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ANTIVIRAL COMPOUNDS

20250059171 ยท 2025-02-20

Assignee

Inventors

Cpc classification

International classification

Abstract

The invention provides viral protease inhibitors having the general formula (I)

##STR00001##

wherein the variables are as described herein, compositions including the compounds, processes of manufacturing the compounds and methods of using the compounds.

Claims

1-31. (canceled)

32. A compound of formula (I) ##STR00511## or a pharmaceutically acceptable salt thereof, wherein: L is C.sub.1-C.sub.6-alkyl; L.sup.1 is selected from a covalent bond, O, NH, and ##STR00512## A is selected from C.sub.6-C.sub.14-aryl and 3- to 14-membered heteroaryl; R.sup.1 is selected from a group ##STR00513## and a group ##STR00514## and R.sup.2 is selected from hydrogen, C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-cycloalkyl-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkyl-C.sub.3-C.sub.10-cycloalkyl, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkyl-SC.sub.1-C.sub.6-alkyl, 3- to 14-membered heteroaryl, (3- to 14-membered heteroaryl)-C.sub.1-C.sub.6-alkyl, C.sub.6-C.sub.14-aryl, and C.sub.6-C.sub.14-aryl-C.sub.1-C.sub.6-alkyl, wherein said C.sub.3-C.sub.10-cycloalkyl is optionally substituted with 1 C.sub.1-C.sub.6-alkyl substituent; or R.sup.1 and R.sup.2, taken together with the carbon atom to which they are attached, form a 3- to 14-membered heteroaryl or a C.sub.6-C.sub.14-aryl, wherein said 3- to 14-membered heteroaryl or C.sub.6-C.sub.14-aryl is optionally substituted with 1 to 2 substituents selected from halogen and halo-C.sub.1-C.sub.6-alkyl; R.sup.1a is selected from C.sub.3-C.sub.10-cycloalkyl, C.sub.6-C.sub.14-aryl, 3- to 14-membered heteroaryl, C.sub.1-C.sub.6-alkyl, and halo-C.sub.1-C.sub.6-alkyl, wherein said C.sub.3-C.sub.10-cycloalkyl and 3- to 14-membered heteroaryl are optionally substituted with 1 to 2 substituents selected from halogen, C.sub.1-C.sub.6-alkyl and halo-C.sub.1-C.sub.6-alkyl; R.sup.3a, R.sup.3b, R.sup.4a, and R.sup.4b are each independently selected from hydrogen, halogen, C.sub.1-C.sub.6-alkyl, and halo-C.sub.1-C.sub.6-alkyl; or R.sup.3a and R.sup.3b, taken together with the carbon atom to which they are attached, form a C.sub.3-C.sub.10-cycloalkyl; and R.sup.4a and R.sup.4b are each independently selected from hydrogen and C.sub.1-C.sub.6-alkyl; wherein said C.sub.3-C.sub.10-cycloalkyl is optionally substituted with 1 to 2 C.sub.1-C.sub.6-alkyl substituents; or R.sup.4a and R.sup.4b, taken together with the carbon atom to which they are attached, form a C.sub.3-C.sub.10-cycloalkyl; and R.sup.3a and R.sup.3b are each independently selected from hydrogen and C.sub.1-C.sub.6-alkyl; wherein said C.sub.3-C.sub.10-cycloalkyl is optionally substituted with 1 to 2 C.sub.1-C.sub.6-alkyl substituents; or R.sup.3a and R.sup.4a, taken together with the carbon atoms to which they are attached, form a C.sub.3-C.sub.10-cycloalkyl; and R.sup.3b and R.sup.4b are each independently selected from hydrogen and C.sub.1-C.sub.6-alkyl; wherein said C.sub.3-C.sub.10-cycloalkyl is optionally substituted with 1 to 2 C.sub.1-C.sub.6-alkyl substituents; R.sup.5 is selected from 3- to 14-membered heterocycloalkyl, 3- to 14-membered heteroaryl, carbamoyl, and C.sub.1-C.sub.6-alkyl-NHC(O); wherein said 3- to 14-membered heterocycloalkyl is optionally substituted with 1 oxo substituent; R.sup.6 is selected from fluoro and chloro; R.sup.7 is selected from hydrogen, chloro, and acyl; and R.sup.8 and R.sup.9 are each independently selected from hydrogen, halogen and halo-C.sub.1-C.sub.6-alkyl.

33. The compound of formula (I) according to claim 32, or a pharmaceutically acceptable salt thereof, wherein: L.sup.1 is selected from a covalent bond, O, NH, and ##STR00515## A is selected from C.sub.6-C.sub.14-aryl and 3- to 14-membered heteroaryl; R.sup.1 is selected from a group ##STR00516## and a group ##STR00517## and R.sup.2 is selected from hydrogen, C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-cycloalkyl-C.sub.1-C.sub.6-alkyl, (3- to 14-membered heteroaryl)-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkyl, C.sub.6-C.sub.14-aryl, C.sub.6-C.sub.14-aryl-C.sub.1-C.sub.6-alkyl, and C.sub.1-C.sub.6-alkyl-SC.sub.1-C.sub.6-alkyl, wherein said C.sub.3-C.sub.10-cycloalkyl is optionally substituted with 1 C.sub.1-C.sub.6-alkyl substituent; or R.sup.1 and R.sup.2, taken together with the carbon atom to which they are attached, form a C.sub.6-C.sub.14-aryl which is substituted with 2 substituents selected from halogen and halo-C.sub.1-C.sub.6-alkyl; R.sup.1a is selected from C.sub.3-C.sub.10-cycloalkyl, C.sub.6-C.sub.14-aryl, 3- to 14-membered heteroaryl, C.sub.1-C.sub.6-alkyl, and halo-C.sub.1-C.sub.6-alkyl, wherein said C.sub.3-C.sub.10-cycloalkyl and 3- to 14-membered heteroaryl are optionally substituted with 1 to 2 substituents selected from halogen, C.sub.1-C.sub.6-alkyl and halo-C.sub.1-C.sub.6-alkyl; and R.sup.8 and R.sup.9 are each independently selected from hydrogen, halogen and halo-C.sub.1-C.sub.6-alkyl.

34. The compound of formula (I) according to claim 32, or a pharmaceutically acceptable salt thereof, wherein: L.sup.1 is selected from a covalent bond, O, NH, and ##STR00518## A is selected from phenyl, pyridyl, pyrimidinyl; R.sup.1 is selected from a group ##STR00519## and a group ##STR00520## and R.sup.2 is selected from hydrogen, cyclopropyl, 1-methylcyclopropyl, cyclobutyl, 1-bicyclo[1.1.1]pentanylmethyl, methyl, ethyl, propyl, sec-butyl, tert-butyl, isobutyl, 1-ethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 2-methylsulfanylethyl, phenyl, benzyl, and pyridylmethyl; or R.sup.1 and R.sup.2, taken together with the carbon atom to which they are attached, form a phenyl, which is substituted with 2 substituents selected from fluoro and CF.sub.3; R.sup.1a is selected from bicyclo[1.1.1]pentanyl, cyclopropyl, 1-fluorocyclopropyl, 2,2-difluorocyclopropyl, 1-methylclopropyl, 1-fluorocyclobutyl, 3,3-difluorocyclobutyl, cyclobutyl, phenyl, isoxazolyl, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, CHFCl, CHCl.sub.2, CHF.sub.2, CF.sub.3, 1-fluoro-1-methyl-ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1-fluoroethyl, and 1,1,2,2,2-pentachloroethyl; and R.sup.8 and R.sup.9 are each independently selected from hydrogen, fluoro and CF.sub.3.

35. The compound of formula (I) according to claim 33, or a pharmaceutically acceptable salt thereof, wherein: R.sup.1 is a group ##STR00521## R.sup.2 is selected from C.sub.3-C.sub.10-cycloalkyl and C.sub.1-C.sub.6-alkyl; and R.sup.1a is selected from C.sub.3-C.sub.10-cycloalkyl, C.sub.1-C.sub.6-alkyl and halo-C.sub.1-C.sub.6-alkyl, wherein said C.sub.3-C.sub.10-cycloalkyl is optionally substituted with 1 to 2 halogen substituents.

36. The compound of formula (I) according to claim 35, or a pharmaceutically acceptable salt thereof, wherein: R.sup.1 is a group ##STR00522## R.sup.2 is selected from cyclopropyl, 1,1-dimethylpropyl, 1-ethylpropyl, sec-butyl and tert-butyl; and R.sup.1a is selected from cyclopropyl, 1-fluorocyclopropyl, 2,2-difluorocyclopropyl, isopropyl, tert-butyl, 1-fluoroethyl, CHFCl, CF.sub.3, and CHF.sub.2.

37. The compound of formula (I) according to claim 32, or a pharmaceutically acceptable salt thereof, wherein R.sup.3a is C.sub.1-C.sub.6-alkyl; R.sup.3b is hydrogen or C.sub.1-C.sub.6-alkyl; and R.sup.4a and R.sup.4b are both hydrogen; or R.sup.3a and R.sup.3b, taken together with the carbon atom to which they are attached, form a C.sub.3-C.sub.10-cycloalkyl; and R.sup.4a and R.sup.4b are both hydrogen; or R.sup.3a and R.sup.4a, taken together with the carbon atoms to which they are attached, form a C.sub.3-C.sub.10-cycloalkyl; and R.sup.3b and R.sup.4b are both hydrogen; wherein said C.sub.3-C.sub.10-cycloalkyl is optionally substituted with 1 to 2 C.sub.1-C.sub.6-alkyl substituents.

38. The compound of formula (I) according to claim 37, or a pharmaceutically acceptable salt thereof, wherein R.sup.3a and R.sup.3b are both C.sub.1-C.sub.6-alkyl; and R.sup.4a and R.sup.4b are both hydrogen; or R.sup.3a and R.sup.3b, taken together with the carbon atom to which they are attached, form a C.sub.3-C.sub.10-cycloalkyl; and R.sup.4a and R.sup.4b are both hydrogen; or R.sup.3a and R.sup.4a, taken together with the carbon atoms to which they are attached, form a C.sub.3-C.sub.10-cycloalkyl; and R.sup.3b and R.sup.4b are both hydrogen; wherein said C.sub.3-C.sub.10-cycloalkyl is optionally substituted with 2 C.sub.1-C.sub.6-alkyl substituents.

39. The compound of formula (I) according to claim 38, or a pharmaceutically acceptable salt thereof, wherein R.sup.3a and R.sup.3b are both methyl; and R.sup.4a and R.sup.4b are both hydrogen; or R.sup.3a and R.sup.3b, taken together with the carbon atom to which they are attached, form a cyclopropyl; and R.sup.4a and R.sup.4b are both hydrogen; or R.sup.3a and R.sup.4a, taken together with the carbon atoms to which they are attached, form a cyclopropyl or a cyclopentyl; and R.sup.3b and R.sup.4b are both hydrogen; wherein said cyclopropyl is substituted with 2 methyl substituents.

40. The compound of formula (I) according to claim 32, or a pharmaceutically acceptable salt thereof, wherein: L is C.sub.1-C.sub.6-alkyl; and R.sup.5 is selected from 3- to 14-membered heterocycloalkyl and 3- to 14-membered heteroaryl; wherein said 3- to 14-membered heterocycloalkyl is substituted with 1 oxo substituent.

41. The compound of formula (I) according to claim 39, or a pharmaceutically acceptable salt thereof, wherein: L is C.sub.1-C.sub.6-alkyl; and R.sup.5 is 3- to 14-membered heterocycloalkyl substituted with 1 oxo substituent.

42. The compound of formula (I) according to claim 41, or a pharmaceutically acceptable salt thereof, wherein: L is CH.sub.2; and R.sup.5 is ##STR00523##

43. The compound of formula (I) according to claim 32, or a pharmaceutically acceptable salt thereof, wherein: R.sup.6 is selected from fluoro and chloro; and R.sup.7 is selected from hydrogen and chloro.

44. The compound of formula (I) according to claim 43, or a pharmaceutically acceptable salt thereof, wherein: R.sup.6 is fluoro; and R.sup.7 is chloro.

45. The compound of formula (I) according to claim 32, or a pharmaceutically acceptable salt thereof, wherein: L is C.sub.1-C.sub.6-alkyl; L.sup.1 is selected from a covalent bond, O, NH, and ##STR00524## A is selected from C.sub.6-C.sub.14-aryl and 3- to 14-membered heteroaryl; R.sup.1 is selected from a group ##STR00525## and a group ##STR00526## and R.sup.2 is selected from hydrogen, C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-cycloalkyl-C.sub.1-C.sub.6-alkyl, (3- to 14-membered heteroaryl)-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkyl, C.sub.6-C.sub.14-aryl, C.sub.6-C.sub.14-aryl-C.sub.1-C.sub.6-alkyl, and C.sub.1-C.sub.6-alkyl-SC.sub.1-C.sub.6-alkyl, wherein said C.sub.3-C.sub.10-cycloalkyl is optionally substituted with 1 C.sub.1-C.sub.6-alkyl substituent; or R.sup.1 and R.sup.2, taken together with the carbon atom to which they are attached, form a C.sub.6-C.sub.14-aryl which is substituted with 2 substituents selected from halogen and halo-C.sub.1-C.sub.6-alkyl; R.sup.1a is selected from C.sub.3-C.sub.10-cycloalkyl, C.sub.6-C.sub.14-aryl, 3- to 14-membered heteroaryl, C.sub.1-C.sub.6-alkyl, and halo-C.sub.1-C.sub.6-alkyl, wherein said C.sub.3-C.sub.10-cycloalkyl and 3- to 14-membered heteroaryl are optionally substituted with 1 to 2 substituents selected from halogen, C.sub.1-C.sub.6-alkyl halo-C.sub.1-C.sub.6-alkyl; R.sup.2 is selected from hydrogen, C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-cycloalkyl-C.sub.1-C.sub.6-alkyl, (3- to 14-membered heteroaryl)-C.sub.1-C.sub.6-alkyl and C.sub.1-C.sub.6-alkyl, wherein said C.sub.3-C.sub.10-cycloalkyl is optionally substituted with 1 C.sub.1-C.sub.6-alkyl substituent; R.sup.3a is C.sub.1-C.sub.6-alkyl; R.sup.3b is hydrogen or C.sub.1-C.sub.6-alkyl; and R.sup.4a and R.sup.4b are both hydrogen; or R.sup.3a and R.sup.3b, taken together with the carbon atom to which they are attached, form a C.sub.3-C.sub.10-cycloalkyl; and R.sup.4a and R.sup.4b are both hydrogen; or R.sup.3a and R.sup.4a, taken together with the carbon atoms to which they are attached, form a C.sub.3-C.sub.10-cycloalkyl; and R.sup.3b and R.sup.4b are both hydrogen; wherein said C.sub.3-C.sub.10-cycloalkyl is optionally substituted with 1 to 2 C.sub.1-C.sub.6-alkyl substituents; R.sup.5 is selected from 3- to 14-membered heterocycloalkyl and 3- to 14-membered heteroaryl; wherein said 3- to 14-membered heterocycloalkyl is substituted with 1 oxo substituent; R.sup.6 is selected from fluoro and chloro; R.sup.7 is selected from hydrogen and chloro; and R.sup.8 and R.sup.9 are each independently selected from hydrogen, halogen and halo-C.sub.1-C.sub.6-alkyl.

46. The compound of formula (I) according to claim 45, or a pharmaceutically acceptable salt thereof, wherein: L is C.sub.1-C.sub.6-alkyl; R.sup.1 is a group ##STR00527## R.sup.1a is selected from C.sub.3-C.sub.10-cycloalkyl, C.sub.1-C.sub.6-alkyl and halo-C.sub.1-C.sub.6-alkyl, wherein said C.sub.3-C.sub.10-cycloalkyl is optionally substituted with 1 to 2 halogen substituents; R.sup.2 is selected from C.sub.3-C.sub.10-cycloalkyl and C.sub.1-C.sub.6-alkyl; R.sup.3a and R.sup.3b are both C.sub.1-C.sub.6-alkyl; and R.sup.4a and R.sup.4b are both hydrogen; or R.sup.3a and R.sup.3b, taken together with the carbon atom to which they are attached, form a C.sub.3-C.sub.10-cycloalkyl; and R.sup.4a and R.sup.4b are both hydrogen; or R.sup.3a and R.sup.4a, taken together with the carbon atoms to which they are attached, form a C.sub.3-C.sub.10-cycloalkyl; and R.sup.3b and R.sup.4b are both hydrogen; wherein said C.sub.3-C.sub.10-cycloalkyl is optionally substituted with 2 C.sub.1-C.sub.6-alkyl substituents; R.sup.5 is 3- to 14-membered heterocycloalkyl substituted with 1 oxo substituent; R.sup.6 is fluoro; and R.sup.7 is chloro.

47. The compound of formula (I) according to claim 45, or a pharmaceutically acceptable salt thereof, wherein: L is CH.sub.2; R.sup.1 is a group ##STR00528## R.sup.1a is selected from cyclopropyl, 1-fluorocyclopropyl, 2,2-difluorocyclopropyl, isopropyl, tert-butyl, 1-fluoroethyl, CHFCl, CF.sub.3, and CHF.sub.2; R.sup.2 is selected from cyclopropyl, 1,1-dimethylpropyl, 1-ethylpropyl, sec-butyl and tert-butyl; R.sup.3a and R.sup.3b are both methyl; and R.sup.4a and R.sup.4b are both hydrogen; or R.sup.3a and R.sup.3b, taken together with the carbon atom to which they are attached, form a cyclopropyl; and R.sup.4a and R.sup.4b are both hydrogen; or R.sup.3a and R.sup.4a, taken together with the carbon atoms to which they are attached, form a cyclopropyl or a cyclopentyl; and R.sup.3b and R.sup.4b are both hydrogen; wherein said cyclopropyl is substituted with 2 methyl substituents; R.sup.5 is ##STR00529## R.sup.6 is fluoro; and R.sup.7 is chloro.

48. The compound of formula (I) according to claim 32, or a pharmaceutically acceptable salt thereof, selected from: N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-3-methyl-butyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1S,2S,5R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-dimethyl-propanamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2-methyl-propanamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]bicyclo[1.1.1]pentane-1-carboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[but-2-ynoyl-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-acetamide; (1R,2S,5S)N-[(2R)-2-chloro-2-fluoro-acetyl]-3-[2-(3,5-difluorophenoxy)acetyl]-6,6-dimethyl-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide; N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-1-cyclopropyl-2-oxo-ethyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(2S,4R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-methyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1S,2S,5R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.2.0]heptane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(6S)-6-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-5-azaspiro[2.4]heptane-5-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-(1H-pyrazol-3-ylmethyl)amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]cyclopropanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-5-(trifluoromethyl)isoxazole-3-carboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[(2-chloroacetyl)-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxo-1-phenyl-ethyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-benzyl-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxo-ethyl]-2,2,2-trifluoro-acetamide; 3-[[(2R)-2-chloro-2-fluoro-acetyl]-[[(1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]amino]propanamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-3,3-dimethyl-butyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-3-methylsulfanyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(6S)-6-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-5-azaspiro[2.4]heptane-5-carbonyl]-2,2-dimethyl-propyl]-2-methyl-propanamide; N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-1-(1-methylcyclopropyl)-2-oxo-ethyl]-2,2,2-trifluoro-acetamide; N-[(1S)-2-[(6S)-6-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-5-azaspiro[2.4]heptan-5-yl]-1-(1-methylcyclopropyl)-2-oxo-ethyl]-2,2,2-trifluoro-acetamide; N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxo-1-(4-pyridylmethyl)ethyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-(1-bicyclo[1.1.1]pentanylmethyl)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxo-ethyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-acetamide; (3S,3aS,6aR)N-[(2R)-2-chloro-2-fluoro-acetyl]-2-[2-(3-fluorophenoxy)acetyl]-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbohydrazide; (3R,3aR,6aS)N-[(2R)-2-chloro-2-fluoro-acetyl]-2-[2-(3,5-difluorophenoxy)acetyl]-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbohydrazide; N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]cyclopropanecarboxamide; N-[(1S)-1-[(2S,4R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-(trifluoromethyl)pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]cyclopropanecarboxamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]cyclopropanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]propyl]-2,2,2-trifluoro-acetamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-propanamide; N-[(1S,2R)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide; N-[(1S)-2-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-cyclobutyl-2-oxo-ethyl]-2,2,2-trifluoro-acetamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]propanamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2-difluoro-propanamide; N-[(1S)-1-[(2S,4S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-methyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-2-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-methyl-2-oxo-ethyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]cyclopropanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]propanamide; Rac-2,2-difluoro-N-[(1S,2S)-2-methyl-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]butyl]cyclopropanecarboxamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-methyl-cyclopropanecarboxamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2-methyl-propanamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; Rac-2,2-difluoro-N-[(1S)-2,2-dimethyl-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]propyl]cyclopropanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2-methyl-propanamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2-dimethyl-propanamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-3,3,3-trifluoro-propanamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]butanamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2-fluoro-2-methyl-propanamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2-fluoro-2-methyl-propanamide; Rac-2-fluoro-N-[(1S)-2,2-dimethyl-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]propyl]propanamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-dichloro-acetamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2-dichloro-acetamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2,3,3,3-pentafluoro-propanamide; Rac-2-fluoro-N-[(1S,2S)-2-methyl-1-[rac-(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]butyl]propanamide; N-[(1S,2R)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2-difluoro-propanamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,3,3,3-pentafluoro-propanamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2,3,3,3-pentafluoro-propanamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-3,3-difluoro-cyclobutanecarboxamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-difluoro-propanamide; Rac-2-fluoro-N-[(1S,2S)-2-methyl-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]butyl]propanamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]butyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,3,3,3-pentafluoro-propanamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-methyl-propanamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide; 2,2-dichloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]acetamide; Rac-2,2-difluoro-N-[(1S,2S)-2-methyl-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]butyl]cyclopropanecarboxamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-dimethyl-propanamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-propanamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]-2,2,2-trifluoro-acetamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]benzamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-3,3-difluoro-cyclobutanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-1-fluoro-cyclobutanecarboxamide; (1S)N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-3,3-difluoro-cyclobutanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-1-fluoro-cyclopropanecarboxamide; (1S)N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1R)N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-1-fluoro-cyclobutanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-3,3-difluoro-cyclobutanecarboxamide; (1S)N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1R)N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-1-fluoro-cyclopropanecarboxamide; (1R)N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclobutanecarboxamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-3,3-difluoro-cyclobutanecarboxamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-methyl-propanamide; 2,2-difluoro-N-[rac-(1S,2S)-2-methyl-1-[rac-(1R,2S,5S)-6,6-dimethyl-2-[[[rac-(2S)-2-chloro-2-fluoro-acetyl]-[[rac-(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]butyl]cyclopropanecarboxamide; N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide; 2,2-difluoro-N-[rac-(1S,2R)-2-methyl-1-[rac-(1R,2S,5S)-6,6-dimethyl-2-[[[rac-(2R)-2-chloro-2-fluoro-acetyl]-[[rac-(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]butyl]cyclopropanecarboxamide; N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-3,3-difluoro-cyclobutanecarboxamide; N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; (2R)N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-propanamide; (2S)N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-propanamide; N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]cyclopropanecarboxamide; N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclobutanecarboxamide; N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide; N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; (2S)N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-propanamide; (2R)N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-propanamide; rac-2,2-difluoro-N-[(1S,2R)-2-methyl-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]butyl]cyclopropanecarboxamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-1-fluoro-cyclobutanecarboxamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-3,3-difluoro-cyclobutanecarboxamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide; N-[(1S,2R)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-3,3-difluoro-cyclobutanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]cyclopropanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]-3,3-difluoro-cyclobutanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]-2,2-difluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]-3,3-difluoro-cyclobutanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]cyclopropanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]-2,2-difluoro-acetamide; rac-2-fluoro-N-[(1S)-2-ethyl-1-[(2S)-4,4-dimethyl-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]pyrrolidine-1-carbonyl]butyl]propanamide; N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2-ethyl-butyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2-ethyl-butyl]-2,2-difluoro-acetamide; (2S)N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-2-fluoro-propanamide; (2R)N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-2-fluoro-propanamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]cyclopropanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-1-fluoro-cyclopropanecarboxamide; rac-2-fluoro-N-[(1S)-2,2-dimethyl-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]butyl]propanamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]cyclopropanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]-1-fluoro-cyclopropanecarboxamide; (1S)N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-cyclopropanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-acetamide; (1S)N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-cyclopropanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-acetamide; N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-butyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(2R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-1-cyclobutyl-2-oxo-ethyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S)-2-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-1-cyclobutyl-2-oxo-ethyl]-1-fluoro-cyclopropanecarboxamide; (1S)N-[(1S)-1-[(2S,4R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-(trifluoromethyl)pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)N-[(1S)-1-[(2S,4R)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-(trifluoromethyl)pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; N-[(1S,2S)-1-[(2S,4R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-(trifluoromethyl)pyrrolidine-1-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S,2S)-1-[(2S,4R)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-(trifluoromethyl)pyrrolidine-1-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-3,3-dimethyl-butyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]cyclopropanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]cyclopropanecarboxamide; N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-butyl]cyclopropanecarboxamide; N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-butyl]cyclopropanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]cyclopropanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]cyclopropanecarboxamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]cyclopropanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]cyclopropanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]cyclopropanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]-2,2-difluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]-2,2-difluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-acetamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide; (1R,2S,5S)-3-[3,5-bis(trifluoromethyl)benzoyl]-N-[(2R)-2-chloro-2-fluoro-acetyl]-6,6-dimethyl-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide; (1R,2S,5S)-3-[2-[3,5-bis(trifluoromethyl)phenyl]acetyl]-N-[(2R)-2-chloro-2-fluoro-acetyl]-6,6-dimethyl-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide; (1R,2S,5S)N-[(2R)-2-chloro-2-fluoro-acetyl]-3-[3-fluoro-5-(trifluoromethyl)benzoyl]-6,6-dimethyl-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide; (1R,2S,5S)-3-[(E)-3-[3,5-bis(trifluoromethyl)phenyl]prop-2-enoyl]-N-[(2R)-2-chloro-2-fluoro-acetyl]-6,6-dimethyl-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide; (1R,2S,5S)N-[(2R)-2-chloro-2-fluoro-acetyl]-3-[(E)-3-(3,5-difluorophenyl)prop-2-enoyl]-6,6-dimethyl-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide; (3S,3aS,6aR)N-[(2R)-2-chloro-2-fluoro-acetyl]-2-[(2S)-2-[(6-fluoropyrimidin-4-yl)amino]-3,3-dimethyl-butanoyl]-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbohydrazide; (3S,3aS,6aR)N-[(2R)-2-chloro-2-fluoro-acetyl]-2-[(2S)-2-[(5-fluoropyrimidin-4-yl)amino]-3,3-dimethyl-butanoyl]-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbohydrazide; (3S,3aS,6aR)N-[(2R)-2-chloro-2-fluoro-acetyl]-2-[(2S)-3,3-dimethyl-2-(2-pyridylamino)butanoyl]-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbohydrazide; (2R)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide; (2S)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide; (2S)-2-chloro-N-[(1S,2S)-1-[(2S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide; (2R)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide; (2S)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide; (2R)N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2-chloro-2-fluoro-acetamide; (2S)N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2-chloro-2-fluoro-acetamide; (2R)N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2-chloro-2-fluoro-acetamide; (2S)N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2-chloro-2-fluoro-acetamide; (2R)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide; (2S)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide; (1S)N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; and (1S)N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide.

49. The compound of formula (I) according to claim 48, or a pharmaceutically acceptable salt thereof, selected from: N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-1-cyclopropyl-2-oxo-ethyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(6S)-6-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-5-azaspiro[2.4]heptane-5-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-dimethyl-propanamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2-methyl-propanamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-acetamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide; N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide; (1S)N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1R)N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide; N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide; N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; (2S)N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-propanamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]-2,2-difluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]-2,2-difluoro-acetamide; (2S)N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-2-fluoro-propanamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]cyclopropanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-acetamide; (1S)N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-cyclopropanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-acetamide; (2R)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide; (2S)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide; (2S)-2-chloro-N-[(1S,2S)-1-[(2S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide; (2R)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide; (2S)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide; (2R)N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2-chloro-2-fluoro-acetamide; and (2S)N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2-chloro-2-fluoro-acetamide.

50. A process of manufacturing a compound of formula (I) according to claim 32, or a pharmaceutically acceptable salt thereof, comprising: (a) reacting a compound of formula (XI) ##STR00530## wherein R.sup.1a, R.sup.2, R.sup.3a, R.sup.3b, R.sup.4a, R.sup.4b, R.sup.5, and L are as defined in claim 1; with a compound of formula (XI-1), ##STR00531## wherein R.sup.6 and R.sup.7 are as defined in claim 1 and LG.sub.2 is a leaving group; in the presence of a coupling reagent and a base; to form a compound of formula (I-a) ##STR00532## wherein R.sup.1a, R.sup.2, R.sup.3a, R.sup.3b, R.sup.4a, R.sup.4b, R.sup.5, R.sup.6, R.sup.7, and L are as defined in claim 1; or (b) reacting a compound of formula (XXIII) ##STR00533## wherein R.sup.1, R.sup.3a, R.sup.3b, R.sup.4a, R.sup.4b, R.sup.5, and L are as defined in claim 1; with a compound of formula (XI-1), ##STR00534## wherein R.sup.6 and R.sup.7 are as defined in claim 1 and LG.sub.2 is a leaving group; in the presence of a coupling reagent and a base; to form a compound of formula (I-b) ##STR00535## wherein R.sup.1, R.sup.3a, R.sup.3b, R.sup.4a, R.sup.4b, R.sup.5, R.sup.6, R.sup.7, and L are as defined in claim 1.

51. A compound of formula (XI), or a salt thereof, ##STR00536## wherein R.sup.1a, R.sup.2, R.sup.3a, R.sup.3b, R.sup.4a, R.sup.4b, R.sup.5, and L are as defined in claim 1.

52. A compound of formula (XXIII), or a salt thereof, ##STR00537## wherein R.sup.1, R.sup.3a, R.sup.3b, R.sup.4a, R.sup.4b, R.sup.5, and L are as defined in claim 1.

53. A pharmaceutical composition comprising a compound of formula (I) according to claim 32, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

54. A method of treatment or prophylaxis of coronavirus infections, said method comprising administering a therapeutically active amount of a compound of formula (I) according to claim 32 or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

55. A method of inhibiting the enzymatic activity of 3C-like proteases, said method comprising contacting a 3C-like protease with a compound of formula (I) according to claim 32, or a pharmaceutically acceptable salt thereof.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0015] FIG. 1 shows the crystal structure of example 165a as assessed by single crystal X-ray diffraction.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

[0016] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein, unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

[0017] The term alkyl refers to a mono- or multivalent, e.g., a mono- or bivalent, linear or branched saturated hydrocarbon group of 1 to 6 carbon atoms (C.sub.1-6-alkyl), e.g., 1, 2, 3, 4, 5, or 6 carbon atoms. In other embodiments, the alkyl group contains 1 to 3 carbon atoms, e.g., 1, 2 or 3 carbon atoms. Some non-limiting examples of alkyl include methyl, ethyl, propyl, 2-propyl (isopropyl), n-butyl, iso-butyl, sec-butyl, tert-butyl, and 2,2-dimethylpropyl. Particularly preferred, yet non-limiting examples of alkyl are methyl, tert-butyl, and 2,2-dimethylpropyl.

[0018] The term halogen or halo refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I). Preferably, the term halogen or halo refers to fluoro (F), chloro (Cl) or bromo (Br). Particularly preferred, yet non-limiting examples of halogen or halo are fluoro (F) and chloro (Cl).

[0019] The term cycloalkyl as used herein refers to a saturated or partly unsaturated monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms (C.sub.3-10-cycloalkyl). In some preferred embodiments, the cycloalkyl group is a saturated monocyclic hydrocarbon group of 3 to 8 ring carbon atoms. Bicyclic cycloalkyl refers to cycloalkyl moieties consisting of two saturated carbocycles having two carbon atoms in common, i.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms, and to spirocyclic moieties, i.e., the two rings are connected via one common ring atom. Preferably, the cycloalkyl group is a saturated monocyclic hydrocarbon group of 3 to 6 ring carbon atoms, e.g., of 3, 4, 5 or 6 carbon atoms. Some non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-bicyclo[1.1.1]pentanyl, norbornanyl, and 1-bicyclo[2.2.2]octanyl. A particularly preferred, yet non-limiting example of cycloalkyl is cyclopropyl.

[0020] The term cycloalkylalkyl refers to a cycloalkyl group that is bound to the parent molecule via an alkylene group. A particularly preferred, yet non-limiting example of cycloalkylalkyl is 1-bicyclo[1.1.1]pentanylmethyl.

[0021] The term alkylcycloalkyl refers to a cycloalkyl group, wherein at least one of the hydrogen atoms of the cycloalkyl group has been replaced by an alkyl group. Preferably, alkylcycloalkyl refers to a cycloalkyl group wherein 1, 2 or 3 hydrogen atoms of the cycloalkyl group have been replaced by an alkyl group. A particularly preferred, yet non-limiting example of alkylcycloalkyl is a cycloalkyl group wherein 1 of the hydrogen atoms of the cycloalkyl group have been replaced by an alkyl group, such as 1-methylcyclopropyl.

[0022] The term aryl refers to a monocyclic, bicyclic, or tricyclic carbocyclic ring system having a total of 6 to 14 ring members (C.sub.6-C.sub.14-aryl), preferably, 6 to 12 ring members, and more preferably 6 to 10 ring members, and wherein at least one ring in the system is aromatic. Some non-limiting examples of aryl include phenyl and 9H-fluorenyl (e.g. 9H-fluoren-9-yl). A particularly preferred, yet non-limiting example of aryl is phenyl.

[0023] The term arylalkyl refers to an aryl group that is bound to the parent molecule via an alkylene group. A particularly preferred, yet non-limiting example of arylalkyl is benzyl.

[0024] The term aryloxy refers to an aryl group that is bound to the parent molecule via an oxygen atom. A non-limiting example of aryloxy is phenoxy.

[0025] The term heteroaryl refers to a mono- or multivalent, monocyclic, bicyclic or tricyclic, preferably bicyclic ring system having a total of 5 to 14 ring members, preferably, 5 to 12 ring members, and more preferably 5 to 10 ring members, wherein at least one ring in the system is aromatic, and at least one ring in the system contains one or more heteroatoms. Preferably, heteroaryl refers to a 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. Most preferably, heteroaryl refers to a 5-10 membered heteroaryl comprising 1 to 2 heteroatoms independently selected from O, S and N. Some non-limiting examples of heteroaryl include spiro[cyclopropane-1,3-indoline](e.g., spiro[cyclopropane-1,3-indoline]-1-yl), 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazin-2-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl, indol-1-yl, 1H-indol-2-yl, 1H-indol-3-yl, 1H-indol-4-yl, 1H-indol-5-yl, 1H-indol-6-yl, 1H-indol-7-yl, 1,2-benzoxazol-3-yl, 1,2-benzoxazol-4-yl, 1,2-benzoxazol-5-yl, 1,2-benzoxazol-6-yl, 1,2-benzoxazol-7-yl, 1H-indazol-3-yl, 1H-indazol-4-yl, 1H-indazol-5-yl, 1H-indazol-6-yl, 1H-indazol-7-yl, pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, pyridazin-3-yl, pyridazin-4-yl, 1,2,4-triazol-4-yl, 1,2,4-triazol-1-yl, 4H-1,2,4-triazol-3-yl, 4,5,6,7-tetrahydroindazol-2-yl, 6,7-dihydro-4H-pyrano[4,3-c]pyrazol-2-yl, thiazolyl, benzofurazan-4-yl, tetrazolyl, isoxazolyl, and morpholinyl. Particularly preferred, yet non-limiting examples of heteroaryl are pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl and triazolyl.

[0026] The term heteroarylalkyl refers to a heteroaryl group that is bound to the parent molecule via an alkylene group. A particularly preferred, yet non-limiting example of heteroarylalkyl is pyridylmethyl.

[0027] The term heterocyclyl or heterocycloalkyl refers to a saturated or partly unsaturated mono- or bicyclic, preferably monocyclic ring system of 3 to 14 ring atoms, preferably 3 to 10 ring atoms, more preferably 3 to 8 ring atoms, wherein 1, 2, or 3 of said ring atoms are heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Preferably, 1 to 2 of said ring atoms are selected from N and O, the remaining ring atoms being carbon. Bicyclic heterocyclyl refers to heterocyclic moieties consisting of two cycles having two ring atoms in common, i.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms, and to spirocyclic moieties, i.e., the two rings are connected via one common ring atom. Some non-limiting examples of heterocyclyl groups include azetidinyl, pyrrolidinyl, oxetanyl, 5-azaspiro[2.5]octan-5-yl, piperidyl, 3,3a,4,5,6,6a-hexahydro-TH-cyclopenta[c]pyrrol-2-yl, 2-azaspiro[3.3]heptan-2-yl, 2,6-diazaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonan-2-yl, 1,2-dihydropyridiynl, piperidyl, pyrrolidinyl, and thietanyl.

[0028] The term haloalkyl refers to an alkyl group, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a halogen atom, preferably fluoro. Preferably, haloalkyl refers to an alkyl group wherein 1, 2 or 3 hydrogen atoms of the alkyl group have been replaced by a halogen atom, most preferably fluoro. Particularly preferred, yet non-limiting examples of haloalkyl are trifluoromethyl, difluoromethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl.

[0029] The term oxo refers to a double bonded oxygen (O).

[0030] The term carbamoyl refers to a group H.sub.2NC(O).

[0031] The term acyl refers to a group CH.sub.3C(O).

[0032] The term pharmaceutically acceptable salt refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, in particular hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcystein and the like. In addition these salts may be prepared by addition of an inorganic base or an organic base to the free acid. Salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium salts and the like. Salts derived from organic bases include, but are not limited to salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins and the like.

[0033] The compounds of formula (I) can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereioisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.

[0034] According to the Cahn-Ingold-Prelog Convention, the asymmetric carbon atom can be of the R or S configuration.

[0035] The term treatment as used herein includes: (1) inhibiting the state, disorder or condition (e.g. arresting, reducing or delaying the development of the disease, or a relapse thereof in case of maintenance treatment, of at least one clinical or subclinical symptom thereof); and/or (2) relieving the condition (i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms). The benefit to a patient to be treated is either statistically significant or at least perceptible to the patient or to the physician. However, it will be appreciated that when a medicament is administered to a patient to treat a disease, the outcome may not always be effective treatment.

[0036] The term prophylaxis as used herein includes: preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a mammal and especially a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition.

Compounds of the Invention

[0037] In a first aspect, the present invention provides a compound of Formula (I)

##STR00003## [0038] or a pharmaceutically acceptable salt thereof, wherein: [0039] L is C.sub.1-C.sub.6-alkyl; [0040] L.sup.1 is selected from a covalent bond, O, NH, and

##STR00004## [0041] A is selected from C.sub.6-C.sub.14-aryl and 3- to 14-membered heteroaryl; [0042] R.sup.1 is selected from a group

##STR00005##

and a group

##STR00006##

and [0043] R.sup.2 is selected from hydrogen, C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-cycloalkyl-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkyl-C.sub.3-C.sub.10-cycloalkyl, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkyl-SC.sub.1-C.sub.6-alkyl, 3- to 14-membered heteroaryl, (3- to 14-membered heteroaryl)-C.sub.1-C.sub.6-alkyl, C.sub.6-C.sub.14-aryl, and C.sub.6-C.sub.14-aryl-C.sub.1-C.sub.6-alkyl, wherein said C.sub.3-C.sub.10-cycloalkyl is optionally substituted with 1 C.sub.1-C.sub.6-alkyl substituent; or [0044] R.sup.1 and R.sup.2, taken together with the carbon atom to which they are attached, form a 3- to 14-membered heteroaryl or a C.sub.6-C.sub.14-aryl, wherein said 3- to 14-membered heteroaryl or C.sub.6-C.sub.14-aryl is optionally substituted with 1 to 2 substituents selected from halogen and halo-C.sub.1-C.sub.6-alkyl; [0045] R.sup.1a is selected from C.sub.3-C.sub.10-cycloalkyl, C.sub.6-C.sub.14-aryl, 3- to 14-membered heteroaryl, C.sub.1-C.sub.6-alkyl, and halo-C.sub.1-C.sub.6-alkyl, wherein said C.sub.3-C.sub.10-cycloalkyl and 3- to 14-membered heteroaryl are optionally substituted with 1 to 2 substituents selected from halogen, C.sub.1-C.sub.6-alkyl and halo-C.sub.1-C.sub.6-alkyl; [0046] R.sup.3a, R.sup.3b, R.sup.4a, and R.sup.4b are each independently selected from hydrogen, halogen, C.sub.1-C.sub.6-alkyl, and halo-C.sub.1-C.sub.6-alkyl; or [0047] R.sup.3a and R.sup.3b, taken together with the carbon atom to which they are attached, form a C.sub.3-C.sub.10-cycloalkyl; and R.sup.4a and R.sup.4b are each independently selected from hydrogen and C.sub.1-C.sub.6-alkyl; wherein said C.sub.3-C.sub.10-cycloalkyl is optionally substituted with 1 to 2 C.sub.1-C.sub.6-alkyl substituents; or [0048] R.sup.4a and R.sup.4b, taken together with the carbon atom to which they are attached, form a C.sub.3-C.sub.10-cycloalkyl; and R.sup.3a and R.sup.3b are each independently selected from hydrogen and C.sub.1-C.sub.6-alkyl; wherein said C.sub.3-C.sub.10-cycloalkyl is optionally substituted with 1 to 2 C.sub.1-C.sub.6-alkyl substituents; or [0049] R.sup.3a and R.sup.4a, taken together with the carbon atoms to which they are attached, form a C.sub.3-C.sub.10-cycloalkyl; and R.sup.3b and R.sup.4b are each independently selected from hydrogen and C.sub.1-C.sub.6-alkyl; wherein said C.sub.3-C.sub.10-cycloalkyl is optionally substituted with 1 to 2 C.sub.1-C.sub.6-alkyl substituents; [0050] R.sup.5 is selected from 3- to 14-membered heterocycloalkyl, 3- to 14-membered heteroaryl, carbamoyl, and C.sub.1-C.sub.6-alkyl-NHC(O); wherein said 3- to 14-membered heterocycloalkyl is optionally substituted with 1 oxo substituent; [0051] R.sup.6 is selected from fluoro and chloro; [0052] R.sup.7 is selected from hydrogen, chloro, and acyl; and [0053] R.sup.8 and R.sup.9 are each independently selected from hydrogen, halogen and halo-C.sub.1-C.sub.6-alkyl.

[0054] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: [0055] L is C.sub.1-C.sub.6-alkyl; [0056] R.sup.1 is selected from a group

##STR00007##

C.sub.6-C.sub.14-aryloxy, and a 3- to 14-membered heteroaryl; wherein said C.sub.6-C.sub.14-aryloxy and said 3- to 14-membered heteroaryl are optionally substituted with 1 to 2 substituents selected from halogen and halo-C.sub.1-C.sub.6-alkyl; and [0057] R.sup.2 is selected from hydrogen, C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-cycloalkyl-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkyl-C.sub.3-C.sub.10-cycloalkyl, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkyl-SC.sub.1-C.sub.6-alkyl, 3- to 14-membered heteroaryl, (3- to 14-membered heteroaryl)-C.sub.1-C.sub.6-alkyl, C.sub.6-C.sub.14-aryl, and C.sub.6-C.sub.14-aryl-C.sub.1-C.sub.6-alkyl, wherein said C.sub.3-C.sub.10-cycloalkyl is optionally substituted with 1 C.sub.1-C.sub.6-alkyl substituent; or [0058] R.sup.1 and R.sup.2, taken together with the carbon atom to which they are attached, form a 3- to 14-membered heteroaryl, wherein said 3- to 14-membered heteroaryl is optionally substituted with 1 halo-C.sub.1-C.sub.6-alkyl substituent; [0059] R.sup.1a is selected from C.sub.3-C.sub.10-cycloalkyl, C.sub.6-C.sub.14-aryl, 3- to 14-membered heteroaryl, C.sub.1-C.sub.6-alkyl, and halo-C.sub.1-C.sub.6-alkyl, wherein said C.sub.3-C.sub.10-cycloalkyl and 3- to 14-membered heteroaryl are optionally substituted with 1 to 2 substituents selected from halogen, C.sub.1-C.sub.6-alkyl and halo-C.sub.1-C.sub.6-alkyl; [0060] R.sup.3a, R.sup.3b, R.sup.4a, and R.sup.4b are each independently selected from hydrogen, halogen, C.sub.1-C.sub.6-alkyl, and halo-C.sub.1-C.sub.6-alkyl; or [0061] R.sup.3a and R.sup.3b, taken together with the carbon atom to which they are attached, form a C.sub.3-C.sub.10-cycloalkyl; and R.sup.4a and R.sup.4b are each independently selected from hydrogen and C.sub.1-C.sub.6-alkyl; wherein said C.sub.3-C.sub.10-cycloalkyl is optionally substituted with 1 to 2 C.sub.1-C.sub.6-alkyl substituents; or [0062] R.sup.4a and R.sup.4b, taken together with the carbon atom to which they are attached, form a C.sub.3-C.sub.10-cycloalkyl; and R.sup.3a and R.sup.3b are each independently selected from hydrogen and C.sub.1-C.sub.6-alkyl; wherein said C.sub.3-C.sub.10-cycloalkyl is optionally substituted with 1 to 2 C.sub.1-C.sub.6-alkyl substituents; or [0063] R.sup.3a and R.sup.4a, taken together with the carbon atoms to which they are attached, form a C.sub.3-C.sub.10-cycloalkyl; and R.sup.3b and R.sup.4b are each independently selected from hydrogen and C.sub.1-C.sub.6-alkyl; wherein said C.sub.3-C.sub.10-cycloalkyl is optionally substituted with 1 to 2 C.sub.1-C.sub.6-alkyl substituents; [0064] R.sup.5 is selected from 3- to 14-membered heterocycloalkyl, 3- to 14-membered heteroaryl, carbamoyl, and C.sub.1-C.sub.6-alkyl-NHC(O); wherein said 3- to 14-membered heterocycloalkyl is optionally substituted with 1 oxo substituent; [0065] R.sup.6 is selected from fluoro and chloro; and [0066] R.sup.7 is selected from hydrogen, chloro, and acyl.

[0067] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: [0068] L is C.sub.1-C.sub.6-alkyl; [0069] R.sup.1 is selected from a group

##STR00008##

C.sub.6-C.sub.14-aryloxy, and a 3- to 14-membered heteroaryl; wherein said C.sub.6-C.sub.14-aryloxy and said 3- to 14-membered heteroaryl are optionally substituted with 1 to 2 substituents selected from halogen and halo-C.sub.1-C.sub.6-alkyl; and [0070] R.sup.2 is selected from hydrogen, C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-cycloalkyl-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkyl-C.sub.3-C.sub.10-cycloalkyl, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkyl-SC.sub.1-C.sub.6-alkyl, 3- to 14-membered heteroaryl, (3- to 14-membered heteroaryl)-C.sub.1-C.sub.6-alkyl, C.sub.6-C.sub.14-aryl, and C.sub.6-C.sub.14-aryl-C.sub.1-C.sub.6-alkyl; or [0071] R.sup.1 and R.sup.2, taken together with the carbon atom to which they are attached, form a 3- to 14-membered heteroaryl, wherein said 3- to 14-membered heteroaryl is optionally substituted with 1 halo-C.sub.1-C.sub.6-alkyl substituent; [0072] R.sup.1a is selected from C.sub.3-C.sub.10-cycloalkyl, 3- to 14-membered heteroaryl, C.sub.1-C.sub.6-alkyl, and halo-C.sub.1-C.sub.6-alkyl, wherein said C.sub.3-C.sub.10-cycloalkyl and 3- to 14-membered heteroaryl are optionally substituted with 1 halo-C.sub.1-C.sub.6-alkyl substituent; [0073] R.sup.3a, R.sup.3b, R.sup.4a, and R.sup.4b are each independently selected from hydrogen, halogen, C.sub.1-C.sub.6-alkyl, and halo-C.sub.1-C.sub.6-alkyl; or [0074] R.sup.3a and R.sup.3b, taken together with the carbon atom to which they are attached, form a C.sub.3-C.sub.10-cycloalkyl; and R.sup.4a and R.sup.4b are each independently selected from hydrogen and C.sub.1-C.sub.6-alkyl; wherein said C.sub.3-C.sub.10-cycloalkyl is optionally substituted with 1 to 2 C.sub.1-C.sub.6-alkyl substituents; or [0075] R.sup.4a and R.sup.4b, taken together with the carbon atom to which they are attached, form a C.sub.3-C.sub.10-cycloalkyl; and R.sup.3a and R.sup.3b are each independently selected from hydrogen and C.sub.1-C.sub.6-alkyl; wherein said C.sub.3-C.sub.10-cycloalkyl is optionally substituted with 1 to 2 C.sub.1-C.sub.6-alkyl substituents; or [0076] R.sup.3a and R.sup.4a, taken together with the carbon atoms to which they are attached, form a C.sub.3-C.sub.10-cycloalkyl; and R.sup.3b and R.sup.4b are each independently selected from hydrogen and C.sub.1-C.sub.6-alkyl; wherein said C.sub.3-C.sub.10-cycloalkyl is optionally substituted with 1 to 2 C.sub.1-C.sub.6-alkyl substituents; [0077] R.sup.5 is selected from 3- to 14-membered heterocycloalkyl, 3- to 14-membered heteroaryl, carbamoyl, and C.sub.1-C.sub.6-alkyl-NHC(O); wherein said 3- to 14-membered heterocycloalkyl is optionally substituted with 1 oxo substituent; [0078] R.sup.6 is selected from fluoro and chloro; and [0079] R.sup.7 is selected from hydrogen, chloro, and acyl.

[0080] In one embodiment, the compound of formula (I) of the present invention is a compound of formula (II)

##STR00009## [0081] or a pharmaceutically acceptable salt thereof, wherein all variables are as defined herein.

[0082] In one embodiment, the compound of formula (I) of the present invention is a compound of formula (III)

##STR00010## [0083] or a pharmaceutically acceptable salt thereof, wherein all variables are as defined herein.

[0084] In one embodiment, the compound of formula (I) of the present invention is a compound of formula (IV)

##STR00011## [0085] or a pharmaceutically acceptable salt thereof, wherein all variables are as defined herein.

[0086] In one embodiment, the compound of formula (I) of the present invention is a compound of formula (V)

##STR00012## [0087] or a pharmaceutically acceptable salt thereof, wherein all variables are as defined herein.

[0088] In one embodiment, the compound of formula (I) of the present invention is a compound of formula (VI)

##STR00013## [0089] or a pharmaceutically acceptable salt thereof, wherein all variables are as defined herein.

[0090] In one embodiment, the compound of formula (I) of the present invention is a compound of formula (VII)

##STR00014## [0091] or a pharmaceutically acceptable salt thereof, wherein all variables are as defined herein.

[0092] In one embodiment, the compound of formula (I) of the present invention is a compound of formula (VIII)

##STR00015## [0093] or a pharmaceutically acceptable salt thereof, wherein all variables are as defined herein.

[0094] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: [0095] L.sup.1 is selected from a covalent bond, O, NH, and

##STR00016## [0096] A is selected from C.sub.6-C.sub.14-aryl and 3- to 14-membered heteroaryl; [0097] R.sup.1 is selected from a group

##STR00017##

and a group

##STR00018##

and [0098] R.sup.2 is selected from hydrogen, C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-cycloalkyl-C.sub.1-C.sub.6-alkyl, (3- to 14-membered heteroaryl)-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkyl, C.sub.6-C.sub.14-aryl, C.sub.6-C.sub.14-aryl-C.sub.1-C.sub.6-alkyl, and C.sub.1-C.sub.6-alkyl-SC.sub.1-C.sub.6-alkyl, wherein said C.sub.3-C.sub.10-cycloalkyl is optionally substituted with 1 C.sub.1-C.sub.6-alkyl substituent; or [0099] R.sup.1 and R.sup.2, taken together with the carbon atom to which they are attached, form a C.sub.6-C.sub.14-aryl which is substituted with 2 substituents selected from halogen and halo-C.sub.1-C.sub.6-alkyl; [0100] R.sup.1a is selected from C.sub.3-C.sub.10-cycloalkyl, C.sub.6-C.sub.14-aryl, 3- to 14-membered heteroaryl, C.sub.1-C.sub.6-alkyl, and halo-C.sub.1-C.sub.6-alkyl, wherein said C.sub.3-C.sub.10-cycloalkyl and 3- to 14-membered heteroaryl are optionally substituted with 1 to 2 substituents selected from halogen, C.sub.1-C.sub.6-alkyl and halo-C.sub.1-C.sub.6-alkyl; and [0101] R.sup.8 and R.sup.9 are each independently selected from hydrogen, halogen and halo-C.sub.1-C.sub.6-alkyl.

[0102] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: [0103] L.sup.1 is selected from a covalent bond, O, NH, and

##STR00019## [0104] A is selected from phenyl, pyridyl, pyrimidinyl; [0105] R.sup.1 is selected from a group

##STR00020##

and a group

##STR00021##

and [0106] R.sup.2 is selected from hydrogen, cyclopropyl, 1-methylcyclopropyl, cyclobutyl, 1-bicyclo[1.1.1]pentanylmethyl, methyl, ethyl, propyl, sec-butyl, tert-butyl, isobutyl, 1-ethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 2-methylsulfanylethyl, phenyl, benzyl, and pyridylmethyl; or [0107] R.sup.1 and R.sup.2, taken together with the carbon atom to which they are attached, form a phenyl, which is substituted with 2 substituents selected from fluoro and CF.sub.3; [0108] R.sup.1a is selected from bicyclo[1.1.1]pentanyl, cyclopropyl, 1-fluorocyclopropyl, 2,2-difluorocyclopropyl, 1-methylclopropyl, 1-fluorocyclobutyl, 3,3-difluorocyclobutyl, cyclobutyl, phenyl, isoxazolyl, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, CHFCl, CHCl.sub.2, CHF.sub.2, CF.sub.3, 1-fluoro-1-methyl-ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1-fluoroethyl, and 1,1,2,2,2-pentachloroethyl; and [0109] R.sup.8 and R.sup.9 are each independently selected from hydrogen, fluoro and CF.sub.3.

[0110] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: bond to A [0111] L.sup.1 is selected from a covalent bond, O, NH, and

##STR00022## [0112] A is selected from phenyl, pyridyl, pyrimidinyl; [0113] R.sup.1 is selected from a group

##STR00023##

and a group

##STR00024##

and [0114] R.sup.2 is selected from hydrogen, cyclopropyl, 1-methylcyclopropyl, cyclobutyl, 1-bicyclo[1.1.1]pentanylmethyl, methyl, ethyl, propyl, sec-butyl, tert-butyl, isobutyl, 1-ethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 2-methylsulfanylethyl, phenyl, benzyl, and pyridylmethyl; or [0115] R.sup.1 and R.sup.2, taken together with the carbon atom to which they are attached, form a phenyl, which is substituted with 2 substituents selected from fluoro and CF.sub.3; [0116] R.sup.1a is selected from bicyclo[1.1.1]pentanyl, cyclopropyl, 1-fluorocyclopropyl, 2,2-difluorocyclopropyl, 1-methylclopropyl, 1-fluorocyclobutyl, 3,3-difluorocyclobutyl, phenyl, isoxazolyl, methyl, ethyl, propyl, isopropyl, tert-butyl, CHFCl, CHCl.sub.2, CHF.sub.2, CF.sub.3, 1-fluoro-1-methyl-ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1-fluoroethyl, and 1,1,2,2,2-pentachloroethyl; and [0117] R.sup.8 and R.sup.9 are each independently selected from hydrogen, fluoro and CF.sub.3.

[0118] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: [0119] R.sup.1 is a group

##STR00025## [0120] R.sup.2 is selected from C.sub.3-C.sub.10-cycloalkyl and C.sub.1-C.sub.6-alkyl; and [0121] R.sup.1a is selected from C.sub.3-C.sub.10-cycloalkyl, C.sub.1-C.sub.6-alkyl and halo-C.sub.1-C.sub.6-alkyl, wherein said C.sub.3-C.sub.10-cycloalkyl is optionally substituted with 1 to 2 halogen substituents.

[0122] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: [0123] R.sup.1 is a group

##STR00026## [0124] R.sup.2 is selected from cyclopropyl, 1,1-dimethylpropyl, 1-ethylpropyl, sec-butyl and tert-butyl; and [0125] R.sup.1a is selected from cyclopropyl, 1-fluorocyclopropyl, 2,2-difluorocyclopropyl, isopropyl, tert-butyl, 1-fluoroethyl, CHFCl, CF.sub.3, and CHF.sub.2.

[0126] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R.sup.1 is a group

##STR00027##

[0127] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: [0128] R.sup.1 is selected from a group

##STR00028##

and C.sub.6-C.sub.14-aryloxy substituted with 1 to 2 halogen substituents; and [0129] R.sup.1a is selected from C.sub.3-C.sub.10-cycloalkyl, C.sub.6-C.sub.14-aryl, 3- to 14-membered heteroaryl, C.sub.1-C.sub.6-alkyl, and halo-C.sub.1-C.sub.6-alkyl, wherein said C.sub.3-C.sub.10-cycloalkyl and 3- to 14-membered heteroaryl are optionally substituted with 1 to 2 substituents selected from halogen, C.sub.1-C.sub.6-alkyl and halo-C.sub.1-C.sub.6-alkyl.

[0130] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: [0131] R.sup.1 is a group

##STR00029##

and [0132] R.sup.1a is selected from C.sub.3-C.sub.10-cycloalkyl, 3- to 14-membered heteroaryl, C.sub.1-C.sub.6-alkyl, and halo-C.sub.1-C.sub.6-alkyl, wherein said 3- to 14-membered heteroaryl is substituted with 1 halo-C.sub.1-C.sub.6-alkyl substituent.

[0133] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: [0134] R.sup.1 is a group

##STR00030##

and [0135] R.sup.1a is selected from C.sub.3-C.sub.10-cycloalkyl, C.sub.1-C.sub.6-alkyl and halo-C.sub.1-C.sub.6-alkyl, wherein said C.sub.3-C.sub.10-cycloalkyl is substituted with 1-2 halogen substituents.

[0136] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: [0137] R.sup.1 is a group

##STR00031##

and [0138] R.sup.1a is selected from C.sub.3-C.sub.10-cycloalkyl, C.sub.1-C.sub.6-alkyl and halo-C.sub.1-C.sub.6-alkyl, wherein said C.sub.3-C.sub.10-cycloalkyl is substituted with 1 halogen substituent.

[0139] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: [0140] R.sup.1 is a group

##STR00032##

and [0141] R.sup.1a is selected from C.sub.1-C.sub.6-alkyl and halo-C.sub.1-C.sub.6-alkyl.

[0142] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: [0143] R.sup.1 is a group

##STR00033##

and [0144] R.sup.1a is selected from 2,2-difluorocyclopropyl, 1-fluorocyclopropyl, isopropyl, tert-butyl, CF.sub.3, and CHF.sub.2.

[0145] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: [0146] R.sup.1 is a group

##STR00034##

and [0147] R.sup.1a is selected from 1-fluorocyclopropyl, isopropyl, tert-butyl, CF.sub.3, and CHF.sub.2.

[0148] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: [0149] R.sup.1 is a group

##STR00035##

and [0150] R.sup.1a is selected from isopropyl, tert-butyl, CF.sub.3, and CHF.sub.2.

[0151] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein [0152] R.sup.1 is a group

##STR00036##

and [0153] R.sup.1a is halo-C.sub.1-C.sub.6-alkyl.

[0154] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein [0155] R.sup.1 is a group

##STR00037##

and [0156] R.sup.1a is selected from CHF.sub.2 and CF.sub.3.

[0157] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein [0158] R.sup.1 is a group

##STR00038##

and [0159] R.sup.1a is CF.sub.3.

[0160] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein [0161] R.sup.1 is a group

##STR00039##

and [0162] R.sup.1a is CHF.sub.2.

[0163] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: [0164] R.sup.1 is a group

##STR00040##

and [0165] R.sup.1a is C.sub.3-C.sub.10-cycloalkyl, wherein said C.sub.3-C.sub.10-cycloalkyl is substituted with 1-2 halogen substituents.

[0166] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: [0167] R.sup.1 is a group

##STR00041##

and [0168] R.sup.1a is selected from 2,2-difluorocyclopropyl and 1-fluorocyclopropyl.

[0169] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: [0170] R.sup.1 is a group

##STR00042##

and [0171] R.sup.1a is 2,2-difluorocyclopropyl.

[0172] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: [0173] R.sup.1 is a group

##STR00043##

and [0174] R.sup.1a is 1-fluorocyclopropyl.

[0175] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is selected from hydrogen, C.sub.3-C.sub.10-cycloalkyl, and C.sub.1-C.sub.6-alkyl.

[0176] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is selected from hydrogen, C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-cycloalkyl-C.sub.1-C.sub.6-alkyl, (3- to 14-membered heteroaryl)-C.sub.1-C.sub.6-alkyl and C.sub.1-C.sub.6-alkyl, wherein said C.sub.3-C.sub.10-cycloalkyl is optionally substituted with 1 C.sub.1-C.sub.6-alkyl substituent.

[0177] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is selected from C.sub.3-C.sub.10-cycloalkyl and C.sub.1-C.sub.6-alkyl.

[0178] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is selected from cyclopropyl and tert-butyl.

[0179] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is selected from cyclopropyl, sec-butyl and tert-butyl. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is C.sub.1-C.sub.6-alkyl.

[0180] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is tert-butyl.

[0181] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein [0182] R.sup.3a is C.sub.1-C.sub.6-alkyl; R.sup.3b is hydrogen or C.sub.1-C.sub.6-alkyl; and R.sup.4a and R.sup.4b are both hydrogen; or [0183] R.sup.3a and R.sup.3b, taken together with the carbon atom to which they are attached, form a C.sub.3-C.sub.10-cycloalkyl; and R.sup.4a and R.sup.4b are both hydrogen; or [0184] R.sup.3a and R.sup.4a, taken together with the carbon atoms to which they are attached, form a C.sub.3-C.sub.10-cycloalkyl; and R.sup.3b and R.sup.4b are both hydrogen; wherein said C.sub.3-C.sub.10-cycloalkyl is optionally substituted with 1 to 2 C.sub.1-C.sub.6-alkyl substituents.

[0185] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein [0186] R.sup.3a and R.sup.3b are both C.sub.1-C.sub.6-alkyl; and R.sup.4a and R.sup.4b are both hydrogen; or [0187] R.sup.3a and R.sup.3b, taken together with the carbon atom to which they are attached, form a C.sub.3-C.sub.10-cycloalkyl; and R.sup.4a and R.sup.4b are both hydrogen; or [0188] R.sup.3a and R.sup.4a, taken together with the carbon atoms to which they are attached, form a C.sub.3-C.sub.10-cycloalkyl; and R.sup.3b and R.sup.4b are both hydrogen; wherein said C.sub.3-C.sub.10-cycloalkyl is optionally substituted with 2 C.sub.1-C.sub.6-alkyl substituents.

[0189] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: [0190] R.sup.3a and R.sup.4a, taken together with the carbon atoms to which they are attached, form a C.sub.3-C.sub.10-cycloalkyl; and R.sup.3b and R.sup.4b are both hydrogen; wherein said C.sub.3-C.sub.10-cycloalkyl is optionally substituted with 2 C.sub.1-C.sub.6-alkyl substituents.

[0191] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein [0192] R.sup.3a and R.sup.3b are both methyl; and R.sup.4a and R.sup.4b are both hydrogen; or [0193] R.sup.3a and R.sup.3b, taken together with the carbon atom to which they are attached, form a cyclopropyl; and R.sup.4a and R.sup.4b are both hydrogen; or [0194] R.sup.3a and R.sup.4a, taken together with the carbon atoms to which they are attached, form a cyclopropyl or a cyclopentyl; and R.sup.3b and R.sup.4b are both hydrogen; wherein said cyclopropyl is substituted with 2 methyl substituents.

[0195] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein [0196] R.sup.3a and R.sup.4a, taken together with the carbon atoms to which they are attached, form a cyclopropyl or a cyclopentyl; and R.sup.3b and R.sup.4b are both hydrogen; wherein said cyclopropyl is substituted with 2 methyl substituents.

[0197] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the group

##STR00044##

is selected from

##STR00045##

[0198] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the group

##STR00046##

[0199] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the group

##STR00047##

[0200] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the group

##STR00048##

[0201] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the group

##STR00049##

[0202] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein L is C.sub.1-C.sub.3-alkyl.

[0203] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein L is CH.sub.2 or CH.sub.2CH.sub.2.

[0204] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein L is CH.sub.2.

[0205] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: [0206] L is C.sub.1-C.sub.6-alkyl; and [0207] R.sup.5 is selected from 3- to 14-membered heterocycloalkyl and 3- to 14-membered heteroaryl; wherein said 3- to 14-membered heterocycloalkyl is substituted with 1 oxo substituent.

[0208] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: [0209] L is C.sub.1-C.sub.6-alkyl; and [0210] R.sup.5 is 3- to 14-membered heterocycloalkyl substituted with 1 oxo substituent.

[0211] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: [0212] L is CH.sub.2; and [0213] R.sup.5 is pyrrolidinyl substituted with 1 oxo substituent.

[0214] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R.sup.5 is a 3- to 9-membered heterocycloalkyl substituted with 1 oxo substituent.

[0215] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R.sup.5 is a 3- to 8-membered heterocycloalkyl substituted with 1 oxo substituent.

[0216] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R.sup.5 is a 3- to 7-membered heterocycloalkyl substituted with 1 oxo substituent.

[0217] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R.sup.5 is a 3- to 6-membered heterocycloalkyl substituted with 1 oxo substituent.

[0218] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R.sup.5 is a 4- to 6-membered heterocycloalkyl substituted with 1 oxo substituent.

[0219] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R.sup.5 is a 5- to 6-membered heterocycloalkyl substituted with 1 oxo substituent.

[0220] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R.sup.5 is selected from pyrrolidinyl and piperidyl, each of which is substituted with 1 oxo substituent.

[0221] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R.sup.5 is pyrrolidinyl substituted with 1 oxo substituent.

[0222] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R.sup.5 is piperidyl substituted with 1 oxo substituent.

[0223] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R.sup.5 is

##STR00050##

[0224] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R.sup.5 is

##STR00051##

[0225] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R.sup.5 is

##STR00052##

[0226] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R.sup.5 is

##STR00053##

[0227] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: [0228] R.sup.6 is selected from fluoro and chloro; and [0229] R.sup.7 is selected from hydrogen and chloro.

[0230] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: [0231] R.sup.6 is fluoro; and [0232] R.sup.7 is chloro.

[0233] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: [0234] L is C.sub.1-C.sub.6-alkyl; [0235] R.sup.1 is selected from a group

##STR00054##

and C.sub.6-C.sub.14-aryloxy substituted with 1 to 2 halogen substituents; [0236] R.sup.1a is selected from C.sub.3-C.sub.10-cycloalkyl, C.sub.6-C.sub.14-aryl, 3- to 14-membered heteroaryl, C.sub.1-C.sub.6-alkyl, and halo-C.sub.1-C.sub.6-alkyl, wherein said C.sub.3-C.sub.10-cycloalkyl and 3- to 14-membered heteroaryl are optionally substituted with 1 to 2 substituents selected from halogen, C.sub.1-C.sub.6-alkyl halo-C.sub.1-C.sub.6-alkyl; [0237] R.sup.2 is selected from hydrogen, C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-cycloalkyl-C.sub.1-C.sub.6-alkyl, (3- to 14-membered heteroaryl)-C.sub.1-C.sub.6-alkyl and C.sub.1-C.sub.6-alkyl, wherein said C.sub.3-C.sub.10-cycloalkyl is optionally substituted with 1 C.sub.1-C.sub.6-alkyl substituent; [0238] R.sup.3a is C.sub.1-C.sub.6-alkyl; R.sup.3b is hydrogen or C.sub.1-C.sub.6-alkyl; and R.sup.4a and R.sup.4b are both hydrogen; or [0239] R.sup.3a and R.sup.3b, taken together with the carbon atom to which they are attached, form a C.sub.3-C.sub.10-cycloalkyl; and R.sup.4a and R.sup.4b are both hydrogen; or [0240] R.sup.3a and R.sup.4a, taken together with the carbon atoms to which they are attached, form a C.sub.3-C.sub.10-cycloalkyl; and R.sup.3b and R.sup.4b are both hydrogen; wherein said C.sub.3-C.sub.10-cycloalkyl is optionally substituted with 1 to 2 C.sub.1-C.sub.6-alkyl substituents; [0241] R.sup.5 is selected from 3- to 14-membered heterocycloalkyl and 3- to 14-membered heteroaryl; wherein said 3- to 14-membered heterocycloalkyl is substituted with 1 oxo substituent; [0242] R.sup.6 is selected from fluoro and chloro; and [0243] R.sup.7 is selected from hydrogen and chloro.

[0244] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: [0245] L is C.sub.1-C.sub.6-alkyl; [0246] R.sup.1 is a group

##STR00055## [0247] R.sup.1a is selected from C.sub.3-C.sub.10-cycloalkyl, C.sub.1-C.sub.6-alkyl and halo-C.sub.1-C.sub.6-alkyl, wherein said C.sub.3-C.sub.10-cycloalkyl is substituted with 1 halogen substituent; [0248] R.sup.2 is selected from C.sub.3-C.sub.10-cycloalkyl and C.sub.1-C.sub.6-alkyl; [0249] R.sup.3a and R.sup.3b are both C.sub.1-C.sub.6-alkyl; and R.sup.4a and R.sup.4b are both hydrogen; or [0250] R.sup.3a and R.sup.3b, taken together with the carbon atom to which they are attached, form a C.sub.3-C.sub.10-cycloalkyl; and R.sup.4a and R.sup.4b are both hydrogen; or [0251] R.sup.3a and R.sup.4a, taken together with the carbon atoms to which they are attached, form a C.sub.3-C.sub.10-cycloalkyl; and R.sup.3b and R.sup.4b are both hydrogen; wherein said C.sub.3-C.sub.10-cycloalkyl is optionally substituted with 2 C.sub.1-C.sub.6-alkyl substituents; [0252] R.sup.5 is 3- to 14-membered heterocycloalkyl substituted with 1 oxo substituent; [0253] R.sup.6 is fluoro; and [0254] R.sup.7 is chloro.

[0255] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: [0256] L is CH.sub.2; [0257] R.sup.1 is a group

##STR00056## [0258] R.sup.1a is selected from 1-fluorocyclopropyl, isopropyl, tert-butyl, CF.sub.3, and CHF.sub.2; [0259] R.sup.2 is selected from cyclopropyl, sec-butyl and tert-butyl; [0260] R.sup.3a and R.sup.3b are both methyl; and R.sup.4a and R.sup.4b are both hydrogen; or [0261] R.sup.3a and R.sup.3b, taken together with the carbon atom to which they are attached, form a cyclopropyl; and R.sup.4a and R.sup.4b are both hydrogen; or [0262] R.sup.3a and R.sup.4a, taken together with the carbon atoms to which they are attached, form a cyclopropyl or a cyclopentyl; and R.sup.3b and R.sup.4b are both hydrogen; wherein said cyclopropyl is substituted with 2 methyl substituents; [0263] R.sup.5 is pyrrolidinyl substituted with 1 oxo substituent; [0264] R.sup.6 is fluoro; and [0265] R.sup.7 is chloro.

[0266] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: [0267] L is C.sub.1-C.sub.6-alkyl; [0268] R.sup.1 is a group

##STR00057## [0269] R.sup.1a is selected from C.sub.3-C.sub.10-cycloalkyl, 3- to 14-membered heteroaryl, C.sub.1-C.sub.6-alkyl, and halo-C.sub.1-C.sub.6-alkyl, wherein said 3- to 14-membered heteroaryl is substituted with 1 halo-C.sub.1-C.sub.6-alkyl substituent; [0270] R.sup.2 is selected from hydrogen, C.sub.3-C.sub.10-cycloalkyl, and C.sub.1-C.sub.6-alkyl; [0271] R.sup.3a is C.sub.1-C.sub.6-alkyl; R.sup.3b is hydrogen or C.sub.1-C.sub.6-alkyl; and R.sup.4a and R.sup.4b are both hydrogen; or [0272] R.sup.3a and R.sup.3b, taken together with the carbon atom to which they are attached, form a C.sub.3-C.sub.10-cycloalkyl; and R.sup.4a and R.sup.4b are both hydrogen; or [0273] R.sup.3a and R.sup.4a, taken together with the carbon atoms to which they are attached, form a C.sub.3-C.sub.10-cycloalkyl; and R.sup.3b and R.sup.4b are both hydrogen; wherein said C.sub.3-C.sub.10-cycloalkyl is optionally substituted with 1 to 2 C.sub.1-C.sub.6-alkyl substituents; [0274] R.sup.5 is selected from 3- to 14-membered heterocycloalkyl and 3- to 14-membered heteroaryl; wherein said 3- to 14-membered heterocycloalkyl is substituted with 1 oxo substituent; [0275] R.sup.6 is selected from fluoro and chloro; and [0276] R.sup.7 is selected from hydrogen and chloro.

[0277] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: [0278] L is C.sub.1-C.sub.6-alkyl; [0279] R.sup.1 is a group

##STR00058## [0280] R.sup.1a is selected from C.sub.1-C.sub.6-alkyl and halo-C.sub.1-C.sub.6-alkyl; [0281] R.sup.2 is selected from C.sub.3-C.sub.10-cycloalkyl and C.sub.1-C.sub.6-alkyl; [0282] R.sup.3a and R.sup.3b are both C.sub.1-C.sub.6-alkyl; and R.sup.4a and R.sup.4b are both hydrogen; or [0283] R.sup.3a and R.sup.3b, taken together with the carbon atom to which they are attached, form a C.sub.3-C.sub.10-cycloalkyl; and R.sup.4a and R.sup.4b are both hydrogen; or [0284] R.sup.3a and R.sup.4a, taken together with the carbon atoms to which they are attached, form a C.sub.3-C.sub.10-cycloalkyl; and R.sup.3b and R.sup.4b are both hydrogen; wherein said C.sub.3-C.sub.10-cycloalkyl is optionally substituted with 2 C.sub.1-C.sub.6-alkyl substituents; [0285] R.sup.5 is 3- to 14-membered heterocycloalkyl substituted with 1 oxo substituent; [0286] R.sup.6 is fluoro; and [0287] R.sup.7 is chloro.

[0288] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: [0289] L is CH.sub.2; [0290] R.sup.1 is a group

##STR00059## [0291] R.sup.1a is selected from isopropyl, tert-butyl, CF.sub.3, and CHF.sub.2; [0292] R.sup.2 is selected from cyclopropyl and tert-butyl; [0293] R.sup.3a and R.sup.3b are both methyl; and R.sup.4a and R.sup.4b are both hydrogen; or [0294] R.sup.3a and R.sup.3b, taken together with the carbon atom to which they are attached, form a cyclopropyl; and R.sup.4a and R.sup.4b are both hydrogen; or [0295] R.sup.3a and R.sup.4a, taken together with the carbon atoms to which they are attached, form a cyclopropyl or a cyclopentyl; and R.sup.3b and R.sup.4b are both hydrogen; wherein said cyclopropyl is substituted with 2 methyl substituents; [0296] R.sup.5 is pyrrolidinyl substituted with 1 oxo substituent; [0297] R.sup.6 is fluoro; and [0298] R.sup.7 is chloro.

[0299] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, selected from: [0300] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; [0301] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-3-methyl-butyl]-2,2,2-trifluoro-acetamide; [0302] N-[(1S)-1-[(1S,2S,5R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; [0303] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-dimethyl-propanamide; [0304] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2-methyl-propanamide; [0305] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]bicyclo[1.1.1]pentane-1-carboxamide; [0306] N-[(1S)-1-[(1R,2S,5S)-2-[[but-2-ynoyl-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; [0307] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-acetamide; [0308] (1R,2S,5S)N-[(2R)-2-chloro-2-fluoro-acetyl]-3-[2-(3,5-difluorophenoxy)acetyl]-6,6-dimethyl-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide; [0309] N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-1-cyclopropyl-2-oxo-ethyl]-2,2,2-trifluoro-acetamide; [0310] N-[(1S)-1-[(2S,4R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-methyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; [0311] N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; [0312] N-[(1S)-1-[(1S,2S,5R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.2.0]heptane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; [0313] N-[(1S)-1-[(6S)-6-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-5-azaspiro[2.4]heptane-5-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; [0314] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-(1H-pyrazol-3-ylmethyl)amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; [0315] N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; [0316] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]cyclopropanecarboxamide; [0317] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-5-(trifluoromethyl)isoxazole-3-carboxamide; [0318] N-[(1S)-1-[(1R,2S,5S)-2-[[(2-chloroacetyl)-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; [0319] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; [0320] N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxo-1-phenyl-ethyl]-2,2,2-trifluoro-acetamide; [0321] N-[(1S)-1-benzyl-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxo-ethyl]-2,2,2-trifluoro-acetamide; [0322] 3-[[(2R)-2-chloro-2-fluoro-acetyl]-[[(1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]amino]propanamide; [0323] N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide; [0324] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-3,3-dimethyl-butyl]-2,2,2-trifluoro-acetamide; [0325] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-3-methylsulfanyl-propyl]-2,2,2-trifluoro-acetamide; [0326] N-[(1S)-1-[(6S)-6-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-5-azaspiro[2.4]heptane-5-carbonyl]-2,2-dimethyl-propyl]-2-methyl-propanamide; [0327] N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-1-(1-methylcyclopropyl)-2-oxo-ethyl]-2,2,2-trifluoro-acetamide; [0328] N-[(1S)-2-[(6S)-6-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-5-azaspiro[2.4]heptan-5-yl]-1-(1-methylcyclopropyl)-2-oxo-ethyl]-2,2,2-trifluoro-acetamide; [0329] N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxo-1-(4-pyridylmethyl)ethyl]-2,2,2-trifluoro-acetamide; [0330] N-[(1S)-1-(1-bicyclo[1.1.1]pentanylmethyl)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxo-ethyl]-2,2,2-trifluoro-acetamide; [0331] N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-acetamide; [0332] (3S,3aS,6aR)N-[(2R)-2-chloro-2-fluoro-acetyl]-2-[2-(3-fluorophenoxy)acetyl]-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbohydrazide; [0333] (3R,3aR,6aS)N-[(2R)-2-chloro-2-fluoro-acetyl]-2-[2-(3,5-difluorophenoxy)acetyl]-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbohydrazide; [0334] N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide; [0335] N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]cyclopropanecarboxamide; [0336] N-[(1S)-1-[(2S,4R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-(trifluoromethyl)pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; [0337] N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]cyclopropanecarboxamide; [0338] N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]cyclopropanecarboxamide; [0339] N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]propyl]-2,2,2-trifluoro-acetamide; [0340] N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]acetamide; [0341] N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]acetamide; [0342] N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-propanamide; [0343] N-[(1S,2R)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide; [0344] N-[(1S)-2-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-cyclobutyl-2-oxo-ethyl]-2,2,2-trifluoro-acetamide; [0345] N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]propanamide; [0346] N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide; [0347] N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2-difluoro-propanamide; [0348] N-[(1S)-1-[(2S,4S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-methyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; [0349] N-[(1S)-2-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-methyl-2-oxo-ethyl]-2,2,2-trifluoro-acetamide; [0350] N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]cyclopropanecarboxamide; [0351] N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]propanamide; [0352] Rac-2,2-difluoro-N-[(1S,2S)-2-methyl-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]butyl]cyclopropanecarboxamide; [0353] N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-methyl-cyclopropanecarboxamide; [0354] N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide; [0355] N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2-methyl-propanamide; [0356] N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; [0357] Rac-2,2-difluoro-N-[(1S)-2,2-dimethyl-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]propyl]cyclopropanecarboxamide; [0358] N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2-methyl-propanamide; [0359] N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2-dimethyl-propanamide; [0360] N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-3,3,3-trifluoro-propanamide; [0361] N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]butanamide; [0362] N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2-fluoro-2-methyl-propanamide; [0363] N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2-fluoro-2-methyl-propanamide; [0364] Rac-2-fluoro-N-[(1S)-2,2-dimethyl-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]propyl]propanamide; [0365] N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-dichloro-acetamide; [0366] N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2-dichloro-acetamide; [0367] N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2,3,3,3-pentafluoro-propanamide; [0368] Rac-2-fluoro-N-[(1S,2S)-2-methyl-1-[rac-(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]butyl]propanamide; [0369] N-[(1S,2R)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-TH-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2-difluoro-propanamide; [0370] N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,3,3,3-pentafluoro-propanamide; [0371] N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-TH-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]-2,2,2-trifluoro-acetamide; [0372] N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2,3,3,3-pentafluoro-propanamide; [0373] N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-3,3-difluoro-cyclobutanecarboxamide; [0374] N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-difluoro-propanamide; [0375] Rac-2-fluoro-N-[(1S,2S)-2-methyl-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]butyl]propanamide; [0376] N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]butyl]-2,2,2-trifluoro-acetamide; [0377] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,3,3,3-pentafluoro-propanamide; [0378] N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-methyl-propanamide; [0379] N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide; [0380] 2,2-dichloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]acetamide; [0381] Rac-2,2-difluoro-N-[(1S,2S)-2-methyl-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]butyl]cyclopropanecarboxamide; [0382] N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-dimethyl-propanamide; [0383] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-propanamide; [0384] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-2,2,2-trifluoro-acetamide; [0385] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]-2,2,2-trifluoro-acetamide; [0386] N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]benzamide; [0387] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-1-fluoro-cyclopropanecarboxamide; [0388] N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-1-fluoro-cyclopropanecarboxamide; [0389] N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; [0390] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-3,3-difluoro-cyclobutanecarboxamide; [0391] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-1-fluoro-cyclobutanecarboxamide; [0392] (1S)N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; [0393] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-3,3-difluoro-cyclobutanecarboxamide; [0394] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-1-fluoro-cyclopropanecarboxamide; [0395] (1S)N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; [0396] (1R)N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; [0397] N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-1-fluoro-cyclobutanecarboxamide; [0398] N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-3,3-difluoro-cyclobutanecarboxamide; [0399] (1S)N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; [0400] (1R)N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; [0401] (1S)N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; [0402] N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; [0403] N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-1-fluoro-cyclopropanecarboxamide; [0404] (1R)N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; [0405] N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclobutanecarboxamide; [0406] N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; [0407] N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide; [0408] N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-3,3-difluoro-cyclobutanecarboxamide; [0409] N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide; [0410] N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-methyl-propanamide; [0411] 2,2-difluoro-N-[rac-(1S,2S)-2-methyl-1-[rac-(1R,2S,5S)-6,6-dimethyl-2-[[[rac-(2S)-2-chloro-2-fluoro-acetyl]-[[rac-(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]butyl]cyclopropanecarboxamide; [0412] N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide; [0413] 2,2-difluoro-N-[rac-(1S,2R)-2-methyl-1-[rac-(1R,2S,5S)-6,6-dimethyl-2-[[[rac-(2R)-2-chloro-2-fluoro-acetyl]-[[rac-(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]butyl]cyclopropanecarboxamide; [0414] N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-3,3-difluoro-cyclobutanecarboxamide; [0415] N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; [0416] (2R)N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-propanamide; [0417] (2S)N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-propanamide; [0418] N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]cyclopropanecarboxamide; [0419] N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclobutanecarboxamide; [0420] N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide; [0421] N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; [0422] (2S)N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-propanamide; [0423] (2R)N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-propanamide; [0424] rac-2,2-difluoro-N-[(1S,2R)-2-methyl-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]butyl]cyclopropanecarboxamide; [0425] N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-1-fluoro-cyclobutanecarboxamide; [0426] N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-3,3-difluoro-cyclobutanecarboxamide; [0427] N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide; [0428] N-[(1S,2R)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-3,3-difluoro-cyclobutanecarboxamide; [0429] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]cyclopropanecarboxamide; [0430] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]-3,3-difluoro-cyclobutanecarboxamide; [0431] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]-2,2-difluoro-acetamide; [0432] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]-1-fluoro-cyclopropanecarboxamide; [0433] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]-1-fluoro-cyclopropanecarboxamide; [0434] N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]-3,3-difluoro-cyclobutanecarboxamide; [0435] N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]cyclopropanecarboxamide; [0436] N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]-2,2-difluoro-acetamide; [0437] rac-2-fluoro-N-[(1S)-2-ethyl-1-[(2S)-4,4-dimethyl-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]pyrrolidine-1-carbonyl]butyl]propanamide; [0438] N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2-ethyl-butyl]-1-fluoro-cyclopropanecarboxamide; [0439] N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2-ethyl-butyl]-2,2-difluoro-acetamide; [0440] (2S)N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-2-fluoro-propanamide; [0441] (2R)N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-2-fluoro-propanamide; [0442] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]cyclopropanecarboxamide; [0443] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-1-fluoro-cyclopropanecarboxamide; [0444] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-acetamide; [0445] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-1-fluoro-cyclopropanecarboxamide; [0446] rac-2-fluoro-N-[(1S)-2,2-dimethyl-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]butyl]propanamide; [0447] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]cyclopropanecarboxamide; [0448] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-acetamide; [0449] N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]-1-fluoro-cyclopropanecarboxamide; [0450] (1S)N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-cyclopropanecarboxamide; [0451] N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-acetamide; [0452] (1S)N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-cyclopropanecarboxamide; [0453] N-[(1S)-1-[(3S,3aS,6aR)-3-[I[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-acetamide; [0454] N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-butyl]-1-fluoro-cyclopropanecarboxamide; [0455] N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; [0456] N-[(1S)-1-[(2R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; [0457] N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-1-cyclobutyl-2-oxo-ethyl]-1-fluoro-cyclopropanecarboxamide; [0458] N-[(1S)-2-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-1-cyclobutyl-2-oxo-ethyl]-1-fluoro-cyclopropanecarboxamide; [0459] (1S)N-[(1S)-1-[(2S,4R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-(trifluoromethyl)pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; [0460] (1S)N-[(1S)-1-[(2S,4R)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-(trifluoromethyl)pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; [0461] N-[(1S,2S)-1-[(2S,4R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-(trifluoromethyl)pyrrolidine-1-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; [0462] N-[(1S,2S)-1-[(2S,4R)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-(trifluoromethyl)pyrrolidine-1-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; [0463] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-3,3-dimethyl-butyl]-1-fluoro-cyclopropanecarboxamide; [0464] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; [0465] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; [0466] N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; [0467] N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; [0468] N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide; [0469] N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide; [0470] N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; [0471] N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; [0472] N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]cyclopropanecarboxamide; [0473] N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]cyclopropanecarboxamide; [0474] N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-butyl]cyclopropanecarboxamide; [0475] N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-butyl]cyclopropanecarboxamide; [0476] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]cyclopropanecarboxamide; [0477] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]cyclopropanecarboxamide; [0478] N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; [0479] N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; [0480] N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]cyclopropanecarboxamide; [0481] N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]cyclopropanecarboxamide; [0482] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]cyclopropanecarboxamide; [0483] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]-2,2-difluoro-acetamide; [0484] N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]-2,2-difluoro-acetamide; [0485] N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-acetamide; [0486] N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide; [0487] (1R,2S,5S)-3-[3,5-bis(trifluoromethyl)benzoyl]-N-[(2R)-2-chloro-2-fluoro-acetyl]-6,6-dimethyl-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide; [0488] (1R,2S,5S)-3-[2-[3,5-bis(trifluoromethyl)phenyl]acetyl]-N-[(2R)-2-chloro-2-fluoro-acetyl]-6,6-dimethyl-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide; [0489] (1R,2S,5S)N-[(2R)-2-chloro-2-fluoro-acetyl]-3-[3-fluoro-5-(trifluoromethyl)benzoyl]-6,6-dimethyl-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide; [0490] (1R,2S,5S)-3-[(E)-3-[3,5-bis(trifluoromethyl)phenyl]prop-2-enoyl]-N-[(2R)-2-chloro-2-fluoro-acetyl]-6,6-dimethyl-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide; [0491] (1R,2S,5S)N-[(2R)-2-chloro-2-fluoro-acetyl]-3-[(E)-3-(3,5-difluorophenyl)prop-2-enoyl]-6,6-dimethyl-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide; [0492] (3S,3aS,6aR)N-[(2R)-2-chloro-2-fluoro-acetyl]-2-[(2S)-2-[(6-fluoropyrimidin-4-yl)amino]-3,3-dimethyl-butanoyl]-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbohydrazide; [0493] (3S,3aS,6aR)N-[(2R)-2-chloro-2-fluoro-acetyl]-2-[(2S)-2-[(5-fluoropyrimidin-4-yl)amino]-3,3-dimethyl-butanoyl]-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbohydrazide; [0494] (3S,3aS,6aR)N-[(2R)-2-chloro-2-fluoro-acetyl]-2-[(2S)-3,3-dimethyl-2-(2-pyridylamino)butanoyl]-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbohydrazide; [0495] (2R)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide; [0496] (2S)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide; and [0497] (2S)-2-chloro-N-[(1S,2S)-1-[(2S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide.

[0498] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, selected from: [0499] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2-methyl-propanamide; [0500] N-[(1S)-1-[(6S)-6-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-5-azaspiro[2.4]heptane-5-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; [0501] N-[(1S)-1-[(1S,2S,5R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.2.0]heptane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; [0502] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; [0503] N-[(1S)-1-[(2S,4R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-methyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; [0504] N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; [0505] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-3-methyl-butyl]-2,2,2-trifluoro-acetamide; [0506] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-dimethyl-propanamide; [0507] N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-1-cyclopropyl-2-oxo-ethyl]-2,2,2-trifluoro-acetamide; [0508] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]bicyclo[1.1.1]pentane-1-carboxamide; [0509] N-[(1S)-1-[(1S,2S,5R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; [0510] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-(1H-pyrazol-3-ylmethyl)amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; [0511] N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; [0512] (1R,2S,5S)N-[(2R)-2-chloro-2-fluoro-acetyl]-3-[2-(3,5-difluorophenoxy)acetyl]-6,6-dimethyl-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide; [0513] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-acetamide; [0514] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]cyclopropanecarboxamide; [0515] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-5-(trifluoromethyl)isoxazole-3-carboxamide; [0516] 3-[[(2R)-2-chloro-2-fluoro-acetyl]-[[(1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]amino]propanamide; [0517] 3-[[(2R)-2-chloro-2-fluoro-acetyl]-[[(1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]amino]-N-methyl-propanamide; [0518] 3-[[(2R)-2-chloro-2-fluoro-acetyl]-[[(1R,2S,5S)-3-[(2S)-2-[(2,2-difluoroacetyl)amino]-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]amino]propanamide; [0519] 3-[[(2R)-2-chloro-2-fluoro-acetyl]-[[(1R,2S,5S)-3-[(2S)-2-[(2,2-difluoroacetyl)amino]-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]amino]-N-methyl-propanamide; [0520] N-[(1S)-1-[(1R,2S,5S)-2-[[(2-chloroacetyl)-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; [0521] 3-[(2-chloroacetyl)-[[(1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]amino]propanamide; [0522] 2,2,2-trifluoro-N-[(1S)-1-[(1R,2S,5S)-2-[[(2-fluoroacetyl)-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]acetamide; [0523] 3-[[[(1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-(2-fluoroacetyl)amino]propanamide; [0524] N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxo-1-phenyl-ethyl]-2,2,2-trifluoro-acetamide; [0525] N-[(1S)-1-benzyl-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxo-ethyl]-2,2,2-trifluoro-acetamide; [0526] N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide; [0527] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-3-methylsulfanyl-propyl]-2,2,2-trifluoro-acetamide; [0528] N-[(1S)-1-[(1R,2S,5S)-2-[[(2-chloro-3-oxo-butanoyl)-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; [0529] N-[(1S)-1-[(2S)-2-[[(2-chloro-2-fluoro-acetyl)-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; [0530] N-[(1S)-1-[(4S)-4-[[(2-chloro-2-fluoro-acetyl)-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-5-azaspiro[2.4]heptane-5-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; [0531] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; [0532] N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-1-(1-methylcyclopropyl)-2-oxo-ethyl]-2,2,2-trifluoro-acetamide; [0533] N-[(1S)-1-[(6S)-6-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-5-azaspiro[2.4]heptane-5-carbonyl]-2,2-dimethyl-propyl]-2-methyl-propanamide; [0534] N-[(1S)-2-[(6S)-6-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-5-azaspiro[2.4]heptan-5-yl]-1-(1-methylcyclopropyl)-2-oxo-ethyl]-2,2,2-trifluoro-acetamide; [0535] N-[(1S)-2-[(6S)-6-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-5-azaspiro[2.4]heptan-5-yl]-1-(1-methylcyclopropyl)-2-oxo-ethyl]-2,2-difluoro-acetamide; [0536] N-[(1S)-1-(1-bicyclo[1.1.1]pentanylmethyl)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxo-ethyl]-2,2,2-trifluoro-acetamide; [0537] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-3,3-dimethyl-butyl]-2,2,2-trifluoro-acetamide; [0538] N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxo-1-(4-pyridylmethyl)ethyl]-2,2,2-trifluoro-acetamide; [0539] N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-difluoro-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; [0540] N-[(1S)-1-(1-bicyclo[1.1.1]pentanyl)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxo-ethyl]-2,2,2-trifluoro-acetamide; [0541] (1R,2S,5S)N-[(2R)-2-chloro-2-fluoro-acetyl]-6,6-dimethyl-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-[3-(trifluoromethyl)isoxazole-5-carbonyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide; [0542] N-[(1S)-1-[(2S,3S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-methyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; [0543] N-[(1S)-1-[(2S,3S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-(trifluoromethyl)pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; and [0544] N-[(1S)-1-[(2S,4R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-(trifluoromethyl)pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide.

[0545] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, selected from: [0546] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2-methyl-propanamide; [0547] N-[(1S)-1-[(6S)-6-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-5-azaspiro[2.4]heptane-5-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; [0548] N-[(1S)-1-[(1S,2S,5R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.2.0]heptane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; [0549] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; [0550] N-[(1S)-1-[(2S,4R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-methyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; [0551] N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; [0552] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-3-methyl-butyl]-2,2,2-trifluoro-acetamide; [0553] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-dimethyl-propanamide; [0554] N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-1-cyclopropyl-2-oxo-ethyl]-2,2,2-trifluoro-acetamide; [0555] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]bicyclo[1.1.1]pentane-1-carboxamide; [0556] N-[(1S)-1-[(1S,2S,5R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; [0557] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-(1H-pyrazol-3-ylmethyl)amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; [0558] N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; [0559] (1R,2S,5S)N-[(2R)-2-chloro-2-fluoro-acetyl]-3-[2-(3,5-difluorophenoxy)acetyl]-6,6-dimethyl-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide; [0560] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-acetamide; [0561] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]cyclopropanecarboxamide; [0562] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-5-(trifluoromethyl)isoxazole-3-carboxamide; and [0563] N-[(1S)-1-[(1R,2S,5S)-2-[[(2-chloroacetyl)-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide. [0564] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, selected from: [0565] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2-methyl-propanamide; [0566] N-[(1S)-1-[(6S)-6-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-5-azaspiro[2.4]heptane-5-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; [0567] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; [0568] N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; [0569] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-dimethyl-propanamide; [0570] N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-1-cyclopropyl-2-oxo-ethyl]-2,2,2-trifluoro-acetamide; [0571] N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-TH-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; [0572] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-acetamide; [0573] N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide; [0574] N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide; [0575] N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide; [0576] N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; [0577] (2R)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide; [0578] (2S)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide; [0579] (2R)N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2-chloro-2-fluoro-acetamide; [0580] (2S)N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2-chloro-2-fluoro-acetamide; [0581] (2R)N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2-chloro-2-fluoro-acetamide; [0582] (2S)N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2-chloro-2-fluoro-acetamide; [0583] (2R)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide; [0584] (2S)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide; [0585] (1S)N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; and [0586] (1S)N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide.

[0587] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, selected from: [0588] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; [0589] N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-1-cyclopropyl-2-oxo-ethyl]-2,2,2-trifluoro-acetamide; [0590] N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; [0591] N-[(1S)-1-[(6S)-6-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-5-azaspiro[2.4]heptane-5-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; [0592] N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; [0593] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-dimethyl-propanamide; [0594] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2-methyl-propanamide; [0595] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-acetamide; [0596] N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide; [0597] N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; [0598] N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide; [0599] N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide; [0600] (1S)N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; [0601] (1R)N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; [0602] N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide; [0603] N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide; [0604] N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; [0605] (2S)N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-propanamide; [0606] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]-2,2-difluoro-acetamide; [0607] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]-1-fluoro-cyclopropanecarboxamide; [0608] N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]-2,2-difluoro-acetamide; [0609] (2S)N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-2-fluoro-propanamide; [0610] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]cyclopropanecarboxamide; [0611] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-1-fluoro-cyclopropanecarboxamide; [0612] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-acetamide; [0613] N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-acetamide; [0614] (1S)N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-cyclopropanecarboxamide; [0615] (1S)N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-cyclopropanecarboxamide; [0616] N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-acetamide; [0617] (2R)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide; [0618] (2S)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide; [0619] (2S)-2-chloro-N-[(1S,2S)-1-[(2S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide; [0620] (2R)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide; [0621] (2S)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide; [0622] (2R)N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2-chloro-2-fluoro-acetamide; and [0623] (2S)N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2-chloro-2-fluoro-acetamide.

[0624] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound is N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2-methyl-propanamide.

[0625] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound is N-[(1S)-1-[(6S)-6-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-5-azaspiro[2.4]heptane-5-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide.

[0626] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound is N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide.

[0627] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound is N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide.

[0628] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound is N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-dimethyl-propanamide.

[0629] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound is N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-1-cyclopropyl-2-oxo-ethyl]-2,2,2-trifluoro-acetamide.

[0630] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound is N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide.

[0631] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound is N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-acetamide.

[0632] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound is N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide.

[0633] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound is N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide.

[0634] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound is N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide.

[0635] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound is N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide.

[0636] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound is (2R)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide.

[0637] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound is (2S)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide.

[0638] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound is (2R)N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-TH-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2-chloro-2-fluoro-acetamide.

[0639] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound is (2S)N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-TH-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2-chloro-2-fluoro-acetamide.

[0640] In a particular embodiment, the present invention provides pharmaceutically acceptable salts of the compounds according to formula (I) as described herein. In a further particular embodiment, the present invention provides compounds according to formula (I) as described herein in their free form (i.e., as free bases or acids).

[0641] In some embodiments, the compounds of formula (I) are isotopically-labeled by having one or more atoms therein replaced by an atom having a different atomic mass or mass number. Such isotopically-labeled (i.e., radiolabeled) compounds of formula (I) are considered to be within the scope of this disclosure. Examples of isotopes that can be incorporated into the compounds of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, and iodine, such as, but not limited to, .sup.2H, .sup.3H, .sup.11C, .sup.13C, .sup.14C, .sup.13N, .sup.15N, .sup.15O, .sup.17O, .sup.18O, .sup.31P, .sup.32P, .sup.35S, .sup.18F, .sup.36Cl, .sup.123I, and .sup.125I, respectively. Certain isotopically-labeled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. .sup.3H, and carbon-14, i.e., .sup.14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. For example, a compound of formula (I) can be enriched with 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99 percent of a given isotope.

[0642] Substitution with heavier isotopes such as deuterium, i.e. .sup.2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

[0643] Substitution with positron emitting isotopes, such as .sup.11C, .sup.18F, .sup.15O and .sup.13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples as set out below using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.

Processes of Manufacturing

[0644] The preparation of compounds of formula (I) of the present invention may be carried out in sequential or convergent synthetic routes. Syntheses of the invention are shown in the following general schemes. The skills required for carrying out the reaction and purification of the resulting products are known to those persons skilled in the art. The substituents and indices used in the following description of the processes have the significance given herein, unless indicated to the contrary.

[0645] If one of the starting materials, intermediates or compounds of formula (I) contain one or more functional groups which are not stable or are reactive under the reaction conditions of one or more reaction steps, appropriate protective groups (as described e.g., in Protective Groups in Organic Chemistry by T. W. Greene and P. G. M. Wutts, 5th Ed., 2014, John Wiley & Sons, N.Y.) can be introduced before the critical step applying methods well known in the art. Such protective groups can be removed at a later stage of the synthesis using standard methods described in the literature.

[0646] If starting materials or intermediates contain stereogenic centers, compounds of formula (I) can be obtained as mixtures of diastereomers or enantiomers, which can be separated by methods well known in the art e.g., chiral HPLC, chiral SFC or chiral crystallization. Racemic compounds can e.g., be separated into their antipodes via diastereomeric salts by crystallization with optically pure acids or by separation of the antipodes by specific chromatographic methods using either a chiral adsorbent or a chiral eluent. It is equally possible to separate starting materials and intermediates containing stereogenic centers to afford diastereomerically/enantiomerically enriched starting materials and intermediates. Using such diastereomerically/enantiomerically enriched starting materials and intermediates in the synthesis of compounds of formula (I) will typically lead to the respective diastereomerically/enantiomerically enriched compounds of formula (I).

[0647] A person skilled in the art will acknowledge that in the synthesis of compounds of formula (I)insofar not desired otherwisean orthogonal protection group strategy will be applied, allowing the cleavage of several protective groups one at a time each without affecting other protective groups in the molecule. The principle of orthogonal protection is well known in the art and has also been described in literature (e.g. Barany and R. B. Merrifield, J. Am. Chem. Soc. 1977, 99, 7363; H. Waldmann et al., Angew. Chem. Int. Ed. Engl. 1996, 35, 2056).

[0648] A person skilled in the art will acknowledge that the sequence of reactions may be varied depending on reactivity and nature of the intermediates.

[0649] In more detail, the compounds of formula (I) can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to a person skilled in the art. Also, for reaction conditions described in literature affecting the described reactions see for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock. John Wiley & Sons, New York, NY. 1999). It was found convenient to carry out the reactions in the presence or absence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent. The described reactions can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. It is convenient to carry out the described reactions in a temperature range between 78 C. to reflux. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 hours to several days will usually suffice to yield the described intermediates and compounds. The reaction sequence is not limited to the one displayed in the schemes, however, depending on the starting materials and their respective reactivity, the sequence of reaction steps can be freely altered.

[0650] If starting materials or intermediates are not commercially available or their synthesis not described in literature, they can be prepared in analogy to existing procedures for close analogues or as outlined in the experimental section.

[0651] All substituents, in particular, R.sup.1 to R.sup.7, R.sup.1a, R.sup.3a, R.sup.3b, R.sup.4a, R.sup.4b and L are as defined above and in the claims, unless otherwise indicated.

##STR00060## ##STR00061##

[0652] In Scheme 1, PG.sub.1 and PG.sub.2 are protective groups selected from Cbz and Boc, respectively; [0653] LG.sub.1 is Cl, OH, OEt or

##STR00062##

and LG.sub.2 is halogen.

[0654] Compound of formula III can be prepared by a protection reaction of compound of formula II with di-tert-butyl dicarbonate in the presence of an organic base, such as TEA, DIPEA or DMAP, in a solvent such as DCM, THF, dioxane or a mixed solvent of dioxane and water. Then compound of formula III reacts with benzyl bromide in the presence of a base such as Na.sub.2CO.sub.3, K.sub.2CO.sub.3 or Cs.sub.2CO.sub.3, in a solvent such as DMF or CH.sub.3CN, to afford compound of formula IV. Deprotection of compound of formula IV can afford compound of formula V-a in the presence of an acid such as HCl or TFA in a solvent such as DCM or dioxane or a neat reaction without any solvent. Compound of formula VI-a can be obtained by a coupling reaction using compound of formula V-1, compound of formula V-a, and coupling reagent(s), such as T.sub.3P, HATU, HOPO, PyBOP or EDCI/HOBt, in the presence of an organic base, such TEA, DIEPA or DMAP. Deprotection of compound of formula VI-a in the presence of an acid such as HCl or TFA in a solvent such as DCM or dioxane, or a neat reaction without any solvent, can afford compound of formula VII. Compound of formula VIII can be obtained by a coupling reaction using compound of formula VII-1, compound of formula VII, and coupling reagent(s), such as T.sub.3P, HATU, PyBOP, HOPO or EDCI/HOBt, in the presence of an organic base, such TEA, DIEPA or DMAP, in a solvent such as THF, EtOAc, DMF or DCM. Alternatively, compound of formula VIII can be obtained by a reaction of compound of formula VII and compound of formula VII-1 in the presence of an organic base such as TEA, DIEPA or DMAP and in a solvent such as MeOH, DCM, THF or DMF. Hydrogenolysis of compound of formula VIII in the presence of Pd/C, Pd(OH).sub.2 or a mixture of Pd/C and Pd(OH).sub.2, and in a solvent such as MeOH can afford compound of formula IX. Compound of formula IX reacts with compound of formula IX-1 in the presence of a coupling reagent, such as T.sub.3P, HATU, PyBOP, HOPO or EDCI/HOBt, and an organic base such as TEA, DIPEA or DMAP, in a solvent such as THF, EtOAc, DMF or DCM, to afford compound of formula X. Deprotection of compound of formula X in the presence of an acid such as HCl or TFA, and (or not) in a solvent such as DCM or dioxane can afford compound of formula XI. Compound of formula XI then reacts with compound of formula XI-1 in the presence of coupling reagent(s), such as T.sub.3P, HATU, PyBOP, HOPO or EDCI/HOBt, and a base such as TEA, DIPEA or DMAP, in a solvent such as THF, EtOAc, DMF or DCM, to afford compound of formula I-a.

##STR00063##

[0655] In Scheme 2, PG.sub.1 and LG.sub.1 are as defined in Scheme 1.

[0656] Alternatively, compound of formula X can be prepared by using compound of formula V-b as starting material. Compound of formula V-b reacts with compound of formula V-1 in the presence of coupling reagent(s), such as T.sub.3P, HATU, PyBOP, HOPO or EDCI/HOBt, and an organic base such as TEA, DIPEA or DMAP, in a solvent such as DMF or DCM, to afford compound of formula VI-b. Hydrolyzation of compound of formula VI-b in the presence of a base such as LiOH.Math.H.sub.2O, NaOH or KOH, and in a mixed solution of MeOH and H.sub.2O can afford compound of formula XII. Compound of formula VIII can be obtained by a coupling reaction using compound of formula XII, compound of formula IX-1-a, and coupling reagent(s), such as T.sub.3P, HATU, HOPO, PyBOP or EDCI/HOBt, in the presence of an organic base, such as TEA, DIEPA or DMAP, in a solvent such as THF, EtOAc, DMF or DCM. Hydrogenolysis of compound of formula XIII in the presence of Pd/C, Pd(OH).sub.2 or a mixture of Pd/C and Pd(OH).sub.2 in a solvent such as MeOH can afford compound of formula XIV. Compound of formula XIV reacts with compound of formula VII-1 in the presence of coupling reagent(s), such as T.sub.3P, HATU, PyBOP, HOPO or EDCI/HOBt, and an organic base such as TEA, DIPEA or DMAP, in a solvent such as DMF or DCM, to afford compound of formula X. Alternatively, compound of formula X can be obtained by a reaction of compound of formula XIV and compound of formula VII-1 in the presence of an organic base such as TEA, DIEPA or DMAP and in a solvent such as MeOH, DCM, THF or DMF. After deprotection and a coupling reaction, compound of formula I-a can be prepared from compound of formula X by following the last two steps of Scheme 1.

##STR00064##

[0657] In Scheme 3, PG.sub.1 is as defined in Scheme 1.

[0658] Alternatively, compound of formula I-a can also be prepared by Scheme 3. Compound of formula II reacts with benzyl carbonochloridate or benzyl carbonochloridate in the presence of an organic base, such as TEA, DIPEA or DMAP, in a solvent such as DCM, THF, dioxane or a mixed solvent of dioxane and water, to afford compound of formula XV. Compound of formula XV reacts with compound of formula IX-1-a in the presence of a coupling reagent, such as T.sub.3P, HATU, PyBOP, HOPO or EDCI/HOBt, and an organic base such as TEA, DIPEA or DMAP, in a solvent such as THF, EtOAc, DMF or DCM, to afford compound of formula XVI. Hydrogenolysis of compound of formula XVI in the presence of Pd/C, Pd(OH).sub.2 or a mixture of Pd/C and Pd(OH).sub.2 in a solvent such as MeOH, EtOH or THF can afford compound of formula XVII. Compound of formula XVII reacts with compound of formula V-1 in presence of a coupling reagent(s), such as T.sub.3P, HATU, HOPO, PyBOP or EDCI/HOBt and an organic base, such TEA, DIEPA or DMAP, in a solvent such as THF, EtOAc, DMF or DCM to afford compound formula XIII. By following the last four steps of Scheme 1, compound of formula I-a can be prepared from compound of formula XIII.

##STR00065##

[0659] In Scheme 4, PG.sub.1 is a protective group selected from Cbz or Boc; LG.sub.1 is Cl, OEt or

##STR00066##

[0660] Alternatively, compound of formula IX can be prepared by using compound of formula VI-a as starting material. Hydrogenolysis of compound of formula VI-a in the presence of Pd/C, Pd(OH).sub.2 or a mixture of Pd/C and Pd(OH).sub.2 in a solvent such as MeOH, EtOH or THF can afford compound of formula XII. Then hydrolyzation of compound of formula XII in the presence of a base such as LiOH.Math.H.sub.2O, NaOH or KOH, and in a mixed solution of MeOH and H.sub.2O can afford compound of formula XX. When PG.sub.1 is Cbz, compound of formula XX can obtained by a hydrogenation reaction of compound of formula VI-a in the presence of Pd/C, Pd(OH).sub.2 or a mixture of Pd/C and Pd(OH).sub.2 in a solvent such as MeOH, EtOH or THF. Compound of formula XX reacts with compound of formula VII-1 in the presence of an organic base such as TEA, DIPEA or DMAP, in a solvent such as MeOH, DMF or DCM, to afford compound of formula IX. By following the last three steps of Scheme 1, compound of formula I-a can be prepared from compound of formula IX.

##STR00067##

[0661] In Scheme 5, LG.sub.2 is as defined in Scheme 1.

[0662] Compound of formula XXI can be prepared by a coupling reaction of compound of formula II with compound of formula II-1 in the presence of an organic base such as TEA, DIPEA or DMAP, in a solvent such as DMF or DCM. Compound of formula IX-1-a reacts with compound of formula XXI, in presence of coupling reagent(s), such as T.sub.3P, HATU, PyBOP, HOPO or EDCI/HOBt, and an organic base, such as TEA, DIEPA or DMAP, in a solvent such as THF, EtOAc, DMF or DCM to afford compound formula XXII. Deprotection of compound formula XXII in the presence of an acid such as HCl or TFA in (or not) a solvent such as DCM or dioxane can afford compound of formula XXIII. Compound of formula XXIII then reacts with compound of formula XI-1 in the presence of coupling reagent(s), such as T.sub.3P. HATU, PyBOP. HOPO or EDCI/HOBt. and a base such as TEA, DIPEA or DMAP, in a solvent such as in a solvent such as THF, EtOAc, DMF or DCM, to afford compound of formula I-b.

##STR00068##

[0663] In Scheme 6, PG.sub.1 and LG.sub.2 is as defined in Scheme 1.

[0664] Compound of formula XIV can be obtained by a hydrogenation reaction of compound of formula XIII in the presence of Pd/C, Pd(OH).sub.2 or a mixture of Pd/C and Pd(OH).sub.2 in a solvent such as MeOH, EtOH or THF. Then compound of formula XIV is deprotected in the presence of an acid such as HCl or TFA in DCM, dioxane or without any solvent to afford compound formula XXIV. When PG.sub.1 is Boc, compound of formula XXIV can also be obtained from compound of formula XIII in the same acid condition above mentioned. Compound of formula XXIV reacts with compound of formula XI-2 in the presence of coupling reagent(s), such as T.sub.3P, HATU, PyBOP, HOPO, EDCI/HOBt or none, and a base such as TEA, DIPEA or DMAP, in a solvent such as THF, EtOAc, DMF or DCM, to afford compound of formula I-c.

[0665] In one aspect, the present invention provides a process of manufacturing a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, comprising: [0666] (a) reacting a compound of formula (XI)

##STR00069## [0667] wherein R.sup.1a, R.sup.2, R.sup.3a, R.sup.3b, R.sup.4a, R.sup.4b, R.sup.5, and L are as defined herein; [0668] with a compound of formula (XI-1),

##STR00070## [0669] wherein R.sup.6 and R.sup.7 are as defined herein and LG.sub.2 is a leaving group; [0670] in the presence of a coupling reagent and a base; [0671] to form a compound of formula (I-a)

##STR00071## [0672] wherein R.sup.1a, R.sup.2, R.sup.3a, R.sup.3b, R.sup.4a, R.sup.4b, R.sup.5, R.sup.6, R.sup.7, and L are as defined herein; or [0673] (b) reacting a compound of formula (XXIII)

##STR00072## [0674] wherein R.sup.1, R.sup.3a, R.sup.3b, R.sup.4a, R.sup.4b, R.sup.5, and L are as defined herein; [0675] with a compound of formula (XI-1),

##STR00073## [0676] wherein R.sup.6 and R.sup.7 are as defined herein and LG.sub.2 is a leaving group; [0677] in the presence of a coupling reagent and a base; [0678] to form a compound of formula (I-b)

##STR00074## [0679] wherein R.sup.1, R.sup.3a, R.sup.3b, R.sup.4a, R.sup.4b, R.sup.5, R.sup.6, R.sup.7, and L are as defined herein.

[0680] In one embodiment, said leaving group LG.sub.2 is a halogen, in particular chloro.

[0681] In one embodiment, the base used in said process is selected from TEA, DIPEA and DMAP.

[0682] In one embodiment, the solvent used in said process is DMF or DCM.

[0683] In one embodiment, the coupling reagent is selected from T.sub.3P, HATU, PyBOP, HOPO and EDCI/HOBt.

[0684] In one aspect, the present invention provides a compound of formula (XI), or a salt thereof,

##STR00075## [0685] wherein R.sup.1a, R.sup.2, R.sup.3a, R.sup.3b, R.sup.4a, R.sup.4b, R.sup.5, and L are as defined herein.

[0686] In one aspect, the present invention provides a compound of formula (XXIII), or a salt thereof,

##STR00076## [0687] wherein R.sup.1, R.sup.3a, R.sup.3b, R.sup.4a, R.sup.4b, R.sup.5, and L are as defined herein.

Using the Compounds of the Invention

[0688] In one aspect, the present invention provides compounds of formula (I), or pharmaceutically acceptable salts thereof, as described herein for use as therapeutically active substance.

[0689] In one aspect, the present invention provides the use of a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, for the treatment or prophylaxis of coronavirus infections.

[0690] In one aspect, the present invention provides the use of a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, for inhibiting the enzymatic activity of 3C-like proteases.

[0691] In one aspect, the present invention provides the use of a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prophylaxis of coronavirus infections.

[0692] In one aspect, the present invention provides the use of a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for inhibiting the enzymatic activity of 3C-like proteases.

[0693] In one aspect, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prophylaxis of coronavirus infections.

[0694] In one aspect, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, for use in inhibiting the enzymatic activity of 3C-like proteases.

[0695] In one aspect, the present invention provides a method of treatment or prophylaxis of coronavirus infections, said method comprising administering a therapeutically active amount of a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, to a subject in need.

[0696] In one aspect, the present invention provides a method of inhibiting the enzymatic activity of 3C-like proteases, said method comprising contacting a 3C-like protease with a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof.

[0697] In one embodiment, said coronavirus is selected from severe acute respiratory syndrome coronavirus (SARS-CoV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Middle East Respiratory Syndrome Coronavirus (MERS-CoV).

[0698] In one embodiment, said coronavirus is severe acute respiratory syndrome coronavirus (SARS-CoV).

[0699] In one embodiment, said coronavirus is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

[0700] In one embodiment, said coronavirus is Middle East Respiratory Syndrome Coronavirus (MERS-CoV).

Pharmaceutical Compositions and Administration

[0701] In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described herein and a therapeutically inert carrier.

[0702] In one embodiment, there is provided a pharmaceutical composition according to Example 193 or 194.

[0703] The compounds of formula (I) and their pharmaceutically acceptable salts and esters can be used as medicaments (e.g. in the form of pharmaceutical preparations). The pharmaceutical preparations can be administered internally, such as orally (e.g. in the form of tablets, coated tablets, drages, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g. in the form of nasal sprays) or rectally (e.g. in the form of suppositories). However, the administration can also be effected parentally, such as intramuscularly or intravenously (e.g. in the form of injection solutions).

[0704] The compounds of formula (I) and their pharmaceutically acceptable salts and esters can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, drages and hard gelatin capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc. can be used, for example, as such adjuvants for tablets, drages and hard gelatin capsules.

[0705] Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols, etc.

[0706] Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose, etc.

[0707] Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.

[0708] Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols, etc.

[0709] Moreover, the pharmaceutical preparations can contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.

[0710] The dosage can vary in wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 0.1 mg to 20 mg per kg body weight, preferably about 0.5 mg to 4 mg per kg body weight (e.g. about 300 mg per person), divided into preferably 1-3 individual doses, which can consist, for example, of the same amounts, should be appropriate. It will, however, be clear that the upper limit given herein can be exceeded when this is shown to be indicated.

EXAMPLES

[0711] The invention will be more fully understood by reference to the following examples. The claims should not, however, be construed as limited to the scope of the examples.

[0712] In case the preparative examples are obtained as a mixture of enantiomers, the pure enantiomers can be separated by methods described herein or by methods known to the man skilled in the art, such as e.g., chiral chromatography (e.g., chiral SFC) or crystallization.

[0713] All reaction examples and intermediates were prepared under an argon atmosphere if not specified otherwise.

ABBREVIATIONS

[0714] Abbreviations used herein are as follows: [0715] aq. Aqueous [0716] ACN acetonitrile [0717] BnBr benzyl bromide [0718] CbzCl benzyl chloroformate [0719] Cbz benzyl formate [0720] CDCl.sub.3 deuterated chloroform [0721] CD.sub.3OD deuterated methanol [0722] DIPEA N, N-diethylpropylamine [0723] DMF dimethyl formamide [0724] DMSO dimethyl sulfoxide [0725] DBU 1,8-Diazabicycloundec-7-ene [0726] EDCI N-Ethyl-N-(3-dimethylaminopropyl)carbodiimide hydrochloride [0727] EDTA ethylenediaminetetraacetic acid [0728] EtOAc or EA ethyl acetate [0729] FAM carboxyfluorescein [0730] FRET fluorescence resonance energy transfer [0731] HATU (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) [0732] HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid [0733] h hour [0734] HPLC high performance liquid chromatography [0735] HOBt N-hydroxybenzotriazole [0736] HOPO 2-Hydroxypyridine-N-oxide [0737] LiHMDS lithium bis(trimethylsilyl)amide [0738] N mol/L [0739] MS (ESI) mass spectroscopy (electron spray ionization) [0740] min(s) minute(s) [0741] NMR nuclear magnetic resonance [0742] NMP 1-methyl-2-pyrrolidone [0743] obsd. Observed [0744] PE Petroleum ether [0745] prep-HPLC preparative high performance liquid chromatography [0746] PyBOP benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate [0747] RT or rt room temperature [0748] sat. saturated [0749] SFC supercritical fluid chromatography [0750] TAMRA carboxytetramethylrhodamine [0751] TCEP tris(2-carboxyethyl)phosphine [0752] TCFH N,N,N,N-tetramethylchloroformamidinium hexafluorophosphate [0753] TEA triethylamine [0754] TFA trifluoroacetic acid [0755] TFAA trifluoroacetic anhydride [0756] THF tetrahydrofuran [0757] T.sub.3P propylphosphonic anhydride

General Experimental Conditions

[0758] Intermediates and final compounds were purified by flash chromatography using one of the following instruments: i) Biotage SP1 system and the Quad 12/25 Cartridge module. ii) ISCO combi-flash chromatography instrument. Silica gel Brand and pore size: i) KP-SIL 60 , particle size: 40-60 m; ii) CAS registry NO: Silica Gel: 63231-67-4, particle size: 47-60 micron silica gel; iii) ZCX from Qingdao Haiyang Chemical Co., Ltd, pore: 200-300 or 300-400.

[0759] Alternatively, intermediates and final compounds were purified by preparative HPLC on reversed phase column using X Bridge Perp C.sub.18 (5 m, OBD 30100 mm) column, X Bridge Perp C.sub.18 (20-40 m, OBD 30100 mm) column, Welch Ultimate X Bridge SiOH 250*50*10 um column, SunFire Perp C.sub.18 (5 m, OBD 30100 mm) column, Phenomenex Luna C18 75*30 mm*3 m column or Phenomenex Synergi C18 150*25 mm*10 m column.

[0760] For SFC chiral separation, intermediates were separated by chiral column (Daicel chiralpak IC, 5 m, 30250 mm), (Daicel chiralpak IC, 10 m, 30250 mm), AS (10 m, 30250 mm), AD (10 m, 30250 mm), Chiralpak IG-3 (504.6 mm I.D., 3 m), using Mettler Toledo Multigram III system SFC, ACSWH-PREP-SFC-C, Waters 80Q preparative SFC or Thar 80 preparative SFC, solvent system: CO.sub.2 and IPA (0.5% TEA in IPA) or CO.sub.2 and MeOH (0.1% NH.sub.3.Math.H.sub.2O in MeOH) or CO.sub.2 and Neu-IPA, back pressure 100 bar, detection UV@254 or 220 nm.

[0761] LC/MS spectra were obtained using a Waters UPLC-SQD Mass or SHIMADZU LCMS-2020. Standard LC/MS conditions were as follows (running time 3 mins):

[0762] Acidic condition: A: 0.1% formic acid and 1% acetonitrile in H.sub.2O; B: 0.1% formic acid in acetonitrile;

[0763] Basic condition: A: 0.05% NH.sub.3.Math.H.sub.2O in H.sub.2O; B: acetonitrile.

[0764] Mass spectra (MS): generally only ions which indicate the parent mass are reported, and unless otherwise stated the mass ion quoted is the positive mass ion (M+H)+.

[0765] NMR Spectra were obtained by using Bruker Avance 400 MHz.

[0766] All reactions involving air-sensitive reagents were performed under an argon atmosphere. Reagents from commercial suppliers were used without further purification unless otherwise noted.

PREPARATIVE EXAMPLES

Preparation of Intermediate

Intermediate 1

Benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate

##STR00077##

Step 1: Preparation of (1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid

##STR00078##

[0767] To a solution of Na.sub.2CO.sub.3 (1.37 g, 12.89 mmol) and (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid; hydrochloride (1.0 g, 6.44 mmol) (Pharmablock, CAS number: 1373205-30-1) in water (15 mL) and 1,4-dioxane (15 mL) was added di-tert-butyldicarbonate (2.1 g, 9.67 mmol). The reaction was stirred at 20 C. for 12 h. The reaction mixture was diluted with H.sub.2O (80 mL) and washed with EtOAc (50 mL). The aqueous layer was acidified with 1M HCl to pH=2-3. The mixture was extracted with EtOAc (50 mL2). The organic layers were washed with brine (40 mL), dried over Na.sub.2SO.sub.4, filtered and the filtrate was concentrated in vacuum to afford (1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (1.4 g) as colorless oil.

[0768] .sup.1H NMR (400 MHz, CDCl.sub.3) : ppm: 4.21 (s, 0.5H), 4.12 (s, 0.5H), 3.69-3.56 (m, 1H), 3.48-3.04 (m, 1H), 1.69 (d, J=7.2 Hz, 0.5H), 1.48-1.39 (m, 10.5H), 1.06-1.05 (m, 3H), 0.99 (d, J=16 Hz, 3H).

Step 2: Preparation of O2-benzyl O3-tert-butyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate

##STR00079##

[0769] To a solution of (1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (1.4 g, 5.48 mmol) in DMF (30 mL) was added K.sub.2CO.sub.3 (1.51 g, 10.97 mmol) and BnBr (1.22 g, 7.13 mmol). The reaction mixture was stirred at 25 C. for 2 h. The mixture was diluted with EtOAc (130 mL), washed with water (50 mL) and brine (50 mL3). The organic layer was dried over Na.sub.2SO.sub.4, filtered and the filtrate was concentrated in vacuum. The residue was purified by silica gel column eluted with PE to PE/EtOAc=4/1 to afford O2-benzyl O3-tert-butyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (1.6 g) as colorless oil.

[0770] MS obsd. (ESI.sup.+) [M+Na].sup.+: 368.2

Step 3: Preparation of benzyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate

##STR00080##

[0771] To a solution of O2-benzyl O3-tert-butyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (1.1 g, 3.18 mmol) in DCM (10 mL) was added TFA (10.0 mL). The reaction mixture was stirred at 25 C. for 1 h. The mixture was concentrated in vacuum to afford (1R,2S,5S)-benzyl 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (780 mg) as colorless oil.

[0772] MS obsd. (ESI.sup.+) [M+H].sup.+: 246.1

Step 4: Preparation of benzyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate

##STR00081##

[0773] To a solution of (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoic acid (0.74 g, 3.18 mmol) (BePharm, CAS number: 62965-35-9) in DMF (30 mL) was added HATU (1.45 g, 3.82 mmol), DIPEA (2.46 g, 19.08 mmol) and (1R,2S,5S)-benzyl 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (0.78 g, 3.18 mmol). The reaction mixture was stirred at 25 C. for 2 h. The mixture was diluted with EtOAc (100 mL), washed with water (50 mL) and brine (50 mL3). The organic layer was dried over Na.sub.2SO.sub.4, filtered and the filtrate was concentrated in vacuum. The residue was purified by silica gel column eluted with PE/EtOAc=10/1 to afford benzyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (1.25 g) as colorless oil.

[0774] MS obsd. (ESI.sup.+) [M+H].sup.+: 459.4

Step 5: Preparation of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1)

##STR00082##

[0775] To a solution of benzyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (1.25 g, 2.73 mmol) in DCM (10 mL) was added TFA (10 mL). The reaction mixture was stirred at 25 C. for 1 h. The mixture was concentrated in vacuum to afford benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (0.97 g, Intermediate 1) as colorless oil.

[0776] MS obsd. (ESI.sup.+) [M+H].sup.+: 359.3.

Intermediate 2

Benzyl (1R,2S,5S)-3-[(2S)-2-amino-2-cyclopropyl-acetyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate

##STR00083##

[0777] The title compound was prepared in analogy to the procedure described for the preparation of Intermediate 1, by (2S)-2-(tert-butoxycarbonylamino)-2-cyclopropyl-acetic acid (BePharm, CAS number: 155976-13-9) instead of (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoic acid to afford benzyl (1R,2S,5S)-3-[(2S)-2-amino-2-cyclopropyl-acetyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 2) as yellow oil.

[0778] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 343.1.

Intermediate 3

Benzyl (3S,3aS,6aR)-2-[(2S)-2-amino-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate

##STR00084##

[0779] The title compound was prepared in analogy to the procedure described for the preparation of Intermediate 1, by using (3S,3aS,6aR)-2-tert-butoxycarbonyl-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid (AstaTech, CAS number: 597569-42-1) instead of (1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid to afford benzyl (3S,3aS,6aR)-2-[(2S)-2-amino-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate (Intermediate 3) as yellow oil.

[0780] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 359.3.

Intermediate 4

Benzyl (1S,2S,5R)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-3-azabicyclo[3.2.0]heptane-2-carboxylate

##STR00085##

[0781] The title compound was prepared in analogy to the procedure described for the preparation of Intermediate 1, by using (1S,2S,5R)-3-azabicyclo[3.2.0]heptane-2-carboxylic acid (Pharmablock, CAS number: 77882-10-1) instead of (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid; hydrochloride to afford benzyl (1S,2S,5R)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-3-azabicyclo[3.2.0]heptane-2-carboxylate (Intermediate 4) as yellow oil.

[0782] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 345.3.

Intermediate 5

Benzyl (6S)-5-[(2S)-2-amino-3,3-dimethyl-butanoyl]-5-azaspiro[2.4]heptane-6-carboxylate

##STR00086##

[0783] The title compound was prepared in analogy to the procedure described for the preparation of Intermediate 1, by using (6S)-5-tert-butoxycarbonyl-5-azaspiro[2.4]heptane-6-carboxylic acid (Wuxiapptec, catalog) instead of (1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid to afford benzyl (6S)-5-[(2S)-2-amino-3,3-dimethyl-butanoyl]-5-azaspiro[2.4]heptane-6-carboxylate (Intermediate 5) as yellow oil.

[0784] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 345.2.

Intermediate 6

Benzyl (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-methyl-pyrrolidine-2-carboxylate

##STR00087##

[0785] The title compound was prepared in analogy to the procedure described for the preparation of Intermediate 1, by using (2S,4R)-4-methylpyrrolidine-2-carboxylic acid; hydrochloride (Wuxiapptec, CAS number: 365280-18-8) instead of (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid; hydrochloride to afford benzyl (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-methyl-pyrrolidine-2-carboxylate (Intermediate 6) as yellow oil.

[0786] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 333.2.

Intermediate 7

Benzyl (2S)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4,4-dimethyl-pyrrolidine-2-carboxylate

##STR00088##

[0787] The title compound was prepared in analogy to the procedure described for the preparation of Intermediate 1, by using (2S)-4,4-dimethylpyrrolidine-2-carboxylic acid; hydrochloride (Porse Fine Chemical, CAS number: 1443252-76-3) instead of (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid; hydrochloride to afford benzyl (2S)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4,4-dimethyl-pyrrolidine-2-carboxylate (Intermediate 7) as yellow oil.

[0788] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 347.2.

Intermediate 8

Benzyl (1S,2S,5R)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxylate

##STR00089##

[0789] The title compound was prepared in analogy to the procedure described for the preparation of Intermediate 1, by using (1S,2S,5R)-3-tert-butoxycarbonyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (Pharmablock, CAS number: 400720-05-0) instead of (1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid to afford benzyl (1S,2S,5R)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 8) as yellow oil.

[0790] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 331.1.

Intermediate 9

Tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate

##STR00090##

Step 1: Preparation of tert-butyl 3-methylene-2-oxo-pyrrolidine-1-carboxylate

##STR00091##

[0791] A solution of tert-butyl 2-oxopyrrolidine-1-carboxylate (100.0 g, 539.9 mmol)(Accela, CAS number: 85909-08-6) in THF (1000 mL) was added to a stirring solution of LiHMDS (1133 mL, 1134 mmol) at 0 C. The reaction mixture was allowed to warm up to 20 C. over 30 min before 2,2,2-trifluoroethyl trifluoroacetate (211.69 g, 1080 mmol) was added. Stirring was continued for additional 20 min at 20 C. before the reaction was quenched with saturated NH.sub.4Cl (500 mL). The mixture was extracted with EtOAc (600 mL2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was dissolved in toluene (1000 mL) then formaldehyde (48.64 g, 1620 mmol) and K.sub.2CO.sub.3 (164.16 g, 1188 mmol) were added into the solution. The reaction mixture was heated at 110 C. for 2 h. The mixture was diluted with EtOAc (800 mL), washed with brine (200 mL3), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum to afford tert-butyl 3-methylene-2-oxo-pyrrolidine-1-carboxylate (80 g) as light yellow oil.

[0792] MS obsd. (ESI.sup.+) [M-Bu+H].sup.+: 142.1.

Step 2: Preparation of tert-butyl 3-[(2-benzyloxycarbonylhydrazino)methyl]-2-oxo-pyrrolidine-1-carboxylate

##STR00092##

[0793] To a solution of tert-butyl 3-methylene-2-oxo-pyrrolidine-1-carboxylate (80.0 g, 405.62 mmol) in i-PrOH (800 mL) was added benzyl N-aminocarbamate (67.41 g, 405.62 mmol). The reaction mixture was stirred at 85 C. for 12 h under N.sub.2. The mixture was concentrated in vacuum to afford the crude product tert-butyl 3-[(2-benzyloxycarbonylhydrazino)methyl]-2-oxo-pyrrolidine-1-carboxylate (147 g) as yellow oil.

[0794] MS obsd. (ESI.sup.+) [2M+H].sup.+: 727.2.

Step 3: Preparation of benzyl N-[(2-oxopyrrolidin-3-yl)methylamino]carbamate

##STR00093##

[0795] To a solution of tert-butyl 3-[(2-benzyloxycarbonylhydrazino)methyl]-2-oxo-pyrrolidine-1-carboxylate (147.0 g, 404.5 mmol) in DCM (700 mL) was added TFA (500 mL). The mixture was stirred at 20 C. for 2 h. The reaction mixture was concentrated in vacuum to afford benzyl N-[(2-oxopyrrolidin-3-yl)methylamino]carbamate (147.0 g) as yellow oil.

[0796] MS obsd. (ESI.sup.+) [M+H].sup.+: 264.0.

Step 4: Preparation of tert-butyl N-(benzyloxycarbonylamino)-N-[(2-oxopyrrolidin-3-yl)methyl]carbamate

##STR00094##

[0797] To a solution of benzyl N-[(2-oxopyrrolidin-3-yl)methylamino]carbamate (150.0 g, 569.71 mmol) in EtOH (800 mL) was added DIPEA (220.9 g, 1709 mmol) and Boc.sub.2O (149.2 g, 683.66 mmol). The reaction mixture was stirred at 50 C. for 12 h. The mixture was concentrated in vacuum. The residue was diluted with EtOAc (1000 mL), washed with brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated to give the crude product. The crude product was purified by silica gel column eluted with PE/EtOAc=1/1 to EtOAc to afford an impure product which was conducted a further purification by reverse flash (0.1% TFA) to afford tert-butyl N-(benzyloxycarbonylamino)-N-[(2-oxopyrrolidin-3-yl)methyl]carbamate (50.0 g) as light yellow oil.

[0798] MS obsd. (ESI.sup.+) [M-Boc+H].sup.+: 264.2.

Step 5: Preparation of tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate

##STR00095##

[0799] To a solution of tert-butyl N-(benzyloxycarbonylamino)-N-[(2-oxopyrrolidin-3-yl)methyl]carbamate (160.0 g, 440.27 mmol) in methanol (1500 mL) was added Pd/C (15.0 g) and Pd(OH).sub.2/C (15.0 g) under N.sub.2. The reaction mixture was degassed under vacuum and purged H.sub.2 for 3 times. The resulting mixture was stirred at 25 C. for 12 h under H.sub.2 balloon. The mixture was filtered through a pad of celite and the filtrate was concentrated in vacuum to afford tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (100 g) as colorless oil. The racemate was split by SFC preparation (Column: Phenomenex-Cellulose-2 (250 mm*50 mm, 10 um); Condition: phase A for CO.sub.2, phase B for Neu-MeOH: B %: 45-45%; Flow Rate (mL/min): 220; Gradient time: 3.55 min, injections: 440) to afford tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (41.4 g, Intermediate 9) as a light yellow solid.

[0800] .sup.1H NMR (400 MHz, CDCl.sub.3) : ppm 5.77 (s, 1H), 3.75-3.55 (m, 2H), 3.45-3.30 (m, 2H), 2.85-2.75 (m, 1H), 2.30-2.20 (m, 1H), 1.99-1.89 (m, 1H), 1.51-1.42 (m, 9H)

[0801] MS obsd. (ESI.sup.+) [M+H].sup.+: 230.1

[0802] SFC: Retention time=1.615 min, ee %=98.05%

Intermediate 10

(2R)-2-chloro-2-fluoro-acetyl chloride

##STR00096##

Step 1: Preparation of 2-chloro-2-fluoroacetic acid

##STR00097##

[0803] To a solution of ethyl chlorofluoroacetate (1000 g, 7142 mmol) (Aldrich, CAS number: 401-56-9) in ethanol (9 L) was added water (1 L) and NaOH (313 g, 7826 mmol). The reaction mixture was stirred at 25 C. for 12 h. .sup.1H NMR showed the reaction was complete. The mixture was concentrated in vacuum to remove most of EtOH. Then the residue was diluted with water (1500 mL) and acidified with 2M HCl to pH=4-5. The mixture was extracted with MTBE (1 L4). The combined organic layers were dried over Na.sub.2SO.sub.4. The mixture was filtered and concentrated to give the crude product 2-chloro-2-fluoroacetic acid (718 g) as colorless oil.

[0804] .sup.1H NMR (400 MHz, CDCl.sub.3) : ppm 6.16 (d, J=50.4 Hz, 1H).

Step 2: Preparation of (2R)-2-chloro-2-fluoro-acetic acid

##STR00098##

[0805] To a solution of 2-chloro-2-fluoro-acetic acid (718.0 g, 3191 mmol) in EtOAc (3000 mL) was added a solution of (S)-1-phenylethanamine (386.7 g, 3191 mmol) in EtOAc (3000 mL) at 0 C. The mixture was stirred at 0 C. for 2 h and then stood overnight. The reaction mixture was filtered and the filter cake was dissolved in acetone (760 g in 7600 mL) at 80 C. The resulting solution was slowly cooled to 20 C. and stood overnight. The precipitate was filtrated, collected and dissolved in acetone (100 g/L) at 80 C. (The recrystallization operation was repeated for 2 times). The collected solid was triturated in acetone for 3 times (acetone, 100 g/500 mL). The solid was collected and dissolved in water (1 L) and acidified with 1M HCl (750 mL). The mixture was extracted with MTBE (1 L3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum to afford (2R)-2-chloro-2-fluoro-acetic acid (121.15 g, 61% purity, containing MTBE) as yellow oil.

[0806] .sup.1H NMR (400 MHz, CDCl.sub.3) : ppm 6.29 (d, J=50.8 Hz, 1H).

Step 3: Preparation of (2R)-2-chloro-2-fluoro-acetyl chloride

##STR00099##

[0807] A mixture of (2R)-2-chloro-2-fluoro-acetic acid (12.0 g, 106.68 mmol) and PCl.sub.5 (24.5 g, 117.47 mmol) was stirred at 20 C. for 1 h and at 70 C. for 1 h. .sup.1H NMR showed the reaction was complete. Then (2R)-2-chloro-2-fluoro-acetyl chloride (22.8 g, 40% purity with POCl.sub.3 and MTBE, Intermediate 10) was collected by distillation (70 C., 20 mmHg) as a colorless liquid.

[0808] .sup.1H NMR (400 MHz, CDCl.sub.3) : ppm 6.40 (d, J=50.8 Hz, 1H).

Intermediate 11

tert-Butyl N-amino-N-(1H-pyrazol-3-ylmethyl)carbamate

##STR00100##

Step 1: Preparation of benzyl N-(1H-pyrazol-3-ylmethylamino)carbamate

##STR00101##

[0809] To a solution of 1H-pyrazole-3-carbaldehyde (5.0 g, 52.03 mmol) (BePharm, CAS number: 3920-50-1) and benzyl carbazate (8.68 g, 52.20 mmol) in methanol (100 mL) was added HOAc (10.0 mL, 174.85 mmol). The mixture was stirred at 25 C. for 3 h. Then to the mixture was added NaBH.sub.3CN (19.6 g, 312.21 mmol). The mixture was stirred at 60 C. for 12 h. The reaction was concentrated in vacuum to remove methanol. The residue was diluted with H.sub.2O (50 mL) and extracted with EtOAc (50 mL3). The organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by reverse column (condition: 330 g Flash Column Welch Ultimate XB_C.sub.18 20-40 um; 120 A, ACN in water (0.1% TFA), 26%26%, 100 mL/min). The fraction was basified with saturated aqueous NaHCO.sub.3 to pH=9 and extracted with EtOAc (100 mL3). The organic phase was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum to afford benzyl N-(1H-pyrazol-3-ylmethylamino)carbamate (10 g) as yellow oil.

[0810] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 246.9

Step 2: Preparation of tert-butyl N-(benzyloxycarbonylamino)-N-(1H-pyrazol-3-ylmethyl)carbamate

##STR00102##

[0811] To a solution of benzyl N-(1H-pyrazol-3-ylmethylamino)carbamate (3.0 g, 12.18 mmol) in EtOH (40 mL) was added DIPEA (6.29 g, 48.67 mmol) and Boc.sub.2O (5.32 g, 24.38 mmol). The mixture was stirred at 50 C. for 12 h. The reaction mixture was concentrated in vacuum. The residue was purified by silica gel column eluted with EtOAc/PE=1/1 to EtOAc to afford tert-butyl N-(benzyloxycarbonylamino)-N-(1H-pyrazol-3-ylmethyl)carbamate (1.2 g) as colorless oil.

[0812] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 347.0.

Step 3: Preparation of tert-butyl N-amino-N-(1H-pyrazol-3-ylmethyl)carbamate

##STR00103##

[0813] To a solution of tert-butyl N-(benzyloxycarbonylamino)-N-(1H-pyrazol-3-ylmethyl)carbamate (1.2 g, 3.46 mmol) in MeOH (15 mL) was added Pd/C (120.0 mg) and Pd(OH).sub.2 (120.0 mg). The mixture was degassed in vacuum and purged H.sub.2 for 3 times. The resulting mixture was stirred at 25 C. for 2 h under hydrogen balloon (760 mmHg). The reaction mixture was filtered through a celite pad and the filtrate was concentrated in vacuum. The residue was purified by silica gel column eluted with EtOAc to MeOH/EtOAc=10/1 to afford tert-butyl N-amino-N-(1H-pyrazol-3-ylmethyl)carbamate (600 mg, Intermediate 11) as colorless oil.

[0814] .sup.1H NMR (400 MHz, CD.sub.3OD) : ppm 7.53 (d, J=2.0 Hz, 1H), 6.24 (d, J=1.6 Hz, 1H), 4.61 (s, 2H), 1.49 (s, 9H).

[0815] MS obsd. (ESI.sup.+) [(2M+Na).sup.+]: 447.3.

Intermediate 12

5-(Trifluoromethyl)isoxazole-3-carboxylic acid

##STR00104##

Step 1: Preparation of ethyl 5-(trifluoromethyl)isoxazole-3-carboxylate

##STR00105##

[0816] To a solution of ethyl (Z)-2-chloro-2-(hydroxyimino)acetate (3.0 g, 19.8 mmol) (Accela, CAS number: 14337-43-0) in EtOAc (50 mL) was added 2-bromo-3,3,3-trifluoroprop-1-ene (10.4 g, 59.39 mmol) and NaHCO.sub.3 (5.5 g, 65.32 mmol). The mixture was stirred at 20 C. for 12 h. The reaction mixture was filtered and the filtrate was concentrated in vacuum at 30 C. to afford ethyl 5-(trifluoromethyl)isoxazole-3-carboxylate (3.75 g) as yellow oil.

[0817] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 7.93 (s, 1H), 4.44-4.39 (m, 2H), 1.34 (t, J=7.2 Hz, 3H).

Step 2: Preparation of 5-(trifluoromethyl)isoxazole-3-carboxylic acid

##STR00106##

[0818] To a solution of ethyl 5-(trifluoromethyl)isoxazole-3-carboxylate (3.75 g, 17.93 mmol) in methanol (40 mL) was added the solution of NaOH (1.58 g, 39.45 mmol) in water (40 mL) at 0 C. The mixture was stirred at 20 C. for 1 h. The reaction mixture was concentrated in vacuum to remove MeOH. The residue was diluted with EtOAc (80 mL) and washed with 1M HCl (40 mL). The aqueous phase was extracted with EtOAc (80 mL6). The organic phase was dried over Na.sub.2SO.sub.4, filtered and the filtrate was concentrated. The residue was purified by silica gel column eluted with PE/EtOAc=7/3 to 1/1 to afford 5-(trifluoromethyl)isoxazole-3-carboxylic acid (2.3 g, Intermediate 12) as a white solid.

[0819] .sup.1H NMR (400 MHz, CDCl.sub.3) : ppm 7.39 (br. s, 1H), 7.18 (s, 1H).

Intermediate 13

2-(3,5-Difluorophenoxy)acetyl chloride

##STR00107##

Step 1: Preparation of ethyl 2-(3,5-difluorophenoxy)acetate

##STR00108##

[0820] To a solution of 3,5-difluorophenol (475 mg, 3.65 mmol) in DMF (10 mL) was added K.sub.2CO.sub.3 (1008 mg, 7.3 mmol) and ethyl bromoacetate (0.4 mL, 3.65 mmol). The mixture was stirred at 25 C. for 4 h. The mixture was diluted with EtOAc (50 mL) and poured into water (50 mL). The aqueous phase was extracted with EtOAc (30 mL3). The combined organic layers were washed with brine (30 mL) and dried over Na.sub.2SO.sub.4. After filtration and concentration, the residue was purified by silica gel column eluted with EtOAc/PE=50/1 to 10/1 to afford ethyl 2-(3,5-difluorophenoxy)acetate (650 mg) as colorless liquid.

Step 2: Preparation of 2-(3,5-difluorophenoxy)acetic acid

##STR00109##

[0821] To a solution of ethyl 2-(3,5-difluorophenoxy)acetate (150 mg, 0.690 mmol) in MeOH (5 mL) and water (2 mL) was added LiOH.Math.H.sub.2O (73 mg, 1.73 mmol). The mixture was stirred at 20 C. for 1 h. The mixture was diluted with H.sub.2O (30 mL) and washed with EtOAc (20 mL2). The aqueous phase was acidified with conc. HCl to pH=5-6 and extracted with EtOAc (30 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum to afford 2-(3,5-difluorophenoxy)acetic acid (130 mg) as a white solid.

Step 3: Preparation of 2-(3,5-difluorophenoxy)acetyl chloride

##STR00110##

[0822] To a solution of 2-(3,5-difluorophenoxy)acetic acid (110 mg, 0.580 mmol) in DCM (5 mL) was added SOCl.sub.2 (1 mL). The mixture was stirred at 40 C. for 2 h. The mixture was concentrated in vacuum to afford 2-(3,5-difluorophenoxy)acetyl chloride (120 mg, Intermediate 13) as colorless oil.

Intermediate 14

tert-butyl N-[[(1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate

##STR00111##

Step 1: Preparation of (1R,2S,5S)-3-benzyloxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid

##STR00112##

[0823] To a solution of (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid hydrochloride (1.5 g, 7.83 mmol) in DCM (20 mL) was added TEA (2.37 g, 23.48 mmol) and CbzOsu (2.93 g, 11.74 mmol) at 0 C. The mixture was warmed up to 25 C. and stirred at 25 C. for 16 h. The mixture was concentrated in vacuum. The residue was purified by reverse flash chromatography eluted with ACN in H.sub.2O (0.1% TFA)=064% to afford (1R,2S,5S)-3-benzyloxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (1.96 g) as black oil.

[0824] .sup.1H NMR (400 MHz, CD.sub.3OD) : ppm 7.37-7.27 (m, 5H), 5.55-5.75 (br. s, 1H), 5.17-5.11 (m, 2H), 4.29 (d, J=12.4 Hz, 1H), 3.74-3.65 (m, 1H), 3.55 (t, J=12.8 Hz, 1H), 1.67-1.53 (m, 1H), 1.50-1.43 (m, 1H), 1.07 (d, J=2.4 Hz, 3H), 0.98 (d, J=5.6 Hz, 1H).

[0825] MS obsd. (ESI.sup.+) [(M+Na).sup.+]: 311.9

Step 2: Preparation of benzyl (1R,2S,5S)-2-[[tert-butoxycarbonyl-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate

##STR00113##

[0826] To a solution of (1R,2S,5S)-3-benzyloxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (1.4 g, 4.84 mmol) in DMF (20 mL) was added DIPEA (3.1 g, 24.19 mmol), EDCI (1113 mg, 5.81 mmol) and HOPO (645 mg, 5.81 mmol) at 0 C. Then tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (1.1 g, 4.84 mmol) was added to the reaction mixture. The resulting mixture was warmed up to 25 C. and stirred for 16 h. The mixture was purified by reverse flash chromatography eluted with ACN in H.sub.2O (0.1% TFA)=054% to afford benzyl (1R,2S,5S)-2-[[tert-butoxycarbonyl-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.9 g) as yellow oil.

[0827] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 501.3.

Step 3: Preparation of tert-butyl N-[[(1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate

##STR00114##

[0828] To a solution of benzyl (1R,2S,5S)-2-[[tert-butoxycarbonyl-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (2.53 g, 5.04 mmol) in MeOH (30 mL) was added Pd/C (100 mg, 10% purity) under N.sub.2 atmosphere. The suspension was degassed and purged with H.sub.2 for 3 times. The mixture was stirred under a H.sub.2 balloon at 25 C. for 2 h. The mixture was filtered and the filtrate was concentrated to afford tert-butyl N-[[(1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (1.6 g, Intermediate 14) as yellow oil.

[0829] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 367.2.

Intermediate 15

Benzyl (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-(trifluoromethyl)pyrrolidine-2-carboxylate

##STR00115##

[0830] The title compound was prepared in analogy to the procedure described for the preparation of Intermediate 1, by using (2S,4R)-1-tert-butoxycarbonyl-4-(trifluoromethyl)pyrrolidine-2-carboxylic acid (PharmaBlock, CAS number: 470482-44-1) instead of (1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid to afford benzyl (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-(trifluoromethyl)pyrrolidine-2-carboxylate (Intermediate 15) as yellow oil.

[0831] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 387.2.

Intermediate 16

(2S)-2-(tert-butoxycarbonylamino)-2-(1-methylcyclopropyl)acetic acid

##STR00116##

Step 1: Preparation of N-methoxy-N,1-dimethyl-cyclopropanecarboxamide

##STR00117##

[0832] To a solution of 1-methylcyclopropane-1-carboxylic acid (3.1 g, 30.96 mmol) in DCM (10 mL) was added DMF (45 mg, 0.620 mmol) and SOCl.sub.2 (3.7 g, 30.96 mmol) at 0 C. dropwise. The mixture was heated to 40 C. for 2 h. After cooled to room temperature, the mixture was added to a solution of Et.sub.3N (934 mg, 92.36 mmol) and 1-methylcyclopropanecarbonyl chloride (3.65 g, 30.79 mmol) in DCM (50 mL) at 0 C. Then the mixture was stirred at 0-25 C. for 1 h. The mixture was concentrated and the residue was purified by silica gel column eluted with PE/EtOAc=20/1 to 4/1 to afford N-methoxy-N,1-dimethyl-cyclopropanecarboxamide (3.3 g) as yellow oil.

[0833] .sup.1H NMR (400 MHz, CDCl.sub.3) : ppm 3.72 (s, 3H), 3.23 (s, 3H), 1.36 (s, 3H), 1.06-1.00 (m, 2H), 0.59-0.53 (m, 2H).

Step 2: Preparation of 1-methylcyclopropanecarbaldehyde

##STR00118##

[0834] To a solution of N-methoxy-N,1-dimethyl-cyclopropanecarboxamide (6.0 g, 41.91 mmol) in THF (60 mL) was added DIBAL-H (50.29 mL, 50.29 mmol, 1 N) dropwise at 70 C. The mixture was stirred at 70 C. for 2 h. The mixture was poured into 1 N HCl (100 mL). The organic layer was separated and the aqueous phase was extracted with DCM (50 mL3). The combined organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated to afford 1-methylcyclopropanecarbaldehyde solution which was used directly for next step without further purification.

[0835] .sup.1H NMR (400 MHz, CDCl.sub.3) : ppm 8.64 (s, 1H), 1.25 (s, 3H), 1.16-1.15 (m, 2H), 0.93-0.92 (m, 2H).

Step 3: Preparation of (2S)-2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-2-(1-methylcyclopropyl)acetonitrile

##STR00119##

[0836] To a solution of 1-methylcyclopropanecarbaldehyde from step 2 was added (R)-()-2-phenylglycinol (4.11 g, 29.96 mmol). The mixture was stirred at 25 C. for 2 h. Then trimethylsilyl cyanide (4.95 g, 49.90 mmol) was added to the mixture dropwise at 0 C. Then the mixture was stirred at 0-25 C. for 12 h. The mixture was and the residue was purified by silica gel column eluted with PE/EtOAc=10/1 to 2/1 to afford (2S)-2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-2-(1-methylcyclopropyl)acetonitrile (5.1 g) as colorless oil.

[0837] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 231.1.

Step 4: Preparation of (2S)-2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-2-(1-methylcyclopropyl)acetic acid

##STR00120##

[0838] To a solution of (2S)-2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-2-(1-methylcyclopropyl)acetonitrile (4.8 g, 20.84 mmol) in AcOH (10.0 mL) was added 12 N HCl (40.0 mL). The mixture was stirred at 80 C. for 1 h. The mixture was concentrated in vacuum. The crude product was purified by prep-HPLC (Column Phenomenex luna C.sub.18 250*80 mm*10 um; Condition ACN in water (HCl: 0%30%; 140 mL/min) to afford (2S)-2-[[(JR)-2-hydroxy-1-phenyl-ethyl]amino]-2-(1-methylcyclopropyl)acetic acid hydrochloride (2.7 g) as a white solid.

[0839] .sup.1H NMR (400 MHz, D.sub.2O) : ppm 7.53-7.40 (m, 5H), 4.20 (dd, J=8.0 Hz, 5.6 Hz, 1H), 4.07 (dd, J=12.0 Hz, 8.4 Hz, 1H), 4.00 (dd, J=12.0 Hz, 5.6 Hz, 1H), 2.57 (s, 1H), 0.98 (s, 3H), 0.60-0.35 (m, 3H), 0.05-0.15 (m, 1H).

[0840] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 249.8.

Step 5: Preparation of (2S)-2-amino-2-(1-methylcyclopropyl)acetic acid

##STR00121##

[0841] To a solution of (2S)-2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-2-(1-methylcyclopropyl)acetic acid; hydrochloride (2.7 g, 9.48 mmol) in AcOH (30 mL) and methanol (150 mL) was added wet Pd(OH).sub.2/C (200 mg, 10% purity). The suspension was degassed under vacuum and purged with H.sub.2 for three times. The resulting mixture was stirred at 45 C. for 16 h under a H.sub.2 balloon. The mixture was filtered and the filtrate was concentrated in vacuum to afford crude (2S)-2-amino-2-(1-methylcyclopropyl)acetic acid; hydrochloride (4.0 g) as yellow oil.

[0842] .sup.1H NMR (400 MHz, D.sub.2O) : ppm 3.07 (s, 1H), 1.20 (s, 3H), 0.96-0.79 (m, 1H), 0.57-0.53 (m, 2H), 0.52-0.46 (m, 1H).

[0843] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 130.3.

Step 6: Preparation of (2S)-2-(tert-butoxycarbonylamino)-2-(1-methylcyclopropyl)acetic acid

##STR00122##

[0844] To a solution of (2S)-2-amino-2-(1-methylcyclopropyl)acetic acid; hydrochloride (4.0 g, 24.15 mmol, crude) in 1,4-dioxane (50 mL) and water (50 mL) was added Na.sub.2CO.sub.3 (12.8 g, 120.76 mmol) and di-t-butyldicarbonate (5271 mg, 24.15 mmol). The suspension was stirred at 25 C. for 12 h. The mixture was diluted with water (100 mL) and washed with EtOAc (50 mL2). The aqueous phase was adjusted pH=4 with 1 N HCl and extracted with EtOAc (100 mL2). The organic layers were washed with brine (60 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuum to afford (2S)-2-(tert-butoxycarbonylamino)-2-(1-methylcyclopropyl)acetic acid (1.9 g, Intermediate 16) as yellow oil.

[0845] .sup.1H NMR (400 MHz, CDCl.sub.3) : ppm 5.20 (d, J=3.6 Hz, 1H), 3.75 (d, J=7.6 Hz, 1H), 1.46 (s, 9H), 1.08 (s, 3H), 0.85-0.78 (m, 1H), 0.75-0.67 (m, 1H), 0.51-0.45 (m, 1H), 0.44-0.36 (m, 1H).

[0846] MS obsd. (ESI.sup.+) [(M-C.sub.4H.sub.9+H).sup.+]: 174.1.

Intermediate 17

Benzyl (6S)-5-azaspiro[2.4]heptane-6-carboxylate hydrochloride

##STR00123##

Step 1: Preparation of 06-benzyl 05-tert-butyl (6S)-5-azaspiro[2.4]heptane-5,6-dicarboxylate

##STR00124##

[0847] To a solution of (6S)-5-tert-butoxycarbonyl-5-azaspiro[2.4]heptane-6-carboxylic acid (2.00 g, 8.29 mmol) (Wuxiapptec, Cas number: 112963444-1) and K.sub.2CO.sub.3 (2.28 g, 16.55 mmol) in DMF (40 mL) was added BnBr (1.28 mL, 10.76 mmol). The mixture was stirred at 25 C. for 12 h. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL2). The combined organic phase was washed with brine (100 mL2), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography eluted with ethyl PE/EtOAc=10/1 to 2/1 to afford O6-benzyl O5-tert-butyl (6S)-5-azaspiro[2.4]heptane-5,6-dicarboxylate (2300 mg) as colorless oil.

[0848] MS obsd. (ESI.sup.+) [(M-Boc+H).sup.+]: 232.2.

Step 2: Preparation of benzyl (6S)-5-azaspiro[2.4]heptane-6-carboxylate; hydrochloride

##STR00125##

[0849] A solution of O6-benzyl O5-tert-butyl (6S)-5-azaspiro[2.4]heptane-5,6-dicarboxylate (2.3 g, 6.94 mmol) in 4 N HCl/dioxane (10.0 mL) was stirred at 25 C. for 1 h. The mixture was concentrated in vacuum to afford benzyl (6S)-5-azaspiro[2.4]heptane-6-carboxylate; hydrochloride (1800 mg, Intermediate 17) as yellow oil. MS obsd. (ESI.sup.+) [(M+H).sup.+]: 232.2.

Intermediate 18

Benzyl (2S,4S)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-methyl-pyrrolidine-2-carboxylate

##STR00126##

[0850] The title compound was prepared in analogy to the procedure described for the preparation of Intermediate 1, by using (2S,4S)-1-tert-butoxycarbonyl-4-methyl-pyrrolidine-2-carboxylic acid (Bide, CAS number: 364750-81-2) instead of (1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid to afford benzyl (2S,4S)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-methyl-pyrrolidine-2-carboxylate (Intermediate 18) as colorless oil.

[0851] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 333.2.

Intermediate 19

(2S)-3-(1-bicyclo[1.1.1]pentanyl)-2-(tert-butoxycarbonylamino)propanoic acid

##STR00127##

Step 1: Preparation of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(3-iodo-1-bicyclo[1.1.1]pentanyl)propanoate

##STR00128##

[0852] To a solution of 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane (30 g, 101.07 mmol) in pentane (30 mL) was added methyllithium (71.73 mL, 222.36 mmol) at 45 C. dropwise. The reaction was stirred at the same temperature for 15 min under N.sub.2 protection. The reaction flask was removed from the dry ice/ethanol bath and placed in an ice-water bath. The reaction mixture was stirred at that temperature for 2 h. The volatiles were collected via a short path distillation condenser under a dry ice-ethanol environment at 50 C. to afford tricyclo[1.1.1.01,3]pentane (7.0 g) in dimethyl ether (50 mL). Boc-3-iodo-1-alanine methyl ester (7.0 g, 21.27 mmol) was added the solution and cooled to 40 C. Triethylborane (2.82 mL, 2.82 mmol) was added slowly. The resulting mixture was stirred at 20 C. for 1 h and then concentrated in vacuum. The residue was purified by reversed phase Flash (0.1% TFA in water, MeCN) to afford methyl (2S)-2-(tert-butoxycarbonylamino)-3-(3-iodo-1-bicyclo[1.1.1]pentanyl)propanoate (7.0 g) as a white solid.

[0853] .sup.1H NMR (400 MHz, CDCl.sub.3) : 4.98 (d, J=7.6 Hz, 1H), 4.30 (q, J=4.4 Hz, 1H), 3.74 (s, 3H), 2.23-2.28 (m, 6H), 2.10-2.16 (m, 1H), 1.84-1.90 (m, 1H), 1.45 (s, 9H).

[0854] MS obsd. (ESI.sup.+) [(M-Boc+H).sup.+]: 295.9.

Step 2: Preparation of methyl (2S)-3-(1-bicyclo[1.1.1]pentanyl)-2-(tert-butoxycarbonylamino)propanoate

##STR00129##

[0855] To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(3-iodo-1-bicyclo[1.1.1]pentanyl)propanoate (4.0 g, 10.12 mmol) and 2,6-lutidine (813 mg, 30.36 mmol) in pentane (30 mL) was added tris(trimethylsilyl)silane (6.24 mL, 20.24 mmol). The mixture was stirred for 20 min at 20 C., then BEt.sub.3 (0.31 mL, 1.01 mmol) was added. The resulting mixture was stirred for 30 min at 20 C. The mixture was diluted with EtOAc (50 mL), washed with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by silica gel column eluted with PE/EtOAc=50/1 to 8/1 to afford methyl (2S)-3-(1-bicyclo[1.1.1]pentanyl)-2-(tert-butoxycarbonylamino)propanoate (2.0 g) as colorless gum.

[0856] .sup.1H NMR (400 MHz, CDCl.sub.3) : 4.98 (d, J=7.6 Hz, 1H), 4.30 (q, J=4.4 Hz, 1H), 3.73 (s, 3H), 2.45 (s, 1H), 1.92-2.03 (m, 1H), 1.76-1.83 (m, 1H), 1.75 (s, 6H), 1.45 (s, 9H).

[0857] MS obsd. (ESI+) [M-Boc+H]+: 169.9.

Step 3: Preparation of methyl (2S)-3-(1-bicyclo[1.1.1]pentanyl)-2-(tert-butoxycarbonylamino)propanoic acid

##STR00130##

[0858] To a solution of methyl (2S)-3-(1-bicyclo[1.1.1]pentanyl)-2-(tert-butoxycarbonylamino)propanoate (1.03 g, 3.81 mmol) in THF (10 mL) and water (5 mL) was added LiOH.Math.H.sub.2O (480 mg, 11.43 mmol). The mixture was stirred at 25 C. for 4 h. The mixture was diluted with water (100 mL) and acidified with 1 N HCl (15 mL) to pH=4. The mixture was extracted with EtOAc (100 mL). The aqueous phase was extracted with EtOAc (50 mL). The combined organic phase was washed with brine (20 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to afford (2S)-3-(1-bicyclo[1.1.1]pentanyl)-2-(tert-butoxycarbonylamino)propanoic acid (802 mg, Intermediate 19) as yellow oil.

[0859] MS obsd. (ESI.sup.+) [(M-Boc+H).sup.+]: 156.2.

Intermediate 20

(2S)-2-(benzyloxycarbonylamino)-4,4-dimethyl-pentanoic acid

##STR00131##

Preparation of (2S)-2-(benzyloxycarbonylamino)-4,4-dimethyl-pentanoic acid

##STR00132##

[0860] To a solution of (S)-2-(((benzyloxy)carbonyl)amino)-4,4-dimethylpentanoic acid (400 mg, 2.75 mmol) in aqueous solution of NaOH (5.52 mL, 1 N) was added a solution of CbzCl (0.48 mL, 3.38 mmol) in MeCN (0.80 mL) at 0 C. slowly over 5 min. The mixture was stirred at 20 C. for 12 h. The reaction was diluted with H.sub.2O (15 mL) and acidified with 1 N HCl to pH=3. The mixture was extracted with EtOAc (30 mL3). The organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by silica gel column eluted with PE/EtOAc=2/1 to 1/1 to afford (2S)-2-(benzyloxycarbonylamino)-4,4-dimethyl-pentanoic acid (700 mg, Intermediate 20) as colorless oil.

[0861] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 280.1.

Intermediate 21

Benzyl (3S,3aS,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-3-carboxylate; 2,2,2-trifluoroacetic acid

##STR00133##

[0862] The title compound was prepared in analogy to the procedure described for the preparation of the intermediate (1R,2S,5S)-benzyl 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate of Intermediate 1, by using (3S,3aS,6aR)-2-tert-butoxycarbonyl-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid (AstaTech, CAS number: 597569-42-1) instead of (1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid to afford benzyl (3S,3aS,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-3-carboxylate; 2,2,2-trifluoroacetic acid (Intermediate 21) as yellow oil.

[0863] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 246.2.

Intermediate 22

Benzyl (3S,3aS,6aR)-2-[(2S,3R)-2-amino-3-methyl-pentanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate; 2,2,2-trifluoroacetic acid

##STR00134##

[0864] The title compound was prepared in analogy to the procedure described for the preparation of Intermediate 1, by using (3S,3aS,6aR)-2-tert-butoxycarbonyl-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid instead of (1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid and Boc-L-isoleucine instead of (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoic acid to afford benzyl (3S,3aS,6aR)-2-[(2S,3R)-2-amino-3-methyl-pentanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate; 2,2,2-trifluoroacetic acid (Intermediate 22) as yellow oil.

[0865] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 359.2.

Intermediate 23

Benzyl (3S,3aS,6aR)-2-[(2S)-2-amino-2-cyclobutyl-acetyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate; 2,2,2-trifluoroacetic acid

##STR00135##

[0866] The title compound was prepared in analogy to the procedure described for the preparation of Intermediate 1, by using (3S,3aS,6aR)-2-tert-butoxycarbonyl-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid instead of (1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid and (2S)-2-(tert-butoxycarbonylamino)-2-cyclobutyl-acetic acid (GL Biochem, CAS number: 155905-77-4) instead of (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoic acid to afford benzyl (3S,3aS,6aR)-2-[(2S)-2-amino-2-cyclobutyl-acetyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate; 2,2,2-trifluoroacetic acid (Intermediate 23) as yellow oil.

[0867] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 357.2.

Intermediate 24

Benzyl (3S,3aS,6aR)-2-[(2S)-2-amino-3-ethyl-pentanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate; 2,2,2-trifluoroacetic acid

##STR00136##

[0868] The title compound was prepared in analogy to the procedure described for the preparation of Intermediate 1, by using (3S,3aS,6aR)-2-tert-butoxycarbonyl-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid instead of (1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid and (2S)-2-(tert-butoxycarbonylamino)-3-ethyl-pentanoic acid (KaiXin Biological, CAS number: 35264-04-1) instead of (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoic acid to afford benzyl (3S,3aS,6aR)-2-[(2S)-2-amino-3-ethyl-pentanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate; 2,2,2-trifluoroacetic acid (Intermediate 24) as yellow oil.

[0869] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 373.2.

Intermediate 25

(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-pentanoic acid

##STR00137##

Step 1: Preparation of N-methoxy-N,2,2-trimethyl-butanamide

##STR00138##

[0870] To a solution of 2, 2-dimethylbutyric acid (15.0 g, 129.13 mmol) in DCM (50 mL) was added (COCl).sub.2 (32.78 g, 258.26 mmol) at 0 C. The mixture was stirred at 20 C. for 8 h and then concentrated in vacuum at 45 C. The residue was dissolve in DCM (30 mL) and added to a solution of O, N-dimethylhydroxylamine HCl (12.6 g, 129.13 mmol) and Et.sub.3N (65.33 g, 645.66 mmol) in DCM (300 mL) at 0 C. Then the mixture was stirred at 20 C. for 4 h. The reaction mixture was diluted with water (200 mL) and extracted with DCM (200 mL2). The organic phase was washed with 1 N HCl (200 mL), brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by silica gel column eluted with PE to PE/EtOAc=6/1 to afford N-methoxy-N, 2, 2-trimethyl-butanamide (15.5 g) as yellow oil.

[0871] .sup.1H NMR (400 MHz, CDCl.sub.3) : ppm 3.67 (s, 3H), 3.18 (s, 3H), 1.66 (q, J=7.6 Hz, 2H), 1.22 (s, 6H), 0.85 (t, J=7.6 Hz, 3H).

[0872] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 160.1.

Step 2: Preparation of 2,2-dimethylbutanal

##STR00139##

[0873] To a solution of N-methoxy-N,2,2-trimethyl-butanamide (5.0 g, 31.4 mmol) in THF (50 mL) was added LiAlH.sub.4/THF (47.1 mL, 47.1 mmol, 1 N) at 78 C. and stirred for 1 h at the same temperature. The reaction was quenched with H.sub.2O (1.8 mL) dropwise at 78 C. in 10 min, and then a aqueous solution of NaOH (1.8 mL, 15%) was added at 78 C. in 5 min. Then H.sub.2O (5.5 mL) was added at 78 C. in 5 min. The white suspension was warmed to 15 C. and stirred for 10 min. After the addition of Na.sub.2SO.sub.4 (10 g), the mixture was stirred at 15 C. for another 10 min. The mixture was filtered and the filter cake was washed with THF (25 mL2). The filtrate was used directly for next step.

Step 3: Preparation of 2-[[(JR)-2-hydroxy-1-phenyl-ethyl]amino]-3,3-dimethyl-pentanenitrile

##STR00140##

[0874] To a solution of 2, 2-dimethylbutanal (3.0 g, 29.95 mmol) in THF (100 mL) was added (R)-()-2-phenylglycinol (4.11 g, 29.95 mmol). The reaction was stirred at 15 C. for 2 h. After cooled to 0 C., trimethylsilyl cyanide (5.94 g, 59.9 mmol) was added at 0 C. dropwise in 15 min. The resulting mixture was stirred at 20 C. for 12 h. The reaction mixture was concentrated and the residue was purified by silica gel column eluted with PE to PE/EtOAc=4/1 to afford 2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-3, 3-dimethyl-pentanenitrile (5.0 g) as yellow oil.

[0875] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 247.2.

Step 4: Preparation of (2S)-2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-3,3-dimethyl-pentanoic acid

##STR00141##

[0876] To a solution of 2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-3,3-dimethyl-pentanoic acid (5.0 g, 18.84 mmol) in acetic acid (10 mL) was added con. HCl (20.0 mL). The reaction was stirred at 80 C. for 12 h. The reaction solution was concentrated and the residue was purified by Prep-HPLC (Phenomenex luna C18 (250*70 mm, 10 um), water (0.1% HCl)-CAN, 20-30%, 140 ml/min) to afford (2S)-2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-3,3-dimethyl-pentanoic acid (2.5 g) as a white solid.

[0877] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 7.40-7.32 (m, 5H), 5.31-5.05 (m, 1H), 3.69-3.52 (m, 3H), 2.77 (s, 1H), 1.39-1.24 (m, 2H), 0.88-0.81 (m, 6H), 0.57 (t, J=7.6 Hz, 3H).

[0878] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 266.1.

Step 5: Preparation of (2S)-2-amino-3,3-dimethyl-pentanoic acid

##STR00142##

[0879] To a solution of (2S)-2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-3,3-dimethyl-pentanoic acid (2.5 g, 9.42 mmol) in methanol (60 mL) and acetic acid (40 mL) was added Pd(OH).sub.2 (750 mg). The suspension was degassed with H.sub.2 for 3 times and stirred for 16 h at 20 C. under a H.sub.2 balloon. The suspension was filtered and the filtrate was concentrated in vacuum to afford (2S)-2-amino-3,3-dimethyl-pentanoic acid; acetic acid (1.93 g) as a white solid.

[0880] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 146.2.

Step 6: Preparation of (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-pentanoic acid

##STR00143##

[0881] To a solution of (2S)-2-amino-3,3-dimethyl-pentanoic acid; acetic acid (1.78 g, 8.67 mmol) in THF (40 mL) and water (40 mL) was added Na.sub.2CO.sub.3 (4.59 g, 43.33 mmol) and (Boc).sub.2O (2.84 g, 12.99 mmol) successively. The suspension was stirred at 20 C. for 12 h. The suspension was diluted with H.sub.2O (40 mL) and extracted with EtOAc (50 mL3). The aqueous phase was acidified with 1 N HCl to pH=4 and extracted with EtOAc (50 mL3). The organic phase was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum to afford (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-pentanoic acid (1.8 g, Intermediate 25) as colorless oil.

[0882] .sup.1H NMR (400 MHz, CDCl.sub.3) : ppm 5.05-5.04 (m, 1H), 4.21 (d, J=9.2 Hz, 1H), 2.11 (s, 1H), 1.46 (s, 9H), 1.50 (q, J=7.2 Hz, 2H), 0.97 (s, 6H), 0.91 (t, J=7.2 Hz, 3H).

[0883] MS obsd. (ESI.sup.+) [(M+Na).sup.+]: 268.1.

Intermediate 26

Benzyl N-amino-N-(3-amino-3-oxo-propyl)carbamate

##STR00144##

Step 1: Preparation of tert-butyl N-[(3-amino-3-oxo-propyl)amino]carbamate

##STR00145##

[0884] To a solution of tert-butyl hydrazinecarboxylate (10.0 g, 75.67 mmol) in iPrOH (100 mL) was added acrylamide (5.38 g, 75.67 mmol). The reaction mixture was stirred at 70 C. for 3 h. The mixture was concentrated and the residue was dissolved in ethyl acetate (60 mL), washed with 1 N HCl (30 mL), brine (20 mL) and dried over anhydrous Na.sub.2SO.sub.4. After filtration and concentration, tert-butyl 2-(3-amino-3-oxopropyl)hydrazine-1-carboxylate (8 g) was obtained as colorless oil.

Step 2: Preparation of benzyl N-(3-amino-3-oxo-propyl)-N-(tert-butoxycarbonylamino)carbamate

##STR00146##

[0885] To a solution of tert-butyl 2-(3-amino-3-oxopropyl)hydrazine-1-carboxylate (1.2 g, 5.9 mmol) was added benzyl (2,5-dioxopyrrolidin-1-yl) carbonate (1.47 g, 5.9 mmol) in DMF (30 mL) at 25 C. The mixture was stirred at 25 C. for 12 h. The reaction mixture was diluted with H.sub.2O (100 mL) and extracted with EtOAc (100 mL3). The organic phase was washed with brine (80 mL3), dried over Na.sub.2SO.sub.4, concentrated in vacuum. The residue was purified by silica gel column eluted with DCM to DCM/MeOH=10/1 to afford benzyl N-(3-amino-3-oxo-propyl)-N-(tert-butoxycarbonylamino)carbamate (580 mg) as a white solid.

[0886] MS obsd. (ESI.sup.+) [(M+Na).sup.+]: 360.1.

Step 3: Preparation of benzyl N-amino-N-(3-amino-3-oxo-propyl)carbamate; 2,2,2-trifluoroacetic acid

##STR00147##

[0887] To a solution of benzyl N-(3-amino-3-oxo-propyl)-N-(tert-butoxycarbonylamino)carbamate (500 mg, 1.48 mmol) in DCM (3 mL) was added TFA (3 mL). The reaction mixture was stirred at 20 C. for 1 h. The mixture was concentrated in vacuum to afford benzyl N-amino-N-(3-amino-3-oxo-propyl)carbamate 2,2,2-trifluoroacetic acid (520 mg, Intermediate 26) as yellow oil which was used directly for the next step.

Intermediate 27

Trans-methyl 1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-3-carboxylate

##STR00148##

Step 1: Preparation of 1,3a,4,5,6,6a-hexahydrocyclopenta[c]pyrrole

##STR00149##

[0888] To a stirred solution of 13% NaClO/H.sub.2O (11.78 mL) and MTBE (10 mL) was added 3-azabicyclo[3.3.0]octane hydrochloride (2.0 g, 13.55 mmol) (Accela, CAS number: 112626-50-3) at 0 C. Then the reaction mixture was stirred at 0 C. for 3 h. The reaction mixture was warmed to room temperature and diluted with MTBE (20 mL). The organic phase was added to a stirred solution of 25% wt. aqueous NaOH/H.sub.2O (8.64 mL) and TBAB (280.0 mg, 0.870 mmol). The mixture stirred at room temperature for 1 h and at 50 C. for 48 h. The reaction mixture was cooled to room temperature and washed with 20% brine (10 mL). The organic phase was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum to afford 1,3a,4,5,6,6a-hexahydrocyclopenta[c]pyrrole (1.23 g) as a white solid.

[0889] .sup.1H NMR (400 MHz, CDCl.sub.3) : ppm 7.31 (s, 1H), 4.10-4.03 (m, 1H), 3.57-3.51 (m, 1H), 3.29 (t, J=8.0 Hz, 1H), 2.71-2.63 (m, 1H), 1.70-1.65 (m, 3H), 1.60-1.54 (m, 1H), 1.42-1.38 (m, 1H), 1.30-1.26 (m, 1H).

Step 2: Preparation of trans-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-3-carbonitrile

##STR00150##

[0890] To a solution of 1,3a,4,5,6,6a-hexahydrocyclopenta[c]pyrrole (1.23 g, 11.27 mmol) in DCM (10 mL) was added methanol (1.23 mL) slowly, followed by TMSCN (2.79 g, 28.17 mmol) at 0 C. The mixture was stirred at 10 C. for 3 h. The reaction mixture was concentrated in vacuum and the residue was purified by silica gel column eluted with PE to PE/EtOAc=1/1 to afford trans-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-3-carbonitrile (1.2 g) as yellow oil.

[0891] .sup.1H NMR (400 MHz, CDCl.sub.3) : ppm 3.67 (d, J=2.4 Hz, 1H), 3.24 (dd, J=10.0 Hz, 7.6 Hz, 1H), 2.83-2.76 (m, 2H), 2.72-2.64 (m, 1H), 1.99-1.82 (m, 3H), 1.70-1.61 (m, 1H), 1.49-1.43 (m, 1H), 1.41-1.33 (m, 2H).

Step 3: Preparation of trans-methyl 1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-3-carboxylate

##STR00151##

[0892] A solution of (3S,3aS,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-3-carbonitrile (1.2 g, 8.81 mmol) in HCl/MeOH (11.0 mL, 4 N) was stirred for 2 h at 25 C. The reaction mixture was concentrated in vacuum to remove HCl/MeOH. The residue was diluted with EtOAc (80 mL) and washed with saturated aqueous solution of Na.sub.2CO.sub.3 (40 mL). The aqueous layer was extracted with EtOAc (50 mL5). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum to afford trans-methyl 1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-3-carboxylate (1.1 g, Intermediate 27) as yellow oil.

[0893] .sup.1H NMR (400 MHz, CDCl.sub.3) : ppm 3.73 (s, 3H), 3.31-3.27 (m, 2H), 2.62-2.57 (m, 2H), 2.52-2.48 (m, 1H), 2.15 (br s, 1H), 1.78-1.74 (m, 1H), 1.67-1.56 (m, 4H), 1.44-1.38 (m, 1H).

Intermediate 28

(2S)-2-chloro-2-fluoro-acetyl chloride

##STR00152##

Step 1: Preparation of (2S)-2-chloro-2-fluoro-acetic acid

##STR00153##

[0894] To a solution of 2-chloro-2-fluoro-acetic acid (160.0 g, 1.42 mol) in EtOAc (600 mL) was added (R)-1-phenylethanamine (186.1 g, 1.54 mol) in EtOAc (600 mL) at 0 C. The reaction was stirred at 0 C. for 2 h. The reaction mixture was filtered and the filter cake was triturated in acetone (720 g, 2.2 L) at 80 C. for 1 h. The resulting solution was slowly cooled to 30 C. and stirred at 30 C. for 16 hous. The trituration was repeated for four times. Optical Rotation (C=3.8 g/100 mL in MeOH at 25 C., salt) showed the specific rotation was +10.896. The suspension was filtered, filter cake dissolved in water (1 L), and then acidified with 1N HCl (1.5 L). The mixture was extracted with MTBE (500 mL10). The combined organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated to afford (2S)-2-chloro-2-fluoro-acetic acid (138.88 g) as a brown liquid.

[0895] .sup.1H NMR (400 MHz, CDCl.sub.3) : ppm 10.12 (s, 1H), 6.26 (d, J=50.4 Hz, 1H).

Step 2: Preparation of (2S)-2-chloro-2-fluoro-acetyl chloride

##STR00154##

[0896] To PCl.sub.5 (28.5 g, 136.65 mmol) was added (2S)-2-chloro-2-fluoro-acetic acid (21.3 g, 124.02 mmol) dropwise at 0 C. under N.sub.2 with stirring (the internal temperature of the suspension did not over 5 C.) for 1 h. The suspension was warmed to 25 C. for 30 min and stirred at 25 C. for 1 h to give a clear solution. The solution was heated to 70 C. and stirred at 70 C. for 1 h. .sup.1H-NMR showed starting material was consumed completely and desired product was formed. The mixture was purified by distillation (70 C., 30 mmHg) to obtained (2S)-2-chloro-2-fluoro-acetyl chloride (42.0 g, Intermediate 28) as colorless liquid.

[0897] .sup.1H NMR (400 MHz, CDCl.sub.3) : ppm 6.47-6.24 (m, 1H).

Alternative Synthetic Method

##STR00155##

[0898] To a solution of (2S)-2-chloro-2-fluoro-acetic acid (1478 mg, 7.89 mmol, 60% purity) in DCM (15 mL) was added oxalyl chloride (841 mg, 6.62 mmol) and 5 drops of DMF at 0 C. Then the mixture was stirred at 25 C. for 1 hr. The solution was used for next step without further purification.

Intermediate 29

Methyl (1R,2S,5S)-3-[(2S,3R)-2-amino-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; 2,2,2-trifluoroacetic acid

##STR00156##

Step 1: Preparation of methyl (1R,2S,5S)-3-[(2S,3R)-2-(tert-butoxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate

##STR00157##

[0899] To a solution of Boc-L-isoleucine (25.0 g, 108.09 mmol) in DMF (200 mL) was added DIPEA (69.88 g, 540.62 mmol). After cooling to 0 C., to the mixture was added HATU (51.5 g, 135.44 mmol) and methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; hydrochloride (23.37 g, 113.65 mmol). Then the reaction mixture was stirred at 15 C. for 12 h. The reaction mixture was poured into water (300 mL) and extracted with EtOAc (300 mL3). The combined organic phase was washed with brine (300 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by silica gel column eluted with PE/EtOAc=5/1 to afford methyl (1R,2S,5S)-3-[(2S,3R)-2-(tert-butoxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (35.0 g) as yellow oil.

[0900] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 383.2.

Step 2: Preparation of methyl (1R,2S,5S)-3-[(2S,3R)-2-amino-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; 2,2,2-trifluoroacetic acid

##STR00158##

[0901] To a solution of methyl (1R,2S,5S)-3-[(2S,3R)-2-(tert-butoxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (5.0 g, 13.07 mmol) in DCM (30 mL) was added TFA (30.0 mL). The reaction mixture was stirred at 25 C. for 30 min. The reaction mixture was concentrated in vacuum to afford methyl (1R,2S,5S)-3-[(2S,3R)-2-amino-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; 2,2,2-trifluoroacetic acid (5.0 g, Intermediate 29) as yellow oil.

[0902] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 283.4.

Intermediate 30

Methyl (1R,2S,5S)-3-[(2S)-2-amino-3-ethyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; 2,2,2-trifluoroacetic acid

##STR00159##

[0903] The title compound was prepared in analogy to the procedure described for the preparation of Intermediate 29, by using (2S)-2-(tert-butoxycarbonylamino)-3-ethyl-pentanoic acid (KaiXin Biological, CAS number: 35264-04-1) instead of Boc-L-isoleucine to afford methyl (1R,2S,5S)-3-[(2S)-2-amino-3-ethyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; 2,2,2-trifluoroacetic acid (Intermediate 30) as yellow oil.

[0904] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 297.0.

Intermediate 31

Benzyl (1R,2S,5S)-3-[(2S)-2-amino-3-ethyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; hydrochloride

##STR00160##

[0905] The title compound was prepared in analogy to the procedure described for the preparation of Intermediate 1, by using (2S)-2-(tert-butoxycarbonylamino)-3-ethyl-pentanoic acid (KaiXin Biological, CAS number: 35264-04-1) instead of (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoic acid to afford benzyl (1R,2S,5S)-3-[(2S)-2-amino-3-ethyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; hydrochloride (Intermediate 31) as yellow oil.

[0906] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 373.4.

Intermediate 32

Benzyl (2S)-1-[(2S)-2-amino-3-ethyl-pentanoyl]-4,4-dimethyl-pyrrolidine-2-carboxylate; hydrochloride

##STR00161##

[0907] The title compound was prepared in analogy to the procedure described for the preparation of Intermediate 1, by using (2S)-4,4-dimethylpyrrolidine-2-carboxylic acid; hydrochloride (Porse Fine Chemical, CAS number: 1443252-76-3) instead of (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid; hydrochloride, and (2S)-1-tert-butoxycarbonyl-4,4-dimethyl-pyrrolidine-2-carboxylic acid instead of (1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid to afford benzyl (2S)-1-[(2S)-2-amino-3-ethyl-pentanoyl]-4,4-dimethyl-pyrrolidine-2-carboxylate; hydrochloride (Intermediate 32) as yellow oil.

[0908] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 361.3.

Intermediate 33

(2S)-2-(benzyloxycarbonylamino)-3,3-dimethyl-pentanoic acid

##STR00162##

Preparation of (2S)-2-(benzyloxycarbonylamino)-3,3-dimethyl-pentanoic acid

##STR00163##

[0909] To a solution of (2S)-2-amino-3,3-dimethyl-pentanoic acid; acetic acid (900 mg, 4.38 mmol, from Intermediate 25, step 5) in water (10 mL) and THF (10 mL) was added Na.sub.2CO.sub.3 (1.4 g, 13.21 mmol). After cooling to 0 C., to the mixture was added CbzCl (1.13 g, 6.62 mmol). The reaction mixture was stirred at 20 C. for 12 h. The suspension was diluted with H.sub.2O (20 mL) and extracted with EtOAc (40 mL). The aqueous phase was acidified with 1N HCl to pH=2 and extracted with EtOAc (40 mL3). The organic phase was dried with Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by reverse flash (condition: 120 g Flash Column Welch Ultimate XB_C18 20-40 m; 120 A, water (0.1% TFA)-ACN, 30-60%, 65 ml/min) to afford (2S)-2-(benzyloxycarbonylamino)-3,3-dimethyl-pentanoic acid (440.0 mg) as colorless oil.

[0910] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 280.1.

Intermediate 34

Benzyl (3S,3aS,6aR)-2-[(2S)-2-amino-3,3-dimethyl-pentanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate; hydrochloride

##STR00164##

[0911] The title compound was prepared in analogy to the procedure described for the preparation of Intermediate 1, by using (3S,3aS,6aR)-2-tert-butoxycarbonyl-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid instead of (1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid, and (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-pentanoic acid (Intermediate 25) instead of (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoic acid to afford benzyl (3S,3aS,6aR)-2-[(2S)-2-amino-3,3-dimethyl-pentanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate (Intermediate 34) as colorless oil.

[0912] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 373.2.

Intermediate 35

Benzyl (2S)-1-[(2S)-2-amino-3,3-dimethyl-pentanoyl]-4,4-dimethyl-pyrrolidine-2-carboxylate; hydrochloride

##STR00165##

[0913] The title compound was prepared in analogy to the procedure described for the preparation of Intermediate 1, by using (2S)-4,4-dimethylpyrrolidine-2-carboxylic acid; hydrochloride (Porse Fine Chemical, CAS number: 1443252-76-3) instead of (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid; hydrochloride, and (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-pentanoic acid (Intermediate 25) instead of (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoic acid (BePharm, CAS number: 62965-35-9) to afford benzyl (2S)-1-[(2S)-2-amino-3,3-dimethyl-pentanoyl]-4,4-dimethyl-pyrrolidine-2-carboxylate; hydrochloride (Intermediate 35) as yellow oil.

[0914] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 361.2.

Intermediate 36

Benzyl 1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-3,3-dimethyl-pyrrolidine-2-carboxylate; 2,2,2-trifluoroacetic acid

##STR00166##

[0915] The title compound was prepared in analogy to the procedure described for the preparation of Intermediate 1, by using 3,3-dimethylpyrrolidine-2-carboxylic acid; hydrochloride (Chengdu AstaTech, CAS number: 61406-78-8) instead of (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid; hydrochloride to afford benzyl 1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-3,3-dimethyl-pyrrolidine-2-carboxylate; 2,2,2-trifluoroacetic acid (Intermediate 36) as yellow oil.

[0916] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 347.2.

Intermediate 37

(1R,2S,5S)-3-[(2S)-2-amino-2-cyclobutyl-acetyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; 2,2,2-trifluoroacetic acid

##STR00167##

[0917] The title compound was prepared in analogy to the procedure described for the preparation of Intermediate 1, by using (2S)-2-(tert-butoxycarbonylamino)-2-cyclobutyl-acetic acid (GL Biochem, CAS number: 155905-77-4) instead of (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoic acid to afford (1R,2S,5S)-3-[(2S)-2-amino-2-cyclobutyl-acetyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; 2,2,2-trifluoroacetic acid (Intermediate 37) as yellow oil.

[0918] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 357.2.

Intermediate 38

Benzyl (2S,4R)-1-[(2S,3S)-2-amino-3-methyl-pentanoyl]-4-(trifluoromethyl)pyrrolidine-2-carboxylate; 2,2,2-trifluoroacetaldehyde

##STR00168##

[0919] The title compound was prepared in analogy to the procedure described for the preparation of Intermediate 1, by using (2S,4R)-1-tert-butoxycarbonyl-4-(trifluoromethyl)pyrrolidine-2-carboxylic acid (PharmaBlock, CAS number: 470482-44-1) instead of (1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid, and Boc-Ile-OH instead of (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoic acid to afford benzyl (2S,4R)-1-[(2S,3S)-2-amino-3-methyl-pentanoyl]-4-(trifluoromethyl)pyrrolidine-2-carboxylate; 2,2,2-trifluoroacetaldehyde (Intermediate 38) as yellow oil.

[0920] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 387.1.

Intermediate 39a and 39b

Tert-butyl N-amino-N-[[(3S)-2-oxo-3-piperidyl]methyl]carbamate and tert-butyl N-amino-N-[[(3R)-2-oxo-3-piperidyl]methyl]carbamate

##STR00169##

Step 1: Preparation of tert-butyl 3-methylene-2-oxo-piperidine-1-carboxylate

##STR00170##

To a solution of 1-Boc-2-piperidone (45.0 g, 225.85 mmol, Bidepharm, CAS number: 85908-96-9) in THF (500 mL) was added LiHMDS (474.3 mL, 474.3 mmol) at 0 C. under N.sub.2 atmosphere. The reaction mixture was stirred at 20 C. for 30 min and then cooled to 0 C. To the mixture was added 2,2,2-trifluoroethyl trifluoroacetate (62.75 g, 320.06 mmol) at 0 C. Then the mixture was stirred at 20 C. for 50 min. The reaction was quenched with saturated NH.sub.4Cl (500 mL) and extracted with EtOAc (300 mL2). The organic layers were washed with brine (100 mL3), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was dissolved in toluene (500 mL). To the solution was added paraformaldehyde (20.3 g, 677.54 mmol) and K.sub.2CO.sub.3 (68.7 g, 496.86 mmol). The reaction mixture was stirred at 110 C. for 2 h under N.sub.2 atmosphere. The reaction was diluted with EtOAc (250 mL) and water (250 mL). The mixture was extracted with EtOAc (200 mL2). The organic layers were washed with brine (150 mL3), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum to afford tert-butyl 3-methylene-2-oxo-piperidine-1-carboxylate (26.5 g, crude) as yellow oil.

[0921] MS obsd. (ESI.sup.+) [(M-tBu+H).sup.+]: 156.0.

Step 2: Preparation of tert-butyl 3-[(2-benzyloxycarbonylhydrazino)methyl]-2-oxo-piperidine-1-carboxylate

##STR00171##

[0922] To a solution of tert-butyl 3-methylene-2-oxo-piperidine-1-carboxylate (26.5 g, 125.4 mmol) in i-PrOH (300 mL) was added benzyl carbazate (20.85 g, 125.44 mmol). The mixture was degassed with N.sub.2 for 3 times. The resulting mixture was stirred at 85 C. for 12 h. The mixture was concentrated in vacuum to afford tert-butyl 3-[(2-benzyloxycarbonylhydrazino)methyl]-2-oxo-piperidine-1-carboxylate (47.3 g, crude) as yellow oil.

[0923] MS obsd. (ESI.sup.+) [(M-Boc+H).sup.+]: 278.4.

Step 3: Preparation of benzyl N-[(2-oxo-3-piperidyl)methylamino]carbamate; 2,2,2-trifluoroacetic acid

##STR00172##

[0924] To a solution of tert-butyl 3-[(2-benzyloxycarbonylhydrazino)methyl]-2-oxo-piperidine-1-carboxylate (47.3 g, 125.3 mmol) in DCM (320 mL) was added TFA (250.0 mL). The mixture was stirred at 20 C. for 30 min and concentrated in vacuum to afford benzyl N-[(2-oxo-3-piperidyl)methylamino]carbamate; 2,2,2-trifluoroacetic acid (49.0 g, crude) as yellow oil.

[0925] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 278.1.

Step 4: Preparation of tert-butyl N-(benzyloxycarbonylamino)-N-[(2-oxo-3-piperidyl)methyl]carbamate

##STR00173##

[0926] To a solution of benzyl N-[(2-oxo-3-piperidyl)methylamino]carbamate; 2,2,2-trifluoroacetic acid (49.0 g, 125.2 mmol) in methanol (500 mL) was added DIPEA (80.9 g, 626.1 mmol) and Boc.sub.2O (32.9 g, 162.8 mmol) at 0 C. Then the mixture was stirred at 50 C. for 12 h and at 80 C. for another 12 h. The resulting mixture was concentrated in vacuum and the residue was purified by reverse flash and silica gel column to afford tert-butyl N-(benzyloxycarbonylamino)-N-[(2-oxo-3-piperidyl)methyl]carbamate (3.07 g) as a light yellow solid. 10 g of the racemic product was split by prep-SFC (Sample preparation: Add MeOH 400 mL into sample; Instrument: Thr 80; Mobile Phase: 45% MeOH (NEU) in Supercritical CO.sub.2; Flow Rate: 70 g/min; Cycle Time: 4.62 min, total time: 600 min; Single injection volume: 3.5 mL; Back Pressure: 100 bar to keep the CO.sub.2 in Supercritical flow) afford tert-butyl N-(benzyloxycarbonylamino)-N-[[(3R)-2-oxo-3-piperidyl]methyl]carbamate (retention time: 3.49 min) (4.1 g) and tert-butyl N-(benzyloxycarbonylamino)-N-[[(3S)-2-oxo-3-piperidyl]methyl]carbamate (retention time: 4.83 min) (4.2 g) as yellow oil.

[0927] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 378.2.

Step 5: Preparation of tert-butyl N-amino-N-[(2-oxo-3-piperidyl)methyl]carbamate

##STR00174##

[0928] To a solution of tert-butyl N-(benzyloxycarbonylamino)-N-[(2-oxo-3-piperidyl)methyl]carbamate (1.0 g, 2.65 mmol) in methanol (20 mL) was added Pd(OH).sub.2 (50 mg) and Pd/C (50 mg, 10% purity) under N.sub.2 atmosphere. The suspension was degassed with H.sub.2 for 3 times. The resulting mixture was stirred at 25 C. for 12 h under a H.sub.2 balloon. The suspension was filtered and the filtrate was concentrated in vacuum to afford the racemic tert-butyl N-amino-N-[(2-oxo-3-piperidyl)methyl]carbamate (570 mg, racemic) as light yellow oil.

[0929] MS obsd. (ESI.sup.+) [(M-Boc+H).sup.+]: 144.2.

Step 6: Preparation of tert-butyl N-amino-N-[[(3S)-2-oxo-3-piperidyl]methyl]carbamate

##STR00175##

[0930] To a solution of tert-butyl N-(benzyloxycarbonylamino)-N-[[(3S)-2-oxo-3-piperidyl]methyl]carbamate (3.6 g, 9.54 mmol) in methanol (40 mL) was added Pd(OH).sub.2 (200 mg) and Pd/C (200.0 mg, 10% purity). The mixture was degassed with H.sub.2 for 3 times and stirred at 25 C. for 2 h under H.sub.2 balloon. The reaction mixture was filtered and the filtrate was concentrated in vacuum to afford tert-butyl N-amino-N-[[(3S)-2-oxo-3-piperidyl]methyl]carbamate (2.3 g, Intermediate 39a) as colorless oil.

[0931] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 244.4.

Step 7: Preparation of tert-butyl N-amino-N-[[(3R)-2-oxo-3-piperidyl]methyl]carbamate

##STR00176##

[0932] To a solution of tert-butyl N-(benzyloxycarbonylamino)-N-[[(3S)-2-oxo-3-piperidyl]methyl]carbamate (3.6 g, 9.54 mmol) in methanol (20 mL) was added Pd(OH).sub.2 (360 mg) and Pd/C (360 mg, 10% purity). The mixture was degassed with H.sub.2 for 3 times and stirred at 25 C. for 2 h under H.sub.2 balloon. The reaction mixture was filtered and the filtrate was concentrated in vacuum to afford tert-butyl N-amino-N-[[(3S)-2-oxo-3-piperidyl]methyl]carbamate (2.3 g, Intermediate 39b) as colorless oil.

[0933] MS obsd. (ESI+) [(M-Boc+H)+]: 144.2.

[0934] Intermediate 39a was used in the preparation of N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide (Example 165a), which was crystallized and analyzed by single crystal X-ray diffraction (FIG. 1). This confirmed the absolute configuration of Intermediate 39a being (S)-configuration and corresponding pressure tert-butyl N-(benzyloxycarbonylamino)-N-[[(3S)-2-oxo-3-piperidyl]methyl]carbamate. The enantiomer of 39a was designated to be (R)-configuration (39b).

[0935] The procedure of preparation of N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide was as follows.

Step 1: Preparation of methyl (1R,2S,5S)-3-[(2S,3S)-2-(tert-butoxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate

##STR00177##

[0936] To a solution of Boc-Ile-OH (96.0 g, 415.06 mmol) in DMF (192 mL) and MeCN (1536 mL) were added methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; hydrochloride (89.64 g, 435.82 mmol) and HATU (173.6 g, 456.57 mmol) at 0 C. under N.sub.2 to give a colorless solution, followed by drop-wise addition of DIPEA (216.88 mL, 1245.19 mmol) at 0 C. under N.sub.2 to give a light yellow solution. The reaction was then allowed to warm to 20 C. and was stirred for 16 h under N.sub.2 atmosphere and concentrated in vacuum. The residue was added to ethyl acetate (2400 mL) and water (3600 mL). The resulting suspension was filtered and the filter cake was washed with ethyl acetate (500 mL), and the filter cake was dried in vacuum to give methyl (1R,2S,5S)-3-[(2S,3S)-2-(tert-butoxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (75.0 g) as a white solid.

[0937] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 383.2.

Step 2: Preparation of (1R,2S,5S)-3-[(2S,3S)-2-(tert-butoxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid

##STR00178##

[0938] To a solution of methyl (1R,2S,5S)-3-[(2S,3S)-2-(tert-butoxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (50.0 g, 130.72 mmol) in THF (500 mL). The mixture was added a solution of LiOH.Math.H.sub.2O (10.97 g, 261.4 mmol) in water (500 mL). Then the mixture was stirred at 25 C. for 2 h. The reaction mixture was poured into ice/water (300 mL) and acidified with 12N HCl to pH=5. Then the mixture was extracted with EA (500 ml2). The combined organic phases were washed with brine (100 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuum to give (1R,2S,5S)-3-[(2S,3S)-2-(tert-butoxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (48.1 g) as yellow oil.

[0939] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 369.2.

Step 3: Preparation of (1R,2S,5S)-3-[(2S,3S)-2-amino-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid; hydrochloride

##STR00179##

[0940] To a solution of (1R,2S,5S)-3-[(2S,3S)-2-(tert-butoxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (48.1 g, 130.54 mmol) in DCM (500 mL) was added HCl/dioxane (500.0 mL, 2000.0 mmol). The mixture was stirred at 25 C. for 2 h and concentrated in vacuum to afford (1R,2S,5S)-3-[(2S,3S)-2-amino-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid; hydrochloride (39.8 g) as a yellow foam.

Step 4: Preparation of (1R,2S,5S)-6,6-dimethyl-3-[(2S,3S)-3-methyl-2-[(2,2,2-trifluoroacetyl)amino]pentanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxylic acid

##STR00180##

[0941] To a solution of (1R,2S,5S)-3-[(2S,3R)-2-amino-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid; hydrochloride (39.79 g, 130.54 mmol) in methanol (400 mL) was added TEA (79.26 g, 783.24 mmol) dropwise at 0 C., followed by ethyl trifluoroacetate (55.64 g, 391.62 mmol). Then the mixture was warmed to 50 C. and stirred at 50 C. for 12 h. The mixture was diluted in EtOAc (500 mL), washed with brine (300 ml), dried over Na.sub.2SO.sub.4 and concentrated to give (1R,2S,5S)-6,6-dimethyl-3-[(2S,3S)-3-methyl-2-[(2,2,2-trifluoroacetyl)amino]pentanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (45.0 g) as a yellow foam.

[0942] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 365.1.

Step 5: Preparation of tert-butyl N-[[(1R,2S,5S)-6,6-dimethyl-3-[(2S,3S)-3-methyl-2-[(2,2,2-trifluoroacetyl)amino]pentanoyl]-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxo-3-piperidyl]methyl]carbamate

##STR00181##

[0943] To a solution of (1R,2S,5S)-6,6-dimethyl-3-[(2S,3S)-3-methyl-2-[(2,2,2-trifluoroacetyl)amino]pentanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (150 mg, 0.41 mmol) in DMF (5 mL) was added DIPEA (266 mg, 2.06 mmol). After cooling to 0 C., to the mixture was added HOPO (55 mg, 0.49 mmol), EDCI (157 mg, 0.49 mmol) and tert-butyl N-amino-N-[[(3S)-2-oxo-3-piperidyl]methyl]carbamate (100 mg, 0.41 mmol). Then the mixture was stirred at 30 C. for 12 h. The resulting mixture was poured into water (30 mL) at 25 C. with stirring, extracted with EtOAc (50 mL2). The combined organic phase was washed brine (40 mL2), followed by 1N HCl (50 mL), 10% aqueous K.sub.2CO.sub.3 solution (50 mL) and brined (30 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuum to afford tert-butyl N-[[(1R,2S,5S)-6,6-dimethyl-3-[(2S,3S)-3-methyl-2-[(2,2,2-trifluoroacetyl)amino]pentanoyl]-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxo-3-piperidyl]methyl]carbamate (242 mg) as a white solid.

[0944] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 590.5.

Step 6: Preparation of N-[(1S,2S)-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(3S)-2-oxo-3-piperidyl]methylamino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide

##STR00182##

[0945] To a solution of tert-butyl N-[[(1R,2S,5S)-6,6-dimethyl-3-[(2S,3S)-3-methyl-2-[(2,2,2-trifluoroacetyl)amino]pentanoyl]-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxo-3-piperidyl]methyl]carbamate (242 mg, 0.41 mmol) in DCM (6 mL) was added TFA (3.0 mL). The mixture was stirred at 25 C. for 1 h. The resulting mixture was concentrated in vacuum and the residue was purified by reverse flash (120 g Flash Column; Welch Ultimate XB_C18 20-40 m; 35 min; 75 mL/min, ACN-Water, 0.1% HCl to afford N-[(1S,2S)-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(3S)-2-oxo-3-piperidyl]methylamino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide; hydrochloride (182 mg) as a white solid.

[0946] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 490.2.

Step 7: Preparation of N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide

##STR00183##

[0947] To a solution of (2R)-2-chloro-2-fluoro-acetic acid (126 mg, 0.69 mmol) in DCM (2 mL) was added POCl.sub.3 (95 mg, 0.62 mmol). The solution was stirred at 25 C. for 1 h. The resulting solution was added dropwise to a solution of N-[(1S,2S)-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(3S)-2-oxo-3-piperidyl]methylamino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide; hydrochloride (182 mg, 0.35 mmol) and DIPEA (447 mg, 3.46 mmol) in DCM (2 mL) at 5 C. The mixture was stirred at the same temperature for 1 h. The reaction was quenched with methanol (2 mL) and 4N HCl/dioxane (2 mL) at 5 C. The resulting mixture was concentrated in vacuum at room temperature. The residue was purified by reverse flash (120 g Flash Column; Welch Ultimate XB_C18 20-40 m; 35 min; 75 mL/min, ACN-Water, 0.1% FA) to afford N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide (120 mg) as a white solid.

[0948] 2 mg of N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide was crystalized in a mixed solvent of MeOH and water (0.2 ml, v/v=4/1) at room temperature to afford a transparence crystal.

[0949] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 11.16 (s, 1H), 9.97 (d, J=7.6 Hz, 1H), 7.57 (s, 1H), 6.90-6.70 (m, 1H), 4.21 (dd, J=10.4 Hz, 7.6 Hz, 1H), 4.15 (s, 1H), 4.00 (dd, J=14.0 Hz, 9.6 Hz, 1H), 3.94-3.83 (m, 2H), 3.46 (dd, J=13.6 Hz, 4.0 Hz, 1H), 3.15-3.07 (m, 2H), 2.48-2.42 (m, 1H), 1.99-1.88 (m, 1H), 1.87-1.73 (m, 2H), 1.69-1.65 (m, 1H), 1.63-1.54 (m, 1H), 1.53-1.40 (m, 3H), 1.17-1.08 (m, 1H), 1.06 (s, 3H), 0.92 (s, 3H), 0.87 (d, J=6.8 Hz, 3H), 0.82 (d, J=7.2 Hz, 3H).

[0950] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 584.2.

Intermediate 40

Benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; 2,2,2-trifluoroacetic acid

##STR00184##

[0951] The title compound was prepared in analogy to the procedure described for the preparation of Intermediate 1, by using (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-pentanoic acid (Intermediate 25) instead of (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoic acid to afford benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; 2,2,2-trifluoroacetic acid (Intermediate 40) as yellow oil.

Intermediate 41

Benzyl (3S,3aS,6aR)-2-[(2S,3S)-2-amino-3-methyl-pentanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate; hydrochloride

##STR00185##

[0952] The title compound was prepared in analogy to the procedure described for the preparation of Intermediate 1, by using (3S,3aS,6aR)-2-tert-butoxycarbonyl-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid instead of (1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid and Boc-Ile-OH instead of (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoic acid to afford benzyl (3S,3aS,6aR)-2-[(2S,3S)-2-amino-3-methyl-pentanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate; hydrochloride (Intermediate 41) as yellow oil.

[0953] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 359.3.

Intermediate 42

Benzyl (1R,2S,5S)-3-[(2S)-2-amino-4,4-dimethyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; 2,2,2-trifluoroacetic acid

##STR00186##

[0954] The title compound was prepared in analogy to the procedure described for the preparation of Intermediate 1, by (2S)-2-(benzyloxycarbonylamino)-4,4-dimethyl-pentanoic acid (Intermediate 20) instead of (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoic acid to afford benzyl (1R,2S,5S)-3-[(2S)-2-amino-4,4-dimethyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; 2,2,2-trifluoroacetic acid (Intermediate 43) as colorless oil.

[0955] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 373.3.

Intermediate 43

(2S)-4,4-dimethylpyrrolidine-2-carboxylate; 2,2,2-trifluoroacetic acid

##STR00187##

Step 1: Preparation of O1-tert-butyl O2-methyl (2S)-4,4-dimethylpyrrolidine-1,2-dicarboxylate

##STR00188##

[0956] To a solution of (2S)-1-tert-butoxycarbonyl-4,4-dimethyl-pyrrolidine-2-carboxylic acid (500 mg, 2.06 mmol) in DMF (10 mL) was added K.sub.2CO.sub.3 (852.07 mg, 6.17 mmol) and Mel (875 mg, 6.17 mmol). The mixture was stirred at 25 C. for 12 h. The mixture was diluted with water (40 mL) and acidified with 1 N HCl to pH=4. The resulting mixture was extracted with EtOAc (50 mL2). The combined organic phase was washed with brine (60 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuum to afford 01-tert-butyl 02-methyl (2S)-4,4-dimethylpyrrolidine-1,2-dicarboxylate (528 mg) as colorless oil.

Step 2: Preparation of (2S)-4,4-dimethylpyrrolidine-2-carboxylate; 2,2,2-trifluoroacetic acid

##STR00189##

[0957] To a solution of 01-tert-butyl 02-methyl (2S)-4,4-dimethylpyrrolidine-1,2-dicarboxylate (528 mg, 2.05 mmol) in DCM (5 mL) was added TFA (2.5 mL). The mixture was stirred at 25 C. for 2 h. The mixture was concentrated in vacuum to afford methyl (2S)-4,4-dimethylpyrrolidine-2-carboxylate; 2,2,2-trifluoroacetic acid (556 mg,) as yellow oil.

Example 1

N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide

##STR00190##

Step 1: Preparation of benzyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate

##STR00191##

[0958] To a solution of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (970 mg, 2.71 mmol, Intermediate 1) in THF (20 mL) was added TEA (601 mg, 5.95 mmol) and TFAA (1131 mg, 5.41 mmol) at 0 C. The reaction mixture was stirred at 25 C. for 1 h. The reaction was quenched with water (50 mL) and extracted with EtOAc (80 mL2). The organic layers were washed with brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by silica gel column eluted with PE to EtOAc/PE=10/1 to afford benzyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (1.2 g) as colorless oil.

[0959] MS obsd. (ESI.sup.+) [M+H].sup.+. 455.3.

Step 2: Preparation of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid

##STR00192##

[0960] To a solution of benzyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (1.2 g, 2.64 mmol) in MeOH (20 mL) was added Pd/C (200 mg, 10% purity). The mixture was degassed under vacuum and purged H.sub.2 for 3 times. The reaction mixture was stirred at 25 C. for 1 h under H.sub.2 balloon. The mixture was filtered through a celite pad and the pad was washed with MeOH (10 mL3). The filtrate was concentrated in vacuum to afford (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (960 mg) as a white solid.

[0961] MS obsd. (ESI.sup.+) [M+H].sup.+. 365.2.

Step 3: Preparation of tert-butyl N-[[(1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate

##STR00193##

[0962] To a solution of (1R,2S,5S)-3-((2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (10 mg, 0.270 mmol) in DMF (10 mL) was added EDCI (63 mg, 0.330 mmol), HOPO (37 mg, 0.330 mmol), DIPEA (177 mg, 1.37 mmol) and tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (63 mg, 0.270 mmol, Intermediate 9). The reaction mixture was stirred at 25 C. for 12 h. The mixture was diluted with EtOAc (100 mL), washed with water (30 mL) and brine (30 mL3). The organic phase was dried over Na.sub.2SO.sub.4, filtered and the filtrate was concentrated. The residue was purified by silica gel column eluted with MeOH/DCM=10/1 to afford tert-butyl N-[[(1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (110 mg) as colorless oil.

[0963] MS obsd. (ESI.sup.+) [M+H].sup.+: 576.3.

Step 4: Preparation of N-((1S)-1-((1R,2S,5S)-6,6-dimethyl-2-(2-(((3S)-2-oxopyrrolidin-3-yl)methyl)hydrazine-1-carbonyl)-3-azabicyclo[3.1.0]hexan-3-yl)-3,3-dimethyl-1-oxobutan-2-yl)-2,2,2-trifluoroacetamide

##STR00194##

[0964] To a solution of tert-butyl N-[[(1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (110 mg, 0.190 mmol) in DCM (4 mL) was added TFA (4 mL). The reaction mixture was stirred at 25 C. for 1 h. The mixture was concentrated in vacuum and the residue was purified by prep-HPLC (Column: YMC Triart 30*150 mm*7 um; Condition: ACN in water (0.1% HCl)=3151%; Flow Rate (mL/min): 25) to afford N-[(1S)-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(3S)-2-oxopyrrolidin-3-yl]methylamino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide (80 mg) as a white solid.

[0965] MS obsd. (ESI.sup.+) [M+H].sup.+: 476.2.

Step 5: Preparation of N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide (Example 1)

##STR00195##

[0966] To a solution of N-[(1S)-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(3S)-2-oxopyrrolidin-3-yl]methylamino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide (80 mg, 0.170 mmol) in THF (20 mL) was added DIPEA (260 mg, 2.02 mmol) and (2R)-2-chloro-2-fluoro-acetyl chloride (110 mg, 0.840 mmol, Intermediate 10). The reaction mixture was stirred at 0 C. for 1 h. The mixture was concentrated in vacuum and the residue was purified by prep-HPLC (Column: Phenomenex Synergi Polar-RP 100*25 mm*4 um; Condition: ACN in water (0.1% TFA)=5070%; Flow Rate (mL/min): 25) to afford N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide (38.5 mg, Example 1) as a white solid.

[0967] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.18 (s, 1H), 9.50 (d, J=8.0 Hz, 1H), 7.75 (s, 1H), 6.90 (d, J=50.8 Hz, 1H), 4.40 (d, J=8.0 Hz, 1H), 4.16 (s, 1H), 3.96-3.92 (m, 1H), 3.82-3.69 (m, 2H), 3.47-3.48 (m, 1H), 3.21-3.12 (m, 2H), 2.60-2.56 (m, 1H), 2.20-2.08 (m, 1H), 1.79-1.74 (m, 1H), 1.69-1.59 (m, 1H), 1.54 (d, J=7.6 Hz, 1H), 1.04 (s, 3H), 0.98 (s, 9H), 0.92-0.86 (m, 3H)

[0968] MS obsd. (ESI.sup.+) [M+H].sup.+: 570.2.

Example 2

N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-1-cyclopropyl-2-oxo-ethyl]-2,2,2-trifluoro-acetamide

##STR00196##

[0969] The title compound was prepared in analogy to the procedure described for the preparation of Example 1, by using benzyl (1R,2S,5S)-3-[(2S)-2-amino-2-cyclopropyl-acetyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 2) instead of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1) to afford N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-1-cyclopropyl-2-oxo-ethyl]-2,2,2-trifluoro-acetamide (Example 2) as a white solid.

[0970] .sup.1H NMR (400 MHz, CDCl.sub.3) : ppm 10.22 (s, 1H), 7.50-7.49 (m, 1H), 6.65-6.52 (m, 1H), 6.22 (s, 1H), 4.59-4.54 (m, 1H), 4.38-4.34 (m, 2H), 4.01-3.97 (m, 1H), 3.82 (d, J=8.8 Hz, 1H), 3.41-3.39 (m, 2H), 2.92-2.81 (m, 2H), 2.42-2.36 (m, 1H), 1.70-1.69 (m, 1H), 1.41-1.39 (m, 1H), 1.20-1.19 (m, 1H), 1.14 (s, 0.5H), 1.07 (s, 3H), 1.00 (s, 0.5H), 0.92 (s, 3H), 0.61-0.59 (m, 2H), 0.55-0.52 (m, 1H), 0.46-0.42 (m, 1H)

[0971] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 554.2.

Example 3

N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-3-methyl-butyl]-2,2,2-trifluoro-acetamide

##STR00197##

Step 1: Preparation of methyl (1R,2S,5S)-3-[(2S)-2-(benzyloxycarbonylamino)-4-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate

##STR00198##

[0972] To a solution of (2S)-2-(benzyloxycarbonylamino)-4-methyl-pentanoic acid (322 mg, 1.22 mmol), methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; hydrochloride (250 mg, 1.22 mmol) in DCM (5 mL) was added DIPEA (471 mg, 3.65 mmol) and HATU (343 mg, 1.46 mmol). The mixture was stirred at 25 C. for 12 h. The mixture was concentrated in vacuum and the residue was purified by reverse flash eluted with ACN in H.sub.2O (0.1% NH.sub.3.Math.H.sub.2O)=070% to afford methyl (1R,2S,5S)-3-[(2S)-2-(benzyloxycarbonylamino)-4-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (330 mg) as colorless oil

[0973] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 417.2.

Step 2: Preparation of (1R,2S,5S)-3-[(2S)-2-(benzyloxycarbonylamino)-4-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid

##STR00199##

[0974] To a solution of methyl (1R,2S,5S)-3-[(2S)-2-(benzyloxycarbonylamino)-4-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (330 mg, 0.790 mmol) in THF (3 mL) and water (3 mL) was added LiOH.Math.H.sub.2O (33 mg, 0.790 mmol). The mixture was stirred at 25 C. for 12 h. The reaction mixture was diluted with water 30 mL and extracted with EtOAc (30 mL3). The combined organic layers were washed with brine 40 mL, dried over Na.sub.2SO.sub.4, filtered and the filtrate was concentrated. The residue was purified by silica gel column eluted with PE/EtOAc=10/1 to 3/1 to afford (1R,2S,5S)-3-[(2S)-2-(benzyloxycarbonylamino)-4-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (310 mg) as yellow oil.

[0975] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 403.1.

Step 3: Preparation of tert-butyl N-[[(1R,2S,5S)-3-[(2S)-2-(benzyloxycarbonylamino)-4-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate

##STR00200##

[0976] To a solution of (1R,2S,5S)-3-[(2S)-2-(benzyloxycarbonylamino)-4-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (310 mg, 0.770 mmol) in DMF (6 mL) was added DIPEA (497 mg, 3.85 mmol), EDCI (177 mg, 0.920 mmol), HOPO (103 mg, 0.920 mmol) and tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (194 mg, 0.850 mmol, Intermediate 9). The mixture was stirred at 25 C. for 12 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL3). The combined organic layers were washed with brine (40 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by silica gel column eluted with PE/EtOAc=10/1 to 3/1 to afford tert-butyl N-[[(1R,2S,5S)-3-[(2S)-2-(benzyloxycarbonylamino)-4-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (460 mg) as yellow oil.

[0977] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 614.1.

Step 4: Preparation of tert-butyl N-[[(1R,2S,5S)-3-[(2S)-2-amino-4-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate

##STR00201##

[0978] To a solution of tert-butyl N-[[(1R,2S,5S)-3-[(2S)-2-(benzyloxycarbonylamino)-4-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (460 mg, 0.750 mmol) in MeOH (6 mL) was added Pd/C (150 mg). The mixture was degassed under vacuum and purged H.sub.2 for 3 times. The resulting mixture was stirred under H.sub.2 at 25 C. for 2 h. The reaction mixture filtered through a celite pad and the pad was washed with MeOH (30 mL). The filtrate was concentrated in vacuum to afford tert-butyl N-[[(1R,2S,5S)-3-[(2S)-2-amino-4-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (310 mg) as yellow oil.

[0979] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 480.4.

Step 5: Preparation of tert-butyl N-[[(1R,2S,5S)-6,6-dimethyl-3-[(2S)-4-methyl-2-[(2,2,2-trifluoroacetyl)amino]pentanoyl]-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate

##STR00202##

[0980] To a solution of tert-butyl N-[[(1R,2S,5S)-3-[(2S)-2-amino-4-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (310 mg, 0.65 mmol) in THF (5 mL) was added TEA (163 mg, 1.62 mmol) and TFAA (0.14 mL, 0.970 mmol) at 0 C. The reaction mixture was stirred at 25 C. for 1 h. The mixture was quenched with water (20 mL) and extracted with EtOAc (30 mL2). The organic layers were washed with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and the filtrate was concentrated. The residue was purified by silica gel column eluted with PE/EtOAc=20/1 to 5/1 to afford tert-butyl N-[[(1R,2S,5S)-6,6-dimethyl-3-[(2S)-4-methyl-2-[(2,2,2-trifluoroacetyl)amino]pentanoyl]-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (310 mg) as yellow oil. MS obsd. (ESI.sup.+) [(M+H).sup.+]: 576.4.

Step 6: Preparation of N-[(1S)-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(3S)-2-oxopyrrolidin-3-yl]methylamino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-3-methyl-butyl]-2,2,2-trifluoro-acetamide

##STR00203##

[0981] To a solution of tert-butyl N-[[(1R,2S,5S)-6,6-dimethyl-3-[(2S)-4-methyl-2-[(2,2,2-trifluoroacetyl)amino]pentanoyl]-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (310 mg, 0.54 mmol) in DCM (5 mL) was added TFA (5.0 mL). The mixture was stirred at 25 C. for 1 h. The mixture was concentrated in vacuum. The residue was purified by reversed-flash eluted with ACN in H.sub.2O (0.1% HCl condition)=070% to afford N-[(1S)-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(3S)-2-oxopyrrolidin-3-yl]methylamino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-3-methyl-butyl]-2,2,2-trifluoro-acetamide; hydrochloride (170 mg) as yellow oil.

[0982] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 476.2.

Step 7: Preparation of N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-3-methyl-butyl]-2,2,2-trifluoro-acetamide Example 3

##STR00204##

[0983] To a solution of N-[(1S)-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(3S)-2-oxopyrrolidin-3-yl]methylamino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-3-methyl-butyl]-2,2,2-trifluoro-acetamide; hydrochloride (170 mg, 0.36 mmol) in THF (60 mL) was added DIPEA (553 mg, 4.29 mmol) and (2R)-2-chloro-2-fluoro-acetyl chloride (234 mg, 1.79 mmol, Intermediate 10) at 0 C. The reaction mixture was stirred at 0 C. for 1 h. The mixture was concentrated in vacuum. The residue was purified by prep-HPLC (0.1% TFA, Phenomenex luna C18 150*40 mm*15 um; mobile phase: [water (0.1% TFA)-ACN]; B %: 35%-65%, 10 min) to afford N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-3-methyl-butyl]-2,2,2-trifluoro-acetamide (20 mg, Example 3) as an off-white solid.

[0984] .sup.1H NMR (400 MHz, CD.sub.3OD) : ppm 6.87-6.68 (d, 1H), 4.60 (dd, J=4.8, 9.6 Hz, 1H), 4.28 (s, 1H), 4.06 (dd, J=8.4, 14.0 Hz, 1H), 3.99-3.87 (m, 2H), 3.59 (dd, J=4.8, 14.0 Hz, 1H), 3.43-3.34 (m, 2H), 2.74 (dq, J=4.8, 8.8 Hz, 1H), 2.38-2.25 (m, 1H), 2.10-1.96 (m, 1H), 1.75-1.57 (m, 5H), 1.13 (s, 3H), 1.06 (s, 3H), 0.99 (dd, J=6.0, 11.6 Hz, 6H)

[0985] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 570.1.

Example 4

N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide

##STR00205##

Example 4

[0986] The title compound was prepared in analogy to the procedure described for the preparation of Example 1, by using benzyl (3S,3aS,6aR)-2-[(2S)-2-amino-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate (Intermediate 3) instead of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1) to afford N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide (Example 4) as an off-white solid.

[0987] .sup.1H NMR (400 MHz, CD.sub.3OD) : ppm 7.16-6.66 (m, 1H), 4.72-4.60 (m, 1H), 4.09 (d, J=5.6 Hz, 1H), 4.06-3.95 (m, 2H), 3.78 (dd, J=3.2, 10.4 Hz, 1H), 3.59 (dd, J=4.8, 14.4 Hz, 1H), 3.42-3.33 (m, 2H), 2.94-2.83 (m, 1H), 2.83-2.75 (m, 1H), 2.74 (br. s, 1H), 2.39-2.21 (m, 1H), 2.09-1.70 (m, 6H), 1.52 (m, 1H), 1.08 (s, 9H).

[0988] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 570.3.

Example 5

N-[(1S)-1-[(1S,2S,5R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.2.0]heptane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide

##STR00206##

[0989] The title compound was prepared in analogy to the procedure described for the preparation of Example 1, by using benzyl (1S,2S,5R)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-3-azabicyclo[3.2.0]heptane-2-carboxylate (Intermediate 4) instead of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1) to afford N-[(1S)-1-[(1S,2S,5R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.2.0]heptane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide (Example 5) as a white solid.

[0990] .sup.1H NMR (400 MHz, CDCl.sub.3) : ppm 9.83 (br, s, 1H), 7.32-7.28 (m, 1H), 6.62 (d, J=50.4 Hz, 1H), 6.42 (br, s, 1H), 4.88-4.85 (m, 1H), 4.81 (d, J=9.6 Hz, 1H), 4.35 (m, 1H), 3.96-3.93 (m, 2H), 3.45-3.41 (m, 2H), 3.20 (m, 1H), 2.90 (m, 3H), 2.39-2.35 (m, 2H), 1.85-1.81 (m, 4H), 1.05 (s, 9H).

[0991] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 556.3.

Example 6

N-[(1S)-1-[(6S)-6-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-5-azaspiro[2.4]heptane-5-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide

##STR00207##

[0992] The title compound was prepared in analogy to the procedure described for the preparation of Example 1, by using benzyl (6S)-5-[(2S)-2-amino-3,3-dimethyl-butanoyl]-5-azaspiro[2.4]heptane-6-carboxylate (Intermediate 5) instead of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1) to afford N-[(1S)-1-[(6S)-6-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-5-azaspiro[2.4]heptane-5-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide (Example 6) as an off-white solid.

[0993] .sup.1H NMR (400 MHz, CD.sub.3OD) : ppm 7.25-6.78 (d, 1H), 4.68-4.60 (m, 1H), 4.48 (t, J=8.0 Hz, 1H), 3.98 (dd, J=8.4, 14.4 Hz, 1H), 3.87 (d, J=10 Hz, 1H), 3.66-3.56 (m, 2H), 3.41-3.34 (m, 2H), 2.69 (dt, J=4.0, 8.8 Hz, 1H), 2.34-2.16 (m, 2H), 2.07-1.96 (m, 2H), 1.08 (s, 9H), 0.81-0.60 (m, 4H)

[0994] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 556.3.

Example 7

N-[(1S)-1-[(2S,4R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-methyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide

##STR00208##

[0995] The title compound was prepared in analogy to the procedure described for the preparation of Example 1, by using benzyl (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-methyl-pyrrolidine-2-carboxylate (Intermediate 6) instead of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1) to afford N-[(1S)-1-[(2S,4R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-methyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide (Example 7) as a white solid.

[0996] .sup.1H NMR (400 MHz, CD.sub.3OD) : ppm 6.98 (d, J=56.0 Hz, 1H), 4.85-4.86 (m, 1H), 4.47-4.37 (m, 1H), 4.06-3.94 (m, 2H), 3.67-3.56 (m, 1H), 3.48-3.34 (m, 3H), 2.78-2.68 (m, 1H), 2.66-2.54 (m, 1H), 2.35-2.23 (m, 1H), 2.23-2.14 (m, 1H), 2.11-1.86 (m, 2H), 1.12-1.04 (m, 12H).

[0997] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 544.2.

Example 8

N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide

##STR00209##

[0998] The title compound was prepared in analogy to the procedure described for the preparation of Example 1, by using benzyl (2S)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4,4-dimethyl-pyrrolidine-2-carboxylate (Intermediate 7) instead of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1) to afford N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide (Example 8) as a white solid.

[0999] .sup.1H NMR (400 MHz, CD.sub.3OD) : ppm 7.10 (d, J=50.4 Hz, 1H), 4.49-4.34 (m, 1H), 4.09-3.93 (m, 1H), 3.82-3.74 (m, 1H), 3.64-3.55 (m, 1H), 3.49-3.44 (m, 1H), 3.41-3.34 (m, 2H), 2.74-2.65 (m, 1H), 2.33-2.25 (m, 1H), 2.13-1.96 (m, 2H), 1.90-1.79 (m, 1H), 1.23 (s, 3H), 1.11 (s, 3H), 1.08 (s, 9H).

[1000] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 558.2.

Example 9

N-[(1S)-1-[(1S,2S,5R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide

##STR00210##

[1001] The title compound was prepared in analogy to the procedure described for the preparation of Example 1, by using benzyl (1S,2S,5R)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 8) instead of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1) to afford N-[(1S)-1-[(1S,2S,5R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide (Example 9) as a white solid.

[1002] .sup.1H NMR (400 MHz, CDCl.sub.3) : ppm 10.15 (s, 1H), 7.33 (s, 1H), 6.61-6.48 (m, 2H), 4.95 (s, 1H), 4.63 (d, J=9.6 Hz, 1H), 4.43-4.39 (m, 1H), 4.05-3.97 (m, 2H), 3.44-3.41 (m, 2H), 2.96-2.88 (m, 2H), 2.42-2.36 (m, 1H), 1.78-1.64 (m, 3H), 1.00 (s, 9H), 0.89 (q, J.sub.1=7.6 Hz, J.sub.2=13.6 Hz, 1H), 0.25 (d, J=4.4 Hz, 1H)

[1003] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 541.9.

Example 10

N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-(1H-pyrazol-3-ylmethyl)amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide

##STR00211##

[1004] The title compound was prepared in analogy to the procedure described for the preparation of Example 1, by using tert-butyl N-amino-N-(1H-pyrazol-3-ylmethyl)carbamate (Intermediate 11) instead of tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (Intermediate 9 in step 3) to afford N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-(1H-pyrazol-3-ylmethyl)amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide (Example 10) as a white solid.

[1005] .sup.1H NMR (400 MHz, CD.sub.3OD) : ppm 10.44-9.88 (m, 1H), 7.52-7.50 (m, 1H), 7.10-7.25 (m, 1H), 6.64-6.52 (m, 1H), 6.39 (s, 1H), 5.39-4.94 (m, 1H), 4.59 (d, J=9.6 Hz, 2H), 4.22-4.03 (m, 3H), 3.87 (d, J=10.0 Hz, 1H), 1.60-1.68 (m, 1H), 1.13-1.37 (m, 0.5H), 1.03 (br, s, 12H), 0.98 (br, s, 0.5H), 0.82 (s, 3H)

[1006] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 553.2.

Example 11

N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-dimethyl-propanamide

##STR00212##

[1007] The title compound was prepared in analogy to the procedure described for the preparation of Example 1, by using 2,2-dimethylpropanoyl chloride instead of TFAA and DCM instead of THF to afford N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-dimethyl-propanamide (Example 11) as an off-white solid.

[1008] .sup.1H NMR (400 MHz, CD.sub.3OD) : ppm 6.92-6.79 (m, 2H), 4.63 (d, J=9.4 Hz, 1H), 4.25 (s, 1H), 4.09-4.01 (m, 2H), 3.94 (br d, J=10.4 Hz, 1H), 3.66-3.57 (m, 1H), 3.43-3.35 (m, 2H), 2.86-2.64 (m, 1H), 2.37-2.22 (m, 1H), 2.11-1.98 (m, 1H), 1.73-1.64 (m, 2H), 1.21 (s, 9H), 1.12 (s, 3H), 1.03 (s, 9H), 0.96 (s, 3H)

[1009] MS obsd. (ESI.sup.+) [(M+Na).sup.+]: 558.2.

Example 12

N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]cyclopropanecarboxamide

##STR00213##

[1010] The title compound was prepared in analogy to the procedure described for the preparation of Example 1, by using cyclopropanecarbonyl chloride instead of TFAA to afford N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]cyclopropanecarboxamide (Example 12) as a white solid.

[1011] .sup.1H NMR (400 MHz, CDCl.sub.3) : ppm 10.13 (d, J=3.2 Hz, 1H), 6.86-6.65 (m, 1H), 6.64-6.47 (m, 1H), 6.21-6.15 (m, 1H), 4.67 (d, J=10.0 Hz, 1H), 4.56-4.22 (m, 2H), 4.06-3.98 (m, 1H), 3.98-3.91 (m, 1H), 3.41 (dd, J=5.2, 8.8 Hz, 2H), 3.19-2.64 (m, 2H), 2.47-2.34 (m, 1H), 1.81 (d, J=6.0 Hz, 1H), 1.56 (m, 4H), 1.34 (d, J=6.4 Hz, 1H), 1.05 (s, 3H), 1.02-0.93 (m, 9H), 0.89 (s, 3H), 0.80-0.68 (m, 2H)

[1012] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 542.3.

Example 13

N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2-methyl-propanamide

##STR00214##

[1013] The title compound was prepared in analogy to the procedure described for the preparation of Example 1, by using 2-methylpropanoyl chloride instead of TFAA to afford N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2-methyl-propanamide (Example 13) as a white solid.

[1014] .sup.1H NMR (400 MHz, CD.sub.3OD) : ppm 6.92 (d, J=50.8 Hz, 1H), 4.54 (s, 1H), 4.24 (s, 1H), 4.09-3.94 (m, 3H), 3.63-3.57 (m, 1H), 3.43-3.35 (m, 2H), 2.80-2.69 (m, 1H), 2.66-2.54 (m, 1H), 2.37-2.25 (m, 1H), 2.11-1.97 (m, 1H), 1.74-1.63 (m, 2H), 1.16-1.11 (m, 6H), 1.09-1.03 (m, 12H), 0.99 (s, 3H).

[1015] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 544.4.

Example 14

N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-acetamide

##STR00215##

[1016] The title compound was prepared in analogy to the procedure described for the preparation of Example 1, by using (2,2-difluoroacetyl) 2,2-difluoroacetate instead of TFAA to afford N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-acetamide (Example 14) as an off-white solid.

[1017] .sup.1H NMR (400 MHz, CD.sub.3OD) : ppm 7.00-6.79 (m, 1H), 6.30-5.97 (m, 1H), 4.53 (s, 1H), 4.26 (s, 1H), 4.10-4.00 (m, 2H), 3.93 (d, J=10.4 Hz, 1H), 3.59 (br dd, J=4.4, 14.4 Hz, 1H), 3.42-3.34 (m, 2H), 2.75 (dq, J=4.4, 8.8 Hz, 1H), 2.37-2.25 (m, 1H), 2.09-1.98 (m, 1H), 1.75-1.63 (m, 2H), 1.12 (s, 3H), 1.08 (s, 9H), 1.01 (s, 3H).

[1018] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 552.3.

Example 15

N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]bicyclo[1.1.1]pentane-1-carboxamide

##STR00216##

Step 1: Preparation of benzyl (1R,2S,5S)-3-[(2S)-2-(bicyclo[1.1.1]pentane-1-carbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate

##STR00217##

[1019] To a solution of bicyclo[1.1.1]pentane-1-carboxylic acid (75 mg, 0.67 mmol) in 1,2-dichloroethane (10 mL) was added N,N-diisopropylethylamine (0.33 mL, 1.9 mmol), 0-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (290 mg, 0.76 mmol) and benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (229 mg, 0.638 mmol, Intermediate 1). The reaction mixture was stirred at 25 C. for 1 h. The mixture was concentrated and the residue was purified by silica gel column eluted with PE/EtOAc=20/1 to 10/1 to afford benzyl (1R,2S,5S)-3-[(2S)-2-(bicyclo[1.1.1]pentane-1-carbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (230 mg) as colorless oil.

[1020] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 453.3.

Step 2: Preparation of (1R,2S,5S)-3-[(2S)-2-(bicyclo[1.1.1]pentane-1-carbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid

##STR00218##

[1021] To a solution of benzyl (1R,2S,5S)-3-[(2S)-2-(bicyclo[1.1.1]pentane-1-carbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (230 mg, 0.51 mmol) in methanol (10 mL) was added Pd/C (100 mg, 10% purity). The reaction mixture was degassed under vacuum and purged H.sub.2 for 3 times. The resulting mixture was stirred at 25 C. for 1 h under H.sub.2 balloon. The suspension was filtered and the filtrate was concentrated in vacuum to afford (1R,2S,5S)-3-[(2S)-2-(bicyclo[1.1.1]pentane-1-carbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (170 mg) as colorless oil.

[1022] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 363.2.

Step 3: Preparation of tert-butyl N-[[(1R,2S,5S)-3-[(2S)-2-(bicyclo[1.1.1]pentane-1-carbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate

##STR00219##

[1023] To a solution of (1R,2S,5S)-3-[(2S)-2-(bicyclo[1.1.1]pentane-1-carbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (170 mg, 0.470 mmol) in DMF (2 mL) was added EDCI (108 mg, 0.56 mmol), HOPO (62 mg, 0.56 mmol), DIPEA (0.41 mL, 2.35 mmol) and tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (118 mg, 0.520 mmol, Intermediate 9). The reaction mixture was stirred at 25 C. for 12 h. The mixture was diluted with EtOAc (30 mL), washed with water (20 mL) and brine (20 mL3). The combined organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by reverse phase (neutral condition) eluted with ACN in H.sub.2O=070% to afford tert-butyl N-[[(1R,2S,5S)-3-[(2S)-2-(bicyclo[1.1.1]pentane-1-carbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (210 mg) as a white solid.

[1024] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 574.3.

Step 4: Preparation of N-[(1S)-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(3S)-2-oxopyrrolidin-3-yl]methylamino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]bicyclo[1.1.1]pentane-1-carboxamide

##STR00220##

[1025] To a solution of tert-butyl N-[[(1R,2S,5S)-3-[(2S)-2-(bicyclo[1.1.1]pentane-1-carbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (210 mg, 0.37 mmol) in DCM (2.8 mL) was added TFA (2.82 mL). The reaction mixture was stirred at 25 C. for 1 h. The residue was purified by reverse phase ACN in H.sub.2O (0.1% HCl)=070% to afford N-[(1S)-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(3S)-2-oxopyrrolidin-3-yl]methylamino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]bicyclo[1.1.1]pentane-1-carboxamide (60 mg) as a yellow solid.

[1026] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 474.4.

Step 5: Preparation of N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]bicyclo[1.1.1]pentane-1-carboxamide (Example 15)

##STR00221##

[1027] To a solution of N-[(1S)-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(3S)-2-oxopyrrolidin-3-yl]methylamino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]bicyclo[1.1.1]pentane-1-carboxamide (60 mg, 0.120 mmol) in THF (10 mL) was added DIPEA (0.25 mL, 1.41 mmol) and (2R)-2-chloro-2-fluoro-acetyl chloride (77 mg, 0.590 mmol, Intermediate 10). The reaction mixture was stirred at 0 C. for 1 h. The mixture was concentrated and the residue was purified by prep-HPLC (0.10% TFA, 3_Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [water (0.1% TFA)-ACN]; B %: 45%-65%, 9 min) to afford N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]bicyclo[1.1.1]pentane-1-carboxamide (31 mg, Example 15) as a white solid.

[1028] .sup.1H NMR (400 MHz, CD.sub.3OD) : ppm 6.97-6.74 (d, J=50.8 Hz, 1H), 4.60-4.51 (m, 1H), 4.24 (s, 1H), 4.10-3.98 (m, 2H), 3.94-3.85 (m, 1H), 3.67-3.58 (m, 1H), 3.46-3.36 (m, 2H), 2.81-2.67 (m, 1H), 2.50-2.40 (m, 1H), 2.36-2.26 (m, 1H), 2.09 (s, 6H), 2.04-1.96 (m, 1H), 1.72-1.64 (m, 2H), 1.12 (s, 3H), 1.03 (s, 9H), 0.97 (s, 3H).

[1029] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 568.4.

Example 16

N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-5-(trifluoromethyl)isoxazole-3-carboxamide

##STR00222##

[1030] The title compound was prepared in analogy to the procedure described for the preparation of Example 1, by using 5-(trifluoromethyl)isoxazole-3-carboxylic acid (Intermediate 12) instead of bicyclo[1.1.1]pentane-1-carboxylic acid to afford N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-5-(trifluoromethyl)isoxazole-3-carboxamide (Example 16) as a yellow solid.

[1031] .sup.1H NMR (400 MHz, CDCl.sub.3) : ppm 10.03-9.78 (m, 1H), 7.69-7.46 (m, 1H), 7.11 (s, 1H), 6.78-6.56 (m, 1H), 6.16-5.90 (m, 1H), 4.72 (d, J=9.6 Hz, 1H), 4.54-4.28 (m, 2H), 4.07 (dd, J=5.2, 10.0 Hz, 1H), 4.00-3.90 (m, 1H), 3.42 (s, 2H), 3.09-2.65 (m, 2H), 2.50-2.29 (m, 1H), 1.90-1.79 (m, 1H), 1.63 (s, 1H), 1.43-1.33 (m, 1H), 1.08-1.03 (m, 12H), 0.93 (s, 3H).

[1032] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 637.2.

Example 17

(1R,2S,5S)N-[(2R)-2-chloro-2-fluoro-acetyl]-3-[2-(3,5-difluorophenoxy)acetyl]-6,6-dimethyl-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide

##STR00223##

Step 1: Preparation of (1R,2S,5S)-3-[2-(3,5-difluorophenoxy)acetyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid

##STR00224##

[1033] To a solution of (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid; hydrochloride (102 mg, 0.530 mmol) in water (2 mL) was added Na.sub.2CO.sub.3 (226 mg, 2.13 mmol) and the solution of 2-(3,5-difluorophenoxy)acetyl chloride (110 mg, 0.530 mmol, Intermediate 13) in THF (5 mL). The mixture was stirred at 25 C. for 5 h. The mixture was diluted with H.sub.2O (30 mL) and washed with EtOAc (20 mL). The aqueous phase was acidified with concentrated HCl to pH=5. The suspension was extracted with EtOAc (30 mL3). The combined organic phase was dried over Na.sub.2SO.sub.4, filtrated and the filtrate was concentrated to afford (1R,2S,5S)-3-[2-(3,5-difluorophenoxy)acetyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (150 mg) as a white solid.

[1034] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 326.1.

Step 2: Preparation of tert-butyl N-[[(1R,2S,5S)-3-[2-(3,5-difluorophenoxy)acetyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate

##STR00225##

[1035] To a solution of (1R,2S,5S)-3-[2-(3,5-difluorophenoxy)acetyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (110 mg, 0.340 mmol) in DMF (10 mL) was added DIPEA (131 mg, 1.01 mmol), tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (78 mg, 0.340 mmol, Intermediate 9), EDCI (155 mg, 0.410 mmol) and HOPO (45 mg, 0.410 mmol). The mixture was stirred at 25 C. for 2 h. The reaction mixture was diluted with EtOAc (40 ml) and poured into water (50 mL). After separation, the aqueous phase was extracted with EtOAc (30 mL3). The combined organic layers were dried over Na.sub.2SO.sub.4. After filtration and concentration, the residue was purified by silica gel column eluted with PE/EtOAc=10/1 to 4/1 to afford tert-butyl N-[[(1R,2S,5S)-3-[2-(3,5-difluorophenoxy)acetyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (150 mg) as colorless oil.

[1036] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 537.4.

Step 3: Preparation of (1R,2S,5S)-3-[2-(3,5-difluorophenoxy)acetyl]-6,6-dimethyl-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide

##STR00226##

[1037] To a solution of tert-butyl N-[[(1R,2S,5S)-3-[2-(3,5-difluorophenoxy)acetyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (120 mg, 0.220 mmol) in DCM (3 mL) was added TFA (1.0 mL). The mixture was stirred at 25 C. for 1 h. The reaction mixture was concentrated and the residue was purified with reverse flash eluted with ACN in H.sub.2O (0.01% HCl)=060% to afford (1R,2S,5S)-3-[2-(3,5-difluorophenoxy)acetyl]-6,6-dimethyl-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide (70 mg) as a white solid.

Step 4: Preparation of (1R,2S,5S)N-[(2R)-2-chloro-2-fluoro-acetyl]-3-[2-(3,5-difluorophenoxy)acetyl]-6,6-dimethyl-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide (Example 17)

##STR00227##

[1038] To a solution of (1R,2S,5S)-3-[2-(3,5-difluorophenoxy)acetyl]-6,6-dimethyl-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide (60 mg, 0.140 mmol) in THF (14 mL) was added DIPEA (179 mg, 1.39 mmol) and a solution of (2R)-2-chloro-2-fluoro-acetyl chloride (90 mg, 0.320 mmol, Intermediate 10) in THF (4 mL) successively at 20 C. The mixture was stirred at 0 C. for 30 min. The reaction mixture was quenched with MeOH (2 mL), adjusted with a solution of 4M HCl in dioxane to pH=5 at 0 C. and concentrated in vacuum. The residue was purified by prep-HPLC (Unisil 3-100 C18 Ultra 150*50 mm*3 um; ACN in water (0.1% FA); 30%-60%; Flow Rate (mL/min):25) to afford (1R,2S,5S)N-[(2R)-2-chloro-2-fluoro-acetyl]-3-[2-(3,5-difluorophenoxy)acetyl]-6,6-dimethyl-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide (21 mg, Example 17) as a white solid.

[1039] .sup.1H NMR (400 MHz, CD.sub.3OD) : ppm 10.02 (s, 1H), 6.49-6.45 (m, 3H), 6.42-6.29 (m, 1H), 5.67 (s, 1H), 4.75-4.72 (m, 1H), 4.59-4.62 (m, 1H), 4.42-4.35 (m, 2H), 3.97-3.93 (m, 1H), 3.65-3.63 (m, 1H), 3.41-3.38 (m, 2H), 2.92-2.79 (m, 2H), 2.37-2.30 (m, 1H), 1.85-1.75 (m, 2H), 1.51-1.49 (m, 1H), 1.11 (s, 3H), 0.94 (s, 3H).

[1040] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 530.9.

Example 18

N-[(1S)-1-[(1R,2S,5S)-2-[[(2-chloroacetyl)-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide

##STR00228##

[1041] The title compound was prepared in analogy to the procedure described for the preparation of Example 1, by using chloroacetyl chloride instead of (2R)-2-chloro-2-fluoro-acetyl chloride (Intermediate 10) to afford N-[(1S)-1-[(1R,2S,5S)-2-[[(2-chloroacetyl)-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide (Example 18) as a white solid.

[1042] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 10.98-10.62 (m, 1H), 9.56-9.37 (m, 1H), 7.82-7.61 (m, 1H), 4.51-4.37 (m, 2H), 4.28-4.03 (m, 2H), 3.92 (dd, J=5.6, 10.4 Hz, 1H), 3.83-3.66 (m, 2H), 3.22-3.10 (m, 2H), 2.69-2.65 (m, 1H), 2.37-2.30 (m, 1H), 2.24-2.06 (m, 1H), 1.84-1.68 (m, 1H), 1.62 (dd, J=5.6, 7.4 Hz, 1H), 1.56-1.43 (m, 1H), 1.04 (s, 3H), 0.99 (s, 9H), 0.89 (s, 3H).

[1043] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 552.0.

Example 19

N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide

##STR00229##

[1044] The title compound was prepared in analogy to the procedure described for the preparation of Example 1, by using 2-chloro-2-fluoro-acetyl chloride (Intermediate 10-rac) instead of (2R)-2-chloro-2-fluoro-acetyl chloride (Intermediate 10) and purified by SFC separation (Column: REGIS(S,S)WHELK-O1(250 mm*25 mm, 10 um); Condition Neu-IPA Begin B 25% End B 25%; Gradient Time(min) 2.8; 100% B Hold Time(min) 5; Rate(ml/min) 50; Injections 135) to afford N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide (Example 19) as a white solid.

[1045] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 10.98 (s, 1H), 9.46 (d, J=7.2 Hz, 1H), 7.84-7.53 (m, 1H) 6.83 (d, J=48.8 Hz, 1H), 4.41 (d, J=6.0 Hz, 1H), 4.26-4.13 (m, 1H), 3.93 (dd, J=10.4, 5.2 Hz, 1H), 3.84-3.63 (m, 2H), 3.52 (d, J=13.20 Hz, 1H), 3.20-3.11 (in, 1H), 3.05-2.95 (m, 1H), 2.64-2.55 (m, 2H), 2.23-2.10 (m, 1H), 1.85-1.71 (m, 1H), 1.68-1.44 (m, 2H), 1.07-1.03 (m, 3H) 1.01-0.96 (m, 8H), 0.89 (s, 3H).

[1046] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 570.3.

Example 20

N-[(1S)-1-benzyl-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxo-ethyl]-2,2,2-trifluoro-acetamide

##STR00230##

Step 1: Preparation of tert-butyl N-[[(1R,2S,5S)-3-[(2S)-2-(benzyloxycarbonylamino)-3-phenyl-propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate

##STR00231##

[1047] To a solution of Cbz-Phe-OH (245 mg, 0.820 mmol) (GL Biochem, CAS number: 1161-13-3) in DCM (6 mL) was added DIPEA (0.43 mL, 2.46 mmol), HATU (231 mg, 0.98 mmol) and tert-butyl N-[[(1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (300 mg, 0.820 mmol, Intermediate 14). The mixture was stirred at 25 C. for 2 h. The mixture was diluted with water (40 mL) and extracted with ethyl acetate (50 mL2). The combined organic phase was washed with brine (50 mL2), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by silica gel column eluted with PE/EtOAc=10/1 to 2/1 to afford tert-butyl N-[[(1R,2S,5S)-3-[(2S)-2-(benzyloxycarbonylamino)-3-phenyl-propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (350 mg) as yellow oil.

[1048] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 648.4.

Step 2: Preparation of tert-butyl N-[[(1R,2S,5S)-3-[(2S)-2-amino-3-phenyl-propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate

##STR00232##

[1049] To a solution of tert-butyl N-[[(1R,2S,5S)-3-[(2S)-2-(benzyloxycarbonylamino)-3-phenyl-propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (350 mg, 0.540 mmol) in methanol (8 mL) was added Pd/C (150 mg, 10% purity) under N.sub.2 atmosphere. The suspension was degassed and purged with H.sub.2 for 3 times. The mixture was stirred under a H.sub.2 balloon at 25 C. for 2 h. The suspension was filtered and the filtrate was concentrated in vacuum to afford tert-butyl N-[[(1R,2S,5S)-3-[(2S)-2-amino-3-phenyl-propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (270 mg) as yellow oil.

[1050] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 514.3.

Step 3: Preparation of tert-butyl N-[[(1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-phenyl-2-[(2,2,2-trifluoroacetyl)amino]propanoyl]-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate

##STR00233##

[1051] To a solution of tert-butyl N-[[(1R,2S,5S)-3-[(2S)-2-amino-3-phenyl-propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (270 mg, 0.530 mmol) in THF (8 mL) was added TEA (133 mg, 1.31 mmol) and TFAA (0.11 mL, 0.790 mmol) at 0 C. The reaction mixture was stirred at 25 C. for 1 h. The mixture was diluted with water (80 mL) and extracted with EtOAc (60 mL3). The organic layers were washed with brine (80 mL) and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified by silica gel column eluted with ethyl PE/EtOAc=20/1 to 9/1 to afford tert-butyl N-[[(1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-phenyl-2-[(2,2,2-trifluoroacetyl)amino]propanoyl]-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (138 mg) as a white solid.

[1052] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 610.2.

Step 4: Preparation of N-[(1S)-1-benzyl-2-[(1R,2S,5S)-6,6-dimethyl-2-[[[(3S)-2-oxopyrrolidin-3-yl]methylamino]carbamoyl]-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxo-ethyl]-2,2,2-trifluoro-acetamide

##STR00234##

[1053] To a solution of tert-butyl N-[[(1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-phenyl-2-[(2,2,2-trifluoroacetyl)amino]propanoyl]-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (138 mg, 0.230 mmol) in DCM (10 mL) was added TFA (5.0 mL). The mixture was stirred at 25 C. for 1 h. The mixture was concentrated in vacuum. The residue was purified with reverse flash eluted with ACN in H.sub.2O (0.01% HCl)=060% to afford N-[(1S)-1-benzyl-2-[(1R,2S,5S)-6,6-dimethyl-2-[[[(3S)-2-oxopyrrolidin-3-yl]methylamino]carbamoyl]-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxo-ethyl]-2,2,2-trifluoro-acetamide (42 mg) as a white solid.

[1054] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 510.2.

Step 5: Preparation of N-[(1S)-1-benzyl-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxo-ethyl]-2,2,2-trifluoro-acetamide (Example 21)

##STR00235##

[1055] To a solution of N-[(1S)-1-benzyl-2-[(1R,2S,5S)-6,6-dimethyl-2-[[[(3S)-2-oxopyrrolidin-3-yl]methylamino]carbamoyl]-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxo-ethyl]-2,2,2-trifluoro-acetamide (42 mg, 0.080 mmol) in THF (20 mL) was added DIPEA (127 mg, 0.990 mmol) and (2R)-2-chloro-2-fluoro-acetyl chloride (53.96 mg, 0.410 mmol, Intermediate 10) at 0 C. The reaction mixture was stirred at 0 C. for 1 h. The mixture was quenched with 4 M HCl/dioxane until pH=56 and then concentrated in vacuum. The residue was purified by prep-HPLC (0.1% TFA, 3_Phenomenex Synergi Polar-RP 100*25 mm*4 um: [water (0.1% TFA)ACN]; B %: 48%-68%, 7 min) to afford N-[(1S)-1-benzyl-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxo-ethyl]-2,2,2-trifluoro-acetamide (19 mg, Example 20) as an off-white solid.

[1056] .sup.1H NMR (400 MHz, CD.sub.3OD) : ppm 7.36-7.21 (m, 5H), 6.97-6.78 (m, 1H), 4.79 (dd, J=5.6, 8.8 Hz, 1H), 4.26 (s, 1H), 4.08 (dd, J=8.8, 14.0 Hz, 1H), 3.85-3.80 (m, 1H), 3.79-3.72 (m, 1H), 3.59 (dd, J=4.4, 14.0 Hz, 1H), 3.44-3.34 (m, 2H), 3.18 (dd, J=5.6, 14.0 Hz, 1H), 2.97 (dd, J=8.8, 14.0 Hz, 1H), 2.75 (dd, J=4.8, 8.4 Hz, 1H), 2.38-2.24 (m, 1H), 2.12-1.97 (m, 1H), 1.74-1.59 (m, 2H), 1.12 (s, 3H), 1.02 (s, 3H).

[1057] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 604.3.

Example 21

N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxo-1-phenyl-ethyl]-2,2,2-trifluoro-acetamide

##STR00236##

[1058] The title compound was prepared in analogy to the procedure described for the preparation of Example 20, by using (2S)-2-(benzyloxycarbonylamino)-2-phenyl-acetic acid (GL Biochem, CAS number: 53990-33-3) instead of Cbz-Phe-OH to afford N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxo-1-phenyl-ethyl]-2,2,2-trifluoro-acetamide (Example 21) as an off-white solid.

[1059] .sup.1H NMR (400 MHz, CD.sub.3OD) : ppm 7.47-7.40 (m, 5H), 7.00-6.79 (d, 1H), 5.70 (s, 1H), 4.36 (s, 1H), 4.07 (dd, J=8.8, 14.0 Hz, 1H), 3.79 (d, J=10.4 Hz, 1H), 3.62-3.50 (m, 1H), 3.44-3.34 (m, 3H), 2.74 (dq, J=4.8, 8.8 Hz, 1H), 2.39-2.23 (m, 1H), 2.12-1.96 (m, 1H), 1.67-1.55 (m, 2H), 1.11 (s, 6H).

[1060] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 590.3.

Example 22

N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,3,3,3-pentafluoro-propanamide

##STR00237##

[1061] The title compound was prepared in analogy to the procedure described for the preparation of Example 3, by using (S)-2-(((benzyloxy)carbonyl)amino)-3,3-dimethylbutanoic acid instead of (2S)-2-(benzyloxycarbonylamino)-4-methyl-pentanoic acid and 2,2,3,3,3-pentafluoropropanoyl 2,2,3,3,3-pentafluoropropanoate instead of TFAA to afford N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,3,3,3-pentafluoro-propanamide (Example 22) as a white solid.

[1062] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.20 (s, 1H), 9.55 (d, J=8.4 Hz, 1H), 7.76 (s, 1H), 6.85 (d, J=50.4 Hz, 1H), 4.54-4.49 (m, 1H), 4.17 (s, 1H), 4.00-3.90 (m, 1H), 3.84-3.76 (m, 1H), 3.71 (d, J=10.8 Hz, 1H), 3.46 (dd, J=14.0, 4.4 Hz, 1H), 3.25-3.00 (m, 2H), 2.62-2.57 (m, 1H), 2.30-2.10 (m, 1H), 1.85-1.71 (m, 1H), 1.69-1.59 (m, 1H), 1.57-1.53 (m, 1H), 1.05 (s, 3H), 0.98 (s, 9H), 0.88 (s, 3H).

[1063] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 620.3.

Example 23

N-[(1S)-1-[(2S,4R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-(trifluoromethyl)pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide

##STR00238##

[1064] The title compound was prepared in analogy to the procedure described for the preparation of Example 1, by (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-(trifluoromethyl)pyrrolidine-2-carboxylate (Intermediate 15) instead of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1) to afford N-[(1S)-1-[(2S,4R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-(trifluoromethyl)pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide (Example 23) as a white solid.

[1065] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.13 (s, 1H), 9.57 (d, J=8.0 Hz, 1H), 7.74 (s, 1H), 6.91 (d, J=50.4 Hz, 1H), 4.56-4.53 (m, 1H), 4.36 (t, J=7.6 Hz, 1H), 4.02-3.97 (m, 2H), 3.73-3.67 (m, 1H), 3.53 (dd, J=4.4, 14.4 Hz, 1H), 3.47-3.38 (m, 1H), 3.18-3.09 (m, 2H), 2.58-2.54 (m, 1H), 2.41-2.35 (m, 1H), 2.27-2.20 (m, 1H), 2.14-2.07 (m, 1H), 1.82-1.74 (m, 1H), 1.00 (s, 9H).

[1066] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 598.2.

Example 24

N-[(1S)-2-[(6S)-6-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-5-azaspiro[2.4]heptan-5-yl]-1-(1-methylcyclopropyl)-2-oxo-ethyl]-2,2,2-trifluoro-acetamide

##STR00239##

Step 1: Preparation of benzyl (6S)-5-[(2S)-2-(tert-butoxycarbonylamino)-2-(1-methylcyclopropyl)acetyl]-5-azaspiro[2.4]heptane-6-carboxylate

##STR00240##

[1067] To a solution of (2S)-2-(tert-butoxycarbonylamino)-2-(1-methylcyclopropyl)acetic acid (900 mg, 3.93 mmol, Intermediate 16) in DMF (2 mL) and ACN (10 mL) was added HATU (1642 mg, 4.32 mmol) and followed by benzyl (6S)-5-azaspiro[2.4]heptane-6-carboxylate; hydrochloride (2033 mg, 5.89 mmol, Intermediate 17). The mixture was cooled to 0 C. and DIPEA (2537 mg, 19.63 mmol) was added to the mixture dropwise. After addition, the mixture was warmed to 15 C. and stirred at 15 C. for 1 h. The mixture was concentrated in vacuum. The residue was purified by silica gel column eluted with PE/EtOAc=20/1 to 4/1 to afford benzyl (6S)-5-[(2S)-2-(tert-butoxycarbonylamino)-2-(1-methylcyclopropyl)acetyl]-5-azaspiro[2.4]heptane-6-carboxylate (1.1 g) as yellow oil.

[1068] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 443.1.

Step 2: Preparation of (6S)-5-[(2S)-2-(tert-butoxycarbonylamino)-2-(1-methylcyclopropyl)acetyl]-5-azaspiro[2.4]heptane-6-carboxylic acid

##STR00241##

[1069] To a solution of benzyl (6S)-5-[(2S)-2-(tert-butoxycarbonylamino)-2-(1-methylcyclopropyl)acetyl]-5-azaspiro[2.4]heptane-6-carboxylate (1.0 g, 2.26 mmol) in methanol (20 mL) was added Pd(OH).sub.2/C (100 mg). The mixture was degassed under vacuum and purged with hydrogen three times. The resulting suspension was stirred at 25 C. for 1 h under a H.sub.2 balloon. The mixture was filtered and the filtrate was concentrated in vacuum to afford (6S)-5-[(2S)-2-(tert-butoxycarbonylamino)-2-(1-methylcyclopropyl)acetyl]-5-azaspiro[2.4]heptane-6-carboxylic acid (790 mg) as colorless oil.

[1070] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 353.1.

Step 3: Preparation of (6S)-5-[(2S)-2-amino-2-(1-methylcyclopropyl)acetyl]-5-azaspiro[2.4]heptane-6-carboxylic acid; hydrochloride

##STR00242##

[1071] To a solution of (6S)-5-[(2S)-2-(tert-butoxycarbonylamino)-2-(1-methylcyclopropyl)acetyl]-5-azaspiro[2.4]heptane-6-carboxylic acid (790 mg, 2.24 mmol) in DCM (5 mL) was added 4 N HCl/dioxane (5.0 mL). The reaction mixture was stirred at 25 C. for 1 h. The mixture was concentrated in vacuum to afford (6S)-5-[(2S)-2-amino-2-(1-methylcyclopropyl)acetyl]-5-azaspiro[2.4]heptane-6-carboxylic acid; hydrochloride (640 mg) as yellow gum.

Step 4: Preparation of (6S)-5-[(2S)-2-(1-methylcyclopropyl)-2-[(2,2,2-trifluoroacetyl)amino]acetyl]-5-azaspiro[2.4]heptane-6-carboxylic acid

##STR00243##

[1072] To a solution of (6S)-5-[(2S)-2-amino-2-(1-methylcyclopropyl)acetyl]-5-azaspiro[2.4]heptane-6-carboxylic acid; hydrochloride (640 mg, 2.22 mmol) in methanol (10 mL) was added triethylamine (1.85 mL, 13.3 mmol) dropwise at 0 C., followed by ethyl trifluoroacetate (944 mg, 6.65 mmol). The mixture was stirred at 50 C. for 12 h. The mixture was concentrated in vacuum. The residue was dissolved in EtOAc (100 mL), washed with 1 N HCl (20 mL), brine (20 mL) and dried over Na.sub.2SO.sub.4. After filtration and concentration, (6S)-5-[(2S)-2-(1-methylcyclopropyl)-2-[(2,2,2-trifluoroacetyl)amino]acetyl]-5-azaspiro[2.4]heptane-6-carboxylic acid (770 mg) was obtained as yellow gum.

[1073] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 349.1.

Step 5: Preparation of tert-butyl N-[[(6S)-5-[(2S)-2-(1-methylcyclopropyl)-2-[(2,2,2-trifluoroacetyl)amino]acetyl]-5-azaspiro[2.4]heptane-6-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate

##STR00244##

[1074] To a solution of (6S)-5-[(2S)-2-(1-methylcyclopropyl)-2-[(2,2,2-trifluoroacetyl)amino]acetyl]-5-azaspiro[2.4]heptane-6-carboxylic acid (760 mg, 2.18 mmol) in DMF (5 mL) was added EDCI (502 mg, 2.62 mmol), DIPEA (846 mg, 6.50 mmol) and HOPO (291 mg, 2.62 mmol). The mixture was stirred at 25 C. for 30 min and then tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (500 mg, 2.18 mmol) was added into the mixture. The resulting mixture was stirred at 25 C. for 12 h. The mixture was diluted with EtOAc (100 mL) and washed with brine (60 mL), dried over Na.sub.2SO.sub.4, filtered and the filtrate was concentrated in vacuum. The residue was purified by reverse flash eluted with ACN in H.sub.2O (0.1% TFA)=10%60% to afford tert-butyl N-[[(6S)-5-[(2S)-2-(1-methylcyclopropyl)-2-[(2,2,2-trifluoroacetyl)amino]acetyl]-5-azaspiro[2.4]heptane-6-carbonyl]amino]-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (340 mg, 0.610 mmol) as a yellow foam.

[1075] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 560.3.

Step 6: Preparation of 2,2,2-trifluoro-N-[(1S)-1-(1-methylcyclopropyl)-2-oxo-2-[(6S)-6-[[[(3S)-2-oxopyrrolidin-3-yl]methylamino]carbamoyl]-5-azaspiro[2.4]heptan-5-yl]ethyl]acetamide

##STR00245##

[1076] To a solution of tert-butyl N-[[(6S)-5-[(2S)-2-(1-methylcyclopropyl)-2-[(2,2,2-trifluoroacetyl)amino]acetyl]-5-azaspiro[2.4]heptane-6-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (330 mg, 0.590 mmol) in DCM (4 mL) was added TFA (2.0 mL). The mixture was stirred at 25 C. for 1 h. The mixture was concentrated in vacuum. The residue dissolved in DCM (50 mL), washed with saturated aqueous solution of NaHCO.sub.3 (10 mL), dried over Na.sub.2SO.sub.4, filtered and the filtrate was concentrated to afford 2,2,2-trifluoro-N-[(1S)-1-(1-methylcyclopropyl)-2-oxo-2-[(6S)-6-[[[(3S)-2-oxopyrrolidin-3-yl]methylamino]carbamoyl]-5-azaspiro[2.4]heptan-5-yl]ethyl]acetamide (180 mg) as a yellow foam.

[1077] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 460.2.

Step 7: Preparation of N-[(1S)-2-[(6S)-6-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-5-azaspiro[2.4]heptan-5-yl]-1-(1-methylcyclopropyl)-2-oxo-ethyl]-2,2,2-trifluoro-acetamide (Example 25)

##STR00246##

[1078] To a solution of 2,2,2-trifluoro-N-[(1S)-1-(1-methylcyclopropyl)-2-oxo-2-[(6S)-6-[[[(3S)-2-oxopyrrolidin-3-yl]methylamino]carbamoyl]-5-azaspiro[2.4]heptan-5-yl]ethyl]acetamide (156 mg, 0.340 mmol) in THF (50 mL) was added DIPEA (439 mg, 3.4 mmol) and (2R)-2-chloro-2-fluoro-acetyl chloride (222 mg, 0.680 mmol) dropwise at 0 C. The mixture was stirred at 0 C. for 30 min. The mixture was adjusted with 4 N HCl/dioxane to pH=5 at 0 C. After concentration at 30 C., the residue was purified by reverse flash (C18, 0.1% FA in water-ACN condition) to afford N-[(1S)-2-[(6S)-6-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-5-azaspiro[2.4]heptan-5-yl]-1-(1-methylcyclopropyl)-2-oxo-ethyl]-2,2,2-trifluoro-acetamide (62 mg, Example 24) as a white solid.

[1079] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 3: ppm 11.02 (s, 1H), 9.83-9.74 (m, 1H), 7.74 (s, 1H), 6.85 (d, J=10.0 Hz, 1H), 4.52-4.46 (m, 1H), 4.43-4.33 (m, 1H), 3.65-3.47 (m, 1H), 3.64-3.54 (m, 2H), 3.50-3.42 (m, 1H), 3.22-3.09 (m, 2H), 2.63-2.58 (m, 1H), 2.15-2.00 (m, 2H), 1.96-1.88 (m, 1H), 1.84-1.70 (m, 1H), 1.06 (s, 3H), 0.87-0.77 (m, 1H), 0.76-0.55 (m, 5H), 0.36-0.24 (m, 2H).

[1080] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 554.2.

Example 25

N-[(1S)-1-[(6S)-6-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-5-azaspiro[2.4]heptane-5-carbonyl]-2,2-dimethyl-propyl]-2-methyl-propanamide

##STR00247##

[1081] The title compound was prepared in analogy to the procedure described for the preparation of Example 1, by benzyl (6S)-5-[(2S)-2-amino-3,3-dimethyl-butanoyl]-5-azaspiro[2.4]heptane-6-carboxylate (Intermediate 5) instead of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1) and isobutyryl chloride instead of TFAA to afford N-[(1S)-1-[(6S)-6-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-5-azaspiro[2.4]heptane-5-carbonyl]-2,2-dimethyl-propyl]-2-methyl-propanamide (Example 25) as a white solid.

[1082] .sup.1H NMR (400 MHz, CD.sub.3OD) : ppm 7.85 (d, J=8.6 Hz, 1H), 7.11 (d, J=50.4 Hz, 1H), 4.59-4.41 (m, 2H), 3.98 (m, 1H), 3.85 (d, J=9.8 Hz, 1H), 3.73-3.56 (m, 2H), 3.42-3.34 (m, 2H), 2.75-2.57 (m, 2H), 2.36-2.15 (m, 2H), 2.11-1.90 (m, 2H), 1.12 (dd, J=6.8, 16.0 Hz, 6H), 1.05 (s, 9H), 0.78-0.59 (m, 4H).

[1083] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 530.3.

Example 26

N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]cyclopropanecarboxamide

##STR00248##

[1084] The title compound was prepared in analogy to the procedure described for the preparation of Example 1, by using benzyl (2S)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4,4-dimethyl-pyrrolidine-2-carboxylate (Intermediate 7) instead of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1) and cyclopropanecarbonyl chloride instead of TFAA to afford N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]cyclopropanecarboxamide (Example 26) as a white solid.

[1085] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.00 (s, 1H), 8.18 (d, J=8.8 Hz, 1H), 7.75 (s, 1H), 7.09 (d, J=50.4 Hz, 1H), 4.39 (d, J=8.4 Hz, 1H), 4.31-4.25 (m, 1H), 3.75-3.64 (m, 2H), 3.42 (dd, J=14.0 Hz, 4.0 Hz, 1H), 3.32-3.27 (m, 2H), 3.22-3.10 (m, 2H), 2.18-2.05 (m, 1H), 1.98-1.85 (m, 2H), 1.80-1.70 (m, 1H), 1.67-1.56 (m, 1H), 1.13 (s, 3H), 0.98 (s, 3H), 0.95 (s, 9H), 0.68-0.58 (m, 4H).

[1086] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 530.3.

Example 27

N-[(1S)-1-[(2S,4S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-methyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide

##STR00249##

[1087] The title compound was prepared in analogy to the procedure described for the preparation of Example 1, by using benzyl (2S,4S)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-methyl-pyrrolidine-2-carboxylate (Intermediate 18) instead of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1) to afford N-[(1S)-1-[(2S,4S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-methyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide (Example 27) as a white solid.

[1088] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.08 (s, 1H), 9.51 (d, J=8.4 Hz, 1H), 7.76 (s, 1H), 7.02 (d, J=50.4 Hz, 1H), 4.58 (d, J=8.4 Hz, 1H), 4.30-4.22 (m, 1H), 4.08-3.95 (m, 1H), 3.80-3.68 (m, 1H), 3.42 (dd, J=14.0 Hz, 4.0 Hz, 1H), 3.23-3.05 (m, 3H), 2.35-2.22 (m, 2H), 2.17-2.05 (m, 1H), 1.82-1.68 (m, 1H), 1.52-1.38 (m, 1H), 1.23-1.14 (m, 1H), 1.07 (d, J=6.0 Hz, 3H), 0.98 (s, 9H).

[1089] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 544.1.

Example 28

N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-acetamide

##STR00250##

[1090] The title compound was prepared in analogy to the procedure described for the preparation of Example 1, by using benzyl (3S,3aS,6aR)-2-[(2S)-2-amino-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate (Intermediate 3) instead of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1) and (2,2-difluoroacetyl) 2,2-difluoroacetate instead of TFAA to afford N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-acetamide (Example 28) as a white solid.

[1091] .sup.1H NMR (400 MHz, CDCl.sub.3) : ppm 9.95 (br. s, 1H), 7.08-7.04 (m, 1H), 6.78-6.66 (m, 1H), 6.08-5.81 (m, 2H), 4.68 (d, J=9.6 Hz, 1H), 4.47-4.42 (m, 1H), 4.35-4.16 (m, 1H), 4.00 (dd, J=10.4 Hz, 7.6 Hz, 1H), 3.76-3.73 (m, 1H), 3.43-3.39 (m, 2H), 2.88-2.64 (m, 4H), 2.42-2.37 (m, 1H), 1.94-1.66 (m, 6H), 1.49-1.42 (m, 1H), 1.04 (s, 9H).

[1092] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 552.2.

Example 29

N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]acetamide

##STR00251##

Step 1: Preparation of methyl (3S,3aS,6aR)-2-[(2S)-2-(benzyloxycarbonylamino)-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate

##STR00252##

[1093] To a solution of Cbz-L-tert-leucine (4.2 g, 15.83 mmol) in DMF (50 mL) was added methyl (3S,3aS,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-3-carboxylate hydrochloride (4.23 g, 15.83 mmol) and HATU (7.2 g, 19.0 mmol) at 0 C. Then DIPEA (10.2 g, 79.16 mmol) was added into above solution to afford a yellow solution. The mixture was stirred at 25 C. for 12 h. The mixture was diluted with EtOAc (400 mL), washed with brine (60 mL4), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by silica gel column eluted with PE to PE/EtOAc=6/1 to afford methyl (3S,3aS,6aR)-2-[(2S)-2-(benzyloxycarbonylamino)-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate (6.5 g) as yellow gum.

[1094] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 417.2.

Step 2: Preparation of (3S,3aS,6aR)-2-[(2S)-2-(benzyloxycarbonylamino)-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid

##STR00253##

[1095] To a solution of methyl (3S,3aS,6aR)-2-[(2S)-2-(benzyloxycarbonylamino)-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate (6.5 g, 15.61 mmol) in THF (100 mL) was added a solution of LiOH.Math.H.sub.2O (2.0 g, 46.82 mmol) in water (40 mL). The mixture was stirred at 25 C. for 1 h. The mixture was acidified with 1 N HCl to pH=4. The mixture was extracted with EtOAc (100 mL3). The organic layers were washed with brine (60 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum to afford (3S,3aS,6aR)-2-[(2S)-2-(benzyloxycarbonylamino)-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid (5.96 g) as a yellow foam.

[1096] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 403.1.

Step 3: Preparation of tert-butyl N-[[(3S,3aS,6aR)-2-[(2S)-2-(benzyloxycarbonylamino)-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate

##STR00254##

[1097] To a solution of (3S,3aS,6aR)-2-[(2S)-2-(benzyloxycarbonylamino)-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid (5.9 g, 14.66 mmol) in DMF (60 mL) was added DIPEA (5.7 g, 43.99 mmol), EDCI (3.4 g, 17.6 mmol), HOPO (1.95 g, 17.6 mmol) and tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (3.4 g, 14.67 mmol, Intermediate 9). The mixture was stirred at 25 C. for 12 h. The mixture was diluted with EtOAc (300 mL), washed with brine (60 mL4), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by reverse flash chromatography ([water (0.1% TFA)-ACN]; B %: 50%-55%, 25 min) to afford tert-butyl N-[[(3S,3aS,6aR)-2-[(2S)-2-(benzyloxycarbonylamino)-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (6.2 g) as a yellow foam.

[1098] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 614.4.

Step 4: Preparation of tert-butyl N-[[(3S,3aS,6aR)-2-[(2S)-2-amino-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate

##STR00255##

[1099] To a solution of tert-butyl N-[[(3S,3aS,6aR)-2-[(2S)-2-(benzyloxycarbonylamino)-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (6.2 g, 10.1 mmol) in methanol (60 mL) was added Pd/C (600 mg, 10% purity). The suspension was degassed under vacuum and purged with hydrogen three times. The resulting mixture was stirred at 25 C. under a H.sub.2 balloon for 2 h. The mixture was filtered and the filter cake was washed with MeOH (50 mL). The filtrate was concentrated in vacuum to afford tert-butyl N-[[(3S,3aS,6aR)-2-[(2S)-2-amino-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (4.5 g) as a yellow foam.

[1100] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 480.2.

Step 5: Preparation of tert-butyl N-[[(1R,2S,5S)-6,6-dimethyl-3-[(2S)-4-methyl-2-[(2,2,2-trifluoroacetyl)amino]pentanoyl]-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate

##STR00256##

[1101] To a solution of tert-butyl N-[[(3S,3aS,6aR)-2-[(2S)-2-amino-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (500 mg, 1.04 mmol) in DCM (6 mL) was added DIPEA (404 mg, 3.13 mmol) and acetic anhydride (159 mg, 1.56 mmol) dropwise at 0 C. The mixture was stirred at 25 C. for 1 h. The mixture was diluted in DCM (30 mL) and washed with 1 N HCl (30 mL). After separation, the aqueous phase was extracted with DCM (30 ml2). The organic layers were washed with brine (40 ml), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum to afford tert-butyl N-[[(1R,2S,5S)-6,6-dimethyl-3-[(2S)-4-methyl-2-[(2,2,2-trifluoroacetyl)amino]pentanoyl]-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (520 mg, crude) as yellow oil.

[1102] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 522.4.

Step 6: Preparation of N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(3S)-2-oxopyrrolidin-3-yl]methylamino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]acetamide; hydrochloride

##STR00257##

[1103] To a solution of tert-butyl N-[[(3S,3aS,6aR)-2-[(2S)-2-acetamido-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-TH-cyclopenta[c]pyrrole-3-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (500 mg, 0.96 mmol) in DCM (5 mL) was added TFA (5 mL). The mixture was stirred at 25 C. for 1 h. The mixture was concentrated in vacuum and the residue was purified by reverse flash chromatography, eluted with ACN in H.sub.2O (0.1% HCl)=060% to afford N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(3S)-2-oxopyrrolidin-3-yl]methylamino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-TH-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]acetamide hydrochloride (350 mg) as a white solid.

[1104] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 422.4.

Step 7: Preparation of N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]acetamide (Example 29)

##STR00258##

[1105] To a solution of N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(3S)-2-oxopyrrolidin-3-yl]methylamino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]acetamide; hydrochloride (350 mg, 0.8 mmol) in THF (100 mL) was added DIPEA (986 mg, 7.6 mmol). The mixture was cooled to 5 C. and then (2R)-2-chloro-2-fluoro-acetyl chloride (500 mg, 1.5 mmol) in THF (10 mL) was added dropwise at 5 C. The reaction mixture was stirred at 5 C. for 30 min. The reaction mixture was quenched with MeOH (10 mL) and acidified by 4 N HCl/dioxane to pH=5 at 10 C. Then the mixture was concentrated in vacuum at 30 C. The residue was purified by pre-HPLC (Instrument ACSWH-PREP-NPLC-A Method Column Welch Ultimate XBSiOH 250*50*10 um Condition Hexane-EtOH Begin B 1 End B 40 Gradient Time (min: 15; 100% B Hold Time (min: 4 FlowRate (ml/min: 100 Injections: 1) to afford N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]acetamide (185 mg, Example 29) as a white solid.

[1106] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.08 (s, 1H), 7.99 (d, J=8.4 Hz, 1H), 7.78 (s, 1H), 7.02 (d, J=50.4 Hz, 1H), 4.40 (d, J=8.4 Hz, 1H), 3.92 (d, J=6.8 Hz, 1H), 3.90-3.82 (m, 1H), 3.80-3.66 (m, 2H), 3.39 (dd, J=14.0 Hz, 3.6 Hz, 1H), 3.24-3.05 (m, 2H), 2.76-2.68 (m, 1H), 2.64-2.54 (m, 1H), 2.48-2.44 (m, 1H), 2.21-2.05 (m, 1H), 1.88 (s, 3H), 1.86-1.68 (m, 5H), 1.68-1.57 (m, 1H), 1.43-1.29 (m, 1H), 0.93 (s, 9H).

[1107] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 516.2.

Example 30

N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-propanamide

##STR00259##

[1108] The title compound was prepared in analogy to the procedure described for the preparation of Example 29, by using 2,2-difluoropropionic acid and T.sub.3P instead of acetic anhydride to afford N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-propanamide (Example 30) as a white solid.

[1109] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.11 (s, 1H), 8.24 (d, J=8.0 Hz, 1H), 7.80 (s, 1H), 6.97 (d, J=50.4 Hz, 1H), 4.57-4.48 (m, 1H), 3.98 (d, J=4.0 Hz, 1H), 3.97-3.83 (m, 1H), 3.78-3.62 (m, 2H), 3.39 (m, 1H), 3.21-3.10 (m, 2H), 2.77-2.71 (m, 1H), 2.61-2.57 (m, 1H), 2.19-2.11 (m, 1H), 1.94-1.55 (m, 10H), 1.42-1.30 (m, 1H), 0.96 (s, 9H).

[1110] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 566.2.

Example 31

N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]cyclopropanecarboxamide

##STR00260##

[1111] The title compound was prepared in analogy to the procedure described for the preparation of Example 29, by using cyclopropanecarbonyl chloride instead of acetic anhydride to afford N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]cyclopropanecarboxamide (Example 31) as a white solid.

[1112] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.08 (s, 1H), 8.18 (d, J=8.4 Hz, 1H), 7.77 (s, 1H), 7.05 (d, J=50.4 Hz, 1H), 4.43 (d, J=8.8 Hz, 1H), 3.93 (d, J=6.4 Hz, 1H), 3.89-3.80 (m, 1H), 3.78-3.69 (m, 2H), 3.42-3.36 (m, 1H), 3.24-3.06 (m, 2H), 2.75-2.69 (m, 1H), 2.28-2.01 (m, 1H), 1.94-1.81 (m, 2H), 1.80-1.69 (m, 4H), 1.68-1.58 (m, 1H), 1.37-1.22 (m, 1H), 1.02-0.95 (m, 11H), 0.70-0.55 (m, 4H).

[1113] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 542.3.

Example 32

N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]propanamide

##STR00261##

[1114] The title compound was prepared in analogy to the procedure described for the preparation of Example 29, by using propionyl chloride instead of acetic anhydride to afford N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]propanamide (Example 32) as a white solid.

[1115] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.07 (s, 1H), 7.89 (d, J=8.4 Hz, 1H), 7.78 (s, 1H), 7.05 (d, J=50.4 Hz, 1H), 4.42 (d, J=8.8 Hz, 1H), 3.92 (d, J=6.4 Hz, 1H), 3.89-3.81 (m, 1H), 3.79-3.67 (m, 2H), 3.39 (dd, J=14.0 Hz, 4.0 Hz, 1H), 3.22-3.10 (m, 2H), 2.77-2.68 (m, 1H), 2.59-2.53 (m, 2H), 2.29-2.08 (m, 3H), 1.90-1.70 (m, 5H), 1.68-1.56 (m, 1H), 1.40-1.30 (m, 1H), 0.97 (t, J=7.6 Hz, 3H), 0.93 (s, 9H).

[1116] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 530.3.

Example 33

N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2-methyl-propanamide

##STR00262##

[1117] The title compound was prepared in analogy to the procedure described for the preparation of Example 29, by using isobutyryl chloride instead of acetic anhydride to afford N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2-methyl-propanamide (Example 33) as a white solid.

[1118] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.09 (s, 1H), 7.85 (d, J=8.8 Hz, 1H), 7.79 (s, 1H), 7.03 (d, J=52.0 Hz, 1H), 4.43 (d, J=8.0 Hz, 1H), 3.93 (d, J=8.0 Hz, 1H), 3.89-3.81 (m, 1H), 3.77-3.67 (m, 2H), 3.38 (dd, J=16.0, 4.0 Hz, 1H), 3.21-3.10 (m, 2H), 2.79-2.56 (m, 3H), 2.19-2.10 (m, 1H), 1.87-1.80 (m, 2H), 1.75-1.60 (m, 4H), 1.67-1.50 (m, 1H), 1.20-1.40 (m, 1H), 0.99 (d, J=4.0 Hz, 3H), 0.95-0.90 (m, 12H).

[1119] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 544.3.

Example 34

Rac-2,2-difluoro-N-[(1S)-2,2-dimethyl-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]propyl]cyclopropanecarboxamide

##STR00263##

[1120] The title compound was prepared in analogy to the procedure described for the preparation of Example 29, by using 2,2-difluorocyclopropanecarboxylic acid and T.sub.3P instead of acetic anhydride to afford rac-2,2-difluoro-N-[(1S)-2,2-dimethyl-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]propyl]cyclopropanecarboxamide (Example 34) as a white solid.

[1121] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.08 (d, J=8.0 Hz, 1H), 8.60-8.45 (m, 1H), 7.87 (s, 1H), 7.03 (d, J=52.0 Hz, 1H), 4.48 (d, J=8.4 Hz, 1H), 3.93 (d, J=8.0 Hz, 1H), 3.89-3.81 (m, 1H), 3.77-3.67 (m, 2H), 3.38 (dd, J=14.0, 3.6 Hz, 1H), 3.21-3.10 (m, 2H), 2.95-2.83 (m, 1H), 2.74-2.69 (m, 1H), 2.58-2.56 (m, 2H), 2.19-2.10 (m, 1H), 1.94-1.82 (m, 3H), 1.80-1.67 (m, 4H), 1.67-1.55 (m, 1H), 1.40-1.25 (m, 1H), 0.95 (s, 9H).

[1122] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 578.3.

Example 35

N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2-fluoro-2-methyl-propanamide

##STR00264##

[1123] The title compound was prepared in analogy to the procedure described for the preparation of Example 29, by using 2-fluoroisobutyric acid and T.sub.3P instead of acetic anhydride to afford N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2-fluoro-2-methyl-propanamide (Example 35) as a white solid.

[1124] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.11 (s, 1H), 7.77 (s, 1H), 7.18 (dd, J=8.4 Hz, 4.0 Hz, 1H), 6.95 (d, J=50.8 Hz, 1H), 4.46 (d, J=8.4 Hz, 1H), 3.98 (d, J=6.0 Hz, 1H), 3.89 (dd, J=10.0 Hz, 7.2 Hz, 1H), 3.73 (dd, J=13.6 Hz, 3.2 Hz, 1H), 3.65 (dd, J=10.8 Hz, 3.2 Hz, 1H), 3.40 (dd, J=14.0 Hz, 4.0 Hz, 1H), 3.22-3.10 (m, 2H), 2.78-2.69 (m, 1H), 2.60-2.54 (m, 1H), 2.53-2.51 (m, 1H), 2.21-2.10 (m, 1H), 1.89-1.69 (m, 5H), 1.67-1.60 (m, 1H), 1.55-1.43 (m, 6H), 1.40-1.31 (m, 1H), 0.94 (s, 9H).

[1125] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 562.2.

Example 36

Rac-2-fluoro-N-[(1S)-2,2-dimethyl-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]propyl]propanamide

##STR00265##

[1126] The title compound was prepared in analogy to the procedure described for the preparation of Example 29, by using 2-fluoropropionic acid and T.sub.3P instead of acetic anhydride to afford Rac-2-fluoro-N-[(1S)-2,2-dimethyl-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]propyl]propanamide (Example 36) as a white solid.

[1127] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.10 (d, J=4.4 Hz, 1H), 8.11-7.82 (m, 1H), 7.72 (s, 1H), 7.07-6.91 (m, 1H), 5.29-5.04 (m, 1H), 4.51-4.40 (m, 1H), 3.98-3.93 (m, 1H), 3.92-3.85 (m, 1H), 3.79-3.64 (m, 2H), 3.44-3.35 (m, 1H), 3.22-3.10 (m, 2H), 2.79-2.69 (m, 1H), 2.60-2.54 (m, 1H), 2.54-2.51 (m, 1H), 2.22-2.10 (m, 1H), 1.92-1.70 (m, 5H), 1.67-1.58 (m, 1H), 1.45-1.31 (m, 4H), 0.94 (d, J=5.6 Hz, 9H).

[1128] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 548.2.

Example 37

N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]cyclopropanecarboxamide

##STR00266##

[1129] The title compound was prepared in analogy to the procedure described for the preparation of Example 29, by using (2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoic acid (TCI, CAS number: 3160-59-6) instead of Cbz-L-tert-leucine and cyclopropanecarbonyl chloride instead of acetic anhydride to afford N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]cyclopropanecarboxamide (Example 37) as a white solid.

[1130] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.05 (s, 1H), 8.45 (d, J=8.4 Hz, 1H), 7.78 (s, 1H), 7.00 (d, J=50.4 Hz, 1H), 4.26 (t, J=8.8 Hz, 1H), 3.94 (d, J=6.0 Hz, 1H), 3.81-3.70 (m, 3H), 3.39 (dd, J=13.6 Hz, 3.2 Hz, 1H), 3.23-3.10 (m, 2H), 2.74-2.70 (m, 1H), 2.57-2.54 (m, 1H), 2.20-2.09 (m, 1H), 1.93-1.57 (m, 9H), 1.54-1.45 (m, 1H), 1.40-1.30 (m, 1H), 1.18-1.04 (m, 1H), 0.91-0.75 (m, 6H), 0.72-0.56 (m, 4H).

[1131] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 542.3.

Example 38

N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]propanamide

##STR00267##

[1132] The title compound was prepared in analogy to the procedure described for the preparation of Example 29, by using (2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoic acid instead of Cbz-L-tert-leucine and propionyl chloride instead of acetic anhydride to afford N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]propanamide (Example 38) as a white solid.

[1133] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.05 (s, 1H), 8.22-8.17 (m, 1H), 7.69 (s, 1H), 6.99 (d, J=50.4 Hz, 1H), 4.31-4.18 (m, 1H), 3.94 (d, J=6.0 Hz, 1H), 3.88-3.79 (m, 1H), 3.77-3.68 (m, 1H), 3.41-3.35 (m, 1H), 3.22-3.10 (m, 2H), 2.80-2.69 (m, 2H), 2.18-2.02 (m, 3H), 1.91-1.62 (m, 8H), 1.55-1.41 (m, 1H), 1.41-1.32 (m, 1H), 1.31-1.21 (m, 1H), 1.13-1.04 (m, 1H), 1.01-0.94 (m, 3H), 0.88-0.78 (m, 6H).

[1134] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 530.2.

Example 39

N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide

##STR00268##

[1135] The title compound was prepared in analogy to the procedure described for the preparation of Example 29, by using (2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoic acid instead of Cbz-L-tert-leucine and (2,2-difluoroacetyl) 2,2-difluoroacetate instead of acetic anhydride to afford N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide (Example 39) as a white solid.

[1136] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.08 (s, 1H), 9.23 (d, J=8.0 Hz, 1H), 7.78 (s, 1H), 6.95 (d, J=50.4 Hz, 1H), 6.24 (t, J=53.6 Hz, 1H), 4.38-4.28 (m, 1H), 3.97 (d, J=6.0 Hz, 1H), 3.90-3.70 (m, 3H), 3.40 (dd, J=4.0, 14.0 Hz, 1H), 3.21-3.10 (m, 2H), 2.79-2.71 (m, 1H), 2.62-2.57 (m, 1H), 2.21-2.11 (m, 1H), 1.91-1.69 (m, 6H), 1.67-1.58 (m, 1H), 1.52-1.47 (m, 1H), 1.46-1.34 (m, 2H), 1.15-1.03 (m, 1H), 0.86 (d, J=6.8 Hz, 3H), 0.81 (t, J=7.2 Hz, 3H).

[1137] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 552.2.

Example 40

N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2-difluoro-propanamide

##STR00269##

[1138] The title compound was prepared in analogy to the procedure described for the preparation of Example 29, by using (2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoic acid instead of Cbz-L-tert-leucine, 2,2-difluoropropionic acid and T.sub.3P instead of acetic anhydride to afford N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2-difluoro-propanamide (Example 40) as a white solid.

[1139] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.06 (s, 1H), 8.98 (d, J=7.2 Hz, 1H), 7.78 (s, 1H), 6.95 (d, J=50.4 Hz, 1H), 4.29-4.20 (m, 1H), 3.97 (d, J=6.0 Hz, 1H), 3.84 (d, J=4.8 Hz, 2H), 3.78-3.71 (m, 2H), 3.40 (dd, J=14.0 Hz, 4.0 Hz, 1H), 3.22-3.11 (m, 2H), 2.79-2.70 (m, 1H), 2.62-2.56 (m, 1H), 2.20-2.11 (m, 1H), 1.98-1.66 (m, 10H), 1.65-1.57 (m, 1H), 1.51-1.43 (m, 1H), 1.42-1.34 (m, 1H), 1.14-1.03 (m, 1H), 0.85 (d, J=6.8 Hz, 3H), 0.80 (t, J=7.2 Hz, 2H).

[1140] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 566.1.

Example 41

Rac-2,2-difluoro-N-[(1S,2S)-2-methyl-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]butyl]cyclopropanecarboxamide

##STR00270##

[1141] The title compound was prepared in analogy to the procedure described for the preparation of Example 29, by using (2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoic acid instead of Cbz-L-tert-leucine, 2,2-difluorocyclopropanecarboxylic acid and T.sub.3P instead of acetic anhydride to afford rac-2,2-difluoro-N-[(1S,2S)-2-methyl-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]butyl]cyclopropanecarboxamide (Example 41) as a white solid.

[1142] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.08-11.04 (m, 1H), 8.78-8.68 (m, 1H), 7.77 (s, 1H), 6.93 (d, J=50.4 Hz, 1H), 4.41-4.13 (m, 1H), 4.06-3.85 (m, 1H), 3.86-3.65 (m, 3H), 3.45-3.40 (m, 1H), 3.21-3.12 (m, 2H), 2.62-2.58 (m, 1H), 2.20-2.11 (m, 2H), 1.89-1.69 (m, 8H), 1.63-1.45 (m, 2H), 1.41-1.29 (m, 1H), 1.27-1.18 (m, 1H), 1.15-1.04 (m, 2H), 0.91-0.72 (m, 6H).

[1143] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 578.3.

Example 42

N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2-fluoro-2-methyl-propanamide

##STR00271##

[1144] The title compound was prepared in analogy to the procedure described for the preparation of Example 29, by using (2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoic acid instead of Cbz-L-tert-leucine, 2-fluoroisobutyric acid and T.sub.3P instead of acetic anhydride to afford N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2-fluoro-2-methyl-propanamide (Example 42) as a white solid.

[1145] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.09 (s, 1H), 8.10 (d, J=1.2 Hz, 1H), 7.79 (s, 1H), 6.92 (d, J=50.4 Hz, 1H), 4.26 (t, J=8.8 Hz, 1H), 4.15-4.05 (m, 1H), 3.96 (d, J=6.0 Hz, 1H), 3.86-3.77 (m, 1H), 3.76-3.69 (m, 1H), 3.39 (dd, J=14.0 Hz, 3.6 Hz, 1H), 3.22-3.10 (m, 2H), 2.78-2.69 (m, 1H), 2.65-2.56 (m, 1H), 2.20-2.10 (m, 1H), 1.96-1.60 (m, 8H), 1.51-1.39 (m, 7H), 1.38-1.31 (m, 1H) 1.10-1.02 (m, 1H) 0.89-0.75 (m, 6H).

[1146] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 562.3.

Example 43

Rac-2-fluoro-N-[(1S,2S)-2-methyl-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]butyl]propanamide

##STR00272##

[1147] The title compound was prepared in analogy to the procedure described for the preparation of Example 29, by using (2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoic acid instead of Cbz-L-tert-leucine, 2-fluoropropionic acid and T.sub.3P instead of acetic anhydride to afford rac-2-fluoro-N-[(1S,2S)-2-methyl-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]butyl]propanamide (Example 43) as a white solid.

[1148] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.08 (d, J=6.0 Hz, 1H), 8.43 (dd, J=34.4 Hz, 8.0 Hz, 1H), 7.80 (s, 1H), 6.96 (dd, J=50.4 Hz, 6.0 Hz, 1H), 5.15-4.91 (m, 1H), 4.28 (q, J=8.4 Hz, 1H), 3.95 (t, J=6.4 Hz, 1H), 3.85-3.69 (m, 3H), 3.39 (dd, J=8.8 Hz, 3.6 Hz, 1H), 3.21-3.10 (m, 2H), 2.76-2.70 (m, 1H), 2.60-2.56 (m, 1H), 2.20-2.08 (m, 1H), 1.90-1.60 (m, 8H), 1.50-1.44 (m, 1H), 1.43-1.25 (m, 4H) 1.15-1.00 (m, 1H), 0.89-0.75 (m, 6H).

[1149] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 548.2.

Example 44

N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2-dimethyl-propanamide

##STR00273##

[1150] The title compound was prepared in analogy to the procedure described for the preparation of Example 29, by using (2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoic acid instead of Cbz-L-tert-leucine and pivaloyl chloride instead of acetic anhydride to afford N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2-dimethyl-propanamide (Example 44) as a white solid.

[1151] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.06 (s, 1H), 7.80 (s, 1H), 7.65 (d, J=8.0 Hz, 1H), 6.93 (d, J=50.4 Hz, 1H), 4.23 (t, J=9.2 Hz, 1H), 3.98-3.86 (m, 2H), 3.81-3.68 (m, 2H), 3.41 (d, J=3.8 Hz, 1H), 3.21-3.10 (m, 2H), 2.75-2.71 (m, 1H), 2.56-2.54 (m, 1H), 2.19-2.10 (m, 1H), 1.93-1.60 (m, 8H), 1.42-1.52 (m, 1H), 1.31-1.40 (m, 1H), 1.09 (s, 9H), 1.06-1.01 (m, 1H), 0.76-0.84 (m, 6H).

[1152] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 558.2.

Example 45

N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-3,3,3-trifluoro-propanamide

##STR00274##

[1153] The title compound was prepared in analogy to the procedure described for the preparation of Example 29, by using (2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoic acid instead of Cbz-L-tert-leucine, 3,3,3-trifluoropropionic acid and T.sub.3P instead of acetic anhydride to afford N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-3,3,3-trifluoro-propanamide (Example 45) as a white solid.

[1154] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.08 (s, 1H), 8.74-8.56 (m, 1H), 7.78 (s, 1H), 6.93 (d, J=50.4 Hz, 1H), 4.33 (t, J=8.8 Hz, 1H), 3.95 (d, J=6.0 Hz, 1H), 3.67-3.88 (m, 3H), 3.43-3.36 (m, 1H), 3.30-3.22 (m, 2H), 3.22-3.10 (m, 2H), 2.80-2.70 (m, 1H), 2.62-2.54 (m, 2H), 2.25-2.09 (m, 1H), 1.92-1.59 (m, 7H), 1.51-1.31 (m, 2H), 1.19-1.02 (m, 1H), 0.88-0.76 (m, 6H).

[1155] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 584.1.

Example 46

N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]butanamide

##STR00275##

[1156] The title compound was prepared in analogy to the procedure described for the preparation of Example 29, by using (2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoic acid instead of Cbz-L-tert-leucine, butyric acid and T.sub.3P instead of acetic anhydride to afford N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]butanamide (Example 46) as a white solid.

[1157] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.05 (s, 1H), 8.24-8.08 (m, 1H), 7.78 (s, 1H), 6.94 (d, J=50.4 Hz, 1H), 4.25 (t, J=9.0 Hz, 1H), 4.07-3.66 (m, 4H), 3.43-3.35 (m, 1H), 3.21-3.09 (m, 2H), 2.78-2.68 (m, 1H), 2.60-2.51 (m, 2H), 2.19-2.00 (m, 3H), 1.89-1.58 (m, 7H), 1.54-1.42 (m, 3H), 1.41-1.30 (m, 1H), 1.16-1.01 (m, 1H), 0.86-0.75 (m, 9H).

[1158] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 544.1.

Example 47

N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2-methyl-propanamide

##STR00276##

[1159] The title compound was prepared in analogy to the procedure described for the preparation of Example 29, by using (2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoic acid instead of Cbz-L-tert-leucine and isobutyryl chloride instead of acetic anhydride to afford N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2-methyl-propanamide (Example 47) as a white solid.

[1160] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.04 (s, 1H), 8.10 (d, J=8.0 Hz, 1H), 7.78 (s, 1H), 6.98 (d, J=50.4 Hz, 1H), 4.30-4.20 (m, 1H), 4.09-3.92 (m, 1H), 3.88-3.68 (m, 3H), 3.43-3.36 (m, 1H), 3.23-3.09 (m, 2H), 2.77-2.69 (m, 1H), 2.60-2.55 (m, 2H), 2.57-2.45 (m, 1H), 2.20-2.10 (m, 1H), 1.91-1.78 (m, 2H), 1.77-1.61 (m, 5H), 1.51-1.43 (m, 1H), 1.40-1.30 (m, 1H), 1.14-1.04 (m, 1H), 0.99 (d, J=6.8 Hz, 3H), 0.94 (d, J=6.8 Hz, 3H), 0.84-0.76 (m, 6H).

[1161] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 544.4.

Example 48

N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide

##STR00277##

[1162] The title compound was prepared in analogy to the procedure described for the preparation of Example 29, by using (2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoic acid instead of Cbz-L-tert-leucine and TFAA instead of acetic anhydride to afford N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide (Example 48) as a white solid.

[1163] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.09 (s, 1H), 9.94 (d, J=7.6 Hz, 1H), 7.78 (s, 1H), 6.93 (d, J=50.4 Hz, 1H), 4.32-4.24 (m, 1H), 3.99 (d, J=6.0 Hz, 1H), 3.91-3.73 (m, 3H), 3.40 (dd, J=13.6 Hz, 4.0 Hz, 1H), 3.20-3.10 (m, 2H), 2.81-2.72 (m, 1H), 2.63-2.57 (m, 1H), 2.21-2.11 (m, 1H), 1.98-1.83 (m, 3H), 1.79-1.71 (m, 3H), 1.68-1.61 (m, 1H), 1.53-1.44 (m, 1H), 1.43-1.35 (m, 1H), 1.20 (t, J=6.5 Hz, 1H), 1.16-1.07 (m, 1H), 0.87 (d, J=6.8 Hz, 3H), 1.81 (t, J=7.2 Hz, 3H).

[1164] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 570.2.

Example 49

N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2-dichloro-acetamide

##STR00278##

[1165] The title compound was prepared in analogy to the procedure described for the preparation of Example 29, by using (2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoic acid instead of Cbz-L-tert-leucine, dichloroacetic acid and T.sub.3P instead of acetic anhydride to afford N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2-dichloro-acetamide (Example 49) as a white solid.

[1166] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.10 (s, 1H), 9.03-8.83 (m, 1H), 7.75 (s, 1H), 6.93 (d, J=50.8 Hz, 1H), 6.49 (s, 1H), 4.32 (t, J=8.5 Hz, 1H), 3.99 (d, J=6.0 Hz, 1H), 3.90-3.82 (m, 1H), 3.80-3.66 (m, 2H), 3.43-3.35 (m, 1H), 3.23-3.10 (m, 2H), 2.78-2.74 (m, 1H), 2.58-2.57 (m, 1H), 2.21-2.10 (m, 1H), 1.92-1.56 (m, 8H), 1.52-1.34 (m, 2H), 1.16-1.03 (m, 1H), 0.90-0.77 (m, 6H).

[1167] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 584.0

Example 50

N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2,3,3,3-pentafluoro-propanamide

##STR00279##

[1168] The title compound was prepared in analogy to the procedure described for the preparation of Example 29, by using (2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoic acid instead of Cbz-L-tert-leucine and 2,2,3,3,3-pentafluoropropanoyl 2,2,3,3,3-pentafluoropropanoate instead of acetic anhydride to afford N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2,3,3,3-pentafluoro-propanamide (Example 50) as a white solid.

[1169] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.10 (s, 1H), 10.04 (d, J=7.2 Hz, 1H), 7.78 (s, 1H), 6.93 (d, J=50.8 Hz, 1H), 4.38-4.27 (m, 1H), 4.12-3.96 (m, 1H), 3.92-3.69 (m, 3H), 3.44-3.36 (m, 1H), 3.22-3.05 (m, 2H), 2.80-2.72 (m, 1H), 2.62-2.57 (m, 2H), 2.21-2.08 (m, 1H), 2.04-1.92 (m, 1H), 1.91-1.57 (m, 6H), 1.52-1.31 (m, 2H), 1.18-1.04 (m, 1H), 0.96-0.76 (m, 6H).

[1170] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 620.3.

Example 51

N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide

##STR00280##

[1171] The title compound was prepared in analogy to the procedure described for the preparation of Example 3, by using (2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoic acid instead of (2S)-2-(benzyloxycarbonylamino)-4-methyl-pentanoic acid and (2,2-difluoroacetyl) 2,2-difluoroacetate instead of TFAA to afford N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide (Example 51) as a white solid.

[1172] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.15 (s, 1H), 9.26 (d, J=8.0 Hz, 1H), 7.76 (s, 1H), 6.85 (d, J=50.4 Hz, 1H), 6.21 (t, J=53.6 Hz, 1H), 4.27-4.17 (m, 1H), 4.15 (s, 1H), 3.95-3.75 (m, 3H), 3.50-3.42 (m, 1H), 3.23-3.10 (m, 2H), 2.64-2.60 (m, 1H), 2.21-2.08 (m, 1H), 1.88-1.70 (m, 2H), 1.68-1.60 (m, 1H), 1.57-1.44 (m, 2H), 1.18-1.15 (m, 1H), 1.06 (s, 3H), 0.92 (s, 3H), 0.88-0.78 (m, 6H).

[1173] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 552.3.

Example 52

N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-dimethyl-propanamide

##STR00281##

[1174] The title compound was prepared in analogy to the procedure described for the preparation of Example 3, by using (2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoic acid instead of (2S)-2-(benzyloxycarbonylamino)-4-methyl-pentanoic acid and pivaloyl chloride instead of TFAA to afford N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-dimethyl-propanamide (Example 52) as a white solid.

[1175] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.13 (s, 1H), 7.76 (s, 1H), 7.67 (d, J=8.4 Hz, 1H), 6.90 (d, J=50.4 Hz, 1H), 4.27-4.18 (m, 1H), 4.13 (s, 1H), 4.00 (d, J=10.4 Hz, 1H), 3.87-3.75 (m, 2H), 3.48-3.41 (dd, J=14.0 Hz, 4.4 Hz, 1H), 3.22-3.10 (m, 2H), 2.63-2.55 (m, 1H), 2.27-2.10 (m, 1H), 1.98-1.84 (m, 1H), 1.83-1.71 (m, 1H), 1.64-1.54 (m, 1H), 1.52-1.39 (m, 2H), 1.10-1.02 (m, 13H), 0.88 (s, 3H), 0.82-0.75 (m, 6H).

[1176] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 558.4.

Example 53

Rac-2,2-difluoro-N-[(1S,2S)-2-methyl-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]butyl]cyclopropanecarboxamide

##STR00282##

[1177] The title compound was prepared in analogy to the procedure described for the preparation of Example 3, by using (2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoic acid instead of (2S)-2-(benzyloxycarbonylamino)-4-methyl-pentanoic acid, 2,2-difluorocyclopropanecarboxylic acid and T.sub.3P instead of TFAA to afford rac-2,2-difluoro-N-[(1S,2S)-2-methyl-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]butyl]cyclopropanecarboxamide (Example 53) as a white solid.

[1178] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.15 (d, J=12.0 Hz, 1H), 8.74 (dd, J=26.8 Hz, 8.8 Hz, 1H), 7.76 (s, 1H), 7.00-6.80 (m, 1H), 4.30-4.20 (m, 1H), 4.14 (d, J=2.0 Hz, 1H), 3.90-3.75 (m, 3H), 3.45 (dd, J=13.0 Hz, 4.4 Hz, 1H), 3.20-3.10 (m, 2H), 2.70-2.60 (m, 2H), 2.20-2.10 (m, 1H), 1.95-1.70 (m, 4H), 1.66-1.58 (m, 1H), 1.55-1.44 (m, 2H), 1.15-1.07 (m, 1H), 1.04 (d, J=4.8 Hz, 3H), 0.91 (s, 2H), 0.89-0.79 (m, 7H).

[1179] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 578.3.

Example 54

N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-methyl-propanamide

##STR00283##

[1180] The title compound was prepared in analogy to the procedure described for the preparation of Example 3, by using (2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoic acid instead of (2S)-2-(benzyloxycarbonylamino)-4-methyl-pentanoic acid and isobutyryl chloride instead of TFAA to afford N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-methyl-propanamide (Example 54) as a white solid.

[1181] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.13 (s, 1H), 8.12 (d, J=8.4 Hz, 1H), 7.76 (s, 1H), 6.90 (d, J=50.4 Hz, 1H), 4.23-4.16 (m, 1H), 4.12 (s, 1H), 3.98-3.92 (m, 1H), 3.89-3.74 (m, 2H), 3.45 (dd, J=14.0 Hz, 4.4 Hz, 1H), 3.21-3.11 (m, 2H), 2.64-2.55 (m, 1H), 2.46-2.39 (m, 1H), 2.20-2.11 (m, 1H), 1.83-1.70 (m, 2H), 1.64-1.56 (m, 1H), 1.52-1.48 (m, 1H), 1.49-1.41 (m, 1H), 1.29-1.24 (m, 1H), 1.05 (s, 3H), 0.97 (d, J=6.8 Hz, 3H), 0.94-0.86 (m, 6H), 0.83-0.76 (m, 6H).

[1182] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 544.4.

Example 55

N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-difluoro-propanamide

##STR00284##

[1183] The title compound was prepared in analogy to the procedure described for the preparation of Example 3, by using (2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoic acid instead of (2S)-2-(benzyloxycarbonylamino)-4-methyl-pentanoic acid, 2,2-difluoropropionic acid and T.sub.3P instead of TFAA to afford N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-difluoro-propanamide (Example 55) as a white solid.

[1184] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.15 (s, 1H), 9.04 (d, J=8.0 Hz, 1H), 7.76 (s, 1H), 6.87 (d, J=50.4 Hz, 1H), 4.25-4.10 (m, 2H), 3.94-3.85 (m, 2H), 3.83-3.76 (m, 1H), 3.45 (dd, J=14.0, 4.4 Hz, 1H), 3.23-3.10 (m, 2H), 2.64-2.55 (m, 1H), 2.30-2.10 (m, 1H), 2.00-1.87 (m, 1H), 1.84-1.77 (m, 1H), 1.77-1.67 (m, 3H), 1.66-1.61 (m, 1H), 1.56-1.52 (m, 1H), 1.50-1.42 (m, 1H), 1.29-1.19 (m, 1H), 1.16-1.06 (m, 1H), 1.05 (s, 3H), 0.91 (s, 3H), 0.85-0.79 (m, 5H).

[1185] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 566.3.

Example 56

Rac-2-fluoro-N-[(1S,2S)-2-methyl-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]butyl]propanamide

##STR00285##

[1186] The title compound was prepared in analogy to the procedure described for the preparation of Example 3, by using (2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoic acid instead of (2S)-2-(benzyloxycarbonylamino)-4-methyl-pentanoic acid, 2-fluoropropionic acid and T.sub.3P instead of TFAA to afford rac-2-fluoro-N-[(1S,2S)-2-methyl-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]butyl]propanamide (Example 56) as a white solid.

[1187] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.14 (d, J=4.0 Hz, 1H), 8.45 (dd, J=15.6, 8.0 Hz, 1H), 7.76 (s, 1H), 6.85 (dd, J=50.4, 4.8 Hz, 1H), 5.10-4.90 (m, 1H), 4.27-4.11 (m, 2H), 3.95-3.75 (m, 3H), 3.45 (dd, J=14.0, 4.4 Hz, 1H), 3.22-3.11 (m, 2H), 2.64-2.56 (m, 1H), 2.25-2.10 (m, 1H), 1.90-1.70 (m, 2H), 1.66-1.57 (m, 1H), 1.53 (d, J=7.6 Hz, 1H), 1.49-1.42 (m, 1H), 1.41-1.31 (m, 3H), 1.13-1.07 (m, 1H), 1.05 (s, 3H), 0.91 (d, J=4.4 Hz, 3H), 0.86-0.77 (m, 6H).

[1188] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 548.3.

Example 57

N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]cyclopropanecarboxamide

##STR00286##

[1189] The title compound was prepared in analogy to the procedure described for the preparation of Example 3, by using (2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoic acid instead of (2S)-2-(benzyloxycarbonylamino)-4-methyl-pentanoic acid and cyclopropanecarbonyl chloride instead of TFAA to afford N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]cyclopropanecarboxamide (Example 57) as a white solid.

[1190] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.12 (s, 1H), 8.44 (d, J=8.4 Hz, 1H), 7.76 (s, 1H), 6.90 (d, J=50.4 Hz, 1H), 4.23-4.15 (m, 1H), 4.12 (s, 1H), 3.95-3.88 (m, 1H), 3.86-3.75 (m, 2H), 3.44 (dd, J=14.0, 4.4 Hz, 1H), 3.20-3.10 (m, 2H), 2.65-2.55 (m, 1H), 2.21-2.10 (m, 1H), 1.85-1.70 (m, 2H), 1.68-1.58 (m, 2H), 1.55-1.45 (m, 2H), 1.15-1.06 (m, 1H), 1.04 (s, 3H), 0.88 (s, 3H), 0.84-0.78 (m, 6H), 0.70-0.60 (m, 3H), 0.58-0.51 (m, 1H).

[1191] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 542.3.

Example 58

N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-3,3-difluoro-cyclobutanecarboxamide

##STR00287##

[1192] The title compound was prepared in analogy to the procedure described for the preparation of Example 3, by using (2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoic acid instead of (2S)-2-(benzyloxycarbonylamino)-4-methyl-pentanoic acid, 3,3-difluorocyclobutanecarboxylic acid and T.sub.3P instead of TFAA to afford N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-3,3-difluoro-cyclobutanecarboxamide (Example 58) as a white solid.

[1193] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.13 (s, 1H), 8.47 (d, J=8.0 Hz, 1H), 7.76 (s, 1H), 6.90 (d, J=50.4 Hz, 1H), 4.25-4.16 (m, 1H), 4.12 (s, 1H), 3.95-3.75 (m, 3H), 3.45 (dd, J=14.0, 4.0 Hz, 1H), 3.21-3.11 (m, 2H), 2.99-2.87 (m, 1H), 2.72-2.62 (m, 4H), 2.60-2.57 (m, 1H), 2.21-2.10 (m, 1H), 1.85-1.68 (m, 2H), 1.66-1.56 (m, 1H), 1.52 (d, J=7.6 Hz, 1H), 1.49-1.40 (m, 1H), 1.13-1.06 (m, 1H), 1.05 (s, 3H), 0.90 (s, 3H), 0.85-0.76 (m, 6H).

[1194] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 592.3.

Example 59

N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide

##STR00288##

[1195] The title compound was prepared in analogy to the procedure described for the preparation of Example 3, by using (2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoic acid instead of (2S)-2-(benzyloxycarbonylamino)-4-methyl-pentanoic acid, 1-fluorocyclopropane-1-carboxylic acid and T.sub.3P instead of TFAA to afford N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide (Example 59) as a white solid.

[1196] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.13 (s, 1H), 8.54 (d, J=8.0 Hz, 1H), 7.80 (s, 1H), 6.97 (d, J=50.4 Hz, 1H), 4.57-4.48 (m, 1H), 3.98 (d, J=4.0 Hz, 1H), 3.97-3.83 (m, 1H), 3.78-3.62 (m, 2H), 3.39 (dd, J=12.0 Hz, 4.0 Hz, 1H), 3.21-3.10 (m, 2H), 2.77-2.71 (m, 1H), 2.61-2.57 (m, 1H), 2.19-2.11 (m, 1H), 1.94-1.55 (m, 10H), 1.42-1.30 (m, 1H), 0.96 (s, 9H).

[1197] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 560.3

Example 60

N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-methyl-cyclopropanecarboxamide

##STR00289##

[1198] The title compound was prepared in analogy to the procedure described for the preparation of Example 3, by using (2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoic acid instead of (2S)-2-(benzyloxycarbonylamino)-4-methyl-pentanoic acid, 1-methylcyclopropane-1-carboxylic acid and T.sub.3P instead of TFAA to afford N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-methyl-cyclopropanecarboxamide (Example 60) as a white solid.

[1199] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.10 (s, 1H), 7.75 (s, 1H), 7.59 (d, J=8.0 Hz, 1H), 6.87 (d, J=50.4 Hz, 1H), 4.28-4.16 (m, 2H), 4.11 (s, 1H), 4.05-3.96 (m, 1H), 3.92-3.68 (m, 1H), 3.43 (m, 1H), 3.21-3.11 (m, 2H), 2.61-2.55 (m, 2H), 2.20-2.05 (m, 1H), 1.98-1.84 (m, 1H), 1.82-1.70 (m, 1H), 1.62-1.55 (m, 1H), 1.54-1.40 (m, 2H), 1.23 (s, 3H), 1.10-1.05 (m, 1H), 1.03 (s, 3H), 1.00-0.95 (m, 1H), 0.88 (s, 3H), 0.85-0.75 (m, 6H), 0.61-0.39 (m, 2H).

[1200] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 556.3.

Example 61

2,2-dichloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]acetamide

##STR00290##

[1201] The title compound was prepared in analogy to the procedure described for the preparation of Example 3, by using (2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoic acid instead of (2S)-2-(benzyloxycarbonylamino)-4-methyl-pentanoic acid, dichloroacetic acid and T.sub.3P instead of TFAA to afford 2,2-dichloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]acetamide (Example 61) as a white solid.

[1202] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.17 (s, 1H), 9.00 (d, J=8.0 Hz, 1H), 7.76 (s, 1H), 6.85 (d, J=50.4 Hz, 1H), 6.43 (s, 1H), 4.26-4.19 (m, 1H), 4.15 (s, 1H), 3.95-3.87 (m, 1H), 3.86-3.75 (m, 2H), 3.46 (dd, J=13.6 Hz, 4.4 Hz, 1H), 3.23-3.05 (m, 2H), 2.64-2.56 (m, 1H), 2.30-2.10 (m, 1H), 1.85-1.70 (m, 2H), 1.68-1.59 (m, 1H), 1.55 (d, J=7.2 Hz, 1H), 1.51-1.41 (m, 1H), 1.15-1.08 (m, 1H), 1.06 (s, 3H), 0.94 (s, 3H), 0.87-0.79 (m, 6H).

[1203] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 584.0.

Example 62

N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,3,3,3-pentafluoro-propanamide

##STR00291##

[1204] The title compound was prepared in analogy to the procedure described for the preparation of Example 3, by using (2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoic acid instead of (2S)-2-(benzyloxycarbonylamino)-4-methyl-pentanoic acid and 2,2,3,3,3-pentafluoropropanoyl 2,2,3,3,3-pentafluoropropanoate instead of TFAA to afford N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,3,3,3-pentafluoro-propanamide (Example 62) as a white solid.

[1205] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.18 (s, 1H), 10.06 (d, J=7.6 Hz, 1H), 7.76 (s, 1H), 6.83 (d, J=50.4 Hz, 1H), 4.31-4.21 (m, 1H), 3.97-3.86 (m, 2H), 3.85-3.75 (m, 1H), 3.45 (dd, J=4.4, 14.0 Hz, 1H), 3.22-3.09 (m, 2H), 2.63-2.55 (m, 2H), 2.21-2.10 (m, 1H), 2.05-1.95 (m, 1H), 1.83-1.72 (m, 1H), 1.55 (d, J=7.6 Hz, 1H), 1.59-1.51 (m, 1H), 1.48-1.39 (m, 1H), 1.16-1.08 (m, 1H), 1.04 (s, 3H), 0.95-0.74 (m, 9H).

[1206] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 620.3.

Example 63

N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide

##STR00292##

[1207] The title compound was prepared in analogy to the procedure described for the preparation of Example 3, by using (2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoic acid instead of (2S)-2-(benzyloxycarbonylamino)-4-methyl-pentanoic acid to afford N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide (Example 63) as a white solid.

[1208] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.16 (s, 1H), 9.97-9.95 (m, 1H), 7.76 (s, 1H), 6.91-6.78 (d, J=50.4 Hz, 1H), 4.22-4.16 (m, 2H), 3.92-3.76 (m, 3H), 3.47 (dd, J=4.0, 14.0 Hz, 1H), 3.18-3.13 (m, 2H), 2.63-2.57 (m, 1H), 2.19-2.11 (m, 1H), 1.96-1.87 (m, 1H), 1.81-1.73 (m, 1H), 1.67-1.63 (m, 1H), 1.55 (d, J=7.6 Hz, 1H), 1.49-1.43 (m, 1H), 1.14-1.05 (s, 4H), 0.91-0.79 (m, 9H).

[1209] MS obsd. (ESI.sup.+) [(M+H)+]: 570.2.

Example 64

N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide

##STR00293##

Step 1: Preparation of methyl (1R,2S,5S)-3-[(2S,3R)-2-(tert-butoxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate

##STR00294##

[1210] To a solution of Boc-L-isoleucine (500 mg, 2.16 mmol) (GL Biochem, CAS number: 35264-07-4) in DMF (5 mL) and ACN (20 mL) was added DIPEA (1400 mg, 10.81 mmol) and HATU (904 mg, 2.38 mmol) at 0 C. After the addition of methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; hydrochloride was added into above solution, the mixture was stirred 25 C. for 1 h. The mixture was diluted with EtOAc (100 mL) and washed with brine (60 mL3). The organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum and the residue was purified by silica gel column eluted with PE to PE/EtOAc=1/1 to afford methyl (1R,2S,5S)-3-[(2S,3R)-2-(tert-butoxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (760 mg) as a yellow foam.

[1211] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 383.2.

Step 2: Preparation of (1R,2S,5S)-3-[(2S,3R)-2-(tert-butoxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid

##STR00295##

[1212] To a solution of methyl (1R,2S,5S)-3-[(2S,3R)-2-(tert-butoxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (760 mg, 1.99 mmol) in water (5 mL) and THF (20 mL) was added LiOH.Math.H.sub.2O (250 mg, 5.96 mmol). The mixture was stirred at 25 C. for 1 h. The mixture was acidified with 1 N HCl to pH=4 and diluted with H.sub.2O (30 mL). The mixture was extracted with EtOAc (50 mL2). The organic phase was washed with brine (60 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuum to afford (1R,2S,5S)-3-[(2S,3R)-2-(tert-butoxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (600 mg) as a yellow foam.

[1213] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 369.2.

Step 3: Preparation of (1R,2S,5S)-3-[(2S,3R)-2-amino-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid; hydrochloride

##STR00296##

[1214] To a solution of (1R,2S,5S)-3-[(2S,3R)-2-(tert-butoxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (600 mg, 1.63 mmol) in DCM (20 mL) was added HCl/dioxane (20 mL, 4 N). The mixture was stirred 25 C. for 1 h. The mixture was concentrated in vacuum to afford (JR,2S,5S)-3-[(2S,3R)-2-amino-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid; hydrochloride (495 mg) as a yellow foam.

[1215] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 269.1.

Step 4: Preparation of (1R,2S,5S)-6,6-dimethyl-3-[(2S,3R)-3-methyl-2-[(2,2,2-trifluoroacetyl)amino]pentanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxylic acid

##STR00297##

[1216] To a solution of (1R,2S,5S)-3-[(2S,3R)-2-amino-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid; hydrochloride (490 mg, 1.61 mmol) in methanol (5 mL) was added Et.sub.3N (1.6 g, 16.08 mmol) and ethyl trifluoroacetate (685 mg, 4.82 mmol). The mixture was stirred at 50 C. for 12 h. The mixture was concentrated in vacuum and the residue was dissolved in EtOAc (150 mL) and washed with 1 N HCl (40 mL), brine (50 mL) and dried over Na.sub.2SO.sub.4. After filtration and concentration, (1R,2S,5S)-6,6-dimethyl-3-[(2S,3R)-3-methyl-2-[(2,2,2-trifluoroacetyl)amino]pentanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (500 mg) was obtained as yellow oil.

[1217] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 365.1.

Step 5: Preparation of tert-butyl N-[[(1R,2S,5S)-6,6-dimethyl-3-[(2S,3R)-3-methyl-2-[(2,2,2-trifluoroacetyl)amino]pentanoyl]-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate

##STR00298##

[1218] To a solution of (1R,2S,5S)-6,6-dimethyl-3-[(2S,3R)-3-methyl-2-[(2,2,2-trifluoroacetyl)amino]pentanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (500 mg, 1.37 mmol) in DMF (8 mL) was added DIPEA (709 mg, 5.49 mmol), EDCI (316 mg, 1.65 mmol), HOPO (183 mg, 1.65 mmol) and tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (378 mg, 1.65 mmol, Intermediate 9). The mixture was stirred at 25 C. for 12 h. The mixture was diluted with EtOAc (100 mL), washed with brine (50 mL3), 1 N HCl (30 mL) and dried over Na.sub.2SO.sub.4. After filtration and concentration, tert-butyl N-[[(1R,2S,5S)-6,6-dimethyl-3-[(2S,3R)-3-methyl-2-[(2,2,2-trifluoroacetyl)amino]pentanoyl]-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (600 mg) was obtained as yellow oil.

[1219] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 576.4.

Step 6: Preparation of N-[(1S,2R)-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(3S)-2-oxopyrrolidin-3-yl]methylamino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide

##STR00299##

[1220] To a solution of tert-butyl N-[[(1R,2S,5S)-6,6-dimethyl-3-[(2S,3R)-3-methyl-2-[(2,2,2-trifluoroacetyl)amino]pentanoyl]-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (600 mg, 1.04 mmol) in DCM (10 mL) was added TFA (10.0 mL). The mixture was stirred at 25 C. for 1 h. The mixture was concentrated and the residue was purified by reverse flash eluted with ACN in H.sub.2O (0.1% HCl)=055% to afford N-[(1S,2R)-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(3S)-2-oxopyrrolidin-3-yl]methylamino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide; hydrochloride (511 mg) as a yellow foam.

[1221] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 476.1.

Step 7: Preparation of N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide (Example 64)

##STR00300##

[1222] To a solution of N-[(1S,2R)-1-[(1R,5S)-6,6-dimethyl-2-[[[(3S)-2-oxopyrrolidin-3-yl]methylamino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide hydrochloride (500 mg, 0.97 mmol) in THF (150 mL) was added DIPEA (2524 mg, 19.53 mmol) in one portion. The mixture was cooled to 0 C. and a solution of (2R)-2-chloro-2-fluoro-acetyl chloride (639 mg, 1.95 mmol, Intermediate 10) in THF (10 mL) was added dropwise over 5 min. The resulting mixture was stirred at 0 C. for 30 min. The reaction was quenched with MeOH (2 mL), followed by 4 N HCl/dioxane (4 mL) at 0 C. Then the mixture was concentrated and the residue was purified by reverse flash eluted with ACN in H.sub.2O (0.1% FA)=050% to afford N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide (150 mg, Example 64) as a white solid.

[1223] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.18 (s, 1H), 9.88 (d, J=8.0 Hz, 1H), 7.77 (s, 1H), 6.82 (d, J=50.4 Hz, 1H), 4.30-4.22 (m, 1H), 4.17 (s, 1H), 3.93-3.76 (m, 3H), 3.45 (dd, J=13.6 Hz, 4.0 Hz, 1H), 3.22-3.11 (m, 2H), 2.64-2.56 (m, 1H), 2.20-2.10 (m, 1H), 1.98-1.86 (m, 1H), 1.84-1.70 (m, 1H), 1.69-1.59 (m, 1H), 1.57-1.52 (m, 1H), 1.50-1.40 (m, 1H), 1.09-1.01 (m, 4H), 0.91 (s, 3H), 0.86 (d, J=6.8 Hz, 3H), 0.84-0.78 (m, 3H).

[1224] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 570.3.

Example 65

N-[(1S)-1-(1-bicyclo[1.1.1]pentanylmethyl)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxo-ethyl]-2,2,2-trifluoro-acetamide

##STR00301##

[1225] The title compound was prepared in analogy to the procedure described for the preparation of Example 64, by using (2S)-3-(1-bicyclo[1.1.1]pentanyl)-2-(tert-butoxycarbonylamino)propanoic acid (Intermediate 19) instead of Boc-L-isoleucine to afford N-[(1S)-1-(1-bicyclo[1.1.1]pentanylmethyl)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxo-ethyl]-2,2,2-trifluoro-acetamide (Example 65) as a white solid.

[1226] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.12 (s, 1H), 10.00-9.90 (m, 1H), 7.76 (s, 1H), 6.75 (d, J=50.4 Hz, 1H), 4.43-4.48 (m, 1H), 4.15 (s, 1H), 3.83-3.76 (m, 2H), 3.71-3.66 (m, 1H), 3.48-3.38 (m, 2H), 3.20-3.14 (m, 2H), 2.62-2.59 (m, 1H), 2.17-2.11 (m, 1H), 1.85-1.79 (m, 3H), 1.71-1.65 (m, 4H), 1.62-1.55 (m, 4H), 1.06 (s, 3H), 0.92 (s, 3H).

[1227] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 594.1.

Example 66

N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-3,3-dimethyl-butyl]-2,2,2-trifluoro-acetamide

##STR00302##

[1228] The title compound was prepared in analogy to the procedure described for the preparation of Example 20, by using (2S)-2-(benzyloxycarbonylamino)-4,4-dimethyl-pentanoic acid (Intermediate 20) instead of Cbz-Phe-OH to afford N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-3,3-dimethyl-butyl]-2,2,2-trifluoro-acetamide (Example 66) as a white solid.

[1229] .sup.1H NMR (400 MHz, CDCl.sub.3) : ppm 10.83-10.23 (m, 1H), 7.34-7.27 (m, 1H), 6.60 (d, J=50.4 Hz, 1H), 6.35-6.22 (m, 1H), 4.82-4.77 (m, 1H), 4.58-4.37 (m, 2H), 4.01-3.80 (m, 2H), 3.44-3.31 (m, 2H), 2.95-2.79 (m, 2H), 2.45-2.25 (m, 1H), 1.81-1.72 (m, 2H), 1.66-1.62 (m, 1H), 1.45-1.39 (m, 2H), 1.13-1.07 (m, 3H), 0.97-0.94 (m, 12H).

[1230] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 584.2.

Example 67

N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxo-1-(4-pyridylmethyl)ethyl]-2,2,2-trifluoro-acetamide

##STR00303##

[1231] The title compound was prepared in analogy to the procedure described for the preparation of Example 64, by using Boc-L-4-pyridylalanine (Bide, CAS number: 37535-57-2) instead of Boc-L-isoleucine to afford N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxo-1-(4-pyridylmethyl)ethyl]-2,2,2-trifluoro-acetamide (Example 67) as a white solid.

[1232] .sup.1H NMR (400 MHz, DMSO) : ppm 11.11 (s, 1H), 10.08 (d, J=8.0 Hz, 1H), 8.45 (d, J=5.6 Hz, 2H), 7.76 (s, 1H), 7.32 (d, J=6.0 Hz, 2H), 6.78 (d, J=50.4 Hz, 1H), 4.73-4.71 (m, 1H), 4.16 (s, 1H), 3.86-3.80 (m, 1H), 3.71 (d, J=10.8 Hz, 1H), 3.47-3.42 (m, 1H), 3.23-3.13 (m, 2H), 3.04-2.95 (m, 2H), 2.67-2.52 (m, 1H), 2.32-2.16 (m, 1H), 1.80-1.75 (m, 1H), 1.65-1.63 (m, 1H), 1.61-1.59 (m, 1H), 1.05 (s, 3H), 0.91 (s, 3H).

[1233] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 605.1.

Example 68

N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-1-(1-methylcyclopropyl)-2-oxo-ethyl]-2,2,2-trifluoro-acetamide

##STR00304##

[1234] The title compound was prepared in analogy to the procedure described for the preparation of Example 64, by using (2S)-2-(tert-butoxycarbonylamino)-2-(1-methylcyclopropyl)acetic acid (Intermediate 16) instead of Boc-L-isoleucine to afford N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-1-(1-methylcyclopropyl)-2-oxo-ethyl]-2,2,2-trifluoro-acetamide (Example 68) as a white solid.

[1235] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.16 (s, 1H), 9.80 (d, J=6.4 Hz, 1H), 7.75 (s, 1H), 6.84-6.63 (m, 1H), 4.38 (d, J=6.0 Hz, 1H), 4.13 (s, 1H), 3.91-3.66 (m, 3H), 3.44 (dd, J=4.4, 13.6 Hz, 1H), 3.21-3.06 (m, 2H), 2.63-2.58 (m, 1H), 2.23-2.09 (m, 1H), 1.79-1.73 (m, 1H), 1.71-1.64 (m, 1H), 1.53 (d, J=7.6 Hz, 1H), 1.06 (d, J=2.8 Hz, 6H), 0.96 (s, 3H), 0.77-0.65 (m, 2H), 0.37-0.25 (m, 2H).

[1236] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 568.3.

Example 69

N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-3-methylsulfanyl-propyl]-2,2,2-trifluoro-acetamide

##STR00305##

[1237] The title compound was prepared in analogy to the procedure described for the preparation of Example 20, by using Cbz-Met-OH (Energy chemical, CAS number: 1152-62-1) instead of Cbz-Phe-OH to afford N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-3-methylsulfanyl-propyl]-2,2,2-trifluoro-acetamide (Example 69) as a white solid.

[1238] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.15 (s, 1H), 9.93 (d, J=6.0 Hz, 1H), 7.76 (s, 1H), 6.74 (d, J=50.4 Hz, 1H), 4.58-4.52 (m, 1H), 4.18 (s, 1H), 3.91-3.85 (m, 1H), 3.82-3.74 (m, 2H), 3.43 (dd, J=14.0 Hz, 4.4 Hz, 1H), 3.18-3.12 (m, 2H), 2.62-2.54 (m, 1H), 2.33-2.23 (m, 2H), 2.20-2.10 (m, 1H), 2.20 (s, 3H), 1.96-1.87 (m, 2H), 1.81-1.71 (m, 1H), 1.68-1.62 (m, 1H), 1.56 (d, J=7.2 Hz, 1H), 1.06 (s, 3H), 0.93 (d, J=10.0 Hz, 3H).

[1239] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 588.2.

Example 70

N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-dichloro-acetamide

##STR00306##

[1240] The title compound was prepared in analogy to the procedure described for the preparation of Example 29, by using dichloroacetic acid and T.sub.3P instead of acetic anhydride to afford N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-dichloro-acetamide (Example 70) as a white solid.

[1241] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.13 (s, 1H), 8.69 (d, J=8.4 Hz, 1H), 7.77 (s, 1H), 6.98 (d, J=50.4 Hz, 1H), 6.66 (d, J=2.0 Hz, 1H), 4.48-4.40 (m, 1H), 3.98 (d, J=6.0 Hz, 1H), 3.90 (dd, J=7.2, 10.4 Hz, 1H), 3.79-3.63 (m, 2H), 3.39 (dd, J=4.0, 13.6 Hz, 1H), 3.22-3.10 (m, 2H), 2.81-2.70 (m, 1H), 2.61-2.54 (m, 1H), 2.54-2.51 (m, 1H), 2.21-2.11 (m, 1H), 1.93-1.70 (m, 5H), 1.69-1.59 (m, 1H), 1.43-1.32 (m, 1H), 0.95 (s, 9H).

[1242] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 584.1.

Example 71

N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2,3,3,3-pentafluoro-propanamide

##STR00307##

[1243] The title compound was prepared in analogy to the procedure described for the preparation of Example 29, by using 2,2,3,3,3-pentafluoropropanoyl 2,2,3,3,3-pentafluoropropanoate instead of acetic anhydride to afford N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2,3,3,3-pentafluoro-propanamide (Example 71) as a white solid.

[1244] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.13 (s, 1H), 9.41 (dd, J=26.8 Hz, 8.0 Hz 1H), 7.78 (s, 1H), 6.94 (d, J=50.8 Hz, 1H), 4.57 (d, J=7.2 Hz, 1H), 3.99 (d, J=6.0 Hz, 1H), 3.92-3.72 (m, 2H), 3.66 (dd, J=10.40 Hz, 2.40 Hz, 1H), 3.39 (dd, J=14.4 Hz, 4.0 Hz, 1H), 3.22-3.06 (m, 2H), 2.79-2.69 (m, 1H), 2.61-2.54 (m, 1H), 2.53-2.41 (m, 1H), 2.20-2.10 (m, 1H), 1.93-1.55 (m, 6H), 1.40-1.27 (m, 1H), 0.98 (s, 9H).

[1245] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 620.2.

Example 72

N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]propyl]-2,2,2-trifluoro-acetamide

##STR00308##

Step 1: Preparation of benzyl (3S,3aS,6aR)-2-[(2S)-2-(benzyloxycarbonylamino)butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate

##STR00309##

[1246] To a solution of (S)-2-(((benzyloxy)carbonyl)amino)butanoic acid (660 mg, 2.78 mmol) in DMF (20 mL) was added DIPEA (1.8 g, 13.91 mmol) and HATU (1.27 g, 3.34 mmol). Then benzyl (3S,3aS,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-3-carboxylate; 2,2,2-trifluoroacetic acid (1.0 g, 2.78 mmol, Intermediate 21) was added into at 0 C. After the addition, the mixture was stirred at 25 C. for 12 h. The reaction was diluted with water (100 mL) and extracted with EtOAc (50 mL2). The organic phase was washed with saturated aqueous solution of K.sub.2CO.sub.3 (20 mL), 1 N HCl (30 mL) and brine (60 mL3). The organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated and the residue was purified by silica gel column eluted with PE to PE/EtOAc=1/1 to afford benzyl (3S,3aS,6aR)-2-[(2S)-2-(benzyloxycarbonylamino)butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate (891 mg) as colorless oil.

[1247] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 465.2.

Step 2: Preparation of (3S,3aS,6aR)-2-[(2S)-2-aminobutanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid

##STR00310##

[1248] To a solution of benzyl (3S,3aS,6aR)-2-[(2S)-2-(benzyloxycarbonylamino)butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate (1.5 g, 3.25 mmol) in THF (15 mL) was added Pd/C (150.0 mg, 10% purity) and Pd(OH).sub.2 (150.0 mg). The suspension was degassed under vacuum and purged hydrogen for three times. The resulting mixture was stirred at 25 C. for 12 h under a H.sub.2 balloon. The mixture was filtrated through a pad of celite and the filtrate was concentrated in vacuum to afford (3S,3aS,6aR)-2-[(2S)-2-aminobutanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid (758 mg) as a white solid.

[1249] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 240.9.

Step 3: Preparation of (3S,3aS,6aR)-2-[(2S)-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid

##STR00311##

[1250] To a solution of (3S,3aS,6aR)-2-[(2S)-2-aminobutanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid (758 mg, 3.15 mmol) in methanol (6 mL) was added Et.sub.3N (958 mg, 9.46 mmol). The mixture was cooled to 5 C. and ethyl trifluoroacetate (448 mg, 3.15 mmol) was added. After the addition, the mixture was stirred at 50 C. for 12 h. The reaction was diluted with water (30 mL) and extracted with EtOAc (65 mL2). The organic phase was washed with 1 N HCl (15 mL), brine (30 mL) and dried over Na.sub.2SO.sub.4. After filtration and concentration, (3S,3aS,6aR)-2-[(2S)-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid (1060 mg) was obtained as yellow oil.

[1251] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 337.1.

Step 4: Preparation of tert-butyl N-[[(3S,3aS,6aR)-2-[(2S)-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate

##STR00312##

[1252] To a solution of (3S,3aS,6aR)-2-[(2S)-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid (1.1 g, 3.22 mmol) in DMF (20 mL) was added DIPEA (1.67 g, 12.9 mmol). Then HOPO (430 mg, 3.87 mmol), EDCI (741 mg, 3.87 mmol) and tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (739 mg, 3.22 mmol, Intermediate 9) were added at 0 C. The mixture was stirred at 30 C. for 12 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (80 mL2). The organic phase was washed with 1 N HCl (30 mL), brine (60 mL3) and dried over Na.sub.2SO.sub.4. After filtration and concentration, tert-butyl N-[[(3S,3aS,6aR)-2-[(2S)-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (1.6 g) was obtained as yellow oil.

[1253] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 548.3.

Step 5: Preparation of N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(3S)-2-oxopyrrolidin-3-yl]methylamino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]propyl]-2,2,2-trifluoro-acetamide

##STR00313##

[1254] To a solution of tert-butyl N-[[(3S,3aS,6aR)-2-[(2S)-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (1.61 g, 2.93 mmol) in DCM (6 mL) was added TFA (12.0 mL). The mixture was stirred at 25 C. for 1 h. The reaction mixture was concentrated and the residue was purified by reverse flash eluted with ACN in H.sub.2O (0.1% HCl)=060% to afford N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(3S)-2-oxopyrrolidin-3-yl]methylamino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]propyl]-2,2,2-trifluoro-acetamide (1.2 g, 2.68 mmol) as a yellow solid.

[1255] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 448.0.

Step 6: Preparation of N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]propyl]-2,2,2-trifluoro-acetamide (Example 72)

##STR00314##

[1256] To a solution of N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(3S)-2-oxopyrrolidin-3-yl]methylamino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]propyl]-2,2,2-trifluoro-acetamide (1.2 g, 2.68 mmol) in THF (350 mL) was added DIPEA (5.2 g, 40.23 mmol). Then (2R)-2-chloro-2-fluoro-acetyl chloride (702 mg, 5.36 mmol, Intermediate 10) in THF (20 mL) was added at 5 C. dropwise. The mixture was stirred at 5 C. for 1 h. The reaction was quenched with MeOH (10 mL) and acidified by 4 N HCl/dioxane to pH=5 at 10 C. Then the mixture was concentrated in vacuum at 30 C. The residue was purified by reverse flash eluted with ACN in H.sub.2O (0.1% FA)=060% to afford N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]propyl]-2,2,2-trifluoro-acetamide (375 mg, Example 72) as a white solid.

[1257] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.06-10.44 (m, 1H), 9.82 (d, J=6.6 Hz, 1H), 7.79 (s, 1H), 6.97-6.76 (m, 1H), 4.52-4.39 (m, 1H), 3.98-4.14 (m, 1H), 3.96-3.60 (m, 3H), 3.42-3.35 (m, 1H), 3.22-3.10 (m, 2H), 2.83-2.76 (m, 1H), 2.61-2.57 (m, 1H), 2.23-2.07 (m, 1H), 1.92-1.56 (m, 9H), 1.46-1.36 (m, 1H), 0.89 (t, J=7.3 Hz, 3H).

[1258] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 542.0.

Example 73

N-[(1S,2R)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide

##STR00315##

[1259] The title compound was prepared in analogy to the procedure described for the preparation of Example 1, by using benzyl (3S,3aS,6aR)-2-[(2S,3R)-2-amino-3-methyl-pentanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate; 2,2,2-trifluoroacetic acid (Intermediate 22) instead of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1) to afford N-[(1S,2R)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide (Example 73) as a white solid.

[1260] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.10 (s, 1H), 9.87-9.62 (m, 1H), 7.78 (s, 1H), 6.96 (d, J=50.8 Hz, 1H), 4.46-4.29 (m, 1H), 4.14-3.97 (m, 1H), 3.89-3.67 (m, 3H), 3.45-3.35 (m, 1H), 3.22-3.08 (m, 2H), 2.83-2.70 (m, 1H), 2.61-2.56 (m, 1H), 2.21-2.08 (m, 1H), 2.01-1.55 (m, 8H), 1.53-1.31 (m, 2H), 1.11-0.98 (m, 1H), 0.92-0.76 (m, 6H).

[1261] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 570.2.

Example 74

N-[(1S)-2-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-cyclobutyl-2-oxo-ethyl]-2,2,2-trifluoro-acetamide

##STR00316##

[1262] The title compound was prepared in analogy to the procedure described for the preparation of Example 1, by using benzyl (3S,3aS,6aR)-2-[(2S)-2-amino-2-cyclobutyl-acetyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate; 2,2,2-trifluoroacetic acid (Intermediate 23) instead of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1) to afford N-[(1S)-2-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-cyclobutyl-2-oxo-ethyl]-2,2,2-trifluoro-acetamide (Example 74) as a white solid.

[1263] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.05 (s, 1H), 9.77 (d, J=7.2 Hz, 1H), 7.78 (s, 1H), 6.84 (d, J=50.4 Hz, 1H), 4.60-4.50 (m, 1H), 3.99 (d, J=5.2 Hz, 1H), 3.94-3.82 (m, 1H), 3.80-3.61 (m, 2H), 3.38 (dd, J=4.0, 14.0 Hz, 1H), 3.23-3.07 (m, 2H), 2.82-2.67 (m, 2H), 2.58-2.57 (m, 1H), 2.21-2.07 (m, 1H), 1.99-1.56 (m, 13H), 1.45-1.30 (m, 1H).

[1264] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 568.3.

Example 75

N-[(1S)-2-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-methyl-2-oxo-ethyl]-2,2,2-trifluoro-acetamide

##STR00317##

[1265] The title compound was prepared in analogy to the procedure described for the preparation of Example 72, by using Cbz-Ala-OH (GL Biochem, CAS number: 142-20-7) instead of (S)-2-(((benzyloxy)carbonyl)amino)butanoic acid to afford N-[(1S)-2-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-methyl-2-oxo-ethyl]-2,2,2-trifluoro-acetamide (Example 75) as a white solid.

[1266] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.02 (s, 1H), 9.85 (d, J=6.4 Hz, 1H), 7.78 (s, 1H), 6.81 (d, J=50.4 Hz, 1H), 4.61-4.49 (m, 1H), 4.16-3.93 (m, 1H), 3.88-3.73 (m, 2H), 3.62-3.52 (m, 1H), 3.40-3.35 (m, 1H), 3.21-3.11 (m, 2H), 2.83-2.73 (m, 1H), 2.61-2.57 (m, 1H), 2.25-2.09 (m, 1H), 2.01-1.51 (m, 7H), 1.46-1.36 (m, 1H), 1.29-1.23 (m, 3H).

[1267] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 528.0.

Example 76

N-[(1S,2R)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2-difluoro-propanamide

##STR00318##

[1268] The title compound was prepared in analogy to the procedure described for the preparation of Example 1, by using benzyl (3S,3aS,6aR)-2-[(2S,3R)-2-amino-3-methyl-pentanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate; 2,2,2-trifluoroacetic acid (Intermediate 22) instead of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1), 2,2-difluoropropionic acid and T.sub.3P instead of TFAA to afford N-[(1S,2R)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2-difluoro-propanamide (Example 76) as a white solid.

[1269] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.10 (s, 1H), 8.77 (d, J=8.0 Hz, 1H), 7.78 (s, 1H), 6.91 (d, J=50.4 Hz, 1H), 4.41-4.31 (m, 1H), 3.99 (d, J=5.2 Hz, 1H), 3.86-3.68 (m, 3H), 3.39 (dd, J=14.0 Hz, 3.6 Hz, 1H), 3.22-3.12 (m, 2H), 2.79-2.66 (m, 2H), 2.22-2.11 (m, 1H), 1.99-1.55 (m, 11H), 1.50-1.35 (m, 2H), 1.12-1.00 (m, 1H), 0.91-0.77 (m, 6H).

[1270] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 566.3.

Example 77

N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]-2,2,2-trifluoro-acetamide

##STR00319##

[1271] The title compound was prepared in analogy to the procedure described for the preparation of Example 1, by using benzyl (3S,3aS,6aR)-2-[(2S)-2-amino-3-ethyl-pentanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate; 2,2,2-trifluoroacetic acid (Intermediate 24) instead of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1) to afford N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]-2,2,2-trifluoro-acetamide (Example 77) as a white solid.

[1272] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.10 (s, 1H), 9.88 (d, J=7.6 Hz 1H), 7.78 (s, 1H), 6.90 (d, J=50.4 Hz, 1H), 4.46 (t, J=8.4 Hz, 1H), 4.00 (d, J=6.0 Hz, 1H), 3.87-3.70 (m, 3H), 3.39 (dd, J=14.00, 4.0 Hz, 1H), 3.21-3.07 (m, 2H), 2.82-2.72 (m, 1H), 2.64-2.56 (m, 2H), 2.22-2.07 (m, 1H), 1.91-1.61 (m, 7H), 1.46-1.18 (m, 5H), 0.85-0.70 (m, 6H).

[1273] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 584.2.

Example 78

N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]butyl]-2,2,2-trifluoro-acetamide

##STR00320##

[1274] The title compound was prepared in analogy to the procedure described for the preparation of Example 3, by using (S)-2-(((benzyloxy)carbonyl)amino)pentanoic acid (Wuxiapptec, CAS number: 21691-44-1) instead of (2S)-2-(benzyloxycarbonylamino)-4-methyl-pentanoic acid and ethyl (3S,3aS,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-3-carboxylate; hydrochloride instead of methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; hydrochloride to afford N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]butyl]-2,2,2-trifluoro-acetamide (Example 78) as a white solid.

[1275] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.06 (s, 1H), 9.82 (d, J=6.8 Hz, 1H), 7.78 (s, 1H), 6.85 (d, J=50.4 Hz, 1H), 4.55-4.43 (m, 1H), 4.13-3.99 (m, 1H), 3.95-3.74 (m, 2H), 3.70-3.60 (m, 1H), 3.39 (d, J=14.0, 4.0 Hz, 1H), 3.22-3.08 (m, 2H), 2.84-2.75 (m, 1H), 2.65-2.58 (m, 2H), 2.30-2.10 (m, 1H), 1.92-1.70 (m, 5H), 1.69-1.59 (m, 3H), 1.49-1.27 (m, 3H), 0.87 (t, J=7.2 Hz, 3H).

[1276] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 556.3.

Example 79

N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide

##STR00321##

[1277] The title compound was prepared in analogy to the procedure described for the preparation of Example 29, by using (2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoic acid instead of Cbz-L-tert-leucine, 1-fluorocyclopropane-1-carboxylic acid and T.sub.3P instead of acetic anhydride to afford N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide (Example 79) as a white solid.

[1278] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.05 (s, 1H), 8.43 (d, J=7.2 Hz, 1H), 7.84-7.70 (m, 1H), 7.07-6.80 (m, 1H), 4.30 (t, J=8.6 Hz, 1H), 3.97 (d, J=6.0 Hz, 1H), 3.88-3.78 (m, 2H), 3.78-3.70 (m, 1H), 3.39 (dd, J=14.0 Hz, 4.0 Hz, 1H), 3.22-3.10 (m, 2H), 2.78-2.68 (m, 1H), 2.60-2.52 (m, 2H), 2.11-2.20 (m, 1H), 1.98-1.90 (m, 1H), 1.87-1.68 (m, 5H), 1.66-1.56 (m, 1H), 1.54-1.44 (m, 1H), 1.41-1.33 (m, 1H), 1.33-1.26 (m, 2H), 1.23-1.03 (m, 3H), 0.88-0.78 (m, 6H).

[1279] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 560.2.

Example 80

N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]benzamide

##STR00322##

[1280] The title compound was prepared in analogy to the procedure described for the preparation of Example 29, by using (2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoic acid instead of Cbz-L-tert-leucine, benzoic acid and T.sub.3P instead of acetic anhydride to afford N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]benzamide (Example 80) as a white solid.

[1281] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.04 (s, 1H), 8.72 (d, J=8.0 Hz, 1H), 7.93-7.87 (m, 2H), 7.77 (s, 1H), 7.56-7.50 (m, 1H), 7.48-7.42 (m, 2H), 7.08-6.80 (m, 1H), 4.46-4.38 (m, 1H), 4.09-4.00 (m, 1H), 3.97 (d, J=6.0 Hz, 1H), 3.93-3.85 (m, 1H), 3.79-3.69 (m, 1H), 3.42 (dd, J=14.0 Hz, 4.0 Hz, 1H), 3.22-3.10 (m, 2H), 2.81-2.72 (m, 1H), 2.62-2.52 (m, 2H), 2.20-2.10 (m, 1H), 2.03-1.93 (m, 1H), 1.93-1.82 (m, 1H), 1.82-1.68 (m, 4H), 1.68-1.52 (m, 2H), 1.48-1.37 (m, 1H), 1.24-1.11 (m, 1H), 0.90 (d, J=6.8 Hz, 3H), 0.84 (t, J=7.2 Hz, 3H).

[1282] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 578.2.

Example 81

N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]acetamide

##STR00323##

[1283] The title compound was prepared in analogy to the procedure described for the preparation of Example 29, by using (2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoic acid instead of Cbz-L-tert-leucine to afford N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]acetamide (Example 81) as a white solid.

[1284] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.03 (s, 1H), 8.23 (d, J=8.4 Hz, 1H), 7.77 (s, 1H), 6.99 (d, J=50.4 Hz, 1H), 4.26-4.21 (m, 1H), 3.93 (d, J=6.0 Hz, 1H), 3.85-3.70 (m, 3H), 3.39 (dd, J=14.0, 4.4 Hz, 1H), 3.22-3.10 (m, 2H), 2.79-2.69 (m, 1H), 2.60-2.55 (m, 1H), 2.21-2.08 (m, 1H), 1.87-1.78 (m, 5H), 1.77-1.56 (m, 6H), 1.54-1.44 (m, 1H), 1.41-1.34 (m, 1H), 1.13-1.03 (m, 1H), 0.85-0.78 (m, 6H).

[1285] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 516.3.

Example 82

N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-1-fluoro-cyclopropanecarboxamide

##STR00324##

[1286] The title compound was prepared in analogy to the procedure described for the preparation of Example 29, by using 1-fluorocyclopropane-1-carboxylic acid and T.sub.3P instead of acetic anhydride to afford N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-1-fluoro-cyclopropanecarboxamide (Example 82) as a white solid.

[1287] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.10 (s, 1H), 7.76 (s, 1H), 7.40 (d, J=7.6 Hz, 1H), 6.97 (d, J=50.4 Hz, 1H), 4.51 (d, J=8.8 Hz, 1H), 3.99 (d, J=6.0 Hz, 1H), 3.93-3.83 (m, 1H), 3.78-3.63 (m, 2H), 3.40 (dd, J=14.0 Hz, 7.6 Hz, 1H), 3.22-3.10 (m, 2H), 2.78-2.69 (m, 1H), 2.60-2.55 (m, 2H), 2.25-2.10 (m, 1H), 1.90-1.70 (m, 5H), 1.66-1.56 (m, 1H), 1.40-1.30 (m, 3H), 1.25-1.12 (m, 2H), 0.97 (s, 9H).

[1288] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 560.3.

Example 83

N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-1-fluoro-cyclopropanecarboxamide

##STR00325##

[1289] The title compound was prepared in analogy to the procedure described for the preparation of Example 29, by using 1-fluorocyclopropane-1-carboxylic acid and T.sub.3P instead of acetic anhydride, methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; hydrochloride instead of methyl (3S,3aS,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-3-carboxylate; hydrochloride to afford N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-1-fluoro-cyclopropanecarboxamide (Example 83) as a white solid.

[1290] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.10 (s, 1H), 7.76 (s, 1H), 7.40 (d, J=7.6 Hz, 1H), 6.97 (d, J=50.4 Hz, 1H), 4.51 (d, J=8.8 Hz, 1H), 3.99 (d, J=6.0 Hz, 1H), 3.93-3.83 (m, 1H), 3.78-3.63 (m, 2H), 3.40 (dd, J=14.0 Hz, 7.6 Hz, 1H), 3.22-3.10 (m, 2H), 2.78-2.69 (m, 1H), 2.60-2.55 (m, 2H), 2.25-2.10 (m, 1H), 1.90-1.70 (m, 5H), 1.66-1.56 (m, 1H), 1.40-1.30 (m, 3H), 1.25-1.12 (m, 2H), 0.97 (s, 9H).

[1291] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 560.3.

Example 84

N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]-2,2,2-trifluoro-acetamide

##STR00326##

[1292] The title compound was prepared in analogy to the procedure described for the preparation of Example 64, by using (2S)-2-(tert-butoxycarbonylamino)-3-ethyl-pentanoic acid (KaiXin Biological, CAS number: 35264-04-1) instead of Boc-L-isoleucine to afford N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]-2,2,2-trifluoro-acetamide (Example 84) as a white solid.

[1293] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.18 (s, 1H), 9.94 (d, J=8.0 Hz, 1H), 7.77 (s, 1H), 6.80 (d, J=50.4 Hz, 1H), 4.42-4.34 (m, 1H), 4.17 (s, 1H), 3.95-3.75 (m, 3H), 3.48-3.40 (dd, J=14.0 Hz, 4.4 Hz, 1H), 3.21-3.10 (m, 2H), 2.63-2.57 (m, 1H), 2.25-2.10 (m, 1H), 1.95-1.85 (m, 1H), 1.83-1.72 (m, 1H), 1.68-1.61 (m, 1H), 1.57-1.52 (m, 1H), 1.48-1.38 (m, 1H), 1.35-1.19 (m, 3H), 1.06 (s, 3H), 0.89 (s, 3H), 0.83-0.72 (m, 6H).

[1294] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 584.1.

Example 85

N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-propanamide

##STR00327##

[1295] The title compound was prepared in analogy to the procedure described for the preparation of Example 29, by using 2,2-difluoropropionic acid and T.sub.3P instead of acetic anhydride, methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; hydrochloride instead of methyl (3S,3aS,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-3-carboxylate; hydrochloride and (2S)-2-chloro-2-fluoro-acetyl chloride (Intermediate 28) instead of (2R)-2-chloro-2-fluoro-acetyl chloride (Intermediate 10) to afford N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-propanamide (Example 85) as a white solid.

[1296] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.10-10.85 (m, 1H), 8.26 (d, J=8.8 Hz, 1H), 7.80-7.67 (m, 1H), 7.15-6.55 (m, 1H), 4.43-4.37 (m, 1H), 4.25-4.12 (m, 1H), 3.95-3.88 (m, 1H), 3.82-3.67 (m, 2H), 3.53 (dd, J=14.0 Hz, 4.4 Hz, 1H), 3.20-2.95 (m, 2H), 2.53-2.52 (m, 1H), 2.24-2.10 (m, 1H), 1.82-1.55 (m, 6H), 1.06 (s, 3H), 1.01-0.95 (m, 9H), 0.88 (s, 3H).

[1297] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 566.5.

Example 86

N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-2,2,2-trifluoro-acetamide

##STR00328##

[1298] The title compound was prepared in analogy to the procedure described for the preparation of Example 64, by using (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-pentanoic acid (Intermediate 25) instead of Boc-L-isoleucine to afford N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-2,2,2-trifluoro-acetamide (Example 86) as a white solid.

[1299] .sup.1H NMR (400 MHz, CDCl.sub.3) : ppm 10.01-9.95 (m, 1H), 7.04-6.98 (m, 1H), 6.69-6.57 (m, 1H), 6.07-5.99 (m, 1H), 4.65 (d, J=8.8 Hz, 1H), 4.44 (s, 2H), 4.06-4.02 (m, 1H), 3.88 (d, J=9.6 Hz, 1H), 3.43 (s, 2H), 2.91-2.80 (m, 2H), 2.42-2.39 (m, 1H), 1.83-1.78 (m, 1H), 1.62 (s, 1H), 1.36-1.31 (m, 3H), 1.07 (s, 3H), 0.98 (d, J=12.8 Hz, 6H), 0.91-0.86 (m, 6H).

[1300] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 584.2.

Example 87

3-[[(2R)-2-chloro-2-fluoro-acetyl]-[[(1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]amino]propanamide

##STR00329##

Step 1: Preparation of methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate

##STR00330##

[1301] To a solution of methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; hydrochloride (50.0 g, 243.1 mmol) in a mixed solution of DMF (95 mL) and MeCN (850 mL) was added HATU (101.6 g, 267.41 mmol). Then DIPEA (94.3 g, 729.29 mmol) was added at 0 C. The reaction was allowed to warm to 25 C. and stirred for 2 h. The reaction solution was concentered and the residue was diluted with EtOAc (500 mL) and washed with water (200 mL). The aqueous phase was extracted with EtOAc (100 mL2). The combined organic layers were washed with 1 N HCl (100 mL), an aqueous solution of K.sub.2CO.sub.3 (100 mL, 5%) and brine (100 mL). The organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by silica gel column eluted with PE to PE/EtOAc=10/1 to afford methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (80.0 g) as colorless oil.

[1302] MS obsd. (ESI.sup.+) [(M+Na).sup.+]: 405.3.

Step 2: Preparation of (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid

##STR00331##

[1303] To a solution of methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (72.0 g, 188.24 mmol) in THF (400 mL) was added a solution of LiOH.Math.H.sub.2O (23.7 g, 564.72 mmol) in water (100 mL). The solution was stirred at 25 C. for 2 h. The reaction was acidified with 1 N HCl to pH=5. The resulting solution was concentrated to remove most of the THF. The residue was diluted with H.sub.2O (200 mL) and extracted with EtOAc (150 mL3). The combined organic layers were washed with brine (200 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to afford (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (68.0 g) as a white solid.

[1304] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 369.3.

Step 3: Preparation of (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid; hydrochloride

##STR00332##

[1305] To a solution of (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (68.0 g, 184.55 mmol) in DCM (180 mL) was added HCl/dioxane (230.68 mL, 4 N). The mixture was stirred at 25 C. for 4 h. The reaction was concentrated to afford (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid; hydrochloride (56.0 g) as a white solid.

[1306] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 269.3.

Step 4: Preparation of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid

##STR00333##

[1307] To a solution of (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid hydrochloride (56.0 g, 183.72 mmol) in methanol (180 mL) was added triethylamine (153.6 mL, 1102.33 mmol) and ethyl trifluoroacetate (70.5 g, 496.05 mmol) dropwise. The reaction was warmed to 50 C. and stirred for 16 h. The mixture was concentrated to remove MeOH. The residue was dissolved in EtOAc (400 mL) and washed with 0.5 N HCl (300 mL). The aqueous phase was extracted with EtOAc (300 mL3). The combined organic phase was washed with brine (100 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was triturated in PE (300 mL) for 10 min. The suspension was filtered. The cake was washed with PE (50 mL), collected and dried in vacuum to afford (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (65.0 g) as a white solid.

[1308] MS obsd. (ESI.sup.+) [(M+H)+]: 365.3.

Step 5: Preparation of benzyl N-(3-amino-3-oxo-propyl)-N-[[(1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]carbamate

##STR00334##

[1309] To a solution of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (540 mg, 1.48 mmol) in DMF (5 mL) was added DIPEA (1149 mg, 8.89 mmol), EDCI (341 mg, 1.78 mmol), HOPO (198 mg, 1.78 mmol) and benzyl N-amino-N-(3-amino-3-oxo-propyl)carbamate; 2,2,2-trifluoroacetic acid (520.62 mg, 1.48 mmol, Intermediate 26) at 0 C. The reaction mixture was stirred at 20 C. for 12 h and the mixture was purified by prep-HPLC (TFA condition, column: Phenomenex Luna C18 150*25 mm*10 um; mobile phase: [water(TFA)-ACN]; B %: 42%-72%, 1 min) to afford benzyl N-(3-amino-3-oxo-propyl)-N-[[(1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]carbamate (500 mg) as colorless oil.

[1310] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 584.3.

Step 6: Preparation of 3-[2-[(1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]hydrazino]propanamide

##STR00335##

[1311] To a solution of benzyl N-(3-amino-3-oxo-propyl)-N-[[(1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]carbamate (500 mg, 0.860 mmol) in methanol (3 mL) was added Pd/C (50 mg, 10% purity). The reaction mixture was degassed under vacuum and purged H.sub.2 for 3 times. The resulting mixture was stirred at 25 C. for 2 h under a H.sub.2 balloon. The mixture was filtered through a pad of celite and washed with EtOAc (10 mL3). The filtrate was concentrated in vacuum to afford 3-[2-[(1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]hydrazino]propanamide (480 mg) as colorless oil.

[1312] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 450.2.

Step 7: Preparation of 3-[[(2R)-2-chloro-2-fluoro-acetyl]-[[(1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]amino]propanamide (Example 87)

##STR00336##

[1313] To a solution of 3-[2-[(1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]hydrazino]propanamide (292 mg, 0.6 mmol) in THF (70 mL) was added DIPEA (840 mg, 6.5 mmol) and a solution of (2R)-2-chloro-2-fluoro-acetyl chloride (428.0 mg, 1.31 mmol, Intermediate 9) in THF (17 mL) successively at 20 C. over 10 min. The mixture was stirred at 0 C. for 30 min. The reaction mixture was quenched with MeOH (6 mL) and acidified with 4 N HCl/dioxane to pH=5 at 0 C. The mixture was concentrated in vacuum and the residue was purified by prep-HPLC (Condition: water (0.1% TFA)-ACN, Column:3_Phenomenex Luna C18 75*30 mm*3 um, 39-59% MeCN in H.sub.2O, FlowRate(ml/min):25) to afford 3-[[(2R)-2-chloro-2-fluoro-acetyl]-[[(1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]amino]propanamide (62 mg, Example 87) as a white solid.

[1314] .sup.1H NMR (400 MHz, CDCl.sub.3) : ppm 9.61 (br. s, 1H), 7.04 (d, J=8.8 Hz, 1H), 6.70-6.57 (m, 1H), 6.39-5.98 (m, 2H), 4.56 (d, J=9.2 Hz, 1H), 4.37-4.17 (m, 2H), 4.05 (dd, J=10.0, 5.6 Hz, 1H), 3.87 (d, J=10.4 Hz, 1H), 3.69-3.43 (m, 1H), 2.71-2.59 (m, 2H), 1.67-1.64 (m, 1H), 1.46 (d, J=7.2 Hz, 1H), 1.09 (s, 3H), 1.03 (s, 9H), 0.92 (s, 3H).

[1315] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 544.2.

Example 88a and Example 88b

(3S,3aS,6aR)N-[(2R)-2-chloro-2-fluoro-acetyl]-2-[2-(3-fluorophenoxy)acetyl]-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbohydrazide and (3R,3aR,6aS)N-[(2R)-2-chloro-2-fluoro-acetyl]-2-[2-(3-fluorophenoxy)acetyl]-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbohydrazide

##STR00337##

Step 1: Preparation of trans-methyl 2-[2-(3-fluorophenoxy)acetyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate

##STR00338##

[1316] To a solution of (3-fluoro-phenoxy)-acetic acid (300 mg, 1.76 mmol) in DCM (5 mL) was added SOCl.sub.2 (416 mg, 3.53 mmol) and DMF (6 mg, 0.090 mmol). The mixture was stirred at 60 C. for 1 h. The mixture was concentrated in vacuum to afford the crude 2-(3-fluorophenoxy)acetyl chloride (330 mg) as yellow oil. Then the crude 2-(3-fluorophenoxy)acetyl chloride and DIPEA (764 mg, 5.91 mmol) was added to a solution of trans-methyl 1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-3-carboxylate (200 mg, 1.18 mmol, Intermediate 27) in DCM (5 mL) at 0 C. The reaction mixture was stirred at 25 C. for 2 h. The mixture was concentrated in vacuum and the residue was purified by reverse flash (condition: 120 g Flash Column Welch Ultimate XB_C18 20-40 m; 120 A, water (0.1% HCl)-ACN, 055%, 60 ml/min) to afford trans-methyl 2-[2-(3-fluorophenoxy)acetyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate (351 mg) as a white solid.

[1317] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 322.2.

Step 2: Preparation of trans-2-[2-(3-fluorophenoxy)acetyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid

##STR00339##

[1318] To a solution of trans-methyl 2-[2-(3-fluorophenoxy)acetyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate (350 mg, 1.09 mmol) in THF (5 mL) was added the solution of LiOH.Math.H.sub.2O (91 mg, 2.18 mmol) in water (2 mL). The mixture was stirred at 25 C. for 2 h. The mixture was poured into 1 N HCl (60 mL) and extracted with EtOAc (40 mL3). The organic phase was washed with brine (40 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by reverse flash chromatography (condition: 120 g Flash Column Welch Ultimate XB_C18 20-40 m; 120 A, water (0.1% HCl)-ACN, 055%, 60 mL/min) to afford trans-2-[2-(3-fluorophenoxy)acetyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid (290 mg) as a yellow solid.

[1319] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 308.1.

Step 3: Preparation of trans-tert-butyl N-[[2-[2-(3-fluorophenoxy)acetyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate

##STR00340##

[1320] To a solution of trans-2-[2-(3-fluorophenoxy)acetyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid (250 mg, 0.810 mmol) in DMF (2 mL) was added HOPO (108 mg, 0.980 mmol), EDCI (187 mg, 0.980 mmol), DIPEA (315 mg, 2.4 mmol) and tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (187 mg, 0.810 mmol) at 0 C. The mixture was stirred at 30 C. for 12 h. The mixture was purified by reverse flash chromatography (condition: 120 g Flash Column Welch Ultimate XB_C18 20-40 m; 120 A, water (0.1% TFA)-ACN, 055%, 60 ml/min) to afford trans-tert-butyl N-[[2-[2-(3-fluorophenoxy)acetyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (250 mg) as a white solid.

[1321] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 519.4.

Step 4: Preparation of trans-2-[2-(3-fluorophenoxy)acetyl]-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbohydrazide

##STR00341##

[1322] To a solution of trans-tert-butyl N-[[2-[2-(3-fluorophenoxy)acetyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (250 mg, 0.480 mmol) in DCM (5 mL) was added TFA (10.0 mL). The mixture was stirred at 25 C. for 2 h. The mixture was concentrated and the residue was purified by reverse flash chromatography (condition: 120 g Flash Column Welch Ultimate XB_C18 20-40 m; 120 A, water (0.1% HCl)-ACN, 055%, 60 mL/min) to afford trans-2-[2-(3-fluorophenoxy)acetyl]-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbohydrazide (160 mg) as a white solid.

Step 5: Preparation of (3S,3aS,6aR)N-[(2R)-2-chloro-2-fluoro-acetyl]-2-[2-(3-fluorophenoxy)acetyl]-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbohydrazide and (3R,3aR,6aS)N-[(2R)-2-chloro-2-fluoro-acetyl]-2-[2-(3-fluorophenoxy)acetyl]-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbohydrazide (Example 88a and 88b)

##STR00342##

[1323] To a solution of trans-2-[2-(3-fluorophenoxy)acetyl]-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbohydrazide (160 mg, 0.380 mmol) in THF (35 mL) was added DIPEA (741 mg, 5.74 mmol) at 0 C. Then (2R)-2-chloro-2-fluoro-acetyl chloride (10 mg, 0.760 mmol in THF (5 mL) was added at 0 C. The resulting mixture was stirred at 0 C. for 30 min. The reaction mixture was quenched with MeOH (10 mL) and acidified by 4 N HCl/dioxane to pH=5 at 10 C. Then the mixture was concentrated in vacuum at 30 C. The residue was purified by reverse flash chromatography (condition: 120 g Flash Column Welch Ultimate XB_C18 20-40 m; 120 A, water (0.1% FA)-ACN, 055%, 60 mL/min) to afford 80 mg of two isomers. These two isomers was purified by prep-SFC (Instrument ACSWH-PREP-SFC-D Method: Column DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); Condition Neu-ETOH Begin B 40 End B 40; Gradient Time (min) 4.5; 100% B Hold Time (min) Flow Rate (mL/min) 70; Injections 50) to afford Example 88a (23 mg, retention time=1.094 min) and Example 88b (48 mg, retention time=2.551 min) as a white solid.

Example 88a

[1324] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 10.82-10.58 (m, 1H), 7.84-7.70 (m, 1H), 7.33-7.23 (m, 1H), 7.05-6.52 (m, 4H), 4.94-4.83 (m, 1H), 4.80-4.40 (m, 1H), 4.13-3.92 (m, 1H), 3.85-3.70 (m, 1H), 3.45 (dd, J=10.4 Hz, 4.4 Hz, 1H), 3.18-3.04 (m, 2H), 2.88-2.77 (m, 1H), 2.70-2.52 (m, 3H), 2.24-2.02 (m, 2H), 1.94-1.85 (m, 1H), 1.85-1.76 (m, 1H), 1.76-1.66 (m, 2H), 1.65-1.54 (m, 2H), 1.53-1.43 (m, 1H).

[1325] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 513.2.

Example 88b

[1326] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.02 (s, 1H), 7.82-7.66 (m, 1H), 7.33-7.22 (m, 1H), 6.85-6.65 (m, 4H), 4.93-4.70 (m, 2H), 4.15-4.01 (m, 1H), 3.96-3.68 (m, 2H), 3.47 (dd, J=10.4 Hz, 4.0 Hz, 1H), 3.40-3.33 (m, 1H), 3.21-2.99 (m, 2H), 2.87-2.74 (m, 1H), 2.61-2.52 (m, 2H), 2.21-2.08 (m, 1H), 1.89-1.55 (m, 6H), 1.53-1.41 (m, 1H).

[1327] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 513.2.

Example 89a and Example 89b

(3S,3aS,6aR)N-[(2R)-2-chloro-2-fluoro-acetyl]-2-[2-(3,5-difluorophenoxy)acetyl]-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbohydrazide and (3R,3aR,6aS)N-[(2R)-2-chloro-2-fluoro-acetyl]-2-[2-(3,5-difluorophenoxy)acetyl]-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbohydrazide

##STR00343##

Step 1: Preparation of trans-methyl 2-(2-chloroacetyl)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate

##STR00344##

[1328] To a solution of methyl trans-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-3-carboxylate (200.0 mg, 1.18 mmol, Intermediate 27) in THF (8 mL) was added DIPEA (1.22 g, 9.46 mmol) and chloroacetyl chloride (267 mg, 2.36 mmol) at 0 C. The mixture was stirred at 0 C. for 30 min. The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL3). The combined organic phase were dried over Na.sub.2SO.sub.4, filtered and concentrated and the residue was purified by silica gel column eluted with PE to PE/EtOAc=6/1 to afford trans-methyl 2-(2-chloroacetyl)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate (272 mg) as light yellow oil.

[1329] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 245.9.

Step 2: Preparation of trans-methyl 2-[2-(3,5-difluorophenoxy)acetyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate

##STR00345##

[1330] To a solution of trans-methyl 2-(2-chloroacetyl)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate (272 mg, 1.11 mmol) in DMF (10 mL) was added K.sub.2CO.sub.3 (306 mg, 2.21 mmol) and 3,5-difluorophenol (144 mg, 1.11 mmol). The mixture was stirred at 50 C. for 2 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (30 mL3). The organic layers were washed with brine (80 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by silica gel column eluted with PE to PE/EtOAc=2/1 to afford trans-methyl 2-[2-(3,5-difluorophenoxy)acetyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate (200 mg) as yellow oil.

[1331] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 340.2.

Step 3: Preparation of trans-2-[2-(3,5-difluorophenoxy)acetyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid

##STR00346##

[1332] To a solution of trans-methyl 2-[2-(3,5-difluorophenoxy)acetyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate (200 mg, 0.590 mmol) in THF (5 mL) was added a solution of LiOH.Math.H.sub.2O (49 mg, 1.18 mmol) in water (5 mL). The mixture was stirred at 25 C. for 1 h. The reaction mixture was diluted with water (30 mL) and washed with EtOAc (30 mL2). The aqueous layer was acidified with concentrated HCl to pH=12 and extracted with EtOAc (30 mL3). The organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum to afford trans-2-[2-(3,5-difluorophenoxy)acetyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid (190 mg) as a white solid.

[1333] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 326.1.

Step 4: Preparation of trans-tert-butyl N-[[2-[2-(3,5-difluorophenoxy)acetyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate

##STR00347##

[1334] To a solution of trans-2-[2-(3,5-difluorophenoxy)acetyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid (190 mg, 0.600 mmol) in DMF (8 mL) was added DIPEA (377 mg, 2.92 mmol), EDCI (157 mg, 0.820 mmol) and HOPO (91 mg, 0.820 mmol) successively at 0 C. Then tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (161 mg, 0.700 mmol, Intermediate 9) was added. The mixture was warmed to 25 C. and stirred for 13 h. The mixture was purified by reverse flash chromatography (40 g Flash Column Welch Ultimate XB_C18 20-40 m; 120 A, water (0.1% TFA)-ACN, 45%, 40 mL/min) to afford trans-tert-butyl N-[[2-[2-(3,5-difluorophenoxy)acetyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (252 mg) as a white solid.

[1335] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 537.1.

Step 5: Preparation of trans-2-[2-(3,5-difluorophenoxy)acetyl]-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbohydrazide

##STR00348##

[1336] To a solution of trans-tert-butyl N-[[2-[2-(3,5-difluorophenoxy)acetyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (252 mg, 0.470 mmol) in DCM (5 mL) was added TFA (5.0 mL). The mixture was stirred at 25 C. for 1 h. The reaction mixture was concentrated and the residue was purified by reverse flash chromatography (40 g Flash Column Welch Ultimate XB_C18 20-40 m; 120 A, water (0.1% HCl)-ACN, 31%, 40 mL/min) to afford trans-2-[2-(3,5-difluorophenoxy)acetyl]-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbohydrazide (157 mg) as a white solid.

[1337] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 437.2.

Step 6: Preparation of (3S,3aS,6aR)N-[(2R)-2-chloro-2-fluoro-acetyl]-2-[2-(3,5-difluorophenoxy)acetyl]-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbohydrazide and (3R,3aR,6aS)N-[(2R)-2-chloro-2-fluoro-acetyl]-2-[2-(3,5-difluorophenoxy)acetyl]-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbohydrazide (Example 89a and Example 89b)

##STR00349##

[1338] To a solution of trans-2-[2-(3,5-difluorophenoxy)acetyl]-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbohydrazide (170 mg, 0.360 mmol) in THF (35 mL) was added DIPEA (558 mg, 4.32 mmol) at 0 C. Then a solution of (2R)-2-chloro-2-fluoro-acetyl chloride (235 mg, 0.720 mmol in THF (5 mL) was added. The reaction mixture was stirred at 0 C. for 30 min. The reaction was quenched with MeOH (10 mL) and acidified by 4 N HCl/dioxane to pH=5 at 10 C. The resulting mixture was concentrated in vacuum at 30 C. The residue was purified by reverse flash chromatography (40 g Flash Column Welch Ultimate XB_C18 20-40 m; 120 A, water (0.1% FA)-ACN, 45%, 40 mL/min) to afford 180 mg of a mixture of two isomers. The mixture was split by prep-SFC (Column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 um), Mobile Phase: 60% of Neu-MeOH in Supercritical CO.sub.2, Flow Rate: 70 g/min, Cycle Time: 4.2 min, Back Pressure: 100 bar to keep the CO.sub.2 in Supercritical flow, UV: 220 nm) to afford Example 89a (50 mg, retention time=0.895 min) and Example 89b (49 mg, retention time=1.722 min) as a white solid.

Example 89a

[1339] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 10.77-10.66 (m, 1H), 7.79-7.72 (m, 1H), 6.98-6.54 (m, 4H), 4.95-4.91 (m, 1H), 4.80 (t, J=13.2 Hz, 1H), 4.09 (s, 1H), 4.09-3.73 (m, 2H), 3.47-3.40 (m, 1H), 3.38-3.30 (m, 1H), 3.20-3.01 (m, 2H), 2.89-2.81 (m, 1H), 2.21-2.16 (m, 1H), 1.93-1.48 (m, 9H).

[1340] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 531.2.

Example 89b

[1341] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.01 (s, 1H), 7.76 (s, 1H), 6.78-6.66 (m, 4H), 4.86 (q, J=34.4 Hz, 15.6 Hz, 2H), 4.04-4.03 (m, 1H), 3.82-3.73 (m, 2H), 3.45 (dd, J=10.4 Hz, 3.6 Hz, 1H), 3.40-3.38 (m, 1H), 3.16-3.13 (m, 2H), 2.82-2.79 (m, 1H), 2.19-2.12 (m, 1H), 1.86-1.45 (m, 9H).

[1342] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 531.2.

Example 90

N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-3,3-difluoro-cyclobutanecarboxamide

##STR00350##

Step 1: Preparation of methyl (1R,2S,5S)-3-[(2S)-2-(benzyloxycarbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate

##STR00351##

[1343] To a solution of methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; hydrochloride (2.87 g, 13.95 mmol) in DMF (10 mL) and ACN (60 mL) was added HATU (6.36 g, 16.74 mmol) and (S)-2-(((benzyloxy)carbonyl)amino)-3,3-dimethylbutanoic acid (3.7 g, 13.95 mmol). After the mixture cooling to 0 C., DIPEA (5.4 g, 41.84 mmol) was added. The resulting mixture was stirred at 25 C. for 16 h. The reaction mixture was concentrated. The residue was dissolved in EtOAc (80 mL) and washed with 1 N HCl (40 mL), brine (40 mL) and dried over Na.sub.2SO.sub.4. After filtration and concentration, methyl (1R,2S,5S)-3-[(2S)-2-(benzyloxycarbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (6.2 g, crude) was obtained as yellow oil.

Step 2: Preparation of (1R,2S,5S)-3-[(2S)-2-(benzyloxycarbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid

##STR00352##

[1344] To a solution of methyl (1R,2S,5S)-3-[(2S)-2-(benzyloxycarbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (5.57 g, 13.38 mmol) in THF (30 mL) and H.sub.2O (15 mL) was added LiOH.Math.H.sub.2O (1122 mg, 26.76 mmol). The mixture was stirred at 25 C. for 2 h. The resulting mixture was diluted with water (80 mL) and extracted with EtOAc (50 mL2). The aqueous phase was acidified with 1 N HCl (45 mL) to pH=45. The mixture was extracted with EtOAc (80 mL3). The combined organic phase was washed with brine (80 mL), dried over Na.sub.2SO.sub.4 and concentrated to afford (1R,2S,5S)-3-[(2S)-2-(benzyloxycarbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (5.4 g) as colorless oil.

[1345] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 403.2.

Step 3: Preparation of tert-butyl N-[[(1R,2S,5S)-3-[(2S)-2-(benzyloxycarbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate

##STR00353##

[1346] To a solution of (3S,3aS,6aR)-2-[(2S)-2-(benzyloxycarbonylamino)pentanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid (5.38 g, 13.86 mmol) in DMF (8 mL) was added DIPEA (7.2 g, 55.44 mmol). After cooling to 0 C., HOPO (1.85 g, 16.63 mmol), EDCI (3.2 g, 16.63 mmol) and tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (3.18, 13.86 mmol) was added. Then the mixture was stirred at 30 C. for 12 h. The mixture was diluted with 0.5 N HCl (100 mL) and extracted with EtOAc (80 mL3). The organic phase was washed with 5% aqueous solution of K.sub.2CO.sub.3 (40 mL), brine (60 mL) and dried over Na.sub.2SO.sub.4. After filtration and concentration, tert-butyl N-[[(1R,2S,5S)-3-[(2S)-2-(benzyloxycarbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (6.87 g) was obtained as a white solid.

[1347] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 614.2.

Step 4: Preparation of tert-butyl N-[[(1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate

##STR00354##

[1348] To a solution of tert-butyl N-[[(1R,2S,5S)-3-[(2S)-2-(benzyloxycarbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (2.5 g, 4.07 mmol) in methanol (70 mL) was added Pd(OH).sub.2 (250 mg). The suspension was degassed under vacuum and purged hydrogen for three times. The resulting mixture was stirred at 25 C. for 12 h under a H.sub.2 balloon. The mixture was filtered through a pad of celite and the filtrate was concentrated to afford tert-butyl N-[[(1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (1.9 g) as yellow oil.

[1349] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 480.4.

Step 5: Preparation of tert-butyl N-[[(1R,2S,5S)-3-[(2S)-2-[(3,3-difluorocyclobutanecarbonyl)amino]-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate

##STR00355##

[1350] To a solution of tert-butyl N-[[(1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (800 mg, 1.67 mmol) in DCM (10 mL) was added DIPEA (1.08 g, 8.36 mmol), T.sub.3P (1.6 g, 2.51 mmol, 50% in EtOAc) and 3,3-difluorocyclobutanecarboxylic acid (228 mg, 1.68 mmol) at 0 C. The reaction mixture was stirred at 25 C. for 12 h. The reaction mixture was poured into EtOAc (150 mL) and washed with 1 N HCl (50 mL2), 5% aqueous solution of K.sub.2CO.sub.3 (50 mL2) and brine (50 mL). The organic phase was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated to afford tert-butyl N-[[(1R,2S,5S)-3-[(2S)-2-[(3,3-difluorocyclobutanecarbonyl)amino]-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (990 mg, 1.66 mmol) as a yellow solid.

[1351] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 598.4.

Step 6: Preparation of N-[(1S)-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(3S)-2-oxopyrrolidin-3-yl]methylamino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-3,3-difluoro-cyclobutanecarboxamide; hydrochloride

##STR00356##

[1352] To a solution of tert-butyl N-[[(1R,2S,5S)-3-[(2S)-2-[(3,3-difluorocyclobutanecarbonyl)amino]-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (800 mg, 1.34 mmol) in DCM (10 mL) was added TFA (10.0 mL). The reaction mixture was stirred at 15 C. for 30 min. The reaction mixture was concentrated in vacuum to give a residue. The residue was purified by reverse flash chromatography (condition: 120 g Flash Column Welch Ultimate XB_C18 20-40 m; 120 A, water(0.1% HCl)-ACN, 45%, 70 mL/min) to afford N-[(1S)-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(3S)-2-oxopyrrolidin-3-yl]methylamino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-3,3-difluoro-cyclobutanecarboxamide; hydrochloride (690.0 mg) as a white solid.

[1353] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 498.3.

Step 7: Preparation of N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-3,3-difluoro-cyclobutanecarboxamide

##STR00357##

[1354] To a solution of N-[(1S)-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(3S)-2-oxopyrrolidin-3-yl]methylamino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-3,3-difluoro-cyclobutanecarboxamide; hydrochloride (500 mg, 0.94 mmol) in THF (150 mL) was added DIPEA (1211.0 mg, 9.37 mmol). After cooling to 5 C., (2R)-2-chloro-2-fluoro-acetyl chloride (522 mg, 1.59 mmol, 40% purity, Intermediate 10) in THF (10 mL) was added at 5 C. Then the reaction mixture was stirred at the same temperature for 30 min. The reaction mixture was quenched with MeOH (10 mL) and acidified by 4 N HCl/dioxane to pH=5 at 10 C. The resulting mixture was concentrated at 30 C. The residue was purified by reversed flash chromatography (condition: 120 g Flash Column Welch Ultimate XB_C18 20-40 m; 120 A, water (0.1% FA)-ACN, 053%, 70 mL/min) to afford N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-3,3-difluoro-cyclobutanecarboxamide (Example 90, 505 mg) as a white solid.

[1355] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.14 (s, 1H), 8.18-8.11 (m, 1H), 7.75-7.69 (m, 1H), 6.89 (d, J=50.4 Hz, 1H), 4.37 (d, J=8.4 Hz, 1H), 4.12 (s, 1H), 3.96-3.86 (m, 1H), 3.85-3.74 (m, 2H), 3.45 (dd, J=13.6 Hz, 4.4 Hz, 1H), 3.22-3.04 (m, 3H), 2.74-2.63 (m, 3H), 2.61-2.54 (m, 2H), 2.21-2.04 (m, 1H), 1.84-1.70 (m, 1H), 1.66-1.58 (m, 1H), 1.53-1.47 (m, 1H), 1.05 (s, 3H), 0.93 (s, 9H), 0.90-0.84 (m, 3H).

[1356] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 592.3.

Example 91

N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-1-fluoro-cyclobutanecarboxamide

##STR00358##

[1357] The title compound was prepared in analogy to the procedure described for the preparation of Example 90, by using 1-fluorocyclobutanecarboxylic acid instead of 3,3-difluorocyclobutanecarboxylic acid to afford N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-1-fluoro-cyclobutanecarboxamide (Example 91) as a white solid.

[1358] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.16 (s, 1H), 7.75-7.69 (m, 1H), 7.33-7.21 (m, 1H), 6.83 (d, J=50.4 Hz, 1H), 4.42 (d, J=8.4 Hz, 1H), 4.15 (s, 1H), 3.96-3.91 (m, 1H), 3.82-3.75 (m, 2H), 3.45 (dd, J=13.6 Hz, 4.0 Hz, 1H), 3.21-3.10 (m, 2H), 2.58-2.55 (m, 1H), 2.43-2.35 (m, 4H), 2.18-2.10 (m, 1H), 1.90-1.82 (m, 1H), 1.81-1.67 (m, 2H), 1.67-1.60 (m, 1H), 1.53-1.52 (m, 1H), 1.04 (s, 3H), 0.94-0.86 (m, 12H).

[1359] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 574.3.

Example 92

(1S)N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide

##STR00359##

[1360] The title compound was prepared in analogy to the procedure described for the preparation of Example 90, by using (1S)-2,2-difluorocyclopropanecarboxylic acid instead of 3,3-difluorocyclobutanecarboxylic acid to afford (1S)N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide (Example 92) as a white solid.

[1361] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.14 (s, 1H), 8.43 (d, J=8.4 Hz, 1H), 7.75 (s, 1H), 6.90 (d, J=50.4 Hz, 1H), 4.37 (d, J=8.8 Hz, 1H), 4.13 (s, 1H), 3.95-3.88 (m, 1H), 3.82-3.73 (m, 2H), 3.44 (dd, J=14.0 Hz, 4.6 Hz, 1H), 3.20-3.12 (m, 2H), 2.90-2.80 (m, 1H), 2.65-2.56 (m, 1H), 2.18-2.11 (m, 1H), 1.86-1.73 (m, 3H), 1.65-1.59 (m, 1H), 1.51 (d, J=7.6 Hz, 1H), 1.04 (s, 3H), 0.95 (s, 9H), 0.90 (s, 3H).

[1362] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 578.1.

Example 93

N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-3,3-difluoro-cyclobutanecarboxamide

##STR00360##

[1363] The title compound was prepared in analogy to the procedure described for the preparation of Example 90, by using (2S)-2-chloro-2-fluoro-acetyl chloride (Intermediate 28) instead of (2R)-2-chloro-2-fluoro-acetyl chloride (Intermediate 10) to afford N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-3,3-difluoro-cyclobutanecarboxamide (Example 93) as a white solid.

[1364] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.08-10.84 (m, 1H), 8.18-8.12 (m, 1H), 7.76-7.70 (m, 1H), 7.12-6.56 (m, 1H), 4.37 (t, J=8.0 Hz, 1H), 4.18-4.10 (m, 1H), 3.92-3.81 (m, 2H), 3.78-3.69 (m, 1H), 3.55-3.47 (m, 1H), 3.17-2.99 (m, 3H), 2.70-2.59 (m, 3H), 2.19-2.10 (m, 1H), 1.83-1.72 (m, 1H), 1.64-1.48 (m, 2H), 1.33-1.14 (m, 2H), 1.05-1.03 (m, 3H), 0.95-0.92 (m, 9H), 0.88 (s, 3H).

[1365] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 592.3.

Example 94

N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-1-fluoro-cyclopropanecarboxamide

##STR00361##

[1366] The title compound was prepared in analogy to the procedure described for the preparation of Example 90, by using 1-fluorocyclopropanecarboxylic acid instead of 3,3-difluorocyclobutanecarboxylic acid and (2S)-2-chloro-2-fluoro-acetyl chloride (Intermediate 28) instead of (2R)-2-chloro-2-fluoro-acetyl chloride (Intermediate 10) to afford N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-1-fluoro-cyclopropanecarboxamide (Example 94) as a white solid.

[1367] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.08-10.87 (m, 1H), 7.75-7.70 (m, 1H), 7.40 (d, J=8.8 Hz, 1H), 7.08-6.57 (m, 1H), 4.43 (d, J=7.6 Hz, 1H), 4.23-4.15 (m, 1H), 3.92-3.88 (m, 1H), 3.79-3.65 (m, 2H), 3.55-3.51 (m, 1H), 3.16-3.00 (m, 2H), 2.66-2.58 (m, 1H), 2.21-2.15 (m, 1H), 1.83-1.74 (m, 1H), 1.64-1.48 (m, 2H), 1.35 (d, J=18.0 Hz, 2H), 1.25-1.09 (m, 2H), 1.04 (s, 3H), 0.99-0.97 (m, 9H), 0.87 (s, 3H).

[1368] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 560.2.

Example 95

(1S)N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide

##STR00362##

[1369] The title compound was prepared in analogy to the procedure described for the preparation of Example 90, by using (1S)-2,2-difluorocyclopropanecarboxylic acid instead of 3,3-difluorocyclobutanecarboxylic acid and (2S)-2-chloro-2-fluoro-acetyl chloride (Intermediate 28) instead of (2R)-2-chloro-2-fluoro-acetyl chloride (Intermediate 10) to afford (1S)N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide (Example 95) as a white solid.

[1370] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.01-10.83 (m, 1H), 8.42 (d, J=8.8 Hz, 1H), 7.76-7.70 (m, 1H), 7.13-6.56 (m, 1H), 4.38 (d, J=8.8 Hz, 1H), 4.19-4.12 (m, 1H), 3.89-3.84 (m, 1H), 3.77-3.69 (m, 2H), 3.57-3.46 (m, 1H), 3.26-3.16 (m, 1H), 3.14-3.00 (m, 1H), 2.90-2.82 (m, 1H), 2.72-2.63 (m, 1H), 2.21-2.07 (m, 1H), 1.87-1.73 (m, 3H), 1.66-1.48 (m, 2H), 1.09-1.01 (m, 3H), 1.01-0.90 (m, 9H), 0.90-0.84 (m, 3H).

[1371] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 578.2.

Example 96

(1R)N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide

##STR00363##

[1372] The title compound was prepared in analogy to the procedure described for the preparation of Example 90, by using (1R)-2,2-difluorocyclopropanecarboxylic acid instead of 3,3-difluorocyclobutanecarboxylic acid and (2S)-2-chloro-2-fluoro-acetyl chloride (Intermediate 28) instead of (2R)-2-chloro-2-fluoro-acetyl chloride (Intermediate 10) to afford (1R)N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide (Example 96) as a white solid.

[1373] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.10-10.86 (m, 1H), 8.48 (d, J=8.8 Hz, 1H), 7.76-7.70 (m, 1H), 7.15-6.57 (m, 1H), 4.43-4.41 (m, 1H), 4.21-4.12 (m, 1H), 3.91-3.69 (m, 3H), 3.53 (dd, J=14.0 Hz, 4.0 Hz, 1H), 3.25-3.13 (m, 1H), 3.05-3.01 (m, 1H), 2.90-2.73 (m, 1H), 2.65-2.55 (m, 1H), 2.24-2.12 (m, 1H), 1.92-1.86 (m, 1H), 1.85-1.76 (m, 2H), 1.63-1.47 (m, 2H), 1.04 (s, 3H), 0.97-0.95 (m, 9H), 0.83 (s, 3H).

[1374] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 578.1.

Example 97

N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-1-fluoro-cyclobutanecarboxamide

##STR00364##

[1375] The title compound was prepared in analogy to the procedure described for the preparation of Example 29, by using 1-fluorocyclobutanecarboxylic acid and T.sub.3P instead of acetic anhydride to afford N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-1-fluoro-cyclobutanecarboxamide (Example 97) as a white solid.

[1376] .sup.1H NMR (400 MHz, CDCl.sub.3) : ppm 9.95 (br. s, 1H), 6.91 (br. s, 1H), 6.82 (d, J=51.6 Hz, 1H), 6.05 (br. s, 1H), 4.67 (d, J=9.2 Hz, 1H), 4.50-4.41 (m, 1H), 4.22-4.12 (m, 1H), 4.00 (dd, J=10.4 Hz, 7.2 Hz, 1H), 3.78 (dd, J=10.4 Hz, 2.8 Hz, 1H), 3.44-3.35 (m, 2H), 2.85-2.56 (m, 5H), 2.49-2.33 (m, 3H), 2.00-1.79 (m, 5H), 1.76-1.59 (m, 4H), 1.50-1.42 (m, 1H), 1.02 (s, 9H).

[1377] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 574.2.

Example 98

N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-3,3-difluoro-cyclobutanecarboxamide

##STR00365##

[1378] The title compound was prepared in analogy to the procedure described for the preparation of Example 29, by using 3,3-difluorocyclobutanecarboxylic acid and T.sub.3P instead of acetic anhydride to afford N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-3,3-difluoro-cyclobutanecarboxamide (Example 98) as a white solid.

[1379] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.07 (s, 1H), 8.17 (d, J=8.8 Hz, 1H), 7.77 (s, 1H), 7.01 (d, J=50.8 Hz, 1H), 4.45 (d, J=8.4 Hz, 1H), 3.94 (d, J=6.4 Hz, 1H), 3.91-3.84 (m, 1H), 3.78-3.68 (m, 2H), 3.39 (dd, J=13.6 Hz, 4.0 Hz, 1H), 3.32 (s, 2H), 3.29-3.08 (m, 3H), 2.77-2.57 (m, 6H), 2.20-2.11 (m, 1H), 1.91-1.81 (m, 1H), 1.79-1.72 (m, 3H), 1.70-1.59 (m, 1H), 1.40-1.30 (m, 1H), 0.93 (s, 9H).

[1380] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 592.3.

Example 99

(1S)N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide

##STR00366##

[1381] The title compound was prepared in analogy to the procedure described for the preparation of Example 29, by using (1S)-2,2-difluorocyclopropanecarboxylic acid and T.sub.3P instead of acetic anhydride to afford (1S)N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide (Example 99) as a white solid.

[1382] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.18 (s, 1H), 8.48 (d, J=8.8 Hz, 1H), 7.77 (s, 1H), 7.00 (d, J=50.6 Hz, 1H), 4.47 (d, J=8.8 Hz, 1H), 4.04-3.93 (m, 1H), 3.90-3.83 (m, 1H), 3.80-3.60 (m, 2H), 3.90 (dd, J=13.6 Hz, 4.0 Hz, 1H), 3.22-3.10 (m, 2H), 2.94-2.84 (m, 1H), 2.75-2.70 (m, 1H), 2.54-2.52 (m, 2H), 2.20-2.10 (m, 1H), 1.91-1.81 (m, 3H), 1.81-1.70 (m, 4H), 1.68-1.57 (m, 1H), 1.39-1.30 (m, 1H), 0.92 (s, 9H).

[1383] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 578.3.

Example 100

(1R)N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide

##STR00367##

[1384] The title compound was prepared in analogy to the procedure described for the preparation of Example 29, by using (1R)-2,2-difluorocyclopropanecarboxylic acid and T.sub.3P instead of acetic anhydride to afford (1R)N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide (Example 100) as a white solid.

[1385] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.11 (s, 1H), 8.51 (d, J=8.8 Hz, 1H), 7.77-7.70 (m, 1H), 7.02 (d, J=50.8 Hz, 1H), 4.48 (d, J=8.8 Hz, 1H), 3.95 (d, J=6.4 Hz, 1H), 3.88-3.83 (m, 1H), 3.73-3.70 (m, 2H), 3.41-3.36 (dd, J=14.0 Hz, 4.0 Hz, 1H), 3.21-3.10 (m, 2H), 2.90-2.82 (m, 1H), 2.76-2.66 (m, 1H), 2.59-2.54 (m, 1H), 2.20-2.11 (m, 1H), 1.94-1.79 (m, 4H), 1.79-1.71 (m, 3H), 1.71-1.58 (m, 2H), 1.35-1.26 (m, 1H), 0.95 (s, 9H).

[1386] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 578.4.

Example 101

(1S)N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide

##STR00368##

[1387] The title compound was prepared in analogy to the procedure described for the preparation of Example 29, by using (1S)-2,2-difluorocyclopropanecarboxylic acid and T.sub.3P instead of acetic anhydride and (2S)-2-chloro-2-fluoro-acetyl chloride (Intermediate 28) instead of (2R)-2-chloro-2-fluoro-acetyl chloride (Intermediate 10) to afford (1S)N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide (Example 101) as a white solid.

[1388] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.05-10.73 (m, 1H), 8.51-8.43 (m, 1H), 7.77-7.70 (m, 1H), 7.21-6.39 (m, 1H), 4.48 (d, J=8.8 Hz, 1H), 4.02-3.92 (m, 1H), 3.89-3.79 (m, 2H), 3.72-3.66 (m, 1H), 3.51-3.43 (m, 1H), 3.18-2.96 (m, 2H), 2.90-2.76 (m, 2H), 2.28-2.13 (m, 2H), 1.93-1.58 (m, 9H), 1.41-1.29 (m, 1H), 1.02-0.92 (m, 9H).

[1389] MS obsd. (ESI.sup.+) [(M+Na).sup.+]: 600.2.

Example 102

N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide

##STR00369##

[1390] The title compound was prepared in analogy to the procedure described for the preparation of Example 29, by using trifluoroacetic anhydride instead of acetic anhydride and (2S)-2-chloro-2-fluoro-acetyl chloride (Intermediate 28) instead of (2R)-2-chloro-2-fluoro-acetyl chloride (Intermediate 10) to afford N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide (Example 102) as a white solid.

[1391] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.06-10.77 (m, 1H), 9.44-9.39 (m, 1H), 7.76-7.71 (m, 1H), 7.14-6.40 (m, 1H), 4.53-4.50 (m, 1H), 4.07-4.02 (m, 1H), 3.88-3.69 (m, 3H), 3.56-3.50 (m, 1H), 3.21-3.00 (m, 2H), 2.80-2.70 (m, 2H), 2.64-2.52 (m, 1H), 2.26-2.09 (m, 1H), 1.92-1.56 (m, 6H), 1.43-1.29 (m, 1H), 1.01-0.99 (m, 9H).

[1392] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 570.0.

Example 103

N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-1-fluoro-cyclopropanecarboxamide

##STR00370##

[1393] The title compound was prepared in analogy to the procedure described for the preparation of Example 29, by using 1-fluorocyclopropanecarboxylic acid and T.sub.3P instead of acetic anhydride and (2S)-2-chloro-2-fluoro-acetyl chloride (Intermediate 28) instead of (2R)-2-chloro-2-fluoro-acetyl chloride (Intermediate 10) to afford N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-1-fluoro-cyclopropanecarboxamide (Example 103) as a white solid.

[1394] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.04-10.76 (m, 1H), 7.70-7.74 (m, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.16-6.42 (m, 1H), 4.52 (d, J=8.4 Hz, 1H), 4.10-4.00 (m, 1H), 3.92-3.82 (m, 1H), 3.80-3.65 (m, 2H), 3.55-3.49 (m, 1H), 3.22-3.00 (m, 2H), 2.80-2.71 (m, 2H), 2.62-2.53 (m, 1H), 2.28-2.10 (m, 1H), 1.90-1.55 (m, 6H), 1.43-1.30 (m, 3H), 1.26-1.13 (m, 2H), 1.00-0.97 (m, 9H).

[1395] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 560.3.

Example 104

(1R)N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide

##STR00371##

[1396] The title compound was prepared in analogy to the procedure described for the preparation of Example 29, by using (1R)-2,2-difluorocyclopropanecarboxylic acid and T.sub.3P instead of acetic anhydride and (2S)-2-chloro-2-fluoro-acetyl chloride (Intermediate 28) instead of (2R)-2-chloro-2-fluoro-acetyl chloride (Intermediate 10) to afford (1R)N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide (Example 104) as a white solid.

[1397] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.06-10.73 (m, 1H), 8.48 (d, J=10.0 Hz, 1H), 7.76-7.70 (m, 1H), 7.21-6.39 (m, 1H), 4.47 (d, J=8.8 Hz, 1H), 4.00-3.95 (m, 1H), 3.85-3.79 (m, 1H), 3.73-3.71 (m, 1H), 3.50-3.44 (m, 1H), 3.20-3.16 (m, 2H), 3.14-2.99 (m, 1H), 2.84-2.73 (m, 2H), 2.71-2.67 (m, 2H), 2.21-2.16 (m, 1H), 1.84-1.66 (m, 8H), 1.32-1.29 (m, 1H), 0.97-0.95 (m, 9H).

[1398] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 578.2.

Example 105

N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclobutanecarboxamide

##STR00372##

Step 1: Preparation of methyl (1R,2S,5S)-3-[(2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate

##STR00373##

[1399] To a solution of Z-ILe-OH (2.84 g, 10.7 mmol) in DMF (30 mL) was added DIPEA (5.03 g, 38.9 mmol), HATU (4.44 g, 11.67 mmol) and methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; hydrochloride (2.0 g, 9.72 mmol) at 0 C. The reaction mixture was stirred at 25 C. for 2 h. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (150 mL3). The combined organic layers were washed with brine (100 mL) and dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by silica gel column eluted with PE to PE/EtOAc=2/1 to afford methyl (1R,2S,5S)-3-[(2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (3.03 g) as a yellow solid.

[1400] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 417.3.

Step 2: Preparation of (1R,2S,5S)-3-[(2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid

##STR00374##

[1401] To a solution of methyl (1R,2S,5S)-3-[(2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (3.0 g, 7.2 mmol) in THF (20 mL) was added a solution of LiOH.Math.H.sub.2O (605 mg, 14.42 mmol) in water (20 mL) at 0 C. The reaction mixture was stirred at 25 C. for 150 min. The resulting mixture was diluted with 1 N HCl (50 mL) and extracted with EtOAc (50 mL3). The combined organic layers were washed with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum to afford (1R,2S,5S)-3-[(2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (2.42 g) as colorless oil.

[1402] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 403.2.

Step 3: Preparation of tert-butyl N-[[(1R,2S,5S)-3-[(2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate

##STR00375##

[1403] To a solution of (1R,2S,5S)-3-[(2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (2.42 g, 6.01 mmol) in DMF (30 mL) was added DIPEA (3.89 g, 30.06 mmol), EDCI (1.38 g, 7.22 mmol) and HOPO (0.8 g, 7.22 mmol) at 0 C. Then tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (1.65 g, 7.2 mmol) was added to the mixture at 0 C. The reaction mixture was stirred at 25 C. for 12 h. The mixture was diluted with brine (50 mL) and acidified with 1N HCl (10 mL). The mixture was extracted with EtOAc (50 mL3). The combined organic phase was washed with brine (100 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The residue was purified by reverse flash chromatography eluted with ACN in H.sub.2O (0.1% TFA)=060% to tert-butyl N-[[(1R,2S,5S)-3-[(2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (2.48 g) as a white solid.

[1404] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 614.4.

Step 4: Preparation of tert-butyl N-[[(1R,2S,5S)-3-[(2S,3S)-2-amino-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate

##STR00376##

[1405] To a solution of tert-butyl N-[[(1R,2S,5S)-3-[(2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (2.48 g, 4.04 mmol) in methanol (30 mL) was added Pd/C (0.5 g, 10% purity). The suspension was degassed under vacuum and purged H.sub.2 for 3 times. The suspension was stirred at 25 C. for 2 h under a H.sub.2 balloon. The resulting suspension was filtered and the filtrate was concentrated to afford tert-butyl N-[[(1R,2S,5S)-3-[(2S,3S)-2-amino-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (1.9 g) as a white solid.

[1406] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 480.3.

Step 5: Preparation of tert-butyl N-[[(1R,2S,5S)-3-[(2S,3S)-2-[(1-fluorocyclobutanecarbonyl)amino]-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate

##STR00377##

[1407] To a solution of tert-butyl N-[[(1R,2S,5S)-3-[(2S,3S)-2-amino-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (358 mg, 0.75 mmol) in DCM (15 mL) was added DIPEA (438 mg, 3.39 mmol), 1-fluorocyclobutanecarboxylic acid (80 mg, 0.68 mmol) and T.sub.3P (647 mg, 1.02 mmol, 50% in EtOAc) at 0 C. The reaction mixture was stirred at 25 C. for 30 min. The reaction mixture was poured into water (50 mL) and extracted with DCM (50 mL3). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated to afford tert-butyl N-[[(1R,2S,5S)-3-[(2S,3S)-2-[(1-fluorocyclobutanecarbonyl)amino]-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (390 mg) as a white solid.

[1408] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 580.4.

Step 6: Preparation of N-[(1S,2S)-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(3S)-2-oxopyrrolidin-3-yl]methylamino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclobutanecarboxamide; hydrochloride

##STR00378##

[1409] To a solution of tert-butyl N-[[(1R,2S,5S)-3-[(2S,3S)-2-[(1-fluorocyclobutanecarbonyl)amino]-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (350 mg, 0.6 mmol) in DCM (5 mL) was added TFA (5.0 mL). The mixture was stirred at 25 C. for 30 min. The resulting solution was concentrated in vacuum and the residue was purified by reverse flash chromatography (condition: 120 g Flash Column Welch Ultimate XB_C18 20-40 m; 120 A, water(0.1% HCl)-ACN, 46%, 70 mL/min) to afford N-[(1S,2S)-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(3S)-2-oxopyrrolidin-3-yl]methylamino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclobutanecarboxamide; hydrochloride (300 mg) as a white solid.

[1410] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 480.4.

Step 7: Preparation of N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclobutanecarboxamide

##STR00379##

[1411] To a solution of N-[(1S,2S)-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(3S)-2-oxopyrrolidin-3-yl]methylamino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclobutanecarboxamide; hydrochloride (270 mg, 0.52 mmol) in THF (90 mL) was added DIPEA (677 mg, 5.24 mmol). After cooling to 5 C., (2R)-2-chloro-2-fluoro-acetyl chloride (292.0 mg, 0.89 mmol, 40% purity, Intermediate 10) in THF (10 mL) was added into the mixture at 5 C. Then the reaction mixture was stirred at 5 C. for 30 min. The reaction was quenched with MeOH (10 mL) and acidified by 4 N HCl/dioxane to pH=5 at 10 C. The resulting mixture was concentrated in vacuum at 30 C. The residue was purified by reversed flash chromatography (condition: 120 g Flash Column Welch Ultimate XB_C18 20-40 m; 120 A, water (0.1% FA)-ACN, 059%, 70 mL/min) to afford N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclobutanecarboxamide (174 mg, Example 105) as a white solid.

[1412] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.13 (s, 1H), 8.26-8.17 (m, 1H), 7.75-7.70 (m, 1H), 6.85 (d, J=50.4 Hz, 1H), 4.22 (t, J=8.0 Hz, 1H), 4.13 (s, 1H), 4.02-3.94 (m, 1H), 3.88-3.84 (m, 1H), 3.79 (dd, J=14.0 Hz, 9.6 Hz, 1H), 3.44 (dd, J=13.6 Hz, 4.0 Hz, 1H), 3.24-3.11 (m, 2H), 2.63-2.54 (m, 1H), 2.53-2.21 (m, 4H), 2.17-2.09 (m, 1H), 1.95-1.81 (m, 2H), 1.79-1.67 (m, 2H), 1.65-1.60 (m, 1H), 1.53-1.49 (d, J=7.6 Hz, 1H), 1.47-1.39 (m, 1H), 1.08-1.01 (m, 4H), 0.90 (s, 3H) 0.81-0.77 (m, 6H).

[1413] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 574.2.

Example 106

N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide

##STR00380##

[1414] The title compound was prepared in analogy to the procedure described for the preparation of Example 105, by using 1-fluorocyclopropanecarboxylic acid instead of 1-fluorocyclobutanecarboxylic acid, and (2S)-2-chloro-2-fluoro-acetyl chloride (Intermediate 28) instead of (2R)-2-chloro-2-fluoro-acetyl chloride (Intermediate 10) to afford N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide (Example 106) as a white solid.

[1415] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 10.07-10.83 (m, 1H), 8.57-8.42 (m, 1H), 7.76-7.72 (m, 1H), 7.16-6.57 (m, 1H), 4.28-4.10 (m, 2H), 3.94 (d, J=10.4 Hz, 1H), 3.87-3.81 (m, 1H), 3.80-3.63 (m, 1H), 3.63-3.50 (m, 1H), 3.19-2.96 (m, 2H), 2.79-2.60 (m, 1H), 2.25-2.09 (m, 1H), 2.05-1.87 (m, 1H), 1.84-1.71 (m, 1H), 1.66-1.52 (m, 2H), 1.51-1.45 (m, 1H), 1.33-1.28 (m, 1H), 1.27-1.23 (m, 1H), 1.22-1.13 (m, 1H), 1.11-1.01 (m, 5H), 0.88 (s, 3H), 0.84 (d, J=6.8 Hz, 3H), 0.80 (t, J=7.2 Hz, 3H).

[1416] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 560.3.

Example 107

N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide

##STR00381##

[1417] The title compound was prepared in analogy to the procedure described for the preparation of Example 105, by using 2,2,2-trifluoroacetic acid instead of 1-fluorocyclobutanecarboxylic acid, and (2S)-2-chloro-2-fluoro-acetyl chloride (Intermediate 28) instead of (2R)-2-chloro-2-fluoro-acetyl chloride (Intermediate 10) to afford N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide (Example 107) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.10-10.87 (m, 1H), 10.00-9.90 (m, 1H), 7.75-7.71 (m, 1H), 7.15-6.58 (m, 1H), 4.23-4.14 (m, 2H), 3.92-3.83 (m, 2H), 3.82-3.64 (m, 1H), 3.55 (dd, J=14.0 Hz, 4.4 Hz, 1H), 3.20-2.98 (m, 2H), 2.75-2.55 (m, 1H), 2.22-2.11 (m, 1H), 2.04-1.86 (m, 1H), 1.84-1.73 (m, 1H), 1.69-1.43 (m, 3H), 1.18-1.09 (m, 1H), 1.06 (d, J=7.2 Hz, 3H), 0.92-0.87 (m, 6H), 0.82 (t, J=7.2 Hz, 3H).

[1418] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 570.1.

Example 108

N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-3,3-difluoro-cyclobutanecarboxamide

##STR00382##

[1419] The title compound was prepared in analogy to the procedure described for the preparation of Example 105, by using 3,3-difluorocyclobutanecarboxylic acid instead of 1-fluorocyclobutanecarboxylic acid, and (2S)-2-chloro-2-fluoro-acetyl chloride (Intermediate 28) instead of (2R)-2-chloro-2-fluoro-acetyl chloride (Intermediate 10) to afford N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-3,3-difluoro-cyclobutanecarboxamide (Example 108) as a white solid.

[1420] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.05-10.81 (m, 1H), 8.44-8.39 (m, 1H), 7.78-7.69 (m, 1H), 7.17-6.57 (m, 1H), 4.25-4.10 (m, 2H), 3.95-3.89 (m, 1H), 3.88-3.82 (m, 1H), 3.81-3.63 (m, 1H), 3.58-3.50 (m, 1H), 3.20-2.85 (m, 3H), 2.75-2.62 (m, 3H), 2.60-2.50 (m, 1H), 2.25-2.10 (m, 1H), 1.85-1.70 (m, 2H), 1.65-1.40 (m, 3H), 1.30-1.19 (m, 1H), 1.14-1.03 (m, 4H), 0.89 (s, 3H), 0.84 (d, J=6.4 Hz, 3H), 0.80 (t, J=7.6 Hz, 3H).

[1421] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 592.4.

Example 109

N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide

##STR00383##

[1422] The title compound was prepared in analogy to the procedure described for the preparation of Example 105, by using 2,2-difluoroacetic acid instead of 1-fluorocyclobutanecarboxylic acid, and (2S)-2-chloro-2-fluoro-acetyl chloride (Intermediate 28) instead of (2R)-2-chloro-2-fluoro-acetyl chloride (Intermediate 10) to afford N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide (Example 109) as a white solid.

[1423] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.09-10.86 (m, 1H), 9.26-9.20 (m, 1H), 7.75-7.71 (m, 1H), 7.15-6.58 (m, 1H), 6.20 (t, J=53.6 Hz, 1H), 4.25-1.42 (m, 2H), 3.93-3.82 (m, 2H), 3.73-3.55 (m, 2H), 3.20-3.04 (m, 2H), 2.24-2.12 (m, 1H), 1.92-1.76 (m, 2H), 1.70-1.57 (m, 2H), 1.55-1.40 (m, 2H), 1.13-1.03 (m, 4H), 0.90 (s, 3H), 0.88 (d, J=6.8 Hz, 3H), 0.81 (t, J=7.2 Hz, 3H).

[1424] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 552.3.

Example 110

N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-methyl-propanamide

##STR00384##

[1425] The title compound was prepared in analogy to the procedure described for the preparation of Example 105, by using isobutyryl chloride without coupling reagent instead of 1-fluorocyclobutanecarboxylic acid, and (2S)-2-chloro-2-fluoro-acetyl chloride (Intermediate 28) instead of (2R)-2-chloro-2-fluoro-acetyl chloride (Intermediate 10) to afford N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-methyl-propanamide (Example 110) as a white solid.

[1426] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.05-10.81 (m, 1H), 8.09 (t, J=8.0 Hz, 1H), 7.73 (d, J=19.2 Hz, 1H), 7.18-6.57 (m, 1H), 4.21-4.11 (m, 2H), 3.96 (d, J=10.0 Hz, 1H), 3.87-3.65 (m, 2H), 3.58-3.50 (m, 1H), 3.20-2.95 (m, 2H), 2.75-2.60 (m, 1H), 2.45-2.37 (m, 1H), 2.23-2.10 (m, 1H), 1.85-1.70 (m, 2H), 1.65-1.42 (m, 3H), 1.15-1.07 (m, 1H), 1.05 (s, 3H), 0.96 (d, J=6.4 Hz, 3H), 0.91 (d, J=6.8 Hz, 3H), 0.88 (s, 3H), 0.83-0.77 (m, 6H).

[1427] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 544.3.

Example 111

Rac-2,2-difluoro-N-[(1S,2S)-2-methyl-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]butyl]cyclopropanecarboxamide

##STR00385##

[1428] The title compound was prepared in analogy to the procedure described for the preparation of Example 105, by using 2,2-difluorocyclopropanecarboxylic acid instead of 1-fluorocyclobutanecarboxylic acid, and (2S)-2-chloro-2-fluoro-acetyl chloride (Intermediate 28) instead of (2R)-2-chloro-2-fluoro-acetyl chloride (Intermediate 10) to afford rac-2,2-difluoro-N-[(1S,2S)-2-methyl-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]butyl]cyclopropanecarboxamide (Example 111) as a white solid.

[1429] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.09-10.83 (m, 1H), 8.75-8.63 (m, 1H), 7.75-7.71 (m, 1H), 7.19-6.57 (m, 1H), 4.30-4.09 (m, 2H), 3.91-3.80 (m, 2H), 3.76-3.49 (m, 2H), 3.22-2.94 (m, 2H), 2.76-2.55 (m, 2H), 2.23-2.09 (m, 1H), 1.94-1.70 (m, 4H), 1.66-1.44 (m, 3H), 1.14-1.00 (m, 4H), 0.90-0.79 (m, 9H).

[1430] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 578.3.

Example 112

N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide

##STR00386##

Step 1: Preparation of methyl (1R,2S,5S)-3-[(2S,3R)-2-amino-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; 2,2,2-trifluoroacetic acid

##STR00387##

[1431] To a solution of methyl (1R,2S,5S)-3-[(2S,3R)-2-(tert-butoxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (3.1 g, 8.1 mmol, from Example 64, step 1) in DCM (20 mL) was added TFA (20.0 mL). The mixture was stirred at 25 C. for 30 min and concentrated in vacuum to afford methyl (1R,2S,5S)-3-[(2S,3R)-2-amino-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; 2,2,2-trifluoroacetic acid (3.2 g) as yellow oil.

[1432] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 283.0

Step 2: Preparation of (1R,2S,5S)-3-[(2S,3R)-2-(benzyloxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate

##STR00388##

[1433] To a solution of methyl (1R,2S,5S)-3-[(2S,3R)-2-amino-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; 2,2,2-trifluoroacetic acid (3.2 g, 8.07 mmol) in THF (20 mL) was added Et.sub.3N (2.46 g, 24.31 mmol) and CbzOSu (3.02 g, 12.13 mmol). The reaction mixture was stirred at 25 C. for 1 h and concentrated in vacuum. The residue was purified by silica gel column eluted with PE/EtOAc=10/1 to 3/1 to afford methyl (1R,2S,5S)-3-[(2S,3R)-2-(benzyloxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (3.3 g) as yellow oil.

[1434] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 417.2.

Step 3: Preparation of (1R,2S,5S)-3-[(2S,3R)-2-(benzyloxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid

##STR00389##

[1435] To a solution of methyl (1R,2S,5S)-3-[(2S,3R)-2-(benzyloxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (3.6 g, 8.64 mmol) in a mixed solvent of THF (15 mL) and water (15 mL) was added LiOH.Math.H.sub.2O (726 mg, 17.3 mmol) at 0 C. The reaction mixture was stirred for 2 h at 25 C. The resulting solution was acidified with 1 N HCl (50 mL) and extracted with EtOAc (50 mL3). The organic phase was washed with brine (50 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuum to afford (1R,2S,5S)-3-[(2S,3R)-2-(benzyloxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (3.3 g) as colorless oil.

[1436] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 403.2.

Step 4: Preparation of tert-butyl N-[[(1R,2S,5S)-3-[(2S,3R)-2-(benzyloxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate

##STR00390##

[1437] To a solution of (1R,2S,5S)-3-[(2S,3R)-2-(benzyloxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (3.3 g, 8.2 mmol) in DMF (30 mL) was added DIPEA (5.3 g, 41.03 mmol). After cooling to 0 C., EDCI (1.89 g, 9.85 mmol), HOPO (1.1 g, 9.84 mmol) and tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (1.89 g, 8.24 mmol) was added into the mixture. Then the reaction mixture was stirred at 30 C. for 12 h. The reaction mixture was poured into EtOAc (150 mL) and washed with 1 N HCl (50 mL), 5% aqueous solution of K.sub.2CO.sub.3 (50 mL) and brine (50 mL). The resulting organic phase was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum to afford tert-butyl N-[[(1R,2S,5S)-3-[(2S,3R)-2-(benzyloxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (4.68 g) as yellow oil.

[1438] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 614.4.

Step 5: Preparation of tert-butyl N-[[(1R,2S,5S)-3-[(2S,3R)-2-amino-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate

##STR00391##

[1439] To a solution of tert-butyl N-[[(1R,2S,5S)-3-[(2S,3R)-2-(benzyloxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (4.68 g, 7.63 mmol) in methanol (50 mL) was added Pd/C (500 mg, 10% purity). The suspension was degassed under vacuum and purged with H.sub.2 for three times. The resulting mixture was stirred at 25 C. for 1 h under a H.sub.2 balloon. The suspension was filtered and the filtrate was concentrated in vacuum to afford tert-butyl N-[[(1R,2S,5S)-3-[(2S,3R)-2-amino-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (3.2 g) as a white solid.

[1440] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 480.3.

Step 6: Preparation of tert-butyl N-[[(1R,2S,5S)-3-[(2S,3R)-2-[(2,2-difluoroacetyl)amino]-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate

##STR00392##

[1441] To a solution of tert-butyl N-[[(1R,2S,5S)-3-[(2S,3R)-2-amino-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (420 mg, 0.88 mmol) in DCM (10 mL) was added DIPEA (339 mg, 2.63 mmol) and (2,2-difluoroacetyl) 2,2-difluoroacetate (228 mg, 1.31 mmol). The mixture was stirred at 25 C. for 1 h. The mixture was diluted with DCM (50 mL), washed with brine (60 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuum to afford tert-butyl N-[[(1R,2S,5S)-3-[(2S,3R)-2-[(2,2-difluoroacetyl)amino]-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (488 mg) as yellow oil.

[1442] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 558.3.

Step 7: Preparation of N-[(1S,2R)-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(3S)-2-oxopyrrolidin-3-yl]methylamino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide; hydrochloride

##STR00393##

[1443] A solution of tert-butyl N-[[(1R,2S,5S)-3-[(2S,3R)-2-[(2,2-difluoroacetyl)amino]-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (400 mg, 0.72 mmol) and TFA (2.0 mL) in DCM (4 mL) was stirred at 25 C. for 1 h. The solution was concentrated in vacuum. The residue was purified by reversed flash chromatography (condition: 120 g Flash Column Welch Ultimate XB_C18 20-40 m; 120 A, water (0.1% HCl)-ACN, 038%, 70 mL/min) to afford N-[(1S,2R)-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(3S)-2-oxopyrrolidin-3-yl]methylamino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide; hydrochloride (290 mg) as a white solid.

[1444] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 458.2.

Step 8: Preparation of N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide

##STR00394##

[1445] To a solution of N-[(1S,2R)-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(3S)-2-oxopyrrolidin-3-yl]methylamino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide; hydrochloride (290 mg, 0.59 mmol) in THF (150 mL) was added DIPEA (1138 mg, 8.81 mmol). After cooling to 0 C., to the mixture was added (2R)-2-chloro-2-fluoro-acetyl chloride (345.89 mg, 1.06 mmol, 40% purity, Intermediate 10) in THF (10 mL). The resulting mixture was stirred at the same temperature for 1 h. The reaction was quenched with MeOH (10 mL) and acidified with 4 N HCl/dioxane until pH=5 at 10 C. The resulting mixture was concentrated in vacuum at 30 C. The residue was purified by reversed flash chromatography (condition: 120 g Flash Column Welch Ultimate XB_C18 20-40 m; 120 A, water (0.1% FA)-ACN, 053%, 70 mL/min) to afford N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide (238 mg, Example 112) as a white solid.

[1446] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.16 (s, 1H), 9.13-9.08 (m, 1H), 7.75-7.70 (m, 1H), 6.80 (d, J=50.4 Hz, 1H), 6.24 (t, J=53.6 Hz, 1H), 4.38-4.29 (m, 1H), 4.17 (s, 1H), 3.91-3.75 (m, 3H), 3.44 (dd, J=13.2 Hz, 4.0 Hz, 1H), 3.22-3.10 (m, 2H), 2.63-2.58 (m, 1H), 2.20-2.09 (m, 1H), 1.95-1.75 (m, 2H), 1.68-1.60 (m, 1H), 1.53 (d, J=7.6 Hz, 1H), 1.45-1.35 (m, 1H), 1.16-1.08 (m, 1H), 1.06 (s, 3H), 0.92 (s, 3H), 0.87-0.80 (m, 6H).

[1447] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 552.3.

Example 113

Rac-2,2-difluoro-N-[(1S,2R)-2-methyl-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]butyl]cyclopropanecarboxamide

##STR00395##

[1448] The title compound was prepared in analogy to the procedure described for the preparation of Example 112, by using 2,2-difluorocyclopropanecarboxylic acid and T.sub.3P instead of (2,2-difluoroacetyl) 2,2-difluoroacetate to afford rac-2,2-difluoro-N-[(1S,2R)-2-methyl-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]butyl]cyclopropanecarboxamide (Example 113) as a white solid.

[1449] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.16-11.13 (m, 1H), 8.67-8.55 (m, 1H), 7.75-7.72 (m, 1H), 6.91-6.77 (m, 1H), 4.36 (t, J=8.4 Hz, 1H), 4.16 (s, 1H), 3.90-3.72 (m, 3H), 3.43 (dd, J=13.6 Hz, 4.0 Hz, 1H), 3.22-3.12 (m, 2H), 2.63-2.58 (m, 1H), 2.20-2.11 (m, 1H), 1.95-1.70 (m, 5H), 1.65-1.52 (m, 2H), 1.44-1.34 (m, 1H), 1.10-1.00 (m, 4H), 0.88 (d, J=10.0 Hz, 3H), 0.86-0.79 (m, 6H).

[1450] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 578.3.

Example 114

N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-3,3-difluoro-cyclobutanecarboxamide

##STR00396##

[1451] The title compound was prepared in analogy to the procedure described for the preparation of Example 112, by using 3,3-difluorocyclobutanecarboxylic acid and T.sub.3P instead of (2,2-difluoroacetyl) 2,2-difluoroacetate to afford N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-3,3-difluoro-cyclobutanecarboxamide (Example 114) as a white solid.

[1452] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.13 (s, 1H), 8.34-8.27 (m, 1H), 7.75 (s, 1H), 6.84 (d, J=50.4 Hz, 1H), 4.32 (t, J=8.4 Hz, 1H), 4.15 (s, 1H), 3.90-3.75 (m, 3H), 3.44 (dd, J=13.6 Hz, 4.4 Hz, 1H), 3.24-3.08 (m, 2H), 3.05-2.94 (m, 1H), 2.74-2.59 (m, 5H), 2.25-2.10 (m, 1H), 1.85-1.70 (m, 2H), 1.67-1.57 (m, 1H), 1.51 (d, J=7.6 Hz, 1H), 1.42-1.30 (m, 1H), 1.05-0.96 (m, 4H), 0.91 (s, 3H), 0.87-0.74 (m, 6H).

[1453] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 592.3.

Example 115

N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide

##STR00397##

[1454] The title compound was prepared in analogy to the procedure described for the preparation of Example 112, by using 1-fluorocyclopropane-1-carboxylic acid and T.sub.3P instead of (2,2-difluoroacetyl) 2,2-difluoroacetate to afford N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide (Example 115) as a white solid.

[1455] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.14 (s, 1H), 8.31-8.18 (m, 1H), 7.75 (s, 1H), 6.84 (d, J=50.4 Hz, 1H), 4.31 (t, J=8.0 Hz, 1H), 4.17 (s, 1H), 3.94-3.77 (m, 3H), 3.43 (dd, J=13.6 Hz, 4.4 Hz, 1H), 3.22-3.10 (m, 2H), 2.64-2.58 (m, 1H), 2.23-2.11 (m, 1H), 2.00-1.88 (m, 1H), 1.84-1.73 (m, 1H), 1.66-1.57 (m, 1H), 1.51 (d, J=7.6 Hz, 1H), 1.47-1.36 (m, 1H), 1.34-1.26 (m, 2H), 1.24-1.10 (m, 2H), 1.10-1.07 (m, 1H), 1.05 (s, 3H), 0.90 (s, 3H), 0.86-0.80 (m, 6H).

[1456] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 560.3.

Example 116

(2R)N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-propanamide

##STR00398##

[1457] The title compound was prepared in analogy to the procedure described for the preparation of Example 112, by using (2R)-2-fluoropropanoic acid and T.sub.3P instead of (2,2-difluoroacetyl) 2,2-difluoroacetate to afford (2R)N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-propanamide (Example 116) as a white solid.

[1458] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.17 (s, 1H), 8.35-8.27 (m, 1H), 7.77-7.70 (m, 1H), 6.83 (d, J=50.8 Hz, 1H), 5.19-4.93 (m, 1H), 4.35-4.25 (m, 1H), 4.16 (s, 1H), 3.91-3.79 (m, 3H), 3.44 (dd, J=14.0 Hz, 4.4 Hz, 1H), 3.21-3.10 (m, 2H), 2.62-2.57 (m, 1H), 2.21-2.15 (m, 1H), 1.88-1.70 (m, 2H), 1.68-1.57 (m, 1H), 1.53 (d, J=7.6 Hz, 1H), 1.45-1.31 (m, 4H), 1.12-0.99 (m, 4H), 0.92 (s, 3H), 0.85-0.79 (m, 6H).

[1459] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 548.4.

Example 117

(2S)N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-propanamide

##STR00399##

[1460] The title compound was prepared in analogy to the procedure described for the preparation of Example 112, by using (2S)-2-fluoropropanoic acid and T.sub.3P instead of (2,2-difluoroacetyl) 2,2-difluoroacetate to afford (2S)N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-propanamide (Example 117) as a white solid.

[1461] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.16 (s, 1H) 8.31-8.15 (m, 1H), 7.70-7.67 (m, 1H), 6.81 (d, J=50.4 Hz, 1H), 5.11-4.92 (m, 1H), 4.31 (t, J=8.0 Hz, 1H), 4.15 (s, 1H), 3.89-3.72 (m, 3H), 3.43 (dd, J=14.0, 4.0 Hz, 1H), 3.21-3.09 (m, 2H), 2.62-2.54 (m, 1H), 2.19-2.08 (m, 1H), 1.87-1.70 (m, 2H), 1.65-1.59 (m, 1H), 1.51 (d, J=7.6 Hz, 1H), 1.37 (dd, J=24.8 Hz, 6.8 Hz, 4H), 1.10-0.97 (m, 4H), 0.92-0.86 (m, 3H), 0.85-0.78 (m, 6H).

[1462] MS obsd. (ESI.sup.+) [(M+H)+]: 548.4.

Example 118

N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]cyclopropanecarboxamide

##STR00400##

Step 1: Preparation of methyl (1R,2S,5S)-3-[(2S,3R)-2-(cyclopropanecarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate

##STR00401##

[1463] To a solution of methyl (1R,2S,5S)-3-[(2S,3R)-2-amino-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; 2,2,2-trifluoroacetic acid (660 mg, 2.07 mmol, Intermediate 29) in DCM (10 mL) was added DIPEA (1337 mg, 10.35 mmol) and cyclopropanecarbonyl chloride (259 mg, 2.48 mmol). The mixture was stirred at 25 C. for 1 h. The reaction mixture was diluted with DCM (200 mL), washed with brine (60 mL3) and dried over Na.sub.2SO.sub.4 and concentrated in vacuum to afford methyl (1R,2S,5S)-3-[(2S,3R)-2-(cyclopropanecarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (725 mg) as yellow foam.

[1464] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 351.1.

Step 2: Preparation of (1R,2S,5S)-3-[(2S,3R)-2-(cyclopropanecarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid

##STR00402##

[1465] To a solution of methyl (1R,2S,5S)-3-[(2S,3R)-2-(cyclopropanecarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (700 mg, 2.0 mmol) in THF (10 mL) and water (5 mL) was added LiOH.Math.H.sub.2O (251 mg, 5.99 mmol). The mixture was stirred at 25 C. for 1 h. The reaction mixture was acidified with 1 N HCl to pH=5. The resulting mixture was extracted with EtOAc (50 mL3). The combined organic phase was washed with brine (60 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuum to afford (1R,2S,5S)-3-[(2S,3R)-2-(cyclopropanecarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (660 mg) as a yellow solid.

Step 3: Preparation of tert-butyl N-[[(1R,2S,5S)-3-[(2S,3R)-2-(cyclopropanecarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate

##STR00403##

[1466] To a solution of (1R,2S,5S)-3-[(2S,3R)-2-(cyclopropanecarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (670 mg, 1.99 mmol) in DMF (10 mL) was added DIPEA (772 mg, 5.97 mmol), HOPO (288 mg, 2.59 mmol), EDCI (496 mg, 2.59 mmol) and tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (547.93 mg, 2.39 mmol, Intermediate 9) at 0 C. The mixture was stirred at 25 C. for 12 h. The reaction mixture was diluted with EtOAc (200 mL), washed with 1 N HCl (30 mL) and brine (60 mL2). The organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum to afford tert-butyl N-[[(1R,2S,5S)-3-[(2S,3R)-2-(cyclopropanecarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (650 mg) as a yellow solid.

[1467] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 548.2.

Step 4: Preparation of N-[(1S,2R)-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(3S)-2-oxopyrrolidin-3-yl]methylamino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]cyclopropanecarboxamide

##STR00404##

[1468] To a solution of tert-butyl N-[[(1R,2S,5S)-3-[(2S,3R)-2-(cyclopropanecarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (690 mg, 1.26 mmol) in DCM (4 mL) was added TFA (2.0 mL). The mixture was stirred at 25 C. for 1 h. The mixture was concentrated under vacuum to give a residue. The residue was purified by reversed flash chromatography (condition: 120 g Flash Column Welch Ultimate XB_C18 20-40 m; 120 A, water (0.1% HCl)-ACN, 040%, 55 mL/min) to afford N-[(1S,2R)-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(3S)-2-oxopyrrolidin-3-yl]methylamino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]cyclopropanecarboxamide; hydrochloride (430 mg) as a white solid.

[1469] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 448.1.

Step 5: Preparation of N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]cyclopropanecarboxamide

##STR00405##

[1470] To a solution of N-[(1S,2R)-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(3S)-2-oxopyrrolidin-3-yl]methylamino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]cyclopropanecarboxamide; hydrochloride (350 mg, 0.72 mmol) in THF (120 mL) was added DIPEA (935 mg, 7.23 mmol). After cooling to 5 C., to the mixture was added (2R)-2-chloro-2-fluoro-acetyl chloride (403 mg, 1.23 mmol, 40% purity) in THF (10 mL). The reaction mixture was stirred at the same temperature for 30 min. The reaction was quenched with MeOH (10 mL) and acidified by 4 N HCl/dioxane to pH=5 at 10 C. Then the mixture was concentrated in vacuum at 30 C. and the residue was purified by reversed flash chromatography (condition: 120 g Flash Column Welch Ultimate XB_C18 20-40 m; 120 A, water (0.1% FA)-ACN, 049%, 55 mL/min) to afford N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]cyclopropanecarboxamide (375.92 mg, Example 118) as a white solid.

[1471] .sup.1H NMR (400 MHz, DMSO-d6) : ppm 11.11 (s, 1H), 8.33-8.20 (m, 1H) 7.75-7.63 (m, 1H), 6.85 (d, J=50.4 Hz, 1H), 4.28 (t, J=8.4 Hz, 1H), 4.13 (s, 1H), 3.85-3.75 (m, 3H), 3.43 (dd, J=12.8, 3.2 Hz, 1H), 3.17-3.09 (m, 2H), 2.62-2.56 (m, 1H), 2.20-2.10 (m, 1H), 1.82-1.65 (m, 3H), 1.62-1.55 (m, 1H), 1.49-1.47 (m, 1H), 1.42-1.32 (m, 1H), 1.09-0.98 (m, 4H), 0.88-0.78 (m, 9H), 0.71-0.52 (m, 4H).

[1472] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 542.3.

Example 119

N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclobutanecarboxamide

##STR00406##

[1473] The title compound was prepared in analogy to the procedure described for the preparation of Example 112, by using 1-fluorocyclobutanecarboxylic acid and T.sub.3P instead of (2,2-difluoroacetyl) 2,2-difluoroacetate to afford N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclobutanecarboxamide (Example 119) as a white solid.

[1474] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.17 (s, 1H), 8.11-7.97 (m, 1H), 7.78 (s, 1H), 6.83 (d, J=50.8 Hz, 1H), 4.30 (t, J=8.4 Hz, 1H), 4.15 (s, 1H), 3.97-3.89 (m, 1H), 3.87-3.84 (m, 1H), 3.84-3.75 (m, 1H), 3.45 (dd, J=14.0 Hz, 4.0 Hz, 1H), 3.20-3.13 (m, 2H), 2.67-2.55 (m, 1H), 2.50-2.48 (m, 1H), 2.47-2.41 (m, 1H), 2.40-2.27 (m, 3H), 2.19-2.11 (m, 1H), 1.95-1.85 (m, 2H), 1.81-1.61 (m, 3H), 1.52 (d, J=7.6 Hz, 1H), 1.44-1.30 (m, 1H), 1.08-0.96 (m, 4H), 0.88 (s, 3H), 0.87-0.75 (m, 5H).

[1475] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 574.4.

Example 120

N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide

##STR00407##

[1476] The title compound was prepared in analogy to the procedure described for the preparation of Example 112, by using (2S)-2-chloro-2-fluoro-acetyl chloride (Intermediate 28) instead of (2R)-2-chloro-2-fluoro-acetyl chloride (Intermediate 10) to afford N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide (Example 120) as a white solid.

[1477] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.05-10.82 (m, 1H), 9.14-9.09 (m, 1H), 7.75-7.71 (m, 1H), 7.11-6.56 (m, 1H), 6.22 (t, J=53.6 Hz, 1H), 4.37-4.26 (m, 1H), 4.21-4.13 (m, 1H), 3.89-3.65 (m, 3H), 3.54-3.50 (m, 1H), 3.20-2.98 (m, 2H), 2.65-2.56 (m, 1H), 2.22-2.09 (m, 1H), 1.87-1.73 (m, 2H), 1.62-1.43 (m, 3H), 1.15-1.10 (m, 4H), 0.90-0.78 (m, 9H).

[1478] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 552.3.

Example 121

N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide

##STR00408##

[1479] The title compound was prepared in analogy to the procedure described for the preparation of Example 112, by using 1-fluorocyclopropane-1-carboxylic acid and T.sub.3P instead of (2,2-difluoroacetyl) 2,2-difluoroacetate, and (2S)-2-chloro-2-fluoro-acetyl chloride (Intermediate 28) instead of (2R)-2-chloro-2-fluoro-acetyl chloride (Intermediate 10) to afford N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide (Example 121) as a white solid.

[1480] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.03-10.82 (m, 1H), 8.27 (dd, J=21.2 Hz, 6.8 Hz, 1H), 7.77-7.70 (m, 1H), 7.13-6.56 (m, 1H), 4.34-4.26 (m, 1H), 4.21-4.13 (m, 1H), 3.91-3.80 (m, 2H), 3.79-3.63 (m, 1H), 3.57-3.48 (m, 1H), 3.20-3.00 (m, 2H), 2.67-2.57 (m, 1H), 2.21-2.13 (m, 1H), 1.97-1.87 (m, 1H), 1.84-1.72 (m, 1H), 1.60-1.43 (m, 3H), 1.33-1.24 (m, 2H), 1.23-1.15 (m, 1H), 1.10-1.01 (m, 5H), 0.95-0.75 (m, 9H).

[1481] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 560.3.

Example 122

(2S)N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-propanamide

##STR00409##

[1482] The title compound was prepared in analogy to the procedure described for the preparation of Example 112, by using (2S)-2-fluoropropanoic acid and T.sub.3P instead of (2,2-difluoroacetyl) 2,2-difluoroacetate, and (2S)-2-chloro-2-fluoro-acetyl chloride (Intermediate 28) instead of (2R)-2-chloro-2-fluoro-acetyl chloride (Intermediate 10) to afford (2S)N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-propanamide (Example 122) as a white solid.

[1483] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.03-10.83 (m, 1H), 8.28-8.10 (m, 1H), 7.82-7.65 (m, 1H), 7.11-6.56 (m, 1H), 5.11-4.92 (m, 1H), 4.35-4.26 (m, 1H), 4.23-4.10 (m, 1H), 3.89-3.79 (m, 2H), 3.75-3.62 (m, 1H), 3.57-3.48 (m, 1H), 3.21-2.98 (m, 2H), 2.65-2.53 (m, 1H), 2.22-2.10 (m, 1H), 1.88-1.74 (m, 2H), 1.61-1.48 (m, 3H), 1.45 (dd, J=29.6 Hz, 6.4 Hz, 3H), 1.10-1.00 (m, 4H), 0.89 (s, 3H), 0.85-0.75 (m, 6H).

[1484] MS obsd. (ESI.sup.+) [(M+H)+]: 548.3.

Example 123

(2R)N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-propanamide

##STR00410##

[1485] The title compound was prepared in analogy to the procedure described for the preparation of Example 112, by using (2R)-2-fluoropropanoic acid and T.sub.3P instead of (2,2-difluoroacetyl) 2,2-difluoroacetate, and (2S)-2-chloro-2-fluoro-acetyl chloride (Intermediate 28) instead of (2R)-2-chloro-2-fluoro-acetyl chloride (Intermediate 10) to afford (2R)N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-propanamide (Example 123) as a white solid.

[1486] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.11-10.76 (m, 1H), 8.38-8.24 (m, 1H), 7.78-7.71 (m, 1H), 7.13-6.56 (m, 1H), 5.14-4.94 (m, 1H), 4.35-4.12 (m, 2H), 3.87-3.64 (m, 3H), 3.57-3.42 (m, 1H), 3.21-2.98 (m, 2H), 2.65-2.55 (m, 1H), 2.20-2.10 (m, 1H), 1.87-1.73 (m, 2H), 1.68-1.42 (m, 3H), 1.36 (dd, J=24.4 Hz, 6.4 Hz, 3H), 1.11-0.98 (m, 4H), 0.91-0.81 (m, 9H).

[1487] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 548.3.

Example 124

Rac-2,2-difluoro-N-[(1S,2R)-2-methyl-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]butyl]cyclopropanecarboxamide

##STR00411##

[1488] The title compound was prepared in analogy to the procedure described for the preparation of Example 112, by using 2,2-difluorocyclopropanecarboxylic acid and T.sub.3P instead of (2,2-difluoroacetyl) 2,2-difluoroacetate, and (2S)-2-chloro-2-fluoro-acetyl chloride (Intermediate 28) instead of (2R)-2-chloro-2-fluoro-acetyl chloride (Intermediate 10) to afford rac-2,2-difluoro-N-[(1S,2R)-2-methyl-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]butyl]cyclopropanecarboxamide (Example 124) as a white solid.

[1489] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.06-10.83 (m, 1H), 8.67-8.49 (m, 1H), 7.77-7.71 (m, 1H), 7.14-6.55 (m, 1H), 4.42-4.30 (m, 1H), 4.21-4.12 (m, 1H), 3.87-3.64 (m, 3H), 3.59-3.46 (m, 1H), 3.21-2.95 (m, 2H), 2.75-2.67 (m, 1H), 2.60-2.52 (m, 1H), 2.23-2.07 (m, 1H), 1.94-1.70 (m, 4H), 1.66-1.49 (m, 2H), 1.45-1.31 (m, 1H), 1.12-0.98 (m, 4H), 0.91-0.89 (m, 1H), 0.88-0.75 (m, 8H).

[1490] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 578.3.

Example 125

N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-1-fluoro-cyclobutanecarboxamide

##STR00412##

[1491] The title compound was prepared in analogy to the procedure described for the preparation of Example 105, by using methyl (3S,3aS,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-3-carboxylate; 2,2,2-trifluoroacetic acid (Intermediate 21) instead of methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; hydrochloride to afford N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-1-fluoro-cyclobutanecarboxamide (Example 125) as a white solid.

[1492] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.05 (s, 1H), 8.14-7.97 (m, 1H), 7.77-7.71 (m, 1H), 6.94 (d, J=50.4 Hz, 1H), 4.30 (t, J=8.8 Hz, 1H), 4.07-3.97 (m, 1H), 3.87-3.80 (m, 2H), 3.78-3.71 (m, 1H), 3.39 (dd, J=14.0 Hz, 4.0 Hz, 1H), 3.22-3.10 (m, 2H), 2.76-2.70 (m, 1H), 2.60-2.55 (m, 1H), 2.45-2.23 (m, 5H), 2.19-2.15 (m, 1H), 1.93-1.78 (m, 4H), 1.77-1.58 (m, 5H), 1.49-1.34 (m, 2H), 1.09-0.99 (m, 1H), 0.84-0.77 (m, 6H).

[1493] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 574.2.

Example 126

N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-3,3-difluoro-cyclobutanecarboxamide

##STR00413##

[1494] The title compound was prepared in analogy to the procedure described for the preparation of Example 105, by using methyl (3S,3aS,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-3-carboxylate; 2,2,2-trifluoroacetic acid (Intermediate 21) instead of methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; hydrochloride, and 3,3-difluorocyclobutanecarboxylic acid instead of 1-fluorocyclobutanecarboxylic acid to afford N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-3,3-difluoro-cyclobutanecarboxamide (Example 126) as a white solid.

[1495] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.04 (s, 1H), 8.44-8.42 (m, 1H), 7.76 (s, 1H), 6.96 (d, J=50.4 Hz, 1H), 4.28 (t, J=8.8 Hz, 1H), 3.94 (d, J=6.4 Hz, 1H), 3.85-3.81 (m, 2H), 3.73 (dd, J=14.0 Hz, 10.0 Hz, 1H), 3.39 (dd, J=13.6 Hz, 4.0 Hz, 1H), 3.21-3.10 (m, 2H), 3.00-2.94 (m, 1H), 2.78-2.68 (m, 2H), 2.67-2.62 (m, 2H), 2.60-2.53 (m, 2H), 2.52-2.51 (m, 1H), 2.19-2.10 (m, 1H), 1.91-1.77 (m, 2H), 1.76-1.66 (m, 4H), 1.65-1.58 (m, 1H), 1.49-1.34 (m, 2H), 1.12-1.03 (m, 1H), 0.85-0.76 (m, 6H).

[1496] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 592.3.

Example 127

N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide

##STR00414##

[1497] The title compound was prepared in analogy to the procedure described for the preparation of Example 105, by using methyl (3S,3aS,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-3-carboxylate; 2,2,2-trifluoroacetic acid (Intermediate 21) instead of methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; hydrochloride and (2S)-2-chloro-2-fluoro-acetyl chloride (Intermediate 28) instead of (2R)-2-chloro-2-fluoro-acetyl chloride (Intermediate 10), and (2,2-difluoroacetyl) 2,2-difluoroacetate without coupling reagent instead of 1-fluorocyclobutanecarboxylic acid to afford N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide (Example 127) as a white solid.

[1498] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.03-10.73 (m, 1H), 9.23-9.17 (m, 1H), 7.76-7.72 (m, 1H), 7.19-6.43 (m, 1H), 6.22 (t, J=53.6 Hz, 1H), 4.39-4.27 (m, 1H), 4.05-4.00 (m, 1H), 3.87-3.68 (m, 3H), 3.56-3.47 (m, 1H), 3.19-2.97 (m, 2H), 2.81-2.68 (m, 2H), 2.64-2.52 (m, 1H), 2.24-2.09 (m, 1H), 1.84-1.61 (m, 7H), 1.53-1.33 (m, 2H), 1.14-1.02 (m, 1H), 0.88 (d, J=6.8 Hz, 3H), 0.81 (t, J=7.2 Hz, 3H).

[1499] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 552.2.

Example 128

N-[(1S,2R)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-3,3-difluoro-cyclobutanecarboxamide

##STR00415##

[1500] The title compound was prepared in analogy to the procedure described for the preparation of Example 1, by using benzyl (3S,3aS,6aR)-2-[(2S,3R)-2-amino-3-methyl-pentanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate; 2,2,2-trifluoroacetic acid (Intermediate 22) instead of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1), 3,3-difluorocyclobutanecarboxylic acid and T.sub.3P instead of TFAA to afford N-[(1S,2R)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-3,3-difluoro-cyclobutanecarboxamide (Example 128) as a white solid.

[1501] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.07 (s, 1H), 8.32-8.20 (m, 1H), 7.77 (s, 1H), 6.91 (d, J=50.4 Hz, 1H), 4.46 (t, J=7.6 Hz, 1H), 4.10-3.93 (m, 1H), 3.86-3.78 (m, 1H), 3.77-3.69 (m, 1H), 3.39 (dd, J=13.6 Hz, 4.4 Hz, 1H), 3.23-3.11 (m, 2H), 3.08-3.01 (m, 1H), 2.80-2.59 (m, 6H), 2.55-2.52 (m, 1H), 2.20-2.10 (m, 1H), 1.92-1.59 (m, 8H), 1.44-1.33 (m, 2H), 1.10-0.98 (m, 1H), 0.88-0.78 (m, 6H).

[1502] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 592.2.

Example 129

N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]cyclopropanecarboxamide

##STR00416##

[1503] The title compound was prepared in analogy to the procedure described for the preparation of Example 118, by using methyl (1R,2S,5S)-3-[(2S)-2-amino-3-ethyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; 2,2,2-trifluoroacetic acid (Intermediate 30) instead of methyl (1R,2S,5S)-3-[(2S,3R)-2-amino-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; 2,2,2-trifluoroacetic acid (Intermediate 29) to afford N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]cyclopropanecarboxamide (Example 129) as a white solid.

[1504] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.12 (s, 1H), 8.36-8.22 (m, 1H), 7.75 (s, 1H), 6.87 (d, J=50.4 Hz, 1H), 4.41 (t, J=8.8 Hz, 1H), 4.14 (s, 1H), 3.91 (d, J=10.4 Hz, 1H), 3.85-3.75 (m, 2H), 3.43 (dd, J=14.0 Hz, 4.4 Hz, 1H), 3.22-3.12 (m, 2H), 2.61-2.56 (m, 1H), 2.20-2.10 (m, 1H), 1.84-1.74 (m, 1H), 1.72-1.58 (m, 3H), 1.52-1.39 (m, 2H), 1.35-1.20 (m, 3H), 1.04 (s, 3H), 0.88 (s, 3H), 0.83-0.73 (m, 6H), 0.70-0.60 (m, 3H), 0.59-0.50 (m, 1H).

[1505] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 556.3.

Example 130

N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]-3,3-difluoro-cyclobutanecarboxamide

##STR00417##

[1506] The title compound was prepared in analogy to the procedure described for the preparation of Example 118, by using methyl (1R,2S,5S)-3-[(2S)-2-amino-3-ethyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; 2,2,2-trifluoroacetic acid (Intermediate 30) instead of methyl (1R,2S,5S)-3-[(2S,3R)-2-amino-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; 2,2,2-trifluoroacetic acid (Intermediate 29), and 3,3-difluorocyclobutanecarboxylic acid and T.sub.3P instead of cyclopropanecarbonyl chloride to afford N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]-3,3-difluoro-cyclobutanecarboxamide (Example 130) as a white solid.

[1507] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.14 (s, 1H), 8.41-8.35 (m, 1H), 7.77-7.72 (m, 1H), 6.80 (d, J=50.4 Hz, 1H), 4.41 (t, J=8.8 Hz, 1H), 4.19-4.13 (m, 1H), 3.91-3.75 (m, 3H), 3.43 (dd, J=14.0 Hz, 4.4 Hz, 1H), 3.21-3.10 (m, 2H), 3.00-2.91 (m, 1H), 2.73-2.53 (m, 5H), 2.18-2.10 (m, 1H), 1.81-1.72 (m, 1H), 1.69-1.60 (m, 2H), 1.50 (d, J=7.6 Hz, 1H), 1.43-1.32 (m, 1H), 1.31-1.14 (m, 3H), 1.04 (s, 3H), 0.89-0.86 (m, 3H), 0.80-0.71 (m, 6H).

[1508] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 606.3.

Example 131

N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]-2,2-difluoro-acetamide

##STR00418##

[1509] The title compound was prepared in analogy to the procedure described for the preparation of Example 15, by using benzyl (1R,2S,5S)-3-[(2S)-2-amino-3-ethyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; hydrochloride (Intermediate 31) instead of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1), and (2,2-difluoroacetyl) 2,2-difluoroacetate without coupling reagent instead of bicyclo[1.1.1]pentane-1-carboxylic acid to afford N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]-2,2-difluoro-acetamide (Example 131) as a white solid.

[1510] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.16 (s, 1H), 9.18-9.07 (m, 1H), 7.75 (s, 1H), 6.92 (d, J=50.8 Hz, 1H), 6.22 (t, J=53.6 Hz, 1H), 4.42 (t, J=8.8 Hz, 1H), 4.15 (s, 1H), 3.88-3.76 (m, 3H), 3.43 (dd, J=14.0 Hz, 4.4 Hz, 1H), 3.19-3.12 (m, 2H), 2.61-2.55 (m, 1H), 2.17-2.10 (m, 1H), 1.80-1.70 (m, 2H), 1.65-1.58 (m, 1H), 1.53-1.51 (m, 1H), 1.44-1.36 (m, 1H), 1.30-1.17 (m, 3H), 1.04 (s, 3H), 0.89 (s, 3H), 0.79 (t, J=7.2 Hz, 3H), 0.74 (t, J=7.2 Hz, 3H).

[1511] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 566.3.

Example 132

N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]-1-fluoro-cyclopropanecarboxamide

##STR00419##

[1512] The title compound was prepared in analogy to the procedure described for the preparation of Example 15, by using benzyl (1R,2S,5S)-3-[(2S)-2-amino-3-ethyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; hydrochloride (Intermediate 31) instead of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1), and 1-fluorocyclopropane-1-carboxylic acid instead of bicyclo[1.1.1]pentane-1-carboxylic acid to afford N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]-1-fluoro-cyclopropanecarboxamide (Example 132) as a white solid.

[1513] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.15 (s, 1H), 8.38 (d, J=8.4 Hz, 1H), 7.76 (s, 1H), 6.82 (d, J=50.8 Hz, 1H), 4.44 (t, J=8.8 Hz, 1H), 4.15 (s, 1H), 3.98-3.93 (m, 1H), 3.85-3.77 (m, 2H), 3.42 (dd, J=13.6 Hz, 2.8 Hz, 1H), 3.21-3.07 (m, 2H), 2.61-2.55 (m, 1H), 2.19-2.11 (m, 1H), 1.93-1.83 (m, 1H), 1.82-1.70 (m, 1H), 1.65-1.55 (m, 1H), 1.52-1.48 (m, 1H), 1.46-1.34 (m, 1H), 1.33-1.15 (m, 6H), 1.12-1.01 (m, 4H), 0.89-0.85 (m, 3H), 0.83-0.71 (m, 6H).

[1514] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 574.2.

Example 133

N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]-1-fluoro-cyclopropanecarboxamide

##STR00420##

[1515] The title compound was prepared in analogy to the procedure described for the preparation of Example 15, by using benzyl (1R,2S,5S)-3-[(2S)-2-amino-3-ethyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; hydrochloride (Intermediate 31) instead of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1), (2S)-2-chloro-2-fluoro-acetyl chloride (Intermediate 28) instead of (2R)-2-chloro-2-fluoro-acetyl chloride (Intermediate 10), and 1-fluorocyclopropane-1-carboxylic acid instead of bicyclo[1.1.1]pentane-1-carboxylic acid to afford N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]-1-fluoro-cyclopropanecarboxamide (Example 133) as a white solid.

[1516] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.05-10.83 (m, 1H), 8.36-8.25 (m, 1H), 7.82-7.61 (m, 1H), 7.12-6.56 (m, 1H), 4.49-4.40 (m, 1H), 4.24-4.11 (m, 1H), 3.98-3.88 (m, 1H), 3.87-3.62 (m, 2H), 3.58-3.39 (m, 1H), 3.21-2.96 (m, 2H), 2.64-2.51 (m, 1H), 2.23-2.11 (m, 1H), 1.97-1.72 (m, 2H), 1.64-1.38 (m, 3H), 1.35-1.14 (m, 6H), 1.11-1.01 (m, 4H), 0.81 (s, 3H), 0.84-0.71 (m, 6H).

[1517] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 574.3.

Example 134

N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]-3,3-difluoro-cyclobutanecarboxamide

##STR00421##

[1518] The title compound was prepared in analogy to the procedure described for the preparation of Example 15, by using benzyl (3S,3aS,6aR)-2-[(2S)-2-amino-3-ethyl-pentanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate; 2,2,2-trifluoroacetic acid (Intermediate 24) instead of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1), and 3,3-difluorocyclobutanecarboxylic acid instead of bicyclo[1.1.1]pentane-1-carboxylic acid to afford N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]-3,3-difluoro-cyclobutanecarboxamide (Example 134) as a white solid.

[1519] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.06 (s, 1H), 8.35-8.24 (m, 1H), 7.71-7.69 (m, 1H), 6.86 (d, J=50.4 Hz, 1H), 4.51 (t, J=8.4 Hz, 1H), 3.96 (d, J=5.6 Hz, 1H), 3.85-3.71 (m, 3H), 3.38 (dd, J=14.0 Hz, 4.0 Hz, 1H), 3.22-3.11 (m, 2H), 3.05-2.96 (m, 1H), 2.75-2.54 (m, 7H), 2.18-2.11 (m, 1H), 1.91-1.78 (m, 2H), 1.76-1.68 (m, 3H), 1.66-1.61 (m, 2H), 1.43-1.30 (m, 2H), 1.29-1.14 (m, 3H), 0.85-0.71 (m, 6H).

[1520] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 606.4.

Example 135

N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]cyclopropanecarboxamide

##STR00422##

[1521] The title compound was prepared in analogy to the procedure described for the preparation of Example 15, by using benzyl (3S,3aS,6aR)-2-[(2S)-2-amino-3-ethyl-pentanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate; 2,2,2-trifluoroacetic acid (Intermediate 24) instead of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1), and cyclopropanecarbonyl chloride without coupling reagent instead of bicyclo[1.1.1]pentane-1-carboxylic acid to afford N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]cyclopropanecarboxamide (Example 135) as a white solid.

[1522] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.07 (s, 1H), 8.36-8.29 (m, 1H), 7.77 (s, 1H), 6.94 (d, J=50.4 Hz, 1H), 4.50 (t, J=8.8 Hz, 1H), 3.96 (d, J=6.0 Hz, 1H), 3.84-3.69 (m, 3H), 3.41-3.36 (m, 1H), 3.23-3.10 (m, 2H), 2.78-2.69 (m, 1H), 2.56-2.53 (m, 1H), 2.22-2.07 (m, 1H), 1.89-1.77 (m, 2H), 1.77-1.68 (m, 4H), 1.67-1.58 (m, 2H), 1.49-1.38 (m, 1H), 1.37-1.30 (m, 1H), 1.28-1.18 (m, 3H), 0.90-0.69 (m, 7H), 0.67-0.55 (m, 4H).

[1523] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 556.3.

Example 136

N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]-2,2-difluoro-acetamide

##STR00423##

[1524] The title compound was prepared in analogy to the procedure described for the preparation of Example 15, by using benzyl (3S,3aS,6aR)-2-[(2S)-2-amino-3-ethyl-pentanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate; 2,2,2-trifluoroacetic acid (Intermediate 24) instead of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1), and (2,2-difluoroacetyl) 2,2-difluoroacetate without coupling reagent instead of bicyclo[1.1.1]pentane-1-carboxylic acid to afford N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]-2,2-difluoro-acetamide (Example 136) as a white solid.

[1525] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.10 (s, 1H), 9.13-9.03 (m, 1H), 7.77-7.74 (m, 1H), 6.90 (d, J=50.4 Hz, 1H), 6.25 (t, J=53.6 Hz, 1H), 4.54 (t, J=8.0 Hz, 1H), 3.99 (d, J=5.6 Hz, 1H), 3.87-3.67 (m, 3H), 3.39 (dd, J=14.0 Hz, 4.0 Hz, 1H), 3.19-3.10 (m, 2H), 2.82-2.70 (m, 1H), 2.60-2.54 (m, 1H), 2.19-2.10 (m, 1H), 1.90-1.78 (m, 2H), 1.77-1.67 (m, 4H), 1.66-1.57 (m, 1H), 1.46-1.35 (m, 2H), 1.31-1.14 (m, 4H), 0.82 (t, J=7.2 Hz, 3H), 0.75 (t, J=7.6 Hz, 3H).

[1526] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 566.3.

Example 137

Rac-2-fluoro-N-[(1S)-2-ethyl-1-[(2S)-4,4-dimethyl-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]pyrrolidine-1-carbonyl]butyl]propanamide

##STR00424##

[1527] The title compound was prepared in analogy to the procedure described for the preparation of Example 15, by using benzyl (2S)-1-[(2S)-2-amino-3-ethyl-pentanoyl]-4,4-dimethyl-pyrrolidine-2-carboxylate; hydrochloride (Intermediate 32) instead of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1), and 2-fluoropropionic acid instead of bicyclo[1.1.1]pentane-1-carboxylic acid to afford rac-2-fluoro-N-[(1S)-2-ethyl-1-[(2S)-4,4-dimethyl-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]pyrrolidine-1-carbonyl]butyl]propanamide (Example 137) as a white solid.

[1528] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.00 (s, 1H), 8.29 (dd, J=33.6 Hz, 8.4 Hz, 1H), 7.75-7.71 (m, 1H), 6.95 (d, J=50.8 Hz, 1H), 5.15-5.07 (m, 1H), 4.49 (q, J=8.0 Hz, 1H), 4.33-4.27 (m, 1H), 3.82-3.68 (m, 2H), 3.40 (dd, J=13.6 Hz, 4.0 Hz, 1H), 3.29-3.27 (m, 2H), 3.19-3.10 (m, 2H), 2.16-2.07 (m, 1H), 1.97-1.92 (m, 1H), 1.78-1.61 (m, 3H), 1.41 (dd, J=6.4 Hz, 2.0 Hz, 2H), 1.35 (dd, J=6.8 Hz, 2.0 Hz, 2H), 1.31-1.18 (m, 3H), 1.14 (s, 3H), 0.99 (d, J=4.4 Hz, 3H), 0.83-0.72 (m, 6H).

[1529] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 550.3.

Example 138

N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2-ethyl-butyl]-1-fluoro-cyclopropanecarboxamide

##STR00425##

[1530] The title compound was prepared in analogy to the procedure described for the preparation of Example 15, by using benzyl (2S)-1-[(2S)-2-amino-3-ethyl-pentanoyl]-4,4-dimethyl-pyrrolidine-2-carboxylate; hydrochloride (Intermediate 32) instead of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1), and 1-fluorocyclopropane-1-carboxylic acid instead of bicyclo[1.1.1]pentane-1-carboxylic acid to afford N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2-ethyl-butyl]-1-fluoro-cyclopropanecarboxamide (Example 138) as a white solid.

[1531] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 10.99 (s, 1H), 8.28 (d, J=8.0 Hz, 1H), 7.75 (s, 1H), 7.00 (d, J=50.4 Hz, 1H), 4.50 (t, J=8.4 Hz, 1H), 4.31 (d, J=10.0 Hz, 7.2 Hz, 1H), 3.84 (d, J=9.6 Hz, 1H), 3.72 (dd, J=14.0 Hz, 10.0 Hz, 1H), 3.41 (dd, J=13.6 Hz, 4.0 Hz, 1H), 3.26 (d, J=9.6 Hz, 1H), 3.20-3.10 (m, 2H), 2.17-2.08 (m, 1H), 1.98-1.92 (m, 1H), 1.90-1.81 (m, 1H), 1.79-1.61 (m, 2H), 1.45-1.17 (m, 9H), 1.13 (s, 3H), 0.97 (s, 3H), 0.81 (t, J=7.6 Hz, 3H), 0.75 (t, J=7.6 Hz, 3H).

[1532] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 562.2.

Example 139

N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2-ethyl-butyl]-2,2-difluoro-acetamide

##STR00426##

[1533] The title compound was prepared in analogy to the procedure described for the preparation of Example 15, by using benzyl (2S)-1-[(2S)-2-amino-3-ethyl-pentanoyl]-4,4-dimethyl-pyrrolidine-2-carboxylate; hydrochloride (Intermediate 32) instead of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1), and (2,2-difluoroacetyl) 2,2-difluoroacetate without coupling reagent instead of bicyclo[1.1.1]pentane-1-carboxylic acid to afford N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2-ethyl-butyl]-2,2-difluoro-acetamide (Example 139) as a white solid.

[1534] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.17-10.45 (m, 1H), 9.25-9.00 (m, 1H), 7.75 (s, 1H), 7.13-6.90 (m, 1H), 6.25 (t, J=24 Hz, 1H), 4.57-4.46 (m, 1H), 4.37-4.27 (m, 1H), 3.80-3.64 (m, 2H), 3.40 (dd, J.sub.1=4 Hz, J.sub.2=16 Hz 1H), 3.31-3.20 (m, 1H), 3.21-3.07 (m, 2H), 2.54-2.51 (br s, 1H), 2.31-2.05 (m, 1H), 2.03-1.92 (m, 1H), 1.80-1.59 (m, 3H), 1.47-1.38 (m, 1H), 1.34-1.20 (m, 3H), 1.15 (s, 3H), 1.00 (s, 3H), 0.86-0.73 (m, 6H).

[1535] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 554.2.

Example 140

(2S)N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-2-fluoro-propanamide

##STR00427##

[1536] The title compound was prepared in analogy to the procedure described for the preparation of Example 90, by using (2S)-2-(benzyloxycarbonylamino)-3,3-dimethyl-pentanoic acid (Intermediate 33) instead of (S)-2-(((benzyloxy)carbonyl)amino)-3,3-dimethylbutanoic acid, and (2S)-2-fluoropropanoic acid instead of 3,3-difluorocyclobutanecarboxylic acid to afford (2S)N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-2-fluoro-propanamide (Example 140) as a white solid.

[1537] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.17 (s, 1H), 7.96-7.87 (m, 1H), 7.76-7.68 (m, 1H), 6.86 (d, J=50.4 Hz, 1H), 5.19-5.03 (m, 1H), 4.46 (d, J=8.8 Hz, 1H), 4.14 (s, 1H), 3.95-3.90 (m, 1H), 3.83-3.76 (m, 2H), 3.46 (dd, J=14.0, 4.0 Hz, 1H), 3.22-3.10 (m, 2H), 2.62-2.56 (m, 1H), 2.20-2.11 (m, 1H), 1.81-1.72 (m, 1H), 1.66-1.60 (m, 1H), 1.53-1.51 (m, 1H), 1.39-1.23 (m, 5H), 1.05 (s, 3H), 0.92-0.88 (m, 9H) 0.78 (t, J=7.2 Hz, 3H).

[1538] MS obsd. (ESI.sup.+) [(M+Na).sup.+]: 584.2.

Example 141

(2R)N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-2-fluoro-propanamide

##STR00428##

[1539] The title compound was prepared in analogy to the procedure described for the preparation of Example 90, by using (2S)-2-(benzyloxycarbonylamino)-3,3-dimethyl-pentanoic acid (Intermediate 33) (S)-2-(((benzyloxy)carbonyl)amino)-3,3-dimethylbutanoic acid, and (2R)-2-fluoropropanoic acid instead of 3,3-difluorocyclobutanecarboxylic acid to afford (2R)N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-2-fluoro-propanamide (Example 141) as a white solid.

[1540] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.19 (s, 1H), 8.11-7.98 (m, 1H), 7.79 (s, 1H), 6.89 (dd, J=50.8 Hz, 1H), 5.21-5.07 (m, 1H), 4.41 (d, J=8.8 Hz, 1H), 4.14 (s, 1H), 3.95-3.89 (m, 1H), 3.83-3.75 (m, 2H), 3.45 (dd, J=13.6 Hz, 4.0 Hz, 1H), 3.23-3.10 (m, 2H), 2.63-2.57 (m, 1H), 2.25-2.09 (m, 1H), 1.85-1.70 (m, 1H), 1.67-1.58 (m, 1H), 1.53 (d, J=7.6 Hz, 1H), 1.37 (dd, J=24.4 Hz, 6.4 Hz, 3H), 1.31-1.18 (m, 2H), 1.05 (s, 3H), 0.93-0.84 (m, 9H), 0.76 (t, J=6.8 Hz, 3H).

[1541] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 562.3.

Example 142

N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]cyclopropanecarboxamide

##STR00429##

[1542] The title compound was prepared in analogy to the procedure described for the preparation of Example 90, by using (2S)-2-(benzyloxycarbonylamino)-3,3-dimethyl-pentanoic acid (Intermediate 33) instead of (S)-2-(((benzyloxy)carbonyl)amino)-3,3-dimethylbutanoic acid, and cyclopropanecarbonyl chloride without coupling reagent instead of 3,3-difluorocyclobutanecarboxylic acid to afford N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]cyclopropanecarboxamide (Example 142) as a white solid.

[1543] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.13 (s, 1H), 8.17-8.09 (m, 1H), 7.75-7.70 (m, 1H), 6.92 (d, J=50.4 Hz, 1H), 4.43 (d, J=9.2 Hz, 1H), 4.11 (s, 1H), 3.85-3.76 (m, 3H), 3.44 (dd, J=14.0 Hz, 4.4 Hz, 1H), 3.18-3.13 (m, 2H), 2.62-2.56 (m, 1H), 2.18-2.10 (m, 1H), 1.87-1.71 (m, 2H), 1.62-1.57 (m, 1H), 1.48 (d, J=7.6 Hz, 1H), 1.35-1.20 (m, 2H), 1.03 (s, 3H), 0.90-0.83 (m, 9H), 0.75 (t, J=7.6 Hz, 3H), 0.68-0.59 (m, 3H) 0.57-0.51 (m, 1H).

[1544] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 556.3.

Example 143

N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-1-fluoro-cyclopropanecarboxamide

##STR00430##

[1545] The title compound was prepared in analogy to the procedure described for the preparation of Example 90, by using (2S)-2-(benzyloxycarbonylamino)-3,3-dimethyl-pentanoic acid (Intermediate 33) instead of (S)-2-(((benzyloxy)carbonyl)amino)-3,3-dimethylbutanoic acid, and 1-fluorocyclopropane-1-carboxylic acid instead of 3,3-difluorocyclobutanecarboxylic acid to afford N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-1-fluoro-cyclopropanecarboxamide (Example 143) as a white solid.

[1546] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.17 (s, 1H), 7.75-7.71 (m, 1H), 7.47-7.35 (m, 1H), 6.84 (d, J=50.4 Hz, 1H), 4.48 (d, J=8.8 Hz, 1H), 4.24-4.16 (m, 1H), 3.94-3.89 (m, 1H), 3.83-3.76 (m, 2H), 3.45 (dd, J=14.0 Hz, 4.4 Hz, 1H), 3.22-3.09 (m, 2H), 2.62-2.57 (m, 1H), 2.20-2.11 (m, 1H), 1.82-1.72 (m, 1H), 1.64-1.57 (m, 1H), 1.52 (d, J=7.6 Hz, 1H), 1.39-1.19 (m, 5H), 1.11-1.03 (m, 4H), 0.97-0.90 (m, 6H), 0.89-0.83 (m, 3H), 0.78 (t, J=7.6 Hz, 3H).

[1547] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 574.3.

Example 144

N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-acetamide

##STR00431##

[1548] The title compound was prepared in analogy to the procedure described for the preparation of Example 90, by using (2S)-2-(benzyloxycarbonylamino)-3,3-dimethyl-pentanoic acid (Intermediate 33) instead of (S)-2-(((benzyloxy)carbonyl)amino)-3,3-dimethylbutanoic acid, and (2,2-difluoroacetyl) 2,2-difluoroacetate without coupling reagent instead of 3,3-difluorocyclobutanecarboxylic acid to afford N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-acetamide (Example 144) as a white solid.

[1549] .sup.1H NMR (400 MHz, CDCl.sub.3) : ppm 10.02 (br. s, 1H), 7.10-7.03 (m, 1H), 6.66 (d, J=50.8 Hz, 1H), 6.22 (br. s, 1H), 5.94 (t, J=54.0 Hz, 1H), 4.67 (d, J=10.0 Hz, 1H), 4.50-4.41 (m, 2H), 4.07-4.03 (m, 1H), 3.94-3.91 (m, 1H), 3.44-3.40 (m, 2H), 2.94-2.80 (m, 1H), 2.43-2.35 (m, 1H), 1.86-1.66 (m, 2H), 1.38-1.25 (m, 4H), 1.07 (s, 3H), 0.99 (s, 3H), 0.96 (s, 3H), 0.91 (s, 3H), 0.87 (t, J=7.6 Hz, 3H).

[1550] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 566.2.

Example 145

N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-1-fluoro-cyclopropanecarboxamide

##STR00432##

[1551] The title compound was prepared in analogy to the procedure described for the preparation of Example 90, by using (2S)-2-(benzyloxycarbonylamino)-3,3-dimethyl-pentanoic acid (Intermediate 33) instead of (S)-2-(((benzyloxy)carbonyl)amino)-3,3-dimethylbutanoic acid, and (2S)-2-chloro-2-fluoro-acetyl chloride (Intermediate 28) instead of (2R)-2-chloro-2-fluoro-acetyl chloride (Intermediate 10), and 1-fluorocyclopropane-1-carboxylic acid instead of 3,3-difluorocyclobutanecarboxylic acid to afford N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-1-fluoro-cyclopropanecarboxamide (Example 145) as a white solid.

[1552] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.03-10.82 (m, 1H), 8.27 (dd, J=21.2 Hz, 6.8 Hz, 1H), 7.77-7.70 (m, 1H), 7.13-6.56 (m, 1H), 4.34-4.26 (m, 1H), 4.21-4.13 (m, 1H), 3.91-3.80 (m, 2H), 3.79-3.63 (m, 1H), 3.57-3.48 (m, 1H), 3.20-3.00 (m, 2H), 2.67-2.57 (m, 1H), 2.21-2.13 (m, 1H), 1.97-1.87 (m, 1H), 1.84-1.72 (m, 1H), 1.60-1.43 (m, 3H), 1.33-1.24 (m, 2H), 1.23-1.15 (m, 1H), 1.10-1.01 (m, 5H), 0.95-0.75 (m, 9H).

[1553] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 560.3.

Example 146

Rac-2-fluoro-N-[(1S)-2,2-dimethyl-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]butyl]propanamide

##STR00433##

[1554] The title compound was prepared in analogy to the procedure described for the preparation of Example 90, by using (2S)-2-(benzyloxycarbonylamino)-3,3-dimethyl-pentanoic acid (Intermediate 33) instead of methyl (S)-2-(((benzyloxy)carbonyl)amino)-3,3-dimethylbutanoic acid, (2S)-2-chloro-2-fluoro-acetyl chloride (Intermediate 28) instead of (2R)-2-chloro-2-fluoro-acetyl chloride (Intermediate 10), and 2-fluoropropanoic acid instead of 3,3-difluorocyclobutanecarboxylic acid to afford rac-2-fluoro-N-[(1S)-2,2-dimethyl-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]butyl]propanamide (Example 146) as a white solid.

[1555] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.15-10.84 (m, 1H), 7.98-7.88 (m, 1H), 7.75-7.69 (m, 1H), 7.15-6.55 (m, 1H), 5.21-5.01 (m, 1H), 4.50-4.39 (m, 1H), 4.24-4.09 (m, 1H), 3.92-3.86 (m, 1H), 3.81-3.68 (m, 2H), 3.56-3.46 (m, 1H), 3.21-2.98 (m, 2H), 2.60-2.55 (m, 1H), 2.21-2.09 (m, 1H), 1.84-1.72 (m, 1H), 1.65-1.46 (m, 2H), 1.40-1.19 (m, 5H), 1.04 (s, 3H), 0.94-0.83 (m, 9H), 0.80-0.72 (m, 3H).

[1556] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 562.3.

Example 147

N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]cyclopropanecarboxamide

##STR00434##

[1557] The title compound was prepared in analogy to the procedure described for the preparation of Example 90, by using (2S)-2-(benzyloxycarbonylamino)-3,3-dimethyl-pentanoic acid (Intermediate 33) instead of (S)-2-(((benzyloxy)carbonyl)amino)-3,3-dimethylbutanoic acid, (2S)-2-chloro-2-fluoro-acetyl chloride (Intermediate 28) instead of (2R)-2-chloro-2-fluoro-acetyl chloride (Intermediate 10), and cyclopropanecarbonyl chloride without coupling reagent instead of 3,3-difluorocyclobutanecarboxylic acid to afford N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]cyclopropanecarboxamide (Example 147) as a white solid.

[1558] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.06-10.82 (m, 1H), 8.13 (d, J=9.2 Hz, 1H), 7.77-7.69 (m, 1H), 7.15-6.55 (m, 1H), 4.48-4.42 (m, 1H), 4.20-4.09 (m, 1H), 3.85-3.67 (m, 3H), 3.57-3.49 (m, 1H), 3.21-2.96 (m, 2H), 2.77-2.55 (m, 1H), 2.22-2.08 (m, 1H), 1.89-1.72 (m, 2H), 1.63-1.50 (m, 2H), 1.48-1.20 (m, 2H), 1.07-1.01 (m, 3H), 0.95-0.87 (m, 6H), 0.84 (s, 3H), 0.80-0.71 (m, 3H), 0.70-0.48 (m, 4H).

[1559] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 556.3.

Example 148

N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-acetamide

##STR00435##

[1560] The title compound was prepared in analogy to the procedure described for the preparation of Example 90, by using (2S)-2-(benzyloxycarbonylamino)-3,3-dimethyl-pentanoic acid (Intermediate 33) instead of (S)-2-(((benzyloxy)carbonyl)amino)-3,3-dimethylbutanoic acid, (2S)-2-chloro-2-fluoro-acetyl chloride (Intermediate 28) instead of (2R)-2-chloro-2-fluoro-acetyl chloride (Intermediate 10), and (2,2-difluoroacetyl) 2,2-difluoroacetate without coupling reagent instead of 3,3-difluorocyclobutanecarboxylic acid to afford N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-acetamide (Example 148) as a white solid.

[1561] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.11-10.88 (m, 1H), 8.91 (d, J=8.8 Hz, 1H), 7.78-7.71 (m, 1H), 7.11-6.57 (m, 1H), 6.42-6.13 (m, 1H), 4.45-4.41 (m, 1H), 4.21-4.13 (m, 1H), 3.95-3.89 (m, 1H), 3.80-3.69 (m, 2H), 3.56-3.52 (m, 1H), 3.21-2.98 (m, 2H), 2.23-2.08 (m, 1H), 2.63-2.61 (m, 1H), 1.84-1.72 (m, 1H), 1.66-1.48 (m, 2H), 1.36-1.22 (m, 2H), 1.07-1.02 (m, 3H), 0.94-0.85 (m, 9H), 0.77 (t, J=7.2 Hz, 3H).

[1562] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 566.3.

Example 149

N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]-1-fluoro-cyclopropanecarboxamide

##STR00436##

[1563] The title compound was prepared in analogy to the procedure described for the preparation of Example 1, by using (2S)-2-(benzyloxycarbonylamino)-3,3-dimethyl-pentanoic acid (Intermediate 33) instead of (S)-2-(((benzyloxy)carbonyl)amino)-3,3-dimethylbutanoic acid, benzyl (3S,3aS,6aR)-2-[(2S)-2-amino-3,3-dimethyl-pentanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate (Intermediate 34) instead of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1), and 1-fluorocyclopropane-1-carboxylic acid and T.sub.3P instead of TFAA to afford N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]-1-fluoro-cyclopropanecarboxamide (Example 149) as a white solid.

[1564] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.12 (s, 1H), 7.77-7.70 (s, 1H), 7.42-7.34 (m, 1H), 6.96 (d, J=50.4 Hz, 1H), 4.56 (d, J=8.8 Hz, 1H), 4.07-3.97 (m, 1H), 3.87 (dd, J=10.4 Hz, 7.2 Hz, 1H), 3.77-3.68 (m, 2H), 3.41 (dd, J=14.0 Hz, 4.0 Hz, 1H), 3.20-3.11 (m, 2H), 2.76-2.69 (m, 1H), 2.59-2.54 (m, 1H), 2.20-2.11 (m, 1H), 1.88-1.53 (m, 6H), 1.40-1.17 (m, 8H), 0.94 (s, 3H), 0.90 (s, 3H), 0.79 (t, J=7.6 Hz, 3H).

[1565] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 574.4.

Example 150

(1S)N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-cyclopropanecarboxamide

##STR00437##

[1566] The title compound was prepared in analogy to the procedure described for the preparation of Example 1, by using (2S)-2-(benzyloxycarbonylamino)-3,3-dimethyl-pentanoic acid (Intermediate 33) instead of (S)-2-(((benzyloxy)carbonyl)amino)-3,3-dimethylbutanoic acid, benzyl (3S,3aS,6aR)-2-[(2S)-2-amino-3,3-dimethyl-pentanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate (Intermediate 34) instead of benzyl (JR, 2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1), and 2,2-difluorocyclopropanecarboxylic acid and T.sub.3P instead of TFAA to afford (1S)N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-cyclopropanecarboxamide (Example 150) as a white solid.

[1567] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.10 (s, 1H), 8.50-8.44 (m, 1H), 7.78-7.72 (m, 1H), 7.03 (d, J=50.8 Hz, 1H), 4.53 (d, J=8.4 Hz, 1H), 3.95 (d, J=6.8 Hz, 1H), 3.90-3.81 (m, 1H), 3.78-3.67 (m, 2H), 3.42-3.37 (m, 1H), 3.21-3.12 (m, 2H), 2.95-2.84 (m, 1H), 2.78-2.71 (m, 1H), 2.58-2.53 (m, 1H), 2.20-2.12 (m, 1H), 1.92-1.81 (m, 3H), 1.80-1.69 (m, 4H), 1.67-1.60 (m, 1H), 1.40-1.30 (m, 2H), 1.29-1.14 (m, 2H), 0.93 (s, 3H), 0.90 (s, 3H), 0.77 (t, J=7.6 Hz, 3H).

[1568] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 592.1.

Example 151

N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-acetamide

##STR00438##

[1569] The title compound was prepared in analogy to the procedure described for the preparation of Example 1, by using (2S)-2-(benzyloxycarbonylamino)-3,3-dimethyl-pentanoic acid (Intermediate 33) instead of (S)-2-(((benzyloxy)carbonyl)amino)-3,3-dimethylbutanoic acid, benzyl (3S,3aS,6aR)-2-[(2S)-2-amino-3,3-dimethyl-pentanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate (Intermediate 34) instead of benzyl (JR, 2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1), and (2,2-difluoroacetyl) 2,2-difluoroacetate instead of TFAA to afford N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-acetamide (Example 151) as a white solid.

[1570] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.25 (s, 1H), 8.95-8.86 (m, 1H), 7.78-7.69 (m, 1H), 6.98 (d, J=50.8 Hz, 1H), 6.31 (t, J=53.6 Hz, 1H), 4.53 (d, J=8.4 Hz, 1H), 3.95 (d, J=6.4 Hz, 1H), 3.90-3.86 (m, 1H), 3.78-3.60 (m, 3H), 3.20-3.11 (m, 2H), 2.77-2.70 (m, 1H), 2.60-2.53 (m, 1H), 2.19-2.12 (m, 1H), 1.91-1.64 (m, 6H), 1.40-1.30 (m, 2H), 1.28-1.19 (m, 2H), 0.93 (s, 3H), 0.89 (s, 3H), 0.76 (t, J=7.2 Hz, 3H).

[1571] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 566.3.

Example 152

(1S)N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-cyclopropanecarboxamide

##STR00439##

[1572] The title compound was prepared in analogy to the procedure described for the preparation of Example 1, by using benzyl (3S,3aS,6aR)-2-[(2S)-2-amino-3,3-dimethyl-pentanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate (Intermediate 34) instead of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1), (2S)-2-chloro-2-fluoro-acetyl chloride (Intermediate 28) instead of (2R)-2-chloro-2-fluoro-acetyl chloride (Intermediate 10), and 2,2-difluorocyclopropanecarboxylic acid and T.sub.3P instead of TFAA to afford (1S)N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-cyclopropanecarboxamide (Example 152) as a white solid.

[1573] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.06-10.73 (m, 1H), 8.45 (t, J=8.8 Hz, 1H), 7.77-7.70 (m, 1H), 7.22-6.40 (m, 1H), 4.53 (d, J=8.8 Hz, 1H), 3.99-3.94 (m 1H), 3.88-3.69 (m, 3H), 3.53-3.44 (m, 1H), 3.26-3.01 (m, 2H), 2.97-2.81 (m, 1H), 2.73-2.72 (m, 1H), 2.69-2.68 (m, 1H), 2.67-2.52 (m, 1H), 2.24-2.15 (m, 1H), 1.86-1.76 (m, 4H), 1.75-1.73 (m, 2H), 1.70-1.66 (m, 1H), 1.65-1.60 (m, 1H), 1.40-1.31 (m, 2H), 1.29-1.21 (m, 1H), 0.93-0.90 (m, 6H), 0.77 (t, J=7.6 Hz, 3H).

[1574] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 592.4.

Example 153

N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-acetamide

##STR00440##

[1575] The title compound was prepared in analogy to the procedure described for the preparation of Example 1, by using benzyl (3S,3aS,6aR)-2-[(2S)-2-amino-3,3-dimethyl-pentanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate (Intermediate 34) instead of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1), (2S)-2-chloro-2-fluoro-acetyl chloride (Intermediate 28) instead of (2R)-2-chloro-2-fluoro-acetyl chloride (Intermediate 10), and (2,2-difluoroacetyl) 2,2-difluoroacetate instead of TFAA to afford N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-acetamide (Example 153) as a white solid.

[1576] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.11-10.88 (m, 1H), 8.91 (d, J=8.8 Hz, 1H), 7.78-7.71 (m, 1H), 7.11-6.57 (m, 1H), 6.42-6.13 (m, 1H), 4.45-4.41 (m, 1H), 4.21-4.13 (m, 1H), 3.95-3.89 (m, 1H), 3.80-3.69 (m, 2H), 3.56-3.52 (m, 1H), 3.21-2.98 (m, 2H), 2.23-2.08 (m, 1H), 2.63-2.61 (m, 1H), 1.84-1.72 (m, 1H), 1.66-1.48 (m, 2H), 1.36-1.22 (m, 2H), 1.07-1.02 (m, 3H), 0.94-0.85 (m, 9H), 0.77 (t, J=7.2 Hz, 3H).

[1577] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 566.3.

Example 154

N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-butyl]-1-fluoro-cyclopropanecarboxamide

##STR00441##

[1578] The title compound was prepared in analogy to the procedure described for the preparation of Example 1, by using benzyl (2S)-1-[(2S)-2-amino-3,3-dimethyl-pentanoyl]-4,4-dimethyl-pyrrolidine-2-carboxylate; hydrochloride (Intermediate 35) instead of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1), and 1-fluorocyclopropane-1-carboxylic acid and T.sub.3P instead of TFAA to afford N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-butyl]-1-fluoro-cyclopropanecarboxamide (Example 154) as a white solid.

[1579] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.02 (s, 1H), 7.85-7.63 (m, 1H), 7.48-7.22 (m, 1H), 7.12-6.81 (m, 1H), 4.53 (d, J=8.8 Hz, 1H), 4.32 (dd, J=9.6, 7.6 Hz, 1H), 3.87-3.59 (m, 2H), 3.42 (dd, J=14, 4 Hz, 1H), 3.35-3.32 (m, 1H), 3.23-3.09 (m, 2H), 2.44-2.37 (m, 1H), 2.20-2.04 (m, 1H), 2.01-1.89 (m, 1H), 1.81-1.56 (m, 2H), 1.45-1.16 (m, 6H), 1.14 (s, 3H), 1.05-0.86 (m, 9H), 0.79 (t, J=7.6 Hz, 3H).

[1580] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 562.4.

Example 155a and 155b

N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide and N-[(1S)-1-[(2R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide

##STR00442##

[1581] The title compound was prepared in analogy to the procedure described for the preparation of Example 1, by using benzyl 1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-3,3-dimethyl-pyrrolidine-2-carboxylate; 2,2,2-trifluoroacetic acid (Intermediate 36) instead of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1) to afford a mixture of N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide and N-[(1S)-1-[(2R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide. The mixture was split by prep-SFC (DAICEL CHIRALPAK IC (250 mm*30 mm, 10 um); Condition 0.1% NH3H2O IPA Begin B 40; End B 40 Gradient Time(min) 3; 100% B Hold Time(min) FlowRate(ml/min) 120; Injections 25) to afford Example 155a (31.7 mg, retention time=1.45 min) and Example 155b (6.5 mg, retention time=2.94 min) as white solids.

Example 155a

[1582] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.15 (s, 1H), 9.48 (d, J=8.4 Hz, 1H), 7.81 (s, 1H), 6.94 (d, J=50.4 Hz, 1H), 4.58 (d, J=8.4 Hz, 1H), 4.06-3.97 (m, 2H), 3.87-3.78 (m, 1H), 3.75-3.68 (m, 1H), 3.25-3.15 (m, 2H), 3.04 (dd, J=13.6 Hz, 3.6 Hz, 1H), 2.60-2.55 (m, 1H), 2.23-2.15 (m, 1H), 1.90-1.83 (m, 1H), 1.81-1.75 (m, 1H), 1.72-1.64 (m, 1H), 1.16-1.09 (m, 3H), 1.02-0.96 (m, 12H).

[1583] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 558.3.

Example 155b

[1584] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.00-10.52 (m, 1H), 9.25-9.07 (m, 1H), 7.83-7.71 (m, 1H), 7.29-6.52 (m, 1H), 4.78-4.63 (m, 1H), 4.00-3.80 (m, 2H), 3.76-3.51 (m, 2H), 3.30-3.06 (m, 3H), 2.66-2.62 (m, 1H), 2.32-2.14 (m, 1H), 2.08-1.94 (m, 1H), 1.80-1.45 (m, 2H), 1.31-1.14 (m, 3H), 1.10-0.93 (m, 12H).

[1585] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 558.2.

Example 156

N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-1-cyclobutyl-2-oxo-ethyl]-1-fluoro-cyclopropanecarboxamide

##STR00443##

[1586] The title compound was prepared in analogy to the procedure described for the preparation of Example 1, by using (1R,2S,5S)-3-[(2S)-2-amino-2-cyclobutyl-acetyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; 2,2,2-trifluoroacetic acid (Intermediate 37) instead of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1), and 1-fluorocyclopropane-1-carboxylic acid and T.sub.3P instead of TFAA to afford N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-1-cyclobutyl-2-oxo-ethyl]-1-fluoro-cyclopropanecarboxamide (Example 156) as a white solid.

[1587] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.08 (s, 1H), 8.33 (d, J=6.8 Hz, 1H), 7.75 (s, 1H), 6.78 (d, J=50.4 Hz, 1H), 4.43 (t, J=8.0 Hz, 1H), 4.14 (s, 1H), 3.92-3.75 (m, 3H), 3.42 (dd, J=14.0 Hz, 4.4 Hz, 1H), 3.22-3.10 (m, 2H), 2.80-2.71 (m, 1H), 2.63-2.53 (m, 2H), 2.20-2.10 (m, 1H), 1.98-1.90 (m, 1H), 1.86-1.71 (m, 5H), 1.66-1.60 (m, 1H), 1.49 (d, J=8.0 Hz, 1H), 1.30-1.25 (m, 2H), 1.21-1.09 (m, 2H), 1.04 (s, 3H), 0.91 (s, 3H).

[1588] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 558.2.

Example 157

N-[(1S)-2-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-1-cyclobutyl-2-oxo-ethyl]-1-fluoro-cyclopropanecarboxamide

##STR00444##

[1589] The title compound was prepared in analogy to the procedure described for the preparation of Example 1, by using (1R,2S,5S)-3-[(2S)-2-amino-2-cyclobutyl-acetyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; 2,2,2-trifluoroacetic acid (Intermediate 37) instead of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1), (2S)-2-chloro-2-fluoro-acetyl chloride (Intermediate 28) instead of (2R)-2-chloro-2-fluoro-acetyl chloride (Intermediate 10), and 1-fluorocyclopropane-1-carboxylic acid and T.sub.3P instead of TFAA to afford N-[(1S)-2-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-1-cyclobutyl-2-oxo-ethyl]-1-fluoro-cyclopropanecarboxamide (Example 157) as a white solid.

[1590] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 10.91-10.72 (m, 1H), 8.32 (s, 1H), 7.73-7.71 (m, 1H), 7.07-6.56 (m, 1H), 4.44 (t, J=8.0 Hz, 1H), 4.18-4.09 (m, 1H), 3.92-3.79 (m, 2H), 3.60 (d, J=7.2 Hz, 1H), 3.23-3.04 (m, 2H), 2.82-2.70 (m, 1H), 2.64-2.56 (m, 1H), 2.20-2.10 (m, 1H), 1.98-1.69 (m, 8H), 1.63-1.44 (m, 2H), 1.33-1.23 (m, 2H), 1.20-1.09 (m, 2H), 1.04 (s, 3H), 0.89 (s, 3H).

[1591] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 558.4.

Example 158

(1S)N-[(1S)-1-[(2S,4R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-(trifluoromethyl)pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide

##STR00445##

[1592] The title compound was prepared in analogy to the procedure described for the preparation of Example 1, by using benzyl (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-(trifluoromethyl)pyrrolidine-2-carboxylate (Intermediate 15) instead of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1), and 2,2-difluorocyclopropanecarboxylic acid and T.sub.3P instead of TFAA to afford (1S)N-[(1S)-1-[(2S,4R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-(trifluoromethyl)pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide (Example 158) as a white solid.

[1593] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.05-10.76 (m, 1H), 8.51 (d, J=8.0 Hz, 1H), 7.70 (s, 1H), 7.18-6.59 (m, 1H), 4.51 (d, J=8.8 Hz, 1H), 4.47-4.25 (m, 1H), 4.05-3.87 (m, 2H), 3.78-3.64 (m, 1H), 3.55-3.45 (m, 1H), 3.20-2.98 (m, 2H), 2.89-2.74 (m, 1H), 2.46-2.35 (m, 1H), 2.24-2.12 (m, 1H), 1.88-1.74 (m, 3H), 1.30-1.17 (m, 2H), 1.02-0.91 (s, 9H), 0.88-0.79 (m, 1H).

[1594] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 606.2.

Example 159

(1S)N-[(1S)-1-[(2S,4R)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-(trifluoromethyl)pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide

##STR00446##

[1595] The title compound was prepared in analogy to the procedure described for the preparation of Example 1, by using benzyl (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-(trifluoromethyl)pyrrolidine-2-carboxylate (Intermediate 15) instead of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1), (2S)-2-chloro-2-fluoro-acetyl chloride (Intermediate 28) instead of (2R)-2-chloro-2-fluoro-acetyl chloride (Intermediate 10), and (1S)-2,2-difluorocyclopropanecarboxylic acid and T.sub.3P instead of TFAA to afford (1S)N-[(1S)-1-[(2S,4R)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-(trifluoromethyl)pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide (Example 159) as a white solid.

[1596] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.10 (br. s, 1H), 8.53 (d, J=8.4 Hz, 1H), 7.72 (s, 1H), 6.96 (d, J=50.4 Hz, 1H), 4.50 (d, J=8.4 Hz, 1H), 4.38-4.30 (m, 1H), 4.07-3.98 (m, 2H), 3.70 (dd, J=14.0 Hz, 8.4 Hz, 1H), 3.53 (dd, J=14.0 Hz, 4.0 Hz, 1H), 3.47-3.39 (m, 1H), 3.19-3.10 (m, 2H), 2.94-2.83 (m, 1H), 2.60-2.55 (m, 1H), 2.40-2.33 (m, 1H), 2.27-2.18 (m, 1H), 2.16-2.07 (m, 1H), 1.93-1.75 (m, 3H), 0.96 (s, 9H).

[1597] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 606.2.

Example 160

N-[(1S,2S)-1-[(2S,4R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-(trifluoromethyl)pyrrolidine-1-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide

##STR00447##

[1598] The title compound was prepared in analogy to the procedure described for the preparation of Example 1, by using benzyl (2S,4R)-1-[(2S,3S)-2-amino-3-methyl-pentanoyl]-4-(trifluoromethyl)pyrrolidine-2-carboxylate; 2,2,2-trifluoroacetaldehyde (Intermediate 38) instead of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1), and 1-fluorocyclopropane-1-carboxylic acid and T.sub.3P instead of TFAA to afford N-[(1S,2S)-1-[(2S,4R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-(trifluoromethyl)pyrrolidine-1-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide (Example 160) as a white solid.

[1599] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.07 (s, 1H), 8.60-8.43 (m, 1H), 7.72 (s, 1H), 6.92 (d, J=50.4 Hz, 1H), 4.43-4.28 (m, 2H), 4.24-4.09 (m, 1H), 4.00-3.90 (m, 1H), 3.76-3.65 (m, 1H), 3.53 (dd, J=14.4 Hz, 4.0 Hz, 1H), 3.43-3.35 (m, 1H), 3.20-3.07 (m, 2H), 2.60-2.53 (m, 1H), 2.40-2.34 (m, 1H), 2.28-2.19 (m, 1H), 2.16-2.03 (m, 1H), 2.02-1.91 (m, 1H), 1.86-1.73 (m, 1H), 1.52-1.45 (m, 1H), 1.35-1.25 (m, 2H), 1.24-1.07 (m, 3H), 0.87-0.79 (m, 6H).

[1600] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 588.3.

Example 161

N-[(1S,2S)-1-[(2S,4R)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-(trifluoromethyl)pyrrolidine-1-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide

##STR00448##

[1601] The title compound was prepared in analogy to the procedure described for the preparation of Example 1, by using benzyl (2S,4R)-1-[(2S,3S)-2-amino-3-methyl-pentanoyl]-4-(trifluoromethyl)pyrrolidine-2-carboxylate; 2,2,2-trifluoroacetaldehyde (Intermediate 38) instead of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1), (2S)-2-chloro-2-fluoro-acetyl chloride (Intermediate 28) instead of (2R)-2-chloro-2-fluoro-acetyl chloride (Intermediate 10), and 1-fluorocyclopropane-1-carboxylic acid and T.sub.3P instead of TFAA to afford N-[(1S,2S)-1-[(2S,4R)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-(trifluoromethyl)pyrrolidine-1-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide (Example 161) as a white solid.

[1602] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.00-10.80 (m, 1H), 8.60-8.47 (m, 1H), 7.72 (s, 1H), 7.22-6.63 (m, 1H), 4.50-4.27 (m, 2H), 4.17-4.02 (m, 1H), 4.00-3.91 (m, 1H), 3.72-3.57 (m, 2H), 3.52-3.36 (m, 1H), 3.18-3.01 (m, 2H), 2.53-2.51 (m, 1H), 2.40-2.34 (m, 1H), 2.27-2.07 (m, 2H), 2.03-1.90 (m, 1H), 1.83-1.73 (m, 1H), 1.57-1.45 (m, 1H), 1.34-1.25 (m, 2H), 1.22-1.08 (m, 3H), 0.86 (d, J=6.8 Hz, 3H), 0.81 (t, J=7.2 Hz, 3H).

[1603] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 588.4.

Example 162

N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-3,3-dimethyl-butyl]-1-fluoro-cyclopropanecarboxamide

##STR00449##

[1604] The title compound was prepared in analogy to the procedure described for the preparation of Example 1, by using benzyl (1R,2S,5S)-3-[(2S)-2-amino-4,4-dimethyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; 2,2,2-trifluoroacetic acid (Intermidiate 42) instead of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1), and 1-fluorocyclopropane-1-carboxylic acid and T.sub.3P instead of TFAA to afford N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-3,3-dimethyl-butyl]-1-fluoro-cyclopropanecarboxamide (Example 162) as a white solid.

[1605] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.09 (s, 1H), 8.56-8.46 (m, 1H), 7.77 (s, 1H), 6.78 (d, J=50.8 Hz, 1H), 4.56-4.51 (m, 1H), 4.14 (s, 1H), 3.86-3.79 (m, 3H), 3.52-3.39 (m, 2H), 3.21-3.13 (m, 2H), 2.63-2.56 (m, 1H), 2.23-2.12 (m, 1H), 1.80-1.69 (m, 2H), 1.66-1.62 (m, 1H), 1.56-1.50 (m, 2H), 1.32-1.24 (m, 2H), 1.19-1.06 (m, 2H), 1.05 (s, 3H), 0.95-0.90 (m, 11H).

[1606] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 574.3.

Example 163a and 163b

N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide and N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide

##STR00450##

Step 1: Preparation of benzyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate

##STR00451##

[1607] To a solution of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (970 mg, 2.71 mmol, Intermediate 1) in THF (20 mL) was added TEA (601 mg, 5.95 mmol) and TFAA (1131 mg, 5.41 mmol) at 0 C. The reaction mixture was stirred at 25 C. for 1 h. The reaction was quenched with water (50 mL) and extracted with EtOAc (80 mL2). The organic layers were washed with brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by silica gel column eluted with PE to EtOAc/PE=10/1 to afford benzyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (1.2 g) as colorless oil.

[1608] MS obsd. (ESI.sup.+) [M+H].sup.+: 455.3.

Step 2: Preparation of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid

##STR00452##

[1609] To a solution of benzyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (1.2 g, 2.64 mmol) in MeOH (20 mL) was added Pd/C (200 mg, 10% purity). The mixture was degassed under vacuum and purged H.sub.2 for 3 times. The reaction mixture was stirred at 25 C. for 1 h under H.sub.2 balloon. The mixture was filtered through a celite pad and the pad was washed with MeOH (10 mL3). The filtrate was concentrated in vacuum to afford (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (960 mg) as a white solid.

[1610] MS obsd. (ESI.sup.+) [M+H].sup.+: 365.2.

Step 3: Preparation of tert-butyl N-[[(1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3R)-2-oxo-3-piperidyl]methyl]carbamate and tert-butyl N-[[(1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxo-3-piperidyl]methyl]carbamate

##STR00453##

[1611] To a solution of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (380 mg, 1.04 mmol) in DMF (4 mL) was added EDCI (280 mg, 1.46 mmol), HOPO (162 mg, 1.46 mmol), DIPEA (674 mg, 5.21 mmol) and tert-butyl N-amino-N-[(2-oxo-3-piperidyl)methyl]carbamate (254 mg, 1.04 mmol, from step 5 of Intermediate 39) at 0 C. Then the mixture was stirred at 20 C. for 12 h. The resulting mixture was poured into EtOAc (150 mL) and washed with 1 N HCl (20 mL), 5% aqueous solution of K.sub.2CO.sub.3 (50 mL) and brine (50 mL). The organic phase was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by reverse flash chromatography (condition: 120 g Flash Column Welch Ultimate XB_C18 20-40 m; 120 A, water (0.1% HCl)-ACN, 050%, 70 mL/min) to afford a mixture of tert-butyl N-[[(1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3R)-2-oxo-3-piperidyl]methyl]carbamate and tert-butyl N-[[(1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxo-3-piperidyl]methyl]carbamate (295 mg) as light yellow solids. The mixture was split by SFC (instrument: ACSWH-PREP-SFC-C, column: DAICEL CHIRALPAK IC (250 mm*30 mm, 10 um), mobile phase: 40% Neu-IPA in supercritical CO.sub.2, flow rate: 75 mL/min, cycle time: 3.2 min, back pressure: 100 bar to keep the CO.sub.2 in suspercritical flow, UV: 220 nm) to afford Peak 1 (106 mg, retention time=1.25 min) and Peak 2 (172 mg, retention time=2.76 min) as light yellow solids.

Peak 1

[1612] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 590.4.

Peak 2

[1613] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 590.4.

Step 4: Preparation of N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide and N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide

##STR00454##

[1614] These compounds were prepared in analogy to the procedure described for the preparation of Example 1, by using tert-butyl N-[[(1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3R)-2-oxo-3-piperidyl]methyl]carbamate or tert-butyl N-[[(1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxo-3-piperidyl]methyl]carbamate instead of tert-butyl N-[[(1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate to afford Example 163a or Example 163b respectively as a white solid.

Example 163a

[1615] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.13 (s, 1H), 9.52 (d, J=7.6 Hz, 1H), 7.54 (s, 1H), 6.82 (d, J=50.8 Hz, 1H), 4.42-4.38 (m, 1H), 4.18 (s, 1H), 3.98-3.86 (m, 2H), 3.72 (d, J=10.4 Hz, 1H), 3.63 (dd, J=14.0 Hz, 8.4 Hz, 1H), 3.16-3.09 (m, 2H), 2.42-2.34 (m, 1H), 1.94-1.87 (m, 1H), 1.80-1.74 (m, 1H), 1.63-1.60 (m, 1H), 1.59-1.52 (m, 3H), 1.05 (s, 3H), 0.99 (s, 9H), 0.91 (s, 3H).

[1616] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 584.3.

Example 163b

[1617] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.21 (s, 1H), 9.55 (d, J=8.0 Hz, 1H), 7.59 (s, 1H), 6.87 (d, J=50.8 Hz, 1H), 4.44 (d, J=8.0 Hz, 1H), 4.19 (s, 1H), 4.09-3.95 (m, 2H), 3.76 (d, J=10.8 Hz, 1H), 3.48 (dd, J=14.0 Hz, 4.0 Hz, 1H), 3.16-3.11 (m, 2H), 2.50-2.45 (m, 1H), 1.88-1.77 (m, 2H), 1.71-1.67 (m, 1H), 1.66-1.55 (m, 1H), 1.53-1.47 (m, 2H), 1.08 (s, 3H), 1.01 (s, 9H), 0.93 (s, 3H).

[1618] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 584.3.

Example 164a and 164b

N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide and N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide

##STR00455##

[1619] The title compound was prepared in analogy to the procedure described for the preparation of Example 1, by using benzyl (3S,3aS,6aR)-2-[(2S)-2-amino-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate (Intermediate 3) instead of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1), and tert-butyl N-amino-N-[(2-oxo-3-piperidyl)methyl]carbamate (racemic, from Intermediate 39) instead of tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (Intermediate 9) to afford a mixture of N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide and N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide. The mixture was split by prep-SFC (Instrument:Waters 80Q; Mobile Phase: 40% EtOH (Neu) in Supercritical CO.sub.2; Flow Rate: 70 g/min; Cycle Time: 2.8 min, total time: 25 min; Single injection volume: 3.0 mL; Back Pressure: 100 bar to keep the CO.sub.2 in Supercritical flow) to afford Example 164a (retention time=1.19 min) and Example 164b (retention time=2.40 min) as white solids.

Example 164a

[1620] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.10 (s, 1H), 9.46 (d, J=8.4 Hz, 1H), 7.57-7.49 (m, 1H), 6.90 (d, J=50.4 Hz, 1H), 4.53 (d, J=8.0 Hz, 1H), 4.05-3.85 (m, 3H), 3.68 (dd, J=10.4 Hz, 2.8 Hz, 1H), 3.42-3.39 (m, 1H), 3.15-3.08 (m, 2H), 2.82-2.70 (m, 1H), 2.58-2.53 (m, 1H), 2.46-2.35 (m, 1H), 1.92-1.71 (m, 6H), 1.69-1.54 (m, 2H), 1.52-1.33 (m, 2H), 0.99 (s, 9H).

[1621] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 584.3.

Example 164b

[1622] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.01 (s, 1H), 9.44 (d, J=7.6 Hz, 1H), 7.49 (s, 1H), 6.94 (d, J=50.4 Hz, 1H), 4.51 (d, J=8.0 Hz, 1H), 4.01 (d, J=8.4 Hz, 1H), 3.96-3.85 (m, 2H), 3.70 (dd, J=10.4 Hz, 2.4 Hz, 1H), 3.57 (dd, J=13.6 Hz, 8.0 Hz, 1H), 3.20-3.02 (m, 2H), 2.79-2.69 (m, 1H), 2.64-2.56 (m, 1H), 2.35-2.25 (m, 1H), 1.95-1.70 (m, 6H), 1.64-1.45 (m, 3H), 1.43-1.31 (m, 1H), 0.99 (s, 9H).

[1623] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 584.3.

Example 165a and 165b

N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide and N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide

##STR00456##

Step 1: Preparation of methyl (1R,2S,5S)-3-[(2S,3S)-2-(tert-butoxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate

##STR00457##

[1624] To a solution of Boc-Ile-OH (96.0 g, 415.06 mmol) in DMF (192 mL) and MeCN (1536 mL) were added methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; hydrochloride (89.64 g, 435.82 mmol) and HATU (173.6 g, 456.57 mmol) at 0 C. under N.sub.2 to give a colorless solution, followed by drop-wise addition of DIPEA (216.88 mL, 1245.19 mmol) at 0 C. under N.sub.2 to give a light yellow solution. The reaction was then allowed to warm to 20 C. and was stirred for 16 h under N.sub.2 atmosphere and concentrated in vacuum. The residue was added to ethyl acetate (2400 mL) and water (3600 mL). The resulting suspension was filtered and the filter cake was washed with ethyl acetate (500 mL), and the filter cake was dried in vacuum to give methyl (1R,2S,5S)-3-[(2S,3S)-2-(tert-butoxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (75.0 g) as a white solid.

[1625] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 383.2.

Step 2: Preparation of (1R,2S,5S)-3-[(2S,3S)-2-(tert-butoxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid

##STR00458##

[1626] To a solution of methyl (1R,2S,5S)-3-[(2S,3S)-2-(tert-butoxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (50.0 g, 130.72 mmol) in THF (500 mL). The mixture was added a solution of LiOH.Math.H.sub.2O (10.97 g, 261.4 mmol) in water (500 mL). Then the mixture was stirred at 25 C. for 2 h. The reaction mixture was poured into ice/water (300 mL) and acidified with 12N HCl to pH=5. Then the mixture was extracted with EA(500 ml2). The combined organic phases were washed with brine (100 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuum to give (1R,2S,5S)-3-[(2S,3S)-2-(tert-butoxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (48.1 g) as yellow oil.

[1627] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 369.2.

Step 3: Preparation of (1R,2S,5S)-3-[(2S,3S)-2-amino-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid; hydrochloride

##STR00459##

[1628] To a solution of (1R,2S,5S)-3-[(2S,3S)-2-(tert-butoxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (48.1 g, 130.54 mmol) in DCM (500 mL) was added HCl/dioxane (500.0 mL, 2000.0 mmol). The mixture was stirred at 25 C. for 2 h and concentrated in vacuum to afford (1R,2S,5S)-3-[(2S,3S)-2-amino-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid; hydrochloride (39.8 g) as a yellow foam.

Step 4: Preparation of (1R,2S,5S)-6,6-dimethyl-3-[(2S,3S)-3-methyl-2-[(2,2,2-trifluoroacetyl)amino]pentanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxylic acid

##STR00460##

[1629] To a solution of (1R,2S,5S)-3-[(2S,3R)-2-amino-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid; hydrochloride (39.79 g, 130.54 mmol) in methanol (400 mL) was added TEA (79.26 g, 783.24 mmol) dropwise at 0 C., followed by ethyl trifluoroacetate (55.64 g, 391.62 mmol). Then the mixture was warmed to 50 C. and stirred at 50 C. for 12 h. The mixture was diluted in EtOAc (500 mL), washed with brine (300 ml), dried over Na.sub.2SO.sub.4 and concentrated to give (1R,2S,5S)-6,6-dimethyl-3-[(2S,3S)-3-methyl-2-[(2,2,2-trifluoroacetyl)amino]pentanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (45.0 g) as a yellow foam.

[1630] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 365.1.

Step 5: Preparation of tert-butyl N-[[(1R,2S,5S)-6,6-dimethyl-3-[(2S,3S)-3-methyl-2-[(2,2,2-trifluoroacetyl)amino]pentanoyl]-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxo-3-piperidyl]methyl]carbamate and tert-butyl N-[[(1R,2S,5S)-6,6-dimethyl-3-[(2S,3S)-3-methyl-2-[(2,2,2-trifluoroacetyl)amino]pentanoyl]-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3R)-2-oxo-3-piperidyl]methyl]carbamate

##STR00461##

[1631] To a solution of (1R,2S,5S)-6,6-dimethyl-3-[(2S,3S)-3-methyl-2-[(2,2,2-trifluoroacetyl)amino]pentanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (500 mg, 1.37 mmol) in DMF (10 mL) was added DIPEA (887 mg, 6.86 mmol), EDCI (368 mg, 1.92 mmol), HOPO (213.44 mg, 1.92 mmol) and tert-butyl N-amino-N-[(2-oxo-3-piperidyl)methyl]carbamate (334 mg, 1.37 mmol, racemic) at 0 C. The mixture was stirred at 20 C. for 12 h. The reaction mixture was poured into EtOAc (150 mL) and washed with 1 N HCl (20 mL), 5% aqueous solution of K.sub.2CO.sub.3 (50 mL) and brine (50 mL). The organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by reverse flash chromatography (condition: 120 g Flash Column Welch Ultimate XB_C18 20-40 m; 120 A, water (0.1% FA)-TFA, 049%, 70 mL/min) to afford a mixture of tert-butyl N-[[(1R,2S,5S)-6,6-dimethyl-3-[(2S,3S)-3-methyl-2-[(2,2,2-trifluoroacetyl)amino]pentanoyl]-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxo-3-piperidyl]methyl]carbamate and tert-butyl N-[[(1R,2S,5S)-6,6-dimethyl-3-[(2S,3S)-3-methyl-2-[(2,2,2-trifluoroacetyl)amino]pentanoyl]-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3R)-2-oxo-3-piperidyl]methyl]carbamate. The mixture was split by prep-SFC (instrument: ACSWH-PREP-SFC-C, column: DAICEL CHIRALPAK IC (250 mm*30 mm, 10 um), mobile phase: 40% Neu-IPA in supercritical CO.sub.2, flow rate: 75 mL/min, cycle time: 3.2 min, back pressure: 100 bar to keep the CO.sub.2 in suspercritical flow, UV: 220 nm) to afford Peak 1 (204 mg, retention time=1.76 min) and Peak 2 (136 mg, retention time=3.77 min) as yellow solids.

Peak 1

[1632] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 590.3.

Peak 2

[1633] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 590.3.

Step 6: Preparation of N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide and N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide

##STR00462##

[1634] These compounds were prepared in analogy to the procedure described for the preparation of Example 64, by using tert-butyl N-[[(1R,2S,5S)-6,6-dimethyl-3-[(2S,3S)-3-methyl-2-[(2,2,2-trifluoroacetyl)amino]pentanoyl]-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxo-3-piperidyl]methyl]carbamate or tert-butyl N-[[(1R,2S,5S)-6,6-dimethyl-3-[(2S,3S)-3-methyl-2-[(2,2,2-trifluoroacetyl)amino]pentanoyl]-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3R)-2-oxo-3-piperidyl]methyl]carbamate instead of tert-butyl N-[[(1R,2S,5S)-6,6-dimethyl-3-[(2S,3R)-3-methyl-2-[(2,2,2-trifluoroacetyl)amino]pentanoyl]-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate to afford Example 165a and Example 165b respectively as a white solid.

Example 165a

[1635] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.19 (s, 1H), 9.99 (d, J=7.6 Hz, 1H), 7.59 (s, 1H), 6.86 (d, J=50.8 Hz, 1H), 4.21-4.17 (m, 1H), 4.19 (s, 1H), 4.08-3.98 (m, 1H), 3.97-3.87 (m, 2H), 3.49 (dd, J=14.0 Hz, 4.0 Hz, 1H), 3.19-3.10 (m, 2H), 2.51-2.43 (m, 1H), 2.01-1.93 (m, 1H), 1.90-1.77 (m, 2H), 1.74-1.68 (m, 1H), 1.67-1.50 (m, 4H), 1.20-1.12 (m, 1H), 1.09 (s, 3H), 0.95 (s, 3H), 0.91 (d, J=6.8 Hz, 3H), 0.85 (t, J=7.2 Hz, 3H).

[1636] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 584.2.

Example 165b

[1637] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.09 (s, 1H), 9.96-9.90 (m, 1H), 7.52 (s, 1H), 6.80 (d, J=50.4 Hz, 1H), 4.18-4.16 (m, 1H), 4.17 (s, 1H), 3.94-3.81 (m, 3H), 3.63 (dd, J=14.4 Hz, 8.8 Hz, 1H), 3.18-3.12 (m, 2H), 2.42-2.35 (m, 1H), 1.96-1.87 (m, 2H), 1.81-1.72 (m, 1H), 1.68-1.61 (m, 1H), 1.59-1.51 (m, 3H), 1.50-1.42 (m, 1H), 1.15-1.11 (m, 1H), 1.05 (s, 3H), 0.91 (s, 3H), 0.86 (d, J=6.8 Hz, 3H), 0.81 (t, J=7.2 Hz, 3H).

[1638] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 584.2.

Example 166a and 166b

N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide and N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide

##STR00463##

[1639] The title compound was prepared in analogy to the procedure described for the preparation of Example 165a and 165b, by using 1-fluorocyclopropane-1-carboxylic acid and T.sub.3P instead of TFAA to afford N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide and N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide as a white solid.

Example 166a

[1640] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.44-11.12 (m, 1H), 8.53-8.42 (m, 1H), 7.56-7.47 (m, 1H), 6.87 (d, J=50.8 Hz, 1H), 4.25-4.20 (m, 1H), 4.13 (s, 1H), 4.02-3.94 (m, 2H), 3.87-3.82 (m, 1H), 3.44 (dd, J=14.0 Hz, 4.0 Hz, 1H), 3.14-3.07 (m, 2H), 2.46-2.40 (m, 1H), 2.00-1.91 (m, 1H), 1.84-1.76 (m, 2H), 1.64-1.57 (m, 2H), 1.56-1.42 (m, 3H), 1.31-1.15 (m, 3H), 1.16-1.07 (m, 2H), 1.04 (s, 3H), 0.89 (s, 3H), 0.83-0.77 (m, 6H).

[1641] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 574.3.

Example 166b

[1642] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.07 (s, 1H), 8.52 (d, J=7.6 Hz, 1H), 7.51 (s, 1H), 6.83 (d, J=50.4 Hz, 1H), 4.21 (dd, J=9.6 Hz, 8.4 Hz, 1H), 4.15 (s, 1H), 3.96-3.82 (m, 3H), 3.63 (dd, J=14.4 Hz, 8.8 Hz, 1H), 3.43-3.36 (m, 1H), 3.15-3.07 (m, 2H), 2.40-2.32 (m, 1H), 2.00-1.90 (m, 2H), 1.81-1.74 (m, 1H), 1.63-1.45 (m, 5H), 1.32-1.15 (m, 3H), 1.11-1.05 (m, 1H), 1.03 (s, 3H), 0.89 (s, 3H), 0.84-0.78 (m, 6H).

[1643] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 574.3.

Example 167a and 167b

N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]cyclopropanecarboxamide and N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]cyclopropanecarboxamide

##STR00464##

[1644] The title compound was prepared in analogy to the procedure described for the preparation of Example 1, by using benzyl (3S,3aS,6aR)-2-[(2S)-2-amino-3,3-dimethyl-pentanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate (Intermediate 34) instead of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1), tert-butyl N-amino-N-[(2-oxo-3-piperidyl)methyl]carbamate (racemic, from Intermediate 39) instead of tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (Intermediate 9), and cyclopropanecarbonyl chloride instead of TFAA to afford a mixture of N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]cyclopropanecarboxamide and N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]cyclopropanecarboxamide. The mixture was split by prep-SFC (Instrument:Waters 80Q; Mobile Phase: 35% EtOH (Neu) in Supercritical CO.sub.2; Flow Rate: 60 g/min; Cycle Time: 3.6 min, total time: 25 min; Single injection volume: 3.5 mL; Back Pressure:100 bar to keep the CO.sub.2 in Supercritical flow.) to afford Example 167a (retention time=1.26 min) and Example 167b (retention time=2.61 min) as a white solid.

Example 167a

[1645] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.06 (s, 1H), 8.18 (d, J=8.8 Hz, 1H), 7.56 (s, 1H), 7.03 (d, J=50.4 Hz, 1H), 4.50 (d, J=8.8 Hz, 1H), 4.02-3.89 (m, 2H), 3.86-3.78 (m, 1H), 3.75-3.67 (m, 1H), 3.46-3.39 (m, 2H), 3.15-3.06 (m, 2H), 2.76-2.65 (m, 1H), 2.60-2.53 (m, 1H), 2.45-2.35 (m, 1H), 1.94-1.70 (m, 6H), 1.67-1.55 (m, 2H), 1.49-1.41 (m, 1H), 1.39-1.20 (m, 3H), 0.95-0.85 (m, 6H), 0.75 (t, J=7.6 Hz, 3H), 0.67-0.57 (m, 4H).

[1646] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 570.4.

Example 167b

[1647] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 10.98 (s, 1H), 8.18 (d, J=8.8 Hz, 1H), 7.50 (s, 1H), 7.00 (d, J=50.4 Hz, 1H), 4.49 (d, J=8.8 Hz, 1H), 3.96-3.86 (m, 2H), 3.85-3.79 (m, 1H), 3.76-3.72 (m, 1H), 3.59-3.52 (m, 1H), 3.42-3.37 (m, 1H), 3.18-3.07 (m, 2H), 2.72-2.66 (m, 1H), 2.60-2.54 (m, 1H), 2.30-2.24 (m, 1H), 1.94-1.72 (m, 6H), 1.67-1.52 (m, 3H), 1.40-1.29 (m, 2H), 1.26-1.21 (m, 1H), 0.92-0.90 (m, 6H), 0.76 (t, J=7.6 Hz, 3H), 0.68-0.61 (m, 4H).

[1648] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 570.4.

Example 168a and 168b

N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-butyl]cyclopropanecarboxamide and N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-butyl]cyclopropanecarboxamide

##STR00465##

[1649] The title compound was prepared in analogy to the procedure described for the preparation of Example 1, by using benzyl (2S)-1-[(2S)-2-amino-3,3-dimethyl-pentanoyl]-4,4-dimethyl-pyrrolidine-2-carboxylate; hydrochloride (Intermediate 35) instead of benzyl (JR, 2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1), tert-butyl N-amino-N-[(2-oxo-3-piperidyl)methyl]carbamate (racemic, from Intermediate 39) instead of tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (Intermediate 9), and cyclopropanecarbonyl chloride instead of TFAA to afford a mixture of N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-butyl]cyclopropanecarboxamide and N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-butyl]cyclopropanecarboxamide. The mixture was split by prep-SFC (DAICEL CHIRALPAK IC (250 mm*50 mm, 10 um); Condition Neu-ETOH Begin B 25, End B 25 Gradient Time (min) 3.7; 100% B Hold Time (min) FlowRate (mL/min) 60; Injections 35) to afford Example 168a and Example 168b as white solids.

Example 168a

[1650] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 10.97 (s, 1H), 8.18 (d, J=8.8 Hz, 1H), 7.56 (s, 1H), 7.08 (d, J=50.4 Hz, 1H), 4.47 (d, J=8.8 Hz, 1H), 4.27 (dd, J=10.0 Hz, 7.6 Hz, 1H), 3.95 (dd, J=14.0 Hz, 10.4 Hz, 1H), 3.71 (d, J=9.6 Hz, 1H), 3.37-3.35 (m, 1H), 3.31-3.26 (m, 1H), 3.15-3.05 (m, 2H), 2.44-2.34 (m, 1H), 1.95-1.84 (m, 2H), 1.83-1.71 (m, 2H), 1.65-1.52 (m, 2H), 1.50-1.32 (m, 2H), 1.27-1.17 (m, 1H), 1.13 (s, 3H), 0.97 (s, 3H), 0.94-0.86 (m, 6H), 0.75 (t, J=7.2 Hz, 3H), 0.67-0.55 (m, 4H).

[1651] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 558.4.

Example 168b

[1652] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 10.90 (s, 1H), 8.17 (d, J=8.8 Hz, 1H), 7.51 (s, 1H), 7.08 (d, J=50.0 Hz, 1H), 4.44 (d, J=8.4 Hz, 1H), 4.30 (dd, J=10.0 Hz, 7.6 Hz, 1H), 3.85 (dd, J=14.0 Hz, 10.4 Hz, 1H), 3.71 (d, J=9.6 Hz, 1H), 3.62-3.54 (m, 1H), 3.30-3.26 (m, 1H), 3.18-3.04 (m, 2H), 2.49-2.18 (m, 1H), 1.95-1.84 (m, 3H), 1.80-1.75 (m, 1H), 1.67-1.45 (m, 3H), 1.41-1.32 (m, 1H), 1.25-1.19 (m, 1H), 1.12 (s, 3H), 0.97 (s, 3H), 0.93-0.87 (m, 6H), 0.79-0.73 (m, 3H), 0.68-0.56 (m, 4H).

[1653] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 558.4.

Example 169a and 169b

N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]cyclopropanecarboxamide and N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]cyclopropanecarboxamide

##STR00466##

[1654] The title compound was prepared in analogy to the procedure described for the preparation of Example 1, by using benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; 2,2,2-trifluoroacetic acid (Intermediate 40) instead of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1), tert-butyl N-amino-N-[(2-oxo-3-piperidyl)methyl]carbamate (racemic, from Intermediate 39) instead of tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (Intermediate 9), and cyclopropanecarbonyl chloride instead of TFAA to afford a mixture of N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]cyclopropanecarboxamide and N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]cyclopropanecarboxamide. The mixture was split by prep-SFC (Instrument:Waters 80Q; Mobile Phase: 35% EtOH (Neu) in Supercritical CO.sub.2; Flow Rate: 60 g/min; Cycle Time: 3.6 min, total time: 25 min; Single injection volume: 3.5 ml; Back Pressure: 100 bar to keep the CO.sub.2 in Supercritical flow) to afford Example 169a (retention time=1.84 min) and Example 169b (retention time=3.69 min) as white solids.

Example 169a

[1655] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.13 (s, 1H), 8.17 (d, J=7.2 Hz, 1H), 7.56 (s, 1H), 6.91 (d, J=50.8 Hz, 1H), 4.44 (d, J=8.8 Hz, 1H), 4.12 (s, 1H), 3.99 (dd, J=13.6 Hz, 10.0 Hz, 1H), 3.92-3.80 (m, 2H), 3.46-3.41 (m, 1H), 3.16-3.06 (m, 2H), 2.48-2.42 (m, 1H), 1.90-1.75 (m, 3H), 1.67-1.54 (m, 2H), 1.53-1.39 (m, 2H), 1.35-1.20 (m, 2H), 1.04 (s, 3H), 0.91 (s, 6H), 0.87 (s, 3H), 0.79-0.73 (m, 3H), 0.70-0.60 (m, 3H), 0.59-0.50 (m, 1H).

[1656] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 570.3.

Example 169b

[1657] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.08 (s, 1H), 8.17-8.10 (m, 1H), 7.52 (s, 1H), 6.90 (d, J=50.4 Hz, 1H), 4.42 (d, J=8.8 Hz, 1H), 4.14 (s, 1H), 3.95-3.80 (m, 3H), 3.63 (dd, J=13.6 Hz, 8.8 Hz, 1H), 3.47-3.39 (m, 1H), 3.17-3.10 (m, 2H), 2.40-2.30 (m, 1H), 1.95-1.75 (m, 3H), 1.65-1.52 (m, 3H), 1.48 (d, J=7.6 Hz, 1H), 1.37-1.20 (m, 2H), 1.03 (s, 3H), 0.91 (d, J=2.0 Hz, 6H), 0.87 (s, 2H), 0.76 (t, J=7.2 Hz, 3H), 0.71-0.60 (m, 3H), 0.59-0.48 (m, 1H).

[1658] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 570.3.

Example 170a and 170b

N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide and N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide

##STR00467##

[1659] The title compound was prepared in analogy to the procedure described for the preparation of Example 1, by using benzyl (3S,3aS,6aR)-2-[(2S,3S)-2-amino-3-methyl-pentanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate; hydrochloride (Intermediate 41) instead of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1), tert-butyl N-amino-N-[(2-oxo-3-piperidyl)methyl]carbamate (racemic, from Intermediate 39) instead of tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (Intermediate 9), and 1-fluorocyclopropane-1-carboxylic acid and T.sub.3P instead of TFAA to afford a mixture of N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide and N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide. The mixture was split by prep-SFC (Column: Chiralpak IG-3 504.6 mm I.D., 3 um Mobile phase: Phase A for C.sub.02, and Phase B for EtOH (0.05% DEA); Gradient elution: EtOH (0.05% DEA) in CO.sub.2 from 5% to 20% Flow rate: 3 mL/min; Detector: PDA Column Temp: 35C; Back Pressure: 100 Bar; YMC-Actus Triart C18 150*30 mm*7 um, water (ammonia hydroxide v/v)-ACN, Gradient Time: 4.9 min; FlowRate: 70 mL/min) to afford Example 170a (retention time=3.59 min) and Example 170b (retention time=4.58 min) as a white solid.

Example 170a

[1660] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 10.96 (s, 1H), 8.44-8.29 (m, 1H), 7.49 (s, 1H), 6.92 (d, J=50.4 Hz, 1H), 4.30 (t, J=8.4 Hz, 1H), 3.99 (d, J=6.0 Hz, 1H), 3.95-3.87 (m, 1H), 3.87-3.77 (m, 2H), 3.58 (dd, J=14.0 Hz, 8.8 Hz, 1H), 3.17-3.08 (m, 2H), 2.77-2.68 (m, 1H), 2.61-2.55 (m, 1H), 2.34-2.25 (m, 1H), 1.98-1.87 (m, 2H), 1.86-1.67 (m, 5H), 1.64-1.46 (m, 4H), 1.40-1.30 (m, 2H), 1.29-1.26 (m, 1H), 1.25-1.17 (m, 1H), 1.16-1.04 (m, 2H), 0.88-0.78 (m, 6H).

[1661] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 574.2.

Example 170b

[1662] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.03 (br. s, 1H), 8.42-8.25 (m, 1H), 7.56-7.45 (m, 1H), 6.92 (d, J=50.4 Hz, 1H), 4.30 (t, J=8.4 Hz, 1H), 4.02-3.91 (m, 2H), 3.87-3.77 (m, 2H), 3.15-3.08 (m, 2H), 2.78-2.69 (m, 1H), 2.44-2.37 (m, 1H), 1.97-1.89 (m, 1H), 1.87-1.67 (m, 6H), 1.65-1.55 (m, 2H), 1.53-1.44 (m, 2H), 1.42-1.27 (m, 3H), 1.27-0.99 (m, 5H), 0.89-0.77 (m, 6H).

[1663] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 574.2.

Example 171a and 171b

N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]cyclopropanecarboxamide and N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]cyclopropanecarboxamide

##STR00468##

[1664] The title compound was prepared in analogy to the procedure described for the preparation of Example 1, by using benzyl (3S,3aS,6aR)-2-[(2S)-2-amino-3-ethyl-pentanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate; 2,2,2-trifluoroacetic acid (Intermediate 24) instead of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1), tert-butyl N-amino-N-[(2-oxo-3-piperidyl)methyl]carbamate (racemic, from Intermediate 39) instead of tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (Intermediate 9), and cyclopropanecarbonyl chloride instead of TFAA to afford a mixture of N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]cyclopropanecarboxamide and N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]cyclopropanecarboxamide. The mixture was split by prep-SFC (Instrument:Waters 80Q; Mobile Phase: 40% EtOH (Neu) in Supercritical CO.sub.2; Flow Rate: 70 g/min; Cycle Time: 3.2 min, total time: 25 min; Single injection volume: 3.5 mL; Back Pressure: 100 bar to keep the CO.sub.2 in Supercritical flow.) to afford Example 171a (retention time=1.64 min) and Example 171b (retention time=3.18 min) as white solids.

Example 171a

[1665] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.06 (s, 1H), 8.36-8.29 (m, 1H), 7.58-7.50 (m, 1H), 6.95 (d, J=50.8 Hz, 1H), 4.52 (t, J=8.4 Hz, 1H), 4.02-3.91 (m, 2H), 3.84-3.69 (m, 2H), 3.37-3.34 (m, 1H), 3.15-3.09 (m, 2H), 2.80-2.71 (m, 1H), 2.45-2.36 (m, 1H), 1.91-1.76 (m, 4H), 1.75-1.69 (m, 3H), 1.68-1.49 (m, 4H), 1.48-1.40 (m, 2H), 1.37-1.30 (m, 1H), 1.29-1.20 (m, 3H), 0.83-0.79 (m, 3H), 0.76 (t, J=7.6 Hz, 3H), 0.69-0.59 (m, 4H).

[1666] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 570.4.

Example 171b

[1667] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 10.97 (s, 1H), 8.36-8.27 (d, J=8.8 Hz, 1H), 7.50 (s, 1H), 6.93 (d, J=50.4 Hz, 1H), 4.50 (t, J=8.4 Hz, 1H), 3.99 (d, J=6.0 Hz, 1H), 3.91 (dd, J=14.0 Hz, 4.4 Hz, 1H), 3.82-3.72 (m, 2H), 3.57 (dd, J=14.0 Hz, 8.4 Hz, 1H), 3.19-3.07 (m, 2H), 2.78-2.69 (m, 1H), 2.61-2.55 (m, 1H), 2.33-2.23 (m, 1H), 1.95-1.70 (m, 7H), 1.66-1.58 (m, 2H), 1.57-1.47 (m, 2H), 1.45-1.31 (m, 2H), 1.30-1.22 (m, 3H), 0.85-0.79 (m, 3H), 0.78-0.72 (m, 3H), 0.68-0.58 (m, 4H).

[1668] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 570.4.

Example 172

N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]cyclopropanecarboxamide

##STR00469##

[1669] The title compound was prepared in analogy to the procedure described for the preparation of Example 1, by using benzyl (1R,2S,5S)-3-[(2S)-2-amino-3-ethyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; hydrochloride (Intermediate 31) instead of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1), tert-butyl N-amino-N-[[(3S)-2-oxo-3-piperidyl]methyl]carbamate (Intermediate 39a) instead of tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (Intermediate 9), and cyclopropanecarbonyl chloride instead of TFAA to afford N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]cyclopropanecarboxamide (Example 172) as a white solid.

[1670] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.12 (s, 1H), 8.35 (d, J=8.8 Hz, 1H), 7.55 (s, 1H), 6.84 (d, J=50.8 Hz, 1H), 4.40 (t, J=8.8 Hz, 1H), 4.13 (s, 1H), 3.99 (dd, J=10.0, 14.0 Hz, 1H), 3.91-3.85 (m, 1H), 3.79 (dd, J=10.4 Hz, 5.6 Hz, 1H), 3.40 (dd, J=13.6 Hz, 4.0 Hz, 1H), 3.14-3.07 (m, 2H), 1.86-1.74 (m, 2H), 1.70-1.60 (m, 3H), 1.51-1.38 (m, 3H), 1.30-1.19 (m, 5H), 1.03 (s, 3H), 0.87 (s, 3H), 0.81-0.71 (m, 6H), 0.69-0.60 (m, 3H), 0.59-0.52 (m, 1H).

[1671] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 570.3.

Example 173

N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]-2,2-difluoro-acetamide

##STR00470##

[1672] The title compound was prepared in analogy to the procedure described for the preparation of Example 1, by using benzyl (1R,2S,5S)-3-[(2S)-2-amino-3-ethyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; hydrochloride (Intermediate 31) instead of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1), tert-butyl N-amino-N-[[(3S)-2-oxo-3-piperidyl]methyl]carbamate (Intermediate 39a) instead of tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (Intermediate 9), and (2,2-difluoroacetyl) 2,2-difluoroacetate instead of TFAA to afford N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]-2,2-difluoro-acetamide (Example 173) as a white solid.

[1673] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.14 (s, 1H), 9.17 (d, J=8.4 Hz, 1H), 7.55 (s, 1H), 6.80 (d, J=50.8 Hz, 1H), 6.22 (t, J=53.6 Hz, 1H), 4.43 (t, J=8.4 Hz, 1H), 4.16 (s, 1H), 4.00 (dd, J=13.6 Hz, 10.0 Hz, 1H), 3.90-3.80 (m, 2H), 3.42 (dd, J=14.0, 4.0 Hz, 1H), 3.14-3.07 (m, 2H), 2.48-2.43 (m, 1H), 1.86-1.71 (m, 3H), 1.70-1.63 (m, 1H), 1.63-1.55 (m, 1H), 1.53-1.38 (m, 3H), 1.31-1.21 (m, 3H), 1.05 (s, 3H), 0.90 (s, 3H), 0.81 (t, J=7.2 Hz, 3H), 0.75 (t, J=7.2 Hz, 3H).

[1674] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 580.2.

Example 174

N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]-2,2-difluoro-acetamide

##STR00471##

[1675] The title compound was prepared in analogy to the procedure described for the preparation of Example 1, by using benzyl (3S,3aS,6aR)-2-[(2S)-2-amino-3-ethyl-pentanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate; 2,2,2-trifluoroacetic acid (Intermediate 24) instead of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1), tert-butyl N-amino-N-[[(3S)-2-oxo-3-piperidyl]methyl]carbamate (Intermediate 39a) instead of tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (Intermediate 9), and (2,2-difluoroacetyl) 2,2-difluoroacetate instead of TFAA to afford N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]-2,2-difluoro-acetamide (Example 174) as a white solid.

[1676] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.08 (s, 1H), 9.13-9.02 (m, 1H), 7.57-7.48 (m, 1H), 6.88 (d, J=50.8 Hz, 1H), 6.26 (t, J=53.6 Hz, 1H), 4.56 (t, J=8.0 Hz, 1H), 3.99 (d, J=5.2 Hz, 1H), 3.98-3.93 (m, 1H), 3.87-3.80 (m, 1H), 3.73 (dd, J=7.6 Hz, 2.8 Hz, 1H), 3.12-3.09 (m, 2H), 2.85-2.70 (m, 1H), 2.45-2.36 (m, 1H), 1.90-1.78 (m, 3H), 1.78-1.67 (m, 4H), 1.67-1.48 (m, 3H), 1.48-1.36 (m, 3H), 1.31-1.15 (m, 4H), 0.86-0.80 (t, J=7.2 Hz, 3H), 0.76 (t, J=7.6 Hz, 3H).

[1677] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 580.3.

Example 175

N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-acetamide

##STR00472##

[1678] The title compound was prepared in analogy to the procedure described for the preparation of Example 1, by using benzyl (3S,3aS,6aR)-2-[(2S)-2-amino-3,3-dimethyl-pentanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate (Intermediate 34) instead of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1), tert-butyl N-amino-N-[[(3S)-2-oxo-3-piperidyl]methyl]carbamate (Intermediate 39) instead of tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (Intermediate 9), and (2,2-difluoroacetyl) 2,2-difluoroacetate instead of TFAA to afford N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-acetamide (Example 175) as a white solid.

[1679] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.08 (s, 1H), 9.13-9.02 (m, 1H), 7.57-7.48 (m, 1H), 6.88 (d, J=50.8 Hz, 1H), 6.26 (t, J=53.6 Hz, 1H), 4.56 (t, J=8.0 Hz, 1H), 3.99 (d, J=5.2 Hz, 1H), 3.98-3.93 (m, 1H), 3.87-3.80 (m, 1H), 3.73 (dd, J=7.6 Hz, 2.8 Hz, 1H), 3.12-3.09 (m, 2H), 2.85-2.70 (m, 1H), 2.45-2.36 (m, 1H), 1.90-1.78 (m, 3H), 1.78-1.67 (m, 4H), 1.67-1.48 (m, 3H), 1.48-1.36 (m, 3H), 1.31-1.15 (m, 4H), 0.86-0.80 (t, J=7.2 Hz, 3H), 0.76 (t, J=7.6 Hz, 3H).

[1680] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 580.3.

Example 176

N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide

##STR00473##

[1681] The title compound was prepared in analogy to the procedure described for the preparation of Example 105, by using tert-butyl N-amino-N-[[(3S)-2-oxo-3-piperidyl]methyl]carbamate (Intermediate 39a) instead of tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (Intermediate 9), and (2,2-difluoroacetyl) 2,2-difluoroacetate without coupling reagent instead of 1-fluorocyclobutanecarboxylic acid to afford N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide (Example 176) as a white solid.

[1682] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.13 (s, 1H), 9.25 (d, J=8.0 Hz, 1H), 7.55 (s, 1H), 6.83 (d, J=50.8 Hz, 1H), 6.20 (t, J=54.0 Hz, 1H), 4.21 (t, J=9.6 Hz, 1H), 4.13 (s, 1H), 4.01-3.96 (m, 1H), 3.91-3.83 (m, 2H), 3.44 (dd, J=14.0 Hz, 4.4 Hz, 1H), 3.13-3.10 (m, 2H), 2.47-2.42 (m, 1H), 1.87-1.74 (m, 3H), 1.68-1.63 (m, 1H), 1.62-1.55 (m, 1H), 1.54-1.42 (m, 3H), 1.14-1.03 (m, 4H), 0.94-0.78 (m, 9H).

[1683] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 566.3.

Example 177

(1R,2S,5S)-3-[3,5-bis(trifluoromethyl)benzoyl]-N-[(2R)-2-chloro-2-fluoro-acetyl]-6,6-dimethyl-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide

##STR00474##

Step 1: Preparation of tert-butyl N-[[(1R,2S,5S)-3-[3,5-bis(trifluoromethyl)benzoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate

##STR00475##

[1684] To a solution of 3,5-bis(trifluoromethyl)benzoic acid (620 mg, 2.4 mmol) in DCM (5 mL) was added DMF (7.98 mg, 0.11 mmol) and oxalyl chloride (416 mg, 3.27 mmol). The mixture was stirred at 25 C. for 1 h and concentrated in vacuum. The residue was dissolved with DCM (4 mL) and added into the solution of tert-butyl N-[[(1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (400 mg, 1.09 mmol, Intermediate 14) and DIPEA (705.34 mg, 5.46 mmol) in DCM (5 mL) at 0 C. The reaction mixture was stirred at 25 C. for 2 h. The resulting mixture was poured into water (20 mL) and extracted with DCM (50 mL2). The combined organic phase was washed with 10% aqueous solution of NaHCO.sub.3 (10 mL), brine (10 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuum. The residue was purified by reverse flash chromatography (condition: 120 g Flash Column Welch Ultimate XB_C18 20-40 m; 120 A, water (0.1% FA)-ACN, 060%, 70 mL/min) to afford tert-butyl N-[[(1R,2S,5S)-3-[3,5-bis(trifluoromethyl)benzoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (500 mg) as a white solid.

[1685] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 607.3.

Step 2: Preparation of (1R,2S,5S)-3-[3,5-bis(trifluoromethyl)benzoyl]-6,6-dimethyl-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide

##STR00476##

[1686] To a solution of tert-butyl N-[[(1R,2S,5S)-3-[3,5-bis(trifluoromethyl)benzoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (500 mg, 0.82 mmol) in DCM (4 mL) was added TFA (2.0 mL). The mixture was stirred at 25 C. for 1 h and concentrated in vacuum. The residue was purified by reverse flash chromatography (condition: 120 g Flash Column Welch Ultimate XB_C18 20-40 m; 120 A, water (0.1% HCl)-ACN, 060%, 70 mL/min) to afford (1R,2S,5S)-3-[3,5-bis(trifluoromethyl)benzoyl]-6,6-dimethyl-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide; hydrochloride (350 mg) as a white solid MS obsd. (ESI.sup.+) [(M+H).sup.+]: 507.1.

Step 3: Preparation of (1R,2S,5S)-3-[3,5-bis(trifluoromethyl)benzoyl]-N-[(2R)-2-chloro-2-fluoro-acetyl]-6,6-dimethyl-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide

##STR00477##

[1687] To a solution of (2R)-2-chloro-2-fluoro-acetic acid (222 mg, 1.38 mmol, 70% purity, Intermediate 10) in DCM (5 mL) was added POCl.sub.3 (190 mg, 1.2 mmol). The mixture was stirred for 90 min at 25 C. The mixture was added to the solution of (1R,2S,5S)-3-[3,5-bis(trifluoromethyl)benzoyl]-6,6-dimethyl-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide; hydrochloride (350 mg, 0.69 mmol) and DIPEA (536 mg, 4.15 mmol) in DCM (5 mL) at 5 C. After addition, the mixture was stirred at 5 C. for 1 h. The reaction mixture was quenched with MeOH (5 mL) and acidified by 4 N HCl/dioxane to pH=5 at 10 C. Then the mixture was concentrated in vacuum at 30 C. The residue was purified by reversed flash chromatography (condition: 120 g Flash Column Welch Ultimate XB_C18 20-40 m; 120 A, water (0.1% FA)-ACN, 060%, 70 mL/min) to afford (1R,2S,5S)-3-[3,5-bis(trifluoromethyl)benzoyl]-N-[(2R)-2-chloro-2-fluoro-acetyl]-6,6-dimethyl-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide (Example 177) (285 mg) as a white solid.

[1688] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.16-10.63 (m, 1H), 8.29 (s, 1H), 8.23-8.11 (m, 2H), 7.76 (s, 1H), 6.83 (d, J=50.0 Hz, 1H), 4.48-4.38 (m, 1H), 4.03-3.88 (m, 1H), 3.84 (dd, J=14.0 Hz, 7.2 Hz, 1H), 3.50 (d, J=14.0 Hz, 4.4 Hz, 1H), 3.29-3.27 (m, 1H), 3.19-3.13 (m, 2H), 2.63-2.57 (m, 1H), 2.21-2.13 (m, 1H), 1.87-1.74 (m, 1H), 1.69-1.57 (m, 2H), 1.09-0.92 (m, 6H).

[1689] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 601.3.

Example 178

(1R,2S,5S)-3-[2-[3,5-bis(trifluoromethyl)phenyl]acetyl]-N-[(2R)-2-chloro-2-fluoro-acetyl]-6,6-dimethyl-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide

##STR00478##

[1690] The title compound was prepared in analogy to the procedure described for the preparation of Example 177, by using 3,5-bis(trifluoromethyl)phenylacetic acid instead of 3,5-bis(trifluoromethyl)benzoic acid to afford (1R,2S,5S)-3-[2-[3,5-bis(trifluoromethyl)phenyl]acetyl]-N-[(2R)-2-chloro-2-fluoro-acetyl]-6,6-dimethyl-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide (Example 178) as a white solid.

[1691] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.03 (s, 1H), 7.97 (s, 1H), 7.95-7.89 (m, 2H), 7.80-7.67 (m, 1H), 6.75 (d, J=50.0 Hz, 1H), 4.14 (s, 1H), 4.03-3.92 (m, 2H), 3.91-3.74 (m, 2H), 3.62 (d, J=10.4 Hz, 1H), 3.37 (dd, J=14.0 Hz, 4.4 Hz, 1H), 3.20-3.02 (m, 2H), 2.62-2.54 (m, 1H), 2.22-2.06 (m, 1H), 1.81-1.70 (m, 1H), 1.68-1.60 (m, 1H), 1.59-1.49 (m, 1H), 1.05 (s, 3H), 0.97-0.85 (m, 3H).

[1692] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 615.2.

Example 179

(1R,2S,5S)N-[(2R)-2-chloro-2-fluoro-acetyl]-3-[3-fluoro-5-(trifluoromethyl)benzoyl]-6,6-dimethyl-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide

##STR00479##

[1693] The title compound was prepared in analogy to the procedure described for the preparation of Example 177, by using 3-fluoro-5-(trifluoromethyl)benzoyl chloride instead of 3,5-bis(trifluoromethyl) benzoyl chloride to afford (1R,2S,5S)N-[(2R)-2-chloro-2-fluoro-acetyl]-3-[3-fluoro-5-(trifluoromethyl)benzoyl]-6,6-dimethyl-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide (Example 179) as a white solid.

[1694] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.16 (br. s, 1H), 7.87 (d, J=19.2 Hz, 1H), 7.83-7.71 (m, 2H), 7.65-7.60 (m, 1H), 6.83 (d, J=50.4 Hz, 1H), 4.44-4.36 (m, 1H), 3.89-3.83 (m, 2H), 3.54-3.47 (m, 3H), 3.14-3.10 (m, 2H), 2.26-2.15 (m, 1H), 1.79-1.74 (m, 1H), 1.70-1.58 (m, 2H), 1.12-0.91 (m, 6H).

[1695] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 551.2.

Example 180

(1R,2S,5S)-3-[(E)-3-[3,5-bis(trifluoromethyl)phenyl]prop-2-enoyl]-N-[(2R)-2-chloro-2-fluoro-acetyl]-6,6-dimethyl-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide

##STR00480##

[1696] The title compound was prepared in analogy to the procedure described for the preparation of Example 177, by using (E)-3-[3,5-bis(trifluoromethyl)phenyl]prop-2-enoic acid instead of 3,5-bis(trifluoromethyl)benzoic acid to afford (1R,2S,5S)-3-[(E)-3-[3,5-bis(trifluoromethyl)phenyl]prop-2-enoyl]-N-[(2R)-2-chloro-2-fluoro-acetyl]-6,6-dimethyl-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide (Example 180) as a white solid.

[1697] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.20 (s, 1H), 8.53 (s, 2H), 8.08 (s, 1H), 7.76 (s, 1H), 7.68 (d, J=15.6 Hz, 1H), 7.34 (d, J=15.2 Hz, 1H), 6.91 (d, J=50.4 Hz, 1H), 4.25 (s, 1H), 3.99-3.92 (m, 2H), 3.85 (dd, J=14.0 Hz, 9.6 Hz, 1H), 3.42 (dd, J=14.0 Hz, 4.4 Hz, 1H), 3.19-3.15 (m, 2H), 2.65-2.56 (m, 1H), 2.21-2.13 (m, 1H), 1.83-1.75 (m, 1H), 1.71-1.62 (m, 1H), 1.58-1.55 (d, J=7.6 Hz, 1H), 1.08 (s, 3H), 0.99-0.93 (m, 3H).

[1698] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 627.2.

Example 181

(1R,2S,5S)N-[(2R)-2-chloro-2-fluoro-acetyl]-3-[(E)-3-(3,5-difluorophenyl)prop-2-enoyl]-6,6-dimethyl-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide

##STR00481##

[1699] The title compound was prepared in analogy to the procedure described for the preparation of Example 177, by using (E)-3-(3,5-difluorophenyl)prop-2-enoic acid instead of 3,5-bis(trifluoromethyl)benzoic acid to afford (1R,2S,5S)N-[(2R)-2-chloro-2-fluoro-acetyl]-3-[(E)-3-(3,5-difluorophenyl)prop-2-enoyl]-6,6-dimethyl-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide (Example 181) as a white solid.

[1700] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.11 (s, 1H), 7.75 (s, 1H), 7.58 (d, J=6.8 Hz, 2H), 7.46 (d, J=15.6 Hz, 1H), 7.29-7.23 (m, 1H), 7.10 (d, J=15.2 Hz, 1H), 6.91 (d, J=50.4 Hz, 1H), 4.23 (s, 1H), 3.96-3.92 (m, 1H), 3.86-3.81 (m, 2H), 3.44-3.39 (m, 1H), 3.18-3.12 (m, 2H), 2.62-2.56 (m, 1H), 2.19-2.11 (m, 1H), 1.82-1.74 (m, 1H), 1.68-1.63 (m, 1H), 1.55 (d, J=7.6 Hz, 1H), 1.07 (s, 3H), 0.96-0.91 (m, 3H).

[1701] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 527.2.

Example 182

(3S,3aS,6aR)N-[(2R)-2-chloro-2-fluoro-acetyl]-2-[(2S)-2-[(6-fluoropyrimidin-4-yl)amino]-3,3-dimethyl-butanoyl]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbohydrazide

##STR00482##

Step 1: Preparation of tert-butyl N-[[(3S,3aS,6aR)-2-[(2S)-2-[(6-fluoropyrimidin-4-yl)amino]-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate

##STR00483##

[1702] To a solution of tert-butyl N-[[(3S,3aS,6aR)-2-[(2S)-2-amino-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (1.0 g, 2.09 mmol, from Example 29, step 4) in NMP (10 mL) was added DIPEA (539 mg, 4.17 mmol) and 4,6-difluoropyrimidine (242 mg, 2.09 mmol). The mixture was stirred at 50 C. for 2 h. The mixture was purified by prep-HPLC (Instrument GX-R, Method Column: Waters Xbridge 150*25 mm*5 um; Condition water (0.1% TFA)-CAN, Begin B 34, End B 64; Gradient Time(min) 8; 100% B Hold Time(min) 2; FlowRate (mL/min) 25; Injections 1) to afford tert-butyl N-[[(3S,3aS,6aR)-2-[(2S)-2-[(6-fluoropyrimidin-4-yl)amino]-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate; 2,2,2-trifluoroacetic acid (1.1 g) as a white solid.

[1703] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 576.4.

Step 2: Preparation of (3S,3aS,6aR)-2-[(2S)-2-[(6-fluoropyrimidin-4-yl)amino]-3,3-dimethyl-butanoyl]-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbohydrazide

##STR00484##

[1704] To a solution of tert-butyl N-[[(3S,3aS,6aR)-2-[(2S)-2-[(6-fluoropyrimidin-4-yl)amino]-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate; 2,2,2-trifluoroacetic acid (500 mg, 0.72 mmol) in DCM (5 mL) was added TFA (2.0 mL). The mixture was stirred at 25 C. for 2 h. The mixture was concentrated in vacuum and the residue was purified by prep-HPLC (Instrument GX-R, Method Column: Waters Xbridge 150*25 mm*5 um; Condition: water (0.1% HCl)-ACN, Begin B: 34, End 64. Gradient Time (min) 8; 100% B Hold Time (min) 2; Flowrate (mL/min) 25; Injections: 25) to afford (3S,3aS,6aR)-2-[(2S)-2-[(6-fluoropyrimidin-4-yl)amino]-3,3-dimethyl-butanoyl]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbohydrazide; hydrochloride (350 mg) as yellow oil.

[1705] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 476.3.

Step 3: Preparation of (3S,3aS,6aR)N-[(2R)-2-chloro-2-fluoro-acetyl]-2-[(2S)-2-[(6-fluoropyrimidin-4-yl)amino]-3,3-dimethyl-butanoyl]-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbohydrazide

##STR00485##

[1706] To a solution of (3S,3aS,6aR)-2-[(2S)-2-[(6-fluoropyrimidin-4-yl)amino]-3,3-dimethyl-butanoyl]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbohydrazide; hydrochloride (280 mg, 0.55 mmol) in THF (150 mL) was added DIPEA (711 mg, 5.5 mmol). After cooling to 5 C., to the mixture was added (2R)-2-chloro-2-fluoro-acetyl chloride (537.0 mg, 1.64 mmol, 40% purity, Intermediate 10) in THF (10 mL). The reaction mixture was stirred at 5 C. for 30 min. The reaction was quenched with MeOH (10 mL) and acidified by 4 N HCl/dioxane to pH=5 at 10 C. The resulting mixture was concentrated in vacuum at 30 C. The residue was purified by reversed flash chromatography (condition: 120 g Flash Column Welch Ultimate XB_C18 20-40 m; 120 A, water (0.1% FA)-ACN, 058%, 70 mL/min) to afford (3S,3aS,6aR)N-[(2R)-2-chloro-2-fluoro-acetyl]-2-[(2S)-2-[(6-fluoropyrimidin-4-yl)amino]-3,3-dimethyl-butanoyl]-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbohydrazide (Example 182) (134 mg) as a white solid.

[1707] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.06 (s, 1H), 8.28 (d, J=2.4 Hz, 1H), 8.23 (d, J=4.0 Hz, 1H), 7.77-7.70 (m, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.03 (d, J=50.4 Hz, 1H), 4.66 (d, J=8.0 Hz, 1H), 4.08-4.02 (m, 1H), 3.93-3.85 (m, 2H), 3.72 (dd, J=13.6 Hz, 10.0 Hz, 1H), 3.42-3.37 (m, 2H), 3.21-3.10 (m, 2H), 2.81-2.69 (m, 1H), 2.61-2.52 (m, 1H), 2.19-2.09 (m, 1H), 1.93-1.89 (m, 1H), 1.80-1.58 (m, 5H), 1.49-1.32 (m, 1H), 1.04 (s, 9H).

[1708] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 570.4.

Example 183

(3S,3aS,6aR)N-[(2R)-2-chloro-2-fluoro-acetyl]-2-[(2S)-2-[(5-fluoropyrimidin-4-yl)amino]-3,3-dimethyl-butanoyl]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbohydrazide

##STR00486##

[1709] The title compound was prepared in analogy to the procedure described for the preparation of Example 182, by using 4-chloro-5-fluoropyrimidine instead of 4,6-difluoropyrimidine to afford (3S,3aS,6aR)N-[(2R)-2-chloro-2-fluoro-acetyl]-2-[(2S)-2-[(5-fluoropyrimidin-4-yl)amino]-3,3-dimethyl-butanoyl]-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbohydrazide (Example 183) as a white solid.

[1710] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.06 (s, 1H), 8.28 (d, J=2.4 Hz, 1H), 8.23 (d, J=4.0 Hz, 1H), 7.77-7.70 (m, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.03 (d, J=50.4 Hz, 1H), 4.66 (d, J=8.0 Hz, 1H), 4.08-4.02 (m, 1H), 3.93-3.85 (m, 2H), 3.72 (dd, J=13.6 Hz, 10.0 Hz, 1H), 3.42-3.37 (m, 2H), 3.21-3.10 (m, 2H), 2.81-2.69 (m, 1H), 2.61-2.52 (m, 1H), 2.19-2.09 (m, 1H), 1.93-1.89 (m, 1H), 1.80-1.58 (m, 5H), 1.49-1.32 (m, 1H), 1.04 (s, 9H).

[1711] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 570.4.

Example 184

(3S,3aS,6aR)N-[(2R)-2-chloro-2-fluoro-acetyl]-2-[(2S)-3,3-dimethyl-2-(2-pyridylamino)butanoyl]-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbohydrazide

##STR00487##

[1712] The title compound was prepared in analogy to the procedure described for the preparation of Example 182, by using pyridine-N-oxide instead of 4,6-difluoropyrimidine in the presence of PyBop to afford (3S,3aS,6aR)N-[(2R)-2-chloro-2-fluoro-acetyl]-2-[(2S)-3,3-dimethyl-2-(2-pyridylamino)butanoyl]-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbohydrazide (Example 184) as a white solid.

[1713] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.01 (s, 1H) 7.88 (d, J=4.0 Hz, 1H), 7.77 (s, 1H), 7.38-7.32 (m, 1H), 7.07 (d, J=50.4 Hz, 1H), 6.77 (d, J=8.0 Hz, 1H), 6.58 (d, J=9.2 Hz, 1H), 6.48 (t, J=6.0 Hz, 1H), 4.49 (d, J=8.8 Hz, 1H), 4.24 (d, J=10.0 Hz, 1H), 3.88-3.84 (m, 2H), 3.70 (dd, J=10.4 Hz, 9.6 Hz, 1H), 3.40 (dd, J=13.2 Hz, 3.6 Hz, 1H), 3.21-3.10 (m, 2H), 2.77-2.70 (m, 1H), 2.60-2.54 (m, 2H), 2.20-2.08 (m, 1H), 1.97-1.87 (m, 1H), 1.81-1.62 (m, 5H), 1.45-1.37 (m, 1H), 1.01 (s, 9H).

[1714] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 551.3.

Example 185

(2R)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide

##STR00488##

Step 1: Preparation of (1R,2S,5S)-3-[(2S,3S)-2-amino-3-methyl-pentanoyl]-6,6-dimethyl-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide

##STR00489##

[1715] To a solution of tert-butyl N-[[(1R,2S,5S)-3-[(2S,3S)-2-amino-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (450 mg, 0.94 mmol, from Example 105, Step 4) in DCM (30 mL) was added TFA (2.0 mL). The mixture was stirred at 25 C. for 1 h and concentrated in vacuum. The residue was purified by reverse flash chromatography (condition: 120 g Flash Column Welch Ultimate XB_C18 20-40 m; 120 A, water (0.1% HCl)-ACN, 040%, 70 mL/min) to afford (1R,2S,5S)-3-[(2S,3S)-2-amino-3-methyl-pentanoyl]-6,6-dimethyl-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide; dihydrochloride (420 mg) as a white solid.

[1716] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 380.3.

Step 2: Preparation of (2R)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide

##STR00490##

[1717] To a solution of (1R,2S,5S)-3-[(2S,3S)-2-amino-3-methyl-pentanoyl]-6,6-dimethyl-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide; dihydrochloride (350 mg, 0.77 mmol) in THF (100 mL) was added DIPEA (1500 mg, 11.6 mmol). After cooling to 5 C., to the mixture was added (2R)-2-chloro-2-fluoro-acetyl chloride (933 mg, 2.71 mmol). The reaction mixture was stirred at 5 C. for 30 min. The reaction was quenched with 2 mL MeOH at 0 C., then acidified by 4 N HCl/dioxane until pH=4. The mixture was concentrated in vacuum and the residue was purified by reversed flash chromatography (condition: 40 g Flash Column Welch Ultimate XB_C18 20-40 m; 120 A, water (0.1% FA)-ACN, 045%, 70 mL/min) to afford (2R)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide (16.8 mg, Example 185) as a white solid.

[1718] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.16 (s, 1H), 9.11-9.09 (m, 1H), 7.76 (s, 1H), 6.78 (m, 2H), 4.24-4.18 (m, 1H), 4.15 (s, 1H), 3.94-3.85 (m, 2H), 3.80 (dd, J=14.4 Hz, 9.6 Hz, 1H), 3.45 (dd, J=14.0 Hz, 4.4 Hz, 1H), 3.21-3.13 (m, 2H), 2.63-2.56 (m, 1H), 2.20-2.11 (m, 1H), 1.87-1.73 (m, 2H), 1.68-1.61 (m, 1H), 1.56-1.53 (m, 1H), 1.51-1.41 (m, 1H), 1.16-1.08 (m, 1H), 1.06 (s, 3H), 0.92 (s, 3H), 0.86 (d, J=6.4 Hz, 3H), 0.81 (t, J=7.2 Hz, 3H).

[1719] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 568.2.

Example 186

(2S)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide

##STR00491##

[1720] The title compound was prepared in analogy to the procedure described for the preparation of Example 185, by using (2S)-2-chloro-2-fluoro-acetyl chloride (Intermediate 28) instead of (2R)-2-chloro-2-fluoro-acetyl chloride (Intermediate 10) to afford (2S)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide (Example 186) as a white solid.

[1721] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.13-10.83 (m, 1H), 9.09-9.04 (m, 1H), 7.75-7.33 (m, 1H), 7.17-6.57 (m, 2H), 4.26-4.13 (m, 2H), 3.90-3.82 (m, 2H), 3.77-3.51 (m, 2H), 3.20-2.96 (m, 2H), 2.64-2.53 (m, 1H), 2.21-2.12 (m, 1H), 1.88-1.73 (m, 2H), 1.66-1.45 (m, 3H), 1.14-1.05 (m, 4H), 0.90-0.80 (m, 9H).

[1722] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 568.3.

Example 187

(2S)-2-chloro-N-[(1S,2S)-1-[(2S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide

##STR00492##

Step 1: Preparation of methyl (2S)-1-[(2S,3S)-2-(tert-butoxycarbonylamino)-3-methyl-pentanoyl]-4,4-dimethyl-pyrrolidine-2-carboxylate

##STR00493##

[1723] To a solution of Boc-Ile-OH (474 mg, 2.05 mmol) in DMF (10 mL) was added DIPEA (1589 mg, 12.3 mmol), HATU (974 mg, 2.56 mmol) and methyl (2S)-4,4-dimethylpyrrolidine-2-carboxylate; 2,2,2-trifluoroacetic acid (556 mg, 2.05 mmol, Intermediate 43) at 0 C. The mixture was stirred at 25 C. for 12 h. The reaction was diluted with H.sub.2O (50 mL) and extracted with EtOAc (50 mL3). The combined organic layers were washed with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by silica gel column eluted with PE/EtOAc=4/1 to afford methyl (2S)-1-[(2S,3S)-2-(tert-butoxycarbonylamino)-3-methyl-pentanoyl]-4,4-dimethyl-pyrrolidine-2-carboxylate (680 mg) as yellow oil.

[1724] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 371.3.

Step 2: Preparation of (2S)-1-[(2S,3S)-2-(tert-butoxycarbonylamino)-3-methyl-pentanoyl]-4,4-dimethyl-pyrrolidine-2-carboxylic acid

##STR00494##

[1725] To a solution of methyl (2S)-1-[(2S,3S)-2-(tert-butoxycarbonylamino)-3-methyl-pentanoyl]-4,4-dimethyl-pyrrolidine-2-carboxylate (680 mg, 1.84 mmol) in THF (6 mL) and water (6 mL) was added LiOH.Math.H.sub.2O (154 mg, 3.67 mmol) at 0 C. The mixture was stirred at 25 C. for 2 h. The reaction was diluted with 40 mL water and acidified with 1 N HCl to pH=4. The resulting mixture was extracted with EtOAc (50 mL2). The organic layers were washed with brine (60 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuum to afford (2S)-1-[(2S,3S)-2-(tert-butoxycarbonylamino)-3-methyl-pentanoyl]-4,4-dimethyl-pyrrolidine-2-carboxylic acid (650 mg) as a white solid.

[1726] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 357.2.

Step 3: Preparation of tert-butyl N-[[(2S)-1-[(2S,3S)-2-(tert-butoxycarbonylamino)-3-methyl-pentanoyl]-4,4-dimethyl-pyrrolidine-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate

##STR00495##

[1727] To a solution of (2S)-1-[(2S,3S)-2-(tert-butoxycarbonylamino)-3-methyl-pentanoyl]-4,4-dimethyl-pyrrolidine-2-carboxylic acid (620 mg, 1.74 mmol) in DMF (10 mL) was added DIPEA (562 mg, 4.35 mmol), EDCI (433 mg, 2.26 mmol), HOPO (251 mg, 2.26 mmol) and tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (399 mg, 1.74 mmol). The mixture was stirred at 25 C. for 12 h. The reaction mixture was diluted with EtOAc (100 mL), washed with 1 N HCl (30 mL), brine (40 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuum to afford tert-butyl N-[[(2S)-1-[(2S,3S)-2-(tert-butoxycarbonylamino)-3-methyl-pentanoyl]-4,4-dimethyl-pyrrolidine-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (913 mg) was obtained as a white solid.

[1728] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 568.4.

Step 4: Preparation of (2S)-1-[(2S,3S)-2-amino-3-methyl-pentanoyl]-4,4-dimethyl-N[[(3S)-2-oxopyrrolidin-3-yl]methyl]pyrrolidine-2-carbohydrazide

##STR00496##

[1729] To a solution of tert-butyl N-[[(2S)-1-[(2S,3S)-2-(tert-butoxycarbonylamino)-3-methyl-pentanoyl]-4,4-dimethyl-pyrrolidine-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (913 mg, 1.61 mmol) in DCM (10 mL) was added TFA (5.0 mL). The mixture was stirred at 25 C. for 1 h and concentrated in vacuum. The residue was purified by reverse flash chromatography (condition: 120 g Flash Column Welch Ultimate XB_C18 20-40 m; 120 A, water (0.1% NH.sub.3)-ACN, 45%, 45 mL/min) to afford (2S)-1-[(2S,3S)-2-amino-3-methyl-pentanoyl]-4,4-dimethyl-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]pyrrolidine-2-carbohydrazide (640 mg) as a white solid.

[1730] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 368.4.

Step 5: Preparation of (2S)-2-chloro-N-[(1S,2S)-1-[(2S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide

##STR00497##

[1731] To a solution of (2S)-2-chloro-2-fluoro-acetic acid (1266 mg, 7.31 mmol, 62% purity) in DCM (40 mL) was added POCl.sub.3 (1041.35 mg, 6.79 mmol). The mixture was stirred at 25 C. for 1 h. The mixture was added to a solution of (2S)-1-[(2S,3S)-2-amino-3-methyl-pentanoyl]-4,4-dimethyl-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]pyrrolidine-2-carbohydrazide (640 mg, 1.74 mmol) and DIPEA (4502 mg, 34.83 mmol) in DCM (40 mL) at 5 C. dropwise. The resulting mixture was stirred for 1 h at 5 C. The reaction mixture was quenched with MeOH (10 mL) and acidified with 4 N HCl/dioxane to pH=5 at 10 C. The resulting mixture was concentrated in vacuum at 30 C. The residue was purified by reversed flash chromatography (condition: 40 g Flash Column Welch Ultimate XB_C18 20-40 m; 120 A, water (0.1% FA)-ACN, 59%, 45 mL/min) to afford (2S)-2-chloro-N-[(1S,2S)-1-[(2S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide (60 mg, Example 187) as a white solid.

[1732] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.02-10.73 (m, 1H), 9.07 (dd, J=23.2 Hz, 8.4 Hz, 1H), 7.74-7.73 (m, 1H), 7.30-6.42 (m, 2H), 4.37-4.25 (m, 2H), 3.78-3.65 (m, 2H), 3.58-3.51 (m, 1H), 3.32-3.10 (m, 1H), 3.20-2.98 (m, 2H), 2.82-2.62 (m, 1H), 2.26-2.08 (m, 1H), 1.99-1.92 (m, 1H), 1.87-1.67 (m, 3H), 1.54-1.45 (m, 1H), 1.16 (s, 3H), 1.13-1.07 (m, 1H), 1.00 (s, 3H), 0.89 (d, J=6.4 Hz, 3H), 0.82 (t, J=7.6 Hz, 3H).

[1733] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 556.1.

Example 188

(2R)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide

##STR00498##

Step 1: Preparation of methyl (2S)-1-[(2S,3S)-2-(tert-butoxycarbonylamino)-3-methyl-pentanoyl]-4,4-dimethyl-pyrrolidine-2-carboxylate

##STR00499##

[1734] To a solution of (1R,2S,5S)-3-[(2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (413 mg, 1.03 mmol, from Example 105, step 2) in DMF (5 mL) was added DIEA (398 mg, 3.08 mmol), EDCI (236 mg, 1.23 mmol), HOPO (137 mg, 1.23 mmol) and tert-butyl N-amino-N-[[(3S)-2-oxo-3-piperidyl]methyl]carbamate (250 mg, 1.03 mmol, Intermediate 39a). The mixture was stirred at 25 C. and 16 h. Then the reaction mixture was poured into water (100 mL) and extracted with EtOAc (60 mL2). The organic layers were washed with 1N HCl(60 mL), 1N NaOH (50 mL) and brine (60 mL2), dried over Na.sub.2SO.sub.4 and concentrated in vacuum to afford tert-butyl N-[[(1R,2S,5S)-3-[(2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxo-3-piperidyl]methyl]carbamate (510 mg) as a yellow foam.

[1735] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 628.4.

Step 2: Preparation of (1R,2S,5S)-3-[(2S,3S)-2-amino-3-methyl-pentanoyl]-6,6-dimethyl-N[[(3S)-2-oxo-3-piperidyl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide

##STR00500##

[1736] To a solution of tert-butyl N-[[(1R,2S,5S)-3-[(2S,3S)-2-amino-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxo-3-piperidyl]methyl]carbamate (280 mg, 0.57 mmol) in DCM (10 mL) was added TFA (5.0 mL). The mixture was stirred at 25 C. for 1 h. The resulting mixture was concentrated in vacuum and the residue was purified by reverse flash (120 g Flash Column; Welch Ultimate XB_C18 20-40 m; 35 min; 75 mL/min, ACN-Water, 0.1% NH.sub.3.Math.H.sub.2O) to afford (1R,2S,5S)-3-[(2S,3S)-2-amino-3-methyl-pentanoyl]-6,6-dimethyl-N-[[(3S)-2-oxo-3-piperidyl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide (135 mg) as a white solid.

[1737] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 394.3.

Step 3: Preparation of (2R)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide

##STR00501##

[1738] To a solution of (1R,2S,5S)-3-[(2S,3S)-2-amino-3-methyl-pentanoyl]-6,6-dimethyl-NV-[[(3S)-2-oxo-3-piperidyl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide (590 mg, 1.5 mmol), (2R)-2-chloro-2-fluoro-acetic acid (816 mg, 4.5 mmol,) and 2,6-lutidine (1.4 mL, 11.99 mmol) in NMP (20 mL) was added TCFH (1052 mg, 3.75 mmol). The suspension was stirred at 25 C. for 30 min. The resulting mixture was poured into 1N HCl (100 mL) and extracted with EtOAc (50 mL2). The organic layers were washed with brine (100 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuum. The residue was purified by reverse flash (120 g Flash Column; Welch Ultimate XB_C18 20-40 m; 55 min; 060%, 65 mL/min, ACN-Water, 0.1% FA) to afford (2R)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide (30 mg, Example 188) as a white solid.

[1739] .sup.1H NMR (400 MHz, DMSO-d6) : ppm 11.14 (s, 1H), 9.10 (d, J=8.0 Hz, 1H), 7.52 (s, 1H), 6.93-6.61 (m, 2H), 4.22 (t, J=8.4 Hz, 1H), 4.14 (s, 1H), 4.04-3.93 (m, 1H), 3.87 (s, 2H), 3.44 (dd, J=14.0 Hz, 4.0 Hz, 1H), 3.11 (s, 2H), 2.48-2.40 (m, 1H), 1.89-1.73 (m, 3H), 1.70-1.55 (m, 2H), 1.54-1.48 (m, 1H), 1.45 (d, J=7.2 Hz, 2H), 1.15-1.07 (m, 1H), 1.05 (s, 3H), 0.89 (s, 3H), 0.85 (d, J=6.8 Hz, 3H), 0.80 (t, J=7.6 Hz, 3H).

[1740] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 582.3.

Example 189

(2S)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide

##STR00502##

[1741] The title compound was prepared in analogy to the procedure described for the preparation of Example 188, by using (2S)-2-chloro-2-fluoro-acetic acid instead of (2R)-2-chloro-2-fluoro-acetic acid to afford (2S)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide (Example 189) as a white solid.

[1742] .sup.1H NMR (400 MHz, DMSO-d6) : ppm 10.95 (d, J=99.2 Hz, 1H), 9.12-9.06 (m, 1H), 7.51 (d, J=31.2 Hz, 1H), 7.20-6.45 (m, 2H), 4.26-4.11 (m, 2H), 3.95-3.83 (m, 2H), 3.79-3.69 (m, 1H), 3.62-3.48 (m, 1H), 3.15-3.03 (m, 2H), 2.61-2.56 (m, 1H), 2.05-1.65 (m, 3H), 1.63-1.44 (m, 4H), 1.43-1.23 (m, 1H), 1.17-1.09 (m, 1H), 1.06 (s, 3H), 0.90 (s, 3H), 0.87 (d, J=6.8 Hz, 3H), 0.82 (d, J=7.2 Hz, 3H).

[1743] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 582.1.

Example 190

(2R)N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2-chloro-2-fluoro-acetamide

##STR00503##

[1744] The title compound was prepared in analogy to the procedure described for the preparation of Example 187, by using ethyl (3S,3aS,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-3-carboxylate; hydrochloride instead of methyl (2S)-4,4-dimethylpyrrolidine-2-carboxylate; 2,2,2-trifluoroacetic acid (Intermediate 43), (2R)-2-chloro-2-fluoro-acetic acid instead of (2S)-2-chloro-2-fluoro-acetic acid, and tert-butyl N-amino-N-[[(3S)-2-oxo-3-piperidyl]methyl]carbamate (Intermediate 39a) instead of tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (Intermediate 9) to afford (2R)N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2-chloro-2-fluoro-acetamide (Example 190) as a white solid.

[1745] .sup.1H NMR (400 MHz, DMSO-d6) : ppm 11.07 (s, 1H), 9.08 (d, J=8.0 Hz, 1H), 7.57 (s, 1H), 6.95 (d, J=50.8 Hz, 1H), 6.73 (d, J=49.6 Hz, 1H), 4.32 (t, J=8.4 Hz, 1H), 4.02-3.92 (m, 2H), 3.90-3.74 (m, 2H), 3.40-3.35 (m, 1H), 3.15-3.07 (m, 2H), 2.82-2.71 (m, 1H), 2.58-2.54 (m, 1H), 2.43-2.36 (m, 1H), 1.93-1.71 (m, 7H), 1.67-1.54 (m, 2H), 1.52-1.36 (m, 3H), 1.17-1.04 (m, 1H), 0.87 (d, J=6.8 Hz, 3H), 0.81 (t, J=7.2 Hz, 3H).

[1746] MS obsd. (ESI.sup.+) [(M+H).sup.+]:582.0.

Example 191

(2S)N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2-chloro-2-fluoro-acetamide

##STR00504##

[1747] The title compound was prepared in analogy to the procedure described for the preparation of Example 187, by using ethyl (3S,3aS,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-3-carboxylate; hydrochloride instead of methyl (2S)-4,4-dimethylpyrrolidine-2-carboxylate; 2,2,2-trifluoroacetic acid (Intermediate 43), and tert-butyl N-amino-N-[[(3S)-2-oxo-3-piperidyl]methyl]carbamate (Intermediate 39a) instead of tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (Intermediate 9) to afford (2S)N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2-chloro-2-fluoro-acetamide (Example 191) as a white solid.

[1748] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 10.9 (d, J=119.2 Hz, 1H), 9.09-9.00 (m, 1H), 7.53 (d, J=28.8 Hz, 1H), 7.20-6.35 (m, 2H), 4.38-4.28 (m, 1H), 4.02 (s, 1H), 3.95-3.45 (m, 4H), 3.10 (s, 2H), 2.78-2.71 (m, 1H), 2.64-2.55 (m, 1H), 2.47-2.36 (m, 1H), 2.10-1.80 (m, 4H), 1.79-1.61 (m, 4H), 1.59-1.32 (m, 4H), 1.17-1.03 (m, 1H), 0.90-0.85 (m, 3H), 0.82 (t, J=7.2 Hz, 3H).

[1749] MS obsd. (ESI.sup.+) [(M+H).sup.+]:582.1.

Example 192

(2R)N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2-chloro-2-fluoro-acetamide

##STR00505##

[1750] The title compound was prepared in analogy to the procedure described for the preparation of Example 187, by using ethyl (3S,3aS,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-3-carboxylate; hydrochloride instead of methyl (2S)-4,4-dimethylpyrrolidine-2-carboxylate; 2,2,2-trifluoroacetic acid (Intermediate 43), (2R)-2-chloro-2-fluoro-acetic acid instead of (2S)-2-chloro-2-fluoro-acetic acid, and tert-butyl N-amino-N-[[(3R)-2-oxo-3-piperidyl]methyl]carbamate (Intermediate 39b) instead of tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (Intermediate 9) to afford (2R)N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2-chloro-2-fluoro-acetamide (Example 192) as a white solid.

[1751] .sup.1H NMR (400 MHz, DMSO-d6) : ppm 10.98 (s, 1H), 9.08 (d, J=8.4 Hz, 1H), 7.49 (s, 1H), 6.93 (d, J=50.4 Hz, 1H), 6.73 (d, J=49.6 Hz, 1H), 4.31 (d, J=8.8 Hz, 1H), 4.00 (d, J=5.6 Hz, 1H), 3.95-3.73 (m, 3H), 3.58 (dd, J=13.6 Hz, 8.4 Hz, 1H), 3.21-3.06 (m, 2H), 2.80-2.70 (m, 1H), 2.65-2.56 (m, 1H), 2.36-2.23 (m, 1H), 2.00-1.69 (m, 7H), 1.66-1.35 (m, 5H), 1.18-1.02 (m, 1H), 0.87 (d, J=6.8 Hz, 3H), 0.81 (t, J=7.2 Hz, 3H).

[1752] MS obsd. (ESI.sup.+) [(M+H).sup.+]:582.0.

Example 193

(2S)N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2-chloro-2-fluoro-acetamide

##STR00506##

[1753] The title compound was prepared in analogy to the procedure described for the preparation of Example 187, by using ethyl (3S,3aS,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-3-carboxylate; hydrochloride instead of methyl (2S)-4,4-dimethylpyrrolidine-2-carboxylate; 2,2,2-trifluoroacetic acid (Intermediate 43), and tert-butyl N-amino-N-[[(3R)-2-oxo-3-piperidyl]methyl]carbamate (Intermediate 39b) instead of tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (Intermediate 9) to afford (2S)N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2-chloro-2-fluoro-acetamide (Example 193) as a white solid.

[1754] .sup.1H NMR (400 MHz, DMSO-d6) : ppm 10.08 (d, J=132.0 Hz, 1H), 9.10-8.89 (m, 1H), 7.53 (d, J=22.8 Hz, 1H), 7.20-6.50 (m, 2H), 4.40-4.25 (m, 1H), 4.10-3.40 (m, 5H), 3.12 (s, 2H), 2.76 (s, 1H), 2.66-2.55 (m, 1H), 2.41-2.25 (m, 1H), 1.94-1.81 (m, 4H), 1.80-1.60 (m, 4H), 1.58-1.32 (m, 4H), 1.18-1.01 (m, 1H), 0.93-0.86 (m, 3H), 0.82 (t, J=7.2 Hz, 3H).

[1755] MS obsd. (ESI.sup.+) [(M+H).sup.+]:582.1.

Example 194

(2R)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide

##STR00507##

[1756] The title compound was prepared in analogy to the procedure described for the preparation of Example 188, by using tert-butyl N-amino-N-[[(3R)-2-oxo-3-piperidyl]methyl]carbamate (Intermediate 39b) instead of tert-butyl N-amino-N-[[(3S)-2-oxo-3-piperidyl]methyl]carbamate (Intermediate 39a) to afford (2R)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide (Example 194) as a white solid.

[1757] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : ppm 11.08 (s, 1H), 9.10 (d, J=8.0 Hz, 1H), 7.51 (s, 1H), 6.93-6.60 (m, 2H), 4.19 (d, J=8.8 Hz, 1H), 4.16 (s, 1H), 3.94-3.82 (m, 3H), 3.62 (dd, J=13.6, 8.4 Hz, 1H), 3.17-3.06 (m, 2H), 2.41-2.30 (m, 1H), 1.95-1.85 (m, 1H), 1.84-1.74 (m, 2H), 1.67-1.60 (m, 1H), 1.60-1.55 (m, 1H), 1.55-1.40 (m, 3H), 1.14-1.06 (m, 1H), 1.04 (s, 3H), 0.91 (s, 3H), 0.84 (d, J=6.8 Hz, 3H), 0.80 (t, J=7.6 Hz, 3H).

[1758] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 582.2.

Example 195

(2S)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide

##STR00508##

[1759] The title compound was prepared in analogy to the procedure described for the preparation of Example 188, by using tert-butyl N-amino-N-[[(3R)-2-oxo-3-piperidyl]methyl]carbamate (Intermediate 39b) instead of tert-butyl N-amino-N-[[(3S)-2-oxo-3-piperidyl]methyl]carbamate (Intermediate 39a), and (2S)-2-chloro-2-fluoro-acetic acid instead of (2R)-2-chloro-2-fluoro-acetic acid to afford (2S)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide (Example 195) as a white solid.

[1760] .sup.1H NMR (400 MHz, DMSO-d6) : ppm 10.93 (d, J=104.8 Hz, 1H), 9.06 (dd, J=33.6 Hz, 7.2 Hz, 1H), 7.51 (s, 1H), 7.17-6.58 (m, 2H), 4.27-4.12 (m, 2H), 3.96-3.77 (m, 3H), 3.11 (s, 2H), 2.68-2.53 (m, 1H), 2.45-2.29 (m, 1H), 1.93-1.73 (m, 3H), 1.71-1.44 (m, 5H), 1.18-1.08 (m, 1H), 1.05 (s, 3H), 0.89 (s, 3H), 0.86 (d, J=6.8 Hz, 3H), 0.81 (t, J=7.2 Hz, 3H).

[1761] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 582.3.

Example 196

(1S)N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide

##STR00509##

[1762] The title compound was prepared in analogy to the procedure described for the preparation of Example 29, by using tert-butyl N-amino-N-[[(3S)-2-oxo-3-piperidyl]methyl]carbamate (Intermediate 39a) instead of tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (Intermediate 9), and (1S)-2,2-difluorocyclopropanecarboxylic acid and T.sub.3P instead of acetic anhydride to afford (1S)N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide (Example 196) as a white solid.

[1763] .sup.1H NMR (400 MHz, DMSO-d6) : ppm 11.07 (s, 1H), 8.48 (d, J=8.4 Hz, 1H), 7.56 (s, 1H), 7.00 (d, J=50.4 Hz, 1H), 4.49 (d, J=8.8 Hz, 1H), 4.01-3.93 (m, 2H), 3.89 (dd, J=10.4, 7.2 Hz, 1H), 3.67 (dd, J=10.4, 2.8 Hz, 1H), 3.38-3.33 (m, 1H), 3.14-3.07 (m, 2H), 2.95-32.84 (m, 1H), 2.78-2.69 (m, 1H), 2.56-2.51 (m, 1H), 2.44-2.36 (m, 1H), 1.90-1.71 (m, 8H), 1.68-1.54 (m, 2H), 1.50-1.41 (m, 1H), 1.39-1.31 (m, 1H), 0.95 (s, 9H).

[1764] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 592.4.

Example 197

(1S)N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide

##STR00510##

[1765] The title compound was prepared in analogy to the procedure described for the preparation of Example 29, by using tert-butyl N-amino-N-[[(3S)-2-oxo-3-piperidyl]methyl]carbamate (Intermediate 39a) instead of tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (Intermediate 9), (2S)-2-chloro-2-fluoro-acetic acid instead of (2R)-2-chloro-2-fluoro-acetic acid, and (1S)-2,2-difluorocyclopropanecarboxylic acid and T.sub.3P instead of acetic anhydride to afford (1S)N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide (Example 197) as a white solid.

[1766] .sup.1H NMR (400 MHz, DMSO-d6) : ppm 10.86 (d, J=130.4 Hz, 1H), 8.50-8.43 (m, 1H), 7.50 (d, J=36.4 Hz, 1H), 6.79 (dd, J=278.8, 48.8 Hz, 1H), 4.48 (d, J=8.4 Hz, 1H), 3.99-3.94 (m, 1H), 3.89-3.63 (m, 3H), 3.15-3.03 (m, 2H), 2.94-2.80 (m, 1H), 2.78-2.52 (m, 3H), 2.42-1.98 (m, 1H), 1.95-1.63 (m, 8H), 1.63-1.37 (m, 3H), 1.37-1.27 (m, 1H), 0.96 (s, 9H).

[1767] MS obsd. (ESI.sup.+) [(M+H).sup.+]: 592.4.

BIOLOGICAL EXAMPLE

Example 198

SARS-CoV-2 3CL.SUP.pro .Inhibition Assay

[1768] The full-length gene encoding SARS-CoV-2 3CL.sup.pro was optimized and synthesized for Escherichia coli (E. coli) expression. The method of cloning and producing authentic SARS-CoV-2 3CL.sup.pro was followed by the protocol published for SARS-CoV 3CL.sup.pro previously (Grum-Tokars V. et al. Evaluating the 3C-like protease activity of SARS-Coronavirus: Recommendations for standardized assays for drug discovery. Virus Res. 2008 April; 133(1):63-73). The protein sequence as follows

TABLE-US-00001 SGFRKMAFPSGKVEGCMVQVTCGTTTLNGLWLDDVVYCPRHVICT SEDMLNPNYEDLLIRKSNHNFLVQAGNVQLRVIGHSMQNCVLKLK VDTANPKTPKYKFVRIQPGQTFSVLACYNGSPSGVYQCAMRPNFT IKGSFLNGSCGSVGFNIDYDCVSFCYMHHMELPTGVHAGTDLEGN FYGPFVDRQTAQAAGTDTTITVNVLAWLYAAVINGDRWFLNRFTT TLNDFNLVAMKYNYEPLTQDHVDILGPLSAQTGIAVLDMCASLKE LLQNGMNGRTILGSALLEDEFTPFDVVRQCSGVTFQ

[1769] For the SARS-CoV-2 3CL.sup.pro assay, 2 L of 0.02 M recombinant SARS-CoV-2 3CL protease were mixed with serial dilutions of each compound in 4 L assay buffer containing 40 mM HEPES, pH=8.0, 1 mM CHAPS, 150 mM NaCl, 1 mM EDTA, 1 mM TCEP in a well of a 384-well plate and pre-incubated at rt for 1 hr. The custom-synthesized fluorogenic 3CL.sup.pro peptide substrate used in the assay is as follows: FAM-KTSAVLQSGFRKMEK-TAMRA. This FRET-based substrate contains a FAM fluorophore attached at the N-terminus of a canonical 3CL.sup.pro peptide substrate. The fluorophore is internally quenched by the TAMRA. The reaction was initiated by the addition of 10 L of the substrate with a final concentration of 15 M and each well was incubated at RT for 30 mins. The final concentration of the protease used at the assay was 25 nM and each compound was at a final concentration range of 100-0.0016 M. The IC.sub.50 value which is the value causing 50% inhibition of the catalytic activity of the SARS-CoV 3CL.sup.pro was calculated by four parameters equation analysis.

Example 199

SARS-CoV 3CL.SUP.pro .Inhibition Assay

TABLE-US-00002 TheSARS-CoV3CL.sup.prowasexpressedinE.coil BL21(DE3)withtheproteinsequenceof SGFRKMAFPSGKVEGCMVQVTCGTTTLNGLWLDDTVYCPRHVICT AEDMLNPNYEDLLIRKSNHSFLVQAGNVQLRVIGHSMQNCLLRLK VDTSNPKTPKYKFVRIQPGQTFSVLACYNGSPSGVYQCAMRPNHT IKGSFLNGSCGSVGFNIDYDCVSFCYMHHMELPTGVHAGTDLEGK FYGPFVDRQTAQAAGTDTTITLNVLAWLYAAVINGDRWFLNRFTT TLNDFNLVAMKYNYEPLTQDHVDILGPLSAQTGIAVLDMCAALKE LLQNGMNGRTILGSTILEDEFTPFDVVRQCSGVTFQ.

[1770] For the SARS-CoV 3CL.sup.pro assay, 2 L of 0.02 M recombinant SARS-CoV 3CL protease were mixed with serial dilutions of each compound in 4 L assay buffer containing 40 mM HEPES, pH=8.0, 1 mM CHAPS, 150 mM NaCl, 1 mM EDTA, 1 mM TCEP in a well of a 384-well plate and pre-incubated at rt for 1 hr. The custom-synthesized fluorogenic 3CL.sup.pro peptide substrate used in the assay is as follows: FAM-KTSAVLQSGFRKMEK-TAMRA.

[1771] This FRET-based substrate contains a FAM fluorophore attached at the N-terminus of a canonical 3CL.sup.pr peptide substrate. The fluorophore is internally quenched by the TAMRA. The reaction was initiated by the addition of 10 L of the substrate with a final concentration of 15 M and each well was incubated at RT for 30 mins. The final concentration of the protease used at the assay was 25 nM and each compound was at a final concentration range of 100-0.0016 M. The IC.sub.50 value which is the value causing 50% inhibition of the catalytic activity of the SARS-CoV 3CL.sup.pr was calculated by four parameters equation analysis.

Example 200

MERS-CoV 3CL.SUP.pro .Inhibition Assay

[1772] The MERS-CoV 3CL.sup.pro was expressed in E. coli BL21 (DE3) with the protein sequence of

TABLE-US-00003 SGLVKMSHPSGDVEACMVQVTCGSMTLNGLWLDNTVWCPRHVMCP ADQLSDPNYDALLISMTNHSFSVQKHIGAPANLRVVGHAMQGTLL KLTVDVANPSTPAYTFTTVKPGAAFSVLACYNGRPTGTFTVVMRP NYTIKGSFLCGSCGSVGYTKEGSVINFCYMHQMELANGTHTGSAF DGTMYGAFMDKQVHQVQLTDKYCSVNVVAWLYAAILNGCAWFVKP NRTSVVSFNEWALANQFTEFVGTQSVDMLAVKTGVAIEQLLYAIQ QLYTGFQGKQILGSTMLEDEFTPEDVNMQIMGVVMQ

[1773] For the MERS-CoV 3CL.sup.pro assay, 2 L of 0.02 M recombinant MERS-CoV 3CL protease were mixed with serial dilutions of each compound in 4 L assay buffer containing 40 mM HEPES, pH=8.0, 1 mM CHAPS, 150 mM NaCl, 1 mM EDTA, 1 mM TCEP in a well of a 384-well plate and pre-incubated at rt for 1 hr. The custom-synthesized fluorogenic 3CL.sup.pro peptide substrate used in the assay is as follows: FAM-KTSAVLQSGFRKMEK-TAMRA. This FRET-based substrate contains a FAM fluorophore attached at the N-terminus of a canonical 3CL.sup.pro peptide substrate. The fluorophore is internally quenched by the TAMRA. The reaction was initiated by the addition of 10 L of the substrate with a final concentration of 15 M and each well was incubated at RT for 30 mins. The final concentration of the protease used at the assay was 25 nM and each compound was at a final concentration range of 100-0.0016 M. The IC.sub.50 value which is the value causing 50% inhibition of the catalytic activity of the MERS-CoV 3CL.sup.pro was calculated by four parameters equation analysis.

Example 201

HCoV-229E 3CL.SUP.pro .Inhibition Assay

[1774] The HCoV-229E 3CL.sup.pro was expressed in E. coli BL21 (DE3) with the protein sequence of

TABLE-US-00004 AGLRKMAQPSGFVEKCVVRVCYGNTVLNGLWLGDIVYCPRHVIAS NTTSAIDYDHEYSIMRLHNFSIISGTAFLGVVGATMHGVTLKIKV SQTNMHTPRHSFRTLKSGEGFNILACYDGCAQGVFGVNMRTNWTI RGSFINGACGSPGYNLKNGEVEFVYMHQIELGSGSHVGSSFDGVM YGGFEDQPNLQVESANQMLTVNVVAFLYAAILNGCTWWLKGEKLF VEHYNEWAQANGFTAMNGEDAFSILAAKTGVCVERLLHAIQVLNN GFGGKQILGYSSLNDEFSINEVVKQMFGVNLQ

[1775] For the HCoV-229E 3CL.sup.pro assay, 2 L of 0.02 M recombinant HCoV-229E 3CL protease were mixed with serial dilutions of each compound in 4 L assay buffer containing 40 mM HEPES, pH=8.0, 1 mM CHAPS, 150 mM NaCl, 1 mM EDTA, 1 mM TCEP in a well of a 384-well plate and pre-incubated at rt for 1 hr. The custom-synthesized fluorogenic 3CL.sup.pro peptide substrate used in the assay is as follows: FAM-KTSAVLQSGFRKMEK-TAMRA. This FRET-based substrate contains a FAM fluorophore attached at the N-terminus of a canonical 3CL.sup.pro peptide substrate. The fluorophore is internally quenched by the TAMRA. The reaction was initiated by the addition of 10 L of the substrate with a final concentration of 15 M and each well was incubated at RT for 30 mins. The final concentration of the protease used at the assay was nM and each compound was at a final concentration range of 100-0.0016 M. The IC.sub.50 value which is the value causing 50% inhibition of the catalytic activity of the HCoV-229E 3CL.sup.pro was calculated by four parameters equation analysis.

Example 202

HCoVOC43 3CL.SUP.pro .Inhibition Assay

[1776] The HCoVOC43 3CL.sup.pro was expressed in E. coli BL21 (DE3) with the protein sequence of

TABLE-US-00005 SGIVKMVNPTSKVEPCVVSVTYHNMTLNGLWLDDKVYCPRHVICS ASDMTNPDYTNLLCVTSSDFTVLFDRLSLTVMSYQMRGCMLVLTV TLQNSRTPKYTFGVVKPGETFTVLAAYNGKPQGAFHVTMRSSYTI KGSFLCGSCGSVGYVIMGDCVKFVYMHQLELSTGCHTGTDFNGDF YGPYKDAQVVQLPIQDYIQSVNFLAWLYAAILNNCNWFIQSDKCS VEDFNVMALSNGFSQVKSDLVIDALASMTGVSLETLLAAIKRLKN GFQGRQIMGSCSFEDELTPSDVYQQLAGIKLQ

[1777] For the HCoVOC43 3CL.sup.pro assay, 2 L of 0.02 M recombinant HCoVOC43 3CL protease were mixed with serial dilutions of each compound in 4 L assay buffer containing 40 mM HEPES, pH=8.0, 1 mM CHAPS, 150 mM NaCl, 1 mM EDTA, 1 mM TCEP in a well of a 384-well plate and pre-incubated at rt for 1 hr. The custom-synthesized fluorogenic 3CL.sup.pro peptide substrate used in the assay is as follows: FAM-KTSAVLQSGFRKMEK-TAMRA. This FRET-based substrate contains a FAM fluorophore attached at the N-terminus of a canonical 3CL.sup.pr peptide substrate. The fluorophore is internally quenched by the TAMRA. The reaction was initiated by the addition of 10 L of the substrate with a final concentration of 15 M and each well was incubated at RT for 30 mins. The final concentration of the protease used at the assay was nM and each compound was at a final concentration range of 100-0.0016 M. The IC.sub.50 value which is the value causing 50% inhibition of the catalytic activity of the HCoVOC43 3CL.sup.pro was calculated by four parameters equation analysis.

TABLE-US-00006 TABLE 1 Activity of Examples and Compounds of present invention in SARS-CoV-2 3CL.sup.pro assay Example IC.sub.50 (M) 1 0.010 2 0.019 3 0.014 4 0.006 5 0.010 7 0.008 8 0.010 9 0.012 10 0.021 11 0.218 12 0.015 13 0.009 14 0.007 15 0.008 16 0.020 17 0.121 18 0.006 19 0.013 20 0.014 21 0.025 22 0.008 23 0.009 24 0.018 25 0.015 26 0.012 27 0.029 28 0.008 29 0.010 30 0.008 31 0.008 32 0.007 33 0.007 34 0.008 35 0.008 36 0.007 37 0.009 38 0.008 39 0.009 40 0.021 41 0.007 42 0.007 43 0.008 44 0.008 45 0.019 46 0.008 47 0.007 48 0.012 49 0.007 50 0.006 51 0.007 52 0.01 53 0.008 54 0.009 55 0.008 56 0.008 57 0.011 58 0.011 59 0.007 60 0.010 61 0.008 62 0.008 63 0.009 64 0.010 65 0.017 66 0.010 67 0.010 68 0.018 69 0.011 70 0.007 71 0.007 72 0.008 73 0.033 74 0.007 75 0.012 76 0.008 77 0.007 78 0.009 79 0.0071 80 0.010 81 0.009 82 0.008 83 0.009 84 0.007 85 0.012 86 0.007 87 0.014 88a 0.042 88b >10 89a 0.051 89b >10 90 0.010 91 0.012 92 0.008 93 0.031 94 0.021 95 0.010 96 0.011 97 0.011 98 0.009 99 0.008 100 0.008 101 0.009 102 0.012 103 0.013 104 0.012 105 0.008 106 0.033 107 0.018 108 0.043 109 0.014 110 0.024 111 0.016 112 0.008 113 0.010 114 0.017 115 0.009 116 0.014 117 0.011 118 0.013 119 0.015 120 0.019 121 0.026 122 0.026 123 0.037 124 0.026 125 0.010 126 0.010 127 0.010 128 0.011 129 0.011 130 0.012 131 0.010 132 0.010 133 0.020 134 0.010 135 0.011 136 0.016 137 0.018 138 0.016 139 0.014 140 0.011 141 0.010 142 0.010 143 0.008 144 0.011 145 0.018 146 0.016 147 0.012 148 0.013 149 0.006 150 0.011 151 0.013 152 0.015 153 0.012 154 0.017 155a 0.024 155b 1.569 156 0.014 157 0.044 158 0.011 159 0.013 160 0.013 161 0.016 162 0.012 163a 0.009 163b 0.017 164a 0.008 164b NA 165a 0.011 165b 0.020 166a 0.013 166b 0.019 167a 0.010 167b 0.019 168a 0.011 168b 0.100 169a 0.009 169b NA 170a 0.016 170b NA 171a 0.008 171b NA 172 0.017 173 0.013 174 0.010 175 0.010 176 0.011 177 0.147 178 0.148 179 0.201 180 0.491 181 0.208 182 0.011 183 0.011 184 0.016 185 0.011 186 0.013 187 0.024 188 0.008 189 0.008 190 0.008 191 0.007 192 0.010 193 0.017 194 0.015 195 0.028 196 0.011 197 0.011 NA: not available

TABLE-US-00007 TABLE 2 Activity of Examples and Compounds of present invention in different coronaviruses Example 229E MERS OC43 SARS 1 0.035 0.115 0.023 0.015 2 0.041 0.177 0.023 0.030 3 0.038 0.174 0.020 0.020 4 0.039 0.07 0.022 0.016 5 0.104 0.303 0.031 0.019 6 0.042 0.109 0.027 0.014 7 0.193 0.379 0.017 0.017 8 0.042 0.136 0.028 0.025 9 0.939 2.785 0.034 0.038 10 1.236 3.040 0.104 0.373 11 0.056 0.260 0.036 0.034 12 0.026 0.106 0.02 0.017 13 0.024 0.094 0.025 0.014 14 0.036 0.121 0.020 0.018 15 0.055 0.204 0.038 0.026 16 0.159 0.43 0.085 0.357 17 0.074 0.408 0.027 0.429 18 0.074 0.408 0.027 0.429 19 0.027 0.092 0.02 0.015 20 0.047 0.106 0.017 0.016 21 0.034 0.109 0.022 0.017 22 0.076 0.183 0.024 0.031 23 0.021 0.065 0.016 0.011 24 0.031 0.114 0.019 0.013 25 0.127 0.408 0.019 0.027 26 0.028 0.098 0.018 0.021 27 0.029 0.136 0.020 0.020 28 0.396 1.019 0.025 0.038 29 0.028 0.068 0.017 0.011 30 0.049 0.143 0.020 0.015 31 0.028 0.076 0.018 0.012 32 0.023 0.080 0.019 0.010 33 0.027 0.079 0.018 0.008 34 0.023 0.066 0.018 0.012 35 0.023 0.060 0.019 0.008 36 0.034 0.093 0.017 0.012 37 0.029 0.076 0.015 0.011 38 0.029 0.072 0.015 0.010 39 0.029 0.071 0.015 0.011 40 0.027 0.050 0.022 0.013 41 0.068 0.221 0.051 0.033 42 0.024 0.082 0.018 0.009 43 0.022 0.058 0.017 0.011 44 0.023 0.055 0.018 0.011 45 0.035 0.104 0.019 0.010 46 0.049 0.152 0.045 0.029 47 0.026 0.076 0.018 0.012 48 0.022 0.056 0.018 0.012 49 0.033 0.096 0.027 0.013 50 0.017 0.042 0.016 0.008 51 0.021 0.059 0.017 0.010 52 0.022 0.057 0.017 0.015 53 0.032 0.087 0.019 0.013 54 0.024 0.056 0.016 0.012 55 0.021 0.056 0.017 0.014 56 0.018 0.052 0.016 0.011 57 0.02 0.062 0.016 0.013 58 0.026 0.073 0.016 0.015 59 0.021 0.062 0.017 0.017 60 0.019 0.047 0.017 0.009 61 0.030 0.121 0.021 0.011 62 0.017 0.043 0.016 0.010 63 0.018 0.06 0.018 0.011 64 0.020 0.071 0.016 0.012 65 0.025 0.086 0.016 0.012 66 0.035 0.141 0.027 0.022 67 0.028 0.084 0.020 0.014 68 0.023 0.081 0.017 0.014 69 0.053 0.249 0.023 0.028 70 0.030 0.101 0.019 0.016 71 0.019 0.041 0.017 0.010 72 0.023 0.058 0.015 0.011 73 0.040 0.110 0.019 0.012 74 0.117 0.358 0.073 0.045 75 0.033 0.083 0.017 0.012 76 0.088 0.194 0.020 0.015 77 0.028 0.069 0.017 0.012 78 0.023 0.057 0.017 0.01 79 0.039 0.114 0.017 0.011 80 0.02 0.058 0.014 0.011 81 0.045 0.093 0.018 0.015 82 0.033 0.084 0.017 0.012 83 0.031 0.097 0.013 0.010 84 0.03 0.087 0.018 0.014 85 0.021 0.069 0.015 0.012 86 0.035 0.086 0.017 0.019 87 0.019 0.073 0.015 0.0093 88a 0.105 0.249 0.017 0.028 88b 0.053 0.155 0.015 0.076 89a >10 >10 3.429 >10 89b 0.047 0.193 0.017 0.101 90 0.022 0.055 0.016 0.012 91 0.039 0.115 0.018 0.015 92 0.023 0.057 0.02 0.018 93 0.042 0.094 0.019 0.054 94 0.059 0.136 0.021 0.029 95 0.028 0.071 0.019 0.014 96 0.025 0.063 0.01 0.014 97 0.074 0.208 0.018 0.013 98 0.022 0.059 0.015 0.011 99 0.030 0.081 0.021 0.012 100 0.032 0.077 0.021 0.014 101 0.040 0.094 0.018 0.013 102 0.112 0.207 0.018 0.016 103 0.167 0.372 0.019 0.025 104 0.055 0.128 0.018 0.020 105 0.027 0.071 0.016 0.011 106 0.066 0.179 0.030 0.057 107 0.040 0.111 0.020 0.025 108 0.050 0.127 0.024 0.074 109 0.029 0.086 0.018 0.020 110 0.037 0.096 0.021 0.033 111 0.037 0.096 0.022 0.028 112 0.022 0.071 0.017 0.014 113 0.023 0.079 0.020 0.015 114 0.029 0.113 0.022 0.025 115 0.030 0.102 0.019 0.015 116 0.036 0.098 0.022 0.018 117 0.025 0.086 0.014 0.011 118 0.027 0.109 0.021 0.018 119 0.056 0.206 0.023 0.020 120 0.038 0.098 0.017 0.034 121 0.043 0.131 0.020 0.050 122 0.046 0.146 0.019 0.036 123 0.051 0.146 0.027 0.062 124 0.041 0.115 0.021 0.045 125 0.042 0.114 0.018 0.012 126 0.028 0.068 0.016 0.011 127 0.035 0.068 0.018 0.012 128 0.036 0.097 0.019 0.018 129 0.029 0.104 0.020 0.016 130 0.032 0.087 0.020 0.019 131 0.026 0.158 0.020 0.014 132 0.025 0.106 0.023 0.014 133 0.040 0.106 0.024 0.032 134 0.036 0.097 0.019 0.014 135 0.039 0.131 0.021 0.015 136 0.055 0.074 0.035 0.015 137 0.046 0.192 0.025 0.027 138 0.054 0.283 0.023 0.025 139 0.035 0.139 0.020 0.018 140 0.031 0.094 0.015 0.025 141 0.035 0.117 0.020 0.015 142 0.031 0.083 0.020 0.013 143 0.028 0.086 0.020 0.013 144 0.033 0.112 0.016 0.015 145 0.077 0.152 0.017 0.027 146 0.069 0.151 0.015 0.023 147 0.040 0.089 0.014 0.016 148 0.03 0.13 0.021 0.02 149 0.045 0.139 0.023 0.015 150 0.033 0.063 0.025 0.016 151 0.031 0.067 0.024 0.014 152 0.028 0.099 0.021 0.02 153 0.043 0.25 0.02 0.015 154 0.052 0.305 0.033 0.021 155a 0.739 1.328 0.037 0.028 155b >10.000 >10.000 1.828 2.442 156 0.032 0.106 0.024 0.028 157 0.060 0.149 0.022 0.058 158 0.034 0.08 0.025 0.017 159 0.040 0.103 0.019 0.013 160 0.024 0.105 0.023 0.019 161 0.099 0.336 0.024 0.027 162 0.033 0.094 0.019 0.015 163a 0.052 0.226 0.028 0.018 163b 0.104 0.469 0.042 0.033 164a 0.098 0.243 0.030 0.016 164b NA NA NA NA 165a 0.038 0.185 0.026 0.012 165b 0.057 0.291 0.037 0.036 166a 0.047 0.229 0.027 0.018 166b 0.051 0.239 0.040 0.030 167a 0.053 0.169 0.018 0.015 167b 0.210 1.630 0.070 0.041 168a 0.104 0.290 0.031 0.016 168b 0.219 2.109 0.149 0.185 169a 0.056 0.118 0.027 0.020 169b NA NA NA NA 170a 0.107 0.276 0.035 0.025 170b NA NA NA NA 171a 0.094 0.130 0.027 0.017 171b NA NA NA NA 172 0.071 0.187 0.031 0.026 173 0.027 0.175 0.027 0.018 174 0.029 0.123 0.023 0.012 175 0.037 0.105 0.023 0.015 176 0.028 0.096 0.020 0.016 177 0.138 0.278 0.041 0.232 178 0.065 0.264 0.024 0.259 179 0.093 0.315 0.025 0.222 180 0.241 0.657 0.035 0.786 181 0.048 0.363 0.032 0.252 182 0.037 0.089 0.014 0.012 183 0.059 0.174 0.015 0.016 184 0.086 0.275 0.017 0.041 185 0.040 0.099 0.017 0.021 186 0.049 0.069 0.019 0.023 187 0.036 0.167 0.020 0.043 188 0.026 0.068 0.016 0.012 189 0.024 0.05 0.015 0.010 190 0.029 0.059 0.017 0.011 191 0.027 0.049 0.018 0.011 192 0.052 0.148 0.019 0.017 193 0.049 0.11 0.015 0.033 194 0.029 0.112 0.026 0.025 195 0.029 0.112 0.023 0.051 196 0.038 0.089 0.02 0.014 197 0.065 0.094 0.016 0.013 NA: not available

Example 203

[1778] 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:

TABLE-US-00008 Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mg Corn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20 mg 425 mg

Example 204

[1779] 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:

TABLE-US-00009 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 220.0 mg