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, R.sup.9, R.sup.10, R.sup.11 and R.sup.23 are as described herein, compositions including the compounds and methods of using the compounds.

Claims

1. A compound of formula (I) ##STR00233## 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.6, R.sup.7, R.sup.9, 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; R.sup.5 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; R.sup.8 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 the arylcarbonyl and the 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 the arylcarbonyl and the 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 the arylcarbonyl and the 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, 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.8, 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.8, 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.1-6-alkylaminocarbonyl-C.sub.1-6-alkyl, 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; and 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 or a pharmaceutically acceptable salt thereof according to claim 1, wherein: R.sup.1 is halo-C.sub.1-6-alkyl; R.sup.2 is selected from: i) C.sub.1-6-alkyl, and ii) C.sub.3-8-cycloalkyl; R.sup.3, R.sup.4, R.sup.6, R.sup.7, R.sup.9, R.sup.10 and R.sup.23 are H; R.sup.5 is phenyl substituted with R.sup.12, R.sup.13 and R.sup.14; R.sup.8 is selected from: i) H, ii) hydroxy, and iii) phenyl 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) phenyl substituted with R.sup.18, R.sup.19 and R.sup.20, iii) phenyl-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, iv) phenyl-C.sub.3-8-cycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20, v) phenyl(halo)-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, and vi) heteroaryl substituted with R.sup.18, R.sup.19 and R.sup.20, wherein the heteroaryl is selected from pyrazinyl, pyridinyl, pyrimidinyl and thiophenyl; 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) C.sub.1-6-alkyl, ii) cyano, iii) halogen, and iv) carboxy-C.sub.1-6-alkoxy; R.sup.16 is selected from: i) H, and ii) halogen; R.sup.18 is selected from: i) H, ii) halogen, iii) halo-C.sub.1-6-alkoxy, iv) cyano, v) amino substituted on the nitrogen atom by two C.sub.1-6-alkyl, vi) C.sub.1-6-alkoxycarbonyl-C.sub.1-6-alkoxy, vii) carboxy-C.sub.1-6-alkoxy, and viii) morpholinyl; R.sup.19 is selected from: i) H, and ii) halogen; R.sup.21 is pyridinylcarbonyl; and R.sup.22 is H.

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

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

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

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

7. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R.sup.3, R.sup.4, R.sup.6, R.sup.7, R.sup.9, R.sup.10 and R.sup.23 are H.

8. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R.sup.5 is phenyl substituted with R.sup.12, R.sup.13 and R.sup.14.

9. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R.sup.5 is phenyl substituted with one C.sub.1-6-alkoxy.

10. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R.sup.8 is selected from: i) H, ii) hydroxy, and iii) phenyl substituted with R.sup.15, R.sup.16 and R.sup.1.

11. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R.sup.8 is selected from: i) hydroxy, and ii) phenyl substituted with R.sup.15, R.sup.16 and R.sup.1.

12. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R.sup.8 is phenyl substituted with R.sup.15, R.sup.16 and R.sup.17.

13. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein 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) phenyl substituted with R.sup.18, R.sup.19 and R.sup.20, iii) phenyl-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, iv) phenyl-C.sub.3-8-cycloalkyl substituted with R.sup.18, R.sup.19 and R.sup.20, v) phenyl(halo)-C.sub.1-6-alkyl substituted with R.sup.18, R.sup.19 and R.sup.20, and vi) heteroaryl substituted with R.sup.18, R.sup.19 and R.sup.20, wherein the heteroaryl is selected from pyrazinyl, pyridinyl, pyrimidinyl and thiophenyl.

14. The compound or a pharmaceutically acceptable salt thereof according to claim 1, 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.1-6-alkyl 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) heteroaryl substituted with R.sup.18, R.sup.19 and R.sup.20, wherein the heteroaryl is selected from pyridinyl and thiophenyl.

15. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R.sup.11 is phenyl substituted with R.sup.18, R.sup.19 and R.sup.20.

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

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

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

19. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R.sup.11 is selected from: i) C.sub.1-6-alkyl, ii) cyano, iii) halogen, and iv) carboxy-C.sub.1-6-alkoxy.

20. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R.sup.15 is selected from: i) cyano, and ii) halogen.

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

22. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R.sup.16 is selected from: i) H, and ii) halogen.

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

24. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R.sup.18 is selected from: i) H, ii) halogen, iii) halo-C.sub.1-6-alkoxy, iv) cyano, v) amino substituted on the nitrogen atom by two C.sub.1-6-alkyl, vi) C.sub.1-6-alkoxycarbonyl-C.sub.1-6-alkoxy, vii) carboxy-C.sub.1-6-alkoxy, and viii) morpholinyl.

25. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R.sup.18 is selected from: i) H, ii) cyano, and iii) halogen.

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

27. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R.sup.19 is selected from: i) H, and ii) halogen.

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

29. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R.sup.21 is pyridinylcarbonyl.

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

31. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein: R.sup.1 is halo-C.sub.1-6-alkyl; R.sup.2 is C.sub.1-6-alkyl; R.sup.3, R.sup.4, R.sup.6, R.sup.7, R.sup.9, R.sup.10 and R.sup.23 are H; R.sup.5 is phenyl substituted with one C.sub.1-6-alkoxy; R.sup.8 is phenyl substituted with R.sup.15, R.sup.16 and R.sup.17; R.sup.11 is phenyl substituted with R.sup.18, R.sup.19 and R.sup.20; R.sup.15 is selected from: i) cyano, and ii) halogen; R.sup.16 is selected from: i) H, and ii) halogen; R.sup.17 and R.sup.20 are H; R.sup.18 is selected from: i) H, ii) cyano, and iii) halogen; and R.sup.19 is selected from: i) H, and ii) halogen.

32. The compound according to claim 1, selected from N-[(2S)-3-(3-chlorophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-2-oxo-1-phenylethyl]amino]-1-oxopropan-2-yl]pyridine-4-carboxamide; N-[(2S)-3-(3-chlorophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-2-oxo-1-phenylethyl]amino]-1-oxopropan-2-yl]pyridine-2-carboxamide; N-[(2S)-3-(3-chlorophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-2-oxo-1-phenylethyl]amino]-1-oxopropan-2-yl]pyrazine-2-carboxamide; N-[(2S)-3-(3-chlorophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-2-oxo-1-phenylethyl]amino]-1-oxopropan-2-yl]pyrimidine-5-carboxamide; N-[(2S)-3-(3,4-dichlorophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]pyridine-2-carboxamide; N-[(2S)-3-(3,4-dichlorophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-2-oxo-1-phenylethyl]amino]-1-oxopropan-2-yl]pyridine-2-carboxamide; N-[(2S)-3-(3-chlorophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]pyridine-2-carboxamide; N-[(2S)-3-(3-chlorophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]-5-(difluoromethoxy)pyridine-2-carboxamide; N-[(2S)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-2-oxo-1-phenylethyl]amino]-3-(3-methylphenyl)-1-oxopropan-2-yl]pyridine-2-carboxamide; N-[(2S)-3-(3-chlorophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-2-oxo-1-phenylethyl]amino]-1-oxopropan-2-yl]-5-(difluoromethoxy)pyridine-2-carboxamide; N-[(2S)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-3-(3-methylphenyl)-1-oxopropan-2-yl]pyridine-2-carboxamide; N-[(2S)-3-(3-chlorophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]-5-morpholin-4-ylpyridine-2-carboxamide; N-[(2S)-3-(3-chlorophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]-5-(dimethylamino)pyridine-2-carboxamide; N-[(2S)-3-(3-cyanophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]pyridine-2-carboxamide; N-[3-(3-chlorophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]benzamide; N-[3-(3-chlorophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-2-oxo-1-phenylethyl]amino]-1-oxopropan-2-yl]benzamide; N-[(2S)-3-(3-cyanophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]benzamide; N-[(2S)-3-(3-chloro-4-cyanophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]pyridine-2-carboxamide; N-[2-[[(2S)-3-(3-chlorophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]amino]-2-oxoethyl]pyridine-2-carboxamide; N-[(2S)-3-(3-chlorophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]benzamide; N-[2-[[(2S)-3-(3-cyanophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]amino]-2-oxoethyl]pyridine-2-carboxamide; 3-chloro-N-[(2S)-3-(3-chlorophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]benzamide; N-[(2S)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-3-hydroxy-1-oxopropan-2-yl]benzamide; 1-(3-chlorophenyl)-N-[(2S)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-3-hydroxy-1-oxopropan-2-yl]cyclopropane-1-carboxamide; 1-(3-chlorophenyl)-N-[(2S,3R)-1-[[(1S)-2-[[(3 S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-3-hydroxy-1-oxobutan-2-yl]cyclopropane-1-carboxamide; N-[(2S)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]benzamide; 1-(3-chlorophenyl)-N-[(2S)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-2-oxo-1-phenylethyl]amino]-1-oxopropan-2-yl]cyclopropane-1-carboxamide; 1-(3-chlorophenyl)-N-[(2S)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]cyclopropane-1-carboxamide; 2,5-dichloro-N-[(2S)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]benzamide; 3-chloro-N-[(2S)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]benzamide; N-[(2R)-3-(3-chlorophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]pyridine-2-carboxamide; 3-chloro-N-[(2S)-3-(3-cyanophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]benzamide; 5-chloro-N-[(2S)-3-(3-chlorophenyl)-1-[[(1S)-2-[[(3 S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]thiophene-2-carboxamide; 5-chloro-N-[(2S)-3-(3-cyanophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]thiophene-2-carboxamide; N-[(2S)-3-(3-chlorophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]-3-cyanobenzamide; 2,5-dichloro-N-[(2S)-3-(3-chlorophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]benzamide; tert-butyl 2-[4-[[(2S)-3-(3-chlorophenyl)-1-[[(1S)-2-[[(3 S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]carbamoyl]phenoxy]acetate; 2-[4-[[(2S)-3-(3-chlorophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]carbamoyl]phenoxy]acetic acid; 2-[4-[(2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-3-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-3-oxopropyl]phenoxy]acetic acid; 2-[4-[(2S)-2-[(3-chlorobenzoyl)amino]-3-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-3-oxopropyl]phenoxy]acetic acid; (4S)-4-[[(2S)-2-[[(2S)-3-(3-chlorophenyl)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]propanoyl]amino]-2-(4-methoxyphenyl)acetyl]amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanamide; 3-chloro-N-[(2S)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-3-(3-fluorophenyl)-1-oxopropan-2-yl]benzamide; N-[(2S)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-3-(3-fluorophenyl)-1-oxopropan-2-yl]pyridine-2-carboxamide; 2,5-dichloro-N-[(2S)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-3-(3-fluorophenyl)-1-oxopropan-2-yl]benzamide; (4S)-4-[[(2S)-2-[[(2S)-3-(3-chlorophenyl)-2-[[2-(3-chlorophenyl)acetyl]amino]propanoyl]amino]-2-(4-methoxyphenyl)acetyl]amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanamide; (4S)-4-[[(2S)-2-[[(2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-3-(3-fluorophenyl)propanoyl]amino]-2-(4-methoxyphenyl)acetyl]amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanamide; N-[(2S)-3-(3-chlorophenyl)-1-[[(1S)-2-[[(1S)-1-cyclobutyl-3,3-difluoro-2,4-dioxo-4-(2,2,2-trifluoroethylamino)butyl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]pyridine-2-carboxamide; 3-chloro-N-[(2S)-3-(4-chloro-3-cyanophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]benzamide; N-[(2S)-3-(3-cyanophenyl)-1-[[(1S)-2-[[(1S)-1-cyclobutyl-3,3-difluoro-2,4-dioxo-4-(2,2,2-trifluoroethylamino)butyl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]pyridine-2-carboxamide; N-[(2S)-3-(3-cyanophenyl)-1-[[(1S)-2-[[(1S)-1-cyclobutyl-3,3-difluoro-2,4-dioxo-4-(2,2,2-trifluoroethylamino)butyl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]benzamide; (4S)-4-[[(2S)-2-[[(2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]propanoyl]amino]-2-(4-methoxyphenyl)acetyl]amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanamide; N-[(2S)-3-(3-chlorophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]-3-fluorobenzamide; 3,5-dichloro-N-[(2S)-3-(3-chlorophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]benzamide; N-[(2S)-3-(3-chlorophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]-1-phenylcyclopropane-1-carboxamide; 1-(3-chlorophenyl)-N-[(2S)-3-(3-chlorophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]cyclopropane-1-carboxamide; 3-cyano-N-[(2S)-3-(3-cyanophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]benzamide; (4S)-4-[[(2S)-2-[[(2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-3-(3-cyanophenyl)propanoyl]amino]-2-(4-methoxyphenyl)acetyl]amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanamide; 3-cyano-N-[(2S)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-3-(3-fluorophenyl)-1-oxopropan-2-yl]benzamide; N-[(2S)-3-(3-chlorophenyl)-1-[[(1S)-2-[[(1S)-1-cyclopropyl-3,3-difluoro-2,4-dioxo-4-(2,2,2-trifluoroethylamino)butyl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]pyridine-2-carboxamide; N-[(2S)-3-(3-cyanophenyl)-1-[[(1S)-2-[[(1S)-1-cyclopropyl-3,3-difluoro-2,4-dioxo-4-(2,2,2-trifluoroethylamino)butyl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]pyridine-2-carboxamide; and (4S)-4-[[(2S)-2-[[(2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-3-hydroxypropanoyl]amino]-2-(4-methoxyphenyl)acetyl]amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanamide; or a pharmaceutically acceptable salt thereof.

33. The compound according to claim 1, selected from N-[(2S)-3-(3-chlorophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]pyridine-2-carboxamide; N-[(2S)-3-(3-cyanophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]pyridine-2-carboxamide; N-[3-(3-chlorophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]benzamide; N-[(2S)-3-(3-cyanophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]benzamide; 5-chloro-N-[(2S)-3-(3-chlorophenyl)-1-[[(1S)-2-[[(3 S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]thiophene-2-carboxamide; 5-chloro-N-[(2S)-3-(3-cyanophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]thiophene-2-carboxamide; N-[(2S)-3-(3-chlorophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]-3-cyanobenzamide; 2,5-dichloro-N-[(2S)-3-(3-chlorophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]benzamide; 3-chloro-N-[(2S)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-3-(3-fluorophenyl)-1-oxopropan-2-yl]benzamide; (4S)-4-[[(2S)-2-[[(2S)-3-(3-chlorophenyl)-2-[[2-(3-chlorophenyl)acetyl]amino]propanoyl]amino]-2-(4-methoxyphenyl)acetyl]amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanamide; 3-chloro-N-[(2S)-3-(4-chloro-3-cyanophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]benzamide; N-[(2S)-3-(3-chlorophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]-3-fluorobenzamide; 3-cyano-N-[(2S)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-3-(3-fluorophenyl)-1-oxopropan-2-yl]benzamide; and (4S)-4-[[(2S)-2-[[(2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-3-hydroxypropanoyl]amino]-2-(4-methoxyphenyl)acetyl]amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanamide; or a pharmaceutically acceptable salt thereof.

34. The compound according to claim 1, selected from (4S)-4-[[(2S)-2-[[(2S)-2-[[2,2-difluoro-2-(3-fluorophenyl)acetyl]amino]-3-hydroxypropanoyl]amino]-2-(4-methoxyphenyl)acetyl]amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanamide; tert-butyl N-[[4-[(2S)-2-[(3-chlorobenzoyl)amino]-3-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-3-oxopropyl]phenyl]methyl]carbamate; tert-butyl N-[[4-[(2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-3-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-3-oxopropyl]phenyl]methyl]carbamate; (4S)-4-[[(2S)-2-[[(2S)-2-[[2,2-difluoro-2-(3-fluorophenyl)acetyl]amino]-3-methoxypropanoyl]amino]-2-(4-methoxyphenyl)acetyl]amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanamide; (4S)-4-[[(2S)-2-[[(2S)-2-[[2-(3,4-dichlorophenyl)-2,2-difluoroacetyl]amino]-3-methoxypropanoyl]amino]-2-(4-methoxyphenyl)acetyl]amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanamide; (4S)-4-[[(2S)-2-[[(2S)-2-[[2-(2,5-dichlorophenyl)-2,2-difluoroacetyl]amino]-3-methoxypropanoyl]amino]-2-(4-methoxyphenyl)acetyl]amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanamide; (4S)-4-[[(2S)-2-[[(2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-3-methoxypropanoyl]amino]-2-(4-methoxyphenyl)acetyl]amino]-N-[2-(1,1-dioxo-1,4-thiazinan-4-yl)ethyl]-2,2-difluoro-5-methyl-3-oxohexanamide; N-[(2S)-1-[[(1S)-2-[[(3S)-6-[2-(1,1-dioxo-1,4-thiazinan-4-yl)ethylamino]-5,5-difluoro-2-methyl-4,6-dioxohexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-3-methoxy-1-oxopropan-2-yl]-1-(trifluoromethyl)cyclopentane-1-carboxamide; or a pharmaceutically acceptable salt thereof, and N-[(2S)-3-[4-(aminomethyl)phenyl]-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]-3-chlorobenzamide trifluoroacetic acid; and (4S)-4-[[(2S)-2-[[(2S)-3-[4-(aminomethyl)phenyl]-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]propanoyl]amino]-2-(4-methoxyphenyl)acetyl]amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanamide, trifluoroacetic acid.

35. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein: R.sup.1 is halo-C.sub.1-6-alkyl; R.sup.2 is C.sub.1-6-alkyl; R.sup.3, R.sup.4, R.sup.6, R.sup.7, R.sup.9, R.sup.13 and R.sup.14 are each H; R.sup.5 is aryl substituted with R.sup.12, R.sup.13 and R.sup.14; and R.sup.12 is C.sub.1-6-alkoxy.

36. The compound or a pharmaceutically acceptable salt thereof according to claim 1, which is prepared according to a process comprising i) reacting a compound of formula (III) with a compound of formula (IV) to produce a compound of formula (II) ##STR00234## and ii) reacting a compound of formula (II) obtained from i) under oxidative conditions ##STR00235##

37. A pharmaceutical composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt thereof.

38. A method for the treatment of high-temperature requirement protein A1 (HtrA1)-mediated ocular disease selected from the group consisting of wet or dry age-related macular degeneration, geographic atrophy, diabetic retinopathy, retinopathy of prematurity and polypoidal choroidal vasculopathy, wherein the method comprises administering an effective amount of a compound according to claim 32, 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 Ia

(3R,4S)-4-amino-2,2-difluoro-3-hydroxy-5-methyl-N-(2,2,2-trifluoroethyl)hexanamide

(3) ##STR00012##

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

(4) ##STR00013##

(5) 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, Eq: 1) in THF (100 ml) under argon at 0° C. was added LiAlH.sub.4 1M in THF (11.5 ml, 11.5 mmol, Eq: 1) 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

(6) ##STR00014##

(7) A solution of the above prepared (S)-tert-butyl (3-methyl-1-oxobutan-2-yl)carbamate (2.01 g, 9.99 mmol, Eq: 1) and ethyl 2-bromo-2,2-difluoroacetate (6.08 g, 3.84 ml, 30 mmol, Eq: 3) in THF (15 ml) was added dropwise to a suspension of activated zinc (1.96 g, 30 mmol, Eq: 3) 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 flash chromatography (silica gel, 120 g, 20% EtOAc in heptane) to deliver 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

(8) ##STR00015##

(9) A mixture of the above prepared ethyl (3R,4S)-4-amino-2,2-difluoro-3-hydroxy-5-methylhexanoate (191.4 mg, 588 μmol, Eq: 1), 3,3,3-trifluoropropan-1-amine (333 mg, 2.94 mmol, Eq: 5) and N,N-diisopropylethylamine (380 mg, 514 μl, 2.94 mmol, Eq: 5) was refluxed in 5 mL of MeOH overnight. TLC after 17 hours showed the reaction to be finished. 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 flash chromatography (silica gel, 20 g, 15% to 50% EtOAc in heptane) to produce 180 mg 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

(10) ##STR00016##

(11) 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 (177 mg, 451 μmol, Eq: 1) was combined with 1,4-dioxane (6 ml) to give a colorless solution. HCl 4M in dioxane (2.25 ml, 9 mmol, Eq: 20) was added at 0° C. and the reaction mixture was stirred overnight at rt. The crude reaction mixture was concentrated in vacuo and scrupulously dried on hv and then used directly for the next step (calculated as dihydrochloride).

Intermediate Ib

(3R,4S)-4-Amino-4-cyclobutyl-2,2-difluoro-3-hydroxy-N-(2,2,2-trifluoroethyl)butanamide

(12) ##STR00017##
was prepared as hydrochloride in analogy to Intermediate Ia, but using in step A] tert-butyl N-[(1S)-1-cyclobutyl-2-oxoethyl]carbamate as starting material, as light yellow foam; MS: 291.1 (M+H).sup.+.

Intermediate Ic

(3R,4S)-4-Amino-4-cyclopropyl-2,2-difluoro-3-hydroxy-N-(2,2,2-trifluoroethyl)butanamide

(13) ##STR00018##
was prepared as hydrochloride in analogy to Intermediate Ia, but using in step A] tert-butyl N-[(1S)-1-cyclopropyl-2-oxoethyl]carbamate as starting material, as light yellow oil.

Intermediate Id

(3R,4S)-4-amino-N-[2-(1,1-dioxo-1,4-thiazinan-4-yl)ethyl]-2,2-difluoro-3-hydroxy-5-methyl-hexanamide

(14) ##STR00019##
was prepared as hydrochloride in analogy to Intermediate Ia, but using in step C] 2-(1,1-dioxo-1,4-thiazinan-4-yl)ethanamine instead of 3,3,3-trifluoropropan-1-amine, as white foam.

Intermediate IIa

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

(15) ##STR00020##

A] tert-Butyl N-[(1S)-2-[[(3S,4R)-5,5-difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-2-oxo-1-phenylethyl]carbamate

(16) ##STR00021##

(17) In a 25 ml flask, (3R,4S)-4-amino-2,2-difluoro-3-hydroxy-5-methyl-N-(2,2,2-trifluoroethyl)hexanamide dihydrochloride [0.3M in DMF] (Intermediate Ia, 1.33 ml, 398 μmol, Eq: 1), (S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid (0.100 g, 398 μmol, Eq: 1) and HATU (166 mg, 438 μmol, Eq: 1.1) were mixed in DMF (4 ml). Hunig's base (257 mg, 348 μl, 1.99 mmol, Eq: 5) was then added, and the reaction mixture was stirred at RT for 2 h. It was diluted with EtOAc, poured into 1M KHSO.sub.4, and the aqueous layer was extracted with EtOAc (2×20 ml). The combined organics layers were washed with NaHCO.sub.3, brine, dried over Na.sub.2SO.sub.4, and evaporated. Purification by flash chromatography (silica gel, 20 g, 20% to 100% EtOAc in heptane) generated 124 mg of the title compound as yellow foam; MS: 512.2 (M+H).sup.+.

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

(18) ##STR00022##

(19) To a solution of the above prepared tert-butyl N-[(1S)-2-[[(3 S,4R)-5,5-difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-2-oxo-1-phenylethyl]carbamate (0.120 g, 235 μmol, Eq: 1) in MeOH (3 ml) was added HCl 4M in dioxane (293 μl, 1.17 mmol, Eq: 5); the reaction mixture was stirred at RT for 2 hours and at 40° C. for 2 hours. LC-MS indicated the reaction to be finished. The solvent was carefully evaporated to dryness to leave 119 mg of the title compound as hydrochloride as light purple foam which was used directly for the next step; MS: 412.2 (M+H).sup.+. Instead of using MeOH, the reaction can also be performed in dioxane only.

(20) In close analogy, using in step A] (2S)-2-(4-methoxyphenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]acetic acid, instead of (S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid, was prepared:

Intermediate IIb

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

(21) ##STR00023##

(22) As yellow oil; MS: 442.2 (M+H).sup.+.

Intermediate IIc

(3R,4S)-4-[[(2S)-2-Amino-2-(4-methoxyphenyl)acetyl]amino]-4-cyclobutyl-2,2-difluoro-3-hydroxy-N-(2,2,2-trifluoroethyl)butanamide

(23) ##STR00024##
Was prepared in close analogy to Intermediate IIb, but starting the reaction sequence with (3R,4S)-4-amino-4-cyclobutyl-2,2-difluoro-3-hydroxy-N-(2,2,2-trifluoroethyl)butanamide hydrochloride (Intermediate Ib) instead of (3R,4S)-4-amino-2,2-difluoro-3-hydroxy-5-methyl-N-(2,2,2-trifluoroethyl)hexanamide hydrochloride (Intermediate Ia) as light brown foam; MS: 454.2 (M+H).sup.+.

Intermediate IId

(3R,4S)-4-[[(2S)-2-Amino-2-(4-methoxyphenyl)acetyl]amino]-4-cyclopropyl-2,2-difluoro-3-hydroxy-N-(2,2,2-trifluoroethyl)butanamide

(24) ##STR00025##
Was prepared in close analogy to Intermediate IIb, but starting the reaction sequence with (3R,4S)-4-amino-4-cyclopropyl-2,2-difluoro-3-hydroxy-N-(2,2,2-trifluoroethyl)butanamide hydrochloride (Intermediate AND Enantiomer Ic) instead of (3R,4S)-4-amino-2,2-difluoro-3-hydroxy-5-methyl-N-(2,2,2-trifluoroethyl)hexanamide hydrochloride (Intermediate Ia), as blue foam; MS: 440.2 (M+H).sup.+.

Intermediate IIe

(3R,4S)-4-[[(2S)-2-amino-2-(4-methoxyphenyl)acetyl]amino]-N-[2-(1,1-dioxo-1,4-thiazinan-4-yl)ethyl]-2,2-difluoro-3-hydroxy-5-methyl-hexanamide

(25) ##STR00026##
Was prepared in close analogy to Intermediate IIb, but starting the reaction sequence with (3R,4S)-4-amino-N-[2-(1,1-dioxo-1,4-thiazinan-4-yl)ethyl]-2,2-difluoro-3-hydroxy-5-methyl-hexanamide hydrochloride (Intermediate Id) instead of (3R,4S)-4-amino-2,2-difluoro-3-hydroxy-5-methyl-N-(2,2,2-trifluoroethyl)hexanamide hydrochloride (Intermediate Ia), as white foam; MS: 621.3 (M+H).sup.+.

Intermediate IIIa

(4S)-4-[[(2S)-2-[[(2S)-2-Amino-3-(3-chlorophenyl)propanoyl]amino]-2-phenylacetyl]amino]-2,2-difluoro-3-hydroxy-5-methyl-N-(2,2,2-trifluoroethyl)hexanamide

(26) ##STR00027##

A] tert-Butyl N-[(2S)-3-(3-chlorophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-2-oxo-1-phenylethyl]amino]-1-oxopropan-2-yl]carbamate

(27) ##STR00028##

(28) In a 50 mL pear-shaped flask, (3R,4S)-4-[[(2S)-2-amino-2-phenylacetyl]amino]-2,2-difluoro-3-hydroxy-5-methyl-N-(2,2,2-trifluoroethyl)hexanamide hydrochloride (Intermediate IIa, 463 mg, 1.03 mmol, Eq: 1) was dissolved in DMF (10 ml); (S)-2-((tert-butoxycarbonyl)amino)-3-(3-chlorophenyl)propanoic acid (310 mg, 1.03 mmol, Eq: 1), HATU (786 mg, 2.07 mmol, Eq: 2) and N,N-diisopropylethylamine (334 mg, 451 μl, 2.58 mmol, Eq: 2.5) were successively added at 0° C. and the reaction mixture was stirred for 3 hours at RT=>brown solution. The reaction was quenched with sat. NaHCO.sub.3 and extracted twice with EtOAc. The organic layers were washed with 1N KHSO.sub.4 and brine, combined, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 100 g, 30% to 80% EtOAc in heptane) to yield 510 mg of the title product as light yellow foam; MS: 693.2 (M+H).sup.+.

B] (4S)-4-[[(2S)-2-[[(2S)-2-Amino-3-(3-chlorophenyl)propanoyl]amino]-2-phenylacetyl]amino]-2,2-difluoro-3-hydroxy-5-methyl-N-(2,2,2-trifluoroethyl)hexanamide

(29) ##STR00029##

(30) In a 50 mL round-bottomed flask, the above prepared tert-butyl N-[(2S)-3-(3-chlorophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-2-oxo-1-phenylethyl]amino]-1-oxopropan-2-yl]carbamate (0.506 g, 730 μmol, Eq: 1) was combined with MeOH (4 ml) to give a colorless solution. HCl in dioxane 4M (913 μl, 3.65 mmol, Eq: 5) was added at 0° C. and the reaction mixture was stirred at RT. LC-MS after 3 hours indicated the reaction to be finished. The crude reaction mixture was concentrated in vacuo and carefully dried on HV to provide the title compound as hydrochloride; it was used directly for the next step without further purification; MS: 593.1 (M+H).sup.+.

Intermediate IIIb

tert-Butyl 2-[4-[(2S)-2-amino-3-[[(1S)-2-[[(3S,4R)-5,5-difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-3-oxopropyl]phenoxy]acetate

(31) ##STR00030##

A] Benzyl (2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-[4-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethoxy]phenyl]propanoate

(32) ##STR00031##

(33) To a solution of commercially available benzyl (2S)-2-(tert-butoxycarbonylamino)-3-(4-hydroxyphenyl)propanoate (0.5 g, 1.35 mmol, Eq: 1) in DMF (20 ml) were successively added potassium carbonate (0.372 g, 2.69 mmol, Eq: 2) and dropwise tert-butyl 2-bromoacetate (0.199 ml, 1.35 mmol, Eq: 1). The reaction mixture was then stirred overnight at room temperature. The mixture was diluted with EtOAc, poured into H.sub.2O (25 ml), and the aqueous layer was extracted with EtOAc (2×20 ml). Combined organics were dried over Na.sub.2SO.sub.4, filtered, and evaporated. The crude material was purified by flash chromatography (silica gel, 20 g, 0% to 60% EtOAc in heptane) to yield the title product (0.588 g) as colorless solid; MS: 484.3 (M−H).sup.−.

B] (2S)-2-[(2-Methylpropan-2-yl)oxycarbonylamino]-3-[4-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethoxy]phenyl]propanoic acid

(34) ##STR00032##

(35) A solution of the above prepared benzyl (2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-[4-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethoxy]phenyl]propanoate (0.588 g, 1.21 mmol, Eq: 1) in methanol (20 ml) was purged several times with Ar, then Pd on C (0.064 g, 0.061 mmol, Eq: 0.05) was added and the reaction mixture was stirred at room temperature under an atmosphere of hydrogen for 1.5 hours. The catalyst was removed by filtration and the filtrate evaporated to dryness to give the title compound (0.468 g) as colorless solid; MS: 394.3 (M−H).sup.−.

C] tert-Butyl 2-[4-[(2S)-3-[[(1S)-2-[[(3S,4R)-5,5-difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-oxopropyl]phenoxy]acetate

(36) ##STR00033##

(37) In analogy to the procedure described for the preparation of intermediate IIIa [A], (3R,4S)-4-[[(2S)-2-amino-2-phenylacetyl]amino]-2,2-difluoro-3-hydroxy-5-methyl-N-(2,2,2-trifluoroethyl)hexanamide hydrochloride (Intermediate IIa) has been reacted with the above prepared (2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-[4-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethoxy]phenyl]propanoic acid under standard HATU coupling conditions to give the title compound as a colorless solid; MS: 819.4 (M+H).sup.+.

D] tert-Butyl 2-[4-[(2S)-2-amino-3-[[(1S)-2-[[(3S,4R)-5,5-difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-3-oxopropyl]phenoxy]acetate

(38) ##STR00034##

(39) In analogy to the procedure described for the preparation of intermediate IIIa, the above prepared tert-butyl 2-[4-[(2S)-3-[[(1S)-2-[[(3S,4R)-5,5-difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-oxopropyl]phenoxy]acetate has been deprotected with 4M HCl in dioxane (step [B]) to give the title compound as hydrochloride as colorless amorphous solid; MS: 719.4 (M+H).sup.+.

Intermediate IIIc

(3R,4S)-4-[[(2S)-2-[[(2S)-2-Amino-3-(3-chlorophenyl)propanoyl]amino]-2-(4-methoxyphenyl)acetyl]amino]-2,2-difluoro-3-hydroxy-5-methyl-N-(2,2,2-trifluoroethyl)hexanamide

(40) ##STR00035##
was prepared as hydrochloride in analogy to Intermediate IIIa, but using in step A] (3R,4S)-4-[[(2S)-2-amino-2-(4-methoxyphenyl)acetyl]amino]-2,2-difluoro-3-hydroxy-5-methyl-N-(2,2,2-trifluoroethyl)hexanamide hydrochloride (Intermediate IIb) instead of (3R,4S)-4-[[(2S)-2-amino-2-phenylacetyl]amino]-2,2-difluoro-3-hydroxy-5-methyl-N-(2,2,2-trifluoroethyl)-hexanamide hydrochloride (Intermediate IIa), as off-white foam; MS: 623.3 (M+H).sup.+.

Intermediate IIId

(3R,4S)-4-[[(2S)-2-[[(2S)-2-Amino-3-(3-fluorophenyl)propanoyl]amino]-2-(4-methoxyphenyl)acetyl]amino]-2,2-difluoro-3-hydroxy-5-methyl-N-(2,2,2-trifluoroethyl)hexanamide

(41) ##STR00036##
was prepared as hydrochloride in analogy to Intermediate IIIc, but using in step A] (2S)-3-(3-fluorophenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid instead of (2S)-3-(3-chlorophenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid, as off-white foam; MS: 607.5 (M+H).sup.+.

Intermediate IIIe

(3R,4S)-4-[[(2S)-2-[[(2S)-2-Amino-3-(3-cyanophenyl)propanoyl]amino]-2-(4-methoxyphenyl)acetyl]amino]-2,2-difluoro-3-hydroxy-5-methyl-N-(2,2,2-trifluoroethyl)hexanamide

(42) ##STR00037##
was prepared as hydrochloride in analogy to Intermediate IIIc, but using in step A] (2S)-3-(3-cyanophenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid instead of (2S)-3-(3-chlorophenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid, as light brown solid; MS: 614.3 (M+H).sup.+.

Intermediate IIIf

(3R,4S)-4-[[(2S)-2-[[(2S)-2-Amino-3-methoxypropanoyl]amino]-2-(4-methoxyphenyl)acetyl]amino]-2,2-difluoro-3-hydroxy-5-methyl-N-(2,2,2-trifluoroethyl)hexanamide

(43) ##STR00038##
was prepared as hydrochloride in analogy to Intermediate IIIc, but using in step A] (2S)-2-(tert-butoxycarbonylamino)-3-methoxy-propanoic acid instead of (2S)-3-(3-chlorophenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid, as off white foam; MS: 543.3 (M+H).sup.+.

Intermediate IIIg

tert-Butyl N-[[4-[(2S)-2-amino-3-[[(1S)-2-[[(3S,4R)-5,5-difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-3-oxopropyl]phenyl]methyl]carbamate

(44) ##STR00039##

A] tert-Butyl N-[[4-[(2S)-3-[[(1S)-2-[[(3S,4R)-5,5-difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-oxopropyl]phenyl]methyl]carbamate

(45) ##STR00040##

(46) To a solution of (3R,4S)-4-[[(2S)-2-amino-2-(4-methoxyphenyl)acetyl]amino]-2,2-difluoro-3-hydroxy-5-methyl-N-(2,2,2-trifluoroethyl)hexanamide hydrochloride (Intermediate IIb, 0.178 g, 0.372 mmol, Eq: 1), (2S)-3-[4-[(tert-butoxycarbonylamino)methyl]phenyl]-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid (0.192 g, 0.372 mmol, Eq: 1) and HATU (0.170 g, 0.447 mmol, Eq: 1.2) in DMF (2 ml) cooled at 0° C., was added Huenig's base (0.195 ml, 1.12 mmol, Eq: 3) and the reaction mixture stirred at room temperature for 2 hours. The mixture was diluted with EtOAc, poured into H.sub.2O and extracted with EtOAc (2×10 ml). Combined organics were washed with brine, dried over Na.sub.2SO.sub.4, filtered and evaporated. The residue was purified by silica gel flash chromatography, eluting with a 10 to 100% EtOAc in heptane gradient to give the title compound as a light brown waxy solid; MS: 940.5 (M+H).sup.+.

B] tert-Butyl N-[[4-[(2S)-2-amino-3-[[(1S)-2-[[(3S,4R)-5,5-difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-3-oxopropyl]phenyl]methyl]carbamate

(47) ##STR00041##

(48) To a solution of tert-butyl N-[[4-[(2S)-3-[[(1S)-2-[[(3S,4R)-5,5-difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-oxopropyl]phenyl]methyl]carbamate (0.361 g, 0.384 mmol, Eq: 1) in DMF (3 ml) was added diethylamine (0.791 ml, 7.68 mmol, Eq: 20) and the reaction mixture was stirred at room temperature over night. The reaction mixture was concentrated in vacuo and the residue purified by silica gel flash chromatography, eluting with a to 100% EtOAc in heptane then from to 2 to 10% MeOH in EtOAc to give the title compound as a light yellow solid; MS: 718.4 (M+H).sup.+.

Intermediate IIIh

(3R,4S)-4-[[(2S)-2-[[(2S)-2-Amino-3-methoxypropanoyl]amino]-2-(4-methoxyphenyl)acetyl]amino]-N-[2-(1,1-dioxo-1,4-thiazinan-4-yl)ethyl]-2,2-difluoro-3-hydroxy-5-methylhexanamide

(49) ##STR00042##
was prepared as hydrochloride in analogy to Intermediate IIIf, but using in step A] (3R,4S)-4-[[(2S)-2-amino-2-(4-methoxyphenyl)acetyl]amino]-N-[2-(1,1-dioxo-1,4-thiazinan-4-yl)ethyl]-2,2-difluoro-3-hydroxy-5-methyl-hexanamide (Intermediate Ile) instead of (3R,4S)-4-[[(2S)-2-amino-2-phenylacetyl]amino]-2,2-difluoro-3-hydroxy-5-methyl-N-(2,2,2-trifluoroethyl)-hexanamide hydrochloride (Intermediate IIa), as pink solid; MS: 622.8 (M+H).sup.+.

Intermediate IVa

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

(50) ##STR00043##

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

(51) ##STR00044##

(52) In a 50 mL flask, picolinic acid (500 mg, 4.06 mmol, Eq: 1) was combined with DCM (20 ml) to give a colorless solution. At 0° C., pyridine (964 mg, 985 μl, 12.2 mmol, Eq: 3), EDC (1.09 g, 5.69 mmol, Eq: 1.4), and 1-hydroxypyrrolidine-2,5-dione (608 mg, 5.28 mmol, Eq: 1.3) were subsequently added, the ice-bath was removed, and the reaction mixture was stirred at room temperature over night. 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 686 mg 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

(53) ##STR00045##

(54) A solution of the above prepared 2,5-dioxopyrrolidin-1-yl picolinate (250 mg, 1.14 mmol, Eq: 1) in DME (4 ml) was added to a mixture of (S)-2-amino-3-(3,4-dichlorophenyl)propanoic acid (266 mg, 1.14 mmol, Eq: 1) in THF (2 ml) and sodium bicarbonate (95.4 mg, 1.14 mmol, Eq: 1) in water (4 ml). This mixture was stirred at rt for 3 h when LC-MS showed the reaction to be finished. The reaction mixture was poured into sat. NH.sub.4Cl sol. and extracted with AcOEt (2×). The organic layers were washed with brine, and the solvent was evaporated under vacuum. Purification by chromatography (silica gel, 10 g CH.sub.2Cl.sub.2/MeOH=8/1) delivered 309 mg of the title compound as white foam; MS: 339.1 (M+H).sup.+.

(55) In close analogy, using the appropriate acidic building blocks, were prepared Intermediates IVb-IVk and IVm-IVt, respectively, as summarized in the following Table:

(56) TABLE-US-00002 Form Color Intermediate Structure Acid 1 Acid 2 MS IVb Foam white 371.1 (M + H.sup.+) IVc 0 Oil Colorless 285.2 (M + H.sup.+) IVd Foam white 390.2 (M + H.sup.+) IVe foam off-white 348.2 (M + H.sup.+) IVf 0 oil light yellow 296.2 (M + H.sup.+) IVg solid white 295.2 (M + H.sup.+) IVh semisolid white 330.2 (M + H.sup.+) IVi Foam colorless 304.1 (M + H.sup.+) IVj 0 solid white 338.1 (M + H.sup.+) IVk foam white 305.1 (M + H.sup.+) IVm oil colorless 362.2 (M + H.sup.+) IVn 0 oil light yellow 353.1 (M + H.sup.+) IVo oil colorless 305.1 (M + H.sup.+) IVp semisolid white 329.1 (M + H.sup.+) IVq 0 Foam white 344.0 (M + H.sup.+) IVr Foam white 335.0 (M + H.sup.+) IVs solid white 329.2 (M + H.sup.+) IVt solid wite 372.2 (M + H.sup.+)

(57) Spot checking the stereochemical integrity by chiral HPLC (Chiralpak AD-H) with intermediate IVi and IVj confirmed that the reaction sequence had proceeded under these mild reaction conditions without racemisation.

Intermediate IVl

(rac)-2-Benzamido-3-(3-chlorophenyl)propanoic acid

(58) ##STR00100##

(59) In a 50 mL pear-shaped flask, (S)-2-amino-3-(3-chlorophenyl)propanoic acid (599 mg, 3 mmol, Eq: 1) and potassium carbonate (1.18 g, 8.55 mmol, Eq: 2.85) were combined with water (10 ml) to give a colorless solution; benzoyl chloride (633 mg, 522 μl, 4.5 mmol, Eq: 1.5) was added via syringe and the resulting suspension stirred at ambient temperature over night; 2M HCl was added to adjust the pH to ˜2, the mixture was extracted twice with AcOEt, washed with a small amount of brine, dried over Na.sub.2SO.sub.4, and evaporate to dryness; flash chromatography SiO2 (50 g, CH.sub.2Cl.sub.2/3% AcOH/5% MeOH), followed by crystallisation from AcOEt/heptane, delivered 358 mg of the title compound as white solid; MS: 304.1 (M+H.sup.+); chiral HPLC (Chiralpak AD-H) revealed that the product had racemised to ˜100% under these reaction conditions!

Intermediate IVu

(2S)-2-Benzamido-3-[tert-butyl(dimethyl)silyl]oxypropanoic acid

(60) ##STR00101##

A] (2S)-2-Benzamido-3-hydroxypropanoic acid

(61) ##STR00102##

(62) In a 100 mL pear-shaped flask, (S)-2-amino-3-hydroxypropanoic acid (631 mg, 6 mmol, Eq: 1) and potassium carbonate (2.36 g, 17.1 mmol, Eq: 2.85) were combined with water (20 ml) to give a colorless solution; benzoyl chloride (1.27 g, 1.04 ml, 9 mmol, Eq: 1.5) was added via syringe, and the resulting suspension stirred at ambient temperature over night; 2M HCl was added (˜15 ml, solid precipitated) to adjust the pH to ˜3.5, the mixture was extracted twice with AcOEt, dried over Na.sub.2SO.sub.4, and evaporated to dryness; the crude product was purified by flash chromatography (SiO.sub.2, CH.sub.2Cl.sub.2/5% AcOH/10% MeOH) to yield, after scrupulous drying, 403 mg of the title compound as white crystals; MS: 210.1 (M+H).sup.+.

B] (2S)-2-Benzamido-3-[tert-butyl(dimethyl)silyl]oxypropanoic acid

(63) ##STR00103##

(64) In a 150 mL pear-shaped flask, the above prepared (S)-2-benzamido-3-hydroxypropanoic acid (399 mg, 1.91 mmol, Eq: 1) and 1H-imidazole (286 mg, 4.2 mmol, Eq: 2.2) were combined with DMF (2 ml) to give an off-white solution; tert-butylchlorodimethylsilane (316 mg, 2.1 mmol, Eq: 1.1) was added and the silylation allowed to proceed over night; after 18 h, the reaction mixture was poured onto brine, extracted twice with AcOEt (pH ˜7), washed with brine, dried over Na.sub.2SO.sub.4, and evaporated to dryness; flash chromatography (SiO2, 20 g, AcOEt/5% MeOH) afforded 388 mg of the title compound as white crystals; MS: 324.2 (M+H).sup.+.

Intermediate IVv

(2S)-3-[tert-Butyl(dimethyl)silyl]oxy-2-[[1-(3-chlorophenyl)cyclopropanecarbonyl]-amino]propanoic acid

(65) ##STR00104##

A] (2,5-Dioxopyrrolidin-1-yl) 1-(3-chlorophenyl)cyclopropane-1-carboxylate

(66) ##STR00105##

(67) In a 100 mL flask, 1-(3-chlorophenyl)cyclopropanecarboxylic acid (0.50 g, 2.54 mmol, Eq: 1) was combined with DCM (15 ml) to give a colorless solution. At 0° C., pyridine (603 mg, 617 μl, 7.63 mmol, Eq: 3), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (634 mg, 3.31 mmol, Eq: 1.3), and 1-hydroxypyrrolidine-2,5-dione (380 mg, 3.31 mmol, Eq: 1.3) were added, the ice-bath was removed, and the reaction allowed to proceed at RT for 2 hours. The reaction mixture was then quenched with sat. NH.sub.4Cl sol. and extracted with DCM (2×, pH ˜4.5). The organic layers were washed with sat. NaHCO.sub.3 (pH ˜8), combined, dried over Na.sub.2SO.sub.4, and concentrated in vacuo; after careful HV-drying, the crude material was crystallized from AcOEt/heptane to give 513 mg of the title compound as white solid.

B] (2S)-2-[[1-(3-Chlorophenyl)cyclopropanecarbonyl]amino]-3-hydroxypropanoic acid

(68) ##STR00106##

(69) A solution of the above synthesized 2,5-dioxopyrrolidin-1-yl 1-(3-chlorophenyl)-cyclopropanecarboxylate (0.25 g, 851 μmol, Eq: 1) in DME (7 ml) was added to a mixture of (S)-2-amino-3-hydroxypropanoic acid (=serine, 89.5 mg, 851 μmol, Eq: 1) in THF (3.5 ml) and sodium bicarbonate (71.5 mg, 851 μmol, Eq: 1) in water (7 ml), and the mixture was vigorously stirred at RT for 4 hours. It was then poured into sat. NH.sub.4Cl sol and extracted with AcOEt (2×). The organic layers were washed with brine and the solvent was evaporated under vacuum. The aqueous layer was back-extracted with CH.sub.2Cl.sub.2/MeOH=9/1 (4×40 mL). The organic layers were combined, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 20 g, CH.sub.2Cl.sub.2/EtOAc/MeOH 95:5:5) to yield 192 mg of the title compound as light brown oil; MS: 284.1 (M+H).sup.+.

C] (2S)-3-[tert-Butyl(dimethyl)silyl]oxy-2-[[1-(3-chlorophenyl)cyclopropanecarbonyl]-amino]propanoic acid

(70) ##STR00107##

(71) In a 10 mL round-bottomed flask, the above prepared (S)-2-(1-(3-chlorophenyl)-cyclopropanecarboxamido)-3-hydroxypropanoic acid (0.218 g, 768 μmol, Eq: 1) and imidazole (115 mg, 1.69 mmol, Eq: 2.2) were combined with DMF (3 ml) to give an off-white suspension; tert-butylchlorodimethylsilane (127 mg, 845 μmol, Eq: 1.1) was added and the reaction stirred at RT overnight. The reaction mixture was poured into brine and extracted with EtOAc. 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 flash chromatography (silica gel, 20 g, 5% MeOH in EtOAc) to provide 94 mg of the title compound as colorless oil; MS: 398.2 (M+H).sup.+.

Intermediate IVw

(2S)-3-[tert-Butyl(dimethyl)silyl]oxy-2-[[1-(3-chlorophenyl)cyclopropanecarbonyl]-amino]butanoic acid

(72) ##STR00108##
Was prepared in analogy to intermediate IVv, but using in step B] (2S,3R)-2-amino-3-hydroxybutanoic acid (=threonine) instead of of (S)-2-amino-3-hydroxypropanoic acid (=serine), as light yellow oil; MS: 412.2 (M+H).sup.+.

Intermediate IVx

(2S)-2-[[1-(3-Chlorophenyl)cyclopropanecarbonyl]amino]propanoic acid

(73) ##STR00109##

A] (2,5-Dioxopyrrolidin-1-yl) 1-(3-chlorophenyl)cyclopropane-1-carboxylate

(74) ##STR00110##

(75) In a 100 mL flask, 1-(3-chlorophenyl)cyclopropanecarboxylic acid (0.5 g, 2.54 mmol, Eq: 1) was combined with DCM (15 ml) to give a colorless solution. At 0° C., pyridine (603 mg, 617 μl, 7.63 mmol, Eq: 3), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (634 mg, 3.31 mmol, Eq: 1.3), and 1-hydroxypyrrolidine-2,5-dione (380 mg, 3.31 mmol, Eq: 1.3) were subsequently added. The ice-bath was removed and the reaction mixture was stirred at rt over night. It was then quenched with sat NH.sub.4Cl sol. and extracted with CH.sub.2Cl.sub.2 (2×, pH ˜4.5). The organic layers were washed with sat. NaHCO.sub.3 (pH ˜8), combined, dried over Na.sub.2SO.sub.4, and concentrated in vacuo; after careful HV-drying, the crude material was crystallized from AcOEt/heptane to yield 486 mg of the title product as white crystals; CI-MS 311.1 (M+NH.sub.4).sup.+.

B] (2S)-2-[[1-(3-Chlorophenyl)cyclopropanecarbonyl]amino]propanoic acid

(76) ##STR00111##

(77) A solution of the above prepared 2,5-dioxopyrrolidin-1-yl 1-(3-chlorophenyl)-cyclopropanecarboxylate (0.200 g, 681 μmol, Eq: 1) in DME (6 ml) was added to a mixture of (S)-2-aminopropanoic acid (60.7 mg, 681 μmol, Eq: 1) in THF (3 ml) and sodium bicarbonate (57.2 mg, 681 μmol, Eq: 1) in water (6 ml), and the reaction allowed to proceed at RT for 4 hours. The mixture was poured into sat. NH.sub.4Cl sol. and extracted with AcOEt (2×). The organic layers were washed with brine, dried over Na.sub.2SO.sub.4, and the solvent was evaporated under vacuum. The aqueous layer was back-extracted with CH.sub.2Cl.sub.2/MeOH=9/1 (4×40 ml). The organic layers were combined, dried over Na.sub.2SO.sub.4, and concentrated in vacuo. Purification by flash chromatography (silica gel, 20 g, 5% to 10% MeOH in CH.sub.2Cl.sub.2) eventually yielded 94 mg of the title compound as colorless oil; MS: 268.1 (M+H).sup.+.

Intermediate IVy

(2S)-2-[(2,5-Dichlorobenzoyl)amino]propanoic acid

(78) ##STR00112##
Was prepared in analogy to intermediate IVx, but starting the reaction sequence with 2,5-dichlorobenzoic acid instead of 1-(3-chlorophenyl)cyclopropanecarboxylic acid, as white solid; MS: 262.1 (M+H).sup.+.

Intermediate IVz

(2S)-2-[(3-Chlorobenzoyl)amino]propanoic acid

(79) ##STR00113##
Was prepared in analogy to intermediate IVx, but starting the reaction sequence with 3-chlorobenzoic acid instead of 1-(3-chlorophenyl)cyclopropanecarboxylic acid, as white solid; MS: 228.1 (M+H).sup.+.

Intermediate IVaa

(2S)-2-[[4-(2-tert-Butoxy-2-oxo-ethoxy)benzoyl]amino]-3-(3-chlorophenyl)propanoic acid

(80) ##STR00114##

A] (2,5-Dioxopyrrolidin-1-yl) 4-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethoxy]benzoate

(81) ##STR00115##

(82) In analogy to the procedure described for the preparation of intermediate IVa [A], 4-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethoxy]benzoic acid (US2011/0207704) has been reacted with pyridine, EDC and 1-hydroxypyrrolidine-2,5-dione to give the title compound as white solid.

B] (2S)-2-[[4-(2-Tert-butoxy-2-oxo-ethoxy)benzoyl]amino]-3-(3-chlorophenyl)propanoic acid

(83) ##STR00116##

(84) In analogy to the procedure described for the preparation of intermediate IVa [B], the above prepared (2,5-dioxopyrrolidin-1-yl) 4-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethoxy]benzoate has been reacted with (2S)-2-amino-3-(3-chlorophenyl)propanoic acid in presence of sodium bicarbonate to give the title compound as off-white foam; MS: 434.3 (M+H).sup.+.

(85) In close analogy to Intermediate IVa, using the appropriate acidic building blocks, were prepared Intermediates IVbb-IVdd and IVgg-IVhh, respectively, as summarized in the following Table:

(86) TABLE-US-00003 Inter- Form mediate Structure Acid 1 Acid 2 Color MS IVbb solid white 322.0 (M + H)+ IVcc 0 oil colorless 287.1 (M + H)+ IVdd solid white 356.0 (M + H)+ IVgg foam white 320.1 (M + H)+ IVhh 0 semisolid light yellow 313.0 (M + H)+

Intermediate IVee

(2S)-2-[(3-Chlorobenzoyl)amino]-3-(4-chloro-3-cyanophenyl)propanoic acid

(87) ##STR00132##

A] Methyl (2S)-2-[(3-chlorobenzoyl)amino]-3-(4-chloro-3-cyanophenyl)propanoate

(88) ##STR00133##

(89) In a 10 mL round-bottomed flask, commercially available (S)-methyl 2-amino-3-(4-chloro-3-cyanophenyl)propanoate hydrochloride (200 mg, 727 μmol, Eq: 1) was combined with DCM (6 ml) to give a light brown suspension; N,N-diisopropylethylamine (282 mg, 403 μl, 2.18 mmol, Eq: 3) was added and the solution was cooled to ˜−10° C. 3-Chlorobenzoyl chloride (127 mg, 727 μmol, Eq: 1) was added and the reaction allowed to proceed for 30 min when LC-MS indicated the absence of starting material. The reaction mixture was poured into ice and sat. NH.sub.4Cl and extracted with DCM (2×20 ml). The organic layers were washed with brine, dried (Na.sub.2SO4) and evaporated. Purification by flash chromatography (silica gel, 20 g, 20% to 60% EtOAc in heptane) yielded 269 mg of the title compound as white semisolid; MS: 377.1 (M+H).sup.+.

B] (2S)-2-[(3-Chlorobenzoyl)amino]-3-(4-chloro-3-cyanophenyl)propanoic acid

(90) ##STR00134##

(91) In a 25 mL round-bottomed flask, the above prepared (S)-methyl 3-(4-chloro-3-cyanophenyl)-2-(3-chlorobenzamido)propanoate (264 mg, 700 μmol, Eq: 1) was combined with THF (3 ml) and MeOH (1.5 ml) to give a colorless solution. LiOH 1M in H.sub.2O (770 μl, 770 μmol, Eq: 1.1) was added at 0° C. and the reaction was stirred at 0° C. for 5 h when LC-MS showed the reaction to be finished. The mixture was quenched with dil. KHSO.sub.4 sol., and extracted with AcOEt (2×); the organic layers were washed with brine, dried (Na.sub.2SO.sub.4) and concentrated in vacuo. Trituration with TBME/heptane afforded the title acid as white semisolid; MS: 363.0 (M+H).sup.+.

Intermediate IVff

(2S)-2-[[2-(3-Chlorophenyl)-2,2-difluoroacetyl]amino]propanoic acid

(92) ##STR00135##

A] Benzyl (2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]propanoate

(93) ##STR00136##

(94) To a mixture of 2-(3-chlorophenyl)-2,2-difluoroacetic acid (207 mg, 1 mmol, Eq: 1) and (S)-benzyl 2-aminopropanoate hydrochloride (216 mg, 1 mmol, Eq: 1) in DMF (8 ml) were added at ˜−10° C. N,N-diisopropylethylamine (646 mg, 873 μl, 5 mmol, Eq: 5) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V)=HATU (456 mg, 1.2 mmol, Eq: 1.2); the reaction mixture was stirred and slowly warmed within 2 h to RT and kept for another 2 h at this temperature; LC-MS indicated only traces of desired product and a lot of starting acid; obviously, the amine competed successfully with the acid for HATU! Therefore, another 2 eq. of HATU and amine were added and the mixture kept over night at ambient temperature; the reaction mixture was quenched with cold 0.1 M HCl and extracted with EtOAc (2×50 mL). The organic layers were washed with brine, combined, dried over Na.sub.2SO.sub.4, and concentrated in vacuo; the crude material was purified by flash chromatography (silica gel, 20 g, 40% EtOAc in heptane) to afford 331 mg of the title compound as white solid; MS: 366.1 (M−H).sup.−; by chiral HPLC, the other enantiomer was not detectable!

B] (2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]propanoic acid

(95) ##STR00137##

(96) In a 50 mL pear-shaped flask, the above prepared (S)-benzyl 2-(2-(3-chlorophenyl)-2,2-difluoroacetamido)-propanoate (324 mg, 881 μmol, Eq: 1) was combined with AcOEt (8.81 ml) to give a colorless solution; Palladium on carbon (10%, 46.9 mg, 44 μmol, Eq: 0.05) was added and hydrogenation allowed to proceed at ambient temperature (balloon of H.sub.2); TLC after 2 h at ambient temperature showed the reaction to be finished; the reaction mixture was filtered over a pad of Celite, generously washed with AcOEt, and the filtrate evaporated to dryness; 257 mg of the title acid was obtained after careful HV-drying as off-white solid; MS: 276.1 (M−H).sup.−.

Intermediate IVii

(2S)-3-[tert-Butyl(dimethyl)silyl]oxy-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]propanoic acid

(97) ##STR00138##

A] Benzyl (2S)-2-amino-3-[tert-butyl(dimethyl)silyl]oxypropanoate

(98) ##STR00139##

(99) DBU (1.31 g, 1.3 ml, 8.63 mmol, Eq: 2) was added to a suspension of (S)-benzyl 2-amino-3-hydroxypropanoate hydrochloride (1 g, 4.32 mmol, Eq: 1) and tert-butylchlorodimethylsilane (683 mg, 4.53 mmol, Eq: 1.05) in Acetonitrile (20 ml) at 0° C. and the homogeneous mixture was stirred at RT for 3 hours when LC-MS showed the reaction to be finished. The mixture was poured into 20 mL sat. NaHCO.sub.3 sol. and extracted with EtOAc (2×50 mL). The organic layers were combined, washed with brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. Purification by flash chromatography (silica gel, 50 g, 30% to 80% EtOAc in heptane) yielded 0.844 g of the title compound as colorless oil; MS: 310.2 (M+H).sup.+.

B] Benzyl (2S)-3-[tert-butyl(dimethyl)silyl]oxy-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]propanoate

(100) ##STR00140##

(101) Step 1: In a 10 mL round-bottomed flask, 2-(3-chlorophenyl)-2,2-difluoroacetic acid (618 mg, 2.99 mmol, Eq: 1.1) was combined with CH2Cl2 (10 ml) and 2 drops of DMF to give a colorless solution; oxalyl chloride (759 mg, 523 μl, 5.98 mmol, Eq: 2.2) was added under ice-bath cooling and the reaction mixture was stirred for 5 min at 0° C. The ice-bath was removed and the reaction allowed to continue at rt for 2 hours. The mixture was concentrated under exclusion of moisture and oxygen and then dried for a short period of time on hv and purged with argon.

(102) Step 2: This crude acid chloride was combined with CH2Cl2 (20 ml) to give a light yellow solution. N,N-diisopropylethylamine (1.76 g, 2.37 ml, 13.6 mmol, Eq: 5) and the above prepared (S)-benzyl 2-amino-3-((tert-butyldimethylsilyl)oxy)propanoate (0.841 g, 2.72 mmol, Eq: 1) were added at 0° C. and the reaction allowed to proceed for 30 min., when LC-MS indicated the reaction to be finished. The mixture was poured into sat. NH.sub.4Cl sol.+ice and extracted with DCM (2×). The organic layers were washed with brine, combined, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 50 g, 0% to 50% EtOAc in heptane) to afford 1.21 g of the title amide as yellow oil; MS: 498.2 (M+H).sup.+.

C] (2S)-3-[tert-Butyl(dimethyl)silyl]oxy-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]propanoic acid

(103) ##STR00141##

(104) In a 50 mL pear-shaped flask, the above prepared (S)-benzyl 3-((tert-butyldimethylsilyl)oxy)-2-(2-(3-chlorophenyl)-2,2-difluoroacetamido)propanoate (604 mg, 1.21 mmol, Eq: 1) was combined with ethyl acetate (12 ml) to give a colorless solution; Pd—C 10% (40 mg, 37.6 μmol, Eq: 0.031) was added and hydrogenation allowed to proceed at ambient temperature (balloon of H2). TLC after 3 h showed the reaction to be complete. The reaction mixture was filtered through a pad of Celite, washed with AcOEt and evaporated to dryness to leave 525 mg of the title acid, containing traces of ethyl acetate, but otherwise pure; MS: 408.2 (M+H).sup.+.

Intermediate IVii

(2S)-3-[tert-Butyl(dimethyl)silyl]oxy-2-[[2-(3-fluorophenyl)-2,2-difluoroacetyl]amino]propanoic acid

(105) ##STR00142##
was prepared in analogy to Intermediate IVii, but using in step B] 2-(3-fluorophenyl)-2,2-difluoroacetic acid instead of 2-(3-chlorophenyl)-2,2-difluoroacetic acid, as colorless oil; MS: 392.2 (M+H).sup.+.

Example 1

N-[(2S)-3-(3-chlorophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-2-oxo-1-phenylethyl]amino]-1-oxopropan-2-yl]pyridine-4-carboxamide

(106) ##STR00143##

A] N-[(2S)-3-(3-Chlorophenyl)-1-[[(1S)-2-[[(3 S,4R)-5,5-difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-2-oxo-1-phenylethyl]amino]-1-oxopropan-2-yl]pyridine-4-carboxamide

(107) ##STR00144##

(108) In a 50 mL pear-shaped flask, (4S)-4-[[(2S)-2-[[(2S)-2-amino-3-(3-chlorophenyl)propanoyl]amino]-2-phenylacetyl]amino]-2,2-difluoro-3-hydroxy-5-methyl-N-(2,2,2-trifluoroethyl)hexanamide hydrochloride (Intermediate IIIa, 0.098 g, 140 μmol, Eq: 1) was combined with DMF (3 ml) to give a light yellow solution; pyridine-4-carboxylic acid (17.3 mg, 140 μmol, Eq: 1), HATU (107 mg, 280 μmol, Eq: 2) and Hunig's base (45.3 mg, 61.2 μl, 350 μmol, Eq: 2.5) were successively added at 0° C. and the reaction mixture was stirred for 3 hours at RT. The reaction mixture was quenched with sat. NaHCO.sub.3 and extracted with EtOAc (2×). The organic layers were washed with 1N KHSO.sub.4 and brine, combined, dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10 g, 30% to 80% EtOAc in heptane) to afford 40 mg of the desired product as white solid; MS: 698.2 (M+H.sup.+).

B] N-[(2S)-3-(3-chlorophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-2-oxo-1-phenylethyl]amino]-1-oxopropan-2-yl]pyridine-4-carboxamide

(109) ##STR00145##

(110) In a 10 mL round-bottomed flask, the above prepared N-[(2S)-3-(3-chlorophenyl)-1-[[(1S)-2-[[(3S,4R)-5,5-difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-2-oxo-1-phenylethyl]amino]-1-oxopropan-2-yl]pyridine-4-carboxamide (0.040 g, 57.3 mol, Eq: 1) was combined with DCM (2 ml) to give a colorless solution. Dess-Martin periodinane 15% in dichloromethane (243 mg, 178 μl, 86 μmol, Eq: 1.5) was added at 0° C. and the reaction mixture was stirred at RT for 2 hours. The reaction mixture was treated with sat. NaHCO.sub.3 and extracted with DCM (2×20 ml). The organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and evaporated i. v. The crude material was purified by flash chromatography (basic alumina, 10 g, 50% to 100% EtOAc) to yield 15 mg of the desired product as colorless oil; MS: 696.2 (M+H.sup.+).

Example 2

N-[(2S)-3-(3-Chlorophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-2-oxo-1-phenylethyl]amino]-1-oxopropan-2-yl]pyridine-2-carboxamide

(111) ##STR00146##
was prepared in analogy to example 1, but using in step A] pyridine-2-carboxylic acid instead of pyridine-4-carboxylic acid, as white foam; MS: 696.2 (M+H.sup.+).

Example 3

N-[(2S)-3-(3-Chlorophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-2-oxo-1-phenylethyl]amino]-1-oxopropan-2-yl]pyrazine-2-carboxamide

(112) ##STR00147##
was prepared in analogy to example 1, but using in step A] pyrazine-2-carboxylic acid instead of pyridine-4-carboxylic acid, as white solid; MS: 697.3 (M+H.sup.+); it contained some diastereomers as impurity.

Example 4

N-[(2S)-3-(3-hlorophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-2-oxo-1-phenylethyl]amino]-1-oxopropan-2-yl]pyrimidine-5-carboxamide

(113) ##STR00148##
was prepared in analogy to example 1, but using in step A] pyrimidine-5-carboxylic acid instead of pyridine-4-carboxylic acid, as white solid; MS: 695.4 (M+H.sup.+).

Example 5

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

(114) ##STR00149##

A] N-[(2S)-3-(3,4-Dichlorophenyl)-1-[[(1S)-2-[[(3S,4R)-5,5-difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]pyridine-2-carboxamide

(115) ##STR00150##

(116) To a mixture of (3R,4S)-4-[[(2S)-2-amino-2-(4-methoxyphenyl)acetyl]amino]-2,2-difluoro-3-hydroxy-5-methyl-N-(2,2,2-trifluoroethyl)hexanamide hydrochloride (Intermediate IIb, 60 mg, 126 μmol, Eq: 1) and (S)-3-(3,4-dichlorophenyl)-2-(picolinamido)propanoic acid (Intermediate IVa, 42.6 mg, 126 μmol, Eq: 1) in DMF (4 ml) were successively added at 0° C. N,N-diisopropylethylamine (81.1 mg, 110 μl, 628 μmol, Eq: 5) and HATU (57.3 mg, 151 μmol, Eq: 1.2), and the reaction allowed to proceed for 1 hr at 0° C. The reaction mixture was subsequently quenched with sat. NaHCO.sub.3 and ice and extracted with EtOAc (2×25 ml). The organic layers were washed with sat. NH.sub.4Cl sol., then with brine. The organic layers were combined, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. Purification by flash chromatography (silica gel, 20 g, 30% to 80% EtOAc in heptane) produced 48 mg of the title compound as off-white foam; MS: 762.4 (M+H.sup.+).

B] N-[(2S)-3-(3,4-Dichlorophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]pyridine-2-carboxamide

(117) ##STR00151##

(118) In a 10 mL round-bottomed flask, the above prepared N-[(2S)-3-(3,4-dichlorophenyl)-1-[[(1S)-2-[[(3 S,4R)-5,5-difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]pyridine-2-carboxamide (46 mg, 60.3 μmol, Eq: 1) was combined with dichloromethane (4 ml) and THF (2 ml) to give a colorless solution. Dess-Martin periodinane 15% in dichloromethane (256 mg, 188 μl, 90.5 μmol, Eq: 1.5) was added at 0° C. and the reaction mixture was stirred at rt for 2 h when LC-MS indicated some starting material to be still present; additional 0.1 ml Dess-Martin periodinane was added and the reaction mixture was further stirred for 2 hr at rt. It was then treated with sat. NaHCO.sub.3 and extracted with DCM (2×20 ml). The organic layers were washed with brine, dried (Na.sub.2SO.sub.4) and evaporated. The crude material was purified by flash chromatography (silica gel, 10 g, 50% EtOAc in heptane) to afford 30 mg of the title product as white foam. Trituration with CH.sub.2Cl.sub.2/heptane afforded 15 mg of pure product as white solid; MS: 760.3 (M+H.sup.+).

(119) In close analogy, using the appropriate intermediates, were prepared examples 6-22 and 31-36, respectively, as summarized in the following Table:

(120) TABLE-US-00004 Intermediates Form Example Structure II and IV Color MS  6   N-[(2S)-3-(3,4-Dichlorophenyl)-1-[[(1S)-2- [[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2- trifluoroethylamino)hexan-3-yl]amino]-2-oxo-1- phenylethyl]amino]-1-oxopropan-2-yl]pyridine- 2-carboxamide IIa and IVa solid white 730.3 M + H)+  7   N-[(2S)-3-(3-Chlorophenyl)-1-[[(1S)-2-[[(3S)- 5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2- trifluoroethylamino)hexan-3-yl]amino]-1-(4- methoxyphenyl)-2-oxoethyl]amino]-1- oxopropan-2-yl]pyridine-2-carboxamide IIb and IVk solid white 726.3 M + H)+  8   N-[(2S)-3-(3-Chlorophenyl)-1-[[(1S)-2-[[(3S)- 5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2- trifluoroethylamino)hexan-3-yl]amino]-1-(4- methoxyphenyl)-2-oxoethyl]amino]-1- oxopropan-2-yl]-5-(difluoromethoxy)pyridine-2- carboxamide IIb and IVb solid white 792.5 M + H)+  9   N-[(2S)-1-[[(1S)-2-[[(3S)-5,5-Difluoro-2- methyl-4,6-dioxo-6-(2,2,2- trifluoroethylamino)hexan-3-yl]amino]-2-oxo-1- phenylethyl]amino]-3-(3-methylphenyl)-1- oxopropan-2-yl]pyridine-2-carboxamide IIa and IVc solid white 676.5 M + H)+ 10   N-[(2S)-3-(3-Chlorophenyl)-1-[[(1S)-2-[[(3S)- 5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2- trifluoroethylamino)hexan-3-yl]amino]-2-oxo-1- phenylethyl]amino]-1-oxopropan-2-yl]-5- (difluoromethoxy)pyridine-2-carboxamide IIa and IVb solid white 762.4 M + H)+ 11   N-[(2S)-1-[[(1S)-2-[[(3S)-5,5-Difluoro-2- methyl-4,6-dioxo-6-(2,2,2- trifluoroethylamino)hexan-3-yl]amino]-1-(4- methoxyphenyl)-2-oxoethyl]amino]-3-(3- methylphenyl)-1-oxopropan-2-yl]pyridine-2- carboxamide IIb and IVc solid white 706.5 M + H)+ 12   N-[(2S)-3-(3-Chlorophenyl)-1-[[(1S)-2-[[(3S)- 5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2- trifluoroethylamino)hexan-3-yl]amino]-1-(4- methoxyphenyl)-2-oxoethyl]amino]-1- oxopropan-2-yl]-5-morpholin-4-ylpyridine-2- carboxamide IIb and IVd foam off- white 811.5 M + H)+ 13   N-[(2S)-3-(3-Chlorophenyl)-1-[[(1S)-2-[[(3S)- 5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2- trifluoroethylamino)hexan-3-yl]amino]-1-(4- methoxyphenyl)-2-oxoethyl]amino]-1- oxopropan-2-yl]-5-(dimethylamino)pyridine-2- carboxamide IIb and IVe foam yellow 769.5 M + H)+ 14 0   N-[(2S)-3-(3-Cyanophenyl)-1-[[(1S)-2-[[(3S)- 5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2- trifluoroethylamino)hexan-3-yl]amino]-1-(4- methoxyphenyl)-2-oxoethyl]amino]-1- oxopropan-2-yl]pyridine-2-carboxamide IIb and IVf foam white 717.3 M + H)+ 15   N-[3-(3-Chlorophenyl)-1-[[(1S)-2-[[(3S)-5,5- difluoro-2-methyl-4,6-dioxo-6-(2,2,2- trifluoroethylamino)hexan-3-yl]amino]-1-(4- methoxyphenyl)-2-oxoethyl]amino]-1- oxopropan-2-yl]benzamide IIb and IVl solid white 725.4 M + H)+ 16   N-[3-(3-Chlorophenyl)-1-[[(1S)-2-[[(3S)-5,5- difluoro-2-methyl-4,6-dioxo-6-(2,2,2- trifluoroethylamino)hexan-3-yl]amino]-2-oxo-1- phenylethyl]amino]-1-oxopropan-2- yl]benzamide IIa and IVl solid white 695.3 M + H)+ 17   N-[(2S)-3-(3-Cyanophenyl)-1-[[(1S)-2-[[(3S)- 5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2- trifluoroethylamino)hexan-3-yl]amino]-1-(4- methoxyphenyl)-2-oxoethyl]amino]-1- oxopropan-2-yl]benzamide IIb and IVg foam white 716.4 M + H)+ 18   N-[(2S)-3-(3-Chloro-4-cyanophenyl)-1-[[(1S)-2- [[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2- trifluoroethylamino)hexan-3-yl]amino]-1-(4- methoxyphenyl)-2-oxoethyl]amino]-1- oxopropan-2-yl]pyridine-2-carboxamide IIb and IVh foam white 751.3 M + H)+ 19   N-[2-[[(2S)-3-(3-Chlorophenyl)-1-[[(1S)-2- [[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2- trifluoroethylamino)hexan-3-yl]amino]-1-(4- methoxyphenyl)-2-oxoethyl]amino]-1- oxopropan-2-yl]amino]-2-oxoethyl]pyridine-2- carboxamide IIb and IVm oil light yellow 783.4 (M + H)+ 20   N-[(2S)-3-(3-Chlorophenyl)-1-[[(1S)-2-[[(3S)- 5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2- trifluoroethylamino)hexan-3-yl]amino]-1-(4- methoxyphenyl)-2-oxoethyl]amino]-1- oxopropan-2-yl]benzamide IIb and IVi solid white 725.3 (M + H)+ 21   N-[2-[[(2S)-3-(3-Cyanophenyl)-1-[[(1S)-2- [[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2- trifluoroethylamino)hexan-3-yl]amino]-1-(4- methoxyphenyl)-2-oxoethyl]amino]-1- oxopropan-2-yl]amino]-2-oxoethyl]pyridine-2- carboxamide IIb and IVn semisolid white 774.4 (M + H)+ 22   3-Chloro-N-[(2S)-3-(3-chlorophenyl)-1-[[(1S)-2- [[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2- trifluoroethylamino)hexan-3-yl]amino]-1-(4- methoxyphenyl)-2-oxoethyl]amino]-1- oxopropan-2-yl]benzamide IIb and IVj solid white 759.3 (M + H)+ 31   N-[(2R)-3-(3-Chlorophenyl)-1-[[(1S)-2-[[(3S)- 5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2- trifluoroethylamino)hexan-3-yl]amino]-1-(4- methoxyphenyl)-2-oxoethyl]amino]-1- oxopropan-2-yl]pyridine-2-carboxamide IIb and IVo semisolid white 726.3 (M + H)+ 32 0   3-Chloro-N-[(2S)-3-(3-cyanophenyl)-1-[[(1S)-2- [[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2- trifluoroethylamino)hexan-3-yl]amino]-1-(4- methoxyphenyl)-2-oxoethyl]amino]-1- oxopropan-2-yl]benzamide IIb and IVp solid white 748.4 (M − H)− 33   5-Chloro-N-[(2S)-3-(3-chlorophenyl)-1-[[(1S)-2- [[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2- trifluoroethylamino)hexan-3-yl]amino]-1-(4- methoxyphenyl)-2-oxoethyl]amino]-1- oxopropan-2-yl]thiophene-2-carboxamide IIb and IVq solid white 765.2 (M + H)+ 34   5-Chloro-N-[(2S)-3-(3-cyanophenyl)-1-[[(1S)-2- [[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2- trifluoroethylamino)hexan-3-yl]amino]-1-(4- methoxyphenyl)-2-oxoethyl]amino]-1- oxopropan-2-yl]thiophene-2-carboxamide IIb and IVr solid white 756.2 (M + H)+ 35   N-[(2S)-3-(3-Chlorophenyl)-1-[[(1S)-2-[[(3S)- 5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2- trifluoroethylamino)hexan-3-yl]amino]-1-(4- methoxyphenyl)-2-oxoethyl]amino]-1- oxopropan-2-yl]-3-cyanobenzamid IIb and IVs solid white 750.2 (M + H)+ 36   2,5-Dichloro-N-[(2S)-3-(3-chlorophenyl)-1- [[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo- 6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]- 1-(4-methoxyphenyl)-2-oxoethyl]amino]-1- oxopropan-2-yl]benzamide IIb and IVt foam off- white 795.2 (M + H)+

Example 23

N-[(2S)-1-[[(1S)-2-[[(3S)-5,5-Difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)-hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-3-hydroxy-1-oxopropan-2-yl]benzamide

(121) ##STR00175##

A] N-[(2S)-3-[tert-Butyl(dimethyl)silyl]oxy-1-[[(1S)-2-[[(3S,4R)-5,5-difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]benzamide

(122) ##STR00176##

(123) To a mixture of (4S)-4-((S)-2-amino-2-(4-methoxyphenyl)acetamido)-2,2-difluoro-3-hydroxy-5-methyl-N-(2,2,2-trifluoroethyl)hexanamide hydrochloride (Intermediate IIb, 100 mg, 209 μmol, Eq: 1) and N,N-diisopropylethylamine (135 mg, 183 μl, 1.05 mmol, Eq: 5) in DMF (5 ml) were added at 0° C. (S)-2-benzamido-3-((tert-butyldimethylsilyl)oxy)propanoic acid (Intermediate IVu, 67.7 mg, 209 μmol, Eq: 1) and HATU (95.5 mg, 251 μmol, Eq: 1.2), and the reaction mixture was stirred for 1 hr at 0° C. It was then quenched with sat. NaHCO.sub.3 and ice and extracted with EtOAc (2×25 ml). The organic layers were washed with NH.sub.4Cl, followed by brine. They were combined, dried over Na.sub.2SO.sub.4, and concentrated in vacuo. Purification by flash chromatography (silica gel, 20 g, 20% to 80% EtOAc in heptane) gave 87 mg of the title product as yellow semisolid; MS: 747.5 (M+H.sup.+).

B] N-[(2S)-3-[tert-Butyl(dimethyl)silyl]oxy-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]benzamide

(124) ##STR00177##

(125) In a 10 mL round-bottomed flask, the above prepared N-((6S,9S,12S)-14,14,18,18,18-pentafluoro-13-hydroxy-12-isopropyl-9-(4-methoxyphenyl)-2,2,3,3-tetramethyl-7,10,15-trioxo-4-oxa-8,11,16-triaza-3-silaoctadecan-6-yl)benzamide (84 mg, 112 μmol, Eq: 1) was combined with CH.sub.2Cl.sub.2 (5 ml) to give a light yellow solution. Dess-Martin periodinane 15% in CH.sub.2Cl.sub.2 (477 mg, 350 μl, 169 μmol, Eq: 1.5) was added at 0° C. and the reaction mixture was stirred for 1 hr at rt. It was then treated with sat. NaHCO.sub.3 and extracted with CH.sub.2Cl.sub.2 (2×20 mL). The organic layers were washed with brine, dried (Na.sub.2SO.sub.4) and evaporated i. V. The crude material was purified by flash chromatography (silica gel, 20 g, 50% EtOAc in heptane) to generate 56 mg of ther title ketone as white foam; MS: 745.4 (M+H.sup.+).

C] N-[(2S)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)-hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-3-hydroxy-1-oxopropan-2-yl]benzamide

(126) ##STR00178##

(127) In a 10 mL round-bottomed flask, the above prepared N-((6S,9S,12S)-14,14,18,18,18-pentafluoro-12-isopropyl-9-(4-methoxyphenyl)-2,2,3,3-tetramethyl-7,10,13,15-tetraoxo-4-oxa-8,11,16-triaza-3-silaoctadecan-6-yl)benzamide (54 mg, 72.5 μmol, Eq: 1) was combined with THF (4 ml) to give a colorless solution. HCl 4M in dioxane (272 μl, 1.09 mmol, Eq: 15) was added at 0° C., followed by 2 drops of H.sub.2O. The reaction mixture was stirred at rt for 30 min., when LC-MS indicated the reaction to be finished. The mixture was poured into H.sub.2O and extracted with EtOAc (2×25 mL). The organic layers were dried over Na.sub.2SO.sub.4 and concentrated in vacuo. Precipitation from AcOEt/Hept afforded 30 mg of pure title product as white solid; MS: 631.3 (M+H.sup.+).

Example 24

1-(3-Chlorophenyl)-N-[(2S)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-3-hydroxy-1-oxopropan-2-yl]cyclopropane-1-carboxamide

(128) ##STR00179##
was prepared in analogy to example 23 but using in step A] Intermediate IVv instead of IVu, as colorless oil; MS: 705.3 (M+H).sup.+.

Example 25

1-(3-Chlorophenyl)-N-[(2S,3R)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-3-hydroxy-1-oxobutan-2-yl]cyclopropane-1-carboxamide

(129) ##STR00180##
was prepared in analogy to example 23, but using in step A] Intermediate IVw instead of IVu, as white foam; MS: 717.4 (M−H).sup.−.

Example 26

N-[(2S)-1-[[(1S)-2-[[(3S)-5,5-Difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]benzamide

(130) ##STR00181##
was prepared in analogy to example 23, but using in step A] (2S)-2-benzamidopropanoic acid (commercially available) instead of IVu, as light yellow foam; MS: 615.3 (M+H).sup.+.

Example 27

1-(3-Chlorophenyl)-N-[(2S)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-2-oxo-1-phenylethyl]amino]-1-oxopropan-2-yl]cyclopropane-1-carboxamide

(131) ##STR00182##
was prepared in analogy to example 23, but using in step A] Intermediate IIa instead of IIb and Intermediate IVx instead of IVu, as white foam; MS: 659.3 (M+H).sup.+.

Example 28

1-(3-Chlorophenyl)-N-[(2S)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]cyclopropane-1-carboxamide

(132) ##STR00183##
was prepared in analogy to example 23, but using in step A] Intermediate IVx instead of IVu, as colorless oil; MS: 689.3 (M+H).sup.+.

Example 29

2,5-Dichloro-N-[(2S)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]benzamide

(133) ##STR00184##
was prepared in analogy to example 23, but using in step A] Intermediate IVy instead of IVu, as white solid; MS: 683.2 (M+H).sup.+.

Example 30

3-Chloro-N-[(2S)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]benzamide

(134) ##STR00185##
was prepared in analogy to example 23, but using in step A] Intermediate IVz instead of IVu, as white solid; MS: 647.4 (M−H).sup.−.

Example 37

tert-Butyl 2-[4-[[(2S)-3-(3-chlorophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]carbamoyl]phenoxy]acetate

(135) ##STR00186##
was prepared in analogy to example 5, but using in step A] Intermediate IVaa instead of IVa, as off-white solid; MS: 855.3 (M+H.sup.+).

Example 38

2-[4-[[(2S)-3-(3-Chlorophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]carbamoyl]phenoxy]acetic acid

(136) ##STR00187##

(137) To a solution of the above prepared tert-butyl 2-[4-[[(2S)-3-(3-chlorophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]carbamoyl]phenoxy]acetate (Example 37, 25 mg, 29.2 μmol, Eq: 1) in DCM (1 ml) was added TFA (45 μl, 585 μmol, Eq: 20) and the reaction mixture was stirred at room temperature for 6 h. The mixture was evaporated to dryness and the residue triturated in diisopropylether. The resulting precipitate was filtered off and further dried on high vaccum to yield 15 mg of the title product as colorless solid; MS: 799.4 (M+H.sup.+).

Example 39

2-[4-[(2S)-2-[[2-(3-Chlorophenyl)-2,2-difluoroacetyl]amino]-3-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-3-oxopropyl]phenoxy]acetic acid

(138) ##STR00188##

A] tert-Butyl 2-[4-[(2S)-2-[[2-(3-Chlorophenyl)-2,2-difluoroacetyl]amino]-3-[[(1S)-2-[[(3S,4R)- 5,5-difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-3-oxopropyl]phenoxy]acetate

(139) ##STR00189##

(140) To a solution of tert-butyl 2-[4-[(2S)-2-amino-3-[[(1S)-2-[[(3S,4R)-5,5-difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-3-oxopropyl]phenoxy]acetate hydrochloride (Intermediate IIIb, 30 mg, 39.7 mol, Eq: 1) in DCM (1 ml), cooled to 0° C. with an ice bath, was added 2-(3-chlorophenyl)-2,2-difluoroacetyl chloride (9.83 mg, 43.7 μmol, Eq: 1.1) and the reaction mixture was stirred at this temperature overnight. The mixture was diluted with EtOAc, poured into 1M HCl and extracted with EtOAc (2×10 ml). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, filtered, and evaporated. The residue was purified by silica gel flash chromatography, eluting with a 0 to 70% EtOAc-heptane gradient, to yield 28 mg of the title product as colorless solid; MS: 851.3 (M-tBu+H.sup.+).

B] tert-Butyl 2-[4-[(2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-3-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-3-oxopropyl]phenoxy]acetate

(141) ##STR00190##

(142) To a solution of the above prepared tert-butyl 2-[4-[(2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-3-[[(1S)-2-[[(3 S,4R)-5,5-difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-3-oxopropyl]phenoxy]acetate (0.028 g, 30.9 μmol, Eq: 1) in CH.sub.2Cl.sub.2 (1 ml), cooled to 0° C., was added Dess-Martin periodinane 15% in dichloromethane (262 mg, 192 μl, 92.6 μmol, Eq: 3), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was treated with sat. NaHCO.sub.3 and extracted with DCM (2×10 ml). The organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and evaporated. The residue was purified by silica gel flash chromatography, eluting with a 0 to 60% EtOAc-heptane gradient, to yield 20 mg of the title product as colorless solid; MS: 905.3 (M+H.sup.+).

C] 2-[4-[(2S)-2-[[2-(3-Chlorophenyl)-2,2-difluoroacetyl]amino]-3-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-3-oxopropyl]phenoxy]acetic acid

(143) ##STR00191##
was prepared in analogy to example 38 from the above prepared tert-butyl 2-[4-[(2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-3-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-3-oxopropyl]phenoxy]acetate as colorless solid; MS: 849.4 (M+H.sup.+).

Example 40

2-[4-[(2S)-2-[(3-Chlorobenzoyl)amino]-3-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-3-oxopropyl]phenoxy]acetic acid

(144) ##STR00192##

A] tert-Butyl 2-[4-[(2S)-2-[(3-chlorobenzoyl)amino]-3-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-3-oxopropyl]phenoxy]acetate

(145) ##STR00193##
was prepared in analogy to example 1, but using in step A] Intermediate IIIb instead of IIIa and 3-chlorobenzoic acid instead of pyridine-4-carboxylic acid, as colorless solid; MS: 855.4 (M+H.sup.+).

B] 2-[4-[(2S)-2-[(3-Chlorobenzoyl)amino]-3-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-3-oxopropyl]phenoxy]acetic acid

(146) ##STR00194##
was prepared in analogy to example 38 from the above prepared tert-butyl 2-[4-[(2S)-2-[(3-chlorobenzoyl)amino]-3-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-3-oxopropyl]phenoxy]acetate, as colorless solid; MS: 799.4 (M+H.sup.+).

Example 41

(4S)-4-[[(2S)-2-[[(2S)-3-(3-Chlorophenyl)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]propanoyl]amino]-2-(4-methoxyphenyl)acetyl]amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanamide

(147) ##STR00195##
was prepared in analogy to example 39, but using in step A] (3R,4S)-4-[[(2S)-2-[[(2S)-2-amino-3-(3-chlorophenyl)propanoyl]amino]-2-(4-methoxyphenyl)acetyl]amino]-2,2-difluoro-3-hydroxy-5-methyl-N-(2,2,2-trifluoroethyl)hexanamide hydrochloride (Intermediate IIIc) instead of tert-butyl 2-[4-[(2S)-2-amino-3-[[(1S)-2-[[(3S,4R)-5,5-difluoro-4-hydroxy-2-methyl-6-oxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-3-oxopropyl]phenoxy]acetate hydrochloride (Intermediate IIIb), as light-yellow foam; MS: 809.3 (M+H.sup.+).

(148) In close analogy to Example 5, using the appropriate intermediates, were prepared examples 42-44, 47-51, 56, and 58-60, respectively, as summarized in the following Table:

(149) TABLE-US-00005 Form Intermediates Color Example Structure/Name II and IV MS 42   3-Chloro-N-[(2S)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2- methyl-4,6-dioxo-6-(2,2,2- trifluoroethylamino)hexan-3-yl]amino]-1-(4- methoxyphenyl)-2-oxoethyl]amino]-3-(3- fluorophenyl)-1-oxopropan-2-yl]benzamide IIb and IVbb foam light yellow 745.4 (M + H) 43   N-[(2S)-1-[[(1S)-2-[[(3S)-5,5-Difluoro-2-methyl-4,6- dioxo-6-(2,2,2-trifluoroethylamino)hexan-3- yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]- 3-(3-fluorophenyl)-1-oxopropan-2-yl]pyridine-2- carboxamide IIb and IVcc solid white 710.5 (M + H)+ 44   2,5-Dichloro-N-[(2S)-1-[[(1S)-2-[[(3S)-5,5-difluoro- 2-methyl-4,6-dioxo-6-(2,2,2- trifluoroethylamino)hexan-3-yl]amino]-1-(4- methoxyphenyl)-2-oxoethyl]amino]-3-(3- fluorophenyl)-1-oxopropan-2-yl]benzamide IIb and IVdd solid white 777.2 (M + H)+ 47   N-[(2S)-3-(3-Chlorophenyl)-1-[[(1S)-2-[[(1S)-1- cyclobutyl-3,3-difluoro-2,4-dioxo-4-(2,2,2- trifluoroethylamino)butyl]amino]-1-(4- methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2- yl]pyridine-2-carboxamide IIc and IVk oil colorless 738.3 (M + H) 48 00   3-Chloro-N-[(2S)-3-(4-chloro-3-cyanophenyl)-1- [[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6- (2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4- methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2- yl]benzamide IIb and IVee solid white 784.2 (M + H)+ 49 01   N-[(2S)-3-(3-Cyanophenyl)-1-[[(1S)-2-[[(1S)-1- cyclobutyl-3,3-difluoro-2,4-dioxo-4-(2,2,2- trifluoroethylamino)butyl]amino]-1-(4- methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2- yl]pyridine-2-carboxamide IIc and IVf foam white 729.3 (M + H) 50 02   N-[(2S)-3-(3-Cyanophenyl)-1-[[(1S)-2-[[(1S)-1- cyclobutyl-3,3-difluoro-2,4-dioxo-4-(2,2,2- trifluoroethylamino)butyl]amino]-1-(4- methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2- yl]benzamide IIc and IVg solid white 728.3 (M + H) 51 03   (4S)-4-[[(2S)-2-[[(2S)-2-[[2-(3-Chlorophenyl)-2,2- difluoroacetyl]amino]propanoyl]amino]-2-(4- methoxyphenyl)acetyl]amino]-2,2-difluoro-5-methyl- 3-oxo-N-(2,2,2-trifluoroethyl)hexanamide IIb and IVff solid white 699.3 (M + H)+ 56 04   3-Cyano-N-[(2S)-3-(3-cyanophenyl)-1-[[(1S)-2- [[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2- trifluoroethylamino)hexan-3-yl]amino]-1-(4- methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2- yl]benzamide IIb and IVgg solid white 741.4 (M + H)+ 58 05   3-Cyano-N-[(2S)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2- methyl-4,6-dioxo-6-(2,2,2- trifluoroethylamino)hexan-3-yl]amino]-1-(4- methoxyphenyl)-2-oxoethyl]amino]-3-(3- fluorophenyl)-1-oxopropan-2-yl]benamide IIb and IVhh solid white 734.4 (M + H)+ 59 06   N-[(2S)-3-(3-Chlorophenyl)-1-[[(1S)-2-[[(1S)-1- cyclopropyl-3,3-difluoro-2,4-dioxo-4-(2,2,2- trifluoroethylamino)butyl]amino]-1-(4- methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2- yl]pyridine-2-carboxamide IId and IVk solid white 724.3 (M + H) 60 07   N-[(2S)-3-(3-Cyanophenyl)-1-[[(1S)-2-[[(1S)-1- cyclopropyl-3,3-difluoro-2,4-dioxo-4-(2,2,2- trifluoroethylamino)butyl]amino]-1-(4- methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2- yl]pyridine-2-carboxamide IId and IVf solid white 715.3 (M + H)

Example 52

N-[(2S)-3-(3-Chlorophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]-3-fluorobenzamide

(150) ##STR00208##
was prepared in analogy to Example 1, but using Intermediate IIIc and 3-fluorobenzoic acid as respective building block, as white solid; MS; 743.3 (M+H).sup.+.

Example 53

3,5-Dichloro-N-[(2S)-3-(3-chlorophenyl)-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]benzamide

(151) ##STR00209##
was prepared in analogy to Example 1, using Intermediate IIIc and 3,5-dichlorobenzoic acid as respective building block, as white solid; MS; 795.2 (M+H).sup.+.

(152) Example 45, 46, 54, 55, and 57, respectively, were prepared in analogy to Example 39 using the appropriate building blocks as indicated in the following Table:

(153) TABLE-US-00006 Form Intermediate Acid Color Ex Structure/Name III chloride MS 45 0   (4S)-4-[[(2S)-2-[[(2S)-3-(3-chlorophenyl)- 2-[[2-(3- chlorophenyl)acetyl]amino]propanoyl]amino]- 2-(4-methoxyphenyl)acetyl]amino]-2,2- difluoro-5-methyl-3-oxo-N-(2,2,2- trifluoroethyl)hexanamide IIIc solid white 773.3 (M + H)+ 46   (4S)-4-[[(2S)-2-[[(2S)-2-[[2-(3- chlorophenyl)-2,2-difluoroacetyl]amino]-3- (3-fluorophenyl)propanoyl]amino]-2-(4- methoxyphenyl)acetyl]amino]-2,2-difluoro- 5-methyl-3-oxo-N-(2,2,2- trifluoroethyl)hexanamide IIId foam white 793.3 (M + H)+ 54   N-[(2S)-3-(3-chlorophenyl)-1-[[(1S)-2- [[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6- (2,2,2-trifluoroethylamino)hexan-3- yl]amino]-1-(4-methoxyphenyl)-2- oxoethyl]amino]-1-oxopropan-2-yl]-1- phenylcyclopropane-1-carboxamide IIIc oil colorless 765.3 (M + H)+ 55   1-(3-chlorophenyl)-N-[(2S)-3-(3- chlorophenyl)-1-[[(1S)-2-[[(3S)-5,5- difluoro-2-methyl-4,6-dioxo-6-(2,2,2- trifluoroethylamino)hexan-3-yl]amino]-1- (4-methoxyphenyl)-2-oxoethyl]amino]-1- oxopropan-2-yl]cyclopropane-1- carboxamide IIIc oil colorless 799.3 (M + H)+ 57   (4S)-4-[[(2S)-2-[[(2S)-2-[[2-(3- chlorophenyl)-2,2-difluoroacetyl]amino]-3- (3-cyanophenyl)propanoyl]amino]-2-(4- methoxyphenyl)acetyl]amino]-2,2-difluoro- 5-methyl-3-oxo-N-(2,2,2- trifluoroethyl)hexanamide IIIe solid white 800.3 (M + H)+

Example 61

(4S)-4-[[(2S)-2-[[(2S)-2-[[2-(3-Chlorophenyl)-2,2-difluoroacetyl]amino]-3-hydroxypropanoyl]-amino]-2-(4-methoxyphenyl)acetyl]amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanamide

(154) ##STR00220##

A] (3R,4S)-4-[[(2S)-2-[[(2S)-3-[tert-Butyl(dimethyl)silyl]oxy-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]propanoyl]amino]-2-(4-methoxyphenyl)acetyl]amino]-2,2-difluoro-3-hydroxy-5-methyl-N-(2,2,2-trifluoroethyl)hexanamide

(155) ##STR00221##

(156) To a mixture of (4S)-4-((S)-2-amino-2-(4-methoxyphenyl)acetamido)-2,2-difluoro-3-hydroxy-5-methyl-N-(2,2,2-trifluoroethyl)hexanamide hydrochloride (Intermediate IIb, 175 mg, 366 μmol, Eq: 1) and (S)-3-((tert-butyldimethylsilyl)oxy)-2-(2-(3-chlorophenyl)-2,2-difluoroacetamido)-propanoic acid Intermediate (IVii, 150 mg, 368 μmol, Eq: 1) in DMF (8 ml) were added at 0° C. N,N-diisopropylethylamine (237 mg, 320 μl, 1.83 mmol, Eq: 5) and HATU (167 mg, 439 μmol, Eq: 1.2), and the reaction mixture was stirred for 1 hr at 0° C. The reaction was quenched with sat. NaHCO.sub.3+ice and extracted with EtOAc (2×25 mL) The organic layers were washed with NH.sub.4Cl sol., then with brine, they were combined, dried over Na.sub.2SO.sub.4 and concentrated in vacuo.

(157) The crude material was purified by flash chromatography (silica gel, 20 g, 10% to 60% EtOAc in heptane) to produce 175 mg of the title compound as off-white foam; MS: 831.3 (M+H).sup.+.

B] (4S)-4-[[(2S)-2-[[(2S)-3-[tert-Butyl(dimethyl)silyl]oxy-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]propanoyl]amino]-2-(4-methoxyphenyl)acetyl]amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanamide

(158) ##STR00222##

(159) In a 10 mL round-bottomed flask, the above prepared (4S)-4-((S)-2-((S)-3-((tert-butyldimethylsilyl)oxy)-2-(2-(3-chlorophenyl)-2,2-difluoroacetamido)propanamido)-2-(4-methoxyphenyl)acetamido)-2,2-difluoro-3-hydroxy-5-methyl-N-(2,2,2-trifluoroethyl)-hexanamide (169 mg, 203 μmol, Eq: 1) was combined with DCM (6 ml) to give a colorless solution. Dess-Martin periodinane 15% in CH2Cl2 (862 mg, 633 μl, 305 μmol, Eq: 1.5) was added at 0° C. and the reaction mixture was stirred at rt for 2 h when LC-MS indicated the reaction to be finished. The mixture was treated with sat NH.sub.4Cl sol. and extracted with DCM (2×20 mL). The organic layers were washed with brine, dried (Na.sub.2SO.sub.4) and evaporated. The crude material was purified by flash chromatography (silica gel, 20 g, 10% to 60% EtOAc in heptane) to yield 139 mg of the title product as white semisolid; MS: 829.3 (M+H).sup.+.

C] (4S)-4-[[(2S)-2-[[(2S)-2-[[2-(3-Chlorophenyl)-2,2-difluoroacetyl]amino]-3-hydroxypropanoyl]amino]-2-(4-methoxyphenyl)acetyl]amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanamide

(160) ##STR00223##

(161) In a 10 mL round-bottomed flask, the above prepared (S)-4-((S)-2-((S)-3-((tert-butyldimethylsilyl)oxy)-2-(2-(3-chlorophenyl)-2,2-difluoroacetamido)propanamido)-2-(4-methoxyphenyl)acetamido)-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanamide (128 mg, 154 μmol, Eq: 1) was combined with THF (8 ml) to give a colorless solution. HCl 4M in dioxane (579 μl, 2.32 mmol, Eq: 15) was added at 0° C., followed by 2 drops H.sub.2O. The reaction mixture was stirred at rt for 1 h when LC-MS showed the reaction to be finished. The reaction mixture was poured into H.sub.2O and extracted with EtOAc (2×25 mL). The combined organic layers were dried over Na.sub.2SO.sub.4 and concentrated in vacuo. Precipitation from AcOEt/heptane afforded finally the pure title product as white solid; MS: 715.3 (M+H).sup.+.

Example 62

(4S)-4-[[(2S)-2-[[(2S)-2-[[2,2-Difluoro-2-(3-fluorophenyl)acetyl]amino]-3-hydroxypropanoyl]amino]-2-(4-methoxyphenyl)acetyl]amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanamide

(162) ##STR00224##
was prepared in analogy to example 61, but using in step A] (2S)-3-[tert-butyl(dimethyl)silyl]oxy-2-[[2-(3-fluorophenyl)-2,2-difluoroacetyl]amino]propanoic acid instead of (S)-3-((tert-butyldimethylsilyl)oxy)-2-(2-(3-chlorophenyl)-2,2-difluoroacetamido)-propanoic acid, as white solid; MS: 699.2 (M+H.sup.+).

Example 63

tert-Butyl N-[[4-[(2S)-2-[(3-chlorobenzoyl)amino]-3-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-3-oxopropyl]phenyl]methyl]carbamate

(163) ##STR00225##
was prepared in analogy to Example 1, using Intermediate IIIg and 3-chlorobenzoic acid as respective building block, as white solid; MS; 795.2 (M+H).sup.+.

Example 64

tert-Butyl N-[[4-[(2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-3-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-3-oxopropyl]phenyl]methyl]carbamate

(164) ##STR00226##
was prepared in analogy to Example 1, using Intermediate IIIg and 2-(3-chlorophenyl)-2,2-difluoro-acetic acid as respective building block, as white solid; MS; 795.2 (M+H).sup.+.

Example 65

N-[(2S)-3-[4-(Aminomethyl)phenyl]-1-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-1-oxopropan-2-yl]-3-chlorobenzamide; TFA

(165) ##STR00227##

(166) To a solution of tert-butyl N-[[4-[(2S)-2-[(3-chlorobenzoyl)amino]-3-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-3-oxopropyl]phenyl]methyl]carbamate (Example 63, 0.007 g, 0.008 mmol, Eq: 1) in DCM (0.5 ml) was added TFA (0.013 ml, 0.171 mmol, Eq: 20) and the reaction mixture was stirred at room temperature over night. The mixture was concentrated in vacuo and the residue triturated with 0.5 ml of diisopropylether, the solvent was pipetted off and the resulting solid further dried on the high vacuum to give the title compound as TFA salt as light brown solid; MS: 754.3 (M+H).sup.+.

Example 66

(167) was prepared in analogy to Example 65, using tert-butyl N-[[4-[(2S)-2-[[2-(3-chlorophenyl)-2,2-difluoroacetyl]amino]-3-[[(1S)-2-[[(3S)-5,5-difluoro-2-methyl-4,6-dioxo-6-(2,2,2-trifluoroethylamino)hexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-3-oxopropyl]phenyl]methyl]carbamate (Example 64) instead of Example 63, as light brown solid; MS: 804.3. (M+H).sup.+.

Example 67

(4S)-4-[[(2S)-2-[[(2S)-2-[[2,2-Difluoro-2-(3-fluorophenyl)acetyl]amino]-3-methoxypropanoyl]amino]-2-(4-methoxyphenyl)acetyl]amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanamide

(168) ##STR00228##
was prepared in analogy to Example 1, using Intermediate IIIf and 2-(3-fluorophenyl)-2,2-difluoro-acetic acid as respective building block, as colorless waxy solid; MS; 713.2.2 (M+H).sup.+.

Example 68

(4S)-4-[[(2S)-2-[[(2S)-2-[[2-(3,4-Dichlorophenyl)-2,2-difluoroacetyl]amino]-3-methoxypropanoyl]amino]-2-(4-methoxyphenyl)acetyl]amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanamide

(169) ##STR00229##
was prepared in analogy to Example 1, using Intermediate IIIf and 2-(3,4-dichlorophenyl)-2,2-difluoro-acetic acid as respective building block, as colorless waxy solid; MS; 763.2 (M+H).sup.+.

Example 69

(4S)-4-[[(2S)-2-[[(2S)-2-[[2-(2,5-Dichlorophenyl)-2,2-difluoroacetyl]amino]-3-methoxypropanoyl]amino]-2-(4-methoxyphenyl)acetyl]amino]-2,2-difluoro-5-methyl-3-oxo-N-(2,2,2-trifluoroethyl)hexanamide

(170) ##STR00230##
was prepared in analogy to Example 1, using Intermediate IIIf and 2-(2,5-dichlorophenyl)-2,2-difluoro-acetic acid as respective building block, as white solid; MS; 763.2 (M+H).sup.+.

Example 70

(4S)-4-[[(2S)-2-[[(2S)-2-[[2-(3-Chlorophenyl)-2,2-difluoroacetyl]amino]-3-methoxypropanoyl]amino]-2-(4-methoxyphenyl)acetyl]amino]-N-[2-(1,1-dioxo-1,4-thiazinan-4-yl)ethyl]-2,2-difluoro-5-methyl-3-oxohexanamide

(171) ##STR00231##
was prepared in analogy to Example 1, using Intermediate IIIh and 2-(3-chlorophenyl)-2,2-difluoro-acetic acid as respective building block, as white solid; MS; 809.0 (M+H).sup.+.

Example 71

N-[(2S)-1-[[(1S)-2-[[(3S)-6-[2-(1,1-Dioxo-1,4-thiazinan-4-yl)ethylamino]-5,5-difluoro-2-methyl-4,6-dioxohexan-3-yl]amino]-1-(4-methoxyphenyl)-2-oxoethyl]amino]-3-methoxy-1-oxopropan-2-yl]-1-(trifluoromethyl)cyclopentane-1-carboxamide

(172) ##STR00232##
was prepared in analogy to Example 1, using Intermediate IIIh and 1-(trifluoromethyl)cyclopentanecarboxylic acid as respective building block, as white solid; MS; 784.7 (M+H).sup.+.

Example A

(173) 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:

(174) TABLE-US-00007 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

(175) 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:

(176) TABLE-US-00008 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