Hepatitis C virus inhibitors

Abstract

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

Claims

1. A compound of formula (I) ##STR00155## or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2; is a single or double bond; R.sup.1 is selected from ##STR00156## wherein R.sup.1 is attached to the parent molecular moiety through any substitutable carbon atom in the group; m is 0, 1, or 2; n is 1, 2, 3, 4, 5, or 6; z is 0, 1, 2, 3, 4, 5, or 6; one of X.sup.1 and X.sup.3 is N and the other is selected from CH and CR.sup.a; X.sup.2 is selected from CH and CR.sup.a; X.sup.2 is selected from CH and CR.sup.a; X.sup.3 is selected from N, CH, and CR.sup.a; X.sup.4 is selected from CH and CR.sup.a; one of X.sup.5, X.sup.6, X.sup.7, and X.sup.8 is N and the others are selected from CH and CR.sup.a; X.sup.9 is selected from CR.sup.a, CH, and N; each R.sup.a and R.sup.a are independently selected from alkoxy, alkoxycarbonyl, alkyl, cycloalkyl, halo, haloalkyl, imidazolyl, oxazolyl, substituted pyrazolyl, thiazolyl, and NR.sup.qR.sup.q, wherein the imidazolyl, the oxazolyl, and the thiazolyl are optionally substituted with one or two groups independently selected from alkoxy, alkyl, halo, and haloalkyl; and wherein the substituted pyrazolyl is substituted with one or two groups independently selected from alkoxy, alkyl, halo, and haloalkyl; and wherein two adjacent R.sup.a groups, together with the carbon atoms to which they are attached, can optionally form a furanyl ring; provided that at least one R.sup.a is other than alkoxy, alkyl, halo, or haloalkyl; R.sup.x is selected from methyl and ethyl; R.sup.y and R.sup.z are independently selected from hydrogen and hydroxy; provided that when is a double bond, R.sup.y and R.sup.z are each hydrogen; R.sup.2 is selected from hydrogen, alkyl, halo, haloalkoxy, haloalkyl, and hydroxyalkyl; R.sup.3 is selected from alkoxycarbonyl, alkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylcarbonyl, cycloalkyloxycarbonyl, deuteroalkoxycarbonyl, deuterohaloalkoxycarbonyl, haloalkoxycarbonyl, 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 m and p are 1.

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

4. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.y and R.sup.z are hydrogen.

5. A compound of claim 1 wherein R.sup.2 is selected from hydrogen and alkyl.

6. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein m and p are 1; is a double bond; R.sup.y and R.sup.z are hydrogen; and R.sup.2 is selected from hydrogen and alkyl.

7. A compound selected from methyl 1-(((2R,6S,7R,9R,13aS,14aR,16aS,Z)-14a-((cyclopropylsulfonyl)carbamoyl)-7-ethyl-9-methyl-5,16-dioxo-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-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-2-yl)oxy)-6-methoxyisoquinoline-4-carboxylate; methyl 1-(((2R,6S,7R,9R,13aS,14aR,16aS,Z)-7-ethyl-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-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-2-yl)oxy)-6-methoxyisoquinoline-4-carboxylate; tert-butyl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-7-ethyl-2-((2-(3-isopropyl-1H-pyrazol-1-yl)-7-methoxyquinolin-4-yl)oxy)-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)-14a-(((1-(fluoromethyl)cyclopropyl)sulfonyl)carbamoyl)-2-((7-methoxy-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)quinolin-4-yl)oxy)-7,9-dimethyl-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)-7-ethyl-2-((7-methoxy-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)quinolin-4-yl)oxy)-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-((2-(3-isopropyl-1H-pyrazol-1-yl)-7-methoxyquinolin-4-yl)oxy)-7,9-dimethyl-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-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)quinolin-4-yl)oxy)-7,9-dimethyl-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)-7-ethyl-2-((2-(3-isopropyl-1H-pyrazol-1-yl)-7-methoxyquinolin-4-yl)oxy)-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-cyclopropyl-6-methoxyquinoxalin-2-yl)oxy)-7,9-dimethyl-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-cyclopropyl-6-methoxyquinoxalin-2-yl)oxy)-14a-((cyclopropylsulfonyl)carbamoyl)-7-ethyl-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-((3-cyclopropyl-7-methoxyquinoxalin-2-yl)oxy)-14a-((cyclopropylsulfonyl)carbamoyl)-7-ethyl-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-((3-cyclopropyl-6-methoxyquinoxalin-2-yl)oxy)-14a-((cyclopropylsulfonyl)carbamoyl)-7-ethyl-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-((3-cyclopropyl-7-methoxyquinoxalin-2-yl)oxy)-14a-((cyclopropylsulfonyl)carbamoyl)-7-ethyl-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-((4-(4-(tert-butyl)thiazol-2-yl)-6-methoxyisoquinolin-1-yl)oxy)-14a-((cyclopropylsulfonyl)carbamoyl)-7-ethyl-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-((2-(1H-imidazol-1-yl)-7-methoxyquinolin-4-yl)oxy)-7-ethyl-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-(1H-imidazol-1-yl)-7-methoxyquinolin-2-yl)oxy)-7-ethyl-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)-7-ethyl-2-((6-methoxy-4-(N-methylbenzamido)isoquinolin-1-yl)oxy)-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)-7-ethyl-2-((6-methoxy-4-(thiazol-2-yl)isoquinolin-1-yl)oxy)-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)-7-ethyl-2-((6-methoxy-4-(thiazol-2-yl)isoquinolin-1-yl)oxy)-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)-7-ethyl-2-((4-(N-ethylbenzamido)-6-methoxyisoquinolin-1-yl)oxy)-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-(4-(tert-butyl)thiazol-2-yl)-6-methoxyisoquinolin-1-yl)oxy)-7-ethyl-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-(4-(tert-butyl)thiazol-2-yl)-6-methoxyisoquinolin-1-yl)oxy)-7-ethyl-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)-7-ethyl-2-((6-methoxy-4-(oxazol-5-yl)isoquinolin-1-yl)oxy)-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)-7-ethyl-2-((6-methoxy-4-(oxazol-5-yl)isoquinolin-1-yl)oxy)-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)-14a-((cyclopropylsulfonyl)carbamoyl)-7-ethyl-2-((6-methoxy-4-(oxazol-5-yl)isoquinolin-1-yl)oxy)-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)-7-ethyl-9-methyl-5,16-dioxo-2-((3-(trifluoromethyl)pyrido[2,3-b]pyrazin-2-yl)oxy)-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)-7-ethyl-9-methyl-5,16-dioxo-2-((2-(trifluoromethyl)pyrido[2,3-b]pyrazin-3-yl)oxy)-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)-7-ethyl-2-((7-methoxy-3-(trifluoromethyl)pyrido[3,4-b]pyrazin-2-yl)oxy)-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-((4-(4-(tert-butyl)thiazol-2-yl)-6-methoxyisoquinolin-1-yl)oxy)-14a-((cyclopropylsulfonyl)carbamoyl)-7-ethyl-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-((2-ethoxy-7-methoxypyrido[3,4-b]pyrazin-3-yl)oxy)-7-ethyl-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)-7-ethyl-2-((7-methoxy-2-(trifluoromethyl)pyrido[3,4-b]pyrazin-3-yl)oxy)-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-((2,3-dihydrofuro[2,3-f]isoquinolin-6-yl)oxy)-7,9-dimethyl-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-((2,3-dihydrofuro[2,3-f]isoquinolin-6-yl)oxy)-7,9-dimethyl-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-((2,3-dihydrofuro[2,3-f]isoquinolin-6-yl)oxy)-7-ethyl-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-((2,3-dihydrofuro[2,3-f]isoquinolin-6-yl)oxy)-7-ethyl-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-((2,3-dihydrofuro[2,3-f]isoquinolin-6-yl)oxy)-7,9-dimethyl-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-((2,3-dihydrofuro[2,3-f]isoquinolin-6-yl)oxy)-7,9-dimethyl-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-((2,3-dihydrofuro[2,3-f]isoquinolin-6-yl)oxy)-7,9-dimethyl-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-((2,3-dihydrofuro[2,3-f]isoquinolin-6-yl)oxy)-7,9-dimethyl-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,13 aS,14aR,16aS,Z)-2-((2,3-dihydrofuro[2,3-f]isoquinolin-6-yl)oxy)-7-ethyl-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,13 aS,14aR,16aS,Z)-2-((2,3-dihydrofuro[2,3-f]isoquinolin-6-yl)oxy)-7-ethyl-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-(imidazo[1,2-a]quinazolin-5-yloxy)-7,9-dimethyl-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-(imidazo[1,2-a]quinazolin-5-yloxy)-7,9-dimethyl-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,13 aS,14aR,16aS,Z)-2-([1,2,4]triazolo[4,3-a]quinazolin-5-yloxy)-7,9-dimethyl-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,13 aS,14aR,16aS,Z)-2-([1,2,4]triazolo[4,3-a]quinazolin-5-yloxy)-7,9-dimethyl-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-chloroimidazo[1,2-a]quinazolin-5-yl)oxy)-7,9-dimethyl-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-(imidazo[1,2-a]quinazolin-5-yloxy)-7,9-dimethyl-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-(imidazo[1,2-a]quinazolin-5-yloxy)-7,9-dimethyl-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-([1,2,4]triazolo[4,3-a]quinazolin-5-yloxy)-7,9-dimethyl-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-([1,2,4]triazolo[4,3-a]quinazolin-5-yloxy)-7,9-dimethyl-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-chloroimidazo[1,2-a]quinazolin-5-yl)oxy)-7,9-dimethyl-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-chloroimidazo[1,2-a]quinazolin-5-yl)oxy)-7,9-dimethyl-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-chloroimidazo[1,2-a]quinazolin-5-yl)oxy)-14a-(((1-(fluoromethyl)cyclopropyl)sulfonyl)carbamoyl)-7,9-dimethyl-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-chloroimidazo[1,2-a]quinazolin-5-yl)oxy)-14a-(((1-(fluoromethyl)cyclopropyl)sulfonyl)carbamoyl)-7,9-dimethyl-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-chloroimidazo[1,2-a]quinazolin-5-yl)oxy)-7-ethyl-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-chloroimidazo[1,2-a]quinazolin-5-yl)oxy)-7-ethyl-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-chloro-2-methylimidazo[1,2-a]quinazolin-5-yl)oxy)-7,9-dimethyl-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-chloro-2-methylimidazo[1,2-a]quinazolin-5-yl)oxy)-7,9-dimethyl-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-chloro-2-methylimidazo[1,2-a]quinazolin-5-yl)oxy)-7,9-dimethyl-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-chloro-2-methylimidazo[1,2-a]quinazolin-5-yl)oxy)-7,9-dimethyl-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-chloro-2-methylimidazo[1,2-a]quinazolin-5-yl)oxy)-14a-(((1-(fluoromethyl)cyclopropyl)sulfonyl)carbamoyl)-7,9-dimethyl-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-chloro-2-methylimidazo[1,2-a]quinazolin-5-yl)oxy)-14a-(((1-(fluoromethyl)cyclopropyl)sulfonyl)carbamoyl)-7,9-dimethyl-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-chloro-2-methylimidazo[1,2-a]quinazolin-5-yl)oxy)-14a-(((1-(fluoromethyl)cyclopropyl)sulfonyl)carbamoyl)-7,9-dimethyl-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-((7-chloro-2-methylimidazo[1,2-a]quinazolin-5-yl)oxy)-14a-(((1-(fluoromethyl)cyclopropyl)sulfonyl)carbamoyl)-7,9-dimethyl-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.

8. A compound selected from ##STR00157## ##STR00158## ##STR00159## ##STR00160## ##STR00161## ##STR00162## ##STR00163## ##STR00164## ##STR00165## ##STR00166## or a pharmaceutically acceptable salt thereof.

9. A compound selected from ##STR00167## 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. 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.

12. The method of claim 11 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.

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

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

15. The method of claim 12 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.

16. The method of claim 12 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 The preparation of intermediates and Compounds for Formula 1 is described in following three sections: Section 1, Section 2 and Section 3. Compounds were named using ChemDraw.

(2) ##STR00012##

Step 1: Preparation of 4-chloro-7-methoxy-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)quinoline

(3) To a solution of 2,4-dichloro-7-methoxyisoquinolin (0.5 g, 2.19 mmol) in DMF (5 ml) was added Cs.sub.2CO.sub.3 (0.3 g, 2.2 mmol) followed by 3-(trifluoromethyl)-1H-pyrazole (0.9 g, 6.58 mmol). The reaction mixture was heated to 80 C. for 18 h. The reaction mass was evaporated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4; filtered; then evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get 4-chloro-7-methoxy-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)quinoline (0.45 g, 1.37 mmol) 54% as white solid. .sup.1H NMR (400 MHz, CDCl.sub.3): ppm 8.60 (d, J=2.51 Hz, 1H) 8.07 (d, J=9.04 Hz, 1H) 8.15 (s, 1H) 8.07 (d, J=9.04 Hz, 1H) 8.15 (s, 1H) 7.26 (s, 2H) 7.16-7.22 (m, 1H) 6.35 (d, J=2.51 Hz, 1H) 3.97-3.99 (m, 4H) MS: MS m/z 330.1 (M.sup.++1).

(4) ##STR00013##

Step 1: Preparation of 6-fluoro-4-hydroxy-7-methoxyquinolin-2(1H)-one

(5) POCl.sub.3 (3.96 ml, 42.5 mmol) was added to the mixture of 4-fluoro-3-methoxy aniline (5.0 g, 35.4 mmol) and Malonic acid (3.69 g, 35.46 mmol). The reaction mass was heated to 105 C. for 1 h. The reaction mass was carefully diluted with water (20 ml) and stirred for 30 min. The precipitated solid isolated via filtration and washed with water. The solid was combined with aq NaOH solution (2N, 30 ml) and the mixture was stirred for 18 h. The mixture was filtered. The filtrate was diluted with ethanol (5 ml) adjusted to pH 2 using aq. conc. HCl. The precipitated solid was isolated via filtration and washed with water. The solid was dried under reduced pressure to afford 6-fluoro-7-methoxyquinoline-2,4-diol (7 g, 33.5 mmol, 94%) as white solid. .sup.1H NMR (400 MHz, DMSO-D.sub.6): ppm 11.09 (b s, 1H), 10.01 (s, 1H), 7.57-7.54 (d, J=12 Hz, 1H), 7.06-7.04 (d, J=12 Hz, 1H), 5.92 (s, 1H), 3.90 (s, 3H). MS: MS m/z 210.55 (M.sup.++1).

Step 2: Preparation of 2,4-dichloro-6-fluoro-7-methoxyquinoline

(6) A solution of 6-fluoro-7-methoxyquinoline-2,4-diol (7.5 g, 35.9 mmol) in POCl.sub.3 (3.66 ml, 39.2 mmol) 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 addition of solid sodium carbonate; then was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulphate; filtered; then concentrated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography (20% ethyl acetate in pet ether) to afford 2,4-dichloro-6-fluoro-7-methoxyquinoline (6 g, 24.38 mmol, 68.0%). .sup.1H NMR (400 MHz, CDCl.sub.3): ppm 7.81-7.78 (d, J=12 Hz, 1H), 7.46-7.44 (d, J=8 Hz, 1H) 7.41 (s, 1H), 4.02 (s, 3H). MS: MS m/z 246.44 (M.sup.++1).

Step 3: 4-chloro-6-fluoro-2-(3-isopropyl-1H-pyrazol-1-yl)-7-methoxyquinoline

(7) To a stirred solution of 2,4-dichloro-6-fluoro-7-methoxyquinoline (0.2 g, 0.813 mmol) in DMF (5 mL) was added cesium carbonate (0.530 g, 1.626 mmol) followed by 3-isopropyl-1H-pyrazole (0.269 g, 2.438 mmol). The reaction mixture was stirred for 12 h at 80 C. Reaction mixture was poured in water; extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulphate; filtered; then concentrated under reduced pressure. The resulting crude compound was purified by silica gel chromatography (1-2% ethyl acetate in pet ether) to afford 4-chloro-6-fluoro-2-(3-isopropyl-1H-pyrazol-1-yl)-7-methoxyquinoline (0.04 g, 0.13 mmol, 16%). .sup.1H NMR (400 MHz, CDCl.sub.3): ppm 8.56-8.55 (dd, J=2.50, 0.50 Hz, 1H) 8.19 (d, J=0.50 Hz, 1H) 7.82-7.79 (d, J=11.76 Hz, 1H) 7.41-7.39 (d, J=8.00 Hz, 1H) 6.35 (s, 1H) 4.05 (s, 3H) 3.12-3.06 (m, 1H) 1.35-1.33 (d, 6H). MS: MS m/z 320.4 (M.sup.++1).

(8) ##STR00014##

Step 1: Synthesis of 1-chloro-6-methoxyisoquinoline-4-carboxylic acid

(9) A solution of 4-bromo-1-chloro-6-methoxyisoquinoline (340 mg, 1.248 mmol) in THF (10 mL) was cooled to 78 C. To the solution was added t-BuLi in pentane (1.715 mL, 2.74 mmol). The resulting colored solution was stirred at the same temperature for 20 min, then was transferred by syringe onto crushed dry ice (CO2) under nitrogen atmosphere. Once the dry ice had fully sublimed, the resulting solution was transferred to a reparatory funnel and was diluted with water. The pH was adjusted to basic using 10% sodium hydroxide solution. The organic layer was separated and discarded. The aqueous phase was washed with ethyl acetate. The aqueous layer was then adjusted to pH 2.0 with aqueous HCl, then was twice extracted with EtOAc. The combined organic layers were washed with brine solution, dried over Na2SO4, filtered and concentrated in vacuo to afford 1-chloro-6-methoxyisoquinoline-4-carboxylic acid (140 mg, 0.589 mmol, 47.2% yield) as light pink solid .sup.1H NMR (400 MHz, CDCl.sub.3): ppm: 13.60 (bs, 1H), 8.82 (s, 1H) 8.43-8.42 (d, J=2.40 Hz, 1H) 7.54-7.51 (dd, J=12.0, 2.4 Hz, 1H) 3.97 (s, 3H). MS: MS m/z 238.06 (M.sup.++1).

Step 2: Synthesis of Methyl 1-chloro-6-methoxyisoquinoline-4-carboxylate

(10) To a suspension of 1-chloro-6-methoxyisoquinoline-4-carboxylic acid (0.15 g, 0.631 mmol) in THF (7 mL) and MeOH (3 mL) at 5 C. was added TMS-Diazomethane in hexanes (0.316 mL, 0.631 mmol). The solution was allowed to warm to room temperature with stirring overnight. The volatiles were removed under vacuum; the resulting residue was purified by silica gel chromatography eluting with 10% ethyl acetate in pet-ether to afford methyl 1-chloro-6-methoxyisoquinoline-4-carboxylate (0.11 g, 0.437 mmol, 69.2% yield) as white solid. .sup.1H NMR (400 MHz, CDCl.sub.3): ppm 8.91 (s, 1H) 8.46 (d, J=2.51 Hz, 1H) 8.31 (s, 1H) 7.34 (dd, J=9.29, 2.51 Hz, 1H) 4.01 (d, J=0.75 Hz, 6H) MS: MS m/z 252.1 (M.sup.++1).

Preparation of tert-butyl((2R,6S,7R,13aS,14aR,16aS,Z)-7-ethyl-2-hydroxy-9-methyl-14a-(((D3-1-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

(11) ##STR00015##

(12) Tert-butyl((2R,6S,7R,13aS,14aR,16aS,Z)-7-ethyl-2-hydroxy-9-methyl-14a-(((CD3-1-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 was synthesized following the procedure reported in synthesis of tert-butyl((2R,6S,7R,13aS,14aR,16aS,Z)-7-ethyl-2-hydroxy-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. CD.sub.3I was used as a reagent instead of MeI. MS: MS m/z 650.43 (M.sup.++23).

Preparation of Compound 4286

(13) ##STR00016##

(14) Compound 4286 was prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 4303 Compound 4286: methyl 1-(((2R,6S,7R,9R,13aS,14aR,16aS,Z)-14a-((cyclopropylsulfonyl)carbamoyl)-7-ethyl-9-methyl-5,16-dioxo-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-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-2-yl)oxy)-6-methoxyisoquinoline-4-carboxylate. .sup.1H NMR (400 MHz, CD.sub.3OD): ppm 8.36 (d, J=3.01 Hz, 1H) 7.84 (d, J=8.53 Hz, 1H) 7.72 (d, J=2.51 Hz, 1H) 7.39 (d, J=9.04 Hz, 1H) 7.23-7.31 (m, 2H) 5.64 (td, J=10.29, 6.02 Hz, 1H) 5.39 (br. s., 1H) 5.02 (t, J=10.04 Hz, 1H) 4.71 (d, J=10.04 Hz, 1H) 4.60 (dd, J=10.04, 7.03 Hz, 1H) 4.22 (q, J=7.03 Hz, 2H) 4.01-4.11 (m, 2H) 2.64-2.74 (m, 2H) 2.45 (ddd, J=13.93, 9.91, 4.77 Hz, 2H) 1.91-2.07 (m, 2H) 1.78 (dd, J=8.28, 5.77 Hz, 1H) 1.62-1.69 (m, 1H) 1.58 (dd, J=9.54, 5.52 Hz, 3H) 1.48-1.54 (m, 9H) 1.44 (dd, J=8.78, 5.27 Hz, 1H) 1.34 (s, 3H) 1.19-1.29 (m, 2H) 1.09-1.16 (m, 3H) 1.01 (d, J=6.53 Hz, 3H) 0.87-0.93 (m, 4H) 0.82 (t, J=7.53 Hz, 3H). MS: MS m/z 880.8 (M.sup.++1).

Preparation of Compound 4287

(15) ##STR00017##

(16) Compound 4287 was prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 4303 Compound 4287: methyl 1-(((2R,6S,7R,9R,13aS,14aR,16aS,Z)-7-ethyl-9-methyl-14a-4(1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-6-(4(1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-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-2-yl)oxy)-6-methoxyisoquinoline-4-carboxylate. .sup.1H NMR (400 MHz, CD.sub.3OD): ppm 8.81 (s, 1H) 8.44 (d, J=2.51 Hz, 1H) 8.19 (d, J=9.03 Hz, 1H) 7.20 (dd, J=9.03, 2.51 Hz, 1H) 5.98 (br. s., 1H) 5.60-5.66 (m, 1H) 5.05 (t, J=9.91 Hz, 2H) 4.81 (s, 2H) 4.64-4.69 (m, 1H) 4.02-4.06 (m, 2H) 3.99 (d, J=1.51 Hz, 6H) 2.92-2.98 (m, 1H) 2.71-2.80 (m, 2H) 2.41-2.50 (m, 2H) 1.96-2.03 (m, 2H) 1.80 (s, 1H) 1.50-1.62 (m, 7H) 1.27-1.38 (m, 6H) 1.05-1.19 (m, 3H) 0.94 (s, 4H) 0.83 (t, J=7.53 Hz, 3H). MS: MS m/z 894.3 (M.sup.++1).

Preparation of Compound 4294

(17) ##STR00018##

(18) Compound 4294 was prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 4303. Compound 4294: tert-butyl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-7-ethyl-2-(2-(3-isopropyl-1H-pyrazol-1-yl)-7-methoxyquinolin-4-yl)oxy)-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 9.04 (s, 1H) 8.70 (d, J=2.76 Hz, 1H) 8.08 (d, J=9.29 Hz, 1H) 7.53 (s, 1H) 7.38 (d, J=2.26 Hz, 1H) 7.03-7.13 (m, 1H) 6.54 (d, J=2.51 Hz, 1H) 5.66 (br. s., 2H) 4.97-5.09 (m, 1H) 4.51-4.67 (m, 1H) 4.06-4.19 (m, 2H) 3.97 (s, 3H) 3.10-3.20 (m, 2H) 2.68-2.92 (m, 2H) 2.33-2.61 (m, 2H) 1.93-2.05 (m, 2H) 1.77 (dd, J=8.41, 5.65 Hz, 1H) 1.55-1.72 (m, 4H) 1.52 (s, 4H) 1.35-1.46 (m, 9H) 1.23-1.32 (m, 2H) 1.15-1.23 (m, 9H) 0.98-1.09 (m, 4H) 0.67-0.95 (m, 6H). MS: MS m/z 890.4 (M.sup.++1).

Preparation of Compound 4295

(19) ##STR00019##

(20) Compound 4295 was prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 4303 Compound 4295: 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-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)quinolin-4-yl)oxy)-7,9-dimethyl-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 8.89-8.96 (m, 1H) 8.09 (d, J=9.04 Hz, 1H) 7.57 (s, 1H) 7.38 (d, J=2.51 Hz, 1H) 7.11 (dd, J=9.04, 2.51 Hz, 1H) 6.93 (d, J=2.51 Hz, 1H) 5.67 (br. s., 1H) 4.59-4.70 (m, 2H) 4.11 (dd, J=11.80, 2.76 Hz, 1H) 3.98 (s, 3H) 3.85 (d, J=10.54 Hz, 1H) 3.50 (d, J=1.51 Hz, 1H) 3.16 (t, J=1.51 Hz, 1H) 2.82 (dd, J=14.81, 6.78 Hz, 1H) 2.50-2.62 (m, 2H) 1.72 (dd, J=8.53, 5.52 Hz, 2H) 1.58 (dd, J=9.54, 5.52 Hz, 2H) 1.49 (br. s., 2H) 1.36 (s, 3H) 1.07 (s, 3H) 1.01 (dd, J=13.80, 6.78 Hz, 10H) 0.79-0.92 (m, 3H). MS: MS m/z 974.8 (M.sup.++1).

Preparation of Compound 4297

(21) ##STR00020##

(22) Compound 4297 was prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 4303

(23) Compound 4297: 1,1,1-trifluoro-2-methylpropan-2-yl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-7-ethyl-2-((7-methoxy-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)quinolin-4-yl)oxy)-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 8.94 (s, 1H) 8.09 (s, 1H) 7.58 (s, 1H) 7.38 (s, 1H) 7.07-7.15 (m, 1H) 6.94 (s, 1H) 5.69 (br. s., 1H) 4.61-4.69 (m, 1H) 4.06-4.14 (m, 7H) 3.98 (s, 3H) 2.84 (d, J=6.02 Hz, 1H) 2.54 (t, J=10.29 Hz, 1H) 1.99 (br. s., 2H) 1.73-1.79 (m, 6H) 1.25-1.65 (m, 12H) 0.80-1.20 (m, 13H). MS: MS m/z 969.9 (M.sup.++1).

Preparation of Compound 4299

(24) ##STR00021##

(25) Compound 4299 was prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 4303 Compound 4299: 1,1,1-trifluoro-2-methylpropan-2-yl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-(2-(3-isopropyl-1H-pyrazol-1-yl)-7-methoxyquinolin-4-yl)oxy)-7,9-dimethyl-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): 8.67 (d, J=3.01 Hz, 1H) 8.06 (s, 1H) 7.50 (s, 1H) 7.31 (d, J=2.51 Hz, 1H) 7.04 (dd, J=9.04, 2.51 Hz, 1H) 6.49 (d, J=2.51 Hz, 1H) 5.62 (br. s., 1H) 5.03 (t, J=9.79 Hz, 1H) 4.66 (dd, J=10.54, 7.03 Hz, 1H) 4.11 (dd, J=11.55, 3.01 Hz, 1H) 3.96 (s, 3H) 3.87 (d, J=10.54 Hz, 1H) 2.82-2.88 (m, 1H) 2.74 (d, J=8.53 Hz, 1H) 2.42-2.58 (m, 1H) 1.77 (dd, J=8.28, 5.77 Hz, 1H) 1.56-1.69 (m, 11H) 1.49-1.54 (m, 9H) 1.33-1.43 (m, 9H) 1.10 (s, 2H) 0.87-1.05 (m, 9H). MS: MS m/z 930.5 (M.sup.++1).

Preparation of Compound 4301

(26) ##STR00022##

(27) Compound 4301 was prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 4303.

(28) Compound 4301: 1,1,1-trifluoro-2-methylpropan-2-yl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((7-methoxy-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)quinolin-4-yl)oxy)-7,9-dimethyl-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 8.85-9.05 (m, 1H) 8.09 (d, J=9.04 Hz, 1H) 7.57 (s, 1H) 7.38 (d, J=2.51 Hz, 1H) 7.11 (dd, J=9.04, 2.51 Hz, 1H) 6.93 (d, J=2.51 Hz, 1H) 5.43-5.84 (m, 2H) 5.04 (br. s., 1H) 4.66 (dd, J=10.29, 6.78 Hz, 1H) 4.11 (dd, J=12.05, 3.01 Hz, 1H) 3.98 (s, 3H) 3.85 (d, J=11.04 Hz, 1H) 2.68-2.93 (m, 2H) 2.33-2.62 (m, 2H) 1.84-2.08 (m, 2H) 1.73-1.84 (m, 2H) 1.66 (d, J=10.54 Hz, 1H) 1.57-1.63 (m, 1H) 1.53 (s, 5H) 1.39-1.48 (m, 2H) 1.31-1.39 (m, 4H) 1.19-1.30 (m, 1H) 1.06 (s, 3H) 0.93-1.06 (m, 7H) 0.74-0.92 (m, 4H). MS: MS m/z 953.9 (M.sup.+1).

Preparation of Compound 4358

(29) ##STR00023##

(30) Compound 4358 was prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 4303 Compound 4358: 1,1,1-trifluoro-2-methylpropan-2-yl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-7-ethyl-2-(2-(3-isopropyl-1H-pyrazol-1-yl)-7-methoxyquinolin-4-yl)oxy)-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 9.07 (s, 1H) 8.70 (d, J=2.51 Hz, 1H) 8.02-8.07 (m, 1H) 7.52 (s, 1H) 7.35 (d, J=2.51 Hz, 1H) 7.07 (dd, J=9.04, 2.51 Hz, 1H) 6.52 (d, J=3.01 Hz, 1H) 5.61-5.68 (m, 1H) 5.00 (s, 1H) 4.66 (dd, J=10.29, 6.78 Hz, 1H) 4.06-4.14 (m, 1H) 3.98 (s, 3H) 3.12-3.18 (m, 1H) 2.85 (dd, J=13.80, 6.78 Hz, 1H) 2.70-2.76 (m, 1H) 2.50-2.58 (m, 1H) 2.43 (d, J=13.05 Hz, 1H) 2.01 (br. s., 1H) 1.78 (dd, J=8.53, 5.52 Hz, 1H) 1.51-1.69 (m, 8H) 1.37-1.45 (m, 9H) 1.15-1.22 (m, 9H) 1.07-1.13 (m, 8H) 0.81-0.92 (m, 6H). MS: MS m/z 944.0 (M.sup.++1).

Preparation of Compound 5506 and Compound 5507

(31) ##STR00024##

(32) Compounds 5506 and 5507 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 4303:

(33) Compound 5506: MS: MS m/z 803.7 (M.sup.++1).

(34) Compound 5507: .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.98 (d, J=5.8 Hz, 1H), 7.69 (d, J=11.6 Hz, 1H), 7.54 (d, J=8.2 Hz, 1H), 7.35 (d, J=5.8 Hz, 1H), 7.17 (d, J=8.2 Hz, 1H), 5.81 (br. s., 1H), 5.50 (br. s., 1H), 4.98 (br. s., 1H), 4.62-4.44 (m, 2H), 3.98 (s, 3H), 3.93-3.86 (m, 2H), 2.71-2.54 (m, 2H), 2.30 (d, J=9.2 Hz, 2H), 1.90 (d, J=11.3 Hz, 2H), 1.63-0.68 (m, 28H). MS: MS m/z 803.8 (M.sup.++1).

Preparation of Compound 5508 and Compound 5509

(35) ##STR00025##

(36) Compounds 5508 and 5509 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 4303:

(37) Compound 5508: MS: MS m/z 817.7 (M.sup.++1).

(38) Compound 5509: MS: MS m/z 817.8 (M.sup.++1).

Preparation of Compound 5510 and Compound 5511

(39) ##STR00026##

(40) Compounds 5510 and 5511 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 4303:

(41) Compound 5510: MS: MS m/z 857.7 (M.sup.++1).

(42) Compound 5511: .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.97 (d, J=5.8 Hz, 1H), 7.82 (d, J=8.2 Hz, 1H), 7.69 (d, J=11.3 Hz, 1H), 7.54 (d, J=8.5 Hz, 1H), 7.35 (d, J=5.5 Hz, 1H), 5.81 (br. s., 1H), 5.51 (d, J=5.2 Hz, 1H), 5.00 (br. s., 1H), 4.50 (d, J=10.1 Hz, 2H), 3.97 (s, 3H), 3.94-3.84 (m, 2H), 2.61 (d, J=7.6 Hz, 2H), 2.29 (d, J=9.5 Hz, 2H), 1.91 (t, J=14.5 Hz, 2H), 1.62-1.07 (m, 16H), 0.99 (t, J=12.8 Hz, 1H), 0.93-0.82 (m, 5H), 0.72 (t, J=7.3 Hz, 3H). MS: MS m/z 857.7 (M.sup.++1).

Preparation of Compound 5512 and Compound 5513

(43) ##STR00027##

(44) Compounds 5512 and 5513 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 4303:

(45) Compound 5512: MS: MS m/z 851.6 (M.sup.++1).

(46) Compound 5513: .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.97 (d, J=6.1 Hz, 1H), 7.69 (d, J=11.6 Hz, 1H), 7.60 (d, J=8.9 Hz, 1H), 7.54 (d, J=8.2 Hz, 1H), 7.35 (d, J=5.8 Hz, 1H), 5.81 (br. s., 1H), 5.51 (d, J=6.4 Hz, 1H), 5.00 (br. s., 1H), 4.54-4.47 (m, 2H), 3.97 (s, 3H), 3.94-3.86 (m, 2H), 2.70-2.56 (m, 2H), 2.36-2.23 (m, 2H), 1.90 (d, J=10.4 Hz, 2H), 1.62-1.11 (m, 16H), 1.03-0.81 (m, 9H), 0.72 (t, J=7.3 Hz, 3H). MS: MS m/z 851.6 (M.sup.++1).

Preparation of Compound 5514 and Compound 5515

(47) ##STR00028##

(48) Compounds 5514 and 5515 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 4303:

(49) Compound 5514: MS: MS m/z 839.8 (M.sup.++1).

(50) Compound 5515: .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.00-7.93 (m, 1H), 7.71-7.62 (m, 2H), 7.53 (d, J=8.5 Hz, 1H), 7.35 (d, J=6.1 Hz, 1H), 5.84-5.57 (m, 2H), 5.51 (d, J=5.5 Hz, 1H), 5.00 (br. s., 1H), 4.58-4.48 (m, 2H), 3.96 (s, 3H), 3.91-3.80 (m, 2H), 2.61 (d, J=7.0 Hz, 2H), 2.34-2.22 (m, 2H), 1.96-1.82 (m, 2H), 1.63-0.81 (m, 22H), 0.70 (t, J=7.5 Hz, 3H). MS: MS m/z 839.7 (M.sup.++1).

Preparation of Compound 5516 and Compound 5517

(51) ##STR00029##

(52) Compounds 5516 and 5517 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 4303:

(53) Compound 5516: MS: MS m/z 839.8 (M.sup.++1).

(54) Compound 5517: .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.98-7.92 (m, 1H), 7.81 (d, J=7.9 Hz, 1H), 7.69 (d, J=11.6 Hz, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.33 (d, J=5.8 Hz, 1H), 5.79 (br. s., 1H), 5.51 (d, J=6.4 Hz, 1H), 5.00 (br. s., 1H), 4.50 (d, J=10.4 Hz, 2H), 4.24 (q, J=6.9 Hz, 2H), 3.93-3.84 (m, 2H), 2.61 (d, J=7.3 Hz, 2H), 2.28 (d, J=10.1 Hz, 2H), 1.98-1.82 (m, 2H), 1.61-1.08 (m, 20H), 0.99 (t, J=13.0 Hz, 1H), 0.93-0.82 (m, 5H), 0.71 (t, J=7.3 Hz, 3H). MS: MS m/z 839.7 (M.sup.++1).

Preparation of Compound 5518 and Compound 5519

(55) ##STR00030##

(56) Compounds 5518 and 5519 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 4303:

(57) Compound 5518: MS: MS m/z 867.8 (M.sup.++1).

(58) Compound 5519: .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.96 (d, J=5.8 Hz, 1H), 7.73-7.63 (m, 2H), 7.52 (d, J=8.2 Hz, 1H), 7.33 (d, J=6.1 Hz, 1H), 5.88-5.61 (m, 2H), 5.50 (d, J=6.1 Hz, 1H), 5.02 (br. s., 1H), 4.58-4.47 (m, 2H), 4.28-4.18 (m, 2H), 3.92-3.80 (m, 2H), 2.60 (d, J=7.3 Hz, 2H), 2.35-2.23 (m, 2H), 1.90 (d, J=9.5 Hz, 2H), 1.62-0.80 (m, 25H), 0.70 (t, J=7.3 Hz, 3H). MS: MS m/z 867.8 (M.sup.++1).

Preparation of Compound 5520 and Compound 5521

(59) ##STR00031##

(60) Compounds 5520 and 5521 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 4303:

(61) Compound 5520: MS: MS m/z 853.8 (M.sup.++1).

(62) Compound 5521: .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.96 (d, J=5.8 Hz, 1H), 7.72-7.64 (m, 2H), 7.52 (d, J=8.2 Hz, 1H), 7.33 (d, J=6.1 Hz, 1H), 5.87-5.61 (m, 2H), 5.50 (d, J=6.1 Hz, 1H), 5.02 (br. s., 1H), 4.59-4.48 (m, 2H), 4.29-4.18 (m, 2H), 3.92-3.80 (m, 2H), 2.60 (d, J=7.3 Hz, 2H), 2.35-2.23 (m, 2H), 1.95-1.85 (m, 2H), 1.59 (br. s., 1H), 1.54-1.03 (m, 17H), 0.98 (t, J=12.5 Hz, 1H), 0.93-0.80 (m, 5H), 0.70 (t, J=7.3 Hz, 3H). MS: MS m/z 853.9 (M.sup.++1).

Preparation of Compound 5538 and Compound 5539

(63) ##STR00032##

(64) Compounds 5538 and 5539 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 4303:

(65) Compound 5538: MS: MS m/z 857.8 (M.sup.++1).

(66) Compound 5539: .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.13 (d, J=5.8 Hz, 1H), 7.79 (d, J=7.9 Hz, 1H), 7.72-7.59 (m, 3H), 5.75 (br. s., 1H), 5.52 (br. s., 1H), 4.96 (br. s., 1H), 4.51 (d, J=9.8 Hz, 2H), 3.95 (s, 3H), 3.92-3.83 (m, 2H), 2.63 (br. s., 2H), 2.28 (d, J=13.4 Hz, 2H), 1.91 (d, J=11.3 Hz, 2H), 1.63-1.09 (m, 12H), 1.05-0.82 (m, 10H), 0.70 (t, J=6.7 Hz, 3H). MS: MS m/z 857.9 (M.sup.++1).

Preparation of Compound 5540 and Compound 5541

(67) ##STR00033##

(68) Compounds 5540 and 5541 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 4303:

(69) Compound 5540: MS: MS m/z 853.9 (M.sup.++1).

(70) Compound 5541: .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.13 (dd, J=9.2, 5.5 Hz, 1H), 7.73-7.54 (m, 4H), 5.76 (br. s., 1H), 5.51 (d, J=6.1 Hz, 1H), 4.99 (br. s., 1H), 4.52 (t, J=10.2 Hz, 2H), 3.96 (s, 3H), 3.93-3.84 (m, 2H), 2.71-2.57 (m, 2H), 2.36-2.23 (m, 2H), 1.96-1.83 (m, 2H), 1.64-1.10 (m, 16H), 1.04-0.81 (m, 9H), 0.72 (t, J=7.5 Hz, 3H). MS: MS m/z 853.8 (M.sup.++1).

Preparation of Compound 5542 and Compound 5543

(71) ##STR00034##

(72) Compounds 5542 and 5543 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 4303:

(73) Compound 5542: MS: MS m/z 839.8 (M.sup.++1).

(74) Compound 5543: .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.12 (dd, J=9.0, 5.6 Hz, 1H), 7.73-7.60 (m, 4H), 5.88-5.61 (m, 2H), 5.52 (d, J=5.5 Hz, 1H), 4.97 (br. s., 1H), 4.61-4.48 (m, 2H), 3.97 (s, 3H), 3.91-3.80 (m, 2H), 2.69-2.57 (m, 2H), 2.35-2.24 (m, 2H), 1.90 (d, J=7.6 Hz, 2H), 1.61 (br. s., 1H), 1.54-0.95 (m, 15H), 0.94-0.82 (m, 6H), 0.70 (t, J=7.3 Hz, 3H). MS: MS m/z 839.8 (M.sup.++1).

Preparation of Compound 5544 and Compound 5545

(75) ##STR00035##

(76) Compounds 5544 and 5545 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 4303:

(77) Compound 5544: MS: MS m/z 839.9 (M.sup.++1).

(78) Compound 5545: .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.10-8.03 (m, 2H), 7.82-7.75 (m, 2H), 7.66-7.58 (m, 2H), 5.77 (br. s., 1H), 5.52 (d, J=6.1 Hz, 1H), 4.98 (br. s., 1H), 4.52 (t, J=11.7 Hz, 2H), 3.99-3.84 (m, 5H), 2.62 (dd, J=14.2, 7.2 Hz, 2H), 2.35-2.24 (m, 2H), 1.99-1.84 (m, 2H), 1.63-0.81 (m, 22H), 0.71 (t, J=7.5 Hz, 3H). MS: MS m/z 839.9 (M.sup.++1).

Preparation of Compound 5546 and Compound 5547

(79) ##STR00036##

(80) Compounds 5546 and 5547 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 4303:

(81) Compound 5546: MS: MS m/z 835.9 (M.sup.++1).

(82) Compound 5547: .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.10-8.02 (m, 2H), 7.78 (t, J=7.6 Hz, 1H), 7.67-7.55 (m, 3H), 5.77 (br. s., 1H), 5.58-5.47 (m, 1H), 4.98 (br. s., 1H), 4.00-3.86 (m, 6H), 2.75-2.57 (m, 2H), 2.39-2.24 (m, 2H), 1.97-1.83 (m, 2H), 1.63-1.09 (m, 17H), 1.00 (t, J=12.1 Hz, 1H), 0.94-0.84 (m, 8H), 0.73 (t, J=7.3 Hz, 3H). MS: MS m/z 835.8 (M.sup.++1).

Preparation of Compound 5548 and Compound 5549

(83) ##STR00037##

(84) Compounds 5548 and 5549 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 4303:

(85) Compound 5548: MS: MS m/z 821.8 (M.sup.++1).

(86) Compound 5549: MS: .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.05 (dd, J=7.9, 3.4 Hz, 2H), 7.78 (t, J=7.6 Hz, 1H), 7.69-7.56 (m, 3H), 5.90-5.63 (m, 2H), 5.57-5.46 (m, 1H), 4.97 (br. s., 1H), 4.63-4.47 (m, 2H), 3.96 (s, 3H), 3.93-3.82 (m, 2H), 2.61 (dd, J=13.7, 6.1 Hz, 2H), 2.37-2.23 (m, 2H), 1.92 (d, J=8.2 Hz, 2H), 1.64-1.56 (m, 1H), 1.54-0.81 (m, 21H), 0.70 (t, J=7.5 Hz, 3H). MS m/z 821.8 (M.sup.++1).

Preparation of 6-chloro-2,3-dihydrofuro[2,3-f]isoquinoline

(87) ##STR00038##

Step 1

(88) (E)-3-(2,3-dihydrobenzofuran-7-yl)acrylic acid (0.19 g, 1.0 mmol), diphenylphosphoryl azide (0.205 mL, 0.949 mmol), and Et.sub.3N (0.278 mL, 2.00 mmol) were dissolved in benzene (30 mL) and stirred for 16 h. The solution was concentrated under vacuum and the residue was purified by silica gel chromatography eluting with 20% EtOAc in hexanes to afford (E)-3-(2,3-dihydrobenzofuran-7-yl)acryloyl azide as a yellow solid (0.19 g), which was taken into PhCH.sub.2Ph (5 mL). The resulting solution was slowly heated to 80 C. for 1 h and then to reflux for 3 h. After cooling to room temperature, the solid was collected washing with benzene to afford 2,3-dihydrofuro[2,3-f]isoquinolin-6-ol as a solid give (0.1 g). .sup.1H NMR (400 MHz, CD.sub.3OD) ppm 3.37 (t, J=9.05 Hz, 1H), 4.73 (t, J=9.05 Hz, 2H), 6.67 (d, J=7.09 Hz, 1H), 7.10 (d, J=7.09 Hz, 1H), 7.37 (d, J=8.07 Hz, 1H), 7.81 (d, J=8.07 Hz, 1H); MS: (M+H).sup.+ 188.

Step 2

(89) A solution of 2,3-dihydrofuro[2,3-f]isoquinolin-6-ol (0.1 g, 0.534 mmol) in POCl.sub.3 (5.0 mL, 54 mmol) was refluxed for 14 h. The solution was concentrated in vacuo and then the residue was taken into the mixture of DCM and aq. NaOH solution (4.0 N). The organic phase was collected and dried over sodium sulfate, filtered, then concentrated under vacuum. The crude material was purified by silica gel chromatography using 20% EtOAc/Hexanes as eluent to give 100 mg of the desired product 6-chloro-2,3-dihydrofuro[2,3-f]isoquinoline. .sup.1H NMR (400 Hz, CDCl.sub.3) ppm 3.43 (t, J=9.05 Hz, 2H), 4.82 (t, J=9.05 Hz, 2H), 7.52 (d, J=8.56 Hz, 1H), 7.66 (d, J=5.62 Hz, 1H), 7.84 (d, J=8.31 Hz, 1H), 8.19 (d, J=5.62 Hz, 1H); MS: MS m/z (M+H).sup.+ 206.

Preparation of 5-chloro-8-methoxy-2-methylimidazo[1,2-a]quinazoline

(90) ##STR00039##

(91) ##STR00040##

Step 1

(92) 2,4-dichloro-7-methoxyquinazoline (500 mg, 2.18 mmol) was suspended in 2% aqueous NaOH (6 mL). THF (1 mL) was added and the reaction was stirred for 4 h. The reaction was diluted with water and the solid that remained was filtered off. The filtrate was diluted with 1 N HCl. The precipitate that formed was isolated via filtration, washed with water and dried to give 2-chloro-7-methoxyquinazolin-4-ol (288 mg, 63% yield). MS: MS m/z 211.1 (M.sup.++1).

Step 2

(93) A mixture of 2-chloro-7-methoxyquinazolin-4(3H)-one (0.88 g, 4.2 mmol) and 1,1-dimethoxypropan-2-amine (2.0 mL, 21 mmol) was heated at 80 C. for 5 h. The reaction was cooled to room temperature. The crude solid was collected and washed with water, filtered and dried to give 2-(1,1-dimethoxypropan-2-ylamino)-7-methoxyquinazolin-4(3H)-one (819 mg, 67%) as a yellow solid. MS: MS m/z 294.2 (M.sup.++1).

Step 3

(94) 2-(1,1-dimethoxypropan-2-ylamino)-7-methoxyquinazolin-4(3H)-one (1.23 g, 4.18 mmol) in acetic acid (6.00 mL, 105 mmol) was heated at reflux for 5 days. The mixture was cooled to r.t. Ether was added to the mixture. The precipitate that formed was isolated via filtration, washed with water and dried to give 8-methoxy-2-methylimidazo[1,2-a]quinazolin-5(4H)-one (400 mg, 70% pure, 30% yield). MS: MS m/z 230.1 (M.sup.++1).

Step 4

(95) The solution of 70% pure 8-methoxy-2-methylimidazo[1,2-a]quinazolin-5(4H)-one (400 mg, 1.31 mmol) in phosphoryl trichloride (10 ml, 1.3 mmol) was stirred at 90 C. for 6 h. The solution was cooled to r.t and then concentrated in vacuo. 1N NaOH was added to the mixture to adjust pH=7. The brown solid was collected and washed with water. The crude product 5-chloro-8-methoxy-2-methylimidazo[1,2-a]quinazoline (300 mg) was used directly for the next step reaction. MS: MS m/z 248.2 (M.sup.++1).

Preparation of 5-chloroimidazo[1,2-a]quinazoline

(96) ##STR00041##

(97) ##STR00042##

Step 1-4

(98) 5-chloroimidazo[1,2-a]quinazoline was then prepared using the similar procedure described for synthesizing 5-chloro-8-methoxy-2-methylimidazo[1,2-a]quinazoline. 2,4-dichloroquinazoline in step 1 and 1,1-dimethoxypropan-2-amine in step 2 were used as starting materials instead of 2,4-dichloro-7-methoxyquinazoline and 1-dimethoxypropan-2-amine respectively. MS: MS m/z 205.0 (M.sup.++1).

Preparation of 5,7-dichloroimidazo[1,2-a]quinazoline

(99) ##STR00043##

(100) ##STR00044##

Step 1-4

(101) 5,7-dichloroimidazo[1,2-a]quinazoline was then prepared using the similar procedure described for synthesizing 5-chloro-8-methoxy-2-methylimidazo[1,2-a]quinazoline. 2,4,6-trichloroquinazoline in step 1 and 1,1-dimethoxypropan-2-amine in step 2 were used as starting materials instead of 2,4-dichloro-7-methoxyquinazoline and 1-dimethoxypropan-2-amine respectively. MS: MS m/z 238.0 (M.sup.++1).

Preparation of 5,7-dichloro-2-methylimidazo[1,2-a]quinazoline

(102) ##STR00045##

(103) ##STR00046##

Step 1-4

(104) 5,7-dichloro-2-methylimidazo[1,2-a]quinazoline was then prepared using the similar procedure described for synthesizing 5-chloro-8-methoxy-2-methylimidazo[1,2-a]quinazoline. 2,4,6-trichloroquinazoline in step 1 was used as starting materials instead of 2,4-dichloro-7-methoxyquinazoline. MS: MS m/z 251.9 (M.sup.++1).

Preparation of 5-chloro-[1,2,4]-triazolo[4,3-a]quinazoline

(105) ##STR00047##

(106) ##STR00048##

Step 1

(107) A solution of 2,4-dichloroquinazoline (2.7 g, 13.6 mmol) in 20 mL THF and 20 mL of aq. 1N NaOH solution was stirred at r.t for 2 h. The volatiles were removed in vacuo and the aqueous solution containing crude product 2-chloroquinazolin-4(3H)-one was used directly in the next step. MS: MS m/z 181.0 (M.sup.++1).

Step 2

(108) To the solution of 2-chloroquinazolin-4(3H)-one (2.46 g, 13.6 mmol) in water from step 1 was added hydrazine (3 mL). The solution was heated at 95 C. for 3 h. The mixture was cooled to r.t. The reaction was worked up by adding acetic acid into the solution to adjust to pH=7. The precipitated solid was isolated via filtrated and washed with water to afford crude product 2-hydrazinylquinazolin-4(3H)-one (2.11 g, 74%) that was used directly in step 3. MS: MS m/z 177.0 (M.sup.++1).

Step 3

(109) 2-hydrazinylquinazolin-4(3H)-one (2.11 g, 12.0 mmol) in formic acid (10 mL) was heated at 100 C. in for 2 h. The reaction was cooled down to r.t and then poured into water to precipitate the product. Sat. aq. NaHCO.sub.3 was added to the mixture to neutralize the acid. The resulting solid was isolated via filtration and washed with water. The product [1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one (1.87 g, 81% yield) was dried and used directly in the next step reaction. MS: MS m/z 187.0 (M.sup.++1).

Step 4

(110) A solution of [1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one (1.87 g, 10.04 mmol) in phosphoryl trichloride (10 mL) was stirred at 90 C. for 2 h. The solution was cooled to r.t and then concentrated in vacuo. To the residue was added aq. 1N NaOH to adjust pH=7. The brown solid was collected and washed with water. The crude product 5-chloro-[1,2,4]triazolo[4,3-a]quinazoline (1.57 g, 73%) was used directly without further purification. MS: MS m/z 205.0 (M.sup.++1).

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

(111) ##STR00049##

(112) ##STR00050##

Step 1

(113) 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 tert-butyl (1-(hydroxymethyl)cyclopropyl)sulfonylcarbamate (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

(114) 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 solution. 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

(115) To a solution of tert-butyl 1-fluoromethyl cyclopropylsulfonylcarbamate (19 g, 75 mmol) in dichlomethane (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 (1 F).

Step 4

(116) 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 solution. 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

(117) 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)

Preparation of 3,3-difluoro-2-methylbutan-2-yl pyridin-2-yl carbonate

(118) ##STR00051##

(119) ##STR00052##

Step 1

(120) Methylmagnesium bromide (24.9 mL, 74.7 mmol) was added dropwise via syringe to a solution of ethyl 2,2-difluoropropanoate (3.44 g, 24.91 mmol) in diethyl ether (50 mL) at 20 C. and stirred at this temp for 1 h before warming up to RT. The reaction was quenched with sat. ammonium chloride and extracted with ether. The organic layer was washed with brine; dried over MgSO.sub.4; filtered and concentrated in vacuo to afford the crude 3,3-difluoro-2-methylbutan-2-ol (1.84 g, 59.5% yield) as an oil. .sup.1H NMR (500 MHz, CDCl.sub.3) 1.68-1.58 (m, 3H), 1.31 (t, J=1.2 Hz, 6H).

Step 2

(121) To a suspension of sodium hydride, 60% in mineral oil (0.652 g, 16.31 mmol) in THF (25 mL) was added 3,3-difluoro-2-methylbutan-2-ol (1.84 g, 14.82 mmol) at 0 C. After stirring 30 min, the solution was transferred to a solution of di(pyridin-2-yl) carbonate (3.20 g, 14.82 mmol) in THF (25 mL) through a cannula. The formed slurry was stirred at 0 C. for 30 min. The slurry was warmed to rt and stirred for 2 h. The reaction was diluted with EtOAc, washed with brine, dried over MgSO.sub.4, filtered, concentrated to give a residue that was purified by silica gel chromatography eluting with 10-50% EtOAc in hexanes to 3,3-difluoro-2-methylbutan-2-yl pyridin-2-yl carbonate (500 mg, 13.76%) as an oil that later crystallized to a white solid upon standing. .sup.1H NMR (500 MHz, CDCl.sub.3) 8.43 (ddd, J=4.9, 2.0, 0.7 Hz, 1H), 7.95-7.75 (m, 1H), 7.31-7.24 (m, 1H), 7.15 (dt, J=8.2, 0.8 Hz, 1H), 1.72 (s, 6H), 1.77-1.66 (m, 3H).

(122) ##STR00053## ##STR00054##

Step 1: Preparation of (S)-5-methylnon-8-en-3-ol

(123) ##STR00055##

(124) Magnesium turnings (3.03 g, 125 mmole) were suspended in dry THF (100 mL) and to the mixture was added iodine (100 mg) at room temperature. To this reaction mass was added a solution of 5-bromohex-1-ene (20.37 g, 125 mmole) in THF (200 mL). The reaction mass was heated with hot air gun to initiate the reaction. Upon full conversion of the bromide, the solution was transferred via cannula to a solution of (S)-2-ethyloxirane (6.05 g, 83 mmol) and copper bromide (1.19 g, 8.32 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 aqueous ammonium chloride solution and extracted with diethyl ether (200 mL3). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4; filtered; then 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 (S)-5-methylnon-8-en-3-ol (9.5 g, 73.1%) as an oily liquid. .sup.1H NMR (400 MHz, CDCl.sub.3): ppm 0.87-0.97 (m, 6H), 1.22-1.32 (m, 4H), 1.52-1.72 (m, 2H), 1.90-2.29 (m, 2H), 3.38-3.45 (m, 2H), 4.16-4.19 (m, 1H), 4.91-5.02 (m, 2H), 5.75-5.82 (m, 1H).

Step 2: Preparation of (S)-5-methylnon-8-en-3-yl 4-methylbenzenesulfonate

(125) ##STR00056##

(126) To a solution of (S)-5-methylnon-8-en-3-ol (9.5 g, 61 mmol) in DCM (100 mL) was added pyridine (20 mL) followed by DMAP (0.74 g, 6.08 mmole) and the solution was stirred for 10 min. p-toluenesulfonyl chloride (17.39 g, 91 mmole) was added to the reaction mass at 0 C. The reaction mass was allowed to come to room temperature and stirred overnight. Solvent was removed under reduced pressure and the residue was diluted with ethyl acetate (100 mL). The organic solution was washed with aqueous 1.5 N HCl solution; saturated bicarbonate solution; brine solution; dried over anhydrous Na.sub.2SO.sub.4; filtered; and evaporated under reduced pressure to get crude compound (15 g, 79%). The crude compound was taken to the next step without further purification. MS: MS m/z 328.4 (M.sup.++18).

Step 3: Preparation of (3R)-ethyl 2-(diphenylmethyleneamino)-3-ethyl-5-methylnon-8-enoate

(127) ##STR00057##

(128) To a solution of (S)-5-methylnon-8-en-3-yl 4-methylbenzenesulfonate (15 g, 48 mmole) and N-(diphenylmethylene)glycinate ethyl ester (15.5 g, 58.0 mmole) in toluene (150 mL) at 0 C. was added lithium bis(trimethylsilyl)amide (LiHMDS, 72.5 mL, 72.5 mmole, 1 M solution in THF). The reaction mass was allowed to come to room temperature, and then was heated at 110 C. for 2 h. The reaction mass was cooled to room temperature, quenched with water and extracted with ethyl acetate (100 mL3). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4; filtered; then concentrated under reduced pressure to get crude compound (7.0 g, 35.7%). The crude compound was taken to the next step without further purification. MS: MS m/z 406.4 (M.sup.++1).

Step 4: Preparation of (3R)-ethyl 2-amino-3-ethyl-5-methylnon-8-enoate hydrochloride

(129) ##STR00058##

(130) A solution of (3R)-ethyl 2-(diphenylmethyleneamino)-3-ethyl-5-methylnon-8-enoate (7.00 g, 17.3 mmole) in diethyl ether (20 mL) was added aqueous 1.5 N HCl solutions (100 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 extracted with ethyl acetate (100 mL3). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4; filtered; then concentrated under reduced pressure to get crude compound (2.6 g, 62.4%). The crude compound was taken to the next step without further purification. MS: MS m/z 242.4 (M.sup.++1).

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

(131) ##STR00059##

(132) A solution of (3R)-ethyl 2-amino-3-ethyl-5-methylnon-8-enoate hydrochloride (2.99 g, 10.8 mmole) in DCM (20 mL) was added N,N-diisopropylethylamine (DIPEA, 1.08 mL, 10.8 mmole) followed by (Boc).sub.2O (2.39 mL, 10.8 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; then concentrated under reduced pressure to get crude compound. The crude compound was purified by column chromatography (Silica gel, 20% ethyl acetate in pet-ether) to get 2.3 g, (62.5%) of (3R)-ethyl 2-(tert-butoxycarbonylamino)-3,5-dimethylnon-8-enoate as an oily liquid. MS: MS m/z 342.4 (M.sup.++1).

Step 6: Preparation of (3R)-2-(tert-butoxycarbonylamino)-3-ethyl-5-methylnon-8-enoic acid

(133) ##STR00060##

(134) To a solution of (3R)-ethyl 2-(tert-butoxycarbonylamino)-3-ethyl-5-methylnon-8-enoate (2.30 g, 6.74 mmole) in THF/water (50 mL, 1:1) was added methanol (10 mL) followed by LiOH (0.84 g, 20 mmol) at room temperature. The reaction mass was stirred at room temperature overnight. Solvent was evaporated under reduced pressure and the residue was diluted with water (10 mL). The aqueous solution was acidified with aqueous 1.5 N HCl solutions to pH 3 and extracted with ethyl acetate (100 mL3). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4; filtered; then concentrated under reduce pressure to get crude compound. The crude compound was purified by column chromatography (Silica gel, 2% methanol in DCM) to get 1.5 g (71%) of Intermediate 9 as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): ppm 1.27-1.09 (m, 8H), 1.02-1.35 (m, 3H), 1.39 (s, 11H), 1.91-1.97 (m, 1H), 1.99-2.02 (m, 2H), 4.03-4.12 (m, 1H), 4.90-5.03 (m, 2H), 5.74-5.84 (m, 1H), 6.80-6.83 (m, 1H), 12.47 (sb, 1H).

Step 7: Preparation of (2S,4R)-methyl 1-((2S,3R)-2-(tert-butoxycarbonylamino)-3-ethyl-5-methylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylate

(135) ##STR00061##

(136) To a solution of (3R)-2-(tert-butoxycarbonylamino)-3-ethyl-5-methylnon-8-enoic acid (2.0 g, 6.4 mmole) in dichloromethane (20 mL) was added DIPEA (1.93 mL, 19.2 mmole) and HATU (2.42 g, 6.38 mmole) followed by (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate (1.15 g, 6.38 mmole) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mass was diluted with DCM and washed with water. The organic layer was dried over anhydrous Na.sub.2SO.sub.4; filtered; then concentrated under reduced pressure to get crude compound as mixture of diastereomers. The material was subjected to SFC purification to afford (2S,4R)-methyl 1-((2S,3R)-2-(tert-butoxycarbonylamino)-3-ethyl-5-methylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylate (1.5 g, 53%). MS: MS m/z 441.6 (M.sup.++1).

Step 8: Preparation of (2S,4R)-1-((2S,3R)-2-(tert-butoxycarbonylamino)-3-ethyl-5-methylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylic acid

(137) ##STR00062##

(138) To a solution of (2S,4R)-methyl 1-((2S,3R)-2-(tert-butoxycarbonylamino)-3-ethyl-5-methylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylate (1.5 g, 3.40 mmole) in THF:water (16 mL, 1:1) was added LiOH (286 mg, 6.80 mmole) followed by 3 mL of methanol at room temperature. The reaction mass was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was diluted with water and acidified with aqueous 1.5 N HCl solutions. The aqueous solution was extracted with ethyl acetate (20 mL3). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4; filtered; then concentrated under reduced pressure to afford (2S,4R)-1-((2S,3R)-2-(tert-butoxycarbonylamino)-3-ethyl-5-methylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylic acid (1.3 g, 90%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): ppm 0.81-0.93 (m, 6H), 1.12-1.29 (m, 5H), 1.30-1.50 (m, 11H), 1.71-1.80 (m, 2H), 1.91-2.51 (m, 4H), 3.57-3.59 (m, 1H), 4.27-4.35 (m, 3H), 4.92-4.97 (m, 2H), 5.01-5.15 (m, 1H), 5.74-5.79 (m, 1H), 6.30-6.80 (m, 1H), 12.50 (sb, 1H). MS: MS m/z 427.6 (M.sup.++1).

Step 9: Preparation of tert-butyl (2S,3R)-1-((2S,4R)-2-((1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamoyl)-4-hydroxypyrrolidin-1-yl)-3-ethyl-5-methyl-1-oxonon-8-en-2-ylcarbamate

(139) ##STR00063##

(140) To a solution of (2S,4R)-1-((2S,3R)-2-(tert-butoxycarbonylamino)-3-ethyl-5-methylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylic acid (1.3 g, 3.05 mmole) in dichloromethane (50 mL) was added HATU (1.15 g, 3.05 mmole) followed by DIPEA (1.6 mL, 9.13 mmole) at room temperature. The reaction mass was stirred at the same temperature for 10 min. (1R,2S)-1-amino-N-(cyclopropylsulfonyl)-2-vinylcyclopropanecarboxamide (1.22 g, 3.05 mmole) was added to the reaction mass and the mixture was stirred at room temperature for 1 h. The reaction mass was diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous Na.sub.2SO.sub.4; filtered; then concentrated under reduced pressure to get the crude compound. The crude compound was purified by silica gel chromatography (6% methanol in chloroform) to get 1.7 g (87%) of tert-butyl (2S,3R)-1-((2S,4R)-2-((1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamoyl)-4-hydroxypyrrolidin-1-yl)-3-ethyl-5-methyl-1-oxonon-8-en-2-ylcarbamate as a white solid. MS: MS m/z 639.55 (M.sup.++1).

Step 10: Preparation of tert-butyl (2R,6S,7R,13aS,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-7-ethyl-2-hydroxy-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-ylcarbamate

(141) ##STR00064##

(142) To a degassed solution of tert-butyl (2S,3R)-1-42S,4R)-2-41R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamoyl)-4-hydroxypyrrolidin-1-yl)-3-ethyl-5-methyl-1-oxonon-8-en-2-ylcarbamate (1.7 g, 2.66 mmole) in dichloroethane (100 mL) was added (1,3-Bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o-isopropoxyphenylmethylene)ruthenium (Hoveyda-Grubbs II generation catalyst, 266 mg) at room temperature under nitrogen atmosphere. The reaction mass was heated at 95 C. overnight. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (5% methanol in chloroform) to afford tert-butyl (2R,6S,7R,13aS,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-7-ethyl-2-hydroxy-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-ylcarbamate (770 mg, 47%) as a pale yellow crystalline solid. MS: MS m/z 609.20 (M.sup.+1).

Preparation of tert-butyl((2S,3R)-3-ethyl-14(2S,4R)-4-hydroxy-2-(((1R,2S)-1-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)pyrrolidin-1-yl)-5-methyl-1-oxonon-8-en-2-yl)carbamate

(143) ##STR00065##

(144) The same procedure was used as described for the 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)-3,5-dimethyl-1-oxonon-8-en-2-yl)carbamate but(2S,4R)-1-((2S,3R)-2-(tert-butoxycarbonylamino)-3-ethyl-5-methylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylic acid was used as starting material instead of (2S,4R)-1-((3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylic acid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): ppm 10.42 (d, J=4.02 Hz, 1H) 8.83 (d, J=8.53 Hz, 1H) 6.24 (m, 1H) 5.81 (m, 1H) 5.57 (m, 1H) 5.05 (m, 5H) 4.32 (m, 3H) 3.59 (m, 2H) 1.92 (m, 8H) 1.25 (m, 21H) 0.84 (m, 8H) MS: MS m/z 653.4 (M.sup.++1)

Preparation of tert-butyl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-7-ethyl-2-hydroxy-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

(145) ##STR00066##

(146) The same procedure was used as described for of tert-butyl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-hydroxy-7,9-dimethyl-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 but tert-butyl((2S,3R)-3-ethyl-1-((2S,4R)-4-hydroxy-2-(((1R,2S)-1-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)pyrrolidin-1-yl)-5-methyl-1-oxonon-8-en-2-yl)carbamate was used as a starting material instead of tert-butyl((2S,3R)-1-((2S,4R)-4-hydroxy-2-(((1R,2S)-1-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)pyrrolidin-1-yl)-3,5-dimethyl-1-oxonon-8-en-2-yl)carbamate. .sup.1H NMR (400 MHz, DMSO-d.sub.6): ppm 8.32 (s, 1H) 7.01 (d, J=9.54 Hz, 1H) 5.38 (m, 2H) 5.08 (m, 1H) 4.40 (br. s., 1H) 4.20 (t, J=7.78 Hz, 1H) 4.00 (m, 1H) 3.67 (m, 2H) 2.85 (q, J=7.53 Hz, 3H) 2.22 (d, J=8.03 Hz, 1H) 1.84 (m, 4H) 1.29 (m, 22H) 0.84 (m, 6H) 0.48 (m, 2H). MS: MS m/z 625.4 (M.sup.++1).

(147) ##STR00067##

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

(148) ##STR00068##

(149) To a solution of lithium aluminum hydride in THF (LAH, 20.1 g, 106 mmol, 509 mL, 1M solution) was added a solution of hex-5-en-2-one (50 g, 102 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

(150) ##STR00069##

(151) 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 hex-5-en-2-yl methanesulfonate as light brown oil (73 g, 82%). .sup.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

(152) ##STR00070##

(153) 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%). .sup.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 (2S)-4-methyloct-7-en-2-ol

(154) ##STR00071##

(155) To magnesium turnings (7.44 g, 0.020 moles) in dry THF (100 mL) and was added iodine (100 mg) at room temperature. To this reaction mass was added a solution of 5-bromohex-1-ene (50.0 g, 362 mmoles) 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 (S)-propylene oxide (14 g, 241 mmol) and copper bromide (3.45 g, 24 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; filtered; then concentrated in vacuo at room temperature to get crude compound. The crude compound was purified by column chromatography (Silica gel, 10% TBME in pet ether) to get (2S)-4-methyloct-7-en-2-ol (12.4 g, 30%) as an oil. .sup.1H NMR (400 MHz, CDCl.sub.3): ppm 5.84-5.77 (m, 1H), 5.02-4.92 (m, 2H), 4.05-3.85 (sb, 1H), 2.08-2.06 (m, 2H), 1.29-1.20 (m, 2H), 1.19-1.16 (m, 4H), 0.97-0.87 (m, 6H).

Step 5: Preparation of (2S)-4-methyloct-7-en-2-yl 4-methylbenzenesulfonate

(156) ##STR00072##

(157) To a solution of (2S)-4-methyloct-7-en-2-ol (39.0 g, 0.274 moles) in pyridine (400 mL) was added 4-(dimethylamino)pyridine (DMAP, 1.67 g, 0.013 moles) and the solution was stirred for 10 min. p-toluenesulfonyl chloride (60 g, 0.315 moles) was added to the reaction mass at 0 C. The reaction mass was allowed to come to room temperature and stirred overnight. Pyridine was removed under reduced pressure and the residue was diluted with ethyl acetate (200 mL). The organic solution 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 (25)-4-methyloct-7-en-2-yl 4-methylbenzenesulfonate (54 g, 61%). The crude compound was taken to the next step without further purification.

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

(158) ##STR00073##

(159) To a solution of (25)-4-methyloct-7-en-2-yl 4-methylbenzenesulfonate (54 g, 0.182 moles) and N-(diphenylmethylene)glycinate ethyl ester (48.7 g, 0.182 moles) in toluene (500 mL) was added LiHMDS (36.5 g, 0.218 moles, 1 M solution in THF) at 0 C. The reaction mass was allowed to come to room temperature and was then heated at 110 C. for 2 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)-3,5-dimethylnon-8-enoate (75 g). The crude compound was taken to the next step without further purification.

Step 7: Preparation of (3R)-ethyl 2-amino-3,5-dimethylnon-8-enoate hydrochloride

(160) ##STR00074##

(161) To a solution of (3R)-ethyl 2-((diphenylmethylene)amino)-3,5-dimethylnon-8-enoate (20 g) in diethyl ether (20 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 (3R)-ethyl 2-amino-3,5-dimethylnon-8-enoate hydrochloride (4 g, 30%). The crude compound was taken to the next step without further purification.

Step 8: Preparation of (3R)-ethyl 2-(tert-butoxycarbonylamino)-3,5-dimethylnon-8-enoate

(162) ##STR00075##

(163) A solution of (3R)-ethyl 2-amino-3,5-dimethylnon-8-enoate hydrochloride (4 g, 0.017 moles) in DCM (40 mL) was added N,N-diisopropylethylamine (DIPEA, 3.4 g, 0.026 moles) followed by di-tert-butyl dicarbonate (4.6 g, 0.021 moles) at room temperature. The reaction mass was stirred at room temperature overnight.

(164) 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 4.7 g, (94%) of (3R)-ethyl 2-(tert-butoxycarbonylamino)-3,5-dimethylnon-8-enoate as an oil.

Step 9: Preparation of (3R)-2-(tert-butoxycarbonylamino)-3,5-dimethylnon-8-enoic acid

(165) ##STR00076##

(166) To a solution of (3R)-ethyl 2-(tert-butoxycarbonylamino)-3,5-dimethylnon-8-enoate (20 g, 0.061 moles) in THF/water (200 mL, 1:1) was added methanol (60 25 mL) followed by LiOH (7.7 g, 0.183 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 (200 mL). The aqueous solution was acidified with aqueous 1.5 N HCl solution to pH 3 and extracted with ethyl acetate (100 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 12.4 g (68%) of (3R)-2-(tert-butoxycarbonylamino)-3,5-dimethylnon-8-enoic acid as a gummy liquid. .sup.1H NMR (400 MHz, DMSO-d6): ppm 12.4 (sb, 1H), 6.92-6.85 (m, 1H), 5.81-5.75 (m, 1H), 5.04-4.93 (m, 2H), 4.12-3.91 (m, 1H), 2.18-1.98 (m, 4H), 1.5 (s, 9H), 1.35-1.02 (m, 3H), 0.98-0.85 (m, 6H).

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

(167) ##STR00077##

(168) O-(7-Azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (HATU, 31.7 g, 83 mmol) was added to a solution of (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate HCl (16.68 g, 92 mmol), (3R)-2-((tertbutoxycarbonyl)amino)-3,5-dimethylnon-8-enoic acid (25 g, 83 mmol) and NEt.sub.3 (34.9 mL, 250 mmol) in DCM (250 mL) and stirred at RT for 16 h. The reaction was washed with 1N HCl (3) and then brine. 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 142R,3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylate (12 g, 34% yield). MS: MS m/z 427.2 (M.sup.++1).

(169) ##STR00078##

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

(170) ##STR00079##

(171) (2S,4R)-methyl 1-((2S,3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylate (10.8 g, 25.3 mmol) was dissolved in THF (50 mL) and MeOH (50 mL) and to this solution was added LiOH (2.425 g, 101 mmol) in Water (50.0 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 crude (2S,4R)-1-((2S,3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylic acid (12 g) as yellow viscous oil. MS: MS m/z 413.2 (M.sup.++1).

Step 2: 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)-3,5-dimethyl-1-oxonon-8-en-2-yl)carbamate

(172) ##STR00080##

(173) HATU (7.60 g, 20.00 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 (7.86 g, 19.05 mmol), (1R,2S)-1-amino-N-((1-methylcyclopropyl)5 sulfonyl)-2-vinylcyclopropanecarboxamide HCl (5.62 g, 20 mmol), and DIPEA (13.31 mL, 76 mmol) in DCM (110 mL). The reaction mixture was stirred at rt for 16 h. The mixture was washed with 1N HCl (3), 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)-4-hydroxy-2-(((1R,2S)-1-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)pyrrolidin-1-yl)-3,5-dimethyl-1-oxonon-8-en-2-yl)carbamate (9 g, 74% yield) as a light orange foam. MS: MS m/z 639.3 (M.sup.++1).

Step 3: Preparation of tert-butyl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-hydroxy-7,9-dimethyl-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

(174) ##STR00081##

(175) 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)-3,5-dimethyl-1-oxonon-8-en-2-yl)carbamate (8.4 g, 13.15 mmol) in DCE (1500 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, 0.413 g, 0.657 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 the mixture of diastereomers as a brown solid (5.6 g, 70% yield). The material was further purified by SFC to afford the single diastereomer tert-butyl((2R,6S,7R,13aS,14aR,16aS,Z)-2-hydroxy-7,9-dimethyl-14a-4(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 611.3 (M.sup.++1).

(176) ##STR00082##

Step 1: Preparation of tert-butyl cyclopropylsulfonylcarbamate

(177) 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-d6): 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

(178) 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-d6): 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

(179) 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

(180) ##STR00083##

(181) 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 solution. 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

(182) ##STR00084##

(183) 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 tert-butyl((2R,6S,7R,13aS,14aR,16aS,Z)-14a-(((1-(fluoromethyl)cyclopropyl)sulfonyl)carbamoyl)-2-hydroxy-7,9-dimethyl-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

(184) ##STR00085##

(185) ##STR00086##

Step 1

(186) To a solution of (2S,4R)-1-((2S,3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylic acid (10.5 g, 25.5 mmol), (1R,2S)-1-amino-N-((1-(fluoromethyl)cyclopropyl)sulfonyl)-2-vinylcyclopropanecarboxamide HCl (8.37 g, 28 mmol), and triethylamine (14.2 mL, 102 mmol) in DCM (220 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 11.61 g, 30.5 mmol). The mixture was stirred at room temperature overnight. The mixture was washed with aq. 1N HCl (3) and then with brine; dried over MgSO.sub.4; filtered; then concentrated in vacuo. The crude material was purified by silica gel chromatography using 20-40% acetone in hexanes. The product fractions were collected and the solvent removed under vacuum to afford tert-butyl((2S,3R)-1-((2S,4R)-2-(((1R,2S)-1-(((1-(fluoromethyl)cyclopropyl)sulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-3,5-dimethyl-1-oxonon-8-en-2-yl)carbamate (15 g, 90% yield). MS: MS m/z 657.3 (M.sup.++1).

Step 2

(187) 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)-3,5-dimethyl-1-oxonon-8-en-2-yl)carbamate (7.5 g, 22.84 mmol) in DCE (2855 ml) was sparged with nitrogen for 30 min. and then Hoveyda-Grubbs Catalyst 2nd Generation (0.718 g, 1.142 mmol) was added and the reaction was heated to 80 C. for 2 hrs. The solution was concentrated in vacuo and the resulting residue was purified by flash chromatography on silica gel (20-60% Acetone in hexanes) to afford tert-butyl((2R,6S,7R,13aS,14aR,16aS,Z)-14a-(((1-(fluoromethyl)cyclopropyl)sulfonyl)carbamoyl)-2-hydroxy-7,9-dimethyl-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 (4 g, 28% yield). MS: MS m/z 629.3 (M.sup.++1).

(188) ##STR00087##

(189) (1-chloro-6-methoxyisoquinolin-4-yl)boronic acid (0.1 g, 0.421 mmol) and 2-bromo-4-(tert-butyl)thiazole (0.111 g, 0.505 mmol) were dissolved in DME (1 mL):water (0.5 mL):ethanol (0.25 mL). The solution was sparged with nitrogen gas for 5 min. Potassium carbonate (0.175 g, 1.263 mmol) was added to the solution, then to the solution was added Pd(PPh.sub.3).sub.4 (0.024 g, 0.021 mmol). The solution was heated at 100 C. for 1 h. The reaction mixture was poured into water, extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude sample was purified by silica gel chromatography using 15% ethyl acetate in Pet-ether to afford 4-(tert-butyl)-2-(1-chloro-6-methoxyisoquinolin-4-yl)thiazole (0.06 g, 41% yield) as white solid. .sup.1H NMR (400 MHz, CDCl.sub.3): ppm 7.34 (dd, J=9.26, 2.50 Hz, 1H) 7.26 (s, 3H) 7.05 (s, 1H) 3.97 (s, 3H) 1.47 (s, 9H). MS: MS m/z 333.5 (M.sup.++1).

(190) ##STR00088##

Step 1: 4-chloro-2-(1H-imidazol-1-yl)-7-methoxyquinoline and 2-chloro-4-(1H-imidazol-1-yl)-7-methoxyquinoline

(191) To a solution of 2,4-dichloro-7-methoxyisoquinolin (0.5 g, 2.19 mmol) in DMF (5 ml) was added Cs.sub.2CO.sub.3 (1.54 g, 4.74 mmol) followed by imidazole (0.16 g, 2.41 mmol). The reaction mixture was heated to 80 C. for 18 h. The reaction mass was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get a mixture of 4-chloro-2-(1H-imidazol-1-yl)-7-methoxyquinoline and 2-chloro-4-(1H-imidazol-1-yl)-7-methoxyquinoline. MS: MS m/z 260.1 (M.sup.++2).

(192) ##STR00089##

Step 1: Synthesis of N-(1-chloro-6-methoxyisoquinolin-4-yl)benzamide

(193) To a suspension of 1-chloro-6-methoxyisoquinolin-4-amine (0.2 g, 0.959 mmol) in pyridine (2 mL) was added benzoyl chloride (0.135 g, 0.959 mmol). The mixture was stirred at room temperature until completion of the reaction. To the solution was added water (4 mL). The mixture was stirred for 10 min, upon which a white solid precipitated. The solid was isolated via filtration, washed with water and dried to afford N-(1-chloro-6-methoxyisoquinolin-4-yl)benzamide (0.26 g, 0.815 mmol, 85% yield) as off-white solid. .sup.1H NMR (400 MHz, DMSO-d6): ppm 10.48 (s, 1H) 8.40 (s, 1H) 8.25 (d, J=9.03 Hz, 1H) 8.06-8.12 (m, 2H) 7.56-7.68 (m, 3H) 7.50 (dd, J=9.29, 2.51 Hz, 1H) 7.37 (d, J=2.51 Hz, 1H) 3.94 (s, 3H). MS: MS m/z 313.5 (M.sup.++1).

Step 2: Synthesis of N-(1-chloro-6-methoxyisoquinolin-4-yl)-N-methylbenzamide

(194) To a 2-neck round-bottom flask under nitrogen, charged with DMF (5 mL) and cooled to 0 C. was added NaH (0.017 g, 0.703 mmol, 60% weight in oil). To the mixture was added N-(1-chloro-6-methoxyisoquinolin-4-yl)benzamide (0.2 g, 0.639 mmol), and the mixture was stirred for 30 min. To the mixture was added methyl iodide (0.040 mL, 0.639 mmol), and the mixture was stirred at room temperature for 18 h. The reaction mixture was poured into ice and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography using 20% ethyl acetate in pet-ether to afford N-(1-chloro-6-methoxyisoquinolin-4-yl)-N-methyl benzamide (0.21 g, 0.611 mmol, 95% yield) as white solid. .sup.1H NMR (400 MHz, DMSO-d6): ppm 8.18 (d, J=9.29 Hz, 1H) 8.06 (s, 1H) 7.48 (dd, J=9.29, 2.26 Hz, 1H) 7.35 (s, 1H) 7.08-7.25 (m, 4H) 4.05 (s, 3H) 3.42 (s, 3H). MS: MS m/z 327.2 (M.sup.++1).

(195) ##STR00090##

Step 1: Synthesis of (1-chloro-6-methoxyisoquinolin-4-yl)boronic acid

(196) To a stirred solution of 4-bromo-1-chloro-6-methoxyisoquinoline (0.75 g, 2.75 mmol) in THF (50 mL) at 78 C. was added n-BuLi (2.27 mL, 3.58 mmol, 1.6 M in hexanes). The reaction solution was stirred for 1 h. To the solution was added triisopropylborate (1.278 mL, 5.50 mmol), and the solution was stirred at the same temperature for 2 h. The solution was allowed to warm to room temperature and then was quenched with water. The volatiles were removed under reduced pressure. The residue was diluted with water; adjusted the pH 1 using 1.5 N HCl solution; and the precipitated solid was isolated via filtration, then was washed with water and dried to afford (1-chloro-6-methoxyisoquinolin-4-yl)boronic acid (0.34 g, 1.289 mmol, 47% yield) as white solid. MS: MS m/z 239.1 (M.sup.++2).

Step 2: Synthesis of 2-(1-chloro-6-methoxyisoquinolin-4-yl)thiazole

(197) (1-chloro-6-methoxyisoquinolin-4-yl)boronic acid (0.1 g, 0.421 mmol) and 2-bromothiazole (0.083 g, 0.505 mmol) were dissolved in DME (1 mL):Water (0.5 mL):Ethanol (0.25 mL). The solution was sparged with nitrogen gas for 5 min. Potassium carbonate (0.175 g, 1.263 mmol) was added to the solution, then to the solution was added Pd(PPh.sub.3).sub.4 (0.024 g, 0.021 mmol). The solution was heated to 100 C. for 1 h. The reaction mixture was poured into water, extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate; then concentrated under reduced pressure. The crude sample was purified by silica gel chromatography using 15% ethyl acetate in Pet-ether to afford 2-(1-chloro-6-methoxyisoquinolin-4-yl)thiazole (0.048 g, 0.139 mmol, 32.9% yield) as white solid.

(198) .sup.1H NMR (400 MHz, DMSO-d6): ppm 8.66 (s, 1H) 8.46 (s, 1H) 8.34 (s, 1H) 8.19 (s, 1H) 8.03 (s, 1H) 7.57 (dd, J=9.29, 2.51 Hz, 1H) 3.97 (s, 3H) MS: MS m/z 278.5 (M.sup.++1).

Preparation of N-(1-chloro-6-methoxyisoquinolin-4-yl)-N-ethylbenzamide

(199) ##STR00091##

(200) To a two-neck round-bottom flask charged under nitrogen and charged with DMF (3 mL) at 0 C. was added NaH (0.019 g, 0.799 mmol). To the mixture was added N-(1-chloro-6-methoxyisoquinolin-4-yl)benzamide (0.1 g, 0.320 mmol). The mixture was stirred for 30 min. Iodoethane (0.031 mL, 0.384 mmol) was added; the mixture was stirred at room temperature for 18 h. The reaction mixture was poured into ice and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude sample was purified by silica gel chromatography using 30% ethyl acetate in Pet-ether as eluent to afford N-(1-chloro-6-methoxyisoquinolin-4-yl)-N-ethylbenzamide (0.04 g, 0.094 mmol, 29.4% yield) as solid. .sup.1H NMR (400 MHz, DMSO-d6): ppm 8.18 (d, J=9.03 Hz, 1H) 8.06 (br. s., 1H) 7.47 (d, J=9.54 Hz, 1H) 7.33 (br. s., 1H) 7.07-7.26 (m, 5H) 4.04 (s, 3H) 3.51-3.60 (m, 2H) 1.16 (t, J=6.90 Hz, 3H). MS: MS m/z 341.2 (M.sup.++1).

(201) ##STR00092##

Step 1: Preparation of 4-chloro-2-(3-isopropyl-1H-pyrazol-1-yl)-7-methoxyquinoline

(202) To a solution of 2,4-dichloro-7-methoxyisoquinolin (0.54 g, 2.36 mmol) in DMF (5 ml) was added Cs.sub.2CO.sub.3 (1.54 g, 4.74 mmol) followed by 3-isopropyl-1H-pyrazole (0.78 g, 7.10 mmol). The reaction mixture was heated to 80 C. for 18 h. The reaction mass was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4 and then concentrated under reduced pressure to get crude compound. The crude compound was silica gel chromatography to get desired compound (0.1 g, 14%) as white solid. .sup.1H NMR (400 MHz, CDCl.sub.3): ppm 8.60 (d, J=2.51 Hz, 1H) 8.07 (d, J=9.04 Hz, 1H) 8.15 (s, 1H) 8.07 (d, J=9.04 Hz, 1H) 8.15 (s, 1H) 7.26 (s, 2H) 7.16-7.22 (m, 1H) 6.35 (d, J=2.51 Hz, 1H) 3.97-3.99 (m, 4H) 3.10 (quin, J=7.03 Hz, 1H) 1.36 (s, 4H) 1.34 (s, 3H). MS: MS m/z 302.1 (M.sup.++1).

(203) ##STR00093##

Step 1: Synthesis of 1-chloro-6-methoxyisoquinoline-4-carbaldehyde

(204) To a stirred solution of 4-bromo-1-chloro-6-methoxyisoquinoline (0.25 g, 0.917 mmol) in THF (10 mL) at 78 C. was added n-BuLi (0.860 mL, 1.376 mmol, 1.6 M in hexanes). Stirred the reaction mixture for 1 h. N-methoxy-N-methylformamide (0.123 g, 1.376 mmol) was added to the solution; stirred at the same temperature for 1 h. The mixture was allowed to warm to room temperature and then was quenched with aq. 1.5N HCl solution; extracted with ethyl acetate. The combined organic layers were washed with brine solution; dried over sodium sulfate and concentrated under reduced pressure. The crude sample was purified by silica gel chromatography using 25% ethyl acetate in Pet-ether to afford 1-chloro-6-methoxyisoquinoline-4-carbaldehyde (0.15 g, 0.474 mmol, 51.6% yield) as white solid. .sup.1H NMR (400 MHz, DMSO-d6): ppm 8.86 (s, 1H) 8.58 (s, 1H) 8.37 (d, J=9.29 Hz, 1H) 8.15-8.23 (m, 1H) 7.56 (dd, J=9.29, 2.51 Hz, 1H) 4.01 (s, 3H). MS: MS m/z 221.8 (M.sup.++1).

Step 2: Synthesis of 5-(1-chloro-6-methoxyisoquinolin-4-yl)oxazole

(205) To a stirred solution of 1-chloro-6-methoxyisoquinoline-4-carbaldehyde (0.15 g, 0.677 mmol) in methanol (10 mL) was added toluenesulphonylmethyl isocyanide (TOSMIC, 0.145 g, 0.744 mmol). The solution was heated at refluxed for 1 h. Removed the volatiles under reduced pressure. To the resulting residue was added water. The mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The crude sample was purified by silica gel chromatography using 35% ethyl acetate in Pet-ether to afford 5-(1-chloro-6-methoxyisoquinolin-4-yl)oxazole (0.08 g, 0.307 mmol, 45.3% yield) as a white solid. .sup.1H NMR (400 MHz, DMSO-d6): ppm 8.68 (s, 1H) 8.52 (s, 1H) 8.32 (d, J=9.29 Hz, 1H) 7.92 (s, 1H) 7.52-7.60 (m, 2H) 4.00 (s, 3H). MS: MS m/z 261.1 (M.sup.++1).

(206) ##STR00094##

Step 1: Synthesis of 3-(trifluoromethyl)pyrido[2,3-b]pyrazin-2-ol and 2-(trifluoromethyl)pyrido[2,3-b]pyrazin-3-ol

(207) To a suspension of pyridine-2,3-diamine (1 g, 9.16 mmol) in ethanol (10 mL) was added ethyl trifluoropyruvate (1.11 mL, 9.16 mmol). The reaction mixture was refluxed at 90 C. for 16 h. The solvent was removed under reduced pressure and the residue was diluted with pet-ether. The precipitated solid was isolated via filtration to get a mixture of 3-(trifluoromethyl)pyrido[2,3-b]pyrazin-2-ol and 2-(trifluoromethyl)pyrido[2,3-b]pyrazin-3-ol (0.70 g, 3.25 mmol). MS: MS m/z 216.0 (M.sup.++1).

Step 2: Synthesis of 2-chloro-3-(trifluoromethyl)pyrido[2,3-b]pyrazine and 3-chloro-2-(trifluoromethyl)pyrido[2,3-b]pyrazine

(208) The suspension of 3-(trifluoromethyl)pyrido[2,3-b]pyrazin-2-ol and 2-(trifluoromethyl)pyrido[2,3-b]pyrazin-3-ol (0.70 g, 3.25 mmol) in POCl.sub.3 (10 mL) was refluxed at 100 C. for 2 h. The solvent was removed under reduced pressure and the residue was diluted with ice cold water. The aqueous solution was basified to pH 9.0 by using sodium bicarbonate, then was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography using 10% ethyl acetate in Pet-ether to get a mixture of 2-chloro-3-(trifluoromethyl)pyrido[2,3-b]pyrazine and 3-chloro-2-(trifluoromethyl)pyrido[2,3-b]pyrazine (0.32 g, 1.233 mmol, 37.9% yield). MS: MS m/z 234.0 (M.sup.++1). The mixture was used without further purification.

(209) ##STR00095##

Step 1: Synthesis of 2-chloro-5-nitropyridin-4-amine

(210) To a solution of 2-chloropyridin-4-amine (10 g, 78 mmol) in conc. sulfuric acid (60 mL) at 0 C. was slowly added fuming nitric acid (30 mL). Then reaction mixture was stirred for 30 min. The reaction mixture was slowly poured into ice; the pH was adjusted to 3 with using ammonia solution. The resultant white solid was isolated via filtration. The solid was dissolved in conc. sulfuric acid, then heated to 100 C. for 2 h. The reaction mixture was cooled to room temperature and poured into ice. The aqueous solution was adjusted to pH 3 using ammonia solution; then was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant residue was purified by silica gel chromatography using 30% ethyl acetate in Pet-ether to afford 2-chloro-5-nitropyridin-4-amine (1.2 g, 6.91 mmol, 8.89% yield) and 2-chloro-3-nitropyridin-4-amine (6 g, 34.6 mmol, 44.4% yield) as yellow solids. .sup.1H NMR (400 MHz, DMSO-d6): ppm 7.90 (d, J=5.77 Hz, 1H) 7.34 (br. s., 2H) 6.83 (s, 1H). MS: MS m/z 172.2 (M.sup.+1).

Step 2: Synthesis of 2-methoxy-5-nitropyridin-4-amine

(211) To a solution of 2-chloro-5-nitropyridin-4-amine (0.5 g, 2.88 mmol) in Methanol was added and sodium methoxide (0.233 g, 4.32 mmol) under nitrogen atmosphere and heated to reflux at t 70 C. for 3 h. Removed the volatiles under reduced pressure, quenched by pouring into ice water, filtered the resulting precipitate, washed with cold water and dried to afford 2-methoxy-5-nitropyridin-4-amine (0.4 g, 2.247 mmol, 78% yield) as pale yellow solid. MS: MS m/z 170.2 (M.sup.++1).

Step 3: Synthesis of 6-methoxypyridine-3,4-diamine

(212) Aq. conc. HCl (1 ml, 32.9 mmol) was diluted with water. To the solution was added tin (II) chloride (0.448 g, 2.365 mmol), followed by 2-methoxy-5-nitropyridin-4-amine (0.1 g, 0.591 mmol). The mixture was heated to 60 C. for 18 h. The reaction mixture was cooled to room temperature, then basified using 10% NaOH solution. The mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant crude compound was triturated with 10% ethyl acetate in Pet-ether to afford 6-methoxypyridine-3,4-diamine (0.06 g, 0.366 mmol, 62.0% yield) as a solid. .sup.1H NMR (400 MHz, DMSO-d6): ppm 7.21 (s, 1H), 5.83 (s, 1H), 5.39 (b s, 2H), 4.04 (b s, 2H), 3.62 (s, 3H).

Step 4: Synthesis of 7-methoxy-3-(trifluoromethyl)pyrido[3,4-b]pyrazin-2-ol and 7-methoxy-2-(trifluoromethyl)pyrido[3,4-b]pyrazin-3-ol

(213) To a solution of 6-methoxypyridine-3,4-diamine (0.45 g, 3.23 mmol) in ethanol was added ethyl trifluoropyruvate (0.393 mL, 3.23 mmol). The reaction mixture was heated to reflux at 90 C. for 16 h. The volatiles were removed under reduced pressure. To the residue was added Pet-ether. The resultant solid was isolated via filtration and dried to afford 7-methoxy-3-(trifluoromethyl)pyrido[3,4-b]pyrazin-2-ol and 7-methoxy-2-(trifluoromethyl)pyrido[3,4-b]pyrazin-3-ol as mixture of regioisomer (0.37 g 46% yield). MS: MS m/z 246.2 (M.sup.++1).

Step 5: Synthesis of 2-chloro-7-methoxy-3-(trifluoromethyl)pyrido[3,4-b]pyrazine and 3-chloro-7-methoxy-2-(trifluoromethyl)pyrido[3,4-b]pyrazine

(214) A solution of 7-methoxy-3-(trifluoromethyl)pyrido[3,4-b]pyrazin-2-ol and 7-methoxy-2-(trifluoromethyl)pyrido[3,4-b]pyrazin-3-ol (0.37 g, 1.509 mmol) in POCl.sub.3 (5 mL) was heated to 100 C. for 2 h. The solvent was removed under reduced pressure and the residue was diluted with ice cold water. The aqueous solution was basified to pH 9.0 by using sodium bicarbonate, then was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography using 10% ethyl acetate in Pet-ether to get 2-chloro-7-methoxy-3-(trifluoromethyl)pyrido[3,4-b]pyrazine (0.135 g, 0.435 mmol, 28.8% yield) and 3-chloro-7-methoxy-2-(trifluoromethyl)pyrido[3,4-b]pyrazine (0.035 g, 0.435 mmol, 4.8% yield) as yellow solids.

(215) 2-chloro-7-methoxy-3-(trifluoromethyl)pyrido[3,4-b]pyrazine: .sup.1H NMR (400 MHz, DMSO-d6): ppm 9.40 (d, J=0.75 Hz, 1H) 7.60 (s, 1H) 4.08 (s, 3H). MS: MS m/z 264.2 (M+1).

(216) 3-chloro-7-methoxy-2-(trifluoromethyl)pyrido[3,4-b]pyrazine: MS: MS m/z 264.2 (M.sup.++1).

Preparation of 2-chloro-3-cyclopropyl-6-methoxyquinoxaline

(217) ##STR00096##

Preparation of 2-chloro-3-cyclopropyl-6-methoxyquinoxaline

(218) A solution of 2,3-dichloro-6-methoxyquinoxaline (100 mg, 0.437 mmol), cyclopropyl boronic acid (82 mg. 0.96 mmol) and cesium carbonate (284 mg, 0.873 mmol) in dioxane (5 mL) was sparged with nitrogen for 30 min. To this reaction mass was added Pd(PPh.sub.3).sub.4 (15 mg, 0.013 mmol) and resultant mixture was heated in a pressure tube at 100 C. for 16 h. The reaction mixture was diluted with EtOAc and washed with water followed by brine solution. The organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography (4% EtOAc in pet ether) to afford a mixture of regioisomer. The material was further purified by SFC to separate the regioisomers and afford 2-chloro-3-cyclopropyl-6-methoxyquinoxaline (30 mg, 0.128 mmol, 29.3% yield) as a white solid and 2-chloro-3-cyclopropyl-6-methoxyquinoxaline (5 mg) as a white solid. 2-Chloro-3-cyclopropyl-6-methoxyquinoxaline: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.88 (d, J=8 Hz, 1H) 7.43-7.40 (m, 1H) 7.32 (d, J=2.8, 1H) 3.93 (s, 3H) 2.69 (m, 1H) 1.23 (m, 4H). MS: MS m/z 234.94 (M.sup.++1).

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

(219) ##STR00097##

(220) 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 Na.sub.2SO.sub.4, 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, CDCL3) 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 4303

(221) ##STR00098##

(222) To a solution of tert-butyl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-hydroxy-7,9-dimethyl-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, 0.082 mmole) and 2-chloro-3-cyclopropyl-6-methoxyquinoxaline 19.21 mg, 0.082 mmole) in DMSO (5 mL) was added t-BuOK (0.164 mL, 0.164 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. The crude compound was purified by prep-HPLC to get 15 mg (21%) of desired compound as a white solid.

(223) Compound 4303: tert-butyl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-(((3-cyclopropyl-6-methoxyquinoxalin-2-yl)oxy)-7,9-dimethyl-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 7.65-7.78 (m, 1H) 7.26 (dq, J=4.83, 2.57 Hz, 2H) 5.83-6.00 (m, 1H) 5.63 (td, J=10.04, 5.52 Hz, 1H) 4.93-5.09 (m, 1H) 4.74 (d, J=11.04 Hz, 1H) 4.54-4.68 (m, 1H) 4.02-4.18 (m, 1H) 3.82-3.98 (m, 4H) 2.67-2.86 (m, 2H) 2.36-2.63 (m, 3H) 1.73-2.09 (m, 4H) 1.60-1.72 (m, 1H) 1.38-1.61 (m, 7H) 1.11-1.34 (m, 11H) 0.79-1.10 (m, 11H). MS: MS m/z 809.4 (M.sup.++1).

Preparation of Compound 4306 and Compound 4307

(224) ##STR00099##

(225) Compound 4306 and 4307 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 4303 but 3-chloro-2-cyclopropyl-6-methoxyquinoxaline and 2-chloro-3-cyclopropyl-6-methoxyquinoxaline (as a mixture) was used instead of 2-chloro-3-cyclopropyl-6-methoxyquinoxaline.

(226) Compound 4306: tert-butyl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-(((3-cyclopropyl-6-methoxyquinoxalin-2-yl)oxy)-14a-((cyclopropylsulfonyl)carbamoyl)-7-ethyl-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): 7.60-7.81 (m, 1H) 7.16-7.32 (m, 2H) 5.90 (br. s., 1H) 5.60 (br. s., 1H) 4.73 (d, J=11.55 Hz, 1H) 4.50-4.67 (m, 1H) 4.01-4.18 (m, 2H) 3.91 (s, 3H) 2.91 (br. s., 1H) 2.63-2.82 (m, 1H) 2.41-2.64 (m, 1H) 1.96 (d, J=11.55 Hz, 2H) 1.76 (br. s., 1H) 1.41-1.67 (m, 6H) 0.73-1.39 (m, 3H). MS: MS m/z 807.0 (M.sup.+1).

(227) Compound 4307: tert-butyl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-(((3-cyclopropyl-7-methoxyquinoxalin-2-yl)oxy)-14a-((cyclopropylsulfonyl)carbamoyl)-7-ethyl-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 7.70 (m, 1H) 7.19 (m, 2H) 5.92 (br. s., 1H) 4.73 (d, J=18.07 Hz, 1H) 4.57 (br. s., 1H) 4.19 (m, 2H) 3.91 (m, 3H) 2.72 (s, 1H) 2.50 (m, 1H) 2.02 (m, 1H) 1.67 (m, 2H) 1.37 (m, 4H) 1.09 (br. s., 11H) 0.94 (m, 11H). MS: MS m/z 806.9 (M.sup.+1).

Preparation of (2R,6S,7R,9R,13aS,14aR,16aS,Z)-6-amino-2-((3-cyclopropyl-6-methoxyquinoxalin-2-yl)oxy)-N-(cyclopropylsulfonyl)-7-ethyl-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]-[1,4]diazacyclopentadecine-14a-carboxamide compound with (2R,6S,7R,9R,13aS,14aR,16aS,Z)-6-amino-2-((3-cyclopropyl-7-methoxyquinoxalin-2-yl)oxy)-N-(cyclopropylsulfonyl)-7-ethyl-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]diazacyclopentadecine-14a-carboxamide (1:1)dihydrochloride

(228) ##STR00100##

(229) A mixture of compounds 4306 and 4307 (110 mg, 0.136 mmole) was treated with HCl in dioxane (4M). The solution was stirred at room temperature for 30 min. The volatiles were removed under reduced pressure to afford a 1:1 mixture of (2R,6S,7R,9R,13aS,14aR,16aS,Z)-6-amino-2-(((3-cyclopropyl-6-methoxyquinoxalin-2-yl)oxy)-N-(cyclopropylsulfonyl)-7-ethyl-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]diazacyclopentadecine-14a-carboxamide and (2R,6S,7R,9R,13aS,14aR,16aS,Z)-6-amino-2-(((3-cyclopropyl-7-methoxyquinoxalin-2-yl)oxy)-N-(cyclopropylsulfonyl)-7-ethyl-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]diazacyclopentadecine-14a-carboxamide as the HCl salts (90 mg, 84%). The crude material was used without further purification. MS: MS m/z 709.4 (M.sup.++1).

Preparation of Compound 4308 and Compound 4309

(230) ##STR00101##

(231) A 1:1 mixture of (2R,6S,7R,9R,13aS,14aR,16aS,Z)-6-amino-2-((3-cyclopropyl-6-methoxyquinoxalin-2-yl)oxy)-N-(cyclopropylsulfonyl)-7-ethyl-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]diazacyclopentadecine-14a-carboxamide and (2R,6S,7R,9R,13aS,14aR,16aS,Z)-6-amino-2-((3-cyclopropyl-7-methoxyquinoxalin-2-yl)oxy)-N-(cyclopropylsulfonyl)-7-ethyl-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]diazacyclopentadecine-14a-carboxamide as the HCl salts (90 mg, 0.127 mmol) was dissolved in DCM (4 mL). To the solution at room temperature was added DIPEA (0.067 mL, 0.381 mmole) followed by pyridin-2-yl (1,1,1-trifluoro-2-methylpropan-2-yl) carbonate (38 mg, 0.152 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. The crude compound was purified by prep-HPLC to get compound 4308 (22 mg, 20%) and Compound 4309 (9 mg, 8%) as white solids.

(232) Compound 4308: 1,1,1-trifluoro-2-methylpropan-2-yl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-(((3-cyclopropyl-6-methoxyquinoxalin-2-yl)oxy)-14a-((cyclopropylsulfonyl)carbamoyl)-7-ethyl-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 7.72 (m, 1H) 7.27 (m, 2H) 5.89 (br. s., 1H) 5.65 (m, 1H) 5.01 (m, 1H) 4.77 (d, J=11.55 Hz, 1H) 4.62 (m, 1H) 4.07 (d, J=11.55 Hz, 2H) 3.92 (s, 3H) 3.07 (q, J=7.53 Hz, 1H) 2.93 (br. s., 1H) 2.75 (m, 2H) 2.50 (m, 2H) 2.00 (br. s., 2H) 1.79 (m, 1H) 1.54 (m, 5H) 1.30 (m, 12H) 1.02 (m, 11H). .sup.19F NMR: ppm 85.01 (1 F). MS: MS m/z 860.9 (M.sup.+1).

(233) Compound 4309: 1,1,1-trifluoro-2-methylpropan-2-yl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-(((3-cyclopropyl-7-methoxyquinoxalin-2-yl)oxy)-14a-((cyclopropylsulfonyl)carbamoyl)-7-ethyl-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 7.73 (m, 1H) 7.27 (d, J=3.01 Hz, 1H) 7.19 (m, 1H) 5.92 (br. s., 1H) 5.62 (br. s., 1H) 4.76 (d, J=11.55 Hz, 1H) 4.62 (m, 1H) 4.08 (m, 2H) 3.94 (m, 3H) 3.05 (m, 1H) 2.93 (br. s., 1H) 2.75 (dd, J=14.05, 7.03 Hz, 1H) 2.49 (m, 2H) 1.98 (m, 2H) 1.78 (br. s., 1H) 1.54 (m, 6H) 1.29 (m, 11H) 1.04 (m, 10H) 0.87 (m, 4H). .sup.19F NMR: ppm 85.01 (1 F). MS: MS m/z 860.9 (M.sup.+1).

Preparation of Compound 4280

(234) ##STR00102##

(235) Compound 4280 was prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 4303.

(236) Compound 4280: tert-butyl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((4-(4-(tert-butyl)thiazol-2-yl)-6-methoxyisoquinolin-1-yl)oxy)-14a-((cyclopropylsulfonyl)carbamoyl)-7-ethyl-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.

(237) .sup.1H NMR (400 MHz, CD.sub.3OD): ppm 8.33-8.53 (m, 1H) 8.21 (d, J=9.29 Hz, 1H) 6.90-7.35 (m, 1H) 5.96 (br. s., 1H) 5.51-5.73 (m, 1H) 5.05 (t, J=9.91 Hz, 1H) 4.65 (dd, J=10.42, 7.15 Hz, 1H) 4.01-4.19 (m, 1H) 3.94 (s, 2H) 3.50 (dt, J=3.26, 1.63 Hz, 1H) 3.15 (dt, J=3.14, 1.69 Hz, 1H) 2.87-3.02 (m, 1H) 2.68-2.86 (m, 1H) 2.30-2.59 (m, 1H) 1.97 (d, J=9.54 Hz, 1H) 1.75-1.87 (m, 1H) 1.52-1.68 (m, 3H) 1.48 (s, 7H) 1.23-1.46 (m, 4H) 0.97-1.21 (m, 11H) 0.73-0.94 (m, 3H). MS: MS m/z 907.76 (M.sup.++1).

Preparation of Compound 4281

(238) ##STR00103##

(239) Compound 4281 was prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 4308.

(240) Compound 4281: 1,1,1-trifluoro-2-methylpropan-2-yl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((2-(1H-imidazol-1-yl)-7-methoxyquinolin-4-yl)oxy)-7-ethyl-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 9.82 (br. s., 1H) 8.58 (br. s., 1H) 8.12 (d, J=9.29 Hz, 1H) 7.78 (br. s., 1H) 7.37-7.59 (m, 2H) 7.21 (dd, J=9.29, 2.51 Hz, 1H) 5.47-5.77 (m, 2H) 4.94-5.14 (m, 2H) 3.85-4.26 (m, 3H) 2.86 (dd, J=13.93, 7.15 Hz, 1H) 2.73 (d, J=9.03 Hz, 1H) 2.54 (ddd, J=14.05, 10.16, 3.89 Hz, 1H) 2.42 (d, J=13.55 Hz, 1H) 1.89-2.10 (m, 1H) 1.79 (dd, J=8.41, 5.65 Hz, 1H) 1.67-1.76 (m, 1H) 1.48-1.67 (m, 7H) 1.43 (dd, J=9.41, 4.89 Hz, 1H) 1.30-1.39 (m, 3H) 1.10-1.29 (m, 2H) 0.99-1.07 (m, 4H) 0.65-0.96 (m, 4H). MS: MS m/z 902.8 (M.sup.++1).

Preparation of Compound 4282

(241) ##STR00104##

(242) Compound 4282 was prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 4308.

(243) Compound 4282: 1,1,1-trifluoro-2-methylpropan-2-yl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((4-(1H-imidazol-1-yl)-7-methoxyquinolin-2-yl)oxy)-7-ethyl-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 8.07 (s, 1H) 7.92 (s, 1H) 7.62 (d, J=9.29 Hz, 1H) 7.55 (s, 1H) 7.42-7.45 (m, 1H) 7.30 (s, 1H) 7.18 (s, 1H) 6.90 (s, 1H) 6.01 (br. s., 1H) 4.81 (s, 1H) 4.66-4.68 (m, 1H) 4.64-4.66 (m, 1H) 4.58 (s, 1H) 4.14 (s, 1H) 4.00 (s, 3H) 3.51 (s, 1H) 3.27-3.30 (m, 1H) 3.16 (s, 1H) 2.63-2.71 (m, 1H) 1.98-2.04 (m, 1H) 1.75-1.81 (m, 1H) 1.52-1.63 (m, 7H) 1.41 (s, 3H) 1.31 (s, 3H) 1.22 (s, 3H) 1.02 (d, J=6.53 Hz, 3H) 0.88-0.93 (m, 1H) 0.86 (s, 1H) 0.84 (s, 1H) 0.83 (s, 1H). MS: MS m/z 902.8 (M.sup.++1).

Preparation of Compound 4248

(244) ##STR00105##

(245) Compound 4248 was prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 4308.

(246) Compound 4248: 1,1,1-trifluoro-2-methylpropan-2-yl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-7-ethyl-2-((6-methoxy-4-(N-methylbenzamido)isoquinolin-1-yl)oxy)-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 8.06-8.16 (m, 1H) 7.30 (d, J=7.03 Hz, 2H) 7.07-7.24 (m, 6H) 3.99-4.05 (m, 4H) 2.62-2.78 (m, 3H) 2.41 (d, J=14.31 Hz, 3H) 1.97 (br. s., 2H) 1.72-1.82 (m, 1H) 1.39-1.61 (m, 14H) 1.25-1.37 (m, 5H) 0.96-1.05 (m, 4H) 0.80-0.94 (m, 8H). MS: MS m/z 969.8 (M.sup.++1).

Preparation of Compound 4255

(247) ##STR00106##

(248) Compound 4255 was prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 4303.

(249) Compound 4255: tert-butyl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-7-ethyl-2-((6-methoxy-4-(thiazol-2-yl)isoquinolin-1-yl)oxy)-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 8.37 (s, 1H) 8.24 (s, 1H) 8.13 (s, 1H) 8.05 (s, 1H) 7.72 (s, 1H) 7.21 (dd, J=9.16, 2.38 Hz, 1H) 5.98 (br. s., 1H) 5.63 (td, J=10.16, 5.77 Hz, 1H) 5.01 (t, J=9.91 Hz, 1H) 4.63-4.69 (m, 1H) 4.05-4.13 (m, 1H) 3.93 (s, 2H) 2.70-2.83 (m, 2H) 2.40-2.51 (m, 1H) 1.96 (br. s., 2H) 1.77 (dd, J=8.28, 5.77 Hz, 1H) 1.50-1.68 (m, 8H) 1.38-1.47 (m, 2H) 1.06-1.19 (m, 8H) 1.02 (d, J=6.53 Hz, 3H) 0.81-0.93 (m, 5H). MS: MS m/z 865.7 (M.sup.++1).

Preparation of Compound 4258

(250) ##STR00107##

(251) Compound 4258 was prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 4308.

(252) Compound 4258: 1,1,1-trifluoro-2-methylpropan-2-yl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-7-ethyl-2-((6-methoxy-4-(thiazol-2-yl)isoquinolin-1-yl)oxy)-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 9.08 (s, 1H) 8.39 (s, 1H) 8.24 (s, 1H) 8.15 (s, 1H) 8.07 (s, 1H) 7.73 (s, 1H) 7.21-7.26 (m, 1H) 5.99 (br. s., 1H) 5.60-5.69 (m, 1H) 5.02 (s, 2H) 4.67-4.74 (m, 2H) 4.03-4.10 (m, 3H) 3.94 (s, 4H) 2.69-2.84 (m, 4H) 2.49 (ddd, J=13.87, 10.10, 3.89 Hz, 3H) 1.94-2.05 (m, 3H) 1.76-1.82 (m, 1H) 1.41-1.70 (m, 18H) 1.27-1.37 (m, 6H) 0.80-1.05 (m, 17H). MS: MS m/z 919.8 (M.sup.++1).

Preparation of Compound 4264

(253) ##STR00108##

(254) Compound 4264 was prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 4308.

(255) Compound 4264: 1,1,1-trifluoro-2-methylpropan-2-yl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-7-ethyl-2-(4-(N-ethylbenzamido)-6-methoxyisoquinolin-1-yl)oxy)-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 8.07-8.15 (m, 1H) 7.68-7.74 (m, 1H) 7.26-7.33 (m, 2H) 7.18-7.24 (m, 3H) 7.08-7.15 (m, 2H) 5.01 (t, J=10.42 Hz, 1H) 4.65 (dd, J=9.91, 6.90 Hz, 1H) 4.46 (dd, J=13.43, 7.15 Hz, 2H) 3.96-4.06 (m, 5H) 2.61-2.78 (m, 3H) 2.35-2.50 (m, 3H) 1.97 (br. s., 2H) 1.78 (dd, J=8.41, 5.65 Hz, 1H) 1.46-1.68 (m, 13H) 1.25-1.38 (m, 13H) 0.78-1.05 (m, 13H). MS: MS m/z 983.18 (M.sup.++1).

Preparation of Compound 4274

(256) ##STR00109##

(257) Compound 4274 was prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 4303.

(258) Compound 4274: tert-butyl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((4-(4-(tert-butyl)thiazol-2-yl)-6-methoxyisoquinolin-1-yl)oxy)-7-ethyl-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 8.45 (d, J=2.26 Hz, 1H) 8.39 (s, 1H) 8.21 (d, J=9.29 Hz, 1H) 7.17-7.24 (m, 2H) 6.64 (d, J=9.03 Hz, 1H) 5.97 (br. s., 1H) 5.63 (td, J=10.04, 5.77 Hz, 1H) 5.01 (t, J=10.04 Hz, 1H) 4.66 (dd, J=10.04, 7.03 Hz, 1H) 4.03-4.15 (m, 3H) 3.94 (s, 4H) 2.70-2.84 (m, 3H) 2.39-2.51 (m, 3H) 1.97 (d, J=13.55 Hz, 3H) 1.77 (dd, J=8.28, 5.77 Hz, 1H) 1.39-1.69 (m, 29H) 1.26-1.36 (m, 4H) 0.97-1.20 (m, 19H) 0.80-0.94 (m, 8H). MS: MS m/z 921.6 (M.sup.++1).

Preparation of Compound 4275

(259) ##STR00110##

(260) Compound 4275 was prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 4308.

(261) Compound 4275: 1,1,1-trifluoro-2-methylpropan-2-yl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-(4-(4-(tert-butyl)thiazol-2-yl)-6-methoxyisoquinolin-1-yl)oxy)-7-ethyl-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 8.47 (d, J=2.51 Hz, 1H) 8.41 (s, 1H) 8.21 (d, J=9.04 Hz, 1H) 7.19-7.25 (m, 2H) 5.96 (br. s., 1H) 5.59-5.68 (m, 1H) 5.02 (t, J=10.04 Hz, 2H) 4.70 (dd, J=10.04, 7.03 Hz, 1H) 4.05 (d, J=11.04 Hz, 2H) 3.95 (s, 3H) 2.70-2.83 (m, 3H) 2.41-2.53 (m, 2H) 1.95-2.04 (m, 2H) 1.78 (dd, J=8.41, 5.65 Hz, 1H) 1.39-1.70 (m, 25H) 1.29-1.35 (m, 6H) 1.02 (d, J=6.78 Hz, 3H) 0.89-0.95 (m, 6H) 0.83 (t, J=7.40 Hz, 3H). MS: MS m/z 975.8 (M.sup.++1).

Preparation of Compound 4285

(262) ##STR00111##

(263) Compound 4285 was prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 4303.

(264) Compound 4285: tert-butyl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-7-ethyl-2-((6-methoxy-4-(oxazol-5-yl)isoquinolin-1-yl)oxy)-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 8.42 (s, 1H) 8.20-8.26 (m, 3H) 7.52 (s, 1H) 7.42 (d, J=2.01 Hz, 1H) 7.21 (dd, J=9.03, 2.26 Hz, 1H) 5.96 (br. s., 1H) 5.58-5.66 (m, 1H) 4.97-5.07 (m, 1H) 4.66 (dd, J=10.04, 7.03 Hz, 2H) 4.04-4.11 (m, 3H) 3.95 (s, 5H) 2.69-2.82 (m, 3H) 2.46 (dd, J=13.55, 4.02 Hz, 3H) 1.97 (d, J=14.05 Hz, 3H) 1.77 (dd, J=8.16, 5.65 Hz, 2H) 1.40-1.66 (m, 18H) 0.99-1.16 (m, 21H) 0.79-0.92 (m, 9H). MS: MS m/z 849.7 (M.sup.++1).

Preparation of Compound 4291

(265) ##STR00112##

(266) Compound 4291 was prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 4308.

(267) Compound 4291: 1,1,1-trifluoro-2-methylpropan-2-yl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-7-ethyl-2-((6-methoxy-4-(oxazol-5-yl)isoquinolin-1-yl)oxy)-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 8.44 (s, 1H) 8.21-8.28 (m, 3H) 7.54 (s, 1H) 7.43 (d, J=2.26 Hz, 1H) 7.24 (dd, J=9.16, 2.38 Hz, 1H) 5.96 (br. s., 1H) 5.64 (td, J=9.98, 6.40 Hz, 1H) 5.02 (t, J=10.04 Hz, 2H) 4.68-4.73 (m, 1H) 4.02-4.08 (m, 3H) 3.96 (s, 4H) 2.71-2.83 (m, 3H) 2.37-2.52 (m, 3H) 1.93-2.05 (m, 3H) 1.78 (dd, J=8.41, 5.65 Hz, 1H) 1.50-1.70 (m, 14H) 1.40-1.46 (m, 2H) 1.30-1.36 (m, 6H) 1.13 (t, J=12.55 Hz, 2H) 1.02 (d, J=6.78 Hz, 4H) 0.90-0.95 (m, 7H) 0.83 (t, J=7.40 Hz, 4H). MS: MS m/z 903.8 (M.sup.++1).

Preparation of Compound 4293

(268) ##STR00113##

(269) Compound 4291 was prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 4308.

(270) Compound 4293: 1,1,1-trifluoro-2-methylpropan-2-yl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-14a-((cyclopropylsulfonyl)carbamoyl)-7-ethyl-2-((6-methoxy-4-(oxazol-5-yl)isoquinolin-1-yl)oxy)-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 8.44 (s, 1H) 8.21-8.28 (m, 3H) 7.54 (s, 1H) 7.43 (d, J=2.26 Hz, 1H) 7.24 (dd, J=9.16, 2.38 Hz, 1H) 5.96 (br. s., 1H) 5.64 (td, J=9.98, 6.40 Hz, 1H) 5.02 (t, J=10.04 Hz, 2H) 4.68-4.73 (m, 1H) 4.02-4.08 (m, 3H) 3.96 (s, 4H) 2.90-2.99 (m, 1H) 2.71-2.83 (m, 3H) 2.37-2.52 (m, 3H) 1.93-2.05 (m, 3H) 1.78 (dd, J=8.41, 5.65 Hz, 1H) 1.50-1.70 (m, 14H) 1.40-1.46 (m, 2H) 1.30-1.36 (m, 3H) 1.13 (t, J=12.55 Hz, 2H) 1.02 (d, J=6.78 Hz, 4H) 0.90-0.95 (m, 7H) 0.83 (t, J=7.40 Hz, 4H). MS: MS m/z 889.7 (M.sup.++1).

Preparation of Compound 4329

(271) ##STR00114##

(272) Compound 4329 was prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 4303.

(273) Compound 4329: tert-butyl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-14a-((cyclopropylsulfonyl)carbamoyl)-7-ethyl-9-methyl-5,16-dioxo-2-((3-(trifluoromethyl)pyrido[2,3-b]pyrazin-2-yl)oxy)-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 9.15 (dd, J=4.52, 1.76 Hz, 1H) 8.63 (dd, J=8.28, 1.76 Hz, 1H) 7.85 (dd, J=8.41, 4.39 Hz, 1H) 6.04 (br. s., 1H) 5.57 (br. s., 1H) 4.93-5.00 (m, 2H) 4.61 (d, J=7.78 Hz, 1H) 4.08 (dd, J=11.92, 3.14 Hz, 1H) 3.96 (d, J=11.04 Hz, 1H) 3.05 (q, J=7.36 Hz, 6H) 2.90 (br. s., 2H) 2.78 (dd, J=13.43, 6.90 Hz, 2H) 2.49-2.61 (m, 2H) 2.37 (br. s., 1H) 1.85-2.05 (m, 3H) 1.74 (br. s., 1H) 1.40-1.64 (m, 10H) 1.32 (t, J=7.28 Hz, 15H) 0.97-1.12 (m, 22H) 0.77 (t, J=7.53 Hz, 4H). MS: MS m/z 808.7 (M.sup.++1).

Preparation of Compound 4330

(274) ##STR00115##

(275) Compound 4280 was prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 4303.

(276) Compound 4330: tert-butyl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-14a-((cyclopropylsulfonyl)carbamoyl)-7-ethyl-9-methyl-5,16-dioxo-2-((2-(trifluoromethyl)pyrido[2,3-b]pyrazin-3-yl)oxy)-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 9.06 (dd, J=4.27, 1.76 Hz, 1H) 8.49-8.56 (m, 1H) 7.93-8.00 (m, 1H) 6.01 (br. s., 1H) 5.56 (br. s., 1H) 4.59 (d, J=7.78 Hz, 2H) 4.05-4.12 (m, 2H) 3.97 (d, J=11.04 Hz, 1H) 3.04 (q, J=7.28 Hz, 4H) 2.90 (br. s., 1H) 2.76 (dd, J=14.18, 6.65 Hz, 2H) 2.55 (br. s., 2H) 2.35 (br. s., 2H) 1.87-2.04 (m, 3H) 1.72 (br. s., 2H) 1.46-1.63 (m, 8H) 1.25-1.37 (m, 12H) 0.99-1.10 (m, 21H) 0.91 (d, J=12.05 Hz, 3H) 0.78 (t, J=7.40 Hz, 4H). MS: MS m/z 808.7 (M.sup.++1).

Preparation of Compound 4368

(277) ##STR00116##

(278) Compound 4368 was prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 4303.

(279) Compound 4368: tert-butyl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-14a-((cyclopropylsulfonyl)carbamoyl)-7-ethyl-2-((7-methoxy-3-(trifluoromethyl)pyrido[3,4-b]pyrazin-2-yl)oxy)-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.

(280) .sup.1H NMR (400 MHz, CD.sub.3OD): ppm 9.15 (s, 1H) 9.07-9.12 (m, 1H) 7.20 (s, 1H) 6.02 (br. s., 1H) 5.63 (td, J=9.98, 5.90 Hz, 2H) 5.05 (t, J=9.91 Hz, 2H) 4.62 (dd, J=10.16, 7.15 Hz, 1H) 4.03-4.13 (m, 6H) 3.96 (d, J=11.29 Hz, 1H) 2.90-2.98 (m, 2H) 2.66-2.78 (m, 3H) 2.35-2.54 (m, 3H) 1.88-2.04 (m, 3H) 1.78 (dd, J=8.41, 5.65 Hz, 2H) 1.44-1.67 (m, 10H) 1.25-1.37 (m, 7H) 0.97-1.18 (m, 25H) 0.86-0.95 (m, 2H) 0.80 (t, J=7.40 Hz, 4H). MS: MS m/z 892.7 (M.sup.++1).

Preparation of Compound 4288

(281) ##STR00117##

(282) Compound 4288 was prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 4308.

(283) Compound 4288: 1,1,1-trifluoro-2-methylpropan-2-yl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-(4-(4-(tert-butyl)thiazol-2-yl)-6-methoxyisoquinolin-1-yl)oxy)-14a-((cyclopropylsulfonyl)carbamoyl)-7-ethyl-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 8.46 (d, J=2.51 Hz, 1H) 8.40 (s, 1H) 8.21 (s, 1H) 7.19-7.23 (m, 3H) 5.95 (br. s., 1H) 5.60-5.68 (m, 1H) 5.04 (t, J=9.91 Hz, 1H) 4.69 (dd, J=10.29, 7.03 Hz, 1H) 4.00-4.08 (m, 3H) 3.94 (s, 4H) 2.91-2.97 (m, 1H) 2.70-2.82 (m, 3H) 2.38-2.50 (m, 3H) 1.97 (d, J=11.80 Hz, 3H) 1.79 (dd, J=8.28, 5.52 Hz, 1H) 1.44-1.63 (m, 21H) 1.27-1.38 (m, 8H) 1.00-1.18 (m, 10H) 0.93 (s, 4H) 0.83 (t, J=7.40 Hz, 4H). MS: MS m/z 961.6 (M.sup.++1).

(284) ##STR00118## ##STR00119##

Step 1: Preparation of tert-butyl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-7-ethyl-2-((7-methoxy-2-(trifluoromethyl)pyrido[3,4-b]pyrazin-3-yl)oxy)-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

(285) The same procedure was followed as described for the preparation of Compound 4303 but tert-butyl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-7-ethyl-2-hydroxy-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-chloro-7-methoxy-2-(trifluoromethyl)pyrido[3,4-b]pyrazine were used as starting materials. MS: MS m/z 852.83 (M.sup.++1). During this conversion tert-butyl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-7-ethyl-2-((2-hydroxy-7-methoxypyrido[3,4-b]pyrazin-3-yl)oxy)-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 was isolated as by product. MS: MS m/z 800.3 (M.sup.++1).

Step 2: Preparation of tert-butyl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((2-ethoxy-7-methoxypyrido[3,4-b]pyrazin-3-yl)oxy)-7-ethyl-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

(286) To a solution of tert-butyl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-7-ethyl-2-((2-hydroxy-7-methoxypyrido[3,4-b]pyrazin-3-yl)oxy)-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 (60 mg, 0.075 mmol) in DMF (2 mL) was added Iodoethane (6.06 l, 0.075 mmol) followed by cesium carbonate (24.44 mg, 0.075 mmol) at room temperature. The reaction mass was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and the residue was diluted with water and extracted with ethyl acetate. The combined organic volume was dried over sodium sulfate and evaporated under reduced pressure to get crude compound. The crude compound was purified by prep HPLC to get tert-butyl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((2-ethoxy-6-methoxypyrido[2,3-b]pyrazin-3-yl)oxy)-7-ethyl-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 (40 mg, 0.048 mmol, 64.4% yield) as white solid. MS: MS m/z 828.4 (M.sup.++1).

Preparation of Compound 4359

(287) ##STR00120##

(288) Compound 4359 was prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 4308. tert-butyl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((2-ethoxy-7-methoxypyrido[3,4-b]pyrazin-3-yl)oxy)-7-ethyl-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 was used as a starting material.

(289) Compound 4359: 1,1,1-trifluoro-2-methylpropan-2-yl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((2-ethoxy-7-methoxypyrido[3,4-b]pyrazin-3-yl)oxy)-7-ethyl-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 8.81 (br. s., 1H) 8.49 (s, 1H) 7.96 (br. s., 1H) 6.81 (s, 1H) 5.79 (br. s., 1H) 5.62 (td, J=9.91, 6.02 Hz, 1H) 4.65 (dd, J=9.66, 7.15 Hz, 1H) 4.29-4.37 (m, 1H) 4.13-4.25 (m, 2H) 3.99-4.07 (m, 5H) 2.65-2.74 (m, 2H) 2.44 (ddd, J=13.99, 9.72, 4.64 Hz, 2H) 1.95-2.02 (m, 2H) 1.77 (dd, J=8.28, 5.77 Hz, 1H) 1.49-1.69 (m, 11H) 1.24-1.43 (m, 20H) 0.79-1.04 (m, 14H). MS: MS m/z 882.8 (M.sup.++1).

Preparation of Compound 4364

(290) ##STR00121##

(291) Compound 4364 was prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 4303.

(292) Compound 4364: tert-butyl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-7-ethyl-2-((7-methoxy-2-(trifluoromethyl)pyrido[3,4-b]pyrazin-3-yl)oxy)-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 9.19 (s, 1H) 9.09-9.12 (m, 1H) 7.37 (s, 1H) 5.98-6.05 (m, 1H) 5.59-5.67 (m, 2H) 5.02 (t, J=10.04 Hz, 2H) 4.63 (dd, J=10.16, 7.15 Hz, 2H) 4.06-4.13 (m, 6H) 3.97 (d, J=11.04 Hz, 2H) 2.68-2.78 (m, 4H) 2.38-2.55 (m, 3H) 1.90-2.02 (m, 3H) 1.77 (dd, J=8.41, 5.65 Hz, 2H) 1.63-1.69 (m, 2H) 1.40-1.61 (m, 17H) 1.07-1.15 (m, 16H) 1.01 (d, J=6.78 Hz, 5H) 0.77-0.92 (m, 9H). MS: MS m/z 906.8 (M.sup.++1).

Preparation of Compound 5490 and Compound 5491

(293) ##STR00122## ##STR00123##

(294) To a mixture of tert-butyl((2R,6S,7R,13aS,14aR,16aS,Z)-2-hydroxy-7,9-dimethyl-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 (9.16 mg, 0.015 mmol), 6-chloro-2,3-dihydrofuro[2,3-f]isoquinoline (3.08 mg, 0.015 mmol), and tert-BuOK (1.683 mg, 0.015 mmol) was added DMSO (3 mL). The mixture was then sonicated for 15 min. The resulting solution was stirred for 4 h. The reaction was quenched with water, acidified with aq. 6 N HCl, extracted with EtOAc, washed with brine, dried over MgSO.sub.4. After concentration, the residue was purified by prep HPLC to afford 1.7 mg of Compound 5490 as a solid and 1.1 mg of Compound 5491 as a solid.

(295) Compound 5490: tert-butyl((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-((2,3-dihydrofuro[2,3-f]isoquinolin-6-yl)oxy)-7,9-dimethyl-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 780.7 (M.sup.++1).

(296) Compound 5491: tert-butyl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((2,3-dihydrofuro[2,3-f]isoquinolin-6-yl)oxy)-7,9-dimethyl-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 780.7 (M.sup.++1).

Preparation of Compound 5492 and Compound 5493

(297) ##STR00124##

(298) Compounds 5492 and 5493 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compounds 5490 and 5491:

(299) Compound 5492: tert-butyl((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-((2,3-dihydrofuro[2,3-f]isoquinolin-6-yl)oxy)-7-ethyl-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 794.7 (M.sup.++1).

(300) Compound 5493: tert-butyl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((2,3-dihydrofuro[2,3-f]isoquinolin-6-yl)oxy)-7-ethyl-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 794.7 (M.sup.++1).

Preparation of Compound 5494 and Compound 5495

(301) ##STR00125##

(302) ##STR00126## ##STR00127##

Step 1

(303) To a mixture of tert-butyl((2R,6S,7R,13aS,14aR,16aS,Z)-2-hydroxy-7,9-dimethyl-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 (0.092 g, 0.15 mmol),6-chloro-2,3-dihydrofuro[2,3-f]isoquinoline (0.037 g, 0.180 mmol), and tert-BuOK (0.084 g, 0.750 mmol) was added DMSO (5 mL) and the mixture was then sonicated for 15 min. The resulting solution was stirred for 4 h. The reaction was quenched with water, acidified with aq. 6 N HCl, extracted with EtOAc, washed with brine, dried over MgSO.sub.4. Concentration gave 150 mg of tert-butyl((2R,6S,7R,13aS,14aR,16aS,Z)-2-((2,3-dihydrofuro[2,3-f]isoquinolin-6-yl)oxy)-7,9-dimethyl-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 that was used in the next step without further purification.

Step 2

(304) To a solution of tert-butyl((2R,6S,7R,13aS,14aR,16aS,Z)-2-((2,3-dihydrofuro[2,3-f]isoquinolin-6-yl)oxy)-7,9-dimethyl-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 (0.078 g, 0.10 mmol) in CH.sub.2Cl.sub.2 (1 mL) was added TFA (0.077 mL, 1.0 mmol). After stirring for 1 h, concentration gave 79 mg of (2R,6S,7R,13aS,14aR,16aS,Z)-6-amino-2-((2,3-dihydrofuro[2,3-f]isoquinolin-6-yl)oxy)-7,9-dimethyl-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 as the TFA salt.

Step 3

(305) A solution of (2R,6S,7R,13aS,14aR,16aS,Z)-6-amino-2-((2,3-dihydrofuro[2,3-f]isoquinolin-6-yl)oxy)-7,9-dimethyl-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 TFA salt (40 mg, 0.050 mmol), 3,3-difluoro-2-methylbutan-2-yl pyridin-2-yl carbonate (14 mg, 0.060 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.044 mL, 0.250 mmol) in CH.sub.2Cl.sub.2 (1 mL) was stirred for 16 h. After concentration, the residue was purified by prep HPLC to afford 3.7 mg of Compounds 5494 as a solid and 5.8 mg of Compound 5995 as a solid.

(306) Compound 5494: 3,3-difluoro-2-methylbutan-2-yl((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-((2,3-dihydrofuro[2,3-f]isoquinolin-6-yl)oxy)-7,9-dimethyl-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 830.7 (M.sup.++1).

(307) Compound 5495: 3,3-difluoro-2-methylbutan-2-yl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((2,3-dihydrofuro[2,3-f]isoquinolin-6-yl)oxy)-7,9-dimethyl-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 830.7 (M.sup.++1).

Preparation of Compound 5496 and Compound 5497

(308) ##STR00128##

(309) Compounds 5496 and 5497 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compounds 5494 and 5495:

(310) Compound 5496: 1,1,1-trifluoro-2-methylpropan-2-yl((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-((2,3-dihydrofuro[2,3-f]isoquinolin-6-yl)oxy)-7,9-dimethyl-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 834.6 (M.sup.++1).

(311) Compound 5497: 1,1,1-trifluoro-2-methylpropan-2-yl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((2,3-dihydrofuro[2,3-f]isoquinolin-6-yl)oxy)-7,9-dimethyl-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 834.6 (M.sup.++1).

Preparation of Compound 5498

(312) ##STR00129##

(313) Compound 5498 was prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 5494:

(314) Compound 5498: 1,1,1-trifluoro-2-methylpropan-2-yl((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-((2,3-dihydrofuro[2,3-f]isoquinolin-6-yl)oxy)-7-ethyl-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 848.7 (M.sup.++1).

Preparation of Compound 5499 and Compound 5500

(315) ##STR00130##

(316) Compounds 5499 and 5500 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compounds 5494 and 5495:

(317) Compound 5499: 1,1,1-trifluoro-2-methylpropan-2-yl((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-((2,3-dihydrofuro[2,3-f]isoquinolin-6-yl)oxy)-7-ethyl-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 848.7 (M.sup.++1).

(318) Compound 5500:1,1,1-trifluoro-2-methylpropan-2-yl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((2,3-dihydrofuro[2,3-f]isoquinolin-6-yl)oxy)-7-ethyl-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 848.7 (M.sup.++1).

Preparation of Compound 6121 and Compound 6122

(319) ##STR00131##

(320) ##STR00132##

(321) To a THF (4 mL) solution of tert-butyl((2R,6S,7R,13aS,14aR,16aS,Z)-2-hydroxy-7,9-dimethyl-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 (70 mg, 0.12 mmol) was added NaH (23 mg, 0.57 mmol) then DMSO (2 mL). The mixture was stirred for 20 min. The mixture was then cooled with an ice bath and 5-chloroimidazo[1,2-a]quinazoline (28.0 mg, 0.138 mmol) was added in one portion. The reaction was complete after 0.5 h. The reaction was quenched with water, acidified with aq. 6 N HCl to pH=4, and extracted with EtOAc. The organic layer was collected, washed with brine, dried over MgSO.sub.4, filtered. After concentration, the residue was purified by prep HPLC to give 1.1 mg of Compound 6121 as a solid and 6.1 mg of Compound 6122 as a solid.

(322) Compound 6121: tert-butyl((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-(imidazo[1,2-a]quinazolin-5-yloxy)-7,9-dimethyl-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 778.5 (M.sup.++1).

(323) Compound 6122: tert-butyl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-(imidazo[1,2-a]quinazolin-5-yloxy)-7,9-dimethyl-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 778.5 (M.sup.++1).

Preparation of Compound 6119 and Compound 6120

(324) ##STR00133##

(325) Compounds 6119 and 6120 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 6121 and Compound 6122:

(326) Compound 6119: tert-butyl((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-([1,2,4]triazolo[4,3-a]quinazolin-5-yloxy)-7,9-dimethyl-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 779.8 (M.sup.++1).

(327) Compound 6120: tert-butyl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-([1,2,4]triazolo[4,3-a]quinazolin-5-yloxy)-7,9-dimethyl-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 (500 MHz, DMSO-d.sub.6) 11.07 (br. s., 1H), 9.71 (s, 1H), 9.19 (br. s., 1H), 8.38 (d, J=8.2 Hz, 1H), 8.14 (d, J=7.6 Hz, 1H), 8.03 (t, J=7.9 Hz, 1H), 7.62 (t, J=7.8 Hz, 1H), 7.22 (d, J=7.0 Hz, 1H), 5.89 (br. s., 1H), 5.53 (m, 1H), 4.97 (m, 1H), 4.84 (d, J=11.9 Hz, 1H), 4.61-4.49 (m, 1H), 3.99-3.91 (m, 1H), 3.64 (dd, J=10.7, 7.6 Hz, 1H), 2.78-2.62 (m, 2H), 2.45-2.32 (m, 3H), 1.94-1.85 (m, 1H), 1.79 (d, J=6.1 Hz, 1H), 1.69 (m, 1H), 1.63 (m, 1H), 1.54 (m, 1H), 1.42 (s, 3H), 1.36-1.16 (m, 6H), 1.02-0.82 (m, 15H), 0.76 (t, J=11.6 Hz, 1H); MS: MS m/z 779.8 (M.sup.++1).

Preparation of Compound 6123

(328) ##STR00134##

(329) Compounds 6123 was prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 6121:

(330) Compound 6123: tert-butyl((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-((7-chloroimidazo[1,2-a]quinazolin-5-yl)oxy)-7,9-dimethyl-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 812.8 (M.sup.++1).

Preparation of Compound 6126 and Compound 6127

(331) ##STR00135##

(332) ##STR00136## ##STR00137##

Step 1

(333) To a THF (4 mL) solution of tert-butyl((2R,6S,7R,13aS,14aR,16aS,Z)-2-hydroxy-7,9-dimethyl-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 (70 mg, 0.12 mmol) was added NaH (23 mg, 0.57 mmol) then DMSO (2 mL). The mixture was stirred for 20 min. The mixture was then cooled with an ice bath and 5-chloroimidazo[1,2-a]quinazoline (28.0 mg, 0.138 mmol) was added in one portion. The reaction was complete after 0.5 h. The reaction was quenched with water, acidified with aq. 6 N HCl to pH=4, and extracted with EtOAc. The organic layer was collected, washed with brine, dried over MgSO.sub.4, filtered, and concentrated to give the crude product tert-butyl((2R,6S,7R,13aS,14aR,16aS,Z)-2-(imidazo[1,2-a]quinazolin-5-yloxy)-7,9-dimethyl-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 that was used in the next step as is. MS: MS m/z 778.5 (M.sup.++1).

Step 2

(334) To a solution of tert-butyl((2R,6S,7R,13aS,14aR,16aS,Z)-2-(imidazo[1,2-a]quinazolin-5-yloxy)-7,9-dimethyl-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 (60 mg, 0.077 mmol) in DCM (2 mL) was added trifluoroacetic acid (TFA, 2 mL). The reaction was stirred for 1 h at room temperature. The volatiles were removed under vacuum to give (2R,6S,7R,13aS,14aR,16aS,Z)-6-amino-2-(imidazo[1,2-a]quinazolin-5-yloxy)-7,9-dimethyl-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 TFA salt (52 mg) which was used in the next step without further purification. MS: MS m/z 678.9 (M.sup.++1).

Step 3

(335) To a solution of (2R,6S,7R,13aS,14aR,16aS,Z)-6-amino-2-(imidazo[1,2-a]quinazolin-5-yloxy)-7,9-dimethyl-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 TFA salt (30 mg, 0.044 mmol) and pyridin-2-yl (1,1,1-trifluoro-2-methylpropan-2-yl) carbonate (13.2 mg, 0.053 mmol) in CH.sub.2Cl.sub.2 (1 mL) was added N-ethyl-N-isopropylpropan-2-amine (Hunig's Base, 0.039 mL, 0.22 mmol). The reaction was stirred for 16 h. After concentration, the residue was purified by prep HPLC to give 0.9 mg of Compound 6126 as a solid and 12.2 mg of Compound 6127 as a solid.

(336) Compound 6126: 1,1,1-trifluoro-2-methylpropan-2-yl((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-(imidazo[1,2-a]quinazolin-5-yloxy)-7,9-dimethyl-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 832.5 (M.sup.++1).

(337) Compound 6127: 1,1,1-trifluoro-2-methylpropan-2-yl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-(imidazo[1,2-a]quinazolin-5-yloxy)-7,9-dimethyl-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 (500 MHz, DMSO-d.sub.6) 11.06 (br. s., 1H), 9.20 (br. s., 1H), 8.38-8.25 (m, 2H), 8.11 (d, J=7.9 Hz, 1H), 7.98 (t, J=7.5 Hz, 1H), 7.84 (d, J=7.3 Hz, 1H), 7.56 (t, J=7.6 Hz, 1H), 7.45 (d, J=1.5 Hz, 1H), 5.87 (br. s., 1H), 5.54 (m, 1H), 4.98 (m, 1H), 4.71 (d, J=11.0 Hz, 1H), 4.58 (m, 1H), 3.95 (d, J=9.2 Hz, 1H), 3.66 (dd, J=11.0, 7.6 Hz, 1H), 2.70 (m, 2H), 2.65 (m, 1H), 2.44-2.25 (m, 2H), 1.95-1.54 (m, 5H), 1.42 (m, 6H), 1.36 (m, 1H), 1.29 (m, 1H), 1.19 (s, 3H), 0.98-0.84 (m, 10H), 0.79 (m, 1H); MS: MS m/z 832.5 (M.sup.++1).

Preparation of Compound 6124 and Compound 6125

(338) ##STR00138##

(339) Compounds 6124 and 6125 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 6126 and Compound 6127:

(340) Compound 6124: 1,1,1-trifluoro-2-methylpropan-2-yl((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-([1,2,4]triazolo[4,3-a]quinazolin-5-yloxy)-7,9-dimethyl-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 833.5 (M.sup.++1).

(341) Compound 6125: 1,1,1-trifluoro-2-methylpropan-2-yl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-([1,2,4]triazolo[4,3-a]quinazolin-5-yloxy)-7,9-dimethyl-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 (500 MHz, METHANOL-d.sub.4) 9.58 (s, 1H), 8.36-8.25 (m, 2H), 8.10-7.98 (m, 1H), 7.69 (t, J=7.6 Hz, 1H), 6.06-5.94 (m, 1H), 5.58 (td, J=10.3, 5.6 Hz, 1H), 5.19 (t, J=10.1 Hz, 1H), 4.68 (dd, J=10.1, 7.0 Hz, 1H), 4.07 (dd, J=12.1, 3.2 Hz, 1H), 3.77 (d, J=10.7 Hz, 1H), 2.92-2.84 (m, 1H), 2.68-2.49 (m, 2H), 2.40 (d, J=13.7 Hz, 1H), 1.88-1.70 (m, 4H), 1.67 (d, J=9.5 Hz, 1H), 1.57 (dd, J=9.6, 5.3 Hz, 2H), 1.51 (s, 3H), 1.50-1.36 (m, 4H), 1.22 (s, 3H), 1.04-0.91 (m, 9H), 0.88-0.78 (m, 3H); MS: MS m/z 833.5 (M.sup.++1).

Preparation of Compound 6128 and Compound 6129

(342) ##STR00139##

(343) Compounds 6128 and 6129 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 6126 and Compound 6127:

(344) Compound 6128: 1,1,1-trifluoro-2-methylpropan-2-yl((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-((7-chloroimidazo[1,2-a]quinazolin-5-yl)oxy)-7,9-dimethyl-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 866.5 (M.sup.++1).

(345) Compound 6129: 1,1,1-trifluoro-2-methylpropan-2-yl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((7-chloroimidazo[1,2-a]quinazolin-5-yl)oxy)-7,9-dimethyl-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 (500 MHz, METHANOL-d.sub.4) 8.22-8.07 (m, 3H), 7.93 (dd, J=8.9, 2.4 Hz, 1H), 7.46 (d, J=1.5 Hz, 1H), 5.95 (br. s., 1H), 5.59 (td, J=10.3, 5.6 Hz, 1H), 5.04 (t, J=9.9 Hz, 1H), 4.93 (d, J=11.9 Hz, 1H), 4.71 (dd, J=10.4, 7.0 Hz, 1H), 4.04 (dd, J=12.1, 3.2 Hz, 1H), 3.72 (d, J=11.0 Hz, 1H), 2.83 (dd, J=13.9, 6.9 Hz, 1H), 2.69 (q, J=9.2 Hz, 1H), 2.57-2.34 (m, 2H), 2.01-1.89 (m, 2H), 1.87-1.73 (m, 3H), 1.68-1.54 (m, 2H), 1.52 (s, 3H), 1.49-1.36 (m, 3H), 1.29-1.19 (m, 1H), 1.14 (s, 3H), 0.97 (d, J=6.4 Hz, 2H), 1.00 (d, J=6.7 Hz, 3H), 0.94-0.75 (m, 6H); MS: MS m/z 866.5 (M.sup.++1).

Preparation of Compound 6130 and Compound 6131

(346) ##STR00140##

(347) Compounds 6130 and 6131 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 6126 and Compound 6127:

(348) Compound 6130:1,1,1-trifluoro-2-methylpropan-2-yl((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-((7-chloroimidazo[1,2-a]quinazolin-5-yl)oxy)-14a-(((1-(fluoromethyl)cyclopropyl)sulfonyl)carbamoyl)-7,9-dimethyl-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 884.6 (M.sup.++1).

(349) Compound 6131: 1,1,1-trifluoro-2-methylpropan-2-yl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((7-chloroimidazo[1,2-a]quinazolin-5-yl)oxy)-14a-(((1-(fluoromethyl)cyclopropyl)sulfonyl)carbamoyl)-7,9-dimethyl-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 (500 MHz, DMSO-d.sub.6) 11.30 (br. s., 1H), 9.13 (br. s., 1H), 8.43-8.33 (m, 2H), 8.08 (dd, J=8.9, 2.4 Hz, 1H), 7.99 (d, J=2.4 Hz, 1H), 7.83 (d, J=6.7 Hz, 1H), 7.48 (d, J=1.5 Hz, 1H), 5.86 (br. s., 1H), 5.53 (br. s., 1H), 5.00 (m, 1H), 4.68 (d, J=11.3 Hz, 1H), 4.65-4.55 (m, 1H), 4.02-3.85 (m, 1H), 3.61 (dd, J=10.8, 7.5 Hz, 1H), 2.73 (d, J=17.4 Hz, 1H), 2.65 (m, 2H), 2.47-2.35 (m, 1H), 2.31 (d, J=11.9 Hz, 1H), 1.90-1.75 (m, 2H), 1.70 (m, 2H), 1.65-1.47 (m, 4H), 1.38 (d, J=15.3 Hz, 2H), 1.26 (d, J=12.8 Hz, 2H), 1.20-1.03 (m, 4H), 0.98-0.91 (m, 6H), 0.88 (d, J=6.1 Hz, 3H), 0.77 (t, J=12.1 Hz, 1H); MS: MS m/z 884.6 (M.sup.++1).

Preparation of Compound 6132 and Compound 6133

(350) ##STR00141##

(351) Compounds 6132 and 6133 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 6126 and Compound 6127:

(352) Compound 6132: 1,1,1-trifluoro-2-methylpropan-2-yl((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-((7-chloroimidazo[1,2-a]quinazolin-5-yl)oxy)-7-ethyl-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 880.7 (M.sup.++1).

(353) Compound 6133: 1,1,1-trifluoro-2-methylpropan-2-yl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((7-chloroimidazo[1,2-a]quinazolin-5-yl)oxy)-7-ethyl-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 (500 MHz, DMSO-d.sub.6) 11.05 (br. s., 1H), 9.19 (br. s., 1H), 8.48-8.30 (m, 2H), 8.08 (dd, J=8.9, 2.4 Hz, 1H), 7.98 (d, J=2.1 Hz, 1H), 7.88 (d, J=7.9 Hz, 1H), 7.48 (d, J=1.5 Hz, 1H), 5.90 (br. s., 1H), 5.53 (br. s., 1H), 4.99 (br. s., 1H), 4.70-4.54 (m, 2H), 3.99 (d, J=8.9 Hz, 1H), 3.80 (dd, J=11.1, 8.1 Hz, 1H), 2.77-2.64 (m, 2H), 2.45-2.25 (m, 2H), 2.00-1.84 (m, 2H), 1.68-1.58 (m, 1H), 1.56 (br. s., 1H), 1.52-1.34 (m, 9H), 1.33-1.28 (m, 1H), 1.15 (s, 3H), 1.03 (t, J=12.2 Hz, 1H), 0.97-0.89 (m, 9H), 0.71 (t, J=7.5 Hz, 3H); MS: MS m/z 880.7 (M.sup.++1).

Preparation of Compound 6134 and Compound 6135

(354) ##STR00142##

(355) Compounds 6134 and 6135 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 6126 and Compound 6127:

(356) Compound 6134: 1,1,1-trifluoro-2-methylpropan-2-yl((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-((7-chloro-2-methylimidazo[1,2-a]quinazolin-5-yl)oxy)-7,9-dimethyl-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 880.6 (M.sup.++1).

(357) Compound 6135: 1,1,1-trifluoro-2-methylpropan-2-yl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((7-chloro-2-methylimidazo[1,2-a]quinazolin-5-yl)oxy)-7,9-dimethyl-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 880.6 (M.sup.++1).

Preparation of Compound 6136 and Compound 6137

(358) ##STR00143##

(359) Compounds 6136 and 6137 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 6126 and Compound 6127:

(360) Compound 6136: 3,3-difluoro-2-methylbutan-2-yl((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-((7-chloro-2-methylimidazo[1,2-a]quinazolin-5-yl)oxy)-7,9-dimethyl-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 876.6 (M.sup.++1).

(361) Compound 6137: 3,3-difluoro-2-methylbutan-2-yl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((7-chloro-2-methylimidazo[1,2-a]quinazolin-5-yl)oxy)-7,9-dimethyl-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 (500 MHz, DMSO-d.sub.6) 11.05 (br. s., 1H), 9.19 (br. s., 1H), 8.22 (d, J=8.9 Hz, 1H), 8.07-7.86 (m, 3H), 7.55 (d, J=7.6 Hz, 1H), 5.81 (br. s., 1H), 5.59-5.38 (m, 1H), 4.99 (br. s., 1H), 4.69 (d, J=12.2 Hz, 1H), 4.60 (dd, J=10.4, 6.7 Hz, 1H), 3.92 (m, 1H), 3.56 (dd, J=10.4, 7.9 Hz, 3H), 2.74-2.58 (m, 2H), 2.37 (t, J=10.1 Hz, 1H), 2.30 (s, 3H), 1.94-1.82 (m, 1H), 1.76 (m, 1H), 1.73-1.58 (m, 2H), 1.50 (t, J=19.5 Hz, 4H), 1.41 (m, 4H), 1.33-1.25 (m, 1H), 0.98-0.89 (m, 8H), 0.87 (m, 5H), 0.72 (m, 4H); MS: MS m/z 876.6 (M.sup.++1).

Preparation of Compound 6138 and Compound 6139

(362) ##STR00144##

(363) Compounds 6138 and 6139 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 6126 and Compound 6127:

(364) Compound 6138: 1,1,1-trifluoro-2-methylpropan-2-yl((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-((7-chloro-2-methylimidazo[1,2-a]quinazolin-5-yl)oxy)-14a-(((1-(fluoromethyl)cyclopropyl)sulfonyl)carbamoyl)-7,9-dimethyl-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 898.6 (M.sup.++1).

(365) Compound 6139: 1,1,1-trifluoro-2-methylpropan-2-yl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((7-chloro-2-methylimidazo[1,2-a]quinazolin-5-yl)oxy)-14a-(((1-(fluoromethyl)cyclopropyl)sulfonyl)carbamoyl)-7,9-dimethyl-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 (500 MHz, DMSO-d.sub.6) 11.05 (br. s., 1H), 9.19 (br. s., 1H), 8.23 (d, J=8.9 Hz, 1H), 8.10-7.97 (m, 2H), 7.95 (d, J=2.1 Hz, 1H), 7.78 (d, J=6.7 Hz, 1H), 5.81 (br. s., 1H), 5.48 (m, 1H), 5.03 (m, 1H), 4.68-4.46 (m, 3H), 3.95-3.86 (m, 1H), 3.64-3.54 (m, 1H), 2.65 (m, 1H), 2.39 (t, J=9.8 Hz, 1H), 2.31 (m, 4H), 1.86 (m, 1H), 1.82-1.73 (m, 1H), 1.70 (m, 1H), 1.54 (m, 2H), 1.48 (m, 2H), 1.35 (d, J=17.1 Hz, 3H), 1.23 (m, 1H), 1.17 (m, 2H), 1.09 (s, 3H), 0.96-0.81 (m, 10H), 0.77-0.68 (m, 1H); MS: MS m/z 898.6 (M.sup.++1).

Preparation of Compound 6140 and Compound 6141

(366) ##STR00145##

(367) Compounds 6140 and 6141 were prepared using the intermediates described herein and by following the general procedure described for the synthesis of Compound 6126 and Compound 6127:

(368) Compound 6140: 3,3-difluoro-2-methylbutan-2-yl((2R,6S,7R,9S,13aS,14aR,16aS,Z)-2-((7-chloro-2-methylimidazo[1,2-a]quinazolin-5-yl)oxy)-14a-(((1-(fluoromethyl)cyclopropyl)sulfonyl)carbamoyl)-7,9-dimethyl-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 894.8 (M.sup.++1).

(369) Compound 6141: 3,3-difluoro-2-methylbutan-2-yl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-((7-chloro-2-methylimidazo[1,2-a]quinazolin-5-yl)oxy)-14a-(((1-(fluoromethyl)cyclopropyl)sulfonyl)carbamoyl)-7,9-dimethyl-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) 8.10-8.00 (m, 2H), 7.89 (dd, J=8.9, 2.4 Hz, 1H), 7.81 (s, 1H), 5.98-5.87 (m, 1H), 5.56 (td, J=10.2, 5.5 Hz, 1H), 5.09 (t, J=9.4 Hz, 1H), 4.77 (d, J=11.3 Hz, 1H), 4.72-4.60 (m, 2H), 4.53 (d, J=11.3 Hz, 1H), 4.02 (dd, J=11.9, 3.1 Hz, 1H), 3.71 (d, J=10.8 Hz, 1H), 2.81 (dd, J=14.1, 6.8 Hz, 1H), 2.64 (q, J=9.1 Hz, 1H), 2.51 (ddd, J=14.1, 10.3, 4.0 Hz, 1H), 2.42-2.33 (m, 4H), 1.98-1.85 (m, 1H), 1.85-1.75 (m, 2H), 1.73-1.52 (m, 5H), 1.51-1.39 (m, 4H), 1.31-1.10 (m, 4H), 1.07-0.94 (m, 9H), 0.81 (s, 3H); MS: MS m/z 894.8 (M.sup.++1).

Preparation of 3,3-difluoro-2-methylbutan-2-yl pyridin-2-yl carbonate

(370) ##STR00146##

(371) ##STR00147##

Step 1

(372) Methylmagnesium bromide (24.9 mL, 74.7 mmol) was added dropwise via syringe to a solution of ethyl 2,2-difluoropropanoate (3.44 g, 24.91 mmol) in diethyl ether (50 mL) at 20 C. and stirred at this temp for 1 h before warming up to room temperature. The reaction was quenched with sat. ammonium chloride and extracted with ether. The organic layer was washed with brine; dried over MgSO.sub.4; filtered and concentrated in vacuo to afford the crude 3,3-difluoro-2-methylbutan-2-ol (1.84 g, 59.5% yield) as an oil. .sup.1H NMR (500 MHz, CDCl.sub.3) 1.68-1.58 (m, 3H), 1.31 (t, J=1.2 Hz, 6H).

Preparation of tert-butyl 3-chloro-2-(trifluoromethyl)quinoxaline-6-carboxylate

(373) ##STR00148##

(374) ##STR00149##

Step 1

(375) To a 30 mL vial equipped with a stir bar was added 3,4-diaminobenzoic acid (3.00 g, 19.7 mmol) and ethanol (30 mL). To the homogenous, dark purple solution was added ethyl 3,3,3-trifluoro-2-oxopropanoate (4.02 g, 23.7 mmol). The vial was placed in a 75 C. heating block with stirring for 16 h. The mixture was cooled to room temperature and then filtered to isolate the solids. Residual solvent was removed in vacuo to afford a light-purple solid, 3-hydroxy-2-(trifluoromethyl)quinoxaline-6-carboxylic acid, 2.57 g (51%). This material was used directly in the next step.

Step 2

(376) To a 15 mL vial equipped with a stir bar was added 3-hydroxy-2-(trifluoromethyl)quinoxaline-6-carboxylic acid (2.57 g, 9.97 mmol), then POCl.sub.3 (6 ml, 64.4 mmol), then DMF (0.154 ml, 1.99 mmol). The vial was sealed and then placed in a 90 C. heating block with stirring for 5 h. The crude reaction solution was added to a 1 L separatory funnel charged with approximately 500 mL ice. The mixture was shaken and then allowed to stand until the mixture had warmed to room temperature. The mixture was extracted with EtOAc (2150 mL). The combined organics were dried over MgSO.sub.4; filtered; then concentrated in vacuo to afford 3-chloro-2-(trifluoromethyl)quinoxaline-6-carboxylic acid as a purple solid, 2.991 g. This material was used directly in the next step.

Step 3

(377) A dry 100 mL r.b. flask equipped with a stir bar was fitted with a Schlenk gas adapter and the top of the Schlenk adapter was sealed with a rubber septum vented to an oil bubbler. The system was placed under a constant slow stream of N.sub.2 gas. To the flask was added 3-chloro-2-(trifluoromethyl)quinoxaline-6-carboxylic acid (2.991 g, 10.81 mmol) in DMF (5 mL). To the flask was slowly added 1,1-di-tert-butoxy-N,N-dimethylmethanamine (20 mL, 83 mmol) upon which a white smoke was immediately evolved and an exotherm leading to mild reflux was noted. The addition rate was controlled to maintain a mild reflux. The flask was placed in a 100 C. oil bath with stirring for 30 minutes. The reaction solution was concentrated in vacuo onto Celite and the resulting powder was subjected to SiO.sub.2 chromatography to afford tert-butyl 3-chloro-2-(trifluoromethyl)quinoxaline-6-carboxylate as a white solid, 1.2811 g (36% over three steps). .sup.1H-NMR (500 MHz, CDCl.sub.3) 8.74 (d, J=1.6 Hz, 1H), 8.45 (dd, J=8.7, 1.8 Hz, 1H), 8.27 (d, J=8.8 Hz, 1H), 1.67 (s, 9H).

Preparation of 3-chloro-N-(prop-2-yn-1-yl)-2-(trifluoromethyl)quinoxaline-6-carboxamide

(378) ##STR00150##

(379) To a 40 mL vial equipped with a stir bar was added 3-chloro-2-(trifluoromethyl)quinoxaline-6-carboxylic acid (0.500 g, 1.81 mmol) and prop-2-yn-1-amine (0.100 g, 1.81 mmol), then CH.sub.2Cl.sub.2 (10 mL), then diisopropylethylamine (0.95 mL, 5.4 mmol). To the stirred solution was added HATU (0.756 g, 1.99 mmol). The solution was stirred at room temperature for 30 minutes. The reaction mixture was transferred to a 500 mL separatory funnel and was diluted with EtOAc (200 mL). The solution was washed with aq. 2M HCl (250 mL); then brine. The organic phase was dried over MgSO.sub.4; filtered; then concentrated in vacuo to afford a brown solid. This material was purified by silica gel chromatography to afford 3-chloro-N-(prop-2-yn-1-yl)-2-(trifluoromethyl)quinoxaline-6-carboxamide as a yellow solid, 0.35 g (62%). .sup.1H-NMR (400 MHz, CD.sub.3OD) 8.55 (d, J=1.5 Hz, 1H), 8.40-8.32 (m, 2H), 4.24 (d, J=2.5 Hz, 2H), 2.67 (t, J=2.5 Hz, 1H).

Preparation of (2R,6S,7R,9R,13aS,14aR,16aS,Z)-6-amino-2-hydroxy-7,9-dimethyl-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 TFA salt and (2R,6S,7R,9R,13aS,14aR,16aS,Z)-6-amino-7-ethyl-2-hydroxy-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 TFA salt

(380) (2R,6S,7R,9R,13aS,14aR,16aS,Z)-6-amino-2-hydroxy-7,9-dimethyl-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 TFA salt was prepared by treating tert-butyl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-2-hydroxy-7,9-dimethyl-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 with a 1:1 solution of CH.sub.2Cl.sub.2:trifluoroacetic acid for 1 h. The volatiles were then removed in vacuo to afford the product in quantitative yield.

(381) Likewise, (2R,6S,7R,9R,13aS,14aR,16aS,Z)-6-amino-7-ethyl-2-hydroxy-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 TFA salt was prepared from tert-butyl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-7-ethyl-2-hydroxy-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 following the same procedure.

Preparation of 2-(3-chloro-2-(trifluoromethyl)quinoxalin-6-yl)-5-methyloxazole

(382) ##STR00151##

(383) To a 7 mL vial equipped with a stir bar was added 3-chloro-N-(prop-2-yn-1-yl)-2-(trifluoromethyl)quinoxaline-6-carboxamide (100 mg, 0.319 mmol) and dioxane (1 mL). To the solution was added triflic acid (0.028 mL, 0.319 mmol). The vial was capped and placed in a 90 C. heat block with stirring for 16 h. The solution was concentrated onto diatomaceous earth (Celite) in vacuo and the resulting powder was subjected to SiO.sub.2 chromatography (30 g SiO.sub.2, hexanes:EtOAc 100:0.fwdarw.70:30 over 12 CV, only one peak elutes, detected at 245 nm) to afford 2-(3-chloro-2-(trifluoromethyl)quinoxalin-6-yl)-5-methyloxazole as a pale yellow solid, 53 mg (53%). .sup.1H NMR (500 MHz, CDCl.sub.3) 8.66 (d, J=1.7 Hz, 1H), 8.55 (dd, J=8.8, 1.9 Hz, 1H), 8.27 (d, J=8.8 Hz, 1H), 7.01 (q, J=1.1 Hz, 1H), 2.49 (d, J=1.3 Hz, 3H).

Preparation of Compound 7001

(384) ##STR00152##

(385) To a 2 mL vial equipped with a stir bar was added tert-butyl 3-chloro-2-(trifluoromethyl)quinoxaline-6-carboxylate (7.2 mg, 0.022 mmol) and (2R,6S,7R,9R,13aS,14aR,16aS,Z)-6-amino-2-hydroxy-7,9-dimethyl-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 TFA salt (18 mg, 0.022 mmol), then THF (0.2 mL). To the solution was added potassium tert-butoxide in THF (0.11 mL, 0.11 mmol). The solution was stirred at 23 C. for 15 minutes. To the vial was added acetic acid (6.2 l, 0.11 mmol) and diisopropylethylamine (0.057 mL, 0.32 mmol) as a solution in THF (0.100 mL). To the vial was then added 3,3-difluoro-2-methylbutan-2-yl pyridin-2-yl carbonate (16 mg, 0.065 mmol) as a solution in THF (0.100 mL). The reaction solution was stirred at room temperature for 10 min. The volatiles were evaporated under a stream of nitrogen and the resulting residue was then dissolved in MeOH. The resulting solution was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 70-100% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 45-85% B over 40 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound, 6.6 mg (32%).

(386) Compound 7001: tert-butyl 3-(((2R,6S,7R,9R,13aS,14aR,16aS,Z)-6-((((3,3-difluoro-2-methylbutan-2-yl)oxy)carbonyl)amino)-7,9-dimethyl-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-2-yl)oxy)-2-(trifluoromethyl)quinoxaline-6-carboxylate.

(387) .sup.1H NMR (400 MHz, CD.sub.3OD) 8.55 (d, J=1.7 Hz, 1H), 8.28-8.22 (m, 1H), 8.21-8.15 (m, 1H), 7.09 (d, J=8.1 Hz, 1H), 6.00 (br. s., 1H), 5.61 (td, J=10.3, 5.6 Hz, 1H), 5.03 (t, J=10.0 Hz, 1H), 4.93-4.90 (m, 1H), 4.66 (dd, J=10.3, 6.8 Hz, 1H), 4.08 (dd, J=12.1, 3.1 Hz, 1H), 3.76-3.68 (m, 1H), 2.77 (dd, J=14.1, 7.0 Hz, 1H), 2.72-2.65 (m, 1H), 2.52 (ddd, J=13.9, 10.3, 3.9 Hz, 1H), 2.48-2.36 (m, 1H), 2.01-1.89 (m, 1H), 1.89-1.73 (m, 3H), 1.69 (s, 9H), 1.68-1.55 (m, 3H), 1.52 (s, 6H), 1.50-1.35 (m, 4H), 1.31-1.17 (m, 1H), 1.07 (s, 3H), 1.03 (s, 3H), 1.01 (d, J=6.8 Hz, 3H), 0.95 (d, J=6.6 Hz, 3H), 0.91-0.87 (m, 2H), 0.87-0.78 (m, 1H). MS: MS m/z 955.7 (M.sup.1).

Preparation of Compound 7002

(388) ##STR00153##

(389) To a 2 mL vial equipped with a stir bar was added 2-(3-chloro-2-(trifluoromethyl)quinoxalin-6-yl)-5-methyloxazole (8.32 mg, 0.027 mmol) and (2R,6S,7R,9R,13aS,14aR,16aS,Z)-6-amino-2-hydroxy-7,9-dimethyl-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 TFA salt (15 mg, 0.022 mmol), then THF (0.2 mL). To the solution was added potassium tert-butoxide in THF (0.11 mL, 0.11 mmol). The solution was stirred at 23 C. for 10 minutes. To the vial was added acetic acid (6.32 l, 0.110 mmol) and diisopropylethylamine (0.058 mL, 0.33 mmol) as a solution in THF (0.10 mL). To the vial was then added pyridin-2-yl (1,1,1-trifluoro-2-methylpropan-2-yl) carbonate (16.5 mg, 0.066 mmol) as a solution in THF (0.100 mL). The reaction solution was stirred at room for 10 minutes. The reaction mixture was concentrated under a stream of N.sub.2 and the resulting residue was dissolved in MeOH, and then was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 50-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound, 8.2 mg (38%).

(390) Compound 7002: 1,1,1-trifluoro-2-methylpropan-2-yl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-7,9-dimethyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-2-((7-(5-methyloxazol-2-yl)-3-(trifluoromethyl)quinoxalin-2-yl)oxy)-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) 8.45 (d, J=1.8 Hz, 1H), 8.27 (dd, J=8.7, 1.9 Hz, 1H), 8.15 (d, J=8.8 Hz, 1H), 7.03 (d, J=1.0 Hz, 1H), 5.95 (br. s., 1H), 5.57 (td, J=10.2, 5.6 Hz, 1H), 5.00 (t, J=9.8 Hz, 1H), 4.83 (s, 1H), 4.61 (dd, J=10.4, 6.9 Hz, 1H), 4.04 (dd, J=12.2, 3.1 Hz, 1H), 3.68 (d, J=10.8 Hz, 1H), 2.73 (dd, J=13.9, 6.7 Hz, 1H), 2.68-2.60 (m, 1H), 2.54-2.30 (m, 5H), 1.97-1.69 (m, 5H), 1.67-1.50 (m, 3H), 1.48 (s, 3H), 1.47-1.30 (m, 4H), 1.25-1.19 (m, 1H), 1.18 (s, 3H), 1.11 (s, 3H), 0.96 (d, J=6.8 Hz, 3H), 0.90 (d, J=6.5 Hz, 3H), 0.87-0.83 (m, 2H), 0.83-0.73 (m, 1H). MS: MS m/z 942.8 (M.sup.++1).

Preparation of Compound 7003

(391) ##STR00154##

(392) To a 2 mL vial equipped with a stir bar was added 2-(3-chloro-2-(trifluoromethyl)quinoxalin-6-yl)-5-methyloxazole (7.5 mg, 0.024 mmol) and (2R,6S,7R,9R,13aS,14aR,16aS,Z)-6-amino-7-ethyl-2-hydroxy-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 TFA salt (15 mg, 0.022 mmol), then THF (0.2 mL). To the solution was added potassium tert-butoxide in THF (0.11 mL, 0.11 mmol). The solution was stirred at 23 C. for 10 minutes. To the vial was added acetic acid (6.22 l, 0.109 mmol) and diisopropylethylamine (0.057 mL, 0.33 mmol) as a solution in THF (0.100 mL). To the vial was then added pyridin-2-yl (1,1,1-trifluoro-2-methylpropan-2-yl) carbonate (16.25 mg, 0.065 mmol) as a solution in THF (0.100 mL). The reaction solution was stirred at room for 10 minutes, then was concentrated under a N.sub.2 stream and the resulting residue was dissolved in MeOH and was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 60-100% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound, 1.3 mg (6%).

(393) Compound 7003: 1,1,1-trifluoro-2-methylpropan-2-yl((2R,6S,7R,9R,13aS,14aR,16aS,Z)-7-ethyl-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-2-(7-(5-methyloxazol-2-yl)-3-(trifluoromethyl)quinoxalin-2-yl)oxy)-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) 8.52 (d, J=1.8 Hz, 1H), 8.31 (dd, J=8.8, 1.8 Hz, 1H), 8.18 (d, J=8.8 Hz, 1H), 7.04 (d, J=1.0 Hz, 1H), 6.01 (br. s., 1H), 5.62-5.51 (m, 1H), 5.06 (br. s., 1H), 4.85-4.80 (m, 1H), 4.65-4.58 (m, 2H), 4.05 (dd, J=12.0, 3.0 Hz, 1H), 3.92 (d, J=11.3 Hz, 1H), 2.73 (dd, J=14.1, 7.0 Hz, 1H), 2.63 (d, J=6.5 Hz, 1H), 2.54-2.49 (m, 1H), 2.48 (d, J=1.3 Hz, 3H), 2.44-2.29 (m, 1H), 1.99-1.86 (m, 2H), 1.77-1.69 (m, 1H), 1.64-1.49 (m, 5H), 1.48 (s, 4H), 1.47-1.19 (m, 5H), 1.16 (s, 6H), 1.12-1.03 (m, 1H), 0.97 (d, J=6.8 Hz, 3H), 0.83 (br. s., 2H), 0.74 (t, J=7.5 Hz, 3H). MS: MS m/z 956.9 (M.sup.++1).

Biological Studies

(394) 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

(395) 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.

(396) 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)).

(397) 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).

(398) NS3/4A protease complex-containing fractions were pooled and loaded on a desalting column Superdex-5200 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

(399) 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.

(400) In order to monitor HCV NS3/4A protease activity, an NS3/4A peptide substrate was used. The substrate was RET 51 (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.

(401) 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.

(402) 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.

(403) 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.

(404) 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.

(405) 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))).

(406) 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

(407) 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.

(408) 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

(409) 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.

(410) 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.

(411) 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; and E=35.01-145 nM.

(412) TABLE-US-00002 TABLE 2 Cmpd LE_1a LE_1a LE_1b LE_1b Number (EC50, nM) (EC50, range) (EC50, nM) (EC50, range) 5491 5.41 D 2.57 C 5493 E D 5495 C B 5497 D C 5500 D D 6120 E E 6122 71.99 E 72.46 E 6125 E E 6127 D D 6129 4.21 C 0.78 B 6131 D C 6133 D B 6135 C B 6137 C B 6139 D C 6141 D C 4248 C C 4255 C B 4258 C C 4264 C C 4274 D C 4275 D D 4280 D C 4281 D D 4282 D C 4285 C C 4288 D D 4291 C B 4293 C B 4303 C C 4306 D D 4307 C C 4308 D D 4309 3.51 C 2.31 C 4329 E E 4330 D D 4286 C B 4287 C C 4294 0.85 B 0.89 B 4299 B B 4301 B B 4358 C C 5507 C B 5509 C B 5511 C C 5513 C B 5515 C B 5517 C C 5519 C B 5521 1.23 C 0.47 A 5549 B B 7001 C B 7002 C B 7003 3.7 C 0.80 B

(413) 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.