Inhibitors of hepatitis C virus
A compound and pharmaceutical technology, applied in the field of hepatitis C virus inhibitors, can solve the problems of decreased antiviral efficacy of HCV protease inhibitors, etc.
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[0485] In certain embodiments, A is -C(O)-, 6-10 membered arylene, or 5-6 membered heteroarylene, wherein the arylene or heteroarylene is surrounded by 1-4 halogen Or haloalkyl is optionally substituted. In some embodiments, A is -C(O)-.
[0486] In certain embodiments, M is -O- or a bond. In some embodiments, M is -O-.
[0487] In certain embodiments, G is -CO 2 H or -CONHSO 2 Z 2 . In some embodiments, G is -CONHSO 2 Z 2 . In some embodiments, G is -CONHSO 2 Z 2 And Z 2 is cyclopropyl optionally substituted with methyl.
[0488] In certain embodiments, G is:
[0489]
[0490]
[0491] In some embodiments, G is:
[0492]
[0493] In some embodiments, Z 2 Yes:
[0494]
[0495] In some embodiments, Z 2 Yes:
[0496]
[0497] In some embodiments, Z 2a is hydrogen, halogen or methyl. In some embodiments, Z 2a Yes:
[0498]
[0499] In other embodiments, Z 2a Yes or (i.e. hydrogen or methyl).
[0500] In other embodiments, Z 2a Yes ...
Embodiment 1
[1079] Example 1. (1aR, 5S, 8S, 9S, 10R, 22aR)-5-tert-butyl-N-[(1R, 2R)-2-(difluoromethyl)-1-{[(1-methyl Cyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10 ,18,19,20,21,22,22a-Tetradetrahydro-8H-7,10-methanecyclopropane[18,19][1,10,3,6]dioxadiazanonadecane[ 11,12-b] Preparation of quinoxaline-8-carboxamides.
[1080]
[1081] step 1. Preparation of 1-1: A mixture of MeCN (40 mL) containing intermediate B4 (2.03 g, 6.44 mmol), intermediate E1 (1.6 g, 5.85 mmol) and cesium carbonate (3.15 g, 9.66 mmol) at room temperature under Ar atmosphere Stir vigorously for 16 hours. The reaction was then filtered through a pad of celite and the filtrate was concentrated in vacuo. The crude product was purified by silica gel chromatography to afford 1-1 (2.5 g) as a white solid. LCMS-ESI + (m / z): C 20 h 27 ClN 3 o 4 [M-Boc+2H] + Analytical calculated: 408.9; found: 408.6.
[1082] step 2. Preparation of 1-2: Add hydrochloric acid in dio...
Embodiment 2
[1089] Example 2. (1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-1-[(cyclopropylsulfonyl)carbamoyl]-2- (Difluoromethyl)cyclopropyl]-9-ethyl-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20 ,21,22,22a-Tetradetrahydro-8H-7,10-methanecyclopropane[18,19][1,10,3,6]dioxadiazanonadecane[11,12-b] Preparation of quinoxaline-8-carboxamide.
[1090]
[1091] The preparation method of Example 2 is similar to that of Example 1, and the intermediate A10 in the 8th step is replaced by the intermediate A9. Example 2 isolated the TFA salt (37.9 mg) in approximately 85% purity. Analytical HPLC retention time: 8.54 min. LCMS-ESI + (m / z): C 39 h 53 f 2 N 6 o 9 [M+H] of S + Analytical calculated: 819.35; found: 819.51. 1 H NMR (400MHz, CDCl 3 )δ10.26(s, 1H); 7.90(d, J=9.2Hz, 1H); 7.26(dd, J=9.2, 2.4Hz, 1H); 7.10(d, J=2.4Hz, 1H); 6.68( br s, 1H); 6.01 (td, J H-F =55.6Hz, J=6.8Hz, 1H); 5.87(d, J=3.6Hz, 1H); 5.38, (d, J=10Hz, 1H); 4.50-4.40(m, 3H); 4.10(dd, J =12, 3.6Hz, 1H); 3.95(s...
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