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HCV Inhibitors

A technology of excipients and compounds, applied in the field of hepatitis C virus inhibitors, can solve the problems of reduced antiviral efficacy of HCV protease inhibitors and the like

Active Publication Date: 2017-08-11
GILEAD SCI INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For example, resistance mutations at positions 155 and 168 in HCV protease usually lead to a significant reduction in the antiviral efficacy of HCV protease inhibitors (Mani, N. Ann Forum Collab HIV Res., 2012, 14, 1-8; Romano, KP et al. People, PNAS, 2010, 107, 20986-20991; Lenz O, Antimicrobial agents and chemotherapy, 2010, 54, 1878–1887.)

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0670] Example 1. (1aS, 2aR, 6S, 9S, 11R, 23aR, 23bS)-6-tert-butyl-N-[(1R,2R)-1-[(cyclopropylsulfonyl)carbamoyl]- 2-(Difluoromethyl)cyclopropyl]-15-methoxy-4,7-dioxo-1a,2,2a,4,5,6,7,10,11,19,20,21 ,22,23,23a,23b-Hexadecahydro-1H,9H-8,11-methylenecyclopropano[4',5']cyclopenta[1',2':18,19][ Preparation of 1,10,3,6]dioxadiazacyclonadecano(nonadecino)[11,12-b]quinoxaline-9-carboxamide.

[0671]

[0672]

[0673] Example 1

[0674] Step 1. Preparation of 1-1. Combine quinoxaline C1 (2.29g, 10.0mmol) with N-Boc-trans-4-hydroxy-L-proline methyl ester (2.65g, 11.0mmol) and Cs 2 CO 3 (3.59 g, 11.0 mmol) were combined as a suspension in MeCN (20 mL). The stirred reaction mixture was heated to 85 °C for 16 h, then filtered through celite and concentrated in vacuo. The crude residue was purified by silica gel chromatography (5%-50% EtOAc / Hex) to give 1-1.LCMS-ESI + (m / z): [M-Boc+2H] + Calculated value C 15 h 17 ClN 3 o 4 : 338.09; measured value: 337.94.

[0675] Step 2....

Embodiment 2

[0682] Example 2. (1aS, 2aR, 6S, 9S, 11R, 23aR, 23bS)-6-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1 -methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-15-methoxy-4,7-dioxo-1a,2,2a,4,5,6,7,10,11 ,19,20,21,22,23,23a,23b-Hexadecahydro-1H,9H-8,11-methylenecyclopropane[4',5']cyclopenta[1',2' : Preparation of 18,19][1,10,3,6]dioxadiazacyclonadecano[11,12-b]quinoxaline-9-carboxamide.

[0683]

[0684] Example 2

[0685] Example 2 was prepared in a similar manner to Example 1, replacing Intermediate A9 in Step 8 with Intermediate A10. Example 2 (107 mg) was isolated as the TFA salt. Analytical HPLC retention time: 8.85min. LCMS-ESI + (m / z): [M+H] + Calculated value C 41 h 55 f 2 N 6 o 9 S: 845.37; measured value: 845.67. 1 H-NMR (400MHz, CD 3 OD)δ9.31(s,1H),7.78(d,J=8.8Hz,1H),7.20(dt,J=3.9,2.6Hz,2H),6.06(t,J=3.5Hz,1H),5.87 (td,J=55.8,6.7Hz,1H),5.00(d,J=7.5Hz,1H),4.51–4.38(m,2H),4.34(s,1H),4.11(dd,J=11.8,3.8 Hz,1H),3.92(s,3H),3.04–2.85(m,1H),2.85–2.67(m,1H),2.49(d...

Embodiment 3

[0686] Example 3. (1aS, 2aR, 6S, 9S, 11R, 23aR, 23bS)-6-tert-butyl-N-[(1R,2S)-1-[(cyclopropylsulfonyl)carbamoyl]- 2-(2,2-Difluoroethylcyclopropyl)-15-methoxy-4,7-dioxo-1a,2,2a,4,5,6,7,10,11,19, 20,21,22,23,23a,23b-Hexadeca-hydro-1H,9H-8,11-methylenecyclopropano[4',5']cyclopenta[1',2':18 ,19][1,10,3,6]dioxadiazacyclonadecano[11,12-b]quinoxaline-9-carboxamide.

[0687]

[0688] Example 3

[0689] Example 3 was prepared in a similar manner to Example 1, substituting Intermediate A7 for Intermediate A9 in Step 8. Example 3 (52 mg) was isolated as the TFA salt. Analytical HPLC retention time: 8.82min. LCMS-ESI + (m / z): [M+H] + Calculated value C 41 h 55 f 2 N 6 o 9 S: 845.37; measured value: 845.96. 1 H-NMR (400MHz, CD 3 OD)δ9.18(s,1H),7.78(dd,J=8.1,1.5Hz,1H),7.26–7.16(m,2H),6.07(t,J=3.6Hz,1H),5.89(tt, J=56.5, 4.1Hz, 1H), 4.99(d, J=7.5Hz, 1H), 4.45(dd, J=11.1, 5.9Hz, 2H), 4.32(s, 1H), 4.11(dd, J=11.9 ,3.8Hz,1H),3.92(s,3H),3.04–2.86(m,2H),2.86–2.68(m,1H),2.47(dd,J=...

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Abstract

Compounds of formula I, or pharmaceutically acceptable salts thereof, wherein the various substituents are as defined herein; methods of using said compounds and pharmaceutical compositions comprising said compounds.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of US Provisional Application No. US 61 / 798,961 in 35 U.S.C. §119(e), filed March 15, 2013, which is incorporated herein by reference in its entirety. technical field [0003] The present invention discloses novel small molecule inhibitors of viral replication, and also discloses compositions comprising such compounds and methods of treatment comprising administering such compounds. Background technique [0004] Hepatitis C virus (HCV), a member of the genus hepacivirus within the family Flaviviridae, is a major cause of chronic liver disease worldwide (Boyer, N. et al. J Hepatol. 2000, 32, 98-112). Therefore, the main focus of current antiviral research is directed to the development of improved methods for the treatment of chronic HCV infection in humans (Ciesek, S., von Hahn T. and Manns, MP., Clin. Liver Dis., 2011, 15, 597-609; Soriano , V. et al., J. Antimicrob. Chemother., 2...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D498/22A61K31/437A61K31/4985A61K31/519A61P31/14
CPCC07D498/22A61K31/437A61K31/519C07D487/00C07D487/02C07D203/02A61P1/16A61P31/14A61P31/20C07K7/64
Inventor K·比约翰逊K·K·卡奇J·O·林克H-J.朴A·J·施里尔K·L·史蒂芬斯J·G·泰勒R·W·薇薇安J·扎布罗奇S·齐普菲尔
Owner GILEAD SCI INC