Difluoroketamide derivatives as HTRA1 inhibitors

Abstract

The invention provides novel compounds having the general formula (I) ##STR00001##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, A, X and R.sup.11 are as described herein, compositions including the compounds and methods of using the compounds.

Claims

1. A compound of formula (I) ##STR00081## or a pharmaceutically acceptable salt thereof, wherein R.sup.1 is selected from i) C.sub.1-6-alkyl, ii) C.sub.3-8-cycloalkyl substituted with R.sup.24, R.sup.25 and R.sup.26, iii) halo-C.sub.1-6-alkyl, iv) heterocycloalkyl-C.sub.1-6-alkyl substituted with R.sup.24, R.sup.25 and R.sup.26, v) aryl-C.sub.1-6-alkyl substituted with R.sup.24, R.sup.25 and R.sup.26, and vi) heteroaryl-C.sub.1-6-alkyl substituted with R.sup.24, R.sup.25 and R.sup.26; R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.7, R.sup.10 and R.sup.23 are independently selected from i) H, ii) C.sub.1-6-alkyl, and iii) C.sub.3-8-cycloalkyl; X is selected from i) —O—, ii) —S—, and iii) —S(O).sub.2—; R.sup.6 is selected from i) aryl substituted with R.sup.12, R.sup.13 and R.sup.14, ii) aryl-C.sub.1-6-alkyl substituted with R.sup.12, R.sup.13 and R.sup.14, iii) heteroaryl substituted with R.sup.12, R.sup.13 and R.sup.14, and iv) heteroaryl-C.sub.1-6-alkyl substituted with R.sup.12, R.sup.13 and R.sup.14; A is selected from i) —O—, ii) —CH.sub.2—, iii) —S(O).sub.2NR.sup.10— and iv) —C(O)NR.sup.10—; R.sup.8 is selected from i) H, ii) —CH.sub.2R.sup.9; R.sup.9 is selected from i) H, ii) hydroxy, iii) amino-C.sub.1-6-alkyl substituted on the nitrogen atom by one or two substituents selected from H, C.sub.1-6-alkylcarbonyl, C.sub.1-6-alkoxycarbonyl, C.sub.1-6-alkyl, arylcarbonyl and heteroarylcarbonyl, wherein arylcarbonyl and heteroarylcarbonyl are substituted with R.sup.15, R.sup.16 and R.sup.17, iv) aminocarbonyl substituted on the nitrogen atom by one or two substituents selected from H, C.sub.1-6-alkylcarbonyl, C.sub.1-6-alkoxycarbonyl, C.sub.1-6-alkyl, arylcarbonyl and heteroarylcarbonyl, wherein arylcarbonyl and heteroarylcarbonyl are substituted with R.sup.15, R.sup.16 and R.sup.17, v) aminocarbonyl-C.sub.1-6-alkyl substituted on the nitrogen atom by one or two substituents selected from H, C.sub.1-6-alkylcarbonyl, C.sub.1-6-alkoxycarbonyl, C.sub.1-6-alkyl, arylcarbonyl and heteroarylcarbonyl, wherein arylcarbonyl and heteroarylcarbonyl are substituted with R.sup.15, R.sup.16 and R.sup.17, vi) carboxy, vii) carboxy-C.sub.1-6-alkyl, viii) C.sub.1-6-alkoxy, ix) C.sub.1-6-haloalkoxy, x) C.sub.1-6-alkoxycarbonyl, xi) C.sub.1-6-alkoxycarbonyl-C.sub.1-6-alkyl, xii) C.sub.3-8-cycloalkyl, xiii) aryl substituted with R.sup.15, R.sup.16 and R.sup.17, xiv) aryl-C.sub.1-6-alkyl substituted with R.sup.15, R.sup.16 and R.sup.17, xv) aryl-C.sub.1-6-alkoxy substituted with R.sup.15, R.sup.16 and R.sup.17, xvi) heteroaryl substituted with R.sup.15, R.sup.16 and R.sup.17, xvii) heteroaryl-C.sub.1-6-alkyl substituted with R.sup.15, R.sup.16 and R.sup.17, and xviii) heteroaryl-C.sub.1-6-alkoxy substituted with R.sup.15, R.sup.16 and R.sup.17 xix) heterocycloalkyl substituted with R.sup.15, R.sup.16 and R.sup.17, xx) heterocycloalkyl —C.sub.1-6-alkyl substituted with R.sup.15, R.sup.16 and R.sup.17, and xxi) heterocycloalkyl —C.sub.1-6-alkoxy substituted with R.sup.15, R.sup.16 and R.sup.17; R.sup.11 is selected from i) amino-C.sub.1-6-alkyl substituted on the nitrogen atom by R.sup.21 and R.sup.22, ii) C.sub.3-8-cycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20, iii) C.sub.3-8-cycloalkyl-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, iv) C.sub.3-8-cycloalkyl(halo)-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, v) aryl substituted with R.sup.18, R.sup.19 and R.sup.20, vi) aryl-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, vii) aryl-C.sub.3-8-cycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20, viii) aryl-heterocycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20 ix) aryl(halo)-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, x) aryl(halo)-C.sub.3-8-cycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xi) aryl(halo)-heterocycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xii) aryloxy-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xiii) aryloxy-C.sub.3-8-cycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xiv) aryloxy-heterocycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xv) aryloxy(halo)-C.sub.3-8-cycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xvi) aryloxy(halo)-heterocycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20 xvii) aryloxy(halo)-C.sub.1-6-alkyl, xviii) heterocycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xix) heterocycloalkyl-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xx) heterocycloalkyl-C.sub.3-8-cycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xxi) heterocycloalkyl(halo)-C.sub.3-8-cycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xxii) heterocycloalkyl(halo)-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xxiii) heteroaryl substituted with R.sup.18, R.sup.19 and R.sup.20, xxiv) heteroaryl-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xxv) heteroaryl-C.sub.3-8-cycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xxvi) heteroaryl(halo)-C.sub.3-8-cycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xxvii) heteroaryl(halo)-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xxviii) heteroaryloxy-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xxix) heteroaryloxy-C.sub.3-8-cycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20, xxx) heteroaryloxy(halo)-C.sub.3-8-cycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20, and xxxi) heteroaryloxy(halo)-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20; R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19, R.sup.20, R.sup.24, R.sup.25 and R.sup.26 are independently selected from i) H, ii) cyano, iii) halogen, iv) oxo, v) C.sub.1-6-alkyl, vi) amino substituted on the nitrogen atom by two substituents independently selected from H, C.sub.1-6-alkyl, C.sub.1-6-alkoxycarbonyl, arylcarbonyl and heteroarylcarbonyl, vii) amino-C.sub.1-6-alkyl substituted on the nitrogen atom by two substituents independently selected from H, C.sub.1-6-alkyl, C.sub.1-6-alkoxycarbonyl, arylcarbonyl and heteroarylcarbonyl, viii) C.sub.1-6-alkyl, ix) halo-C.sub.1-6-alkyl, x) C.sub.3-8-cycloalkyl, xi) C.sub.1-6-alkoxycarbonyl-C.sub.1-6-alkyl, xii) carboxy-C.sub.1-6-alkyl, xiii) C.sub.1-6-alkoxycarbonyl-C.sub.1-6alkylaminocarbonyl-C.sub.1-6alkyl, xiv) carboxy-C.sub.1-6-alkylaminocarbonyl-C.sub.1-6alkyl, xv) C.sub.1-6-alkoxy, xvi) halo-C.sub.1-6-alkoxy, xvii) C.sub.1-6-alkoxycarbonyl-C.sub.1-6-alkoxy, xviii) carboxy-C.sub.1-6-alkoxy, xix) C.sub.1-6-alkoxycarbonyl-C.sub.1-6-alkylaminocarbonyl-C.sub.1-6-alkoxy, xx) carboxy-C.sub.1-6-alkylaminocarbonyl-C.sub.1-6-alkoxy, and xxi) heterocycloalkyl; R.sup.21 and R.sup.22 are independently selected from i) H, ii) C.sub.1-6-alkoxycarbonyl, iii) carboxy-C.sub.1-6-alkyl, iv) arylcarbonyl, and v) heteroarylcarbonyl.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.1 is selected from i) halo-C.sub.1-6-alkyl, and ii) morpholinyl-C.sub.1-6-alkyl substituted with R.sup.24, R.sup.25 and R.sup.26; R.sup.2 is C.sub.1-6-alkyl; R.sup.3, R.sup.4, R.sup.5, R.sup.7, R.sup.10 and R.sup.23 are H; X is selected from i) —O—, ii) —S—, and iii) —S(O).sub.2—; R.sup.6 is phenyl-C.sub.1-6-alkyl substituted with R.sup.12, R.sup.13 and R.sup.14; A is selected from i) —O—, and ii) —C(O)NR.sup.10—; R.sup.8 is —CH.sub.2R.sup.9; R.sup.9 is selected from i) H, ii) hydroxy, iii) C.sub.1-6-alkoxy, and iv) phenyl substituted with R.sup.15, R.sup.16 and R.sup.17; R.sup.11 is selected from i) phenyl substituted with R.sup.18, R.sup.19 and R.sup.20, ii) phenyl-C.sub.3-8-cycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20, iii) phenyl(halo)-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, iv) pyridinyl substituted with R.sup.18, R.sup.19 and R.sup.20; R.sup.12 is selected from i) H, and ii) C.sub.1-6-alkoxy; R.sup.13, R.sup.14, R.sup.17 and R.sup.20 are H; R.sup.15 is selected from i) cyano, ii) halogen, and iii) C.sub.1-6-alkyl; R.sup.16, R.sup.18 and R.sup.19 are independently selected from i) H, and ii) Halogen.

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.1 is selected from i) C.sub.1-6-alkyl, and ii) morpholinyl-C.sub.1-6-alkyl substituted with R.sup.24, R.sup.25 and R.sup.26.

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.1 is halo-C.sub.1-6-alkyl.

5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.1 is trifluoroethyl.

6. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is C.sub.1-6-alkyl.

7. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is isopropyl.

8. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.3, R.sup.4, R.sup.5, R.sup.7, R.sup.10 and R.sup.23 are H.

9. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X is —S(O).sub.2—.

10. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.6 is phenyl-C.sub.1-6-alkyl substituted with R.sup.12, R.sup.13 and R.sup.14.

11. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein A is selected from i) —O—, and ii) —C(O)NR.sup.10—.

12. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein A is —C(O)NR.sup.10—.

13. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.8 is —CH.sub.2R.sup.9.

14. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.9 is selected from i) H, ii) hydroxy, iii) C.sub.1-6-alkoxy, and iv) phenyl substituted with R.sup.15, R.sup.16 and R.sup.17.

15. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.9 is phenyl substituted with R.sup.15, R.sup.16 and R.sup.17.

16. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.11 is selected from i) phenyl substituted with R.sup.18, R.sup.19 and R.sup.20, ii) phenyl-C.sub.3-8-cycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20, iii) phenyl(halo)-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, and iv) pyridinyl substituted with R.sup.18, R.sup.19 and R.sup.20.

17. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.11 is selected from i) phenyl substituted with R.sup.18, R.sup.19 and R.sup.20, and ii) pyridinyl substituted with R.sup.18, R.sup.19 and R.sup.20.

18. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.12 is selected from i) H, and ii) C.sub.1-6-alkoxy.

19. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.12 is C.sub.1-6-alkoxy.

20. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.13, R.sup.14, R.sup.17 and R.sup.20 are H.

21. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.15 is selected from i) cyano, ii) halogen, and iii) C.sub.1-6-alkyl.

22. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.15 is halogen.

23. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.16, R.sup.18 and R.sup.19 are independently selected from i) H, and ii) halogen.

24. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.16 is H.

25. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.18 is halogen.

26. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.19 is H.

27. The compound according to claim 1, selected from (2S,4R)-1-[(2S)-2-[(3-chlorobenzoyl)amino]propanoyl]-N-[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]-4-[(4-methoxyphenyl)methylsulfonyl]pyrrolidine-2-carboxamide; (2S,4R)-1-[(2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]propanoyl]-N-[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]-4-[(4-methoxyphenyl)methyl sulfonyl]pyrrolidine-2-carboxamide; (2S,4R)-1-[(2S)-2-[[2-(2,5-dichlorophenyl)-2,2-difluoroacetyl]amino]propanoyl]-N-[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]-4-[(4-methoxyphenyl)methyl sulfonyl]pyrrolidine-2-carboxamide; (2S,4R)-1-[(2S)-2-[[2,2-difluoro-2-(3-fluorophenyl)acetyl]amino]propanoyl]-N-[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]-4-[(4-methoxyphenyl)methylsulfonyl]pyrrolidine-2-carboxamide; (2S,4R)-1-[(2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-3-[(2-methylpropan-2-yl)oxy]propanoyl]-N-[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]-4-[(4-methoxyphenyl)methylsulfonyl]pyrrolidine-2-carboxamide; (2S,4R)-1-[(2S)-2-[(3-chlorobenzoyl)amino]-3-methoxypropanoyl]-N-[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]-4-[(4-methoxyphenyl)methylsulfonyl]pyrrolidine-2-carboxamide; (2S,4R)-1-[(2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-3-methoxypropanoyl]-N-[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]-4-[(4-methoxyphenyl)methylsulfonyl]pyrrolidine-2-carboxamide; N—((S)-3-(3-cyanophenyl)-1-((2S,4R)-2-(((S)-5,5-difluoro-2-methyl-4,6-dioxo-6-((2,2,2-trifluoroethyl)amino)hexan-3-yl)carbamoyl)-4-((4-methoxybenzyl)sulfonyl)pyrrolidin-1-yl)-1-oxopropan-2-yl)picolinamide; N—((S)-1-((2S,4R)-2-(((S)-5,5-difluoro-2-methyl-4,6-dioxo-6-((2,2,2-trifluoroethyl)amino)hexan-3-yl)carbamoyl)-4-((4-methoxybenzyl)sulfonyl)pyrrolidin-1-yl)-1-oxo-3-(m-tolyl)propan-2-yl)picolinamide; 5-chloro-N-((2S)-3-(3-cyanophenyl)-1-((4R)-2-(((S)-5,5-difluoro-2-methyl-4,6-dioxo-6-((2,2,2-trifluoroethyl)amino)hexan-3-yl)carbamoyl)-4-((4-methoxybenzyl)sulfonyl)pyrrolidin-1-yl)-1-oxopropan-2-yl)picolinamide; (2S,4R)-1-((R)-3-(3-chlorophenyl)-2-(3,5-dichlorophenoxy)propanoyl)-N—((S)-5,5-difluoro-2-methyl-4,6-dioxo-6-((2,2,2-trifluoroethyl)amino)hexan-3-yl)-4-((4-methoxybenzyl)sulfonyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((R)-3-(3-chlorophenyl)-2-((5-chloropyridin-3-yl)oxy)propanoyl)-N—((S)-5,5-difluoro-2-methyl-4,6-dioxo-6-((2,2,2-trifluoroethyl)amino)hexan-3-yl)-4-((4-methoxybenzyl)sulfonyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(3-chlorobenzamido)-3-(3-fluorophenyl)propanoyl)-N—((S)-5,5-difluoro-2-methyl-6-((2-morpholinoethyl)amino)-4,6-dioxohexan-3-yl)-4-((4-methoxybenzyl)sulfonyl)pyrrolidine-2-carboxamide; (2S,4R)—N—((S)-5,5-difluoro-2-methyl-6-((2-morpholinoethyl)amino)-4,6-dioxohexan-3-yl)-1-((S)-3-(3-fluorophenyl)-2-(1-(2-fluorophenyl)cyclopentanecarboxamido)propanoyl)-4-((4-methoxybenzyl)sulfonyl)pyrrolidine-2-carboxamide; N—((S)-3-(3,4-dichlorophenyl)-1-((2S,4R)-2-(((S)-5,5-difluoro-2-methyl-4,6-dioxo-6-((2,2,2-trifluoroethyl)amino)hexan-3-yl)carbamoyl)-4-((4-methoxybenzyl)thio)pyrrolidin-1-yl)-1-oxopropan-2-yl)picolinamide; N—((S)-3-(3-chiorophenyl)-1-((2S,4R)-2-(((S)-5,5-difluoro-2-methyl-4,6-dioxo-6-((2,2,2-trifluoroethyl)amino)hexan-3-yl)carbamoyl)-4-((4-methoxybenzyl)sulfonyl)pyrrolidin-1-yl)-1-oxopropan-2-yl)picolinamide; N—((S)-1-((2S,4R)-4-(benzylsulfonyl)-2-(((S)-5,5-difluoro-2-methyl-4,6-dioxo-6-((2,2,2-trifluoroethyl)amino)hexan-3-yl)carbamoyl)pyrrolidin-1-yl)-3-(3-chlorophenyl)-1-oxopropan-2-yl)picolinamide; (2S,4R)-1-((R)-3-(3-chlorophenyl)-2-(3,5-dichlorophenoxy)propanoyl)-N—((S)-5,5-difluoro-2-methyl-4,6-dioxo-6-((2,2,2-trifluoroethyl)amino)hexan-3-yl)-4-((4-methoxybenzyl)thio)pyrrolidine-2-carboxamide; (2S,4R)-4-(benzylsulfonyl)-1-((R)-3-(3-chlorophenyl)-2-((5-chloropyridin-3-yl)oxy)propanoyl)-N—((S)-5,5-difluoro-2-methyl-4,6-dioxo-6-((2,2,2-trifluoroethyl)amino)hexan-3-yl)pyrrolidine-2-carboxamide; (2S,4R)-1-[(2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-3-hydroxypropanoyl]-N-[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]-4-[(4-methoxyphenyl)methyl sulfonyl]pyrrolidine-2-carboxamide; N—((S)-3-(3,4-dichlorophenyl)-1-((2S,4R)-2-(((S)-5,5-difluoro-2-methyl-4,6-dioxo-6-((2,2,2-trifluoroethyl)amino)hexan-3-yl)carbamoyl)-4-((4-methoxybenzyl)sulfonyl)pyrrolidin-1-yl)-1-oxopropan-2-yl)picolinamide; N—((S)-3-(3-chlorophenyl)-1-((2S,4R)-2-(((S)-5,5-difluoro-2-methyl-4,6-dioxo-6-((2,2,2-trifluoroethyl)amino)hexan-3-yl)carbamoyl)-4-((4-methoxybenzyl)oxy)pyrrolidin-1-yl)-1-oxopropan-2-yl)picolinamide; or pharmaceutically acceptable salts thereof.

28. A pharmaceutical composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

29. A process to prepare a compound according to claim 1 comprising the reaction of a compound of formula (II) in oxidative conditions: ##STR00082## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, X, A, R.sup.11 and R.sup.23 are as defined in claim 1.

30. A compound manufactured according to a process of claim 29.

31. A method for the treatment of a condition selected from the group consisting of conditions of wet or dry age-related macular degeneration, geographic atrophy, diabetic retinopathy, retinopathy of prematurity and polypoidal choroidal vasculopathy, which method comprises administering an effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof.

Description

EXAMPLES

(1) All examples and intermediates were prepared under nitrogen atmosphere if not specified otherwise.

(2) Abbreviations: aq.=aqueous; CAS-RN=Chemical Abstracts Service Registry Number; HPLC=high performance liquid chromatography; MS=mass spectrum; sat.=saturated

Examples

Intermediate P-1

(2S,4R)-4-benzylsulfonyl-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid

(3) ##STR00014##

[A] (2S,4R)-1-tert-Butyl 2-methyl 4-(benzylthio)pyrrolidine-1,2-dicarboxylate

(4) ##STR00015##

(5) In a flask, potassium tert-butoxide 1M in THF (1.9 mL, 1.9 mmol) was combined with THF (7 mL) and the resulting colorless solution was cooled to −5° C. Phenylmethanethiol (267 μL, 2.28 mmol) was added and the reaction mixture was stirred at room temperature for 15 minutes. The reaction was cooled to 0° C. and a solution of (2S,4S)-1-tert-butyl 2-methyl 4-chloropyrrolidine-1,2-dicarboxylate (CAS [169032-99-9], 0.5 g, 1.9 mmol) in DMF (7 mL) was added dropwise. The mixture was stirred at this temperature for 30 minutes at 0° C. then allowed to warm up and stirring was continued at room temperature for 3 hours. The mixture was poured into a sat. NH.sub.4Claqueous solution and extracted with EtOAc. The organic layers were washed with a sat. NaHCO.sub.3 aqueous solution and brine. Combined organics were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude material was purified by silica gel flash chromatography eluting with a 10% to 80% EtOAc-heptanegradient to give the title compound (0.489 g, 73%) as a colorless oil.

[B] (2S,4R)-1-tert-Butyl 2-methyl 4-(benzylsulfonyl)pyrrolidine-1,2-dicarboxylate

(6) ##STR00016##

(7) In a flask, (2S,4R)-1-tert-butyl 2-methyl 4-(benzylthio)pyrrolidine-1,2-dicarboxylate (0.483 g, 1.37 mmol) was combined with DCM (20 mL) and the resulting colorless solution was cooled to 0° C. mCPBA (0.711 g, 2.89 mmol) was added at 0° C. and the reaction mixture was stirred for 1 hour at this temperature. The mixture was poured into a sat. NaHCO.sub.3 aqueous solution and extracted with DCM (2×25 mL). The organic layers were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude material was purified by silica gel flash chromatography eluting with a 20% to 70% EtOAc-heptanegradient to give the title compound (0.454 g, 86%) as a colorless oil. MS: 284.1 (M−Boc+H.sup.+).

[C] (2S,4R)-4-Benzylsulfonyl-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid

(8) ##STR00017##

(9) In a flask, (2S,4R)-1-tert-butyl 2-methyl 4-(benzylsulfonyl)pyrrolidine-1,2-dicarboxylate (0.447 g, 1.17 mmol) was combined with THF (6 mL) and methanol (3 mL) and the resulting colorless solution was cooled to 0° C. A 1M aqueous solution of LiOH (1.52 mL, 1.52 mmol) was added at 0° C. and the reaction mixture was stirred for 2 hours at this temperature. The mixture was quenched with a 1M KHSO.sub.4 aqueous solution and extracted with EtOAc (2×25 mL). The organic layers were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound (0.426 g, 99%) as a colorless foam. MS: 368.3 (M−H.sup.−).

Intermediate P-2

(2S,4R)-4-[(4-methoxyphenyl)methylsulfonyl]-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid

(10) ##STR00018##
was prepared in analogy to intermediate P-1, but using in step [A] (4-methoxyphenyl)methanethiol, to give the title compound as colorless solid; MS: 300.1 (M−Boc+H.sup.+).

Intermediate P-3

(2S,4R)-4-[(4-methoxyphenyl)methylsulfanyl]-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid

(11) ##STR00019##
was prepared by reaction of (2S,4S)-1-tert-butyl 2-methyl 4-chloropyrrolidine-1,2-dicarboxylate and (4-methoxyphenyl)methanethiol in analogy to intermediate P-1, step [A], followed by hydrolysis of the resultant (2S,4R)-1-tert-butyl 2-methyl 4-(benzylsulfanyl)pyrrolidine-1,2-dicarboxylate in analogy to intermediate P-1, step [C].

(12) Colorless and viscous oil; MS: 268.2 (M−Boc+H.sup.+).

Intermediate B-1

(2S,4R)—N-[(3S,4R)-5,5-Difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2-trifluoroethylamino)hexan-3-yl]-4-[(4-methoxyphenyl)methylsulfonyl]pyrrolidine-2-carboxamide

(13) ##STR00020##

[A] (S)-tert-Butyl (3-methyl-1-oxobutan-2-yl)carbamate

(14) ##STR00021##

(15) To a solution of commercially available (S)-tert-butyl (1-(methoxy(methyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (3 g, 11.5 mmol) in THF (100 mL) under argon at 0° C. was added LiAlH.sub.4 1M in THF (11.5 mL, 11.5 mmol) dropwise over 3 min (0.fwdarw.4° C.). After stirring for 20 min in the cold, the reaction mixture was quenched with 1N KHSO.sub.4 solution and extracted with EtOAc; the layers were separated and the aqueous layer was back-extracted with EtOAc. The organic layers were combined, dried over Na.sub.2SO.sub.4 and concentrated in vacuo to yield the title compound as a colorless liquid, 2.38 g, which was used immediately for the next step.

[B] Ethyl (3R,4S)-4-amino-2,2-difluoro-3-hydroxy-5-methylhexanoate

(16) ##STR00022##

(17) A solution of the above prepared (S)-tert-butyl (3-methyl-1-oxobutan-2-yl)carbamate (2.01 g, 9.99 mmol) and ethyl 2-bromo-2,2-difluoroacetate (3.84 mL, 30 mmol) in THF (15 mL) was added dropwise to a suspension of activated zinc (1.96 g, 30 mmol) in THF (65 mL). Afterwards, the reaction was brought to reflux for 2 hours. The heat source was removed and the reaction was allowed to cool to ambient temperature. The reaction mixture was poured into 15 mL 1N KHSO.sub.4 and extracted with EtOAc (2×25 mL). The organic layers were combined, washed with brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The crude material was purified by silica gel flash chromatography eluting with a 0 to 20% EtOAc-heptane gradient to give 1.41 g of the title compound as colorless oil.

[C] tert-Butyl N-[(3S,4R)-5,5-difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]carbamate

(18) ##STR00023##

(19) A mixture of the above prepared ethyl (3R,4S)-4-amino-2,2-difluoro-3-hydroxy-5-methylhexanoate (0.191 g, 0.588 mmol), 3,3,3-trifluoropropan-1-amine (0.333 g, 2.94 mmol) and N,N-diisopropylethylamine (0.514 mL, 2.94 mmol) was refluxed in 5 mL of MeOH overnight. The reaction volume was reduced in vacuo and to the residue was added EtOAc. The organic layer was washed with brine (3×), dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The crude material was purified by silica gel flash chromatography eluting with a 15 to 50% EtOAc-heptane gradient to give 0.180 g of the title compound as white foam. MS: 391.4 (M−H.sup.−).

[D] (3R,4S)-4-Amino-2,2-difluoro-3-hydroxy-5-methyl-N-(2,2,2-trifluoroethyl)hexanamide

(20) ##STR00024##

(21) In a 25 mL round-bottomed flask, the above prepared tert-butyl N-[(3S,4R)-5,5-difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]carbamate (0.177 g, 0.451 mmol) was combined with 1,4-dioxane (6 mL) to give a colorless solution. HCl 4M in dioxane (2.25 mL, 9 mmol) was added at 0° C. and the reaction mixture was stirred overnight at room temperature. The crude reaction mixture was concentrated in vacuo and dried on hv and then used directly for the next step (calculated as dihydrochloride).

[E] tert-Butyl (2S,4R)-2-[[(3S,4R)-5,5-difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]carbamoyl]-4-[(4-methoxyphenyl)methylsulfonyl]pyrrolidine-1-carboxylate

(22) ##STR00025##

(23) To a solution of (2S,4R)-4-[(4-methoxyphenyl)methylsulfonyl]-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid (Intermediate P-2, 0.390 g, 0.976 mmol) (3R,4S)-4-amino-2,2-difluoro-3-hydroxy-5-methyl-N-(2,2,2-trifluoroethyl)hexanamide×HCl (0.307 g, 0.976 mmol) and HATU (0.445 g, 1.17 mmol) in DMF (4 mL) cooled to 0° C. was added Huenig's base (0.512 mL, 2.93 mmol) and the reaction mixture stirred at room temperature for 1.5 hours. The mixture was diluted with EtOAc and washed with water and brine. The organic phase was dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude material was purified by silica gel flash chromatography eluting with a 0 to 75% EtOAc-heptane gradient to give the title compound (0.408 g, 63%) as an off-white solid. MS: 658.5 (M−H).sup.−.

[F] (2S,4R)—N-[(3S,4R)-5,5-Difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]-4-[(4-methoxyphenyl)methyl sulfonyl]pyrrolidine-2-carboxamide

(24) ##STR00026##

(25) To a solution of tert-butyl (2S,4R)-2-[[(3S,4R)-5,5-difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]carbamoyl]-4-[(4-methoxyphenyl)methylsulfonyl]pyrrolidine-1-carboxylate (0.385 g, 0.584 mmol) in MeOH (1 mL) was added 4M HCl in dioxane (0.730 mL, 2.92 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was evaporated to dryness and the resulting crude material triturated with diisopropylether. The solid precipitate was filtered off and further dried under the high vacuum to give the title compound (0.320 g, 92%, HCl salt) as a colorless solid. MS: 560.2 (M+H.sup.+).

Intermediate B-2

(2S,4R)—N-[(3S,4R)-5,5-Difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]-4-(benzylsulfonyl)pyrrolidine-2-carboxamide

(26) ##STR00027##
was prepared in analogy to intermediate B-1, but using in step [E] (2S,4R)-4-benzylsulfonyl-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid (Intermediate P-1), to give the title compound as a colorless solid as hydrochloride.

Intermediate B-3

(2S,4R)—N-((3S,4R)-5,5-Difluoro-4-hydroxy-2-methyl-6-oxo-6-((2,2,2-trifluoroethyl)amino)hexan-3-yl)-4-((4-methoxybenzyl)thio)pyrrolidine-2-carboxamide

(27) ##STR00028##
was prepared in analogy to intermediate B-1, but using in step [E] (2S,4R)-4-[(4-methoxyphenyl)methylsulfanyl]-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid (Intermediate P-3), to give the title compound as an off-white foam as hydrochloride.

Intermediate B-4

(2S,4R)-[(2S)-2-Aminopropanoyl]-N-[(3S,4R)-5,5-difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]-4-[(4-methoxyphenyl)methylsulfonyl]pyrrolidine-2-carboxamide

(28) ##STR00029##

[A] tert-Butyl N-[(2S)-1-[(2S,4R)-2-[[(3S,4R)-5,5-difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]carbamoyl]-4-[(4-methoxyphenyl)methylsulfonyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]carbamate

(29) ##STR00030##

(30) To a solution of (2S,4R)—N-[(3S,4R)-5,5-difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]-4-[(4-methoxyphenyl)methyl sulfonyl]pyrrolidine-2-carboxamide hydrochloride (Intermediate B-1, 0.312 g, 0.523 mmol), (2S)-2-(tert-butoxycarbonylamino)propanoic acid (0.099 g, 0.523 mmol) and HATU (0.219 g, 0.576 mmol) was added Huenig's base (0.274 mL, 1.57 mmol) and the reaction mixture stirred at room temperature overnight. The mixture was diluted with EtOAc and washed with water and brine. The organic phase was dried over Na.sub.2SO.sub.4, filtered and evaporated. The residue was purified by silica gel flash chromatography eluting with a 0 to 85% EtOAc-heptane gradient to give the title compound (0.345 g, 90%) as a colorless solid. MS: 731.4 (M+H.sup.+).

[B] (2S,4R)-1-[(2S)-2-Aminopropanoyl]-N-[(3S,4R)-5,5-difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]-4-[(4-methoxyphenyl)methylsulfonyl]pyrrolidine-2-carboxamide

(31) ##STR00031##

(32) To a solution of tert-butyl N-[(2S)-1-[(2S,4R)-2-[[(3S,4R)-5,5-difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]carbamoyl]-4-[(4-methoxyphenyl)methylsulfonyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]carbamate (0.340 g, 0.465 mmol) in MeOH (1 mL) was added 4M HCl in dioxane (0.582 mL, 2.33 mmol) and the reaction mixture stirred at room temperature overnight. The mixture was evaporated to dryness and triturated with diisopropylether. The solid precipitate was filtered off and further dried under the high vacuum to give the title compound (0.304 g, 98%, HCl salt) as a light green solid. MS: 631.5 (M+H.sup.+).

Intermediate B-5

(2S,4R)-1-[(2S)-2-Amino-3-[(2-methylpropan-2-yl)oxy]propanoyl]-N-[(3S,4R)-5,5-difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]-4-[(4-methoxyphenyl)methylsulfonyl]pyrrolidine-2-carboxamide

(33) ##STR00032##
was prepared in analogy to intermediate B-4, but using in step [A] (2S)-3-tert-butoxy-2-(tert-butoxycarbonylamino)propanoic acid and replacing in step [B] methanol by dioxane as solvent, to give the title compound as an off-white solid as hydrochloride. MS: 703.3 (M+H.sup.+).

Intermediate B-6

(2S,4R)-1-[(2S)-2-Amino-3-methoxypropanoyl]-N-[(3S,4R)-5,5-difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]-4-[(4-methoxyphenyl)methylsulfonyl]pyrrolidine-2-carboxamide

(34) ##STR00033##
was prepared in analogy to intermediate B-4, but using in step [A] (2S)-2-(tert-butoxycarbonylamino)-3-methoxy-propanoic acid, to give the title compound as colorless solid as hydrochloride. MS: 761.4 (M+H.sup.+).

Intermediate C-1

(2S,4R)—N-[(1S,2R)-3,3-Difluoro-2-hydroxy-1-isopropyl-4-(2-morpholinoethylamino)-4-oxo-butyl]-4-[(4-methoxyphenyl)methylsulfonyl]pyrrolidine-2-carboxamide

(35) ##STR00034##
was prepared in analogy to intermediate B-1, but using in step [C] 2-morpholinoethanamine, to give the title compound as light yellow foam as dihydrochloride.

Intermediate E-1

(2S)-3-(3,4-Dichlorophenyl)-2-(pyridine-2-carbonylamino)propanoic acid

(36) ##STR00035##

[A] (2,5-Dioxopyrrolidin-1-yl) pyridine-2-carboxylate

(37) ##STR00036##

(38) In a flask, pyridine-2-carboxylic acid (0.5 g, 4.06 mmol) was combined with DCM (20 mL) to give a colorless solution. At 0° C., pyridine (0.985 mL, 12.2 mmol), EDC (1.09 g, 5.69 mmol), and 1-hydroxypyrrolidine-2,5-dione (0.608 g, 5.28 mmol) were subsequently added, the ice-bath was removed, and the reaction mixture was stirred at rt overnight. The reaction mixture was then quenched with sat. NH.sub.4Cl sol. and extracted with DCM (2×20 mL). The organic layers were washed with sat NaHCO.sub.3, then with brine. The organic layers were combined, dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The crude material was triturated with CH.sub.2Cl.sub.2/heptane to give 0.686 g of the title compound as light brown solid. MS: 221.1 (M+H).sup.+.

[B] (2S)-3-(3,4-Dichlorophenyl)-2-(pyridine-2-carbonylamino)propanoic acid

(39) ##STR00037##

(40) A solution of the above prepared 2,5-dioxopyrrolidin-1-yl picolinate (0.250 g, 1.14 mmol) in DME (4 mL) was added to a mixture of (S)-2-amino-3-(3,4-dichlorophenyl)propanoic acid (0.266 g, 1.14 mmol) in THF (2 mL) and sodium bicarbonate (0.095 g, 1.14 mmol) in water (4 mL) and the reaction mixture was stirred at room temperature for 3 h. The mixture was poured into sat. NH.sub.4Cl sol. and extracted with EtOAc. The organic layers were washed with brine and the solvent was evaporated under vacuum. The residue was purified by silica gel flash chromatography eluting with a 0 to 10% DCM-MeOH gradient to give the title compound (0.309 g, 80%) as a colorless solid. MS: 339.1 (M+H).sup.+.

(41) In close analogy, using the appropriate acidic building blocks, were prepared Intermediates E-2 to E-6, respectively, as summarized in the following Table:

(42) TABLE-US-00002 Name Structure Reactant to be used in MS Intermediate Aspect step [A] and [B] (M + H.sup.+) E-2 pyridine-2-carboxylic acid and (2S)-2-(tert- butoxycarbonylamino)- 3-(3- chlorophenyl)propanoic acid 305.1 E-3 pyridine-2-carboxylic acid and (2S)-2-(tert- butoxycarbonylamino)- 3-(3- cyanophenyl)propanoic acid 296.1 E-4 0 pyridine-2-carboxylic acid and (2S)-2-(tert- butoxycarbonylamino)- 3-(3- methylphenyl)propanoic acid 285.2 E-5 3-chlorobenzoic acid and (2S)-2-(tert- butoxycarbonylamino)- 3-(3- fluorophenyl)propanoic acid 322.1 E-6 5-chloropyridine-2- carboxylic acid and (2S)-2-(tert- butoxycarbonylamino)- 3-(3- cyanophenyl)propanoic acid 330.1

Intermediate E-7

(2S)-3-(3-fluorophenyl)-2-[[1-(2-fluorophenyl)cyclopentanecarbonyl]amino]propanoic acid

(43) ##STR00043##

[A] Methyl (2S)-2-amino-3-(3-fluorophenyl)propanoate

(44) ##STR00044##

(45) In a flask, acetyl chloride (1.16 mL, 16.4 mmol) was combined with MeOH (15 mL) under ice-bath cooling to give a colorless solution. The solution was stirred 15 min at room temperature then cooled to 0° C. (2S)-2-amino-3-(3-fluorophenyl)propanoic acid (300 mg, 1.64 mmol) was added, then the reaction mixture was heated to 65° C. and stirred at this temperature for 30 min. The crude reaction mixture was concentrated in vacuo. The residue was suspended in CH.sub.2Cl.sub.2 and concentrated in vacuo (3 times) to give the title compound (0.380 g, 99%) as a colorless solid as hydrochloride. The crude material was used in the next step. MS: 198.1 (M+H.sup.+).

[B] Methyl (2S)-3-(3-fluorophenyl)-2-[[1-(2-fluorophenyl)cyclopentanecarbonyl]amino]propanoate

(46) ##STR00045##

(47) In a flask, methyl (2S)-2-amino-3-(3-fluorophenyl)propanoate×HCl (0.380 g, 1.63 mmol) was combined with DMF (15 mL) to give a colorless solution. N,N-diisopropylethylamine (1.42 mL, 8.13 mmol) and 1-(2-fluorophenyl)cyclopentanecarboxylic acid (0.339 g, 1.63 mmol) were added at −10° C. followed by HATU (0.680 g, 1.79 mmol) and the reaction mixture was stirred at −10° C. for 1 hour. The mixture was quenched with a sat. NaHCO.sub.3 aqueous solution and extracted with EtOAc The organic layer was washed with a 1N KHSO.sub.4 solution and brine. The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude material was purified by silica gel flash chromatography eluting with a 10 to 50% EtOAc-heptane gradient to give the title compound (0.488 g, 78%) as a colorless amorphous solid. MS: 388.2 (M+H.sup.+).

[C] (2S)-3-(3-fluorophenyl)-2-[[1-(2-fluorophenyl)cyclopentanecarbonyl]amino]propanoic acid

(48) ##STR00046##

(49) To a solution of methyl (2S)-3-(3-fluorophenyl)-2-[[1-(2-fluorophenyl)cyclopentanecarbonyl]amino]propanoate (0.291 g, 0.751 mmol) in THF (3 mL), methanol (1.5 mL) cooled to 0° C. was added a solution of LiOH (0.018 g, 0.751 mmol) in water (1.5 mL) and the reaction mixture was stirred at room temperature for 6 hours. The mixture was extracted with tBuOMe. The aqueous layer was acidified with a 1N KHSO.sub.4 aqueous solution and back-extracted with EtOAc. The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude material was triturated with CH.sub.2Cl.sub.2/heptane. The solid precipitate was filtered off and further dried under the high vacuum to give the title compound (0.280 g, 46%) as a colorless solid. MS: 374.2 (M+H.sup.+).

Intermediate F-1

(2R)-3-(3-chlorophenyl)-2-(3,5-dichlorophenoxy)propanoic acid

(50) ##STR00047##

[A] Methyl (2S)-3-(3-chlorophenyl)-2-hydroxy-propanoate

(51) ##STR00048##

(52) In a flask, (S)-methyl oxirane-2-carboxylate (0.4 g, 3.92 mmol) and copper bromide dimethyl sulfide (0.2 g, 0.980 mmol) were combined with THF (25 mL) and cooled to −35° C. Then, (3-chlorophenyl)magnesium bromide (7.84 mL, 7.84 mmol) was added dropwise over 15 minutes while keeping the temperature below −33° C. The reaction mixture was slowly warmed up to −25° C. The mixture was quenched with a sat. NH.sub.4Cl aqueous solution at −20° C. and extracted with EtOAc. The organic layer was washed with water, dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness. The crude material was purified by silica gel flash chromatography eluting with a 0 to 35% EtOAc-heptane gradient to give the title compound (0.615 g, 73%) as a colorless oil.

[B] Methyl (2R)-3-(3-chlorophenyl)-2-(3,5-dichlorophenoxy)propanoate

(53) ##STR00049##

(54) In a flask, methyl (2S)-3-(3-chlorophenyl)-2-hydroxy-propanoate (0.611 g, 2.85 mmol) and 3,5-dichlorophenol (0.487 g, 2.99 mmol) were combined with THF (11 mL) and cooled at −10° C. Triphenylphosphine (0.971 g, 3.7 mmol) and (E)-diisopropyl diazene-1,2-dicarboxylate (726 μL, 3.7 mmol) were subsequently added and the reaction mixture was stirred at 0° C. for 1.5 hours. The mixture was quenched with a 0.5 N aqueous HCl solution and extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness. The crude material was purified by silica gel flash chromatography eluting with a 0 to 15% EtOAc-heptane gradient to give the title compound (0.763 g, 70%) as a light yellow oil.

[C] (2R)-3-(3-Chlorophenyl)-2-(3,5-dichlorophenoxy)propanoic acid

(55) ##STR00050##

(56) In a flask, methyl (2R)-3-(3-chlorophenyl)-2-(3,5-dichlorophenoxy)propanoate (0.763 g, 2.12 mmol) was combined with THF (5 mL) and MeOH (2 mL) and cooled to 0° C. Lithium hydroxide (0.127 g, 5.3 mmol) in water (1 mL) was added and the reaction mixture stirred for 2 hours. The mixture was quenched with a 0.5 N aqueous HCl solution and extracted with EtOAc. The organic layer was washed with water until pH>2, over Na.sub.2SO.sub.4, filtered and evaporated to dryness. The residue was recrystallized from EtOAc/heptane to give the title compound (0.668 g, 91%) as a white crystalline solid. MS: 343.2 (M−H.sup.−).

Intermediate F-2

(2R)-3-(3-chlorophenyl)-2-(5-chloropyridin-3-yl)oxypropanoic acid

(57) ##STR00051##
was prepared in analogy to intermediate F-1, but using in step [B] 5-chloropyridin-3-ol and replacing THF by DCM as solvent, to give the title compound as a white foam. MS: 312.1 (M+H.sup.+).

Example 1

(2S,4R)-1-[(2S)-2-[(3-Chlorobenzoyl)amino]propanoyl]-N-[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]-4-[(4-methoxyphenyl)methylsulfonyl]pyrrolidine-2-carboxamide

(58) ##STR00052##

[A] (2S,4R)-1-[(2S)-2-[(3-Chlorobenzoyl)amino]propanoyl]-N-[(3S,4R)-5,5-difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]-4-[(4-methoxyphenyl)methylsulfonyl]pyrrolidine-2-carboxamide

(59) ##STR00053##

(60) A solution of (2S,4R)-1-[(2S)-2-aminopropanoyl]-N-[(3S,4R)-5,5-difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]-4-[(4-methoxyphenyl)methylsulfonyl]pyrrolidine-2-carboxamide hydrochloride (Intermediate B-4, 0.05 g, 0.075 mmol), 3-chlorobenzoic acid (0.012 g, 0.075 mmol) and HATU (0.031 g, 0.082 mmol) in DMF (1 mL) was cooled to 0° C. Huenig's base (0.039 mL, 0.225 mmol) was added and the reaction mixture was stirred at this temperature for 15 minutes then allowed to warm to room temperature and stirred for a further 1 hour. The mixture was diluted with EtOAc and washed with water and brine. The organic phase was dried over Na.sub.2SO.sub.4, filtered and evaporated. The residue was purified by silica gel flash chromatography eluting with a 0 to 100% EtOAc-heptane gradient to give the title compound (0.041 g, 71%) as a colorless solid. MS: 769.3 (M+H.sup.+).

[B] (2S,4R)-1-[(2S)-2-[(3-Chlorobenzoyl)amino]propanoyl]-N-[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]-4-[(4-methoxyphenyl)methylsulfonyl]pyrrolidine-2-carboxamide

(61) ##STR00054##

(62) To a suspension of (2S,4R)-1-[(2S)-2-[(3-chlorobenzoyl)amino]propanoyl]-N-[(3S,4R)-5,5-difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]-4-[(4-methoxyphenyl)methylsulfonyl]pyrrolidine-2-carboxamide (0.037 g, 0.048 mmol) in DCM (1 mL) was added a 15% Dess-Martin periodinane in DCM solution (0.449 mL, 0.216 mmol) and the reaction mixture stirred at room temperature for 2 hours. The mixture was diluted with DCM and washed with a saturated NH.sub.4Cl aqueous solution and brine. The organic phase was dried over Na.sub.2SO.sub.4, filtered and evaporated. The residue was purified by silica gel flash chromatography, eluting with a 0-95% EtOAc-heptane gradient to give the title compound (0.018 g, 50%) as a colorless solid. MS: 767.3 (M+H.sup.+).

(63) The following examples listed in Table 1 were prepared in analogy to the procedures described for the preparation of example 1 by using the indicated intermediate and carboxylic acid in step [A]

(64) TABLE-US-00003 TABLE 1 Name Structure Reactant to be used in MS Ex Aspect step [A] (M + H.sup.+)  2 (2S,4R)-1-[(2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]propanoyl]- Intermediate B-4 817.3 N-[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan- and 3-yl]-4-[(4-methoxyphenyl)methylsulfonyl]pyrrolidine-2-carboxamide 2-(3-chlorophenyl)-2,2- difluoro-acetic acid Colorless solid  3 (2S,4R)-1-[(2S)-2-[[2-(2,5-dichlorophenyl)-2,2-difluoroacetyl]amino]propanoyl]- Intermediate B-4 851.2 N-[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan- and 3-yl]-4-[(4-methoxyphenyl)methylsulfonyl]pyrrolidine-2-carboxamide 2-(2,5-chlorophenyl)-2,2- difluoro-acetic acid Colorless solid  4 (2S,4R)-1-[(2S)-2-[[2,2-difluoro-2-(3-fluorophenyl)acetyl]amino]propanoyl]-N- Intermediate B-4 801.2 [(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3- and yl]-4-[(4-methoxyphenyl)methylsulfonyl]pyrrolidine-2-carboxamide 2-(3-fluorophenyl)-2,2- difluoro-acetic acid Colorless solid  5 (2S,4R)-1-[(2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-3-[(2- Intermediate B-5 889.3 methylpropan-2-yl)oxy]propanoyl]-N-[(3S)-5,5-difluoro-2-methyl-4,6-dioxo- and 6-(2,2,2-trifluoroethylamino)hexan-3-yl]-4-[(4- 2-(3-chlorophenyl)-2,2- methoxyphenyl)methylsulfonyl]pyrrolidine-2-carboxamide difluoro-acetic acid Colorless solid  6 (2S,4R)-1-[(2S)-2-[(3-chlorobenzoyl)amino]-3-methoxypropanoyl]-N- Intermediate B-6 797.2 [(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan- and 3-yl]-4-[(4-methoxyphenyl)methylsulfonyl]pyrrolidine-2-carboxamide 3-chlorobenzoic acid Colorless solid  7 (2S,4R)-1-[(2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-3-methoxypropanoyl]- Intermediate B-6 847.2 N-[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan- and 3-yl]-4-[(4-methoxyphenyl)methylsulfonyl]pyrrolidine-2-carboxamide 2-(3-chlorophenyl)-2,2- difluoro-acetic acid 0 Colorless solid  8 N-[(2S)-3-(3-cyanophenyl)-1-[(2S,4R)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo- Intermediate B-1 835.4 6-(2,2,2-trifluoroethylamino)hexan-3-yl]carbamoyl]-4-[(4-methoxy- and phenyl)methylsulfonyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]pyridine-2-carboxamide (2S)-3-(3-cyanophenyl)-2- (pyridine-2- carbonylamino)propanoic acid (Intermediate E-3) Off-white foam  9 N-[(2S)-1-[(2S,4R)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2- Intermediate B-1 824.4 trifluoroethylamino)hexan-3-yl]carbamoyl]-4-[(4-methoxy- and phenyl)methylsulfonyl]pyrrolidin-1-yl]-3-(3-methylphenyl)-1-oxopropan-2- (2S)-3-(3-methylphenyl)-2- yl]pyridine-2-carboxamide (pyridine-2-carbonyl- amino)propanoic acid (Intermediate E-4) Colorless foam 10 5-chloro-N-[(2S)-3-(3-cyanophenyl)-1-[(2S,4R)-2-[[(3S)-5,5-difluoro-2-methyl- Intermediate B-1 869.3 4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]carbamoyl]-4-[(4- and methoxyphenyl)methylsulfonyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]pyridine-2- (2S)-2-[(5-chloropyridine-2- carboxamide carbonyl)amino]-3-(3- cyanophenyl)propanoic acid (Intermediate E-6) colorless foam 11 (2S,4R)-1-[(2R)-3-(3-chlorophenyl)-2-(3,5-dichlorophenoxy)propanoyl]-N-[(3S)-5,5- Intermediate B-1 886.2 difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]-4-[(4- and methoxyphenyl)methylsulfonyl]pyrrolidine-2-carboxamide (2R)-3-(3-chlorophenyl)-2- (3,5-dichloro- phenoxy)propanoic acid (Intermediate F-1) colorless foam 12 (2S,4R)-1-[(2R)-3-(3-chlorophenyl)-2-(5-chloropyridin-3-yl)oxypropanoyl]-N- Intermediate B-1 835.4 [(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan- and 3-yl]-4-[(4-methoxyphenyl)methylsulfonyl]pyrrolidine-2-carboxamide (2R)-3-(3-chlorophenyl)-2- (5-chloropyridin-3- yl)oxypropanoic acid (Intermediate F-2) Off-white foam 13 (2S,4R)-1-[(2S)-2-[(3-chlorobenzoyl)amino]-3-(3-fluorophenyl)propanoyl]- Intermediate C-1 892.4 N-[(3S)-5,5-difluoro-2-methyl-6-(2-morpholin-4-ylethylamino)-4,6- and dioxohexan-3-yl]-4-[(4-methoxyphenyl)methylsulfonyl]pyrrolidine- (2S)-2-[(3- 2-carboxamide chlorobenzoyl)amino]-3-(3- fluorophenyl)propanoic acid (Intermediate E-6) Colorless foam 14 (2S,4R)-N-[(3S)-5,5-difluoro-2-methyl-6-(2-morpholin-4-ylethylamino)-4,6-dioxohexan- Intermediate C-1 944.6 3-yl]-1-[(2S)-3-(3-fluorophenyl)-2-[[1-(2-fluorophenyl)cyclopentanecarbonyl]amino] and propanoyl]-4-[(4-methoxyphenyl)methylsulfonyl]pyrrolidine-2-carboxamide (2S)-3-(3-fluorophenyl)-2- [[1-(2-fluorophenyl)cyclo- pentanecarbonyl]amino] propanoic acid (Intermediate E-7) Colorless foam 15 N-[(2S)-3-(3,4-dichlorophenyl)-1-[(2S,4R)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo- Intermediate B-3 846.5 6-(2,2,2-trifluoroethylamino)hexan-3-yl]carbamoyl]-4-[(4-methoxyphenyl)methyl- and sulfanyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]pyridine-2-carboxamide (2S)-3-(3,4-Dichloro- phenyl)-2-(pyridine-2- carbonylamino)propanoic acid (Intermediate E-1) Colorless foam 16 N-[(2S)-3-(3,4-dichlorophenyl)-1-[(2S,4R)-2-[[(3S)-5,5-difluoro-2-methyl-4,6- Intermediate B-1 844.3 dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]carbamoyl]-4-[(4- and methoxyphenyl)methylsulfonyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]pyridine- (2S)-3-(3-chlorophenyl)- 2-carboxamide 2-(pyridine-2-carbonyl- amino)propanoic acid (Intermediate E-2) Colorless solid 17 N-[(2S)-1-[(2S,4R)-4-benzylsulfonyl-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo- Intermediate B-2 814.4 6-(2,2,2-trifluoroethylamino)hexan-3-yl]carbamoyl]pyrrolidin-1-yl]-3-(3- and chlorophenyl)-1-oxopropan-2-yl]pyridine-2-carboxamide (2S)-3-(3-chlorophenyl)-2- (pyridine-2-carbonyl- 0 amino)propanoic acid (Intermediate E-2) Colorless foam 18 (2S,4R)-1-[(2R)-3-(3-chlorophenyl)-2-(3,5-dichlorophenoxy)propanoyl]-N-[(3S)- Intermediate B-3 854.4 5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]-4-[(4- and methoxyphenyl)methylsulfanyl]pyrrolidine-2-carboxamide (2R)-3-(3-chlorophenyl)-2- (3,5-dichloro- phenoxy)propanoic acid (Intermediate F-1) Colorless foam 19 Intermediate B-2 and (2R)-3-(3-chlorophenyl)-2-(5- chloropyridin-3- yl)oxypropanoic acid (Intermediate F-2) 821.3 Colorless foam

Example 20

(2S,4R)-1-[(2S)-2-[[2-(3-Chlorophenyl)-2,2-difluoroacetyl]amino]-3-hydroxypropanoyl]-N-[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]-4-[(4-methoxyphenyl)methylsulfonyl]pyrrolidine-2-carboxamide

(65) ##STR00073##

(66) To a solution of (2S,4R)-1-[(2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-3-[(2-methylpropan-2-yl)oxy]propanoyl]-N-[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]-4-[(4-methoxyphenyl)methylsulfonyl]pyrrolidine-2-carboxamide (Example 5, 0.007 g, 0.008 mmol) in DCM (1 mL) was added TFA (0.061 mL, 0.008 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo, the residue was triturated in diisopropylether, filtered and further dried under high vacuum to give the title compound (0.006 g, 96%) as a colorless solid. MS: 833.2 (M+H.sup.+).

Example 21

N-[(2S)-3-(3,4-Dichlorophenyl)-1-[(2S,4R)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]carbamoyl]-4-[(4-methoxyphenyl)methylsulfonyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]pyridine-2-carboxamide

(67) ##STR00074##

(68) In a flask, N-[(2S)-3-(3,4-dichlorophenyl)-1-[(2S,4R)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]carbamoyl]-4-[(4-methoxyphenyl)methylsulfanyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]pyridine-2-carboxamide (Example 15, 0.030 g, 0.035 mmol) was combined with DCM (2 mL) at 0° C. to give a colorless solution. Then, mCPBA (0.019 g, 78 μmol) was added and the reaction mixture stirred at 0° C. for 2 hours. The mixture was poured into sat. NaHCO.sub.3 aqueous solution and extracted with DCM (2×10 mL). The organic layers were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude material was purified by silica gel flash chromatography, eluting with a 5 to 65% EtOAc-heptane gradient to give the title compound (0.022 g, 71%) as a colorless foam. MS: 878.4 (M+H.sup.+).

Example 22

N-[(2S)-3-(3-chlorophenyl)-1-[(2S,4R)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]carbamoyl]-4-[(4-methoxyphenyl)methoxy]pyrrolidin-1-yl]-1-oxopropan-2-yl]pyridine-2-carboxamide

(69) ##STR00075##

[A] Methyl (2S,4R)-1-[(2S)-3-(3-chlorophenyl)-2-(pyridine-2-carbonylamino)propanoyl]-4-hydroxy-pyrrolidine-2-carboxylate

(70) ##STR00076##

(71) To a mixture of (2S)-3-(3-chlorophenyl)-2-(pyridine-2-carbonylamino)propanoic acid (Intermediate E-2, 0.150 g, 0.492 mmol) and (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate (0.071 g, 0.492 mmol) in DMF (6 mL) were added at 0° C., Huenig's base (0.258 mL, 1.48 mmol) and HATU (0.225 g, 0.591 mmol) and the reaction mixture was stirred at 0° C. for 1 hour. The reaction mixture was quenched with a sat. NaHCO.sub.3 aqueous solution and extracted with EtOAc (2×25 mL). Combined organic layers were washed with a sat. NH.sub.4Cl aqueous solution, brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude material was purified by silica gel flash chromatography, eluting with a 50% to 100% EtOAc-heptanegradient to give the title compound (0.156 g, 73%) as a light yellow oil. MS: 432.3 (M+H.sup.+).

[B] Methyl (2S,4R)-1-[(2S)-3-(3-chlorophenyl)-2-(pyridine-2-carbonylamino)propanoyl]-4-[(4-methoxyphenyl)methoxy]pyrrolidine-2-carboxylate

(72) ##STR00077##

(73) To a solution of methyl (2S,4R)-1-[(2S)-3-(3-chlorophenyl)-2-(pyridine-2-carbonylamino)propanoyl]-4-hydroxy-pyrrolidine-2-carboxylate (0.152 g, 0.352 mmol) in DCE (5 mL) cooled to 0° C., 4-methoxybenzyl 2,2,2-trichloroacetimidate (0.146 mL, 0.704 mmol) and pTsOH (0.007 g, 0.035 mmol) were added. The reaction mixture was heated to 40° C. and stirred overnight. The reaction was incomplete, thus more 4-methoxybenzyl 2,2,2-trichloroacetimidate (0.146 mL, 704 μmol) and pTsOH (0.007 g, 0.035 mmol) were added and the reaction mixture was stirred at 40° C. for a further 6 hours. The mixture was quenched with a sat. NaHCO.sub.3 aqueous solution and extracted with CH.sub.2Cl.sub.2. The organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude material was purified by silica gel flash chromatography, eluting with a 10% to 70% EtOAc-heptanegradient to give the title compound (0.108 g, 56%) as a light yellow gum. MS: 552.4 (M+H.sup.+).

[C] (2S,4R)-1-[(2S)-3-(3-Chlorophenyl)-2-(pyridine-2-carbonylamino)propanoyl]-4-[(4-methoxyphenyl)methoxy]pyrrolidine-2-carboxylic acid

(74) ##STR00078##

(75) In a flask, methyl (2S,4R)-1-[(2S)-3-(3-chlorophenyl)-2-(pyridine-2-carbonylamino)propanoyl]-4-[(4-methoxyphenyl)methoxy]pyrrolidine-2-carboxylate (0.105 g, 0.190 mmol) was combined with THF (1 mL) and MeOH (0.5 mL) and cooled to 0° C. A 1M aqueous solution of LiOH (0.190 mL, 0.190 mmol) was added and the reaction mixture was stirred at 0° C. for 6 hours. The mixture was quenched with a 1M KHSO.sub.4 aqueous solution and extracted with EtOAc. The organic layers were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound (0.099 g, 97%) as a white foam. MS: 538.4 (M+H.sup.+).

[D] N-[(2S)-3-(3-Chlorophenyl)-1-[(2S,4R)-2-[[(3S,4R)-5,5-difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]carbamoyl]-4-[(4-methoxyphenyl)methoxy]pyrrolidin-1-yl]-1-oxopropan-2-yl]pyridine-2-carboxamide

(76) ##STR00079##

(77) To a solution of (3R,4S)-4-amino-2,2-difluoro-3-hydroxy-5-methyl-N-(2,2,2-trifluoroethyl)hexanamide (Intermediate B-1 [D], 0.056 g, 180 mmol) and (2S,4R)-1-[(2S)-3-(3-chlorophenyl)-2-(pyridine-2-carbonylamino)propanoyl]-4-[(4-methoxyphenyl)methoxy]pyrrolidine-2-carboxylic acid (0.097 g, 0.180 mmol) in DMF (5 mL) cooled to 0° C. were added Huenig's base (0.157 mL, 0.902 mmol) and HATU (0.082 g, 0.216 mmol). The reaction mixture was stirred at 0° C. for 1 hour. The mixture was quenched with a sat. NaHCO.sub.3 aqueous solution and extracted with EtOAc (2×25 mL). Combined organics were washed with a sat. NH.sub.4Cl aqueous solution, brine then dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude material was purified by silica gel flash chromatography, eluting with a 50% to 100% EtOAc-heptanegradient to give the title compound (0.105 g, 73%) as a white foam. MS: 798.5 (M+H.sup.+).

[E] N-[(2S)-3-(3-Chlorophenyl)-1-[(2S,4R)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]carbamoyl]-4-[(4-methoxyphenyl)methoxy]pyrrolidin-1-yl]-1-oxopropan-2-yl]pyridine-2-carboxamide

(78) ##STR00080##

(79) In a flask, N-[(2S)-3-(3-chlorophenyl)-1-[(2S,4R)-2-[[(3S,4R)-5,5-difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]carbamoyl]-4-[(4-methoxyphenyl)methoxy]pyrrolidin-1-yl]-1-oxopropan-2-yl]pyridine-2-carboxamide (0.100 g, 0.125 mmol) was combined with DCM (4 mL) and cooled to 0° C. Dess-Martin periodinane 15% in DCM (0.390 mL, 0.188 mmol) was added and the reaction mixture stirred at room temperature for 2 hours. The mixture was diluted with DCM and washed with a saturated NH.sub.4Cl aqueous solution and brine. The organic phase was dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude material was purified by flash chromatography, eluting with a 0-60% EtOAc-heptane gradient to give the title compound (0.070 g, 70%) as a white foam. MS: 796.4 (M+H.sup.+).

Example A

(80) A compound of formula (I) can be used in a manner known per se as the active ingredient for the production of tablets of the following composition:

(81) TABLE-US-00004 Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mg Corn starch  25 mg Talc  25 mg Hydroxypropylmethylcellulose  20 mg Total amount 425 mg

Example B

(82) A compound of formula (I) can be used in a manner known per se as the active ingredient for the production of capsules of the following composition:

(83) TABLE-US-00005 Per capsule Active ingredient 100.0 mg Corn starch  20.0 mg Lactose  95.0 mg Talc  4.5 mg Magnesium stearate  0.5 mg Total amount 220.0 mg