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Antiviral Compound Inhibitors of HCV NS5A

A technology for compounds and compositions, which can be used in antiviral agents, medical preparations containing active ingredients, drug combinations, etc., can solve problems such as limited practicality

Active Publication Date: 2016-10-26
GILEAD SCI INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although drugs targeting the liver are widely used and have shown effectiveness, toxicity and other side effects limit their usefulness

Method used

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  • Antiviral Compound Inhibitors of HCV NS5A
  • Antiviral Compound Inhibitors of HCV NS5A
  • Antiviral Compound Inhibitors of HCV NS5A

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0230] In one embodiment, compounds of general formula (I) are provided:

[0231] E. 1a -V 1a –C(=O)-P 1a -W 1a -P 1b -C(=O)-V 1b -E 1b (I)

[0232] in:

[0233] W 1a Yes

[0234]

[0235] and W 1a optionally substituted with one or more groups independently selected from halogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted heterocycle, and cyano;

[0236] Y 5 Yes-O-CH 2 -, -CH 2 -O-, -O-C(=O)- or -C(=O)-O-; X 5 is-CH 2 -CH 2 -or-CH=CH-;

[0237] E. 1a is -N(H)(alkoxycarbonyl), -N(H)(cycloalkylcarbonyl), or -N(H)(cycloalkoxycarbonyl); or E 1a -V 1a together is R 9a ;

[0238] E. 1b is -N(H)(alkoxycarbonyl), -N(H)(cycloalkylcarbonyl), or -N(H)(cycloalkoxycarbonyl); or E 1b -V 1b together is R 9b ;

[0239] V 1a and V 1b each independently selected from:

[0240]

[0241] P 1a selected from:

[0242]

[0243]

[0244] P 1b selected from:

[0245]

[0246] and

[0247] R 9a and R 9b each independently ...

Embodiment AA

[0316]

[0317]

[0318] 3,4-Dihydronaphthalen-1(2H)-one: Dissolve 7-hydroxy-1-tetralone (13.9 g, 85.7 mmol) and 1-bromo-2- To a stirred solution of (bromomethyl)-4-chlorobenzene (25.6 g, 90.0 mmol), potassium carbonate (24 g, 172 mmol) was added. The reaction was stirred under argon for 18 hours, then diluted with ethyl acetate (1 L). The organics were washed three times with water and once with brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated. To the resulting oil was added methanol (500 mL), and the suspension was stirred for thirty minutes. 7-(2-Bromo-5-chlorobenzyloxy)-(27.8 g, 89% yield) was isolated by filtration.

[0319] 3-Chloro-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one: Add palladium(II) pivalate (1.18g, 3.8mmol), tri( In a 1L flask of 4-fluorophenyl)phosphine (1.20g, 3.8mmol), pivalic acid (2.33g, 22.8mmol) and potassium carbonate (31.8g, 228mmol), add dimethylacetamide (380mL) A solution of 7-(2-bromo-5-chlo...

Embodiment AB

[0327]

[0328]

[0329] (2S,4S)-1-tert-butyl 2,4-dimethylpyrrolidine-1,2,4-tricarboxylate. To a solution of (2S,4S)-1-tert-butyl 2-methyl 4-cyanopyrrolidine-1,2-dicarboxylate (9.0 g, 35.4 mmol) in MeOH (196 mL) was added HCl ( 4M in 1,4-dioxane, 100 mL, 403 mmol). The solution was stirred at room temperature for 16 h, and concentrated in vacuo. The crude intermediate was dissolved in ethyl acetate (180 mL) and basified with aqueous bicarbonate (sat.). Di-tert-butyl bicarbonate (8.5 g, 38.9 mmol) was added and the biphasic solution was stirred at room temperature for 12 h. The layers were then separated, and the aqueous layer was back extracted with ethyl acetate. The combined organic layers were washed with brine, passed through Na 2 SO 4 Dried and concentrated. The crude oil was purified by silica gel chromatography (15% to 40% to 100% ethyl acetate / hexanes) to provide (2S,4S)-1-tert-butyl 2,4-dimethylpyrrolidine-1,2 , 4-Tricarboxylate (9.56 g, 94%).

[0330] (...

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Abstract

The present invention relates to antiviral compounds of general formula (I), compositions containing said compounds and methods of treatment comprising administering said compounds, as well as processes and intermediates for the preparation of said compounds.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to U.S. Application No. 13 / 831,116, filed March 14, 2013, and U.S. Provisional Application No. 61 / 647,966, filed May 16, 2012, both of which are incorporated by reference in their entirety In this application. Background technique [0003] Hepatitis C is considered a chronic viral disease of the liver characterized by liver disease. Although drugs that target the liver are widely used and have shown effectiveness, toxicity and other side effects limit their usefulness. Inhibitors of hepatitis C virus (HCV) are used to limit the establishment and progression of HCV infection and in diagnostic tests for HCV. [0004] There is a need for new HCV therapeutics. In particular, there is a need for HCV therapeutics that are active against a broad range of HCV genotypes (eg, genotypes 1a, 1b, 2a, 3a, 4a). There is also a particular need for agents that are less prone to viral resistance. Inhi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D491/052A61K31/4188
CPCC07D491/052A61K31/4188A61P31/12A61K45/06A61K31/7068C07D491/04A61K31/7056A61K38/21A61K31/7072A61P1/16A61P31/00A61P31/14A61P43/00A61K2300/00C07D413/14
Inventor 约翰·O.·林克杰瑞米·J.·柯特尔特里萨·亚历杭德拉·特雷霍·马丁伊丽莎白·M.·培根
Owner GILEAD SCI INC
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