Hepatitis C virus inhibitors

Abstract

Hepatitis C virus inhibitors having the general formula (I) are disclosed. Compositions comprising the compounds and methods for using the compounds to inhibit HCV are also disclosed. ##STR00001##

Claims

1. A compound of formula (I) ##STR00102## or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2; custom character is a single or double bond; m is 0, 1, or 2; R.sup.1 is ##STR00103## wherein R.sup.1 is attached to the parent molecular moiety through any substitutable carbon atom in the ring; n is 0, 1, 2, 3, 4, 5, or 6; X.sup.0 is selected from CH and N; X.sup.1 is selected from CH and N; X.sup.2 and X.sup.3 are independently selected from CH, C(R.sup.a) and N; provided that at least one of X.sup.1, X.sup.2, and X.sup.3 is other than N; each R.sup.a is independently selected from alkenyloxy, alkoxy, alkoxyalkoxy, alkoxycarbonyl, alkyl, benzodioxanyl, carboxamido, carboxy, carboxyalkoxy, cyano, cycloalkyl, cycloalkylalkoxy, cycloalkyloxy, deuteroalkoxy, dialkylamino, halo, haloalkyl, haloalkoxy, haloalkoxycarbonyl, hydroxy, imidazolyl, morpholinyl, oxazolyl, phenyl, piperazinyl, pyrazolyl, pyridinyl, pyrrolidinyl, thiazolyl, and NR.sup.qR.sup.q, wherein the imidazolyl, the morpholinyl, the oxazolyl, the phenyl, the piperazinyl, the pyridinyl, the pyrrolidinyl, and the thiazolyl are optionally substituted with one or two groups independently selected from alkoxy, alkyl, alkylsulfonyl, halo, haloalkoxy, haloalkyl, and morpholinyl; and wherein two adjacent R.sup.a groups, together with the carbon atoms to which they are attached, can optionally form a ring selected from dioxanyl, dioxolanyl, furanyl, morpholinyl, pyranyl, and phenyl, wherein the ring is optionally substituted with one or two groups independently selected from alkyl and halo; R.sup.x is selected from hydrogen and methyl; R.sup.2 is selected from hydrogen, alkyl, deuteroalkyl, halo, haloalkoxy, haloalkyl, and hydroxyalkyl; R.sup.3 is selected from hydrogen, alkoxyalkoxycarbonyl, alkoxycarbonyl, alkylaminocarbonyl, alkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylcarbonyl, cycloalkyloxycarbonyl, deuteroalkoxycarbonyl, deuterohaloalkoxycarbonyl, dialkylaminocarbonyl, dialkylaminocarbonylcarbonyl, haloalkoxycarbonyl, haloalkylaminocarbonyl, haloalkylcarbonyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, phenylcarbonyl, and phenyloxycarbonyl, wherein the cycloalkyl part of the cycloalkylalkoxycarbonyl, the cycloalkylcarbonyl, and the cycloalkyloxycarbonyl, the heterocyclyl part of the heterocyclylcarbonyl and the heterocyclyloxycarbonyl, and the phenyl part of the phenylcarbonyl and the phenyloxycarbonyl, is optionally substituted with one, two, or three groups independently selected from alkyl, alkylamino, alkylcarbonyl, cycloalkyl, dialkylamino, halo, haloalkoxy, and haloalkyl; and one of R.sup.q and R.sup.q is selected from hydrogen and alkyl and the other is selected from alkylcarbonyl and phenylcarbonyl.

2. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein p is 1.

3. A compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein custom character is a double bond.

4. A compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein m is 1.

5. A compound of claim 4 wherein R.sup.1 is ##STR00104## wherein R.sup.1 is attached to the parent molecular moiety through any substitutable carbon atom in the ring; n is 1, q is 0, 1, 2, 3, or 4; X.sup.0 is selected from CH and N; X.sup.1 is selected from CH and N; X.sup.2 and X.sup.3 are independently selected from CH, C(R.sup.a) and N; provided that at least one of X.sup.1, X.sup.2, and X.sup.3 is other than N; X.sup.4 is selected from CH and CR.sup.a; each R.sup.a is independently selected from alkoxy, alkyl, halo, and haloalkyl.

6. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is selected from hydrogen, alkyl, and haloalkyl.

7. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.3 is selected from alkoxycarbonyl and haloalkoxycarbonyl.

8. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein p is 1; custom character is a double bond; m is 1; and R.sup.1 is ##STR00105## wherein wherein R.sup.1 is attached to the parent molecular moiety through any substitutable carbon atom in the ring; n is 1, q is 0, 1, 2, 3, or 4; X.sup.0 is selected from CH and N; X.sup.1 is selected from CH and N; X.sup.2 and X.sup.3 are independently selected from CH, C(R.sup.a) and N; provided that at least one of X.sup.1, X.sup.2, and X.sup.3 is other than N; X.sup.4 is selected from CH and CR.sup.a; and each R.sup.a is independently selected from alkoxy, alkyl, halo, and haloalkyl.

9. A compound selected from tert-butyl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((4-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; tert-butyl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-((4-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((4-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-((4-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,13aS,14aR,16aS,Z)-2-((6-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,13aS,14aR,16aS,Z)-2-((4-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; tert-butyl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-14a-((cyclopropylsulfonyl)carbamoyl)-2-((4-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-9-methyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; tert-butyl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-14a-((cyclopropylsulfonyl)carbamoyl)-2-((4-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-9-methyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; tert-butyl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((6-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; tert-butyl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-((6-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; tert-butyl ((2R,6S,7R,13aS,14aR,16aS,Z)-2-((4-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; tert-butyl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-14a-((cyclopropylsulfonyl)carbamoyl)-2-((6-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-9-methyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; tert-butyl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-14a-((cyclopropylsulfonyl)carbamoyl)-2-((6-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-9-methyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-14a-((cyclopropylsulfonyl)carbamoyl)-2-((4-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-9-methyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-14a-((cyclopropylsulfonyl)carbamoyl)-2-((4-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-9-methyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; 1,1,1-trifluoro-2-methylpropan-2-yl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((6-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; 1,1,1-trifluoro-2-methylpropan-2-yl((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-((6-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-14a-((cyclopropylsulfonyl)carbamoyl)-2-((6-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-9-methyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-14a-((cyclopropylsulfonyl)carbamoyl)-2-((6-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-9-methyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; tert-butyl ((2R,6S,7R,13aS,14aR,16aS,Z)-14a-((cyclopropylsulfonyl)carbamoyl)-2-((7-methoxy-3-(trifluoromethyl)quinoxalin-2-yl)oxy)-7-(methoxymethyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,13aS,14aR,16aS,Z)-14a-((cyclopropylsulfonyl)carbamoyl)-2-((7-methoxy-3-(trifluoromethyl)quinoxalin-2-yl)oxy)-7-(methoxymethyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; tert-butyl ((2R,6S,7R,13aS,14aR,16aS,Z)-14a-((cyclopropylsulfonyl)carbamoyl)-2-((7-fluoro-6-methoxynaphthalen-1-yl)oxy)-7-(methoxymethyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,13aS,14aR,16aS,Z)-14a-((cyclopropylsulfonyl)carbamoyl)-2-((7-fluoro-6-methoxynaphthalen-1-yl)oxy)-7-(methoxymethyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; tert-butyl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-14a-(((1-(fluoromethyl)cyclopropyl)sulfonyl)carbamoyl)-2-((3-isopropyl-7-methoxyquinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; tert-butyl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-14a-(((1-(fluoromethyl)cyclopropyl)sulfonyl)carbamoyl)-2-((3-isopropyl-7-methoxyquinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; tert-butyl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-14a-((cyclopropylsulfonyl)carbamoyl)-2-((7-fluoro-6-methoxynaphthalen-1-yl)oxy)-7-(methoxymethyl)-9-methyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; tert-butyl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-((7-methoxy-3-(trifluoromethyl)quinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; tert-butyl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((7-methoxy-3-(trifluoromethyl)quinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; tert-butyl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-((3-isopropyl-7-methoxyquinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; tert-butyl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((3-isopropyl-7-methoxyquinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-((7-methoxy-3-(trifluoromethyl)quinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((7-methoxy-3-(trifluoromethyl)quinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-((3-isopropyl-7-methoxyquinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((3-isopropyl-7-methoxyquinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; tert-butyl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-14a-(((1-(fluoromethyl)cyclopropyl)sulfonyl)carbamoyl)-2-((7-methoxy-3-(trifluoromethyl)quinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; tert-butyl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-14a-(((1-(fluoromethyl)cyclopropyl)sulfonyl)carbamoyl)-2-(((3-isopropyl-7-methoxyquinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-14a-(((1-(fluoromethyl)cyclopropyl)sulfonyl)carbamoyl)-2-((7-methoxy-3-(trifluoromethyl)quinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-14a-(((1-(fluoromethyl)cyclopropyl)sulfonyl)carbamoyl)-2-((7-methoxy-3-(trifluoromethyl)quinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-14a-(((1-(fluoromethyl)cyclopropyl)sulfonyl)carbamoyl)-2-((3-isopropyl-7-methoxyquinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-14a-(((1-(fluoromethyl)cyclopropyl)sulfonyl)carbamoyl)-2-((3-isopropyl-7-methoxyquinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-14a-((cyclopropylsulfonyl)carbamoyl)-2-((7-methoxy-3-(trifluoromethyl)quinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-14a-((cyclopropylsulfonyl)carbamoyl)-2-((7-methoxy-3-(trifluoromethyl)quinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((7-fluoro-4-methoxynaphthalen-1-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; tert-butyl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-((6-fluoro-7-methoxy-3-(trifluoromethyl)quinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; tert-butyl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((6-fluoro-7-methoxy-3-(trifluoromethyl)quinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-((6-fluoro-7-methoxy-3-(trifluoromethyl)quinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((6-fluoro-7-methoxy-3-(trifluoromethyl)quinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; tert-butyl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-((7-ethoxy-3-(trifluoromethyl)quinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; tert-butyl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((7-ethoxy-3-(trifluoromethyl)quinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; 3,3-difluoro-2-methylbutan-2-yl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-((7-ethoxy-3-(trifluoromethyl)quinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((l-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; 3,3-difluoro-2-methylbutan-2-yl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((7-ethoxy-3-(trifluoromethyl)quinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-((7-ethoxy-3-(trifluoromethyl)quinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((7-ethoxy-3-(trifluoromethyl)quinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; 3,3-difluoro-2-methylbutan-2-yl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-((7-isopropoxy-3-(trifluoromethyl)quinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; 3,3-difluoro-2-methylbutan-2-yl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((7-isopropoxy-3-(trifluoromethyl)quinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-((7-isopropoxy-3-(trifluoromethyl)quinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((7-isopropoxy-3-(trifluoromethyl)quinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-((4,5-dimethoxyquinazolin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((4,5-dimethoxyquinazolin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; tert-butyl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((4,5-dimethoxyquinazolin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; 3,3-difluoro-2-methylbutan-2-yl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((4,5-dimethoxyquinazolin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; tert-butyl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-((4-ethoxy-6-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; tert-butyl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((4-ethoxy-6-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-((4-ethoxy-6-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((4-ethoxy-6-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; 3,3-difluoro-2-methylbutan-2-yl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-((4-ethoxy-6-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; and 3,3-difluoro-2-methylbutan-2-yl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((4-ethoxy-6-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate; or a pharmaceutically acceptable salt thereof.

10. A composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

11. The composition of claim 10 further comprising at least one additional compound having anti-HCV activity.

12. The composition of claim 11 wherein at least one of the additional compounds is an interferon or a ribavirin.

13. The composition of claim 12 wherein the interferon is selected from interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, and lymphoblastoid interferon tau.

14. The composition of claim 11 wherein at least one of the additional compounds is selected from interleukin 2, interleukin 6, interleukin 12, Imiquimod, ribavirin, an inosine 5-monophosphate dehydrogenase inhibitor, amantadine, and rimantadine.

15. The composition of claim 11 wherein at least one of the additional compounds is effective to inhibit the function of a target selected from HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, and IMPDH for the treatment of an HCV infection.

16. A method of treating an HCV infection in a patient, comprising administering to the patient a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

17. The method of claim 16 further comprising administering at least one additional compound having anti-HCV activity prior to, after, or simultaneously with the compound of formula (I), or a pharmaceutically acceptable salt thereof.

18. The method of claim 17 wherein at least one of the additional compounds is an interferon or a ribavirin.

19. The method of claim 18 wherein the interferon is selected from interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, and lymphoblastoid interferon tau.

20. The method of claim 17 wherein at least one of the additional compounds is selected from interleukin 2, interleukin 6, interleukin 12, Imiquimod, ribavirin, an inosine 5-monophosphate dehydrogenase inhibitor, amantadine, and rimantadine.

21. The method of claim 17 wherein at least one of the additional compounds is effective to inhibit the function of a target selected from HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, and IMPDH for the treatment of an HCV infection.

Description

(1) The following methods set forth below are provided for illustrative purposes and are not intended to limit the scope of the claims. It will be recognized that it may be necessary to prepare such a compound in which a functional group is protected using a conventional protecting group then to remove the protecting group to provide a compound of the present disclosure. The details concerning the use of protecting groups in accordance with the present disclosure are known to those skilled in the art Compounds were named using ChemDraw.

Preparation of (2S,4R)-1-((2S,3R)-2-((tert-butoxycarbonyl)amino)-3-(methoxymethyl)-5-methylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylic acid

(2) ##STR00008## ##STR00009##

Step 1: Preparation of Hex-5-en-2-ol

(3) ##STR00010##

(4) To a solution of lithium aluminum hydride in THF (LAH, 20.1 g, 106.12 mmol, 509 mL, 1M solution) was added a solution of hex-5-en-2-one (50 g, 102.04 mmol) over a period of 30 min. at 20 C. under nitrogen. The reaction mass was allowed to warm to room temperature and stirred for 1 h. The solution was cooled to 20 C. and to it was added aqueous 10% NaOH solution (100 mL). The organic layer was separated and the aqueous layer was extracted with ether. The combined organics were dried over anhydrous sodium sulfate and concentrated to get crude compound Hex-5-en-2-ol as colorless liquid (50 g, 98%). .sup.1H NMR (400 MHz, CDCl.sub.3): ppm 5.87-5.02 (m, 1H), 4.99-4.95 (m, 2H), 3.81-3.83 (m, 1H), 2.17-2.13 (m, 2H), 1.58-1.53 (m, 2H), 1.20-1.19 (d, J=8 Hz, 3H).

Step 2: Preparation of Hex-5-en-2-yl methanesulfonate

(5) ##STR00011##

(6) To a solution of Hex-5-en-2-ol (50 g crude, 500 mmole) in dichloromethane was added triethylamine (103 m 5 L, 750 mmol) at room temperature. The reaction mass was cooled to 0 C. and to it was added a solution of methane sulfonyl chloride (50.4 mL, 650 mmol) in DCM over a period of 30 min. The reaction mass was allowed to come to room temperature and stirred for 2 h. The solution was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to get crude compound hex-5-en-2-yl methanesulfonate as light brown oily liquid (73 g, 82%). 1H NMR (400 MHz, CDCl.sub.3): ppm 5.84-5.80 (m, 1H), 5.10-5.0 (m, 2H), 4.99-4.98 (m, 1H), 3.15 (s, 3H), 2.52-2.09 (m, 2H), 1.75-1.66 (m, 2H), 1.36-1.34 (d, J=6.4 Hz, 3H).

Step 3: Preparation of 5-bromohex-1-ene

(7) ##STR00012##

(8) To a solution of hex-5-en-2-yl methanesulfonate (20 g, 0.112 moles) in dry THF (200 mL) was added LiBr (14.6 g, 0.168 moles) portion wise at room temperature over a period of 15 min. The reaction mass was heated at 70 C. for 3 h. The reaction mass was cooled to room temperature and was diluted with water (200 mL). The aqueous solution was extracted with ether (100 mL3). The combined organics were dried over anhydrous Na.sub.2SO.sub.4 and concentrated at room temperature. The crude compound was distilled under reduced pressure at 115 C. to afford 5-bromohex-1-ene as colorless liquid (14.5 g, 80%). 1H NMR (400 MHz, CDCl.sub.3): ppm 5.80-5.74 (m, 1H), 5.08-4.98 (m, 2H), 4.14-4.09 (m, 1H), 2.28-2.17 (m, 2H), 1.94-1.81 (m, 2H), 1.71-1.70 (d, J=6.8 Hz, 3H); MS: GC-MS m/z 162.

Step 4: Preparation of (2R)-1-methoxy-4-methyloct-7-en-2-ol

(9) ##STR00013##

(10) To magnesium turnings (4.14 g, 170 mmole) in dry THF (140 mL) and was added an iodine (10 mg) at room temperature. To this reaction mass was added a solution of 5-bromohex-1-ene (27.8 g, 170 mmole) in THF (200 mL). The reaction mass was heated with hot air gun to initiate the reaction. Upon completion of the reaction the solution was transferred by cannula to a solution of (R)-2-(methoxymethyl)oxirane (10 g, 114 mmol) and copper bromide (1.62 g, 11.35 mmol) in THF (100 mL) at 78 C. The reaction mass was allowed to come to room temperature and was stirred overnight. The reaction mass was quenched with saturated aq. ammonium chloride solution and extracted with diethyl ether (200 mL3). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4 and concentrated at room temperature to get crude compound. The crude compound was purified by column chromatography (Silica gel, 10% TBME in pet ether) to get (2R)-1-methoxy-4-methyloct-7-en-2-ol (16 g, 82%) as an oil.

Step 5: Preparation of (2R)-1-methoxy-4-methyloct-7-en-2-yl 4-methylbenzenesulfonate

(11) ##STR00014##

(12) To a solution of (2R)-1-methoxy-4-methyloct-7-en-2-ol (15 g, 87 mmole) in DCM (150 mL) was added pyridine (36 mL, 435 mmol) followed by 4-(dimethylamino)pyridine (DMAP, 1.06 g, 8.71 mmol) and the solution was stirred for 10 min. p-toluenesulfonyl chloride (18.26 g, 96 mmole) was added to the reaction mass at 0 C. The reaction mass was allowed to come to room temperature and stirred overnight. The reaction mass was washed with aqueous 1.5 N HCl solution, saturated aq. sodium bicarbonate solution, brine solution, dried over anhydrous Na.sub.2SO.sub.4, filter, and concentrated under reduced pressure to get crude compound (2R)-1-methoxy-4-methyloct-7-en-2-yl 4-methylbenzenesulfonate (18 g, 63%). The crude compound was taken to the next step without further purification.

Step 6: Preparation of (3R)-ethyl 2-((diphenylmethylene)amino)-3-(methoxymethyl)-5-methylnon-8-enoate

(13) ##STR00015##

(14) To a solution of (2R)-1-methoxy-4-methyloct-7-en-2-yl 4-methylbenzenesulfonate (15.88 g, 48.6 mmole) and N-(diphenylmethylene)glycinate ethyl ester (13 g, 48.6 moles) in toluene (500 mL) was added t-BuOK (72.9 mL, 72.9 mmole, 1 M solution in THF) at room temperature. The reaction mass was allowed to come to room temperature and was then heated at 110 C. for 18 h. The reaction mass was cooled to room temperature and quenched aqueous citric acid solution. The organic layers were dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to get crude compound (14 g, 41%). The crude compound was taken to the next step without further purification. MS: MS m/z 423.65 (M.sup.++1).

Step 7: Preparation of (3R)-ethyl 2-amino-3-(methoxymethyl)-5-methylnon-8-enoate

(15) ##STR00016##

(16) To a solution of (3R)-ethyl 2-((diphenylmethylene)amino)-3-(methoxymethyl)-5-methylnon-8-enoate (14 g, 33.2 mmol) in diethyl ether (50 mL) was added aqueous 1.5 N HCl solution (200 mL) and the reaction mass was stirred at room temperature overnight. The reaction mass was washed with diethyl ether (100 mL). The aqueous solution was basified using saturated sodium bicarbonate solution and was extracted with ethyl acetate (100 mL3). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to get crude compound (4.8 g, 47.7%). The crude compound was taken to the next step without further purification.

Step 8: Preparation of (3R)-ethyl 2-((tert-butoxycarbonyl)amino)-3-(methoxymethyl)-5-methylnon-8-enoate

(17) ##STR00017##

(18) A solution of (3R)-ethyl 2-amino-3-(methoxymethyl)-5-methylnon-8-enoate hydrochloride (4.8 g, 18.6 mmole) in DCM (40 mL) was added N,N-diisopropylethylamine (6.5 mL, 37.3 mmole) followed by di-tert-butyl dicarbonate (6.5 mL, 28 mmole) at room temperature. The reaction mass was stirred at room temperature overnight. The reaction mass was diluted with DCM and washed with water. The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to afford the crude compound. The crude compound was purified by column chromatography (Silica gel, 20% ethyl acetate in pet-ether) to get 4.9 g, (66%) of (3R)-ethyl 2-((tert-butoxycarbonyl)amino)-3-(methoxymethyl)-5-methylnon-8-enoate as an oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6): ppm 5.8 (m, 1H), 5.5 (m, 1H), 5.1-4.9 (m, 2H), 4.3 m, 1H), 4.1 (m, 2H), 3.3 (s, 3H), 3.4 (m, 2H), 2.3 (m, 1H), 2.1 (m, 2H), 1.5 (s, 9H), 1.3 (m, 6H), 0.9 (m, 4H).

Step 9: Preparation of (3R)-2-((tert-butoxycarbonyl)amino)-3-(methoxymethyl)-5-methylnon-8-enoic acid

(19) ##STR00018##

(20) To a solution of (3R)-ethyl 2-((tert-butoxycarbonyl)amino)-3-(methoxymethyl)-5-methylnon-8-enoate (4.9 g, 13.7 mmole) in THF/water (50 mL, 1:1) was added methanol (10 mL) followed by LiOH (0.98 g, 41 mmole) at room temperature. The reaction mass was stirred at room temperature overnight. The solution was concentrated under reduced pressure and the residue was diluted with water (50 mL). The aqueous solution was acidified with aqueous 1.5 N HCl solutions to pH 3 and extracted with ethyl acetate (15 mL3). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduce pressure to get crude compound. The crude compound was purified by column chromatography (Silica gel, 3% methanol in DCM) to get (3R)-2-(tert-butoxycarbonylamino)-3,5-dimethylnon-8-enoic acid (4 g, 84%) of as gummy liquid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): ppm 12.4 (sb, 1H), 6.72-6.65 (m, 1H), 5.81-5.75 (m, 1H), 5.04-4.93 (m, 2H), 4.12-3.91 (m, 1H), 3.6-3.10 (m, 8H), 2.18-1.98 (m, 2H), 1.5 (s, 9H), 1.35-1.02 (m, 2H), 1.0 (m, 1H), 0.98-0.85 (m, 3H).

Step 10: Preparation of (2S,4R)-methyl 1-((2S,3R)-2-((tert-butoxycarbonyl)amino)-3-(methoxymethyl)-5-methylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylate

(21) ##STR00019##

(22) O-(7-Azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (HATU, 5.5 g, 14.5 mmol) was added to a solution of (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate HCl (2.65 g, 14.5 mmol), (3R)-2-((tert-butoxycarbonyl)amino)-3-(methoxymethyl)-5-methylnon-8-enoic acid (4 g, 12.14 mmol) and DIPEA (6.4 mL, 36.4 mmol) in DCM (40 mL) and stirred at RT for 16 h. The reaction was washed with 1N HCl and then brine solutions. The organics were dried with magnesium sulfate, filtered and concentrated under vacuum. The crude material was purified via silica gel chromatography using 20-60% acetone in hexanes to give the desired product (2S,4R)-methyl 1-((2S,3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylate (10.8 g, 30% yield), MS: MS m/z 427.2 (M.sup.++1) and the undesired product (2S,4R)-methyl 1-((2S,3R)-2-((tert-butoxycarbonyl)amino)-3-(methoxymethyl)-5-methylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylate (1.4 g, 24%), MS: MS m/z 457.5 (M.sup.++1).

Step 11: Preparation of (2S,4R)-1-((2S,3R)-2-((tert-butoxycarbonyl)amino)-3-(methoxymethyl)-5-methylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylic acid

(23) ##STR00020##

(24) (2S,4R)-methyl 1-((2S,3R)-2-((tert-butoxycarbonyl)amino)-3-(methoxymethyl)-5-methylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylate (1.4 g, 3.07 mmol) was dissolved in THF (20 mL), MeOH (5 mL) and to this solution was added LiOH (0.22 g, 24 mmol) in water (20.0 mL). The reaction mixture was stirred at rt for 16 h. The solvent was removed under vacuum and the resulting aqueous residue was diluted with water, and EtOAc. The mixture was neutralized with 1 N HCl and adjusted the pH 2.5 and the mixture was extracted with EtOAc. The organic layer was collected, washed with brine, dried over Na.sub.2SO.sub.4, and concentrated to give (2S,4R)-1-((2S,3R)-2-((tert-butoxycarbonyl)amino)-3-(methoxymethyl)-5-methylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylic acid (1.2 g, 80%) as yellow viscous oil. MS: MS m/z 443.45 (M.sup.++1).

(25) ##STR00021##

Step 1: Preparation of tert-butyl ((2S,3R)-1-((2S,4R)-2-(((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-3-(methoxymethyl)-5-methyl-1-oxonon-8-en-2-yl)carbamate

(26) ##STR00022##

(27) HATU (0.62 g, 1.62 mmol) was added to a solution of (2S,4R)-1-((2S,3R)-2-((tert-butoxycarbonyl)amino)-3-(methoxymethyl)-5-methylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylic acid (0.6 g, 1.35 mmol), (1R,2S)-1-amino-N-(cyclopropylsulfonyl)-2-vinylcyclopropanecarboxamide (3.75 g, 1.62 mmol), and DIPEA (4.0 mL, 76 mmol) in DCM (25 mL). The reaction mixture was stirred at rt for 16 h. The mixture was washed with 1N HCl and then brine solution. The organic layer was collected, dried over sodium sulfate, and concentrated under vacuum. The crude material was purified by silica gel chromatography using a gradient of 20-60% acetone in hexanes. The product fractions were collected and the solvent removed under vacuum to give tert-butyl ((2S,3R)-1-((2S,4R)-2-(((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-3-(methoxymethyl)-5-methyl-1-oxonon-8-en-2-yl)carbamate (0.6 g, 61%). MS: MS m/z 655.6 (M.sup.++1).

Step 2: Preparation of tert-butyl ((2R,6S,7R,13aS,14aR,16aS,Z)-14a-((cyclopropylsulfonyl)carbamoyl)-2-hydroxy-7-(methoxymethyl)-9-methyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate

(28) ##STR00023##

(29) A solution of tert-butyl ((2S,3R)-1-((2S,4R)-2-(((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-3-(methoxymethyl)-5-methyl-1-oxonon-8-en-2-yl)carbamate (0.6 g, 0.92 mmol) in DCE (100 ml) was degassed with nitrogen for 30 min. and then (1,3-Bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o-isopropoxyphenylmethylene)ruthenium), (Hoveyda-Grubbs Catalyst 2nd Generation, 0.078 g, 0.092 mmol) was added. The reaction solution was heated to 80 C. for 4 h. The reaction solution was concentrated in vacuo and the resulting residue was purified by silica gel chromatography using a gradient of 20-60% acetone in hexanes to give the mixture of diastereomers as a brown solid (0.410 g, 71% yield). MS: MS m/z 627.6 (M.sup.++1).

(30) ##STR00024##

Step 1: Preparation of tert-butyl ((2S,3R)-1-((2S,4R)-4-hydroxy-2-(((1R,2S)-1-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)pyrrolidin-1-yl)-3-(methoxymethyl)-5-methyl-1-oxonon-8-en-2-yl)carbamate

(31) ##STR00025##

(32) HATU (0.516 g, 1.35 mmol) was added to a solution of (2S,4R)-1-((2S,3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylic acid (0.5 g, 1.13 mmol), (1R,2S)-1-amino-N-((1-methylcyclopropyl)sulfonyl)-2-vinylcyclopropanecarboxamide hydrochloride (0.331 g, 1.35 mmol), and DIPEA (0.6 mL, 3.4 mmol) in DCM (20 mL). The reaction mixture was stirred at rt for 16 h. The mixture was washed with 1 N HCl, and then brine solution. The organic layer was collected, dried over sodium sulfate, and concentrated under vacuum. The crude material was purified by silica gel chromatography using a gradient of 20-60% acetone in hexanes. The product fractions were collected and the solvent removed under vacuum to give tert-butyl ((2S,3R)-1-((2S,4R)-4-hydroxy-2-(((1R,2S)-1-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)pyrrolidin-1-yl)-3-(methoxymethyl)-5-methyl-1-oxonon-8-en-2-yl)carbamate (0.51, 57%). MS: MS m/z 669.6 (M.sup.++1).

Step 2: Preparation of tert-butyl ((2R,6S,7R,13aS,14aR,16aS,Z)-2-hydroxy-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate

(33) ##STR00026##

(34) A solution of tert-butyl ((2S,3R)-1-((2S,4R)-4-hydroxy-2-(((1R,2S)-1-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)pyrrolidin-1-yl)-3-(methoxymethyl)-5-methyl-1-oxonon-8-en-2-yl)carbamate (0.5 g, 0.75 mmol) in DCE (100 ml) was degassed with nitrogen for 30 min. and then (1,3-Bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o-isopropoxyphenylmethylene)ruthenium) (Hoveyda-Grubbs Catalyst 2nd Generation, 0.06 g, 0.07 mmol) was added. The reaction solution was heated to 80 C. for 25. The reaction solution was concentrated in vacuo the and resulting residue was purified by silica gel chromatography using a gradient of 20-60% acetone in hexanes to give the mixture of diastereomers as a brown solid (0.37 g, 76% yield). MS: MS m/z 641.6 (M.sup.++1).

(35) ##STR00027##

Step 1: Preparation of tert-butyl ((2S,3R)-1-((2S,4R)-2-(((1R,2S)-1-(((1-(fluoromethyl)cyclopropyl)sulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-3-(methoxymethyl)-5-methyl-1-oxonon-8-en-2-yl)carbamate

(36) ##STR00028##

(37) HATU (0.56 g, 1.46 mmol) was added to a solution of (2S,4R)-1-((2S,3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylic acid (0.5 g, 1.13 mmol), (1R,2S)-1-amino-N-((1-(fluoromethyl)cyclopropyl)sulfonyl)-2-vinylcyclopropanecarboxamide hydrochloride (0.445 g, 1.35 mmol), and DIPEA (0.6 mL, 3.3 mmol) in DCM (20 mL). The reaction mixture was stirred at rt for 16 h. The mixture was washed with 1N HCl, and then brine solutions. The organic layer was collected, dried over sodium sulfate, and concentrated under vacuum. The crude material was purified by silica gel chromatography using a gradient of 20-60% Acetone in hexanes. The product fractions were collected and the solvent removed under vacuum to give tert-butyl ((2S,3R)-1-((2S,4R)-2-(((1R,2S)-1-(((1-(fluoromethyl)cyclopropyl)sulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-3-(methoxymethyl)-5-methyl-1-oxonon-8-en-2-yl)carbamate (400 mg, 44%). MS: MS m/z 688.2 (M.sup.++1).

(38) Step 2: Preparation of tert-butyl ((2R,6S,7R,13aS,14aR,16aS,Z)-14a-(((1-(fluoromethyl)cyclopropyl)sulfonyl)carbamoyl)-2-hydroxy-7-(methoxymethyl)-9-methyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate

(39) ##STR00029##

(40) A solution of tert-butyl ((2S,3R)-1-(((2S,4R)-2-(((1R,2S)-1-(((1-(fluoromethyl)cyclopropyl)sulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-3-(methoxymethyl)-5-methyl-1-oxonon-8-en-2-yl)carbamate (0.35 g, 0.5 mmol) in DCE (100 ml) was degassed with nitrogen for 30 min. and then (1,3-Bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o-isopropoxyphenylmethylene)ruthenium) (Hoveyda-Grubbs Catalyst 2nd Generation, 0.022 g, 0.02 mmol) was added. The reaction solution was heated to 80 C. for 2 h. The reaction solution was concentrated in vacuum the and resulting residue was purified by silica gel chromatography using a gradient of 20-60% acetone in hexanes to give the mixture of diastereomers as a brown solid (0.15 g, 45% yield). MS: MS m/z 659.3 (M.sup.++1).

(41) ##STR00030## ##STR00031##

Step 1: Preparation of (R)-1-methoxyoct-7-en-2-ol

(42) ##STR00032##

(43) To magnesium turnings (3.39 g, 140 mmole) in dry THF (100 mL) and was added an iodine (10 mg) at room temperature. To this reaction mass was added a solution of 5-bromopent-1-ene (20.8 g, 140 mmole) in THF (200 mL). The reaction mass was heated with hot air gun to initiate the reaction. Upon completion of the reaction the solution was transferred by cannula to a solution of (R)-2-(methoxymethyl)oxirane (8.2 g, 93 mmol) and copper bromide (1.33 g, 9.31 mmol) in THF (100 mL) at 78 C. The reaction mass was allowed to come to room temperature and was stirred Overnight. The reaction mass was quenched with saturated aq. ammonium chloride solution and extracted with diethyl ether (50 mL3). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4 and concentrated at room temperature to get crude compound. The crude compound was purified by column chromatography (Silica gel, 10% TBME in pet ether) to get (R)-1-methoxyoct-7-en-2-ol (12 g, 81%) as an oil.

Step 2: Preparation of (R)-1-methoxyoct-7-en-2-yl 4-methylbenzenesulfonate

(44) ##STR00033##

(45) To a solution of (R)-1-methoxyoct-7-en-2-ol (13 g, 82 mmole) in DCM (150 mL) was added pyridine (33.2 mL, 411 mmol) followed by 4-(dimethylamino)pyridine (DMAP, 1 g, 8.22 mmole) and the solution was stirred for 10 min. p-toluenesulfonyl chloride (17.23 g, 90 mmole) was added to the reaction mass at 0 C. The reaction mass was allowed to come to room temperature and stirred overnight. The reaction mass was washed with aqueous 1.5 N HCl solution, saturated aq. bicarbonate solution, brine solution, dried over anhydrous Na.sub.2SO.sub.4, filter, and concentrated under reduced pressure to get crude compound (R)-1-methoxyoct-7-en-2-yl 4-methylbenzenesulfonate (15 g, 58%). The crude compound was taken to the next step without further purification.

Step 3: Preparation of (3R)-ethyl 2-((diphenylmethylene)amino)-3-(methoxymethyl)non-8-enoate

(46) ##STR00034##

(47) To a solution of (R)-1-methoxyoct-7-en-2-yl 4-methylbenzenesulfonate (10 g, 32 mmole) and N-(diphenylmethylene)glycinate ethyl ester (8.56 g, 32 mmole) in toluene (100 mL) was added t-BuOK (48 mL, 48 mmole, 1 M solution in THF) at 0 C. The reaction mass was allowed to come to room temperature and was heated at 110 C. for 4 h. The reaction mass was cooled to room temperature, quenched with water and extracted with ethyl acetate (200 mL3). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to get crude compound (3R)-ethyl 2-((diphenylmethylene)amino)-3-(methoxymethyl)non-8-enoate (11 g, 22%). The crude compound was taken to the next step without further purification.

Step 4: Preparation of (3R)-ethyl 2-amino-3-(methoxymethyl)non-8-enoate

(48) ##STR00035##

(49) To a solution of (3R)-ethyl 2-((diphenylmethylene)amino)-3-(methoxymethyl)non-8-enoate (10 g, 25.54 mmol) in diethyl ether (20 mL) was added aqueous 1.5 N HCl solution (50 mL) and the reaction mass was stirred at room temperature overnight. The reaction mass was washed with diethyl ether (50 mL). The aqueous solution was basified using saturated sodium bicarbonate solution and was extracted with ethyl acetate (20 mL3). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to get crude compound (3R)-ethyl 2-amino-3-(methoxymethyl)non-8-enoate hydrochloride (3 g, 50%). The crude compound was taken to the next step without further purification.

Step 5: Preparation of (3R)-ethyl 2-((tert-butoxycarbonyl)amino)-3-(methoxymethyl)non-8-enoate

(50) ##STR00036##

(51) A solution of (3R)-ethyl 2-amino-3-(methoxymethyl)non-8-enoate hydrochloride (4 g, 0.017 moles) in DCM (40 mL) was added N,N-diisopropylethylamine (DIPEA, 5.7 mL, 0.033 moles) followed by di-tert-butyl dicarbonate (4.5 g, 0.020 moles) at room temperature. The reaction mass was stirred at room temperature overnight. The reaction mass was diluted with DCM and washed with water. The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to afford the crude compound. The crude compound was purified by column chromatography (Silica gel, 20% ethyl acetate in pet-ether) to get (3R)-ethyl 2-amino-3-(methoxymethyl) non-8-enoate hydrochloride (5.1 g, 90%) as an oil.

Step 6: Preparation of (3R)-2-((tert-butoxycarbonyl)amino)-3-(methoxymethyl)non-8-enoic acid

(52) ##STR00037##

(53) To a solution of (3R)-ethyl 2-((tert-butoxycarbonyl)amino)-3-(methoxymethyl)non-8-enoate (5 g, 0.014 moles) in THF/water (60 mL, 1:1) was added methanol (10 mL) followed by LiOH (1.4 g, 0.058 moles) at room temperature. The reaction mass was stirred at room temperature overnight. The solution was concentrated under reduced pressure and the residue was diluted with water (50 mL). The aqueous solution was acidified with aqueous 1.5 N HCl solution to pH 3 and extracted with ethyl acetate (25 mL3). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduce pressure to get crude compound. The crude compound was purified by column chromatography (Silica gel, 3% methanol in DCM) to get 3.0 g (65%) of (3R)-2-((tert-butoxycarbonyl)amino)-3-(methoxymethyl)non-8-enoic acid as gummy liquid. .sup.1H NMR (400 MHz, DMSO-d6): PPM 12.4 (sb, 1H), 6.82-6.65 (m, 1H), 5.81-5.75 (m, 1H), 5.04-4.93 (m, 2H), 4.12-3.91 (m, 1H), 3.31-3.14 (m, 3H), 2.10-1.9 (m, 5H), 1.4 (s, 9H), 1.35-1.15 (m, 6H).

Step 7: Preparation of (2S,4R)-methyl 1-((2S,3R)-2-((tert-butoxycarbonyl)amino)-3-(methoxymethyl)non-8-enoyl)-4-hydroxypyrrolidine-2-carboxylate

(54) ##STR00038##

(55) O-(7-Azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (HATU, 4.22 g, 11.1 mmol) was added to a solution of (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate HCl (2.0 g, 11.1 mmol), (3R)-2-((tert-butoxycarbonyl)amino)-3-(methoxymethyl)non-8-enoic acid (3.5 g, 11.1 mmol) and DIPEA (5.8 mL, 33.3 mmol) in DCM (50 mL) and stirred at RT for 16 h. The reaction was washed with 1N HCl and then brine solution. The organics were dried with magnesium sulfate, filtered and concentrated under vacuum. The crude material was purified via silica gel chromatography using 20-60% Acetone in hexanes to give the desired product (2S,4R)-methyl 1-((2S,3R)-2-((tert-butoxycarbonyl)amino)-3-(methoxymethyl)non-8-enoyl)-4-hydroxypyrrolidine-2-carboxylate (1.75 g, 11% yield), MS: MS m/z 443.4 (M.sup.++1).

Step 8: Preparation of (2S,4R)-1-((2S,3R)-2-((tert-butoxycarbonyl)amino)-3-(methoxymethyl)non-8-enoyl)-4-hydroxypyrrolidine-2-carboxylic acid

(56) ##STR00039##

(57) (2S,4R)-methyl 1-((2S,3R)-2-((tert-butoxycarbonyl)amino)-3-(methoxymethyl)non-8-enoyl)-4-hydroxypyrrolidine-2-carboxylate (1.75 g, 3.9 mmol) was dissolved in THF (15 mL), MeOH (5 mL) and to this solution was added LiOH (0.38 g, 15.8 mmol) in water (15 mL). The reaction mixture was stirred at rt for 16 h. The solvent was removed under vacuum and the resulting aqueous residue was diluted with water, and EtOAc. The mixture was neutralized with 1 N HCl and adjusted the pH 2.5 and the mixture was extracted with EtOAc. The organic layer was collected, washed with brine, dried over Na.sub.2SO.sub.4, and concentrated to give (2S,4R)-1-((2S,3R)-2-((tert-butoxycarbonyl)amino)-3-(methoxymethyl)non-8-enoyl)-4-hydroxypyrrolidine-2-carboxylic acid (1.25 g, 70% yield) as yellow viscous oil. MS: MS m/z 429.4 (M.sup.++1).

(58) ##STR00040##

(59) ##STR00041##

(60) HATU (0.488 g, 1.28 mmol) was added to a solution of (2S,4R)-1-((2S,3R)-2-((tert-butoxycarbonyl)amino)-3-(methoxymethyl)non-8-enoyl)-4-hydroxypyrrolidine-2-carboxylic acid (0.5 g, 1.16 mmol), (1R,2S)-1-amino-N-(cyclopropylsulfonyl)-2-vinylcyclopropanecarboxamide, pTSA (0.57 g, 1.28 mmol), and DIPEA (0.8 mL, 4.67 mmol) in DCM (30 mL). The reaction mixture was stirred at rt for 16 h. The mixture was washed with 1N HCl, and then brine. The organic layer was collected, dried over sodium sulfate, and concentrated under vacuum. The crude material was purified by silica gel chromatography using a gradient of 20-60% Acetone in hexanes. The product fractions were collected and the solvent removed under vacuum to give tert-butyl ((2S,3R)-1-((2S,4R)-2-(((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-3-(methoxymethyl)-1-oxonon-8-en-2-yl)carbamate (350 mg, 47%) as pale yellow gummy mass. MS: MS m/z 441.46 (M.sup.++1).

Step 2: Preparation of tert-butyl ((2R,6S,7R,13aS,14aR,16aS,Z)-14a-((cyclopropylsulfonyl)carbamoyl)-2-hydroxy-7-(methoxymethyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate

(61) ##STR00042##

(62) A solution of tert-butyl ((2S,3R)-1-((2S,4R)-2-(((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-3-(methoxymethyl)-1-oxonon-8-en-2-yl)carbamate (0.35 g, 0.54 mmol) in DCE (50 ml) was degassed with nitrogen for 30 min. and then (1,3-Bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o-isopropoxyphenylmethylene)ruthenium) (Hoveyda-Grubbs Catalyst 2nd Generation, 0.046 g, 0.054 mmol) was added. The reaction solution was heated to 80 C. for 2 h. The reaction solution was concentrated in vacuum the and resulting residue was purified by silica gel chromatography using a gradient of 20-60% acetone in hexanes to give the mixture of diastereomers as a brown solid (0.2 g, 52% yield). MS: MS m/z 613.5 (M.sup.++1).

(63) ##STR00043##

(64) ##STR00044##

(65) HATU (2.1 g, 5.6 mmol) was added to a solution of (2S,4R)-1-((2S,3R)-2-((tert-butoxycarbonyl)amino)-3-(methoxymethyl)non-8-enoyl)-4-hydroxypyrrolidine-2-carboxylic acid (2.0 g, 4.7 mmol), (1R,2S)-1-amino-N-((1-methylcyclopropyl)sulfonyl)-2-vinylcyclopropanecarboxamide (1.6 g, 5.6 mmol), and DIPEA (2.5 mL, 14 mmol) in DCM (25 mL). The reaction mixture was stirred at rt for 16 h. The mixture was washed with 1N HCl and then brine. The organic layer was collected, dried over sodium sulfate, and concentrated under vacuum. The crude material was purified by silica gel chromatography using a gradient of 20-60% Acetone in hexanes. The product fractions were collected and the solvent removed under vacuum to give ((2S,3R)-1-((2S,4R)-4-hydroxy-2-(((1R,2S)-1-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)pyrrolidin-1-yl)-3-(methoxymethyl)-1-oxonon-8-en-2-yl)carbamate (1.5 g, 49%) as crystalline solid. MS: MS m/z 655.6 (M.sup.++1).

Step 2: Preparation of tert-butyl ((2R,6S,7R,13aS,14aR,16aS,Z)-2-hydroxy-7-(methoxymethyl)-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate

(66) ##STR00045##

(67) A solution of tert-butyl ((2S,3R)-1-((2S,4R)-4-hydroxy-2-(((1R,2S)-1-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)pyrrolidin-1-yl)-3-(methoxymethyl)-1-oxonon-8-en-2-yl)carbamate (1.6 g, 2.44 mmol) in DCE (100 ml) was degassed with nitrogen for 30 min. and then (1,3-Bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o-isopropoxyphenylmethylene)ruthenium) (Hoveyda-Grubbs Catalyst 2nd Generation, 0.2 g, 0.02 mmol) was added. The reaction solution was heated to 80 C. for 2 h. The reaction solution was concentrated in vacuo the and resulting residue was purified by silica gel chromatography using a gradient of 20-60% Acetone in hexanes to give tert-butyl ((2R,6S,7R,13aS,14aR,16aS,Z)-2-hydroxy-7-(methoxymethyl)-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate (700 mg, 55%) as a brown solid (5.6 g, 70% yield). MS: MS m/z 627.55 (M.sup.++1).

Preparation of (1R,2S)-1-amino-N-((1-(fluoromethyl)cyclopropyl)sulfonyl)-2-vinylcyclopropanecarboxamide hydrochloride

(68) ##STR00046##

(69) ##STR00047##

Step 1: Preparation of tert-butyl (1-(hydroxymethyl)cyclopropyl)sulfonylcarbamate

(70) To a solution of tert-butyl cyclopropylsulfonylcarbamate (30 g, 136 mmol) in 750 mL of THF was added dropwise butyllithium (1.6 M in hexane, 212 mL, 339 mmol) over 30 min at 78 C. and the resulting mixture was stirred at 78 C. for 1 h. Formaldehyde gas was generated from para-formaldehyde (by heating at 180 C.) and was purged in to the above reaction mass for 30 min at 30 C. The reaction was stirred at the same temperature for 1 h and then allowed to warm to room temperature. The reaction was quenched with aqueous ammonium chloride solution and diluted with water. The resulting mass was washed with ethyl acetate and the aqueous layer was acidified to pH 2 and extracted with ethyl acetate. The combined organics were dried over sodium sulfate and evaporated under reduced pressure to get desired compound (27 g, 79%) as white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): ppm 10.90 (sb, 1H), 4.95 (sb, 1H), 3.75 (s, 2H), 1.42 (s, 9H), 1.27 (m, 2H), 1.08 (m, 2H).

Step 2: Preparation of tert-butyl (1-(fluoromethyl)cyclopropyl)sulfonylcarbamate

(71) A solution of tert-butyl 1-hydroxymethylcyclopropylsulfonylcarbamate (26.0 g, 103 mmol) in DCM (300 mL) was cooled to 78 C. To this solution was added diethylaminosulfur trifluoride (DAST, 41.0 mL, 310 mmol). The reaction mass was stirred at the same temperature for 30 min. The reaction mass was quenched with aqueous 1N NaOH solution. The organic layer was discarded and the aqueous layer was acidified to pH 2 by using aq. 1.5 N HCl solutions. The aqueous solution was extracted with DCM (50 mL4). The combined organic layers were dried over anhydrous sodium sulfate; filtered; then concentrated to afford desired tert-butyl (1-(fluoromethyl)cyclopropyl)sulfonylcarbamate (19 g, 72%) as gummy solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): ppm 11.25 (sb, 1H), 4.75 (s, 1H), 4.63 (s, 1H), 1.44 (s, 9H), 1.28 (m, 2H), 1.07 (m, 2H). .sup.19F NMR: 211.7 (1F).

Step 3: Preparation of 1-(fluoromethyl)cyclopropane-1-sulfonamide

(72) To a solution of tert-butyl 1-fluoromethyl cyclopropylsulfonylcarbamate (19 g, 75 mmol) in dichloromethane (200 mL) at room temperature was added trifluoroacetic acid (TFA, 50 mL). The reaction mass was stirred at room temperature for 1 h. The solvent was evaporated under reduced pressure and the residue was diluted with hexane. The precipitated solid was isolated via filtration and washed with hexane to afford pure 1-(fluoromethyl)cyclopropane-1-sulfonamide (11 g, 96%) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): ppm 6.98 (sb, 2H), 4.75 (s, 1H), 4.63 (s, 1H), 1.28 (m, 2H), 1.08 (m, 2H). .sup.19F NMR: 211.74 (1F).

Step 4: Preparation of tert-butyl (1R,2S)-1-(1-(fluoromethyl)cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamate

(73) To a solution of (1R,2S)-1-(tert-butoxycarbonylamino)-2-vinylcyclopropanecarboxylic acid (7.5 g, 33 mmol) in DMF (50 mL) was added 1,1-carbonyldiimidazole (CDI, 10.7 g, 66.0 mmol) and the reaction mass was heated at 55 C. for 4 h. To this reaction mass was added 1-fluoromethylcyclopropane-1-sulfonamide (6.5 g, 42.9 mmol) followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 6.0 mL, 43 mmol). The reaction mixture was stirred at 55 C. for 18 h. The solvent was evaporated under reduced pressure and the residue was diluted with water and acidified to pH 2 by using aq. 1.5 N HCl solutions. The precipitated solid was isolated via filtration and washed with water to afford tert-butyl (1R,2S)-1-(1-(fluoromethyl)cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamate as off-white solid (11.5 g, 96%). MS: MS m/z 361.4 (M.sup.+1).

Step 5: Preparation of (1R,2S)-1-amino-N-(1-(fluoromethyl)cyclopropylsulfonyl)-2-vinylcyclopropanecarboxamide hydrochloride

(74) A solution of tert-butyl (1R,2S)-1-(1-(fluoromethyl)cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamate (11.5 g, 31.7 mmol) in 4 N HCl in dioxane (100 mL) was stirred at room temperature for 1 h. The volatiles were removed under reduced pressure and the residue was washed with diethyl ether to afford crude (1R,2S)-1-amino-N-(1-(fluoromethyl)cyclopropylsulfonyl)-2-vinylcyclopropanecarboxamide hydrochloride (6 g, 72%). The crude compound was taken to the next step without further purification. MS: MS m/z 263.14 (M.sup.++1).

(75) ##STR00048##

Step 1: Preparation of tert-butyl cyclopropylsulfonylcarbamate

(76) To a solution of cyclopropanesulfonamide (100 g, 82.6 mmol) in DCM (800 ml) was added triethylamine (234 ml, 165 mmol) followed by DMAP (10.28 g, 82.6 mmol) at 0 C. under nitrogen. To this reaction mixture Boc anhydride (247 ml, 107 mmol) in DCM (400 ml) was added slowly. The resulting mixture was stirred for 4 h at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The combine organic layer was washed with 1.5 N HCl solution and 10% NaHCO.sub.3 and dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get crude compound (143 g, 65%) as a solid. The crude compound was directly taken for the next step. .sup.1H NMR (400 MHz, DMSO-d.sub.6): ppm 11.08 (s, 1H), 2.90 (m, 1H), 1.48 (s, 9H), 1.06 (m, 4H).

Step 2: Preparation of tert-butyl(1-methylcyclopropyl) sulfonylcarbamate

(77) A solution of tert-butyl cyclopropylsulfonylcarbamate (4.3 g, 20 mmol) was dissolved in dry THF (100 ml) and cooled to 78 C. To this solution was added n-BuLi (17.6 ml, 44 mmol, 2.5 M in hexane) slowly. The reaction mixture was allowed to warm to room temperature over a period of 1.5 h. This mixture was then cooled to 78 C., and a solution of n-BuLi (20 mmol, 8 ml, 2.5M in hexane) was added, stirred for 1 h and a neat solution of methyl iodide (5.68 g, 40 mmol) was added. The reaction mixture was allowed to warm to room temperature with stirring overnight; then was quenched with aqueous saturated NH.sub.4Cl (100 ml) at room temperature. The mixture was extracted with EtOAc (100 ml). The organic layer was washed with brine; dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give a yellow oil which was crystallized from hexane to afford the product as a slightly yellow solid (3.1 g, 81%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): ppm 10.97 (s, 1H), 1.44 (s, 12H), 1.35-1.33 (m, 2H), 0.93-0.91 (m, 2H).

Step 3: Preparation of 1-methylcyclopropane-1-sulfonamide

(78) A solution of N-tert-butyl-(1-methyl)-cyclopropyl-sulfonamide (1.91 g, 10 mmol) was dissolved in 4M HCl in dioxane (30 ml) and the reaction mixture stirred at rt for 16 h. The solvent was removed in vacuo to give a yellow oil which was crystallized from EtOAc/hexane (1:4, 40 ml) to yield 1-methyl-cyclopropylsulfonamide, as a white solid (1.25 g, 96%). .sup.1H NMR (400 MHz, CDCl.sub.3): ppm 6.73 (s, 2H), 1.43 (s, 3H), 1.14-1.12 (m, 2H), 0.75-0.73 (m, 2H).

Preparation of tert-butyl ((1R,2S)-1-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamate

(79) ##STR00049##

(80) To a solution of (1R,2S)-1-(tert-butoxycarbonylamino)-2-vinylcyclopropanecarboxylic acid (25 g, 110 mmol) in THF (300 mL) was added CDI (205 g, 127 mmol) and the reaction mass was heated at 85 C. for 1 h. The reaction mass was cooled to rt and to this reaction mass was added 1-methylcyclopropane-1-sulfonamide (17.7 g, 131 mmol) followed by DBU (33.2 mL, 33.5 mmol). The reaction mixture was stirred at rt for 18 h. The solvent was evaporated under reduced pressure and the residue was diluted with water and acidified to pH 2 by using aq. 1.5 N HCl solutions. The precipitated solid was isolated via filtration and washed with water to get desired compound (22 g, 58%) as off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 11.01-11.17 (m, 1H), 7.17-7.33 (m, 1H), 5.35-5.51 (m, 1H), 5.18-5.29 (m, 1H), 4.99-5.09 (m, 1H), 2.21 (s, 1H), 1.69 (dd, J=7.78, 5.27 Hz, 1H), 1.40 (d, J=3.01 Hz, 14H), 1.20 (dd, J=9.29, 5.27 Hz, 1H), 0.82-0.96 (m, 2H). MS: MS m/z 343 (M.sup.++1).

Preparation of (1R,2S)-1-amino-N-((1-methylcyclopropyl)sulfonyl)-2-vinylcyclopropanecarboxamide hydrochloride

(81) ##STR00050##

(82) A solution of tert-butyl ((1R,2S)-1-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamate (40 g, 116 mmol) in 4 N HCl in dioxane (400 mL) was stirred at room temperature for 1 h. The solvent was evaporated under reduced pressure and the residue was washed with diethyl ether to get crude compound (31 g, 95%). The crude compound was used without further purification. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.97-9.29 (m, 2H), 5.47-5.66 (m, 1H), 5.32-5.44 (m, 1H), 5.22 (dd, J=10.04, 1.51 Hz, 1H), 2.38 (s, 1H), 2.03 (s, 1H), 1.71 (d, J=3.51 Hz, 1H), 1.46-1.52 (m, 4H), 1.25-1.35 (m, 1H), 0.88-1.01 (m, 2H). MS: MS m/z 245.14 (M.sup.++1).

Preparation of 1-Fluoro-4-methoxyisoquinoline

(83) ##STR00051##

Step 1: Preparation of 1-chloro-4-methoxyisoquinoline

(84) To a solution of 1-chloroisoquinolin-4-ol (5.0 g, 27.8 mmol) in acetonitrile (50 mL) was added TMS-diazomethane (12.73 g, 111.2 mmol) at 0 C. The reaction mixture was allowed to come to room temperature and stirred for 2 h. Solvent was evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get 1-chloro-4-methoxyisoquinoline (2.5 g, 46.4%) as off-white solid. .sup.1H NMR (400 MHz, CD.sub.3OD): ppm 8.29-8.17 (m, 2H), 7.97 (s, 1H), 7.91-7.82 (m, 2H), 4.05 (s, 3H); MS: MS m/z 194.7 (M.sup.++1).

Step 2: Preparation of 1-Fluoro-4-methoxyisoquinoline

(85) To a solution of 1-chloro-4-methoxyisoquinolin (2.5 g, 12.91 mmol) in DMSO was added cesium fluoride (4.01 g, 25.82 mmol) at room temperature. The reaction vessel (Pressure tube) was sealed and heated at 145 C. for 18 h. The reaction mass was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get desired compound (700 mg, 62%) as a white solid. .sup.1H NMR (400 MHz, CD.sub.3OD): ppm 8.10 (m, 1H), 8.08 (m, 1H), 7.78-7.75 (m, 1H), 7.69-7.65 (m, 1H), 7.49 (m, 1H), 4.04 (s, 3H); .sup.19F NMR: ppm 78.66 (1F); MS: MS m/z 178.1 (M.sup.++1).

(86) ##STR00052##

Step 1: Preparation of (E)-3-(4-fluorophenyl) acryloyl azide

(87) To a solution of (E)-3-(4-fluorophenyl) acrylic acid (25 g, 150 mmol) in benzene (120 mL) was added triethylamine (30.5 g, 301 mmol) followed by DPPA (41.4 g, 150 mmol) at room temperature. The reaction mass was stirred at the same temperature for 18 h. The solvent was evaporated under reduced pressure and the residue was diluted with water and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to get crude compound. The crude compound was purified by conventional column chromatography (Silica gel, 60-120 mesh) using 10% ethyl acetate in pet ether as mobile phase to get the desired compound as a white solid (26 g, 90%). .sup.1H NMR (400 MHz, CDCl.sub.3): ppm 7.73-7.69 (d, J=16 Hz, 1H), 7.55-7.51 (m, 2H), 7.11-7.07 (m, 2H), 6.36-6.32 (d, J=16 Hz, 1H).

Step 2: Preparation of 7-fluoroisoquinolin-1(2H)-one

(88) To a hot (125 C.) diphenyl ether (25 ml) was added (E)-3-(4-fluorophenyl) acryloyl azide (5 g, 26.2 mmol) portion wise. The reaction was heated at 250 C. for 4 h. The reaction mass was cooled to room temperature and diluted with pet ether. The precipitated solid was filtered washed with pet ether to get crude compound (2.45 g, 57%). The crude compound was taken to the next step without further purification. .sup.1H NMR (400 MHz, CD.sub.3OD): ppm 7.96-7.93 (m, 1H), 7.76-7.72 (m, 1H), 7.56-7.51 (m, 1H), 7.18-7.16 (m, 1H), 6.72-6.70 (m, 1H); MS: MS m/z 164.1 (M.sup.++1).

Step 3: Preparation of 7-fluoro-4-methoxyisoquinolin-1(2H)-one

(89) To a solution of 7-fluoroisoquinolin-1(2H)-one (11 g, 67.4 mmol) in methanol was added iodozobenzenediacetate (21.7 g, 67.4 mmol) followed by methane sulphonic acid (7.78 g, 81 mmol) at room temperature. The reaction mass was heated at reflux for 3 h. The solvent was evaporated and the residue was diluted with cold water. The precipitated solid was filtered and washed with water to get crude compound (11 g, 84%) as light red color solid. .sup.1H NMR (400 MHz, CD.sub.3OD): ppm 8.06-8.04 (m, 1H), 7.96-7.93 (m, 1H), 7.62-7.54 (m, 2H), 6.74 (s, 1H), 3.89 (s, 3H); MS: MS m/z 194.1 (M.sup.++1).

Step 4: Preparation of 1-chloro-7-fluoro-4-methoxyisoquinoline

(90) A solution of 7-fluoro-4-methoxyisoquinolin-1(2H)-one (11 g, 56.9 mmol) in POCl.sub.3 (100 ml) was refluxed for 18 h. The solvent was evaporated under reduced pressure and the residue was diluted with cold water. The aqueous solution was basified by solid sodium carbonate and extracted with ethyl acetate. The combine organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography (20% ethyl acetate in pet ether) to get desired compound (2.9 g, 24%) as off-white solid. .sup.1H NMR (400 MHz, CDCl.sub.3): ppm 8.36-8.32 (m, 1H), 7.93-7.90 (m, 1H), 7.88 (s, 1H), 7.70-7.65 (m, 1H), 4.11 (s, 3H); MS: MS m/z 212.1 (M.sup.++1).

Step 5: Preparation of 1,7-difluoro-4-methoxyisoquinoline

(91) To a solution of 1-chloro-7-fluoro-4-methoxyisoquinoline (3.7 g, 17.48 mmol) in DMSO was added cesium fluoride (10.26 g, 69.9 mmol) at room temperature. The reaction vessel (Pressure tube) was sealed and heated at 145 C. for 18 h. The reaction mass was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get desired compound (1.7 g, 49%) as white solid. .sup.1H NMR (400 MHz, CD.sub.3OD): ppm 8.20-8.18 (m, 1H), 7.69-7.66 (m, 1H), 7.54-7.47 (m, 1H), 7.46 (s, 1H), 4.04 (s, 3H); .sup.19F NMR: ppm 109.65 (1F), 78.53 (1F); MS: MS m/z 196.1 (M.sup.++1).

(92) ##STR00053##

Step 1: Preparation of (E)-3-(4-fluoro-3-methoxyphenyl) acrylic acid

(93) To a solution of 4-fluoro-3-methoxybenzaldehyde (30 g, 195 mmol) in pyridine (134 ml) and piperidine (4.12 ml) was added malonic acid (30.4 g, 292 mmol) at room temperature. The reaction mass was refluxed for 18 h. The solvent was evaporated under reduced pressure and the residue was acidified with 1.5N HCl solution. The precipitated solid was filtered washed with pet ether to get crude compound (37 g, 97%) as white solid. The crude compound was taken to the next step without further purification. .sup.1H NMR (400 MHz, CDCl.sub.3): ppm 12.37 (s, 1H), 7.59-7.55 (d, J=16 Hz, 1H), 7.53 (s, 1H), 7.26-7.22 (m, 2H), 6.59-6.55 (d, J=16 Hz, 1H), 3.89 (s, 3H); MS: MS m/z 195.0 (M.sup.+1).

Step 2: Preparation of (E)-3-(4-fluoro-3-methoxyphenyl) acryloyl azide

(94) To a solution of (E)-3-(4-fluoro-3-methoxyphenyl) acrylic acid (5 g, 25.5 mmol) in benzene (30 ml) was added triethylamine (5.16 g, 51 mmol) followed by DPPA (7.01 g, 25.5 mmol) at room temperature. The reaction mass was stirred at the same temperature for 18 h. The solvent was evaporated under reduced pressure and the residue was diluted with water and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to get crude compound. The crude compound was purified by conventional column chromatography (Silica gel, 60-120 mesh) using 10% ethyl acetate in pet ether as mobile phase to get the desire compound as white solid (4 g, 71%). .sup.1H NMR (400 MHz, CDCl.sub.3): ppm 7.70-7.66 (d, J=16 Hz, 1H), 7.12-7.07 (m, 3H), 6.35-6.31 (d, J=16 Hz, 1H), 3.92 (s, 3H).

Step 3: Preparation of 7-fluoro-6-methoxyisoquinolin-1(2H)-one

(95) To a hot (125 C.) diphenyl ether (20 ml) was added (E)-3-(4-fluoro-3-methoxyphenyl) acryloyl azide (4 g, 18.08 mmol) portionwise. The reaction was heated at 250 C. for 4 h. The reaction mass was cooled to room temperature and diluted with pet ether. The precipitated solid was filtered washed with pet ether to get crude compound (3.1 g, 89%). The crude compound was taken to the next step without further purification. MS: MS m/z 194.1 (M.sup.++1).

Step 4: Preparation of 1-chloro-7-fluoro-6-methoxyisoquinoline

(96) A solution of 7-fluoro-6-methoxyisoquinolin-1(2H)-one (3.1 g, 16.05 mmol) in POCl.sub.3 (25 ml) was refluxed for 18 h. The solvent was evaporated under reduced pressure and the residue was diluted with cold water. The aqueous solution was basified by solid sodium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography (20% ethyl acetate in pet ether) to get desired compound (1.9 g, 55%) as off-white solid. .sup.1H NMR (400 MHz, CDCl.sub.3): ppm 8.22-8.20 (d, J=8 Hz, 1H), 7.97-7.94 (m, 1H), 7.49-7.48 (m, 1H), 7.18-7.16 (d, J=8 Hz, 1H), 4.04 (s, 3H); MS: MS m/z 211.7 (M.sup.++1).

Step 5: Preparation of 1,7-difluoro-6-methoxyisoquinoline

(97) To a solution of 1-chloro-7-fluoro-6-methoxyisoquinoline (1.5 g, 7.09 mmol) in DMSO was added cesium fluoride (2.15 g, 14.18 mmol) at room temperature. The reaction vessel (Pressure tube) was sealed and heated at 145 C. for 18 h. The reaction mass was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get desired compound (950 mg, 68%) as white solid. .sup.1H NMR (400 MHz, CDCl.sub.3): ppm 8.0-7.98 (m, 1H), 7.77-7.74 (d, J=12 Hz, 1H), 7.42-7.40 (m, 1H), 7.21-7.19 (m, 1H), 4.04 (s, 3H); .sup.19F NMR: ppm 129.05 (1F), 71.98 (1F); MS: MS m/z 196.1 (M.sup.++1).

(98) ##STR00054##

Step 1: Preparation of 6-methoxy-3-(trifluoromethyl)quinoxalin-2(1H)-one and 7-methoxy-3-(trifluoromethyl)quinoxalin-2(1H)-one

(99) To a solution of 4-methoxybenzene-1,2-diamine (1 g, 7.24 mmol) in ethanol (10 ml) was added ethyl 3,3,3-trifluoro-2-oxopropanoate (1.23 g, 7.24 mmol)). The reaction mass was heated at reflux for overnight. The solvent was evaporated under reduced pressure and the residue was diluted with ethyl acetate and then evaporated to dryness to get the crude compound. The crude compound was washed with pet ether to get the product (1.55 g, 88% yield) as a mixture of regioisomer (black solid). This crude compound was taken to the next step without separation of isomers. .sup.1H NMR (400 MHz, DMSO-d.sub.6): ppm 12.92 (br, s, 2H), 7.84-7.81 (d, J=12 Hz, 1H), 7.44-7.33 (m, 4H), 7.82 (s, 1H), 3.87 (s, 6H), MS: MS m/z 245.15 (M.sup.++1).

Steps 2 and 3: Preparation of 2-chloro-6-methoxy-3-(trifluoromethyl)quinoxaline and 3-chloro-6-methoxy-2-(trifluoromethyl)quinoxaline

(100) A solution of 6-methoxy-3-(trifluoromethyl)quinoxalin-2(1H)-one & 7-methoxy-3-(trifluoromethyl)quinoxalin-2(1H)-one (0.90 g, 3.69 mmol) in POCl.sub.3 (10 ml) was refluxed for 3 h. The solvent was evaporated under reduced pressure and the residue was diluted with cold water. The aqueous solution was basified by solid sodium carbonate and extracted with ethyl acetate. The combine organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography (20% ethyl acetate in pet ether) to get mixture of regioisomer. The mixture of regioisomer were separated by SFC purification to afford 2-chloro-6-methoxy-3-methylquinoxaline (required isomer) (0.31 g, 32%) and 3-chloro-6-methoxy-2-methylquinoxaline (0.15 g, 15.5%) as off white solids.

(101) 2-chloro-6-methoxy-3-(trifluoromethyl)quinoxaline: .sup.1H NMR (400 MHz, DMSO-d.sub.6): ppm 8.10-8.07 (d, J=12 Hz, 1H), 7.75-7.44 (m, 2H), 3.95 (s, 3H); .sup.19F NMR: 6 ppm 65.36 (1F) MS: MS m/z 263.10 (M.sup.++1).

(102) 3-chloro-6-methoxy-2-(trifluoromethyl)quinoxaline: .sup.1H NMR (400 MHz, DMSO-d6): ppm 8.11-8.08 (d, J=12 Hz, 1H), 7.78-7.75 (d, J=12 Hz, 1H), 7.68 (s, 1H), 4.00 (s, 3H); .sup.19F NMR: ppm 65.36 (1F) MS: MS m/z 263.09 (M.sup.++1).

(103) ##STR00055##

Step 1: Preparation of 3-isopropyl-6-methoxyquinoxalin-2(1H)-one and 3-isopropyl-7-methoxyquinoxalin-2(1H)-one

(104) The same procedure was followed as described for 6-methoxy-3-(trifluoromethyl)quinoxalin-2(1H)-one but ethyl 3-methyl-2-oxobutanoate was used as starting material instead of ethyl 3,3,3-trifluoro-2-oxopropanoate. MS: MS m/z 219.1 (M.sup.++1).

Step 2: Preparation of 2-chloro-3-isopropyl-6-methoxyquinoxaline and 3-chloro-2-isopropyl-6-methoxyquinoxaline

(105) The same procedure was followed as described for 2-chloro-6-methoxy-3-(trifluoromethyl)quinoxaline but 3-isopropyl-6-methoxyquinoxalin-2(1H)-one and 3-isopropyl-7-methoxyquinoxalin-2(1H)-one was used as starting material instead of 6-methoxy-3-(trifluoromethyl)quinoxalin-2(1H)-one and 7-methoxy-3-(trifluoromethyl)quinoxalin-2(1H)-one.

(106) 3-chloro-2-isopropyl-6-methoxyquinoxaline: .sup.1H NMR (400 MHz, CDCl.sub.3): ppm .sup.1H NMR (400 MHz, CDCl.sub.3): 7.94 (d, J=9.2 Hz, 1H) 7.38-7.35 (dd, J=9.2 Hz, 2.8 Hz, 1H) 7.27-7.26 (m, 1H) 3.91 (s, 3H) 3.70-3.63 (m, 1H) 1.40 (d, J=8 Hz, 6H). MS: MS m/z 237.05 (M.sup.++1).

(107) 2-chloro-3-isopropyl-6-methoxyquinoxaline: MS: MS m/z 237.06 (M.sup.++1).

Preparation of pyridin-2-yl (1,1,1-trifluoro-2-methylpropan-2-yl) carbonate

(108) ##STR00056##

(109) To a solution of 1,1,1-trifluoro-2-methylpropan-2-ol (10 g, 78 mmol) in DIPEA (40.9 ml, 234 mmol) was added DMAP (9.54 g, 78 mmol) and the solution was stirred 10 min at room temperature. To the solution was added dipyridin-2-yl carbonate (16.8 g, 78 mmol). The solution was stirred overnight. The reaction mass was filtered, washing with DIPEA (2*10 mL); the filtrate was concentrated under vacuum and then diluted with DCM (300 mL). The solution was washed with aq. 1.5N HCl solution (2150 mL), followed by brine solution (100 mL). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude product as red color liquid. The crude compound was purified by silica gel chromatography eluting with EtOAc in pet-ether [0-5% over 25 min] as gradient, using 40 g silica column, collected the product fractions and concentrated to afford pyridin-2-yl (1,1,1-trifluoro-2-methylpropan-2-yl) carbonate (9.0 g, 36 mmol, 46% yield) as colorless liquid. .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 8.41-8.40 (d, J=4.8 Hz, 1H), 7.84-7.79 (m, 1H), 7.28-7.24 (m, 1H), 7.13-7.10 (d, J=10 Hz, 1H), 1.78 (s, 6H). MS: MS m/z 250.54 (M.sup.++1).

Preparation of Compound 1010 and Compound 1011

(110) ##STR00057##

(111) To a solution of tert-butyl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-hydroxy-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate (50 mg, 0.078 mmole) and 1-fluoro-4-methoxyisoquinoline (13.8 mg, 0.078 mmole) in DMSO (5 mL) was added t-BuOK (0.234 mL, 0.234 mmol, 1M solution in THF) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 h. The reaction mass was quenched with aqueous citric acid solution and extracted with ethyl acetate (50 mL3). The combined organic layer was washed with water, brine solution, dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to get crude compound tert-butyl ((2R,6S,7R,13aS,14aR,16aS,Z)-2-((4-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate as diastereomer mixture. The crude compound was purified by prep-HPLC to get 25 mg (40%) of compound 1010 and 12 mg (19%) of compound 1011 as white solid.

(112) Compound 1010: tert-butyl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((4-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, CD.sub.3OD): ppm 8.15 (m, 2H) 7.72 (t, J=7.40 Hz, 1H) 7.55 (m, 2H) 6.60 (d, J=8.03 Hz, 1H) 5.84 (br. s., 1H) 5.62 (td, J=10.23, 5.65 Hz, 1H) 5.00 (t, J=10.04 Hz, 1H) 4.79 (d, J=11.29 Hz, 1H) 4.63 (dd, J=9.91, 7.15 Hz, 1H) 4.26 (dd, J=10.54, 8.03 Hz, 1H) 4.03 (m, 4H) 3.47 (m, 2H) 2.73 (m, 2H) 2.42 (m, 2H) 1.92 (m, 2H) 1.76 (dd, J=8.28, 5.77 Hz, 1H) 1.65 (m, 1H) 1.55 (m, 5H) 1.44 (m, 3H) 1.28 (m, 4H) 1.11 (m, 9H) 1.00 (m, 4H) 0.90 (m, 2H). MS: MS m/z 796.2 (M.sup.+1).
Compound 1011: tert-butyl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-((4-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. MS: MS m/z 796.2 (M.sup.+1).

Preparation of (2R,6S,7R,13aS,14aR,16aS,Z)-6-amino-2-((4-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-9-methyl-N-((1-methylcyclopropyl)sulfonyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide hydrochloride

(113) ##STR00058##

(114) A solution of tert-butyl ((2R,6S,7R,13aS,14aR,16aS,Z)-2-((4-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate (95 mg, 0.119 mmol) in dioxane. HCl (10 mL) was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure to get crude compound (90 mg, 93%). The crude compound was washed with diethyl ether and taken to the next step without further purification. MS: MS m/z 698.5 (M.sup.++1).

Preparation of Compound 1016 and Compound 1017

(115) ##STR00059##

(116) A solution of (2R,6S,7R,13aS,14aR,16aS,Z)-6-amino-2-((4-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-9-methyl-N-((1-methylcyclopropyl)sulfonyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide hydrochloride (90 mg, 0.110 mmol) in DCM (4 mL) was added DIPEA (0.068 mL, 0.387 mmole) followed by pyridin-2-yl (1,1,1-trifluoro-2-methylpropan-2-yl) carbonate (38 mg, 0.155 mmole). The reaction mixture was stirred at room temperature for 30 min. The reaction mass was diluted with DCM and washed with water. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to get crude compound as diastereomer mixture. The crude compound was purified by prep-HPLC to get compound 1008 (14 mg, 12%) and Compound 1009 (19 mg, 17%) as white solids.

(117) Compound 1016: 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((4-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, CD.sub.3OD): ppm 8.15 (m, 2H) 7.74 (td, J=7.72, 1.13 Hz, 1H) 7.56 (m, 2H) 5.83 (br. s., 1H) 5.61 (m, 1H) 5.01 (t, J=9.91 Hz, 1H) 4.78 (s, 1H) 4.67 (dd, J=10.29, 7.28 Hz, 1H) 4.22 (m, 1H) 4.00 (m, 4H) 3.46 (m, 2H) 3.30 (s, 4H) 2.73 (m, 2H) 2.43 (m, 2H) 1.95 (m, 2H) 1.77 (dd, J=8.41, 5.65 Hz, 1H) 1.66 (d, J=10.29 Hz, 1H) 1.55 (m, 6H) 1.44 (m, 2H) 1.28 (m, 5H) 0.96 (m, 8H). .sup.19F NMR (400 MHz, CD.sub.3OD): ppm 85.2 (s, 3F). MS: MS m/z 850.2 (M.sup.+1).
Compound 1017: 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-((4-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, CD.sub.3OD): ppm 8.20 (d, J=8.28 Hz, 1H) 8.12 (d, J=8.28 Hz, 1H) 7.74 (ddd, J=8.34, 7.09, 1.13 Hz, 1H) 7.57 (m, 2H) 5.85 (br. s., 1H) 5.73 (d, J=8.53 Hz, 1H) 5.04 (br. s., 1H) 4.72 (t, J=8.41 Hz, 1H) 4.53 (m, 2H) 4.04 (m, 4H) 3.49 (m, 3H) 3.37 (m, 4H) 2.72 (dd, J=13.43, 7.40 Hz, 1H) 2.59 (br. s., 1H) 2.45 (m, 2H) 2.15 (m, 1H) 1.98 (m, 1H) 1.71 (m, 1H) 1.60 (m, 3H) 1.51 (s, 3H) 1.45 (m, 4H) 1.33 (m, 2H) 1.22 (m, 2H) 0.93 (m, 6H). .sup.19F NMR (400 MHz, CD.sub.3OD): ppm 85.13 (s, 3F). MS: MS m/z 850.2 (M-1).

Preparation of Compound 1001

(118) ##STR00060##

(119) Compound 1001 was prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 1016.

(120) Compound 1001: 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,13aS,14aR,16aS,Z)-2-((6-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, CD.sub.3OD): ppm 8.11 (d, J=9.04 Hz, 1H) 7.93 (d, J=6.02 Hz, 1H) 7.27 (s, 1H) 7.21 (d, J=2.26 Hz, 1 H) 7.11 (dd, J=9.16, 2.38 Hz, 1H) 5.87 (br. s., 1H) 5.66 (d, J=8.78 Hz, 1H) 4.71 (m, 2H) 4.26 (d, J=10.79 Hz, 1H) 4.02 (dd, J=11.54, 3.26 Hz, 1H) 3.94 (s, 3H) 3.44 (d, J=2.76 Hz, 2H) 2.73 (m, 1H) 2.50 (m, 3H) 1.95 (m, 3H) 1.75 (dd, J=8.16, 5.40 Hz, 1H) 1.58 (m, 7H) 1.37 (m, 10H) 1.02 (s, 3H) 0.88 (m, 3H). .sup.19F NMR (400 MHz, CD.sub.3OD): ppm 85.10 (s, 3F). MS: MS m/z 838.2 (M.sup.++1).

Preparation of Compound 1002

(121) ##STR00061##

(122) Compound 1002 was prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 1016.

(123) Compound 1002: 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,13aS,14aR,16aS,Z)-2-((4-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, CD.sub.3OD): ppm 8.15 (m, 2H) 7.73 (m, 1H) 7.57 (m, 2H) 5.84 (br. s., 1H) 5.69 (m, 1H) 5.06 (t, J=9.54 Hz, 1H) 4.80 (d, J=11.54 Hz, 1H) 4.70 (dd, J=9.91, 7.15 Hz, 1H) 4.24 (d, J=10.79 Hz, 1H) 4.01 (m, 4H) 3.44 (d, J=2.76 Hz, 2H) 3.29 (s, 3H) 2.75 (dd, J=13.80, 7.03 Hz, 1H) 2.52 (m, 3H) 1.94 (m, 2H) 1.75 (dd, J=8.28, 5.52 Hz, 1H) 1.63 (m, 2H) 1.52 (s, 4H) 1.43 (m, 5H) 1.32 (s, 4H) 0.88 (m, 5H). .sup.19F NMR (400 MHz, CD.sub.3OD): ppm 85.21 (s, 3F) MS: MS m/z 838.2 (M.sup.++1).

Preparation of Compound 1003 and Compound 1004

(124) ##STR00062##

(125) Compound 1003 and compound 1004 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 1010.

(126) Compound 1003: tert-butyl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-14a-((cyclopropylsulfonyl)carbamoyl)-2-((4-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-9-methyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, CD.sub.3OD): ppm 8.15 (m, 2H) 7.72 (t, J=7.53 Hz, 1H) 7.55 (m, 2H) 5.83 (br. s., 1H) 5.62 (td, J=10.16, 5.52 Hz, 1H) 4.78 (d, J=11.54 Hz, 1H) 4.61 (m, 1H) 4.25 (d, J=10.79 Hz, 1H) 4.00 (m, 4H) 3.45 (m, 2H) 3.30 (s, 3H) 2.92 (m, 1H) 2.73 (m, 2H) 2.42 (m, 2H) 1.94 (m, 2H) 1.78 (m, 3H) 1.53 (m, 6H) 1.28 (m, 11H) 1.07 (m, 4H). MS: MS m/z 784.2 (M.sup.++1).
Compound 1004: tert-butyl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-14a-((cyclopropylsulfonyl)carbamoyl)-2-((4-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-9-methyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, CD.sub.3OD): ppm 8.15 (m, 2H) 7.73 (t, J=7.65 Hz, 1H) 7.58 (m, 2H) 5.85 (br. s., 1H) 5.71 (d, J=8.53 Hz, 1H) 4.66 (m, 2H) 4.46 (d, J=11.29 Hz, 1H) 4.07 (m, 4H) 3.47 (m, 5H) 2.89 (br. s., 1H) 2.71 (dd, J=13.55, 7.53 Hz, 1H) 2.45 (m, 3H) 2.05 (m, 3H) 1.74 (dd, J=7.78, 5.52 Hz, 1H) 1.62 (dd, J=9.41, 5.40 Hz, 1H) 1.51 (d, J=12.80 Hz, 3H) 1.28 (m, 11H) 1.04 (m, 8H). MS: MS m/z 784.2 (M.sup.++1).

Preparation of Compound 1005 and Compound 1006

(127) ##STR00063##
Compound 1005 and compound 1006 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 1010.
Compound 1005: tert-butyl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((6-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, CD.sub.3OD): ppm 8.13 (d, J=9.03 Hz, 2H) 7.92 (d, J=5.77 Hz, 1H) 7.25 (d, J=5.77 Hz, 1H) 7.19 (d, J=2.26 Hz, 1H) 7.09 (dd, J=9.16, 2.13 Hz, 1H) 5.88 (br. s., 1H) 5.61 (td, J=10.16, 5.77 Hz, 1H) 4.77 (d, J=11.80 Hz, 1H) 4.61 (m, 1H) 4.26 (m, 1H) 4.03 (dd, J=11.42, 3.14 Hz, 1H) 3.94 (s, 3H) 3.48 (m, 2H) 3.30 (s, 3H) 2.74 (m, 2H) 2.43 (m, 2H) 1.93 (m, 2H) 1.76 (dd, J=8.28, 5.77 Hz, 1H) 1.57 (m, 7H) 1.42 (m, 1H) 1.28 (m, 2H) 1.17 (s, 8H) 1.03 (m, 4H) 0.88 (br. s., 2H). MS: MS m/z 798.2 (M.sup.++1).
Compound 1006: tert-butyl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-((6-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, CD.sub.3OD): ppm 8.14 (d, J=9.04 Hz, 1H) 7.92 (d, J=5.77 Hz, 1H) 7.27 (d, J=5.77 Hz, 1H) 7.20 (d, J=1.76 Hz, 1H) 7.11 (d, J=9.29 Hz, 1H) 5.90 (br. s., 1H) 5.73 (br. s., 1H) 4.65 (m, 2H) 4.45 (d, J=10.54 Hz, 1H) 4.10 (m, 1H) 3.94 (s, 3H) 3.50 (d, J=1.51 Hz, 2H) 3.40 (br. s., 3H) 2.71 (dd, J=14.05, 7.28 Hz, 1H) 2.44 (d, J=8.78 Hz, 2H) 2.13 (br. s., 1H) 1.97 (m, 1H) 1.71 (m, 1H) 1.51 (m, 9H) 1.29 (br. s., 8H) 1.15 (m, 3H) 0.92 (m, 5H). MS: MS m/z 798.2 (M.sup.++1).

Preparation of Compound 1007

(128) ##STR00064##

(129) Compound 1007 was prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 1010.

(130) Compound 1007: tert-butyl ((2R,6S,7R,13aS,14aR,16aS,Z)-2-((4-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, CD.sub.3OD): ppm 8.15 (m, 2H) 7.73 (t, J=7.15 Hz, 1H) 7.56 (m, 2H) 5.85 (br. s., 1H) 5.71 (m, 1H) 5.06 (m, 1H) 4.79 (m, 2H) 4.67 (dd, J=9.79, 7.28 Hz, 1H) 4.29 (d, J=10.79 Hz, 1H) 4.05 (m, 4H) 3.44 (m, 2H) 3.29 (m, 3H) 2.74 (dd, J=13.43, 7.15 Hz, 1H) 2.54 (m, 3H) 1.75 (dd, J=8.28, 5.52 Hz, 1H) 1.62 (m, 2H) 1.52 (s, 4H) 1.40 (m, 9H) 1.12 (s, 8H) 0.91 (m, 3H). MS: MS m/z 784.2 (M.sup.++1).

Preparation of Compound 1008 and Compound 1009

(131) ##STR00065##

(132) Compound 1008 and compound 1009 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 1010.

(133) Compound 1008: tert-butyl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-14a-((cyclopropylsulfonyl)carbamoyl)-2-((6-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-9-methyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, CD.sub.3OD): ppm 8.14 (d, J=9.03 Hz, 1H) 7.91 (d, J=5.77 Hz, 1H) 7.26 (d, J=6.02 Hz, 1H) 7.20 (d, J=2.01 Hz, 1H) 7.11 (d, J=8.78 Hz, 1H) 5.88 (br. s., 1H) 5.68 (d, J=7.78 Hz, 1H) 4.66 (d, J=4.77 Hz, 2H) 4.43 (d, J=11.04 Hz, 1H) 4.11 (m, 1H) 3.94 (s, 3H) 3.51 (m, 2H) 3.43 (s, 3H) 2.83 (br. s., 1H) 2.70 (dd, J=13.18, 7.40 Hz, 1H) 2.49 (d, J=13.55 Hz, 2H) 2.30 (br. s., 1H) 2.02 (m, 4H) 1.76 (dd, J=8.03, 5.27 Hz, 1H) 1.63 (dd, J=9.54, 5.02 Hz, 1H) 1.50 (m, 3H) 1.28 (m, 9H) 1.06 (m, 10H). MS: MS m/z 784.2 (M.sup.++1).
Compound 1009: tert-butyl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-14a-((cyclopropylsulfonyl)carbamoyl)-2-((6-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-9-methyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, CD.sub.3OD): ppm 8.13 (d, J=9.29 Hz, 2H) 7.91 (d, J=6.02 Hz, 1H) 7.25 (d, J=6.02 Hz, 1H) 7.19 (d, J=2.26 Hz, 1H) 7.09 (dd, J=9.16, 2.13 Hz, 1H) 5.87 (br. s., 1H) 5.59 (m, 1H) 4.75 (m, 1H) 4.60 (m, 1H) 4.26 (d, J=10.79 Hz, 1H) 4.02 (dd, J=11.42, 3.14 Hz, 1H) 3.94 (s, 3H) 3.47 (m, 2H) 3.30 (s, 3H) 2.89 (br. s., 1H) 2.71 (m, 2H) 2.44 (m, 2H) 1.93 (m, 4H) 1.77 (m, 1H) 1.57 (m, 2H) 1.46 (m, 2H) 1.28 (m, 3H) 1.18 (s, 8H) 1.08 (m, 3H) 1.01 (d, J=6.78 Hz, 4H). MS: MS m/z 784.2 (M.sup.++1).

Preparation of Compound 1012 and Compound 1013

(134) ##STR00066##

(135) Compound 1012 and compound 1013 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 1016.

(136) Compound 1012: 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-14a-((cyclopropylsulfonyl)carbamoyl)-2-((4-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-9-methyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, CD.sub.3OD): ppm 8.15 (m, 2H) 7.73 (ddd, J=8.28, 7.03, 1.25 Hz, 1H) 7.56 (m, 2H) 5.83 (m, 1H) 5.62 (td, J=10.23, 5.90 Hz, 1H) 5.07 (br. s., 1H) 4.78 (s, 1H) 4.66 (dd, J=10.16, 7.15 Hz, 1H) 4.22 (m, 1H) 4.03 (s, 3H) 3.97 (d, J=3.26 Hz, 1H) 3.44 (m, 2H) 2.93 (d, J=4.52 Hz, 1H) 2.72 (m, 2H) 2.43 (m, 2H) 1.94 (m, 2H) 1.78 (dd, J=8.41, 5.65 Hz, 1H) 1.54 (m, 4H) 1.31 (m, 6H) 1.13 (m, 5H) 1.00 (m, 7H). .sup.19F NMR (400 MHz, CD.sub.3OD): ppm 85.2 (s, 3F) MS: MS m/z 836.2 (M.sup.+1).
Compound 1013: 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-14a-((cyclopropylsulfonyl)carbamoyl)-2-((4-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-9-methyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, CD.sub.3OD): ppm 8.20 (m, 1H) 8.19 (d, J=8.28 Hz, 2H) 8.15 (m, 1H) 8.12 (d, J=8.28 Hz, 1H) 7.74 (td, J=7.72, 1.13 Hz, 1H) 7.57 (m, 2H) 5.84 (br. s., 1H) 5.74 (m, 1H) 5.07 (t, J=9.79 Hz, 1H) 4.71 (dd, J=9.54, 7.28 Hz, 1H) 4.53 (m, 2H) 4.02 (m, 4H) 3.47 (m, 2H) 3.38 (s, 3H) 2.93 (tt, J=7.84, 4.96 Hz, 1H) 2.72 (dd, J=13.55, 7.28 Hz, 1H) 2.45 (m, 2H) 2.15 (m, 1H) 1.98 (dd, J=13.80, 7.53 Hz, 1H) 1.72 (dd, J=8.03, 5.52 Hz, 1H) 1.60 (dd, J=9.54, 5.52 Hz, 2H) 1.48 (m, 3H) 1.32 (m, 3H) 1.22 (m, 4H) 1.08 (m, 2H) 0.95 (d, J=6.78 Hz, 4H). .sup.19F NMR (400 MHz, CD.sub.3OD): ppm 85.2 (s, 3F). MS: MS m/z 836.2 (M.sup.+1).

Preparation of Compound 1014 and Compound 1015

(137) ##STR00067##

(138) Compound 1014 and compound 1015 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 1016.

(139) Compound 1014: 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((6-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, CD.sub.3OD): ppm 8.11 (d, J=9.29 Hz, 1H) 7.93 (d, J=5.77 Hz, 1H) 7.27 (d, J=6.02 Hz, 1H) 7.21 (d, J=2.51 Hz, 1H) 7.11 (dd, J=9.03, 2.51 Hz, 1H) 5.88 (br. s., 1H) 5.62 (m, 1H) 5.02 (br. s., 1H) 4.77 (d, J=11.54 Hz, 1H) 4.66 (dd, J=10.16, 7.15 Hz, 1H) 4.23 (m, 1H) 4.01 (m, 1H) 3.93 (m, 3H) 3.45 (m, 2H) 3.30 (s, 4H) 2.74 (dt, J=13.30, 6.90 Hz, 2H) 2.44 (ddd, J=13.87, 9.98, 4.27 Hz, 2H) 1.94 (m, 2H) 1.77 (dd, J=8.41, 5.65 Hz, 1H) 1.56 (m, 6H) 1.44 (m, 2H) 1.36 (s, 3H) 1.27 (m, 4H) 1.04 (m, 3H) 1.00 (d, J=6.78 Hz, 3H) 0.90 (m, 2H). .sup.19F NMR (400 MHz, CD.sub.3OD): ppm 85.13 (s, 3F). MS: MS m/z 850.2 (M.sup.+1).
Compound 1015: 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-((6-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, CD.sub.3OD): ppm 8.14 (d, J=9.04 Hz, 1H) 7.92 (d, J=6.02 Hz, 1H) 7.27 (d, J=5.77 Hz, 1H) 7.21 (d, J=2.51 Hz, 1H) 7.12 (dd, J=9.16, 2.38 Hz, 1H) 5.88 (br. s., 1H) 5.70 (br. s., 1H) 4.71 (m, 1H) 4.58 (m, 2H) 4.47 (d, J=11.54 Hz, 1H) 4.06 (d, J=9.29 Hz, 1H) 3.94 (s, 3H) 3.50 (d, J=1.51 Hz, 2H) 3.40 (s, 3H) 2.72 (dd, J=13.55, 7.28 Hz, 1H) 2.46 (m, 2H) 2.15 (br. s., 1H) 1.97 (m, 2H) 1.73 (br. s., 1H) 1.59 (m, 2H) 1.49 (m, 8H) 1.35 (m, 6H) 1.20 (m, 1H) 0.94 (d, J=6.53 Hz, 3H) 0.85 (br. s., 2H). .sup.19F NMR (400 MHz, CD.sub.3OD): ppm 85.12 (s, 3F). MS: MS m/z 850.2 (M.sup.+1).

Preparation of Compound 1018 and Compound 1019

(140) ##STR00068##

(141) Compound 1018 and compound 1019 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 1016.

(142) Compound 1018: 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-14a-((cyclopropylsulfonyl)carbamoyl)-2-((6-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-9-methyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, CD.sub.3OD): ppm 8.14 (d, J=9.29 Hz, 1H) 7.93 (m, 1H) 7.28 (d, J=5.77 Hz, 1H) 7.22 (d, J=2.51 Hz, 1H) 7.12 (dd, J=9.03, 2.51 Hz, 1H) 5.89 (br. s., 1H) 5.74 (m, 1H) 5.08 (t, J=9.54 Hz, 1H) 4.81 (s, 1H) 4.71 (dd, J=9.54, 7.53 Hz, 1H) 4.55 (m, 1H) 4.04 (dd, J=11.54, 3.51 Hz, 1H) 3.95 (s, 3H) 3.48 (d, J=5.52 Hz, 2H) 3.38 (m, 8H) 3.28 (dt, J=3.33, 1.73 Hz, 2H) 2.93 (m, 1H) 2.72 (m, 2H) 2.45 (m, 2H) 1.72 (dd, J=8.28, 5.52 Hz, 1H) 1.55 (m, 5H) 1.32 (m, 3H) 1.06 (m, 5H). .sup.19F NMR (400 MHz, CD.sub.3OD): ppm 85.01 (s, 3F). MS: MS m/z 838.2 (M.sup.++1).
Compound 1019: 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-14a-((cyclopropylsulfonyl)carbamoyl)-2-((6-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-9-methyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. MS: MS m/z 838.2 (M.sup.++1).

Preparation of Compound 1020

(143) ##STR00069##

(144) Compound 1020 was prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 1010.

(145) Compound 1020: tert-butyl ((2R,6S,7R,13aS,14aR,16aS,Z)-14a-((cyclopropylsulfonyl)carbamoyl)-2-((7-methoxy-3-(trifluoromethyl)quinoxalin-2-yl)oxy)-7-(methoxymethyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, CD.sub.3OD): ppm 7.97 (d, J=9.03 Hz, 1H) 7.38 (m, 2H) 5.97 (br. s., 1H) 5.66 (d, J=8.78 Hz, 1H) 4.66 (dd, J=9.54, 7.28 Hz, 1H) 4.19 (m, 1H) 4.04 (m, 4H) 3.40 (m, 3H) 3.28 (m, 4H) 2.89 (br. s., 1H) 2.70 (dd, J=13.68, 6.90 Hz, 1H) 2.55 (m, 3H) 1.99 (s, 2H) 1.85 (m, 1H) 1.76 (m, 1H) 1.63 (dd, J=9.41, 5.14 Hz, 2H) 1.45 (m, 7H) 1.08 (m, 10H). .sup.19F NMR (400 MHz, CD.sub.3OD): ppm 68.70 (s, 3F). MS: MS m/z 837.2 (M.sup.+1).

Preparation of Compound 1021

(146) ##STR00070##

(147) Compound 1021 was prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 1016.

(148) Compound 1021: 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,13aS,14aR,16aS,Z)-14a-((cyclopropylsulfonyl)carbamoyl)-2-((7-methoxy-3-(trifluoromethyl)quinoxalin-2-yl)oxy)-7-(methoxymethyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, CD.sub.3OD): ppm 7.99 (d, J=9.29 Hz, 1H) 7.40 (m, 1H) 7.24 (d, J=7.53 Hz, 1H) 5.97 (br. s., 1H) 5.69 (d, J=9.79 Hz, 1H) 5.10 (t, J=9.66 Hz, 1H) 4.91 (br. s., 2H) 4.81 (s, 1H) 4.68 (dd, J=9.79, 7.03 Hz, 2H) 4.15 (dd, J=10.92, 7.65 Hz, 2H) 4.01 (m, 3H) 3.39 (m, 3H) 3.28 (m, 2H) 2.55 (m, 4H) 1.90 (t, J=10.04 Hz, 2H) 1.75 (dd, J=8.28, 5.52 Hz, 2H) 1.64 (dd, J=9.54, 5.52 Hz, 2H) 1.46 (m, 3H) 1.32 (m, 6H) 1.07 (m, 4H). .sup.19F NMR (400 MHz, CD.sub.3OD): ppm 68.72 (s, 3F) 85.26 (s, 3F). MS: MS m/z 891.0 (M.sup.+1).

Preparation of Compound 1022

(149) ##STR00071##

(150) Compound 1022 was prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 1010.

(151) Compound 1022: tert-butyl ((2R,6S,7R,13aS,14aR,16aS,Z)-14a-((cyclopropylsulfonyl)carbamoyl)-2-((7-fluoro-6-methoxynaphthalen-1-yl)oxy)-7-(methoxymethyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, CD.sub.3OD): ppm 7.93 (m, 1H) 7.79 (d, J=11.54 Hz, 1H) 7.38 (d, J=8.28 Hz, 1H) 7.29 (d, J=6.02 Hz, 1H) 5.89 (br. s., 1H) 5.68 (m, 1H) 5.09 (m, 1H) 4.76 (m, 1H) 4.65 (dd, J=9.66, 7.15 Hz, 1H) 4.24 (d, J=10.79 Hz, 1H) 4.00 (m, 3H) 3.45 (br. s., 2H) 3.29 (s, 3H) 2.93 (tt, J=7.87, 4.93 Hz, 1H) 2.73 (m, 1H) 2.52 (m, 3H) 1.93 (m, 5H) 1.75 (m, 3H) 1.44 (m, 8H) 1.07 (m, 10H). MS: MS m/z 786.2 (M.sup.+1).

Preparation of Compound 1023

(152) ##STR00072##

(153) Compound 1023 was prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 1016.

(154) Compound 1023: 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,13aS,14aR,16aS,Z)-14a-((cyclopropylsulfonyl)carbamoyl)-2-((7-fluoro-6-methoxynaphthalen-1-yl)oxy)-7-(methoxymethyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, CD.sub.3OD): ppm 7.95 (d, J=5.77 Hz, 1H) 7.80 (d, J=11.80 Hz, 1H) 7.40 (d, J=8.03 Hz, 1H) 7.30 (d, J=5.77 Hz, 1H) 5.89 (br. s., 1H) 5.69 (m, 1H) 5.10 (m, 1H) 4.70 (m, 2H) 4.23 (d, J=10.79 Hz, 1H) 4.00 (m, 4H) 3.45 (m, 2H) 3.38 (m, 3H) 3.29 (m, 4H) 2.94 (tt, J=7.91, 4.89 Hz, 1H) 2.74 (dd, J=13.80, 6.78 Hz, 1H) 2.52 (m, 3H) 1.95 (m, 2H) 1.76 (dd, J=8.28, 5.52 Hz, 1H) 1.62 (dd, J=9.41, 5.40 Hz, 1H) 1.45 (m, 7H) 1.31 (m, 1H) 1.08 (m, 6H). .sup.19F NMR (400 MHz, CD.sub.3OD): ppm 85.23 (s, 3F) 133.68 (s, 1F). MS: MS m/z 840.2 (M.sup.+1).

Preparation of Compound 1024 and Compound 1025

(155) ##STR00073##

(156) Compound 1024 and compound 1025 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 1010.

(157) Compound 1024: tert-butyl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-14a-(((1-(fluoromethyl)cyclopropyl)sulfonyl)carbamoyl)-2-((3-isopropyl-7-methoxyquinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, CD.sub.3OD): ppm 7.84 (d, J=9.04 Hz, 1H) 7.27 (d, J=2.51 Hz, 1H) 7.24 (s, 1H) 5.98 (br. s., 1H) 5.69 (br. s., 1H) 4.67 (m, 3H) 4.40 (d, J=11.55 Hz, 1H) 4.13 (d, J=8.53 Hz, 1H) 3.96 (s, 3H) 3.48 (m, 5H) 2.68 (m, 2H) 2.53 (m, 2H) 1.98 (m, 5H) 1.62 (m, 12H) 1.32 (m, 14H) 0.94 (m, 5H). MS: MS m/z 859.4 (M.sup.++1).

(158) sCompound 1025: tert-butyl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-14a-(((1-(fluoromethyl)cyclopropyl)sulfonyl)carbamoyl)-2-((3-isopropyl-7-methoxyquinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, CD.sub.3OD): ppm 7.83 (d, J=9.04 Hz, 1H) 7.26 (d, J=2.51 Hz, 1H) 7.21 (dd, J=9.04, 3.01 Hz, 1H) 5.95 (br. s., 1H) 5.59 (d, J=5.02 Hz, 1H) 4.66 (m, 3H) 4.26 (d, J=11.04 Hz, 1H) 4.09 (m, 1H) 3.95 (m, 3H) 3.48 (m, 3H) 3.28 (s, 3H) 2.67 (m, 2H) 2.46 (m, 2H) 1.94 (m, 3H) 1.73 (m, 1H) 1.54 (m, 5H) 1.30 (m, 7H) 1.19 (m, 14H) 0.98 (m, 4H). MS: MS m/z 859.4 (M.sup.++1).

Preparation of Compound 1026

(159) ##STR00074##

(160) Compound 1026 was prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 1010.

(161) Compound 1026: tert-butyl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-14a-((cyclopropylsulfonyl)carbamoyl)-2-((7-fluoro-6-methoxynaphthalen-1-yl)oxy)-7-(methoxymethyl)-9-methyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. MS: MS m/z 802 (M.sup.++1).

Preparation of Compound 1027 and Compound 1028

(162) ##STR00075##

(163) Compound 1027 and compound 1028 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 1010.

(164) Compound 1027: tert-butyl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-((7-methoxy-3-(trifluoromethyl)quinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, CD.sub.3OD): ppm 7.98 (d, J=9.04 Hz, 1H) 7.38 (m, 2H) 6.02 (br. s., 1H) 5.69 (br. s., 1H) 4.69 (m, 1H) 4.55 (m, 2H) 4.13 (d, J=8.53 Hz, 1H) 4.01 (m, 3H) 3.48 (m, 5H) 2.68 (m, 1H) 2.55 (m, 2H) 2.00 (m, 3H) 1.74 (m, 5H) 1.57 (m, 8H) 1.31 (m, 14H) 0.95 (m, 4H). MS: MS m/z 865.2 (M.sup.+1).
Compound 1028: tert-butyl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((7-methoxy-3-(trifluoromethyl)quinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, CD.sub.3OD): ppm 7.96 (m, 1H) 7.38 (m, 2H) 5.98 (br. s., 1H) 5.62 (m, 1H) 4.99 (m, 1H) 4.63 (m, 1H) 4.16 (m, 1H) 4.04 (m, 4H) 3.45 (m, 2H) 3.27 (s, 3H) 2.72 (m, 2H) 2.48 (m, 2H) 1.93 (m, 2H) 1.77 (m, 2H) 1.61 (m, 3H) 1.46 (m, 5H) 1.27 (m, 4H) 1.07 (s, 9H) 0.95 (m, 5H). MS: MS m/z 865.2 (M.sup.+1).

Preparation of Compound 1029 and Compound 1030

(165) ##STR00076##

(166) Compound 1029 and compound 1030 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 1010.

(167) Compound 1029: tert-butyl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-((3-isopropyl-7-methoxyquinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, CD.sub.3OD): ppm 7.83 (d, J=9.04 Hz, 1H) 7.23 (m, 2H) 5.96 (br. s., 1H) 5.64 (br. s., 1H) 4.66 (m, 2H) 4.26 (d, J=10.54 Hz, 1H) 4.08 (d, J=9.54 Hz, 1H) 3.96 (s, 3H) 3.48 (m, 4H) 3.29 (s, 3H) 2.71 (br. s., 1H) 2.48 (m, 2H) 1.94 (d, J=17.07 Hz, 1H) 1.78 (m, 2H) 1.50 (m, 7H) 1.32 (m, 9H) 1.17 (m, 11H) 0.92 (m, 5H). MS: MS m/z 839.2 (M.sup.+1).
Compound 1030: tert-butyl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((3-isopropyl-7-methoxyquinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, CD.sub.3OD): ppm 7.84 (d, J=9.04 Hz, 1H) 7.24 (m, 2H) 5.96 (br. s., 1H) 5.61 (br. s., 1H) 4.62 (m, 2H) 4.37 (br. s., 1H) 4.17 (br. s., 1H) 3.96 (s, 3H) 2.65 (m, 1H) 2.01 (m, 2H) 1.79 (m, 7H) 1.57 (m, 12H) 1.40-1.32 (m, 19H) 0.93 (m, 5H). MS: MS m/z 839.2 (M.sup.+1).

Preparation of Compound 1031 and Compound 1032

(168) ##STR00077##

(169) Compound 1031 and compound 1032 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 1016.

(170) Compound 1031: 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-((7-methoxy-3-(trifluoromethyl)quinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. MS: MS m/z 921.2 (M.sup.++1).
Compound 1032: 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((7-methoxy-3-(trifluoromethyl)quinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, CD.sub.3OD): ppm 7.99 (d, J=9.04 Hz, 1H) 7.40 (m, 2H) 5.98 (br. s., 1H) 5.63 (m, 1H) 5.01 (m, 1H) 4.13 (m, 1H) 4.04 (m, 4H) 3.45 (m, 2H) 3.27 (m, 3H) 2.71 (m, 2H) 2.48 (m, 2H) 1.94 (m, 2H) 1.77 (dd, J=8.28, 5.77 Hz, 1H) 1.67 (d, J=10.04 Hz, 1H) 1.59 (m, 1H) 1.53 (s, 4H) 1.43 (m, 2H) 1.20 (d, J=9.54 Hz, 6H) 1.00 (m, 7H) 0.90 (m, 3H). .sup.19F NMR (400 MHz, CD.sub.3OD): ppm 68.72 (s, 3F) 85.26 (s, 3F). MS: MS m/z 921.2 (M.sup.++1).

Preparation of Compound 1033 and Compound 1034

(171) ##STR00078##

(172) Compound 1033 and compound 1034 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 1016.

(173) Compound 1033: 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-((3-isopropyl-7-methoxyquinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, CD.sub.3OD): ppm 7.84 (d, J=9.04 Hz, 1H) 7.29 (d, J=3.01 Hz, 1H) 7.23 (m, 1H) 5.98 (br. s., 1H) 5.75 (d, J=10.54 Hz, 1H) 5.02 (m, 1H) 4.72 (t, J=8.53 Hz, 1H) 4.57 (m, 1H) 4.45 (d, J=12.55 Hz, 1H) 4.09 (m, 1H) 3.97 (s, 3H) 3.47 (m, 7H) 2.70 (m, 1H) 2.48 (m, 1H) 1.99 (m, 1H) 1.72 (m, 1H) 1.63 (m, 2H) 1.52 (m, 5H) 1.45 (m, 7H) 1.34 (m, 12H) 0.93 (m, 4H). .sup.19F NMR (400 MHz, CD.sub.3OD): ppm 85.1 (s, 3F) MS: MS m/z 893.2 (M.sup.+1).
Compound 1034: 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((3-isopropyl-7-methoxyquinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. MS: MS m/z 893.2 (M.sup.+1).

Preparation of Compound 1035 and Compound 1036

(174) ##STR00079##

(175) Compound 1035 and compound 1036 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 1010.

(176) Compound 1035: tert-butyl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-14a-(((1-(fluoromethyl)cyclopropyl)sulfonyl)carbamoyl)-2-((7-methoxy-3-(trifluoromethyl)quinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. MS: MS m/z 884.2 (M.sup.+1).
Compound 1036: tert-butyl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-14a-(((1-(fluoromethyl)cyclopropyl)sulfonyl)carbamoyl)-2-((3-isopropyl-7-methoxyquinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. MS: MS m/z 884.2 (M.sup.+1).

Preparation of Compound 1037 and Compound 1038

(177) ##STR00080##

(178) Compound 1037 and compound 1038 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 1016.

(179) Compound 1037: 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-14a-(((1-(fluoromethyl)cyclopropyl)sulfonyl)carbamoyl)-2-((7-methoxy-3-(trifluoromethyl)quinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, CD.sub.3OD): ppm 7.98 (m, 1H) 7.38 (m, 2H) 5.96 (br. s., 1H) 5.57 (br. s., 1H) 4.67 (m, 3H) 4.14 (d, J=11.04 Hz, 1H) 4.01 (m, 4H) 3.46 (m, 3H) 3.26 (m, 3H) 2.71 (m, 1H) 2.47 (m, 1H) 1.93 (m, 4H) 1.66 (m, 5H) 1.38 (m, 5H) 1.07 (m, 11H). MS: MS m/z 939.2 (M.sup.++1).
Compound 1038: 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-14a-(((1-(fluoromethyl)cyclopropyl)sulfonyl)carbamoyl)-2-((7-methoxy-3-(trifluoromethyl)quinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, CD.sub.3OD): ppm 7.98 (d, J=9.04 Hz, 1H) 7.39 (m, 2H) 5.95 (br. s., 1H) 5.61 (br. s., 1H) 4.60 (m, 5H) 4.12 (d, J=8.53 Hz, 1H) 4.00 (m, 3H) 3.51 (m, 2H) 3.43 (s, 3H) 2.64 (m, 2H) 2.00 (m, 2H) 1.73 (br. s., 2H) 1.49 (m, 6H) 1.32 (m, 9H) 1.06 (br. s., 2H) 0.92 (d, J=6.53 Hz, 3H). MS: MS m/z 939.2 (M.sup.++1).

Preparation of Compound 1039 and Compound 1040

(180) ##STR00081##

(181) Compound 1039 and compound 1040 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 1016.

(182) Compound 1039: 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-14a-(((1-(fluoromethyl)cyclopropyl)sulfonyl)carbamoyl)-2-(3-isopropyl-7-methoxyquinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, CD.sub.3OD): ppm 7.83 (d, J=9.04 Hz, 1H) 7.28 (d, J=3.01 Hz, 1H) 7.22 (dd, J=9.29, 2.76 Hz, 1H) 5.92 (br. s., 1H) 5.59 (d, J=5.52 Hz, 1H) 4.65 (m, 3H) 4.24 (d, J=11.04 Hz, 1H) 4.07 (dd, J=11.80, 3.26 Hz, 1H) 3.95 (m, 3H) 3.46 (m, 3H) 3.26 (m, 3H) 2.56 (m, 3H) 1.94 (m, 2H) 1.61 (m, 6H) 1.33 (m, 11H) 1.21 (m, 9H) 1.01 (d, J=6.53 Hz, 3H). .sup.19F NMR (400 MHz, CD.sub.3OD): ppm 85.1 (s, 3F). MS: MS m/z 913.4 (M.sup.++1).
Compound 1040: 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-14a-(((1-(fluoromethyl)cyclopropyl)sulfonyl)carbamoyl)-2-((3-isopropyl-7-methoxyquinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, CD.sub.3OD): ppm 7.84 (d, J=9.04 Hz, 1H) 7.28 (d, J=3.01 Hz, 1H) 7.22 (m, 1H) 5.94 (br. s., 1H) 5.67 (br. s., 1H) 4.62 (m, 3H) 4.44 (d, J=12.05 Hz, 1H) 3.96 (m, 3H) 3.48 (m, 5H) 2.69 (m, 2H) 1.57 (m, 9H) 1.32 (m, 11H) 1.21 (m, 9H) 0.93 (m, 4H). MS: MS m/z 913.4 (M.sup.++1).

Preparation of Compound 1041 and Compound 1042

(183) ##STR00082##

(184) Compound 1041 and compound 1042 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 1016.

(185) Compound 1041: 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-14a-((cyclopropylsulfonyl)carbamoyl)-2-((7-methoxy-3-(trifluoromethyl)quinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, CD.sub.3OD): ppm 8.00 (m, 1H) 7.39 (m, 2H) 5.97 (br. s., 1H) 5.62 (td, J=9.91, 5.77 Hz, 1H) 5.07 (br. s., 1H) 4.64 (m, 1H) 4.12 (d, J=11.04 Hz, 1H) 4.01 (m, 4H) 3.43 (m, 2H) 3.28 (m, 3H) 2.94 (br. s., 1H) 2.71 (m, 2H) 2.47 (m, 2H) 1.93 (m, 2H) 1.78 (dd, J=8.53, 5.52 Hz, 1H) 1.56 (m, 5H) 1.25 (m, 11H) 1.07 (m, 6H). .sup.19F NMR (400 MHz, CD.sub.3OD): ppm 68.72 (s, 3F) 85.26 (s, 3F). MS: MS m/z 907.2 (M.sup.++1).
Compound 1042: 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-14a-((cyclopropylsulfonyl)carbamoyl)-2-((7-methoxy-3-(trifluoromethyl)quinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, CD.sub.3OD): ppm 7.99 (d, J=9.04 Hz, 1H) 7.39 (m, 2H) 5.99 (br. s., 1H) 5.70 (br. s., 1H) 4.71 (t, J=8.28 Hz, 1H) 4.60 (m, 1H) 4.45 (d, J=6.02 Hz, 1H) 4.04 (m, 5H) 3.46 (m, 6H) 2.94 (br. s., 1H) 2.69 (m, 1H) 2.06 (m, 2H) 1.68 (m, 4H) 1.44 (d, J=9.54 Hz, 2H) 1.28 (m, 10H) 1.08 (m, 4H) 0.94 (d, J=7.03 Hz, 3H). MS: MS m/z 907.2 (M.sup.++1).

Preparation of Compound 1043

(186) ##STR00083##

(187) Compound 1043 was prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 1016.

(188) Compound 1043: 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((7-fluoro-4-methoxynaphthalen-1-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, CD.sub.3OD): ppm 8.19 (dd, J=9.29, 5.27 Hz, 1H) 7.76 (m, 1H) 7.55 (m, 2H) 5.84 (br. s., 1H) 5.61 (br. s., 1H) 4.78 (m, 1H) 4.64 (m, 1H) 4.22 (m, 1H) 4.00 (m, 4H) 3.47 (m, 2H) 2.75 (m, 2H) 2.44 (m, 2H) 1.94 (d, J=8.03 Hz, 2H) 1.77 (m, 1H) 1.52 (m, 9H) 1.29 (m, 7H) 1.06 (s, 3H) 0.96 (m, 5H). MS: MS m/z 867.2 (M.sup.+1).

(189) ##STR00084##

Step 1: Preparation of (E)-3-(3-methoxyphenyl)acryloyl azide

(190) To a solution of (E)-3-(3-methoxyphenyl)acrylic acid (15 g, 84 mmol) in benzene (100 ml) was added triethylamine (11.73 ml, 84 mmol) followed by DPPA (23.17 g, 84 mmol) at room temperature. The reaction mass was stirred at the same temperature for 18 h. The solvent was evaporated under reduced pressure and the residue was diluted with water and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to get crude compound. The crude compound was purified by conventional column chromatography (Silica gel, 60-120 mesh) using 10% ethyl acetate in pet ether as mobile phase to get the desire compound as white solid (15 g, 88%). .sup.1H NMR (400 MHz, CDCl.sub.3): ppm 7.75-7.70 (d, J=20 Hz, 1H), 7.36-6.97 (m, 4H), 6.45-6.40 (d, J=20 Hz, 1H), 3.85 (s, 3H).

Step 2: Preparation of 6-methoxyisoquinolin-1(2H)-one

(191) To a solution of (E)-3-(3-methoxyphenyl)acryloylazide (2.0 g, 9.84 mmol) in 1,2-dichlorobenzene (10 ml) was added mercuric acetate (0.031 g, 0.098 mmol). The reaction was heated at 120 C. and stirred for 5 minutes at this temperature and then it was heated to 180 C. for 1 h. The reaction mass was cooled to room temperature and diluted with pet ether. The precipitated solid was filtered washed with pet ether to get crude compound (1.2 g, 69.6%). The crude compound was taken to the next step without further purification. .sup.1H NMR (400 MHz, DMSO-d.sub.6): ppm 11.03 (s, 1H), 8.08-8.06 (d, J=8 Hz, 1H), 7.14-7.03 (m, 3H), 6.48-6.46 (d, J=8 Hz, 1H), 3.87 (s, 3H); MS: MS m/z 176.1 (M.sup.++1).

Step 3: Preparation of 4-bromo-6-methoxyisoquinolin-1(2H)-one

(192) To a solution of 6-methoxyisoquinolin-1(2H)-one (2.5 g, 14.27 mmol) in acetonitrile (10 ml) was added NBS (2.54 g, 14.27 mmol) at room temperature under argon atmosphere. The reaction mass was stirred at the same temperature for 2 hr. The precipitated solid was filtered to get crude compound (2 g, 55.2%). The crude compound was taken to the next step without further purification. .sup.1H NMR (400 MHz, DMSO-d.sub.6): ppm 11.41 (s, 1H), 8.17-8.15 (d, J=8 Hz, 1H), 7.53 (s, 1H), 7.19-7.11 (m, 2H), 3.93 (s, 3H); MS: MS m/z 256.06 (M.sup.++2).

Step 4: Preparation of 4-bromo-1-chloro-6-methoxyisoquinoline

(193) A solution of 4-bromo-6-methoxyisoquinolin-1(2H)-one (1.5 g, 5.90 mmol) in POCl.sub.3 (15 ml) was refluxed for overnight. The solvent was evaporated under reduced pressure and the residue was diluted with cold water. The aqueous solution was basified by solid sodium carbonate and extracted with ethyl acetate. The combine organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography (10% ethyl acetate in pet ether) to get desired compound (1.1 g, 65%) as white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): ppm 8.53 (s, 1H), 8.27-8.24 (d, J=12 Hz, 1H), 7.56-7.53 (d, J=12 Hz, 1H), 7.41 (s, 1H), 4.02 (s, 3H); MS: MS m/z 273.99 (M.sup.++1).

Step 5: Preparation of 1-chloro-6-methoxyisoquinolin-4-ol

(194) To a solution of 4-bromo-1-chloro-6-methoxyisoquinoline (0.25 g, 0.917 mmol) in THF (30 ml) was added n-butyllithium (1.147 ml, 1.835 mmol) at 78 C. under nitrogen. The reaction mixture was stirred for 30 minutes and triisopropyl borate (0.426 ml, 1.835 mmol) was added and stirred for another 30 minutes. To this hydrogen peroxide (0.273 ml, 8.90 mmol) (30% solution 1.5M) was added followed by the addition of sodium hydroxide (0.917 ml, 0.917 mmol). The resulting mixture was stirred for additional 1 h at room temperature. The reaction mixture was cooled to 40 C. and added sodium sulfite solution in water (1.156 g, 9.17 mmol). The resulting slurry was neutralized with 6N HCl solution and extracted with ethyl acetate. The combine organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography (20% ethyl acetate in pet ether) to get desired compound (0.13 g, 67.6%) as solid. MS: MS m/z 210.06 (M.sup.++1).

Step 6: Preparation of 1-chloro-4-ethoxy-6-methoxyisoquinoline

(195) To a solution of 1-chloro-6-methoxyisoquinolin-4-ol (0.05 g, 0.239 mmol) in acetonitrile (5 ml) was added potassium carbonate (0.099 g, 0.716 mmol) followed by iodoethane (0.039 ml, 0.477 mmol) at room temperature. The reaction mass was stirred at the same temperature for 18 h. The solvent was evaporated under reduced pressure and the residue was diluted with water and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to get crude compound. The crude compound was purified by silica gel chromatography (10% ethyl acetate in pet ether) to get desired compound (0.015 g, 25.1%) as solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): ppm 8.14-8.12 (d, J=8 Hz, 1H), 7.90 (s, 1H), 7.46-7.42 (m, 2H), 4.34-4.27 (q, J=8 Hz, 2H), 3.95 (s, 3H), 1.48 (t, J=10 Hz, 3H).

(196) ##STR00085##

Step 1: Preparation of 4-ethoxy-2-nitroaniline

(197) To a solution of 4-amino-3-nitrophenol (5.0 g, 32.4 mmol) in acetonitrile (100 mL) was added K.sub.2CO.sub.3 (13.45 g, 97 mmol) followed by ethyl iodide (13.11 mL, 162 mmol) at room temperature. The reaction mixture was stirred at room temperature for overnight. The reaction mixture was filtered through celite bed and washed with acetonitrile. The filtrate was evaporated under reduced pressure to get crude compound. The crude compound was purified by ISCO using 10-30% ethyl acetate in hexane as mobile phase to get 4-ethoxy-2-nitroaniline (3.0 g, 16.47 mmol, 50.8% yield) as red color solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): ppm 7.35-7.34 (d, J=4 Hz, 1H), 7.23 (s, 2H), 7.16-7.13 (dd, J=9.2 Hz, 3.2 Hz, 1H), 7.00-6.97 (d, J=90.6 Hz, 1H), 3.99-3.94 (q, J=6.8 Hz, 6H), 1.31-1.28 (t, J=6.8 Hz, 3H). MS: MS m/z 181.2 (M.sup.+1).

Step 2: Preparation of 4-ethoxybenzene-1,2-diamine

(198) The same procedure was followed as described for 4-fluoro-5-methoxybenzene-1,2-diamine but 4-ethoxy-2-nitroaniline used as starting materials instead of 4-fluoro-5-methoxy-2-nitroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6): ppm 6.40-6.38 (d, J=8 Hz, 1H), 6.15-6.14 (d, J=3.6 Hz, 1H), 5.97-5.93 (dd, J=11.2 Hz, 3.6 Hz, 1H), 4.45 (bs, 2H), 3.975-3.970 (bs, 2H), 3.84-3.77 (q, J=9.2 Hz, 2H), 1.29-1.21 (t, J=16.4 Hz, 3H).

Step 3: Preparation of 6-ethoxy-3-(trifluoromethyl)quinoxalin-2(1H)-one and 7-ethoxy-3-(trifluoromethyl)quinoxalin-2(1H)-one

(199) The same procedure was followed as described for 7-fluoro-6-methoxy-3-(trifluoromethyl)quinoxalin-2(1H)-one but 4-ethoxybenzene-1,2-diamine was used as starting material instead of 4-fluoro-5-methoxybenzene-1,2-diamine. .sup.1H NMR (400 MHz, DMSO-d6): ppm 12.92 (br, s, 2H), 7.84-7.81 (d, J=12 Hz, 1H), 7.44-7.33 (m, 4H), 7.82 (s, 1H), 3.87 (s, 6H), MS: MS m/z 245.15 (M.sup.++1).

Step 4: Preparation of 2-chloro-6-ethoxy-3-(trifluoromethyl)quinoxaline and 3-chloro-6-ethoxy-2-(trifluoromethyl)quinoxaline

(200) The same procedure was followed as described for 2-chloro-7-fluoro-6-methoxy-3-(trifluoromethyl)quinoxaline but 6-ethoxy-3-(trifluoromethyl)quinoxalin-2(1H)-one and 7-ethoxy-3-(trifluoromethyl)quinoxalin-2(1H)-one was used as starting material instead of 2-chloro-7-fluoro-6-methoxy-3-(trifluoromethyl)quinoxaline and 2-chloro-6-fluoro-7-methoxy-3-(trifluoromethyl)quinoxaline.

(201) 2-chloro-6-ethoxy-3-(trifluoromethyl)quinoxaline: .sup.1H NMR (400 MHz, DMSO-d6): ppm 8.10-8.07 (d, J=12 Hz, 1H), 7.75-7.44 (m, 2H), 3.95 (s, 3H); .sup.19F NMR: 6 ppm 65.36 (1F) MS: MS m/z 263.10 (M.sup.++1).

(202) 3-chloro-6-ethoxy-2-(trifluoromethyl)quinoxaline: .sup.1H NMR (400 MHz, DMSO-d6): ppm 8.11-8.08 (d, J=12 Hz, 1H), 7.78-7.75 (d, J=12 Hz, 1H), 7.68 (s, 1H), 4.00 (s, 3H). .sup.19F NMR: ppm 65.36 (1F) MS: MS m/z 263.09 (M.sup.++1).

(203) ##STR00086##

Step 1: Preparation of 4-isopropoxy-2-nitroaniline

(204) To a solution of 4-amino-3-nitrophenol (5 g, 32.4 mmol) in DMF (30 mL) was added cesium carbonate (21.14 g, 64.9 mmol) and 2-bromopropane (3.05 mL, 32.4 mmol) at room temperature. The reaction mass was heated at 80 C. for 3 h. Solvent was removed under educed pressure and the residue was diluted with ethyl acetate. The organic solution was washed with water, dried over anhydrous sodium sulphate and concentrated to get the crude compound. The crude compound was purified using flash column chromatography and the product was eluted with 30% ethyl acetate in pet-ether to afford 4-isopropoxy-2-nitroaniline (6 g, 26.9 mmol, 83% yield) as a brown crystalline solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): ppm 7.37 (d, J=2.51 Hz, 1H) 7.21 (s, 2H) 7.14 (dd, J=9.29, 2.76 Hz, 1H) 6.99 (d, J=9.04 Hz, 1H) 4.38-4.52 (m, 1H) 1.13-1.31 (m, 6H) MS: MS m/z 197.15 (M.sup.++1).

Step 2: Preparation of 4-isopropoxybenzene-1,2-diamine

(205) The same procedure was followed as described for 4-fluoro-5-methoxybenzene-1,2-diamine but 4-isopropoxy-2-nitroaniline was used as starting materials instead of 4-fluoro-5-methoxy-2-nitroaniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6): ppm 6.39 (d, J=8.31 Hz, 1H) 6.15 (d, J=3.02 Hz, 1H) 5.96 (dd, J=8.31, 2.64 Hz, 1H) 4.36 (bs, 2H) 4.19-4.32 (m, 1H) 3.9 (bs, 2H) 1.17 (d, J=6.04 Hz, 6H) MS: MS m/z 167.1 (M.sup.++1).

Step 3: Preparation of 6-isopropoxy-3-(trifluoromethyl)quinoxalin-2(1H)-one and 7-isopropoxy-3-(trifluoromethyl)quinoxalin-2(1H)-one

(206) The same procedure was followed as described for 7-fluoro-6-methoxy-3-(trifluoromethyl)quinoxalin-2(1H)-one but 4-isopropoxybenzene-1,2-diamine was used as starting material instead of 4-fluoro-5-methoxybenzene-1,2-diamine. .sup.1H NMR (400 MHz, DMSO-d6): ppm 12.98 (s, 1H) 7.40-7.31 (m, 3H) 4.73 (m, 1H) 4.19-4.32 (m, 1H) 1.28 (m, 6H).sup.19F NMR: ppm 67.86 (3F) MS: MS m/z 273.1 (M.sup.++1).

Step 4: Preparation of 2-chloro-7-isopropoxy-3-(trifluoromethyl)quinoxaline

(207) The same procedure was followed as described for 2-chloro-7-fluoro-6-methoxy-3-(trifluoromethyl)quinoxaline but 6-isopropoxy-3-(trifluoromethyl)quinoxalin-2(1H)-one and 7-isopropoxy-3-(trifluoromethyl)quinoxalin-2(1H)-one was used as starting material instead of 2-chloro-7-fluoro-6-methoxy-3-(trifluoromethyl)quinoxaline and 2-chloro-6-fluoro-7-methoxy-3-(trifluoromethyl)quinoxaline. .sup.1H NMR (400 MHz, DMSO-d6): ppm 8.04-8.20 (m, 1H) 7.55-7.75 (m, 2H) 4.92-5.05 (m, 1H) 1.33-1.43 (m, 6H).sup.19F NMR: ppm 66.10 (3F) MS: MS m/z 291.5 (M.sup.++1). Structure was confirmed by single crystal X-ray studies.

(208) ##STR00087##

Step 1: 2,4-dichloro-5-methoxyquinazoline

(209) To the stirred solution of 5-methoxyquinazoline-2,4-diol (1.1 g, 5.72 mmol) in was added POCl.sub.3 (5.34 ml, 57.2 mmol) at room temperature, then the reaction mixture was stirred at 110 C. for overnight. After completion of the reaction, reaction mixture was quenched with ice water (100 mL), extracted with DCM (2150 mL), then the combined organic layer was washed with 10% sodium bicarbonate solution (100 mL, brine solution, dried over sodium sulphate and concentrated to get residue. The crude compound was purified by ISCO (Silica gel) using 7% ethyl acetate in hexane as mobile phase to get 2,4-dichloro-5-methoxyquinazoline (0.8 g, 3.49 mmol, 61.0% yield). MS: MS m/z 229.0 (M.sup.++1), .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 7.86 (t, J=8.28 Hz, 1H) 7.44-7.64 (m, 1H) 7.02 (dd, J=8.13, 0.53 Hz, 1H) 3.84-4.28 (m, 3H).

Step 2: 2-chloro-4,5-dimethoxyquinazoline

(210) To a stirred solution of 2,4-dichloro-5-methoxyquinazoline (250 mg, 1.091 mmol) in MeOH (5 mL) was added SODIUM METHOXIDE (64.9 mg, 1.201 mmol) at room temperature, then the reaction mixture was stirred at room temperature and stirred for 24 hours. After completion of the reaction mixture was concentrated under vacuum to get crude residue, then the residue was quenched with 1.5 N HCl (pH=6-7) and extracted with ethyl acetate (225 mL), then the combined organic layer was washed with brine solution, dried over sodium sulphate and concentrated under vacuum to get crude compound. The crude compound was purified by ISCO (Silica gel) using 5% ethyl acetate in hexane as mobile phase to get 2-chloro-4,5-dimethoxyquinazoline (150 mg, 0.668 mmol, 61.2% yield). MS: MS m/z 225.0 (M.sup.++1), .sup.1H NMR (300 MHz, CHLOROFORM-d) ppm 7.74 (t, J=8.26 Hz, 1H) 7.46 (dd, J=8.36, 0.94 Hz, 1H) 6.94 (dd, J=8.10, 0.59 Hz, 1H) 4.21 (s, 3H) 4.01 (s, 3H).

(211) ##STR00088##

Step 1: Preparation of 4-fluoro-5-methoxy-2-nitroaniline

(212) To an ice cooled 100 ml round bottom flask charged with methanol (30 mL) was added sodium methoxide (1.551 g, 28.7 mmol). After the solution was homogeneous, 4,5-difluoro-2-nitroaniline (2 g, 11.49 mmol) was added portion wise. The solution turns a bright yellow and slowly yellow precipitation was observed. Solvent was removed under reduced pressure and the residue was diluted with water and acidified using 1.5N HCl solution. The aqueous layer was extracted with ethyl acetate twice, the combined organic layer was washed with water, brine solution, dried over anhydrous sodium sulphate and concentrated to dryness to get 4-fluoro-5-methoxy-2-nitroaniline (1.8 g, 9.48 mmol, 82% yield) as pale yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3): ppm 7.76 (d, J=12.55 Hz, 1H) 7.54 (br. s., 2H) 6.65 (s, 1H) 3.86 (s, 3H). .sup.19F NMR: ppm 147.64 (1F); MS: MS m/z 185.2 (M.sup.+1)

Step 2: Preparation of 4-fluoro-5-methoxybenzene-1,2-diamine

(213) To the Suspension of tin(II) chloride di-hydrate (6.55 g, 29.0 mmol) in water (40 mL) was added con. HCl (8 mL) slowly and the resulting solution was stirred for 10 min. 5-fluoro-4-methoxy-2-nitroaniline (1.8 g, 9.67 mmol) was added portion wise to the reaction mass and heated to 70 C. overnight. The reaction was allowed to cool to room temperature and was made alkaline by drop wise addition of 10% NaOH solution (pH=10-11). The aqueous reaction mass was extracted with ethyl acetate. The combined organic layer was washed with water, brine Solution, dried over anhydrous sodium sulphate and concentrated to get crude 4-fluoro-5-methoxybenzene-1,2-diamine (1.2 g, 7.68 mmol, 79% yield) as brown solid. The crude compound was taken to the next step without further purification. .sup.1H NMR (400 MHz, DMSO-d.sub.6): ppm 6.32-6.43 (m, 2H) 4.32 (br. s., 4H) 3.65 (s, 3H); .sup.19F NMR: ppm 149.03 (1F); MS: MS m/z 157.3 (M.sup.++1).

Step 3: Preparation of 7-fluoro-6-methoxy-3-(trifluoromethyl)quinoxalin-2(1H)-one and 6-fluoro-7-methoxy-3-(trifluoromethyl)quinoxalin-2(1H)-one

(214) To a solution of 4-fluoro-5-methoxybenzene-1,2-diamine (13 g, 83 mmol) in ethanol (100 mL) was added ethyl 3,3,3-trifluoro-2-oxopropanoate (13.15 mL, 108 mmol) at room temperature. The reaction mass was heated at reflux for 18 h. The solvent was evaporated under reduced pressure and the residue was washed with diethyl ether to get crude compound 7-fluoro-6-methoxy-3-(trifluoromethyl)quinoxalin-2-ol (15 g, 49.2 mmol, 59.1% yield) as mixture of regioisomer. The crude compound was taken directly to the next step without separation of isomers. MS: MS m/z 263.1 (M.sup.++1).

Step 4: Preparation of 2-chloro-7-fluoro-6-methoxy-3-(trifluoromethyl)quinoxaline and 2-chloro-6-fluoro-7-methoxy-3-(trifluoromethyl)quinoxaline

(215) A solution of 7-fluoro-6-methoxy-3-(trifluoromethyl)quinoxalin-2-ol (12 g, 45.8 mmol) in POCl.sub.3 (100 mL) was heated at reflux for 3 h. Excess POCl.sub.3 was removed under reduced pressure and the residue was diluted with cold water and basified by using 10% NaOH Solution (.sub.pH=10). The aqueous reaction mass was extracted with ethyl acetate. The combined organic layer was washed with water, brine Solution, dried over anhydrous sodium sulphate and concentrated to get crude compound as mixture of regioisomer. The mixture of regioisomer was separated by SFC to get 2-chloro-7-fluoro-6-methoxy-3-(trifluoromethyl)quinoxaline (3.5 g, 12.22 mmol, 26.7% yield) and 2-chloro-6-fluoro-7-methoxy-3-(trifluoromethyl)quinoxaline (5 g, 17.46 mmol, 38.1% yield).

(216) 2-chloro-6-fluoro-7-methoxy-3-(trifluoromethyl)quinoxaline: .sup.1H NMR (400 MHz, CDCl.sub.3): ppm 7.83-7.81 (d, J=10.4 Hz, 1H) 7.46-7.44 (d, J=8 Hz, 1H), 4.09 (s, 3H). .sup.19F NMR: ppm 66.32 (3F), 122.46 (1F). The structure was confirmed by single crystal x-ray studies.
2-chloro-7-fluoro-6-methoxy-3-(trifluoromethyl)quinoxaline: .sup.1H NMR (400 MHz, CDCl.sub.3): ppm 7.73-7.71 (d, J=10.8 Hz, 1H) 7.58-7.56 (d, J=8.4 Hz, 1H), 4.08 (s, 3H). .sup.19F NMR: ppm 66.58 (3F), 119.04 (1F).

Preparation of Compound 1045 and Compound 1047

(217) ##STR00089##

(218) Compound 1045 and compound 1047 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 1010.

(219) Compound 1045: tert-butyl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-((6-fluoro-7-methoxy-3-(trifluoromethyl)quinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 7.77 (d, J=11.04 Hz, 1H) 7.58 (d, J=8.53 Hz, 1H) 6.01 (br. s., 1H) 5.73 (m, J=10.04 Hz, 1H) 5.06 (m, 1H) 4.71 (t, J=8.03 Hz, 1H) 4.44-4.63 (m, 3H) 4.12 (s, 4H) 3.42-3.49 (m, 2H) 2.51-2.72 (m, 3H) 2.38-2.50 (m, 1H) 2.05-2.17 (m, 1H) 1.93-2.05 (m, 1H) 1.69-1.76 (m, 1H) 1.55-1.69 (m, 3H) 1.52 (s, 3H) 1.38-1.49 (m, 3H) 1.24-1.37 (m, 3H) 1.15-1.23 (m, 8H) 0.94 (d, J=7.03 Hz, 6H). MS: MS m/z 885.3 (M.sup.++1).
Compound 1047: tert-butyl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((6-fluoro-7-methoxy-3-(trifluoromethyl)quinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 7.77 (d, J=11.04 Hz, 1H) 7.58 (d, J=8.53 Hz, 1H) 6.01 (br. s., 1H) 5.73 (m, J=10.04 Hz, 1H) 5.06 (m, 1H) 4.71 (t, J=8.03 Hz, 1H) 4.44-4.63 (m, 3H) 4.12 (s, 4H) 3.42-3.49 (m, 2H) 2.51-2.72 (m, 3H) 2.38-2.50 (m, 1H) 2.05-2.17 (m, 1H) 1.93-2.05 (m, 1H) 1.69-1.76 (m, 1H) 1.55-1.69 (m, 3H) 1.52 (s, 3H) 1.38-1.49 (m, 3H) 1.24-1.37 (m, 3H) 1.15-1.23 (m, 8H) 0.94 (d, J=7.03 Hz, 6H). MS: MS m/z 885.4 (M.sup.++1).

Preparation of Compound 1046 and Compound 1048

(220) ##STR00090##

(221) Compound 1046 and Compound 1048 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 1016.

(222) Compound 1046: 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-((6-fluoro-7-methoxy-3-(trifluoromethyl)quinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 7.80 (s, 1H) 7.59 (s, 1H) 6.00 (br. s., 1H) 5.71 (m., 1H) 5.06 (t, 2H) 4.96 (s, 1H) 4.67-4.78 (m, 2H) 4.51-4.62 (m, 2H) 4.46 (d, J=6.02 Hz, 1H) 4.04-4.16 (m, 4H) 3.41-3.49 (m, 2H) 2.68 (t, J=7.28 Hz, 2H) 2.54 (m, 1H) 2.36-2.49 (m, 1H) 2.00 (m, 2H) 1.71 (d, J=8.03 Hz, 1H) 1.61 (m, 1H) 1.52 (s, 4H) 1.39-1.50 (m, 4H) 1.15-1.38 (m, 7H) 0.81-0.98 (m, 6H). MS: MS m/z 939.4 (M.sup.++1).
Compound 1048: 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((6-fluoro-7-methoxy-3-(trifluoromethyl)quinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 7.81 (s, 1H) 7.58 (s, 1H) 5.97 (br. s., 1H) 5.63 (td, J=10.16, 5.77 Hz, 1H) 5.02 (t, J=10.04 Hz, 2H) 4.56-4.71 (m, 2H) 4.12 (d, J=10.54 Hz, 5H) 4.04 (dd, J=12.05, 3.51 Hz, 1H) 3.44 (dd, J=7.53, 2.51 Hz, 2H) 2.63-2.79 (m, 2H) 2.33-2.58 (m, 2H) 1.86-2.02 (m, 2H) 1.77 (s, 1H) 1.64-1.71 (m, 1H) 1.36-1.62 (m, 8H) 1.14-1.34 (m, 8H) 1.00 (d, J=6.53 Hz, 3H) 0.90 (s, 3H). MS: MS m/z 839.4 (M.sup.++1).

Preparation of Compound 1049 and Compound 1050

(223) ##STR00091##

(224) Compound 1049 and Compound 1050 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 1010.

(225) Compound 1049: tert-butyl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-((7-ethoxy-3-(trifluoromethyl)quinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 7.97 (d, J=9.04 Hz, 1H) 7.29-7.43 (m, 2H) 6.03 (br. s., 1H) 5.73 (m, J=9.54 Hz, 1H) 5.07 (m, 1H) 4.71 (t, J=8.28 Hz, 2H) 4.47-4.63 (m, 3H) 4.28 (qd, J=7.03, 1.51 Hz, 3H) 4.06-4.18 (m, 1H) 3.47 (br. s., 3H) 2.50-2.71 (m, 4H) 2.38-2.49 (m, 1H) 2.06-2.17 (m, 1H) 1.92-2.05 (m, 1H) 1.69-1.76 (m, 1H) 1.56-1.68 (m, 1H) 1.37-1.55 (m, 9H) 1.29 (s, 3H) 1.10-1.23 (m, 9H) 0.83-0.98 (m, 5H). MS: MS m/z 880.4 (M.sup.++1).
Compound 1050: tert-butyl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((7-ethoxy-3-(trifluoromethyl)quinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 7.97 (d, J=9.04 Hz, 1H) 7.29-7.43 (m, 2H) 6.03 (br. s., 1H) 5.73 (m, J=9.54 Hz, 1H) 5.07 (m, 1H) 4.71 (t, J=8.28 Hz, 2H) 4.47-4.63 (m, 3H) 4.28 (qd, J=7.03, 1.51 Hz, 3H) 4.06-4.18 (m, 1H) 3.47 (br. s., 3H) 2.50-2.71 (m, 4H) 2.38-2.49 (m, 1H) 2.06-2.17 (m, 1H) 1.92-2.05 (m, 1H) 1.69-1.76 (m, 1H) 1.56-1.68 (m, 1H) 1.37-1.55 (m, 9H) 1.29 (s, 3H) 1.10-1.23 (m, 9H) 0.83-0.98 (m, 5H). MS: MS m/z 880.5 (M.sup.++1).

Preparation of Compound 1051 and Compound 1052

(226) ##STR00092##

(227) Compound 1051 and Compound 1052 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 1016 using 3,3-difluoro-2-methylbutan-2-ylpyridin-2-yl carbonate instead of pyridin-2-yl (1,1,1-trifluoro-2-methylpropan-2-yl) carbonate.

(228) Compound 1051: 3,3-difluoro-2-methylbutan-2-yl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-((7-ethoxy-3-(trifluoromethyl)quinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 7.92-8.04 (m, 1H) 7.38 (dq, J=5.02, 2.51 Hz, 2H) 7.02 (d, J=8.03 Hz, 1H) 5.98 (br. s., 1H) 5.63 (td, J=10.29, 5.52 Hz, 1H) 5.02 (t, J=9.79 Hz, 1H) 4.66 (dd, J=10.29, 7.28 Hz, 1H) 4.29 (m, J=10.35, 6.75, 6.75, 3.26 Hz, 2H) 4.15 (d, J=3.01 Hz, 1H) 4.05 (dd, J=11.80, 3.26 Hz, 1H) 3.39-3.48 (m, 2H) 2.71 (d, J=8.53 Hz, 2H) 2.37-2.55 (m, 2H) 1.94 (d, J=12.55 Hz, 2H) 1.77 (m, J=8.03, 5.52 Hz, 1H) 1.67 (d, J=10.54 Hz, 1H) 1.37-1.62 (m, 13H) 1.19-1.35 (m, 3H) 1.10 (d, J=9.54 Hz, 5H) 1.00 (d, J=6.53 Hz, 3H) 0.84-0.94 (m, 2H) MS: MS m/z 931.4 (M.sup.++1).
Compound 1052: 3,3-difluoro-2-methylbutan-2-yl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((7-ethoxy-3-(trifluoromethyl)quinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 7.91-8.05 (m, 1H) 7.38 (dq, J=5.02, 2.51 Hz, 2H) 7.02 (d, J=8.03 Hz, 1H) 5.98 (br. s., 1H) 5.63 (td, J=10.29, 5.52 Hz, 1H) 5.02 (t, J=9.79 Hz, 1H) 4.66 (dd, J=10.29, 7.28 Hz, 1H) 4.22-4.35 (m, 2H) 4.15 (d, J=3.01 Hz, 1H) 4.05 (dd, J=11.80, 3.26 Hz, 1H) 3.40-3.48 (m, 2H) 2.71 (d, J=8.53 Hz, 2H) 2.36-2.55 (m, 2H) 1.94 (d, J=12.55 Hz, 2H) 1.77 (m, J=8.03, 5.52 Hz, 1H) 1.67 (d, J=10.54 Hz, 1H) 1.40-1.62 (m, 13H) 1.18-1.34 (m, 3H) 1.10 (d, J=9.54 Hz, 5H) 1.00 (d, J=6.53 Hz, 3H) 0.83-0.94 (m, 2H). MS: MS m/z 931.4 (M.sup.++1).

Preparation of Compound 1053 and Compound 1054

(229) ##STR00093##

(230) Compound 1053 and Compound 1054 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 1016.

(231) Compound 1053: 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-((7-ethoxy-3-(trifluoromethyl)quinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 7.95-8.02 (m, 1H) 7.34-7.43 (m, 2H) 7.20-7.28 (m, 1H) 5.99 (d, J=12.55 Hz, 1H) 5.73 (d, J=8.53 Hz, 1H) 5.63 (td, J=10.16, 5.77 Hz, 1H) 4.98-5.09 (m, 1H) 4.70-4.77 (m, 1H) 4.66 (dd, J=10.04, 7.03 Hz, 1H) 4.58 (d, J=12.05 Hz, 1H) 4.46 (d, J=6.53 Hz, 1H) 4.21-4.36 (m, 2H) 4.12 (br. s., 2H) 3.42-3.49 (m, 2H) 2.70 (d, J=9.54 Hz, 2H) 2.38-2.63 (m, 3H) 2.07-2.17 (m, 1H) 1.85-2.05 (m, 2H) 1.77 (dd, J=8.28, 5.77 Hz, 1H) 1.64-1.73 (m, 2H) 1.59 (dd, J=9.54, 5.52 Hz, 2H) 1.39-1.55 (m, 7H) 1.15-1.38 (m, 7H) 0.84-1.05 (m, 5H). MS: MS m/z 835.3 (M.sup.++41).
Compound 1054: 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((7-ethoxy-3-(trifluoromethyl)quinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 7.94-8.01 (m, 1H) 7.33-7.44 (m, 2H) 5.98 (br. s., 1H) 5.63 (td, J=10.42, 5.27 Hz, 1H) 5.02 (t, J=10.29 Hz, 1H) 4.66 (dd, J=10.04, 7.03 Hz, 1H) 4.22-4.36 (m, 2H) 4.13 (d, J=11.04 Hz, 2H) 3.99-4.08 (m, 2H) 3.44 (dd, J=7.03, 2.51 Hz, 2H) 2.71 (s, 2H) 2.49 (s, 3H) 1.84-2.02 (m, 2H) 1.77 (dd, J=8.03, 5.52 Hz, 1H) 1.64-1.72 (m, 2H) 1.59 (dd, J=9.29, 5.77 Hz, 2H) 1.35-1.55 (m, 9H) 1.26 (br. s., 2H) 1.20 (d, J=7.03 Hz, 5H) 1.00 (d, J=6.53 Hz, 3H) 0.85-0.94 (m, 2H). MS: MS m/z 835.4 (M.sup.++1).

Preparation of Compound 1055 and Compound 1056

(232) ##STR00094##
Compound 1055 and Compound 1056 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 1016 using 3,3-difluoro-2-methylbutan-2-ylpyridin-2-yl carbonate instead of pyridin-2-yl (1,1,1-trifluoro-2-methylpropan-2-yl) carbonate.
Compound 1055: 3,3-difluoro-2-methylbutan-2-yl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-((7-isopropoxy-3-(trifluoromethyl)quinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 7.99 (s, 1H) 7.27-7.44 (m, 2H) 6.02 (br. s., 1H) 5.64-5.79 (m, 1H) 5.06 (t, J=9.54 Hz, 1H) 4.90-4.97 (m, 1H) 4.67-4.77 (m, 1H) 4.56 (d, J=13.55 Hz, 1H) 4.48 (d, J=6.02 Hz, 1H) 4.06-4.16 (m, 1H) 3.47 (d, J=6.02 Hz, 2H) 2.66 (d, J=7.03 Hz, 1H) 2.55 (dd, J=9.04, 4.02 Hz, 3H) 2.07-2.19 (m, 1H) 2.01 (s, 1H) 1.72 (dd, J=8.03, 5.52 Hz, 1H) 1.38-1.69 (m, 15H) 1.15-1.37 (m, 9H) 0.83-0.98 (m, 6H). MS: MS m/z 945.4 (M.sup.++1).
Compound 1056: 3,3-difluoro-2-methylbutan-2-yl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((7-isopropoxy-3-(trifluoromethyl)quinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 7.99 (s, 1H) 7.30-7.42 (m, 2H) 5.99 (br. s., 1H) 5.63 (td, J=10.29, 6.02 Hz, 1H) 5.02 (t, J=10.04 Hz, 1H) 4.89-4.97 (m, 1H) 4.55-4.69 (m, 2H) 4.16 (d, J=11.04 Hz, 1H) 4.06 (dd, J=11.80, 3.26 Hz, 1H) 3.44 (dd, J=4.77, 2.76 Hz, 2H) 3.27 (s, 2H) 2.71 (d, J=9.04 Hz, 2H) 2.48 (d, J=13.55 Hz, 2H) 1.94 (d, J=11.04 Hz, 2H) 1.77 (dd, J=8.28, 5.77 Hz, 1H) 1.67 (d, J=10.04 Hz, 1H) 1.40-1.62 (m, 14H) 1.27 (d, J=11.55 Hz, 3H) 0.96-1.16 (m, 9H) 0.83-0.95 (m, 3H). MS: MS m/z 945.4 (M.sup.++1).

Preparation of Compound 1057 and Compound 1058

(233) ##STR00095##
Compound 1057 and Compound 1058 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 1016.
Compound 1057: 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-((7-isopropoxy-3-(trifluoromethyl)quinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 7.99 (s, 1H) 7.30-7.42 (m, 2H) 6.01 (br. s., 1H) 5.66-5.81 (m, 1H) 5.00-5.11 (m, 1H) 4.90-4.98 (m, 1H) 4.66-4.78 (m, 1H) 4.57 (d, J=11.55 Hz, 1H) 4.47 (d, J=6.53 Hz, 1H) 4.09 (dd, J=11.80, 3.26 Hz, 1H) 3.40-3.49 (m, 2H) 2.69 (dd, J=13.55, 7.53 Hz, 3H) 2.49-2.63 (m, 3H) 2.44 (d, J=8.03 Hz, 3H) 2.11 (br. s., 1H) 2.01 (br. s., 2H) 1.69-1.76 (m, 1H) 1.55-1.68 (m, 2H) 1.39-1.54 (m, 9H) 1.13-1.38 (m, 7H) 0.79-1.02 (m, 7H). MS: MS m/z 949.5 (M.sup.++1).
Compound 1058: 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((7-isopropoxy-3-(trifluoromethyl)quinoxalin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 7.99 (s, 1H) 7.30-7.41 (m, 2H) 5.98 (br. s., 1H) 5.63 (td, J=10.16, 5.27 Hz, 1H) 5.02 (t, J=10.29 Hz, 1H) 4.90-4.97 (m, 1H) 4.53-4.71 (m, 1H) 4.15 (d, J=10.54 Hz, 1H) 4.05 (d, J=8.53 Hz, 1H) 3.44 (dd, J=5.77, 2.76 Hz, 2H) 2.70 (d, J=8.53 Hz, 3H) 2.48 (d, J=14.06 Hz, 3H) 1.85-2.05 (m, 3H) 1.77 (dd, J=8.28, 5.77 Hz, 1H) 1.63-1.72 (m, 1H) 1.59 (dd, J=9.29, 5.77 Hz, 2H) 1.36-1.55 (m, 11H) 1.11-1.34 (m, 7H) 1.00 (d, J=6.53 Hz, 4H) 0.83-0.95 (m, 3H). MS: MS m/z 949.5 (M.sup.++1).

Preparation of Compound 1059 and 1060

(234) ##STR00096##
Compound 1059 and compound 1060 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 1016.
Compound 1059: 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-((4,5-dimethoxyquinazolin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 7.68 (t, J=8.28 Hz, 1H) 7.13-7.27 (m, 1H) 6.90 (d, J=7.78 Hz, 1H) 5.76 (br. s., 1H) 5.60 (td, J=10.35, 5.65 Hz, 1H) 5.00 (t, J=10.16 Hz, 1H) 4.73-4.80 (m, 1H) 4.50-4.68 (m, 1H) 4.08-4.25 (m, 4H) 3.96-4.08 (m, 1H) 3.83 (s, 3H) 3.37-3.50 (m, 2H) 3.21-3.29 (m, 3H) 2.57-2.72 (m, 2H) 2.28-2.47 (m, 2H) 1.83-2.02 (m, 2H) 1.75 (dd, J=8.41, 5.65 Hz, 1H) 1.59-1.69 (m, 1H) 1.39-1.55 (m, 9H) 1.20-1.34 (m, 6H) 1.05-1.15 (m, 3H) 0.90-1.00 (m, 3H) 0.81 (br. s., 2H). MS: MS m/z 883.4 (M.sup.++1)
Compound 1060: 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((4,5-dimethoxyquinazolin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 7.69 (t, J=8.28 Hz, 1H) 7.21 (d, J=8.03 Hz, 1H) 6.90 (d, J=8.03 Hz, 1H) 5.64-5.83 (m, 2H) 5.03 (br. s., 1H) 4.66 (t, J=8.66 Hz, 1H) 4.47-4.59 (m, 3H) 4.16 (s, 3H) 4.06 (d, J=8.78 Hz, 1H) 3.95 (s, 3H) 3.38-3.53 (m, 3H) 2.53-2.68 (m, 4H) 2.44 (br. s., 3H) 2.05-2.17 (m, 2H) 1.98 (s, 1H) 1.36-1.72 (m, 14H) 1.15-1.33 (m, 6H) 0.80-0.97 (m, 5H). MS: MS m/z 883.3 (M.sup.++1).

Preparation of Compound 1061

(235) ##STR00097##

(236) Compound 1061 was prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 1010.

(237) Compound 1061: tert-butyl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((4,5-dimethoxyquinazolin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 7.69 (t, J=8.28 Hz, 1H) 7.21 (d, J=8.53 Hz, 1H) 6.90 (d, J=8.03 Hz, 1H) 5.80 (br. s., 1H) 5.62 (td, J=10.29, 5.52 Hz, 1H) 4.91-5.10 (m, 2H) 4.71-4.81 (m, 2H) 4.52-4.66 (m, 3H) 4.14-4.29 (m, 3H) 4.06 (dd, J=11.80, 3.26 Hz, 1H) 3.91-4.01 (m, 3H) 3.37-3.52 (m, 2H) 3.24-3.30 (m, 3H) 2.63-2.78 (m, 2H) 2.33-2.51 (m, 2H) 1.88-2.05 (m, 10H) 1.77 (dd, J=8.28, 5.77 Hz, 1H) 1.61-1.69 (m, 1H) 1.41-1.55 (m, 6H) 1.04-1.38 (m, 10H) 0.93-1.04 (m, 3H) 0.80-0.92 (m, 3H), MS: MS m/z 829.2 (M.sup.++1).

Preparation of Compound 1062

(238) ##STR00098##

(239) Compound 1062 was prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 1016 using 3,3-difluoro-2-methylbutan-2-ylpyridin-2-yl carbonate instead of pyridin-2-yl (1,1,1-trifluoro-2-methylpropan-2-yl) carbonate.

(240) Compound 1062: 3,3-difluoro-2-methylbutan-2-yl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((4,5-dimethoxyquinazolin-2-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 7.71 (t, J=8.28 Hz, 1H) 7.22 (d, J=7.53 Hz, 1H) 6.94 (s, 1H) 5.79 (br. s., 1H) 5.62 (s, 1H) 4.99 (s, 1H) 4.81 (d, J=13.05 Hz, 2H) 4.51-4.70 (m, 1H) 4.14-4.32 (m, 4H) 4.06 (dd, J=12.05, 3.51 Hz, 1H) 3.98 (s, 3H) 3.38-3.50 (m, 2H) 3.28 (s, 4H) 2.68 (dd, J=14.31, 7.28 Hz, 2H) 2.31-2.53 (m, 2H) 1.85-2.05 (m, 2H) 1.77 (dd, J=8.28, 5.77 Hz, 1H) 1.39-1.64 (m, 14H) 1.09-1.34 (m, 6H) 0.92-1.08 (m, 6H) 0.89 (br. s., 2H). MS: MS m/z 880.3 (M.sup.++1).

Preparation of Compound 1063 and 1064

(241) ##STR00099##
Compound 1063 and Compound 1064 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 1010.
Compound 1063: tert-butyl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-((4-ethoxy-6-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 8.09 (br. s., 1H) 7.39-7.57 (m, 2H) 7.05-7.23 (m, 1H) 5.66-5.92 (m, 2H) 4.98-5.10 (m, 1H) 4.54-4.73 (m, 2H) 4.36-4.50 (m, 1H) 4.24 (q, J=6.86 Hz, 2H) 4.01-4.15 (m, 1H) 3.96 (s, 3H) 3.38-3.56 (m, 4H) 2.53-2.77 (m, 2H) 2.28-2.51 (m, 2H) 2.07-2.23 (m, 1H) 1.89-2.03 (m, 1H) 1.72 (br. s., 1H) 1.39-1.66 (m, 9H) 1.03-1.35 (m, 9H) 0.82-1.00 (m, 4H). MS: MS m/z 842.6 (M.sup.++1).
Compound 1064: tert-butyl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((4-ethoxy-6-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. MS: MS m/z 842.6 (M.sup.++1).

Preparation of Compound 1065 and 1066

(242) ##STR00100##

(243) Compound 1065 and Compound 1066 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 1016.

(244) Compound 1065: 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-((4-ethoxy-6-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. MS: MS m/z 896.5 (M.sup.++1).
Compound 1066: 1,1,1-trifluoro-2-methylpropan-2-yl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((4-ethoxy-6-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 8.08 (d, J=9.54 Hz, 1H) 7.53 (s, 1H) 7.45 (d, J=2.51 Hz, 1H) 7.15 (dd, J=9.29, 2.76 Hz, 1H) 5.80 (br. s., 1H) 5.55-5.70 (m, 1H) 4.94-5.08 (m, 1H) 4.72-4.79 (m, 1H) 4.53-4.69 (m, 2H) 4.16-4.33 (m, 3H) 3.96 (s, 4H) 3.46 (dd, J=5.27, 2.76 Hz, 2H) 2.63-2.82 (m, 2H) 2.25-2.52 (m, 3H) 1.87-2.10 (m, 2H) 1.73-1.82 (m, 1H) 1.62-1.71 (m, 1H) 1.16-1.61 (m, 14H) 0.96-1.09 (m, 4H) 0.90 (s, 2H). MS: MS m/z 896.5 (M.sup.++1).

Preparation of Compound 1067 and 1068

(245) ##STR00101##
Compound 1067 and Compound 1068 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 1016 using 3,3-difluoro-2-methylbutan-2-ylpyridin-2-yl carbonate instead of pyridin-2-yl (1,1,1-trifluoro-2-methylpropan-2-yl) carbonate.
Compound 1067: 3,3-difluoro-2-methylbutan-2-yl ((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-((4-ethoxy-6-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. .sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 8.10 (d, J=9.04 Hz, 1H) 7.52 (s, 1H) 7.45 (d, J=2.51 Hz, 1H) 7.15 (dd, J=9.04, 2.51 Hz, 1H) 5.82 (br. s., 2H) 4.99-5.11 (m, 1H) 4.70 (br. s., 1H) 4.58 (s, 1H) 4.45 (d, J=11.04 Hz, 1H) 4.24 (q, J=7.03 Hz, 2H) 4.05 (br. s., 1H) 3.96 (s, 2H) 3.45-3.56 (m, 2H) 2.70 (br. s., 2H) 2.43 (br. s., 2H) 1.83-2.25 (m, 3H) 1.72 (br. s., 1H) 1.39-1.67 (m, 9H) 1.14-1.36 (m, 3H) 0.80-1.01 (m, 3H). MS: MS m/z 892.4 (M.sup.++1).
Compound 1068: 3,3-difluoro-2-methylbutan-2-yl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((4-ethoxy-6-methoxyisoquinolin-1-yl)oxy)-7-(methoxymethyl)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate. MS: MS m/z 892.3 (M.sup.++1).

Biological Studies

(246) HCV NS3/4A protease complex enzyme assays and cell-based HCV replicon assays were utilized in the present disclosure, and were prepared, conducted and validated as follows:

Generation of Recombinant HCV NS3/4A Protease Complex

(247) HCV NS3 protease complexes, derived from the BMS strain, H77 strain or J4L6S strain, were generated, as described below. These purified recombinant proteins were generated for use in a homogeneous assay (see below) to provide an indication of how effective compounds of the present disclosure would be in inhibiting HCV NS3 proteolytic activity.

(248) Serum from an HCV-infected patient was obtained from Dr. T. Wright, San Francisco Hospital. An engineered full-length cDNA (compliment deoxyribonucleic acid) template of the HCV genome (BMS strain) was constructed from DNA fragments obtained by reverse transcription-PCR (RT-PCR) of serum RNA (ribonucleic acid) and using primers selected on the basis of homology between other genotype 1a strains. From the determination of the entire genome sequence, a genotype 1a was assigned to the HCV isolate according to the classification of Simmonds et al. (See P Simmonds, K A Rose, S Graham, S W Chan, F McOmish, B C Dow, E A Follett, P L Yap and H Marsden, J. Clin. Microbiol., 31(6), 1493-1503 (1993)). The amino acid sequence of the nonstructural region, NS2-5B, was shown to be >97% identical to HCV genotype 1a (H77) and 87% identical to genotype 1b (J4L6S). The infectious clones, H77 (1a genotype) and J4L6S (1b genotype) were obtained from R. Purcell (NIH) and the sequences are published in Genbank (AAB67036, see Yanagi, M., Purcell, R. H., Emerson, S. U. and Bukh, J. Proc. Natl. Acad. Sci. U.S.A. 94(16), 8738-8743 (1997); AF054247, see Yanagi, M., St Claire, M., Shapiro, M., Emerson, S. U., Purcell, R. H. and Bukh, J., Virology 244 (1), 161-172. (1998)).

(249) The H77 and J4L6S strains were used for production of recombinant NS3/4A protease complexes. DNA encoding the recombinant HCV NS3/4A protease complex (amino acids 1027 to 1711) for these strains was manipulated as described by P. Gallinari et al. (see Gallinari P, Paolini C, Brennan D, Nardi C, Steinkuhler C, De Francesco R. Biochemistry. 38(17):5620-32, (1999)). Briefly, a three-lysine solubilizing tail was added at the 3-end of the NS4A coding region. The cysteine in the P1 position of the NS4A-NS4B cleavage site (amino acid 1711) was changed to a glycine to avoid the proteolytic cleavage of the lysine tag. Furthermore, a cysteine to serine mutation was introduced by PCR at amino acid position 1454 to prevent the autolytic cleavage in the NS3 helicase domain. The variant DNA fragment was cloned in the pET21b bacterial expression vector (Novagen) and the NS3/4A complex was expressed in Escherichia coli strain BL21 (DE3) (Invitrogen) following the protocol described by P. Gallinari et al. (see Gallinari P, Brennan D, Nardi C, Brunetti M, Tomei L, Steinkuhler C, De Francesco R., J Virol. 72(8):6758-69 (1998)) with modifications. Briefly, the NS3/4A protease complex expression was induced with 0.5 millimolar (mM) Isopropyl -D-1-thiogalactopyranoside (IPTG) for 22 hours (h) at 20 C. A typical fermentation (1 Liter (L)) yielded approximately 10 grams (g) of wet cell paste. The cells were resuspended in lysis buffer (10 mL/g) consisting of 25 mM N-(2-Hydroxyethyl)Piperazine-N-(2-Ethane Sulfonic acid) (HEPES), pH 7.5, 20% glycerol, 500 mM Sodium Chloride (NaCl), 0.5% Triton X-100, 1 microgram/milliliter (g/mL) lysozyme, 5 mM Magnesium Chloride (MgCl.sub.2), 1 g/ml DnaseI, 5 mM -Mercaptoethanol (ME), Protease inhibitor-Ethylenediamine Tetraacetic acid (EDTA) free (Roche), homogenized and incubated for 20 minutes (min) at 4 C. The homogenate was sonicated and clarified by ultra-centrifugation at 235000 g for 1 hour (h) at 4 C. Imidazole was added to the supernatant to a final concentration of 15 mM and the pH adjusted to 8.0. The crude protein extract was loaded on a Nickel-Nitrilotriacetic acid (Ni-NTA) column pre-equilibrated with buffer B (25 mM HEPES, pH 8.0, 20% glycerol, 500 mM NaCl, 0.5% Triton X-100, 15 mM imidazole, 5 mM ME). The sample was loaded at a flow rate of 1 mL/min. The column was washed with 15 column volumes of buffer C (same as buffer B except with 0.2% Triton X-100). The protein was eluted with 5 column volumes of buffer D (same as buffer C except with 200 mM Imidazole).

(250) NS3/4A protease complex-containing fractions were pooled and loaded on a desalting column Superdex-S200 pre-equilibrated with buffer D (25 mM HEPES, pH 7.5, 20% glycerol, 300 mM NaCl, 0.2% Triton X-100, 10 mM ME). Sample was loaded at a flow rate of 1 mL/min. NS3/4A protease complex-containing fractions were pooled and concentrated to approximately 0.5 mg/ml. The purity of the NS3/4A protease complexes, derived from the BMS, H77 and J4L6S strains, were judged to be greater than 90% by SDS-PAGE and mass spectrometry analyses. The enzyme was stored at 80 C., thawed on ice and diluted prior to use in assay buffer.

FRET Peptide Assay to Monitor HCV NS3/4A Proteolytic Activity

(251) The purpose of this in vitro assay was to measure the inhibition of HCV NS3 protease complexes, derived from the BMS strain, H77 strain or J4L6S strain, as described above, by compounds of the present disclosure. This assay provides an indication of how effective compounds of the present disclosure would be in inhibiting HCV NS3 proteolytic activity.

(252) In order to monitor HCV NS3/4A protease activity, an NS3/4A peptide substrate was used. The substrate was RET S1 (Resonance Energy Transfer Depsipeptide Substrate; AnaSpec, Inc. cat #22991)(FRET peptide), described by Taliani et al. in Anal. Biochem. 240(2):60-67 (1996). The sequence of this peptide is loosely based on the NS4A/NS4B natural cleavage site for the HCV NS3 protease except there is an ester linkage rather than an amide bond at the cleavage site. The peptide also contains a fluorescence donor, EDANS, near one end of the peptide and an acceptor, DABCYL, near the other end. The fluorescence of the peptide is quenched by intermolecular resonance energy transfer (RET) between the donor and the acceptor, but as the NS3 protease cleaves the peptide the products are released from RET quenching and the fluorescence of the donor becomes apparent.

(253) The peptide substrate was incubated with one of the three recombinant NS3/4A protease complexes, in the absence or presence of a compound of the present disclosure. The inhibitory effects of a compound were determined by monitoring the formation of fluorescent reaction product in real time using a Cytofluor Series 4000.

(254) The reagents were as follow: HEPES and Glycerol (Ultrapure) were obtained from GIBCO-BRL. Dimethyl Sulfoxide (DMSO) was obtained from Sigma. -Mercaptoethanol was obtained from Bio Rad.

(255) Assay buffer: 50 mM HEPES, pH 7.5; 0.15 M NaCl; 0.1% Triton; 15% Glycerol; 10 mM ME. Substrate: 2 M final concentration (from a 2 mM stock solution in DMSO stored at 20 C.). HCV NS3/4A protease type 1a (1b), 2-3 nM final concentration (from a 5 M stock solution in 25 mM HEPES, pH 7.5, 20% glycerol, 300 mM NaCl, 0.2% Triton-X100, 10 mM ME). For compounds with potencies approaching the assay limit, the assay was made more sensitive by adding 50 g/ml Bovine Serum Albumin (Sigma) to the assay buffer and reducing the end protease concentration to 300 pM.

(256) The assay was performed in a 96-well polystyrene black plate from Falcon. Each well contained 25 l NS3/4A protease complex in assay buffer, 50 l of a compound of the present disclosure in 10% DMSO/assay buffer and 25 l substrate in assay buffer. A control (no compound) was also prepared on the same assay plate. The enzyme complex was mixed with compound or control solution for 1 min before initiating the enzymatic reaction by the addition of substrate. The assay plate was read immediately using the Cytofluor Series 4000 (Perspective Biosystems). The instrument was set to read an emission of 340 nm and excitation of 490 nm at 25 C. Reactions were generally followed for approximately 15 min.

(257) The percent inhibition was calculated with the following equation:
100[(F.sub.inh/F.sub.con)100]
where F is the change in fluorescence over the linear range of the curve. A non-linear curve fit was applied to the inhibition-concentration data, and the 50% effective concentration (IC.sub.50) was calculated by the use of Excel XLfit software using the equation, y=A+((BA)/(1+((C/x)^D))).

(258) Compounds of the present disclosure, which were tested against more than one type of NS3/4A complex, were found to have similar inhibitory properties though the compounds uniformly demonstrated greater potency against the 1b strains as compared to the 1a strains.

Generation of HCV Replicon

(259) An HCV replicon whole cell system was established as described by Lohmann V, Korner F, Koch J, Herian U, Theilmann L, Bartenschlager R., Science 285(5424):110-3 (1999) and modified to introduce a luciferase reporter, as first described by Krieger et al (Krieger N, Lohmann V, and Bartenschlager R, J. Virol. 75(10):4614-4624 (2001)). CDNA encoding a humanized form of the Renilla luciferase gene and a linker sequence fused directly to the 3-end of the luciferase gene were introduced into the replicon construct using an Asc1 restriction site located in core, directly upstream of the neomycin marker gene. The adaptive mutation at position 1179 (serine to isoleucine) was also introduced (Blight K J, Kolykhalov, A A, Rice, C M, Science 290(5498):1972-1974). A stable cell line constitutively expressing this HCV replicon construct was generated by first linearizing plasmid DNAs with ScaI. RNA transcripts were synthesized in vitro using the T7 MegaScript transcription kit (Ambion, Austin, Tex.) according to manufacturer's directions. In vitro transcripts of the cDNA were transfected into the human hepatoma cell line, HUH-7. Selection for cells constitutively expressing the HCV replicon was achieved in the presence of the selectable marker, neomycin (G418). Resulting cell lines were characterized for positive and negative strand RNA production and protein production over time.

(260) A stable HCV replicon luciferase reporter cell line representing the genotype 1a H77 strain (Yanagi M, Purcell R H, Emerson S U, et al. Transcripts from a single full-length cDNA clone of hepatitis C virus are infectious when directly transfected into the liver of a chimpanzee. Proc Natl Acad Sci USA 1997; 94(16):8738-8743) was generated as described previously for the genotype 1b (Con1) replicon luciferase cell line. The replicon construct was modified by introducing mutations were introduced into the genes encoding the NS3 helicase domain (proline replaced by leucine at position 1496) and NS5A (serine to isoleucine at position 2204) to improve replication in cell culture.

HCV Replicon Luciferase Reporter Assay

(261) HCV replicon luciferase assays were developed to monitor the inhibitory effects of compounds described in the disclosure on HCV genotypes 1a and 1b viral replication. HUH-7 cells, constitutively expressing the HCV replicon, were grown in Dulbecco's Modified Eagle Media (DMEM) (Gibco-BRL) containing 10% Fetal calf serum (FCS) (Sigma) and 1 mg/mL G418 (Gibco-BRL). Compounds were serially diluted 3 folds in DMSO for a twenty-point titration and subsequently transferred to sterile 384-well tissue-culture treated plates (Corning cat #3571). The plates were then seeded with 50 L of cells at a density of 3.010.sup.3 cells/well in DMEM containing 4% FCS (final DMSO concentration at 0.5%). After 3 days incubation at 37 C., cells were analyzed for Renilla Luciferase activity using the EnduRen as substrate (Promega cat #E6485). The EnduRen substrate was diluted in DMEM and then added to the plates to a final concentration of 7.5 M. The plates were incubated for 2 hrs at 37 C. and then read immediately for 30 seconds with Viewlux Imager (PerkinElmer) using a luminescence program. To assess cytotoxicity of compounds, CC.sub.50 values were generated by multiplexing the EnduRen-containing plates with Cell Titer-Blue (Promega, cat # G8082). Cell-Titer Blue (3 L) was added to each well and incubated for 8 hrs at 37 C. The fluorescence signal from each well was read, with an excitation wavelength at 525/10 nm and an emission wavelength of 598/10 nm, using the Viewlux Imager.

(262) The EC.sub.50 values for compounds were calculated by using a four-parameter logistic equation:
y=A+((BA)/(1+((C/x)^D))),
where A and B denotes minimal and maximal % inhibition, respectively, C is the EC.sub.50, D is the hill slope and x represents compound concentration.

(263) Table 2 shows the EC50 values of representative compounds of the present disclosure. Ranges are as follows: A=0.10 nM-0.50 nM; B=0.51 nM-1.00 nM; C=1.01 nM-5.00 nM; D=5.01 nM-35.00 nM; E=35.01 nM-620 nM.

(264) TABLE-US-00002 TABLE 2 LE_1a LE_1a LE_1b LE_1b Compound (EC50, (EC50, (EC50, (EC50, Number nM) range) nM) range) 1001 C B 1002 B A 1003 B A 1004 C C 1005 C A 1006 D C 1007 C B 1008 C C 1009 C C 1010 B A 1011 C C 1012 B A 1013 C C 1014 C B 1015 C C 1016 0.84 B 0.26 A 1017 C B 1018 C C 1019 C B 1020 C B 1021 C A 1022 C C 1023 C A 1024 E D 1025 7.01 D 1.38 C 1027 D C 1028 B A 1029 1.78 C 0.63 B 1030 E D 1031 D C 1032 B A 1033 D C 1034 C B 1035 C C 1036 E D 1037 C C 1038 35.02 E 14.72 D 1039 D C 1040 E E 1041 0.61 B 0.75 B 1042 D C 1043 C B 1045 C 1046 C 1047 B 1048 0.27 A 1049 C 1050 A 1051 C 1052 A 1053 C 1054 A 1055 C 1056 A 1057 D 1058 A 1059 E 1060 C 1061 D 1062 C 1063 A 1064 A 1065 A 1066 A 1067 0.50 1068 A

(265) It will be evident to one skilled in the art that the present disclosure is not limited to the foregoing illustrative examples, and that it can be embodied in other specific forms without departing from the essential attributes thereof. It is therefore desired that the examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing examples, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

Hepatitis C virus inhibitors

Assignee

Inventors

Cpc classification

Classification Explorer

C07K5/081

CHEMISTRY; METALLURGY

Classification Explorer

A61K45/06

HUMAN NECESSITIES

Classification Explorer

A61P31/14

HUMAN NECESSITIES

Classification Explorer

A61K38/07

HUMAN NECESSITIES

Classification Explorer

A61P31/22

HUMAN NECESSITIES

Classification Explorer

C07K5/1002

CHEMISTRY; METALLURGY

Classification Explorer

C07K5/1013

CHEMISTRY; METALLURGY

Classification Explorer

A61K38/06

HUMAN NECESSITIES

International classification

Classification Explorer

A61K38/06

HUMAN NECESSITIES

Classification Explorer

C07K5/10

CHEMISTRY; METALLURGY

Classification Explorer

C07K5/103

CHEMISTRY; METALLURGY

Classification Explorer

A61K45/06

HUMAN NECESSITIES

Classification Explorer

C07K5/083

CHEMISTRY; METALLURGY

Abstract

Claims

Description