015-01-21
THERAVANCE BIOPHARMA R&D IP LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, there remains a serious unmet need in the treatment of HCV

Method used

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  • Piperazine-piperidine compounds as hepatitis C virus inhibitors
  • Piperazine-piperidine compounds as hepatitis C virus inhibitors
  • Piperazine-piperidine compounds as hepatitis C virus inhibitors

Examples

Experimental program
Comparison scheme
Effect test

example

[0262] The following synthetic and biological examples are provided to illustrate the invention but are not to be construed in any way as limiting the scope of the invention. In the following examples, the following abbreviations have the following meanings unless otherwise specified. Abbreviations not defined below have their generally accepted meanings.

[0263] ACN = acetonitrile

[0264] AcOH = acetic acid

[0265] CDI = 1,1'-carbonyldiimidazole

[0266] DCM = dichloromethane

[0267] DIPEA = N,N-Diisopropylethylamine

[0268] DMA = N,N-dimethylacetamide

[0269] DMF = N,N-Dimethylformamide

[0270]DMSO = dimethyl sulfoxide

[0271] EDC = N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride

[0272] EtOAc = ethyl acetate

[0273] Et 3 N = Triethylamine

[0274] h = hour

[0275] HATU = N,N,N'N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate

[0276] HCTU = 2-(6-chloro-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylammonium hexafluorophosph...

example 1

[0440] Example 1: ((S)-1-{(S)-2-[4-(4'-{[(S)-4-(1-cyclopropanecarbonyl-piperidin-4-yl)-3-methan Base-piperazine-1-carbonyl]-amino}-2'-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl methyl-propyl)-carbamate

[0441]

[0442] ((S)-1-{(S)-2-[4-(4'-amino-2'-trifluoromethoxy-biphenyl-4-yl)-1H-imidazole-2-yl) was stirred at RT Base]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-methyl carbamate (20 mg, 0.04 mmol) and p-nitrophenyl chloroformate (8.9 mg, 0.04 mmol) in DMA (5 mL) 30min in the mixture, followed by successive addition of cyclopropyl-[4-((S)-2-methyl-piperazin-1-yl)-piperidin-1-yl]-methanone 2HCl (18mg, 0.06mmol; Preparation 6) and DIPEA (32 μL, 0.18 mmol). The reaction mixture was stirred at RT for 1 h, concentrated, dissolved in 1:1 acetic acid:water (1.5 mL), and purified by reverse phase HPLC to give the di-trifluoroacetate salt of the title product (6.8 mg, 20% yield) . (m / z):C 42 h 53 f 3 N 8 o 6 [M+H] of + The calculated ...

example 2

[0443] Example 2: [(S)-1-((S)-2-{4-[5'-chloro-4'-({4-[1-(2,2-dichlorocyclopropanecarbonyl)-piperidine -4-yl]-piperazine-1-carbonyl}-amino)-2'-trifluoromethoxy-biphenyl-4-yl]-1H-imidazol-2-yl}-4-methyl-pyrrolidine -1-carbonyl)-2-methyl-propyl]-methyl carbamate

[0444]

[0445] 4-[4-(5-Chloro-4'-{2-[(2S,4S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl) was stirred at RT -4-Methyl-pyrrolidin-2-yl]-1H-imidazol-4-yl}-2-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-piperazin-1-yl]- A solution of tert-butyl piperidine-1-carboxylate di-trifluoroacetate (12.94 mg, 0.012 mmol; Preparation 14) in 4M HCl in 1,4-dioxane (0.21 mL) for 30 min gave the intermediate {(S)-1-[(2S,4S)-2-(4-(5'-chloro-4'-[(4-piperidin-4-yl-piperazine-1-carbonyl)-amino]- 2'-Trifluoromethoxy-biphenyl-4-yl}-1H-imidazol-2-yl)-4-methyl-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester.

[0446] A 0.5M solution of 2,2-dichlorocyclopropane-1-carboxylic acid in DMA (27.8 μL, 0.014 mmol) and HATU (5...

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Abstract

The invention provides compounds of formula (I): wherein the variables are defined in the specification, or a pharmaceutically-acceptable salt thereof, that are inhibitors of replication of the hepatitis C virus. The invention also provides pharmaceutical compositions comprising such compounds, methods of using such compounds to treat hepatitis C viral infections, and processes and intermediates useful for preparing such compounds.

Description

technical field [0001] The present invention is directed to compounds suitable for use as inhibitors of hepatitis C virus (HCV) replication. The invention is also directed to pharmaceutical compositions comprising the compounds, methods of using the compounds to treat HCV infection, and processes and intermediates suitable for the preparation of the compounds. Background technique [0002] Recent estimates put the number of people infected with hepatitis C virus (HCV) at more than 170 million worldwide, including 3 million in the United States. The infection rate is thought to be approximately 4 to 5 times that of the human immunodeficiency virus (HIV). Although in some individuals the natural immune response is able to defeat the virus, in most cases chronic infection results, leading to an increased risk of cirrhosis and hepatocellular carcinoma. Therefore, hepatitis C infection presents a serious public health problem. [0003] Prior to mid-2011, the accepted standard ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/04C07D403/14C07D407/14
CPCC07D487/08A61K31/506C07D405/14A61K31/496C07D401/14A61K45/06A61K31/55A61P31/14
Inventor 丹尼尔·D·朗罗伯特·默里·麦金内尔洛里·琼·范奥登加文·奥加瓦唐纳·威尔顿
Owner THERAVANCE BIOPHARMA R&D IP LLC
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