Hepatitis C virus inhibitors

Abstract

The present disclosure relates to compounds, compositions and methods for the treatment of hepatitis C virus (HCV) infection. Also disclosed are pharmaceutical compositions containing such compounds and methods for using these compounds in the treatment of HCV infection.

Claims

1. A compound selected from (1S,1′S)-2,2′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl))bis(1-cyclohexyl-2-oxoethanol); (2S,2′S)-1,1′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl))bis(4-methyl-1-oxo-2-pentanol); (2S,2′S)-1,1′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl))bis(3-methyl-1-oxo-2-butanol); 3-buten-1-yl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-(((3-buten-1-yloxy)carbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-2-methyl-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N-methylglycyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate; (2S,2′S)-1,1′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl))bis(N-methyl-1-oxo-2-propanamine); (4S,4′S)-4,4′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediylcarbonyl))bis(1,3-oxazinan-2-one); methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N-ethylglycyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N-benzylglycyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N-isobutylglycyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N-sec-butylglycyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N-isopropylglycyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N,N-diisopropylglycyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2-(3-oxetanyl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-2-(3-oxetanyl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-2-methyl-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S,2R)-2-methoxy-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-O-methyl-L-threonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-2-methyl-1-pyrrolidinyl)carbonyl)propyl)carbamate; methyl ((1R)-2-((2R)-2-(5-(4′-(2-((2S,5R)-1-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-5-phenyl-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate; rel-(1R)-2-((2S)-2-(4-(4′-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)octahydro-1H-indol-2-yl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-N,N-dimethyl-2-oxo-1-phenylethanamine; methyl rel-((1R)-2-((2S)-2-(4-(4′-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)octahydro-1H-indol-2-yl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate; (1R)—N-ethyl-2-((2S)-2-(4-(4′-(2-((2S)-1-((2R)-2-(ethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethanamine; (1R)—N-methyl-2-((2S)-2-(4-(4′-(2-((2S)-1-((2R)-2-(methylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethanamine; N-((1R)-2-oxo-1-phenyl-2-((2S)-2-(4-(4′-(2-((2S)-1-((2R)-2-phenyl-2-(propylamino)acetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)ethyl)-1-propanamine; N-((1R)-2-((2S)-2-(4-(4′-(2-((2S)-1-((2R)-2-(butylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)-1-butanamine; ethyl ((1S)-1-(((2S)-2-(4-(4′-(2-((2S)-1-((2S)-2-((ethoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; propyl ((1S)-1-methyl-2-oxo-2-((2S)-2-(4-(4′-(2-((2S)-1-(N-(propoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)ethyl)carbamate; butyl ((1S)-2-((2S)-2-(4-(4′-(2-((2S)-1-(N-(butoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate; (2S)-2-hydroxy-N-((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-(N-((2S)-2-hydroxy-3-methylbutanoyl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)-3-methylbutanamide; ethyl ((1S)-1-(((2S)-2-(4-(4′-(2-((2S)-1-((2S)-2-((ethoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; isopropyl ((1S)-1-(((2S)-2-(4-(4′-(2-((2S)-1-((2S)-2-((isopropoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; and (2S)-1-((2S)-2-(4-(4′-(2-((2S)-1-((2S)-2-hydroxypropanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-oxo-2-propanol; or a pharmaceutically acceptable salt thereof.

2. A compound selected from tert-butyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-((tert-butoxycarbonyl)(methyl)amino)-4-methylpentanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-3-methylbutyl)methylcarbamate; tert-butyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-((tert-butoxycarbonyl)(methyl)amino)-3-methylpentanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylbutyl)methylcarbamate; tert-butyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-((tert-butoxycarbonyl)(methyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)methylcarbamate; tert-butyl ((1S,2R)-1-(((2S)-2-(4-(4′-(2-((2S)-1-(N-(tert-butoxycarbonyl)-N-methyl-L-alloisoleucyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylbutyl)methylcarbamate; (2S)—N,4-dimethyl-1-((2S)-2-(4-(4′-(2-((2S)-1-((2S)-4-methyl-2-(methylamino)pentanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-oxo-2-pentanamine; (2S)—N,3-dimethyl-1-((2S)-2-(4-(4′-(2-((2S)-1-((2S)-3-methyl-2-(methylamino)pentanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-oxo-2-pentanamine; (2S)—N,3-dimethyl-1-((2S)-2-(4-(4′-(2-((2S)-1-((2S)-3-methyl-2-(methylamino)butanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-oxo-2-butanamine; (2S,3R)—N,3-dimethyl-1-((2S)-2-(4-(4′-(2-((2S)-1-((2S,3R)-3-methyl-2-(methylamino)pentanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-oxo-2-pentanamine; methyl ((1S)-1-(((2S)-2-(4-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-2,3-dimethylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-1,2-dimethylpropyl)carbamate; methyl ((1S)-2-((2S)-2-(4-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate; methyl (2-((2S)-2-(4-(4′-(2-((2S)-1-(((methoxycarbonyl)amino)(tetrahydro-2H-pyran-4-yl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate; methyl ((1S)-2-((2S)-2-(4-(4′-(2-((2S)-1-((2R)-2-(ethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-1,2-dimethylpropyl)carbamate; methyl ((1S)-2-methyl-1-(((2S)-2-(4-(4′-(2-((2S)-1-(N-(tetrahydro-2H-pyran-4-yl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate; methyl ((1S)-2-methyl-1-(((2S)-2-(4-(4′-(2-((2S)-1-(N-(tetrahydro-2H-pyran-4-yl)-L-valyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate; methyl ((1S)-2-methyl-1-(((2S)-2-(4-(4′-(2-((2S)-1-(N-(tetrahydro-2H-pyran-4-yl)glycyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate; methyl ((1S)-2-methyl-1-(((2S)-2-(4-(4′-(2-((2S)-1-(N-(tetrahydro-2H-pyran-4-yl)-D-valyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate; methyl ((1S)-2-methyl-1-(((2S)-2-(4-(4′-(2-((2S)-1-(N-(tetrahydro-2H-pyran-4-yl)-D-alanyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate; (3S)-tetrahydro-3-furanyl ((1S)-1-(((2S)-2-(4-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-valyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; tetrahydro-2H-pyran-4-yl ((1S)-1-(((2S)-2-(4-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-valyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; (3R)-tetrahydro-3-furanyl ((1S)-1-(((2S)-2-(4-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-valyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-1-(((2S)-2-(4-(4′-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-1-(((2S)-2-(4-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; N-((1S)-1-(((2S)-2-(4-(4′-(2-((2S)-1-((2S)-2-acetamido-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)acetamide; N-((1S)-2-methyl-1-(((2S)-2-(4-(4′-(2-((2S)-1-((2S)-3-methyl-2-(propionylamino)butanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)propanamide; 2-methoxy-N-((1S)-1-(((2S)-2-(4-(4′-(2-((2S)-1-((2S)-2-((methoxyacetyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)acetamide; 1-methyl-3-((1S)-2-methyl-1-(((2S)-2-(4-(4′-(2-((2S)-1-(N-(methylcarbamoyl)-L-valyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)urea; and 1-ethyl-3-((1S)-1-(((2S)-2-(4-(4′-(2-((2S)-1-((2S)-2-((ethylcarbamoyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)urea; or a pharmaceutically acceptable salt thereof.

3. A compound selected from N-((1S)-2-methyl-1-(((2S)-2-(4-(4′-(2-((2S)-1-((2S)-3-methyl-2-((methylsulfonyl)amino)butanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)methanesulfonamide; N-((1S)-1-(((2S)-2-(4-(4′-(2-((2S)-1-((2S)-2-((ethylsulfonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)ethanesulfonamide; N-((1S)-1-(((2S)-2-(4-(4′-(2-((2S)-1-((2S)-2-((cyclopropylsulfonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)cyclopropanesulfonamide; N-((1S)-1-methyl-2-((2S)-2-(5-(4′-(2-((2S)-1-(N-(methylsulfonyl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxoethyl)methanesulfonamide; methyl ((1S)-2-methyl-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N-2-pyrimidinyl-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate; methyl ((1S)-1-methyl-2-oxo-2-((2S)-2-(5-(4′-(2-((2S)-1-(N-2-pyrimidinyl-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)ethyl)carbamate; methyl ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1-(N-2-pyrimidinyl-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)ethyl)carbamate; N-((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)-2-pyrimidinamine; methyl ((1S)-2-methyl-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N-(4,5-dihydro-1H-imidazol-2-yl)-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-(N-(4,5-dihydro-1H-imidazol-2-yl)-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate; N-((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)-4,5-dihydro-1H-imidazol-2-amine; methyl ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1-(N-2-pyrimidinyl-D-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)ethyl)carbamate; methyl ((1S)-2-methyl-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N-2-pyrimidinyl-D-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate; methyl ((1S)-1-methyl-2-oxo-2-((2S)-2-(5-(4′-(2-((2S)-1-(N-2-pyrimidinyl-D-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)ethyl)carbamate; N-((1R)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)-2-pyrimidinamine; methyl ((1S)-2-methyl-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)-D-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N-(4,5-dihydro-1H-imidazol-2-yl)-D-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-1-cyclopropyl-2-((2S)-2-(5-(4′-(2-((2S)-1-(N-(4,5-dihydro-1H-imidazol-2-yl)-D-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxoethyl)carbamate; N-((1R)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)-4,5-dihydro-1H-imidazol-2-amine; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N-(5-amino-1-methyl-1H-1,2,4-triazol-3-yl)-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N-(4,5-dihydro-1,3-thiazol-2-yl)-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-2-methyl-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N-4-pyrimidinyl-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N-(5-amino-1,2,4-oxadiazol-3-yl)-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N-(cyano(dimethyl)carbamimidoyl)-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-2-methyl-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N-3-pyridinyl-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate; methyl ((1S)-1-methyl-2-oxo-2-((2S)-2-(5-(4′-(2-((2S)-1-(N-3-pyridinyl-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)ethyl)carbamate; methyl ((1S,2R)-2-methoxy-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N-3-pyridinyl-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate; and N-((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)-3-pyridinamine; or a pharmaceutically acceptable salt thereof.

4. A compound selected from methyl ((1S)-2-methyl-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N-5-pyrimidinyl-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate; methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-(1H-1,2,3-triazol-4-ylmethyl)ethyl)carbamate; methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-(1H-1,2,3-triazol-4-ylmethyl)ethyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-(1H-1,2,3-triazol-4-yl)propanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2S,3R)-3-methoxy-2-((methoxycarbonyl)amino)butanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-(1H-1,2,3-triazol-4-ylmethyl)ethyl)carbamate; methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-(1H-pyrazol-1-ylmethyl)ethyl)carbamate; methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-(1H-pyrazol-1-ylmethyl)ethyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-(1H-pyrazol-1-yl)propanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-2S)-2-(5-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-O-methyl-L-threonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-(1H-pyrazol-1-ylmethyl)ethyl)carbamate; methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-((1-methyl-1H-imidazol-4-yl)methyl)-2-oxoethyl)carbamate; methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-((1-methyl-1H-imidazol-4-yl)methyl)-2-oxoethyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-(1-methyl-1H-imidazol-4-yl)propanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2S,3R)-3-methoxy-2-((methoxycarbonyl)amino)butanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-((1-methyl-1H-imidazol-4-yl)methyl)-2-oxoethyl)carbamate; methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-((1-methyl-1H-imidazol-5-yl)methyl)-2-oxoethyl)carbamate; methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-((1-methyl-1H-imidazol-5-yl)methyl)-2-oxoethyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-(1-methyl-1H-imidazol-5-yl)propanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2S,3R)-3-methoxy-2-((methoxycarbonyl)amino)butanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-((1-methyl-1H-imidazol-5-yl)methyl)-2-oxoethyl)carbamate; methyl ((1S)-1-methyl-2-oxo-2-((2S)-2-(5-(4′-(2-((2S)-1-(((2S)-4-oxo-2-azetidinyl)carbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)ethyl)carbamate; methyl (2S)-2-(((2S)-2-(5-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-1-azetidinecarboxylate; methyl (2S)-2-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-1-azetidinecarboxylate; methyl ((1S)-3-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-3-oxopropyl)carbamate; methyl ((1R)-3-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-isopropyl-3-oxopropyl)carbamate; methyl ((1S)-1-benzyl-3-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-3-oxopropyl)carbamate; methyl ((1R)-3-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-3-oxo-1-(2-thienylmethyl)propyl)carbamate; methyl ((1R)-3-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-3-oxo-1-(3-thienylmethyl)propyl)carbamate; methyl ((1S)-3-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-3-oxo-1-(2-thienylmethyl)propyl)carbamate; methyl ((1S,3R)-3-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)cyclopentyl)carbamate; and methyl ((1R)-1-benzyl-3-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-3-oxopropyl)carbamate; or a pharmaceutically acceptable salt thereof.

5. A compound selected from methyl ((1R)-3-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-(2-fluorobenzyl)-3-oxopropyl)carbamate; methyl ((1R,3S)-3-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)cyclopentyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(((1R,3S)-3-((methoxycarbonyl)amino)cyclopentyl)carbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(((1S,3R)-3-((methoxycarbonyl)amino)cyclopentyl)carbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-(((1R,3S)-3-((methoxycarbonyl)amino)cyclopentyl)carbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate; methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-(((1S,3R)-3-((methoxycarbonyl)amino)cyclopentyl)carbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-(2-pyridinyl)propanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-(2-pyridinylmethyl)ethyl)carbamate; methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2S,3R)-3-methoxy-2-((methoxycarbonyl)amino)butanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-(2-pyridinylmethyl)ethyl)carbamate; methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-(2-pyridinylmethyl)ethyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((cis-4-((methoxycarbonyl)amino)cyclohexyl)carbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((trans-4-((methoxycarbonyl)amino)cyclohexyl)carbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((cis-4-(diethylamino)cyclohexyl)carbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S,2R)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((cis-4-(diethylamino)cyclohexyl)carbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methoxypropyl)carbamate; cis-4-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-N,N-diethylcyclohexanamine; methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-((cis-4-(diethylamino)cyclohexyl)carbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate; methyl ((1S)-1-((1-benzyl-1H-imidazol-4-yl)methyl)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2S,3R)-3-methoxy-2-((methoxycarbonyl)amino)butanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxoethyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-3-(1-benzyl-1H-imidazol-4-yl)-2-((methoxycarbonyl)amino)propanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2S)-3-(1-benzyl-1H-imidazol-4-yl)-2-((methoxycarbonyl)amino)propanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate; methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2S,3R)-3-methoxy-2-((methoxycarbonyl)amino)butanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-(1,3-thiazol-4-ylmethyl)ethyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-(1,3-thiazol-4-yl)propanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-(1,3-thiazol-4-ylmethyl)ethyl)carbamate; methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-(1,3-thiazol-4-ylmethyl)ethyl)carbamate; methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2S,3R)-3-methoxy-2-((methoxycarbonyl)amino)butanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-(3-pyridinylmethyl)ethyl)carbamate; methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-(3-pyridinylmethyl)ethyl)carbamate; methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-(3-pyridinylmethyl)ethyl)carbamate; methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-(3-pyridinylmethyl)ethyl)carbamate; methyl ((1R,3S)-3-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-3-methoxy-2-((methoxycarbonyl)amino)butanoyl-pyrrolidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)cyclopentyl)carbamate; and methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2S,3R)-3-methoxy-2-((methoxycarbonyl)amino)butanoyl-pyrrolidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-(4-pyridinylmethyl)ethyl)carbamate; or a pharmaceutically acceptable salt thereof.

6. A compound selected from methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-(4-pyridinylmethyl)ethyl)carbamate; methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-(4-pyridinylmethyl)ethyl)carbamate; methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-(4-pyridinylmethyl)ethyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(O-(hydroxy(methoxy)phosphoryl)-N-(methoxycarbonyl)-L-tyrosyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S,2R)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(O-(hydroxy(methoxy)phosphoryl)-N-(methoxycarbonyl)-L-tyrosyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methoxypropyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(((1S,2R)-2-((methoxycarbonyl)amino)cyclohexyl)carbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1R,2S)-2-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)cyclohexyl)carbamate; methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-(((1S,2R)-2-((methoxycarbonyl)amino)cyclohexyl)carbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate; methyl ((1R,2S)-2-(((2S)-2-(5-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)cyclohexyl)carbamate; methyl ((1R,2S)-2-(((2S)-2-(5-(4′-(2-((2S)-1-((cis-4-(diethylamino)cyclohexyl)carbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)cyclohexyl)carbamate; methyl ((1R,2S)-2-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-acetamido-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)cyclohexyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-3-(1H-indol-3-yl)-2-((methoxycarbonyl)amino)propanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-1-(1H-indol-3-ylmethyl)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2S,3R)-3-methoxy-2-((methoxycarbonyl)amino)butanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxoethyl)carbamate; methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-(1H-indol-3-ylmethyl)-2-oxoethyl)carbamate; methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2S)-3-(1H-indol-3-yl)-2-((methoxycarbonyl)amino)propanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate; methyl ((1S)-1-(4-(aminomethyl)benzyl)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxoethyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(O-benzyl-N-(methoxycarbonyl)-L-tyrosyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S,2R)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(O-benzyl-N-(methoxycarbonyl)-L-tyrosyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methoxypropyl)carbamate; methyl ((1S)-1-(4-(benzyloxy)benzyl)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxoethyl)carbamate; methyl ((1S)-1-(4-(benzyloxy)benzyl)-2-((2S)-2-(5-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxoethyl)carbamate; methyl ((1R,2R)-2-(((2S)-2-(5-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)cyclopentyl)carbamate; methyl ((1R,2R)-2-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)cyclopentyl)carbamate; methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-(((1R,2R)-2-((methoxycarbonyl)amino)cyclopentyl)carbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate; methyl ((1S)-1-(4-hydroxybenzyl)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxoethyl)carbamate; methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-(4-hydroxybenzyl)-2-oxoethyl)carbamate; methyl ((1S)-1-(4-hydroxybenzyl)-2-((2S)-2-(5-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxoethyl)carbamate; methyl ((1S)-1-(4-(acetamidomethyl)benzyl)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxoethyl)carbamate; methyl ((1S)-1-(4-(((ethylcarbamoyl)amino)methyl)benzyl)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxoethyl)carbamate; and methyl ((1S,2S)-2-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)cyclopentyl)carbamate; or a pharmaceutically acceptable salt thereof.

7. A compound selected from methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-(41S,2S)-2-((methoxycarbonyl)amino)cyclopentyl)carbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate; methyl ((1S,2S)-2-(((2S)-2-(5-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)cyclopentyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-O-methyl-L-homoseryl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-3-methoxy-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate; methyl ((1S,2R)-2-methoxy-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-O-methyl-L-homoseryl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate; methyl ((1S,2S)-2-(((2S)-2-(5-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-O-methyl-L-homoseryl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)cyclopentyl)carbamate; methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-(1H-1,2,3-triazol-4-yl)propanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-(1H-1,2,3-triazol-4-ylmethyl)ethyl)carbamate; dimethyl (4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl((2S)-4-oxo-4,2-butanediyl)))biscarbamate; dimethyl (4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl((3R)-4-methyl-1-oxo-1,3-pentanediyl)))biscarbamate; methyl ((1R)-3-((2S)-2-(5-(4′-(2-(1-43R)-3-((methoxycarbonyl)amino)-3-phenylpropanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-3-oxo-1-phenylpropyl)carbamate; methyl ((1S)-3-((2S)-2-(5-(4′-(2-(1-((3S)-3-((methoxycarbonyl)amino)-3-phenylpropanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-3-oxo-1-phenylpropyl)carbamate; methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-(2-pyridinyl)propanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-(2-pyridinylmethyl)ethyl)carbamate; methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2S)-3-(1H-imidazol-4-yl)-2-((methoxycarbonyl)amino)propanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-(1H-imidazol-4-ylmethyl)-2-oxoethyl)carbamate; (6S,6′S)-6,6′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediylcarbonyl))didihydro-2,4 (1H,3H)-pyrimidinedione; (4S,5R,4′S,5′R)-4,4′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediylcarbonyl))bis(5-methyl-1,3-oxazolidin-2-one); N-(3-((2S)-2-(5-(4′-(2-((2S)-1-(3-acetamidopropanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-3-oxopropyl)acetamide; dimethyl (4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl((3R)-1-oxo-5-phenyl-1,3-pentanediyl)))biscarbamate; dimethyl (4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl((2R)-4-oxo-1-(2-thienyl)-4,2-butanediyl)))biscarbamate; dimethyl (4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl((2R)-4-oxo-1-(3-thienyl)-4,2-butanediyl)))biscarbamate; dimethyl (4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl((2S)-4-oxo-1-(2-thienyl)-4,2-butanediyl)))biscarbamate; dimethyl (4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediylcarbonyl(1R,2R)-2,1-cyclohexanediyl))biscarbamate; di-tert-butyl (4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl((2S)-4-(dimethylamino)-1-oxo-1,2-butanediyl)))biscarbamate; dimethyl (4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediylcarbonyl(1R,2S)-2,1-cyclohexanediyl))biscarbamate; (3S,3′S)-4,4′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl))bis(N˜1˜,N˜1˜-dimethyl-4-oxo-1,3-butanediamine); dimethyl (4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl((2R)-4-oxo-1-phenyl-4,2-butanediyl)))biscarbamate; dimethyl (4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediylcarbonyl(1R,3S)-3,1-cyclopentanediyl))biscarbamate; methyl ((1R)-1-benzyl-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-3-phenylpropanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxoethyl)carbamate; dimethyl (4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl((2S)-4-(dimethylamino)-1-oxo-1,2-butanediyl)))biscarbamate; (2R,2′R)-1,1′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl))bis(N,N-dimethyl-1-oxo-3-phenyl-2-propanamine); methyl ((1S)-1-benzyl-2-((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-phenylpropanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxoethyl)carbamate; dimethyl (4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediylcarbonyl(1R,3S)-3,1-cyclopentanediyl))biscarbamate; dimethyl (4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediylcarbonylcis-4,1-cyclohexanediyl))biscarbamate; dimethyl (4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediylcarbonyltrans-4,1-cyclohexanediyl))biscarbamate; ({cis)-4,4′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediylcarbonyl))bis(N,N-diethylcyclohexanamine); and methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-(1,3-thiazol-4-yl)propanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-(1,3-thiazol-4-ylmethyl)ethyl)carbamate; or a pharmaceutically acceptable salt thereof.

8. A compound selected from methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2S)-3-(1-benzyl-1H-imidazol-4-yl)-2-((methoxycarbonyl)amino)propanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-((1-benzyl-1H-imidazol-4-yl)methyl)-2-oxoethyl)carbamate; dimethyl (4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediylcarbonyl(1S,2S)-2,1-cyclopentanediyl))biscarbamate; methyl ((1S)-3-methoxy-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-O-methyl-L-homoseryl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate; methyl ((1S)-2-((2S,4R)-4-fluoro-2-(5-(4′-(2-((2S,4R)-4-fluoro-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate; methyl ((1S)-2-((2S,4R)-4-hydroxy-2-(5-(4′-(2-((2S,4R)-4-hydroxy-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate; methyl ((1S)-1-(((2S,4R)-4-hydroxy-2-(5-(4′-(2-((2S,4R)-4-hydroxy-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; dimethyl (4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl((2S,4R)-4-hydroxy-2,1-pyrrolidinediyl)((1S)-1-cyclopropyl-2-oxo-2,1-ethanediyl)))biscarbamate; (3S,5S,3′S,5′S)-5,5′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl))bis(1-((2R)-2-(diethylamino)-2-phenylacetyl)-3-pyrrolidinol); methyl ((1S)-2-((2S,4S)-4-hydroxy-2-(5-(4′-(2-((2S,4S)-4-hydroxy-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate; methyl ((1S)-1-(((2S,4S)-4-hydroxy-2-(5-(4′-(2-((2S,4S)-4-hydroxy-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-1-(((2S,4S)-4-fluoro-2-(5-(4′-(2-((2S,4S)-4-fluoro-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-1-4 (2S,4R)-4-fluoro-2-(5-(4′-(2-((2S,4R)-4-fluoro-1-((2S)-2-((methoxycarbonyl)amino)-4-methylpentanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-3-methylbutyl)carbamate; methyl ((1S)-2-((2S,4S)-4-fluoro-2-(5-(4′-(2-((2S,4S)-4-fluoro-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate; methyl ((1S)-2-((2S,4S)-2-(5-(4′-(2-((2S,4S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-4-fluoro-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-4-fluoro-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate; methyl ((1S)-1-((2S,4S)-2-(5-(4′-(2-((2S,4S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-4-fluoro-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-4-fluoro-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-1-(((2S,4R)-4-fluoro-2-(5-(4′-(2-((2S,4R)-4-fluoro-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; (1R,1′R)-2,2′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl((2S,4R)-4-fluoro-2,1-pyrrolidinediyl)))bis(N,N-diethyl-2-oxo-1-phenylethanamine); 3-((1S)-1-(((2S)-2-(4-(4′-(2-((2S)-1-((2S)-2-((dimethylcarbamoyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)-1,1-dimethylurea; 3-((1S)-2-((2S)-2-(4-(4′-(2-((2S)-1-(N-(dimethylcarbamoyl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)-1,1-dimethylurea; 2-fluoroethyl ((1S)-1-(((2S)-2-(4-(4′-(2-((2S)-1-((2S)-2-(((2-fluoroethoxy)carbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-2-ethyl-1-(((2S)-2-(4-(4′-(2-((2S)-1-((2S)-3-ethyl-2-((methoxycarbonyl)amino)pentanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)butyl)carbamate; 1,1′-(4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl(2S)-2,1-pyrrolidinediyl((2S)-3-methyl-1-oxo-1,2-butanediyl)))ditetrahydro-2(1H)-pyrimidinone; methyl ((1S)-1-(((2S)-2-(4-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-4-methylpentanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-3-methylbutyl)carbamate; methyl ((1S)-1-(((2S)-2-(4-(4′-(2-((2S)-4,4-difluoro-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-4,4-difluoro-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; (1R,1′R)-2,2′-(4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl((2S)-4,4-difluoro-2,1-pyrrolidinediyl)))bis(N,N-dimethyl-2-oxo-1-phenylethanamine); (1R,1′R)-2,2′-(4,4′-biphenyldiylbis(1H-imidazole-4,2-diyl((2S)-4,4-difluoro-2,1-pyrrolidinediyl)))bis(N,N-diethyl-2-oxo-1-phenylethanamine); methyl ((1S,2R)-1-(((2S)-2-(4-(4′-(2-((2S)-4,4-difluoro-1-(N-(methoxycarbonyl)-O-methyl-L-threonyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-4,4-difluoro-1-pyrrolidinyl)carbonyl)-2-methoxypropyl)carbamate; methyl ((1S)-2-((2S)-2-(4-(4′-(2-((2S)-4,4-difluoro-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-4,4-difluoro-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate; methyl ((1S)-1-(((2S)-2-(4-(4′-(2-((2S)-4,4-difluoro-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; and rac-(1R)-2-((2S)-2-(4-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-4,4-difluoro-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-N,N-diethyl-2-oxo-1-phenylethanamine; or a pharmaceutically acceptable salt thereof.

9. A compound selected from methyl ((1S)-1-(((2R,3S)-3-hydroxy-2-(4-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-2-((2S)-2-(4-(4′-(2-((2R,3S)-3-hydroxy-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate; methyl ((1S)-1-(((2R)-3-hydroxy-2-(4-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl 2-((2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinyl)-5-(4′-(2-((2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazole-4-carboxylate; ethyl 2-((2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinyl)-5-(4′-(2-((2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazole-4-carboxylate; benzyl 2-((2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinyl)-5-(4′-(2-((2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazole-4-carboxylate; tert-butyl (2S)-2-(5-(4′-(2-((2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-4-(methylcarbamoyl)-1H-imidazol-2-yl)-1-pyrrolidinecarboxylate; methyl 2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-pyrrolidinyl)-5-(4′-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazole-4-carboxylate; methyl 2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-5-(4′-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazole-4-carboxylate; methyl 2-((2S)-1-((2R)-2-phenyl-2-(1-piperidinyl)acetyl)-2-pyrrolidinyl)-5-(4′-(2-((2S)-1-((2R)-2-phenyl-2-(1-piperidinyl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazole-4-carboxylate; ethyl 2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-pyrrolidinyl)-5-(4′-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazole-4-carboxylate; ethyl 2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-5-(4′-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazole-4-carboxylate; benzyl 2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-pyrrolidinyl)-5-(4′-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazole-4-carboxylate; benzyl 2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-5-(4′-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazole-4-carboxylate; benzyl 2-((2S)-1-((2R)-2-phenyl-2-(1-piperidinyl)acetyl)-2-pyrrolidinyl)-5-(4′-(2-((2S)-1-((2R)-2-phenyl-2-(1-piperidinyl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazole-4-carboxylate; benzyl 2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-5-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazole-4-carboxylate; methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-4-(methylcarbamoyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate; 2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-5-(4′-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-N-methyl-1H-imidazole-4-carboxamide; N-methyl-2-((2S)-1-((2R)-2-phenyl-2-(1-piperidinyl)acetyl)-2-pyrrolidinyl)-5-(4′-(2-((2S)-1-((2R)-2-phenyl-2-(1-piperidinyl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazole-4-carboxamide; methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-4-(methylcarbamoyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate; methyl ((1R)-2-((2S)-2-(4-carbamoyl-5-(4′-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate; 2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-pyrrolidinyl)-5-(4′-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazole-4-carboxylic acid; 2-((2S)-1-((2R)-2-phenyl-2-(1-piperidinyl)acetyl)-2-pyrrolidinyl)-5-(4′-(2-((2S)-1-42R)-2-phenyl-2-(1-piperidinyl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazole-4-carboxylic acid; tert-butyl (2S)-2-(5-(4′-(2-((2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)-1-pyrrolidinecarboxylate; tert-butyl (2S)-2-(5-(4′-(2-((2S)-1-((benzyloxy)carbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)-1-pyrrolidinecarboxylate; methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate; methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-4-(trifluoromethyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; (1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-N,N-diethyl-2-oxo-1-phenylethanamine; and methyl ((1S)-1-cyclopropyl-2-((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-cyclopropyl-2-((methoxycarbonyl)amino)acetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxoethyl)carbamate; or a pharmaceutically acceptable salt thereof.

10. A compound selected from methyl ((1S,2R)-2-methoxy-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-O-methyl-L-threonyl)-2-pyrrolidinyl)-4-(trifluoromethyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate; benzyl (2S)-2-(5-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-4-(trifluoromethyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinecarboxylate; methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate; tert-butyl (2S)-2-(4-(4′-(2-((2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-methoxy-3-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinecarboxylate; di-tert-butyl (2S,2′S)-2,2′-((3-fluoro-4,4′-biphenyldiyl)bis(1H-imidazole-4,2-diyl))di(1-pyrrolidinecarboxylate); tert-butyl (2S)-2-(4-(4′-(2-((2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-2,5-difluoro-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinecarboxylate; di-tert-butyl (2S,2′S)-2,2′-((3,3′-difluoro-4,4′-biphenyldiyl)bis(1H-imidazole-5,2-diyl))di(1-pyrrolidinecarboxylate); tert-butyl (2S)-2-(4-(4′-(2-((2S)-1-((benzyloxy)carbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-3-fluoro-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinecarboxylate; tert-butyl (2S)-2-(4-(4′-(2-((2S)-1-((benzyloxy)carbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-3,3′-difluoro-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinecarboxylate; tert-butyl(2S)-2-(5-(3-fluoro-4′-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinecarboxylate; tert-butyl (2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-3-fluoro-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinecarboxylate; tert-butyl(2S)-2-(5-(3-fluoro-4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinecarboxylate; tert-butyl (2S)-2-(5-(3,3′-difluoro-4′-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinecarboxylate; tert-butyl (2S)-2-(5-(3,3′-difluoro-4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinecarboxylate; tert-butyl (2S)-2-(5-(3-fluoro-4′-(2-((2S)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinecarboxylate triacetate; tert-butyl (2S)-2-(5-(3,3′-difluoro-4′-(2-((2S)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinecarboxylate; methyl ((1R)-2-((2S)-2-(5-(3′-fluoro-4′-(2-((2S)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(3′-fluoro-4′-(2-((2S)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; (1R)—N,N-diethyl-2-((2S)-2-(5-(3′-fluoro-4′-(2-((2S)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethanamine; methyl ((1S)-1-(((2S)-2-(5-(3,3′-difluoro-4′-(2-((2S)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1R)-2-((2S)-2-(5-(3,3′-difluoro-4′-(2-((2S)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate; 5,5′-(4-methoxy-3,4′-biphenyldiyl)bis(2-((2S)-2-pyrrolidinyl)-1H-imidazole); 5,5′-(3-fluoro-4,4′-biphenyldiyl)bis(2-((2S)-2-pyrrolidinyl)-1H-imidazole) tetraacetate; 5,5′-(2,5-difluoro-4,4′-biphenyldiyl)bis(2-((2S)-2-pyrrolidinyl)-1H-imidazole); (1R,1′R)-2,2′-((4-methoxy-3,4′-biphenyldiyl)bis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl))bis(N,N-dimethyl-2-oxo-1-phenylethanamine); dimethyl ((4-methoxy-3,4′-biphenyldiyl)bis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl((1R)-2-oxo-1-phenyl-2,1-ethanediyl)))biscarbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-3-fluoro-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-3-fluoro-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate; methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-3-fluoro-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate; methyl ((1R)-2-((2S)-2-(5-(3′-fluoro-4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate; methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-3′-fluoro-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(3′-fluoro-4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(3′-fluoro-4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S,2R)-1-(((2S)-2-(5-(3-fluoro-4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methoxypropyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N,N-diethyl-D-alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-3′-fluoro-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; and methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-3′-fluoro-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; or a pharmaceutically acceptable salt thereof.

11. A compound selected from methyl ((1S)-2-((2S)-2-(5-(3′-fluoro-4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate; dimethyl ((3-fluoro-4,4′-biphenyldiyl)bis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl((1R)-2-oxo-1-phenyl-2,1-ethanediyl)))biscarbamate; (1R,1′R)-2,2′-((3-fluoro-4,4′-biphenyldiyl)bis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl))bis(N,N-diethyl-2-oxo-1-phenylethanamine); methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-(N,N-diethyl-D-alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-3′-fluoro-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate; methyl ((1S)-1-cyclopropyl-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-3-fluoro-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxoethyl)carbamate; methyl ((1S)-1-cyclopropyl-2-((2S)-2-(5-(3-fluoro-4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxoethyl)carbamate; methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-(N,N-diethyl-D-alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-3′-fluoro-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate; methyl ((1S)-2-((2S)-2-(5-(2′,5′-difluoro-4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate; dimethyl ((2,5-difluoro-4,4′-biphenyldiyl)bis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl((1R)-2-oxo-1-phenyl-2,1-ethanediyl)))biscarbamate; (1R,1′R)-2,2′-((2,5-difluoro-4,4′-biphenyldiyl)bis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl))bis(N,N-diethyl-2-oxo-1-phenylethanamine); methyl ((1S)-1-cyclopropyl-2-((2S)-2-(5-(3,3′-difluoro-4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxoethyl)carbamate; methyl ((1S,2R)-1-(((2S)-2-(5-(3,3′-difluoro-4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methoxypropyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(3,3′-difluoro-4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(3,3′-difluoro-4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N,N-diethyl-D-alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-3,3′-difluoro-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(3,3′-difluoro-4′-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-2-((2S)-2-(5-(3,3′-difluoro-4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate; methyl ((1R)-2-((2S)-2-(5-(3,3′-difluoro-4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate; methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-(N,N-diethyl-D-alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-3,3′-difluoro-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate; methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-3,3′-difluoro-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate; methyl ((1S,2R)-1-(((2S)-2-(5-(3,3′-difluoro-4′-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methoxypropyl)carbamate bis(trifluoroacetate); methyl ((1S)-1-cyclopropyl-2-((2S)-2-(5-(3,3′-difluoro-4′-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxoethyl)carbamate; 7,7′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl(2-oxo-1-phenyl-2,1-ethanediyl)))bis(7-azabicyclo[2.2.1]heptane); 7,7′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl(2-oxo-1-phenyl-2,1-ethanediyl)))bis(7-azabicyclo[2.2.1]heptane); N,N′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl((1R)-2-oxo-1-phenyl-2,1-ethanediyl)))bis(N-ethylcyclopropanamine); ethyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-(N-(ethoxycarbonyl)-D-alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate; ethyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-(N-(ethoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate; dimethyl (4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediylcarbonyl-1,1-cyclopropanediyl))biscarbamate; methyl (2-((2S)-2-(5-(4′-(2-((2S)-1-(2-((methoxycarbonyl)amino)-2-methylpropanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1,1-dimethyl-2-oxoethyl)carbamate; (2R,2′R)-1,1′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl))bis(N,N-dimethyl-1-oxo-2-propanamine); (2R,2′R)-1,1′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl))bis(N,N-diethyl-1-oxo-2-propanamine); and (2R,2′R)-1,1′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl))bis(N,N-diethyl-3-methyl-1-oxo-2-butanamine); or a pharmaceutically acceptable salt thereof.

12. A compound selected from methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)(methyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)methylcarbamate; dimethyl (4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl((1S)-2-oxo-1-phenyl-2,1-ethanediyl)))biscarbamate; N,N′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl((2R)-1-oxo-1,2-propanediyl)))bis(N-propyl-1-propanamine); methyl ((1S)-2-hydroxy-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-3-hydroxy-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S,2R)-2-hydroxy-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S,3R)-3-hydroxy-2-((methoxycarbonyl)amino)butanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate; methyl ((1S,2S)-2-hydroxy-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S,3S)-3-hydroxy-2-((methoxycarbonyl)amino)butanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate; methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate; methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-D-alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate; (2S,2′S)-1,1′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl))bis(N,N-dimethyl-1-oxo-2-propanamine); dimethyl (4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl((2R)-1-oxo-1,2-butanediyl)))biscarbamate; dimethyl (4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl((2S)-1-oxo-1,2-butanediyl)))biscarbamate; dimethyl (4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl((1R)-1-cyclopropyl-2-oxo-2,1-ethanediyl)))biscarbamate; dimethyl (4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl((1S)-1-cyclopropyl-2-oxo-2,1-ethanediyl)))biscarbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3,3-dimethylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2,2-dimethylpropyl)carbamate; dimethyl (4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl((4S)-5-oxo-1-pentene-5,4-diyl)))biscarbamate; methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-O-methyl-L-seryl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-(methoxymethyl)-2-oxoethyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)pentanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)butyl)carbamate; methyl ((1S)-1-(((2R)-2-(5-(4′-(2-((2R)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2R)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; dimethyl (4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2R)-2,1-pyrrolidinediyl((1R)-1-cyclopropyl-2-oxo-2,1-ethanediyl)))biscarbamate; ethyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate; ethyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate; (5S)-5-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-pyrrolidinone; methyl (1-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)cyclopropyl)carbamate; methyl (2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1,1-dimethyl-2-oxoethyl)carbamate; (2R)-1-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-N,N-diethyl-1-oxo-2-propanamine; (2S)-1-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-N,N-diethyl-1-oxo-2-propanamine; (1R)—N,N-diethyl-2-((2S)-2-(5-(4′-(2-((2S)-1-(1,3-oxazol-2-ylcarbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethanamine; (1R)—N,N-diethyl-2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1-(3-pyridinylcarbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)ethanamine; (2R)-1-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-oxo-2-propanol; and (2S)-1-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-oxo-2-propanol; or a pharmaceutically acceptable salt thereof.

13. A compound selected from methyl (1-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)cyclobutyl)carbamate; methyl (1-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)cyclopentyl)carbamate; N-((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)-N-propyl-1-propanamine; (4S)-4-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-1,3-oxazolidin-2-one; (2R)-1-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-N,N-diethyl-3-methyl-1-oxo-2-butanamine; N-((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)-N-propyl-1-propanamine; methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate; (1R)—N,N-diethyl-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(4-morpholinyl)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethanamine; methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate; methyl (2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxoethyl)carbamate; (1R)—N,N-diethyl-2-((2S)-2-(5-(4′-(2-((2S)-1-(4-morpholinylcarbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethanamine; (1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-N,N-dimethyl-2-oxo-1-phenylethanamine; methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate; methyl ((1R)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate; methyl ((1R)-1-cyclopropyl-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxoethyl)carbamate; methyl ((1S)-1-cyclopropyl-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxoethyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2,2-dimethylpropyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-3-buten-1-yl)carbamate; methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-(methoxymethyl)-2-oxoethyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)butyl)carbamate; methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-(N,N-diethyl-D-alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate; methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-(N,N-dipropyl-D-alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate; methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-(1H-imidazol-5-ylcarbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate; M66a: methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-(4-(diethylamino)-2-((methoxycarbonyl)amino)butanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate; methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)butanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(4-(diethylamino)-2-((methoxycarbonyl)amino)butanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; and methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-3-(4-morpholinyl)propyl)carbamate; or a pharmaceutically acceptable salt thereof.

14. A compound selected from methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N,N-diethyl-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N,N-diethyl-D-alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-(methoxymethyl)-2-oxoethyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3,3-dimethylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl (2-((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxoethyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)butanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)butyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-3-buten-1-yl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-cyclopropyl-2-((methoxycarbonyl)amino)acetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(ethyl(methyl)amino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N,N-diethyl-D-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-2-methyl-1-(((2S)-2-(5-(4′-(2-((2S)-1-(3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate; methyl ((1S)-2-methyl-1-(((2S)-2-(5-(4′-(2-((2S)-1-((4-methyl-1-piperazinyl)carbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N,N-dipropyl-D-alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N,N-dipropyl-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)butanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-(diethylamino)butanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(1H-imidazol-4-ylcarbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N,N-diethyl-O-methyl-L-seryl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N.sup.2,N.sup.2-diethyl-D-asparaginyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2R)-1-((2R)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N,N-diethyl-O-methyl-D-seryl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N,N-diethyl-3-methyl-D-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-3-amino-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-3-oxopropyl)carbamate; methyl ((1S)-1-methyl-2-((2S)-2-(5-(4′-(2-((2S)-1-(1,3-oxazol-2-ylcarbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxoethyl)carbamate; methyl ((1S)-1-cyclopropyl-2-((2S)-2-(5-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxoethyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)propanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)butyl)carbamate; and methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2,2-dimethylpropyl)carbamate; or a pharmaceutically acceptable salt thereof.

15. A compound selected from methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-(N,N-diethyl-D-alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate; methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-(7-azabicyclo[2.2.1]hept-7-yl(phenyl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate; methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-hydroxy-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate; methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(ethyl(methyl)amino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate; methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-(methoxymethyl)-2-oxoethyl)carbamate; methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-(N,N-diethyl-D-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate; methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-(N,N-dipropyl-D-alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate; methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-(N,N-dipropyl-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(3-hydroxy-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-3-hydroxy-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S,3R)-4-hydroxy-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S,3S)-4-hydroxy-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-2-methyl-1-(((2S)-2-(5-(4′-(2-((2S)-1-L-valyl-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate; benzyl (3S)-3-((methoxycarbonyl)amino)-4-((2S)-2-(5-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-4-oxobutanoate; methyl (3S)-3-((methoxycarbonyl)amino)-4-((2S)-2-(5-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-4-oxobutanoate; (3S)-3-((methoxycarbonyl)amino)-4-((2S)-2-(5-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-4-oxobutanoic acid; methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-4-(4-methyl-1-piperazinyl)-4-oxobutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-3-(dimethylamino)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-3-oxopropyl)carbamate; 4,4′-bis(2-((2S)-1-(N-(methoxycarbonyl)-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-2-biphenylcarboxylic acid; 4,4′-bis(2-((2S)-1-((2R)-2-cyclopropyl-2-((methoxycarbonyl)amino)acetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-2-biphenylcarboxylic acid; 4,4′-bis(2-((2S)-1-((2S)-2-cyclopropyl-2-((methoxycarbonyl)amino)acetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-2-biphenylcarboxylic acid; 4,4′-bis(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-2-biphenylcarboxylic acid; methyl ((1S)-1-(((2S)-2-(5-(2′-carbamoyl-4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(2-(hydroxymethyl)-4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; methyl ((1S)-1-(((2S)-2-(5-(2-((dimethylamino)methyl)-4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate; dimethyl ((2-((dimethylamino)methyl)-4,4′-biphenyldiyl)bis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl((1R)-2-oxo-1-phenyl-2,1-ethanediyl)))biscarbamate; methyl ((1S)-1-(((1S,3S,5S)-3-(5-(4′-(2-((1S,3S,5S)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate; methyl ((1R)-1-(((1S,3S,5S)-3-(5-(4′-(2-((1S,3S,5S)-2-((2R)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate; dimethyl (4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3,2-diyl((1R)-2-oxo-1-phenyl-2,1-ethanediyl)))biscarbamate; methyl ((1S)-2-hydroxy-1-(((1S,3S,5S)-3-(5-(4′-(2-((1S,3S,5S)-2-((2S)-3-hydroxy-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate; dimethyl (4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3,2-diyl((2S)-1-oxo-1,2-butanediyl)))biscarbamate; dimethyl (4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3,2-diyl((1S)-1-cyclopropyl-2-oxo-2,1-ethanediyl)))biscarbamate; methyl ((1S)-1-(((1S,3S,5S)-3-(5-(4′-(2-((1S,3S,5S)-2-((2S)-2-((methoxycarbonyl)amino)-3,3-dimethylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2,2-dimethylpropyl)carbamate; methyl (2-((1S,3S,5S)-3-(5-(4′-(2-((1S,3S,5S)-2-(((methoxycarbonyl)amino)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)carbamate; methyl ((1S)-2-((1S,3S,5S)-3-(5-(4′-(2-((1S,3S,5S)-2-(N-(methoxycarbonyl)-L-alanyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-1-methyl-2-oxoethyl)carbamate; and methyl ((1S)-1-(((1R,3R,5R)-3-(5-(4′-(2-((1R,3R,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate; or a pharmaceutically acceptable salt thereof.

Description

EXAMPLES

(1) The present disclosure will now be described in connection with certain embodiments which are not intended to limit its scope. On the contrary, the present disclosure covers all alternatives, modifications, and equivalents as can be included within the scope of the claims. Thus, the following examples, which include specific embodiments, will illustrate one practice of the present disclosure, it being understood that the examples are for the purposes of illustration of certain embodiments and are presented to provide what is believed to be the most useful and readily understood description of its procedures and conceptual aspects.

(2) Solution percentages express a weight to volume relationship, and solution ratios express a volume to volume relationship, unless stated otherwise. Nuclear magnetic resonance (NMR) spectra were recorded either on a Bruker 300, 400, or 500 MHz spectrometer; the chemical shifts (δ) are reported in parts per million. Flash chromatography was carried out on silica gel (SiO.sub.2) according to Still's flash chromatography technique (J. Org. Chem. 1978, 43, 2923).

(3) Purity assessment and low resolution mass analysis were conducted on a Shimadzu LC system coupled with Waters Micromass ZQ MS system. It should be noted that retention times may vary slightly between machines. The LC conditions employed in determining the retention time (RT) were:

(4) Condition 1

(5) Column=Phenomenex-Luna 3.0×50 mm S10

(6) Start % B=0

(7) Final % B=100

(8) Gradient time=2 min

(9) Stop time=3 min

(10) Flow Rate=4 mL/min

(11) Wavelength=220 nm

(12) Solvent A=0.1% TFA in 10% methanol/90% H.sub.2O

(13) Solvent B=0.1% TFA in 90% methanol/10% H.sub.2O

(14) Condition 2

(15) Column=Phenomenex-Luna 4.6×50 mm S10

(16) Start % B=0

(17) Final % B=100

(18) Gradient time=2 min

(19) Stop time=3 min

(20) Flow Rate=5 mL/min

(21) Wavelength=220 nm

(22) Solvent A=0.1% TFA in 10% methanol/90% H.sub.2O

(23) Solvent B=0.1% TFA in 90% methanol/10% H.sub.2O

(24) Condition 3

(25) Column=HPLC XTERRA C18 3.0×50 mm S7

(26) Start % B=0

(27) Final % B=100

(28) Gradient time=3 min

(29) Stop time=4 min

(30) Flow Rate=4 mL/min

(31) Wavelength=220 nm

(32) Solvent A=0.1% TFA in 10% methanol/90% H.sub.2O

(33) Solvent B=0.1% TFA in 90% methanol/10% H.sub.2O

(34) Method A: LCMS-Xterra MS C-18 3.0×50 mm, 0 to 100% B over 30.0 minute gradient, 1 minute hold time, A=5% acetonitrile, 95% water, 10 mm ammonium acetate, B=95% acetonitrile, 5% water, 10 mm ammonium acetate.

(35) Method B: HPLC-X-Terra C-18 4.6×50 mm, 0 to 100% B over 10.0 minute gradient, 1 minute hold time, A=10% methanol 90% water 0.1% TFA, B=90% methanol 10% water 0.1% TFA

(36) Method C: HPLC-YMC C-18 4.6×50 mm, 0 to 100% B over 10.0 minute gradient, 1 minute hold time, A=10% methanol 90% water 0.2% H.sub.3PO.sub.4, B=90% methanol 10% water 0.2% H.sub.3PO.sub.4.

(37) Method D: HPLC-Phenomenex C-18 4.6×150 mm, 0 to 100% B over 10.0 minute gradient, 1 minute hold time, A=10% methanol 90% water 0.2% H.sub.3PO.sub.4, B=90% methanol 10% water 0.2% H.sub.3PO.sub.4

(38) Method E: LCMS-Gemini C-18 4.6×50 mm, 0 to 100% B over 10.0 minute gradient, 1 minute hold time, A=5% acetonitrile, 95% water, 10 mm ammonium acetate, B=95% acetonitrile, 5% water, 10 mm ammonium acetate.

(39) Method F: LCMS—Luna C-18 3.0×50 mm, 0 to 100% B over 7.0 minute gradient, 1 minute hold time, A=5% acetonitrile, 95% water, 10 mm ammonium acetate, B=95% acetonitrile, 5% water, 10 mm ammonium acetate.

Example 1

(1R,1′R)-2,2′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl))bis(N,N-dimethyl-2-oxo-1-phenylethanamine)

(40) ##STR00165##

Example 1

Step a

(41) ##STR00166##

(42) N,N-Diisopropylethylamine (18 mL, 103.3 mmol) was added dropwise, over 15 minutes, to a heterogeneous mixture of N-Boc-L-proline (7.139 g, 33.17 mmol), HATU (13.324 g, 35.04 mmol), the HCl salt of 2-amino-1-(4-bromophenyl)ethanone (8.127 g, 32.44 mmol), and DMF (105 mL), and stirred at ambient condition for 55 minutes. Most of the volatile component was removed in vacuo, and the resulting residue was partitioned between ethyl acetate (300 mL) and water (200 mL). The organic layer was washed with water (200 mL) and brine, dried (MgSO.sub.4), filtered, and concentrated in vacuo. A silica gel mesh was prepared from the residue and submitted to flash chromatography (silica gel; 50-60% ethyl acetate/hexanes) to provide ketoamide 1a as a white solid (12.8 g). .sup.1H NMR (DMSO-d.sub.6, δ=2.5 ppm, 400 MHz): δ 8.25-8.14 (m, 1H), 7.92 (br d, J=8.0, 2H), 7.75 (br d, J=8.6, 2H), 4.61 (dd, J=18.3, 5.7, 1H), 4.53 (dd, J=18.1, 5.6, 1H), 4.22-4.12 (m, 1H), 3.43-3.35 (m, 1H), 3.30-3.23 (m, 1H), 2.18-2.20 (m, 1H), 1.90-1.70 (m, 3H), 1.40/1.34 (two app br s, 9H). LC (Cond. 1): RT=1.70 min; LC/MS: Anal. Calcd. for [M+Na].sup.+ C.sub.18H.sub.23BrN.sub.2NaO.sub.4: 433.07. found 433.09.

(43) Analogous compounds such as intermediate 1-1a to 1-5a can be prepared by incorporating the appropriately substituted amino acid and aryl bromide isomer.

(44) ##STR00167##

(45) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.35/1.40 (two br s, 9H), 2.27-2.42 (m, 1H), 2.73-2.95 (m, 1H), 3.62-3.89 (m, 2H), 4.36-4.50 (m, 1H), 4.51-4.60 (m, 1H), 4.62-4.73 (m, 1H), 7.75 (d, J=8.24 Hz, 2H), 7.92 (d, J=7.63 Hz, 2H), 8.31-8.49 (m, 1H). HPLC XTERRA C-18 4.6×30 mm, 0 to 100% B over 4 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.2% H.sub.3PO.sub.4, B=10% water, 90% methanol, 0.2% H.sub.3PO.sub.4, RT=1.59 minutes, 99% homogeneity index. LCMS: Anal. Calcd. for C.sub.18H.sub.21BrF.sub.2N.sub.2O.sub.4: 446.06. found: 445.43 (M−H).sup.−.

(46) ##STR00168##

(47) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm (8.25 1H, s), 7.91 (2H, d, J=8.24 Hz), 7.75 (2H, d, J=8.24 Hz), 4.98 (1H, s), 4.59-4.63 (1H, m), 4.46-4.52 (1H, m), 4.23 (1H, m), 3.37 (1H, s), 3.23-3.28 (1H, m), 2.06 (1H, m), 1.88 (1H, s), 1.38 (3H, s), 1.33 (6H, s). LCMS-Phenomenex C-18 3.0×50 mm, 0 to 100% B over 4.0 minute gradient, 1 minute hold time, A=10% methanol 90% water 0.1% TFA, B=90% methanol 10% water 0.1% TFA mobile phase, RT=3.34 minutes, Anal Calcd. for C.sub.18H.sub.23BrN.sub.2O.sub.5 427.30. found 428.08 (M+H).sup.+.

(48) ##STR00169##

(49) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 8.30 (1H, s) 7.93-7.96 (2H, m) 7.76 (2H d, J=8.24 Hz) 5.13 (1H, s) 4.66-4.71 (1H, m) 4.52-4.55 (1H, m) 4.17 (1H, m) 3.51 (1H, s) 3.16-3.19 (1H, m) 2.36 (1H, m) 1.78 (1H, s) 1.40 (s, 3H), 1.34 (s, 6H). LCMS-Phenomenex C-18 3.0×50 mm, 0 to 100% B over 4.0 minute gradient, 1 minute hold time, A=10% methanol 90% water 0.1% TFA, B=90% methanol 10% water 0.1% TFA, RT=3.69 minutes, Anal Calcd. for C.sub.18H.sub.23BrN.sub.2O.sub.5 427.30. found 428.16 (M+H).sup.+.

(50) ##STR00170##

(51) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.29-1.47 (m, 9H), 1.67-1.90 (m, 3H), 2.00-2.20 (m, 1H), 3.23-3.30 (m, 1H), 3.34-3.44 (m, 1H), 4.16 (dd, 1H), 4.57 (q, 2H), 7.51 (t, J=7.78 Hz, 1H), 7.86 (dd, J=7.93, 1.22 Hz, 1H), 7.98 (d, J=7.63 Hz, 1H), 8.11 (s, 1H), 8.15-8.29 (m, 1H). LC/MS (M+Na).sup.+=433.12/435.12.

(52) ##STR00171##

(53) LCMS conditions: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume. RT=1.93 min; LRMS: Anal. Calcd. for C.sub.19H.sub.18BrN.sub.2O.sub.4 418.05. found: 419.07 (M+H).sup.+.

Example 1

Step b

(54) ##STR00172##

(55) A mixture of ketoamide 1a (12.8 g, 31.12 mmol) and NH.sub.4OAc (12.0 g, 155.7 mmol) in xylenes (155 mL) was heated in a sealed tube at 140° C. for 2 hours. The volatile component was removed in vacuo, and the residue was partitioned carefully between ethyl acetate and water, whereby enough saturated NaHCO.sub.3 solution was added so as to make the pH of the aqueous phase slightly basic after the shaking of the biphasic system. The layers were separated, and the aqueous layer was extracted with an additional ethyl acetate. The combined organic phase was washed with brine, dried (MgSO.sub.4), filtered, and concentrated in vacuo. The resulting material was recrystallized from ethyl acetate/hexanes to provide two crops of imidazole 1b as a light-yellow dense solid, weighing 5.85 g. The mother liquor was concentrated in vacuo and submitted to a flash chromatography (silica gel; 30% ethyl acetate/hexanes) to provide an additional 2.23 g of imidazole 1b. .sup.1H NMR (DMSO-d.sub.6, δ=2.5 ppm, 400 MHz): δ 12.17/11.92/11.86 (m, 1H), 7.72-7.46/7.28 (m, 5H), 4.86-4.70 (m, 1H), 3.52 (app br s, 1H), 3.36 (m, 1H), 2.30-1.75 (m, 4H), 1.40/1.15 (app br s, 9H). LC (Cond. 1): RT=1.71 min; >98% homogeneity index; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.18H.sub.23BrN.sub.3O.sub.2: 392.10. found 391.96. HRMS: Anal. Calcd. for [M+H].sup.+ C.sub.18H.sub.23BrN.sub.3O.sub.2: 392.0974. found 392.0959.

(56) The optical purity of the two samples of 1b were assessed using the chiral HPLC conditions noted below (ee >99% for the combined crops; ee=96.7% for the sample from flash chromatography):

(57) Column: Chiralpak AD, 10 um, 4.6×50 mm

(58) Solvent: 2% ethanol/heptane (isocratic)

(59) Flow rate: 1 mL/min

(60) Wavelength: either 220 or 254 nm

(61) Relative retention time: 2.83 minutes (R), 5.34 minutes (S)

(62) Analogous compounds such as intermediates 1-1b to 1-4b can be prepared by incorporating the appropriate ketoamide.

(63) ##STR00173##

(64) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.17/1.40 (two br s, 9H), 2.50-2.74 (m, J=25.64 Hz, 1H), 2.84-3.07 (m, 1H), 3.88 (d, J=10.07 Hz, 2H), 5.03 (s, 1H), 7.50 (d, J=8.55 Hz, 2H), 7.60 (s, 1H), 7.70 (d, J=8.55 Hz, 2H), 12.10 (s, 1H). HPLC XTERRA C-18 4.6×30 mm, 0 to 100% B over 4 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.2% H.sub.3PO.sub.4, B=10% water, 90% methanol, 0.2% H.sub.3PO.sub.4, RT=1.59 minutes, 99% homogeneity index; LCMS: Anal. Calcd. for C.sub.18H.sub.20BrF.sub.2N.sub.3O.sub.2: 428.27. found: 428.02 (M).sup.+.

(65) ##STR00174##

(66) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 11.89-11.99 (1H, m), 7.68 (2H, d, J=8.54 Hz), 7.52-7.59 (1H, m), 7.48 (2H, d, J=8.54 Hz), 4.80 (1H, m), 4.33 (1H, s), 3.51-3.60 (1H, m), 3.34 (1H, d, J=10.99 Hz), 2.14 (1H, s), 1.97-2.05 (1H, m), 1.37 (3H, s), 1.10 (6H, s); LCMS—Phenomenex C-18 3.0×50 mm, 0 to 100% B over 4.0 minute gradient, 1 minute hold time, A=10% methanol 90% water 0.1% TFA, B=90% methanol 10% water 0.1% TFA, (RT=3.23 min) Anal Calcd. for C.sub.18H.sub.22BrN.sub.3O.sub.3408.30. found 409.12 (M+H).sup.+.

(67) ##STR00175##

(68) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 12.06-12.24 (1H, m), 7.58-7.69 (5H, m), 4.84-4.95 (1H, m), 4.34 (1H, s), 3.61 (1H, s), 3.34-3.40 (1H, m), 2.52 (1H, s), 1.92-2.20 (1H, m), 1.43 (3H, s), 1.22 (6H, s); LCMS—Phenomenex C-18 3.0×50 mm, 0 to 100% B over 4.0 minute gradient, 1 minute hold time, A=10% methanol 90% water 0.1% TFA, B=90% methanol 10% water 0.1% TFA, (RT=3.41 min) Anal Calcd. for C.sub.18H.sub.22BrN.sub.3O.sub.3408.30. found 409.15 (M+H).sup.+.

(69) ##STR00176##

(70) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 0.98-1.51 (m, 9H), 1.82-2.12 (m, 3H), 2.31-2.48 (m, 1H), 3.30-3.51 (m, 1H), 3.52-3.66 (m, 1H), 4.88-5.16 (m, 1H), 7.47 (t, J=7.93 Hz, 1H), 7.61 (d, J=7.93 Hz, 1H), 7.81 (d, J=7.93 Hz, 1H), 8.04 (s, 1H), 8.12 (d, J=28.38 Hz, 1H), 14.65 (s, 1H). LC/MS (M+H).sup.+=391.96/393.96.

(71) Additional imidazole analogs made following procedures similar to those described above.

(72) LC Conditions:

(73) Condition 1: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

(74) Condition 2: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

(75) TABLE-US-00010 Example Structure Data 1-5b RT = 1.70 minutes (condition 2, 98%); LRMS: Anal Calcd. for C.sub.19H.sub.18BrN.sub.3O.sub.2 399.05; found: 400.08 (M + H).sup.+. 1-6b RT = 1.64 minutes (condtion 2, 98%); LRMS: Anal Calcd. for C.sub.17H.sub.22N.sub.3O.sub.2 379.09; found: 380.06 (M + H).sup.+. 1-7b RT = 2.28 minutes (95%); LRMS: Anal Calcd. for C.sub.20H.sub.21BrN.sub.3O.sub.2 414.08; found: 414.08 (M + H).sup.+; HRMS: Anal. Calcd. for C.sub.20H.sub.21BrN.sub.3O.sub.2 414.0817; found: 414.0798 (M + H).sup.+.

Example 1

Step c

(76) ##STR00180##

(77) Pd(Ph.sub.3P).sub.4 (469 mg, 0.406 mmol) was added to a pressure tube containing a mixture of bromide 1b (4.008 g, 10.22 mmol), bis(pinacolato)diboron (5.422 g, 21.35 mmol), potassium acetate (2.573 g, 26.21 mmol) and 1,4-dioxane (80 mL). The reaction flask was purged with nitrogen, capped and heated with an oil bath at 80° C. for 16.5 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The crude material was partitioned carefully between CH.sub.2Cl.sub.2 (150 mL) and an aqueous medium (50 mL water+10 mL saturated NaHCO.sub.3 solution). The aqueous layer was extracted with CH.sub.2C.sub.12, and the combined organic phase was dried (MgSO.sub.4), filtered, and concentrated in vacuo. The resulting material was purified with flash chromatography (sample was loaded with eluting solvent; 20-35% ethyl acetate/CH.sub.2Cl.sub.2) to provide boronate 1c, contaminated with pinacol, as an off-white dense solid; the relative mole ratio of 1c to pinacol was about 10:1 (.sup.1H NMR). The sample weighed 3.925 g after ˜2.5 days exposure to high vacuum. .sup.1H NMR (DMSO-d.sub.6, δ=2.5 ppm, 400 MHz): 12.22/11.94/11.87 (m, 1H), 7.79-7.50/7.34-7.27 (m, 5H), 4.86-4.70 (m, 1H), 3.52 (app br s, 1H), 3.36 (m, 1H), 2.27-1.77 (m, 4H), 1.45-1.10 (m, 21H). LC (Cond. 1): RT=1.64 min; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.24H.sub.35BN.sub.3O.sub.4: 440.27. found 440.23.

(78) Analogous compounds such as intermediates 1-1c to 1-4c can be prepared by incorporating the appropriate aryl bromide.

(79) ##STR00181##

(80) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.16 (s, 8H), 1.29 (s, 13H), 2.51-2.72 (m, 1H), 2.84-3.03 (m, 1H), 3.79-4.00 (m, 2H), 4.88-5.21 (m, 1H), 7.62 (d, J=7.93 Hz, 2H), 7.67 (s, 1H), 7.76 (d, J=7.93 Hz, 2H), 12.11/12.40 (two br s, 1H). HPLC GEMINI C-18 4.6×50 mm, 0 to 100% B over 4 minutes, 1 minute hold time, A=95% water, 5% acetonitrile, 0.1% NH.sub.4OAc, B=5% water, 95% acetonitrile, 0.1% NH.sub.4OAc, RT=1.62 minutes, 99% homogeneity index. LCMS: Anal. Calcd. for C.sub.34H.sub.32BF.sub.2N.sub.3O.sub.4: 475.34. found: 474.78 (M−H).sup.−.

(81) ##STR00182##

(82) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 11.97 (1H, m), 7.62-7.75 (5H, m), 5.05 (1H d, J=3.36 Hz), 4.82 (m, 1H), 4.35 (m, 1H), 3.58 (1H, m), 2.389 (1H, s), 2.17 (1H, m), 1.38 (3H, s), 1.30 (12H, s), 1.1 (6H, s); LCMS—Phenomenex C-18 3.0×50 mm, 0 to 100% B over 4.0 minute gradient, 1 minute hold time, A=5% acetonitrile, 95% water, 10 mm ammonium acetate, B=95% acetonitrile, 5% water, 10 mm ammonium acetate, RT=3.63 minutes, Anal. Calcd. for C.sub.24H.sub.34BN.sub.3O.sub.5 455.30. found 456.31 (M+H).sup.+.

(83) ##STR00183##

(84) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 12.05-12.24 (1H, m), 7.61-7.73 (5H, m), 4.83-5.01 (1H, m), 4.33 (1H, s), 3.54-3.63 (1H, m), 3.39-3.80 (1H, m), 2.38-2.49 (1H, m), 1.98-2.01 (1H, m), 1.42 (3H, s), 1.34 (12H, s), 1.21 (6H, s); LCMS-Phenomenex C-18 3.0×50 mm, 0 to 100% B over 4.0 minute gradient, 1 minute hold time, A=10% methanol 90% water 0.1% TFA, B=90% methanol 10% water 0.1% TFA, RT=3.64 minutes, Anal. Calcd. for C.sub.24H.sub.34BN.sub.3O.sub.5 455.30. found 456.30 (M+H).sup.+.

(85) ##STR00184##

(86) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.02-1.54 (m, 21H), 1.75-2.07 (m, 3H), 2.09-2.33 (m, 1H), 3.32-3.44 (m, 1H), 3.55 (s, 1H), 4.69-4.94 (m, 1H), 7.33 (t, J=7.32 Hz, 1H), 7.41-7.57 (m, 2H), 7.84 (d, J=7.32 Hz, 1H), 8.08 (s, 1H), 11.62-12.07 (m, 1H). LC/MS (M+H).sup.+=440.32.

(87) Additional boronic esters: Conditions for 1-5c through 1-10c

(88) LCMS conditions: Condition 1: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

(89) Condition 2: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

(90) TABLE-US-00011 1-5c RT = 1.84 minutes (condition 2); LCMS: Anal. Calcd. for C.sub.27H.sub.32BN.sub.3O.sub.4 473; found: 474 (M + H).sup.+. 1-6c RT = 1.84 minutes (condition 2); LCMS: Anal. Calcd. for C.sub.22H.sub.32BN.sub.3O.sub.4 413; found: 414 (M + H).sup.+. 1-7c RT = 1.85 minutes (condition 2); LRMS: Anal. Calcd. for C.sub.25H.sub.31BN.sub.3O.sub.4 448; found: 448 (M + H).sup.+. 1-8c RT = 2.49 (76%, boronic ester) and 1.81 (21.4%, boronic acid); LCMS: Anal. Calcd. for C.sub.23H.sub.35N.sub.3O.sub.4B 428.27; found: 428.27 (M + H).sup.+; HRMS: Anal. Calcd. for C.sub.23H.sub.35N.sub.3O.sub.4B 428.2721; found: 428.2716 (M + H).sup.+. 1-9c RT = 2.54 (74.2%, boronic ester) and 1.93 (25.8%, boronic acid); LRMS: Anal. Calcd. for C.sub.26H.sub.33N.sub.3O.sub.4B 462.26; found: 462.25 (M + H).sup.+; HRMS: Anal. Calcd. for C.sub.26H.sub.33N.sub.3O.sub.4B 462.2564; found: 462.2570 (M + H).sup.+. 1-10c 0 RT = 1.91 (64.5%, boronic ester) and 1.02 (33.8 %, boronic acid); LRMS: Anal. Calcd. for C.sub.26H.sub.32N.sub.4O.sub.3.sup.10B 458.26; found: 458.28 (M + H).sup.+; HRMS: Anal. Calcd. for C.sub.26H.sub.32N.sub.4O.sub.3.sup.10B 458.2604; found: 458.2617 (M + H).sup.+.

Example 1

Step d

di-tert-butyl (2S,2′S)-2,2′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl))di(1-pyrrolidinecarboxylate)

(91) ##STR00191##

(92) Pd(Ph.sub.3P).sub.4 (59.9 mg, 0.0518 mmol) was added to a mixture of bromide 1b (576.1 mg, 1.469 mmol), boronate 1c (621.8 mg, 1.415 mmol), NaHCO.sub.3 (400.4 mg, 4.766 mmol) in 1,2-dimethoxyethane (12 mL) and water (4 mL). The reaction mixture was flushed with nitrogen, heated with an oil bath at 80° C. for 5.75 hours, and then the volatile component was removed in vacuo. The residue was partitioned between 20% methanol/CHCl.sub.3 (60 mL) and water (30 mL), and the aqueous phase was extracted with 20% methanol/CHCl.sub.3 (30 mL). The combined organic phase was washed with brine, dried (MgSO.sub.4), filtered, and concentrated in vacuo. A silica gel mesh was prepared from the resulting crude material and submitted to flash chromatography (ethyl acetate) to provide dimer 1d, contaminated with Ph.sub.3PO, as an off-white solid (563 mg). .sup.1H NMR (DMSO-d.sub.6, δ=2.5 ppm, 400 MHz): δ 12.21-12-16/11.95-11.78 (m, 2H), 7.85-7.48/7.32-7.25 (m, 10H), 4.90-4.71 (m, 2H), 3.60-3.32 (m, 4H), 2.30-1.79 (m, 8H), 1.46-1.10 (m, 18H). LC (Cond. 1b): RT=1.77 min; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.36H.sub.45BN.sub.6O.sub.4: 625.35. found 625.48.

(93) Additional symmetric analogs can be prepared in similar fashion.

(94) ##STR00192##

(95) Example 1-1d was prepared using intermediates 1-2c and 1-2b. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 11.94-12.22 (2H, m) 7.53-7.82 (10H, m) 4.82-4.92 (2H, m) 4.34-4.43 (2H, m) 3.55-3.64 (2H, m) 3.36 (2H, d, J=11.29 Hz) 2.12-2.22 (2H, m) 2.02-2.11 (2H, m) 1.40 (6H, s) 1.14 (12H, s); LCMS—Phenomenex C-18 3.0×50 mm, 0 to 100% B over 4.0 minute gradient, 1 minute hold time, A=10% methanol 90% water 0.1% TFA, B=90% methanol 10% water 0.1% TFA, RT=3.32 min, Anal. Calcd. for 656.79. found 657.40 (M+H).sup.+. Nominal/LRMS—(M+H).sup.+−657.42, (M−H).sup.− −655.28.

(96) ##STR00193##

(97) Example 1-2d was prepared using intermediates 1-3b and 1-3c. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 12.00-12.20 (2H, m) 7.56-7.76 (10H, m) 4.90 (1H, s) 4.82 (1H, s) 4.25-4.34 (2H, m) 3.56 (2H, s) 3.34-3.47 (2H, m) 1.97-2.13 (4H, m) 1.39 (9H, m) 1.20 (9H, s); LCMS—Phenomenex C-18 3.0×50 mm, 0 to 100% B over 4.0 minute gradient, 1 minute hold time, A=10% methanol 90% water 0.1% TFA, B=90% methanol 10% water 0.1% TFA; RT=3.35 min, Anal. Calcd. for 656.79. found 657.30 (M+H).sup.+.

(98) ##STR00194##

tert-butyl (2S)-2-(4-(3′-(2-((2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-3-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinecarboxylate

(99) Example 1-2d-1 was prepared using intermediates 1-4c and 1-4b. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.09-1.51 (m, 18H), 1.84-2.15 (m, 6H), 2.34-2.50 (m, 2H), 3.35-3.52 (m, 2H), 3.54-3.67 (m, 2H), 5.08 (d, J=5.49 Hz, 2H), 7.68 (t, J=7.78 Hz, 2H), 7.78-7.92 (m, 4H), 8.11-8.30 (m, 4H), 14.81 (s, 2H). LC/MS (M+H).sup.+=625.48.

(100) ##STR00195##

(101) Diol 1-1d (0.15 g, 0.23 mmol) was added as a solid to a solution of bis(2-methoxyethyl) aminosulfur trifluoride (0.1 mL, 0.51 mmol) in 1.0 mL CH.sub.2Cl.sub.2 cooled to −78° C. The reaction was stirred at −78° C. for two hours and then warmed to room temperature and stirred for 2 hours. The reaction was poured into saturated sodium bicarbonate solution and stirred until bubbling ceased. The layers were separated and the aqueous layer was extracted one time with CH.sub.2C.sub.12. The combined organics were washed with brine, dried (MgSO.sub.4), filtered, and concentrated to give a yellow oil. The oil was triturated with CH.sub.2Cl.sub.2 and pentane to provide the desired product as a tan solid (0.092 g, 61%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 11.76-11.94 (2H, m), 7.77-7.85 (4H, m), 7.66-7.72 (4H, m), 7.60-7.66 (2H, m, J=11.60 Hz), 5.39 (1H, s), 5.28 (1H, s), 5.03 (2H, s), 3.66-3.79 (4H, m), 2.61-2.70 (2H, m), 2.28-2.38 (2H, m), 1.42 (10H, s), 1.24 (8H, s). LCMS-Phenomenex C-18 3.0×50 mm, 0 to 100% B over 4.0 minute gradient, 1 minute hold time, A=10% methanol 90% water 0.1% TFA, B=90% methanol 10% water 0.1% TFA, (t.sub.R=3.58 min) Anal Calcd. for C.sub.36H.sub.42F.sub.2N.sub.6O.sub.4 660.70. found 661.68 (M+H).sup.+.

(102) ##STR00196##

(103) Prepared from 1-1b and 1-1c in the same manner as the preparation of 1d from 1b and 1c. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.18/1.40 (two br. s., 18H), 2.53-2.75 (m, J=25.94 Hz, 2H), 2.86-3.06 (m, 2H), 3.78-4.02 (m, 4H), 5.04 (br s, 2H), 7.17-8.24 (m, 10H), 12.07/12.37 (two br. s., 2H); HPLC XTERRA C-18 3.0×50 mm, 0 to 100% B over 2 minutes, 1 minutes hold time, A=90% water, 10% methanol, 0.2% H.sub.3PO.sub.4, B=10% water, 90% methanol, 0.2% H.sub.3PO.sub.4, RT=1.31 min, 99% homogeneity index. LCMS: Anal. Calcd. for C.sub.36H.sub.40F.sub.4N.sub.6O.sub.4: 696.73. found: 967.64 (M+H).sup.+.

(104) Dissymmetric compounds such as intermediate 1-3d and 1-4d can be prepared by the same method. For example, reaction of 1-1c with 1b in the same manner as described above for the preparation of 1d provided 1-3d. Similarly, reaction of 1-4c with 1b in the same manner as described above for the preparation of 1d provided 1-4d.

(105) ##STR00197##

(106) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ □ppm 1.40/1.18 (two br s, 18H), 1.90-2.02 (m, 2H), 2.02-2.12 (m, 1H), 2.28-2.46 (m, 2H), 2.68-2.87 (m, 1H), 3.35-3.49 (m, 1H), 3.53-3.62 (m, 1H), 3.82-4.10 (m, 2H), 4.92-5.11 (m, 1H), 5.28 (s, 1H), 7.79-8.00 (m, 8H), 8.03-8.25 (m, 2H), 13.77-15.16 (m, 2H); HPLC XTERRA C-18 3.0×50 mm, 0 to 100% B over 4 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.2% H.sub.3PO.sub.4, B=10% water, 90% methanol, 0.2% H.sub.3PO.sub.4, RT=1.22 minutes, 99% homogeneity index. LCMS: Anal. Calcd. for C.sub.36H.sub.42F.sub.2N.sub.6O.sub.4: 660.75. found: 661.98 (M+H).sup.+.

(107) ##STR00198##

(108) Example 1-4d was prepared from 1-4c and 1b in similar fashion to the preparation of 1d from 1b and 1c. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 0.99-1.60 (m, 18H) 1.75-2.11 (m, J=73.24 Hz, 6H) 2.12-2.32 (m, 2H) 3.32-3.41 (m, 2H) 3.56 (s, 2H) 4.63-5.02 (m, 2H) 6.98-8.28 (m, 10H) 11.67-12.33 (m, 2H); LC conditions: Phenomenex Luna 3.0×5.0 mm S10, Solvent A—0.1% TFA in 10% MeOH/90% H.sub.2O, Solvent B—0.1% TFA in 90% MeOH/10% H.sub.2O, 0 to 100% B over 2 min, Stop time=3 min, Flow rate=4 ml/min, Wavelength=220 nm, LC/MS (M+H).sup.+=625.32. Retention time=1.438 min

(109) Additional biphenyl analogs were prepared similarly.

(110) LC Conditions for Examples 1-5d Through 1-7d:

(111) Condition 1: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

(112) Condition 2: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

(113) TABLE-US-00012 Characterization Example Compound Name Structure Data 1-5d di-tert-butyl (4,4′- biphenyldiylbis(1H- imidazole-5,2- diyl(1S)-1,1- ethanediyl))bis (methylcarbamate) RT = 1.64 minutes (>95%); Condition 2; LCMS: Anal. Calcd C.sub.34H.sub.45N.sub.6O.sub.4 601.35; found: 601.48 (M+ H).sup.+; LRMS: Anal. Calcd. for C.sub.34H.sub.44N.sub.6O.sub.4 600.34; found: 601.32 (M + H).sup.+. 1-6d tert-butyl (2S)-2-(5- (4′-(2-((1S)-1-((tert- butoxycarbonyl) (methyl)amino)ethyl)- 1H-imidazol-5-yl)- 4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinecarboxylate 00 RT = 1.63 minutes (>95%); Condition 2; LCMS: Anal. Calcd C.sub.35H.sub.45N.sub.6O.sub.4 613.34; found: 613.56 (M + H).sup.+; LRMS: Anal. Calcd. for C.sub.35H.sub.44N.sub.6O.sub.4 612.34; found: 613.33 (M + H).sup.+. 1-7d benzyl (2S)-2-(5-(4′- (2-((1S)-1-((tert- butoxycarbonyl) (methyl)amino)ethyl)- 1H-imidazol-5-yl)- 4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinecarboxylate 01 RT = 1.65 minutes (>95%); Condition 2; LCMS: Anal. Calcd C.sub.38H.sub.43N.sub.6O.sub.4 647.33; found: 647.44 (M + H).sup.+; LRMS: Anal. Calcd. for C.sub.38H.sub.42N.sub.6O.sub.4 646.33; found: 647.34 (M + H).sup.+.

Example 1

Step e

5,5′-(4,4′-biphenyldiyl)bis(2-((2S)-2-pyrrolidinyl)-1H-imidazole)

(114) ##STR00202##

(115) A mixture of carbamate 1d (560 mg) and 25% TFA/CH.sub.2Cl.sub.2 (9.0 mL) was stirred at ambient condition for 3.2 hours. The volatile component was removed in vacuo, and the resulting material was free based using an MCX column (methanol wash; 2.0 M NH.sub.3/methanol elution) to provide pyrrolidine 1e as a dull yellow solid (340 mg). .sup.1H NMR (DMSO-d.sub.6, δ=2.5 ppm, 400 MHz): δ 11.83 (br s, 2H), 7.80 (d, J=8.1, 4H), 7.66 (d, J=8.3, 4H), 7.46 (br s, 2H), 4.16 (app t, J=7.2, 2H), 2.99-2.69 (m, 6H), 2.09-2.00 (m, 2H), 1.94-1.66 (m, 6H). LC (Cond. 1): RT=1.27 min; >98% homogeneity index; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.26H.sub.29N.sub.6: 425.25. found 425.25. HRMS: Anal. Calcd. for [M+H].sup.+ C.sub.26H.sub.29N.sub.6: 425.2454. found 425.2448.

(116) Additional analogs such as 1-1e to 1-4e can be prepared in a similar fashion.

(117) ##STR00203##

(118) To a solution of 1-1d (3R,3′R,5S,5′S)-tert-butyl 5,5′-(5,5′-(biphenyl-4,4′-diyl)bis(1H-imidazole-5,2-diyl))bis(3-hydroxypyrrolidine-1-carboxylate) in 3 mL dioxane was added 0.8 mL of a 4.0M solution of HCl in dioxane. The reaction was stirred for 2 hours at room temperature and concentrated under reduced pressure. The resulting tan solid was dried under vacuum to give 1-1e (3R,3′R,5S,5′S)-5,5′-(5,5′-(biphenyl-4,4′-diyl)bis(1H-imidazole-5,2-diyl))dipyrrolidin-3-oltetrahydrochloride (0.55 g, 100% yield). Used without further purification. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 10.33 (s, 2H), 9.85 (s, 2H), 8.09 (s, 2H), 8.01 (d, J=8.24 Hz, 4H), 7.88 (d, J=8.24 Hz, 4H), 5.14 (m, 2H), 4.62 (m, 2H), 3.61 (m, 2H), 3.23 (d, J=11.29 Hz, 2H), 2.64 (m, 2H), 2.44 (dd, J=13.43, 6.71 Hz, 2H); LCMS—Waters-Sunfire C-18 4.6×50 mm, 0 to 100% B over 4.0 minute gradient, 1 minute hold time, A=10% methanol 90% water 0.1% TFA, B=90% methanol 10% water 0.1% TFA, RT=1.35 minutes Anal. Calcd. for 456.30. found 457.25 (M+H).sup.+. Nominal/LRMS—(M+H).sup.+−457.35.

(119) ##STR00204##

(120) Example 1-2e was prepared in similar fashion to the method described for the preparation of 1-1e. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 10.32 (1H, s) 8.01 (2H, s) 7.97 (4H, d, J=8.24 Hz) 7.86 (4H, d, J=8.24 Hz) 5.01-5.10 (2H, m) 4.52-4.60 (2H, m) 3.36-3.45 (2H, m) 3.25 (2H, s) 2.60-2.68 (2H, m) 2.40-2.48 (2H, m); LCMS—Phenomenex C-18 3.0×50 mm, 0 to 100% B over 4.0 minute gradient, 1 minute hold time, A=10% methanol 90% water 0.1% TFA, B=90% methanol 10% water 0.1% TFA, RT=2.10 min., Anal. Calcd. for 456.30. found 457.22 (M+H).sup.+.

(121) ##STR00205##

2-((2S)-2-pyrrolidinyl)-4-(3′-(2-((2S)-2-pyrrolidinyl)-1H-imidazol-5-yl)-3-biphenylyl)-1H-imidazole

(122) Example 1-2e-1 was prepared from 1-2d-1 in similar fashion described for the preparation of 1-1e. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.74-2.44 (m, 12H), 4.83 (s, 2H), 7.37-7.72 (m, 4H), 7.74-8.03 (m, 4H), 8.10 (s, 2H), 9.14 (s, 2H), 9.81 (s, 2H). LC/MS (M+H).sup.+=425.30.

(123) ##STR00206##

(124) To a solution of 1-2d-2 (0.084 g, 0.13 mmol) in 1 mL dioxane was added 0.5 mL of a 4.0M solution of HCl in dioxane. The reaction was stirred for 2 hours at room temperature and concentrated under reduced pressure. The resulting tan solid was dried under vacuum to give 1-2e-2 (0.077 g, 100% yield). The compound was used without further purification. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 8.00 (2H, s), 7.97 (4H, d, J=8.55 Hz), 7.85 (4H, d, J=8.24 Hz), 5.63 (1H, s), 5.52 (1H, s), 5.09-5.17 (2H, m), 3.67-3.74 (2H, m), 3.63-3.67 (2H, m), 3.07-3.14 (1H, m), 2.89-2.96 (1H, m), 2.81-2.87 (2H, m); LCMS—Phenomenex C-18 3.0×50 mm, 0 to 100% B over 4.0 minute gradient, 1 minute hold time, A=10% methanol 90% water 0.1% TFA, B=90% methanol 10% water 0.1% TFA, (t.sub.R=2.22 min) Anal Calcd. for C.sub.26H.sub.26F.sub.2N.sub.6 460.53. found 461.37 (M+H).sup.+.

(125) ##STR00207##

(126) Prepared from 1-2d-3 in the same manner as the preparation of 1-1e from 1-1d. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 2.97-3.13 (m, 4H), 3.64-3.91 (m, 4H), 5.16 (d, J=6.41 Hz, 2H), 7.84 (d, J=7.93 Hz, 4H), 7.96 (d, J=7.93 Hz, 4H), 8.00 (s, 2H); HPLC XTERRA C-18 3.0×50 mm, 0 to 100% B over 4 minutes, 1 minutes hold time, A=90% water, 10% methanol, 0.2% H.sub.3PO.sub.4, B=10% water, 90% methanol, 0.2% H.sub.3PO.sub.4, RT=1.66 min, 92% homogeneity index. LCMS: Anal. Calcd. for C.sub.26H.sub.24F.sub.4N.sub.6: 496.50. found: 495.53 (M−H).sup.−.

(127) Analogous dissymmetric compounds such as intermediates 1-3e and 1-4e can be prepared by the same method.

(128) ##STR00208##

(129) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.87-2.09 (m, 1H), 2.13-2.26 (m, 1H), 2.37-2.47 (m, 2H), 2.92-3.12 (m, 2H), 3.37 (s, 1H), 3.40-3.49 (m, 1H), 3.67-3.91 (m, 2H), 4.96-5.05 (m, 1H), 5.14 (t, J=8.70 Hz, 1H), 7.86 (t, J=9.00 Hz, 4H), 7.93-8.03 (m, 5H), 8.10 (s, 1H), 10.26/9.75 (two br s., 2H); HPLC XTERRA C-18 3.0×50 mm, 0 to 100% B over 4 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.2% H.sub.3PO.sub.4, B=10% water, 90% methanol, 0.2% H.sub.3PO.sub.4, RT=0.8622 minutes, 99% homogeneity index; LCMS: Anal. Calcd. for C.sub.26H.sub.26F.sub.2N.sub.6: 460.52. found: 461.45 (M+H).sup.+.

(130) ##STR00209##

(131) Example 1-4e was prepared from 1-4d in similar fashion to that described for the preparation of 1-1e from 1-1d. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.90-2.13 (m, 2H) 2.12-2.31 (m, 2H) 2.36-2.60 (m, 4H) 3.29-3.55 (m, 4H) 5.00 (s, 2H) 7.35-8.50 (m, 10H) 9.76 (s, 2H) 10.12-10.45 (m, 2H). LC conditions: Phenomenex Luna 3.0×5.0 mm S10, Solvent A—0.1% TFA in 10% MeOH/90% H.sub.2O, Solvent B—0.1% TFA in 90% MeOH/10% H.sub.2O, 0 to 100% B over 2 min, Stop time=3 min, Flow rate=4 ml/min, Wavelength=220 nm, LC/MS (M+H).sup.+=425.28. Retention time=0.942 min.

(132) Additional analogs were prepared similarly:

(133) TABLE-US-00013 Example Compound Name Structure Data 1-5e 0 RT = 1.37 min; LCMS: Anal. Calcd. for C.sub.25H.sub.28N.sub.6 412; found: 413 (M + H).sup.+. 1-6e RT = 1.43 min; LCMS: Anal. Calcd. for C.sub.33H.sub.35N.sub.6O.sub.2 547; found: 547 (M + H).sup.+. 1-7e RT = 1.12 min; LRMS: Anal. Calcd. for C.sub.24H.sub.28N.sub.6 400.24; found: 401.22 (M + H).sup.+.

(134) LC Conditions for 1-5e through 1-7e: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

Alternative Synthesis of Example 1

Step e

5,5′-(4,4′-biphenyldiyl)bis(2-((2S)-2-pyrrolidinyl)-1H-imidazole)

(135) ##STR00213##

Example A-1e-1

(136) ##STR00214##

(137) A 1 L, 3-neck round bottom flask, fitted with a nitrogen line, overhead stirrer and thermocouple was charged with 20 g (83.9 mmol, 1 equiv) 1,1′-(biphenyl-4,4′-diyl)diethanone, 200 mL CH.sub.2Cl.sub.2 and 8.7 mL (27.1 g, 169.3 mmol, 2.02 quiv) bromine. The mixture was allowed to stir under nitrogen for about 20 h under ambient conditions. The resulting slurry was charged with 200 mL CH.sub.2Cl.sub.2 and concentrated down to about 150 mL via vacuum distillation. The slurry was then solvent exchanged into THF to a target volume of 200 mL via vacuum distillation. The slurry was cooled to 20-25° C. over 1 h and allowed to stir at 20-25° C. for an additional hour. The off-white crystalline solids were filtered and washed with 150 mL CH.sub.2C.sub.12. The product was dried under vacuum at 60° C. to provide 27.4 g (69.2 mmol, 82%) of the desired product: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.95-7.85 (m, 4H), 7.60-7.50 (m, 4H), 4.26 (s, 4H); .sup.13C NMR (100 MHz, CDCl.sub.3) δ 191.0, 145.1, 133.8, 129.9, 127.9, 30.8; IR (KBr, cm-1) 3007, 2950, 1691, 1599, 1199; Anal calcd for C.sub.16H.sub.12Br.sub.2O.sub.2: C, 48.52; H, 3.05; Br, 40.34. Found: C, 48.53; H, 3.03; Br, 40.53. HRMS calcd for C.sub.16H.sub.13Br.sub.2O.sub.2+H; DCI.sup.+): 394.9282. Found: 394.9292. mp 224-226° C.

Example A-1e-2

(138) ##STR00215##

(139) A 500 mL jacketed flask, fitted with a nitrogen line, thermocouple and overhead stirrer, was charged with 20 g (50.5 mmol, 1 equiv) of Example A-1e-1, 22.8 g (105.9 moles, 2.10 equiv) 1-(tert-butoxycarbonyl)-L-proline, and 200 mL acetonitrile. The slurry was cooled to 20° C. followed by the addition of 18.2 mL (13.5 g, 104.4 mmol, 2.07 equiv) DIPEA. The slurry was warmed to 25° C. and allowed to stir for 3 h. The resulting clear, organic solution was washed with 3×100 mL 13 wt % aqueous NaCl. The rich acetonitrile solution was solvent exchanged into toluene (target volume=215 mL) by vacuum distillation until there was less than 0.5 vol % acetonitrile.

Example A-1e-3

(140) ##STR00216##

(141) The above toluene solution of Example A-1e-2 was charged with 78 g (1.011 moles, 20 equiv) ammonium acetate and heated to 95-100° C. The mixture was allowed to stir at 95-100° C. for 15 h. After reaction completion, the mixture was cooled to 70-80° C. and charged with 7 mL acetic acid, 40 mL n-butanol, and 80 mL of 5 vol % aqueous acetic acid. The resulting biphasic solution was split while maintaining a temperature >50° C. The rich organic phase was charged with 80 mL of 5 vol % aqueous acetic acid, 30 mL acetic acid and 20 mL n-butanol while maintaining a temperature >50° C. The resulting biphasic solution was split while maintaining a temperature >50° C. and the rich organic phase was washed with an additional 80 mL of 5 vol % aqueous acetic acid. The rich organic phase was then solvent exchanged into toluene to a target volume of 215 mL by vacuum distillation. While maintaining a temperature >60° C., 64 mL MeOH was charged. The resulting slurry was heated to 70-75° C. and aged for 1 h. The slurry was cooled to 20-25° C. over 1 h and aged at that temperature for an additional hour. The slurry was filtered and the cake was washed with 200 mL 10:3 toluene:MeOH. The product was dried under vacuum at 70° C., resulting in 19.8 g (31.7 mmol, 63%) of the desired product: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 13.00-11.00 (s, 2H), 7.90-7.75 (m, 4H), 7.75-7.60 (m, 4H), 7.60-7.30 (s, 2H), 4.92-4.72 (m, 2H), 3.65-3.49 (m, 2H), 3.49-3.28 (m, 2H), 2.39-2.1 (m, 2H), 2.10-1.87 (m, 6H), 1.60-1.33 (s, 8H), 1.33-1.07 (s, 10H); .sup.13C NMR (100 MHz, DMSO-d.sub.6) δ 154.1, 153.8, 137.5, 126.6, 125.0, 78.9, 78.5, 55.6, 55.0, 47.0, 46.7, 33.7, 32.2, 28.5, 28.2, 24.2, 23.5; IR (KBr, cm-1) 2975, 2876, 1663, 1407, 1156, 1125; HRMS calcd for C.sub.36H.sub.45N.sub.6O.sub.4 (M+H; ESI.sup.+): 625.3502. Found: 625.3502. mp 190-195° C. (decomposed).

Example A-1e-4

(142) ##STR00217##

(143) To a 250 ml reactor equipped with a nitrogen line and overhead stirrer, 25.0 g of Example A-1e-3 (40.01 mmol, 1 equiv) was charged followed by 250 mL methanol and 32.85 mL (400.1 mmol, 10 equiv) 6M aqueous hydrogen chloride. The temperature was increased to 50° C. and agitated at 50° C. for 5 h. The resulting slurry was cooled to 20-25° C. and held with agitation for ca. 18 h. Filtration of the slurry afforded a solid which was washed successively with 100 ml 90% methanol/water (V/V) and 2×100 ml of methanol. The wet cake was dried in a vacuum oven at 50° C. overnight to give 18.12 g (31.8 mmol, 79.4%) of the desired product.

Recrystallization of Example A-1e-4

(144) To a 250 ml reactor equipped with a nitrogen line and an overhead stirrer, 17.8 g of crude Example A-1e-4 was charged followed by 72 mL methanol. The resulting slurry was agitated at 50° C. for 4 h, cooled to 20-25° C. and held with agitation at 20-25° C. for 1 h. Filtration of the slurry afforded a crystalline solid which was washed with 60 ml methanol. The resulting wet cake was dried in a vacuum oven at 50° C. for 4 days to yield 14.7 g (25.7 mmol, 82.6%) of the desired product: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.5-10.25 (br, 2H), 10.1-9.75 (br, 2H), 8.19 (s, 2H), 7.05 (d, J=8.4, 4H), 7.92 (d, J=8.5, 4H), 5.06 (m, 2H), 3.5-3.35 (m, 4H), 2.6-2.3 (m, 4H), 2.25-2.15 (m, 2H), 2.18-1.96 (m, 2H); .sup.13C NMR (100 MHz, DMSO-d.sub.6) δ 156.6, 142.5, 139.3, 128.1, 127.5, 126.1, 116.9, 53.2, 45.8, 29.8, 24.3; IR (KBr, cm.sup.−1) 3429, 2627, 1636, 1567, 1493, 1428, 1028. Anal calcd for C.sub.26H.sub.32N.sub.6Cl.sub.4: C, 54.75; H, 5.65; Cl, 24.86; Adjusted for 1.9% water: C, 53.71; H, 5.76; N, 14.46; Cl, 24.39. Found: C, 53.74; H, 5.72; N, 14.50; Cl, 24.49; KF=1.9. mp 240° C. (decomposed).

(145) ##STR00218##

Example 1

(1R,1′R)-2,2′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl))bis(N,N-dimethyl-2-oxo-1-phenylethanamine)

(146) HATU (44.6 mg, 0.117 mmol) was added to a mixture of pyrrolidine 1e (22.9 mg, 0.054 mmol), diisopropylethylamine (45 μL, 0.259 mmol) and Cap-1 (28.1 mg, 0.13 mmol) in DMF (1.5 mL), and the resulting mixture was stirred at ambient for 90 minutes. The volatile component was removed in vacuo, and the residue was purified first by MCX (methanol wash; 2.0 M NH.sub.3/methanol elution) and then by a reverse phase HPLC system (H.sub.2O/methanol/TFA) to provide the TFA salt of Example 1 as an off-white foam (44.1 mg). .sup.1H NMR (DMSO-d.sub.6, δ=2.5 ppm, 400 MHz): δ 10.25 (br s, 2H), 8.20-7.10 (m, 20H), 5.79-5.12 (m, 4H), 4.05-2.98 (m, 4H), 2.98-2.62 (m, 6H), 2.50-1.70 (m, 14H), [Note: the signal of the imidazole NH was too broad to assign a chemical shift]; LC (Cond. 1): RT=1.40 min; >98% homogeneity index; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.46H.sub.51N.sub.8O.sub.2: 747.41. found 747.58.

Examples 2 to 24-4d

(147) ##STR00219##

(148) Examples 2 to 24-4 h were prepared as TFA salts by substituting the respective acids for Cap-1 using the same method described for Example 1. Caps in the following table without a number are commercially available.

(149) TABLE-US-00014 Example Compound Name 0 RT (LC-Cond.); % homogeneity index; MS data  2 (1R, 1′R)-2,2′-(4,4′- biphenyldiylbis(1H-imidazole- 5,2-diyl(2S)-2,1- pyrrolidinediyl))bis(2-oxo-1- phenylethanol) 1.55 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.41N.sub.6O.sub.4: 693.32; found 693.46; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.41N.sub.6O.sub.4: 693.3189; found 693.3182  3 (2S,2′S)-1,1′-(4,4′- biphenyldiylbis(1H-imidazole- 5,2-diyl(2S)-2,1- pyrrolidinediyl))bis(1-oxo-2- phenyl-2-propanol) 1.77 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.44H.sub.45N.sub.6O.sub.4: 721.35; found 721.52; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.44H.sub.45N.sub.6O.sub.4: 721.3502; found 721.3515  4 dimethyl (4,4′- biphenyldiylbis(1H-imidazole- 5,2-diyl(2S)-2,1- pyrrolidinediyl((1R)-2-oxo-1- phenyl-2,1- ethanediyl)))biscarbamate 1.64 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.46H.sub.47N.sub.8O.sub.6: 807.36; found 807.58  5 (1S,1′S)-2,2′-(4,4′- biphenyldiylbis(1H-imidazole- 5,2-diyl(2S)-2,1- pyrrolidinediyl))bis(N,N- dimethyl-2-oxo-1- phenylethanamine) 1.33 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.46H.sub.51N.sub.8O.sub.2: 747.41; found 747.64; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.46H.sub.51N.sub.8O.sub.2: 747.4135; found 747.4103  6 5,5′-(4,4′-biphenyldiyl)bis(2- ((2S)-1-benzoyl-2- pyrrolidinyl)-1H-imidazole) 1.65 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.37N.sub.6O.sub.2: 633.30; found 633.51  7 5,5′-(4,4′-biphenyldiyl)bis(2- ((2S)-1-(phenylacetyl)-2- pyrrolidinyl)-1H-imidazole) 1.71 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.41N.sub.6O.sub.2: 661.33; found 661.53; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.41N.sub.6O.sub.2: 661.3291; found 661.3300  8 5,5′-(4,4′-biphenyldiyl)bis(2- ((2S)-1-((2R)-2-methoxy-2- phenylacetyl)-2-pyrrolidinyl)- 1H-imidazole) 1.63 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.44H.sub.45N.sub.6O.sub.4: 721.35; found 721.59; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.44H.sub.45N.sub.6O.sub.4: 721.3502; found 721.3536  9 (2R,2′R)-1,1′-(4,4′- biphenyldiylbis(1H-imidazole- 5,2-diyl(2S)-2,1- pyrrolidinediyl))bis(1-oxo-3- phenyl-2-propanol) 1.71 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.44H.sub.45N.sub.6O.sub.4: 721.35; found 721.58; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.44H.sub.45N.sub.6O.sub.4: 721.3502; found 721.3497 10 5,5′-(4,4′-biphenyldiyl)bis(2- ((2S)-1-propionyl-2- pyrrolidinyl)-1H-imidazole) 1.47 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.32H.sub.37N.sub.6O.sub.2: 537.30; found 537.40; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.32H.sub.37N.sub.6O.sub.2: 537.2978; found 537.2952 11 5,5′-(4,4′-biphenyldiyl)bis(2- ((2S)-1-(cyclopropylcarbonyl)- 2-pyrrolidinyl)-1H-imidazole) 0 1.48 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.34H.sub.37N.sub.6O.sub.2: 561.30; found 561.44 12 5,5′-(4,4′-biphenyldiyl)bis(2- ((2S)-1-(cyclopropylacetyl)-2- pyrrolidinyl)-1H-imidazole) 1.57 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.36H.sub.41N.sub.6O.sub.2: 589.33; found 589.48; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.36H.sub.41N.sub.6O.sub.2: 589.3291; found 589.3268 13 5,5′-(4,4′-biphenyldiyl)bis(2- ((2S)-1-((2R)-tetrahydro-2- furanylcarbonyl)-2- pyrrolidinyl)-1H-imidazole) 1.44 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.36H.sub.41N.sub.6O.sub.4: 621.32; found 621.52; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.36H.sub.41N.sub.6O.sub.4: 621.3189; found 621.3191 14 2,2′-(4,4′-biphenyldiylbis(1H- imidazole-5,2-diyl(2S)-2,1- pyrrolidinediyl))bis(N,N- dimethyl-2-oxoethanamine) 1.27 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.34H.sub.43N.sub.8O.sub.2: 595.35; found 595.54; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.34H.sub.43N.sub.8O.sub.2: 595.3509; found 595.3503 15 (2R,2′R)-1,1′-(4,4′- biphenyldiylbis(1H-imidazole- 5,2-diyl(2S)-2,1- pyrrolidinediyl))bis(1-oxo-2- propanol) 1.36 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.32H.sub.37N.sub.6O.sub.4: 569.29; found 569.44; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.32H.sub.37N.sub.6O.sub.4: 569.2876; found 569.2872 16 (2R,2′R)-1,1′-(4,4′- biphenyldiylbis(1H-imidazole- 5,2-diyl(2S)-2,1- pyrrolidinediyl))bis(3-methyl- 1-oxo-2-butanol) 1.51 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.36H.sub.45N.sub.6O.sub.4: 625.35; found 625.50; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.36H.sub.45N.sub.6O.sub.4: 625.3502; found 625.3517 17 5,5′-(4,4′-biphenyldiyl)bis(2- ((2S)-1-((2R)-2-phenyl-2-(1- pyrrolidinyl)acetyl)-2- pyrrolidinyl)-1H-imidazole) 1.13 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.50H.sub.55N.sub.8O.sub.2: 799.45; found 799.67 18 4,4′-(4,4′-biphenyldiylbis(1H- imidazole-5,2-diyl(2S)-2,1- pyrrolidinediyl((1R)-2-oxo-1- phenyl-2,1- ethanediyl)))dimorpholine 1.11 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.50H.sub.55N.sub.8O.sub.4: 831.44; found 831.71 19 5,5′-(4,4′-biphenyldiyl)bis(2- ((2S)-1-(((3S)-3-fluoro-1- pyrrolidinyl)(phenyl)acetyl)-2- pyrrolidinyl)-1H-imidazole) 1.17 minutes (Cond. 1); 97%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.50H.sub.53F.sub.2N.sub.8O.sub.2: 835.43; found 835.51; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.50H.sub.53F.sub.2N.sub.8O.sub.2; 835.4260; found 835.4261 20 5,5′-(4,4′-biphenyldiyl)bis(2- ((2S)-1-(((3S)-3-fluoro-1- pyrrolidinyl)(phenyl)acetyl)-2- pyrrolidinyl)-1H-imidazole) 1.03 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.50H.sub.53F.sub.2N.sub.8O.sub.2: 835.43; found 835.51; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.50H.sub.53F.sub.2N.sub.8O.sub.2: 835.4260; found 835.4266 21 (1R,1′R)-2,2′-(4,4′- biphenyldiylbis(1H-imidazole- 5,2-diyl(2S)-2,1- pyrrolidinediyl))bis(N,N- diethyl-2-oxo-1- phenylethanamine) 0 1.13 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.50H.sub.59N.sub.8O.sub.2: 803.48; found 803.56; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.50H.sub.59N.sub.8O.sub.2: 803.4761; found 803.4728 22 (1R,1′R)-2,2′-(4,4′- biphenyldiylbis(1H-imidazole- 5,2-diyl(2S)-2,1- pyrrolidinediyl))bis(N-ethyl- N-methyl-2-oxo-1- phenylethanamine) 1.10 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.48H.sub.55N.sub.8O.sub.2: 775.45; found 775.52; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.50H.sub.59N.sub.8O.sub.2: 775.4448; found 775.4456 23 N,N′-(4,4′-biphenyldiylbis(1H- imidazole-5,2-diyl(2S)-2,1- pyrrolidinediyl((1R)-2-oxo-1- phenyl-2,1- ethanediyl)))diformamide 1.22 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.44H.sub.43N.sub.8O.sub.4: 747.34; found 747.38 24 1,1′-(4,4′-biphenyldiylbis(1H- imidazole-5,2-diyl(2S)-2,1- pyrrolidinediylcarbonyl)) dicyclopropanol 1.77 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.34H.sub.37N.sub.6O.sub.4: 593.29; found 593.16 24-1 1,1′-(4,4′-biphenyldiylbis(1H- imidazole-5,2-diyl(2S)-2,1- pyrrolidinediyl((1R)-2-oxo-1- phenyl-2,1- ethanediyl)))dipiperidine .sup.1HNMR (400 MHz, DMSO- d.sub.6) δ 12.18 (m, 0.4H), 11.96 (m, 0.4H), 11.79 (m, 1.2H), 7.84-7.70 (m, 4H), 7.69-7.65 (m, 4H), 7.53-7.50 (m, 2H), 7.43-7.28 (m, 4H), 7.09-7.01 (m, 2H), 6.87-6.85 (m, 2H), 5.51-5.48 (m, 0.5H), 5.01- 4.98 (m, 1.5H), 4.29 (m, 1.5H), 4.16 (m, 0.5H), 3.98 (m, 2H), 3.65-3.49 (m, 2H), 3.43-3.36 (m, 2H), 2.41-2.31 (m, 8H), 2.14-1.82 (m, 8H), 1.47-1.31 (m, 12H); LCMS: Anal. Calcd. for C.sub.52H.sub.58N.sub.8O.sub.2: 826; found: 827 (M + H).sup.+. 24-2 1,1′-(4,4′-biphenyldiylbis(1H- imidazole-5,2-diyl(2S)-2,1- pyrrolidinediyl((1R)-2-oxo-1- phenyl-2,1-ethanediyl)))bis(4- methyl-4-piperidinol) .sup.1HNMR (400 MHz, DMSO- d.sub.6) δ 12.02 (br s, 1H), 11.82 (br s, 1H), 7.90-7.79 (m, 4H), 7.79-7.65 (m, 5H), 7.55 (br s, 2H), 7.45 (d, J = 7.6 Hz, 2H), 7.39-7.25 (m, 3H), 7.34 (d, J = 7.6 Hz, 2H), 7.04 (t, J = 7.6 Hz, 2H), 6.85 (d, J = 8.1 Hz, 2H), 5.15-4.96 (m, 2H), 4.31-3.96 (m, 6H), 2.35-2.20 (m, 2H), 2.05-1.94 (m, 4H), 1.94-1.81 (m, 4H), 1.50-1.35 (m, 9H), 1.35-1.20 (m, 5H), 1.09 (s, 2H), 1.05 (s, 4H); LCMS: Anal. Calcd. for C.sub.54H.sub.62N.sub.8O.sub.4: 886; found: 887 (M + H).sup.+. 24-3 dimethyl (4,4′- biphenyldiylbis(1H-imidazole- 5,2-diyl(2S)-2,1- pyrrolidinediyl((1R)-1-(2- chlorophenyl)-2-oxo-2,1- ethanediyl)))biscarbamate LCMS: Anal. Calcd. for C.sub.46H.sub.44Cl.sub.2N.sub.8O.sub.6: 874; found: 875 (M + H).sup.+. 24-4a N′,N′″-(4,4′- biphenyldiylbis(1H-imidazole- 4,2-diyl(2S)-2,1- pyrrolidinediyl((1R)-2-oxo-1- phenyl-2,1- ethanediyl)))bis (1,1- dimethylurea) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.89-2.00 (m, J = 17 .09 , 7.02 Hz, 4H), 2.06-2.13 (m, J = 14.95, 3.97 Hz, 3H), 2.24-2.33 (m, J = 8.70, 6.56 Hz, 2H), 2.79- 2.84 (m, 12H), 3.29 (q, 2H), 3.95-4.03 (m, 3H), 5.26 (dd, J = 8.55, 2.14 Hz, 3H), 5.52 (d, J = 5.80 Hz, 3H), 6.72 (d, J = 6.10 Hz, 3H), 7.02-7.07 (m, 1H), 7.29-7.36 (m, 3H), 7.39 (t, J = 7.17 Hz, 4H), 7 .46 (d, J = 7.02 Hz, 3H), 7.92 (s, 8H), 8.12 (s, 2H); HPLC XTERRA C-18 4.6 × 30 mm, 0 to 100% B over 4 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.2% H.sub.3PO.sub.4, B = 10% water, 90% methanol, 0.2% H.sub.3PO.sub.4, RT = 2.13 minutes, 96% homogeneity index; LCMS: Anal. Calcd. for C.sub.48H.sub.53N.sub.10O.sub.4: 832.42; found: 833.43 (M + H).sup.+; HRMS: Anal. Calcd. for C.sub.48H.sub.54N.sub.10O.sub.4 833.4251; found: 833.4267 (M + H).sup.+. 24-4b N′,N′″-(4,4′- biphenyldiylbis(1H-imidazole- 5,2-diyl(2S)-2,1- pyrrolidinediyl((1R)-2-oxo-1- phenyl-2,1-ethanediyl)))bis(1- methylurea) RT = 4.45 minutes (Gemini C-18 4.6 × 50 mm, 0 to 100% B over 10.0 minute gradient, 1 minute hold time, A = 5% acetonitrile, 95% water, 10 mm ammonium acetate, B = 95% acetonitrile, 5% water, 10 mm ammonium acetate); LCMS: Anal. Calcd. for C.sub.46H.sub.48N.sub.10O.sub.4 804.95; found: 805.41 (M + H).sup.+; HRMS: Anal. Calcd. for C.sub.46H.sub.49N.sub.10O.sub.4 805.3938; found: 805.3929 (M + H).sup.+. 24-4c N′,N′″-(4,4′- biphenyldiylbis(1H-imidazole- 5,2-diyl(2S)-2,1- pyrrolidinediyl((1R)-2-oxo-1- phenyl-2,1-ethanediyl)))bis(1- ethylurea) RT = 4.20 minutes (Gemini C-18 4.6 × 50 mm, 0 to 100% B over 10.0 minute gradient, 1 minute hold time, A = 5% acetonitrile, 95% water, 10 mm ammonium acetate, B = 95% acetonitrile, 5% water, 10 mm ammonium acetate); LCMS: Anal. Calcd. for C.sub.48H.sub.52N.sub.10O.sub.4 833.00; found: 833.48 (M + H).sup.+. 24-4d N′,N′″-(4,4′- biphenyldiylbis(1H-imidazole- 5,2-diyl(2S)-2,1- pyrrolidinediyl((1R)-2-oxo-1- phenyl-2,1-ethanediyl)))bis(1- cyclopentylurea) 0 RT = 4.92 minutes (Gemini C-18 4.6 × 50 mm, 0 to 100% B over 10.0 minute gradient, 1 minute hold time, A = 5% acetonitrile, 95% water, 10 mm ammonium acetate, B = 95% acetonitrile, 5% water, 10 mm ammonium acetate); LCMS: Anal. Calcd. for C.sub.54H.sub.60N.sub.10O.sub.4 912.49; found: 913.68 (M + H).sup.+; HRMS: Anal. Calcd. for C.sub.54H.sub.61N.sub.10O.sub.4 913.4877; found: 913.4899 (M + H).sup.+. 24-4e 2,2′-(4,4′-biphenyldiylbis(1H- imidazole-5,2-diyl(2S)-2,1- pyrrolidinediyl))bis(N-benzyl- N-methyl-2-oxoethanamine) .sup.1HNMR (500 MHz, DMSO- d.sub.6) δ ppm 1.97-2.43 (m, 8H), 2.64-2.91 (m, 6H), 3.45-3.63 (m, 2H), 3.62-3.76 (m, 2H), 4.14 (dd, 4H), 4.22-4.45 (m, 4H), 5.29 (s, 2H), 7.28-7.65 (m, 10H), 7.90 (s, 8H), 8.06 (s, 2H), 14.62 (s, 2H); HPLC Xterra 4.6 × 50 mm, 0 to 100% B over 10 minutes, one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid. RT = 3.06 min; LCMS: Anal. Calcd. for: C.sub.46H.sub.50N.sub.8O.sub.2 746.96; Found: 747.41 (M + H).sup.+. 24-4f (2S,2′S)-1,1′-(4,4′- biphenyldiylbis(1H-imidazole- 5,2-diyl(2S)-2,1- pyrrolidinediyl))bis(N-benzyl- N-methyl-1-oxo-2- propanamine) RT = 2.95 minutes (99%); HPLC Xterra 4.6 × 50 mm, 0 to 100% B over 10 minutes, one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid; LCMS: Anal. Calcd. for: C.sub.48H.sub.54N.sub.8O.sub.2 775.02; Found: 775.45 (M + H).sup.+. 24-4g 1,1′-(4,4′-biphenyldiylbis(1H- imidazole-5,2-diyl(2S)-2,1- pyrrolidinediyl))bis(N-benzyl- N,3-dimethyl-1-oxo-2- butanamine) RT = 3.86 minutes (100%); HPLC Xterra 4.6 × 50 mm, 0 to 100% B over 10 minutes, one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid; LCMS: Anal. Calcd. for: C.sub.52H.sub.62N.sub.8O.sub.2 831.13; Found: 831.51 (M + H).sup.+. 24-4h 1,1′-(4,4′-biphenyldiylbis(1H- imidazole-5,2-diyl(2S)-2,1- pyrrolidinediyl(2-oxo-1- phenyl-2,1-ethanediyl)))di(4- piperidinol) RT = 2.86 minutes (100%); HPLC Xterra 4.6 × 50 mm, 0 to 100% B over 10 minutes, one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid; LCMS: Anal. Calcd. for: C.sub.52H.sub.58N.sub.8O.sub.4 859.09; Found: 859.45 (M + H).sup.+.

Examples 24-5 to 24-18

(150) TABLE-US-00015 Example Compound Name Structure Data 24-5 1,1′-(4,4′- biphenyldiylbis (1H-imidazole- 5,2-diyl((2S,4S)- 4-fluoro-2,1- pyrrolidinediyl) ((1R)-2-oxo-1- phenyl-2,1- ethanediyl))) dipiperidine Gemini C-18 4.6 x 50 mm, 0 to 100% B over 10.0 minute gradient, 1 minute hold time, A = 5% acetonitrile, 95% water, 10 mm ammonium acetate, B = 95% acetonitrile, 5% water, 10 mm ammonium acetate. (RT = 4.163 min); Nominal/LRMS- Calcd. for C.sub.46H.sub.48F.sub.2N.sub.8O.sub.2 782.93; found 783.40 (M + H).sup.+; Accurate/HRMS- Calcd. for C.sub.46H.sub.49F.sub.2N.sub.8O.sub.2 783.3946; 783.3934 (M + H).sup.+. 24-6 (1R,1′R)-2,2′- (4,4′- biphenyldiylbis (1H-imidazole- 5,2-diyl((2S,4S)- 4-fluoro-2,1- pyrrolidinediyl))) bis(N,N-diethyl- 2-oxo-1- phenyl- ethanamine) Gemini C-18 4.6 x 50 mm, 0 to 100% B over 10.0 minute gradient, 1 minute hold time, A = 5% acetonitrile, 95% water, 10 mm ammonium acetate, B = 95% acetonitrile, 5% water, 10 mm ammonium acetate. (RT = 3.76 min); LCMS: Anal. Calcd. for C.sub.50H.sub.56F.sub.2N.sub.8O.sub.2 839.04; found: 839.49 (M + H).sup.+; HRMS: Anal. Calcd. for C.sub.50H.sub.57F.sub.2N.sub.8O.sub.2 839.4572; found: 839.4590 (M + H).sup.+. 24-7 (1R,1′R)-2,2′- (4,4′- biphenyldiylbis (1H-imidazole- 5,2-diyl((2S,4S)- 4-fluoro-2,1- pyrrolidinediyl))) bis(N,N- dimethyl-2-oxo- 1-phenyl- ethanamine) Gemini C-18 4.6 x 50 mm, 0 to 100% B over 10.0 minute gradient, 1 minute hold time, A = 5% acetonitrile, 95% water, 10 mm ammonium acetate, B = 95% acetonitrile, 5% water, 10 mm ammonium acetate. RT = 3.99 min; LCMS: Anal. Calcd. for C.sub.52H.sub.56F.sub.2N.sub.8O.sub.2 863.06; found: 863.47 (M + H).sup.+; HRMS: Anal. Calcd. for C.sub.52H.sub.57F.sub.2N.sub.8O.sub.2 863.4572; found: 863.4553 (M + H).sup.+. 24-8 1,1′-(4,4′- biphenyldiylbis (1H-imidazole- 4,2-diyl((2S)- 4,4-difluoro-2,1- pyrrolidinediyl) ((1R)-2-oxo-1- phenyl-2,1- ethanediyl))) dipiperidine RT = 1.64 minutes, method B; LCMS: Anal. Calcd. for C.sub.52H.sub.54F.sub.4N.sub.8O.sub.6: 898.43; found: 899.46 (M + H).sup.+; HRMS: Anal. Calcd. for C.sub.52H.sub.55F.sub.4N.sub.8O.sub.6 899.4384; found: 899.4380 (M + H).sup.+. 24-9 dimethyl (4,4′- biphenyldiylbis (1H-imidazole- 4,2-diyl((2S)- 4,4-difluoro-2,1- pyrrolidinediyl) ((1R)-2-oxo-1- phenyl-2,1- ethanediyl))) biscarbamate RT = 2.62 minutes, method C; LCMS: Anal. Calcd. for C.sub.46H.sub.42F.sub.4N.sub.8O.sub.6: 878.88; found: 879.81 (M + H).sup.+; HRMS: Anal. Calcd. for C.sub.46H.sub.43F.sub.4N.sub.8O.sub.6 879.33242; found: 879.3273 (M + H).sup.+. 24-10 1-((1R)-2-((2S)-2- (4-(4′-(2-((2S)- 4,4-difluoro-1- ((2R)-2-phenyl-2- (1-piperidinyl) acetyl)-2- pyrrolidinyl)- 1H-imidazol-4- yl)-4-biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl)-2- oxo-1-phenyl- ethyl)piperidine 0 RT = 1.54 minutes, method B; LCMS: Anal. Calcd. for C.sub.52H.sub.56F.sub.2N.sub.8O.sub.6: 862.45; found: 863.46 (M + H).sup.+; HRMS: Anal. Calcd. for C.sub.52H.sub.57F.sub.2N.sub.8O.sub.6 863.4573; found: 863.4572 (M + H).sup.+. 24-11 dimethyl (4,4′- biphenyldiylbis (1H-imidazole- 5,2-diyl((2S,4R)- 4-hydroxy-2,1- pyrrolidinediyl) ((1R)-2-oxo-1- phenyl-2,1- ethanediyl))) biscarbamate RT = 8.54 minutes, method A; LCMS: Anal. Calcd. for C.sub.46H.sub.46N.sub.8O.sub.8 838.93; found: 839.41 (M + H).sup.+; HRMS: Anal. Calcd. for C.sub.46H.sub.47N.sub.8O.sub.8 839.9300; found: 839.3527 (M + H).sup.+. 24-12 (3R,5S,3′R,5′S)- 5,5′-(4,4′- biphenyldiylbis (1H-imidazole- 5,2-diyl))bis(1- ((2R)-2-hydroxy- 2-phenylacetyl)- 3-pyrrolidinol) RT = 6.92 minutes, method A; LCMS: Anal. Calcd. for C.sub.42H.sub.40N.sub.6O.sub.6 724.81; found: 725.43 (M + H).sup.+; HRMS: Anal. Calcd. for C.sub.42H.sub.41N.sub.6O.sub.6 725.3087; found: 725.3088 (M + H).sup.+. 24-13 N,N″-(4,4′- biphenyldiylbis (1H-imidazole- 5,2-diyl((2S,4R)- 4-hydroxy-2,1- pyrrolidinediyl) ((1R)-2-oxo-1- phenyl-2,1- ethanediyl))) bis(3-methylurea) RT = 3.80 minutes, method C; LCMS: Anal. Calcd. for C.sub.46H.sub.48N.sub.10O.sub.6 836.95; found: 837.52 (M + H).sup.+; HRMS: Anal. Calcd. for C.sub.46H.sub.49N.sub.10O.sub.6 837.3836; found: 837.3809 (M + H).sup.+. 24-14 N′,N′′′-(4,4′- biphenyldiylbis (1H-imidazole- 5,2-diyl((2S,4R)- 4-hydroxy-2,1- pyrrolidinediyl) ((1R)-2-oxo-1- phenyl-2,1- ethanediyl)))bis (1-ethylurea) RT = 4.39 minutes, method C; LRMS: Anal. Calcd. for C.sub.48H.sub.52N.sub.10O.sub.6 865.003; found: 865.56 (M + H).sup.+; HRMS: Anal. Calcd. for C.sub.48H.sub.53N.sub.10O.sub.6 865.4149; found: 865.4139 (M + H).sup.+. 24-15 N′,N′′′-(4,4′- biphenyldiylbis (1H-imidazole- 5,2-diyl((2S,4R)- 4-hydroxy-2,1- pyrrolidinediyl) ((1R)-2-oxo-1- phenyl-2,1- ethanediyl)))bis (1-cyclopentyl- urea) RT = 4.88 minutes, method B; LRMS: Anal. Calcd. for C.sub.54H.sub.60N.sub.10O.sub.6 944.13; found: 945.65 (M + H).sup.+; HRMS: Anal. Calcd. for C.sub.54H.sub.61N.sub.10O.sub.6 945.4775; found: 945.4769 (M + H).sup.+. 24-16 (3S,5S,3′S,5′S)- 5,5′-(4,4′- biphenyldiylbis (1H-imidazole- 5,2-diyl))bis (1-((2R)-2- (dimethylamino)- 2-phenylacetyl)- 3-pyrrolidinol) RT = 3.66 minutes, method D; LRMS: Anal. Calcd. for C.sub.46H.sub.50N.sub.8O.sub.4 778.39 found: 779.39 (M + H).sup.+; HRMS: Anal. Calcd. for C.sub.46H.sub.51N.sub.8O.sub.4 779.4033; found: 779.4021 (M + H).sup.+. 24-17 dimethyl (4,4′- biphenyldiylbis (1H-imidazole- 5,2-diyl((2S,4S)- 4-hydroxy-2,1- pyrrolidinediyl) ((1R)-2-oxo-1- phenyl-2,1- ethanediyl))) biscarbamate RT = 5.75 minutes, method C; LRMS: Anal. Calcd. for C.sub.46H.sub.46N.sub.8O.sub.8 838.93; found: 839.44 (M + H).sup.+; HRMS: Anal. Calcd. for C.sub.46H.sub.47N.sub.8O.sub.8 839.3517 found: 839.3519 (M + H).sup.+. 24-18 (3S,5S,3′S,5′S)- 5,5′-(4,4′- biphenyldiylbis (1H-imidazole- 5,2-diyl))bis (1-((2R)- 2-hydroxy-2- phenylacetyl)-3- pyrrolidinol) RT = 4.41 minutes, method D; LRMS: Anal. Calcd. for C.sub.42H.sub.40N.sub.6O.sub.6 724.81; found: 725.13 (M + H).sup.+. 24-18-1 dimethyl (4,4′- biphenyldiylbis (1H-imidazole- 5,2-diyl(1S)-1,1- ethanediyl(methyl- imino)((1R)-2- oxo-1-phenyl- 2,1-ethanediyl))) biscarbamate RT = 1.55 min.sup.1; LRMS: Anal. Calcd. for C.sub.44H.sub.46N.sub.8O.sub.6 782.35; found: 783.37 (M + H).sup.+; HRMS: Anal. Calcd. for C.sub.44H.sub.47N.sub.8O.sub.6 783.3619 found: 783.3630 (M + H).sup.+. 24-18-2 (2R,2′R)-N,N′- (4,4′- biphenyldiylbis (1H-imidazole- 5,2-diyl(1S)-1,1- ethanediyl))bis (2-(dimethyl- amino)-N-methyl- 2-phenyl- acetamide) 0 RT = 1.16 mm.sup.1; LRMS: Anal. Calcd. for C.sub.44H.sub.50N.sub.8O.sub.2 722.41; found: 723.41 (M + H).sup.+; HRMS: Anal. Calcd. for C.sub.44H.sub.51N.sub.8O.sub.2 723.4135 found: 723.4152 (M + H).sup.+. 24-18-3 (2R,2′R)-N,N′- (4,4′- biphenyldiylbis (1H-imidazole- 5,2-diyl(1S)-1,1- ethanediyl))bis (N-methyl-2- phenyl-2-(1- piperidinyl) acetamide) RT = 1.28 min.sup.1; LRMS: Anal. Calcd. for C.sub.50H.sub.58N.sub.8O.sub.2 802.47; found: 803.50 (M + H).sup.+; HRMS: Anal. Calcd. for C.sub.50H.sub.59N.sub.8O.sub.2 803.4761 found: 803.4778 (M + H).sup.+. 24-18-4 methyl ((1R)-2- ((2S)-2-(5-(4′-(2- ((1S)-1-(((2R)-2- ((methoxy- carbonyl)amino)- 2-phenylacetyl) (methyl)amino) ethyl)-1H- imidazol-5- yl)-4-biphenylyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl)-2- oxo-1- phenylethyl) carbamate RT = 1.53 min.sup.1; LRMS: Anal. Calcd. for C.sub.45H.sub.46N.sub.8O.sub.6 794.35; found: 795.39 (M + H).sup.+; HRMS: Anal. Calcd. for C.sub.45H.sub.47N.sub.8O.sub.6 795.3619 found: 795.3616 (M + H).sup.+. 24-18-5 (2R)-2- (dimethylamino)- N-((1S)-1-(5-(4′- (2-((2S)-1-((2R)- 2- (dimethylamino)- 2-phenylacetyl)- 2-pyrrolidinyl)- 1H-imidazol-5- yl)-4-biphenylyl)- 1H-imidazol-2- yl)ethyl)-N- methyl-2- phenylacetamide RT = 1.21.sup.1; LRMS: Anal. Calcd. for C.sub.45H.sub.50N.sub.8O.sub.2 734.41; found: 735.46 (M + H).sup.+; HRMS: Anal. Calcd. for C.sub.45H.sub.51N.sub.8O.sub.2 735.4135 found: 735.4136 (M + H).sup.+. 24-18-6 (2R)-N-methyl-2- phenyl-N-((1S)-1- (5-(4′-(2-((2S)-1- ((2R)-2-phenyl-2- (1-piperidinyl) acetyl)-2- pyrrolidinyl)- 1H-imidazol-5- yl)-4-biphenylyl)- 1H-imidazol-2- yl)ethyl)-2-(1- piperidinyl) acetamide RT = 1.30.sup.1; LRMS: Anal. Calcd. for C.sub.51H.sub.58N.sub.8O.sub.2 814.47; found: 815.48 (M + H).sup.+; HRMS: Anal. Calcd. for C.sub.51H.sub.59N.sub.8O.sub.2 815.4761 found: 815.4744 (M + H).sup.+. .sup.1LC Conditions for 24-18-1 through 24-18-6: Phenomenex LUNA C-18 4.6 × 50 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

Examples 24-19 to 24-20

(151) ##STR00275##

(152) Example 24-19 and 24-20 were prepared as TFA salts from 1-2e-1 and the respective acids using the same method described for Example 1.

(153) TABLE-US-00016 Example Compound Name Data 24-19 methyl ((1R)-2-((2S)-2- (4-(3′-(2-((2S)-1-((2R)- 2-((methoxycarbonyl) amino)-2-phenylacetyl)- 2-pyrrolidinyl)-1H- imidazol-5-yl)-3- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.82-1.97 (m, 2H), 1.97-2.17 (m, 4H), 2.18-2.37 (m, 2H), 3.18 (d, J = 9.77 Hz, 2H), 3.44-3.58 (m, 6H), 3.79-4.04 (m, 2H), 5.09-5.46 (m, 2H), 5.45-5.84 (m, 2H), 6.97-7.49 (m, 10H), 7.61-7.74 (m, 4H), 7.75- 7.93 (m, 4H), 8.10-8.32 (m, 4H), 14.48 (app br s, 2H); RT = 1.34 min; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.46H.sub.47N.sub.8O.sub.6: 807.36; found 807.40 24-20 (1R)-2-((2S)-2-(4-(3′- (2-((2S)-1-(2R)-2- (dimethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-3- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-N,N- dimethyl-2-oxo-1- phenylethanamine .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.71-2.32 (m, 8H), 3.33-3.68 (m, 2H), 3.89-4.16 (m, J = 2.75 Hz, 2H), 4.96 (app br s, 12H), 5.26 (s, 2H), 5.45 (s, 2H), 7.03-7.78 (m, 12H), 7.84 (s, 4H), 8.07-8.43 (m, 4H), 9.90-10.87 (m, 2H); RT = 1.10 min; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.46H.sub.51N.sub.8O.sub.2: 747.41; found 747.45

(154) LC conditions for 24-19 and 24-20:

(155) Column=Phenomenex-Luna 3.0×50 mm S10

(156) Start % B=0

(157) Final % B=100

(158) Gradient time=2 min

(159) Stop time=3 min

(160) Flow Rate=4 mL/min

(161) Wavelength=220 nm

(162) Solvent A=0.1% TFA in 10% methanol/90% H.sub.2O

(163) Solvent B=0.1% TFA in 90% methanol/10% H.sub.2O

Examples 24-21 to 24-22

(164) ##STR00279##

(165) Example 24-21 and 24-22 were prepared as TFA salts from 1-4e and the respective carboxylic acids using the same method described for Example 1.

(166) TABLE-US-00017 Example Compound Name 0 Data 24-21 methyl ((1R)-2- ((2R)-2-(4-(3′- (2-((2S)-1-((2R)-2- ((methoxycarbonyl) amino)-2-phenyl- acetyl)-2- pyrrolidinyl)-1H- imidazol-4-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxo-1- phenylethyl) carbamate .sup.1H NMR (500 MHz, DMSO- d.sub.6) δ ppm 1.73- 2.37 (m, 8H), 3.13 (s, 2H), 3.36- 4.29 (m, 8H), 5.26 (s, 2H), 5.53 (s, 2H), 6.99-8.61 (m, 22H), 14.51 (s, 2H); RT = 1.33 min; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.46H.sub.47N.sub.8O.sub.6: 807.36; found 807.58 24-22 (1R)-2-((2R)-2- (4-(3′-(2-((2S)-1- ((2R)-2- (dimethylamino)- 2-phenylacetyl)- 2-pyrrolidinyl)- 1H-imidazol-4- yl)-4-biphenylyl)- 1H-imidazol-2- yl)-1-pyrrolidinyl)- N,N-dimethyl-2- oxo-1-phenyl- .sup.1H NMR (500 MHz, DMSO- d.sub.6) δ ppm 1.84- 2.32 (m, 8H), 2.92-3.10 (m, 2H), 3.92-4.08 (m, 2H), 4.43 (app br s, 12H), 5.16-5.37 (m, 2H), 5.39-5.58 (m, 2H), 7.16- 8.24 (m, 20H), ethanamine 9.60-10.46 (m, 2H); RT = 1.08 min; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.46H.sub.51N.sub.8O.sub.2: 747.41; found 747.45

(167) LC conditions for 24-21 and 24-22:

(168) Column=Phenomenex-Luna 3.0×50 mm S10

(169) Start % B=0

(170) Final % B=100

(171) Gradient time=2 min

(172) Stop time=3 min

(173) Flow Rate=4 mL/min

(174) Wavelength=220 nm

(175) Solvent A=0.1% TFA in 10% methanol/90% H.sub.2O

(176) Solvent B=0.1% TFA in 90% methanol/10% H.sub.2O

Example 24-23

(177) ##STR00283##

methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

(178) A 50 mL flask equipped with a stir bar was sequentially charged with 2.5 mL acetonitrile, 0.344 g (2.25 mmol, 2.5 equiv) hydroxy benzotriazole hydrate, 0.374 g (2.13 mmol, 2.4 equiv)N-(methoxycarbonyl)-L-valine, 0.400 g (2.09 mmol, 2.4 equiv) 1-(3-dimethyaminopropyl)-3-ethylcarbodiimide hydrochloride and an additional 2.5 mL acetonitrile. The resulting solution was agitated at 20° C. for 1 hour and charged with 0.501 g (0.88 mmol, 1 equiv) Example A-1e-4. The slurry was cooled to about 0° C. and 0.45 g (3.48 mmol, 4 equiv) diisopropylethylamine was added over 30 minutes while maintaining a temperature below 10° C. The solution was slowly heated to 15° C. over 3 hours and held at 15° C. for 16 hours. The temperature was increased to 20° C. and stirred for 3.25 hours. The resulting solution was charged with 3.3 g of 13 wt % aqueous NaCl and heated to 50° C. for 1 hour. After cooling to 20° C., 2.5 mL of isopropyl acetate was added. The rich organic phase was washed with 2×6.9 g of a 0.5 N NaOH solution containing 13 wt % NaCl followed by 3.3 g of 13 wt % aqueous NaCl. The mixture was then solvent exchanged into isopropyl acetate by vacuum distillation to a target volume of 10 mL. The resulting hazy solution was cooled to 20° C. and filtered through a 0.45 μm filter. The clear solution was then solvent exchanged into ethanol by vacuum distillation with a target volume of 3 mL. 1.67 mL (2.02 mmol, 2.3 equiv) of 1.21 M HCl in ethanol was added. The mixture was then stirred at 25° C. for 15 hours. The resulting slurry was filtered and the wet cake was washed with 2.5 mL of 2:1 acetone:ethanol. The solids were dried in a vacuum oven at 50° C. to give 0.550 g (0.68 mmol, 77%) of the desired product.

Recrystallization of Example 24-23

(179) A solution of Example 24-23 prepared above was prepared by dissolving 0.520 g of the above product in 3.65 mL methanol. The solution was then charged with 0.078 g of type 3 Cuno Zeta loose carbon and allowed to stir for 0.25 hours. The mixture was then filtered and washed with 6 ml of methanol. The product rich solution was concentrated down to 2.6 mL by vacuum distillation. 7.8 mL acetone was added and allowed to stir at 25° C. for 15 h. The solids were filtered, washed with 2.5 mL 2:1 acetone:ethanol and dried in a vacuum oven at 70° C. to give 0.406 g (57.0%) of the desired product as white crystals: .sup.1H NMR (400 MHz, DMSO-d.sub.6, 80° C.): 8.02 (d, J=8.34 Hz, 4H), 7.97 (s, 2H), 7.86 (d, J=8.34 Hz, 4H), 6.75 (s, 2H), 5.27 (t, J=6.44 Hz, 2H), 4.17 (t, J=6.95 Hz, 2H), 3.97-4.11 (m, 2H), 3.74-3.90 (m, 2H), 3.57 (s, 6H), 2.32-2.46 (m, 2H), 2.09-2.31 (m, 6H), 1.91-2.07 (m, 2H), 0.88 (d, J=6.57 Hz, 6H), 0.79 (d, J=6.32 Hz, 6H); .sup.13C NMR (75 MHz, DMSO-d.sub.6): δ 170.9, 156.9, 149.3, 139.1, 131.7, 127.1, 126.5, 125.9, 115.0, 57.9, 52.8, 51.5, 47.2, 31.1, 28.9, 24.9, 19.6, 17.7; IR (neat, cm.sup.−1): 3385, 2971, 2873, 2669, 1731, 1650. Anal. Calcd for C.sub.40H.sub.52N.sub.8O.sub.6Cl.sub.2: C, 59.18; H, 6.45; N, 13.80; Cl, 8.73. Found C, 59.98; H, 6.80; N, 13.68; Cl, 8.77. mp 267° C. (decomposed). Characteristic diffraction peak positions (degrees 2θ±0.1) @ RT, based on a high quality pattern collected with a diffractometer (CuKα) with a spinning capillary with 2θ calibrated with a NIST other suitable standard are as follows: 10.3, 12.4, 12.8, 13.3, 13.6, 15.5, 20.3, 21.2, 22.4, 22.7, 23.7.

Example 25

N,N′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl((1R)-2-oxo-1-phenyl-2,1-ethanediyl)))diacetamide

(180) ##STR00284##

Example 25

Step a

di-tert-butyl (4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl((1R)-2-oxo-1-phenyl-2,1-ethanediyl)))biscarbamate

and

Example 25

Step b

(181) ##STR00285##

(182) HATU (96.2 mg, 0.253 mmol) was added to a mixture of pyrrolidine 1e (52.6 mg, 0.124 mmol), diisopropylethylamine (100 μL, 0.57 mmol) and Boc-D-Phg-OH (69 mg, 0.275 mmol) in DMF (3.0 mL). The reaction mixture was stirred for 25 minutes, and then diluted with methanol and purified by a reverse phase HPLC system (H.sub.2O/methanol/TFA). The HPLC elute was neutralized with excess 2.0 M/NH.sub.3 in CH.sub.3OH and the volatile component was removed in vacuo. The residue was carefully partitioned between CH.sub.2Cl.sub.2 and saturated NaHCO.sub.3. The aqueous phase was extracted with more CH.sub.2Cl.sub.2 (2×). The combined organic phase was dried (MgSO.sub.4), filtered, and concentrated in vacuo to provide 25a as a film of semisolid oil (78.8 mg). LC (Cond. 1): RT=1.99 min; >98% homogeneity index. LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.52H.sub.59N.sub.8O.sub.6: 891.46. found 891.55.

(183) Carbamate 25a was converted to amine 25b according to the procedure described for the preparation of 1e. LC(Cond. 1): RT=1.44 min; 97% homogeneity index. LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.42H.sub.43N.sub.8O.sub.2: 691.35. found 691.32.

Example 25

N,N′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl((1R)-2-oxo-1-phenyl-2,1-ethanediyl)))diacetamide

(184) Acetic anhydride (20 μL, 0.21 mmol) was added to a DMF (1.5 mL) solution of amine 25b (29 mg, 0.042 mmol) and triethylamine (30 μL, 0.22 mmol) and stirred for 2.5 hours. The reaction mixture was then treated with NH.sub.3/methanol (1 mL of 2 M) and stirred for an additional 1.5 hours. The volatile component was removed in vacuo and the residue was purified by a reverse phase HPLC system (H.sub.2O/methanol/TFA) to provide the TFA salt of Example 25 as a white foam (28.1 mg). LC (Cond. 1): RT=1.61 min; >98% homogeneity index; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.46H.sub.47N.sub.8O.sub.4: 775.37. found 775.40. HRMS: Anal. Calcd. for [M+H].sup.+ C.sub.46H.sub.47N.sub.8O.sub.4: 775.3720. found 775.3723.

Example 25-1 to 25-5

(185) ##STR00286##

(186) Examples 25-1 to 25-5 were prepared from 25b and the appropriate carboxylic acid using standard amide forming conditions similar to that described for the preparation of example 1 from 1e. Examples 25-6 to 25-8 were prepared from 25b and the appropriate carbamoyl chloride or isocyanate.

(187) TABLE-US-00018 RT (LC-Cond.); Example % homogeneity Number Compound Name R index; MS data 25-1 (2R,2′R)-N,N′- (4,4′-biphenyl- diylbis(1H- imidazole-5,2- diyl(2S)-2,l- pyrrolidinediyl ((1R)-2-oxo-1- phenyl-2,1- RT = 5.68 minutes; HPLC Xterra 4.6 X 50 mm, 0 to 100% B over 10 minutes, one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, ethanediyl))) B = 10% water, 90% ditetrahydro-2- methanol, 0.2% furancarboxamide phosphoric acid; LCMS: Anal. Calcd. for: C.sub.52H.sub.54N.sub.8O.sub.6: 887.06; Found: 887.58 (M + H).sup.+ 25-2 N,N′-(4,4′- biphenyldiyl- bis(1H- imidazole-5,2- diyl(2S)-2,1- pyrrolidinediyl ((1R)-2-oxo- 1-phenyl-2,1- ethanediyl)))bis RT = 3.54 minutes; HPLC Xterra 4.6 X 50 mm, 0 to 100% B over 10 minutes, one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% (1-methyl-1H- methanol, 0.2% imidazole-5- phosphoric acid; carboxamide) LCMS: Anal. Calcd. for: C.sub.52H.sub.50N.sub.12O.sub.4: 907.06; Found: 907.42 (M + H).sup.+ 25-3 (2S,2′S)-N,N′- (4,4′-biphenyl- diylbis(1H- imidazole-5,2- diyl(2S)-2,1- pyrrolidinediyl ((1R)-2-oxo- 1-phenyl-2,1- ethanediyl))) RT = 3.1 minutes; HPLC Xterra 4.6 X 50 mm, 0 to 100% B over 10 minutes, one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% bis(1-methyl- methanol, 0.2% 2-pyrrolidine- phosphoric acid; carboxamide) LCMS: Anal. Calcd. for: C.sub.54H.sub.60N.sub.10O.sub.4 913.14; Found: 913.54 (M + H).sup.+ 25-4 N,N′-(4,4′- biphenyldiyl- bis(1H- imidazole-5,2- diyl(2S)-2,1- pyrrolidine- diyl((1R)-2- oxo-1-phenyl- 2,1-ethane- diyl)))bis(2-(3- pyridinyl) acetamide) 0 RT = 3.37 minutes; HPLC Xterra 4.6 X 50 mm, 0 to 100% B over 10 minutes, one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid; LCMS: Anal. Calcd. for: C.sub.56H.sub.52N.sub.10O.sub.4 929.10 Found: 929.42 (M + H).sup.+ 25-5 N,N′-(4,4′- biphenyldiyl- bis(1H- imidazole-5,2- diyl(2S)-2,1- pyrrolidinediyl ((1R)-2-oxo- 1-phenyl-2,1- ethanediyl)))bis RT = 7.07 minutes; HPLC Xterra 4.6 X 50 mm, 0 to 100% B over 10 minutes, one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% (2-(dimethyl- methanol, 0.2% amino) phosphoric acid; acetamide) LCMS: Anal. Calcd. (non-preferred for: C.sub.50H.sub.56N.sub.10O.sub.4 name) 861.07 Found: 859.69 (M + H).sup.+ 25-6 N,N′-(4,4′- biphenyldiyl- bis(1H- imidazole-5,2- diyl(2S)-2,1- pyrrolidinediyl ((1R)-2-oxo- 1-phenyl-2,1- ethanediyl))) di(4-morpholine- .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.86-2.18 (m, 6H), 2.23-2.39 (m, 2H), 3.20-3.40 (m, 8H), 3.40-3.61 (m, 8H), 3.90-4.19 (m, 4H), 5.27 (dd, J = 8.09, 3.51 Hz, 2H), 5.37- 5.63 (m, 2H), 6.92- carboxamide) 7.11 (m, 3H), 7.30- 7.45 (m, 5H), 7.44- 7.56 (m, 4H), 7.83- 8.04 (m, 8H), 8.15 (s, 2H), 14.29 (s, 2H); HPLC Xterra 4.6 X 50 mm, 0 to 100% B over 10 minutes, one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid, RT = 6.01 minutes; LCMS: Anal. Calcd. for: C.sub.52H.sub.56N.sub.10O.sub.6 917.09; Found: 917.72 (M + H).sup.+ 25-7 N,N′-(4,4′- biphenyldiyl- bis(1H- imidazole-5,2- diyl(2S)-2,1- pyrrolidinediyl ((1R)-2-oxo-1- phenyl-2,1- ethanediyl)))bis (4-methyl-1- piperazine- carboxamide) RT = 3.74 minutes; HPLC Xterra 4.6 X 50 mm, 0 to 100% B over 10 minutes, one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid; LCMS: Anal. Calcd. for: C.sub.54H.sub.62N.sub.12O.sub.4 943.17; Found: 943.84 (M + H).sup.+ 25-8 N,N″-(4,4′- biphenyldiyl- bis(1H- imidazole-5,2- diyl(2S)-2,1- pyrrolidinediyl ((1R)-2-oxo- 1-phenyl-2,1- ethanediyl)))bis (3-(3-pyridinyl) urea) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.79-2.17 (m, 6H), 2.29 (d, J = 9.77 Hz, 2H), 3.06-3.39 (m, 2H), 3.72-4.14 (m, 2H), 5.27 (dd, J = 8.24, 2.75 Hz, 2H), 5.66 (d, J = 7.02 Hz, 2H), 7.26-7.65 (m, 12H), 7.82-8.11 (m, 12H), 8.17 (s, 2H), 8.23-8.45 (m, 2H), 8.61-8.97 (m, 2H), 9.38 (s, 2H), 14.51 (s, 2H); HPLC Xterra 4.6 X 50 mm, 0 to 100% B over 10 minutes, one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid, RT = 4.05 minutes; LCMS: Anal. Calcd. for: C.sub.54H.sub.50N.sub.12O.sub.4 931.08; Found: 931.78 (M + H).sup.+.

Example 26

methyl ((1R)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

(188) ##STR00295##

Example 26

Step a

(2R,2′R)-1,1′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl))bis(3-methyl-1-oxo-2-butanamine)

(189) ##STR00296##

(190) Diamine 26a was prepared starting from pyrrolidine 1e and BOC-D-Val-OH according to the procedure described for the synthesis of diamine 25b.

Example 26

methyl ((1R)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

(191) Methyl chloroformate (18 μL, 0.23 mmol) was added to a THF (1.5 mL) solution of diamine 26a (30 mg, 0.048 mmol) and triethylamine (30 μL, 0.22 mmol), and the reaction mixture was stirred at ambient condition for 3 hours. The volatile components was removed in vacuo, and the residue was treated with NH.sub.3/methanol (2 mL of 2 M) and stirred at ambient conditions for 15 minutes. All the volatile component was removed in vacuo, and the crude product was purified by reverse phase prep-HPLC (H.sub.2O/methanol/TFA) to provide the TFA salt of Example 26 as a white solid (13.6 mg). LC (Cond. 2): RT=2.00 min; >98% homogeneity index; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.40H.sub.51N.sub.8O.sub.6: 739.39. found 739.67. HRMS: Anal. Calcd. for [M+H].sup.+ C.sub.40H.sub.51N.sub.8O.sub.6: 739.3932. found 739.3966.

Example 27

N-((1R)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-acetamido-3-methylbutanoyl)-2-pyrrolidinyl)carbonyl)-2-methylpropyl)acetamide

(192) ##STR00297##

(193) Diamine 26a was converted to Example 27 (TFA salt) according to a method described in the preparation of Example 25. LC (Cond. 2): RT=1.93 min; >98% homogeneity index; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.40H.sub.51N.sub.8O.sub.4: 707.40. found 707.59. HRMS: Anal. Calcd. for [M+H].sup.+ C.sub.40H.sub.51N.sub.8O.sub.4: 707.4033. found 707.4054.

Example 28

methyl ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1-(phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)ethyl) carbamate

(194) ##STR00298##

Example 28

Step a

(195) ##STR00299##

(196) HATU (19.868 g, 52.25 mmol) was added to a heterogeneous mixture of N-Cbz-L-proline (12.436 g, 49.89 mmol) and the HCl salt of 2-amino-1-(4-bromophenyl) ethanone (12.157 g, 48.53 mmol) in DMF (156 mL). The mixture was lowered in an ice-water bath, and immediately afterward N,N-diisopropylethylamine (27 mL, 155 mmol) was added dropwise to it over 13 minutes. After the addition of the base was completed, the cooling bath was removed and the reaction mixture was stirred for an additional 50 minutes. The volatile component was removed in vacuo; water (125 mL) was added to the resulting crude solid and stirred for about 1 hour. The off-white solid was filtered and washed with copious water, and dried in vacuo to provide ketoamide 28a as a white solid (20.68 g). .sup.1H NMR (DMSO-d.sub.6, δ=2.5 ppm, 400 MHz): δ 8.30 (m, 1H), 7.91 (m, 2H), 7.75 (d, J=8.5, 2H), 7.38-7.25 (m, 5H), 5.11-5.03 (m, 2H), 4.57-4.48 (m, 2H), 4.33-4.26 (m, 1H), 3.53-3.36 (m, 2H), 2.23-2.05 (m, 1H), 1.94-1.78 (m, 3H); LC (Cond. 1): RT=1.65 min; 98% homogeneity index; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.21H.sub.22BrN.sub.2O.sub.4: 445.08. found 445.31.

Example 28

Step b

(197) ##STR00300##

(198) Ketoamide 28a (10.723 g, 24.08 mmol) was converted to 28b according to the procedure described for the synthesis of carbamate 1b, with the exception that the crude material was purified by flash chromatography (sample was loaded with eluting solvent; 50% ethyl acetate/hexanes). Bromide 28b was retrieved as an off-white foam (7.622 g). .sup.1H NMR (DMSO-d.sub.6, δ=2.5 ppm, 400 MHz): δ 12.23/12.04/11.97 (m, 1H), 7.73-6.96 (m, 10H), 5.11-4.85 (m, 3H), 3.61 (m, 1H), 3.45 (m, 1H), 2.33-184 (m, 4H). LC (Cond. 1): RT=1.42 min; >95% homogeneity index; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.21H.sub.21BrN.sub.3O.sub.2: 426.08. found 426.31. HRMS: Anal. Calcd. for [M+H].sup.+ C.sub.21H.sub.21BrN.sub.3O.sub.2: 426.0817. found: 426.0829. The optical purity of 28b was assessed using the following chiral HPLC methods, and an ee of 99% was observed.

(199) Column: Chiralpak AD, 10 um, 4.6×50 mm

(200) Solvent: 20% ethanol/heptane (isocratic)

(201) Flow rate: 1 mL/min

(202) Wavelength: 254 nm

(203) Relative retention time: 1.82 minutes (R), 5.23 minutes (S)

Example 28

Step c

benzyl tert-butyl (2S,2′S)-2,2′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl)di(1-pyrrolidinecarboxylate)

(204) ##STR00301##

(205) Pd(Ph.sub.3P).sub.4 (711.4 mg, 0.616 mmol) was added to a mixture of boronate ester 1c (7.582 g, ˜17 mmol), bromide 28b (7.62 g, 17.87 mmol), NaHCO.sub.3 (4.779 g, 56.89 mmol) in 1,2-dimethoxyethane (144 mL) and water (48 mL). The reaction mixture was purged with N.sub.2 and heated with an oil bath at 80° C. for 15.5 hours, and then the volatile component was removed in vacuo. The residue was partitioned between CH.sub.2Cl.sub.2 and water, and the aqueous layer was extracted with CH.sub.2C.sub.12. The combined organic phase was dried (MgSO.sub.4), filtered, and concentrated in vacuo. The resulting material was submitted to flash chromatography (sample was loaded as a silica gel mesh; ethyl acetate used as eluent) to provide biphenyl 28c as an off-white foam containing Ph.sub.3PO impurity (7.5 g). .sup.1H NMR (DMSO-d.sub.6, δ=2.5 ppm, 400 MHz): δ 12.24-12.19 (m, 0.36H), 12.00-11.82 (m, 1.64H), 7.85-6.98 (15H), 5.12-4.74 (4H), 3.68-3.34 (4H), 2.34-1.79 (8H), 1.41/1.17 (two br S, 9H); LC (Cond. 1): RT=1.41 minutes; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.39H.sub.43N.sub.6O.sub.4: 659.34. found 659.52. HRMS: Anal. Calcd. for [M+H].sup.+ C.sub.39H.sub.43N.sub.6O.sub.4: 659.3346. found 659.3374.

Example 28

Step d

tert-butyl (2S)-2-(5-(4′-(2-((2S)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinecarboxylate

(206) ##STR00302##

(207) K.sub.2CO.sub.3 (187.8 mg, 1.36 mmol) was added to a mixture of catalyst (10% Pd/C; 205.3 mg), carbamate 28c (1.018 g, 1.5 mmol), methanol (20 mL) and 3 pipet-drops of water. A balloon of H.sub.2 was attached and the mixture was stirred for 6 hours. Then, additional catalyst (10% Pd/C, 100.8 mg) and K.sub.2CO.sub.3 (101.8 mg, 0.738 mmol) were added and stirring continued for 3.5 hours. During the hydrogenation process, the balloon of H.sub.2 was changed at intervals three times. The reaction mixture was filtered through a pad of diatomaceous earth (Celite® 521), and the filterate was removed in vacuo. The resulting crude material was submitted to flash chromatography using a short column (sample was loaded as a silica gel mesh; O-20% methanol/CH.sub.2Cl.sub.2 used as eluent) to provide 28d as a light-yellow foam (605.6 mg). .sup.1H NMR (DMSO-d.sub.6, δ=2.5 ppm, 400 MHz): δ 12.18/11.89/11.82 (three br s, 2H), 7.83-7.29 (m, 10H), 4.89-4.73 (m, 1H), 4.19 (app t, J=7.2, 1H), 3.55 (app br s, 1H), 3.40-3.35 (m, 1H), 3.02-2.96 (m, 1H), 2.91-2.84 (m, 1H), 2.30-1.69 (m, 8H), 1.41/1.16 (two br s, 9H). Note: the signal of pyrrolidine NH appears to have overlapped with signals in the 3.6-3.2 ppm region; LC (Cond. 1): RT=1.21 min; >95% homogeneity index; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.31H.sub.37N.sub.6O.sub.2: 525.30. found 525.40.

Example 28

Step e-f

Example 28

Step e

tert-butyl (2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinecarboxylate

Example 28

Step f

methyl ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2-((2S)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)ethyl)carbamate

(208) ##STR00303##
Step e:

(209) HATU (316.6 mg, 0.833 mmol) was added to a DMF (7.0 mL) solution of pyrrolidine 28d (427 mg, 0.813 mmol), Cap-4 (177.6 mg, 0.849 mmol) and diisopropylethylamine (0.32 mL, 1.84 mmol), and the reaction mixture was stirred for 45 minutes. The volatile component was removed in vacuo, and the residue was partitioned between CH.sub.2Cl.sub.2 (50 mL) and an aqueous medium (20 mL H.sub.2O+1 mL saturated NaHCO.sub.3 solution). The aqueous phase was re-extracted with CH.sub.2C.sub.12, and the combined organic phase was dried (MgSO.sub.4), filtered, and concentrated in vacuo. The resulting yellow oil was purified by flash chromatography (silica gel; ethyl acetate) to provide 28e as a yellow foam (336 mg).

(210) LC (Cond. 1): RT=1.68 min; 91% homogeneity index; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.41H.sub.46N.sub.7O.sub.5: 716.35. found 716.53.

(211) Step f:

(212) Carbamate 28e was elaborated to amine 28f by employing the procedure described in the conversion of 1d to 1e. LC (Cond. 1): RT=1.49 min; >98% homogeneity index. LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.36H.sub.38N.sub.7O.sub.3: 616.30. found 616.37. HRMS: Anal. Calcd. for [M+H].sup.+ C.sub.36H.sub.38N.sub.7O.sub.3: 616.3036. found 616.3046.

Example 28

methyl ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1-(phenylacetyl)-2-pyrrolidinyl)ethyl) carbamate

(213) ##STR00304##

(214) Amine 28f was converted to the TFA salt of Example 28 by employing the last step of the synthesis of Example 1. .sup.1H NMR (DMSO-d.sub.6, δ=2.5 ppm, 400 MHz): δ 8.21-7.03 (m, 21H), 5.78-5.14 (3H), 3.98-3.13 (m, 9H; includes the signal for OCH.sub.3 at 3.54 & 3.53), 2.45-1.72 (m, 8H). LC (Cond. 1): RT=1.66 minutes, >98% homogeneity index; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.44H.sub.44N.sub.7O.sub.4: 734.35. found 734.48. HRMS: Anal. Calcd. for [M+H].sup.+ C.sub.44H.sub.44N.sub.7O.sub.4: 734.3455; 734.3455.

Example 28-1 to 28-4

(215) ##STR00305##

(216) Examples 28-1 through 28-4 (R groups shown in the table below) were prepared in similar fashion to example 28 via the intermediacy of intermediate 28d.

Example 28-1

(1R)—N,N-dimethyl-2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-phenyl-2-(1-piperidinyl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)ethanamine

(217) Cap-1 was appended, the Boc carbamate was removed with TFA or HCl, and Cap-14 was appended.

Example 28-2

1-((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-tetrahydro-2-furanylcarbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)ethyl)piperidine

(218) Tetrahydrofuroic acid was appended, the Boc carbamate was removed with TFA or HCl, and Cap-14 was appended.

Example 28-3

methyl ((1R)-1-(2-chlorophenyl)-2-oxo-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-phenyl-2-(1-piperidinyl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)ethyl)carbamate

(219) Cap-40 was appended, the Boc carbamate was removed with TFA or HCl, and Cap-14 was appended.

Example 28-4

(1R)-1-(2-chlorophenyl)-N,N-dimethyl-2-oxo-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-phenyl-2-(1-piperidinyl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)ethanamine

(220) Cap-39 was appended, the Boc carbamate was removed with TFA or HCl, and Cap-14 was appended.

Example 28-5

(1R)-1-(2-fluorophenyl)-N,N-dimethyl-2-oxo-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-phenyl-2-(1-piperidinyl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)ethanamine

(221) Cap-38 was appended, the Boc carbamate was removed with TFA or HCl, and Cap-14 was appended.

(222) TABLE-US-00019 Exam- Compound ple Name R Data 28-1 (1R)-N,N- dimethyl-2- oxo-1- phenyl-2- ((2S)-2-(5- (4′-(2-((2S)- 1-((2R)-2- phenyl-2-(1- piperidinyl) acetyl)-2- 06 LCMS: Anal. Calcd. for C.sub.49H.sub.54N.sub.8O.sub.2: 786; found: 787 (M + H).sup.+. pyrrolidinyl)- 1H-imidazol- 5-yl)-4- biphenylyl)- 1H-imidazol- 2-yl)-1- pyrrolidinyl) ethanamine 28-2 1-((1R)-2- oxo-1-phenyl- 2-((2S)-2-(5- (4′-(2-((2S)-1- ((2R)-tetra- hydro-2-furan- carbonyl)-2- pyrrolidinyl)- 07 LCMS: Anal. Calcd. for C.sub.44H.sub.49N.sub.7O.sub.3: 723; found: 724 (M + H).sup.+. 1H-imidazol- 5-yl)-4- biphenylyl)- 1H-imidazol- 2-yl)-1- pyrrolidinyl) ethyl) piperidine 28-3 methyl ((1R)- 1-(2-chloro- phenyl)-2-oxo- 2-((2S)-2-(5- (4′-(2-((2S)-1- ((2R)-2- phenyl-2-(1- piperidinyl) acetyl)-2- pyrrolidinyl)- 1H-imidazol- 5-yl)-4- biphenylyl)- 08 LCMS: Anal. Calcd. for C.sub.49H.sub.51ClN.sub.8O.sub.4: 850; found: 851 (M + H).sup.+. 1H-imidazol- 2-yl)-1- pyrrolidinyl) ethyl) carbamate 28-4 (1R)-1-(2- chlorophenyl)- N,N-dimethyl- 2-oxo-2- ((2S)-2-(5-(4′- (2-((2S)-1- ((2R)-2- phenyl-2-(1- piperidinyl) acetyl)-2- pyrrolidinyl)- 09 LCMS: Anal. Calcd. for C.sub.49H.sub.53ClN.sub.8O.sub.2: 820; found: 821 (M + H).sup.+. 1H-imidazol- 5-yl)-4- biphenylyl)- 1H-imidazol- 2-yl)-1- pyrrolidinyl) ethanamine 28-5 (1R)-1-(2- fluorophenyl)- N,N-dimethyl- 2-oxo-2-((2S)- 2-(5-(4′-(2- ((2S)-1-((2R)- 2-phenyl-2-(1- piperidinyl) acetyl)-2- pyrrolidinyl)- 1H-imidazol- 0 LCMS: Anal. Calcd. for C.sub.49H.sub.53FN.sub.8O.sub.2: 804; found: 805 (M + H).sup.+. 5-yl)-4- biphenylyl)- 1H-imidazol- 2-yl)-1- pyrrolidinyl) ethanamine

Example 29

methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-((4-methyl-1-piperazinyl)carbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

(223) ##STR00311##

(224) 4-Methylpiperazine-1-carbonyl chloride/HCl (11.6 mg, 0.58 mmol) was added to a mixture of 28f (30 mg, 0.049 mmol), triethylamine (15 μl, 0.11 mmol) and THF (1.0 mL), and stirred at ambient conditions for 1 hour. The volatile component was removed in vacuo, and the residue was purified by a reverse phase HPLC (H.sub.2O/methanol/TFA) to provide the TFA salt of Example 29 as a light yellow foam (29.3 mg). LC (Cond. 2): RT=1.82 minutes, >98% homogeneity index; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.42H.sub.48N.sub.9O.sub.4: 742.38. found 742.49.

Example 30

methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-glycyl-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

(225) ##STR00312##

Example 30

Step a

methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-(N-(tert-butoxycarbonyl)glycyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

(226) ##STR00313##

(227) Carbamate 30a was prepared from pyrrolidine 28f and Boc-Glycine by using the procedure described for the preparation of 25a from 1e. LC (Cond. 2): RT=2.12 minutes, >98% homogeneity index; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.43H.sub.49N.sub.8O.sub.6: 773.38. found 773.46.

Example 30

methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-glycyl-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

(228) Carbamate 30a was converted to Example 30 according to the procedure described for the preparation of 1e from 1d. LC (Cond. 2): RT=1.81 minutes, >98% homogeneity index; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.38H.sub.41N.sub.8O.sub.4: 673.33. found 673.43.

(229) HRMS: Anal. Calcd. for [M+H].sup.+ C.sub.38H.sub.41N.sub.8O.sub.4: 673.3251. found 673.3262.

Example 30-1

methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate

(230) ##STR00314##

(231) Example 30-1 was prepared in three steps from Example 28d. Step one: Append Cap-2 using the procedure describing the synthesis of 28e from 28d. Step two: Hydrolyze the Boc carbamate using the procedure describing the synthesis of 28f from 28e. Step three: Append Cap-52 using the procedure describing the synthesis of 28e from 28d. RT=1.70 min (Cond. 1b); >95% homogeneity index. LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.43H.sub.51N.sub.8O.sub.4: 743.40. found, 743.50. HRMS: Anal. Calcd. for [M+H].sup.+ C.sub.43H.sub.51N.sub.8O.sub.4: 743.4033. found, 743.4053.

(232) Substituting the appropriate acid chloride or carboxylic acid into Example 29 or 30, the following compounds (Example 31 to 84-87) were prepared as TFA salts.

Example 31 to 84-88

(233) ##STR00315##

(234) TABLE-US-00020 Example Compound Name Retention time (LC-Condition); homogeneity index MS data 31 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- acetyl-2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate 1.54 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.38H.sub.40N.sub.7O.sub.4: 658.31; found 658.42; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.38H.sub.40N.sub.7O.sub.4: 658.3142; found 658.3135 32 methyl ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5- (4′-(2-((2S)-1-propionyl-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)ethyl)carbamate 1.57 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.39H.sub.42N.sub.7O.sub.4: 672.33; found 672.46; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.39H.sub.42N.sub.7O.sub.4: 672.3298; found 672.3299 33 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- (cyclopropylcarbonyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate 1.59 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.42N.sub.7O.sub.4: 684.33; found 684.44; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.42N.sub.7O.sub.4: 684.3298; found 684.3324 34 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- (cyclopropylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate 0 1.61 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.42N.sub.7O.sub.4: 698.35; found 698.48; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.42N.sub.7O.sub.4: 698.3455; found 698.3489 35 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((2R)-2-hydroxypropanoyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate 1.54 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.39H.sub.42N.sub.7O.sub.5: 688.33; found 688.47 36 methyl ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5- (4′-(2-((2S)-1-((2R)-tetrahydro-2- furanylcarbonyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)ethyl)carbamate 1.59 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.44N.sub.7O.sub.5: 714.34; found 714.49; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.44N.sub.7O.sub.5: 714.3404; found 714.3430 37 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- (N,N-dimethylglycyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate 1.48 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.45N.sub.8O.sub.4: 701.36; found 701.49; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.45N.sub.8O.sub.4: 701.3564; found 701.3553 38 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((2S)-2-(dimethylamino)-2-phenylacetyl)- 2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate 1.20 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.46H.sub.49N.sub.8O.sub.4: 777.39; found 777.61; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.46H.sub.49N.sub.8O.sub.4: 777.3877; found 777.3909 39 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- (4-morpholinylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2-oxo- 1-phenylethyl)carbamate 1.79 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.47N.sub.8O.sub.5: 743.37; found 743.49; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.47N.sub.8O.sub.5: 743.3669; found 743.3672 40 methyl (2-((2S)-2-(5-(4′-(2-((2S)-1- ((2R)-2-((methoxycarbonyl)amino)- 2-phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2- oxoethyl)carbamate 1.92 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.43N.sub.8O.sub.6: 731.33; found 731.42; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.43N.sub.8O.sub.6: 731.3306; found 731.3333 41 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- (N-acetylglycyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate 1.86 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.43N.sub.8O.sub.5: 715.34; found 715.49; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.43N.sub.8O.sub.5: 715.3356; found 715.3369 42 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((2R)-2-(dimethylamino)-2-phenylacetyl)- 2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate 1.85 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.46H.sub.49N.sub.8O.sub.4: 777.39; found 777.56 43 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((2R)-2-hydroxy-2-phenylacetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate 1.96 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.44H.sub.44N.sub.7O.sub.5: 750.34; found 750.51; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.44H.sub.44N.sub.7O.sub.5: 750.3404; found 750.3437 44 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((1-methyl-4-piperidinyl)carbonyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate 0 1.78 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.43H.sub.49N.sub.8O.sub.4: 741.39; found 741.55; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.43H.sub.49N.sub.8O.sub.4: 741.3877; found 741.3893 45 methyl ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5- (4′-(2-((2S)-1-(tetrahydro-2H-pyran-4- ylcarbonyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)ethyl)carbamate 1.87 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.46N.sub.7O.sub.5: 728.36; found 728.52; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.46N.sub.7O.sub.5: 728.3560; found 728.3587 46 methyl ((1R)-2-oxo-1-phenyl-2-((2S)-2- (5-(4′-(2-((2S)-1-(2-pyridinylacetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)ethyl)carbamate 1.80 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.43H.sub.43N.sub.8O.sub.4: 735.34; found 735.51; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.43H.sub.43N.sub.8O.sub.4: 735.3407; found 735.3416 47 methyl ((1R)-2-oxo-1-phenyl-2-((2S)-2- (5-(4′-(2-((2S)-1-(3-pyridinylacetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)ethyl)carbamate 1.76 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.43H.sub.43N.sub.8O.sub.4: 735.34; found 735.52 48 methyl ((1R)-2-oxo-1-phenyl-2-((2S)-2- (5-(4′-(2-((2S)-1-(4-pyridinylacetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)ethyl)carbamate 1.77 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.43H.sub.43N.sub.8O.sub.4: 735.34; found 735.50; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.43H.sub.43N.sub.8O.sub.4: 735.3407; found 735.3405 49 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((1-methyl-1H-imidazol-5-yl)carbonyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate 1.77 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.42N.sub.9O.sub.4: 724.34; found 724.51; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.42N.sub.9O.sub.4: 724.3360; found 724.3380 50 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- (dimethylcarbamoyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate 1.91 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.39H.sub.43N.sub.8O.sub.4: 687.34; found 687.49; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.39H.sub.43N.sub.8O.sub.4: 687.3407; found 687.3414 51 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- (1-methyl-D-prolyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate 1.79 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.47N.sub.8O.sub.4: 727.37; found 727.34; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.47N.sub.8O.sub.4: 727.3720; found 727.3719 52 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)- 1-(1-methyl-L-prolyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate 1.77 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.47N.sub.8O.sub.4: 727.37; found 727.33; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.47N.sub.8O.sub.4: 727.3720; found 727.3738 53 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- (N-acetyl-D-alanyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate 1.92 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.45N.sub.8O.sub.5: 729.35; found 729.33; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.45N.sub.8O.sub.5: 729.3513; found 729.3530 54 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- (N-acetyl-L-alanyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate 0 1.87 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.45N.sub.8O.sub.5: 729.35; found 729.33 55 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- (methoxyacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate 1.89 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.39H.sub.42N.sub.7O.sub.5: 688.32; found 688.28; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.39H.sub.42N.sub.7O.sub.5: 688.3247; found 688.3231 56 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((2R)-2-hydroxybutanoyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate 1.91 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.44N.sub.7O.sub.5: 702.34; found 702.30; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.44N.sub.7O.sub.5: 702.3404; found 702.3393 57 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-((4- methyl-1-piperazinyl)acetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate 1.80 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.43H.sub.50N.sub.9O.sub.4: 756.40; found 756.36; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.43H.sub.30N.sub.9O.sub.4: 756.3986; found 756.3965 58 methyl ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5- (4′-(2-((2S)-1-(1-pyrrolidinylacetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)ethyl)carbamate 1.82 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.47N.sub.8O.sub.4: 727.37; found 727.33; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.47N.sub.8O.sub.4: 727.3720; found 727.3696 59 methyl ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5- (4′-(2-((2S)-1-((2S)-tetrahydro-2- furanylcarbonyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)ethyl)carbamate 1.94 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.43N.sub.7O.sub.5: 714.34; found 714.24 60 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((1-hydroxycyclopropyl)carbonyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate 1.93 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.42N.sub.7O.sub.5: 700.32; found 700.23; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.42N.sub.7O.sub.5: 700.3247; found 700.3265 61 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- (1H-imidazol-5-ylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate 1.84 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.42N.sub.9O.sub.4: 724.34; found 724.21; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.42N.sub.9O.sub.4: 724.3360; found 724.3365 62 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)- 1-((1-methyl-1H-imidazol-4-yl)acetyl)- 2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate 1.85 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.44N.sub.9O.sub.4: 738.35; found 738.22; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.44N.sub.9O.sub.4: 738.3516; found 738.3539 63 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- (1H-imidazol-2-ylcarbonyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate 1.95 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.41N.sub.9O.sub.4: 710.32; found 710.17 64 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((4-hydroxy-1-piperidinyl)(phenyl)acetyl)- 2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate 0 1.92 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.49H.sub.53N.sub.8O.sub.5: 833.41; found 833.32; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.49H.sub.53N.sub.8O.sub.5: 833.4139; found 833.4163 65 methyl ((1R)-2-oxo-1-phenyl-2-((2S)-2- (5-(4′-(2-((2S)-1-(1H-tetrazol-5- ylacetyl)-2-pyrrolidinyl)-1H-imidazol- 5-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)ethyl)carbamate 1.92 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.39H.sub.40N.sub.11O.sub.4: 726.33; found 726.22; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.39H.sub.40N.sub.11O.sub.4: 726.3265; found 726.3290 67 methyl ((1R)-2-oxo-1-phenyl-2-((2S)-2- (5-(4′-(2-((2S)-1-(2-pyridinylcarbonyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)ethyl)carbamate 2.03 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.41N.sub.8O.sub.4: 721.33; found 721.31; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.41N.sub.8O.sub.4: 721.3251; found 721.3247 68 methyl ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5- (4′-(2-((2S)-1-(3-pyridinylcarbonyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)ethyl)carbamate 1.91 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.41N.sub.8O.sub.4: 721.33; found 721.31; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.41N.sub.8O.sub.4: 721.3251; found 721.3226 69 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- isonicotinoyl-2-pyrrolidinyl)-1H-imidazol- 5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate 1.89 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.41N.sub.8O.sub.4: 721.33; found 721.29; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.41N.sub.8O.sub.4: 721.3251; found 721.3251 70 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((4R)-4-fluoro-1-methyl-L-prolyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate 1.84 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.46FN.sub.8O.sub.4: 745.36; found 745.27; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.46FN.sub.8O.sub.4: 745.3626; found 745.3658 71 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- (1,3-oxazol-2-ylcarbonyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate 1.97 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.39N.sub.8O.sub.5: 711.30; found 711.27 72 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- (1,3-oxazol-5-ylcarbonyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate 1.95 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.39N.sub.8O.sub.5: 711.30; found 711.27; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.39N.sub.8O.sub.5: 711.3043; found 711.3078 73 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((dimethylamino)(oxo)acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate 1.92 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.43N.sub.8O.sub.5: 715.34; found 715.40 74 methyl ((1R)-2-oxo-1-phenyl-2-((2S)- 2-(5-(4′-(2-((2S)-1-(tetrahydro-3- furanylcarbonyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)ethyl)carbamate 1.91 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.44N.sub.7O.sub.5: 714.34; found 714.39; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.44N.sub.7O.sub.5: 714.3404; found 714.3433 75 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)- 1-(N-(methoxycarbonyl)-L-alanyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate 0 1.94 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.45N.sub.8O.sub.6: 745.35 found 745.34; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.45N.sub.8O.sub.6: 745.3462; found 745.3486 76 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- (N,N-dimethyl-L-alanyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate 1.80 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.47N.sub.8O.sub.4 715.37; found 715.35; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.47N.sub.8O.sub.4 715.3720; found 715.3737 77 methyl (2S)-2-(5-(4′-(2-((2S)-1-((2R)-2- ((methoxycarbonyl)amino)-2-phenyl- acetyl)-2-pyrrolidinyl)-1H-imidazol- 5-yl)-4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinecarboxylate 1.97 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.38H.sub.40N.sub.7O.sub.5: 674.31; found 674.66; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.38H.sub.40N.sub.7O.sub.5: 674.3091; found 674.3110 78 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- (4-morpholinylcarbonyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate 1.95 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.45N.sub.8O.sub.5: 729.35; found 729.40; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.45N.sub.8O.sub.5: 729.3513; found 729.3502 79 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((4S)-4-fluoro-L-prolyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate 1.80 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.44FN.sub.8O.sub.4: 731.84; found 731.26 80 methyl ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5- (4′-(2-((2S)-1-L-prolyl-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)ethyl)carbamate 1.84 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.45N.sub.8O.sub.4: 713.36; found 713.36; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.45N.sub.8O.sub.4: 713.3564; found 713.3563 81 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- (4,4-difluoro-L-prolyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate 1.88 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.43F.sub.2N.sub.8O.sub.4: 749.34; found 749.31; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.43F.sub.2N.sub.8O.sub.4: 749.3375; found 749.3390 82 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((4R)-4-fluoro-L-prolyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate 1.83 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.44FN.sub.8O.sub.4: 731.35; found 731.37; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.44FN.sub.8O.sub.4: 731.3470; found 731.3502 83 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((1S,3S,5S)-2-azabicyclo[3.1.0]hex-3- ylcarbonyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate 1.82 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.45N.sub.8O.sub.4: 725.36; found 725.39; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.45N.sub.8O.sub.4: 725.3564; found 725.3574 84 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-L- alanyl-2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate 1.82 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.39H.sub.43N.sub.8O.sub.4: 687.34; found 687.32; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.39H.sub.43N.sub.8O.sub.4: 687.3407; found 687.3435 84-1 methyl ((1R)-2-oxo-1-phenyl-2-((2S)-2- (5-(4′-(2-((2S)-1-((2R)-2-phenyl-2-(1- piperidinyl)acetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)ethyl) carbamate 0 .sup.1HNMR (400 MHz, CD.sub.3OD) δ 7.90-7.85 (m, 9H), 7.81-7.79 (m, 1H), 7.63-7.57 (m, 5H), 7.45-7.32 (m, 6H), 5.51 (s, 1H), 5.45 (s, 1H), 5.33-5.29 (m, 2H), 4.06- 4.01 (m, 2H), 3.63 (d, J = 4.04 Hz, 3H), 3.59-3.50 (m, 2H), 3.19-3.12 (m, 1H), 3.07- 3.01 (m, 1H), 2.93-2.76 (m, 2H), 2.57-2.51 (m, 1H), 2.40- 2.31 (m, 2H), 2.22-2.06 (m, 4H), 2.00-1.90 (m, 3H), 1.84- 1.64 (m, 4H), 1.52-1.43 (m, 2H); LCMS: Anal. Calcd. for C.sub.49H.sub.52N.sub.8O.sub.4: 816; found: 817 (M + H).sup.+. 84-2 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((2S)-2-(2-fluorophenyl)-2- hydroxypropanoyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate .sup.1HNMR (400 MHz, CD.sub.3OD) δ 7.89-7.85 (m, 8H), 7.81- 7.73 (2H), 7.67-7.65 (m, 1H), 7.45-7.26 (m, 7H), 7.13- 7.08 (m, 1H), 6.94-6.89 (m, 0.5H), 6.72-6.67 (0.5H), 6.09-6.07 (m, 0.4H), 5.51 (s, 1H), 5.32- 5.25 (m, 1.6H), 4.08-3.95 (m, 2H), 3.85-3.79 (1H), 3.64-3.63 (m, 3H), 3.56- 3.49 (1H), 3.09-3.03 (m, 1H), 2.59-2.50 (m, 1H), 2.42- 2.33 (m, 2H), 2.21-2.00 (m, 6H), 1.82-1.74 (m, 1H), 1.66 (d, J = 4.55 Hz, 3H); LCMS: Anal. Calcd. for C.sub.45H.sub.46FN.sub.7O.sub.3: 781; found: 782 (M + H).sup.+. 84-3 methyl ((1R)-2-oxo-2-((2S)-2-(5-(4′-(2- ((2S)-1-(5-oxo-D-prolyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-1- phenylethyl)carbamate LCMS: Anal. Calcd. for C.sub.41H.sub.42N.sub.8O.sub.5: 726; found: 727 (M + H).sup.+. 84-4 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((2R)-2-(4-hydroxy-4-methyl-1-piperidinyl)- 2-phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate LCMS: Anal. Calcd. for C.sub.50H.sub.54N.sub.8O.sub.5: 846; found: 847 (M + H).sup.+. 84-5 tert-butyl (4R)-4-(((2S)-2-(5-(4′-(2-((2S)- 1-((2R)-2-((methoxycarbonyl)amino)-2- phenylacetyl)-2-pyrrolidinyl)-1H-imidazol- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-1,3-thiazolidine-3- carboxylate LCMS: Anal. Calcd. for C.sub.45H.sub.50N.sub.8O.sub.6S: 830; found: 831 (M + H).sup.+. 84-6 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)- 1-((1-((tert- butoxycarbonyl)amino)cyclopentyl) carbonyl)-2-pyrrolidinyl)-1H-imidazol- 5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate LCMS: Anal. Calcd. for C.sub.47H.sub.54FN.sub.8O.sub.6: 826; found: 827 (M + H).sup.+. 84-7 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-(N- benzoylglycyl)-2-pyrrolidinyl)-1H-imidazol- 5-yl)-4-biphenlyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate LCMS: Anal. Calcd. for C.sub.45H.sub.44FN.sub.8O.sub.5: 776; found: 777 (M + H).sup.+. 84-8 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- (4-(4-methyl-1-piperazinyl)benzoyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate LCMS: Anal. Calcd. for C.sub.48H.sub.51N.sub.9O.sub.4: 817; found: 818 (M + H).sup.+. 84-9 methyl ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5- (4′-(2-((2S)-1-((5-phenyl-2-thienyl) carbonyl)-2-pyrrolidinyl)-1H-imidazol- 5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)ethyl)carbamate LCMS: Anal. Calcd. for C.sub.47H.sub.43N.sub.7O.sub.4S: 801; found: 802 (M + H).sup.+. 84-10 methyl ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5- (4′-(2-((2S)-1-((4-phenyl-1,2,3-thiadiazol- 5-yl)carbonyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)ethyl)carbamate LCMS: Anal. Calcd. for C.sub.45H.sub.41N.sub.9O.sub.4S: 803; found: 804 (M + H).sup.+. 84-11 methyl ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5- (4′-(2-((2S)-1-((2-phenyl-1,3-thiazol-4- yl)carbonyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)ethyl)carbamate 0 LCMS: Anal. Calcd. for C.sub.46H.sub.42N.sub.8O.sub.4S: 802; found: 803 (M + H).sup.+. 84-12 tert-butyl 4-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)- 2-((methoxycarbonyl)amino)-2-phenyl- acetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)- 4-biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-4-methyl-1- piperidinecarboxylate LCMS: Anal. Calcd. for C.sub.48H.sub.56N.sub.8O.sub.6: 840; found: 841 (M + H).sup.+. 84-13 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- (4-(dimethylamino)butanoyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate LCMS: Anal. Calcd. for C.sub.42H.sub.48N.sub.8O.sub.4: 728; found: 729 (M + H).sup.+. 84-14 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((3-hydroxyphenyl)acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate LCMS: Anal. Calcd. for C.sub.44H.sub.43N.sub.7O.sub.5: 749; found: 750 (M + H).sup.+. 84-15 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- (N,N-dimethyl-beta-alanyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate LCMS: Anal. Calcd. for C.sub.41H.sub.46N.sub.8O.sub.4: 714; found: 715 (M + H).sup.+. 84-16 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-(4- (hydroxymethyl)benzoyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate LCMS: Anal. Calcd. for C.sub.44H.sub.43N.sub.7O.sub.5: 749; found: 750 (M + H).sup.+. 84-17 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- (((3R)-1-benzyl-3-pyrrolidinyl)carbonyl)- 2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate LCMS: Anal. Calcd. for C.sub.48H.sub.50N.sub.8O.sub.4: 802; found: 803 (M + H).sup.+. 84-18 tert-butyl (2S)-2-(2-((2S)-2-(5-(4′-(2-((2S)- 1-((2R)-2-((methoxycarbonyl)amino)-2- phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2- oxoethyl)-1-pyrrolidinecarboxylate LCMS: Anal. Calcd. for C.sub.47H.sub.54N.sub.8O.sub.6: 826; found: 827 (M + H).sup.+. 84-19 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)- 1-((5-methyl-1H-pyrazol-3-yl)acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate LCMS: Anal. Calcd. for C.sub.42H.sub.43N.sub.9O.sub.4: 737; found: 738 (M + H).sup.+. 84-20 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- (((3S)-7-hydroxy-1,2,3,4-tetrahydro-3- isoquinolinyl)carbonyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate LCMS: Anal. Calcd. for C.sub.46H.sub.46N.sub.8O.sub.5: 790; found: 791 (M + H).sup.+. 84-21 tert-butyl (2R)-2-(((2S)-2-(5-(4′-(2-((2S)-1- ((2R)-2-((methoxycarbonyl)amino)-2- phenylacetyl)-2-pyrrolidinyl)-1H-imidazol- 5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-1- piperidinecarboxylate 0 LCMS: Anal. Calcd. for C.sub.47H.sub.54N.sub.8O.sub.6: 826; found: 827 (M + H).sup.+. 84-22 methyl ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5- (4′-(2-((2S)-1-((5-phenyl-4- isoxazolyl)carbonyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)ethyl) carbamate LCMS: Anal. Calcd. for C.sub.46H.sub.42N.sub.8O.sub.5: 786; found: 787 (M + H).sup.+. 84-23 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- (((1R,3S)-3-((tert-butoxycarbonyl) amino)cyclopentyl)carbonyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate LCMS: Anal. Calcd. for C.sub.47H.sub.54N.sub.8O.sub.6: 826; found: 827 (M + H).sup.+. 84-24 methyl ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5- (4′-(2-((2S)-1-(3-(1-piperidinyl)propanoyl)- 2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)ethyl)carbamate LCMS: Anal. Calcd. for C.sub.44H.sub.50N.sub.8O.sub.4: 754; found: 755 (M + H).sup.+. 84-25 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- (2-benzoylbenzoyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)-2-ozo-1- phenylethyl)carbamate LCMS: Anal. Calcd. for C.sub.50H.sub.45N.sub.7O.sub.5: 823; found: 824 (M + H).sup.+. 84-26 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)- 1-((2-methoxyphenoxy)acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate LCMS: Anal. Calcd. for C.sub.45H.sub.45N.sub.7O.sub.6: 779; found: 780 (M + H).sup.+. 84-27 tert-butyl 3-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2- ((methoxycarbonyl)amino)-2-phenylacetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl) carbonyl)-1-azetidinecarboxylate LCMS: Anal. Calcd. for C.sub.45H.sub.50N.sub.8O.sub.6: 798; found: 799 (M + H).sup.+. 84-28 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- (((3S)-1-benzyl-3-pyrrolidinyl)carbonyl)- 2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate LCMS: Anal. Calcd. for C.sub.48H.sub.50N.sub.8O.sub.4: 802; found: 803 (M + H).sup.+. 84-29 methyl ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5- (4′-(2-((2S)-1-(3-(1-pyrrolidinyl)benzoyl)- 2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)ethyl)carbamate LCMS: Anal. Calcd. for C.sub.47H.sub.48N.sub.8O.sub.4: 788; found: 789 (M + H).sup.+. 84-30 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- (2-((tert-butoxycarbonyl)amino)benzoyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate LCMS: Anal. Calcd. for C.sub.48H.sub.50N.sub.8O.sub.6: 834; found: 835 (M + H).sup.+. 84-31 tert-butyl (3R)-3-(((2S)-2-(5-(4′-(2-((2S)-1- ((2R)-2-((methoxycarbonyl)amino)-2- phenylacetyl)-2-pyrrolidinyl)-1H-imidazol- 5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-1- piperidinecarboxylate 00 LCMS: Anal. Calcd. for C.sub.47H.sub.54N.sub.8O.sub.6: 826; found: 827 (M + H).sup.+. 84-32 methyl ((1R)-2-oxo-1-phenyl-2-((2S)-2- (5-(4′-(2-((2S)-1-((1- (trifluoromethyl)cyclopropyl)carbonyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)ethyl)carbamate 01 LCMS: Anal. Calcd. for C.sub.41H.sub.40F.sub.3N.sub.7O.sub.4: 751; found: 752 (M + H).sup.+. 84-33 methyl ((1R)-2-((2S)-2-(3-(4′-(2-((2S)-1-(4- (dimethylamino)benzoyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate 02 LCMS: Anal. Calcd. for C.sub.45H.sub.46N.sub.8O.sub.4: 762; found: 763 (M + H).sup.+. 84-34 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- (3-benzoylbenzoyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate 03 LCMS: Anal. Calcd. for C.sub.50H.sub.45N.sub.7O.sub.5: 823; found: 824 (M + H).sup.+. 84-35 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((cis-4-((tert-butoxycarbonyl)amino) cyclohexyl)carbonyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2- oxo-1-phenylethyl)carbamate 04 LCMS: Anal. Calcd. for C.sub.48H.sub.56N.sub.8O.sub.6: 840; found: 841 (M + H).sup.+. 84-36 tert-butyl 4-(((2S)-2-(5-(4′-(2-((2S)-1- ((2R)-2-((methoxycarbonyl)amino)-2- phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl) carbonyl)-1-piperidinecarboxylate 05 LCMS: Anal. Calcd. for C.sub.47H.sub.54N.sub.8O.sub.6: 826; found: 827 (M + H).sup.+. 84-37 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((cis-4-((tert-butoxycarbonyl)amino) cyclohexyl)carbonyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate 06 LCMS: Anal. Calcd. for C.sub.48H.sub.56N.sub.8O.sub.6: 840; found: 841 (M + H).sup.+. 84-38 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- (diphenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate 07 LCMS: Anal. Calcd. for C.sub.50H.sub.47N.sub.7O.sub.4: 809; found: 810 (M + H).sup.+. 84-39 methyl ((1R)-2-oxo-2-((2S)-2-(5-(4′-(2-((2S)- 1-(4-oxopentanoyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)-1-phenylethyl)carbamate 08 LCMS: Anal. Calcd. for C.sub.41H.sub.43N.sub.7O.sub.5: 713; found: 714 (M + H).sup.+. 84-40 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-(2- fluorobenzoyl)-2-pyrrolidinyl)-1H-imidazol- 5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate 09 LCMS: Anal. Calcd. for C.sub.43H.sub.40FN.sub.7O.sub.4: 737; found: 738 (M + H).sup.+. 84-41 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-(2- biphenylylcarbonyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate 0 LCMS: Anal. Calcd. for C.sub.49H.sub.45N.sub.7O.sub.4: 795; found: 796 (M + H).sup.+. 84-42 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-(2- benzylbenzoyl)-2-pyrrolidinyl)-1H-imidazol- 5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate LCMS: Anal. Calcd. for C.sub.50H.sub.47N.sub.7O.sub.4: 809; found: 810 (M + H).sup.+. 84-43 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((2E)-3-(4-(dimethylamino)phenyl)-2- propenoyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate LCMS: Anal. Calcd. for C.sub.47H.sub.48N.sub.8O.sub.4: 788; found: 789 (M + H).sup.+. 84-44 methyl ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5- (4′-(2-((2S)-1-(1,3-thiazol-4-ylcarbonyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)ethyl)carbamate LCMS: Anal. Calcd. for C.sub.40H.sub.38N.sub.8O.sub.4S: 726; found: 727 (M + H).sup.+. 84-45 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((((1R,2S,5R)-2-isopropyl-5- methylcyclohexyl)oxy)acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate LCMS: Anal. Calcd. for C.sub.48H.sub.57N.sub.7O.sub.5: 811; found: 812 (M + H).sup.+. 84-46 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((dimethylamino)(2-thienyl)acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate LCMS: Anal. Calcd. for C.sub.44H.sub.46N.sub.8O.sub.4S: 782; found: 782 (M + H).sup.+. 84-47 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((dimethylamino)(3-thienyl)acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate LCMS: Anal. Calcd. for C.sub.44H.sub.46N.sub.8O.sub.4S: 782; found: 782 (M + H).sup.+. 84-48 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((dimethylamino)(2-methyl-1,3-thiazol-4- yl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate LCMS: Anal. Calcd. for C.sub.44H.sub.47N.sub.9O.sub.4S: 797; found: 798 (M + H).sup.+. 84-49 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- (1,2-benzisoxazol-3-yl(dimethylamino) acetyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate LCMS: Anal. Calcd. for C.sub.47H.sub.47N.sub.9O.sub.5: 817; found: 818 (M + H).sup.+. 84-50 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-(1- benzothiophen-3-yl(dimethylamino)acetyl)- 2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate LCMS: Anal. Calcd. for C.sub.48H.sub.48N.sub.8O.sub.4S: 832; found: 833 (M + H).sup.+. 84-51 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((dimethylamino)(1-naphthyl)acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate 0 LCMS: Anal. Calcd. for C.sub.50H.sub.50N.sub.8O.sub.4: 826; found: 827 (M + H).sup.+. 84-52 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((dimethylamino)(3-quinolinyl)acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate LCMS: Anal. Calcd. for C.sub.49H.sub.49N.sub.9O.sub.4: 827; found: 828 (M + H).sup.+. 84-53 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((dimethylamino)(2-methyl-1,3-benzothiazol- 5-yl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate LCMS: Anal. Calcd. for C.sub.48H.sub.49N.sub.9O.sub.4S: 847; found: 848 (M + H).sup.+. 84-54 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((dimethylamino)(3- (trifluoromethyl)phenyl)acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate LCMS: Anal. Calcd. for C.sub.47H.sub.47F.sub.3N.sub.8O.sub.4: 844; found: 845 (M + H).sup.+. 84-55 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)- 1-((dimethylamino)(2- (trifluoromethyl)phenyl)acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate LCMS: Anal. Calcd. for C.sub.47H.sub.47F.sub.3N.sub.8O.sub.4: 844; found: 845 (M + H).sup.+. 84-56 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2- chlorophenyl)(dimethylamino)acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate LCMS: Anal. Calcd. for C.sub.46H.sub.47ClN.sub.8O.sub.4: 810; found: 811 (M + H).sup.+. 84-57 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((3-chlorophenyl)(dimethylamino)acetyl)- 2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate LCMS: Anal. Calcd. for C.sub.46H.sub.47ClN.sub.8O.sub.4: 810; found: 811 (M + H).sup.+. 84-58 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((4-chlorophenyl)(dimethylamino)acetyl)- 2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate LCMS: Anal. Calcd. for C.sub.46H.sub.47ClN.sub.8O.sub.4: 810; found: 811 (M + H).sup.+. 84-59 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((dimethylamino)(2-fluorophenyl) acetyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate LCMS: Anal. Calcd. for C.sub.46H.sub.47FN.sub.8O.sub.4: 794; found: 795 (M + H).sup.+. 84-60 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((dimethylamino)(3-fluorophenyl)acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate LCMS: Anal. Calcd. for C.sub.46H.sub.47FN.sub.8O.sub.4: 794; found: 795 (M + H).sup.+. 84-61 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((dimethylamino)(2-pyridinyl)acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate 0 LCMS: Anal. Calcd. for C.sub.45H.sub.47N.sub.9O.sub.4: 777; found: 778 (M + H).sup.+. 84-62 methyl ((1R)-2-((2S)-2-(4-(4′-(2-((2S)-1- ((dimethylamino)(3-pyridinyl)acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate LCMS: Anal. Calcd. for C.sub.45H.sub.47N.sub.9O.sub.4: 777; found: 778 (M + H).sup.+. 84-63 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-((4- methoxyphenyl)acetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate LCMS: Anal. Calcd. for C.sub.45H.sub.45N.sub.7O.sub.5: 763; found: 764 (M + H).sup.+. 84-64 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-((3- methoxyphenyl)acetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate LCMS: Anal. Calcd. for C.sub.45H.sub.45N.sub.7O.sub.5: 763; found: 764 (M + H).sup.+. 84-65 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((2-methoxyphenyl)acetyl)-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate LCMS: Anal. Calcd. for C.sub.45H.sub.45N.sub.7O.sub.5: 763; found: 764 (M + H).sup.+. 84-66 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((2-chlorophenyl)acetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate LCMS: Anal. Calcd. for C.sub.44H.sub.42ClN.sub.7O.sub.4: 767; found: 768 (M + H).sup.+. 84-67 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((3-chlorophenyl)acetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate LCMS: Anal. Calcd. for C.sub.44H.sub.42ClN.sub.7O.sub.4: 767; found: 768 (M + H).sup.+. 84-68 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((4-chlorophenyl)acetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate LCMS: Anal. Calcd. for C.sub.44H.sub.42ClN.sub.7O.sub.4: 767; found: 768 (M + H).sup.+. 84-69 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((2-methylphenyl)acetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate LCMS: Anal. Calcd. for C.sub.45H.sub.45N.sub.7O.sub.4: 747; found: 748 (M + H).sup.+. 84-70 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((4-methylphenyl)acetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate LCMS: Anal. Calcd. for C.sub.45H.sub.45N.sub.7O.sub.4: 747; found: 748 (M + H).sup.+. 84-71 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((3-methylphenyl)acetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate 0 LCMS: Anal. Calcd. for C.sub.45H.sub.45N.sub.7O.sub.4: 747; found: 748 (M + H).sup.+. 84-72 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((2-methyl-1,3-thiazol-4-yl)acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate LCMS: Anal. Calcd. for C.sub.42H.sub.42N.sub.8O.sub.4S: 754; found: 755 (M + H).sup.+. 84-73 methyl ((1R)-2-oxo-1-phenyl-2-((2S)- 2-(5-(4′-(2-((2S)-1-(3-thienylacetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)ethyl)carbamate LCMS: Anal. Calcd. for C.sub.42H.sub.41N.sub.7O.sub.4S: 739; found: 740 (M + H).sup.+. 84-74 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((3-methyl-5-isoxazolyl)acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate LCMS: Anal. Calcd. for C.sub.42H.sub.42N.sub.8O.sub.5: 738; found: 739 (M + H).sup.+. 84-75 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- (cyclohexylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate LCMS: Anal. Calcd. for C.sub.44H.sub.49N.sub.7O.sub.4: 739; found: 740 (M + H).sup.+. 84-76 methyl ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5- (4′-(2-((2S)-1-((2R)-2-phenylpropanoyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)ethyl)carbamate LCMS: Anal. Calcd. for C.sub.45H.sub.45N.sub.7O.sub.4: 747; found: 748 (M + H).sup.+. 84-77 methyl ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5- (4′-(2-((2S)-1-((1-phenylcyclopropyl) carbonyl)-2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)ethyl)carbamate LCMS: Anal. Calcd. for C.sub.46H.sub.45N.sub.7O.sub.4: 759; found: 760 (M + H).sup.+. 84-78 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((1-(4-chlorophenyl)cyclopropyl)carbonyl)- 2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate LCMS: Anal. Calcd. for C.sub.46H.sub.44ClN.sub.7O.sub.4: 793; found: 794 (M + H).sup.+. 84-79 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-(2- (4-chlorophenyl)-2-methylpropanoyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate LCMS: Anal. Calcd. for C.sub.46H.sub.46ClN.sub.7O.sub.4: 795; found: 796 (M + H).sup.+. 84-80 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((2R)-2-methoxy-2-phenylacetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate LCMS: Anal. Calcd. for C.sub.45H.sub.45N.sub.7O.sub.5: 763; found: 764 (M + H).sup.+. 84-81 methyl ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5- (4′-(2-((2S)-1-((2S)-3,3,3-trifluoro-2- methoxy-2-phenylpropanoyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)ethyl)carbamate 0 LCMS: Anal. Calcd. for C.sub.46H.sub.44F.sub.3N.sub.7O.sub.5: 831; found: 832 (M + H).sup.+. 84-82 (1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2- ((methoxycarbonyl)amino)-2-phenylacetyl)- 2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl acetate LCMS: Anal. Calcd. for C.sub.46H.sub.45N.sub.7O.sub.6: 791; found: 792 (M + H).sup.+. 84-83 (1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2- ((methoxycarbonyl)amino)-2-phenylacetyl)- 2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl acetate LCMS: Anal. Calcd. for C.sub.46H.sub.45N.sub.7O.sub.6: 791; found: 792 (M + H).sup.+. 84-84 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((2-(4-morpholinylmethyl)phenyl)acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1-phenylethyl) carbamate LCMS: Anal. Calcd. for C.sub.49H.sub.52N.sub.8O.sub.5: 832; found: 833 (M + H).sup.+. 84-85 methyl ((1R)-2-oxo-1-phenyl-2-((2S)-2- (5-(4′-(2-((2S)-1-((2-(1- piperidinylmethyl)phenyl)acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)ethyl)carbamate LCMS: Anal. Calcd. for C.sub.50H.sub.54N.sub.8O.sub.4: 830; found: 831 (M + H).sup.+. 84-86 methyl ((1R)-2-oxo-1-phenyl-2-((2S)-2-(5- (4′-(2-((2S)-1-((2-(1- pyrrolidinylmethyl)phenyl)acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)ethyl)carbamate LCMS: Anal. Calcd. for C.sub.49H.sub.52N.sub.8O.sub.4: 816; found: 816 (M + H).sup.+. 84-87 methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2- ((dimethylamino)methyl)phenyl)acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)- 2-oxo-1-phenylethyl)carbamate LCMS: Anal. Calcd. for C.sub.47H.sub.50N.sub.8O.sub.4: 790; found: 791 (M + H).sup.+.

Examples 85-94

(235) ##STR00457##

(236) TABLE-US-00021 Example Compound Name Retention time (LC-Condition); homogeneity index MS data 85 (1R)-N,N-dimethyl-2-oxo-1- phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1- (3-pyridinylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)- 1H-imidazol-2-yl)-1- pyrrolidinyl)ethanamine 1.64 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.43H.sub.45N.sub.8O.sub.2: 705.37; found 705.43; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.43H.sub.45N.sub.8O.sub.2: 705.3665; found 705.3675 86 (1R)-N,N-dimethyl-2-oxo-1- phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1- ((2R)-tetrahydro-2- furanylcarbonyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)- 1H-imidazol-2-yl)-1- pyrrolidinyl)ethanamine 0 1.73 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.46N.sub.7O.sub.3: 684.37; found 684.44; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.46N.sub.7O.sub.3: 684.3662; found 684.3671 87 (1R)-N,N-dimethyl-2-oxo-1- phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1- ((2S)-tetrahydro-2- furanylcarbonyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)- 1H-imidazol-2-yl)-1- pyrrolidinyl)ethanamine 1.12 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.46N.sub.7O.sub.3: 684.37; found 684.68; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.46N.sub.7O.sub.3: 684.3662; found 684.3692 88 (1R)-N,N-dimethyl-2-((2S)-2-(5- (4′-(2-((2S-1-((1-methyl-1H- imidazol-4-yl)acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1- phenylethanamine 1.66 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.46N.sub.9O.sub.2: 708.38; found 708.36 89 (1R)-N,N-dimethyl-2-((2S)-2-(5- (4′-(2-((2S)-1-((2R)-2-(4- morpholinyl)-2-phenylacetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1- phenylethanamine   Cap-6 1.70 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.45N.sub.8O.sub.4: 701.36; found 701.34; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.45N.sub.8O.sub.4: 701.3564; found 701.3576 90 (1R)-N,N-dimethyl-2-oxo-1- phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1- ((2R)-2-phenyl-2-(1- pyrrolidinyl)acetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)- 1H-imidazol-2-yl)-1- pyrrolidinyl)ethanamine   Cap-5 1.80 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.48H.sub.53N.sub.8O.sub.2: 773.43; found 773.42; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.48H.sub.53N.sub.8O.sub.2: 773.4291; found 773.4309 91 methyl (2-((2S)-2-(5-(4′-(2-((2S)-1- ((2R)-2-(dimethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2- oxoethyl)carbamate 1.66 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.46N.sub.9O.sub.2: 708.38; found 708.36; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.46N.sub.9O.sub.2: 708.3744; found 708.3770 92 methyl ((1S)-2-((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2-(dimethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-1- methyl-2-oxoethyl)carbamate   Cap-12 1.73 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.47N.sub.8O.sub.4: 715.37; found 715.41; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.47N.sub.8O.sub.4: 715.3720; found 715.3729 93 (1R)-N,N-dimethyl-2-((2S)-2-(5- (4′-(2-((2S)-1-(4- morpholinylcarbonyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1- phenylethanamine 1.76 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.47N.sub.8O.sub.3: 699.38; found 699.45; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.47N.sub.8O.sub.3: 699.3771; found 699.3803 94 (1R)-N,N-dimethyl-2-oxo-1- phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1- (1-pyrrolidinylcarbonyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)ethanamine 1.86 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.47N.sub.8O.sub.2: 683.38; found 683.46; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.47N.sub.8O.sub.2: 683.3822; found 683.3835 94-1 (2S)-1-((2S)-2-(5-(4′-(2-((2S)-1- ((2R)-2-(dimethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2-(2- fluorophenyl)-1-oxo-2-propanol .sup.1HNMR (400 MHz, CD.sub.3OD) δ 7.90-7.84 (m, 9H), 7.79-7.73 (m, 2H), 7.67-7.65 (m, 1H), 7.63-7.52 (m, 5H), 7.39-7.36 (m, 1H), 7.30-7.26 (m, 1H), 7.13-7.08 (m, 1H), 6.93-6.88 (m, 0.5H), 6.72-6.67 (m, 0.5H), 5.51 (s, 0.2H), 5.46 (s, 0.8H), 5.33-5.30 (m, 1H), 5.28-5.24 (m, 1H), 4.05-3.94 (m, 2H), 3.84-3.73 (m, 1H), 3.69-3.55 (m, 1H), 3.21-3.04 (m, 2H), 2.79 (br s, 6H), 2.39-2.33 (m, 2H), 2.21-1.93 (m, 5H), 1.65 (d,J = 4.55 Hz, 3H).; LCMS: Anal. Calcd. for C.sub.45H.sub.46FN.sub.7O.sub.3: 751; found: 752 (M + H).sup.+. 94-2 (5R)-5-(((2S)-2-(5-(4′-(2-((2S)-1- ((2R)-2-(dimethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-2- pyrrolidinone 0 LCMS: Anal. Calcd. for C.sub.41H.sub.44N.sub.8O.sub.3: 696; found: 697 (M + H).sup.+. 94-3 1-((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((2R)-2-(dimethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2- oxo-1-phenylethyl)-4-methyl-4- piperidinol   Cap-15 LCMS: Anal. Calcd. for C.sub.50H.sub.56N.sub.8O.sub.3: 816; found: 817 (M + H).sup.+. 94-4 tert-butyl (4R)-4-(((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2-(dimethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-1,3- thiazolidine-3-carboxylate LCMS: Anal. Calcd. for C.sub.45H.sub.52N.sub.8O.sub.4S: 800; found: 801 (M + H).sup.+. 94-5 tert-butyl (1-(((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2-(dimethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)cyclopentyl) carbamate LCMS: Anal. Calcd. for C.sub.47H.sub.56FN.sub.8O.sub.4: 796; found: 797 (M + H).sup.+. 94-6 N-(2-((2S)-2-(5-(4′-(2-((2S)-1- ((2R)-2-(dimethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2- oxoethyl)benzamide LCMS: Anal. Calcd. for C.sub.45H.sub.46FN.sub.8O.sub.3: 746; found: 747 (M + H).sup.+. 94-7 (1R)-N,N-dimethyl-2-((2S)-2-(5-(4′- (2-((2S)-1-(4-(4-methyl-1- piperazinyl)benzoyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1- phenylethanamine LCMS: Anal. Calcd. for C.sub.48H.sub.53N.sub.9O.sub.2: 787; found: 788 (M + H).sup.+. 94-8 (1R)-N,N-dimethyl-2-oxo-1-phenyl- 2-((2S)-2-(5-(4′-(2-((2S)-1-((5- phenyl-2-thienyl)carbonyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)ethanamine LCMS: Anal. Calcd. for C.sub.47H.sub.45N.sub.7O.sub.2S: 771; found: 772 (M + H).sup.+. 94-9 (1R)-N,N-dimethyl-2-((2S)-2-(5-(4′- (2-((2S)-1-(4-(4- morpholinyl)benzoyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1- phenylethanamine LCMS: Anal. Calcd. for C.sub.47H.sub.50N.sub.8O.sub.3: 774; found: 775 (M + H).sup.+. 94-10 (1R)-N,N-dimethyl-2-oxo-1-phenyl- 2-((2S)-2-(5-(4′-(2-((2S)-1-((4- phenyl-1,2,3-thiadiazol-5- yl)carbonyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)ethanamine LCMS: Anal. Calcd. for C.sub.45H.sub.43N.sub.9O.sub.2S: 773; found: 774 (M + H).sup.+. 94-11 (1R)-N,N-dimethyl-2-oxo-1-phenyl- 2-((2S)-2-(5-(4′-(2-((2S)-1-((2- phenyl-1,3-thiazol-4-yl)carbonyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)ethanamine LCMS: Anal. Calcd. for C.sub.46H.sub.44N.sub.8O.sub.2S: 772; found: 773 (M + H).sup.+. 94-12 tert-butyl 4-(((2S)-2-(5-(4′-(2-((2S)- 1-((2R)-2-(dimethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-4-methyl-1- piperidinecarboxylate 0 LCMS: Anal. Calcd. for C.sub.48H.sub.58N.sub.8O.sub.4: 810; found: 811 (M + H).sup.+. 94-13 3-(2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)- 2-(dimethylamino)-2-phenylacetyl)- 2-pyrrolidinyl)-1H-imidazol-5-yl)- 4-biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxoethyl)phenol LCMS: Anal. Calcd. for C.sub.44H.sub.45N.sub.7O.sub.3: 719; found: 720 (M + H).sup.+. 94-14 3-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2- (dimethylamino)-2-phenylacetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-N,N-dimethyl-3-oxo- 1-propanamine LCMS: Anal. Calcd. for C.sub.41H.sub.48N.sub.8O.sub.2: 684; found: 685 (M + H).sup.+. 94-15 (4-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)- 2-(dimethylamino)-2-phenylacetyl)- 2-pyrrolidinyl)-1H-imidazol-5-yl)- 4-biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)carbonyl)phenyl)methanol LCMS: Anal. Calcd. for C.sub.44H.sub.45N.sub.7O.sub.3: 719; found: 720 (M + H).sup.+. 94-16 (1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- (1H-indol-3-ylcarbonyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-N,N-dimethyl-2-oxo- 1-phenylethanamine LCMS: Anal. Calcd. for C.sub.45H.sub.44N.sub.8O.sub.2: 728; found: 729 (M + H).sup.+. 94-17 (1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- (((3R)-1-benzyl-3- pyrrolidinyl)carbonyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-N,N-dimethyl-2-oxo- 1-phenylethanamine LCMS: Anal. Calcd. for C.sub.48H.sub.52N.sub.8O.sub.2: 772; found: 773 (M + H).sup.+. 94-18 tert-butyl (2S)-2-(2-((2S)-2-(5-(4′- (2-((2S)-1-((2R)-2- (dimethylamino)-2-phenylacetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxoethyl)-1- pyrrolidinecarboxylate LCMS: Anal. Calcd. for C.sub.47H.sub.56N.sub.8O.sub.4: 796; found: 797 (M + H).sup.+. 94-19 (1R)-N,N-dimethyl-2-((2S)-2-(5-(4′- (2-((2S)-1-((5-methyl-1H-pyrazol- 3-yl)acetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2- oxo-1-phenylethanamine LCMS: Anal. Calcd. for C.sub.42H.sub.45N.sub.9O.sub.2: 707; found: 708 (M + H).sup.+. 94-20 tert-butyl (2R)-2-(((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2-(dimethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-1- piperidinecarboxylate LCMS: Anal. Calcd. for C.sub.47H.sub.56N.sub.8O.sub.4: 796; found: 797 (M + H).sup.+. 94-21 tert-butyl ((1S,3R)-3-(((2S)-2-(5-(4′- (2-((2S)-1-((2R)-2- (dimethylamino)-2-phenylacetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)carbonyl)cyclopentyl) carbamate LCMS: Anal. Calcd. for C.sub.47H.sub.56N.sub.8O.sub.4: 796; found: 797 (M + H).sup.+. 94-22 (1R)-N,N-dimethyl-2-oxo-1-phenyl- 2-((2S)-2-(5-(4′-(2-((2S)-1-(3-(1- piperidinyl)propanoyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)ethanamine 0 LCMS: Anal. Calcd. for C.sub.44H.sub.52N.sub.8O.sub.2: 724; found: 725 (M + H).sup.+. 94-23 (2-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)- 2-(dimethylamino)-2-phenylacetyl)- 2-pyrrolidinyl)-1H-imidazol-5-yl)- 4-biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)carbonyl)phenyl) (phenyl)methanone LCMS: Anal. Calcd. for C.sub.50H.sub.47N.sub.7O.sub.3: 793; found: 794 (M + H).sup.+. 94-24 (1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2- methoxyphenoxy)acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-N,N-dimethyl-2-oxo- 1-phenylethanamine LCMS: Anal. Calcd. for C.sub.45H.sub.47N.sub.7O.sub.4: 749; found: 750 (M + H).sup.+. 94-25 tert-butyl 3-(((2S)-2-(5-(4′-(2-((2S)- 1-((2R)-2-(dimethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-1- azetidinecarboxylate LCMS: Anal. Calcd. for C.sub.45H.sub.52N.sub.8O.sub.4: 768; found: 769 (M + H).sup.+. 94-26 (1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- (((3S)-1-benzyl-3- pyrrolidinyl)carbonyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-N,N-dimethyl-2-oxo- 1-phenylethanamine LCMS: Anal. Calcd. for C.sub.48H.sub.52N.sub.8O.sub.2: 772; found: 773 (M + H).sup.+. 94-27 (1R)-N,N-dimethyl-2-oxo-1-phenyl- 2-((2S)-2-(5-(4′-(2-((2S)-1-(3-(1- pyrrolidinyl)benzoyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)ethanamine LCMS: Anal. Calcd. for C.sub.47H.sub.50N.sub.8O.sub.2: 758; found: 759 (M + H).sup.+. 94-28 tert-butyl (2-(((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2-(dimethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)phenyl)carbamate LCMS: Anal. Calcd. for C.sub.48H.sub.52N.sub.8O.sub.4: 804; found: 805 (M + H).sup.+. 94-29 tert-butyl (3R)-3-(((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2-(dimethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-1- piperidinecarboxylate LCMS: Anal. Calcd. for C.sub.47H.sub.56N.sub.8O.sub.4: 796; found: 797 (M + H).sup.+. 94-30 (1R)-N,N-dimethyl-2-oxo-1-phenyl- 2-((2S)-2-(5-(4′-(2-((2S)-1-((1- (trifluoromethyl)cyclopropyl)carbonyl)- 2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)ethanamine LCMS: Anal. Calcd. for C.sub.41H.sub.42F.sub.3N.sub.7O.sub.2: 721; found: 722 (M + H).sup.+. 94-31 4-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2- (dimethylamino)-2-phenylacetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-N,N- dimethylaniline LCMS: Anal. Calcd. for C.sub.45H.sub.48N.sub.8O.sub.2: 732; found: 733 (M + H).sup.+. 94-32 (3-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)- 2-(dimethylamino)-2-phenylacetyl)- 2-pyrrolidinyl)-1H-imidazol-5-yl)- 4-biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)carbonyl)phenyl) (phenyl)methanone 00 LCMS: Anal. Calcd. for C.sub.50H.sub.47N.sub.7O.sub.3: 793; found: 794 (M + H).sup.+. 94-33 tert-butyl (cis-4-(((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2-(dimethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)cyclohexyl) carbamate 01 LCMS: Anal. Calcd. for C.sub.48H.sub.58N.sub.8O.sub.4: 810; found: 811 (M + H).sup.+. 94-34 +40 tert-butyl 4-(((2S)-2-(5-(4′-(2-((2S)- 1-((2R)-2-(dimethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-1- piperidinecarboxylate 02 LCMS: Anal. Calcd. for C.sub.47H.sub.56N.sub.8O.sub.4: 796; found: 797 (M + H).sup.+. 94-35 tert-butyl (cis-4-(((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2-(dimethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)cyclohexyl) carbamate 03 LCMS: Anal. Calcd. for C.sub.48H.sub.58N.sub.8O.sub.4: 810; found: 811 (M + H).sup.+. 94-36 (1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- (diphenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)- 1H-imidazol-2-yl)-1-pyrrolidinyl)- N,N-dimethyl-2-oxo-1- phenylethanamine 04 LCMS: Anal. Calcd. for C.sub.50H.sub.49N.sub.7O.sub.2: 779; found: 780 (M + H).sup.+. 94-37 5-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2- (dimethylamino)-2-phenylacetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-5-oxo-2-pentanone 05 LCMS: Anal. Calcd. for C.sub.41H.sub.45N.sub.7O.sub.3: 683; found: 684 (M + H).sup.+. 94-38 (1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-(2- fluorobenzoyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-N,N- dimethyl-2-oxo-1- phenylethanamine 06 LCMS: Anal. Calcd. for C.sub.43H.sub.42FN.sub.7O.sub.2: 707; found: 708 (M + H).sup.+. 94-39 (1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-(2- biphenylylcarbonyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-N,N-dimethyl-2-oxo- 1-phenylethanamine 07 LCMS: Anal. Calcd. for C.sub.49H.sub.47N.sub.7O.sub.2: 765; found: 766 (M + H).sup.+. 94-40 (1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-(2- benzylbenzoyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-N,N- dimethyl-2-oxo-1- phenylethanamine 08 LCMS: Anal. Calcd. for C.sub.50H.sub.49N.sub.7O.sub.2: 779; found: 780 (M + H).sup.+. 94-41 4-((1E)-3-((2S)-2-(5-(4′-(2-((2S)-1- ((2R)-2-(dimethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-3- oxo-1-propen-1-yl)-N,N- dimethylaniline 09 LCMS: Anal. Calcd. for C.sub.47H.sub.50N.sub.8O.sub.2: 758; found: 759 (M + H).sup.+. 94-42 (1R)-N,N-dimethyl-2-oxo-1-phenyl- 2-((2S)-2-(5-(4′-(2-((2S)-1-(1,3- thiazol-4-ylcarbonyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)ethanamine 0 LCMS: Anal. Calcd. for C.sub.40H.sub.40N.sub.8O.sub.2S: 696; found: 697 (M + H).sup.+. 94-43 (1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((((1R,2S,5R)-2-isopropyl-5- methylcyclohexyl)oxy)acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-N,N-dimethyl-2-oxo- 1-phenylethanamine LCMS: Anal. Calcd. for C.sub.48H.sub.59N.sub.7O.sub.3: 781; found: 782 (M + H).sup.+. 94-44 1-(6-chloro-3-pyridinyl)-2-((2S)-2- (5-(4′-(2-((2S)-1-((2R)-2- (dimethylamino)-2-phenylacetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-N,N-dimethyl-2- oxoethanamine   Cap-21 LCMS: Anal. Calcd. for C.sub.45H.sub.48ClN.sub.9O.sub.2: 781; found: 782 (M + H).sup.+. 94-45 2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2- (dimethylamino)-2-phenylacetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-N,N-dimethyl-2-oxo- 1-(3-pyridinyl)ethanamine   Cap-19 LCMS: Anal. Calcd. for C.sub.45H.sub.49N.sub.9O.sub.2: 747; found: 748 (M + H).sup.+. 94-46 2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2- (dimethylamino)-2-phenylacetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-N,N-dimethyl-2-oxo- 1-(2-pyridinyl)ethanamine   Cap-20 LCMS: Anal. Calcd. for C.sub.45H.sub.49N.sub.9O.sub.2: 747; found: 748 (M + H).sup.+. 94-47 (1R)-N,N-dimethyl-2-oxo-1- phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1- (2-thienylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)- 1H-imidazol-2-yl)-1- pyrrolidinyl)ethanamine LCMS: Anal. Calcd. for C.sub.42H.sub.43N.sub.7O.sub.2S: 709; found: 710 (M + H).sup.+. 94-48 (1R)-N,N-dimethyl-2-oxo-1- phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1- (3-thienylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)- 1H-imidazol-2-yl)-1- pyrrolidinyl)ethanamine LCMS: Anal. Calcd. for C.sub.42H.sub.43N.sub.7O.sub.2S: 709; found: 710 (M + H).sup.+. 94-49 (1R)-N,N-dimethyl-2-((2S)-2-(5- (4′-(2-((2S)-1-(1-naphthylacetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1- phenylethanamine LCMS: Anal. Calcd. for C.sub.48H.sub.47N.sub.7O.sub.2: 753; found: 754 (M + H).sup.+. 94-50 (1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- (1H-imidazol-5-ylacetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-N,N-dimethyl-2-oxo- 1-phenylethanamine LCMS: Anal. Calcd. for C.sub.41H.sub.43N.sub.9O.sub.2: 693; found: 694 (M + H).sup.+. 94-51 (1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((2-fluorophenyl)acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-N,N-dimethyl-2-oxo- 1-phenylethanamine LCMS: Anal. Calcd. for C.sub.44H.sub.44FN.sub.7O.sub.2: 721; found: 722 (M + H).sup.+. 94-52 (1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((3-fluorophenyl)acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-N,N-dimethyl-2-oxo- 1-phenylethanamine 0 LCMS: Anal. Calcd. for C.sub.44H.sub.44FN.sub.7O.sub.2: 721; found: 722 (M + H).sup.+. 94-53 (1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((4-fluorophenyl)acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-N,N-dimethyl-2-oxo- 1-phenylethanamine LCMS: Anal. Calcd. for C.sub.44H.sub.44FN.sub.7O.sub.2: 721; found: 722 (M + H).sup.+. 94-54 (1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-(1- benzothiophen-3-ylacetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-N,N-dimethyl-2-oxo- 1-phenylethanamine LCMS: Anal. Calcd. for C.sub.46H.sub.45N.sub.7O.sub.2S: 759; found: 760 (M + H).sup.+. 94-55 (1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- (1,2-benzisoxazol-3-ylacetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-N,N-dimethyl-2-oxo- 1-phenylethanamine LCMS: Anal. Calcd. for C.sub.45H.sub.44N.sub.8O.sub.3: 744; found: 745 (M + H).sup.+. 94-56 (1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- (1H-indol-3-ylacetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-N,N-dimethyl-2-oxo- 1-phenylethanamine LCMS: Anal. Calcd. for C.sub.46H.sub.46N.sub.8O.sub.2: 742; found: 743 (M + H).sup.+.

Examples 95-103

(237) ##STR00525##

(238) TABLE-US-00022 Example Compound Name Retention time (LC- Condition); homogeneity index MS data  95 2-((2S)-1-((2R)-2-phenyl-2-(1- pyrrolidinyl)acetyl)-2- pyrrolidinyl)-5-(4′-(2-((2S)-1- ((2S)-tetrahydro-2- furanylcarbonyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)- 4-biphenylyl)-1H-imidazole 1.16 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.43H.sub.48N.sub.7O.sub.3: 710.38; found 710.60  96 4-((1R)-2-oxo-1-phenyl-2-((2S)- 2-(5-(4′-(2-((2S)-1-((2R)-2- phenyl-2-(1-pyrrolidinyl)acetyl)- 2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1- pyrrolidinyl)ethyl)morpholine   Cap-6 1.82 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.50H.sub.55N.sub.8O.sub.3: 815.44; found 815.45; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.50H.sub.55N.sub.8O.sub.3: 815.4397; found 815.4395  97 1-(2-oxo-1-phenyl-2-((2S)-2-(5- (4′-(2-((2S)-1-((2R)-2-phenyl-2- (1-pyrrolidinyl)acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)- 4-biphenylyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)ethyl)-4- piperidinol   A single diastereomer Cap-8 1.79 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.51H.sub.57N.sub.8O.sub.3: 829.46; found 829.43; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.51H.sub.57N.sub.8O.sub.3: 829.4554; found 829.4585  98 1-methyl-4-(2-oxo-1-phenyl-2- ((2S)-2-(5-(4′-(2-((2S)-1-((2R)- 2-phenyl-2-(1- pyrrolidinyl)acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)- 4-biphenylyl)-1H-imidazol-2- yl)-1- pyrrolidinyl)ethyl)piperazine 0   A single diastereomer Cap-17c 1.84 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.51H.sub.58N.sub.9O.sub.2: 828.47; found 828.45; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.51H.sub.58N.sub.9O.sub.2: 828.4713; found 828.4722  99 (1R)-N,N-diethyl-2-oxo-1- phenyl-2-((2S)-2-(5-(4′-(2-((2S)- 1-((2R)-2-phenyl-2-(1- pyrrolidinyl)acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)- 4-biphenylyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)ethanamine   Cap-2 1.86 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.50H.sub.57N.sub.8O.sub.2: 801.46; found 801.44; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.50H.sub.57N.sub.8O.sub.2: 801.4604; found 801.4595 100 methyl ((1R)-2-oxo-1-phenyl-2- ((2S)-2-(5-(4′-(2-((2S)-1-((2R)- 2-phenyl-2-(1- pyrrolidinyl)acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)- 4-biphenylyl)-1H-imidazol-2- yl)-1- pyrrolidinyl)ethyl)carbamate   Cap-4 1.93 minutes (Cond. 2); LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.48H.sub.51N.sub.8O.sub.4: 803.40; found 803.47; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.48H.sub.51N.sub.8O.sub.4: 803.4033; found 803.4058 101 methyl ((1S)-1-methyl-2-oxo-2- ((2S)-2-(5-(4′-(2-((2S)-1-((2R)- 2-phenyl-2-(1- pyrrolidinyl)acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)- 4-biphenylyl)-1H-imidazol-2- yl)-1- pyrrolidinyl)ethyl)carbamate   Cap-12 1.80 minutes (Cond. 2); LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.43H.sub.49N.sub.8O.sub.4: 741.39; found 741.33; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.43H.sub.49N.sub.8O.sub.4: 741.3877; found 741.3900 102 methyl (2-oxo-2-((2S)-2-(5-(4′- (2-((2S)-1-((2R)-2-phenyl-2-(1- pyrrolidinyl)acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)- 4-biphenylyl)-1H-imidazol-2- yl)-1- pyrrolidinyl)ethyl)carbamate 1.80 minutes (Cond. 2); LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.47N.sub.8O.sub.4: 727.37; found 727.24; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.47N.sub.8O.sub.4: 727.3720; found 727.3743 103 (2S)-N,N-dimethyl-1-oxo-1- ((2S)-2-(5-(4′-(2-((2S)-1-((2R)- 2-phenyl-2-(1- pyrrolidinyl)acetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)- 4-biphenylyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)-2- propanamine   Cap-13 1.69 minutes (Cond. 2); LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.43H.sub.51N.sub.8O.sub.2: 711.41; found 711.37; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.43H.sub.51N.sub.8O.sub.2: 711.4135; found 711.4154

Examples 103-1 to 103-12

(239) ##STR00536##

(240) TABLE-US-00023 103-1 1-(2-oxo-1-phenyl-2-((2S)-2- (5-(4′-(2-((2S)-1-((2R)- tetrahydro-2-furanylcarbonyl)- 2-pyrrolidinyl)-1H-imidazol-4- yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)ethyl)-4- phenylpiperidine RT = 4.80 minutes; HPLC Xterra 4.6 X 50 mm, 0 to 100% B over 10 minutes, one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid; LCMS: Anal. Calcd. for: C.sub.50H.sub.53N.sub.7O.sub.3 800.03 Found: 800.49 (M + H).sup.+ 103-2 1-(2-oxo-1-phenyl-2-((2S)-2- (5-(4′-(2-((2S)-1-((2R)- tetrahydro-2-furanylcarbonyl)- 2-pyrrolidinyl)-1H-imidazol-4- yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)ethyl)-4- phenylpiperidine RT = 4.59 minutes; HPLC Xterra 4.6 X 50 mm, 0 to 100% B over 10 minutes, one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid; LCMS: Anal. Calcd. for: C.sub.50H.sub.53N.sub.7O.sub.3 800.03 Found: 800.48 (M + H).sup.+ 103-3 1-methyl-4-(2-oxo-1-phenyl-2- ((2S)-2-(5-(4′-(2-((2S)-1-((2R)- tetrahydro-2-furanylcarbonyl)- 2-pyrrolidinyl)-1H-imidazol-4- yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1- pyrrolidinyl)ethyl)piperazine RT = 3.36; HPLC Xterra 4.6 X 50 mm, 0 to 100% B over 10 minutes, one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid; LCMS: Anal. Calcd. for: C.sub.44H.sub.50N.sub.8O.sub.3 738.94 Found: 739.49 (M + H).sup.+ 103-4 1-methyl-4-(2-oxo-1-phenyl-2- ((2S)-2-(5-(4′-(2-((2S)-1-((2R)- tetrahydro-2-furanylcarbonyl)- 2-pyrrolidinyl)-1H-imidazol-4- yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1- pyrrolidinyl)ethyl)piperazine 0 RT = 3.47 minutes; HPLC Xterra 4.6 X 50 mm, 0 to 100% B over 10 minutes, one minute hold time, A = 90% water, 10% methanol 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid; LCMS: Anal. Calcd. for: C.sub.44H.sub.50N.sub.8O.sub.3 738.94 Found: 739.51 (M + H).sup.+ 103-5 benzyl 4-(2-oxo-1-phenyl-2- ((2S)-2-(5-(4′-(2-((2S)-1-((2R)- tetrahydro-2-furanylcarbonyl)- 2-pyrrolidinyl)-1H-imidazol-4- yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)ethyl)-1- piperazinecarboxylate RT = 5.00 minutes; HPLC Xterra 4.6 X 50 mm, 0 to 100% B over 10 minutes, one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid; LCMS: Anal. Calcd. for: C.sub.51H.sub.54N.sub.8O.sub.5 859.05 Found: 859.51 (M + H).sup.+ 103-6 benzyl 4-(2-oxo-1-phenyl-2- ((2S)-2-(5-(4′-(2-((2S)-1-((2R)- tetrahydro-2-furanylcarbonyl)- 2-pyrrolidinyl)-1H-imidazol-4- yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)ethyl)-1- piperazinecarboxylate RT = 5.10 minutes; HPLC Xterra 4.6 X 50 mm, 0 to 100% B over 10 minutes, one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol 0.2% phosphoric acid; LCMS: Anal. Calcd. for: C.sub.51H.sub.54N.sub.8O.sub.5 859.05 Found: 859.49 (M + H).sup.+ 103-7 1-(2-oxo-1-phenyl-2-((2S)-2- (5-(4′-(2-((2S)-1-((2R)- tetrahydro-2-furanylcarbonyl)- 2-pyrrolidinyl)-1H-imidazol-4- yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1- pyrrolidinyl)ethyl)piperazine RT = 3.61 minutes; HPLC Xterra 4.6 X 50 mm, 0 to 100% B over 10 minutes, one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid; LCMS: Anal. Calcd. for: C.sub.43H.sub.48N.sub.8O.sub.3 724.91 Found: 725.47 (M + H).sup.+ 103-8 4-(2-oxo-1-phenyl-2-((2S)-2- (5-(4′-(2-((2S)-1-((2R)- tetrahydro-2-furanylcarbonyl)- 2-pyrrolidinyl)-1H-imidazol-4- yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)ethyl)-2- piperazinone RT = 3.97; HPLC Xterra 4.6 X 50 mm, 0 to 100% B over 10 minutes, one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid; LCMS: Anal. Calcd. for: C.sub.43H.sub.46N.sub.8O.sub.4 738.90 Found: 739.56 (M + H).sup.+ 103-9 1-methyl-3-((1R)-2-oxo-1- phenyl-2-((2S)-2-(4-(4′-(2- ((2S)-1-((2R)-tetrahydro-2- furanylcarbonyl)-2- pyrrolidinyl)-1H-imidazol-4- yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)ethyl)urea HPLC XTERRA C-18 4.6 × 30 mm, 0 to 100% B over 4 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.2% H.sub.3PO.sub.4, B = 10% water, 90% methanol, 0.2% H.sub.3PO.sub.4, RT = 1.81 minutes, 96% homogeneity index.; LCMS: Anal. Calcd. for C.sub.41H.sub.44N.sub.8O.sub.4: 712.84; found: 713.37 (M + H).sup.+; HRMS: Anal. Calcd. for C.sub.41H.sub.45N.sub.8O.sub.4 713.3564; found: 713.3564 (M + H).sup.+. 103-10 1-ethyl-3-((1R)-2-oxo-1- phenyl-2-((2S)-2-(4-(4′-(2- ((2S)-1-((2R)-tetrahydro-2- furanylcarbonyl)-2- pyrrolidinyl)-1H-imidazol-4- yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)ethyl)urea HPLC XTERRA C-18 4.6 × 30 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.2% H.sub.3PO.sub.4, B = 10% water, 90% methanol, 0.2% H.sub.3PO.sub.4, RT = 1.88 minutes, 95% homogeneity index; LCMS: Anal. Calcd. for C.sub.42H.sub.46N.sub.8O.sub.4: 726.87; found: 727.71 (M + H).sup.+; HRMS: Anal. Calcd. for C.sub.42H.sub.47N.sub.8O.sub.4 727.3720; found: 727.3695 (M + H).sup.+. 103-11 1-cyclopentyl-3-((1R)-2-oxo- 1-phenyl-2-((2S)-2-(4-(4′-(2- ((2S)-1-((2R)-tetrahydro-2- furanylcarbonyl)-2- pyrrolidinyl)-1H-imidazol-4- yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)ethyl)urea HPLC XTERRA C-18 4.6 × 30 mm, 0 to 100% B over 2 minutes. 1 minute hold time, A = 90% water, 10% methanol, 0.2% H.sub.3PO.sub.4, B = 10% water, 90% methanol, 0.2% H.sub.3PO.sub.4, RT = 2.11 minutes, 96% homogeneity index; LCMS: Anal. Calcd. for C.sub.45H.sub.50N.sub.8O.sub.4: 766.93; found: 767.45 (M + H).sup.+; HRMS: Anal. Calcd. for C.sub.45H.sub.51N.sub.8O.sub.4 767.4033; found: 767.4032 (M + H).sup.+. 103-12 1,1-dimethyl-3-((1R)-2-oxo-1- phenyl-2-((2S)-2-(4-(4′-(2- ((2S)-1-((2R)-tetrahydro-2- furanylcarbonyl)-2- pyrrolidinyl)-1H-imidazol-4- yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)ethyl)urea HPLC XTERRA C-18 4.6 × 30 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.2% H.sub.3PO.sub.4, B = 10% water, 90% methanol, 0.2% H.sub.3PO.sub.4, RT = 1.87 minutes, 97% homogeneity index; LCMS: Anal. Calcd. for C.sub.42H.sub.46N.sub.8O.sub.4: 726.87; found: 727.38 (M + H).sup.+; HRMS: Anal. Calcd. for C.sub.42H.sub.47N.sub.8O.sub.4 727.3720; found: 727.3723 (M + H).sup.+.

Examples 104-107

(241) ##STR00549##

(242) TABLE-US-00024 Example Compound Name 0 Retention time (LC-Condition); homogeneity index MS data 104 1-methyl-4-(2-oxo-1-phenyl-2- ((2S)-2-(5-(4′-(2-((2S)-1-((2S)- tetrahydro-2-furanylcarbonyl)- 2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1- pyrrolidinyl)ethyl)piperazine 1.12 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.44H.sub.51N.sub.8O.sub.3: 739.41; found 739.63; HRMS: Anal. Calcd. for [M +H].sup.+ C.sub.44H.sub.51N.sub.8O.sub.3: 739.4084; found 739.4054 105 4-((1R)-2-oxo-1-phenyl-2-((2S)- 2-(5-(4′-(2-((2S)-1-((2S)- tetrahydro-2-furanylcarbonyl)- 2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1- pyrrolidinyl)ethyl)morpholine 1.13 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.43H.sub.48N.sub.7O.sub.4: 726.38; found 726.63; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.43H.sub.48N.sub.7O.sub.4: 726.3768; found 726.3803 106 (1R)-N,N-diethyl-2-oxo-1- phenyl-2-((2S)-2-(5-(4′-(2- ((2S)-1-((2S)-tetrahydro-2- furanylcarbonyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)- 4-biphenylyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)ethanamine 1.12 minutes (Cond. 1); 97%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.43H.sub.50N.sub.7O.sub.3: 712.40; found 712.45; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.43H.sub.50N.sub.7O.sub.3: 712.3975; found 712.3998 107 (1R)-N-ethyl-N-methyl-2-oxo- 1-phenyl-2-((2S)-2-(5-(4′-(2- ((2S)-1-((2S)-tetrahydro-2- furanylcarbonyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)- 4-biphenylyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)ethanamine 1.10 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.48N.sub.7O.sub.3: 698.38; found 698.45; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.48N.sub.7O.sub.3: 698.3819; 698.3823

Examples 107-1 to 107-30

(243) ##STR00555##

(244) TABLE-US-00025 Example Number Compound Name Structure Data Example 107-1 (1S)-2-oxo-1-phenyl- 2-((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2- phenyl-2-(1- piperidinyl)accetyl)- 2-pyrrolidinyl)- 1H-imidazol-5-yl)-4- biphenylyl)-1H- .sup.1HNMR (400 MHz, CDCl.sub.3) δ 7.63-7.85 (m, 8H), 7.48-7.54 (m, 2H), 7.26-7.46 (m, 7H), 6.94-7.17 (m, 3H), 6.22 and 6.18 (s, 1H, rotamers, 1:1), 5.99 and 5.68 (s, 1H, rotamers, 1:1), 5.61 and 5.54 (d, J = 7.8 Hz, 1H, rotamers, 1:1), 5.20-5.23 and 5.10-5.13 (m, 1H, rotamers, 1:1), 4.46 and 4.43 (s, 1H, imidazol-2-yl)-1- rotamers, 1:1), 3.97-4.06 (m, 1H), 3.89- pyrrolidinyl)ethyl 3.93 and 3.78-3.84 (m, 1H, rotamers, acetate 1:1), 3.63-3.72 and 3.46-3.60 (m, 1H, rotamers, 1:1), 3.23-3.32 (m, 2H), 2.41- 2.59 (m, 4H), 2.13-2.26 (m, 2H), 2.11 and 2.10 (s, 3H, rotamers, 1:1), 2.05- 2.09 (m, 2H), 1.97-1.98 (m, 1H), 1.82- 1.90 (m, 1H), 1.58 (br s, 4H), 1.45 (br s, 2H); LCMS: Anal. Calcd. for C.sub.49H.sub.51N.sub.7O.sub.4: 801; found: 802 (M + H).sup.+. Example 107-2 4-methyl-1-((1R)-2- oxo-1-phenyl-2- ((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2- phenyl-2-(1- piperidinyl)acetyl)- 2-pyrrolidinyl)- 1H-imidazol-5- LCMS: Anal. Calcd. for C.sub.53H.sub.60N.sub.8O.sub.3: 856; found: 857 (M + H).sup.+. yl)-4-biphenylyl)- 1H-imidazol-2-yl)-1- pyrrolidinyl)ethyl)- 4-piperidinol Example 107-3 1-((1R)-2-((2S)-2- (5-(4′-(2-((2S)-1-(2- fluorobenzoyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- LCMS: Anal. Calcd. for C.sub.46H.sub.56FN.sub.7O.sub.2: 747; found: 748 (M + H).sup.+. oxo-1-phenyl- ethyl)piperidine Example 107-4 N,N-dimethyl-4- (((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2- phenyl-2-(1- piperidinyl)acetyl)- 2-pyrrolidinyl)- 1H-imidazol-5-yl)- 4-biphenylyl)-1H- LCMS: Anal. Calcd. for C.sub.48H.sub.52N.sub.8O.sub.2: 772; found: 773 (M + H).sup.+. imidazol-2-yl)-1- pyrrolidinyl) carbonyl)aniline Example 107-5 5-oxo-5-((2S)-2-(5- (4′-(2-((2S)-1-((2R)- 2-phenyl-2-(1- piperidinyl)acetyl)- 2-pyrrolidinyl)- 1H-imidazol-5-yl)- 4-biphenylyl)-1H- imidazol-2-yl)-1- 0 LCMS: Anal. Calcd. for C.sub.44H.sub.49N.sub.7O.sub.3: 723; found: 724 (M + H).sup.+. pyrrolidinyl)-2- pentanone Example 107-6 1-((1R)-2-((2S)-2- (5-(4′-(2-((2S)-1- (diphenylacetyl)- 2-pyrrolidinyl)- 1H-imidazol-5-yl)- 4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxo-1-phenyl- LCMS: Anal. Calcd. for C.sub.53H.sub.53N.sub.7O.sub.2: 819; found: 820 (M + H).sup.+. ethyl)piperidine Example 107-7 1-(3-oxo-3-((2S)-2- (5-(4′-(2-((2S)-1- ((2R)-2-phenyl-2-(1- piperidinyl)acetyl)- 2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl) LCMS: Anal. Calcd. for C.sub.47H.sub.56N.sub.8O.sub.2: 764; found: 765 (M + H).sup.+. propyl)piperidine Example 107-8 1-((1R)-2-((2S)- 2-(5-(4′-(2-((2S)- 1-((2-methoxy- phenoxy)acetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- LCMS: Anal. Calcd. for C.sub.48H.sub.51N.sub.7O.sub.4: 789; found: 790 (M + H).sup.+. oxo-1-phenyl- ethyl)piperidine Example 107-9 tert-butyl 4- (((2S)-2-(5-(4′- (2-((2S)-1-((2R)- 2-phenyl-2-(1- piperidinyl)acetyl)- 2-pyrrolidinyl)- 1H-imidazol-5-yl)- 4-biphenylyl)-1H- LCMS: Anal. Calcd. for C.sub.50H.sub.60N.sub.8O.sub.4: 836; found: 837 (M + H).sup.+. imidazol-2-yl)-1- pyrrolidinyl) carbonyl)-1- piperidinecarboxylate Example 107-10 4-(4-(((2S)-2-(5- (4′-2-((2S)-1- ((2R)-2-phenyl-2-(1- piperidinyl)acetyl)- 2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- LCMS: Anal Calcd. for C.sub.50H.sub.54N.sub.8O.sub.3: 814; found: 815 (M + H).sup.+. pyrrolidinyl) carbonyl)phenyl) morpholine Example 107-11 1-((1R)-2-oxo-1- phenyl-2-((2S)-2- (5-(4′-(2-((2S)-1- (1,3-thiazol-4- ylcarbonyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- LCMS: Anal Calcd. for C.sub.43H.sub.44N.sub.8O.sub.2S: 736; found: 737 (M + H).sup.+. imidazol-2-yl)-1- pyrrolidinyl)ethyl) piperidine Example 107-12 tert-butyl 3- (((2S)-2-(5-(4′- (2-((2S)-1-((2R)- 2-phenyl-2-(1- piperidinyl)acetyl)- 2-pyrrolidinyl)- 1H-imidazol-5-yl)-4- biphenylyl)-1H- LCMS: Anal. Calcd. for C.sub.48H.sub.56N.sub.8O.sub.4: 808; found: 809 (M + H).sup.+. imidazol-2-yl)-1- pyrrolidinyl) carbonyl)-1- azetidinecarboxylate Example 107-13 tert-butyl (cis-4- (((2S)-2-(5-(4′- (2-((2S)-1-((2R)- 2-phenyl-2-(1- piperidinyl)acetyl)- 2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- LCMS: Anal. Calcd. for C.sub.51H.sub.62N.sub.8O.sub.4: 850; found: 851 (M + H).sup.+. imidazol-2-yl)-1- pyrrolidinyl) carbonyl)cyclohexyl) carbamate Example 107-14 tert-butyl 4-methyl- 4-(((2S)-2-(5-(4′- (2-((2S)-1-((2R)-2- phenyl-2-(1- piperidinyl)acetyl)- 2-pyrrolidinyl)- 1H-imidazol-5-yl)- 4-biphenylyl)-1H- LCMS: Anal. Calcd. for C.sub.51H.sub.62N.sub.8O.sub.4: 850; found: 851 (M + H).sup.+. imidazol-2-yl)-1- pyrrolidinyl) carbonyl)-1- piperidinecarboxylate Example 107-15 1-((1R)-2-oxo-1- phenyl-2-((2S)-2- (5-(4′-(2-((2S)-1- ((1-(trifluoromcthyl) cyclopropyl) carbonyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- 0 LCMS: Anal. Calcd. for C.sub.44H.sub.46F.sub.3N.sub.7O.sub.2: 761; found: 762 (M + H).sup.+. imidazol-2-yl)-1- pyrrolidinyl)ethyl) piperidine Example 107-16 1-((1R)-2-((2S)- 2-(5-(4′-(2-((2S)- 1-((5-methyl-1H- pyrazol-3- yl)acetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- LCMS: Anal. Calcd. for C.sub.45H.sub.49N.sub.9O.sub.3: 747; found: 748 (M + H).sup.+. pyrrolidinyl)-2-oxo- 1-phenylethyl) piperidine Example 107-17 1-((1R)-2-((2S)- 2-(5-(4′-(2-((2S)- 1-(((3R)-1- benzyl-3- pyrrolidinyl) carbonyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- LCMS: Anal. Calcd. for C.sub.51H.sub.56N.sub.8O.sub.3: 812; found: 813 (M + H).sup.+. biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2-oxo- 1-phenylethyl) piperidine Example 107-18 1-((1R)-2-((2S)- 2-(5-(4′-(2-((2S)- 1-(((3S)-1- benzyl-3- pyrrolidinyl) carbonyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- LCMS: Anal. Calcd. for C.sub.51H.sub.56N.sub.8O.sub.2: 812; found: 813 (M + H).sup.+. biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2-oxo- 1-phenylethyl) piperidine Example 107-19 1-((1R)-2-((2S)- 2-(5-(4′-(2-((2S)- 1-((2R)-2- methoxy-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- LCMS: Anal. Calcd. for C.sub.48H.sub.51N.sub.7O.sub.3: 773; found: 774 (M + H).sup.+. pyrrolidinyl)-2-oxo- 1-phenylethyl) piperidine Example 107-20 1-((1R)-2-((2S)- 2-(5-(4′-(2-((2S)- 1-(2S)-2- methoxy-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- LCMS: Anal. Calcd. for C.sub.48H.sub.51N.sub.7O.sub.3: 773; found: 774 (M + H).sup.+. pyrrolidinyl)-2-oxo- 1-phenylethyl) piperidine Example 107-21 (1R)-2-oxo-1- phenyl-2-((2S)-2- (5-(4′-(2-((2S)-1- ((2R)-2-phenyl-2-(1- piperidinyl)acetyl)- 2-pyrrolidinyl)- 1H-imidazol-5-yl)-4- biphenylyl)-1H- LCMS: Anal. Calcd. for C.sub.49H.sub.51N.sub.7O.sub.4: 801; found: 802 (M + H).sup.+. imidazol-2-yl)-1- pyrrolidinyl)ethyl acetate Example 107-22 1-((1R)-2-oxo-1- phenyl-2-((2S)-2- (5-(4′-(2-((2S)-1- ((1-phenylcyclo- propyl)carbonyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- LCMS: Anal. Calcd. for C.sub.49H.sub.51N.sub.7O.sub.2: 769; found: 770 (M + H).sup.+. imidazol-2-yl)-1- pyrrolidinyl)ethyl) piperidine Example 107-23 N,N-dimethyl-1- (2-(2-oxo-2- ((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2- phenyl-2-(1- piperidinyl)acetyl)- 2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- LCMS: Anal. Calcd. for C.sub.50H.sub.56N.sub.8O.sub.2: 800; found: 801 (M + H).sup.+. imidazol-2-yl)-1- pyrrolidinyl)ethyl) phenyl)methanamine Example 107-24 1-((1R)-2-((2S)- 2-(5-(4′-(2-((2S)- 1-((3-methyl-5- isoxazolyl)acetyl)- 2-pyrrolidinyl)- 1H-imidazol-5-yl)- 4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2-oxo- LCMS: Anal. Calcd. for C.sub.45H.sub.48N.sub.8O.sub.3: 748; found: 749 (M + H).sup.+. 1-phenylethyl) piperidine Example 107-25 1-((1R)-2-((2S)- 2-(5-(4′-(2-((2S)- 1-((2-methyl-1,3- thiazol-4-yl)acetyl)- 2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2-oxo- 1-phenylethyl) 0 LCMS: Anal. Calcd. for C.sub.45H.sub.48N.sub.8O.sub.2S: 764; found: 765 (M + H).sup.+. piperidine Example 107-26 4-(2-(2-oxo-2- ((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2- phenyl-2-(1- piperidinyl)acetyl)- 2-pyrrolidinyl)- 1H-imidazol-5-yl)- 4-biphenylyl)-1H- imidazol-2-yl)-1- LCMS: Anal. Calcd. for C.sub.52H.sub.58N.sub.8O.sub.3: 842; found: 843 (M + H).sup.+. pyrrolidinyl)ethyl) benzyl)morpholine Example 107-27 1-((1R)-2-oxo-1- phenyl-2-((2S)-2- (5-(4′-(2-((2S)-1- ((2-(1-pyrrolidinyl- methyl)phenyl) acetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4- biphenylyl)-1H- LCMS: Anal. Calcd. for C.sub.52H.sub.58N.sub.8O.sub.2: 826; found: 827 (M + H).sup.+. imidazol-2-yl)-1- pyrrolidinyl)ethyl) piperidine Example 107-28 1-((1R)-2-((2S)-2- (5-(4′-(2-((2S)-1-((2- fluorophenyl)acetyl)- 2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1- LCMS: Anal. Calcd. for C.sub.47H.sub.48FN.sub.7O.sub.2: 800; found: 801 (M + H).sup.+. phenylethyl) piperidine Example 107-29 1-((1R)-2-((2S)- 2-(5-(4′-(2-((2S)- 1-acetyl-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1- phenylethyl)piperidine LCMS: Anal. Calcd. for C.sub.41H.sub.45FN.sub.7O.sub.2: 667; found: 668 (M + H).sup.+. Example 107-30 1-((1R)-2-oxo-1- phenyl-2-((2S)-2- (5-(4′-(2-((2S)-1- (2-thienylacetyl)- 2-pyrrolidinyl)- 1H-imidazol-5- yl)-4-biphenylyl)- 1H-imidazol-2-yl)-1- pyrrolidinyl)ethyl) LCMS: Anal. Calcd. for C.sub.45H.sub.47N.sub.7O.sub.2S: 749; found: 750 (M + H).sup.+. piperidine

Example 107-31 to 107-34

(245) ##STR00586##

(246) Examples 107-31 through 107-34 were prepared in similar fashion to example 28. Cap-38 was appended to intermediate 28d, the Boc carbamate was removed with TFA or HCl and the appropriate carboxylic acid was coupled.

(247) TABLE-US-00026 Example Compound Name Structure Data Example 107-31 (1R)-2-((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2- (dimethylamino)-2-(2- fluorophenyl)acetyl)-2- pyrrolidinyl)-1H-imidazol- 5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-N,N- dimethyl-2-oxo-1- LCMS: Anal. Calcd. for C.sub.46H.sub.49FN.sub.8O.sub.2: 764; found: 765 (M + H).sup.+. phenylethanamine Example 107-32 (1R)-1-(2-fluorophenyl)-2- ((2S)-2-(5-(4′-(2-((2S)-1- ((2R)-2-methoxy-2- phenylacetyl)-2- pyrrolidinyl)-1H-imidazol- 5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-N,N- dimethyl-2-oxoethanamine LCMS: Anal. Calcd. for C.sub.45H.sub.46FN.sub.7O.sub.3: 751; found: 752 (M + H).sup.+. Example 107-33 (1R)-2-((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2- (dimethylamino)-2-(2- fluorophenyl)acetyl)-2- pyrrolidinyl)-1H-imidazol- 5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1- phenylethyl acetate LCMS: Anal. Calcd. for C.sub.46H.sub.46FN.sub.7O.sub.4: 779; found: 780 (M + H).sup.+. Example 107-34 (1R)-1-(2-fluorophenyl)- N,N-dimethyl-2-oxo-2- ((2S)-2-(5-(4′-(2-((2S)-1- ((1- phenylcyclopropyl)carbonyl)- 2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H-imidazol- 2-yl)-1- 0 LCMS: Anal. Calcd. for C.sub.46H.sub.46FN.sub.7O.sub.2: 747: found 748 (M + H).sup.+. pyrrolidinyl)ethanamine

Example 107-35 to 107-38

(248) ##STR00591##

(249) Examples 107-35 through 107-38 were prepared in similar fashion to example 28. Cap-39 was appended to intermediate 28d, the Boc carbamate was removed with TFA or HCl and the appropriate carboxylic acid was coupled.

(250) TABLE-US-00027 Example Compound Name Structure Data Example 107-35 (1R)-1-(2-chlorophenyl)- 2-((2S)-2-(5-(4′-(2-((2S)- 1-((2R)-2- (dimethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)- LCMS: Anal. Calcd. for C.sub.46H.sub.49ClN.sub.8O.sub.2: 780; found: 781 (M + H).sup.+. N,N-dimethyl-2- oxoethanamine Example 107-36 methyl ((1R)-2-((2S)-2- (5-(4′-(2-((2S)-1-((2R)-2- (2-chlorophenyl)-2- (dimethylamino)acetyl)- 2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)-2- oxo-1- LCMS: Anal. Calcd. for C.sub.46H.sub.47ClN.sub.8O.sub.4: 810; found: 811 (M + H).sup.+. phenylethyl)carbamate Example 107-37 (1R)-1-(2-chlorophenyl)- 2-((2S)-2-(5-(4′-(2-((2S)- 1-((2R)-2-methoxy-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)- N,N-dimethyl-2- LCMS: Anal. Calcd. for C.sub.45H.sub.46ClN.sub.7O.sub.3: 767; found 768 (M + H).sup.+. oxoethanamine Example 107-38 (1R)-1-(2-chlorophenyl)- N,N-dimethyl-2-oxo-2- ((2S)-2-(5-(4′-(2-((2S)-1- ((2R)-tetrahydro-2- furanylcarbonyl)-2- pyrrolidinyl-1H- imidazol-5-yl)-4- LCMS: Anal. Calcd. for C.sub.41H.sub.44ClN.sub.7O.sub.3: 717; found: 718 (M + H).sup.+. biphenylyl)-1H-imidazol- 2-yl)-1- pyrrolidinyl)ethanamine

Example 107-39 to 107-43

(251) ##STR00596##

(252) Examples 107-39 through 107-44 were prepared in similar fashion to example 28. Cap-40 was appended to intermediate 28d, the Boc carbamate was removed with TFA or HCl and the appropriate carboxylic acid was coupled.

(253) TABLE-US-00028 Example Compound Name Structure Data Example 107-39 methyl ((1R)-1-(2- chlorophenyl)-2-oxo-2- ((2S)-2-(5-(4′-(2-((2S)-1- ((2R)-tetrahydro-2- furanylcarbonyl)-2- prrolidinyl)-1H-imidazol- 5-yl)-4-biphenyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)ethyl)carbamate .sup.1HNMR (400 MHz, CD.sub.3OD) δ 7.58-7.77 (m, 8H), 7.42-7.55 (m, 2H), 7.19- 7.39 (m, 4H), 5.94 and 5.89 (s, 1H, rotamers, 1:1), 5.80 and 5.61 (s, 1H, rotamers, 1:1), 5.43-5.47 and 5.35-5.38 (m, 1H, rotamers, 1:1), 5.20-5.24 (m, 1H), 5.15-5.18 (m, 1H), 4.67- 4.70 and 4.39- 4.42 (m, 1H, rotamers, 1:1), 3.92-3.98 (m, 1H), 3.85-3.90 (m, 1H), 3.69- 3.84 (m, 2H), 3.64 and 3.63 (s, 3H, rotamers. 1:1), 3.53-3.59 (m, 1H), 2.35- 2.46 (m, 1H), 2.21-2.29 (m, 2H), 2.06-2.17 (m, 3H), 1.84- 2.01 (m, 4H), 1.66-1.76 and 1.41-1.47 (m, 1H, rotamers, 1:1); LCMS: Anal. Calcd. for C.sub.41H.sub.42ClN.sub.7O.sub.5: 747; found: 748 (M + H).sup.+. Example 107-40 methyl ((1R)-1-(2- chlorophenyl)-2-((2S)-2-(5- (4′-(2-((2S)-1-((2R)-2- (dimethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H-imidazol- 5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- LCMS: Anal. Calcd. for C.sub.46H.sub.47C1N.sub.8O.sub.4: 810; found: 811 (M + H).sup.+. oxoethyl)carbamate Example 107-41 methyl ((1R)-2-((2S)-2-(5- (4′-(2-((2S)-1-((2R)-2-(2- chlorophenyl)-2- ((methoxycarbonyl)amino) acetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate LCMS: Anal. Calcd. for C.sub.46H.sub.45ClN.sub.8O.sub.6: 840; found: 841 (M + H).sup.+. Example 107-42 methyl ((1R)-1-(2- chlorophenyl)-2-((2S)-2-(5- (4′-(2-((2S)-1-((2R)-2-(4- hydroxy-4-methyl-1- piperidinyl)-2- phenylacetyl)-2- pyrrolidinyl)-1H-imidazol- 5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxoethyl)carbamate 00 LCMS: Anal. Calcd. for C.sub.50H.sub.53ClN.sub.8O.sub.5: 880; found: 881 (M + H).sup.+. Example 107-43 methyl ((1R)-1-(2- chlorophenyl)-2-((2S)-2-(5- (4′-(2-((2S)-1-((2R)-2- methoxy-2-phenylacetyl)-2- pyrrolidinyl)-1H-imidazol- 5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxoethyl)carbamate 01 LCMS: Anal. Calcd. for C.sub.45H.sub.44ClN.sub.7O.sub.5: 797; found: 798 (M + H).sup.+. Example 107-44 methyl ((1R)-1-(2- chlorophenyl)-2-((2S)-2-(5- (4′-(2-((2S)-1-((2R)-2-(2- chlorophenyl)-2- (dimethylamino)acetyl)-2- pyrrolidinyl)-1H-imidazol- 5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- 02 LCMS: Anal. Calcd. for C.sub.46H.sub.46Cl.sub.2N.sub.8O.sub.4: 844; found: 845 (M + H).sup.+. oxoethyl)carbamate

Example 108

methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-(ethylcarbamoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

(254) ##STR00603##

(255) Ethyl isocyanate (5 μL, 0.063 mmol) was added to a methanol (1.0 mL) solution of 28f (30 mg, 0.049 mmol) and stirred at ambient condition for 1.8 hours. The residue was treated with 2.0 M NH.sub.3/methanol (2 mL) and stirred for an additional 30 minutes, and all the volatile components were removed in vacuo. The resulting material was purified by a reverse phase HPLC (H.sub.2O/methanol/TFA) to provide the TFA salt of Example 108 as a light yellow foam (16.7 mg) LC: 1.95 minutes (Cond. 2); >98% homogeneity index; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.39H.sub.43N.sub.8O.sub.4: 687.34. found 687.53. HRMS: Anal. Calcd. for [M+H].sup.+ C.sub.39H.sub.43N.sub.8O.sub.4: 687.3407. found 687.3417.

Example 109

dibenzyl (2S,2′S)-2,2′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl))di(1-pyrrolidinecarboxylate)

(256) ##STR00604##

Example 109

Step a

benzyl (2S)-2-(5-(4′-(2-((2S)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinecarboxylate

(257) ##STR00605##

(258) The Boc-deprotection of 28c using the procedure described for the synthesis of pyrrolidine 1e from carbamate 1d provided 109a. RT=1.92 minutes (Cond 2); >98% homogeneity index; LC/MS: Anal. Calcd. C.sub.34H.sub.35N.sub.6O.sub.2: 559.28. found 559.44.

Example 109

dibenzyl (2S,2′S)-2,2′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl))di(1-pyrrolidinecarboxylate)

(259) ##STR00606##

(260) Benzyl chloroformate (10.5 μL, 0.0736 mmol) was added to a THF (2.0 mL) solution of 109a (37.1 mg, 0.664 mmol) and triethylamine (15 μl, 0.107 mmol), and stirred under ambient conditions for 6 hours. The volatile component was removed in vacuo, and the residue was treated with 2N NH.sub.3/methanol (2 mL) and stirred for 15 minutes. The volatile component was removed in vacuo, and the residue purified by a reverse phase HPLC (H.sub.2O/methanol/TFA) to provide the TFA salt of Example 109 as an off-white foam (37.9 mg). LC (Cond. 2): RT=2.25 min; >98% homogeneity index; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.42H.sub.41N.sub.6O.sub.4: 693.32. found 693.59. HRMS: Anal. Calcd. for [M+H].sup.+ C.sub.42H.sub.41N.sub.6O.sub.4: 693.3189. found 693.3220.

Example 110

(2R)—N-((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1-((2S)-tetrahydro-2-furanylcarbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)ethyl)tetrahydro-2-furancarboxamide

(261) ##STR00607##

Example 110

Step a

(1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1-((2S)-tetrahydro-2-furanylcarbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)ethanamine

(262) ##STR00608##

(263) Amine 110a was synthesized starting from 28d and (S)-tetrahydrofuran-2-carboxylic by sequentially employing procedures described in the preparation of 28f (from 28d) and 25b (from 1e). LC (Cond. 1): RT=1.13 min; >98% homogeneity index; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.39H.sub.42N.sub.7O.sub.3: 656.34. found 656.49. HRMS: Anal. Calcd. for [M+H].sup.+ C.sub.39H.sub.42N.sub.7O.sub.3: 656.3349. found 656.3377.

Example 110

(2R)—N-((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1-((2S)-tetrahydro-2-furanylcarbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)ethyl)tetrahydro-2-furancarboxamide

(264) ##STR00609##

(265) Example 110 (TFA salt) was prepared from Example 110a and (S)-tetrahydrofuran-2-carboxylic acid using the conditions described for the synthesis Example 1 from amine 1e. LC (Cond. 1): RT=1.28 min; >98% homogeneity index; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.44H.sub.48N.sub.7O.sub.5: 754.37. found 754.60. HRMS: Anal. Calcd. for [M+H].sup.+ C.sub.44H.sub.48N.sub.7O.sub.5: 754.3717. found 754.3690.

Example 111

N-((1R)-2-oxo-1-phenyl-2-((2S)-2-(5-(4′-(2-((2S)-1-((2S)-tetrahydro-2-furanylcarbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)ethyl)-4-morpholinecarboxamide

(266) ##STR00610##

(267) Example 111 (TFA salt) was prepared from amine 110a and morpholine 4-carbonyl chloride using the procedure described for the synthesis of Example 29 from amine 28f. LC (Cond. 1): RT=1.28 min; >98% homogeneity index; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.44H.sub.49N.sub.8O.sub.5: 769.38. found 769.60.

(268) Using similar methods described for the preparation of Example 111, the following compounds (Example 112-120) were synthesized as TFA salts.

Example 112-117

(269) ##STR00611##

(270) TABLE-US-00029 Example Compound Name Retention time (LC-Condition); homogeneity index MS data 112 (2S)-N-((1R)-2-oxo-1- phenyl-2-((2S)-2-(5-(4′-2- ((2S)-1-((2S)-tetrahydro- 2-furanylcarbonyl)-2- pyrrolidinyl)-1H-imidazol- 5-yl)-4-biphenylyl)-1H- 1.28 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.44H.sub.48N.sub.7O.sub.5: 754.37; found 754.59; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.44H.sub.48N.sub.7O.sub.5: 754.3717; found 754.3731 imidazol-2-yl)-1- pyrrolidinyl)ethyl)tetrahydro- 2-furancarboxamide 113 1-methyl-N-((1R)-2-oxo- 1-phenyl-2-((2S)-2-(5-(4′- (2-((2S)-1-((2S)- tetrahydro-2- furanylcarbonyl)-2- pyrrolidinyl)-1H-imidazol- 1.14 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.44H.sub.51N.sub.8O.sub.4: 767.40; found 767.68; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.44H.sub.51N.sub.8O.sub.4; 767.4033; found 767.4035 5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)ethyl)-L- prolinamide 114 1-methyl-N-((1R)-2-oxo- 1-phenyl-2-((2S)-2-(5-(4′- (2-((2S)-1-((2S)- tetrahydro-2- furanylcarbonyl)-2- pyrrolidinyl)-1H-imidazol- 1.12 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.46H.sub.53N.sub.8O.sub.4: 781.42; found 781.67; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.46H.sub.53N.sub.8O.sub.4: 781.4190; found 781.4195 5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)ethyl)-4- piperidinecarboxamide 115 N-((1R)-2-oxo-1-phenyl- 2-((2S)-2-(5-(4′-(2-((2S)- 1-((2S)-tetrahydro-2- furanylcarbonyl)-2- pyrrolidinyl)-1H-imidazol- 5-yl)-4-biphenylyl)-1H- 1.24 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.45H.sub.50N.sub.7O.sub.5: 768.39; found 768.66; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.45H.sub.50N.sub.7O.sub.5: 768.3873; found 768.3897 imidazol-2-yl)-1- pyrrolidinyl)ethyl)tetrahydo- 2H-pyran-4- carboxamide 116 (4R)-4-fluoro-1-methyl-N- ((1R)-2-oxo-1-phenyl-2- ((2S)-2-(5-(4′-(2-((2S)-1- ((2S)-tetrahydro-2- furanylcarbonyl)-2- pyrrolidinyl)-1H-imidazol- 5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)ethyl)-L- prolinamide 1.16 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.45H.sub.50FN.sub.8O.sub.4: 785.39; found 785.63; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.45H.sub.50FN.sub.8O.sub.4: 785.3939; found: 785.3940 117 4-methyl-N-((1R)-2-oxo- 1-phenyl-2-((2S)-2-(5-(4′- (2-((2S)-1-((2S)- tetrahydro-2- furanylcarbonyl)-2- pyrrolidinyl)-1H-imidazol- 1.15 minutes (Cond. 1); 97.6%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.45H.sub.52N.sub.9O.sub.4: 782.41; found 782.64; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.45H.sub.52N.sub.9O.sub.4: 782.4142; found 782.4161 5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)ethyl)-1- piperazinecarboxamide

Examples 118 to 120-9

(271) ##STR00619##

(272) Examples 118 to 120-9 were prepared as described in the preparation of Example 110a substituting (R)-tetrahydrofuryl carboxylic acid and the appropriate carboxylic acid, carboxylic acid chloride, carbamoyl chloride, or isocyanate.

(273) TABLE-US-00030 Example Compound Name 0 Retention time (LC-Condition); homogeneity index; MS data 118 N-((1R)-2-oxo-1-phenyl- 2-((2S)-2-(5-(4′-(2-((2S)- l-((2R)-tetrahydro-2- furanylcarbonyl)-2- pyrrolidinyl)-1H-imidazol- 1.89 minutes (Cond. 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.44N.sub.7O.sub.4: 69835; found 698.25; HRMS: Anal. Calcd for 5-yl)-4-biphenylyl)-1H- [M + H].sup.+ C.sub.41H.sub.44N.sub.7O.sub.4: imidazol-2-yl)-1- 698.3455; found 698.3474 pyrrolidinyl)ethyl)acetamide 119 (2R)-N-((1R)-2-oxo-1- phenyl-2-((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-tetrahydro- 2-furanylcarbonyl)-2- pyrrolidinyl)-1H-imidazol- 5-yl)-4-biphenylyl)-1H- 1.99 minutes (Cond 2); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.44H.sub.48N.sub.7O.sub.5: 754.37; found 754.28; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.44H.sub.48N.sub.7O.sub.5: imidazol-2-yl)-1- 754.3717; found 754.3705 pyrrolidinyl)ethyl)tetrahydro- 2-furancarboxamide 120 N-((1R)-2-oxo-1-phenyl- 2-((2S)-2-(5-(4′-(2-((2S)- 1-((2R)-tetrahydro-2- furanylcarbonyl)-2- pyrrolidinyl)-1H-imidazol- 5-yl)-4-biphenylyl)-1H- 2.00 minutes (Cond. 2); >98%: LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.44H.sub.49N.sub.8O.sub.5: 769.38; found 769.32 imidazol-2-yl)-1- pyrrolidinyl)ethyl)-4- morpholinecarboxamide 120-5 1-methyl-N-((1R)-2-oxo- 1-phenyl-2-((2S)-2-(5-(4′- (2-((2S)-1-((2R)- tetrahydro-2- furanylcarbonyl)-2- pyrrolidinyl)-1H-imidazol- RT = 4.02 (97%): HPLC XTERRA C-18 4.6 × 30 mm, 0 to 100% B over 2 minutes. 1 minute hold time, A = 90% water, 10% methanol, 0.2% H.sub.3PO.sub.4, B = 10% water, 90% 4-yl)-4-biphenylyl)-1H- methanol, 0.2% H.sub.3PO.sub.4, RT = imidazol-2-yl)-1- 1.87 minutes, 97% pyrrolidinyl)ethyl)-1H- homogeneity index; LCMS: imidazole-5-carboxamide Anal. Calcd. for: C.sub.44H.sub.45N.sub.9O.sub.4 763.91; Found: 764.52 (M + H).sup.+ 120-6 1-methyl-N-((1R)-2-oxo- 1-phenyl-2-((2S)-2-(5-(4′- (2-((2S)-1-((2R)- tetrahydro-2- furanylcarbonyl)-2- pyrrolidinyl)-1H-imidazol- RT = 3.68 (99%); HPLC XTERRA C-18 4.6 × 30 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.2% H.sub.3PO.sub.4, B = 10% water, 90% 4-yl)-4-biphenylyl)-1H- methanol, 0.2% H.sub.3PO.sub.4, RT = imidazol-2-yl)-1- 1.87 minutes, 97% pyrrolidinyl)ethyl)-L- homogeneity index; LCMS: prolinamidc Anal. Calcd. for: C.sub.45H.sub.50N.sub.8O.sub.4 766.95; Found: 767.47 (M + H).sup.+ 120-7 N-((1R)-2-oxo-1-phenyl- 2-((2S)-2-(5-(4′-(2-((2S)- 1-((2R)-tetrahydro-2- furanylcarbonyl)-2- pyrrolidinyl)-1H-imidazol- 4-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)ethyl)-2-(3- RT = 3.81 (99%); HPLC XTERRA C-18 4.6 × 30 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.2% H.sub.3PO.sub.4, B = 10% water, 90% methanol, 0.2% H.sub.3PO.sub.4, RT = 1.87 minutes, 97% pyridinyl)acetamide homogeneity index; LCMS: Anal. Calcd for: C.sub.46H.sub.46N.sub.8O.sub.4 774.93; Found: 775.47 (M + H).sup.+ 120-8 N.sup.2,N.sup.2-dimethyl-N-((1R)- 2-oxo-1-phenyl-2-((2S)-2- (5-(4′-(2-((2S)-1-((2R)- tetrahydro-2- furanylcarbonyl)-2- pyrrolidinyl)-1H-imidazol- .sup.1H NMR (500 MHz, DMSO- d.sub.6) δ ppm 1.71-2.44 (m, 12H), 2.65-2.89 (m, 6H), 3.04-3.21 (m, J = 8.55 Hz, 1H), 3.46-3.68 (m, 1H), 3.64- 4.07 (m, 6H), 4.64 (dd, 4-yl)-4-biphenylyl)-1H- J = 8.09, 5.34 Hz, 1H), 5.09- imidazol-2-yl)-1- 5.30 (m, 2H), 5.66-5.86 (m, pyrrolidinyl)ethyl) 1H), 7.32-7.49 (m, 4H), 7.82- glycinamide 8.22 (m, 10H), 9.15-9.38 (m, 1H), 9.68 (s, 1H), 14.60 (s, 2H); HPLC Xterra 4.6 × 50 mm, 0 to 100% B over 10 minutes, one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid, RT = 3.61 min; LCMS: Anal. Calcd. for: C.sub.52H.sub.56N.sub.10O.sub.6 740.91; Found: 741.48 (M + H).sup.+. 120-9 1-((1R)-2-oxo-1-phenyl-2- ((2S)-2-(5-(4′-(2-((2S)-1- ((2R)-tetrahydro-2- furanylcarbonyl)-2- pyrrolidinyl)-1H-imidazol- 4-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)ethyl)-3-(3- pyridinyl)urea .sup.1H NMR (500 MHz, DMSO- d.sub.6) δ ppm 1.64-2.40 (m, 12H), 3.11-3.27 (m, 1H), 3.51-3.65 (m, 1H), 3.80 (dd, J = 18.46, 6.87 Hz, 3H), 3.96- 4.11 (m, 1H), 4.64 (dd, J = 7.78, 5.34 Hz, 1H), 5.13- 5.23 (m, 1H), 5.21-5.35 (m, 1H), 5.66 (d, J = 7.02 Hz, 1H), 7.29-7.57 (m, 7H), 7.82-8.07 (m, 10H), 8.14 (s, 1H), 8.22 (d, J = 4.58 Hz, 1H), 8.68 (s, 1H), 9.32 (s, 1H), 14.46 (s, 2H); HPLC Xterra 4.6 × 50 mm, 0 to 100% B over 10 minutes, one minute hold time, A = 90% water, 10%, methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid, RT = 3.83 min; LCMS: Anal. Calcd. for: C.sub.45H.sub.45N.sub.9O.sub.4 775.92; Found: 776.53 (M + H).sup.+.

Example 121

(1R,1′R)-2,2′-((2,2′-dimethyl-4,4′-biphenyldiyl)bis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl))bis(N,N-dimethyl-2-oxo-1-phenylethanamine)

(274) ##STR00629##

Example 121

Step a-b

(275) ##STR00630##

(276) PdCl.sub.2(Ph.sub.3P).sub.2 (257 mg, 0.367 mmol) was added to a dioxane (45 mL) solution of 1-bromo-4-iodo-2-methylbenzene (3.01 g, 10.13 mmol) and tri-n-butyl(1-ethoxyvinyl)stannane (3.826 g, 10.59 mmol) and heated at 80° C. for ˜17 hours. The reaction mixture was treated with water (15 mL), cooled to ˜0° C. (ice/water), and then NBS (1.839 g, 10.3 mmol) was added in batches over 7 minutes. After about 25 minutes of stirring, the volatile component was removed in vacuo, and the residue was partitioned between CH.sub.2Cl.sub.2 and water. The aqueous layer was extracted with CH.sub.2C.sub.12, and the combined organic phase was dried (MgSO.sub.4), filtered, and concentrated in vacuo. The resulting crude material was purified by a gravity chromatography (silica gel; 4% ethyl acetate/hexanes) to provide bromide 121a as a brownish-yellow solid (2.699 g); the sample is impure and contains stannane-derived impurities, among others. .sup.1H NMR (CDCl.sub.3, δ=7.24, 400 MHz): 7.83 (s, 1H), 7.63 (s, 2H), 4.30 (s, 2H), 2.46 (s, 3H).

(277) A CH.sub.3CN (15 mL) solution of 121a (2.69 g, <9.21 mmol) was added dropwise over 3 minutes to a CH.sub.3CN (30 mL) solution of (S)-Boc-proline (2.215 g, 10.3 mmol) and triethylamine (1.40 mL, 10.04 mmol), and stirred for 90 minutes. The volatile component was removed in vacuo, and the residue was partitioned between water and CH.sub.2C.sub.12, and the organic phase was dried (MgSO.sub.4), filtered, and concentrated in vacuo. The resulting crude material was purified by a flash chromatography (silica gel; 15-20% ethyl acetate/hexanes) to provide 121b as a colorless viscous oil (2.74 g). .sup.1H NMR (DMSO-d.sub.6, δ=2.50, 400 MHz): δ 7.98 (m, 1H), 7.78 (d, J=8.3, 1H), 7.72-7.69 (m, 1H), 5.61-5.41 (m, 2H), 4.35-4.30 (m, 1H), 3.41-3.30 (m, 2H), 2.43 (s, 3H), 2.33-2.08 (m, 2H), 1.93-1.83 (m, 2H), 1.40/1.36 (s, 9H); LC (Cond. 1): RT=1.91 min; >95% homogeneity index; LC/MS: Anal. Calcd. for [M+Na].sup.+ C.sub.19H.sub.24BrNNaO.sub.5 448.07. found 448.10.

(278) Additional keto-esters can be prepared in analogous fashion.

(279) LC Conditions:

(280) Condition 1: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

(281) Condition 2: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

(282) TABLE-US-00031 Exam- ple Structure Data 121b-1 RT = 2.15 minutes (condition 2, 98%); LRMS: Anal. Calcd. for C.sub.17H.sub.22NO.sub.5 399.07; found: 400.10 (M + H).sup.+. 121b-2 RT = 2.78 minutes (condition 1, >90%); LRMS: Anal. Calcd. for C.sub.20H.sub.20.sup.37BrNO.sub.5 435.05 found: 458.02 (M + Na).sup.+.

Example 121

Step c

(283) ##STR00633##

(284) A mixture of ketoester 121b (1.445 g, 3.39 mmol) and NH.sub.4OAc (2.93 g, 38.0 mmol) in xylenes (18 mL) was heated with a microwave at 140° C. for 80 minutes. The volatile component was removed in vacuo, and the residue was carefully partitioned between CH.sub.2Cl.sub.2 and water, where enough saturated NaHCO.sub.3 solution was added to neutralize the aqueous medium. The aqueous phase was extracted with CH.sub.2C.sub.12, and the combined organic phase was dried (MgSO.sub.4), filtered, and concentrated in vacuo. The crude product was purified by a flash chromatography (silica gel, 40% ethyl acetate/hexanes) to provide imidzaole 121c as an off-white solid (1.087 g). .sup.1H NMR (DMSO-d.sub.6, δ=2.50, 400 MHz): 12.15/11.91/11.84 (br s, 1H), 7.72-7.24 (m, 4H), 4.78 (m, 1H), 3.52 (m, 1H), 3.38-3.32 (m, 1H), 2.35 (s, 3H), 2.28-1.77 (m, 4H), 1.40/1.14 (s, 9H); LC (Cond. 1): RT=1.91 min; >98% homogeneity index; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.19H.sub.25BrN.sub.3O.sub.2 405.96. found 406.11.

Example 121

Step d

(285) ##STR00634##

(286) PdCl.sub.2dppf.CH.sub.2Cl.sub.2 (50.1 mg, 0.061 mmol) was added to a pressure tube containing a mixture of bromide 121c (538.3 mg, 1.325 mmol), bis(pinacolato)diboron (666.6 mg, 2.625 mmol), potassium acetate (365.8 mg, 3.727 mmol) and DMF (10 mL). The reaction mixture was flushed with N.sub.2 and heated at 80° C. for 24.5 hours. The volatile component was removed in vacuo and the residue was partitioned between CH.sub.2Cl.sub.2 and water, where enough saturated NaHCO.sub.3 solution was added to make the pH of the aqueous medium neutral. The aqueous phase was extracted with CH.sub.2C.sub.12, and the combined organic phase was dried (MgSO.sub.4), filtered, and concentrated in vacuo. The resulting material was purified by a Biotage system (silica gel, 40-50% ethyl acetate/hexanes) to provide boronate 121d as a white foam (580 mg). According to .sup.1H NMR the sample contains residual pinacol in a product/pinacol ratio of ˜3. .sup.1H NMR (DMSO-d.sub.6, δ=2.50, 400 MHz): δ 12.16/11.91/11.83 (br s, 1H), 7.63-7.25 (m, 4H), 4.78 (m, 1H), 3.53 (m, 1H), 3.39-3.32 (m, 1H), 2.48/2.47 (s, 3H), 2.28-1.78 (m, 4H), 1.40/1.14/1.12 (br s, 9H), 1.30 (s, 12H); LC (Cond. 1): RT=1.62 min; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.25H.sub.37BN.sub.3O.sub.4 454.29. found 454.15.

Example 121

Step e

and

Example 121

Step f

(287) ##STR00635##

(288) Carbamate 121e was prepared from bromide 121c and boronate 121d according to the preparation of dimer 1d; LC (Cond. 1): RT=1.43 min; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.38H.sub.49N.sub.6O.sub.4 653.38. found 653.65.

(289) The deprotection of carbamate 121e, according to the preparation of pyrrolidine 1e, provided 121f as an off-white foam. .sup.1H NMR (DMSO-d.sub.6, δ=2.50, 400 MHz): 11.79 (br s, 2H), 7.66 (s, 2H), 7.57 (d, J=7.8, 2H), 7.41 (br s, 2H), 7.02 (d, J=7.8, 2H), 4.15 (app t, J=7.2, 2H), 3.00-2.94 (m, 2H), 2.88-2.82 (m, 2H), 2.09-2.01 (m, 2H), 2.04 (s, 6H), 1.93-1.85 (m, 2H), 1.82-1.66 (m, 4H). Note: although broad signals corresponding to the pyrrolidine NH appear in the 2.8-3.2 ppm region, the actual range for their chemical shift could not be determined. LC (Cond. 1): RT=1.03 min; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.28H.sub.33N.sub.6 453.28. found 453.53.

(290) ##STR00636##

Example 121

(1R,1′R)-2,2′-((2,2′-dimethyl-4,4′-biphenyldiyl)bis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl))bis(N,N-dimethyl-2-oxo-1-phenylethanamine)

(291) Example 121 (TFA salt) was synthesized from 121f according to the preparation of Example 1 from 1e; LC (Cond. 1): RT=1.14 min; >98% homogeneity index; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.48H.sub.55N.sub.8O.sub.2 775.45; 775.75; HRMS: Anal. Calcd. for [M+H].sup.+ C.sub.48H.sub.55N.sub.8O.sub.2 775.4448. found 775.4473.

Example 122

dimethyl ((2,2′-dimethyl-4,4′-biphenyldiyl)bis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl((1R)-2-oxo-1-phenyl-2,1-ethanediyl)))biscarbamate

(292) ##STR00637##

(293) Example 122 (TFA salt) was prepared from pyrrolidine 121f and Cap-4 by using the procedure described for the preparation of Example 1 from pyrrolidine 1e.

(294) LC (Cond. 1): RT=1.35 min; >98% homogeneity index; HRMS: Anal. Calcd. for [M+H].sup.+ C.sub.48H.sub.51N.sub.8O.sub.6 835.3932. found 835.3954.

Example 123-125

(295) ##STR00638##

(296) Example 123-125 were prepared starting from boronate 1c and bromide 121c by using the methods described in Example 1, step d, Example 1, step e, and in the step describing the final preparation of Example 1.

(297) TABLE-US-00032 Example Compound Name RT (LC-Cond.); % homogeneity index; MS data 123 (1R,1′R)-2,2′-((2- methyl-4,4′- biphenyldiyl)bis (1H-imidazole- 5,2-diyl(2S)-2,1- pyrrolidinediyl)) bis(N,N- dimethyl-2-oxo- 1-phenyl- ethanamine) 0 1.12 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.47H.sub.53N.sub.8O.sub.2: 761.43; found 761.49; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.47H.sub.53N.sub.8O.sub.2: 761.4291; found 761.4311 124 dimethyl ((2- methyl-4,4′- biphenyldiyl) bis(1H- imidazole-5,2- diyl(2S)-2,1- pyrrolidinediyl ((1R)-2-oxo-1- phenyl-2,1- ethanediyl))) biscarbamate 1.34 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.47H.sub.49N.sub.8O.sub.6: 821.38; found 821.45; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.47H.sub.49N.sub.8O.sub.6: 821.3775; found 821.3785 125 (1R,1′R)-2,2′- ((2-methyl- 4,4′-biphenyl- diyl)bis(1H- imidazole-5,2- diyl(2S)-2,1- pyrrolidine- diyl))bis(2- oxo-1- 1.23 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.43H.sub.43N.sub.6O.sub.4: 707.34; found 707.38; HRMS: Anal. Calcd. for [M + H].sup.+ phenylethanol) C.sub.43H.sub.43N.sub.6O.sub.4: 707.3346; found 707.3356

Examples 126-128

(298) ##STR00643##

(299) Example 126-128 were prepared starting from bromide 28b and boronate 121d by using the methods described in Example 28 starting with step c.

(300) TABLE-US-00033 Exam- ple Compound Name RT (LC-Cond.); % homogeneity index; MS data 126 methyl ((1R)-2- ((2S)-2-(5-(4′- (2-((2S)-1- ((2R)-2- (dimethyl- amino)-2- phenylacetyl)- 2-pyrrolidinyl)- 1H-imidazol- 5-yl)-2′-methyl- 4-biphenylyl)- 1H-imidazol- 1.22 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.47H.sub.51N.sub.8O.sub.4: 791.40; found 791.70; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.47H.sub.51N.sub.8O.sub.4: 791.4033; 2-yl)-1- found pyrrolidinyl)-2- 791.4061 oxo-1-phenyl- ethyl)carbamate 127 methyl ((1R)-2- ((2S)-2-(5-(2′- methyl-4′-(2- ((2S)-1-(3- pyridinyl- acetyl)-2- pyrrolidinyl)- 1H-imidazol- 5-yl)-4- 1.19 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.44H.sub.45N.sub.8O.sub.4: 749.36; found 749.62; HRMS: Anal. Calcd. biphenylyl)- for [M + H].sup.+ 1H-imidazol- C.sub.44H.sub.45N.sub.8O.sub.4: 2-yl)-1- 749.3564; pyrrolidinyl)- found 2-oxo-1- 749.3592 phenylethyl) carbamate 128 methyl ((1R)-2- ((2S)-2-(5-(2′- methyl-4′-(2- ((2S)-1-((2S)- tetrahydro-2- furanyl- carbonyl)-2- pyrrolidinyl)- 1H-imidazol- 5-yl)-4- 1.27 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.46N.sub.7O.sub.5: 728.36; found 728.59; HRMS: Anal. Calcd. for [M + H].sup.+ biphenylyl)- C.sub.42H.sub.46N.sub.7O.sub.5: 1H-imidazol- 728.3560; 2-yl)-1- found pyrrolidinyl)- 728.3593 2-oxo-1- phenylethyl) carbamate

Example 129

methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-2,2′-dimethyl-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

(301) ##STR00648##

Example 129

Step a

(302) ##STR00649##

(303) HATU (104.3 mg, 0.274 mmol) was added to a mixture of 121f, Cap-4 (58.8 mg, 0.281 mmol) and diisopropylethylamine (110 μL, 0.631 mmol) in DMF (6.0 mL), and stirred for 90 minutes. The volatile component was removed in vacuo and the resulting crude material was purified by reverse phase HPLC (H.sub.2O/methanol/TFA), and free-based by MCX column (methanol wash; 2.0 M NH.sub.3/methanol) to provide 129a (89.9 mg). LC (Cond. 1): RT=1.22 min; 95% homogeneity index; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.38H.sub.42N.sub.7O.sub.3 644.34. found 644.55.

Example 129

methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

(304) ##STR00650##

(305) Example 129 (TFA salt) was prepared from 129a by the method used to convert Example 1e to Example 1. LC (Cond. 1): RT=1.27 min; 97% homogeneity index; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.48H.sub.53N.sub.8O.sub.4 805.42. found 805.61.

Example 130

(1R,1′R)-2,2′-((2-(trifluoromethyl)-4,4′-biphenyldiyl)bis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl))bis(N,N-dimethyl-2-oxo-1-phenylethanamine)

(306) ##STR00651##

Example 130

Step a

(307) ##STR00652##

(308) Glyoxal (2.0 mL of 40% in water) was added dropwise over 11 minutes to a methanol solution of NH.sub.4OH (32 mL) and (S)-Boc-prolinal (8.564 g, 42.98 mmol) and stirred at ambient temperature for 19 hours. The volatile component was removed in vacuo and the residue was purified by a flash chromatography (silica gel, ethyl acetate) followed by a recrystallization (ethyl acetate, room temperature) to provide imidazole 130a as a white fluffy solid (4.43 g). .sup.1H NMR (DMSO-d.sub.6, δ=2.50, 400 MHz): 11.68/11.59 (br s, 1H), 6.94 (s, 1H), 6.76 (s, 1H), 4.76 (m, 1H), 3.48 (m, 1H), 3.35-3.29 (m, 1H), 2.23-1.73 (m, 4H), 1.39/1.15 (s, 9H). LC (Cond. 1): RT=0.87 min; >95% homogeneity index; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.12H.sub.20N.sub.3O.sub.2 238.16. found 238.22. Imidazole 130a had an ee of 98.9% when analyzed under chiral HPLC condition noted below.

(309) Column: Chiralpak AD, 10 um, 4.6×50 mm

(310) Solvent: 1.7% ethanol/heptane (isocratic)

(311) Flow rate: 1 mL/min

(312) Wavelength: either 220 or 256 nm

(313) Relative retention time: 3.25 min (R), 5.78 minutes (S)

Example 130

Step b

(314) ##STR00653##

(315) N-Bromosuccinimide (838.4 mg, 4.71 mmol) was added in batches, over 15 minutes, to a cooled (ice/water) CH.sub.2Cl.sub.2 (20 mL) solution of imidazole 130a (1.0689 g, 4.504 mmol), and stirred at similar temperature for 75 minutes. The volatile component was removed in vacuo. The crude material was purified by a reverse phase HPLC system (H.sub.2O/methanol/TFA) to separate bromide 130b from its dibromo-analog and the non-consumed starting material. The HPLC elute was neutralized with excess NH.sub.3/methanol and the volatile component was removed in vacuo. The residue was partitioned between CH.sub.2Cl.sub.2 and water, and the aqueous layer was extracted with water. The combined organic phase was dried (MgSO.sub.4), filtered, and concentrated in vacuo to provide 130b as a white solid (374 mg). .sup.1H NMR (DMSO-d.sub.6, δ=2.50, 400 MHz): 12.12 (br s, 1H), 7.10 (m, 1H), 4.70 (m, 1H), 3.31 (m, 1H; overlapped with water signal), 2.25-1.73 (m, 4H), 1.39/1.17 (s, 3.8H+5.2H). LC (Cond. 1): RT=1.10 min; >95% homogeneity index; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.12H.sub.19BrN.sub.3O.sub.2 316.07. found 316.10.

Example 130

Step c

(316) ##STR00654##

(317) Pd(Ph.sub.3P).sub.4 (78.5 mg, 0.0679 mmol) was added to a mixture of bromide 130b (545 mg, 1.724 mmol), 2-(4-chloro-3-(trifluoromethyl)phenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (542.8 mg, 1.771 mmol) (commercially available), NaHCO.sub.3 (477 mg, 5.678 mmol) in 1,2-dimethoxyethane (12.5 mL) and water (4.2 mL). The reaction mixture was purged with nitrogen, heated with an oil bath at 80° C. for 27 hours, and then the volatile component was removed in vacuo. The residue was partitioned between CH.sub.2Cl.sub.2 and water, and the organic layer was dried (MgSO.sub.4), filtered, and concentrated in vacuo. The resulting crude material was purified by a Biotage system (silica gel, 40-50% ethyl acetate/hexanes) followed by a reverse phase HPLC (water/methanol/TFA). The HPLC elute was treated with excess NH.sub.3/methanol and concentrated. The residue was partitioned between water and CH.sub.2C.sub.12, and the organic layer was dried (MgSO.sub.4), filtered, and concentrated in vacuo to provide 130c as a white foam (317.4 mg). .sup.1H NMR (DMSO-d.sub.6, δ=2.50, 400 MHz): 12.36/12.09/12.03 (br s, 1H), 8.15 (d, J=1.8, 0.93H), 8.09 (br s, 0.07H), 8.01 (dd, J=8.3/1.3, 0.93H), 7.93 (m, 0.07H), 7.74 (m, 1H), 7.66 (d, J=8.3, 0.93H), 7.46 (m, 0.07H), 4.80 (m, 1H), 3.53 (m, 1H), 3.36 (m, 1H), 2.30-1.77 (m, 4h), 1.40/1.15 (s, 3.8H+5.2H). LC (Cond. 1): RT=1.52 min; >95% homogeneity index; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.19H.sub.22ClF.sub.3N.sub.3O.sub.2 416.14. found 416.17.

Example 130

Step d-e

(318) ##STR00655##

(319) Pd[P(t-Bu).sub.3].sub.2 (48 mg, 0.094 mmol) was added to a mixture of chloride 130c (245 mg, 0.589 mmol), boronate 1c (277.1 mg, 0.631 mmol), KF (106.7 mg, 1.836 mmol) in DMF (6 mL), and heated at 110° C. for ˜30 hours. The volatile component was removed in vacuo, and the residue was partitioned between CH.sub.2Cl.sub.2 (50 mL), water (20 mL) and saturated NaHCO.sub.3 (1 mL). The aquous layer was extracted with CH.sub.2Cl.sub.2 (2×), and the combined organic phase was dried (MgSO.sub.4), filtered, and concentrated in vacuo. The resulting material was purified by a Biotage system (silica gel, ethyl acetate) to provide carbamate 130d as an off-white foam (297 mg). LC (Cond. 1): RT=1.44 min; >95% homogeneity index; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.37H.sub.44F.sub.3N.sub.6O.sub.4 693.34. found 693.34.

(320) The deprotection of 130d, which was conducted according to the preparation of pyrrolidine 1e, provided 130e as a light yellow foam. .sup.1H NMR (DMSO-d.sub.6, δ=2.50, 400 MHz): 11.88 (br s, 2H), 8.16 (d, J=1.5, 1H), 8.02 (d, J=7.8, 1H), 7.78 (d, J=8.1, 2H), 7.66 (br s, 1H), 7.48 (br s, 1H), 7.37 (d, J=8.1, 1H), 7.28 (d, J=8.3, 2H), 4.18 (m, 2H), 2.99-2.93 (m, 2H), 2.89-2.83 (m, 2H), 2.11-2.01 (m, 2H), 1.94-1.85 (m, 2H), 1.82-1.67 (m, 4H). Note: although broad signals corresponding to the pyrrolidine NH appear in the 2.8-3.2 ppm region, the actual range for their chemical shift could not be determined. LC (Cond. 1): RT=1.12 min; >95% homogeneity index; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.27H.sub.28F.sub.3N.sub.6 493.23. found 493.14.

Example 130

(1R,1′R)-2,2′-((2-(trifluoromethyl)-4,4′-biphenyldiyl)bis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl))bis(N,N-dimethyl-2-oxo-1-phenylethanamine)

(321) ##STR00656##

(322) Example 130 (TFA salt) was prepared from 130e and Cap-1 according to the preparation of Example 1 from pyrrolidine 1e. LC (Cond. 1): RT=1.17 min; >98% homogeneity index; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.47H.sub.50F.sub.3N.sub.8O.sub.2 815.40. found 815.44. HRMS: Anal. Calcd. for [M+H].sup.+ C.sub.47H.sub.50F.sub.3N.sub.8O.sub.2 815.4009. found 815.4013.

Example 131

5,5′-(2-(trifluoromethyl)-4,4′-biphenyldiyl)bis(2-((2S)-1-((2R)-2-phenyl-2-(1-pyrrolidinyl)acetyl)-2-pyrrolidinyl)-1H-imidazole)

(323) ##STR00657##

(324) Example 131 (TFA salt) was synthesized from 130e and Cap-5 according to the preparation of Example 130.

(325) LC (Cond. 1): RT=1.19 min; >98% homogeneity index

(326) LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.51H.sub.54F.sub.3N.sub.8O.sub.2 867.43. found 867.51.

(327) HRMS: Anal. Calcd. for [M+H].sup.+ C.sub.51H.sub.54F.sub.3N.sub.8O.sub.2 867.4322. found 867.4315.

Example 131.1-1 to 131.1-2

(328) ##STR00658##

(329) Examples 131.1-1 through 131.1-2 were prepared in similar fashion to example 28 via the intermediacy of intermediate 1-6e after appending Cap-4.

Example 131.1-1

methyl ((1R)-2-(((1S)-1-(5-(4′-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)ethyl)(methyl)amino)-2-oxo-1-phenylethyl)carbamate

(330) ##STR00659##

(331) Cap-1 was appended after the CBz carbamate was removed from 1-6e with Pd/C/H.sub.2.

(332) LCMS conditions: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume. t.sub.R=1.42 min

(333) LRMS: Anal. Calcd. for C.sub.45H.sub.49N.sub.8O.sub.4 765.39. found: 765.38 (M+H).sup.+.

(334) HRMS: Anal. Calcd. for C.sub.45H.sub.49N.sub.8O.sub.4 Calcd 765.3877 found: 765.3905 (M+H).sup.+.

Example 131.1-2

methyl ((1R)-2-(methyl((1S)-1-(5-(4′-(2-((2S)-1-((2R)-2-phenyl-2-(1-piperidinyl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)ethyl)amino)-2-oxo-1-phenylethyl)carbamate

(335) ##STR00660##

(336) Cap-14 was appended after the CBz carbamate was removed from 1-6e with Pd/C/H.sub.2.

(337) LCMS Conditions:

(338) Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume. t.sub.R=1.45 min (>95%)

(339) LRMS: Anal. Calcd. for C.sub.48H.sub.52N.sub.8O.sub.4 805.42. found: 805.41 (M+H).sup.+.

(340) HRMS: Anal. Calcd. C.sub.48H.sub.52N.sub.8O.sub.4 Calcd 805.4190 found: 805.4214 (M+H).sup.+.

Example 131.2

(2R)-2-(dimethylamino)-N-methyl-2-phenyl-N-((1S)-1-(5-(4′-(2-((2S)-1-((2R)-2-phenyl-2-(1-piperidinyl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)ethyl)acetamide

(341) ##STR00661##

(342) Example 131. 2 was prepared in similar fashion to example 131.1-1 and example 131.1-2 via the intermediacy of intermediate 1-6e after appending Cap-1. Cap-14 was appended after the CBz carbamate was removed with Pd/C/H.sub.2.

(343) LCMS conditions: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume. t.sub.R=1.28 min

(344) LRMS: Anal. Calcd. for C.sub.48H.sub.54N.sub.8O.sub.2 775.44. found: 775.45 (M+H).sup.+.

(345) HRMS: Anal. Calcd. C.sub.48H.sub.54N.sub.8O.sub.2 Calcd 775.4448 found: 775.4460 (M+H).sup.+.

Example 132

(1R)-2-((2S)-2-(5-(6-(4-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)phenyl)-3-pyridinyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-N,N-dimethyl-2-oxo-1-phenylethanamine

(346) ##STR00662##

Example 132

Step a-b

(347) ##STR00663##

(348) A CH.sub.2Cl.sub.2 (10 mL) solution of Br.sub.2 (7.63 g, 47.74 mmol) was added-drop wise over 5 min to a cooled (ice/water) CH.sub.2Cl.sub.2 (105 mL) solution of 1-(6-bromopyridine-3-yl)ethanone (9.496 g, 47.47 mmol) and 48% HBr (0.4 mL). The cooling bath was removed 40 min later, and stirring was continued at ambient temperature for about 66 hr. The cake of solid that formed was filtered, washed with CH.sub.2Cl.sub.2 and dried in vacuo to afford impure 132a as an off-white solid (15.94 g).

(349) Boc-L-proline (9.70 g, 45.06 mmol) was added in one batch to a heterogeneous mixture of crude 132a (15.4 g) and CH.sub.3CN (150 mL), and immediately afterward Et.sub.3N (13.0 mL, 93.2 mmol) was added drop-wise over 6 min. The reaction mixture was stirred for 50 min, the volatile component was removed in vacuo and the residue was partitioned between CH.sub.2Cl.sub.2 and water. The CH.sub.2Cl.sub.2 layer was dried (MgSO.sub.4), filtered and concentrated in vacuo, and the resultant material was purified by flash chromatography (silica gel; sample was loaded with eluting solvent; 25% EtOAc/hexanes) to afford 132b as a highly viscous yellow oil (11.44 g). .sup.1H NMR (DMSO, δ=2.5 ppm; 400 MHz): 8.95 (m, 1H), 8.25-8.21 (m, 1H), 7.88 (d, J=8.3, 1H), 5.65-5.46 (m, 2H), 4.36-4.31 (m, 1H), 3.41-3.29 (m, 2H), 2.36-2.22 (m, 1H), 2.14-2.07 (m, 1H), 1.93-1.83 (m, 2H), 1.40 & 1.36 (two s, 9H).

(350) LC (Cond. 1): RT=2.01 min; >90% homogeneity index

(351) LC/MS: Anal. Calcd. for [M+Na].sup.+ C.sub.17H.sub.21NaBrN.sub.2O.sub.5: 435.05. found 435.15.

(352) HRMS: Anal. Calcd. for [M+H].sup.+ C.sub.17H.sub.22BrN.sub.2O.sub.5: 413.0712. found 413.0717.

Example 132

Step c

(353) ##STR00664##

(354) A mixture of ketoester 132b (1.318 g, 3.19 mmol) and NH.sub.4OAc (2.729 g, 35.4 mmol) in xylenes (18 mL) was heated with a microwave at 140° C. for 90 min. The volatile component was removed in vacuo and the residue was partitioned between CH.sub.2Cl.sub.2 and water, where enough saturated NaHCO.sub.3 solution was added to neutralize the aqueous medium. The aqueous phase was extracted with CH.sub.2C.sub.12, and the combined organic phase was dried (MgSO.sub.4), filtered, and concentrated in vacuo. The resulting crude material was purified by a Biotage system (silica gel; 50% EtOAc/hexanes) to afford imidzaole 132c as an off-white foam (1.025 g). .sup.1H NMR (DMSO, δ=2.5 ppm, 400 MHz): 12.33/12.09/12.02 (br m, 1H), 8.74 (d, J=2.3, 0.93H), 8.70 (app br s, 0.07H), 8.03/7.98 (dd for the first peak, J=8.3, 1H), 7.69/7.67 (br m, 1H), 7.58/7.43 (d for the first peak, J=8.3, 1H), 4.80 (m, 1H), 3.53 (m, 1H), 3.36 (m, 1H), 2.33-2.11 (m, 1H), 2.04-1.79 (m, 3H), 1.39/1.15 (app br s, 3.9H+5.1H).

(355) LC (Cond. 1): RT=1.52 min; >98% homogeneity index

(356) LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.17H.sub.22BrN.sub.4O.sub.2: 393.09. found 393.19.

(357) HRMS: Anal. Calcd. for [M+H].sup.+ C.sub.17H.sub.22BrN.sub.4O.sub.2: 393.0926. found 393.0909.

Example 132

Step d-e

(358) ##STR00665##

(359) Pd(Ph.sub.3P).sub.4 (115.1 mg, 0.10 mmol) was added to a mixture of bromide 132c (992 mg, 2.52 mmol), boronate 1c (1.207 g, 2.747 mmol), NaHCO.sub.3 (698.8 mg, 8.318 mmol) in 1,2-dimethoxyethane (18 mL) and water (4 mL). The reaction mixture was flushed with nitrogen, heated with an oil bath at 90° C. for 37 hr and allowed to cool to ambient temperature. The suspension that formed was filtered and washed with water followed by 1,2-dimethoxyethane, and dried in vacuo. A silica gel mesh was prepared from the crude solid and submitted to flash chromatography (silica gel; EtOAc) to afford carbamate 132d as a white solid, which yellowed slightly upon standing at ambient conditions (1.124 g). .sup.1H NMR indicated that the sample contains residual MeOH in a product/MeOH mole ratio of 1.3.

(360) LC (Cond. 1): RT=1.71 min; >98% homogeneity index

(361) LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.35H.sub.44N.sub.7O.sub.4: 626.35. found 626.64.

(362) HRMS: Anal. Calcd. for [M+H].sup.+ C.sub.35H.sub.44N.sub.7O.sub.4: 626.3455; 626.3479.

(363) Carbamate 132d (217 mg) was treated with 25% TFA/CH.sub.2Cl.sub.2 (3.6 mL) and stirred at ambient condition for 6 hr. The volatile component was removed in vacuo, and the resultant material was free based by MCX column (MeOH wash; 2.0 M NH.sub.3/MeOH elution) to afford 132e as a dull yellow foam that solidified gradually upon standing (150.5 mg; mass is above theoretical yield). .sup.1H NMR (DMSO, δ=2.5 ppm; 400 MHz): 11.89 (very broad, 2H), 9.01 (d, J=1.8, 1H), 8.13 (dd, J=8.3, 2.2, 1H), 8.07 (d, J=8.6, 2H), 7.92 (d, J=8.3, 1H), 7.83 (d, J=8.5, 2H), 7.61 (br s, 1H), 7.50 (br s, 1H), 4.18 (m, 2H), 3.00-2.93 (m, 2H), 2.90-2.82 (m, 2H), 2.11-2.02 (m, 2H), 1.94-1.85 (m, 2H), 1.83-1.67 (m, 4H). [Note: the exchangeable pyrrolidine hydrogens were not observed]

(364) LC (Cond. 1): RT=1.21 min; >98% homogeneity index

(365) LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.25H.sub.28N.sub.7: 426.24. found 426.40.

(366) HRMS: Anal. Calcd. for [M+H].sup.+ C.sub.25H.sub.28N.sub.7: 426.2406. found 426.2425.

Example 132

(1R)-2-((2S)-2-(5-(6-(4-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)phenyl)-3-pyridinyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-N,N-dimethyl-2-oxo-1-phenylethanamine

(367) ##STR00666##

(368) HATU (41.4 mg, 0.109 mmol) was added to a mixture of pyrrolidine 132e (23.1 mg, 0.054 mmol), (i-Pr).sub.2EtN (40 μL, 0.23 mmol) and Cap-1 (25.3 mg, 0.117 mmol) in DMF (1.5 mL), and the mixture was stirred at ambient for 1 hr. The volatile component was removed in vacuo, and the residue was purified first by MCX (MeOH wash; 2.0 M NH.sub.3/MeOH elution) and then by a reverse phase HPLC (H.sub.2O/MeOH/TFA) to afford the TFA salt of Example 132 as a yellow foam (39.2 mg).

(369) LC (Cond. 1): RT=1.37 min; >98% homogeneity index

(370) LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.45H.sub.50N.sub.9O.sub.2: 748.41. found 748.53.

(371) HRMS: Anal. Calcd. for [M+H].sup.+ C.sub.45H.sub.50N.sub.9O.sub.2: 748.4087. found 748.4090.

(372) Example 133-135 were prepared as TFA salts from 132e by using the same method of preparations as Example 132 and appropriate reagents.

Example 133-135

(373) ##STR00667##

(374) TABLE-US-00034 Example Compound Name RT (LC-Cond.); % homogeneity index; MS data 133 (1R)-2-((2S)-2- (5-(6-(4-(2- ((2S)-1-((2R)- 2-hydroxy-2- phenylacetyl)- 2-pyrrolidinyl)- 1H-imidazol- 5-yl)phenyl)- 3-pyridinyl)- 1.49 min (Cond. 1); >98% LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.40N.sub.7O.sub.4: 694.31; found 694.42 HRMS: Anal. 1H-imidazol- Calcd. for 2-yl)-1- [M + H].sup.+ pyrrolidinyl)- C.sub.41H.sub.40N.sub.7O.sub.4: 2-oxo-1- 694.3142, phenylethanol found: 694.3164 134 methyl ((1R)- 2-((2S)-2-(5- (6-(4-(2-((2S)- 1-((2R)-2- ((methoxy- carbonyl) amino)-2- phenylacetyl)- 2-pyrrolidinyl)- 1H-imidazol- 5-yl)phenyl)- 3-pyridinyl)- 1H-imidazol- 2-yl)-1- 0 1.60 min (Cond. 1); >98% LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.45H.sub.46N.sub.9O.sub.6: 808.36; found 808.51 HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.45H.sub.46N.sub.9O.sub.6: 808.3571; found pyrrolidinyl)- 808.3576 2-oxo-1- phenylethyl) carbamate 135 5-(2-((2S)- 1-((2R)-2- methoxy-2- phenylacetyl)- 2-pyrrolidinyl)- 1H-imidazol- 5-yl)-2-(4-(2- ((2S)-1-((2R)-2- methoxy-2- phenylacetyl)- 1.60 min (Cond. 1); >98% LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.43H.sub.44N.sub.7O.sub.4: 722.35; found 722.40 HRMS: Anal. Calcd. for 2-pyrrolidinyl)- [M + H].sup.+ 1H-imidazol- C.sub.43H.sub.44N.sub.7O.sub.4: 5-yl)phenyl) 722.3455; pyridine found 722.3464

Example 136

(1R)-2-((2S)-2-(5-(6-(4-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-2-methylphenyl)-3-pyridinyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-N,N-dimethyl-2-oxo-1-phenylethanamine

(375) ##STR00672##

Example 136

Step a and b

(376) ##STR00673##

(377) PdCl.sub.2(Ph.sub.3P).sub.2 (257 mg, 0.367 mmol) was added to a dioxane (45 mL) solution of 1-bromo-4-iodo-2-methylbenzene (3.01 g, 10.13 mmol) and tri-n-butyl(1-ethoxyvinyl)stannane (3.826 g, 10.59 mmol) and heated at 80° C. for ˜17 hr. The reaction mixture was treated with water (15 mL), cooled to ˜0° C. (ice/water), and then NBS (1.839 g, 10.3 mmol) was added in batches over 7 min. About 25 min of stirring, the volatile component was removed in vacuo, and the residue was partitioned between CH.sub.2Cl.sub.2 and water. The aqueous layer was extracted with CH.sub.2C.sub.12, and the combined organic phase was dried (MgSO.sub.4), filtered, and concentrated in vacuo. The resulting crude material was purified by a gravity chromatography (silica gel; 4% EtOAc/hexanes) to afford bromide 136a as a brownish-yellow solid (2.699 g); the sample is impure and contains stannane-derived impurities, among others. .sup.1H NMR (CDCl.sub.3, δ=7.24, 400 MHz): 7.83 (s, 1H), 7.63 (s, 2H), 4.30 (s, 2H), 2.46 (s, 3H).

(378) An CH.sub.3CN (15 mL) solution of 136a (2.69 g, <9.21 mmol) was added drop wise over 3 min to a CH.sub.3CN (30 mL) solution of (S)-Boc-proline (2.215 g, 10.3 mmol) and Et.sub.3N (1.40 mL, 10.04 mmol), and stirred for 90 min. The volatile component was removed in vacuo, and the residue was partitioned between water and CH.sub.2Cl.sub.2, and the organic phase was dried (MgSO.sub.4), filtered, and concentrated in vacuo. The resultant crude material was purified by a flash chromatography (silica gel; 15-20% EtOAc/hexanes) to afford 136b as a colorless viscous oil (2.74 g). .sup.1H NMR (DMSO-d.sub.6, δ=2.50, 400 MHz): 7.98 (m, 1H), 7.78 (d, J=8.3, 1H), 7.72-7.69 (m, 1H), 5.61-5.41 (m, 2H), 4.35-4.30 (m, 1H), 3.41-3.30 (m, 2H), 2.43 (s, 3H), 2.33-2.08 (m, 2H), 1.93-1.83 (m, 2H), 1.40/1.36 (s, 9H).

(379) LC (Cond. 1): RT=1.91 min; >95% homogeneity index

(380) LC/MS: Anal. Calcd. for [M+Na].sup.+ C.sub.19H.sub.24BrNNaO.sub.5 448.07. found 448.10.

Example 136

Step c

(381) ##STR00674##

(382) A mixture of ketoester 136b (1.445 g, 3.39 mmol) and NH.sub.4OAc (2.93 g, 38.0 mmol) in xylenes (18 mL) was heated with a microwave at 140° C. for 80 min. The volatile component was removed in vacuo, and the residue was carefully partitioned between CH.sub.2Cl.sub.2 and water, where enough saturated NaHCO.sub.3 solution was added to neutralize the aqueous medium. The aqueous phase was extracted with CH.sub.2C.sub.12, and the combined organic phase was dried (MgSO.sub.4), filtered, and concentrated in vacuo. The crude was purified by a flash chromatography (silica gel, 40% EtOAc/hexanes) to afford imidzaole 136c as an off-white solid (1.087 g). .sup.1H NMR (DMSO-d.sub.6, δ=2.50, 400 MHz): 12.15/11.91/11.84 (br s, 1H), 7.72-7.24 (m, 4H), 4.78 (m, 1H), 3.52 (m, 1H), 3.38-3.32 (m, 1H), 2.35 (s, 3H), 2.28-1.77 (m, 4H), 1.40/1.14 (s, 9H).

(383) LC (Cond. 1): RT=1.91 min; >98% homogeneity index

(384) LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.19H.sub.25BrN.sub.3O.sub.2 405.96. found 406.11.

Example 136

Step d

(385) ##STR00675##

(386) PdCl.sub.2dppf.CH.sub.2Cl.sub.2 (50.1 mg, 0.061 mmol) was added to a pressure tube containing a mixture of bromide 136c (538.3 mg, 1.325 mmol), bis(pinacolato)diboron (666.6 mg, 2.625 mmol), KOAc (365.8 mg, 3.727 mmol) and DMF (10 mL). The reaction mixture was flushed with N.sub.2 and heated at 80° C. for 24.5 hr. The volatile component was removed in vacuo and the residue was partitioned between CH.sub.2Cl.sub.2 and water, where enough saturated NaHCO.sub.3 solution was added to make the pH of the aqueous medium neutral. The aqueous phase was extracted with CH.sub.2C.sub.12, and the combined organic phase was dried (MgSO.sub.4), filtered, and concentrated in vacuo. The resulting material was purified by a Biotage system (silica gel, 40-50% EtOAc/hexanes) to afford boronate 136d as a white foam (580 mg). According to .sup.1H NMR the sample contains residual pinacol in a product/pinacol ratio of ˜3. .sup.1H NMR (DMSO-d.sub.6, δ=2.50, 400 MHz): 12.16/11.91/11.83 (br s, 1H), 7.63-7.25 (m, 4H), 4.78 (m, 1H), 3.53 (m, 1H), 3.39-3.32 (m, 1H), 2.48/2.47 (s, 3H), 2.28-1.78 (m, 4H), 1.40/1.14/1.12 (br s, 9H), 1.30 (s, 12H).

(387) LC (Cond. 1): RT=1.62 min

(388) LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.25H.sub.37BN.sub.3O.sub.4 454.29. found 454.15.

Example 136

Step e-f

(389) ##STR00676##

(390) Biaryl 136e was prepared from bromide 132c and boronate 136d according to the coupling condition described for the preparation of biaryl 132d.

(391) LC (Cond. 1a): RT=1.32 min; >90% homogeneity index

(392) LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.36H.sub.45N.sub.7O.sub.4 640.36. found 640.66.

(393) The deprotection of biaryl 136e was done according to the preparation of pyrrolidine 132e to afford 136f as a light yellow foam. .sup.1H NMR (DMSO-d.sub.6, δ=2.50, 400 MHz): 11.88 (br s, 2H), 9.02 (d, J=2, 1H), 8.12 (dd, J=8.4, 2.3, 1H), 7.67 (s, 1H), 7.64-7.62 (m, 2H), 7.50 (d, J=8.3, 1H), 7.46 (br s, 1H), 7.40 (d, J=7.8, 1H), 4.21-4.14 (m, 2H), 3.00-2.93 (m, 2H), 2.90-2.82 (m, 2H), 2.40 (s, 3H), 2.11-2.01 (m, 2H), 1.94-1.85 (m, 2H), 1.82-1.66 (m, 4H). [Note: the signal for the pyrrolidine NH appears in the region 3.22-2.80 and is too broad to make a chemical shift assignment.]

(394) LC (Cond. 1): RT=0.84 min

(395) LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.26H.sub.30N.sub.7 440.26. found 440.50.

Example 136

(1R)-2-((2S)-2-(5-(6-(4-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-2-methylphenyl)-3-pyridinyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-N,N-dimethyl-2-oxo-1-phenylethanamine

(396) ##STR00677##

(397) Example 136 (TFA salt) was synthesized from 136f according to the preparation of Example 132 from 132e. 1.05 min (Cond. 1); >98%

(398) LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.46H.sub.52N.sub.9O.sub.2: 762.42. found: 762.77.

(399) HRMS: Anal. Calcd. for [M+H].sup.+ C.sub.46H.sub.52N.sub.9O.sub.2: 762.4244. found 762.4243.

Example 138

methyl ((1R)-2-((2S)-2-(5-(6-(4-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-2-methylphenyl)-3-pyridinyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

(400) ##STR00678##

(401) Example 138 was prepared similarly from pyrrolidine 136f and Cap-4. 1.60 min (Cond. 1); >98%

(402) LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.46H.sub.48N.sub.9O.sub.6: 822.37. found 822.74.

(403) HRMS: Anal. Calcd. for [M+H].sup.+ C.sub.46H.sub.48N.sub.9O.sub.6: 822.3728. found 822.3760.

Example 139

N-((1R)-2-((2S)-2-(5-(6-(4-(2-((2S)-1-((2R)-2-acetamido-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)phenyl)-3-pyridinyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)acetamide

(404) ##STR00679##

Example 139

Step a

(405) ##STR00680##

(406) HATU (99.8 mg, 0.262 mmol) was added to a mixture of 132e (54.1 mg, 0.127 mmol), (R)-2-(t-butoxycarbonylamino)-2-phenylacetic acid (98.5 mg, 0.392 mmol) and i-Pr.sub.2EtN (100 μL, 0.574 mol), and the reaction mixture was stirred for 70 min. The volatile component was removed in vacuo, and the residue was purified by a reverse phase HPLC (H.sub.2O/MeOH/TFA), where the HPLC elute was treated with excess 2.0 N NH.sub.3/MeOH before the removal of the volatile component in vacuo. The resulting material was partitioned between CH.sub.2Cl.sub.2 and water, and the aqueous phase was extracted with CH.sub.2Cl.sub.2 (2×). The combined organic phase was dried (MgSO.sub.4), filtered, and concentrated in vacuo. Carbamate 139a was obtained as a white film of foam (82.3 mg).

(407) LC (Cond. 1): RT=1.97 min; >95% homogeneity index.

(408) LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.51H.sub.58N.sub.9O.sub.6: 892.45. found 892.72.

Example 139b

Step b

(409) ##STR00681##

(410) Carbamate 139a was deprotected to amine 139b by using the procedure described for the preparation of pyrrolidine 132e from 132d.

(411) LC (Cond. 1): RT=1.37 min; >95% homogeneity index

(412) LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.41H.sub.42N.sub.9O.sub.2: 692.35. found 692.32.

Example 139

N-((1R)-2-((2S)-2-(5-(6-(4-(2-((2S)-1-((2R)-2-acetamido-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)phenyl)-3-pyridinyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)acetamide

(413) ##STR00682##

(414) Acetic anhydride (20 μL, 0.212 mmol) was added to a DMF (1.5 mL) solution of 139b (31.2 mg, 0.045 mmol), and the reaction mixture was stirred for 1 hr. NH.sub.3/MeOH (1.0 mL of 2N) was added to the reaction mixture and stirring continued for 100 min. The volatile component was removed in vacuo and the resulting crude material was purified by a reverse phase HPLC (H.sub.2O/MeOH/TFA) to afford the TFA salt of Example 139 as a light yellow solid (24.1 mg).

(415) LC (Cond. 1): RT=1.53 min; >98% homogeneity index

(416) LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.45H.sub.46N.sub.9O.sub.4: 776.37. found 776.38.

(417) HRMS: Anal. Calcd. for [M+H].sup.+ C.sub.45H.sub.46N.sub.9O.sub.4: 776.3673. found 776.3680.

Example 140

methyl ((1R)-2-((2S)-2-(5-(4-(5-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-2-pyridinyl)phenyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

(418) ##STR00683##

Example 140

Step a

(419) ##STR00684##

(420) HATU (19.868 g, 52.25 mmol) was added to a heterogeneous mixture of N-Cbz-L-proline (12.436 g, 49.89 mmol) and the HCl salt of 2-amino-1-(4-bromophenyl) ethanone (12.157 g, 48.53 mmol) in DMF (156 mL). The mixture was lowered in an ice-water bath, and immediately afterward N,N-diisopropylethylamine (27 mL, 155 mmol) was added drop wise to it over 13 min. After the addition of the base was completed, the cooling bath was removed and the reaction mixture was stirred for an additional 50 min. The volatile component was removed in vacuo; water (125 mL) was added to the resultant crude solid and stirred for about 1 hr. The off-white solid was filtered and washed with copious water, and dried in vacuo to afford ketoamide 140a as a white solid (20.68 g). .sup.1H NMR (DMSO-d.sub.6, δ=2.5 ppm, 400 MHz): 8.30 (m, 1H), 7.91 (m, 2H), 7.75 (d, J=8.5, 2H), 7.38-7.25 (m, 5H), 5.11-5.03 (m, 2H), 4.57-4.48 (m, 2H), 4.33-4.26 (m, 1H), 3.53-3.36 (m, 2H), 2.23-2.05 (m, 1H), 1.94-1.78 (m, 3H).

(421) LC (Cond. 1): RT=1.65 min; 98% homogeneity index

(422) LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.21H.sub.22BrN.sub.2O.sub.4: 445.08. found 445.31.

Example 140

Step b

(423) ##STR00685##

(424) Ketoamide 140a (10.723 g, 24.08 mmol) was converted to 140b according to the procedure described for the synthesis of carbamate 132c, with the exception that the crude material was purified by flash chromatography (silica gel; 50% EtOAc/hexanes). Bromide 140b was retrieved as an off-white foam (7.622 g). .sup.1H NMR (DMSO-d.sub.6, δ=2.5 ppm, 400 MHz): 12.23/12.04/11.97 (m, 1H), 7.73-6.96 (m, 10H), 5.11-4.85 (m, 3H), 3.61 (m, 1H), 3.45 (m, 1H), 2.33-184 (m, 4H).

(425) LC (Cond. 1): RT=1.42 min; >95% homogeneity index

(426) LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.21H.sub.21BrN.sub.3O.sub.2: 426.08. found 426.31.

(427) HRMS: Anal. Calcd. for [M+H].sup.+ C.sub.21H.sub.21BrN.sub.3O.sub.2: 426.0817. found: 426.0829.

(428) The optical purity of 140b was assessed using the following chiral HPLC methods, and an ee of 99% was observed.

(429) Column: Chiralpak AD, 10 um, 4.6×50 mm

(430) Solvent: 20% ethanol/heptane (isocratic)

(431) Flow rate: 1 ml/min

(432) Wavelength: 254 nm

(433) Relative retention time: 1.82 min (R), 5.23 min (S)

Example 140

Step c

(434) ##STR00686##

(435) Pd(Ph.sub.3P).sub.4 (208 mg, 0.180 mmol) was added to a pressure tube containing a mixture of bromide 140b (1.80 g, 4.22 mmol), bis(pinacolato)diboron (2.146 g, 8.45 mmol), KOAc (1.8 g, 11.0 mmol) and 1,4-dioxane (34 mL). The reaction flask was purged with nitrogen, capped and heated with an oil bath at 80° C. for 23 hr. The volatile component was removed in vacuo, and the residue was partitioned carefully between CH.sub.2Cl.sub.2 (70 mL) and an aqueous medium (22 mL water+5 mL saturated NaHCO.sub.3 solution). The aqueous layer was extracted with CH.sub.2C.sub.12, and the combined organic phase was dried (MgSO.sub.4), filtered, and concentrated in vacuo. The oily reside was crystallized from EtOAc/hexanes to afford two crops of boronate 140c as a yellow solid (1.52 g). The mother liquor was evaporated in vacuo and the resulting material was purified by flash chromatography (silica gel; 20-35% EtOAc/CH.sub.2Cl.sub.2) to afford additional 140c as an off-white solid, containing residual pinacol (772 mg).

(436) LC (Cond. 1): RT=1.95 min

(437) LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.27H.sub.33BN.sub.3O.sub.4: 474.26. found 474.31.

Example 140

Step d-e

(438) ##STR00687##

(439) Arylbromide 132c was coupled with boronate 140c to afford 140d by using the same procedure described for the synthesis of biaryl 132d. The sample contains the desbromo version of 132c as an impurity. Proceeded to the next step without further purification.

(440) LC (Cond. 1): RT=1.72 min; ˜85% homogeneity index

(441) LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.38H.sub.42N.sub.7O.sub.4: 660.33. found 660.30.

(442) A mixture of 10% Pd/C (226 mg), biaryl 140d (1.25 g) and MeOH (15 mL) was stirred under a balloon of hydrogen for ˜160 hr, where the hydrogen supply was replenished periodically as needed. The reaction mixture was filtered through a pad of diatomaceous earth (Celite®), and the filtrate was evaporated in vacuo to afford crude 140e as a yellowish-brown foam (911 mg). Proceeded to the next step without further purification.

(443) LC (Cond. 1): RT=1.53 min

(444) LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.30H.sub.36N.sub.7O.sub.2: 526.29. found 526.23.

Example 140

Step f-g

(445) ##STR00688##

(446) Pyrrolidine 140 g was prepared from 140e and Cap-4, via the intermediacy of carbamate 140f, by sequentially employing the amide forming and Boc-deprotection protocols used in the synthesis of Example 132.

(447) LC (Cond. 1): RT=1.09 min; ˜94% homogeneity index

(448) LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.35H.sub.37N.sub.8O.sub.3: 617.30. found 617.38.

Example 140

methyl ((1R)-2-((2S)-2-(5-(4-(5-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-2-pyridinyl)phenyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

(449) ##STR00689##

(450) The TFA salt of Example 140 was synthesized from pyrrolidine 140 g and Cap-1 by using the procedure described for the preparation of Example 132 from intermediate 132e.

(451) 1.15 min (Cond. 1); >98% homogeneity index

(452) LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.45H.sub.40N.sub.7O.sub.4: 778.38. found 778.48.

(453) HRMS: Anal. Calcd. for [M+H].sup.+ C.sub.45H.sub.40N.sub.7O.sub.4: 778.3829. found 778.3849.

(454) The TFA salt of Example 141-143 were synthesized from intermediate 140 g and appropriate reagents in a similar manner.

Example 141-143

(455) ##STR00690##

(456) TABLE-US-00035 Exam- ple Compound Name RT (LC-Cond.); % homogeneity index; MS data 141 methyl ((1R)-2- oxo-1-phenyl-2- ((2S)-2-(5-(4-(5- (2-((2S)-1- ((2R)-tetra- hydro-2-furanyl- carbonyl)-2- pyrrolidinyl)- 1H-imidazol- 5-yl)-2- 1.15 min (Cond. 1); >98% LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.43N.sub.8O.sub.5: 715.34; found 715.44 HRMS: Anal. Calcd. for pyridinyl) [M + H].sup.+ phenyl)-1H- C.sub.40H.sub.43N.sub.8O.sub.5: imidazol-2- 715.3356; yl)-1- found pyrrolidinyl) 715.3381 ethyl)carbamate 142 methyl ((1R)-2- ((2S)-2-(5-(4- (5-(2-((2S)-1- ((1-methyl- 4-piperidinyl) carbonyl)-2- pyrrolidinyl)- 1H-imidazol- 5-yl)-2- 1.07 min (Cond. 1); >98% LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.48N.sub.9O.sub.4: 742.38; found 742.48 HRMS: Anal. pyridinyl) Calcd. for phenyl)-1H- [M + H].sup.+ imidazol-2-yl)- C.sub.42H.sub.48N.sub.9O.sub.4: 1-pyrrolidinyl)- 742.3829; 2-oxo-1- found phenylethyl) 742.3859 carbamate 143 methyl ((1R)-2- oxo-1-phenyl- 2-((2S)-2-(5- (4-(5-(2-((2S)- 1-(3-pyridinyl- acetyl)-2- pyrrolidinyl)- 1H-imidazol- 1.09 min (Cond. 1); >98% LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.42N.sub.9O.sub.4: 736.34; found 736.44 5-yl)-2- HRMS: Anal. pyridinyl) Calcd. for phenyl)-1H- [M + H].sup.+ imidazol-2- C.sub.42H.sub.42N.sub.9O.sub.4: yl)-1- 736.3360; pyrrolidinyl) 736.3344 ethyl) carbamate

Example 144

methyl ((1R)-2-((2S)-2-(5-(4-(5-(2-((2S)-1-(4-morpholinylcarbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-2-pyridinyl)phenyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

(457) ##STR00695##

(458) A DMF (1.5 mL) solution of morpholine-4-carbonyl chloride (8.5 mg, 0.057 mmol) was added to a mixture of i-Pr.sub.2EtN (20 μL, 0.115 mmol) and 140 g (27.3 mg, 0.044 mmol), and stirred for 100 min. The volatile component was removed in vacuo and the residue was purified by a reverse phase HPLC (H.sub.2O/MeOH/TFA) to afford the TFA salt of Example 144 as a yellow foam (34.6 mg).

(459) 1.17 min (Cond. 1); >98%

(460) LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.40H.sub.44N.sub.9O.sub.5: 730.35. found 730.42.

(461) HRMS: Anal. Calcd. for [M+H].sup.+ C.sub.40H.sub.44N.sub.9O.sub.5: 730.3465. found 730.3477.

Example 145

dimethyl (2,2′-bipyridine-5,5′-diylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl((1R)-2-oxo-1-phenyl-2,1-ethanediyl)))biscarbamate

(462) ##STR00696##

Example 145

Step a-b

(463) ##STR00697##

(464) Pd(Ph.sub.3P).sub.4 (9.6 mg, 0.008 mmol) and LiCl (28 mg, 0.67 mmol) were added to a mixture of arylbromide 132c (98.7 mg, 0.251 mmol) and hexamethylditin (51.6 mg, 0.158 mmol), and heated at 80° C. for ˜3 days. The volatile component was removed in vacuo and the resultant crude material was purified by flash chromatography (silica gel; 0-10% MeOH/EtOAc) followed by a reverse phase HPLC (H.sub.2O/MeOH/TFA). The HPLC elute was neutralized with excess 2.0 N NH.sub.3/MeOH, and the volatile component was removed in vacuo. The residue was partitioned between CH.sub.2Cl.sub.2 and water, and the aqueous phase was washed with CH.sub.2Cl.sub.2 (2×). The combined organic phase was dried (MgSO.sub.4), filtered, and concentrated in vacuo to afford carbamate 145a as a film of oil (8.7 mg).

(465) LC (Cond. 1): RT=1.68 min; >98% homogeneity index

(466) LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.34H.sub.43N.sub.8O.sub.4: 627.34. found 627.47.

(467) Carbamate 145a was elaborated to pyrrolidine 145b according to the preparation of 132e from 132d. .sup.1H NMR (DMSO, δ=2.5 ppm; 400 MHz): 12.02 (br signal, 2H), 9.04 (d, J=1.6, 2H), 8.34 (d, J=8.3, 2H), 8.20 (dd, J=8.3, 2.3, 2H), 7.67 (br s, 1H), 4.21 (m, 2H), 3.00-2.85 (m, 4H), 2.12-2.04 (m, 2H), 1.95-1.68 (m, 6H). [Note: the pyrrolidine-NH signal was not observed].

(468) LC (Cond. 1): RT=1.17 min; >98% homogeneity index

(469) LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.24H.sub.27N.sub.8: 427.24. found 427.13.

Example 145

dimethyl (2,2′-bipyridine-5,5′-diylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl((1R)-2-oxo-1-phenyl-2,1-ethanediyl)))biscarbamate

(470) ##STR00698##

(471) Example 145 (TFA salt) was synthesized from 145b according to the preparation of Example 132 from 132e.

(472) LC (Cond. 1): RT=1.63 min; 98% homogeneity index

(473) LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.44H.sub.45N.sub.10O.sub.6: 809.35. found 809.40.

Example 146

(1R)-2-((2S)-2-(5-(5-(4-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)phenyl)-2-pyridinyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-N,N-dimethyl-2-oxo-1-phenylethanamine

(474) ##STR00699##

Example 146

Step a

(475) ##STR00700##

(476) n-BuLi (12.0 mL of 2.5M/hexanes, 30 mmol) was added drop-wise over 15 min to a cooled (−78° C.) toluene (300 mL) semi-solution of 2,5-dibromopyridine (6.040 g, 25.5 mmol), and stirred for 2.5 hr. t-Butyl 2-(methoxy(methyl)amino)-2-oxoethylcarbamate (2.809 g, 12.87 mmol) was added in batches over 7 min, and stirring continued for 1.5 hr at −78° C. The −78° C. bath was replaced with −60° C. bath, which was allowed to warm up to −15° C. over 2.5 hr. The reaction was quenched with saturated NH.sub.4Cl solution (20 mL), and the mixture was allowed to thaw to ambient temperature and the organic layer was separated and evaporated in vacuo. The resulting crude material was purified by flash chromatography (silica gel; 15% EtOAc/hexanes) to afford a reddish brown semisolid, which was washed with hexanes to removed the colored residue. Pyridine 146a was retrieved as an ash colored solid (842 mg). .sup.1H NMR (DMSO, δ=2.5 ppm; 400 MHz): 8.89 (d, J=2.3, 1H), 8.30 (dd, J=8.4, 2.4, 1H), 7.90 (d, J=8.3, 1H), 7.03 (br t, J=5.7; 0.88H), 6.63 (app br s, 0.12H), 4.55 (d, J=5.8, 2H), 1.40/1.28 (two app s, 7.83H+1.17H).

(477) LC (Cond. 1): RT=2.00 min; >95% homogeneity index

(478) LC/MS: Anal. Calcd. for [M+Na].sup.+ C.sub.12H.sub.15BrNaN.sub.2O.sub.3: 337.02. found 337.13.

Example 146

Step b

(479) ##STR00701##

(480) 48% HBr (1.0 mL) was added drop-wise to a dioxane (5.0 mL) solution of carbamate 146a (840 mg, 2.66 mmol) over 3 min, and the reaction mixture was stirred at ambient temperature for 17.5 hr. The precipitate was filtered and washed with dioxane, and dried in vacuo to afford amine the HBr salt of 146b as an off-white solid (672.4 mg; the exact mole equivalent of the HBr salt was not determined). .sup.1H NMR (DMSO, δ=2.5 ppm; 400 MHz): 8.95 (d, J=2.3, 1H), 8.37 (dd, J=8.4, 2.3, 1H), 8.2 (br s, 3H), 8.00 (d, J=8.3, 1H), 4.61 (s, 2H).

(481) LC (Cond. 1): RT=0.53 min

(482) LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.7H.sub.8BrN.sub.2O: 214.98. found 215.00.

Example 146

Step c

(483) ##STR00702##

(484) i-Pr.sub.2EtN (2.3 mL, 13.2 mmol) was added drop-wise over 15 min to a heterogonous mixture of amine 146b (1.365 g), (S)-Boc-proline (0.957 g, 4.44 mmol) and HATU (1.70 g, 4.47 mmol) in DMF (13.5 mL), and stirred at ambient temperature for 1 hr. The volatile component was removed in vacuo and the residue was partitioned between EtOAc (40 mL) and an aqueous medium (20 mL water+1 ml saturated NaHCO.sub.3 solution). The aqueous layer was washed with EtOAc (20 mL), and the combined organic phase was dried (MgSO.sub.4), filtered, and concentrated in vacuo. The resultant crude material was purified by flash chromatography (silica gel; 40-50% EtOAc/hexanes) to afford ketoamide 146c as a faint-yellow foam (1.465 g). .sup.1H NMR (DMSO, δ=2.5 ppm; 400 MHz): 8.90 (d, J=2.3, 1H), 8.30 (dd, J=8.5, 2.4, 1H), 8.01-8.07 (m, 1H), 7.90 (d, J=8.3, 1H), 4.6 (m, 1H), 4.64 (dd, J=19.1, 5.5, 1H); 4.19 (m, 1H), 3.39 (m, 1H), 3.32-3.26 (m, 1H), 2.20-2.01 (m, 1H), 1.95-1.70 (m, 3H), 1.40/1.35 (two app s, 9H).

(485) LC (Cond. 1): RT=1.91 min

(486) LC/MS: Anal. Calcd. for [M+Na].sup.+ C.sub.17H.sub.22BrN.sub.3NaO.sub.4: 434.07. found 433.96.

Example 146

Step d

(487) ##STR00703##

(488) A mixture of ketoamide 146c (782.2 mg, 1.897 mmol) and NH.sub.4OAc (800 mg, 10.4 mmol) in xylenes was heated with a microwave (140° C.) for 90 min. The volatile component was removed in vacuo and the residue was carefully partitioned between CH.sub.2Cl.sub.2 and water, where enough saturated NaHCO.sub.3 solution was added to neutralize it. The aqueous phase was extracted with CH.sub.2Cl.sub.2 (2×), and the combined organic phase was dried (MgSO.sub.4), filtered, and concentrated in vacuo. The resultant crude material was purified by flash chromatography (silica gel; 50% CH.sub.2C.sub.12/EtOAc) to afford imidazole 146d as an off-white solid (552.8 mg). .sup.1H NMR (DMSO, δ=2.5 ppm; 400 MHz): 12.49/12.39/12.15/12.06 (br s, 1H), 8.62 (app br s, 0.2H), 8.56 (d, J=2, 0.8H), 8.02 (br d, J=8.5, 0.2H), 7.97 (br d, J=7.8, 0.8H), 7.77 (d, J=8.6, 0.8H), 7.72 (d, J=8.6, 0.2H), 7.61-7.49 (m, 1H), 4.93-4.72 (m, 1H), 3.53 (m, 1H), 3.41-3.32 (m, 1H), 2.33-1.77 (m, 4H), 1.39/1.14 (app br s, 3.7H+5.3H).

(489) LC (Cond. 1): RT=1.67 min; >95% homogeneity index

(490) LC/MS: Anal. Calcd. for [M+Na].sup.+ C.sub.17H.sub.21BrN.sub.4NaO.sub.2: 415.08. found 415.12.

Example 146

Step e

(491) ##STR00704##

146e (R1=H, R2=SEM) or (R1=SEM, R2=H)

(492) NaH (60%; 11.6 mg, 0.29 mmol) was added in one batch to a heterogeneous mixture of imidazole 146d (80 mg, 0.203 mmol) and DMF (1.5 mL), and stirred at ambient condition for 30 min. SEM-Cl (40 μL, 0.226 mmol) was added drop-wise over 2 min to the above reaction mixture, and stirring was continued for 14 hr. The volatile component was removed in vacuo and the residue was partitioned between water and CH.sub.2C.sub.12. The aqueous layer was extracted with CH.sub.2C.sub.12, and the combined organic phase was dried (MgSO.sub.4), filtered, and concentrated in vacuo. The crude material was purified by a flash chromatography (silica gel; 20% EtOAc/hexanes) to afford 146e as a colorless viscous oil (87.5 mg). The exact regiochemistry of 146e was not determined. .sup.1H NMR (CDCl.sub.3, δ=7.4 ppm; 400 MHz): 8.53 (d, J=2.2, 1H), 7.90-7.72 (m, 2H), 7.52 (s, 1H), 5.87 (m, 0.46H), 5.41 (m, 0.54H), 5.16 (d, J=10.8, 1H), 5.03-4.85 (m, 1H), 3.76-3.42 (m, 4H), 2.54-1.84 (m, 4H), 1.38/1.19 (br s, 4.3H+4.7H), 0.97-0.81 (m, 2H), −0.03 (s, 9H).

(493) LC (Cond. 1): RT=2.1 min

(494) LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.23H.sub.36BrN.sub.4O.sub.3Si: 523.17. found 523.24.

Example 146

Step f

(495) ##STR00705##

(496) Pd(Ph.sub.3P).sub.4 (24.4 mg, 0.021 mmol) was added to a mixture of imidazole 146e (280 mg, 0.535 mmol), 1c (241.5 mg, 0.55 mmol) and NaHCO.sub.3 (148.6 mg, 1.769 mmol) in 1,2-dimethoxyethane (4.8 mL) and water (1.6 mL). The reaction mixture was flushed with nitrogen, heated with an oil bath at 80° C. for ˜24 hr and then the volatile component was removed in vacuo. The residue was partitioned between CH.sub.2Cl.sub.2 and water, and the organic phase was dried (MgSO.sub.4), filtered, and concentrated in vacuo. The crude material was purified by a Biotage system (silica gel; 75-100% EtOAc/hexanes) followed by a reverse phase HPLC (H.sub.2O/MeOH/TFA). The HPLC elute was neutralized with 2M NH.sub.3/MeOH and evaporated in vacuo, and the residue was partitioned between water and CH.sub.2C.sub.12. The organic layer was dried (MgSO.sub.4), filtered, and concentrated in vacuo to afford 146f as a white foam (162 mg).

(497) LC (Cond. 1): RT=2.1 min

(498) LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.41H.sub.58N.sub.7O.sub.5Si: 756.43. found 756.55.

Example 146

Step g

(499) ##STR00706##

(500) Carbamate 146f (208 mg, 0.275 mmol) was treated with 25% TFA/CH.sub.2C.sub.12 (4.0 mL) and stirred at ambient temperature for 10 hr. The volatile component was removed in vacuo and the residue was first free-based by MCX (MeOH wash; 2.0 M NH.sub.3/MeOH elution) and then purified by a reverse phase HPLC (H.sub.2O/MeOH/TFA), and the resultant material was free-based again (MCX) to afford pyrrolidine 146 g as a film of oil (53.7 mg). .sup.1H NMR (DMSO, δ=2.5 ppm; 400 MHz): 1.88 (app br s, 2H), 8.83 (d, J=2.1, 1H), 8.07 (dd, J=8.3/2.3, 1H0, 7.87 (d, J=8.5, 1H), 7.84 (d, J=8.3, 2H), 7.71 (d, J=8.3, 2H), 7.55 (s, 1H), 7.50 (br s, 1H), 4.18 (m, 2H), 3.00-2.94 (m, 2H), 2.89-2.83 (m, 2H), 2.11-2.02 (m, 2H), 1.95-1.86 (m, 2H), 1.83-1.67 (m, 4H).

(501) LC (Cond. 1): RT=0.95 min; >98% homogeneity index

(502) LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.25H.sub.28N.sub.7: 426.24. found 426.27.

Example 146

(1R)-2-((2S)-2-(5-(5-(4-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)phenyl)-2-pyridinyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-N,N-dimethyl-2-oxo-1-phenylethanamine

(503) ##STR00707##

(504) Example 146 (TFA salt) was synthesized from pyrrolidine 146 g according to the preparation of Example 132 from intermediate 132e.

(505) LC (Cond. 1): RT=1.42 min; 96.5% homogenity index

(506) LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.45H.sub.50N.sub.9O.sub.2: 748.41. found 748.57.

(507) HRMS: Anal. Calcd. for [M+H].sup.+ C.sub.45H.sub.50N.sub.9O.sub.2: 748.4087. found 748.4100.

Example 147

methyl ((1R)-2-((2S)-2-(5-(5-(4-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)phenyl)-2-pyridinyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate

(508) ##STR00708##

(509) The TFA salt of Example 147 was prepared similarly from intermediate 146 g by using Cap-4.

(510) LC (Cond. 1): RT=1.66 min; 95% homogenity index

(511) LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.45H.sub.46N.sub.9O.sub.6: 808.36. found 808.55.

Example 148

(1R,1′R)-2,2′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(4R)-1,3-thiazolidine-4,3-diyl))bis(N,N-dimethyl-2-oxo-1-phenylethanamine)

(512) ##STR00709##

Example 148

Step a

(513) ##STR00710##

(514) A solution of bromine (1.3 mL, 25.0 mmol) in 15 mL glacial acetic acid was added drop-wise to a solution of 4-4′-diacetylbiphenyl (3.0 g, 12.5 mmol) in 40 mL acetic acid at 50° C. Upon completion of addition the mixture was stirred at room temperature overnight. The precipitated product was filtered off and re-crystallized from chloroform to give 1,1′-(biphenyl-4,4′-diyl)bis(2-bromoethanone) (3.84 g, 77.5%) as a white solid.

(515) .sup.1H NMR (500 MHz, CHLOROFORM-D) δ ppm 8.09 (4H, d, J=7.93 Hz) 7.75 (4H, d, J=8.24 Hz) 4.47 (4H, s)

(516) Nominal/LRMS—Anal. Calcd. for 369.07 found; (M+H).sup.+−397.33, (M−H).sup.−-395.14.

Example 148

Step b

(517) ##STR00711##

(518) Sodium diformylamide (3.66 g, 38.5 mmol) was added to a suspension of 1,1′-(biphenyl-4,4′-diyl)bis(2-bromoethanone) (6.1 g, 15.4 mmol) in 85 mL acetonitrile. The mixture was heated at reflux for 4 hours and concentrated under reduced pressure. The residue was suspended in 300 mL 5% HCl in ethanol and heated at reflux for 3.5 hours. Reaction was cooled to room temperature and placed in the freezer for 1 hour. Precipitated solid was collected, washed with 200 mL 1:1 ethanol/ether followed by 200 mL pentane, and dried under vacuum to give 1,1′-(biphenyl-4,4′-diyl)bis(2-aminoethanone) dihydrochloride (4.85 g, 92%). Carried on without further purification.

(519) .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ ppm 8.47-8.55 (4H, m) 8.11-8.17 (4H, m) 8.00 (4H, d, J=8.42 Hz) 4.59-4.67 (4H, m).

(520) LCMS—Phenomenex C-18 3.0×50 mm, 0 to 100% B over 4.0 minute gradient, 1 minute hold time, A=10% methanol 90% water 0.1% TFA, B=90% methanol 10% water 0.1% TFA, t.sub.R=0.44 minutes, Anal. Calcd. for C.sub.16H.sub.16N.sub.2O.sub.2 268.31 found; 269.09 (M+H).sup.+.

Example 148

Step c

(521) ##STR00712##

(522) To a stirred solution of 1,1′-(biphenyl-4,4′-diyl)bis(2-aminoethanone) dihydrochloride (0.7 g, 2.1 mmol), N-(tert-butoxycarbonyl)-L-thioproline (0.96 g, 4.2 mmol), and HATU (1.68 g, 4.4 mmol) in 14 mL DMF was added diisopropylethyl amine (1.5 mL, 8.4 mmol) drop-wise over 5 minutes. The resulting clear yellow solution was stirred at room temperature overnight (14 hours) and concentrated under reduced pressure. The residue was partitioned between 20% methanol/chloroform and water. The aqueous phase was washed once with 20% methanol/chloroform. The combined organics were washed with brine, dried (MgSO.sub.4), filtered, and concentrated under reduced pressure. The crude product was chromatographed on silica gel by gradient elution with 10-50% ethyl acetate/CH.sub.2Cl.sub.2 to give (4S,4′S)-tert-butyl 4,4′-(2,2′-(biphenyl-4,4′-diyl)bis(2-oxoethane-2,1-diyl))bis(azanediyl)bis(oxomethylene)dithiazolidine-3-carboxylate (0.39 g, 27%) as an orange foam.

(523) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 8.38 (2H, s) 8.12 (4H, d, J=8.56 Hz) 7.94 (4H, d, J=8.56 Hz) 4.60-4.68 (4H, m) 4.33-4.38 (2H, m) 3.58-3.68 (2H, m) 3.38 (2H, s) 3.08-3.18 (2H, m) 1.40 (18H, s)

(524) LCMS—Water-Sunfire C-18 4.6×50 mm, 0 to 100% B over 4.0 minute gradient, 1 minute hold time, A=10% methanol 90% water 0.1% TFA, B=90% methanol 10% water 0.1% TFA, t.sub.R=3.69 min., Anal. Calcd. for C.sub.34H.sub.42N.sub.4O.sub.8S.sub.2 698.85 found; 699.12 (M+H).sup.+.

Example 148

Step d

(525) ##STR00713##

(526) (4S,4′S)-tert-butyl 4,4′-(5,5′-(biphenyl-4,4′-diyl)bis(1H-imidazole-5,2-diyl))dithiazolidine-3-carboxylate (0.39 g, 0.56 mmol) and ammonium acetate (0.43 g, 5.6 mmol) were suspended in 8 mL o-xylene in a microwave reaction vessel. The mixture was heated under standard microwave conditions at 140° C. for 70 minutes and concentrated under reduced pressure. The residue was dissolved in 30 mL 20% methanol/chloroform and washed with 10% NaHCO.sub.3(aq). The organic layer was washed with brine, dried (MgSO.sub.4), filtered, and concentrated under reduced pressure. The crude product was chromatographed on silica gel by gradient elution with 1-6% methanol/CH.sub.2Cl.sub.2 to give (4S,4′S)-tert-butyl 4,4′-(5,5′-(biphenyl-4,4′-diyl)bis(1H-imidazole-5,2-diyl))dithiazolidine-3-carboxylate (0.15 g, 41%) as a yellow solid.

(527) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 12.02 (2H, s) 7.70-7.88 (10H, m) 5.28-5.37 (2H, m) 4.68 (2H, d, J=9.16 Hz) 4.47-4.55 (2H, m) 3.46 (2H, s) 3.23 (2H, s) 1.26-1.43 (18H, m)

(528) LCMS—Luna C-18 3.0×50 mm, 0 to 100% B over 3.0 minute gradient, 1 minute hold time, A=5% acetonitrile, 95% water, 10 mm ammonium acetate, B=95% acetonitrile, 5% water, 10 mm ammonium acetate, tR=1.96 min., Anal. Calcd. for C.sub.34H.sub.40N.sub.6O.sub.4S.sub.2 660.85 found; 661.30 (M+H).sup.+, 659.34 (M−H).sup.−.

Example 148

Step e

(529) ##STR00714##

(530) To a solution of (4S,4′S)-tert-butyl 4,4′-(5,5′-(biphenyl-4,4′-diyl)bis(1H-imidazole-5,2-diyl))dithiazolidine-3-carboxylate in 1 mL dioxane was added 0.3 mL of a 4.0M solution of HCl in dioxane. The reaction was stirred for 3 hours at room temperature and concentrated under reduced pressure. The resulting tan solid was dried under vacuum to give 4,4′-bis(2-((S)-thiazolidin-4-yl)-1H-imidazol-5-yl)biphenyl tetrahydrochloride (0.12 g, 100%) as a yellow solid.

(531) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 8.09 (2H, s) 8.01 (4H, d, J=8.55 Hz) 7.90 (4H, d, J=8.55 Hz) 5.08 (2H, t, J=6.10 Hz) 4.38 (2H, d, J=9.16 Hz) 4.23 (2H, d, J=9.46 Hz) 3.48-3.54 (2H, m,) 3.35-3.41 (2H, m)

(532) LCMS—Luna C-18 3.0×50 mm, 0 to 100% B over 4.0 minute gradient, 1 minute hold time, A=5% acetonitrile, 95% water, 10 mm ammonium acetate, B=95% acetonitrile, 5% water, 10 mm ammonium acetate, t.sub.R=1.70 min., Anal. Calcd. for C.sub.24H.sub.24N.sub.6S.sub.2 460.62 found; 461.16 (M+H).sup.+, 459.31 (M−H).sup.−.

Example 148

(1R,1′R)-2,2′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(4R)-1,3-thiazolidine-4,3-diyl))bis(N,N-dimethyl-2-oxo-1-phenylethanamine)

(533) ##STR00715##

(534) To a stirred solution of (4,4′-bis(2-((S)-thiazolidin-4-yl)-1H-imidazol-5-yl)biphenyl tetrahydrochloride (0.028 g, 0.046 mmol), (R)-2-(dimethylamino)-2-phenylacetic acid (Cap-1, 0.017 g, 0.0.10 mmol), and HATU (0.039 g, 0.10 mmol) in 2 mL DMF was added diisopropylethylamine (0.05 mL, 0.28 mmol). The reaction was stirred at room temperature overnight (16 hours) and concentrated under reduced pressure. The crude product was purified by reverse-phase preparative HPLC to provide (2R,2′R)-1,1′-((4S,4′S)-4,4′-(5,5′-(biphenyl-4,4′-diyl)bis(1H-imidazole-5,2-diyl))bis(thiazolidine-4,3-diyl))bis(2-(dimethylamino)-2-phenylethanone), TFA salt (0.012 g, 21%)

(535) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 7.59-7.91 (20H, m) 5.62 (2H, dd, J=6.56, 2.59 Hz) 4.99 (2H, d, J=8.85 Hz) 4.82/4.35 (2H, s) 4.22 (2H, s) 3.42 (2H, s) 3.25 (2H, s) 2.35-2.61 (12H, m).

(536) LCMS—Luna C-18 3.0×50 mm, 0 to 100% B over 7.0 minute gradient, 1 minute hold time, A=5% acetonitrile, 95% water, 10 mm ammonium acetate, B=95% acetonitrile, 5% water, 10 mm ammonium acetate mobile phase t.sub.R=3.128 min.

(537) Nominal/LRMS—Calcd. for C.sub.44H.sub.46N.sub.8O.sub.2S.sub.2 783.03. found 783.28 (M+H).sup.+.

(538) Accurate/HRMS—Calcd. for C.sub.44H.sub.47N.sub.8O.sub.2S.sub.2 783.3263; 783.3246 (M+H).sup.+

(539) Examples 149 and 150 were prepared in similar fashion as described for the preparation of example 148.

(540) TABLE-US-00036 Example Compound Name Structure Data Example 149 dimethyl (4,4′- biphenyldiylbis (1H-imidazole- 5,2-diyl(4R)- 1,3-thiazolidine- 4,3-diyl((1R)-2- oxo-1-phenyl- 2,1-ethanediyl))) biscarbamate t.sub.R = 3.36 min (LCMS-Luna C- 18 3.0 × 50 mm, 0 to 100% B over 7.0 minute gradient, 1 minute hold time, A = 5% acetonitrile, 95% water, 10 mm ammonium acetate, B = 95% acetoni- trile, 5% water, 10 mm ammonium acetate) LRMS: Anal. Calcd. for C.sub.44H.sub.42N.sub.8O.sub.6S.sub.2 842.99 found: 843.25 (M + H).sup.+ Example 150 (4R,4′R)-4,4′-(4,4′- biphenyldiylbis (1H-imidazole-5,2- diyl))bis(3-((2R)- tetrahydro-2- furanylcarbonyl)- 1,3-thiazolidine) t.sub.R = 4.32 min (HPLC-X- Terra C-18 4.6 × 50 mm, 0 to 100% B over 10.0 minute gradient, 1 minute hold time, A = 10% methanol 90% water 0.1% TFA, B = 90% methanol 10% water 0.1% TFA) LRMS: Anal. Calcd. for C.sub.34H.sub.36N.sub.6O.sub.4S.sub.2 656.83 found: 657.32 (M + H).sup.+

Example 151

(1R,1′R)-2,2′-(4,4′-biphenyldiylbis((1-methyl-1H-imidazole-4,2-diyl)(2S)-2,1-pyrrolidinediyl))bis(N,N-dimethyl-2-oxo-1-phenylethanamine)

(541) ##STR00718##

Example 151

Step a

(542) ##STR00719##

(543) To a stirred solution of 1d, (2S,2′S)-tert-butyl 2,2′-(4,4′-(biphenyl-4,4′-diyl)bis(1H-imidazole-4,2-diyl))dipyrrolidine-1-carboxylate (100 mg, 0.16 mmole) and iodomethane (40 μL, 0.16 mmole) in CH.sub.2Cl.sub.2 (2 mL) was added sodium hydride (40%) (21.2 mg, 0.352 mmole). After five hours at ambient temperature, it was concentrated under reduced pressure. The crude reaction product 151a, (2S,2′S)-tert-butyl 2,2′-(4,4′-(biphenyl-4,4′-diyl)bis(1-methyl-1H-imidazole-4,2-diyl))dipyrrolidine-1-carboxylate (˜90 mg) was moved onto next step without further purification (purity ˜85%) LCMS: Anal. Calcd. for: C.sub.38H.sub.48N.sub.6O.sub.4 652.83. Found: 653.51 (M+H).sup.+. It should be recognized that multiple methylation isomers are possible in this reaction and no attempt to assign these was made.

Example 151

Step b

(544) ##STR00720##

(545) 151a, (2S,2′S)-tert-butyl 2,2′-(4,4′-(biphenyl-4,4′-diyl)bis(1-methyl-1H-imidazole-4,2-diyl))dipyrrolidine-1-carboxylate (100 mg, 0.153 mmole) treated with 4 M HCl/dioxane (20 mL). After three hours at ambient temperature, it was concentrated under reduced pressure. The crude reaction product, 4,4′-bis(1-methyl-2-((S)-pyrrolidin-2-yl)-1H-imidazol-4-yl)biphenyl(˜110 mg, HCl salt) was moved onto the next step without further purification (purity ˜85%) LCMS: Anal. Calcd. for: C.sub.28H.sub.32N.sub.6 452.59. Found: 453.38 (M+H).sup.+. Multiple imidazole isomers were present and carried forward.

Example 151

(546) HATU (58.9 mg, 0.150 mmol) was added to a mixture of 151b, 4,4′-bis(1-methyl-2-((S)-pyrrolidin-2-yl)-1H-imidazol-4-yl)biphenyl (45.0 mg, 0.075 mmol), (i-Pr).sub.2EtN (78 μL, 0.451 mmol) and Cap-1, (R)-2-(dimethylamino)-2-phenylacetic acid (0.026 mg 0.150 mmol) in DMF (1.0 mL). The resultant mixture was stirred at ambient temperature until the coupling was complete as determined by LC/MS analysis. Purification was accomplished by reverse-phase preparative HPLC (Waters-Sunfire 30×100 mm S5, detection at 220 nm, flow rate 30 mL/min, 0 to 90% B over 14 min; A=90% water, 10% ACN, 0.1% TFA, B=10% water, 90% ACN, 0.1% TFA) to provide two isomer of 151, (2R,2′R)-1,1′-((2S,2′S)-2,2′-(4,4′-(biphenyl-4,4′-diyl)bis(1-methyl-1H-imidazole-4,2-diyl))bis(pyrrolidine-2,1-diyl))bis(2-(dimethylamino)-2-phenylethanone), TFA salts.

Isomer 1: (1R,1′R)-2,2′-(4,4′-biphenyldiylbis((1-methyl-1H-imidazole-4,2-diyl)(2S)-2,1-pyrrolidinediyl))bis(N,N-dimethyl-2-oxo-1-phenylethanamine)

(547) (8 mg, 8.6%) as a colorless wax.

(548) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.84-2.25 (m, 8H) 2.32-2.90 (m, 12H) 3.67-3.92 (m, 8H) 4.07 (s, 2H) 5.23 (s, 2H) 5.51 (s, 2H) 7.51-7.91 (m, 20H)

(549) HPLC Xterra 4.6×50 mm, 0 to 100% B over 10 minutes, one minutes hold time, A=90% water, 10% methanol, 0.2% phosphoric acid, B=10% water, 90% methanol, 0.2% phosphoric acid, RT=2.74 min, 98%.

(550) LCMS: Anal. Calcd. for: C.sub.48H.sub.54N.sub.8O.sub.2 775.02. Found: 775.50 (M+H).sup.+.

Isomer 2: (1R,1′R)-2,2′-(4,4′-biphenyldiylbis((1-methyl-1H-imidazole-4,2-diyl)(2S)-2,1-pyrrolidinediyl))bis(N,N-dimethyl-2-oxo-1-phenylethanamine)

(551) (10.2 mg, 11%) as a colorless wax.

(552) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.83-2.26 (m, 8H) 2.30-2.92 (m, 12H) 3.68-3.94 (m, 8H) 4.06 (s, 2H) 5.25 (d, J=2.14 Hz, 2H) 5.50 (s, 2H) 7.52-7.91 (m, 20H).

(553) HPLC Xterra 4.6×50 mm, 0 to 100% B over 10 minutes, one minutes hold time, A=90% water, 10% methanol, 0.2% phosphoric acid, B=10% water, 90% methanol, 0.2% phosphoric acid, RT=2.75 min, 90%.

(554) LCMS: Anal. Calcd. for: C.sub.48H.sub.54N.sub.8O.sub.2 775.02. Found: 775.52 (M+H).sup.+.

Example 152

(555) ##STR00721##

Example 152a-1

Step a

2-Chloro-5-(1-ethoxyvinyl)pyrimidine

(556) ##STR00722##

(557) To a solution of 5-bromo-2-chloropyrimidine (12.5 g, 64.62 mmol) in dry DMF (175 mL) under N.sub.2 was added tributyl(1-ethoxyvinyl)tin (21.8 mL, 64.62 mmol) and dichlorobis(triphenylphosphine)palladium (II) (2.27 g, 3.23 mmol). The mixture was heated at 100° C. for 3 h before being allowed to stir at room temperature for 16 hr. The mixture was then diluted with ether (200 mL) and treated with aqueous KF soln (55 g of potassium fluoride in 33 mL of water). The two phase mixture was stirred vigorously for 1 h at room temperature before being filtered through diatomaceous earth (Celite®). The filtrate was washed with sat'd NaHCO.sub.3 soln and brine prior to drying (Na.sub.2SO.sub.4). The original aqueous phase was extracted with ether (2×) and the organic phase was treated as above. Repetition on 13.5 g of 5-bromo-2-chloropyrimidine and combined purification by Biotage™ flash chromatography on silica gel (gradient elution on a 65M column using 3% ethyl acetate in hexanes to 25% ethyl acetate in hexanes with 3.0 L) afforded the title compound as a white, crystalline solid (18.2 g, 73%).

(558) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.97 (s, 2H), 5.08 (d, J=3.7 Hz, 1H), 4.56 (d, J=3.4 Hz, 1H), 3.94 (q, J=7.0 Hz, 2H), 1.35 (t, J=7.0 Hz, 3H).

(559) LCMS Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, RT=2.53 min, 98.8% homogeneity index.

(560) LCMS: Anal. Calcd. for C.sub.8H.sub.10C.sub.1N.sub.20 185.05. found: 185.04 (M+H).sup.+.

(561) HRMS: Anal. Calcd. for C.sub.8H.sub.10C.sub.1N.sub.20 185.0482. found: 185.0490 (M+H).sup.+.

(562) The same method was used for the preparation of Examples 152a-2 & 152a-3:

(563) LC Conditions:

(564) Condition 1: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

(565) Condition 2: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

(566) TABLE-US-00037 Example 152a-2 t.sub.R = 2.24 min 96.4%, condition 1 LRMS: Anal. Calcd. for C.sub.8H.sub.10ClN.sub.2O 185.05; found: 185.06 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.8H.sub.10ClN.sub.2O 185.0482; found: 185.0476 (M + H).sup.+. Example 152a-3 t.sub.R = 2.82 min (52.7%, inseparable with 2,5- dibrompyrazine (t.sub.R = 1.99 min, 43.2%)); condition 1 LRMS: Anal. Calcd. for C.sub.8H.sub.10BrN.sub.2O 229.00; found: 228.93 (M + H).sup.+.

Example 152d-1 to 152d-6

Example 152b-1

Step b

(S)-tert-Butyl 2-(5-(2-chloropyrimidin-5-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate or (S)-2-[5-(2-Chloro-pyrimidin-5-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester

(567) ##STR00725##

(568) NBS (16.1 g, 90.7 mmol) was added in one portion to a stirred solution of 2-chloro-5-(1-ethoxyvinyl)pyrimidine (152a-1, 18.2 g, 98.6 mmol) in THF (267 mL) and H.sub.2O (88 mL) at 0° C. under N.sub.2. The mixture was stirred for 1 h at 0° C. before it was diluted with more H.sub.2O and extracted with ethyl acetate (2×). The combined extracts were washed with sat'd NaHCO.sub.3 soln and brine prior to drying (Na.sub.2SO.sub.4), filtration, and solvent evaporation. LCMS Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, RT=1.52 min (unsymmetrical peak).

(569) LCMS: Anal. Calcd. for C.sub.6H.sub.14BrClN.sub.2O 235.92. found: 236.85 (M+H).sup.+.

Example 152c-1

Step c

(570) Half of the crude residue (2-bromo-1-(2-chloropyrimidin-5-yl)ethanone, ˜14.5 g) was dissolved into anhydrous acetonitrile (150 mL) and treated directly with N-Boc-L-proline (9.76 g, 45.35 mmol) and diisopropylethylamine (7.9 mL, 45.35 mmol). After being stirred for 3 h, the solvent was removed in vacuo and the residue was partitioned into ethyl acetate and water. The organic phase was washed with 0.1N hydrochloric acid, sat'd NaHCO.sub.3 soln and brine prior to drying (Na.sub.2SO.sub.4), filtration, and concentration. LCMS Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, RT=2.66 min.

(571) The same method was used to prepare Examples 152c through 152c-6.

(572) LC Conditions:

(573) Condition 1: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

(574) Condition 2: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

(575) TABLE-US-00038 Example 152c-2 t.sub.R = 1.81 min (condition 2, ~95 %) LRMS: Anal. Calcd. for C.sub.15H.sub.19BrN.sub.4O.sub.2 386.05 found: 387.07 (M + H).sup.+. Example 152c-3 t.sub.R = 1.84 min (condition 2, 94%) LRMS: Anal. Calcd. for C.sub.15H.sub.19BrN.sub.2O.sub.5 386.05; found: 387.07 (M + H).sup.+. Example 152c-3a t.sub.R = 2.65 min; condition 1 LCMS: Anal. Calcd. for C.sub.16H.sub.20ClN.sub.3O.sub.5 369.11 found: 391.89 (M + Na).sup.+. Example 152c-4 t.sub.R = 1.94 min, (condition 2) LCMS: Anal. Calcd. for C.sub.16H.sub.21BrN.sub.3O.sub.5 414.07 found: 414.11 (M + H).sup.+. Example 152c-5 0 t.sub.R = 2.22 min; condition 1 LCMS: Anal. Calcd. for C.sub.14H.sub.18ClN.sub.3O.sub.5 343.09 found: undetermined. Example 152c-6 t.sub.R = 2.41 min, condition 1 LCMS: Anal. Calcd. for C.sub.14H.sub.18.sup.37BrN.sub.3O.sub.5 389.04 found: 412.03 (M + Na).sup.+.

Example 152d-1

Step d

(576) This residue ((S)-1-tert-butyl 2-(2-(2-chloropyrimidin-5-yl)-2-oxoethyl) pyrrolidine-1,2-dicarboxylate) was taken up in xylenes (200 mL) and treated to NH.sub.4OAc (17.5 g, 0.23 mol). The mixture was heated at 140° C. for 2 hr in a thick-walled, screw-top flask before it was cooled to ambient temperature and suction-filtered. The filtrate was then concentrated, partitioned into ethyl acetate and sat'd NaHCO.sub.3 soln and washed with brine prior to drying (Na.sub.2SO.sub.4), filtration, and concentration. The original precipitate was partitioned into aqueous NaHCO.sub.3 soln and ethyl acetate and sonicated for 2 min before being suction-filtered. The filtrate was washed with brine, dried over (Na.sub.2SO.sub.4), filtered, and concentrated to dryness. Purification of the combined residues by Biotage™ flash chromatography on silica gel (65M column, preequilibration with 2% B for 900 mL followed by gradient elution with 2% B to 2% B for 450 ml followed by 2% B to 40% B for 3000 mL where B=methanol and A=dichloromethane) afforded the title compound (7.0 g, 44% yield, 2 steps, pure fraction) as an yellowish orange foam. The mixed fractions were subjected to a second Biotage™ chromatography on silica gel (40M column, preequilibration with 1% B for 600 mL followed by gradient elution with 1% B to 1% B for 150 ml followed by 1% B to 10% B for 1500 mL where B=MeOH and A=CH.sub.2Cl.sub.2) afforded additional title compound (2.8 g, 18%) as a brownish-orange foam. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 12.24-12.16 (m, 1H), 9.05 (s, 2H), 7.84-7.73 (m, 1H), 4.90-4.73 (m, 1H), 3.59-3.46 (m, 1H), 3.41-3.31 (m, 1H), 2.32-2.12 (m, 1H), 2.03-1.77 (m, 3H), 1.39 and 1.15 (2s, 9H).

(577) LCMS Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, RT=1.92 min, 94.7% homogeneity index.

(578) LRMS: Anal. Calcd. for C.sub.16H.sub.21ClN.sub.5O.sub.2 350.14. found: 350.23 (M+H).sup.+.

(579) HRMS: Anal. Calcd. for C.sub.16H.sub.21ClN.sub.5O.sub.2 350.1384. found: 350.1398 (M+H).sup.+.

(580) The same method was used to prepare Examples 152d-2 through 152d-6.

(581) LC Conditions:

(582) Condition 1: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

(583) Condition 2: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

(584) TABLE-US-00039 Example 152d-2 t.sub.R = 1.92 min (86.5%); condition 1 LRMS: Anal. Calcd. for C.sub.16H.sub.21ClN.sub.5O.sub.2 350.14; found: 350.23 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.16H.sub.21ClN.sub.5O.sub.2 350.1384; found: 350.1393 (M + H).sup.+. Example 152d-3 t.sub.R = 1.90 min (>95%); condition 1 LRMS: Anal. Calcd. for C.sub.16H.sub.21BrN.sub.5O.sub.2 394.09; found: 393.82 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.16H.sub.21BrN.sub.5O.sub.2 394.0879; found: 394.0884 (M + H).sup.+. Example 152d-4 t.sub.R = 1.45 min (condition 2, 100%) LRMS: Anal. Calcd. for C.sub.15H.sub.19BrN.sub.4O.sub.2 366.07 found: 367.07 (M + H).sup.+. Example 152d-5 t.sub.R = 1.88 min (>95%); condition 1 LRMS: Anal. Calcd. for C.sub.14H.sub.18BrN.sub.5O.sub.2 367.06; found: 368.10 (M + H).sup.+. Example 152d-6 t.sub.R = 1.66 min (85%); condition 1 LRMS: Anal. Calcd. for C.sub.14H.sub.18ClN.sub.5O.sub.2 323.11; found: 324.15 (M + H).sup.+.

Example 152e-1

Step e

Example 152e-1

(S)-tert-Butyl 2-(5-(2-chloropyrimidin-5-yl)-1-((2-(trimethyl-silyl)ethoxy)methyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

(585) ##STR00737##

(586) Sodium hydride (60% dispersion in mineral oil, 0.23 g, 5.72 mmol) was added in one portion to a stirred solution of (S)-tert-butyl 2-(5-(2-chloropyrimidin-5-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (152d-1, 2.0 g, 5.72 mmol) in dry DMF (45 mL) at ambient temperature under N.sub.2. The mixture was stirred for 5 min. before SEM chloride (1.01 mL, 5.72 mmol) was added in approx. 0.1 mL increments. The mixture was stirred for 3 h before being quenched with sat'd NH.sub.4Cl soln and diluted with ethyl acetate. The organic phase was washed with sat'd NaHCO.sub.3 soln and brine, dried over (Na.sub.2SO.sub.4), filtered, and concentrated. The original aqueous phase was extracted twice more and the combined residue was purified by Biotage™ flash chromatography (40M column, 50 mL/min, preequilibration with 5% B for 750 mL, followed by step gradient elution with 5% B to 5% B for 150 mL, 5% B to 75% B for 1500 mL, then 75% B to 100% B for 750 mL where solvent B is ethyl acetate and solvent A is hexanes). Concentration of the eluant furnished the title compound as a pale yellow foam (2.35 g, 85%).

(587) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 9.04 (s, 2H), 7.98-7.95 (m, 1H), 5.70-5.31 (3m, 2H), 5.02-4.91 (m, 1H), 3.59-3.49 (m, 3H), 3.45-3.35 (m, 1H), 2.30-2.08 (m, 2H), 1.99-1.83 (m, 2H), 1.36 and 1.12 (2s, 9H), 0.93-0.82 (m, 2H), −0.02 (s, 9H).

(588) LCMS Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 2 minutes, 2 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, RT=2.38 min, 95% homogeneity index.

(589) LRMS: Anal. Calcd. for C.sub.22H.sub.35C.sub.1N.sub.5O.sub.3S.sub.i 480.22. found: 480.23 (M+H).sup.+.

(590) HRMS: Anal. Calcd. for C.sub.22H.sub.35C.sub.1N.sub.5O.sub.3S.sub.i 480.2198. found: 480.2194 (M+H).sup.+.

(591) The same method was used to prepare 152e-2 through 152e-4

(592) LC Conditions:

(593) Condition 1: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

(594) Condition 2: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

(595) TABLE-US-00040 Exam- ple 152e-2 t.sub.R = 2.34 min (85.7%); condition 1 LCMS: Anal. Calcd. for C.sub.22H.sub.35ClN.sub.5O.sub.3Si 480.22; found: 480.22 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.22H.sub.35ClN.sub.5O.sub.3Si 480.2198 found: 480.2198 (M + H).sup.+. Exam- ple 152e-3 t.sub.R = 3.18 min (>95%); condition 1 LCMS: Anal. Calcd. for C.sub.22H.sub.35.sup.37BrN.sub.5O.sub.3Si 526.17; found: 525.99 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.22H.sub.35.sup.37BrN.sub.5O.sub.3Si 526.1692; found: 526.1674 (M + H).sup.+. Exam- ple 152e-4 0 t.sub.R = 2.14 min (condition 2, 96%) LRMS: Anal. Calcd. For C.sub.21H.sub.33BrN.sub.4O.sub.3Si 496.15 found: 497.13 (M + H).sup.+.

Examples 152f-1 to 152f-2

Example 152f-1

(S)-1-(2-(5-(2-chloropyrimidin-5-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-(pyridin-3-yl)ethanone

(596) ##STR00741##

(597) Cold (0° C.) 4 NHCl in dioxanes (5 mL) was added via syringe to (S)-tert-butyl 2-(5-(2-chloropyrimidin-5-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (152d-1, 0.50 g, 1.43 mmol) in a 100 mL pear-shaped flask followed by MeOH (1.0 mL). The suspension was stirred at room temperature for 4 h before it was concentrated down to dryness and placed under high vacuum for 1 h. There was isolated intermediate (S)-2-chloro-5-(2-(pyrrolidin-2-yl)-1H-imidazol-5-yl)pyrimidine trihydrochloride as a pale yellow solid (with an orange tint) which was used without further purification.

(598) HATU (0.60 g, 1.57 mmol) was added in one portion to a stirred solution of intermediate (S)-2-chloro-5-(2-(pyrrolidin-2-yl)-1H-imidazol-5-yl)pyrimidine trihydrochloride (0.46 g, 1.43 mmol, theoretical amount), 2-(pyridin-3-yl)acetic acid (0.25 g, 1.43 mmol) and DIEA (1.0 mL, 5.72 mmol) in anhydrous DMF (10 mL) at ambient temperature. The mixture was stirred at room temperature for 2 h before the DMF was removed in vacuo. The residue was taken up in CH.sub.2Cl.sub.2 and subjected to Biotage™ flash chromatography on silica gel (40M column, preequilibration with 0% B for 600 mL followed by step gradient elution with 0% B to 0% B for 150 mL followed by 0% B to 15% B for 1500 mL followed by 15% B to 25% B for 999 mL where B=MeOH and A=CH.sub.2Cl.sub.2). There was isolated the title compound (0.131 g, 25%, 2 steps) as a yellow solid.

(599) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 9.10-9.08 (2s, 2H), 8.72-8.55 (series of m, 2H), 8.21-8.20 and 8.11-8.10 (2m, 1H), 8.00 and 7.93 (2s, 1H), 7.84-7.77 (series of m, 1H), 5.43-5.41 and 5.17-5.15 (2m, 1H), 4.02-3.94 (3m, 2H), 3.90-3.58 (3m, 2H), 2.37-2.26 (m, 1H), 2.16-1.85 (2m, 3H).

(600) LCRMS Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, RT=0.92 min, 95.1% homogeneity index.

(601) LRMS: Anal. Calcd. for C.sub.18H.sub.18C.sub.1N.sub.6O 369.12. found: 369.11 (M+H).sup.+.

(602) HRMS: Anal. Calcd. for C.sub.18H.sub.18ClN.sub.6O 369.1231. found: 369.1246 (M+H).sup.+.

(603) Example 152f-2 LCMS conditions: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

(604) TABLE-US-00041 Example 152f-2 t.sub.R = 1.56 min (>95%) LRMS: Anal. Calcd. for C.sub.20H.sub.20BrN.sub.4O 413.08; found: 412.99 (M + H).sup.+.

Examples 152g-1 to 152g-16

Example 152g-1 from 1c and 152e-1. (S)-2-[5-(2-{4-[2-((S)-1-tert-Butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-phenyl}-pyrimidin-5-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester

(605) ##STR00743##

(606) Pd (Ph.sub.3).sub.4 (0.12 g, 0.103 mmol) was added in one portion to a stirred suspension of (S)-tert-butyl 2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (1c, 1.00 g, 2.27 mmol), (S)-tert-butyl 2-(5-(2-chloropyrimidin-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (152c-1, 0.99 g, 2.06 mmol) and NaHCO.sub.3 (0.87 g, 10.3 mmol) in a solution of DME (20 mL) and H.sub.2O (6 mL) at room temperature under N.sub.2. The vessel was sealed and the mixture was placed into a preheated (80° C.) oil bath and stirred at 80° C. for 16 h before additional catalyst (0.12 g) was added. After heating the mixture for an additional 12 h at 80° C., the mixture was cooled to ambient temperature, diluted with ethyl acetate and washed with sat'd NaHCO.sub.3 soln and brine prior to drying over anhydrous sodium sulfate and solvent concentration. Purification of the residue by Biotage™ flash chromatography on silica gel using a 40M column (preequilibrated with 40% B followed by step gradient elution with 40% B to 40% B for 150 mL, 40% B to 100% B for 1500 mL, 100% B to 100% B for 1000 mL where B=ethyl acetate and A=hexanes) furnished the title compound as a yellow foam (1.533 g, 98%). A small amount of the yellow foam was further purified for characterization purposes by pHPLC (Phenomenex GEMINI, 30×100 mm, S10, 10 to 100% B over 13 minutes, 3 minute hold time, 40 mL/min, A=95% water, 5% acetonitrile, 10 mM NH.sub.4OAc, B=10% water, 90% acetonitrile, 10 mM NH.sub.4OAc) to yield 95% pure title compound as a white solid.

(607) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 12.30-11.88 (3m, 1H), 9.17-9.16 (m, 2H), 8.43-8.31 (m, 2H), 7.99-7.35 (series of m, 4H), 5.72-5.30 (3m, 2H), 5.03-4.76 (2m, 2H), 3.64-3.50 (m, 4H), 3.48-3.31 (m, 2H), 2.36-2.07 (m, 2H), 2.05-1.80 (m, 4H), 1.46-1.08 (2m, 18H), 0.95-0.84 (m, 2H), −0.01 (s, 9H).

(608) HPLC Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, RT=2.91 min, 95% homogeneity index.

(609) LRMS: Anal. Calcd. for C.sub.40H.sub.57N.sub.8O.sub.5Si 757.42. found: 757.42 (M+H).sup.+.

(610) HRMS: Anal. Calcd. for C.sub.40H.sub.57N.sub.8O.sub.5Si 757.4221. found: 757.4191 (M+H).sup.+.

(611) The same procedure was used to prepare Examples 152g-2 through 152g-17:

(612) LC Conditions:

(613) Condition 1: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

(614) Condition 2: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

(615) TABLE-US-00042 Example 152g-2 t.sub.R = 2.81 min (79%); Condition 1 LRMS: Anal. Calcd. for C.sub.40H.sub.57N.sub.8O.sub.5Si 757.42; found: 758.05 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.40H.sub.57N.sub.8O.sub.5Si 757.4221; found: 757.4196 (M + H).sup.+. Example 152g-3 t.sub.R = 2.89 min (>95%); Condition 1 LRMS: Anal. Calcd. for C.sub.40H.sub.57N.sub.8O.sub.5Si 757.42; found: 757.35 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.40H.sub.57N.sub.8O.sub.5Si 757.4221; found: 757.4191 (M + H).sup.+. Example 152g-4 t.sub.R = 2.87 min (97%); Condition 1 LRMS: Anal. Calcd. for C.sub.38H.sub.55N.sub.8O.sub.5Si 731.41; found: 731.26 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.38H.sub.55N.sub.8O.sub.5Si 731.4065; found: 731.4070 (M + H).sup.+. Example 152g-5 t.sub.R = 2.94 min (>95%); Condition 1 LRMS: Anal. Calcd. for C.sub.38H.sub.55N.sub.8O.sub.5Si 731.41; found: 731.26 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.38H.sub.55N.sub.8O.sub.5Si 731.4065; found: 731.4046 (M + H).sup.+. Example 152g-6 t.sub.R = 1.99 min (condition 2, 96%) LRMS: Anal. Calcd. for C.sub.37H.sub.53N.sub.7O.sub.2Si 703.39; found: 704.34 (M + H).sup.+. Example 152g-7 t.sub.R = 1.99 min (condition 2, 96%) LRMS: Anal. Calcd. for C.sub.39H.sub.55N.sub.7O.sub.5Si 729.40 found: 730.42 (M + H).sup.+. Example 152g-8 0 t.sub.R = 2.15 min (>95%); Condition 1 LRMS: Anal. Calcd. for C.sub.37H.sub.41N.sub.8O.sub.4 661.33; found: 661.39 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.37H.sub.41N.sub.8O.sub.4 661.3251; found: 661.3268 (M + H).sup.+. Example 152g-9 t.sub.R = 1.71 min (>95%); Condition 1 LRMS: Anal. Calcd. for C.sub.36H.sub.40N.sub.9O.sub.3 646.76; found: 646.47 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.36H.sub.40N.sub.9O.sub.3 not done found: not done (M + H).sup.+. Example 152g-10 t.sub.R = 1.71 min (>95%); Condition 1 LRMS: Anal. Calcd. for C.sub.36H.sub.40N.sub.9O.sub.3 646.33; found: 646.37 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.36H.sub.40N.sub.9O.sub.3 646.3254; found: 646.3240 (M + H).sup.+. Example 152g-11 t.sub.R = 2.12 min (>93.9%); Condition 1 LRMS: Anal. Calcd. for C.sub.33H.sub.42N.sub.7O.sub.4 600.33; found: 600.11 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.33H.sub.42N.sub.7O.sub.4 600.3298; found: 600.3312 (M + H).sup.+. Example 152g-12 t.sub.R = 2.13 min (97.3%); Condition 1 LRMS: Anal. Calcd. for C.sub.32H.sub.41N.sub.8O.sub.4 601.33; found: 601.36 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.32H.sub.41N.sub.8O.sub.4 601.3251; found: 601.3253 (M + H).sup.+. Example 152g-13 t.sub.R = 2.11 min (98.5%); Condition 1 LRMS: Anal. Calcd. for C.sub.32H.sub.41N.sub.8O.sub.4 601.33; found: 601.36 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.32H.sub.41N.sub.8O.sub.4 601.3251; found: 601.3253 (M + H).sup.+. Example 152g-14 t.sub.R = 2.18 min (>95%); Condition 1 LRMS: Anal. Calcd. for C.sub.33H.sub.43N.sub.8O.sub.4 615.34; found: 615.38 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.33H.sub.43N.sub.8O.sub.4 615.3407; found: 615.3433 (M + H).sup.+. Example 152g-15 t.sub.R = 2.20 min (97.7%); Condition 1 LRMS: Anal. Calcd. for C.sub.35H.sub.39N.sub.8O.sub.4 635.31; found: 635.36 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.35H.sub.39N.sub.8O.sub.4 635.3094; found 635.3119 (M + H).sup.+. Example 152g-16 t.sub.R = 2.26 min (>95%); Condition 1 LRMS: Anal. Calcd C.sub.36H.sub.41N.sub.8O.sub.4 649.33; found: 649.39 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.36H.sub.41N.sub.8O.sub.4 649.3251; found: 649.3276 (M + H).sup.+. Example 152g-17 t.sub.R = 2.98 min (98.5%); Condition 1 LRMS: Anal. Calcd. for C.sub.38H.sub.54N.sub.8O.sub.5Si 730.39; found: 731.40 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.38H.sub.54N.sub.8O.sub.5Si 731.4065; found: 731.4045 (M + H).sup.+.

Example 152h-1-152h-7

Example 152h-1 from 152g-1

5-((S)-2-Pyrrolidin-2-yl-3H-imidazol-4-yl)-2-[4-((S)-2-pyrrolidin-2-yl-3H-imidazol-4-yl)-phenyl]-pyrimidine

(616) ##STR00760##

(617) TFA (8 mL) was added in one portion to a stirred solution of (S)-2-[5-(2-{4-[2-((S)-1-tert-butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-phenyl}-pyrimidin-5-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (1.50 g, 1.98 mmol) in dry CH.sub.2Cl.sub.2 (30 mL) at room temperature. The flask was sealed and the mixture was stirred at room temperature for 16 h before the solvent(s) were removed in vacuo. The residue was taken up in methanol, filtered through a PVDF syringe filter (13 mm×0.45 μm), distributed to 8 pHPLC vials and chromatographed by HPLC (gradient elution from 10% B to 100% B over 13 min on a Phenomenex C18 column, 30×100 mm, 10 μm, where A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA). After concentration of the selected test tubes by speed vacuum evaporation, the product was dissolved in methanol and neutralized by passing the solution through an UCT CHQAX 110M75 anion exchange cartridge. There was isolated the title compound as a yellow mustard-colored solid (306.7 mg, 36% yield) upon concentration of the eluant.

(618) .sup.1H NMR (500 MHz, DMSO-d.sub.6) μ 12.50-11.80 (br m, 2H), 9.18 (s, 2H), 8.36 (d, J=8.5 Hz, 2H), 7.89 (d, J=8.2 Hz, 2H), 7.77 (s, 1H), 7.61 (s, 1H), 4.34-4.24 (m, 2H), 3.09-2.89 (m, 4H), 2.18-2.07 (m, 2H), 2.02-1.89 (m, 2H), 1.88-1.72 (m, 4H).

(619) LCMS Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, RT=1.33 min, >95% homogeneity index.

(620) LRMS: Anal. Calcd. for C.sub.24H.sub.27N.sub.8 427.24. found: 427.01 (M+H).sup.+.

(621) HRMS: Anal. Calcd. for C.sub.24H.sub.27N.sub.8 427.2359. found: 427.2363 (M+H).sup.+.

(622) The same conditions were used to prepare Examples 152h-2 through 152h-14.

(623) LC Conditions:

(624) Condition 1: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

(625) Condition 2: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

(626) TABLE-US-00043 Example 152h-2 t.sub.R = 1.36 min (98%); Condition 1 LRMS: Anal. Calcd. for C.sub.24H.sub.27N.sub.8 427.24; found: 427.48 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.24H.sub.27N.sub.8 427.2359; found: 427.2339 (M + H).sup.+. Example 152h-3 t.sub.R = 1.17 min (>95%); Condition 1 LRMS: Anal. Calcd. for C.sub.22H.sub.25N.sub.8 401.22; found: 401.16 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.22H.sub.25N.sub.8 401.2202; found: 401.2193 (M + H).sup.+. Example 152h-4 t.sub.R = 1.28 min (89.3%); Condition 1 LRMS: Anal. Calcd. for C.sub.22H.sub.25N.sub.8 401.22; found: 401.16 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.22H.sub.25N.sub.8 401.2202; found: 401.2201 (M + H).sup.+. Example 152h-5 t.sub.R = 0.93 min; Condition 2 LRMS: Anal. Calcd. for C.sub.23H.sub.25N.sub.7 399; found: 400 (M + H).sup.+. Example 152h-6 t.sub.R = 0.81 min; Condition 2 LRMS: Anal. Calcd. for C.sub.21H.sub.23N.sub.7 373; found: 374 (M + H).sup.+. Example 152h-7 t.sub.R = 1.14 min (>95%); Condition 1 LRMS: Anal. Calcd. for C.sub.23H.sub.26N.sub.7 400.23; found: 400.14 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.23H.sub.26N.sub.7 400.2250; found: 400.2234 (M + H).sup.+. Example 152h-8 t.sub.R = 1.29 min (>95%); Condition 1 LRMS: Anal. Calcd. for C.sub.22H.sub.25N.sub.8 401.22; found: 401.21 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.22H.sub.25N.sub.8 401.2202; found: 401.2204 (M + H).sup.+. Example 152h-9 t.sub.R = 1.29 min (97.6%); Condition 1 LRMS: Anal. Calcd. for C.sub.22H.sub.25N.sub.8 401.22; found: 401.21 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.22H.sub.25N.sub.8 401.2202; found: 401.2220 (M + H).sup.+. Example 152h-10 t.sub.R = 1.26 min (86.4%); Condition 1 LRMS: Anal. Calcd. for C.sub.24H.sub.27N.sub.8 427.24; found: 427.48 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.24H.sub.27N.sub.8 427.2359; found: 427.2339 (M + H).sup.+. Example 152h-11 0 t.sub.R = 1.26 min (>95%); Condition 1 LRMS: Anal. Calcd. for C.sub.31H.sub.32N.sub.9O 546.27; found: 546.28 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.31H.sub.32N.sub.9O 546.2730 found: 546.2739 (M + H).sup.+. Example 152h-12 t.sub.R = 1.39 min (95%); Condition 1 LRMS: Anal. Calcd. for C.sub.31H.sub.32N.sub.9O 546.27; found: 546.32 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.31H.sub.32N.sub.9O 546.2730; found: 546.2719 (M + H).sup.+. Example 152h-13 t.sub.R = 1.42 min; Condition 1 LRMS: Anal. Calcd. for C.sub.23H.sub.26N.sub.8 414.24; found: 415.27 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.23H.sub.26N.sub.8 415.2359; found: 415.2371 (M + H).sup.+. Example 152h-14 t.sub.R = 1.30 min; Condition 1 LRMS: Anal. Calcd. for C.sub.22H.sub.24N.sub.8 400.21; found: 401.24 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.22H.sub.24N.sub.8 401.2202; found: 401.2198 (M + H).sup.+.

Example 152i-1 to 152i-3

Example 152i-1 from 152g-8

(S)-2-(5-{2-[4-((S)-2-Pyrrolidin-2-yl-3H-imidazol-4-yl)-phenyl]-pyrimidin-5-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester

(627) ##STR00774##

(628) A solution of (S)-2-[5-(2-{4-[2-((S)-1-Benzyloxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-phenyl}-pyrimidin-5-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (317.1 mg, 0.48 mmol) in MeOH (1 mL) was added to a stirred suspension of 10% palladium on carbon (60 mg) and K.sub.2CO.sub.3 (70 mg) in a solution of MeOH (5 mL) and H.sub.2O (0.1 mL) at room temperature under N.sub.2. The flask was charged and evacuated three times with H.sub.2 and stirred for 3 h at atmosphere pressure. Additional catalyst (20 mg) was then added and the reaction mixture was stirred further for 3 h before it was suction-filtered through diatomaceous earth (Celite®) and concentrated. The residue was diluted with MeOH, filtered through a PVDF syringe filter (13 mm×0.45m), distributed into 4 pHPLC vials and chromatographed (gradient elution from 20% B to 100% B over 10 min on a Phenomenex-Gemini C18 column (30×100 mm, 10 μm) where A=95% water, 5% acetonitrile, 10 mM NH.sub.4OAc, B=10% water, 90% acetonitrile, 10 mM NH.sub.4OAc). After concentration of the selected test tubes by speed vacuum evaporation, there was isolated the title compound as a yellow solid (142.5 mg, 56% yield).

(629) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.35-12.09 (br m, 1H), 9.17 (s, 2H), 8.35 (d, J=8.3 Hz, 2H), 7.87 (d, J=8.3 Hz, 2H), 7.80-7.72 (m, 1H), 7.56 (s, 1H), 4.92-4.77 (m, 1H), 4.21-4.13 (m, 1H), 3.61-3.05 (2m, 4H), 3.02-2.80 (2m, 2H), 2.37-1.67 (series of m, 6H), 1.41 and 1.17 (2s, 9H).

(630) LCMS Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, RT=1.77 min, >95% homogeneity index.

(631) LRMS: Anal. Calcd. for C.sub.29H.sub.35N.sub.8O.sub.2 527.29. found: 527.34 (M+H).sup.+.

(632) HRMS: Anal. Calcd. for C.sub.29H.sub.35N.sub.8O.sub.2 527.2883. found: 527.2874 (M+H).sup.+.

(633) The same procedure was used to prepare Examples 152i-2 through 152i-3.

(634) LC Conditions:

(635) Condition 1: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

(636) Condition 2: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

(637) TABLE-US-00044 Example 152i-2 t.sub.R = 1.70 min (95.7%); Condition 1 LRMS: Anal. Calcd. for C.sub.27H.sub.33N.sub.8O.sub.2 501.27; found: 501.35 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.27H.sub.33N.sub.8O.sub.2 501.2726 found: 501.2709 (M + H).sup.+. Example 152i-3 t.sub.R = 1.77 min (>95%); Condition 1 LRMS: Anal. Calcd. for C.sub.28H.sub.35N.sub.8O.sub.2 515.29; found: 515.37 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.28H.sub.35N.sub.8O.sub.2 515.2883 found: 515.2869 (M + H).sup.+.

Examples 152j-1 to 152j-28

(638) Examples 152j were isolated as TFA or AcOH salts prepared using the procedure to convert Example 148e to 148.

(639) LC Conditions:

(640) Condition 1: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

(641) Condition 2: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

(642) TABLE-US-00045 Example Compound Name Structure Data Example 152j-1 (1R)-2-((2S)-2-(5-(2- (4-(2-((2S)-1-((2R)- 2-(dimethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5- yl)phenyl)-5- pyrimidinyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-N,N- dimethyl-2-oxo-1- phenylethanamine t.sub.R 1.61 min; (>95%); Condition 1 LRMS: Anal. Calcd. for C.sub.44H.sub.49N.sub.10O.sub.2 749.40 found: 749.32 (M + H).sup.+ HRMS: Anal. Calcd. for C.sub.44H.sub.49N.sub.10O.sub.2 749.4040 found: 749.4042 (M + H).sup.+ Example 152j-2 methyl ((1R)-2-((2S)- 2-(5-(2-(4-(2-((2S)-1- ((2R)-2- ((methoxycarbonyl) amino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5- yl)phenyl)-5- pyrimidinyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxo-1-phenylethyl) carbamate t.sub.R = 1.99 min (>95%); Condition 1 LRMS: Anal. Calcd. for C.sub.44H.sub.45N.sub.10O.sub.6 809.35 found: 809.17 (M + H).sup.+ HRMS: Anal. Calcd. for C.sub.44H.sub.45N.sub.10O.sub.6 809.3524 found: 809.3505 (M + H).sup.+ Example 152j-3 methyl ((1R)-2-oxo- 1-phenyl-2-((2S)-2- (5-(4-(5-(2-((2S)-1- (3-pyridinylacetyl)- 2-pyrrolidinyl)- 1H-imidazol-5-yl)-2- pyrimidinyl)phenyl)- 1H-imidazol-2-yl)-1- pyrrolidinyl)ethyl) carbamate t.sub.R = 1.65 min (92.3%); Condition 1 LRMS: Anal. Calcd. for C.sub.41H.sub.41N.sub.10O.sub.2 737.33 found: 737.49 (M + H).sup.+ HRMS: Anal. Calcd. for C.sub.41H.sub.41N.sub.10O.sub.4 737.3312 found: 737.3342 (M + H).sup.+ Example 152j-4 methyl ((1R)-2-oxo- 1-phenyl-2-((2S)-2- (5-(2-(4-(2-((2S)-1- (3-pyridinylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl) phenyl)-5- pyrimidinyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)ethyl) carbamate 0 t.sub.R = 1.64 min (>95%); Condition 1 LRMS: Anal. Calcd. for C.sub.41H.sub.41N.sub.10O.sub.4 737.33 found: 737.75 (M + H).sup.+ HRMS: Anal. Calcd. for C.sub.41H.sub.41N.sub.10O.sub.4 737.3312 found: 737.3284 (M + H).sup.+ Example 152j-5 5-(2-((2S)-1-((2R)-2- phenyl-2-(1- piperidinyl)acetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-2-(4- (2-((2S)-1-((2R)-2- phenyl-2-(1- piperidinyl)acetyl)- 2-pyrrolidinyl)-1H- imidazol-4-yl) phenyl)pyrimidine t.sub.R = 1.70 min (>95%); Condition 1 LRMS: Anal. Calcd. for C.sub.50H.sub.57N.sub.10O.sub.2 829.47 found: 829.39 (M + H).sup.+ HRMS: Anal. Calcd. for C.sub.50H.sub.57N.sub.10O.sub.2 829.4666 found: 829.4658 (M + H).sup.+ Example 152j-6 (2R)-N-methyl-2- phenyl-N-((1S)-1-(4- (4-(5-((2S)-1- ((2R)-2-phenyl-2-(1- piperidinyl)acetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-2- pyrimidinyl)phenyl)- 1H-imidazol-2- yl)ethyl)-2-(1- piperidinyl)acetamide t.sub.R = 1.66 min (>95%); Condition 1 LRMS: Anal. Calcd. for C.sub.49H.sub.57N.sub.10O.sub.2 817.47 found: 817.44 (M + H).sup.+ HRMS: Anal. Calcd. for C.sub.49H.sub.57N.sub.10O.sub.2 817.4666 found: 817.4673 (M + H).sup.+ Example 152j-7 (1R)-2-((2S)-2-(5-(5- (4-(2-((2S)-1-((2R)- 2-(dimethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl) phenyl)-2- pyrazinyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-N,N- dimethyl-2-oxo-1- phenylethanamine t.sub.R = 1.60 min (>95%); Condition 1 LRMS: Anal. Calcd. for C.sub.41H.sub.49N.sub.10O.sub.2 749.40 found: 749.31 (M + H).sup.+ HRMS: Anal. Calcd. for C.sub.44H.sub.49N.sub.10O.sub.2 749.4040 found: 749.4031 (M + H).sup.+ Example 152j-8 methyl ((1R)-2-((2S)- 2-(5-(5-(4-(2-((2S)-1- ((2R)-2-(methoxy- carbonyl)amino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl) phenyl)-2-pyrazinyl)- 1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo- 1-phenylethyl) carbamate t.sub.R = 2.01 min (>95%); Condition 1 LRMS: Anal. Calcd. for C.sub.44H.sub.45N.sub.10O.sub.6 809.35 found: 809.24 (M + H).sup.+ HRMS: Anal. Calcd. for C.sub.44H.sub.45N.sub.10O.sub.6 809.3523 found: 809.3493 (M + H).sup.+ Example 152j-9 (1R)-2-((2S)-2-(5-(6- (4-(2-((2S)-1-((2R)- 2-(dimethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl) phenyl)-3- pyridazinyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-N,N- dimethyl-2-oxo-1- phenylethanamine t.sub.R = 1.76 min (>95%); Condition 1 LRMS: Anal. Calcd. for C.sub.44H.sub.49N.sub.10O.sub.2 749.40 found: not obsd (M + H).sup.+ HRMS: Anal. Calcd. for C.sub.44H.sub.49N.sub.10O.sub.2 749.4040 found: 749.4056 (M + H).sup.+ Example 152j-10 methyl ((1R)-2-((2S)- 2-(5-(6-(4-(2-((2S)-1- ((2R)-2-((methoxy- carbonyl)amino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl) phenyl)-3- pyridazinyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2-oxo- 1-phenylethyl) carbamate t.sub.R = 2.17 min (>95%); Condition 1 LRMS: Anal. Calcd. for C.sub.44H.sub.45N.sub.10O.sub.6 809.35 found: 809.59 (M + H).sup.+ HRMS: Anal. Calcd. for C.sub.45H.sub.45N.sub.10O.sub.6 809.3524 found: 809.3499 (M + H).sup.+ Example 152j-11 (2R)-2-(dimethyl- amino)-N-((1S)-1- (5-(4-(5-(2-((2S)-1- ((2R)-2-(dimethyl- amino)-2-phenyl- acetyl)-2- pyrrolidinyl)- 1H-imidazol-5-yl)-2- pyridinyl)phenyl)- 1H-imidazol-2-yl) ethyl)-2- phenylacetamide t.sub.R = 1.56 min (>95%); Condition 1 LRMS: Anal. Calcd. for C.sub.43H.sub.48N.sub.9O.sub.2 722.39 found: 722.89 (M + H).sup.+ HRMS: Anal. Calcd. for C.sub.43H.sub.48N.sub.9O.sub.2 722.3931 found: 722.3930 (M + H).sup.+ Example 152j-12 methyl ((1R)-2-((2S)- 2-(5-(6-(4-(2-((1S)-1- (((2R)-2- ((methoxycarbonyl) amino)-2-phenyl- acetyl)amino)ethyl)- 1H-imidazol-5-yl) phenyl)-3-pyridinyl)- 1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo- 1-phenylethyl) carbamate t.sub.R = 1.95 min (>95%); Condition 1 LRMS: Anal. Calcd. for C.sub.43H.sub.44N.sub.9O.sub.6 782.34 found: 782.93 (M + H).sup.+ HRMS: Anal. Calcd. for C.sub.43H.sub.44N.sub.9O.sub.6 782.3415 found: 782.3398 (M + H).sup.+ Example 152j-13 (2R)-2-(dimethyl- amino)-N-((1S)-1-(5- (4-(6-(2-((2S)-1- ((2R)-2-(dimethyl- amino)-2-phenyl- acetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-3- pyridazinyl)phenyl)- 1H-imidazol-2-yl) ethyl)-2-phenyl- acetamide t.sub.R = 1.55 min (>95%); Condition 1 LRMS: Anal. Calcd. for C.sub.42H.sub.47N.sub.10O.sub.2 723.39 found: 723.88 (M + H).sup.+ HRMS: Anal. Calcd. for C.sub.42H.sub.47N.sub.10O.sub.2 723.3883 found: 723.3903 (M + H).sup.+ Example 152j-14 methyl ((1R)-2-((2S)- 2-(5-(6-(4-(2-((1S)-1- (((2R)-2-((methoxy- carbonyl)amino)-2- phenylacetyl)amino) ethyl)-1H-imidazol- 5-yl)phenyl)-3- pyridazinyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2-oxo- 1-phenylethyl) carbamate 0 t.sub.R = 1.95 min (>95%); Conditon 1 LRMS: Anal. Calcd. for C.sub.42H.sub.43N.sub.10O.sub.6 783.34 found: 783.95 (M + H).sup.+ HRMS: Anal. Calcd. for C.sub.42H.sub.43N.sub.10O.sub.6 783.3367 found: 783.3337 (M + H).sup.+ Example 152j-15 methyl ((1R)-2-((2S)- 2-(5-(2-(4-((1S)-1- (((2R)-2-((methoxy- carbonyl)amino)-2- phenylacetyl)amino) ethyl)-1H-imidazol-5- yl)phenyl)-5- pyrimidinyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2-oxo- 1-phenylethyl) carbamate t.sub.R = 1.97 min (>95%); Condition 1 LRMS: Anal. Calcd. for C.sub.42H.sub.43N.sub.10O.sub.6 783.34 found: 783.97 (M + H).sup.+ HRMS: Anal. Calcd. for C.sub.42H.sub.43N.sub.10O.sub.6 783.3367 found: 783.3357 (M + H).sup.+ Example 152j-16 (2R)-2-(dimethyl- amino)-N-((1S)-1-(5- (2-(4-(2-((2S)-1- ((2R)-2-(dimethyl- amino)-2-phenyl- acetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl) phenyl)-5- pyrimidinyl)-1H- imidazol-2-yl)ethyl)- 2-phenylacetamide t.sub.R = 1.61 min (>95%); Condition 1 LRMS: Anal. Calcd. for C.sub.42H.sub.47N.sub.10O.sub.2 723.39 found: 723.52 (M + H).sup.+ HRMS: Anal. Calcd. for C.sub.42H.sub.47N.sub.10O.sub.2 723.3883 found: 723.3893 (M + H).sup.+ Example 152j-17 methyl ((1R)-2-((2S)- 2-(5-(4-(5-(2-((1S)-1- (((2R)-2-((methoxy- carbonyl)amino)-2- phenylacetyl)amino) ethyl)-1H-imidazol- 5-yl)-2-pyrimidinyl) phenyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)- 2-oxo-1-phenylethyl) carbamate t.sub.R = 1.99 min (95.6%); Condition 1 LRMS: Anal. Calcd. for C.sub.42H.sub.43N.sub.10O.sub.6 783.34 found: 783.44 (M + H).sup.+ HRMS: Anal. Calcd. for C.sub.42H.sub.43N.sub.10O.sub.6 783.3367 found: 783.3328 (M + H).sup.+ Example 152j-18 (2R)-2-(dimethyl- amino)-N-((1S)-1-(5- (5-(4-(2-((2S)-1-((2R)- 2-(dimethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)phenyl)- 2-pyrazinyl)-1H- imidazol-2-yl)ethyl)- 2-phenylacetamide t.sub.R = 1.60 min (>95%); Condition 1 LRMS: Anal. Calcd. for C.sub.42H.sub.47N.sub.10O.sub.2 723.39 found: 723.47 (M + H).sup.+ HRMS: Anal. Calcd. for C.sub.42H.sub.47N.sub.10O.sub.2 723.3883 found: 723.3861 (M + H).sup.+ Example 152j-19 methyl ((1R)-2-((2S)- 2-(5-(4-(5-(2-((1S)-1- (((2R)-2-((methoxy- carbonyl)amino)-2- phenylacetyl)amino) ethyl)-1H-imidazol-5- yl)-2-pyrazinyl) phenyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)- 2-oxo-1-phenylethyl) carbamate t.sub.R = 1.97 min (94.7%); Condition 1 LRMS: Anal. Calcd. for C.sub.42H.sub.43N.sub.10O.sub.6 783.34 found: 783.69 (M + H).sup.+ HRMS: Anal. Calcd. for C.sub.42H.sub.43N.sub.10O.sub.6 783.3367 found: 783.3345 (M + H).sup.+ Example 152j-20 (2R)-2-(dimethyl- amino)-N-((1S)-1-(5- (4-(5-(2-((2S)-1-((2R)- 2-(dimethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-2- pyrimidinyl)phenyl)- 1H-imidazol-2- yl)ethyl)-N-methyl-2- phenylacetamide t.sub.R = 1.54 min (>95%); Condition 1 LRMS: Anal. Calcd. for C.sub.43H.sub.49N.sub.10O.sub.2 737.40 found: 737.54 (M + H).sup.+ HRMS: Anal. Calcd. for C.sub.43H.sub.49N.sub.10O.sub.2 737.4040 found: 7374066 (M + H).sup.+ Example 152j-21 methyl ((1R)-2-((2S)- 2-(5-(2-(4-(2-((1S)-1- (((2R)-2-((methoxy- carbonyl)amino)-2- phenylacetyl)(methyl) amino)ethyl)-1H- imidazol-5-yl)phenyl)- 5-pyrimidinyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate t.sub.R = 2.00 min (>95%); Condition 1 LRMS: Anal. Calcd. for C.sub.43H.sub.45N.sub.10O.sub.6 797.35 found: 797.38 (M + H).sup.+ HRMS: Anal. Calcd. for C.sub.43H.sub.45N.sub.10O.sub.6 797.3524 found: 797.3528 (M + H).sup.+ Example 152j-22 methyl ((1R)-2-((2S)- 2-(5-(4-(5-(2-((1S)-1- (((2R)-2-((methoxy- carbonyl)amino)-2- phenylacetyl)amino) ethyl)-1H-imidazol-5- yl)-2-pyridinyl) phenyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)- 2-oxo-1-phenylethyl) carbamate t.sub.R = 1.46 min (condition 2, 98%) LRMS: Anal. Calcd. for C.sub.43H.sub.43N.sub.9O.sub.6 781.33; found: 782.34 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.43H.sub.44N.sub.9O.sub.6 782.3415 found: 782.3417 (M + H).sup.+ Example 152j-23 methyl ((1R)-2- (((1S)-1-(5-(6-(4-(2- ((1S)-1-(((2R)-2- ((methoxycarbonyl) amino)-2- phenylacetyl)amino) ethyl)-1H-imidazol-5- yl)phenyl)-3- pyridinyl)-1H- imidazol-2-yl)ethyl) amino)-2-oxo-1- phenylethyl) carbamate t.sub.R = 1.44 min condition 2, 90%) LRMS: Anal. Calcd. for C.sub.41H.sub.41N.sub.9O.sub.6 755.32; found: 756.35 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.41H.sub.42N.sub.9O.sub.6 756.3258 found: 756.3239 (M + H).sup.+. Example 152j-24 (2R)-2- (dimethylamino)-N- ((1S)-1-(5-(6-(4-(2- ((1S)-1-(((2R)-2- (dimethylamino)-2- phenylacetyl)amino) ethyl)-1H-imidazol-5- yl)phenyl)-3- pyridinyl)-1H- imidazol-2-yl)ethyl)- 2-phenylacetamide 00 t.sub.R = 1.18 min (condition 2, 91%) LRMS: Anal. Calcd. for C.sub.41H.sub.45N.sub.9O.sub.2 695.37; found: 696.37 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.41H.sub.46N.sub.9O.sub.2 696.3774 found: 696.3806 (M + H).sup.+. Example 152j-25 01 t.sub.R = 2.08 min (95.8%); Condition 1 LRMS: Anal. Calcd. for C.sub.38H.sub.44N.sub.9O.sub.5 706.35; found: 706.53 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.38H.sub.44N.sub.9O.sub.5 706.3465; found: 706.3492 (M + H).sup.+. Example 152j-26 02 t.sub.R = 2.04 min (96.4%); Condition 1 LRMS: Anal. Calcd. for C.sub.37H.sub.42N.sub.9O.sub.5 692.33; found: 692.49 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.37H.sub.42N.sub.9O.sub.5 692.3309; found: 692.3322 (M + H).sup.+. Example 152j-27 03 t.sub.R = 2.04 min (>95%); Condition 1 LRMS: Anal. Calcd. for C.sub.39H.sub.44N.sub.9O.sub.5 718.35; found: 718.49 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.39H.sub.44N.sub.9O.sub.5 718.3465; found: 718.3483 (M + H).sup.+. Example 152j-28 methyl ((1R)-2-((2S)- 2-(5-(5-(4-(2-((1S)-1- (((2R)-2-((methoxy- carbonyl)amino)-2- phenylacetyl)amino) ethyl)-1H-imidazol-5- yl)phenyl)-2- pyrazinyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate 04 t.sub.R = 2.00 min (>95%); Condition 1 LRMS: Anal. Calcd. for C.sub.42H.sub.43N.sub.10O.sub.6 783.34 found: 783.96 (M + H).sup.+ HRMS: Anal. Calcd. for C.sub.42H.sub.43N.sub.10O.sub.6 783.3367 found: 783.3375 (M + H).sup.+

Examples 152k-1 to 152k-

Example 152k-1 from 152j-27

{(R)-2-Oxo-1-phenyl-2-[(S)-2-(5-{4-[5-((S)-2-pyrrolidin-2-yl-3H-imidazol-4-yl)-pyrimidin-2-yl]-phenyl}-1H-imidazol-2-yl)-pyrrolidin-1-yl]-ethyl}-carbamic acid methyl ester

(643) ##STR00805##

(644) Cold (0° C.) 4 N HCl in dioxanes (4 mL) was added via syringe to (S)-2-{5-[2-(4-{2-[(S)-1-((R)-2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-pyrimidin-5-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (104.6 mg, 0.146 mmol) in a 100 mL pear-shaped flask followed by MeOH (0.5 mL). The homogeneous mixture was stirred at room temperature for 15 min before a precipitate was observed. After stirring further for 1.75 h, the suspension was diluted with ether and hexanes. Suction-filtration of a small portion of the suspension yielded the title compound as a yellow solid which was used for characterization purposes. The balance of the suspension was concentrated down to dryness and placed under high vacuum for 16 h. There was isolated the rest of the title compound also as a yellow solid (137.7 mg, 123%) which was used without further purification.

(645) .sup.1HNMR (500 MHz, DMSO-d.sub.6) δ 15.20 and 14.66 (2m, 1H), 10.29 (br s, 0.7H), 9.38-9.36 (m, 2H), 8.55-8.00 (series of m, 4H), 7.42-7.28 (2m, 3H), 5.53-4.00 (series of m, 7H), 3.99-3.13 (series of m, 4H), 3.57 and 3.52 (2s, 3H), 2.50-1.84 (series of m, 8H).

(646) LCMS Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, RT=1.79 min, >95% homogeneity index.

(647) LRMS: Anal. Calcd. for C.sub.34H.sub.36N.sub.9O.sub.3 618.29. found: 618.42 (M+H).sup.+.

(648) HRMS: Anal. Calcd. for C.sub.34H.sub.36N.sub.9O.sub.3 618.2921. found: 618.2958 (M+H).sup.+.

(649) The same procedure was used to prepare Examples 152k-2 through 152k-3.

(650) LC Conditions:

(651) Condition 1: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

(652) Condition 2: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

(653) TABLE-US-00046 Compound Example Name Structure Data Example 152k-2 06 t.sub.R = 1.74 min (>95%); Condition 1 LRMS: Anal. Calcd. for C.sub.32H.sub.34N.sub.9O.sub.3 592.28; found: 592.41 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.32H.sub.34N.sub.9O.sub.3 592.2785; found: 592.2775 (M + H).sup.+. Example 152k-3 07 t.sub.R = 1.79 min (>95%); Condition 1 LRMS: Anal. Calcd. for C.sub.33H.sub.36N.sub.9O.sub.3 606.29; found: 606.43 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.33H.sub.36N.sub.9O.sub.3 606.2941; found: 606.2925 (M + H).sup.+.

Examples 152l-1 to 152l-

(654) Examples 152l-1 through 152l-3 were isolated as TFA or AcOH salts prepared using the same procedure to convert Example 148e to 148.

(655) LC Conditions:

(656) Condition 1: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

(657) Condition 2: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

(658) TABLE-US-00047 Example Compound Name Structure Data Example 152l-1 methyl ((1R)-2- (methyl((1S)-1-(4-(4-(5- (2-((2S)-1-((2R)-2- phenyl-2-(1- piperidinyl)acetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-2- pyrimidinyl)phenyl)-1H- imidazol-2- yl)ethyl)amino)-2-oxo- 1-phenylethyl)carbamate 08 t.sub.R = 1.87 min (>95%); Condition 1 LRMS: Anal. Calcd. for C.sub.46H.sub.51N.sub.10O.sub.4 807.41 found: 807.57 (M + H).sup.+ HRMS: Anal. Calcd. for C.sub.46H.sub.51N.sub.10O.sub.4 807.4095 found: 807.4128 (M + H).sup.+ Example 152l-2 methyl ((1R)-2-oxo-1- phenyl-2-(((1S)-1-(4-(4- (5-(2-((2S)-1-((2R)-2- phenyl-2-(1- piperidinyl)acetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-2- pyrimidinyl)phenyl)-1H- imidazol-2- yl)ethyl)amino)ethyl) carbamate 09 t.sub.R = 1.83 min (>95%); Condition 1 LRMS: Anal. Calcd. for C.sub.45H.sub.49N.sub.10O.sub.4 793.39 found: 793.52 (M + H).sup.+ HRMS: Anal. Calcd. for C.sub.45H.sub.49N.sub.10O.sub.4 793.3938 found: 793.3934 (M + H).sup.+ Example 152l-3 methyl ((1R)-2-oxo-1- phenyl-2-((2S)-2-(4-(4- (5-(2-((2S)-1-((2R)-2- phenyl-2-(1- piperidinyl)acetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-2- pyrimidinyl)phenyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)ethyl) carbamate 0 t.sub.R = 1.87 min (>95%); Condition 1 LRMS: Anal. Calcd. for C.sub.47H.sub.51N.sub.10O.sub.4 819.41 found: 819.50 (M + H).sup.+ HRMS: Anal. Calcd. for C.sub.47H.sub.51N.sub.10O.sub.4 819.4095 found: 819.4127 (M + H).sup.+

Example 153a-1 from 153a-4

Example 153a-1 prepared from 152e-1. (S)-2-[5-{5′-[2-((S)-1-tert-Butoxycarbonyl-pyrrolidin-2-yl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-yl]-[2,2′]bipyrimidinyl-5-yl}-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester

(659) ##STR00811##

(660) To a stirred solution of (S)-tert-butyl 2-(5-(2-chloropyrimidin-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (1.0 g, 2.08 mmol) and dichlorobis(benzonitrile) palladium (40 mg, 0.104 mmol) in dry DMF (10 mL) at room temperature under argon was added neat tetrakis(dimethylamino)ethylene (1.0 mL, 4.16 mmol). The mixture was heated to 60° C. for 15 h before it was diluted with ethyl acetate and suction-filtered through diatomaceous earth (Celite®). The filtrate was washed with sat'd NaHCO.sub.3 soln and brine prior to drying over Na.sub.2SO.sub.4 and solvent evaporation. Purification of the residue by Biotage™ flash chromatography on silica gel (step gradient elution with 15% B to 15% B for 150 mL, 15% B to 75% B for 1500 mL, 75% B to 100% B for 1000 mL, 100% B to 100% B for 1000 mL where B=ethyl acetate and A=hexane followed by a second gradient elution with 10% B to 100% B for 700 mL where B=methanol and A=ethyl acetate) furnished the title compound as a caramel-colored, viscous oil (487.8 mg, 26% yield).

(661) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 9.27 (s, 4H), 8.09-8.06 (m, 2H), 5.73-5.66 and 5.50-5.44 (2m, 2H), 5.06-4.93 (m, 2H), 3.60-3.39 (2m, 8H), 2.32-2.08 (3m, 4H), 2.00-1.85 (m, 4H), 1.37 and 1.14 (2s, 18H), 0.95-0.84 (m, 4H), −0.01 (s, 18H).

(662) LCMS Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, RT=3.37 min, >95% homogeneity index.

(663) LRMS: Anal. Calcd. for C.sub.44H.sub.69N.sub.10O.sub.6S.sub.i2 889.49. found: 889.57 (M+H).sup.+.

(664) HRMS: Anal. Calcd. for C.sub.44H.sub.69N.sub.10O.sub.6S.sub.i2 889.4940. found: 889.4920 (M+H).sup.+.

(665) The same procedure was used to prepare Examples 153a-2 through 153a-4.

(666) LC Conditions:

(667) Condition 1: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

(668) Condition 2: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

(669) TABLE-US-00048 Compound Example Name Structure Data Example 153a-2 t.sub.R = 3.37 min (89.6%); Condition 1 LRMS: Anal. Calcd. for C.sub.44H.sub.69N.sub.10O.sub.6Si.sub.2 889.49; found: 889.56 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.44H.sub.69N.sub.10O.sub.6Si.sub.2 889.494; found: 889.4951 (M + H).sup.+. Example 153a-3 t.sub.R = 3.37 min (95%); Condition 1 LRMS: Anal. Calcd. for C.sub.44H.sub.69N.sub.10O.sub.6S.sub.12 889.49; found: 889.51 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.44H.sub.69N.sub.10O.sub.6S.sub.12 889.4940; found: 889.4915 (M + H).sup.+. Example 153a-4 tr = 2.3 min (condition 2) LRMS: Anal. Calcd. for C.sub.42H.sub.66N.sub.8Si.sub.2 834; found: 835 (M + H).sup.+.

Example 153b-1-153b-3

(670) The hydrolysis reactions was performed as above for Example 152h.

(671) LC Conditions:

(672) Condition 1: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

(673) Condition 2: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

(674) TABLE-US-00049 Example Compound Name Structure Data Example 153b-1 t.sub.R = 1.18 min (>95%); Condition 1 LRMS: Anal. Calcd. for C.sub.22H.sub.25N.sub.10 429.23; found: 429.01 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.22H.sub.25N.sub.10 429.2264; found: 429.2259 (M + H).sup.+. Example 153b-2 t.sub.R = 1.26 min (>95%); Condition 1 LRMS: Anal. Calcd. for C.sub.41H.sub.41N.sub.10O.sub.2 737.33 found: 737.49 (M + H).sup.+ HRMS: Anal. Calcd. for C.sub.41H.sub.41N.sub.10O.sub.4 737.3312 found: 737.3342 (M + H).sup.+ Example 153b-3 t.sub.R = 1.40 min (>95%); Condition 1 LRMS: Anal. Calcd. for C.sub.22H.sub.25N.sub.10 429.23; found: 429.20 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.22H.sub.25N.sub.10: 429.2264; Found: 429.2254 (M + H).sup.+ Example 153b-4 t.sub.R = 0.85 min (condition 1) LCMS: Anal. Calcd. for C.sub.20H.sub.22N.sub.8 374; found: 375 (M + H).sup.+.

Examples 153c-1 to 153c-7

(675) Examples 153c-1 through 153c-7 were isolated as TFA or AcOH salts using the procedure used to convert Example 148e to 148.

(676) LC Conditions:

(677) Condition 1: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

(678) Condition 2: Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, 220 nm, 5 μL injection volume.

(679) TABLE-US-00050 Ex- ample Compound Name Structure Data Ex- ample 153c- 1 (1R,1′R)-2,2′-(3,3′- bipyridazine-6,6′- diylbis(1H- imidazole- 5,2-diyl(2S)-2,1- pyrrolidinediyl)) bis(N,N- dimethyl-2-oxo-1- phenylethanamine) t.sub.R = 1.55 min (>95%); Condition 1 LRMS: Anal. Calcd. for C.sub.42H.sub.47N.sub.12O.sub.2 751.39 found: 751.64 (M + H).sup.+ HRMS: Anal. Calcd. for C.sub.42H.sub.47N.sub.12O.sub.2 751.3945 found: 751.3936 (M + H).sup.+ Ex- ample 153c- 2 dimethyl (3,3′- bipyridazine-6,6′- diylbis(1H- imidazole-5,2- diyl(2S)-2,1- pyrrolidinediyl ((1R)-2-oxo- 1-phenyl-2,1- ethanediyl))) biscarbamate 0 t.sub.R = 1.95 min (>95%); Condition 1 LRMS: Anal. Calcd. for C.sub.42H.sub.43N.sub.12O.sub.6 811.34 found: 811.22 (M + H).sup.+ HRMS: Anal. Calcd. for C.sub.42H.sub.43N.sub.12O.sub.6 811.3429 found: 811.3406 (M + H).sup.+ Ex- ample 153c- 3 (1,1′R)-2,2′-(2,2′- bipyrimidine-5,5′- diylbis(1H- imidazole- 5,2-diyl(2S)-2,1- pyrrolidinediyl)) bis(N,N- dimethyl-2-oxo-1- phenylethanamine) t.sub.R = 1.51 min (>90%*); Condition 1 LRMS: Anal. Calcd. for C.sub.42H.sub.47N.sub.12O.sub.2 751.39 found: 751.21 (M + H).sup.+ HRMS: Anal. Calcd. for C.sub.42H.sub.47N.sub.12O.sub.2 751.3945 found: 751.3921 (M + H).sup.+ Ex- ample 153c- 4 dimethyl (2,2′- bipyrimidine-5,5′- diylbis(1H- imidazole- 5,2-diyl(2S)-2,1- pyrrolidinediyl ((1R)-2-oxo- 1-phenyl-2,1- ethanediyl))) biscarbamate t.sub.R = 1.88 min (>95%); Condition 1 LRMS: Anal. Calcd. for C.sub.42H.sub.43N.sub.12O.sub.6 811.34 found: 811.10 (M + H).sup.+ HRMS: Anal. Calcd. for C.sub.42H.sub.43N.sub.12O.sub.6 811.3429 found: 811.3401 (M + H).sup.+ Ex- ample 153c- 5 (1R,1′R)-2,2′-(2,2′- bipyrazine-5,5′- diylbis(1H- imidazole-5,2- diyl(2S)-2,1- pyrrolidinediyl)) bis(N,N- dimethyl-2-oxo-1- phenylethanamine) t.sub.R = 1.61 min (>95%); Condition 1 LRMS: Anal. Calcd. for C.sub.42H.sub.47N.sub.12O.sub.2 751.39 found: 751.30 (M + H).sup.+ HRMS: Anal. Calcd. for C.sub.42H.sub.47N.sub.12O.sub.2 751.3945 found: 751.3943 (M + H).sup.+ Ex- ample 153c- 6 dimethyl (2,2′- bipyrazine-5,5′- diylbis(1H- imidazole- 5,2-diyl(2S)-2,1- pyrrolidinediyl ((1R)-2-oxo-1- phenyl-2,1- ethanediyl))) biscarbamate t.sub.R = 2.00 min (>95%); Condition 1 LRMS: Anal. Calcd. for C.sub.42H.sub.43N.sub.12O.sub.6 811.34 found: 811.23 (M + H).sup.+ HRMS: Anal. Calcd. for C.sub.42H.sub.43N.sub.12O.sub.6 811.3429 found: 811.3407 (M + H).sup.+ Ex- ample 153c- 7 dimethyl (2,2′- bipyridine-5,5′- diylbis(1H- imidazole- 5,2-diyl(1S)-1,1- ethanediylimino ((1R)-2-oxo-1- phenyl-2,1- ethanediyl))) biscarbamate t.sub.R = 1.42 min (condition 2, 94%) LRMS: Anal. Calcd. for C.sub.40H.sub.40N.sub.10O.sub.6 756.31; found: 757.34 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.40H.sub.41N.sub.10O.sub.6 757.3211 found: 757.3180 (M + H).sup.+.
Section LS LC Conditions:

(680) Condition 1: Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 90% methanol/10% water/0.1% TFA; Column: Phenomenex-Luna 3.0×5.0 mm S10; Wavelength: 220 nM; Flow rate: 4 mL/min; 0% B to 100% B over 4 min with a 1 min hold time.

(681) Condition 2: Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 90% methanol/10% water/0.1% TFA; Column: Phenomenex 10u C18 3.0×5.0 mm; Wavelength: 220 nM; Flow rate: 4 mL/min; 0% B to 100% B over 4 min with a 1 min hold time

(682) Condition 3: Solvent A: 5% acetonitrile/95% water/10 mmol ammonium acetate; Solvent B: 95% acetonitrile/5% water/10 mmol ammonium acetate; Column: Phenomenex 10u C18 4.6×5.0 mm; Wavelength: 220 nM; Flow rate: 4 mL/min; 0% B to 100% B over 4 min with a 1 min hold time

(683) Condition 4: Solvent A: 5% acetonitrile/95% water/10 mmol ammonium acetate; Solvent B: 95% acetonitrile/5% water/10 mmol ammonium acetate; Column: Luna 4.6×50 mm S10; Wavelength: 220 nM; Flow rate: 4 mL/min; 0% B to 100% B over 3 min with a 1 min hold time

(684) Condition 5: Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 90% methanol/10% water/0.1% TFA; Column: Phenomenex 10u C18 3.0×5.0 mm; Wavelength: 220 nM; Flow rate: 4 mL/min; 0% B to 100% B over 3 min with a 1 min hold time

(685) Condition 6: Solvent A: 5% acetonitrile/95% water/10 mmol ammonium acetate; Solvent B: 95% acetonitrile/5% water/10 mmol ammonium acetate; Column: Phenomenex-Luna 3.0×50 mm S10; Wavelength: 220 nM; Flow rate: 4 mL/min; 0% B to 100% B over 8 min with a 2 min hold time

(686) Condition 7: Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 90% methanol/10% water/0.1% TFA; Column: Phenomenex-Luna 3.0×5.0 mm S10; Wavelength: 220 nM; Flow rate: 4 mL/min; 0% B to 100% B over 3 min with a 1 min hold time

(687) Condition 8: Solvent A: 10% methanol/90% water/0.2% H.sub.3PO.sub.4; Solvent B: 90% methanol/10% water/0.2% H.sub.3PO.sub.4; Column: YMC ODS-A 4.6×50 mm S5; Wavelength: 220 nM; Flow rate: 4 mL/min; 0% B to 100% B over 4 min with a 1 min hold time

(688) Condition 9: Solvent A: 10% methanol/90% water/0.2% H.sub.3PO.sub.4; Solvent B: 90% methanol/10% water/0.2% H.sub.3PO.sub.4; Column: YMC ODS-A 4.6×50 mm S5; Wavelength: 220 nM; Flow rate: 2.5 mL/min; 0% B to 50% B over 8 min with a 3 min hold time

(689) Condition 10: Xbridge C18, 150×4.6 mm I.D. S-3.5 um; Mobile Phase A: 95% Water-5% Acetonitrile with 10 mM ammonium acetate (pH=5); Mobile phase B: 95% Acetonitrile-5% Water with 10 mM ammonium acetate (pH=5); Isocratic 30% B for 20 min; Flow rate: 1 mL/min; UV detection: 220 nm

(690) Condition 11: Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 90% methanol/10% water/0.1% TFA; Column: Phenomenex 10u C18 3.0×5.0 mm; Wavelength: 220 nM; Flow rate: 4 mL/min; 30% B to 100% B over 4 min with a 1 min hold time

(691) Condition 12: Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 90% methanol/10% water/0.1% TFA; Column: Phenomenex 10u C18 3.0×5.0 mm; Wavelength: 220 nM; Flow rate: 4 mL/min; 20% B to 100% B over 4 min with a 1 min hold time

(692) Condition 13: Solvent A: 10% methanol/90% water/0.2% H.sub.3PO.sub.4; Solvent B: 90% methanol/10% water/0.2% H.sub.3PO.sub.4; Column: YMC ODS-A 4.6×50 mm S5; Wavelength: 220 nM; Flow rate: 2.5 mL/min; 0% B to 100% B over 8 min with a 3 min hold time

(693) Section LS Preparative HPLC Conditions:

(694) Condition 1: Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 90% methanol/10% water/0.1% TFA; Column: Phenomenex-Luna 30×100 mm S10; Wavelength: 220 nM; Flow rate: 30 mL/min; 0% B to 100% B over 10 min with a 2 min hold time

(695) Condition 2: Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 90% methanol/10% water/0.1% TFA; Column: Xterra Prep MS C18 30×50 mm 5u; Wavelength: 220 nM; Flow rate: 30 mL/min; 0% B to 100% B over 8 min with a 3 min hold time

(696) Condition 3: Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 90% methanol/10% water/0.1% TFA; Column: Xterra Prep MS C18 30×50 mm 5u; Wavelength: 220 nM; Flow rate: 25 mL/min; 10% B to 100% B over 8 min with a 2 min hold time

(697) Condition 4: Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 90% methanol/10% water/0.1% TFA; Column: Xterra 19×100 mm S5; Wavelength: 220 nM; Flow rate: 20 mL/min; 30% B to 100% B over 5 min with a 3 min hold time

(698) Condition 5: Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 90% methanol/10% water/0.1% TFA; Column: Phenomenex-Luna 30×100 mm S10; Wavelength: 220 nM; Flow rate: 30 mL/min; 10% B to 100% B over 8 min with a 2 min hold time

(699) Condition 6: Solvent A: 10% Acetonitrile/90% water/0.1% TFA; Solvent B: 90% Acetonitrile/10% water/0.1% TFA; Column: Phenomenex-Luna 21×100 mm S10; Wavelength: 220 nM; Flow rate: 25 mL/min; 0% B to 60% B over 10 min with a 5 min hold time

Experimentals

Compound LS2

(1S,1′S)-2,2′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl))bis(1-cyclohexyl-2-oxoethanol)

(700) ##STR00826##
Step a:

(701) To 1d (1.4 g; 2.24 mmol) was added 30 mL 4N HCl in dioxane. After 3 h, 60 mL ether was added and the precipitate was filtered and dried under high vacuum providing 1.02 g (80%) intermediate LS1 as a pale yellow powder. .sup.1H NMR (DMSO-d.sub.6, δ=2.5 ppm, 500 MHz): δ 10.41 (s, 2H), 9.98 (s, 2H), 8.22 (s, 2H), 8.06 (d, J=8.54 Hz, 4H), 7.92 (d, J=8.55 Hz, 4H), 5.07 (s, 2H), 3.43-3.54 (m, 2H), 3.33-3.43 (m, 2H), 2.43-2.59 (m, 4H), 2.16-2.28 (m, 2H), 1.94-2.09 (m, 2H). LC (Cond. 1): RT=1.28 min; MS: Anal. Calcd. for [M+H].sup.+ C.sub.26H.sub.28N.sub.6: 425.24. found 425.56.

(702) Step b:

(703) To intermediate LS1 (200 mg; 0.35 mmol) in 2 mL DMF was added DIPEA (0.30 mL; 1.75 mmol), (S)-2-cyclohexyl-2-hydroxyacetic acid (61 mg; 0.39 mmol), followed by HATU (147 mg; 0.38 mmol). After stirring at ambient temperature for 18 h, the reaction mixture was split into two portions and purified via preparative HPLC (Cond'n 1). Fractions containing desired product were pooled and passed through an MCX cartridge (Oasis; 6 g; preconditioned with two column lengths of methanol). The cartridge was washed with two column lengths of methanol and product was eluted with ammonia/methanol. Concentration provided 65 mg of LS2 (26%) as a colorless powder. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 0.87-1.30 (m, 12H) 1.38-1.53 (m, J=24.72, 11.90 Hz, 4H) 1.54-1.75 (m, 8H) 1.95-2.21 (m, 6H) 3.72-3.86 (m, 6H) 5.13 (t, J=6.56 Hz, 2H) 7.87 (d, J=7.93 Hz, 4H) 7.96 (d, J=6.41 Hz, 4H) 8.13 (s, 2H) (imidazole NH and hydroxyl protons unaccounted for). LC (Cond'n 2): RT=3.07 min; MS: Anal. Calcd. for [M+H].sup.+ C.sub.42H.sub.52N.sub.6O.sub.4: 705.9. found 705.6.

(704) The following analogs were prepared in similar fashion to the preparation of LS2 from intermediate LS1 employing the appropriate carboxylic acid:

(705) TABLE-US-00051 Ex- ample Num- Compound Analytical ber Name Structure Data LS3 (2S,2′S)-1,1′- (4,4′- biphenyldiylbis (1H-imidazole- 5,2-diyl(2S)-2,1- pyrrolidinediyl)) bis(4-methyl-1- oxo-2-pentanol) LC/MS: 2.02 min (Cond'n 1); Anal. Calcd. for [M + H].sup.+ C.sub.38H.sub.48N.sub.6O.sub.4: 653.4; found 653.2. LS4 (2S,2′S)-1,1′- (4,4′- biphenyldiylbis (1H- imidazole-5,2- diyl(2S)-2,1- pyrrolidinediyl)) bis (3-methyl-1-oxo- 2-butanol) LC/MS: 1.99 min (Cond'n 3); Anal. Calcd. for [M + H].sup.+ C.sub.36H.sub.44N.sub.6O.sub.4: 625.3; found 625.3. LS16 3-buten-1-yl ((1S)-1- (((2S)-2-(5-(4′- (2-((2S)-1-((2S)- 2-(((3-buten-1- yloxy)carbonyl) amino)-3-methyl- butanoyl)-2- pyrrolidinyl)- 1H-imidazol- 5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl) carbonyl)-2- methylpropyl) carbamate .sup.1H NMR (500 MHz, CH.sub.3OD) δ ppm 0.81-1.10 (m, 12H) 1.90- 2.15 (m, 4H) 2.15-2.51 (m, 8H) 3.82-3.96 (m, 2H), 3.97- 4.05 (m, 2H) 4.05-4.19 (m, 4H) 4.25 (d, J = 7.02 Hz, 2H) 4.62 (s, 2H) 5.00- 5.17 (m, 4H) 5.20 (t, J = 5.65 Hz, 2H) 5.79- 5.93 (m, 2H) 7.20-7.47 (m, 2H) 7.59-7.90 (m, 8H)

Example LS6

(2S,2′S)-1,1′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl))bis(N-methyl-1-oxo-2-propanamine)

(706) ##STR00830##
Step a:

(707) To intermediate LS1 (64 mg; 0.11 mmol) in 1 mL DMF was added (S)-2-(tert-butoxycarbonyl(methyl)amino)propanoic acid (48 mg; 0.24 mmol), Hunig's base (0.12 mL; 0.67 mmol) and HATU (90 mg; 0.24 mmol). After 3 h, the reaction was purified via preparative HPLC (Cond'n 2). Fractions containing intermediate LS5 were pooled and concentrated providing intermediate LS5 as a colorless powder (43 mg; 48%) after drying under high vacuum. LC (Cond'n 4): RT=2.12 min; MS: Anal. Calcd. for [M+H].sup.+ C.sub.44H.sub.58N.sub.8O.sub.6: 795.4. found 795.5.

(708) Step b:

(709) Intermediate LS5 was allowed to stir in 2 mL HCl/Dioxane (4N) for 18 h at which time 10 mL ether was added and the resultant precipitate was filtered and dried under high vacuum providing LS6 (45 mg; 155%) as a colorless solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 2.00-2.11 (m, 2H) 2.12-2.27 (m, 4H) 2.38-2.47 (m, 2H) 2.39-2.48 (m, 2H) 2.58 (t, J=5.19 Hz, 2H) 3.78-3.85 (m, 2H) 3.91-4.02 (m, 2H) 4.21-4.32 (m, 2H) 5.26 (t, J=7.17 Hz, 2H) 7.93 (d, J=7.32 Hz, 4H) 8.02 (d, J=7.94 Hz, 4H) 8.12-8.21 (m, 2H) 8.69-8.81 (m, 2H) 9.09-9.17 (m, 2H); N-Me protons obscured by DMSO peak with 2 other protons unaccounted for. LC (Cond'n 5): RT=1.71 min; MS: Anal. Calcd. for [M+H].sup.+ C.sub.34H.sub.42N.sub.8O.sub.2: 595.3. found 595.6.

Example LS11

(4S,4′S)-4,4′-(4,4′-biphenyldiylbis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediylcarbonyl))bis(1,3-oxazinan-2-one)

(710) ##STR00831##
Step a:

(711) To intermediate LS1 (65 mg; 0.11 mmol) in 1 mL DMF was added HATU (91 mg; 0.24 mmol), (S)-2-oxo-1,3-oxazinane-4-carboxylic acid (intermediate LS10; 35 mg; 0.24 mmol), followed by DIPEA (0.12 mL; 0.68 mmol. After 3 h, the reaction mixture was twice purified via preparative HPLC (Cond'n 3). Appropriate fractions were pooled and concentrated under high vacuum providing 8 mg (10%) bis TFA LS11 as a colorless oil. .sup.1H NMR (500 MHz, CH.sub.3OD) δ ppm .sup.1H NMR (500 MHz, CH.sub.3OD) δ ppm 1.99-2.43 (m, 10H) 2.48-2.66 (m, 1.98 Hz, 2H) 3.82-3.95 (m, 4H) 4.17-4.40 (m, 4H) 4.57 (t, J=5.80 Hz, 2H) 5.23-5.41 (m, 2H) 7.73-7.97 (m, 10H); imidazole and carbamate NH protons are unaccounted for. LC (Cond'n 6): RT=2.28 min; MS: Anal. Calcd. for [M+H].sup.+ C.sub.34H.sub.42N.sub.8O.sub.2: 679.3. found 679.4.

(712) Step a:

(713) Performed as in Baldwin et al, Tetrahedron 1988, 44, 637

(714) Step a:

(715) Performed as in Sakaitani and Ohfune, J. Am. Chem. Soc. 1990, 112, 1150 for the conversion of compound 1 to 5. Purification via Biotage (40M cartridge; 1:1 ether/ethyl acetate) then preparative HPLC (Cond'n 4) provided 77 mg (8%) intermediate LS9 as a viscous oil. .sup.1H NMR (300 MHz, CDCl.sub.3) δ ppm 2.02-2.21 (m, 1H) 2.23-2.41 (m, 1H) 4.11-4.38 (m, 3H) 5.11-5.31 (m, 2H) 6.15 (s, 1H) 7.27-7.46 (m, 5H). LC (Cond'n 7): RT=1.24 min; MS: Anal. Calcd. for [M+H].sup.+ C.sub.34H.sub.42N.sub.8O.sub.2: 236.1. found 236.4.

(716) Step a:

(717) Intermediate LS9 was hydrogenated under 1 atm H.sub.2 in 3 mL methanol with 10 mg Pd/C (10%) for 18 h. The reaction mixture was filtered through a pad of diatomaceous earth (Celite®) and concentrated to provide intermediate LS10 (40 mg; 83%) as a colorless powder. .sup.1H NMR (500 MHz, CH.sub.3OD) δ ppm 2.08-2.18 (m, 1H) 2.26-2.38 (m, 1H) 4.19 (t, J=5.95 Hz, 1H) 4.25-4.40 (m, 2H).

Example LS14

methyl ((1S)-2-((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate

(718) ##STR00832##
Step a:

(719) To 28 (1.5 g; 2.86 mmol) in 25 mL DMF was added sequentially Cap-2 (697 mg; 2.86 mmol), HATU (1.2 g; 3.14 mmol), and Hunig's base (1.5 mL; 8.57 mmol). After 3 h, the solution was concentrated to 10 mL and partitioned between chloroform and water. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to an amber oil which was subjected to silica gel chromatography (Biotage; loaded on 40 samplet with dichloromethane; eluted on 40M cartridge with 0 to 12% dichloromethane/methanol over 1200 mL). Fractions containing intermediate LS12 were pooled and concentrated to provide material which contained residual DMF. This material was redissolved in dichloromethane and washed with water (3×50 mL) and then brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated to 761 mg powder which was repurified via silica gel chromatography (Biotage; loaded on 40 samplet with dichloromethane; eluted on 40M cartridge with 0 to 80% 4:1 chloroform:methanol/ethyl acetate over 1500 mL) to provide intermediate LS12 (501 mg; 25%) as a colorless powder. LC (Cond'n 8): RT=1.24 min.

(720) Step a:

(721) To intermediate LS12 (490 mg; 0.69 mmol) was added 6 mL HCl/Dioxane followed by 25 mL dichloromethane. After 24 h, 75 mL ether was added, the reaction mixture was filtered and the precipitate was dried under vacuum providing intermediate LS13.4HCl (434 mg; quant) as a tan solid. .sup.1H NMR (300 MHz, CH.sub.3OD) δ ppm 1.16-1.29 (m, 3H) 1.37 (t, J=6.95 Hz, 3H) 1.89-2.06 (m, 6.95 Hz, 1H) 2.12-2.51 (m, 5H) 2.52-2.85 (m, 4H) 3.02-3.24 (m, 2H) 3.42-3.55 (m, 7.32 Hz, 1H) 3.58-3.71 (m, 2H) 4.26-4.41 (m, 1H) 5.18-5.37 (m, 2H) 5.65 (s, 1H) 7.57-7.66 (m, 3H) 7.67-7.75 (m, 1H) 7.86-8.04 (m, 10H) 8.14 (s, 1H). LC (Cond'n 8): RT=1.92 min.

(722) Step a:

(723) To intermediate LS13.4HCl (75 mg; 0.099 mmol) in 0.7 mL DMF was added sequentially intermediate LS16 (26 mg; 0.118 mmol), HATU (45 mg; 0.118 mmol), and Hunig's base (0.10 mL; 0.591 mmol). After 2 h, the reaction mixture was filtered through diatomaceous earth (Celite®), the pad washed with 0.3 mL methanol and the resultant filtrate was purified via preparative HPLC (Cond'n 5) in two separate injections. The fractions containing desired product were passed through an MCX cartridge (Oasis; 1 g; preconditioned with two column lengths of methanol). The cartridge was washed with two column lengths of methanol and product was eluted with ammonia/methanol. Concentration provided 36 mg of LS14 as a colorless powder which was assayed to be of 82% diastereomeric purity (most likely epimeric at the stereogenic carbon in intermediate 16). Resubjected to preparative HPLC purification (2×) providing LS14 (13 mg; 16%) as a colorless solid. .sup.1H NMR (500 MHz, CH.sub.3OD) δ ppm 0.99 (q, J=6.92 Hz, 6H) 1.25-1.72 (m, 5H) 1.80-2.42 (m, 10H) 2.47-2.61 (m, 3H) 2.66-2.78 (m, 2H) 3.35-3.43 (m, 2H) 3.65-3.71 (m, 3H) 3.89-4.01 (m, 4H) 4.01-4.10 (m, 1H) 4.32 (d, J=8.24 Hz, 1H) 5.11-5.22 (m, 1H) 6.95-7.17 (m, 3H) 7.30-7.44 (m, 3H) 7.53 (d, J=7.02 Hz, 1H) 7.62-7.89 (m, 8H). LC (Cond'n 9): RT=5.31 min.

(724) Step a:

(725) Intermediate LS16 was prepared in analogous fashion to the procedure describing the synthesis of Cap-51 substituting (S)-2-amino-2-(tetrahydro-2H-pyran-4-yl)acetic acid (available from Astatech) for L-Valine. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ ppm 1.15-1.63 (m, 5H) 1.75-2.03 (m, 1H) 3.54 (s, 3H) 3.76-3.98 (m, 4H) 7.45 (d, J=8.42 Hz, 1H); one proton obscured by water peak.

Example LS20

methyl ((1S)-2-methyl-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N-methylglycyl)-2-pyrrolidinyl)-pyrrolidinyl)carbonyl)propyl)carbamate

(726) ##STR00833##

(727) Step a & b: Intermediate LS18 was prepared in analogous fashion to the procedure describing the synthesis of intermediate LS13 substituting Cap-51 for Cap-2.

(728) Step a:

(729) To intermediate LS18 (100 mg; 0.14 mmol) in 1.4 mL DMF was added sequentially N-Boc Sarcosine (30 mg; 0.16 mmol), Hunig's base (0.13 mL; 0.72 mmol) and HATU (60 mg; 0.16 mmol). After 2 h the reaction mixture was partitioned into dichloromethane, washed with NaHCO.sub.3 (aq), brine, dried over magnesium sulfate, filtered and concentrated to crude intermediate LS19 which was used directly in the next step. LC (Cond'n 5): RT=2.42 min; MS: Anal. Calcd. for [M+H].sup.+ C.sub.41H.sub.52N.sub.8O.sub.6: 753.4. found 753.9.

(730) Step a:

(731) Crude intermediate LS19 was dissolved in 0.5 mL methanol and 5 mL 4N HCl/Dioxane. After stirring for 1 h, the reaction was concentrated and purified via preparative HPLC (Cond'n 6) and the fractions containing desired product were passed through an MCX cartridge (Oasis; 1 g; preconditioned with two column lengths of methanol). The cartridge was washed with two column lengths of methanol and product was eluted with ammonia/methanol. Concentration provided LS20 (32 mg; 34%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 0.74-0.98 (m, 6H) 1.79-2.24 (m, 9H) 2.29-2.38 (m, 2H) 3.19-3.51 (m, 8H) 3.50-3.56 (m, 3H) 3.59-3.71 (m, 1H) 3.81 (s, 1H) 3.97-4.17 (m, 1H) 5.01-5.16 (m, 2H) 7.30 (d, J=7.93 Hz, 1H) 7.51 (s, 1H) 7.59-7.74 (m, 4H) 7.79 (d, J=7.63 Hz, 4H) 11.78 (s, 1H). LC (Cond'n 5): RT=2.00 min; MS: Anal. Calcd. for [M+H].sup.+ C.sub.36H.sub.44N.sub.8O.sub.4: 653.4. found 653.7.

(732) The following analogs were prepared in similar fashion to the preparation of LS20 from LS18 substituting the appropriate carboxylic acid for N-Boc Sarcosine:

(733) TABLE-US-00052 Ex- ample Num- ber Compound Name Structure Analytical Data LS21 methyl ((1S)-1- (((2S)-2-(5-(4′-(2- ((2S)-1-(N- ethylglycyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl) carbonyl)-2- methylpropyl) carbamate LC/MS: 2.34 min (Cond'n 2); Anal. Calcd. for [M + H].sup.+ C.sub.37H.sub.46N.sub.8O.sub.4: 667.4; found 667.7. LS22 methyl ((1S)-1- (((2S)-2-(5-(4′-(2- ((2S)-1-(N- benzylglycyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl) carbonyl)-2- methylpropyl) carbamate LC/MS: 2.34 min (Cond'n 5); Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.48N.sub.8O.sub.4: 729.4; found 729.8. LS23 methyl ((1S)-1- (((2S)-2-(5-(4′-(2- ((2S)-1-(N- isobutylglycyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl) carbonyl)-2- methylpropyl) LC/MS: 2.07 min (Cond'n 5); Anal. Calcd. for [M + H].sup.+ C.sub.39H.sub.50N.sub.8O.sub.4: 695.4; found 695.8. carbamate LS24 methyl ((1S)-1- (((2S)-2-(5-(4′-(2- ((2S)-1-(N-sec- butylglycyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl) carbonyl)-2- methylpropyl) LC/MS: 2.03 min (Cond'n 5); Anal. Calcd. for [M + H].sup.+ C.sub.39H.sub.50N.sub.8O.sub.4: 695.4; found 695.9. carbamate LS25 methyl ((1S)-1- (((2S)-2-(5-(4′-(2- ((2S)-1-(N- isopropylglycyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl) carbonyl)-2- methylpropyl) LC/MS: 1.97 min (Cond'n 5); Anal. Calcd. for [M + H].sup.+ C.sub.38H.sub.48N.sub.8O.sub.4: 681.4; found 681.7. carbamate

Example LS26

methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N,N-diisopropylglycyl-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

(734) ##STR00839##
Step a:

(735) Compound LS26 was prepared in a similar fashion to the preparation of intermediate LS19 employing 2-(diisopropylamino)acetic acid as the carboxylic acid coupling partner. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 0.74-1.04 (m, 18H) 1.74-2.21 (m, 13H) 2.86-3.09 (m, 3H) 3.54 (s, 3H) 3.71-3.89 (m, 3H) 4.06 (t, J=8.55 Hz, 1H) 4.98-5.13 (m, 2H) 5.56 (d, J=8.55 Hz, 1H) 7.21-7.34 (m, 1H) 7.42-7.54 (m, 1H) 7.61-7.87 (m, 8H). LC (Cond'n 5): RT=1.98 min; MS: Anal. Calcd. for [M+H].sup.+ C.sub.41H.sub.54N.sub.8O.sub.4: 723.4. found 723.4.

Example LS27

Diastereomer 1

methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2-(3-oxetanyl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

Example LS27

Diastereomer 2

methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-2-(3-oxetanyl)acetyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

(736) ##STR00840##
Step a:

(737) Compound LS27 was prepared in a similar fashion to the preparation of intermediate LS19 employing 2-(methoxycarbonylamino)-2-(oxetan-3-yl)acetic acid (intermediate LS29) as the carboxylic acid coupling partner. The two diastereomers of LS27 were separated via preparative HPLC (Xbridge C18, 100×19 mm I.D. S-5 μm; Mobile Phase A: 95% Water-5% Acetonitrile with 10 mM ammonium acetate (pH=5); Mobile phase B: 95% Acetonitrile-5% Water with 10 mM ammonium acetate (pH=5); Isocratic 30% B for 7 min; Flow rate: 25 mL/min; UV detection: 220 nm; Sample amount: ˜5 mg/each injection, 300 μl sample solution in methanol (˜17 mg/mL)). Diastereomer 1: .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 0.80-0.96 (m, 6H) 1.91-2.06 (m, 6H) 2.09-2.21 (m, 3H) 3.54 (s, 3H) 3.59 (s, 3H) 3.77-3.83 (m, 2H) 3.87 (t, J=7.63 Hz, 1H) 4.06 (t, J=8.24 Hz, 1H) 4.31 (t, J=6.41 Hz, 1H) 4.43 (t, J=6.10 Hz, 1H) 4.49 (t, J=7.17 Hz, 1H) 4.51-4.57 (m, 1H) 4.80 (t, J=8.55 Hz, 1H) 5.00-5.05 (m, 1H) 5.06-5.11 (m, 1H) 7.30 (d, J=8.55 Hz, 1H) 7.50 (s, 1H) 7.58-7.89 (m, 8H) 11.77 (s, 2H). LC (Cond'n 10): RT=7.14 min; MS: Anal. Calcd. for [M+H].sup.+ C.sub.40H.sub.48N.sub.8O.sub.7: 753.4. found 753.9. Diastereomer 2: .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 0.79-0.98 (m, 6H) 1.91-2.06 (m, 4H) 2.07-2.23 (m, 4H) 3.51-3.69 (m, 8H) 3.74-3.90 (m, 2H) 4.06 (t, J=7.48 Hz, 1H) 4.20-4.33 (m, 1H) 4.36-4.49 (m, 2H) 4.55 (s, 2H) 4.71 (s, 1H) 4.97-5.05 (m, 1H) 5.08 (s, 1H) 5.53 (s, 1H) 7.30 (d, J=7.93 Hz, 1H) 7.51 (s, 1H) 7.58-7.91 (m, 8H) 11.53 (s, 1H) 11.78 (s, 1H). LC (Cond'n 10): RT=8.79 min; MS: Anal. Calcd. for [M+H].sup.+ C.sub.40H.sub.48N.sub.8O.sub.7: 753.4. found 753.9.

(738) Step a:

(739) A solution of methyl 2-(benzyloxycarbonylamino)-2-(oxetan-3-ylidene)acetate (intermediate LS28; Source: Moldes et al, Il Farmaco, 2001, 56, 609 and Wuitschik et al, Ang. Chem. Int. Ed. Engl, 2006, 45, 7736; 200 mg, 0.721 mmol) in ethyl acetate (7 mL) and CH.sub.2Cl.sub.2 (4.00 mL) was degassed by bubbling nitrogen for 10 min. Dimethyl dicarbonate (0.116 mL, 1.082 mmol) and Pd/C (20 mg, 0.019 mmol) were then added, the reaction mixture was fitted with a hydrogen balloon and allowed to stir at ambient temperature overnight. The reaction mixture was filtered through diatomaceous earth (Celite®) and concentrated. The residue was purified via Biotage (load with dichloromethane on 25 samplet; elute on 25S column with dichloromethane for 3CV then 0 to 5% methanol/dichloromethane over 250 mL then hold at 5% methanol/dichloromethane for 250 mL; 9 mL fractions). Fractions containing the desired product were concentrated to provide 167 mg methyl 2-(methoxycarbonylamino)-2-(oxetan-3-yl)acetate as a colorless oil which solidified on standing. .sup.1H NMR (500 MHz, CHLOROFORM-D) δ ppm 3.29-3.40 (m, 1H) 3.70 (s, 3H) 3.74 (s, 3H) 4.55 (t, J=6.41 Hz, 1H) 4.58-4.68 (m, 2H) 4.67-4.78 (m, 2H) 5.31 (br s, 1H). MS: Anal. Calcd. for [M+H].sup.+ C.sub.8H.sub.13NO.sub.5: 204.1. found 204.0. To methyl 2-(methoxycarbonylamino)-2-(oxetan-3-yl)acetate (50 mg, 0.246 mmol) in THF (2 mL) and Water (0.5 mL) was added lithium hydroxide monohydrate (10.33 mg, 0.246 mmol). The resultant solution was allowed to stir overnite at ambient temperature then concentrated to dryness to provide intermediate LS29 as a colorless powder. .sup.1H NMR (500 MHz, CH.sub.3OD) δ ppm 3.38-3.50 (m, 1H) 3.67 (s, 3H) 4.28 (d, J=7.63 Hz, 1H) 4.57-4.79 (m, 4H).

Example LS36

methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-2-methyl-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

(740) ##STR00841##
Step a:

(741) To (S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-2-methylpyrrolidine-2-carboxylic acid (intermediate LS30; 1.5 g; 4.3 mmol) in 50 mL DMF was added sequentially 2-amino-1-(4-bromophenyl)ethanone hydrochloride (1.2 g; 4.7 mmol), HOAT (290 mg; 2.1 mmol), Hunig's base (0.7 mL; 4.3 mmol) and EDCI (1.2 g; 6.4 mmol). After 1 h, the reaction mixture was poured into 150 mL water and allowed to stir for 15 min before filtering the resultant precipitate which was dissolved in dichloromethane and dried over magnesium sulfate. The dichloromethane mixture was filtered and applied to a Biotage 40 samplet. Chromatography on a 40M column (25 to 60% ethyl acetate/hexane over 1200 mL) provided (S)-(9H-fluoren-9-yl)methyl 2-(2-(4-bromophenyl)-2-oxoethylcarbamoyl)-2-methylpyrrolidine-1-carboxylate (intermediate LS31; 2.4 g; quant) as a yellow foam. LC (Cond'n 11): RT=3.75 min; MS: Anal. Calcd. for [M+H].sup.+ C.sub.29H.sub.27BrN.sub.2O4: 547.1. found 547.0.

(742) Step b:

(743) A mixture of ammonium acetate (844 mg; 10.97 mmol) and (S)-(9H-fluoren-9-yl)methyl 2-(2-(4-bromophenyl)-2-oxoethylcarbamoyl)-2-methylpyrrolidine-1-carboxylate (intermediate LS31; 1.00 g; 1.83 mmol) was heated to 140° C. in 25 mL xylene for 2.5 h at which time the reaction mixture was concentrated and loaded with dichloromethane onto a Biotage 40 samplet. Purification via Biotage (5 to 60% ethyl acetate/hexane over 1000 mL with 400 mL hold time) provided (S)-(9H-fluoren-9-yl)methyl 2-(5-(4-bromophenyl)-1H-imidazol-2-yl)-2-methylpyrrolidine-1-carboxylate (intermediate LS32; 469 mg; 49%) as an amber liquid. LC (Cond'n 12): RT=3.09 min; MS: Anal. Calcd. for [M+H].sup.+ C.sub.29H.sub.26BrN.sub.3O.sub.2: 528.1. found 528.5.

(744) Step c:

(745) To (S)-(9H-fluoren-9-yl)methyl 2-(5-(4-bromophenyl)-1H-imidazol-2-yl)-2-methylpyrrolidine-1-carboxylate (intermediate LS32; 329 mg; 0.62 mmol) in 3 mL DMF was added 1.5 mL piperidine. The reaction mixture was concentrated via a nitrogen stream overnite. The resultant residue was washed with hexane and passed through an MCX cartridge (Oasis; 6 g; preconditioned with two column lengths of methanol). The cartridge was washed with two column lengths of methanol and product was eluted with ammonia/methanol. Concentration provided 193 mg of (S)-5-(4-bromophenyl)-2-(2-methylpyrrolidin-2-yl)-1H-imidazole which was dissolved in 6 mL dichloromethane and combined with di-t-butyldicarbonate (413 mg; 1.89 mmol), DMAP (15 mg; 0.13 mmol) and TEA (0.17 mL; 1.30 mmol). After 48 h, the reaction mixture was concentrated and purified via chromatography on a Biotage system providing (S)-tert-butyl 5-(4-bromophenyl)-2-(1-(tert-butoxycarbonyl)-2-methylpyrrolidin-2-yl)-1H-imidazole-1-carboxylate (intermediate LS33; 150 mg; 48%) as an off white solid. LC (Cond'n 5): RT=3.75 min; MS: Anal. Calcd. for [M+H].sup.+ C.sub.24H.sub.32BrN.sub.3O.sub.4: 506.2. found 506.4.

(746) Step d:

(747) (S)-tert-butyl 2-(5-(4′-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-2-methylpyrrolidine-1-carboxylate (intermediate LS34) was prepared in a similar fashion to the preparation of 1d employing intermediate LS33 in place of 1b. .sup.1H NMR (300 MHz, DMSO-d.sub.6; 100° C.) δ ppm 1.18-1.29 (m, 9H) 1.29-1.40 (m, 9H) 1.75-1.82 (m, 3H) 1.81-2.39 (m, 8H) 3.35-3.75 (m, 4H) 4.81-4.92 (m, 1H) 7.36-7.45 (m, 1H) 7.57-7.74 (m, 5H) 7.76-7.89 (m, 4H) 11.29-11.63 (m, 2H). LC (Cond'n 5): RT=2.49 min; MS: Anal. Calcd. for [M+H].sup.+ C.sub.37H.sub.46N.sub.6O.sub.4: 639.4. found 639.9.

(748) Step e:

(749) 2-((S)-2-methylpyrrolidin-2-yl)-5-(4′-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazole (intermediate LS35) was prepared in a similar fashion to the preparation of 1e employing intermediate LS34 in place of 1d. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.76-1.83 (m, 3H) 1.92-2.23 (m, 6H) 3.31-3.49 (m, 4H) 4.88-4.97 (m, 1H) 7.76-7.88 (m, 5H) 7.90-8.04 (m, 5H) 9.72-9.82 (m, 1H) 10.04-10.16 (m, 1H); imidazole and pyrrolidine NH protons unaccounted for. LC (Cond'n 5): RT=1.79 min; MS: Anal. Calcd. for [M+H].sup.+ C.sub.27H.sub.30N.sub.6: 439.2. found 439.5.

(750) Step f:

(751) Compound LS36 was prepared in a similar fashion to the preparation of example 1 employing intermediate LS35 in place of 1e and Cap-51 in place of Cap-1. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 0.72-0.97 (m, 12H) 1.77 (s, 3H) 1.86-2.08 (m, 8H) 2.09-2.19 (m, 2H) 2.25-2.39 (m, 2H) 3.49-3.59 (m, 6H) 3.81 (d, J=6.71 Hz, 4H) 4.06 (q, J=7.83 Hz, 2H) 5.08 (dd, J=7.02, 3.05 Hz, 1H) 7.12 (d, J=8.85 Hz, 1H) 7.27-7.34 (m, 1H) 7.46-7.55 (m, 1H) 7.59-7.73 (m, 4H) 7.75-7.86 (m, 3H) 11.66 (s, 1H) 11.77 (s, 1H). LC (Cond'n 5): RT=2.25 min; MS: Anal. Calcd. for [M+H].sup.+ C.sub.41H.sub.52N.sub.8O.sub.6: 753.4. found 754.0.

Example LS37

methyl ((1S,2R)-2-methoxy-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-O-methyl-L-threonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-2-methyl-1-pyrrolidinyl)carbonyl)propyl)carbamate

(752) ##STR00842##

(753) Compound LS37 was prepared in a similar fashion to the preparation of LS36 from intermediate LS30 using Cap-86 in place of Cap-51. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 0.99-1.17 (m, 6H) 1.76 (s, 3H) 1.87-2.09 (m, 4H) 2.10-2.23 (m, 2H) 2.34-2.38 (m, 2H) 2.56-2.60 (m, 1H) 2.63 (d, J=1.83 Hz, 1H) 3.17 (s, 3H) 3.19 (s, 3H) 3.37-3.51 (m, 2H) 3.54 (s, 6H) 3.75-3.96 (m, 4H) 4.13-4.36 (m, 2H) 5.07 (dd, J=7.48, 3.20 Hz, 1H) 7.20 (d, J=8.54 Hz, 1H) 7.24-7.34 (m, 1H) 7.50 (dd, J=7.17, 1.98 Hz, 1H) 7.59-7.73 (m, 4H) 7.76-7.86 (m, 3H) 11.65 (s, 1H) 11.77 (s, 1H). LC (Cond'n 13): RT=4.30 min; MS: Anal. Calcd. for [M+H].sup.+ C.sub.41H.sub.52N.sub.8O.sub.8: 785.4. found 785.4.

(754) Section F LC Conditions for Determining Retention Time

(755) Condition 1

(756) Column: Phenomenex-Luna 4.6×50 mm S10

(757) Start % B=0

(758) Final % B=100

(759) Gradient Time=4 min

(760) Flow Rate=4 mL/Min

(761) Wavelength=220

(762) Solvent A=10% methanol-90% H.sub.2O-0.1% TFA

(763) Solvent B=90% methanol-10% H.sub.2O-0.1% TFA

(764) Condition 2

(765) Column: Waters-Sunfire 4.6×50 mm S5

(766) Start % B=0

(767) Final % B=100

(768) Gradient Time=2 min

(769) Flow Rate=4 mL/Min

(770) Wavelength=220

(771) Solvent A=10% methanol-90% H.sub.2O-0.1% TFA

(772) Solvent B=90% methanol-10% H.sub.2O-0.1% TFA

(773) Condition 3

(774) Column: Phenomenex 10u 3.0×50 mm

(775) Start % B=0

(776) Final % B=100

(777) Gradient Time=2 min

(778) Flow Rate=4 mL/Min

(779) Wavelength=220

(780) Solvent A=10% methanol-90% H.sub.2O-0.1% TFA

(781) Solvent B=90% methanol-10% H.sub.2O-0.1% TFA

(782) Condition 4

(783) Column: Phenomenex-Luna 3.0×50 mm S10

(784) Start % B=0

(785) Final % B=100

(786) Gradient Time=3 min

(787) Flow Rate=4 mL/Min

(788) Wavelength=220

(789) Solvent A=10% methanol-90% H.sub.2O-0.1% TFA

(790) Solvent B=90% methanol-10% H.sub.2O-0.1% TFA

(791) Condition 5

(792) Column: Phenomenex-Luna 4.6×50 mm S10

(793) Start % B=0

(794) Final % B=100

(795) Gradient Time=3 min

(796) Flow Rate=4 mL/Min

(797) Wavelength=220

(798) Solvent A=10% methanol-90% H.sub.2O-0.1% TFA

(799) Solvent B=90% methanol-10% H.sub.2O-0.1% TFA

(800) Condition 6

(801) Column: Xbridge C18 4.6×50 mm S5

(802) Start % B=0

(803) Final % B=100

(804) Gradient Time=3 min

(805) Flow Rate=4 mL/Min

(806) Wavelength=220

(807) Solvent A=H.sub.2O:ACN 95%:5% 10 mm Ammonium Acetate

(808) Solvent B=H.sub.2O:ACN 5%:95% 10 mm Ammonium Acetate

(809) Condition 7

(810) Column: Phenomenex C18 10u 4.6×30 mm

(811) Start % B=0

(812) Final % B=100

(813) Gradient Time=3 min

(814) Flow Rate=4 mL/Min

(815) Wavelength=220

(816) Solvent A=10% methanol-90% H.sub.2O-0.1% TFA

(817) Solvent B=90% methanol-10% H.sub.2O-0.1% TFA

(818) Condition 8

(819) Column: Phenomenex LunaC18 10u 4.6×30 mm

(820) Start % B=0

(821) Final % B=100

(822) Gradient Time=2 min

(823) Flow Rate=5 mL/Min

(824) Wavelength=220

(825) Solvent A=10% methanol-90% H.sub.2O-0.1% TFA

(826) Solvent B=90% methanol-10% H.sub.2O-0.1% TFA

(827) Condition 9

(828) Column: Phenomenex C18 10u 4.6×30 mm

(829) Start % B=0

(830) Final % B=100

(831) Gradient Time=10 min

(832) Flow Rate=4 mL/Min

(833) Wavelength=220

(834) Solvent A=H.sub.2O:ACN 95%:5% 10 mm Ammonium Acetate

(835) Solvent B=H.sub.2O:ACN 5%:95% 10 mm Ammonium Acetate

(836) Condition 10

(837) Column: Phenomenex 10u 3.0×50 mm

(838) Start % B=0

(839) Final % B=100

(840) Gradient Time=3 min

(841) Flow Rate=4 mL/Min

(842) Wavelength=220

(843) Solvent A=10% methanol-90% H.sub.2O-0.1% TFA

(844) Solvent B=90% methanol-10% H.sub.2O-0.1% TFA

(845) Condition 11

(846) Column: Xterra 4.6×30 mm S5

(847) Start % B=0

(848) Final % B=100

(849) Gradient Time=2 min

(850) Flow Rate=5 mL/Min

(851) Wavelength=220

(852) Solvent A=H.sub.2O:ACN 95%:5% 10 mm Ammonium Acetate

(853) Solvent B=H.sub.2O:ACN 5%:95% 10 mm Ammonium Acetate

(854) ##STR00843## ##STR00844##

(855) Compound F1 was prepared in analogous fashion to the procedure used to synthesize 1a with following modification: (2S,5R)-1-(tert-butoxycarbonyl)-5-phenylpyrrolidine-2-carboxylic acid was used in place of N-Boc-L-proline.

(856) Compound F2 was prepared in analogous fashion to the procedure used to sythesize 1b.

(857) Compound F3 was prepared in analogous fashion to the procedure used to sythesize 1d.

(858) Compound F4 was prepared in analogous fashion to the procedure used to sythesize 1e.

(859) Compound F5, F6 was prepared in analogous fashion to the procedure used to sythesize example 1 from Compound F4.

(860) Compound F7, F8 was prepared in analogous fashion to the procedure used to sythesize F5 with following modification: (2S)-1-(tert-butoxycarbonyl)octahydro-1H-indole-2-carboxylic acid was used in place of (2S,5R)-1-(tert-butoxycarbonyl)-5-phenylpyrrolidine-2-carboxylic acid.

(861) TABLE-US-00053 Retention time (LC-Condition); Entry Compound Name homogeneity index MS data F1 RT = 3.838 minutes (condition 1, 94%); LRMS: Anal. Calcd. for C24H27BrN2O4 486.12; found: 487.26 (M + H).sup.+. F2 RT = 3.175 minutes (condition 1, 83%); LRMS: Anal. Calcd. for C24H27BrN2O4 467.12; found: 468.26 (M + H).sup.+. F3 RT = 2.965 minutes (condition 1, 93%); LRMS: Anal. Calcd. for C42H48N6O4 700.37; found: 701.49 (M + H).sup.+. F4 RT = 2.083 minutes (condition 1, 98%); LRMS: Anal. Calcd. for C32H32N6 500.27; found: 501.40 (M + H).sup.+. F5 RT = 1.222 minutes (condition 3, 98%); LRMS: Anal. Calcd. for C52H54N8O2 822.44; found: 823.5 (M + H).sup.+. F6 methyl ((1R)-2-((2R)-2-(5-(4′- RT = 1.512 minutes (condition (2-((2S,5R)-1-((2R)-2- 3, 98%); LRMS: Anal. Calcd. ((methoxycarbonyl)amino)-2- for C52H50N8O6 882.39; phenylacetyl)-5-phenyl-2- found: 883.45 (M + H).sup.+. pyrrolidinyl)-1H-imidazol-5-yl)- 4-biphenylyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate F7 rel-(1R)-2-((2S)-2-(4-(4′-(2- RT = 1.223 minutes (condition ((2S)-1-((2R)-2- 3, 98%); LRMS: Anal. Calcd. (dimethylamino)-2- for C50H56N8O2 800.45; phenylacetyl)octahydro-1H- found: 801.51 (M + H).sup.+. indol-2-yl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)-N,N-dimethyl-2- oxo-1-phenylethanamine F8 methyl rel-((1R)-2-((2S)-2-(4- RT = 1.513 minutes (condition (4′-(2-((2S)-1-((2R)-2- 3, 98%); LRMS: Anal. Calcd. ((methoxycarbonyl)amino)-2- for C50H56N8O2 860.40; phenylacetyl)octahydro-1H- found: 861.42 (M + H).sup.+. indol-2-yl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate

(862) ##STR00845## ##STR00846##

(863) Compound F9, F10, and F11 was prepared in analogous fashion to the procedure used to sythesize Cap-3 first half procedure using acetaldehyde, propionaldehyde, and butyraldehyde respectively.

(864) Compound F12

(865) (Boc).sub.2O (2.295 g, 10.20 mmol) was added to a mixture of compound F9 (1.0 g, 4.636 mmol), hunig's base (1.78 mL, 10.20 mmol) in CH.sub.2Cl.sub.2 (12 mL), and the resulting mixture was stirred over night. The volatile component was removed in vacuo, and the residue was purified by a reverse phase HPLC system (H.sub.2O/methanol/TFA) to provide compound F12 as a clear wax (0.993 g).

(866) LC (Cond. 3): RT=1.663 min; >95% homogeneity index; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.15H.sub.21NO.sub.4: 279.33. found [M+Na].sup.+ 302.30.

(867) Compound F13 was prepared in analogous fashion to the procedure used to sythesized example 1 from Compound 1e and F12.

(868) Compound F14 was prepared in analogous fashion to the procedure used to sythesized 132e.

(869) Compound F15, F16, and F17 was prepared in analogous fashion to the procedure used to sythesize F14.

(870) TABLE-US-00054 Retention time (LC-Condition); Entry Compound Name homogeneity index MS data F9 RT = 0.580 minutes (condition 1, 94%); LRMS: Anal. Calcd. for C10H13NO2 179.09; found: 180.26 (M + H).sup.+. F10 RT = 0.563 minutes (condition 3, 94%); LRMS: Anal. Calcd. for C11H15NO2 193.11; found: 194.26 (M + H).sup.+. F11 RT = 1.023 minutes (condition 3, 94%); LRMS: Anal. Calcd. for C12H17NO2 207.13; found: 208.31 (M + H).sup.+. F12 RT = 1.663 minutes (condition 3, 95%); LRMS: Anal. Calcd. for C15H21NO4 279.15; found: 302.30 (Na + H).sup.+. F13 RT = 2.595 minutes (condition 4, 94%); LRMS: Anal. Calcd. for C56H66N8O6 946.51; found: 947.64 (M + H).sup.+. F14 (1R)-N-ethyl-2-((2S)-2-(4-(4′-(2- RT = 1.55 minutes (condition 5, ((2S)-1-((2R)-2-(ethylamino)-2- 90%); LRMS: Anal. Calcd. for phenylacetyl)-2-pyrrolidinyl)- C46H50N8O2 746.41; found: 1H-imidazol-5-yl)-4- 747.72 (M + H).sup.+. biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)-2-oxo-1- phenylethanamine F15 (1R)-N-methyl-2-((2S)-2-(4-(4′- RT = 1.50 minutes (condition 5, (2-((2S)-1-((2R)-2- 94%); LRMS: Anal. Calcd. for (methylamino)-2-phenylacetyl)- C44H46N8O2 718.37; found: 2-pyrrolidinyl)-1H-imidazol-5- 719.69 (M + H).sup.+. yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)-2-oxo-1- phenylethanamine F16 N-((1R)-2-oxo-1-phenyl-2-((2S)- RT = 1.63 minutes (condition 5, 2-(4-(4′-(2-((2S)-1-((2R)-2- 90%); LRMS: Anal. Calcd. for phenyl-2-(propylamino)acetyl)- C48H54N8O2 774.43; found: 2-pyrrolidinyl)-1H-imidazol-5- 775.76(M + H).sup.+. yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)ethyl)-1- propanamine F17 N-((1R)-2-((2S)-2-(4-(4′-(2- RT = 1.81 minutes (condition 5, ((2S)-1-((2R)-2-(butylamino)-2- 85%); LRMS: Anal. Calcd. for phenylacetyl)-2-pyrrolidinyl)- C50H58N8O2 802.47; found: 1H-imidazol-5-yl)-4- 803.79 (M + H).sup.+. biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)-2-oxo-1- phenylethyl)-1-butanamine

(871) ##STR00847## ##STR00848##

(872) Compound F18 and F23 was prepared in analogous fashion to the procedure used to sythesize example1 with following modification: N-Boc-L-alanine and N-Boc-L-valine was used in place of N-Boc-L-proline respectively.

(873) Compound F22 was prepared in analogous fashion to the procedure used to sythesize example 1 from Compound F19.

(874) Compound F19, F24 was prepared in analogous fashion to the procedure used to sythesize 132e.

Compound F25

ethyl ((1S)-1-(((2S)-2-(4-(4′-(2-((2S)-1-((2S)-2-((ethoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

(875) To a solution of F24 (0.06 g, 0.074 mmol) in DMF (1 mL) was added Hunig's base (0.105 mL, 0.593 mmol) and ethyl carbonochloridate (0.016 mL, 0.163 mmol) then stirred it at room temperature. Two hours later, checked it by LCMS. There were three major peaks which indicated desired compound, tri-coupled, and tetra-coupled compound. Stopped reaction and concentrated it by reduced pressure to get light brown oil which was treated with 10 mL of 2 M NH.sub.3 in methanol for 20 minutes then concentrated it again to a yellow solid which was purified by preparative LC to provide compound F25 as a white TFA salt (57.6 mg).

(876) LC (Cond. 6): RT=1.932 min, LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.42H.sub.54N.sub.8O.sub.6: 766.42. found 767.55.

(877) .sup.1HNMR (500 MHz, DMSO-d.sub.6) δ ppm 0.69-0.94 (m, 12H) 1.16 (t, J=7.02 Hz, 6H) 1.90-2.26 (m, 8H) 2.40 (d, J=4.88 Hz, 2H) 3.73-3.92 (m, 4H) 3.94-4.08 (m, 4H) 4.12 (t, J=7.78 Hz, 2H) 5.15 (t, J=7.02 Hz, 2H) 7.26 (d, J=8.54 Hz, 2H) 7.85-7.93 (m, 4H) 7.93-8.01 (m, 4H) 8.13 (s, 2H) 14.68 (s, 2H)

(878) Compound F20, F21, and F26 was prepared in analogous fashion to the procedure used to sythesize example1.

(879) TABLE-US-00055 Retention time (LC-Condition); Entry Compound Name homogeneity index MS data F18 RT = 2.257 minutes (condition 5, 96%); LRMS: Anal. Calcd. for C42H54N8O6 766.42; found: 767.88 (M + H).sup.+. F19 RT = 1.462 minutes (condition 5, 95%); LRMS: Anal. Calcd. for C32H38N8O2 566.31; found: 567.79 (M + H).sup.+. F20 propyl ((1S)-1-methyl-2-oxo-2- RT = 1.338 minutes (condition 3, ((2S)-2-(4-(4′-(2-((2S)-1-(N- 89%); LRMS: Anal. Calcd. for (propoxycarbonyl)-L-alanyl)-2- C40H50N8O6 738.39; found: pyrrolidinyl)-1H-imidazol-5-yl)- 739.95 (M + H).sup.+. 4-biphenylyl)-1H-imidazol-2- yl)-1- pyrrolidinyl)ethyl)carbamate F21 butyl ((1S)-2-((2S)-2-(4-(4′-(2- RT = 1.447 minutes (condition 3, ((2S)-1-(N-(butoxycarbonyl)-L- 96%); LRMS: Anal. Calcd. for alanyl)-2-pyrrolidinyl)-1H- C42H54N8O6 766.93; found: imidazol-5-yl)-4-biphenylyl)- 768.02 (M + H).sup.+. 1H-imidazol-2-yl)-1- pyrrolidinyl)-1-methyl-2- oxoethyl)carbamate F22 (2S)-2-hydroxy-N-((1S)-2-((2S)- RT = 1.703 minutes (condition 4, 2-(5-(4′-(2-((2S)-1-(N-((2S)-2- 98%); LRMS: Anal. Calcd. for hydroxy-3-methylbutanoyl)-L- C42H54N8O 766.93; found: alanyl)-2-pyrrolidinyl)-1H- 768.02 (M + H).sup.+. imidazol-4-yl)-4-biphenylyl)- 1H-imidazol-2-yl)-1- pyrrolidinyl)-1-methyl-2- oxoethyl)-3-methylbutanamide F23 RT = 2.881 minutes (condition 7, 93%); LRMS: Anal. Calcd. for C46H62N8O6 822.48; found: 823.95 (M + H).sup.+. F24 RT = 1.743 minutes (condition 7, 98%); LRMS: Anal. Calcd. for C36H46N8O2 622.37; found: 624.07 (M + H).sup.+. F25 ethyl ((1S)-1-(((2S)-2-(4-(4′-(2- RT = 1.932 minutes (condition 6, ((2S)-1-((2S)-2- 97%); LRMS: Anal. Calcd. for ((ethoxycarbonyl)amino)-3- C42H54N8O6 766.42; found: methylbutanoyl)-2-pyrrolidinyl)- 767.55 (M + H).sup.+. 1H-imidazol-4-yl)-4- biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate F26 isopropyl ((1S)-1-(((2S)-2-(4- RT = 2.122 minutes (condition 6, (4′-(2-((2S)-1-((2S)-2- 98%); LRMS: Anal. Calcd. for ((isopropoxycarbonyl)amino)-3- C44H58N8O6 794.45; found: methylbutanoyl)-2-pyrrolidinyl)- 795.58 (M + H).sup.+. 1H-imidazol-4-yl)-4- biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate

(880) ##STR00849##

(881) TABLE-US-00056 Retention time (LC-Condition); Entry Compound Name homogeneity index MS data F27 (2S)-1-((2S)-2-(4-(4′-(2-((2S)-1- RT = 1.03 minutes (condition 3, ((2S)-2-hydroxypropanoyl)-2- 98%); LRMS: Anal. Calcd. for pyrrolidinyl)-1H-imidazol-5-yl)- C32H36N6O4 568.28; found: 4-biphenylyl)-1H-imidazol-2-yl)- 569.76 (M + H).sup.+. 1-pyrrolidinyl)-1-oxo-2-propanol F28 tert-butyl ((1S)-1-(((2S)-2-(5-(4′- RT = 1.847 minutes (condition 3, (2-((2S)-1-((2S)-2-((tert- 95%); LRMS: Anal. Calcd. for butoxycarbonyl)(methyl)amino)- C50H70N8O6 878.54; found: 4-methylpentanoyl)-2- 879.53 (M + H).sup.+. pyrrolidinyl)-1H-imidazol-4-yl)- 4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)carbonyl)-3- methylbutyl)methylcarbamate F29 tert-butyl ((1S)-1-(((2S)-2-(5-(4′- RT = 2.202 minutes (condition 8, (2-((2S)-1-((2S)-2-((tert- 98%); LRMS: Anal. Calcd. for butoxycarbonyl)(methyl)amino)- C50H70N8O6 878.54; found: 3-methylpentanoyl)-2- 879.57 (M + H).sup.+. pyrrolidinyl)-1H-imidazol-4-yl)- 4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)carbonyl)-2- methylbutyl)methylcarbamate F30 tert-butyl ((1S)-1-(((2S)-2-(5-(4′- RT = 1.743 minutes (condition 8, (2-((2S)-1-((2S)-2-((tert- 96%); LRMS: Anal. Calcd. for butoxycarbonyl)(methyl)amino)- C48H66N8O6 850.51; found: 3-methylbutanoyl)-2- 851.52 (M + H).sup.+. pyrrolidinyl)-1H-imidazol-4-yl)- 4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)carbonyl)-2- methylpropyl)methylcarbamate F31 tert-butyl ((1S,2R)-1-(((2S)-2-(4- RT = 1.82 minutes (condition 8, (4′-(2-((2S)-1-(N-(tert- 98%); LRMS: Anal. Calcd. for butoxycarbonyl)-N-methyl-L- C50H70N8O6 878.54; found: alloisoleucyl)-2-pyrrolidinyl)- 879.54 (M + H).sup.+. 1H-imidazol-5-yl)-4-biphenylyl)- 1H-imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-2- methylbutyl)methylcarbamate F32 (2S)-N,4-dimethyl-1-((2S)-2-(4- RT = 3.715 minutes (condition 9, (4′-(2-((2S)-1-((2S)-4-methyl-2- 98%); LRMS: Anal. Calcd. for (methylamino)pentanoyl)-2- C40H54N8O2 678.44; found: pyrrolidinyl)-1H-imidazol-5-yl)- 679.46 (M + H).sup.+. 4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)-1-oxo-2- pentanamine F33 (2S)-N,3-dimethyl-1-((2S)-2-(4- RT = 3.058 minutes (condition 9, (4′-(2-((2S)-1-((2S)-3-methyl-2- 99%); LRMS: Anal. Calcd. for (methylamino)pentanoyl)-2- C36H46N8O2 678.44; found: pyrrolidinyl)-1H-imidazol-5-yl)- 679.61 (M + H).sup.+. 4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)-1-oxo-2- pentanamine F34 (2S)-N,3-dimethyl-1-((2S)-2-(4- RT = 3.206 minutes (condition 9, (4′-(2-((2S)-1-((2S)-3-methyl-2- 99%); LRMS: Anal. Calcd. for (methylamino)butanoyl)-2- C38H50N8O2 650.41; found: pyrrolidinyl)-1H-imidazol-5-yl)- 651.41 (M + H).sup.+. 4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)-1-oxo-2- butanamine F35 (2S,3R)-N,3-dimethyl-1-((2S)-2- RT = 3.43 minutes (condition 9, (4-(4′-(2-((2S)-1-((2S,3R)-3- 98%); LRMS: Anal. Calcd. for methyl-2- C40H54N8O2 678.44; found: (methylamino)pentanoyl)-2- 679.44 (M + H).sup.+. pyrrolidinyl)-1H-imidazol-5-yl)- 4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)-1-oxo-2- pentanamine

(882) Compound F27 to F31 was prepared in analogous fashion to the procedure used to sythesize example 1.

(883) Compound F32 to F35 was prepared in analogous fashion to the procedure used to synthesize 1e.

(884) ##STR00850##

(885) Compound F36 was prepared in analogous fashion to the procedure used to sythesize Cap-52.

(886) Compound F37, F38, and F39 was prepared in analogous fashion to the procedure used to synthesize example 1 from Compound F36 and LS16 respectively.

(887) TABLE-US-00057 Retention time (LC- Condition); homogeneity Entry Compound index MS data F36 RT = 1.55 minutes (condition 10); LRMS: Anal. Calcd. for C10H13NO2 189.1; found: 190.13 (M + H).sup.+. .sup.1H NMR (500 MHz, DMSO- d.sub.6) δ ppm 0.71-1.00 (m, 6H) 1.16-1.41 (m, 3H) 1.75-2.09 (m, 1H) 3.39-3.64 (m, 3H) 7.13 (s, 1H) 12.27 (s, 1H) F37 methyl ((1S)-1-(((2S)-2-(4-(4′-(2- RT = 2.572 minutes ((2S)-1-((2S)-2- (condition 4, 98%); LRMS: ((methoxycarbonyl)amino)-2,3- Anal. Calcd. for dimethylbutanoyl)-2- C42H54N8O6 766.42; pyrrolidinyl)-1H-imidazol-5-yl)-4- found: 767.48 (M + H).sup.+. biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-1,2- dimethylpropyl)carbamate F38 methyl ((1S)-2-((2S)-2-(4-(4′-(2- RT = 2.128 minutes ((2S)-1-((2S)-2- (condition 7, 98%); LRMS: ((methoxycarbonyl)amino)-2- Anal. Calcd. for (tetrahydro-2H-pyran-4-yl)acetyl)- C44H54N8O8 822.41; found: 2-pyrrolidinyl)-1H-imidazol-5-yl)- 823.45 (M + H).sup.+. 4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)-2-oxo-1- (tetrahydro-2H-pyran-4- yl)ethyl)carbamate F39 methyl (2-((2S)-2-(4-(4′-(2-((2S)- RT = 2.162 minutes 1-(((methoxycarbonyl)amino) (condition 7, 98%); LRMS: (tetrahydro-2H-pyran-4-yl)acetyl)- Anal. Calcd. for 2-pyrrolidinyl)-1H-imidazol-5-yl)- C44H54N8O8 822.42; found: 4-biphenylyl)-1H-imidazol-2-yl)- 823.49 (M + H).sup.+. 1-pyrrolidinyl)-2-oxo-1- (tetrahydro-2H-pyran-4-yl) ethyl)carbamate

(888) ##STR00851##

(889) Compound F41 was prepared in analogous fashion to the procedure used to sythesize example 1.

(890) Compound F42 was prepared in analogous fashion to the procedure used to sythesize 1e.

(891) TABLE-US-00058 Retention time (LC- Condition); homogeneity Entry Compound Name index MS data F40 RT = 2.72 minutes (condition 10); LRMS: Anal. Calcd. for C46H54N8O6 814.42; found: 815.98 (M + H).sup.+. F41 methyl ((1S)-2-((2S)-2-(4-(4′-(2- RT = 2.048 minutes (condition ((2S)-1-((2R)-2-(ethylamino)-2- 10, 95%); LRMS: Anal. Calcd. phenylacetyl)-2-pyrrolidinyl)- for C41H46N8O4 714.36; 1H-imidazol-5-yl)-4- found: 715.84 (M + H).sup.+. biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)-1-methyl-2- oxoethyl)carbamate

(892) ##STR00852##

(893) Compound F42 was prepared in analogous fashion to the procedure used to sythesize example 28f employing Cap-2 in place of Cap-4. Compound F43 was prepared in analogous fashion to the procedure used to sythesize 2 from Compound F42.

(894) TABLE-US-00059 Retention time (LC- Condition); homogeneity Entry Compound Name index MS data F42 RT = 2.0 minutes (condition 10, 95%); LRMS: Anal. Calcd. for C38H43N7O 613.35; found: 614.40 (M + H).sup.+. F43 methyl ((1S)-1-(((2S)-2-(5-(4′- RT = 2.308 minutes (condition (2-((2S)-1-((2R)-2- 10, 98%); LRMS: Anal. Calcd. (diethylamino)-2-phenylacetyl)- for C50H70N8O6 784.44; found: 2-pyrrolidinyl)-1H-imidazol-4- 785.49 (M + H).sup.+. yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)carbonyl)- 1,2-dimethylpropyl)carbamate

(895) ##STR00853##

(896) Compound F44 was prepared following below paper with following modification: glycine was used in place of leucine.

(897) A simple method for preparation of N-mono- and N,N-di-alkylated α-amino acids Yuntao Song et al., Tetrahedron Lett. 41, October 2000, Pages 8225-8230.

(898) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.37-1.62 (m, 2H) 1.86 (dd, J=12.36, 1.98 Hz, 2H) 3.01-3.12 (m, 1H) 3.15 (s, 2H) 3.25 (t, J=11.75 Hz, 2H) 3.86 (dd, J=11.44, 4.12 Hz, 2H) 7.67-8.48 (m, 1H).

(899) Compound F45

(900) 2-(tetrahydro-2H-pyran-4-ylamino)acetic acid (0.2 g, 1.256 mmol) F44 was dissolved in DMF (22.5 mL) and Et.sub.3N (2.5 mL, 17.94 mmol). After 5 minutes BOC.sub.2O (0.583 mL, 2.51 mmol) was added and the reaction solution was heated to 60° C. for 1 h. The reaction was concentrated by reduced pressure providing a light yellow oil to which was added 20 mL HCl/H.sub.2O which was adjusted to PH3 at 0° C. and stirred for 10 minutes. The reaction mixture was extracted by ethyl acetate 3×20 mL, dried (MgSO.sub.4), filtered, and concentrated to dryness. Ether was added and the mixture was sonicated and filtered providing a white solid F45 2-(tert-butoxycarbonyl(tetrahydro-2H-pyran-4-yl)amino)acetic acid (0.14 g, 0.540 mmol, 43.0% yield).

(901) .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ ppm 1.27-1.44 (m, 9H) 1.43-1.69 (m, 4H) 3.19-3.39 (m, 2H) 3.74 (s, 2H) 3.79-3.92 (m, 2H) 3.97-4.16 (m, 1H) 12.46 (s, 1H).

(902) ##STR00854##

(903) Compound F46 was prepared following the below referenced procedure with following modification: (S)-tert-butyl 2-amino-3-methylbutanoate was used in place of (S)-methyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methylbutanoate. Hans-Joachim Knölker, et al. Synlett 1997; 925-928

(904) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 0.77-0.97 (m, 6H) 1.32-1.45 (m, 9H) 1.45-1.56 (m, 2H) 1.74-1.91 (m, 2H) 1.94-2.11 (m, 1H) 3.36-3.53 (m, 2H) 3.76 (dd, J=8.09, 6.26 Hz, 1H) 3.77-3.90 (m, 2H) 4.69 (dd, J=9.00, 4.73 Hz, 1H) 7.35 (d, J=8.24 Hz, 1H).

(905) Compound F47

(906) To a Compound 46 (S)-tert-butyl 3-methyl-2-((tetrahydro-2H-pyran-4-yloxy)carbonylamino)butanoate (0.21 g, 0.697 mmol) was added HCl in dioxane (15 mL, 60.0 mmol) and the mixture was stirred at room temperature under nitrogen for three hours. The reaction was done and concentrated under reduced pressure to provide F47(S)-3-methyl-2-((tetrahydro-2H-pyran-4-yloxy)carbonylamino)butanoic acid (0.1694 g, 0.691 mmol, 100% yield) as a clear wax.

(907) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 0.88 (t, J=6.71 Hz, 6H) 1.41-1.60 (m, 2H) 1.85 (d, J=12.21 Hz, 2H) 1.97-2.08 (m, 1H) 3.41 (t, J=10.68 Hz, 1H) 3.45-3.52 (m, 1H) 3.64-3.74 (m, 1H) 3.77-3.89 (m, 2H) 4.63-4.72 (m, 1H) 7.32 (d, J=8.55 Hz, 1H) 12.52 (s, 1H).

(908) ##STR00855## ##STR00856## ##STR00857##

(909) Compound F48 to F58 except F51 was prepared in analogous fashion to the procedure used to sythesize example 1 from LS18.

(910) Compound F51 was prepared in analogous fashion to the procedure used to sythesize 1e from F50.

(911) TABLE-US-00060 Retention time (LC- Condition); homogeneity Entry Compound Name index MS data F48 methyl ((1S)-2-methyl-1-(((2S)-2- RT = 2.103 minutes (4-(4′-(2-((2S)-1-(N-(tetrahydro- (condition 7, 98%); LRMS: 2H-pyran-4-yl)-L-alanyl)-2- Anal. Calcd. for pyrrolidinyl)-1H-imidazol-4-yl)-4- C41H52N8O5 736.41; biphenylyl)-1H-imidazol-2-yl)-1- found: 737.07 (M + H).sup.+. pyrrolidinyl)carbonyl)propyl) carbamate F49 methyl ((1S)-2-methyl-1-(((2S)-2- RT = 2.117 minutes (4-(4′-(2-((2S)-1-(N-(tetrahydro- (condition 7, 98%); LRMS: 2H-pyran-4-yl)-L-valyl)-2- Anal. Calcd. for pyrrolidinyl)-1H-imidazol-4-yl)-4- C43H56N8O5 764.44; biphenylyl)-1H-imidazol-2-yl)-1- found: 765.75 (M + H).sup.+. pyrrolidinyl)carbonyl)propyl) carbamate F50 RT = 2.547 minutes (condition 7, 98%); LRMS: Anal. Calcd. for C45H58N8O7 822.44; found: 823.17 (M + H).sup.+. F51 methyl ((1S)-2-methyl-1-(((2S)-2- RT = 2.138 minutes (4-(4′-(2-((2S)-1-(N-(tetrahydro- (condition 7, 96%); LRMS: 2H-pyran-4-yl)glycyl)-2- Anal. Calcd. for pyrrolidinyl)-1H-imidazol-4-yl)-4- C40H50N8O5 722.39; biphenylyl)-1H-imidazol-2-yl)-1- found: 723.63 (M + H).sup.+. pyrrolidinyl)carbonyl)propyl) carbamate F52 methyl ((1S)-2-methyl-1-(((2S)-2- RT = 2.083 minutes (4-(4′-(2-((2S)-1-(N-(tetrahydro- (condition 7, 98%); LRMS: 2H-pyran-4-yl)-D-valyl)-2- Anal. Calcd. for pyrrolidinyl)-1H-imidazol-4-yl)-4- C43H56N8O5 764.44; biphenylyl)-1H-imidazol-2-yl)-1- found: 765.78 (M + H).sup.+. pyrrolidinyl)carbonyl)propyl) carbamate F53 methyl ((1S)-2-methyl-1-(((2S)-2- RT = 0.963 minutes (4-(4′-(2-((2S)-1-(N-(tetrahydro- (condition 11, 95%); LRMS: 2H-pyran-4-yl)-D-alanyl)-2- Anal. Calcd. for pyrrolidinyl)-1H-imidazol-4-yl)-4- C43H54N8O7 736.41; biphenylyl)-1H-imidazol-2-yl)-1- found: 737.54 (M + H).sup.+. pyrrolidinyl)carbonyl)propyl) carbamate F54 (3S)-tetrahydro-3-furanyl ((1S)-1- RT = 2.378 minutes (((2S)-2-(4-(4′-(2-((2S)-1-(N- (condition 7, 95%); LRMS: (methoxycarbonyl)-L-valyl)-2- Anal. Calcd. for pyrrolidinyl)-1H-imidazol-4-yl)-4- C43H54N8O7 794.41; biphenylyl)-1H-imidazol-2-yl)-1- found: 795.94 (M + H).sup.+. pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate F55 tetrahydro-2H-pyran-4-yl ((1S)-1- RT = 2.447 minutes (((2S)-2-(4-(4′-(2-((2S)-1-(N- (condition 7, 99%); LRMS: (methoxycarbonyl)-L-valyl)-2- Anal. Calcd. for pyrrolidinyl)-1H-imidazol-4-yl)-4- C44H56N8O7 808.43; biphenylyl)-1H-imidazol-2-yl)-1- found: 809.42 (M + H).sup.+. pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate F56 (3R)-tetrahydro-3-furanyl ((1S)-1- RT = 2.398 minutes (((2S)-2-(4-(4′-(2-((2S)-1-(N- (condition 7, 96%); LRMS: (methoxycarbonyl)-L-valyl)-2- Anal. Calcd. for pyrrolidinyl)-1H-imidazol-4-yl)-4- C43H54N8O7 794.41; biphenylyl)-1H-imidazol-2-yl)-1- found: 795.36 (M + H).sup.+. pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate F57 methyl ((1S)-1-(((2S)-2-(4-(4′-(2- RT = 2.272 minutes ((2S)-1-((2R)-2- (condition 7, 98%); LRMS: ((methoxycarbonyl)amino)-2- Anal. Calcd. for (tetrahydro-2H-pyran-4-yl)acetyl)- C42H52N8O7 780.40; 2-pyrrolidinyl)-1H-imidazol-5-yl)- found: 781.34 (M + H).sup.+. 4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate F58 methyl ((1S)-1-(((2S)-2-(4-(4′-(2- RT = 2.225 minutes ((2S)-1-((2S)-2- (condition 7, 98%); LRMS: ((methoxycarbonyl)amino)-2- Anal. Calcd. for (tetrahydro-2H-pyran-4-yl)acetyl)- C42H52N8O7 780.40; 2-pyrrolidinyl)-1H-imidazol-5-yl)- found: 781.27 (M + H).sup.+. 4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate

(912) ##STR00858##

(913) Compound F59 was prepared in analogous fashion to the procedure used to sythesize 26a with following modification: Boc-L-val-OH was used in place of Boc-D-val-OH.

(914) Compound F60 to F62 were prepared in analogous fashion to the procedure used to sythesize example 29 from F59.

(915) Compound F63 and F64 were prepared in analogous fashion to the procedure used to sythesized Cap45.

(916) TABLE-US-00061 Retention time (LC- Condition); homogeneity Entry Compound Name index MS data F59 RT = 1.743 minutes (condition 7, 98%); LRMS: Anal. Calcd. for C36H46N8O2 622.37; found: 624.07 (M + H).sup.+. F60 N-((1S)-1-(((2S)-2-(4-(4′-(2-((2S)- RT = 2.047 minutes 1-((2S)-2-acetamido-3- (condition 10, 98%); LRMS: methylbutanoyl)-2-pyrrolidinyl)- Anal. Calcd. for 1H-imidazol-4-yl)-4-biphenylyl)- C40H50N8O4 706.44; 1H-imidazol-2-yl)-1-pyrrolidinyl) found: 707.77 (M + H).sup.+. carbonyl)-2-methylpropyl) acetamide F61 N-((1S)-2-methyl-1-(((2S)-2-(4- RT = 2.215 minutes (4′-(2-((2S)-1-((2S)-3-methyl-2- (condition 10 98%); LRMS: (propionylamino)butanoyl)-2- Anal. Calcd. for pyrrolidinyl)-1H-imidazol-4-yl)-4- C42H54N8O4 734.43; biphenylyl)-1H-imidazol-2-yl)-1- found: 735.87(M + H).sup.+. pyrrolidinyl)carbonyl)propyl) propanamide F62 2-methoxy-N-((1S)-1-(((2S)-2-(4- RT = 2.232 minutes (4′-(2-((2S)-1-((2S)-2- (condition 10, 99%); LRMS: ((methoxyacetyl)amino)-3- Anal. Calcd. for methylbutanoyl)-2-pyrrolidinyl)- C42H54N8O6 766.93; 1H-imidazol-4-yl)-4-biphenylyl)- found: 768.05 (M + H).sup.+. 1H-imidazol-2-yl)-1-pyrrolidinyl) carbonyl)-2-methylpropyl) acetamide F63 1-methyl-3-((1S)-2-methyl-1- RT = 2.082 minutes (((2S)-2-(4-(4′-(2-((2S)-1-(N- (condition 10, 95%); LRMS: (methylcarbamoyl)-L-valyl)-2- Anal. Calcd. for pyrrolidinyl)-1H-imidazol-4-yl)- C40H52N10O4 736.42; 4-biphenylyl)-1H-imidazol-2-yl)- found: 737.86 (M + H).sup.+. 1-pyrrolidinyl)carbonyl)propyl) urea F64 1-ethyl-3-((1S)-1-(((2S)-2-(4-(4′- RT = 1.617 minutes (2-((2S)-1-((2S)-2- (condition 12, 93%); LRMS: ((ethylcarbamoyl)amino)-3- Anal. Calcd. for methylbutanoyl)-2-pyrrolidinyl)- C42H56N10O4 764.45; 1H-imidazol-4-yl)-4-biphenylyl)- found: 765.57 (M + H).sup.+. 1H-imidazol-2-yl)-1-pyrrolidinyl) carbonyl)-2-methylpropyl)urea

(917) ##STR00859## ##STR00860##

(918) To a solution of F59 (0.06 g, 0.074 mmol in DMF (1 mL) was added dimethylsulfamoyl chloride (0.016 mL, 0.148 mmol) and Hunig's Base (0.078 mL, 0.445 mmol) then stirred it at room temperature for 3 h. Solvent was removed by reduced pressure to get light brown oil which was purified by PreHPLC providing F65 N—((S)-1-((S)-2-(5-(4′-(2-((S)-1-((S)-2-(N,N-dimethylsulfamoylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)propane-2-sulfonamide (19.0 mg, 0.018 mmol, 24.08% yield)

(919) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 0.65-1.03 (m, 12H) 1.87-2.08 (m, 4H) 2.06-2.27 (m, 4H) 2.37-2.46 (m, 2H) 2.56-2.69 (m, 12H) 3.66-3.92 (m, 6H) 5.14 (t, J=7.63 Hz, 2H) 7.49 (d, J=9.16 Hz, 2H) 7.89 (d, J=8.24 Hz, 4H) 7.96 (s, 4H) 8.14 (s, 2H) 14.72 (s, 2H)

(920) RT=2.047 minutes (condition 10, 98%); LRMS: Anal. Calcd. for C40H50N8O4 706.38. found: 707.77 (M+H).sup.+.

(921) 1b Fret (EC50, uM)=0.21

(922) Compound F66 to F69 was prepared in analogous fashion to the procedure used to sythesize F65 from Compound F59.

(923) TABLE-US-00062 Retention time (LC- Condition); homogeneity Entry Compound Name index MS data F66 N-((1S)-2-methyl-1-(((2S)-2-(4- RT = 2.02 minutes (4′-(2-((2S)-1-((2S)-3-methyl-2- (condition 10, 98%); LRMS: ((methylsulfonyl)amino) Anal. Calcd. for butanoyl)-2-pyrrolidinyl)-1H- C38H50N8O6S2 778.38; imidazol-4-yl)-4-biphenylyl)-1H- found: 779.60 (M + H).sup.+. imidazol-2-yl)-1-pyrrolidinyl) carbonyl)propyl) methanesulfonamide F67 N-((1S)-1-(((2S)-2-(4-(4′-(2-((2S)- RT = 2.172 minutes 1-((2S)-2-((ethylsulfonyl)amino)- (condition 10 98%); LRMS: 3-methylbutanoyl)-2- Anal. Calcd. for pyrrolidinyl)-1H-imidazol-4-yl)-4- C40H54N8O6S2 807.04; biphenylyl)-1H-imidazol-2-yl)-1- found: 808.42 (M + H).sup.+. pyrrolidinyl)carbonyl)-2- methylpropyl)ethanesulfonamide F68 N-((1S)-1-(((2S)-2-(4-(4′-(2-((2S)- RT = 2.217 minutes 1-((2S)-2-((cyclopropylsulfonyl) (condition 10, 93%); LRMS: amino)-3-methylbutanoyl)-2- Anal. Calcd. for pyrrolidinyl)-1H-imidazol-4-yl)-4- C42H54N8O6S2 831.06; biphenylyl)-1H-imidazol-2-yl)-1- found: 832.49 (M + H).sup.+. pyrrolidinyl)carbonyl)-2- methylpropyl) cyclopropanesulfonamide F69 N-((1S)-1-methyl-2-((2S)-2-(5- RT = 1.983 minutes (4′-(2-((2S)-1-(N- (condition 10, 95%); LRMS: (methylsulfonyl)-L-alanyl)-2- Anal. Calcd. for pyrrolidinyl)-1H-imidazol-4-yl)-4- C34H42N8O6S2 722.27; biphenylyl)-1H-imidazol-2-yl)-1- found: 723.68 (M + H).sup.+. pyrrolidinyl)-2-oxoethyl) methanesulfonamide

(924) ##STR00861##

(925) Compound F70 was prepared following the procedure described in Anna Helms et al., J. Am. Chem. Soc. 1992 114(15) pp 6227-6238.

(926) Compound F71 was prepared in analogous fashion to the procedure used to sythesize Example 1.

(927) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 0.69-0.95 (m, 12H) 1.92 (s, 12H) 1.97-2.27 (m, 8H) 2.40 (s, 2H) 3.55 (s, 6H) 3.73-3.97 (m, 4H) 4.12 (t, J=7.78 Hz, 2H) 5.14 (t, J=7.02 Hz, 2H) 7.34 (d, J=8.24 Hz, 2H) 7.49-7.70 (m, 4H) 8.04 (s, 2H) 14.59 (s, 2H)

(928) RT=2.523 minutes (condition 7, 96%); LRMS: Anal. Calcd. for C44H58N8O6 794.45. found: 795.48 (M+H).sup.+.

Section cj

Synthesis of Carbamate Replacements

Example cj-2 and cj-3

(929) ##STR00862##

Preparation of (S)-tert-Butyl 2-(5-(4′-(2-((S)-1-((S)-2-amino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (cj-2)

(930) ##STR00863##

(931) To a solution of (S)-tert-butyl 2-(5-(4′-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (cj-1) (1.00 g, 1.91 mmol), iPr.sub.2NEt (1.60 mL, 9.19 mmol) and N—Z-valine (0.62 g, 2.47 mmol) in DMF (10 mL) was added HATU (0.92 g, 2.42 mmol). The solution was allowed to stir at rt for 1 h and then it was poured into ice water (ca. 250 mL) and allowed to stand for 20 min. The mixture was filtered and the solid washed with water and then dried in vacuo overnight to afford a colorless solid (1.78 g) which was used as such in the next step. LCMS: Anal. Calcd. for C.sub.44H.sub.51N.sub.7O.sub.5: 757. found: 758 (M+H).sup.+.

(932) A mixture of this material (1.70 g) and 10% Pd—C (0.37 g) in MeOH (100 mL) was hydrogenated (balloon pressure) for 12 h. The mixture was then filtered and the solvent removed in vacuo. The residue was purified by silica gel chromatography (Biotage system/0-10% MeOH—CH.sub.2Cl.sub.2) to afford the title compound as a light yellow foam (0.90 g, 76%).

(933) .sup.1HNMR (400 MHz, DMSO-d.sub.6) δ 12.18 (s, 0.35H), 11.73 (s, 0.65H), 11.89 (s, 0.65H), 11.82 (s, 0.35H), 7.77-7.81 (m, 3H), 7.57-7.71 (m, 5H), 7.50-7.52 (m, 2H), 5.17 (dd, J=3.6, 6.5 Hz, 0.3H), 5.08 (dd, J=3.6, 6.5 Hz, 0.7H), 4.84 (m, 0.3H), 4.76 (m, 0.7H), 3.67-3.69 (m, 1H), 3.50-3.62 (m, 1H), 3.34-3.47 (m, 2H), 2.22-2.28 (m, 2H), 2.10-2.17 (m, 2H), 1.74-2.05 (m, 6H), 1.40 (s, 4H), 1.15 (s, 5H), 0.85-0.91 (m, 4H), 0.79 (d, J=6.5 Hz, 2H).

(934) LCMS: Anal. Calcd. for C.sub.36H.sub.45N.sub.7O.sub.3: 623. found: 624 (M+H).sup.+.

Preparation of (S)-tert-Butyl 2-(5-(4′-(2-((S)-1-((R)-2-amino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (cj-3)

(935) ##STR00864##

(936) (S)-tert-Butyl 2-(5-(4′-(2-((S)-1-((R)-2-amino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (cj-3) was prepared using the same method used to prepare cj-2 to give a colorless foam (1.15 g, 76%). .sup.1HNMR (400 MHz, DMSO-d.sub.6) δ 12.17 (s, 0.35H), 12.04 (s, 0.65H), 11.89 (s, 0.65H), 11.81 (s, 0.35H), 7.78-7.83 (m, 3H), 7.60-7.71 (m, 5H), 7.43-7.52 (m, 2H), 5.22-5.25 (m, 0.4H), 5.05-5.07 (m, 0.6H), 4.83-4.86 (m, 0.5H), 4.72-4.78 (m, 0.5H), 3.78-3.84 (m, 1H), 3.49-3.64 (m, 2H), 3.35-3.43 (m, 2H), 2.19-2.32 (m, 1H), 2.04-2.17 (m, 3H), 1.95-2.04 (m, 2H), 1.76-1.90 (m, 3H), 1.40 (s, 4H), 1.15 (s, 5H), 0.85-0.91 (m, 4H), 0.67 (d, J=6.5 Hz, 1H), 0.35 (d, J=6.5 Hz, 1H). LCMS: Anal. Calcd. for C.sub.36H.sub.45N.sub.7O.sub.3: 623. found: 624 (M+H).sup.+.

Example cj-4 and cj-5

(937) ##STR00865##

Preparation of (S)-tert-Butyl 2-(5-(4′-(2-((S)-1-((S)-3-methyl-2-(pyrimidin-2-ylamino)butanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (cj-4)

(938) ##STR00866##

(939) A mixture of (S)-tert-butyl 2-(5-(4′-(2-((S)-1-((S)-2-amino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (cj-2) (0.45 g, 0.72 mmol), 2-bromopyrimidine (0.37 g, 2.34 mmol) and iPr.sub.2NEt (0.20 mL, 1.18 mmol) in toluene-DMSO (4:1, 5 mL) was heated at 90° C. overnight. The volatiles were removed in vacuo and the residue was purified by preparative HPLC (YMC Pack C-18, 30×100 mm/MeCN—H.sub.2O-TFA). The title compound (0.56 g, 74%), as its TFA salt, was obtained as a yellow-orange glass.

(940) .sup.1HNMR (400 MHz, DMSO-d.sub.6) δ 14.56 (br s, 2H), 8.28 (d, J=5.0 Hz, 1H), 8.12-8.20 (m, 2H), 7.94-7.97 (m, 3H), 7.83-7.91 (m, 5H), 7.06 (d, J=8.1 Hz, 1H), 6.62 (app t, J=5.0 Hz, 1H), 4.99-5.10 (m, 2H), 4.50 (app t, J=7.7 Hz, 1H), 4.07-4.12 (m, 2H), 3.83-3.87 (m, 1H), 3.56-3.62 (m, 1H), 3.40-3.47 (m, 2H), 2.36-2.41 (m, 1H), 1.94-2.22 (m, 6H), 1.40 (s, 4H), 1.17 (s, 5H), 0.88 (app t, J=6.5 Hz, 6H).

(941) LCMS: Anal. Calcd. for C.sub.40H.sub.47N.sub.9O.sub.3: 701. found: 702 (M+H).sup.+.

Preparation of (S)-tert-Butyl-2-(5-(4′-(2-((S)-1-((R)-3-methyl-2-(pyrimidin-2-ylamino)butanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (cj-5)

(942) ##STR00867##

(943) The TFA salt of the title compound was prepared following the same method used to prepare cj-4 to give a light yellow solid (0.375 g, 59%).

(944) .sup.1HNMR (400 MHz, DMSO-d.sub.6) δ 14.67 (br s, 2H), 8.30 (d, J=4.3 Hz, 1H), 8.04-8.19 (m, 2H), 7.84-7.96 (m, 8H), 6.88 (d, J=8.6 Hz, 1H), 6.61 (app t, J=4.5 Hz, 1H), 5.17 (dd, J=4.4, 8.0 Hz, 1H), 5.00-5.07 (m, 1H), 4.67 (dd, J=7.3, 8.1 Hz, 1H), 3.91-3.96 (m, 1H), 3.70-3.75 (m, 1H), 3.56-3.62 (m, 1H), 3.42-3.45 (m, 1H), 2.39-2.43 (m, 2H), 2.04-2.16 (m, 5H), 1.94-1.97 (m, 2H), 1.40 (s, 4H), 1.17 (s, 5H), 0.95 (d, J=6.6 Hz, 2.5H), 0.91 (d, J=6.6 Hz, 2.5H), 0.86 (d, J=6.6 Hz, 0.5H), 0.81 (d, J=6.6 Hz, 0.5H).

(945) LCMS: Anal. Calcd. for C.sub.40H.sub.47N.sub.9O.sub.3: 701. found: 702 (M+H).sup.+.

Example cj-6 and cj-7

(946) ##STR00868##

Preparation of 1-Methyl-2-(methylthio)-4,5-dihydro-1H-imidazole hydroiodide

(947) ##STR00869##

(948) The title compound was prepared according to: Kister, J.; Assef, G.; Dou, H. J.-M.; Metzger, J. Tetrahedron 1976, 32, 1395. Thus, a solution of N-methylethylenediamine (10.8 g, 146 mmol) in EtOH-H.sub.2O (1:1, 90 mL) was preheated to 60° C. and CS.sub.2 (9.0 mL, 150 mmol) was added dropwise. The resulting mixture was heated at 60° C. for 3 h and then conc. HCl (4.7 mL) was slowly added. The temperature was raised to 90° C. and stirring was continued for 6 h. After the cooled mixture had been stored at −20° C., it was filtered and the resulting solid dried in vacuo to afford 1-methylimidazolidine-2-thione (8.43 g, 50%) as a beige solid.

(949) .sup.1HNMR (400 MHz, CDCl.sub.3) δ 5.15 (s, br, 1H), 3.67-3.70 (m, 2H), 3.53-3.58 (m, 2H), 3.11 (s, 3H).

(950) To a suspension of 1-methylimidazolidine-2-thione (5.17 g, 44.5 mmol) in acetone (50 mL) was added MeI (2.9 mL, 46.6 mmol). The solution was allowed to stir at room temperature for 4 h and the resulting solid was quickly filtered and then dried in vacuo to give 1-methyl-2-(methylthio)-4,5-dihydro-1H-imidazole hydroiodide (8.79 g, 77%) as beige solid.

(951) .sup.1HNMR (400 MHz, CDCl.sub.3) δ 9.83 (s, br, 1H), 3.99-4.12 (m, 4H), 3.10 (s, 3H), 2.99 (s, 3H).

Preparation of (S)-tert-Butyl 2-(5-(4′-(2-((S)-1-((S)-3-methyl-2-(1-methyl-4-5-dihydroimidazol-2-ylamino)butanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (cj-6)

(952) ##STR00870##

(953) A mixture of (S)-tert-butyl 2-(5-(4′-(2-((S)-1-((S)-2-amino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-pyrrolidine-1-carboxylate (cj-2) (0.280 g, 0.448 mmol) and 1-methyl-2-(methylthio)-4,5-dihydro-1H-imidazole hydroiodide (cj-3a) (0.121 g, 0.468 mmol) in CH.sub.3CN (5 mL) was heated at 90° C. for 12 h. Another 0.030 g of 1-methyl-2-(methylthio)-4,5-dihydro-1H-imidazole hydroiodide (cj-3a) was added and heating continued for a further 12 h. The crude reaction mixture was directly purified by prep HPLC (Luna C-18/MeCN—H.sub.2O-TFA) to give the TFA salt of the title compound (0.089 g) as a light yellow solid which was used as such in the subsequent steps.

(954) LCMS: Anal. Calcd. for C.sub.40H.sub.51N.sub.9O.sub.3: 705. found: 706 (M+H).sup.+.

Preparation of (S)-tert-Butyl 2-(5-(4′-(2-((S)-1-((R)-3-methyl-2-(1-methyl-4-5-dihydroimidazol-2-ylamino)butanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (cj-7)

(955) ##STR00871##

(956) The title compound was prepared from cj-3 according to the method described for the synthesis of cj-6, except that the reaction mixture was initially purified by prep HPLC (YMC-Pack 25×250 mm/MeCN—H.sub.2O—NH.sub.4OAc) and then repurified by prep HPLC (Luna Phenyl-hexyl//MeCN—H.sub.2O—NH.sub.4OAc). This gave the desired product (0.005 g) as a foam which was used as such in the subsequent steps.

(957) LCMS: Anal. Calcd. for C.sub.40H.sub.51N.sub.9O.sub.3: 705. found: 706 (M+H).sup.+.

Example cj-8 and cj-9

(958) ##STR00872##

Preparation of (S)-tert-Butyl 2-(5-(4′-(2-((S)-1-((S)-3-methyl-2-(3,4-dihydroimidazol-2-ylamino)butanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (cj-8)

(959) ##STR00873##

(960) A mixture of (S)-tert-butyl 2-(5-(4′-(2-((S)-1-((S)-2-amino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (cj-2) (0.298 g, 0.480 mmol), 4,5-dihydro-1H-imidazole-2-sulfonic acid (AstaTech) (0.090 g, 0.60 mmol) and iPr.sub.2NEt (0.083 mL, 0.48 mmol) in EtOH (4 mL) was heated at 100° C. for 12 h. The cooled mixture was evaporated to dryness and the residue was purified by prep HPLC (Luna 5u C18/MeCN—H.sub.2O-TFA, ×2) to afford the TFA salt of the title compound (0.390 g, 73%) as a light yellow solid.

(961) .sup.1HNMR (400 MHz, DMSO-d.sub.6) δ 14.66 (br s, 2H), 8.51 (br s, 1H), 8.20 (d, J=10.1 Hz, 2H), 8.10 (br s, 1H), 7.82-7.91 (m, 7H), 7.30 (br s, 1H), 5.12 (t, J=7.1 Hz, 1H), 4.97-5.05 (m, 2H), 4.37 (dd, J=4.3, 10.1 Hz, 2H), 3.82-3.86 (m, 2H), 3.73-3.77 (m, 2H), 3.59 (s, 4H), 3.39-3.48 (m, 2H), 2.15-2.25 (m, 2H), 1.93-2.07 (m, 5H), 1.40 (s, 4H), 1.17 (s, 5H), 0.93 (d, J=6.6 Hz, 3H), 0.69 (br s, 3H).

(962) LCMS: Anal. Calcd. for C.sub.39H.sub.49N.sub.9O.sub.3: 691. found: 692 (M+H).sup.+.

Preparation of (S)-tert-Butyl 2-(5-(4′-(2-((S)-1-((R)-3-methyl-2-(3,4-dihydroimidazol-2-ylamino)butanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (cj-9)

(963) ##STR00874##

(964) The title compound was prepared from cj-3 according to the same method used to prepare cj-8 to afford the TFA salt (0.199 g, 57%) as a yellow glass.

(965) .sup.1HNMR (400 MHz, DMSO-d.sub.6) δ 14.58 (br s, 4H), 8.23 (d, J=9.6 Hz, 1H), 8.11 (s, 1H), 7.87-7.89 (m, 6H), 7.25 (br s, 1H), 5.17-5.20 (m, 1H), 4.96-5.04 (m, 1H), 4.37 (dd, J=5.5, 9.6 Hz, 1H), 3.91-3.95 (m, 2H), 3.37-3.46 (m, partially obscured by H.sub.2O, 4H), 2.39-2.42 (m, partially obscured by solvent, 2H), 2.01-2.09 (m, 4H), 1.94-1.98 (m, 2H), 1.40 (s, 3H), 1.17 (s, 6H), 0.95 (d, J=6.5 Hz, 2.5H), 0.85 (d, J=6.5 Hz, 2.5H), 0.66 (d, J=7.0 Hz, 0.5H), 0.54 (d, J=6.5 Hz, 0.5H).

(966) LCMS: Anal. Calcd. for C.sub.39H.sub.49N.sub.9O.sub.3: 691. found: 692 (M+H).sup.+.

Example cj-11

(967) ##STR00875##

Preparation of (S)-3-Methyl-2-(pyrimidin-2-ylamino)-1-((S)-2-(5-(4′-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-1-one (cj-10a)

(968) ##STR00876##

(969) Step 1: A solution of the TFA salt of (S)-tert-butyl 2-(5-(4′-(2-((S)-1-((S)-3-methyl-2-(pyrimidin-2-ylamino)butanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (cj-4) (0.208 g, 0.199 mmol) in a mixture CH.sub.2Cl.sub.2 (4 mL) and TFA (3 mL) was stirred at room temperature for 1.5 h. The solvents were then removed in vacuo and the residue was purified by prep HPLC (Luna 5u C18/MeCN—H.sub.2O-TFA) to give the TFA salt of the title compound (0.391 g) as an orange gum.

(970) .sup.1HNMR (400 MHz, DMSO-d.sub.6) δ 14.53 (br s, 3H), 9.52-9.57 (m, 2H), 8.98-9.04 (m, 2H), 8.28 (d, J=4.6 Hz, 2H), 8.13 (br s, 1H), 7.79-7.91 (m, 7H), 7.07 (d, J=8.1 Hz, 1H), 6.62 (app t, J=4.8 Hz, 1H), 5.07 (t, J=7.1 Hz, 1H), 4.72-4.78 (m, 2H), 4.48-4.51 (m, 1H), 4.08-4.12 (m, 2H), 3.28-3.36 (m, 2H), 2.37-2.42 (m, 2H), 1.97-2.22 (m, 6H), 0.88 (app t, J=4.5 Hz, 6H).

(971) LCMS: Anal. Calcd. for C.sub.35H.sub.39N.sub.9O: 601. found: 602 (M+H).sup.+.

(972) Similarly, the following examples were prepared according to the representative method above;

(973) TABLE-US-00063 Example Structure LCMS cj-10a (from cj-3) LCMS: Anal. Calcd. for C.sub.35H.sub.39N.sub.9O: 601; found: 602 (M + H).sup.+. cj-10b (from cj-2) LCMS: Anal. Calcd. for C.sub.35H.sub.43N.sub.9O: 605; found: 606 (M + H).sup.+. cj-10c (from cj-3) LCMS: Anal. Calcd. for C.sub.35H.sub.43N.sub.9O: 605; found: 606 (M + H).sup.+. cj-10d (from cj-2) 0 LCMS: Anal. Calcd. for C.sub.34H.sub.41N.sub.9O: 591; found: 592 (M + H).sup.+. cj-10e (from cj-3) LCMS: Anal. Calcd. for C.sub.34H.sub.41N.sub.9O: 591; found: 592 (M + H).sup.+.

Preparation of methyl ((1S)-2-methyl-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N-2-pyrimidinyl-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate (cj-11)

(974) ##STR00882##

methyl ((1S)-2-methyl-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N-2-pyrimidinyl-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate

(975) Step 2: To a solution of the TFA salt of (S)-3-methyl-2-(pyrimidin-2-ylamino)-1-((S)-2-(5-(4′-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-1-one (cj-10) (0.208 g, 0.197 mmol) in DMF (4 mL) was added iPr.sub.2NEt (0.20 mL, 1.15 mmol), (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (0.049 g, 0.28 mmol) and HATU (0.105 g, 0.276 mmol). The solution was stirred for 1.5 h at room temperature, diluted with MeOH (2 mL) and purified directly by prep HPLC (Luna 5u C18/MeCN—H.sub.2O—NH.sub.4OAc). This material was repurified by flash chromatography (SiO.sub.2/2-10% MeOH—CH.sub.2Cl.sub.2) to give a solid which was lyophilized from CH.sub.3CN—H.sub.2O to give the title compound (48.6 mg, 32%) as a colourless solid.

(976) .sup.1HNMR (400 MHz, DMSO-d.sub.6) δ 11.78 (br s, 1H), 8.28 (d, J=4.5 Hz, 1H), 7.76-7.79 (m, 4H), 7.66-7.69 (m, 4H), 7.48-7.51 (m, 2H), 7.29 (d, J=8.6 Hz, 1H), 6.93 (d, J=8.1 Hz, 1H), 6.60 (app t, J=4.5 Hz, 1H), 5.03-5.09 (m, 2H), 4.48 (t. J=8.1 Hz, 1H), 3.99-4.08 (m, 2H), 3.78-3.85 (m, 2H) 3.53 (s, 3H), 2.12-2.21 (m, 4H), 1.87-2.05 (m, 7H), 0.83-0.97 (m, 12H).

(977) LCMS: Anal. Calcd. for C.sub.42H.sub.50N.sub.10O.sub.4: 758. found: 759 (M+H).sup.+.

(978) Similarly, the following examples were prepared according to the representative method above;

(979) TABLE-US-00064 Ex- Compound ample Name Structure LCMS cj-11a (from cj-10 and Cap-52) methyl ((1S)-1- methyl-2-oxo-2- ((2S)-2-(5-(4′- (2-((2S)-1-(N-2- pyrimidinyl-L- valyl)-2- pyrrolidinyl)- 1H-imidazol-5- yl)-4- biphenylyl)-1H- imidazol-2-yl)- LCMS: Anal. Calcd. for C.sub.40H.sub.46N.sub.10O.sub.4: 730; found: 731 (M + H).sup.+. 1-pyrrolidinyl) ethyl) carbamate cj-11b (from cj-10 and Cap-4) methyl ((1R)-2- oxo-1-phenyl-2- ((2S)-2-(5-(4′- (2-((2S)-1-(N-2- pyrimidinyl-L- valyl)-2- pyrrolidinyl)- 1H-imidazol-5- yl)-4- biphenylyl)-1H- imidazol-2-yl)- LCMS: Anal. Calcd. for C.sub.45H.sub.48N.sub.10O.sub.4: 792; found: 793 (M + H).sup.+. 1-pyrrolidinyl) ethyl) carbamate cj-11c (from cj-10 and Cap-2) N-((1S)-1- (((2S)-2-(5-(4′- (2-((2S)-1-((2R)- 2- (diethylamino)- 2-phenylacetyl)- 2-pyrrolidinyl)- 1H-imidazol-5- yl)-4- biphenylyl)-1H- imidazol-2-yl)- LCMS: Anal. Calcd. for C.sub.47H.sub.54N.sub.10O.sub.2: 790; found: 791 (M + H).sup.+. 1-pyrrolidinyl) carb- onyl)-2- methylpropyl)- 2- pyrimidinamine cj-11d (from cj-10b and Cap-51) methyl ((1S)-2- methyl-1-(((2S)- 2-(5-(4′-(2- ((2S)-1-(N-(1- methyl-4,5- dihydro-1H- imidazol-2-yl)- L-valyl)-2- pyrrolidinyl)- 1H-imidazol-5- yl)-4- LCMS: Anal. Calcd. for C.sub.42H.sub.54N.sub.10O.sub.4: 762; found: 763 (M + H).sup.+. biphenylyl)-1H- imdiazol-2-y)- 1-pyrrolidinyl) carbonyl) propyl)carb- amate cj-11e (from cj-10d and Cap-51) methyl ((1S)-1- (((2S)-2-(5-(4′- (2-((2S)-1-(N- (4,5-dihydro- 1H-imidazol-2- yl)-L-valyl)-2- pyrrolidinyl)- 1H-imidazol-5- yl)-4- biphenylyl)-1H- imidazol-2-yl)- LCMS: Anal. Calcd. for C.sub.41H.sub.52N.sub.10O.sub.4: 748; found: 749 (M + H).sup.+. 1- pyrrolidinyl)carb- onyl)-2- methylpropyl) carbamate cj-11f (from cj-10d and Cap-52) methyl ((1S)-2- ((2S)-2-(5-(4′- (2-((2S)-1-(N- (4,5-dihydro- 1H-imidazol-2- yl)-L-valyl)-2- pyrrolidinyl)- 1H-imidazol-5- yl)-4- biphenylyl)-1H- imidazol-2-yl)- LCMS: Anal. Calcd. for C.sub.39H.sub.48N.sub.10O.sub.4: 720; found: 721 (M + H).sup.+. 1-pyrrolidinyl)- 1-methyl-2- oxoethyl)carba- mate cj-11g (from cj-10d and Cap-2) N-((1S)-1- (((2S)-2-(5-(4′- (2-((2S)-1-((2R)- 2- (diethylamino)- 2-phenylacetyl)- 2-pyrrolidinyl)- 1H-imidazol-5- yl)-4- biphenylyl)-1H- imidazol-2-yl)- 1- pyrrolidinyl)carb- onyl)-2- methylpropyl)- 4,5-dihydro-1H- imidazol-2- amine LCMS: Anal. Calcd. for C.sub.46H.sub.56N.sub.10O.sub.2: 780; found: 781 (M + H).sup.+. cj11h (from cj-10d and Cap-4) methyl ((1R)-2- oxo-1-phenyl-2- ((2S)-2-(5-(4′- (2-((2S)-1-(N-2- pyrimidin-D- valyl)-2- pyrrolidinyl)- 1H-imidazol-5- yl)-4- biphenylyl)-1H- imidazol-2-yl)- 0 LCMS: Anal. Calcd. for C.sub.44H.sub.50N.sub.10O.sub.4: 782; found: 783 (M + H).sup.+. 1-pyrrolidinyl) ethyl) carbamate cj-11i (from cj-10a and Cap-51) methyl ((1S)-2- methyl-1-(((2S)- 2-(5-(4′-(2- ((2S)-1-(N-2- pyrimidinyl-D- valyl)-2- pyrrolidinyl)- 1H-imdidazol-5- yl)-4- biphenylyl)-1H- imidazol-2-yl)- 1- LCMS: Anal. Calcd. for C.sub.42H.sub.50N.sub.10O.sub.4: 758; found: 759 (M + H).sup.+. pyrrolidinyl)carb- onyl)propyl)carb- amate cj-11j (from cj-10a and Cap-52) methyl ((1S)-1- methyl-2-oxo-2- ((2S)-2-(5-(4′- (2-((2S)-1-(N-2- pyrimidinyl-D- valyl)-2- pyrrolidinyl)- 1H-imidazol-5- yl)-4- biphenylyl)-1H- imidazol-2-yl)- 1- LCMS: Anal. Calcd. for C.sub.40H.sub.46N.sub.10O.sub.4: 730; found: 731 (M + H).sup.+. pyrrolidinyl)ethyl) carbamate cj-11k (from cj-10a and Cap-2) N-((1R)-1- (((2S)-2-(5-(4′- (2-((2S)-1-((2R)- 2- (diethylamino)- 2-phenylacetyl)- 2-pyrrolidinyl)- 1H-imidazol-5- yl)-4- biphenylyl)-1H- imidazol-2-yl)- 1- LCMS: Anal. Calcd. for C.sub.47H.sub.54N.sub.10O.sub.2: 790; found: 791 (M + H).sup.+. pyrrolidinyl)carb- onyl)-2- methylpropyl)- 2- pyrimidinamine cj-11l (from cj-10a and Cap-4) LCMS: Anal. Calcd. for C.sub.45H.sub.48N.sub.10O.sub.4: 792; found: 793 (M + H).sup.+. cj-11m (from cj-10c and Cap-51) methyl ((1S)-2- methyl-1-(((2S)- 2-(5-(4′-(2- ((2S)-1-(N-(1- methyl-4,5- dihydro-1H- imidazol-2-yl)- D-valyl)-2- pyrrolidinyl)- 1H-imidazol-5- yl)-4- LCMS: Anal. Calcd. for C.sub.42H.sub.54N.sub.10O.sub.4: 762; found: 763 (M + H).sup.+. biphenylyl)-1H- imidazol-2-yl)- 1- pyrrolidinyl)carb- onyl)propyl)carb- amate cj-11n (from cj-10e and Cap-51) methyl ((1S)-1- (((2S)-2-(5-(4′- (2-((2S)-1-(N- (4,5-dihydro- 1H-imidazol-2- yl)-D-valyl)-2- pyrrolidinyl)- 1H-imidazol-5- yl)-4- biphenylyl)-1H- imidazol-2-yl)- LCMS: Anal. Calcd. for C.sub.41H.sub.52N.sub.10O.sub.4: 748; found: 749 (M + H).sup.+. 1- pyrrolidinyl)carb- onyl)-2- methylpropyl) carbamate cj-11o (from cj-10e and Cap- 54b) methyl ((1S)-1- cyclopropyl-2- ((2S)-2-(5-(4′- (2-((2S)-1-(N- (4,5-dihydro- 1H-imidazol-2- yl)-D-valyl)-2- pyrrolidinyl)- 1H-imidazol-5- yl)-4- biphenylyl)-1H- LCMS: Anal. Calcd. for C.sub.41H.sub.50N.sub.10O.sub.4: 746; found: 747 (M + H).sup.+. imidazol-2-yl)- 1-pyrrolidinyl)- 2-oxoethyl) carbamate cj-11p (from cj-10e and Cap-2) N-((1R)-1- (((2S)-2-(5-(4′- (2-((2S)-1-((2R)- 2- (diethylamino)- 2-phenylacetyl)- 2-pyrrolidinyl)- 1H-imidazol-5- yl)-4- biphenylyl)-1H- imidazol-2-yl)- LCMS: Anal. Calcd. for C.sub.46H.sub.56N.sub.10O.sub.2: 780; found: 781 (M + H).sup.+. 1- pyrrolidinyl) carbonyl)-2- methylpropyl)- 4,5-dihydro-1H- imidazol-2- amine

Example cj-13

(980) ##STR00899##

Preparation of Methyl (S)-1-((S)-2-(5-(4′-(2-((S)-1-((S)-2-amino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (cj-13)

(981) ##STR00900##

(982) To a solution of methyl (S)-3-methyl-1-oxo-1-((S)-2-(5-(4′-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate (cj-12) (1.16 g, 1.99 mmol), Z-Val-OH (0.712 g, 2.83 mmol) and iPr.sub.2NEt (0.70 mL, 5.42 mmol) in DMF (40 mL) was added HATU (1.10 g, 2.89 mmol) portionwise. The mixture was allowed to stir at room temperature for 1 h and was then poured into ice-water (400 mL) and allowed to stand for 20 min. The mixture was filtered and the solid washed with cold water and allowed to air dry overnight to give the Z-protected intermediate. LCMS: Anal. Calcd. for C.sub.46H.sub.54N.sub.8O.sub.6: 814. found: 815 (M+H).sup.+.

(983) The obtained solid was dissolved in MeOH (80 mL), 10% Pd—C (1.0 g) was added and the mixture was hydrogenated at room temperature and atmospheric pressure for 3 h. The mixture was then filtered and the filtrate concentrated in vacuo. The resulting residue was purified by flash chromatography (SiO.sub.2/5-20% MeOH—CH.sub.2Cl.sub.2) to afford the title compound (1.05 g, 77%) as a colorless foam. .sup.1HNMR (400 MHz, DMSO-d.sub.6) δ 11.75 (s, 1H), 7.75-7.79 (m, 3H), 7.61-7.67 (m, 5H), 7.49 (s, 1H), 7.26-7.28 (m, 1H), 5.05-5.09 (m, 2H), 4.03-4.09 (m, 2H), 3.77-3.80 (m, 1H), 3.66-3.70 (m, 1H), 3.52 (s, 3H), 3.40-3.47 (m, 2H), 2.21-2.26 (m, 1H), 2.10-2.17 (m, 3H), 1.81-2.02 (m, 6H), 0.77-0.92 (m, 12H).

(984) LCMS: Anal. Calcd. for C.sub.38H.sub.48N.sub.8O.sub.4: 680. found: 681 (M+H).sup.+.

Example cj-15

(985) ##STR00901##

Preparation of Methyl (S)-1-((S)-2-(5-(4′-(2-((S)-1-((S)-2-((Z/E)-(cyanoimino)(phenoxy)methylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (cj-14)

(986) ##STR00902##

(987) A mixture of methyl (S)-1-((S)-2-(5-(4′-(2-((S)-1-((S)-2-amino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (cj-13) (0.329 g, 0.527 mmol) and diphenyl cyanocarbonimidate (0.128 g, 0.537 mmol) in iPrOH (10 mL) was stirred at room temperature for 12 h. The resulting solid was filtered and air-dried to give the title compound (0.187 g, 43%) as a cream-colored solid. This material was used as such in the next step without further purification.

(988) LCMS: Anal. Calcd. for C.sub.46H.sub.52N.sub.10O.sub.5: 824. found: 825 (M+H).sup.+.

Preparation of methyl ((S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N-(5-amino-1-methyl-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate (cj-15a, R═H)

(989) ##STR00903##

(990) A solution of methyl (S)-1-((S)-2-(5-(4′-(2-((S)-1-((S)-2-((Z/E)-(cyanoimino)(phenoxy)methylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (cj-14) (0.074 g, 0.090 mmol) and hydrazine hydrate (0.05 mL, 0.88 mmol) in iPrOH (2 mL) was heated at 75° C. for 7 h. The solvent was then removed in vacuo and the residue was purified by prep HPLC (Luna 5u C18/MeCN—H.sub.2O—NH.sub.4OAc) to give foam which was lyophilized from CH.sub.3CN—H.sub.2O to give the title compound (0.032 g, 46%) as a colorless solid.

(991) .sup.1HNMR (400 MHz, DMSO-d.sub.6) δ 12.17 (s, 1H), 11.75 (m, 2H), 10.66-10.84 (m, 2H), 7.76-7.79 (m, 3H), 7.62-7.74 (m, 4H), 7.49-7.51 (m, 1H), 7.24-7.29 (m, 2H), 5.28-5.32 (m, 1H), 5.05-5.08 (m, 2H), 4.04-4.09 (m, 3H), 3.87-3.94 (m, 2H), 3.72-3.81 (m, 2H), 3.53 (s, 3H), 2.09-2.17 (m, 2H), 1.90-2.02 (m, 6H), 0.81-0.99 (m, 12H).

(992) LCMS: Anal. Calcd. for C.sub.40H.sub.50N.sub.12O.sub.4: 762. found: 763 (M+H).sup.+.

Preparation of Methyl (S)-1-((S)-2-(5-(4′-(2-((S)-1-((S)-2-(5-amino-1-methyl-1H-1,2,4-triazol-3-ylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (cj-15b, R=Me)

(993) ##STR00904##

(994) A solution of methyl (S)-1-((S)-2-(5-(4′-(2-((S)-1-((S)-2-((Z/E)-(cyanoimino)(phenoxy)methylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (cj-14) (0.105 g, 0.128 mmol) and N-methylhydrazine (0.010 mL, 0.188 mmol) in iPrOH (2 mL) was heated at 75° C. for 3 h. A second portion of N-methylhydrazine (0.010 mL, 0.188 mmol) was added and heating was continued for 7 h. The volatiles were then removed in vacuo and the residue was purified by prep HPLC (Luna 5u C18/MeCN—H.sub.2O—NH.sub.4OAc) to give a foam which was further purified by flash chromatography (SiO.sub.2/0-20% MeOH—CH.sub.2Cl.sub.2). The resulting material was lyophilized from CH.sub.3CN—H.sub.2O to give the title compound (0.029 g, 29%) as a colorless solid.

(995) .sup.1HNMR (400 MHz, DMSO-d.sub.6) δ 13.79 (s, 0.4H), 12.19 (s, 1H), 11.76 (m, 1.6H), 7.77-7.85 (m, 4H), 7.62-7.71 (m, 4H), 7.49-7.51 (m, 1H), 7.24-7.29 (m, 1H), 6.31 (d, J=9.1 Hz, 0.5H), 6.09 (d, J=9.1 Hz, 1.5H), 5.87 (s, 1H), 5.34-5.36 (m, 1H), 5.04-5.08 (m, 2H), 4.89 (s, 1H), 4.75 (s, 2H), 3.53 (s, 3H), 2.10-2.17 (s, 3H), 1.94-2.02 (m, 6H), 0.81-0.98 (m, 12H).

(996) LCMS: Anal. Calcd. for C.sub.41H.sub.52N.sub.12O.sub.4: 776. found: 777 (M+H).sup.+.

(997) HRMS: Anal. Calcd. for C.sub.41H.sub.52N.sub.12O.sub.4: 776.4234. found: 777.4305 (M+H).sup.+.

Example cj-15c

methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N-(4,5-dihydro-1,3-thiazol-2-yl)-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

(998) ##STR00905##

(999) Example cj-15c was prepared by the condensation of Intermediate cj-13 with 2-(methylthio)-4,5-dihydrothiazole (Aldrich) using conditions analgous to those in the preparation of Intermediate cj-4. LCMS: Anal. Calcd. for C.sub.41H.sub.51N.sub.9O.sub.4S: 765. found: 766 (M+H).sup.+.

Example 15-d

methyl ((1S)-2-methyl-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N-4-pyrimidinyl-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate

(1000) ##STR00906##

(1001) Example cj-15d was prepared by the condensation of Intermediate cj-13 with 4,6-dichloropyrimidine (Aldrich) using conditions analgous to those in the preparation of Intermediate cj-4, followed by hydrogenation with 10% Pd—C. LCMS: Anal. Calcd. for C.sub.42H.sub.50N.sub.10O.sub.4: 758. found: 759 (M+H).sup.+.

Example cj-16 and cj-17

(1002) ##STR00907##

Preparation of methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N-(5-amino-1,2,4-oxadiazol-3-yl)-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate (cj-16)

(1003) ##STR00908##

(1004) A solution of methyl (S)-1-((S)-2-(5-(4′-(2-((S)-1-((S)-2-((Z/E)-(cyanoimino)(phenoxy)methylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (cj-14) (0.120 g, 0.205 mmol) and hydroxylamine hydrochloride (0.0213 g, 0.307 mmol) in iPrOH (5 mL) was heated at 75° C. for 3 h. A second portion of hydroxylamine hydrochloride (0.0213 g, 0.307 mmol) was added and heating continued for 7 h. The volatiles were then removed in vacuo and the residue was purified by prep HPLC (Luna 5u C18/MeCN—H.sub.2O—NH.sub.4OAc) to give a foam which was further purified by flash chromatography (SiO.sub.2/5% MeOH—CH.sub.2Cl.sub.2). The resulting colorless wax was lyophilized from CH.sub.3CN—H.sub.2O to give the title compound (0.0344 g, 22%) as a colorless solid.

(1005) .sup.1HNMR (400 MHz, DMSO-d.sub.6) δ 12.18-12.22 (m, 1H), 11.80 (s, 1H), 11.75 (s, 1h), 8.03-8.06 (m, 1H), 7.77 (app d, J=8.1 Hz, 2H), 7.62-7.73 (m, 4H), 7.50 (dd, J=2.0, 5.5 Hz, 1H), 7.24-7.29 (m, 2H), 5.69 (s, 1H), 5.06-5.11 (m, 2H), 4.14 (t, J=8.6 Hz, 1H), 4.06 (unresolved dd, J=8.0, 8.6 Hz, 1H), 3.78-3.90 (m, 3H), 3.53 (s, 3H), 3.01 (br s, 2H), 2.10-2.19 (m, 3H), 1.90-2.04 (m, 5H), 0.81-0.96 (m, 12H).

(1006) LCMS: Anal. Calcd. for C.sub.40H.sub.49N.sub.11O.sub.5: 763. found: 764 (M+H).sup.+.

Preparation of methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N-(cyano(dimethyl)carbamimidoyl)-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate (cj-17)

(1007) ##STR00909##

(1008) A solution of methyl (S)-1-((S)-2-(5-(4′-(2-((S)-1-((S)-2-((Z/E)-(cyanoimino)(phenoxy)methylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (cj-14) (0.115 g, 0.198 mmol) and dimethylamine hydrochloride (0.0257 g, 0.315 mmol) in iPrOH (5 mL) was heated at 90° C. for 12 h. A second portion of dimethylamine hydrochloride (0.0257 g, 0.315 mmol) was added and heating was continued for 48 h. The volatiles were then removed in vacuo and the residue was purified by prep HPLC (Luna 5u C18/MeCN—H.sub.2O—NH.sub.4OAc) and then repurified by flash chromatography (SiO.sub.2/5% MeOH—CH.sub.2Cl.sub.2). The resulting colorless wax was lyophilized from CH.sub.3CN—H.sub.2O to give the title compound (0.0318 g, 21%) as a colorless solid.

(1009) .sup.1HNMR (400 MHz, DMSO-d.sub.6) δ 12.22 (m, 0.6H), 11.81 (s, 1H), 11.75 (s, 1H), 12.17-12.22 (m, 0.5H), 11.99-12.04 (m, 0.5H), 11.75-11.81 (m, 1H), 7.76-7.79 (m, 3H), 7.62-7.73 (m, 5H), 7.50 (t, J=2.0 Hz, 1H), 7.23-7.29 (m, 1H), 6.64 (d, J=8.1 Hz, 1H), 5.06-5.08 (m, 2H), 4.47 (t, J=8.1 Hz, 2H), 4.06 (unresolved dd, J=8.0, 8.6 Hz, 1H), 3.84-3.90 (m, 2H), 3.76-3.82 (m, 3H), 3.53 (s, 3H), 3.00 (s, 6H), 2.11-2.20 (m, 3H), 1.90-2.04 (m, 5H), 0.97 (d, J=6.5 Hz, 3H), 0.89-0.91 (m, 6H), 0.84 (d, J=6.5 Hz, 3H).

(1010) LCMS: Anal. Calcd. for C.sub.42H.sub.53N.sub.11O.sub.4: 775. found: 776 (M+H).sup.+.

Example cj-20

(1011) ##STR00910##

Preparation of methyl ((1S)-2-methyl-1-(((2S)-2-(5-(4′-(2-((2S)-1-(N-3-pyridinyl-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate (cj-20)

(1012) ##STR00911##

(1013) To a solution of methyl (S)-3-methyl-1-oxo-1-((S)-2-(5-(4′-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate (cj-13) (0.060 g, 0.103 mmol) in DMF (2 mL) was added iPr.sub.2NEt (0.18 mL, 1.02 mmol), (S)-3-methyl-2-(pyridin-3-ylamino)butanoic acid (Cap-88) (0.040 g, 0.206 mmol) and HATU (0.078 g, 0.205 mmol). The reaction mixture was stirred for 1.5 h at room temperature and then it was directly purified by prep HPLC (Luna 5u C18/MeCN—H.sub.2O—NH.sub.4OAc). The resulting solid was repurified by flash chromatography (SiO.sub.2/0-10% MeOH—CH.sub.2Cl.sub.2) and the obtained product was lyophilized from CH.sub.3CN—H.sub.2O to give the title compound (0.044 g, 56%) as a solid.

(1014) .sup.1HNMR (400 MHz, DMSO-d.sub.6) δ 12.19 (s, 1H), 11.76 (s, 1H), 8.07 (d, J=2.6 Hz, 1H), 7.62-7.85 (m, 8H), 7.49-7.51 (m, 2H), 7.24-7.29 (m, 1H), 6.99-7.06 (m, 2H), 6.46-6.49 (m, 0.5H), 5.97-5.99 (m, 0.5H), 5.71 (d, J=9.0 Hz, 1H), 5.55 (d, J=10.6 Hz, 1H), 5.22-5.44 (m, 1H), 5.03-5.09 (m, 2H), 4.04-4.13 (m, 2H), 3.78-3.90 (m, 3H), 3.66-3.71 (m, 1H), 3.53 (s, 3H), 2.03-2.19 (m, 2H), 1.84-2.01 (m, 4H), 0.81-1.01 (m, 12H).

(1015) LCMS: Anal. Calcd. for C.sub.43H.sub.51N.sub.9O.sub.4: 757. found: 758 (M+H).sup.+.

(1016) Similarly, the following examples were prepared according to the representative method above;

(1017) TABLE-US-00065 Ex- Compound ample Name Structure LCMS cj-20a (from cj- 22 and Cap- 88) methyl ((1S)-1- methyl-2-oxo-2- ((2S)-2-(5-(4′-(2- ((2S)-1-(N-3- pyridinyl-L- valyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl) ethyl) LCMS: Anal. Calcd. for C.sub.41H.sub.47N.sub.9O.sub.4: 729; found: 730 (M + H).sup.+. carbamate cj-20b (from cj- 23 and Cap- 88) methyl ((1S,2R)- 2-methoxy- 1-(((2S)-2- (5-(4′-(2-((2S)-1- (N-3-pyridinyl-L- valyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl) carbonyl) LCMS: Anal. Calcd. for C.sub.43H.sub.51N.sub.9O.sub.5: 773; found: 774 (M + H).sup.+. propyl)carbamate cj-20c (from cj- 24 and cap- 88) N-((1S)-1-((2S)- 2-(5-(4′-(2- ((2S)-1-((2R)-2- (diethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl) carbonyl)-2- methylpropyl)-3- LCMS: Anal. Calcd. for C.sub.48H.sub.55N.sub.9O.sub.2: 789; found: 790 (M + H).sup.+. pyridinamine cj-20d (from cj- 12 and Cap- 88) methyl ((1S)-2- methyl-1- (((2S)-2- (5-(4′-(2-((2S)-1- (N-5-pyrimidinyl- L-valyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl) carbonyl) LCMS: Anal. Calcd. for C.sub.42H.sub.50N.sub.10O.sub.4: 758; found: 759 (M + H).sup.+. propyl)carbamate

Preparation of Methyl (S)-3-methyl-1-oxo-1-((S)-2-(5-(4′-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate (cj-12)

(1018) ##STR00916##

(1019) Synthesized from Intermediate-28d and Cap-51 as in Example 28e, followed by Boc removal with TFA/CH.sub.2Cl.sub.2 and free base formation with MCX resin.

(1020) .sup.1HNMR (400 MHz, MeOH-d.sub.4) δ 7.79-7.82 (m, 3H), 7.65-7.75 (m, 5H), 7.48 (s, 1H), 7.32 (s, 1H), 5.19 (dd, J=5.5, 5.7 Hz, 1H), 4.75 (t, J=7.8 Hz, 1H), 4.25 (d, J=7.3 Hz, 1H), 3.88-4.04 (m, 2H), 3.67 (s, 3H), 3.35-3.51 (m, 3H), 2.43-2.51 (m, 1H), 2.02-2.38 (m, 7H), 0.97 (d, J=6.5 Hz, 3H), 0.92 (d, J=6.9 Hz, 3H).

(1021) LCMS: Anal. Calcd. for C.sub.33H.sub.39N.sub.7O.sub.3: 581. found: 582 (M+H).sup.+.

Preparation of Methyl (S)-1-oxo-1-((S)-2-(5-(4′-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)propan-2-ylcarbamate (cj-22)

(1022) ##STR00917##

(1023) Synthesized from Intermediate-28d and Cap-52 as in Example 28e, followed by Boc removal with TFA/CH.sub.2Cl.sub.2 and free base formation with MCX resin.

(1024) .sup.1HNMR (400 MHz, MeOH-d.sub.4) δ 7.68-7.79 (m, 4H), 7.59-7.65 (m, 4H), 7.44 (d, J=6.6 Hz, 1H), 7.37 (s, 0.3H), 7.27 (s, 0.7H), 5.18 (dd, J=4.0, 7.6 Hz, 1H), 4.74 (t, J=8.0 Hz, 1H), 4.46 (dd, J=6.8, 13.9 Hz, 1H), 3.84 (unresolved dd, J=6.1, 6.5 Hz, 1H), 3.62 (s, 3H), 3.54 (s, 1H), 3.32-3.46 (m, 3H), 2.40-2.46 (m, 1H), 2.26-2.39 (m, 2H), 2.14-2.24 (m, 2H), 2.01-2.12 (m, 2H), 0.32 (d, J=7.1 Hz, 3H).

(1025) LCMS: Anal. Calcd. for C.sub.31H.sub.35N.sub.7O.sub.3: 553. found: 554 (M+H).sup.+.

Preparation of Methyl (2S,3R)-3-methoxy-1-oxo-1-((S)-2-(5-(4′-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate (cj-23)

(1026) ##STR00918##

(1027) Synthesized from Intermediate-28d and Cap-86 as in Example 28e, followed by Boc removal with TFA/CH.sub.2Cl.sub.2 and free base formation with MCX resin.

(1028) .sup.1HNMR (400 MHz, MeOH-d.sub.4) δ 7.72 (m, 4H), 7.64-7.69 (m, 4H), 7.48 (d, J=4.1 Hz, 1H), 7.38 (s, 0.3H), 7.33 (s, 0.7H), 5.51-5.54 (m, 0.2H), 5.22 (dd, J=4.9, 7.6 Hz, 0.8H), 4.76 (t, J=8.0 Hz, 1H), 4.48 (d, J=5.1 Hz, 0.8H), 4.35-4.36 (m, 0.2H), 3.90-3.99 (m, 1H), 3.68 (s, 3H), 3.54 (s, 1H), 3.35-3.48 (m, 4H), 3.29 (s, 3H), 2.42-2.50 (m, 1H), 2.30-2.37 (m, 2H), 2.19-2.26 (m, 2H), 2.05-2.15 (m, 2H), 1.19 (d, J=6.1 Hz, 3H).

(1029) LCMS: Anal. Calcd. for C.sub.33H.sub.39N.sub.7O.sub.4: 597. found: 598 (M+H).sup.+.

Preparation of (R)-2-(Diethylamino)-2-phenyl-1-((S)-2-(5-(4′-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)ethanone (cj-24)

(1030) ##STR00919##

(1031) Synthesized from Intermediate-28d and Cap-2 as in Example 28e, followed by Boc removal with TFA/CH.sub.2Cl.sub.2 and free base formation with MCX resin.

(1032) .sup.1HNMR (400 MHz, MeOH-d.sub.4) δ 7.59-7.82 (m, 10H), 7.36-7.51 (m, 4H), 7.01-7.15 (m, 1H), 5.09-5.13 (m, 2H), 4.77 (t, J=8.5 Hz, 1H), 4.03-4.05 (m, 1H), 3.67-3.93 (m, 1H), 3.35-3.47 (m, 2H), 3.18-3.23 (m, 1H), 2.91-3.07 (m, 2H), 2.70-2.84 (m, 2H), 2.34-2.60 (m, 2H), 1.97-2.24 (m, 5H), 1.07-1.17 (m, 6H).

(1033) LCMS: Anal. Calcd. for C.sub.38H.sub.43N.sub.7O: 613. found: 614 (M+H).sup.+.

(1034) The following were prepared according to the procedure in example 28 starting with 28d. The caps are given in the table in the order they were appended to 28d. Where a cap number is not given the corresponding carboxylic acid is commercially available.

(1035) TABLE-US-00066 Example Compound Name Structure LCMS Cap cj-32 methyl ((1S)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2- (diethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxo-1-(1H-1,2,3- triazol-4- ylmethyl)ethyl)carb- amate 0 LCMS: Anal. Calcd. for C.sub.45H.sub.51N.sub.11O.sub.4: 809; found: 810 (M + H).sup.+. 2/128 cj-33 methyl ((1S)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-(N- (methoxycarbonyl)- L-alanyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxo-1-(1H-1,2,3- triazol-4- ylmethyl)ethyl)carb- amate LCMS: Anal. Calcd. for C.sub.38H.sub.43N.sub.11O.sub.6: 749; found: 750 (M + H).sup.+. 52/128 cj-34 methyl ((1S)-1- (((2S)-2-(5-(4′-(2- ((2S)-1-((2S)-2- ((methoxycarbonyl) amino)-3-(1H- 1,2,3-triazol-4- yl)propanoyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbon- yl)-2- methylpropyl)carba- mate LCMS: Anal. Calcd. for C.sub.40H.sub.47N.sub.11O.sub.6: 777; found: 777 (M + H).sup.+. 51/128 cj-35 methyl ((1S)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-((2S,3R)-3- methoxy-2- ((methoxycarbonyl) amino)butanoyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxo-1-(1H-1,2,3- triazol-4- ylmethyl)ethyl)carb- amate LCMS: Anal. Calcd. for C.sub.40H.sub.47N.sub.11O.sub.7: 793; found: 794 (M + H).sup.+. 86/128 cj-36 methyl ((1S)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2- (diethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxo-1-(1H-pyrazol- 1- ylmethyl)ethyl)carb- amate LCMS: Anal. Calcd. for C.sub.46H.sub.52N.sub.10O.sub.4: 808; found: 809 (M + H).sup.+. 2/129 cj-37 methyl ((1S)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-(N- (methoxycarbonyl)- L-alanyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxo-1-(1H-pyrazol- 1- ylmethyl)ethyl)carb- amate LCMS: Anal. Calcd. for C39H44N10O6: 748; found: 749 (M + H).sup.+. 52/129 cj-38 methyl ((1S)-1- (((2S)-2-(5-(4′-(2- ((2S)-1-((2S)-2- ((methoxycarbonyl) amino)-3-(1H- pyrazol-1- yl)propanoyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbon- yl)-2-methyl- propyl)carbamate LCMS: Anal. Calcd. for C.sub.40H.sub.47N.sub.11O.sub.7: 776; found: 777 (M + H).sup.+. 51/129 cj-39 methyl ((1S)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-(N- (methoxycarbonyl)- O-methyl-L- threonyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxo-1-(1H-pyrazol- 1- ylmethyl)ethyl)carb- amate LCMS: Anal. Calcd. for C.sub.41H.sub.48N.sub.10O.sub.7: 792; found: 793 (M + H).sup.+. 86/129 cj-40 methyl ((1S)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2- (diethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-1-((1- methyl-1H- imidazol-4- yl)methyl)-2- oxoethyl)carbamate LCMS: Anal. Calcd. for C.sub.47H.sub.54N.sub.10O.sub.4: 822; found: 823 (M + H).sup.+. 2/127 cj-41 methyl ((1S)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-(N- (methoxycarbonyl)- L-alanyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-1-((1- methyl-1H- imidazol-4- yl)methyl)-2- oxoethyl)carbamate LCMS: Anal. Calcd. for C.sub.40H.sub.46N.sub.10O.sub.6: 762; found: 763 (M + H).sup.+. 52/127 cj-42 methyl ((1S)-1- (((2S)-2-(5-(4′-(2- ((2S)-1-((2S)-2- ((methoxycarbonyl) amino)-3-(1- methyl-1H- imidazol-4- yl)propanoyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbon- yl)-2- methylpropyl)carba- mate 0 LCMS: Anal. Calcd. for C.sub.42H.sub.50N.sub.10O.sub.6 790; found: 791 (M + H).sup.+. 51/127 cj-43 methyl ((1S)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-((2S,3R)-3- methoxy-2- ((methoxycarbonyl) amino)butanoyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-1-((1- methyl-1H- imidazol-4- yl)methyl)-2- oxoethyl)carbamate LCMS: Anal. Calcd. for C.sub.42H.sub.50N.sub.10O.sub.7 806; found: 806 (M + H).sup.+. 86/127 cj-44 methyl ((1S)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2- (diethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-1-((1- methyl-1H- imidazol-5- yl)methyl)-2- oxoethyl)carbamate LCMS: Anal. Calcd. for C.sub.47H.sub.54N.sub.10O.sub.4 822; found: 823 (M + H).sup.+. 2/126 cj-45 methyl ((1S)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-(N- (methoxycarbonyl)- L-alanyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-1-((1- methyl-1H- imidazol-5- yl)methyl)-2- oxoethyl)carbamate LCMS: Anal. Calcd. for C.sub.40H.sub.46N.sub.10O.sub.6: 762; found: 763 (M + H).sup.+. 52/126 cj-46 methyl ((1S)-1- (((2S)-2-(5-(4′-(2- ((2S)-1-((2S)-2- ((methoxycarbonyl) amino)-3-(1- methyl-1H- imidazol-5- yl)propanoyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbon- yl)-2- methylpropyl)carba- mate LCMS: Anal. Calcd. for C.sub.42H.sub.50N.sub.10O.sub.6 790; found: 791 51/126 cj-47 methyl ((1S)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-((2S,3R)-3- methoxy-2- ((methoxycarbonyl) amino)butanoyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-1-((1- methyl-1H- imidazol-5- yl)methyl)-2- oxoethyl)carbamate LCMS: Anal. Calcd. for C.sub.42H.sub.50N.sub.10O.sub.7 806; found: 807 (M + H).sup.+. 86/126 cj-48 methyl ((1S)-1- methyl-2-oxo-2- ((2S)-2-(5-(4′-(2- ((2S)-1-(((2S)-4- oxo-2- azetidinyl)carbonyl)- 2-pyrrolidinyl)- 1H-imidazol-5-yl)- 4-biphenylyl)-1H- imidazol-2-yl)-1- LCMS: Anal. Calcd. for C.sub.35H.sub.38N.sub.8O.sub.5 650; found: 651 (M + H).sup.+. 52/— pyrrolidinyl)ethyl) carbamate cj-49 methyl (2S)-2- (((2S)-2-(5-(4′-(2- ((2S)-1-(N- (methoxycarbonyl)- L-alanyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbon- LCMS: Anal. Calcd. for C.sub.37H.sub.42N.sub.8O.sub.6 694; found: 695 M + H).sup.+. 52/114 yl)-1- azetidinecarboxylate cj-50 methyl (2S)-2- (((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2- (diethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbon- yl)-1- azetidinecarboxylate LCMS: Anal. Calcd. for C.sub.44H.sub.50N.sub.8O.sub.4 754; found: 755 (M + H).sup.+. 2/114 cj-51 methyl ((1S)-3- ((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2- (diethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-1- methyl-3- oxopropyl)carbamate LCMS: Anal. Calcd. for C.sub.44H.sub.52N.sub.8O.sub.4 756; found: 757 (M + H).sup.+. 2/115 cj-52 methyl ((1R)-3- ((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2- (diethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-1- isopropyl-3- oxopropyl)carbamate 0 LCMS: Anal. Calcd. for C.sub.46H.sub.56N.sub.8O.sub.4 784; found: 785 (M + H).sup.+. 2/116 cj-53 methyl ((1S)-1- benzyl-3-((2S)-2- (5-(4′-(2-((2S)-1- ((2R)-2- (diethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-3- oxopropyl)carbamate LCMS: Anal. Calcd. for C.sub.50H.sub.56N.sub.8O.sub.4 833; found: 834 (M + H).sup.+. 2/96 cj-54 methyl ((1R)-3- ((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2- (diethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-3- oxo-1-(2- thienylmethyl)pro- pyl)carbamate LCMS: Anal. Calcd. for C.sub.48H.sub.54N.sub.8O.sub.4S 838; found: 839 (M + H).sup.+. 2/119 cj-55 methyl ((1R)-3- ((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2- (diethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-3- oxo-1-(3- thienylmethyl)pro- pyl)carbamate LCMS: Anal. Calcd. for C.sub.48H.sub.54N.sub.8O.sub.4S 838; found: 839 (M + H).sup.+. 2/120 cj-56 methyl ((1S)-3- ((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2- (diethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-3- oxo-1-(2- thienylmethyl)pro- pyl)carbamate LCMS: Anal. Calcd. for C.sub.48H.sub.54N.sub.8O.sub.4S 838; found: 839 (M + H).sup.+. 2/118 cj-57 methyl ((1S,3R)-3- (((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2- (diethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbon- yl)cyclopentyl)carb- amate LCMS: Anal. Calcd. for C.sub.46H.sub.54N.sub.8O.sub.4 782; found: 783 (M + H).sup.+. 2/99a cj-58 methyl ((1R)-1- benzyl-3-((2S)-2- (5-(4′-(2-((2S)-1- ((2R)-2- (diethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-3- oxopropyl)carbamate LCMS: Anal. Cacd. for C.sub.50H.sub.56N.sub.8O.sub.4 832; found: 833 (M + H).sup.+. 2/117 cj-59 methyl ((1R)-3- ((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2- (diethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-1-(2- fluorobenzyl)-3- oxopropyl)carbamate LCMS: Anal. Calcd. for C.sub.50H.sub.55N.sub.8O.sub.4F 850; found: 851 (M + H).sup.+. 2/100 cj-60 methyl ((1R,3S)-3- (((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2- (diethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbon- yl)cyclopentyl)carb- amate LCMS: Anal. Calcd. for C.sub.46H.sub.54N.sub.8O.sub.4 782; found: 783 (M + H).sup.+. 2/99 cj-61 methyl ((1S)-1- (((2S)-2-(5-(4′-(2- ((2S)-1-(((1R,3S)- 3- ((methoxycarbonyl) amino)cyclopentyl) carbonyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbon- yl)-2- methylpropyl)carba- mate LCMS: Anal. Calcd. for C.sub.41H.sub.50N.sub.8O.sub.6 750; found: 751 (M + H).sup.+. 52/99a cj-62 methyl ((1S)-1- (((2S)-2-(5-(4′-(2- ((2S)-1-(((1S,3R)- 3- ((methoxycarbonyl) amino)cyclopentyl) carbonyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbon- yl)-2- methylpropyl)carba- mate 0 LCMS: Anal. Calcd. for C.sub.41H.sub.50N.sub.8O.sub.6 750; found: 751 (M + H).sup.+. 52/99 cj-63 methyl ((1R)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-(((1R,3S)- 3- ((methoxycarbonyl) amino)cyclopentyl) carbonyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxo-1- phenylethyl)carbamate LCMS: Anal. Calcd. for C.sub.44H.sub.48N.sub.8O.sub.6 784; found: 785 (M + H).sup.+. 4/99a cj-64 methyl ((1R)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-(((1S,3R)- 3- ((methoxycarbonyl) amino)cyclopentyl) carbonyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxo-1- phenylethyl)carbamate LCMS: Anal. Calcd. for C.sub.44H.sub.48N.sub.8O.sub.6 784; found: 785 (M + H).sup.+. 4/99 cj-65 methyl ((1S)-1- (((2S)-2-(5-(4′-(2- ((2S)-1-((2S)-2- ((methoxycarbonyl) amino)-3-(2- pyridinyl)propanoyl)- 2-pyrrolidinyl)- 1H-imidazol-5-yl)- 4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbon- yl)-2-methyl propyl)carbamate LCMS: Anal. Calcd. for C.sub.43H.sub.49N.sub.9O.sub.6 787; found: 788 (M + H).sup.+. 51/93 cj-66 methyl ((1S)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-(N- (methoxycarbonyl)- L-alanyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxo-1-(2- pyridinylmethyl)eth- LCMS: Anal. Calcd. for C.sub.41H.sub.45N.sub.9O.sub.6 759; found: 760 (M + H).sup.+. 52/93 yl)carbamate cj-67 methyl ((1S)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-((2S,3R)-3- methoxy-2- ((methoxycarbonyl) amino)butanoyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxo-1-(2- LCMS: Anal. Calcd. for C.sub.43H.sub.49N.sub.9O.sub.7 803; found: 804 (M + H).sup.+. 86/93 pyridinylmethyl)eth- yl)carbamate cj-68 methyl ((1S)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2- (diethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxo-1-(2- pyridinylmethyl)eth- yl)carbamate LCMS: Anal. Calcd. for C.sub.48H.sub.53N.sub.9O.sub.4 819; found: 820 (M + H).sup.+. 2/93 cj-69 methyl ((1S)-1- (((2S)-2-(5-(4′-(2- ((2S)-1-((cis-4- ((methoxycarbonyl) amino)cyclohexyl)car- bonyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbon- yl)-2-methyl- propyl)carbamate LCMS: Anal. Calcd. for C.sub.42H.sub.52N.sub.8O.sub.6 764; found: 765 (M + H).sup.+. 51/104 cj-70 methyl ((1S)-1- (((2S)-2-(5-(4′-(2- ((2S)-1-((trans--4- ((methoxycarbonyl) amino)cyclohexyl)car- bonyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbon- yl)-2-methyl propyl)carbamate LCMS: Anal. Calcd. for C.sub.42H.sub.52N.sub.8O.sub.6 764; found: 765 (M + H).sup.+. 51/105 cj-71 methyl ((1S)-1- (((2S)-2-(5-(4′-(2- ((2S)-1-((cis-4- (diethylamino)cyclo- hexyl)carbonyl)- 2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbon- yl)-2- methylpropyl)carba- mate LCMS: Anal. Calcd. for C.sub.44H.sub.58N.sub.8O.sub.4 762; found: 763 (M + H).sup.+. 51/106 cj-72 methyl ((1S,2R)-1- (((2S)-2-(5-(4′-(2- ((2S)-1-((cis-4- (diethylamino)cyclo- hexyl)carbonyl)- 2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbon- yl)-2- methoxypropyl)car- bamate 0 LCMS: Anal. Calcd. for C.sub.44H.sub.58N.sub.8O.sub.5 778; found: 779 (M + H).sup.+. 86/106 cj-73 cis-4-(((2S)-2-(5- (4′-(2-((2S)-1- ((2R)-2- (diethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbon- yl)-N,N- diethylcyclohexana- mine LCMS: Anal. Calcd. for C.sub.49H.sub.62N.sub.8O.sub.2 794; found: 795 (M + H).sup.+. 2/106 cj-74 methyl ((1S)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-((cis-4- (diethylamino)cyclo- hexyl)carbonyl)- 2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-1- methyl-2- oxoethyl)carbamate LCMS: Anal. Calcd. for C.sub.42H.sub.54N.sub.8O.sub.4 734; found: 735 (M + H).sup.+. 52/106 cj-75 methyl ((1S)-1-((1- benzyl-1H- imidazol-4- yl)methyl)-2-((2S)- 2-(5-(4′-(2-((2S)-1- ((2S,3R)-3- methoxy-2- ((methoxycarbonyl) amino)butanoyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxoethyl)carbamate LCMS: Anal. Calcd. for C.sub.48H.sub.54N.sub.10O.sub.7 882; found: 883 (M + H).sup.+. 86/108 cj-76 methyl ((1S)-1- (((2S)-2-(5-(4′-(2- ((2S)-1-((2S)-3-(1- benzyl-1H- imidazol-4-yl)-2- ((methoxycarbonyl) amino)propanoyl)- 2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbon- yl)-2- methylpropyl)carba- mate LCMS: Anal. Calcd. for C.sub.48H.sub.54N.sub.10O.sub.6 866; found: 867 (M + H).sup.+. 51/108 cj-77 methyl ((1S)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-((2S)-3-(1- benzyl-1H- imidazol-4-yl)-2- ((methoxycarbonyl) amino)propanoyl)- 2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-1- methyl-2- oxoethyl)carbamate LCMS: Anal. Calcd. for C.sub.46H.sub.50N.sub.10O.sub.6 838; found: 839 (M + H).sup.+. 52/108 cj-78 methyl ((1S)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-((2S,3R)-3- methoxy-2- ((methoxycarbonyl) amino)butanoyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxo-1-(1,3-thiazol- 4-ylmethyl) LCMS: Anal. Calcd. for C.sub.41H.sub.47N.sub.9O.sub.7S 809; found: 810 (M + H).sup.+. 86/107 ethyl)carbamate cj-79 methyl ((1S)-1- (((2S)-2-(5-(4′-(2- ((2S)-1-((2S)-2- ((methoxycarbonyl) amino)-3-(1,3- thiazol-4- yl)propanoyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbon- yl)-2-methyl propyl)carbamate LCMS: Anal. Calcd. for C.sub.41H.sub.47N.sub.9O.sub.6S 793; found: 794 (M + H).sup.+. 51/107 cj-80 methyl ((1S)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2- (diethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxo-1-(1,3-thiazol- 4-ylmethyl) ethyl)carbamate LCMS: Anal. Calcd. for C.sub.46H.sub.51N.sub.9O.sub.4S 825; found: 826 (M + H).sup.+. 2/107 cj-81 methyl ((1S)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-(N- (methoxycarbonyl)- L-alanyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxo-1-(1,3-thiazol- 4-ylmethyl) ethyl)carbamate LCMS: Anal. Calcd. for C.sub.39H.sub.43N.sub.9O.sub.6S 765; found: 766 (M + H).sup.+. 51/107 cj-82 methyl ((1S)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-((2S,3R)-3- methoxy-2- ((methoxycarbonyl) amino)butanoyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrroldiniyl)-2- oxo-1-(3- pyridinylmethyl)eth- 0 LCMS: Anal. Calcd. for C.sub.43H.sub.49N.sub.9O.sub.7 803; found: 804 (M + H).sup.+. 86/109 yl)carbamate cj-83 methyl ((1S)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-((2S)-2- ((methoxycarbonyl) amino)-3- methylbutanoyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxo-1-(3- pyridinylmethyl)eth- LCMS: Anal. Calcd. for C.sub.43H.sub.49N.sub.9O.sub.6 787; found: 788 (M + H).sup.+. 51/109 yl)carbamate cj-84 methyl ((1S)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2- (diethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxo-1-(3- pyridinylmethyl)eth- yl)carbamate LCMS: Anal. Calcd. for C.sub.48H.sub.53N.sub.9O.sub.4 819; found: 820 (M + H).sup.+. 2/109 cj-85 methyl ((1S)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-(N- (methoxycarbonyl)- L-alanyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxo-1-(3- pyridinylmethyl)eth- yl)carbamate LCMS: Anal. Calcd. for C.sub.41H.sub.45N.sub.9O.sub.6 759; found: 760 (M + H).sup.+. 52/109 cj-86 methyl ((1R,3S)-3- (((2S)-2-(5-(4′-(2- ((2S)-1-((2S)-3- methoxy-2- ((methoxycarbonyl) amino)butanoyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbon- yl)cyclopentyl)carb- amate LCMS: Anal. Calcd. for C.sub.42H.sub.50N.sub.8O.sub.7 766; found: 767 (M + H).sup.+. 86/99 cj-87 methyl ((1S)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-((2S,3R)-3- methoxy-2- ((methoxycarbonyl) amino)butanoyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxo-1-(4- pyridinylmethyl)eth- LCMS: Anal. Calcd. for C.sub.43H.sub.49N.sub.9O.sub.7 803; found: 804 (M + H).sup.+. 86/110 yl)carbamate cj-88 methyl ((1S)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-((2S)-2- ((methoxycarbonyl) amino)-3- methylbutanoyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxo-1-(4- pyridinylmethyl)eth- LCMS: Anal. Calcd. for C.sub.43H.sub.49N.sub.9O.sub.6 787; found: 788 (M + H).sup.+. 51/110 yl)carbamate cj-89 methyl ((1S)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2- (diethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxo-1-(4- pyridinylmethyl)eth- yl)carbamate LCMS: Anal. Calcd. for C.sub.48H.sub.53N.sub.9O.sub.4 819; found: 820 (M + H).sup.+. 2/110 cj-90 methyl ((1S)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-(N- (methoxycarbonyl)- L-alanyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxo-1-(4- pyridinylmethyl)eth- yl)carbamate LCMS: Anal. Calcd. for C.sub.41H.sub.45N.sub.9O.sub.6 759; found: 760 (M + H).sup.+. 52/110 cj-91 methyl ((1S)-1- (((2S)-2-(5-(4′-(2- ((2S)-1-(O- (hydroxy(methoxy) phosphoryl)-N- (methoxycarbonyl)- L-tyrosyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbon- yl)-2- LCMS: Anal. Calcd. for C.sub.45H.sub.53N.sub.8O.sub.10 P 896; found: 897 (M + H).sup.+. 51/111 methylpropyl)carba- mate cj-92 methyl ((1S,2R)-1- (((2S)-2-(5-(4′-(2- ((2S)-1-(O- (hydroxy(methoxy) phosphoryl)-N- (methoxycarbonyl)- L-tyrosyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrollidinyl)carbon- yl)-2-methoxy- propyl)carbamate 0 LCMS: Anal. Calcd. for C.sub.45H.sub.53N.sub.8O.sub.11 P912; found: 913 (M + H).sup.+. 86/111 cj-93 methyl ((1S)-1- (((2S)-2-(5-(4′-(2- ((2S)-1-(((1S,2R)- 2- ((methoxycarbonyl) amino)cyclohexyl)car- bonyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbon- yl)-2- methylpropyl)carba- mate LCMS: Anal. Calcd. for C.sub.42H.sub.52N.sub.8O.sub.6 764; found: 765 (M + H).sup.+. 98/51 cj-94 methyl ((1R,2S)-2- (((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2- (diethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbon- yl)cyclohexyl)carba- mate LCMS: Anal. Calcd. for C.sub.47H.sub.56N.sub.8O.sub.4 796; found: 797 (M + H).sup.+. 98/2 cj-95 methyl ((1R)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-(((1S,2R)- 2- ((methoxycarbonyl) amino)cyclohexyl)carbo- nyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxo-1- phenylethyl)carbamate LCMS: Anal. Calcd. for C.sub.45H.sub.50N.sub.8O.sub.6 798; found: 799 (M + H).sup.+. 98/4 cj-96 methyl ((1R,2S)-2- (((2S)-2-(5-(4′-(2- ((2S)-1-(N- (methoxycarbonyl)- L-alanyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbon- yl)cyclohexyl)carba- mate LCMS: Anal. Calcd. for C.sub.40H.sub.48N.sub.8O.sub.6 736; found: 737 (M + H).sup.+. 98/51 cj-97 methyl ((1R,2S)-2- (((2S)-2-(5-(4′-(2- ((2S)-1-((cis-4- (diethylamino)cyclo- hexyl)carbonyl)- 2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbon- yl)cyclohexyl)carba- mate LCMS: Anal. Calcd. for C.sub.46H.sub.60N.sub.8O.sub.4 788; found: 789 (M + H).sup.+. 98/106 cj-98 methyl ((1R,2S)-2- (((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2- acetamido-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbon- yl)cyclohexyl)carba- mate LCMS: Anal. Calcd. for C.sub.45H.sub.50N.sub.8O.sub.5 782; found: 783 (M + H).sup.+. 98/130 cj-99 methyl ((1S)-1- (((2S)-2-(5-(4′-(2- ((2S)-1-((2S)-3- (1H-indol-3-yl)-2- ((methoxycarbonyl) amino)propanoyl)- 2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbon- yl)-2-methyl- propyl)carbamate LCMS: Anal. Calcd. for C.sub.56H.sub.51N.sub.9O.sub.6 825; found: 826 (M + H).sup.+. 51/112 cj-100 methyl ((1S)-1- (1H-indol-3- ylmethyl)-2-((2S)- 2-(5-(4′-(2-((2S)-1- ((2S,3R)-3- methoxy-2- ((methoxycarbonyl) amino)butanoyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- LCMS: Anal. Calcd. for C.sub.46H.sub.51N.sub.9O.sub.7 841; found: 842 (M + H).sup.+. 86/112 oxoethyl)carbamate cj-101 methyl ((1S)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2- (diethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-1- (1H-indol-3- ylmethyl)-2- oxoethyl)carbamate LCMS: Anal. Calcd. for C.sub.51H.sub.55N.sub.9O.sub.4 857; found: 858 (M + H).sup.+. 2/112 cj-102 methyl ((1S)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-((2S)-3- (1H-indol-3-yl)-2- ((methoxycarbonyl) amino)propanoyl)- 2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-1- methyl-2- oxoethyl)carbamate 0 LCMS: Anal. Calcd. for C.sub.44H.sub.47N.sub.9O.sub.6 797; found: 798 (M + H).sup.+. 52/112 cj-103 methyl ((1S)-1-(4- (aminomethyl)benz- yl)-2-((2S)-2-(5-(4′- (2-((2S)-1-((2S)-2- ((methoxycarbonyl) amino)-3- methylbutanoyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxoethyl)carbamate LCMS: Anal. Calcd. for C.sub.45H.sub.53N.sub.9O.sub.6 815; found: 816 (M + H).sup.+. see text cj-104 methyl ((1S)-1- (((2S)-2-(5-(4′-(2- ((2S)-1-(O-benzyl- N- (methoxycarbonyl)- L-tyrosyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbon- yl)-2- methylpropyl)carba- mate LCMS: Anal. Calcd. for C.sub.51H.sub.56N.sub.8O.sub.7 892; found: 893 (M + H).sup.+. 51/113 cj-105 methyl ((1S,2R)-1- (((2S)-2-(5-(4′-(2- ((2S)-1-(O-benzyl- N- (methoxycarbonyl)- L-tyrosyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbon- yl)-2- methoxypropyl) carbamate LCMS: Anal. Calcd. for C.sub.51H.sub.56N.sub.8O.sub.8 908; found: 909 (M + H).sup.+. 86/113 cj-106 methyl ((1S)-1-(4- (benzyloxy)benzyl)- 2-((2S)-2-(5-(4′- (2-((2S)-1-((2R)-2- (diethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-2- pyrrolidinyl)-2- oxoethyl)carbamate LCMS: Anal. Calcd. for C.sub.56H.sub.60N.sub.8O.sub.5 924; found: 925 (M + H).sup.+. 2/113 cj-107 methyl ((1S)-1-(4- (benzyloxy)benzyl)- 2-((2S)-2-(5-(4′- (2-((2S)-1-(N- (methoxycarbonyl)- L-alanyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxoethyl)carbamate LCMS: Anal. Calcd. for C.sub.49H.sub.52N.sub.8O.sub.7 864; found: 865 (M + H).sup.+. 52/113 cj-108 methyl ((1R,2R)-2- (((2S)-2-(5-(4′-(2- ((2S)-1-(N- (methoxycarbonyl)- L-alanyl)-2- pyrrolidnyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbon- yl)cyclopentyl) carbamate LCMS: Anal. Calcd. for C.sub.39H.sub.46N.sub.8O.sub.6 722; found: 723 (M + H).sup.+. 122/52 cj-109 methyl ((1R,2R)-2- (((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2- (diethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbon- yl)cyclopentyl)carb- amate LCMS: Anal. Calcd. for C.sub.46H.sub.54N.sub.8O.sub.4 782; found: 783 (M + H).sup.+. 122/2 cj-110 methyl ((1R)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-(((1R,2R)- 2- ((methoxycarbonyl) amino)cyclopentyl) carbonyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxo-1- phenylethyl)carbamate LCMS: Anal. Calcd. for C.sub.44H.sub.48N.sub.8O.sub.6 784; found: 785 (M + H).sup.+. 122/4 cj-111 methyl ((1S)-1-(4- hydroxybenzyl)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-((2S)-2- ((methoxycarbonyl) amino)-3- methylbutanoyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxoethyl)carbamate LCMS: Anal. Calcd. for C.sub.44H.sub.50N.sub.8O.sub.7 802; found: 803 (M + H).sup.+. see text cj-112 methyl ((1S)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2- (diethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-1-(4- hydroxybenzyl)-2- oxoethyl)carbamate 000 LCMS: Anal. Calcd. for C.sub.49H.sub.54N.sub.8O.sub.5 834; found: 835 (M + H).sup.+. see text cj-113 methyl ((1S)-1-(4- hydroxybenzyl)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-(N- (methoxycarbonyl)- L-alanyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxoethyl)carbamate 001 LCMS: Anal. Calcd. for C.sub.42H.sub.46N.sub.8O.sub.7 774; found: 775 (M + H).sup.+. see text cj-114 methyl ((1S)-1-(4- (acetamidomethyl) benzyl)-2-((2S)-2- (5-(4′-(2-((2S)-1- ((2S)-2- ((methoxycarbonyl) amino)-3- methylbutanoyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- 002 LCMS: Anal. Calcd. for C.sub.47H.sub.55N.sub.9O.sub.7 857; found: 585 (M + H).sup.+. see text pyrrolidinyl)-2- oxoethyl)carbamate cj-115 methyl ((1S)-1-(4- (((ethylcarbamoyl)a- mino)methyl)benzyl)- 2-((2S)-2-(5-(4′- (2-((2S)-1-((2S)-2- ((methoxycarbonyl) amino)-3- methylbutanoyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- 003 LCMS: Anal. Calcd. for C.sub.48H.sub.58N.sub.10O.sub.7 886; found: 887 (M + H).sup.+. see text oxoethyl)carbamate cj-116 methyl ((1S,2S)-2- (((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2- (diethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl) cyclopentyl) carbamate 004 LCMS: Anal. Calcd. for C.sub.46H.sub.54N.sub.8O.sub.4 782; found: 783 (M + H).sup.+. 121/2 cj-117 methyl ((1R)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-(((1S,2S)- 2- ((methoxycarbonyl) amino)cyclopentyl) carbonyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxo-1- phenylethyl)carbamate 005 LCMS: Anal. Calcd. for C.sub.44H.sub.48N.sub.8O.sub.6 784; found: 785 (M + H).sup.+. 121/4 cj-118 methyl ((1S,2S)-2- (((2S)-2-(5-(4′-(2- ((2S)-1-(N- (methoxycarbonyl)- L-alanyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbon- yl)cyclopentyl) carbamate 006 LCMS: Anal. Calcd. for C.sub.39H.sub.46N.sub.8O.sub.6 722; found: 723 (M + H).sup.+. 121/52 cj-119 methyl ((1S)-1- (((2S)-2-(5-(4′-(2- ((2S)-1-(N- (methoxycarbonyl)- O-methyl-L- homoseryl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbon- yl)-2- methylpropyl) 007 LCMS: Anal. Calcd. for C.sub.40H.sub.50N.sub.8O.sub.7 754; found: 755 (M + H).sup.+. 51/87 carbamate cj-120 methyl ((1S)-3- methoxy-1-(((2S)- 2-(5-(4′-(2-((2S)-1- (N- (methoxycarbonyl)- L-alanyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbon- yl)propyl)carbamate 008 LCMS: Anal. Calcd. for C.sub.38H.sub.46N.sub.8O.sub.7 726; found: 727 (M + H).sup.+. 52/87 cj-121 methyl ((1S,2R)-2- methoxy-1-(((2S)- 2-(5-(4′-(2-((2S)-1- (N- (methoxycarbonyl)- O-methyl-L- homoseryl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbon- yl)propyl)carbamate 009 LCMS: Anal. Calcd. for C.sub.40H.sub.50N.sub.8O.sub.8 770; found: 771 (M + H).sup.+. 86/87 cj-122 methyl ((1S,2S)-2- (((2S)-2-(5-(4′-(2- ((2S)-1-(N- (methoxycarbonyl)- O-methyl-L- homoseryl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbon- yl)cyclopentyl) carbamate 010 LCMS: Anal. Calcd. for C.sub.41H.sub.50N.sub.8O.sub.7 766; found: 767 (M + H).sup.+. 121/87

Examples cj-111 to cj-113

(1036) For Examples cj-111 to cj-113 the compounds of Examples cj-105 to cj-107 were hydrogenated under conditions analogous to those used in Example 28, step d (with the exception that K.sub.2CO.sub.3 was not employed).

Preparation of examples cj-103, cj-114 and cj-115

(1037) ##STR01011##

(1038) Intermediate cj-124 was prepared by coupling of intermediate cj-12 and Cap-122, as described in Example 28, step e. LCMS: Anal. Calcd. for C.sub.60H.sub.63N.sub.9O.sub.8 1037. found: 520 (½M+H).sup.+. This corresponds to the doubly charged molecular ion.

Example cj-103

(1039) ##STR01012##

(1040) Intermediate cj-124 (83.0 mg, 0.08 mmol) was dissolved in DMF (5 mL) and piperidine (1 mL) was added at room temperature. After 2 h the volatiles were removed in vacuo and the residue was purified by preparative HPLC (YMC-Pack C-18, 30×100 mm, CH.sub.3CN—H.sub.2O-TFA) to give the TFA salt of the amine (87.0 mg, 94%). LCMS: Anal. Calcd. for C.sub.45H.sub.53N.sub.9O.sub.6 815. found: 816 (M+H).sup.+.

Examples cj-114 to cj-115

(1041) ##STR01013##

(1042) The product from Example cj-103 was acylated with either acetic anhydride or ethyl isocyanate as shown in scheme under conditions analogous to those in Example 25. Example cj-114, LCMS: Anal. Calcd. for C.sub.47H.sub.55N.sub.9O.sub.7 857. found: 858 (M+H).sup.+. Example cj-115, LCMS: Anal. Calcd. for C.sub.45H.sub.55N.sub.10O.sub.7 886. found: 887 (M+H).sup.+.

(1043) The following examples were prepared from intermediate 1e using a procedure analogous to Example 1. The appended cap is indicated in the Table and where no cap number is give the carboxylic acid was commercially available.

(1044) TABLE-US-00067 Example Compound Name Structure Cap LCMS cj-125 methyl ((1S)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-((2S)-2- ((methoxycarbonyl) amino)-3-(1H- 1,2,3-triazol-4- yl)propanoyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxo-1-(1H-1,2,3- triazol-4- ylmethyl)ethyl) carbamate 014 128 LCMS: Anal. Calcd. for C.sub.40H.sub.44N.sub.14O.sub.6: 816; found: 817 (M + H).sup.+. cj-126 dimethyl (4,4′- biphenyldiylbis(1H- imidazole-5,2- diyl(2S)-2,1- pyrrolidinediyl((2S)- 4-oxo-4,2- butanediyl))) biscarbamate 015 115 LCMS: Anal. Calcd. for C.sub.38H.sub.46N.sub.8O.sub.6 710; found: 711 (M + H).sup.+. cj-127 dimethyl (4,4′- biphenyldiylbis(1H- imidazole-5,2- diyl(2S)-2,1- pyrrolidinediyl((3R)- 4-methyl-1-oxo- 1,3-pentanediyl))) biscarbamate 016 116 LCMS: Anal. Calcd. for C.sub.42H.sub.54N.sub.8O.sub.6 766; found: 777 (M + H).sup.+. cj-128 methyl ((1R)-3- ((2S)-2-(5-(4′-(2- (1-((3R)-3- ((methoxycarbonyl) amino)-3- phenylpropanoyl)- 2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-3- oxo-1- phenylpropyl) carbamate 017 92 LCMS: Anal. Calcd. for C.sub.48H.sub.50N.sub.8O.sub.6 834; found: 835 (M + H).sup.+. cj-129 methyl ((1S)-3- ((2S)-2-(5-(4′-(2- (1-((3S)-3- ((methoxycarbonyl) amino)-3- phenylpropanoyl)- 2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-3- oxo-1- phenylpropyl) carbamate 018 91 LCMS: Anal. Calcd. for C.sub.48H.sub.50N.sub.8O.sub.6 834; found: 835 (M + H).sup.+. cj-130 methyl ((1S)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-((2S)-2- ((methoxycarbonyl) amino)-3-(2- pyridinyl)propanoyl)- 2-pyrrolidinyl)- 1H-imidazol-5-yl)- 4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxo-1-(2- pyridinylmethyl) ethyl)carbamate 019 93 LCMS: Anal. Calcd. for C.sub.46H.sub.48N.sub.10O.sub.6 836; found: 837 (M + H).sup.+. cj-131 methyl ((1S)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-((2S)-3- (1H-imidazol-4-yl)- 2- ((methoxycarbonyl) amino)propanoyl)- 2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-1- (1H-imidazol-4- ylmethyl)-2- oxoethyl)carbamate 020 94 LCMS: Anal. Calcd. for C.sub.42H.sub.46N.sub.12O.sub.6 814; found: 815 (M + H).sup.+. cj-132 (6S,6′S)-6,6′-(4,4′- biphenyldiylbis(1H- imidazole-5,2- diyl(2S)-2,1- pyrrolidinediylcarbonyl)) didihydro-2,4(1H,3H)- pyrimidinedione 021 — LCMS: Anal. Calcd. for C.sub.36H.sub.36N.sub.10O.sub.6 704; found: 705 (M + H).sup.+. cj-133 (4S,5R,4′S,5′R)- 4,4′-(4,4′- biphenyldiylbis(1H- imidazole-5,2- diyl(2S)-2,1- pyrrolidinediylcarbonyl)) bis(5-methyl- 1,3-oxazolidin-2- one) 022 124 LCMS: Anal. Calcd. for C.sub.37H.sub.40N.sub.8O.sub.5 676; found: 677 (M + H).sup.+. cj-134 N-(3-((2S)-2-(5-(4′- (2-((2S)-1-(3- acetamidopropanoyl)-2- pyrrolidinyl)- 1H-imidazol-5-yl)- 4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-3- oxopropypacetamide 023 — LCMS: Anal. Calcd. for C.sub.36H.sub.42N.sub.8O.sub.4 650; found: 651 (M + H).sup.+. cj-135 dimethyl (4,4′- biphenyldiylbis(1H- imidazole-5,2- diyl(2S)-2,1- pyrrolidinediyl((3R)- 1-oxo-5-phenyl- 1,3- pentanediyl))) biscarbamate 024 95 LCMS: Anal. Calcd. for C.sub.52H.sub.58N.sub.8O.sub.6 890; found: 890 (M + H).sup.+. cj-136 dimethyl (4,4′- biphenyldiylbis(1H- imidazole-5,2- diyl(2S)-2,1- pyrrolidinediyl((2R)- 4-oxo-1-(2- thienyl)-4,2- butanediyl))) biscarbamate 025 119 LCMS: Anal. Calcd. for C.sub.46H.sub.50N.sub.8O.sub.6S.sub.2 874; found: 875 (M + H).sup.+. cj-137 dimethyl (4,4′- biphenyldiylbis(1H- imidazole-5,2- diyl(2S)-2,1- pyrrolidinediyl((2R)- 4-oxo-1-(3- thienyl)-4,2- butanediyl))) biscarbamate 026 120 LCMS: Anal. Calcd. for C.sub.46H.sub.50N.sub.8O.sub.6S.sub.2 874; found: 875 (M + H).sup.+. cj-138 dimethyl (4,4′- biphenyldiylbis(1H- imidazole-5,2- diyl(2S)-2,1- pyrrolidinediyl((2S)- 4-oxo-1-(2- thienyl)-4,2- butanediyl))) biscarbamate 027 118 LCMS: Anal. Calcd. for C.sub.46H.sub.50N.sub.8O.sub.6S.sub.2 874; found: 875 (M + H).sup.+. cj-139 dimethyl (4,4′- biphenyldiylbis(1H- imidazole-5,2- diyl(2S)-2,1- pyrrolidinediylcarbonyl (1R,2R)-2,1- cyclohexanediyl)) biscarbamate 028 97 LCMS: Anal. Calcd. for C.sub.44H.sub.54N.sub.8O.sub.6 790; found: 791 (M + H).sup.+. cj-140 di-tert-butyl (4,4′- biphenyldiylbis(1H- imidazole-5,2- diyl(2S)-2,1- pyrrolidinediyl((2S)- 4- (dimethylamino)-1- oxo-1,2- butanediyl))) biscarbamate 029 125 LCMS: Anal. Calcd. for C.sub.48H.sub.68N.sub.10O.sub.6 880; found: 881 (M + H).sup.+. cj-141 dimethyl (4,4′- biphenyldiylbis(1H- imidazole-5,2- diyl(2S)-2,1- pyrrolidinediylcarbonyl (1R,2S)-2,1- cyclohexanediyl)) biscarbamate 030 98 LCMS: Anal. Calcd. for C.sub.44H.sub.54N.sub.8O.sub.6 790; found: 791 (M + H).sup.+. cj-142 (3S,3′S)-4,4′-(4,4′- biphenyldiylbis(1H- imidazole-5,2- diyl(2S)-2,1- pyrrolidinediyl))bis (N~1~, N~1~- dimethyl-4-oxo- 1,3-butanediamine) 031 see text LCMS: Anal. Calcd. for C.sub.38H.sub.52N.sub.10O.sub.2 680; found: 681 (M + H).sup.+. cj-143 dimethyl (4,4′- biphenyldiylbis(1H- imidazole-5,2- diyl(2S)-2,1- pyrrolidinediyl((2R)- 4-oxo-1-phenyl- 4,2- butanediyl))) biscarbamate 032 117 LCMS: Anal. Calcd. for C.sub.30H.sub.54N.sub.8O.sub.6 862; found: 863 (M + H).sup.+. cj-144 dimethyl (4,4′- biphenyldiylbis(1H- imidazole-5,2- diyl(2S)-2,1- pyrrolidinediylcarbonyl (1R,3S)-3,1- cyclopentanediyl)) biscarbamate 033 99 LCMS: Anal. Calcd. for C.sub.42H.sub.50N.sub.8O.sub.6 762; found: 763 (M + H).sup.+. cj-145 methyl ((1R)-1- benzyl-2-((2S)-2- (5-(4′-(2-((2S)-1- ((2R)-2- ((methoxycarbonyl) amino)-3- phenylpropanoyl)- 2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxoethyl)carbamate 034 101 LCMS: Anal. Calcd. for C.sub.48H.sub.50N.sub.8O.sub.6 834; found: 835 (M + H).sup.+. cj-146 dimethyl (4,4′- biphenyldiylbis(1H- imidazole-5,2- diyl(2S)-2,1- pyrrolidinediyl((2S)-4- (dimethylamino)-1- oxo-1,2- butanediyl))) biscarbamate 035 see text LCMS: Anal. Calcd. for C.sub.42H.sub.56N.sub.10O.sub.6 796; found: 797 (M + H).sup.+. cj-147 (2R,2′R)-1,1′-(4,4′- biphenyldiylbis(1H- imidazole-5,2- diyl(2S)-2,1- pyrrolidinediyl))bis (N,N-dimethyl-1- oxo-3-phenyl-2- propanamine) 036 90 LCMS: Anal. Calcd. for C.sub.48H.sub.54N.sub.8O.sub.2 774; found: 775 (M + H).sup.+. cj-148 methyl ((1S)-1- benzyl-2-((2S)-2- (5-(4′-(2-((2S)-1- ((2S)-2- ((methoxycarbonyl) amino)-3- phenylpropanoyl)- 2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxoethyl)carbamate 037 102 LCMS: Anal. Calcd. for C.sub.48H.sub.50N.sub.8O.sub.6 834; found: 835 (M + H).sup.+. cj-149 dimethyl (4,4′- biphenyldiylbis(1H- imidazole-5,2- diyl(2S)-2,1- pyrrolidinediylcarbonyl (1R,3S)-3,1- cyclopentanediyl)) biscarbamate 038  99a LCMS: Anal. Calcd. for C.sub.42H.sub.50N.sub.8O.sub.6 806; found: 807 (M + H).sup.+. cj-150 dimethyl (4,4′- biphenyldiylbis(1H- imidazole-5,2- diyl(2S)-2,1- pyrrolidinediylcarbonylcis- 4,1- cyclohexanediyl)) biscarbamate 039 104 LCMS: Anal. Calcd. for C.sub.44H.sub.54N.sub.8O.sub.6 790; found: 791 (M + H).sup.+. cj-151 dimethyl (4,4′- biphenyldiylbis(1H- imidazole-5,2- diyl(2S)-2,1- pyrrolidinediylcarbonyltrans- 4,1- cyclohexanediyl)) biscarbamate 040 105 LCMS: Anal. Calcd. for C.sub.44H.sub.54N.sub.8O.sub.6 790; found: 791 (M + H).sup.+. cj-152 ({cis)-4,4′-(4,4′- biphenyldiylbis(1H- imidazole-5,2- diyl(2S)-2,1- pyrrolidinediylcarbonyl)) bis(N,N- diethylcyclohexanamine) 041 106 LCMS: Anal. Calcd. for C.sub.48H.sub.66N.sub.8O.sub.2 766; found: 777 (M + H).sup.+. cj-153 methyl ((1S)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-((2S)-2- ((methoxycarbonyl) amino)-3-(1,3- thiazol-4- yl)propanoyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxo-1-(1,3-thiazol-4- ylmethyl)ethyl) carbamate 042 107 LCMS: Anal. Calcd. for C.sub.42H.sub.44N.sub.10O.sub.6S.sub.2 848; found: 849 (M + H).sup.+. cj-154 methyl ((1S)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-((2S)-3-(1- benzyl-1H- imidazol-4-yl)-2- ((methoxycarbonyl) amino)propanoyl)- 2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-1-((1- benzyl-1H- imidazol-4- yl)methyl)-2- oxoethyl)carbamate 043 108 LCMS: Anal. Calcd. for C.sub.42H.sub.50N.sub.8O.sub.6 762; found: 763 (M + H).sup.+. cj-155 dimethyl (4,4′- biphenyldiylbis(1H- imidazole-5,2- diyl(2S)-2,1- pyrrolidinediylcarbonyl (1S,2S)-2,1- cyclopentanediyl)) biscarbamate 044 121 LCMS: Anal. Calcd. for C.sub.42H.sub.50N.sub.8O.sub.6 762; found: 763 (M + H).sup.+. cj-156 methyl ((1S)-3- methoxy-1-(((2S)- 2-(5-(4′-(2-((2S)-1- (N- (methoxycarbonyl)- O-methyl-L- homoseryl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl) propyl)carbamate 045 87 LCMS: Anal. Calcd. for C.sub.40H.sub.50N.sub.8O.sub.8 770; found: 771 (M + H).sup.+.

Example cj-142

(1045) ##STR01046##

(1046) Example cj-142 was prepared from the product obtained in Example cj-140 by treatment with 40% TFA in CH.sub.2C.sub.12. The mixture was allowed to stir for 3 h at room temperature and then concentrated in vacuo. The residue was purified by prep HPLC (YMC-Pack, C18 30×100 mm, CH.sub.3CN—H.sub.2O-TFA).

Example cj-156

(1047) ##STR01047##

(1048) The compound of Example-cj-156 was prepared by carbamoylation of the compound prepared in Example-cj-142 according to the method shown for Cap-51.

(1049) Section JG

(1050) Method A: LCMS—Xterra MS C-18 3.0×50 mm, 0 to 100% B over 30.0 minute gradient, 1 minute hold time, A=5% acetonitrile, 95% water, 10 mm ammonium acetate, B=95% acetonitrile, 5% water, 10 mm ammonium acetate.

(1051) Method B: HPLC-X-Terra C-18 4.6×50 mm, 0 to 100% B over 10.0 minute gradient, 1 minute hold time, A=10% methanol 90% water 0.1% TFA, B=90% methanol 10% water 0.1% TFA.

(1052) Method C: HPLC-YMC C-18 4.6×50 mm, 0 to 100% B over 10.0 minute gradient, 1 minute hold time, A=10% methanol 90% water 0.2% H.sub.3PO.sub.4, B=90% methanol 10% water 0.2% H.sub.3PO.sub.4.

(1053) Method D: HPLC-Phenomenex C-18 4.6×150 mm, 0 to 100% B over 10.0 minute gradient, 1 minute hold time, A=10% methanol 90% water 0.2% H.sub.3PO.sub.4, B=90% methanol 10% water 0.2% H.sub.3PO.sub.4.

(1054) Method E: LCMS—Gemini C-18 4.6×50 mm, 0 to 100% B over 10.0 minute gradient, 1 minute hold time, A=5% acetonitrile, 95% water, 10 mm ammonium acetate, B=95% acetonitrile, 5% water, 10 mm ammonium acetate.

(1055) Method F: LCMS—Luna C-18 3.0×50 mm, 0 to 100% B over 7.0 minute gradient, 1 minute hold time, A=5% acetonitrile, 95% water, 10 mm ammonium acetate, B=95% acetonitrile, 5% water, 10 mm ammonium acetate.

(1056) Method G: HPLC-Phenomenex Gemini C-18 4.6×150 mm, 10 to 80% B over 35 minute gradient, 1 minute hold time, A=5% acetonitrile, 95% water, 10 mm ammonium acetate, B=95% acetonitrile, 5% water, 10 mm ammonium acetate.

(1057) Method H: HPLC-Phenomenex Gemini C-18 4.6×150 mm, 10 to 80% B over 25 minute gradient, 1 minute hold time, A=5% acetonitrile, 95% water, 10 mm ammonium acetate, B=95% acetonitrile, 5% water, 10 mm ammonium acetate.

(1058) Method I: HPLC-Waters-X-Bridge C-18 4.6×150 mm, 10 to 70% B over 30 minute gradient, 1 minute hold time, A=5% acetonitrile, 95% water, 10 mm ammonium acetate, B=95% acetonitrile, 5% water, 10 mm ammonium acetate.

(1059) ##STR01048##
Step a:

(1060) (3S,3′S,5S,5′S)-tert-butyl 5,5′-(5,5′-(biphenyl-4,4′-diyl)bis(1H-imidazole-5,2-diyl))bis(3-hydroxypyrrolidine-1-carboxylate) (1.40 g, 2.13 mmol) was added as a solid to a solution of bis(2-methoxyethyl) aminosulfur trifluoride (0.87 mL, 4.69 mmol) in 14.0 mL CH.sub.2Cl.sub.2 cooled to −78° C. Reaction was stirred at −78° C. for two hours and then warmed to room temperature and stirred for 2 hours. Reaction was poured into saturated sodium bicarbonate solution and stirred until bubbling ceased. Layers were separated and aqueous layer washed one time with CH.sub.2C.sub.12. Combined organics were washed with brine, dried (MgSO.sub.4), filtered, and concentrated to give a yellow oil. The oil was triturated with CH.sub.2Cl.sub.2 and pentane to yield (3R,3′R,5S,5′S)-tert-butyl 5,5′-(5,5′-(biphenyl-4,4′-diyl)bis(1H-imidazole-5,2-diyl))bis(3-fluoropyrrolidine-1-carboxylate) JG-1 as a tan solid (0.98 g, 71%).

(1061) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 12.10 (2H, m) 7.60-7.82 (8H, m) 7.35 (2H, m) 5.45 (1H, s) 5.35 (1H, s) 4.85-4.90 (2H, m) 3.69-3.79 (4H, m) 2.53-2.61 (2H, m) 2.28-2.37 (2H, m) 1.40 (8H, s) 1.12 (10H, s)

(1062) LCMS—Phenomenex C-18 3.0×50 mm, 0 to 100% B over 4.0 minute gradient, 1 minute hold time, A=10% methanol 90% water 0.1% TFA, B=90% methanol 10% water 0.1% TFA, (t.sub.R=3.04 min) Anal Calcd. for C.sub.36H.sub.42F.sub.2N.sub.6O.sub.4 660.70. found 661.68 (M+H).sup.+.

(1063) Step b:

(1064) To a solution of (3R,3R,5S,5′S)-tert-butyl 5,5′-(5,5′-(biphenyl-4,4′-diyl)bis(1H-imidazole-5,2-diyl))bis(3-hydroxypyrrolidine-1-carboxylate) (0.098 g, 1.48 mmol) in 4 mL dioxane was added 2.0 mL of a 4.0M solution of HCl in dioxane. The reaction was stirred for 2 hours at room temperature and concentrated under reduced pressure. The resulting tan solid was dried under vacuum to give 4,4′-bis(2-((2S,4S)-4-fluoropyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl tetrahydrochloride JG-2 (0.89 g, 100% yield). No further purification.

(1065) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 9.05 (2H, s), 8.18 (2H, s), 8.00-8.09 (4H, m) 7.89 (4H, d, J=7.63 Hz) 5.71 (1H, s) 5.61 (1H, s) 5.24-5.33 (2H, m) 3.92 (2H, d, J=10.68 Hz) 3.63-3.71 (2H, m) 2.79-2.89 (2H, m)

(1066) LCMS—Phenomenex C-18 3.0×50 mm, 0 to 100% B over 4.0 minute gradient, 1 minute hold time, A=10% methanol 90% water 0.1% TFA, B=90% methanol 10% water 0.1% TFA, (t.sub.R=2.12 min) Anal Calcd. for C.sub.26H.sub.26F.sub.2N.sub.6 460.53. found 461.37 (M+H).sup.+.

(1067) Step c:

(1068) To a stirred solution of 4,4′-bis(2-((2S,4R)-4-fluoropyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyltetrahydrochloride (0.060 g, 0.10 mmol), (S)-2-(methoxycarbonylamino)propanoic acid (0.031 g, 0.21 mmol), and HATU (0.081 g, 0.21 mmol) in 3 mL DMF was added diisopropylethylamine (0.11 mL, 0.61 mmol). The reaction was stirred at room temperature overnight (16 hours) and concentrated under reduced pressure. The crude product was purified by reverse-phase preparative HPLC and secondly by passing it through a Waters MCX extraction cartridge to provide Dimethyl (2S,2′S)-1,1′-((3R,3′R,5S,5′S)-5,5′-(5,5′-(biphenyl-4,4′-diyl)bis(1H-imidazole-5,2-diyl))bis(3-fluoropyrrolidine-5,1-diyl))bis(1-oxopropane-2,1-diyl)dicarbamate JG-3, free base (0.0097 g, 7.5%).

(1069) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 11.91 (2H, m), 7.76-7.84 (3H, m), 7.64-7.84 (5H, m), 7.48-7.58 (2H, m), 5.55 (1H, s), 5.11 (1H, s), 4.29-4.38 (2H, m), 4.13 (2H, d, J=12.51 Hz), 3.89-3.98 (2H, m), 3.53 (6H, s), 2.54-2.64 4H, m), 1.21 (6H, s)

(1070) LCMS—Luna C-18 3.0×50 mm, 0 to 100% B over 7.0 minute gradient, 1 minute hold time, A=5% acetonitrile, 95% water, 10 mm ammonium acetate, B=95% acetonitrile, 5% water, 10 mm ammonium acetate, (t.sub.R=2.40 min)

(1071) Nominal/LRMS—Calcd. for C.sub.36H.sub.40F.sub.2N.sub.8O.sub.6 718.30. found 719.24 (M+H).sup.+.

(1072) Accurate/HRMS—Calcd. for C.sub.36H.sub.41F.sub.2N.sub.8O.sub.6 719.3117. found 719.3114 (M+H).sup.+.

(1073) TABLE-US-00068 Structure Compound Data Name 049 methyl ((1S)-2- ((2S,4R)- 4-fluoro-2- (5-(4′-(2- ((2S,4R)-4- fluoro-1-(N- (methoxy- carbonyl)-L- alanyl)-2- pyrrolidinyl)- 1H-imidazol- 5-yl)-4- biphenylyl)- 1H-imidazol- 2-yl)-1- pyrrolidinyl)- 1-methyl-2- oxoethyl) carbamate RT = 13.60 min, method I LRMS: Anal. Calcd. for C.sub.36H.sub.40F.sub.2N.sub.8O.sub.6 718.30 found: 719.24 (M + H).sup.+ HRMS: Anal. Calcd. for C.sub.36H.sub.41F.sub.2N.sub.8O.sub.6 719.3117 found 719.3114 (M+H).sup.+ 050 methyl ((1S)- 2-((2S,4R)- 4-hydroxy- 2-(5-(4′-(2- ((2S,4R)-4- hydroxy-1- (N-(methoxy- carbonyl)-L- alanyl)-2- pyrrolidinyl)- 1H-imidazol- 5-yl)-4- biphenylyl)- 1H-imidazol- 2-yl)-1- pyrrolidinyl)-1- methyl-2- oxoethyl) carbamate RT = 9.27 min, method H LRMS: Anal. Calcd. for C.sub.36H.sub.42N.sub.8O.sub.8 714.77 found: 715.33 (M + H).sup.+ HRMS: Anal. Calcd. for C.sub.36H.sub.43N.sub.8O.sub.8 715.3204 found: 715.3186 (M + H).sup.+ 051 methyl ((1S)- 1-(((2S,4R)- 4-hydroxy-2- (5-(4′-(2- ((2S,4R)-4- hydroxy-1- ((2S)-2- ((methoxy- carbonyl) amino)- 3-methyl- butanoyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl-1H- imidazol-2-yl)-1- pyrrolidinyl) carbonyl)-2- methylpropyl) carbamate RT = 15.08 min, method G LRMS: Anal. Calcd. for C.sub.40H.sub.50N.sub.8O.sub.8 770.88 found: 771.76 (M +H).sup.+ HRMS: Anal. Calcd. for C.sub.40H.sub.51N.sub.8O.sub.8 771.3830 found: 771.3798 (M + H).sup.+ 052 dimethyl (4,4′- biphenyldiylbis (1H-imidazole- 5,2-diyl((2S,4R)- 4-hydroxy- 2,1-pyrrolidine- diyl)((1S)- 1-cyclopropyl- 2-oxo-2,1- ethanediyl))) biscarbamate RT = 13.67 min, method G LRMS: Anal. Calcd. for C.sub.40H.sub.46N.sub.8O.sub.8 766.85 found: 767.65 (M +H).sup.+ HRMS: Anal Calcd. for C.sub.40H.sub.47N.sub.8O.sub.8 767.3517 found: 767.3483 (M + H).sup.+ 053 (3S,5S,3′S,5′S)- 5,5′-(4,4′- biphenyldiylbis- (1H-imidazole- 5,2-diyl))bis(1- ((2R)-2- (diethylamino)-2- phenylacetyl)-3- pyrrolidinol) RT = 15.88 min. method H LRMS: Anal. Calcd. for C.sub.50H.sub.58N.sub.8O.sub.4 834.45 found: 835.38 (M + H).sup.+ HRMS: Anal. Calcd. for C.sub.50H.sub.59N.sub.8O.sub.4 835.4659 found: 835.4627 (M + H).sup.+ 054 methyl ((1S)- 2-((2S,4S)- 4-hydroxy-2- (5-(4′-(2- ((2S,4S)-4- hydroxy-1-(N- (methoxy- carbonyl)-L- alanyl)-2- pyrrolidinyl)- 1H-imidazol- 5-yl)-4- biphenylyl)- 1H-imidazol- 2-yl)-1- pyrrolidinyl)-1- methyl-2- oxoethyl) carbamate RT = 9.99 min, method H LRMS: Anal. Calcd. for C.sub.36H.sub.42N.sub.8O.sub.8 714.77 found: 715.71 (M + H).sup.+ HRMS: Anal. Calcd. for C.sub.35H.sub.43N.sub.8O.sub.8 715.3204 found: 715.3188 (M + H).sup.+ 055 methyl ((1S)- 1-(((2S,4S)- 4-hydroxy-2- (5-(4′-(2- ((2S,4S)-4- hydroxy-1- ((2S)-2- ((methoxy- carbonyl) amino)- 3-methyl- butanoyl)-2- pyrrolidinyl)- 1H-imidazol- 5-yl)-4- biphenylyl)- 1H-imidazol- 2-yl)-1- pyrrolidinyl) carbonyl)-2- RT = 14.12 min, method H LRMS: Anal. Calcd. for C.sub.40H.sub.50N.sub.8O.sub.8 770.88 found: 771.74 (M + H).sup.+ HRMS: Anal. Calcd. for C.sub.40H.sub.51N.sub.8O.sub.8 771.3830 found: 771.3799 (M + H)+ methylpropyl) carbamate 056 methyl ((1S)- 1-(((2S,4S)- 4-fluoro-2- (5-(4′-(2- ((2S,4S)-4- fluoro-1- ((2S)-2- ((metboxy- carbonyl) amino)- 3-methyl- butanoyl)-2- pyrrolidinyl)- 1H-imidazol- 5-yl)-4- biphenylyl)- 1H-imidazol- 2-yl)-1- pyrrolidinyl) carbonyl)-2- RT = 17.66 min, method I LRMS: Anal. Calcd. for C.sub.40H.sub.48F.sub.2N.sub.8O.sub.6 774.86 found: 775.49 (M + H).sup.+ HRMS: Anal. Calcd. for C.sub.40H.sub.49F.sub.2N.sub.8O.sub.6 775.3743 found: 775.3717 (M + H).sup.+ methylpropyl) carbamate 057 methyl ((1S)- 1-(((2S,4R)- 4-fluoro-2- (5-(4′-(2- ((2S,4R)-4- fluoro-1- ((2S)-2- ((methoxy- carbonyl) amino)-4- methyl- pentanoyl)-2- pyrrolidinyl)- 1H-imidazol- 5-yl)-4- biphenylyl)- 1H-imidazol- 2-yl)-1- pyrrolidinyl) carbonyl)-3- RT = 9.69 min. method I LRMS: Anal. Calcd. for C.sub.42H.sub.52F.sub.2N.sub.8O.sub.6 802.92 found: 803.42 (M + H).sup.+ HRMS: Anal. Calcd. for C.sub.42H.sub.53F.sub.2N.sub.8O.sub.6 803.4056 found: 803.4018 (M + H).sup.+ methylbutyl) carbamate 058 methyl ((1S)- 2-((2S,4S)- 4-fluoro-2- (5-(4-(2- ((2S,4S)-4- fluoro-1-(N- (methoxy- carbonyl)-L- alanyl)-2- pyrrolidinyl)- 1H-imidazol- 5-yl)-4- biphenylyl)- 1H-imidazol- 2-yl)-1- pyrrolidinyl)- 1-methyl-2- oxoethyl) carbamate RT = 13.60 min. method I LRMS: Anal. Calcd. for C.sub.36H.sub.40F.sub.2N.sub.8O.sub.6 718.30 found: 719.45 (M + H).sup.+ HRMS: Anal. Calcd. for C.sub.36H.sub.41F.sub.2N.sub.8O.sub.6 719.3117 found 719.3090 (M + H).sup.+ 059 methyl ((1S)- 2-((2S,4S)- 2-(5-(4′-(2- ((2S,4S)-1- ((2R)-2- (diethyl- amino)- 2-phenyl- acetyl)-4- fluoro-2- pyrrolidinyl)- 1H-imidazol- 5-yl)-4- biphenyylyl)- 1H-imidazol- 2-yl)-4-fluoro- 1-pyrrolidinyl)- 1-methyl-2- oxoethyl) carbamate RT = 15.13 min. method I LCMS: Anal. Calcd. for C.sub.43H.sub.48F.sub.2N.sub.8O.sub.4 778.91 found: 779.79 (M + H).sup.+ 060 methyl ((1S)-1-(((2S,4S) 2-(5-(4′-(2- ((2S,4S)-1- ((2R)-2- (diethyl- amino)-2- phenyl- acetyl)-4- fluoro-2- pyrrolidinyl)- 1H-imidazol- 5-yl)-4- biphenylyl)- 1H-imidazol- 2-yl)-4- fluoro-1- pyrrolidinyl) carbonyl)-2- RT = 17.51 min. method I LCMS: Anal. Calcd. for C.sub.45H.sub.52F.sub.2N.sub.8O.sub.4 806.96 found: 807.50 (M + H).sup.+ methyl- propyl) carbamate 061 methyl ((S)-1-(((2S,4R)- 4-fluoro-2- (5-(4′-(2- ((2S,4R)-4- fluoro-1- ((2S)-2- ((methoxy- carbonyl) amino)-3- methyl- butanoyl)-2- pyrrolidinyl)- 1H-imidazol- 5-yl)-4- biphenylyl)- 1H-imidazol- 2-yl)-1- pyrrolidinyl) RT = 16.51 min. method I LRMS: Anal. Calcd. for C40H48F2N8O6 774.86 found: 775.39 (M+H).sup.+ HRMS: Anal. Calcd. for C.sub.40H.sub.49F.sub.2N.sub.8O.sub.6 775.3743 found: 775.3740 (M+H).sup.+ carbonyl)-2- methyl- propyl) carbamate 062 (1R,1′R)-2,2′- (4,4′- biphenyldiyl- bis(1H- imidazole-5,2- diyl((2S,4R)- 4-fluoro-2,1- pyrrolidine- diyl)))bis (N,N-diethyl- 2-oxo-1- phenyl- ethanamine) RT = 8.13 min, method I LCMS: Anal. Calcd. for C.sub.50H.sub.56N.sub.8O.sub.2 839.04 found: 839.46 (M + H).sup.+ HRMS: Anal. Calcd. for C.sub.50H.sub.57F.sub.2N.sub.8O.sub.2 839.4572 found: 839.4543 (M + H).sup.+
Synthesis of JG-18 as in Example 28 Step a Using Hydroxyproline in Place of Proline.

(1074) ##STR01063##

(1075) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 7.89 (2H, t, J=8.39 Hz) 7.74 (2H, t, J=8.24 Hz) 7.28-7.37 (5H, m) 5.01-5.08 (3H, m) 4.27-4.57 (4H, m) 3.44-3.53 (1H, m) 3.37 (1H, d, J=10.99 Hz) 2.12 (1H, d, J=11.60 Hz) 1.93 (1H, dd, J=12.05 Hz, 6.56 Hz)

(1076) LCMS—Phenomenex C-18 3.0×50 mm, 0 to 100% B over 4.0 minute gradient, 1 minute hold time, A=10% methanol 90% water 0.1% TFA, B=90% methanol 10% water 0.1% TFA mobile phase, t.sub.R=3.62 min, Anal Calcd. for C.sub.21H.sub.21BrN.sub.2O.sub.5 461.32. found 462.64 (M+H).sup.+.

(1077) Synthesis of JG-19 from JG-18 as in Example 28 Step b.

(1078) ##STR01064##

(1079) LCMS—Luna C-18 3.0×50 mm, 0 to 100% B over 4.0 minute gradient, 1 minute hold time, A=5% acetonitrile, 95% water, 10 mm ammonium acetate, B=95% acetonitrile, 5% water, 10 mm ammonium acetate, t.sub.R=1.88 min, Anal. Calcd. for C.sub.21H.sub.20BN.sub.3O.sub.3 441.07. found 442.22 (M+H).sup.+.

(1080) ##STR01065##

(1081) (2S,4R)-benzyl 2-(5-(4-bromophenyl)-1H-imidazol-2-yl)-4-hydroxypyrrolidine-1-carboxylate (1.5 g, 3.4 mmol) was added as a solid to a solution of bis(2-methoxyethyl) aminosulfur trifluoride (0.98 mL, 5.1 mmol) in 15 mL CH.sub.2Cl.sub.2 cooled to −78° C. Reaction was stirred at −78° C. for two hours and then warmed to room temperature and stirred for 2 hours. Reaction was poured into saturated sodium bicarbonate solution and stirred until bubbling ceased. Layers were separated and aqueous layer washed one time with CH.sub.2C.sub.12. Combined organics were washed with brine, dried (MgSO.sub.4), filtered, and concentrated to give a yellow oil. The oil was triturated with CH.sub.2Cl.sub.2 and pentane to yield (2S,4S)-benzyl 2-(5-(4-bromophenyl)-1H-imidazol-2-yl)-4-fluoropyrrolidine-1-carboxylate JG-20 as a yellow solid (0.96 g, 62%).

(1082) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 7.70 (2H, d, J=7.02 Hz) 7.48-7.55 (3H, m) 7.41-7.35 (3H, m) 7.19-7.11 (2H, m) 5.15-5.02 (3H, m) 3.84-3.78 (2H, m) 3.33 (2H, s) 2.53-2.61 (1H, m) 2.33-2.42 (1H, m).

(1083) LCMS—Luna C-18 3.0×50 mm, 0 to 100% B over 4.0 minute gradient, 1 minute hold time, A=5% acetonitrile, 95% water, 10 mm ammonium acetate, B=95% acetonitrile, 5% water, 10 mm ammonium acetate, t.sub.R=2.10 min, Anal. Calcd. for C.sub.21H.sub.19Br.sub.1F.sub.1N.sub.3O.sub.2 443.06. found 444.05 (M+H).sup.+.

(1084) ##STR01066##

(1085) (2S,4R)-tert-butyl 4-hydroxy-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate, 1-2c (1.5 g, 3.3 mmol) was added as a solid to a solution of bis(2-methoxyethyl) aminosulfur trifluoride (0.91 mL, 5.0 mmol) in 15 mL CH.sub.2Cl.sub.2 cooled to −78° C. Reaction was stirred at −78° C. for two hours and then warmed to room temperature and stirred for 2 hours. Reaction was poured into saturated sodium bicarbonate solution and stirred until bubbling ceased. Layers were separated and aqueous layer washed one time with CH.sub.2Cl.sub.2. Combined organics were washed with brine, dried (MgSO.sub.4), filtered, and concentrated to give a brown oil. The oil was chromatographed on silica gel with with 5% MeOH/CH.sub.2Cl.sub.2 to yield 4-(2-((2S,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-2-yl)-1H-imidazol-5-yl)phenylboronic acid as a tan solid (0.46 g, 37%).

(1086) LCMS—Luna C-18 3.0×50 mm, 0 to 100% B over 4.0 minute gradient, 1 minute hold time, A=5% acetonitrile, 95% water, 10 mm ammonium acetate, B=95% acetonitrile, 5% water, 10 mm ammonium acetate, t.sub.R=1.46 min, Anal. Calcd. for C.sub.18H.sub.23B.sub.1F.sub.1N.sub.3O.sub.4 375.18. found 376.12 (M+H).sup.+.

(1087) JG-22 is synthesized from JG-20 and JG-21 as described in Example 28 step c.

(1088) ##STR01067##

(1089) LCMS—Luna C-18 3.0×50 mm, 0 to 100% B over 4.0 minute gradient, 1 minute hold time, A=5% acetonitrile, 95% water, 10 mm ammonium acetate, B=95% acetonitrile, 5% water, 10 mm ammonium acetate, t.sub.R=2.27 min, Anal. Calcd. for C.sub.39H.sub.40F.sub.2N.sub.6O.sub.4 694.31. found 695.35 (M+H).sup.+.

(1090) JG-23 is synthesized from JG-22 as described in Example 28 step d.

(1091) ##STR01068##

(1092) LCMS—Phenomenex C-18 3.0×50 mm, 0 to 100% B over 4.0 minute gradient, 1 minute hold time, A=10% methanol 90% water 0.1% TFA, B=90% methanol 10% water 0.1% TFA mobile phase, t.sub.R=2.62 min, Anal Calcd. for C.sub.31H.sub.34F.sub.2N.sub.6O.sub.2 560.27. found 561.52 (M+H).sup.+.

(1093) JG-24 is synthesized from JG-22 and Cap-2 as in Example 28 step e.

(1094) ##STR01069##

(1095) LCMS—Luna C-18 3.0×50 mm, 0 to 100% B over 4.0 minute gradient, 1 minute hold time, A=5% acetonitrile, 95% water, 10 mm ammonium acetate, B=95% acetonitrile, 5% water, 10 mm ammonium acetate, t.sub.R=2.30 min, Anal. Calcd. for C.sub.41H.sub.45F.sub.2N.sub.7O.sub.3 721.36. found 722.42 (M+H).sup.+.

(1096) JG-25 is synthesized from JG-24 via reaction with methanolic HCl as described in Example LS14 step b.

(1097) ##STR01070##

(1098) LCMS—Luna C-18 3.0×50 mm, 0 to 100% B over 4.0 minute gradient, 1 minute hold time, A=5% acetonitrile, 95% water, 10 mm ammonium acetate, B=95% acetonitrile, 5% water, 10 mm ammonium acetate, t.sub.R=1.98 min, Anal. Calcd. for C.sub.36H.sub.37F.sub.2N.sub.7O.sub.1 621.30. found 622.48 (M+H).sup.+.

(1099) Section OL LC Conditions:

(1100) Condition 1: Solvent A: 5% acetonitrile/95% water/10 mmol ammonium acetate; Solvent B: 95% acetonitrile/5% water/10 mmol ammonium acetate; Column: Phenomenex GEMINI 5u C18 4.6×5.0 mm; Wavelength: 220 nM; Flow rate: 4 ml/min; 0% B to 100% B over 3 min with a 1 min hold time.

(1101) Condition 2: Solvent A: 5% acetonitrile/95% water/10 mmol ammonium acetate; Solvent B: 95% acetonitrile/5% water/10 mmol ammonium acetate; Column: Phenomenex GEMINI 5u C18 4.6×5.0 mm; Wavelength: 220 nM; Flow rate: 4 ml/min; 0% B to 100% B over 2 min with a 1 min hold time

(1102) Condition 3: Solvent A: 5% acetonitrile/95% water/10 mmol ammonium acetate; Solvent B: 95% acetonitrile/5% water/10 mmol ammonium acetate; Column: Phenomenex GEMINI 5u C18 4.6×5.0 mm; Wavelength: 220 nM; Flow rate: 4 ml/min; 0% B to 100% B over 4 min with a 1 min hold time

(1103) Condition 4: Solvent A: 10% MeOH/90% water/0.1% TFA; Solvent B: 90% MeOH/10% water/0.1% TFA; Column: Phenomenex 10u C18 3.0×5.0 mm; Wavelength: 220 nM; Flow rate: 4 ml/min; 0% B to 100% B over 4 min with a 1 min hold time

(1104) Condition 5: Solvent A: 5% acetonitrile/95% water/10 mmol ammonium acetate; Solvent B: 95% acetonitrile/5% water/10 mmol ammonium acetate; Column: Phenomenex GEMINI 5u C18 4.6×5.0 mm; Wavelength: 220 nM; Flow rate: 4 ml/min; 0% B to 100% B over 9 min with a 1 min hold time

(1105) Condition 6: Solvent A: 10% MeOH/90% water/0.2% H.sub.3PO.sub.4; Solvent B: 90% MeOH/10% water/0.2% H.sub.3PO.sub.4; Column: Phenomenex 5u C-18 4.6×50 mm; Wavelength: 220 nM; Flow rate: 1.5 ml/min; 0% B to 100% B over 14 min with a 3 min hold time

(1106) Condition 7: Solvent A: 10% MeOH/90% water/0.1% TFA; Solvent B: 90% MeOH/10% water/0.1% TFA; Column: Phenomenex 10u C18 3.0×5.0 mm; Wavelength: 220 nM; Flow rate: 4 ml/min; 0% B to 100% B over 3 min with a 1 min hold time

(1107) Condition 8: Solvent A: 10% MeOH/90% water/0.1% TFA; Solvent B: 90% MeOH/10% water/0.1% TFA; Column: Phenomenex 10u C18 3.0×5.0 mm; Wavelength: 220 nM; Flow rate: 4 ml/min; 0% B to 100% B over 2 min with a 1 min hold time

(1108) Experimentals Caps:

(1109) ##STR01071##
Step a:

(1110) Dimethylcarbamoyl chloride (0.92 mL, 10 mmol) was added slowly to a solution of (S)-benzyl 2-amino-3-methylbutanoate hydrochloride (2.44 g; 10 mmol) and Hunig's base (3.67 mL, 21 mmol) in THF (50 mL). The resulting white suspension was stirred at room temperature overnight (16 hours) and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO.sub.4), filtered, and concentrated under reduced pressure. The resulting yellow oil was purified by flash chromatography, eluting with ethyl acetate:hexanes (1:1). Collected fractions were concentrated under vacuum providing 2.35 g (85%) of Intermediate Cap OL-1 as a clear oil. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ ppm 0.84 (d, J=6.95 Hz, 3H) 0.89 (d, J=6.59 Hz, 3H) 1.98-2.15 (m, 1H) 2.80 (s, 6H) 5.01-5.09 (m, J=12.44 Hz, 1H) 5.13 (d, J=12.44 Hz, 1H) 6.22 (d, J=8.05 Hz, 1H) 7.26-7.42 (m, 5H). LC (Cond. 1): RT=1.76 min; MS: Anal. Calcd. for [M+H].sup.+ C.sub.16H.sub.22N.sub.2O.sub.3: 279.17. found 279.03.

(1111) Step b:

(1112) To Intermediate Cap OL-1 (2.35 g; 8.45 mmol) in 50 ml MeOH was added Pd/C (10%; 200 mg) and the resulting black suspension was flushed with N.sub.2 (3×) and placed under 1 atm of H.sub.2. The mixture was stirred at room temperature overnight and filtered though a microfiber filter to remove the catalyst. The resulting clear solution was then concentrated under reduced pressure to obtain 1.43 g (89%) of Cap OL-2 as a white foam, which was used without further purification. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 0.87 (d, J=4.27 Hz, 3H) 0.88 (d, J=3.97 Hz, 3H) 1.93-2.11 (m, 1H) 2.80 (s, 6H) 3.90 (dd, J=8.39, 6.87 Hz, 1H) 5.93 (d, J=8.54 Hz, 1H) 12.36 (s, 1H).). LC (Cond. 1): RT=0.33 min; MS: Anal. Calcd. for [M+H].sup.+ C.sub.8H.sub.17N.sub.2O.sub.3: 1898.12. found 189.04.

(1113) ##STR01072##

(1114) Cap OL-3 was prepared from (S)-benzyl 2-aminopropanoate hydrochloride according to the method described for Cap OL-2. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.27 (d, J=7.32 Hz, 3H) 2.80 (s, 6H) 4.06 (qt, 1H) 6.36 (d, J=7.32 Hz, 1H) 12.27 (s, 1H).

(1115) LC (Cond. 1): RT=0.15 min; MS: Anal. Calcd. for [M+H].sup.+ C61413N.sub.2O.sub.3: 161.09. found 161.00.

(1116) ##STR01073##

(1117) Cap OL-4 was prepared from (S)-tert-butyl 2-amino-3-methylbutanoate hydrochloride and 2-fluoroethyl chloroformate according to the method described for Cap-47. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 0.87 (t, J=6.71 Hz, 6H) 1.97-2.10 (m, 1H) 3.83 (dd, J=8.39, 5.95 Hz, 1H) 4.14-4.18 (m, 1H) 4.20-4.25 (m, 1H) 4.50-4.54 (m, 1H) 4.59-4.65 (m, 1H) 7.51 (d, J=8.54 Hz, 1H) 12.54 (s, 1H).

(1118) ##STR01074##

(1119) Cap OL-5 was prepared from (S)-diethyl alanine and methyl chloroformate according to the method described for Cap-51. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 0.72-0.89 (m, 6H) 1.15-1.38 (m, 4H) 1.54-1.66 (m, 1H) 3.46-3.63 (m, 3H) 4.09 (dd, J=8.85, 5.19 Hz, 1H) 7.24 (d, J=8.85 Hz, 1H) 12.55 (s, 1H). LC (Cond. 2): RT=0.66 min; MS: Anal. Calcd. for [M+H].sup.+ C.sub.9H.sub.18NO.sub.4: 204.12. found 204.02.

New Examples

(1120) The following analogs were prepared from 1e in similar fashion to the preparation of Example 1 and employing the appropriate Cap.

(1121) TABLE-US-00069 Example Number Compound Name Structure Analytical Data OL-1 3-((1S)-1-(((2S)-2-(4-(4′- (2-((2S)-1-((2S)-2- ((dimethylcarbamoyl)amino)- 3-methylbutanoyl)-2-pyrrolidinyl)- 1H-imidazol-4-yl)-4- biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)carbonyl)-2- methylpropyl)-1,1-dimethylurea 075 From 1e and Cap OL-2 LC/MS: 2.16 min (Cond'n 3); Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.57N.sub.10O.sub.4: 765.45; found 765.47. OL-2 3-((1S)-2-((2S)-2-(4-(4′-(2-((2S)-1-(N- (dimethylcarbamoyl)-L- alanyl)-2-pyrrolidinyl)- 1H-imidazol-4-yl)-4- biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)-1- methyl-2-oxoethyl)-1,1-dimethylurea 076 From 1e and Cap OL-3 LC/MS: 1.86 min (Cond'n 3); Anal. Calcd. for [M + H].sup.+ C.sub.38H.sub.49N.sub.10O.sub.4: 709.39; found 709.43. OL-3 2-fluoroethyl ((1S)-1-(((2S)-2-(4-(4′-(2-((2S)-1- ((2S)-2-(((2-fluoroethoxy)carbonyl)amino)-3- methylbutanoyl)-2-pyrrolidinyl)-1H- imidazol-4-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate 077 From 1e and Cap OL-4 LC/MS: 2.83 min (Cond'n 4); Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.53F.sub.2N.sub.8O.sub.6: 803.40; found 803.47. OL-4 methyl ((1S)-2-ethyl-1-(((2S)-2-(4-(4′-(2-((2S)-1- ((2S)-3-ethyl-2-((methoxycarbonyl)amino) pentanoyl)-2-pyrrolidinyl)-1H- imidazol-4-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)carbonyl)butyl)carbamate 078 From 1e and Cap OL-5 LC/MS: 2.64 min (Cond'n 3); Anal. Calcd. for [M + H].sup.+ C.sub.44H.sub.59N.sub.8O.sub.6: 795.45; found 895.48. OL-5 1,1′-(4,4′-biphenyldiylbis(1H-imidazole- 4,2-diyl(2S)-2,1-pyrrolidinediyl((2S)- 3-methyl-1-oxo-1,2-butanediyl))) ditetrahydro-2(1H)-pyrimidinone 079 From 1e and (S)-3-methyl-2- (2-oxotetrahydropyrimidin- 1(2H)-yl)butanoic acid LC/MS: 2.95 min (Cond'n 4); Anal. Calcd. for [M + H].sup.+ C.sub.44H.sub.57N.sub.10O.sub.6: 789.46; found 789.52. OL-6 methyl ((1S)-1-(((2 S)-2-(4-(4′-(2-((2S)-1-((2S)-2- ((methoxycarbonyl)amino)- 4-methylpentanoyl)-2-pyrrolidinyl)-1H- imidazol-4-yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)carbonyl)-3- methylbutyl)carbamate 080 From 1e and (S)-2- (methoxycarbonylamino)-4- methylpentanoic acid which was prepared from L- Isoleucine and methylchloroformate in similar fashion to the preparation of Cap-51 LC/MS: 2.95 min (Cond'n 3); Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.53N.sub.8O.sub.6: 767.42; found 767.43.

(1122) ##STR01081##

Example OL-7

methyl ((1S)-1-(((2S)-2-(4-(4′-(2-((2S)-4,4-difluoro-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-4,4-difluoro-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

(1123) Example OL-7 was prepared from 1-2e-3 in similar fashion to the preparation of Example 1, using Cap-51 as the coupling partner. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 0.80 (dd, J=6.41, 2.44 Hz, 12H) 1.87-1.98 (m, 2H) 2.79-2.91 (m, 2H) 3.01-3.13 (m, 2H) 3.54 (s, 6H) 3.98 (t, J=7.93 Hz, 2H) 4.22-4.37 (m, 2H) 4.52 (t, J=14.19 Hz, 2H) 5.31 (t, J=8.39 Hz, 2H) 7.50 (d, J=7.93 Hz, 2H) 7.82-7.87 (m, 4H) 7.88-7.97 (m, 6H) 8.08 (s, 2H). LC (Cond'n 6): 7.64 min; MS: Anal. Calcd. for [M+H].sup.+ C.sub.40H.sub.47F.sub.4N.sub.8O.sub.6: 811.35. found 811.46. HRMS: Anal. Calcd. for (M+H).sup.+ C.sub.40R.sub.47F.sub.4N.sub.8O.sub.6 811.3549 found 811.3553.

(1124) The following analogs were prepared from 1-2e-3 in similar fashion to the preparation of Example 1 and employing the appropriate Cap.

(1125) TABLE-US-00070 Example Number Compound Name Structure Analytical Data OL-8 (1R, 1′R)-2,2′-(4,4′- biphenyldiylbis(1H-imidazole-4,2- diyl((2S)-4,4-difluoro-2,1-pyrrolidinediyl))) bis(N,N-dimethyl-2-oxo-1-phenylethanamine) 082 LC/MS: 3.98 min (Cond'n 5); Anal. Calcd. for [M + H].sup.+ C.sub.46H.sub.47F.sub.4N.sub.8O.sub.2: 819.37; found 819.78. OL-9 (1R,1′R)-2,2′-(4,4′-biphenyldiylbis (1H-imidazole-4,2-diyl((2S)-4,4- difluoro-2,1-pyrrolidinediyl))) bis(N,N-diethyl-2- oxo-1-phenylethanamine) 083 LC/MS: 4.58 min (Cond'n 5); Anal. Calcd. for [M + H].sup.+ C.sub.50H.sub.55F.sub.4N.sub.8O.sub.2: 875.449; found 875.90. OL-10 methyl ((1S,2R)-1-(((2S)-2-(4-(4′-(2- ((2S)-4,4-difluoro-1-(N- (methoxycarbonyl)- O-methyl-L- threonyl)-2- pyrrolidinyl)-1H- imidazol-4-yl)-4- biphenylyl)-1H- imidazol-2-yl)-4,4- difluoro-1- pyrrolidinyl)carbonyl)- 2-methoxypropyl)carbamate 084 LC/MS: 2.18 min (Cond'n 7); Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.47F.sub.4N.sub.8O.sub.8: 843.84; found 844.04. OL-11 methyl ((1S)-2-((2S)-2-(4-(4′-(2- ((2S)-4,4-difluoro-1-(N- (methoxycarbonyl)- L-alanyl)-2- pyrrolidinyl)-1H- imidazol-4-yl)-4- biphenylyl)-1H- imidazol-2-yl)-4,4- difluoro-1- pyrrolidinyl)-1- methyl-2-oxoethyl)carbamate 085 LC/MS: 2.04 min (Cond'n 7); Anal. Calcd. for [M + H].sup.+ C.sub.36H.sub.39F.sub.4N.sub.8O.sub.6: 755.29; found 855.78.

(1126) The following analogs were prepared from 1-3e in similar fashion to the preparation of Example 1 and employing the appropriate Cap.

(1127) TABLE-US-00071 Example Number Compound Name Structure Analytical Data OL-12 methyl ((1S)-1- (((2S)-2-(4-(4′-(2- ((2S)-4,4-difluoro-1- ((2S)-2- ((methoxycarbonyl) amino)-3- methylbutanoyl)-2- pyrrolidinyl)-1H- imidazol-4-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl) carbonyl)-2- methylpropyl) carbamate 086 LC/MS: 2.33 min (Cond'n 3); Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.49F.sub.2N.sub.8O.sub.2: 775.37; found 775.37. OL-13 rac-(1R)-2-((2S)-2- (4-(4′-(2-((2S)-1- ((2R)-2- (diethylamino)-2- phenylacetyl)-4,4- difluoro-2- pyrrolidinyl)-1H- imidazol-4-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-N,N- diethyl-2-oxo-1- phenylethanamine 087 LC/MS: 3.93 min (Cond'n 5); Anal. Calcd. for [M + H].sup.+ C.sub.50H.sub.57F.sub.2N.sub.8O.sub.2: 839.40; found 839.93.

(1128) ##STR01088##

Example OL-19

methyl ((1S)-1-(((2R,3S)-3-hydroxy-2-(4-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

(1129) Step a:

(1130) Intermediate OL-15 was prepared in similar fashion as intermediate 1a, where N-Boc-L-proline was substituted for N-Boc-trans-3-hydroxy-L-proline. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.34/1.4) (2 br. s., 9H) 1.65-1.77 (m, 1H) 1.83-1.95 (m, 1H) 3.33-3.42 (m, 1H) 3.43-3.51 (m, 1H) 3.96-4.07 (m, 1H) 4.16 (s, 1H) 4.44-4.65 (m, 2H) 5.22-5.28 (m, 1H) 7.74 (d, J=8.54 Hz, 2H) 7.86-7.94 (m, 2H) 8.15-8.32 (m, 1H). LC (Cond. 4): RT=3.33 min; MS: Anal. Calcd. for [2M+Na].sup.+ C.sub.36H.sub.46Br.sub.2N.sub.4NaO.sub.10: 877.57. found 877.11.

(1131) Step b:

(1132) Intermediate OL-16 was prepared from intermediate OL-15 in similar fashion as intermediate 1b. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.16/1.39 (2 br. s., 9H) 1.71-1.81 (m, J=6.10 Hz, 1H) 2.01-2.17 (m, 1H) 3.37-3.50 (m, 1H) 3.50-3.62 (m, 1H) 4.15 (s, 1H) 4.49-4.70 (m, 1H) 5.36 (dd, J=6.71, 3.66 Hz, 1H) 7.44-7.62 (m, 3H) 7.68 (d, J=7.02 Hz, 2H) 11.96/11.99/12.26/12.30 (m, 1H). LC (Cond. 8): RT=1.87 min; MS: Anal. Calcd. for [M+H].sup.+ C.sub.18H.sub.23BrN.sub.3O.sub.3: 408.08. found 408.09.

(1133) Step c:

(1134) Intermediate OL-17 was prepared by coupling intermediate OL-16 with 1c in similar fashion to the preparation of 1d. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.09-1.49 (m, 18H) 1.71-2.04 (m, 4H) 2.06-2.28 (m, 2H) 3.33-3.40 (m, 1H) 3.41-3.65 (m, 3H) 4.18 (s, 1H) 4.52-4.69 (m, 1H) 4.70-4.88 (m, 1H) 5.38 (s, 1H) 6.64-7.35 (m, 1H) 7.39-7.96 (m, 9H) 11.71-12.0/12.10-12.36 (m, 2H). LC (Cond. 2): RT=1.36 min; MS: Anal. Calcd. for [M+H].sup.+ C.sub.36H.sub.45N.sub.6O.sub.5: 641.77. found 641.39.

(1135) Step d:

(1136) Intermediate OL-18 was prepared by deprotection of intermediate OL-17 with HCl in similar fashion to the preparation of 1-1e. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 1.92-2.07 (m, 2H) 2.14-2.25 (m, 1H) 2.35-2.44 (m, 1H) 3.15 (s, 4H) 3.32-3.41 (m, J=7.02, 7.02, 7.02 Hz, 1H) 3.41-3.51 (m, J=7.32 Hz, 2H) 3.54-3.66 (m, 1H) 4.68 (d, J=4.27 Hz, 1H) 4.78-4.89 (m, J=4.88 Hz, 1H) 5.04 (s, 1H) 6.89/7.73 (2d, J=8.70 Hz, 1H) 7.89 (dd, J=8.24, 4.58 Hz, 4H) 7.96-8.07 (m, 4H) 8.15 (d, J=23.19 Hz, 2H) 9.62-10.12 (m, 2H) 10.21-10.74 (m, 2H).). LC (Cond. 8): RT=1.30 min; MS: Anal. Calcd. for [M-41].sup.+ C.sub.26H.sub.29N.sub.6O: 441.24. found 441.18.

(1137) Step e:

(1138) Example OL-19 was prepared by coupling of intermediate OL-18 with Cap-51 in similar fashion to the preparation of Example 1. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 0.78 (d, J=6.41 Hz, 6H) 0.83 (d, J=6.71 Hz, 6H) 1.92-2.12 (m, 5H) 2.12-2.21 (m, 1H) 2.31 (dd, J=12.21, 5.80 Hz, 1H) 2.35-2.43 (m, 1H) 3.54 (d, J=4.27 Hz, 6H) 3.78-3.89 (m, 3H) 3.91-4.02 (m, 1H) 4.07-4.19 (m, 2H) 4.36-4.50 (m, 1H) 4.81 (d, J=3.66 Hz, 1H) 5.13 (t, J=7.17 Hz, 1H) 5.79 (s, 1H) 7.34 (dd, J=11.29, 8.85 Hz, 2H) 7.83-7.90 (m, 4H) 7.90-8.01 (m, 4H) 8.12 (s, 2H) [Note: the signal for the imidazole NH was too broad to assign a chemical shift].). LC (Cond. 4): RT=2.76 min; MS: Anal. Calcd. for [M+H].sup.+ C.sub.40H.sub.51N.sub.8O.sub.7: 755.39. found 755.38. HRMS: Anal. Calcd. for (M+H).sup.+ C.sub.40H.sub.51N.sub.8O.sub.7: 755.3881 found 755.3873.

(1139) The following analog was prepared from intermediate OL-18 in similar fashion to the preparation of Example 1 and employing Cap-52.

(1140) TABLE-US-00072 Example Number Compound Name Structure Analytical Data OL-20 methyl ((1S)-2-((2S)-2- (4-(4′-(2-((2R,3S)-3- hydroxy-1-(N- (methoxycarbonyl)-L- alanyl)-2-pyrrolidinyl)- 1H-imidazol-4-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-1-methyl- 2-oxoethyl)carbamate 089 LC/MS: 2.32 min (Cond'n 4); Anal. Calcd. for [M + H].sup.+ C.sub.36H.sub.43N.sub.8O.sub.7: 699.78; found 699.32.

(1141) The following analog was prepared in similar fashion to the preparation of OL-19 but using N-Boc-cis-3-hydroxy-L-proline as starting material.

(1142) TABLE-US-00073 Example Number Compound Name Structure Analytical Data OL-21 methyl ((1S)-1-(((2R)-3- hydroxy-2-(4-(4′-(2- ((2S)-1-((2S)-2- ((methoxycarbonyl) amino)-3-methylbutanoyl)- 2-pyrrolidinyl)-1H- imidazol-4-yl)-4- biphenylyl)-1H-imidazol- 2-yl)-1- pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate 090 LC/MS: 2.74 min (Cond'n 4); Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.51N.sub.8O.sub.7: 755.39; found 755.34.

(1143) TABLE-US-00074 Analytical Data (Cond 1: 3 min gradient, 4 min run; Example Cond 2: 2 min Number Compound Name Heterocycles with New Caps gradient, 3 min run) D71 tert-butyl (2S)-2- (5-(2-(4-(2-((2S)-1- ((2R)-2- (diethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5- yl)phenyl)-5- pyrimidinyl)-1H- imidazol-2-yl)-1- pyrrolidinecarboxylate 091 t.sub.R = 1.82 min, (97.7%), (Cond 1) LRMS: Anal. Calcd. for C.sub.41H.sub.50N.sub.9O.sub.3 716.40; found: 716.44 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.41H.sub.50N.sub.9O.sub.3 716.4037; found: 716.4056 (M + H).sup.+. D72 (1R)-N,N-diethyl- 2-oxo-1-phenyl-2- ((2S)-2-(5-(4-(5-(2- ((2S)-2- pyrrolidinyl)-1H- imidazol-5-yl)-2- pyrimidinyl)phenyl)- 1H-imidazol-2- yl)-1- pyrrolidinyl)ethanamine 092 t.sub.R = 1.56 min, (~95.3%, has shoulder), (Cond 1) LRMS: Anal. Calcd. for C.sub.36H.sub.42N.sub.9O 616.35; found: 616.37 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.36H.sub.42N.sub.9O 616.3512; found: 616.3540 (M + H).sup.+. D73 methyl ((1S)-2- ((2S)-2-(5-(4-(5-(2- ((2S)-1-(N- (methoxycarbonyl)- L-alanyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-2- pyrimidinyl)phenyl)- 1H-imidazol-2- yl)-1-pyrrolidinyl)- 1-methyl-2- oxoethyl)carbamate 093 t.sub.R = 1.52 min, (96.2%), (Cond 1) LRMS: Anal. Calcd. for C.sub.34H.sub.41N.sub.10O.sub.6 685.32; found: 685.21 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.34H.sub.41N.sub.10O.sub.6 685.3211; found: 685.3196 (M + H).sup.+. D74 methyl ((1S)-1- (((2S)-2-(5-(2-(4- (2-((2S)-1-((2S)-2- ((methoxycarbonyl) amino)-3- methylbutanoyl)-2- pyrrolidinyl)-1H- imidazol-5- yl)phenyl)-5- pyrimidinyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate 094 t.sub.R = 2.09 min, (95%), (Cond 1) LRMS: Anal. Calcd. for C.sub.38H.sub.49N.sub.10O.sub.6 741.38; found: 741.26 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.38H.sub.49N.sub.10O.sub.6 741.3837; found: 741.3824 (M + H).sup.+. D75 methyl ((1S)-1- cyclopropyl-2- ((2S)-2-(5-(2-(4-(2- ((2S)-1-((2S)-2- cyclopropyl-2- ((methoxycarbonyl) amino)acetyl)-2- pyrrolidinyl)-1H- imidazol-5- yl)phenyl)-5- pyrimidinyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxoethyl)carbamate 095 t.sub.R = 1.98 min, (95%), (Cond 1) LRMS: Anal. Calcd. for C.sub.38H.sub.45N.sub.10O.sub.6 737.35; found: 737.22 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.38H.sub.45N.sub.10O.sub.6 737.3524; found: 737.3555 (M + H).sup.+. D76 methyl ((1S)-1- (((2S)-2-(5-(2-(4- (2-((2S)-1-((2R)-2- (diethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5- yl)phenyl)-5- pyrimidinyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate 096 t.sub.R = 1.69 min, (95%), (Cond 1) LRMS: Anal. Calcd. for C.sub.43H.sub.53N.sub.10O.sub.4 773.43; found: 773.30 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.43H.sub.53N.sub.10O.sub.4 773.4251; found: 773.4280 (M + H).sup.+. D77 methyl ((1S)-2- ((2S)-2-(5-(2-(4-(2- ((2S)-1-((2R)-2- (diethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5- yl)phenyl)-5- pyrimidinyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-1- methyl-2- oxoethyl)carbamate 097 t.sub.R = 1.81 min, (97.5%), (Cond 1) LRMS: Anal. Calcd. for C.sub.41H.sub.49N.sub.10O.sub.4 745.39; found: 745.27 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.41H.sub.49N.sub.10O.sub.4 745.3938; found: 745.3939 (M + H).sup.+.
Section J

(1144) TABLE-US-00075 Example Number Compound Name Structure Analytical Data J.1a 098 t.sub.R = 1.7 min, (Cond 2); LCMS: C.sub.10H.sub.9BrO.sub.3 found: 257 (M + H) .sup.+. J.1b 099 t.sub.R = 1.9 min, (Cond 2); LCMS: C.sub.11H.sub.11BrO.sub.3 found: 271 (M + H) .sup.+. J.1c 00 t.sub.R = 2.1 min, (Cond 2); LCMS: C.sub.16H.sub.13BrO.sub.3 found: 332 (M + H) .sup.+. J1 01 t.sub.R = 2.2 min, (Cond 2); LCMS: C.sub.20H.sub.24BrNO.sub.7 found: 470 (M + H) .sup.+. J2 02 t.sub.R = 2.2 min, (Cond 2); LCMS: C.sub.21H.sub.26BrNO.sub.7 found: 484 (M + H) .sup.+. J3 03 t.sub.R = 2.3 min, (Cond 2); LCMS: C.sub.26H.sub.28BrNO.sub.7 found: 546 (M + H) .sup.+. J4 04 t.sub.R = 1.84 min, (100%) (Cond 2); LRMS: Anal. Calcd. for C.sub.20H.sub.24BrN.sub.3O.sub.4; 450.10; found: 450.13 and 452.13 (M + H) .sup.+. J5 05 t.sub.R = 1.93 min, (99%) (Cond 2); Reported in J5. J6 06 t.sub.R = 2.1 min, (93%) (Cond 2); LRMS: Anal. Calcd. for C.sub.26H.sub.29BrN.sub.3O.sub.4 526.13; found: 526.16 and 528.16 (M + H) .sup.+. J7 07 t.sub.R = 1.7 min, (100%) (Cond 2); Reported in J7. J8 methyl 2-((2S)-1- (tert- butoxycarbonyl)-2- pyrrolidinyl)-5-(4′- (2-((2S)-1-(tert- butoxycarbonyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazole-4- carboxylate 08 t.sub.R = 1.70 min, (95%) (Cond 2); LRMS: Anal. Calcd. for C.sub.38H.sub.47N.sub.6O.sub.6 683.36; found: 683.42 (M + H) .sup.+. J9 ethyl 2-((2S)-1- (tert- butoxycarbonyl)-2- pyrrolidinyl)-5-(4′- (2-((2S)-1-(tert- butoxycarbonyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazole-4- carboxylate 09 t.sub.R = 1.78 min, (97.5%) (Cond 2); LRMS: Anal. Calcd. for C.sub.39H.sub.49N.sub.6O.sub.6 697.37; found: 697.38 (M + H) .sup.+. J10 benzyl 2-((2S)-1- (tert- butoxycarbonyl)-2- pyrrolidinyl)-5-(4′- (2-((2S)-1-(tert- butoxycarbonyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazole-4- carboxylate 0 t.sub.R = 1.88 min, (85%) (Cond 2); LRMS: Anal. Calcd. for C.sub.44H.sub.51N.sub.6O.sub.6 759.39; found: 759.48 (M + H) .sup.+. J11 tert-butyl (2S)-2- (5-(4′-(2-((2S)-1- (tert- butoxycarbonyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-4- (methylcarbamoyl)- 1H-imidazol-2-yl)- 1-pyrrolidinecarboxylate t.sub.R = 1.65 min, (90%) (Cond 2); LRMS: Anal. Calcd. for C.sub.38H.sub.48N.sub.7O.sub.5 682.37; found: 682.42 (M + H) .sup.+. J11.a t.sub.R = 1.60 min, (Cond 2); LCMS: C.sub.37H.sub.46N.sub.7O.sub.5 found: 668 (M + H) .sup.+. J12 t.sub.R = 1.25 min, (97%) (Cond 2); LCMS: C.sub.28H.sub.31N.sub.6O.sub.2 found: 483 (M + H) .sup.+. J13 t.sub.R = 1.34 min, (Cond 2); LCMS: C.sub.29H.sub.33N.sub.6O.sub.2 found: 497 (M + H) .sup.+. J14 t.sub.R = 1.51 min, (90%) (Cond 2); LCMS: C.sub.34H.sub.35N.sub.6O.sub.2 found: 559 (M + H) .sup.+. J15 t.sub.R = 1.32 min, (99%) (Cond 2); LCMS: C.sub.28H.sub.32N.sub.7O found: 482 (M + H) .sup.+. J15.a t.sub.R = 1.07 min, (98%) (Cond 2); LCMS: C.sub.27H.sub.30N.sub.7O found: 468 (M + H) .sup.+. J16 methyl 2-((2S)-1- ((2R)-2- ((methoxycarbonyl) amino)-2- phenylacetyl)-2- pyrrolidinyl)-5-(4′- (2-((2S)-1-((2R)-2- ((methoxycarbonyl) amino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazole-4- carboxylate t.sub.R = 1.62 min, (99.5%) (Cond 2); LRMS: Anal. Calcd. for C48H49N8O8 865.37; found: 865.34 (M + H) .sup.+. HRMS: Anal. Calcd. for C48H49N8O8 865.3673; found: 865.3715 (M + H) .sup.+. J17 methyl 2-((2S)-1- ((2R)-2- (dimethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-5-(4′- (2-((2S)-1-((2R)-2- (dimethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazole-4- carboxylate t.sub.R = 1.37 min, (92%) (Cond 2); LRMS: Anal. Calcd. for C48H53N8O4 804.42; found: 805.51 (M + H) .sup.+. HRMS: Anal. Calcd. for C48H53N8O4 805.4190; found: 805.4211 (M + H) .sup.+. J18 methyl 2-((2S)-1- ((2R)-2-phenyl-2- (1- piperidinyl)acetyl)- 2-pyrrolidinyl)-5- (4′-(2-((2S)-1- ((2R)-2-phenyl-2- (1- piperidinyl)acetyl)- 2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazole-4- carboxylate 0 t.sub.R = 1.46 min, (94%) (Cond 2); LRMS: Anal. Calcd. for C54H61N8O6 885.48; found: 885.48 (M + H) .sup.+. HRMS: Anal. Calcd. for C54H61N8O6 885.4816; found: 885.4852 (M + H) .sup.+. J19 ethyl 2-((2S)-1- ((2R)-2- ((methoxycarbonyl) amino)-2- phenylacetyl)-2- pyrrolidinyl)-5-(4′- (2-((2S)-1-((2R)-2- ((methoxycarbonyl) amino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazole-4- carboxylate t.sub.R = 1.68 min, (99%) (Cond 2); LRMS: Anal. Calcd. for C49H51N8O8 879.38; found: 879.37 (M + H) .sup.+. HRMS: Anal. Calcd. for C49H51N8O8 879.3830; found: 879.3814 (M + H) .sup.+. J20 ethyl 2-((2S)-1- ((2R)-2- (dimethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-5-(4′- (2-((2S)-1-((2R)-2- (dimethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazole-4- carboxylate t.sub.R = 1.45 min, (89%) (Cond 2); LRMS: Anal. Calcd. for C49H55N8O4 818.44; found: 818.40 (M + H) .sup.+. HRMS: Anal. Calcd. for C49H55N8O4 819.4346; found: 819.4340 (M + H) .sup.+. J21 benzyl 2-((2S)-1- ((2R)-2- ((methoxycarbonyl) amino)-2- phenylacetyl)-2- pyrrolidinyl)-5-(4′- (2-((2S)-1-((2R)-2- ((methoxycarbonyl) amino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazole-4- carboxylate t.sub.R = 1.80 min, (92%) (Cond 2); LRMS: Anal. Calcd. for C54H53N8O8 941.40; found: 941.39 (M + H) .sup.+. HRMS: Anal. Calcd. for C54H53N8O8 941.3986; found: 941.4033 (M + H) .sup.+. J22 benzyl 2-((2S)-1- ((2R)-2- (dimethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-5-(4′- (2-((2S)-1-((2R)-2- (dimethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazole-4- carboxylate t.sub.R = 1.56 min, (96%) (Cond 2); LRMS: Anal. Calcd. for C54H57N8O4 881.45; found: 881.46 (M + H) .sup.+. HRMS: Anal. Calcd. for C54H57N8O4 881.4503; found: 881.4536 (M + H) .sup.+. J23 benzyl 2-((2S)-1- ((2R)-2-phenyl-2- (1-piperidinyl)acetyl)- 2-pyrrolidinyl)-5- (4′-(2-((2S)-1- ((2R)-2-phenyl-2- (1-piperidinyl)acetyl)- 2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazole-4- carboxylate t.sub.R = 1.63 min, (96%) (Cond 2); LRMS: Anal. Calcd. for C60H65N8O4 961.51; found: 961.54 (M + H) .sup.+. HRMS: Anal. Calcd. for C60H65N8O4 961.5129; found: 961.5164 (M + H) .sup.+. J24 benzyl 2-((2S)-1- (N-(methoxycarbonyl)- L-alanyl)-2- pyrrolidinyl)-5-(4′- (2-((2S)-1-(N- (methoxycarbonyl)- L-alanyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazole-4- carboxylate t.sub.R = 1.64 min, (94%) (Cond 2); LRMS: Anal. Calcd. for C44H49N8O8 817.37; found: 817.38 (M + H) .sup.+. HRMS: Anal. Calcd. for C44H49N8O8 817.3673; found: 817.3675 (M + H) .sup.+. J25 methyl ((1R)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2- ((methoxycarbonyl) amino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-4- (methylcarbamoyl)- 1H-imidazol-2-yl)- 1-pyrrolidinyl)-2- oxo-1- phenylethyl)carbamate t.sub.R = 1.58 min, (99.6%) (Cond 2); LRMS: Anal. Calcd. for C48H50N9O7 864.38; found: 864.47 (M + H) .sup.+. HRMS: Anal. Calcd. for C48H50N9O7 864.3833; found: 864.3849 (M + H) .sup.+. J26 2-((2S)-1-((2R)-2- (dimethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-5-(4′- (2-((2S)-1-((2R)-2- (dimethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-N- methyl-1H- imidazole-4- carboxamide t.sub.R = 1.31 min, (93.2%) (Cond 2); LRMS: Anal. Calcd. for C48H54N9O3 804.44; found: 804.51 (M + H) .sup.+. HRMS: Anal. Calcd. for C48H54N9O3 804.4350; found: 804.4369 (M + H) .sup.+. J27 N-methyl-2-((2S)- 1-((2R)-2-phenyl- 2-(1-piperidinyl)acetyl)- 2-pyrrolidinyl)-5- (4′-(2-((2S)-1- ((2R)-2-phenyl-2- (1-piperidinyl)acetyl)- 2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazole-4- carboxamide t.sub.R = 1.39 min, (95.4%) (Cond 2); LRMS: Anal. Calcd. for C54H62N9O3 884.50; found: 884.52 (M + H) .sup.+. HRMS: Anal. Calcd. for C54H62N9O3 884.4976; found: 884.4973 (M + H) .sup.+. J28 methyl ((1S)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-(N- (methoxycarbonyl)- L-alanyl)-2- pyrrolidinyl)-4- (methylcarbamoyl)- 1H-imidazol-5-yl)- 4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-1- methyl-2- oxoethyl)carbamate 0 t.sub.R = 1.34 min, (89.3%) (Cond 2); LRMS: Anal. Calcd. for C38H46N9O7 740.35; found: 740.31 (M + H) .sup.+. HRMS: Anal. Calcd. for C38H46N9O7 740.3520; found: 740.3497 (M + H) .sup.+. J29 methyl ((1R)-2- ((2S)-2-(4- carbamoyl-5-(4′-(2- ((2S)-1-((2R)-2- ((methoxycarbonyl) amino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxo-1- phenylethyl)carbamate t.sub.R = 1.55 min, (96.4%) (Cond 2); LRMS: Anal. Calcd. for C47H48N9O7 740.35; found: 740.31 (M + H) .sup.+. HRMS: Anal. Calcd. for C47H48N9O7 740.3520; found: 740.3497 (M + H) .sup.+. J30 2-((2S)-1-((2R)-2- ((methoxycarbonyl) amino)-2- phenylacetyl)-2- pyrrolidinyl)-5-(4′- (2-((2S)-1-((2R)-2- ((methoxycarbonyl) amino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazole-4- carboxylic acid t.sub.R = 1.52 min, (92.8%) (Cond 2); LRMS: Anal. Calcd. for C47H47N8O8 851.35; found: 851.37 (M + H) .sup.+. HRMS: Anal. Calcd. for C47H47N8O8 851.3517; found: 851.3553 (M + H) .sup.+. J31 2-((2S)-1-((2R)-2- phenyl-2-(1- piperidinyl)acetyl)- 2-pyrrolidinyl)-5- (4′-(2-((2S)-1- ((2R)-2-phenyl-2- (1- piperidinyl)acetyl)- 2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazole-4- carboxylic acid t.sub.R = 1.36 min, (96.5%) (Cond 2); LRMS: Anal. Calcd. for C53H59N8O4 871.47; found: 871.47 (M + H) .sup.+. HRMS: Anal. Calcd. for C53H59N8O4 871.4659; found: 871.4692 (M + H) .sup.+. J32 t.sub.R = 1.96 min, (96%) (Cond 2); LRMS: Anal. Calcd. for C.sub.11H.sub.11BrF.sub.3N.sub.2O 323.00; found: 323.05 and 325.05 (M + H) .sup.+. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 7.58 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 3.06 (s, 6H) J32.a t.sub.R = 2.19 min, (96%) (Cond 2); Reported in J32.a J32.b t.sub.R = 2.3 min, (73%) (Cond 2); LCMS: C.sub.25H.sub.34BF.sub.3N.sub.3O.sub.4 found: 508 (M + H) .sup.+. J33 tert-butyl (2S)-2- (5-(4′-(2-((2S)-1- (tert- butoxycarbonyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-4- (trifluoromethyl)- 1H-imidazol-2-yl)- 1-pyrrolidinecarboxylate t.sub.R = 2.7 min, (95%) (Cond 2); LRMS: Anal. Calcd. for C.sub.37H.sub.44F.sub.3N.sub.6O.sub.4 693.34; found: 693.33 (M + H) .sup.+. HRMS: Anal. Calcd. for C.sub.37H.sub.44F.sub.3N.sub.6O.sub.4 693.3376; found: 693.3370 (M + H) .sup.+. J33.a tert-butyl (2S)-2- (5-(4′-(2-((1S)-1- ((tert- butoxycarbonyl) (methyl)amino)ethyl)- 1H-imidazol-5-yl)- 4-biphenylyl)-4- (trifluoromethyl)- 1H-imidazol-2-yl)- 1-pyrrolidinecarboxylate t.sub.R = 1.97 min, (97%) (Cond 2); LRMS: Anal. Calcd. for C.sub.36H.sub.44F.sub.3N.sub.6O.sub.4 681.34; found: 681.31 (M + H) .sup.+. HRMS: Anal. Calcd. for C.sub.36H.sub.44F.sub.3N.sub.6O.sub.4 681.3376; found: 681.3383 (M + H) .sup.+. J34 tert-butyl (2S)-2- (5-(4′-(2-((2S)-1- ((benzyloxy)carbonyl)- 2-pyrrolidinyl)- 1H-imidazol-5-yl)- 4-biphenylyl)-4- (trifluoromethyl)- 1H-imidazol-2-yl)- 1-pyrrolidinecarboxylate t.sub.R = 2.0 min, (95%) (Cond 2); LRMS: Anal. Calcd. for C.sub.40H.sub.42F.sub.3N.sub.6O.sub.4 727.32; found: 727.19 (M + H) .sup.+. HRMS: Anal. Calcd. for C.sub.40H.sub.42F.sub.3N.sub.6O.sub.4 727.3220; found: 727.3251 (M + H) .sup.+. J34.a tert-butyl (2S)-2- (5-(4-(5-(2-((2S)-1- (tert- butoxycarbonyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-2- pyrimidinyl)phenyl)- 4-(trifluoromethyl)- 1H-imidazol-2-yl)- 1-pyrrolidinecarboxylate 0 t.sub.R = 1.97 min, (93%) (Cond 2); LRMS: Anal. Calcd. for C.sub.35H.sub.42F.sub.3N.sub.8O.sub.4 695.33; found: 695.28 (M + H) .sup.+. J35 t.sub.R = 1.46 min, (92%) (Cond 2); LCMS: C.sub.27H.sub.28F.sub.3N.sub.6O found: 493 (M + H) .sup.+. J35.a LCMS: C.sub.26H.sub.28F.sub.3N.sub.6 found: 481 (M + H) .sup.+. J36 LCMS: C.sub.35H.sub.34F.sub.3N.sub.6O.sub.2 found: 626 (M + H) .sup.+. J36.a t.sub.R = 1.45 min, (Cond 2); LCMS: C.sub.25H.sub.26F.sub.3N.sub.8 found: 495 (M + H) .sup.+. J37 methyl ((1R)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2- ((methoxycarbonyl) amino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-4- (trifluoromethyl)- 1H-imidazol-2-yl)- 1-pyrrolidinyl)-2- oxo-1- phenylethyl)carbamate t.sub.R = 1.9 min, (95%) (Cond 2); LRMS: Anal. Calcd. for C.sub.47H.sub.46F.sub.3N.sub.8O.sub.4 875.35; found: 875.35 (M + H) .sup.+. HRMS: Anal. Calcd. for C.sub.47H.sub.46F.sub.3N.sub.8O.sub.4 875.3492; found: 875.3504 (M + H) .sup.+. J38 methyl ((1S)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-(N- (methoxycarbonyl)- L-alanyl)-2- pyrrolidinyl)-4- (trifluoromethyl)- 1H-imidazol-5-yl)- 4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-1- methyl-2- oxoethyl)carbamate t.sub.R = 1.7 min, (95.5%) (Cond 2); LRMS: Anal. Calcd. for C.sub.37H.sub.42F.sub.3N.sub.8O.sub.6 751.32; found: 751.32 (M + H) .sup.+. HRMS: Anal. Calcd. for C.sub.37H.sub.42F.sub.3N.sub.8O.sub.6 751.3179; found: 751.3163 (M + H) .sup.+. J39 methyl ((1S)-1- (((2S)-2-(5-(4′-(2- ((2S)-1-((2S)-2- ((methoxycarbonyl) amino)-3- methylbutanoyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-4- (trifluoromethyl)- 1H-imidazol-2-yl)- 1-pyrrolidinyl)carbonyl)- 2-methylpropyl)carbamate t.sub.R = 1.9 min, (96%) (Cond 2); LRMS: Anal. Calcd. for C.sub.41H.sub.50F.sub.3N.sub.8O.sub.6 807.38; found: 807.33 (M + H) .sup.+. HRMS: Anal. Calcd. for C.sub.41H.sub.50F.sub.3N.sub.8O.sub.6 807.3805; found: 807.3773 (M + H) .sup.+. J40 (1R)-2-((2S)-2-(5- (4′-(2-((2S)-1- ((2R)-2- (diethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-4- (trifluoromethyl)- 1H-imidazol-2-yl)- 1-pyrrolidinyl)- N,N-diethyl-2-oxo- 1-phenylethanamine t.sub.R = 1.6 min, (95%) (Cond 2); LRMS: Anal. Calcd. for C.sub.51H.sub.58F.sub.3N.sub.8O.sub.2 871.46; found: 871.48 (M + H) .sup.+. HRMS: Anal. Calcd. for C.sub.51H.sub.58F.sub.3N.sub.8O.sub.2 871.4635; found: 871.4647 (M + H) .sup.+. J41 methyl ((1S)-1- cyclopropyl-2- ((2S)-2-(5-(4′-(2- ((2S)-1-((2S)-2- cyclopropyl-2- ((methoxycarbonyl) amino)acetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-4- (trifluoromethyl)- 1H-imidazol-2-yl)- 1-pyrrolidinyl)-2- oxoethyl)carbamate t.sub.R = 1.8 min, (96.9%) (Cond 2); LRMS: Anal. Calcd. for C.sub.41H.sub.46F.sub.3N.sub.8O.sub.6 803.35; found: 803.35 (M + H) .sup.+. HRMS: Anal. Calcd. for C.sub.41H.sub.46F.sub.3N.sub.8O.sub.6 803.3492; found: 803.3507 (M + H) .sup.+. J42 methyl ((1S,2R)-2- methoxy-1-(((2S)- 2-(5-(4′-(2-((2S)-1- (N-(methoxycarbonyl)- O-methyl-L- threonyl)-2- pyrrolidinyl)-4- (trifluoromethyl)- 1H-imidazol-5-yl)- 4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl) propyl)carbamate 0 t.sub.R = 1.8 min, (92%) (Cond 2); LRMS: Anal. Calcd. for C.sub.41H.sub.50F.sub.3N.sub.8O.sub.8 839.37; found: 839.30 (M + H) .sup.+. HRMS: Anal. Calcd. for C.sub.41H.sub.50F.sub.3N.sub.8O.sub.8 839.3704; found: 839.3677 (M + H) .sup.+. J42.a methyl ((1S)-2- ((2S)-2-(5-(4′-(2- ((1S)-1-((N- (methoxycarbonyl)- L-alanyl)(methyl)amino) ethyl)-1H- imidazol-5-yl)-4- biphenylyl)-4- (trifluoromethyl)- 1H-imidazol-2-yl)- 1-pyrrolidinyl)-1- methyl-2- oxoethyl)carbamate t.sub.R = 1.69 min, (100%) (Cond 2); LRMS: Anal. Calcd. for C.sub.36H.sub.42F.sub.3N.sub.8O.sub.6 739.32; found: 739.31 (M + H) .sup.+. HRMS: Anal. Calcd. for C.sub.36H.sub.42F.sub.3N.sub.8O.sub.6 739.3179; found: 739.3195 (M + H) .sup.+. J43 benzyl (2S)-2-(5- (4′-(2-((2S)-1-(N- (methoxycarbonyl)- L-alanyl)-2- pyrrolidinyl)-4- (trifluoromethyl)- 1H-imidazol-5-yl)- 4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinecarboxylate t.sub.R = 1.9 min, (95%) (Cond 2); LRMS: Anal. Calcd. for C.sub.40H.sub.41F.sub.3N.sub.7O.sub.5 756.31; found: 756.19 (M + H) .sup.+. HRMS: Anal. Calcd. for C.sub.40H.sub.41F.sub.3N.sub.7O.sub.5 756.3121; found: 756.3127 (M + H) .sup.+. J44 LCMS: C.sub.32H.sub.35F.sub.3N.sub.7O.sub.3 found: 622 (M + H) .sup.+. J45 methyl ((1S)-2- ((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2- (diethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-4- (trifluoromethyl)- 1H-imidazol-2-yl)- 1-pyrrolidinyl)-1- methyl-2- oxoethyl)carbamate t.sub.R = 1.7 min, (93%) (Cond 2); LRMS: Anal. Calcd. for C.sub.44H.sub.50F.sub.3N.sub.8O.sub.4 811.39; found: 811.34 (M + H) .sup.+. HRMS: Anal. Calcd. for C.sub.44H.sub.50F.sub.3N.sub.8O.sub.4 811.3907; found: 811.3913 (M + H) .sup.+. J46 methyl ((1R)-2- ((2S)-2-(5-(4-(5-(2- ((2S)-1-((2R)-2- ((methoxycarbonyl) amino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-2- pyrimidinyl)phenyl)- 4-(trifluoromethyl)- 1H-imidazol-2-yl)- 1-pyrrolidinyl)-2- oxo-1- phenylethyl)carbamate t.sub.R = 1.82 min, (98%) (Cond 2); LRMS: Anal. Calcd. for C.sub.45H.sub.44F.sub.3N.sub.10O.sub.6 877.34; found: 877.29 (M + H) .sup.+. HRMS: Anal. Calcd. for C.sub.45H.sub.44F.sub.3N.sub.10O.sub.6 877.3397; found: 877.3403 (M + H) .sup.+. J47 (1R)-2-((2S)-2-(5- (4-(5-(2-((2S)-1- ((2R)-2- (diethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-2- pyrimidinyl)phenyl)- 4-(trifluoromethyl)- 1H-imidazol-2-yl)- 1-pyrrolidinyl)- N,N-diethyl-2-oxo- 1-phenylethanamine t.sub.R = 1.58 min, (97%) (Cond 2); LRMS: Anal. Calcd. for C.sub.49H.sub.56F.sub.3N.sub.10O.sub.2 873.44; found: 873.40 (M + H) .sup.+. HRMS: Anal. Calcd. for C.sub.49H.sub.56F.sub.3N.sub.10O.sub.2 873.4540; found: 873.4536 (M + H) .sup.+. J48 methyl ((1S)-1- (((2S)-2-(5-(2-(4- (2-((2S)-1-((2S)-2- ((methoxycarbonyl) amino)-3- methylbutanoyl)-2- pyrrolidinyl)-4- (trifluoromethyl)- 1H-imidazol-5- yl)phenyl)-5- pyrimidinyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)- 2-methylpropyl)carbamate t.sub.R = 1.85 min, (99%) (Cond 2); LRMS: Anal. Calcd. for C.sub.39H.sub.48F.sub.3N.sub.10O.sub.6 809.37; found: 809.37 (M + H) .sup.+. HRMS: Anal. Calcd. for C.sub.39H.sub.48F.sub.3N.sub.10O.sub.6 809.3710; found: 809.3683 (M + H) .sup.+. J49 methyl ((1S)-1- cyclopropyl-2- ((2S)-2-(5-(4-(5-(2- ((2S)-1-((2S)-2- cyclopropyl-2- ((methoxycarbonyl) amino)acetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-2- pyrimidinyl)phenyl)- 4-(trifluoromethyl)- 1H-imidazol-2-yl)- 1-pyrrolidinyl)-2- oxoethyl)carbamate t.sub.R = 1.75 min, (100%) (Cond 2); LRMS: Anal. Calcd. for C.sub.39H.sub.44F.sub.3N.sub.10O.sub.6 805.34; found: 805.34 (M + H) .sup.+. HRMS: Anal. Calcd. for C.sub.39H.sub.44F.sub.3N.sub.10O.sub.6 805.3397; found: 805.3384 (M + H) .sup.+. J50 methyl ((1S)-2- ((2S)-2-(5-(4-(5-(2- ((2S)-1-(N- (methoxycarbonyl)- L-alanyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-2- pyrimidinyl)phenyl)- 4-(trifluoromethyl)- 1H-imidazol-2-yl)- 1-pyrrolidinyl)-1- methyl-2- oxoethyl)carbamate t.sub.R = 1.61 min, (94%) (Cond 2); LRMS: Anal. Calcd. for C.sub.35H.sub.40F.sub.3N.sub.10O.sub.6 753.31; found: 753.31 (M + H) .sup.+. HRMS: Anal. Calcd. for C.sub.35H.sub.40F.sub.3N.sub.10O.sub.6 753.3084; found: 753.3099 (M + H) .sup.+. J51 (2R)-1-((2S)-2-(5- (4-(5-(2-((2S)-1- ((2R)-2- (diethylamino)propanoyl)- 2-pyrrolidinyl)-1H- imidazol-5-yl)-2- pyrimidinyl)phenyl)- 4-(trifluoromethyl)- 1H-imidazol-2-yl)- 1-pyrrolidinyl)- N,N-diethyl-1-oxo- 2-propanamine 0 t.sub.R = 1.41 min, (92%) (Cond 2); LRMS: Anal. Calcd. for C.sub.39H.sub.52F.sub.3N.sub.10O.sub.2 749.42; found: 749.37 (M + H) .sup.+. HRMS: Anal. Calcd. for C.sub.39H.sub.52F.sub.3N.sub.10O.sub.2 749.4227; found: 749.4223 (M + H) .sup.+. Cond 1: LCMS conditions: Phenomenex-Luna 4.6 × 50 mm S10, 0 to 100% B over 3 min, 4 min stop time, 4 mL/min, 220 nm, A: 10% MeOH—90% H2O—0.1% TFA; B: 90% MeOH—10% H2O—0.1% TFA Cond 2: LCMS conditions: Phenomenex-Luna 4.6 × 50 mm S10, 0 to 100% B over 2 min, 3 min stop time, 4 mL/min, 220 nm, A: 10% MeOH—90% H2O—0.1% TFA; B: 90% MeOH—10% H2O—0.1% TFA

(1145) Cond 1: LCMS conditions: Phenomenex-Luna 4.6×50 mm S10, 0 to 100% B over 3 min, 4 min stop time, 4 mL/min, 220 nm, A: 10% MeOH-90% H2O-0.1% TFA; B: 90% MeOH-10% H2O-0.1% TFA

(1146) Cond 2: LCMS conditions: Phenomenex-Luna 4.6×50 mm S10, 0 to 100% B over 2 min, 3 min stop time, 4 mL/min, 220 nm, A: 10% MeOH-90% H2O-0.1% TFA; B: 90% MeOH-10% H2O-0.1% TFA

Example J2

(2S)-2-(1-(4-bromophenyl)-3-ethoxy-1,3-dioxopropan-2-yl) 1-tert-butyl pyrrolidine-1,2-dicarboxylate

(1147) ##STR01161##

(1148) The ethyl 3-(4-bromophenyl)-3-oxopropanoate (15 g, 55 mmol) was dissolved in CH.sub.2Cl.sub.2 (600 mL) and freshly recrystallized NBS (9.8 g, 55 mmol) was added and the solution stirred 18 hr. The reaction mixture was washed with NaHCO.sub.3 solution, brine, and dried (MgSO.sub.4), filtered, and concentrated to give a residue which was not purified. Ethyl 2-bromo-3-(4-bromophenyl)-3-oxopropanoate (16.5 g, 48 mmol) and N-Boc-L-proline (10 g, 48 mmol) were taken up in acetonitrile (450 mL) and Hunig's base (16 mL, 95 mmol) was added and the solution stirred 18 hr. The solvent was removed by rotary evaporation and the residue taken up in ethyl acetate, washed with 0.1 N HCl, and brine. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 7.95 (d, J=8.4 Hz, 2H), 7.79 (d, J=8.4 Hz, 2H), 6.68-6.65 (m, 1H), 4.39-4.30 (m, 1H), 4.21-4.12 (m, 2H), 2.27-2.21 (m, 1H), 2.0-1.95 (m, 1H), 1.90-1.76 (m, 2H), 1.39 (s, 2H), 1.31 (s, 9H), 1.11 (t, J=7.3 Hz, 3H).

(1149) LRMS: Anal. Calcd. for C.sub.21H.sub.26BrNO.sub.7 484.09. found: 410.08 (M+H).sup.+.

Example J5

(S)-ethyl 5-(4-bromophenyl)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazole-4-carboxylate

(1150) ##STR01162##

(1151) A 1 L pressure bottle was charged with (2S)-2-(1-(4-bromophenyl)-3-ethoxy-1,3-dioxopropan-2-yl) 1-tert-butyl pyrrolidine-1,2-dicarboxylate J2 (7 g, 35 mmol) and 11 g of NH.sub.4OAc in 125 mL of Xylene, and the reaction was heated at 140° C. for 3.5 hr. After being cooled, the solution was partition between ethyl actate and water. The organic layer was concentrated and the resultant residue applied to a Biotage 40 m silica gel cartridge and eluted by 20-100% gradient, ethyl acetate/Hex to give 3 g (45%). .sup.1H NMR (300 MHz, CDCl.sub.3) δ 12.75 (br. s, 7.82), (br. s, 2H), 7.50 (d, J=8.4 Hz, 2H), 4.96-4.92 (m, 1H), 4.23 (q, J=6.6 Hz, 2H), 3.68-3.50 (m, 1H), 3.40-3.32 (m, 1H), 2.19-2.15 (m, 1H), 1.99-1.89 (m, 3H), 1.48/1.13 (s, 9H), 1.23 (t, J=7.3 Hz, 3H). LRMS: Anal. Calcd. for C.sub.21H.sub.26BrN.sub.3O.sub.4 464.12. found: 464.15 and 466.15 (M+H).sup.+.

Example J7

(S)-tert-butyl 2-(5-(4-bromophenyl)-4-(methylcarbamoyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

(1152) ##STR01163##

(1153) (S)-ethyl 5-(4-bromophenyl)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazole-4-carboxylate (1 g, 2.1 mmol) was dissolved in 2M methylamine in MeOH (35 mL) and heated in a pressure vessel at 70° C. for 48 h. The reaction mixture was concentrated and the residue applied to a Biotage 25 m silica gel cartridge and eluted by 10-100% gradient, ethyl acetate/Hex to give 556 mg (57%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.5 (br.s, 1H), 7.86-7.82 (m, 1H), 7.77 (d, J=8.4 Hz, 2H), 7.61 (d, J=8.7 Hz, 2H), 4.83-4.70 (m, 1H), 3.69-3.52 (br.s, 1H), 3.42-3.32 (m, 1H), 2.71 (d, 4.8 Hz, 3H), 2.30-1.78 (m, 4H), 1.19-1.14 (m, 9H).

(1154) LRMS: Anal. Calcd. for C.sub.20H.sub.26BrN.sub.4O.sub.3 449.12. found: 449.15 and 451.14 (M+H).sup.+.

Example J11.a

(1155) ##STR01164##

(1156) Entry J9 (1.1 g, 1.58 mmol) was taken up in ethanol (60 mL), 28% concentrated ammonium hydroxide soln (10 mL) was added, and the reaction heated in a pressure vessel at 75° C. for 48 h. The solvent was removed by rotary evaporation and the residue taken up in ethyl acetate and washed with water, brine. Concentration and application to a 25 M Biotage cartridge, gradient elution with 10%-100% ethyl acetate/CH.sub.2C.sub.12, gave J11.a 90 mg (8.5%) and recovered starting material J9 696 mg (63%).

Example J32.a

(S)-tert-butyl 2-(5-(4-bromophenyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

(1157) ##STR01165##

(1158) 3-(4-bromophenyl)-3-(2,2-dimethylhydrazono)-1,1,1-trifluoropropan-2-one (2.0 g, 6.2 mmol) was suspended in 5N sulfuric acid (60 mL) and heated at 45° C. for 6 h. The temperature was raised to 85° C. for 2 h, and upon cooling a precipitate formed. This material which was isolated by filtration to give 1-(4-bromophenyl)-3,3,3-trifluoropropane-1,2-dione 1.6 g (92%) as a yellow solid. The dione (1.6 g, 5.7 mmol) was taken up in methanol (30 mL), N-(tert-butoxycarbonyl)-L-prolinal (1 g, 5.0 mmol) was added, followed by addition of 28% ammonium hydroxide solution (10 mL). The reaction was stirred at room temperature for 18 h, poured onto dichloromethane (200 mL), washed with water and dried with MgSO.sub.4. Filtration, concentration and application to a 40 M Biotage cartridge, gradient elution with 5%-30% ethyl acetate/Hexanes, gave J32.a 1.3 g (50%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.88 (br.s, 1H), 7.72 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.0 Hz, 2H), 4.84-4.70 (m, 1H), 3.57-3.49 (m, 1H), 3.39-3.29 (m, 1H), 2.31-2.20 (m, 1H), 1.98-1.78 (m, 3H), 1.39/1.13 (m, 9H). LRMS: Anal. Calcd. for C.sub.19H.sub.20BrF.sub.3N.sub.3O.sub.2 458.07. found: 458.06 and 460.06 (M−H).sup.−. HRMS: Anal. Calcd. for C.sub.19H.sub.22BrF.sub.3N.sub.3O.sub.2 460.0847. found: 460.0866 and 462.0840 (M+H).sup.+.

(1159) Section D

(1160) TABLE-US-00076 Entry Compound Name Structure **Data D1 t.sub.R = 2.65 min, (86.7%) LCMS: Anal. Calcd. for C.sub.8H.sub.15BrFO 296.88; found: 296.91 (M + H).sup.+. D2 t.sub.R = 2.66 min, (80%) LCMS: Anal. Calcd. for C.sub.8H.sub.4BrClFO 270.92; found: ND (M + H).sup.+. D3 t.sub.R = 2.57 min, (95%) LCMS: Anal. Calcd. for C.sub.9H.sub.9BrO.sub.2 228.99; found: 229.00 (M + H).sup.+. D4 t.sub.R = 2.38 min, (95.0%) LRMS: Anal. Calcd. for C.sub.19H.sub.20.sup.79BrFN.sub.3O.sub.2 444.07; found: 444.04 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.19H.sub.20.sup.79BrFN.sub.3O.sub.2 444.0721; found: 444.0736 (M + H).sup.+ D5 0 t.sub.R = 2.27 min, (95%) LRMS: Anal. Calcd. for C.sub.18H.sub.22BrFN.sub.3O.sub.2 410.09 and 412.08; found: 410.08 and 412.08 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.18H.sub.22.sup.79BrFN.sub.3O.sub.2 410.0879; found: 410.0893 (M + H).sup.+. D6 t.sub.R = 2.26 min, (95%) LRMS: Anal. Calcd. for C.sub.19H.sub.25BrN.sub.3O.sub.3 422.11 and 424.11; found: 422.10 and 424.10 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.19H.sub.25.sup.79BrN.sub.3O.sub.3 422.1079; found: 422.1089 (M + H).sup.+. D7 t.sub.R = 2.28 min, (95%) LRMS: Anal. Calcd. for C.sub.18H.sub.21ClF.sub.2N.sub.3O.sub.2 384.13; found: 384.13 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.18H.sub.21ClF.sub.2N.sub.3O.sub.2 384.1290; found: 384.1301 (M + H).sup.+. D8 t.sub.R = 2.62 min, (~50%) and 1.95 min (~50%, boronic acid) LRMS: Anal. Calcd. for C.sub.24H.sub.34BFN.sub.3O.sub.4 458.26; found: 458.23 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.24H.sub.34BFN.sub.3O.sub.4 458.2626; found: 458.2610 (M + H).sup.+ D9 tert-butyl (2S)-2-(4- (4′-(2-((2S)-1-(tert- butoxycarbonyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- methoxy-3- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinecarboxylate t.sub.R = 2.28 min, (95%) LRMS: Anal. Calcd. for C.sub.37H.sub.47N.sub.6O.sub.5 655.36; found: 655.37 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.37H.sub.47N.sub.6O.sub.5 655.3608; found: 655.3627 (M + H).sup.+. D10 di-tert-butyl (2S,2′S)- 2,2′-((3-fluoro-4,4′- biphenyldiyl)bis(1H- imidazole-4,2- diyl))di(1- pyrrolidinecarboxylate) t.sub.R = 2.21 min, (99.2%) LCMS: Anal. Calcd. for C.sub.36H.sub.44FN.sub.6O.sub.4 643.34; found: 643.51 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.36H.sub.44FN.sub.6O.sub.4 643.3403; found: 643.3390 (M + H).sup.+. D11 tert-butyl (2S)-2-(4- (4′-(2-((2S)-1-(tert- butoxycarbonyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-2,5- difluoro-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinecarboxylate t.sub.R = 2.24 min, (95%) LRMS: Anal. Calcd. for C.sub.36H.sub.43F.sub.2N.sub.6O.sub.4 661.33; found: 661.35 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.36H.sub.43F.sub.2N.sub.6O.sub.4 661.3314; found: 661.3336 (M + H).sup.+. D12 di-tert-butyl (2S,2′S)- 2,2′-((3,3′-difluoro- 4,4′- biphenyldiyl)bis(1H- imidazole-5,2- diyl))di(1- pyrrolidinecarboxylate) t.sub.R = 2.20 min, (95%) LRMS: Anal. Calcd. for C.sub.36H.sub.43F.sub.2N.sub.6O.sub.4 661.33; found: 661.22 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.36H.sub.43F.sub.2N.sub.6O.sub.4 661.3314; found: 661.3307 (M + H).sup.+ D13 tert-butyl (2S)-2-(5- (2-(4-(2-((2S)-1-(tert- butoxycarbonyl)-2- pyrrolidinyl)-1H- imidazol-4-yl)-3- fluorophenyl)-5- pyrimidinyl)-1H- imidazol-2-yl)-1- pyrrolidinecarboxylate t.sub.R = 2.27 min, (95%) LRMS: Anal. Calcd. for C.sub.34H.sub.42FN.sub.8O.sub.4 645.33; found: 645.34 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.34H.sub.42FN.sub.8O.sub.4 645.3313; found: 645.3323 (M + H).sup.+. D14 tert-butyl (2S)-2-(4- (4′-(2-((2S)-1- ((benzyloxy)carbonyl)- 2-pyrrolidinyl)-1H- imidazol-5-yl)-3- fluoro-4-biphenylyl)- 1H-imidazol-2-yl)-1- pyrrolidinecarboxylate t.sub.R = 2.26 min, (95%) LRMS: Anal. Calcd. for C.sub.39H.sub.42FN.sub.6O.sub.4 677.33; found: 677.33 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.39H.sub.42FN.sub.6O.sub.4 677.3252; found: 677.3278 (M + H).sup.+. D15 tert-butyl (2S)-2-(4- (4′-(2-((2S)-1- ((benzyloxy)carbonyl)- 2-pyrrolidinyl)-1H- imidazol-5-yl)-3,3′- difluoro-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinecarboxylate 0 t.sub.R = 2.36 min, (97.3%) LRMS: Anal. Calcd. for C.sub.39H.sub.41F.sub.2N.sub.6O.sub.4 695.32; found: 695.33 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.39H.sub.41F.sub.2N.sub.6O.sub.4 695.3157; found: 695.3151 (M + H).sup.+. D16 tert-butyl (2S)-2-(5- (3-fluoro-4′-(2-((2S)- 1-((2R)-2- ((methoxycarbonyl) amino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinecarboxylate t.sub.R = 2.16 min, (91.0%) LRMS: Anal. Calcd. for C.sub.41H.sub.45FN.sub.7O.sub.5 734.35; found: 734.36 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.41H.sub.45FN.sub.7O.sub.5 734.3466; found: 734.3474 (M + H).sup.+. D17 tert-butyl (2S)-2-(5- (4′-(2-((2S)-1-((2R)- 2-(diethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-3- fluoro-4-biphenylyl)- 1H-imidazol-2-yl)-1- pyrrolidinecarboxylate t.sub.R = 1.95 min, (95%) LRMS: Anal. Calcd. for C.sub.43H.sub.51FN.sub.7O.sub.3 732.40; found: 732.44 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.43H.sub.51FN.sub.7O.sub.3 732.4037; found: 732.4065 (M + H).sup.+. D18 tert-butyl (2S)-2-(5- (3-fluoro-4′-(2-((2S)- 1-(N- (methoxycarbonyl)- L-valyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinecarboxylate t.sub.R = 2.14 min, (95%) LRMS: Anal. Calcd. for C.sub.38H.sub.47FN.sub.7O.sub.5 700.36; found: 700.37 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.38H.sub.47FN.sub.7O.sub.5 700.3623; found: 700.3596 (M + H).sup.+. D19 tert-butyl (2S)-2-(5- (3,3′-difluoro-4′-(2- ((2S)-1-((2R)-2- ((methoxycarbonyl) amino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinecarboxylate t.sub.R = 2.23 min, (95%) LRMS: Anal. Calcd. for C.sub.41H.sub.44F.sub.2N.sub.7O.sub.5 752.34; found: 752.35 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.41H.sub.44F.sub.2N.sub.7O.sub.5 752.3372; found: 752.3385 (M + H).sup.+. D20 tert-butyl (2S)-2-(5- (3,3′-difluoro-4′-(2- ((2S)-1-(N- (methoxycarbonyl)- L-valyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinecarboxylate t.sub.R = 2.16 min, (90%) LRMS: Anal. Calcd. for C.sub.38H.sub.46F.sub.2N.sub.7O.sub.5 718.35; found: 718.36 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.38H.sub.46F.sub.2N.sub.7O.sub.5 718.3528; found: 718.3505 (M + H).sup.+. D21 tert-butyl (2S)-2-(5- (3-fluoro-4′-(2-((2S)- 2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinecarboxylate triacetate t.sub.R = 1.94 min, (95%) LRMS: Anal. Calcd. for C.sub.31H.sub.36FN.sub.6O.sub.2 543.29; found: 543.30. HRMS: Anal. Calcd. for C.sub.31H.sub.36FN.sub.6O.sub.2 543.2884; found: 543.2872 (M + H).sup.+. D22 tert-butyl (2S)-2-(5- (3,3′-difluoro-4′-(2- ((2S)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinecarboxylate t.sub.R = 2.14 min, (95%) LRMS: Anal. Calcd. for C.sub.31H.sub.35F.sub.2N.sub.6O.sub.2 561.28; found: 561.29 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.31H.sub.35F.sub.2N.sub.6O.sub.2 561.2790; found: 561.2766 (M + H).sup.+. D23 methyl ((1R)-2-((2S)- 2-(5-(3′-fluoro-4′-(2- ((2S)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2-oxo- 1-phenylethyl)carbamate t.sub.R = 1.90 min, (94%) LRMS: Anal. Calcd. for C.sub.36H.sub.37FN.sub.7O.sub.3 634.29; found: 634.29 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.36H.sub.37FN.sub.7O.sub.3 634.2942; found: 634.2948 (M + H).sup.+. D24 methyl ((1S)-1- (((2S)-2-(5-(3′-fluoro- 4′-(2-((2S)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)- 2-methylpropyl)carbamate t.sub.R = 1.89 min, (95%) LRMS: Anal. Calcd. for for C.sub.33H.sub.39FN.sub.7O.sub.3 600.31; found: 600.32 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.33H.sub.39FN.sub.7O.sub.3 600.3098; found: 600.3121 (M + H).sup.+. D25 (1R)-N,N-diethyl-2- ((2S)-2-(5-(3′-fluoro- 4′-(2-((2S)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2-oxo- 1-phenylethanamine 0 t.sub.R = 1.72 min, (90%) LRMS: Anal. Calcd. for C.sub.38H.sub.43FN.sub.7O 632.35; found: 632.36 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.38H.sub.43FN.sub.7O 632.3513; found: 632.3527 (M + H).sup.+. D26 methyl ((1S)-1- (((2S)-2-(5-(3,3′- difluoro-4′-(2-((2S)- 2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate t.sub.R = 1.96 min, (95%) LRMS: Anal. Calcd. for C.sub.33H.sub.38F.sub.2N.sub.7O.sub.3 618.30; found: 618.31 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.33H.sub.38F.sub.2N.sub.7O.sub.3 618.3004; found: 618.3024 (M + H).sup.+. D27 methyl ((1R)-2-((2S)- 2-(5-(3,3′-difluoro-4′- (2-((2S)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2-oxo- 1-phenylethyl)carbamate t.sub.R = 1.63 min, (95%) LRMS: Anal. Calcd. for C.sub.36H.sub.36F.sub.2N.sub.7O.sub.3 652.28; found: 652.29 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.36H.sub.36F.sub.2N.sub.7O.sub.3 652.2848; found: 652.2858 (M + H).sup.+. D28 5,5′-(4-methoxy-3,4′- biphenyldiyl)bis(2- ((2S)-2-pyrrolidinyl)- 1H-imidazole) t.sub.R = 1.53 min, (98.2%) LRMS: Anal. Calcd. for C.sub.27H.sub.31N.sub.6O 455.26; found: 455.26 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.27H.sub.31N.sub.6O 455.2559; found: 455.2576 (M + H).sup.+. D29 5,5′-(3-fluoro-4,4′- biphenyldiyl)bis(2- ((2S)-2-pyrrolidinyl)- 1H-imidazole) tetraacetate t.sub.R = 1.55 min, (95%) LRMS: Anal. Calcd. for C.sub.26H.sub.28FN.sub.6 443.24; found: 443.24 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.26H.sub.28FN.sub.6 443.2359; found: 443.2371 (M + H).sup.+. D30 t.sub.R = 1.72 min, (77.5%) LRMS: Anal. Calcd. for C.sub.26H.sub.27F.sub.2N.sub.6 461.23; found: 461.25 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.26H.sub.27F.sub.2N.sub.6 461.2265; found: 461.2272 (M + H).sup.+. D31 5,5′-(2,5-difluoro- 4,4′-biphenyldiyl)bis(2- ((2S)-2-pyrrolidinyl)- 1H-imidazole) t.sub.R = 1.67 min, (95%) LRMS: Anal. Calcd. for C.sub.26H.sub.27F.sub.2N.sub.6 461.23; found: 461.23 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.26H.sub.27F.sub.2N.sub.6 461.2265; found: 461.2287 (M + H).sup.+. D32 2-(3-fluoro-4-(2- ((2S)-2-pyrrolidinyl)- 1H-imidazol-5- yl)phenyl)-5-(2-((2S)- 2-pyrrolidinyl)-1H- imidazol-5- yl)pyrimidine t.sub.R = 1.63 min, (95%) LRMS: Anal. Calcd. for C.sub.24H.sub.26FN.sub.8 445.23; found: 445.23 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.24H.sub.26FN.sub.8 445.2264; found: 445.2268 (M + H).sup.+. D33 (1R,1′R)-2,2′-((4- methoxy-3,4′- biphenyldiyl)bis(1H- imidazole-5,2- diyl(2S)-2,1- pyrrolidinediyl))bis(N,N- dimethyl-2-oxo-1- phenylethanamine) t.sub.R = 1.71 min, (95%) LRMS: Anal. Calcd. for C.sub.47H.sub.53N.sub.8O.sub.3 777.42; found: 777.41 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.47H.sub.53N.sub.8O.sub.3 777.4241; found: 777.4254 (M + H).sup.+. D34 dimethyl ((4- methoxy-3,4′- biphenyldiyl)bis(1H- imidazole-5,2- diyl(2S)-2,1- pyrrolidinediyl((1R)- 2-oxo-1-phenyl-2,1- ethanediyl)))biscarbamate t.sub.R = 2.09 min, (95%) LRMS: Anal. Calcd. for C.sub.47H.sub.49N.sub.8O.sub.7 837.37; found: 837.34 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.47H.sub.49N.sub.8O.sub.7 837.3724; found: 837.3690 (M + H).sup.+. D35 methyl ((1S)-1- (((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2- (diethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-3- fluoro-4-biphenylyl)- 1H-imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate 00 t.sub.R = 1.85 min, (97.2%) LRMS: Anal. Calcd. for C.sub.45H.sub.54FN.sub.8O.sub.4 789.43; found: 789.43 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.45H.sub.54FN.sub.8O.sub.4 789.4252; found: 789.4225 (M + H).sup.+. D36 methyl ((1S)-2-((2S)- 2-(5-(4′-(2-((2S)-1- ((2R)-2- (diethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-3- fluoro-4-biphenylyl)- 1H-imidazol-2-yl)-1- pyrrolidinyl)-1- methyl-2- oxoethyl)carbamate 01 t.sub.R = 1.76 min, (97.9%) LRMS: Anal. Calcd. for C.sub.43H.sub.50FN.sub.8O.sub.4 761.39; found: 761.26 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.43H.sub.50FN.sub.8O.sub.4 761.3939; found: 761.3967 (M + H).sup.+. D37 methyl ((1R)-2-((2S)- 2-(5-(4′-(2-((2S)-1- ((2R)-2- (diethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-3- fluoro-4-biphenylyl)- 1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo- 1-phenylethyl)carbamate 02 t.sub.R = 1.90 min, (98.6%) LRMS: Anal. Calcd. for C.sub.48H.sub.52FN.sub.8O.sub.4 823.41; found: 823.42 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.48H.sub.52FN.sub.8O.sub.4 823.4096; found: 823.4102 (M + H).sup.+. D38 methyl ((1R)-2-((2S)- 2-(5-(3′-fluoro-4′-(2- ((2S)-1-(N- (methoxycarbonyl)- L-alanyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2-oxo- 1-phenylethyl)carbamate 03 t.sub.R = 1.89 min, (98.2%) LRMS: Anal. Calcd. for C.sub.47H.sub.49N.sub.8O.sub.7 763.34; found: 763.32 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.41H.sub.44FN.sub.8O.sub.6 763.3368; found: 763.3358 (M + H).sup.+. D39 methyl ((1R)-2-((2S)- 2-(5-(4′-(2-((2S)-1- ((2R)-2- (diethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-3′- fluoro-4-biphenylyl)- 1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo- 1-phenylethyl)carbamate 04 t.sub.R = 1.88 min, (98.7%) LRMS: Anal. Calcd. for C.sub.48H.sub.52FN.sub.8O.sub.4 823.41; found: 823.39 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.48H.sub.52FN.sub.8O.sub.4 823.4096; found: 823.4127 (M + H).sup.+. D40 methyl ((1S)-1- (((2S)-2-(5-(3′-fluoro- 4′-(2-((2S)-1-((2S)-2- ((methoxycarbonyl) amino)-3- methylbutanoyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate 05 t.sub.R = 1.97 min, (98.4%) LRMS: Anal. Calcd. for C.sub.40H.sub.50FN.sub.8O.sub.6 757.38; found: 757.32 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.40H.sub.50FN.sub.8O.sub.6 757.3837; found: 757.3815 (M + H).sup.+. D41 methyl ((1S)-1- (((2S)-2-(5-(3′-fluoro- 4′-(2-((2S)-1-(N- (methoxycarbonyl)- L-alanyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate 06 t.sub.R = 1.82 min, (95.0%) LRMS: Anal. Calcd. for C.sub.38H.sub.46FN.sub.8O.sub.6 729.35; found: 729.29 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.38H.sub.46FN.sub.8O.sub.6 729.3524; found: 729.3523 (M + H).sup.+. D42 methyl ((1S,2R)-1- (((2S)-2-(5-(3-fluoro- 4′-(2-((2S)-1-(N- (methoxycarbonyl)- L-valyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-2- methoxypropyl)carbamate 07 t.sub.R = 1.91 min, (94.0%) LRMS: Anal. Calcd. for C.sub.40H.sub.50FN.sub.8O.sub.7 773.38; found: 773.31 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.40H.sub.50FN.sub.8O.sub.7 773.3786; found: 773.3759 (M + H).sup.+. D43 methyl ((1S)-1- (((2S)-2-(5-(4′-(2- ((2S)-1-(N,N-diethyl- D-alanyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-3′- fluoro-4-biphenylyl)- 1H-imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate 08 t.sub.R = 1.72 min, (97.6%) LRMS: Anal. Calcd. for C.sub.40H.sub.52FN.sub.8O.sub.4 727.41; found: 727.35 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.40H.sub.52FN.sub.8O.sub.4 727.4096; found: 727.4091 (M + H).sup.+. D44 methyl ((1S)-1- (((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2- (diethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-3′- fluoro-4-biphenylyl)- 1H-imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate 09 t.sub.R = 1.83 min, (96.9%) LRMS: Anal. Calcd. for C.sub.45H.sub.54FN.sub.8O.sub.4 789.43; found: 789.36 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.45H.sub.54FN.sub.8O.sub.4 789.4252; found: 789.4225 (M + H).sup.+. D45 methyl ((1S)-2-((2S)- 2-(5-(3′-fluoro-4′-(2- ((2S)-1-(N- (methoxycarbonyl)- L-alanyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-1- methyl-2- oxoethyl)carbamate 0 t.sub.R = 1.69 min, (97.7%) LRMS: Anal. Calcd. for for C.sub.36H.sub.42FN.sub.8O.sub.6 701.32; found: 701.30 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.36H.sub.42FN.sub.8O.sub.6 701.3222; found: 701.3211 (M + H).sup.+. D46 dimethyl ((3-fluoro- 4,4′- biphenyldiyl)bis(1H- imidazole-5,2- diyl(2S)-2,1- pyrrolidinediyl((1R)- 2-oxo-1-phenyl-2,1- ethanediyl)))biscarbamate t.sub.R = 2.05 min, (99.9%) LRMS: Anal. Calcd. for for C.sub.46H.sub.46FN.sub.8O.sub.6 825.35; found: 825.35 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.46H.sub.46FN.sub.8O.sub.6 825.3524; found: 825.3522 (M + H).sup.+. D47 (1R,1′R)-2,2′-((3- fluoro-4,4′- biphenyldiyl)bis(1H- imidazole-5,2- diyl(2S)-2,1- pyrrolidinediyl))bis(N,N- diethyl-2-oxo-1- phenylethanamine) t.sub.R = 1.72 min, (99.5%) LRMS: Anal. Calcd. for for C.sub.50H.sub.58FN.sub.8O.sub.2 821.47; found: 821.44 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.50H.sub.58FN.sub.8O.sub.2 821.4667; found: 821.4636 (M + H).sup.+. D48 methyl ((1R)-2-((2S)- 2-(5-(4′-(2-((2S)-1- (N,N-diethyl-D- alanyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-3′- fluoro-4-biphenylyl)- 1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo- 1-phenylethyl)carbamate t.sub.R = 1.76 min, (99.7%) LRMS: Anal. Calcd. for C.sub.43H.sub.50FN.sub.8O.sub.4 761.39; found: 761.27 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.43H.sub.50FN.sub.8O.sub.4 761.3939; found: 761.3952 (M + H).sup.+. D49 methyl ((1S)-1- cyclopropyl-2-((2S)- 2-(5-(4′-(2-((2S)-1- ((2R)-2- (diethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-3- fluoro-4-biphenylyl)- 1H-imidazol-2-yl)-1- pyrrolidinyl)-2- oxoethyl)carbamate t.sub.R = 1.92 min, (98.7%) LRMS: Anal. Calcd. for C.sub.45H.sub.52FN.sub.8O.sub.4 787.41; found: 787.36 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.45H.sub.52FN.sub.8O.sub.4 787.4096; found: 787.4074 (M + H).sup.+. D50 methyl ((1S)-1- cyclopropyl-2-((2S)- 2-(5-(3-fluoro-4′-(2- ((2S)-1-(N- (methoxycarbonyl)- L-valyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxoethyl)carbamate t.sub.R = 1.94 min, (99.0%) LRMS: Anal. Calcd. for C.sub.40H.sub.48F.sub.2N.sub.8O.sub.7 755.37; found: 755.32 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.40H.sub.48FN.sub.8O.sub.6 755.3681; found: 755.3670 (M + H).sup.+. D51 methyl ((1R)-2-((2S)- 2-(5-(4′-(2-((2S)-1- (N,N-diethyl-D- alanyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-3′- fluoro-4-biphenylyl)- 1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo- 1-phenylethyl)carbamate t.sub.R = 1.92 min, (98.3%) LRMS: Anal. Calcd. for C.sub.43H.sub.50FN.sub.8O.sub.4 761.39; found: 761.35 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.43H.sub.50FN.sub.8O.sub.4 761.3939; found: 761.3956 (M + H).sup.+. D52 methyl ((1S)-2-((2S)- 2-(5-(2′,5′-difluoro-4′- (2-((2S)-1-(N- (methoxycarbonyl)- L-alanyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-1- methyl-2- oxoethyl)carbamate t.sub.R = 1.69 min, (99.2%) LRMS: Anal. Calcd. for C.sub.36H.sub.41F.sub.2N.sub.8O.sub.6 719.31; found: 719.29 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.36H.sub.41F.sub.2N.sub.8O.sub.6 719.3117; found: 719.3109 (M + H).sup.+. D53 dimethyl ((2,5- difluoro-4,4′- biphenyldiyl)bis(1H- imidazole-5,2- diyl(2S)-2,1- pyrrolidinediyl((1R)- 2-oxo-1-phenyl-2,1- ethanediyl)))biscarbamate t.sub.R = 2.08 min, (100.0%) LRMS: Anal. Calcd. for C.sub.46H.sub.45F.sub.2N.sub.8O.sub.6 843.34; found: 843.34 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.46H.sub.45F.sub.2N.sub.8O.sub.6 843.3430; found: 843.3458 (M + H).sup.+. D54 (1R,1′R)-2,2′-((2,5- difluoro-4,4′- biphenyldiyl)bis(1H- imidazole-5,2- diyl(2S)-2,1- pyrrolidinediyl))bis (N,N-diethyl-2-oxo-1- phenylethanamine) t.sub.R = 1.76 min, (99.8%) LRMS: Anal. Calcd. for C.sub.50H.sub.57F.sub.2N.sub.8O.sub.2: 839.46; found: 839.43 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.50H.sub.57F.sub.2N.sub.8O.sub.2 839.4573; found: 839.4585 (M + H).sup.+. D55 methyl ((1S)-1- cyclopropyl-2-((2S)- 2-(5-(3,3′-difluoro-4′- (2-((2S)-1-(N- (methoxycarbonyl)- L-valyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxoethyl)carbamate 0 t.sub.R = 1.93 min, (98.5%) LRMS: Anal. Calcd. for C.sub.40H.sub.47F.sub.2N.sub.8O.sub.6 773.36; found: 773.31 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.40H.sub.47F.sub.2N.sub.8O.sub.6 773.3567; found: 773.3587 (M + H).sup.+. D56 methyl ((1S,2R)-1- (((2S)-2-(5-(3,3′- difluoro-4′-(2-((2S)- 1-(N- (methoxycarbonyl)- L-valyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-2- methoxypropyl)carbamate t.sub.R = 2.00 min, (98.0%) LRMS: Anal. Calcd. for C.sub.40H.sub.49F.sub.2N.sub.8O.sub.7 791.37; found: 791.32 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.40H.sub.49F.sub.2N.sub.8O.sub.7 791.3692; found: 791.3682 (M + H).sup.+. D57 methyl ((1S)-1- (((2S)-2-(5-(3,3′- difluoro-4′-(2-((2S)- 1-(N- (methoxycarbonyl)- L-alanyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate t.sub.R = 1.86 min, (95.6%) LRMS: Anal. Calcd. for C.sub.38H.sub.45F.sub.2N.sub.8O.sub.6 747.34; found: 747.30 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.38H.sub.45F.sub.2N.sub.8O.sub.6 747.3430; found: 747.3425 (M + H).sup.+. D58 methyl ((1S)-1- (((2S)-2-(5-(3,3′- difluoro-4′-(2-((2S)- 1-((2S)-2- ((methoxycarbonyl) amino)-3- methylbutanoyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate t.sub.R = 2.02 min, (96.3%) LRMS: Anal. Calcd. for C.sub.40H.sub.49F.sub.2N.sub.8O.sub.6 775.37; found: 775.31 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.40H.sub.49F.sub.2N.sub.8O.sub.6 775.3743; found: 775.37.34 (M + H).sup.+. D59 methyl ((1S)-1- (((2S)-2-(5-(4′-(2- ((2S)-1-(N,N-diethyl- D-alanyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-3,3′- difluoro-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)- 2-methylpropyl)carbamate t.sub.R = 1.78 min, (98.2%) LRMS: Anal. Calcd. for C.sub.40H.sub.51F.sub.2N.sub.8O.sub.4 745.40; found: 745.34 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.40H.sub.51F.sub.2N.sub.8O.sub.4 745.4001; found: 745.4008 (M + H).sup.+. D60 methyl ((1S)-1- (((2S)-2-(5-(3,3′- difluoro-4′-(2-((2S)- 1-((2R)-2- ((methoxycarbonyl) amino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate t.sub.R = 2.08 min, (99.1%) LRMS: Anal. Calcd. for C.sub.43H.sub.47F.sub.2N.sub.8O.sub.6 809.36; found: 809.29 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.43H.sub.47F.sub.2N.sub.8O.sub.6 809.3587; found: 809.3568 (M + H).sup.+. D61 methyl ((1S)-2-((2S)- 2-(5-(3,3′-difluoro-4′- (2-((2S)-1-(N- (methoxycarbonyl)- L-alanyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-1- methyl-2- oxoethyl)carbamate t.sub.R = 1.71 min, (94.3%) LRMS: Anal. Calcd. for C.sub.36H.sub.41F.sub.2N.sub.8O.sub.6 719.31; found: 719.19 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.36H.sub.41F.sub.2N.sub.8O.sub.6 719.3117; found: 719.3115 (M + H).sup.+. D62 methyl ((1R)-2-((2S)- 2-(5-(3,3′-difluoro-4′- (2-((2S)-1-(N- (methoxycarbonyl)- L-alanyl)-2- pyrrolidinyl)- 1H-imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2-oxo- 1-phenylethyl)carbamate t.sub.R = 1.94 min, (98.3%) LRMS: Anal. Calcd. for C.sub.41H.sub.43F.sub.2N.sub.8O.sub.6 781.33; found: 781.26 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.41H.sub.43F.sub.2N.sub.8O.sub.6 781.3274; found: 781.3264 (M + H).sup.+. D63 methyl ((1R)-2-((2S)- 2-(5-(4′-(2-((2S)-1- (N,N-diethyl-D- alanyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-3,3′- difluoro-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2-oxo- 1-phenylethyl)carbamate t.sub.R = 1.44 min, (99.0%) LRMS: Anal. Calcd. for C.sub.43H.sub.49F.sub.2N.sub.8O.sub.4 779.38; found: 779.32 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.43H.sub.49F.sub.2N.sub.8O.sub.4 779.3845; found: 779.3842 (M + H).sup.+. D64 methyl ((1R)-2-((2S)- 2-(5-(4′-(2-((2S)-1- ((2R)-2- (diethylamino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-3,3′- difluoro-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2-oxo- 1-phenylethyl)carbamate t.sub.R = 1.94 min, (95.3%) LRMS: Anal. Calcd. for C.sub.48H.sub.51F.sub.2N.sub.8O.sub.4 841.40; found: 841.33 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.48H.sub.51F.sub.2N.sub.8O.sub.4 841.4001; found: 841.3991 (M + H).sup.+. D65 methyl ((1S,2R)-1- (((2S)-2-(5-(3,3′- difluoro-4′-(2-((2S)- 1-((2R)-2- ((methoxycarbonyl) amino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-2- methoxypropyl)carbamate bis(trifluoroacetate) 0 t.sub.R = 2.00 min, (96.2%) LRMS: Anal. Calcd. for C.sub.43H.sub.47F.sub.2N.sub.8O.sub.7 825.35; found: 825.28 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.43H.sub.47F.sub.2N.sub.8O.sub.7 825.3536; found: 825.3527 (M + H).sup.+. D66 methyl ((1S)-1- cyclopropyl-2-((2S)- 2-(5-(3,3′-difluoro-4′- (2-((2S)-1-((2R)-2- ((methoxycarbonyl) amino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2- oxoethyl)carbamate t.sub.R = 2.01 min, (99.5%) LRMS: Anal. Calcd. for C.sub.43H.sub.45F.sub.2N.sub.8O.sub.6 807.34; found: 807.29 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.43H.sub.45F.sub.2N.sub.8O.sub.6 807.3430; found: 807.3409 (M + H).sup.+. D67 methyl ((1S)-2-((2S)- 2-(5-(2-fluoro-4-(5- (2-((2S)-1-(N- (methoxycarbonyl)- L-alanyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-2- pyrimidinyl)phenyl)- 1H-imidazol-2-yl)-1- pyrrolidinyl)-1- methyl-2- oxoethyl)carbamate t.sub.R = 1.58 min, (91.1%) LRMS: Anal. Calcd. for C.sub.34H.sub.40FN.sub.10O.sub.6 703.31; found: 703.27 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.34H.sub.40FN.sub.10O.sub.6 703.3116; found: 703.3101 (M + H).sup.+. D68 methyl ((1S)-1- (((2S)-2-(5-(2-fluoro- 4-(5-(2-((2S)-1-((2S)- 2-((methoxycarbonyl) amino)-3- methylbutanoyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-2- pyrimidinyl)phenyl)- 1H-imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate t.sub.R = 1.95 min, (99.3%) LRMS: Anal. Calcd. for C.sub.38H.sub.48FN.sub.10O.sub.6 759.37; found: 759.30 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.38H.sub.48FN.sub.10O.sub.6 759.3742; found: 759.3715 (M + H).sup.+. D69 methyl ((1R)-2-((2S)- 2-(5-(2-(3-fluoro-4- (2-((2S)-1-((2R)-2- ((methoxycarbonyl) amino)-2- phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5- yl)phenyl)-5- pyrimidinyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-2-oxo- 1-phenylethyl)carbamate t.sub.R = 2.05 min, (99.3%) LRMS: Anal. Calcd. for C.sub.44H.sub.44FN.sub.10O.sub.6 827.34; found: 827.27 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.44H.sub.44FN.sub.10O.sub.6 827.3429; found: 827.3407 (M + H).sup.+. D70 methyl ((1S,2R)-1- (((2S)-2-(5-(2-fluoro- 4-(5-(2-((2S)-1-(N- (methoxycarbonyl)- O-methyl-L- threonyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-2- pyrimidinyl)phenyl)- 1H-imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-2- methoxypropyl)carbamate t.sub.R = 1.79 min, (93.0%) LRMS: Anal. Calcd. for C.sub.38H.sub.48FN.sub.10O.sub.8 791.36; found: 791.31 (M + H).sup.+. HRMS: Anal. Calcd. for C.sub.38H.sub.48FN.sub.10O.sub.8 791.3641; found: 791.3636 (M + H).sup.+. **LCMS conditions: Phenomenex-Luna 4.6 × 50 mm S10, 0 to 100% B over 3 min, 4 min stop time, 4 mL/min, 220 nm, A: 10% MeOH-90% H2O-0.1% TFA; B: 90% MeOH-10% H2O-0.1% TFA

Example D5

(S)-tert-butyl 2-(5-(4-bromo-2-fluorophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

(1161) ##STR01236##

(1162) Bromine (0.54 mL, 10.6 mmol) was added dropwise to a cold (0° C.) solution of 4-bromo-2-fluoroacetophenone (2.30 g, 10.6 mmol) in dioxane (80 mL) and tetrahydrofuran (80 mL). The mixture was stirred for 1 h at 0° C. and warmed to RT for 15 h. The mixture was diluted with ethyl acetate, washed with saturated NaHCO.sub.3 solution, 5% sodium thiosulfate solution and brine prior to drying (Na.sub.2SO.sub.4). 2-Bromo-1-(4-bromo-2-fluorophenyl)ethanone (D1) was isolated as a colorless film which solidified upon further concentration under high vacuum. This solid was dissolved into anhydrous acetonitrile (50 mL) and treated with N-Boc-L-proline (2.28 g, 10.6 mmol) and diisopropylethylamine (1.85 mL, 10.6 mmol). After being stirred for 3 h at RT, the solvent was removed in vacuo and the residue was partitioned into ethyl acetate and water. The organic phase was washed with 0.1N hydrochloric acid, saturated NaHCO.sub.3 solution and brine prior to drying (Na.sub.2SO.sub.4), filtration, and concentration. This residue was taken up in xylenes (50 mL) and treated to solid NH.sub.4OAc (4.1 g, 53.0 mmol). The mixture was heated at 140° C. for 2 hr in a thick-walled, screw-top flask before it was cooled to ambient temperature, diluted with ethyl acetate and washed with saturated NaHCO.sub.3 solution and brine prior to drying (Na.sub.2SO.sub.4) and concentration. Purification of the residue by Biotage™ flash chromatography on silica gel (65M column, preequilibration with 16% B for 1800 mL followed by gradient elution with 16% B to 16% B for 450 mL, 16% B to 50% B for 2199 ml and finally 50% B to 100% B for 2199 mL) afforded title compound (D5) (3.61 g, 83%) as a brownish/caramel-colored oil. A small portion (40 mg) of the title compound was further purified by preparative HPLC (20% B to 100% B over 14 min where B is 10 mM NH.sub.4OAc in 10:90 H.sub.2O/ACN and A is 10 mM NH.sub.4OAc in 95:5 H.sub.2O/CAN using a Phenomenex-Gemini 30×100 mm S10 column flowing at 40 mL/min) to afford pure title compound (31.8 mg) as a white solid.

(1163) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 12.13-11.95 (m, 1H), 7.94 (br s, 1H), 7.54 (d, J=10.7 Hz, 1H), 7.42 (d, J=7.9 Hz, 1H), 7.36-7.34 (m, 1H), 4.86-4.77 (2m, 1H), 3.54 (m, 1H), 3.38-3.32 (m, 1H), 2.28-2.14 (2m, 1H), 2.05-1.78 (2m, 3H), 1.39 and 1.14 (2s, 9H).

(1164) HPLC Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, RT=2.27 min, 95% homogeneity index.

(1165) LRMS: Anal. Calcd. for C.sub.18H.sub.22BrFN.sub.3O.sub.2 410.09 and 412.09. found: 410.08 and 412.08 (M+H).sup.+.

(1166) HRMS: Anal. Calcd. for C.sub.18H.sub.22BrFN.sub.3O.sub.2 410.0879. found: 410.0893 (M+H).sup.+.

Examples M1-M27

(1167) ##STR01237##

(1168) Example M1-M27 were prepared from 1e and the respective acids using the method described for Example 1. The products were prepared as TFA salts, unless noted otherwise. LC Conditions were as follows:

(1169) Condition 1

(1170) Column=Phenomenex-Luna 3.0×50 mm S10

(1171) Start % B=0

(1172) Final % B=100

(1173) Gradient time=2 min

(1174) Stop time=3 min

(1175) Flow Rate=4 mL/min

(1176) Wavelength=220 nm

(1177) Solvent A=0.1% TFA in 10% methanol/90% H.sub.2O

(1178) Solvent B=0.1% TFA in 90% methanol/10% H.sub.2O

(1179) Condition 2

(1180) Column=Phenomenex-Luna 4.6×50 mm S10

(1181) Start % B=0

(1182) Final % B=100

(1183) Gradient time=2 min

(1184) Stop time=3 min

(1185) Flow Rate=5 mL/min

(1186) Wavelength=220 nm

(1187) Solvent A=0.1% TFA in 10% methanol/90% H.sub.2O

(1188) Solvent B=0.1% TFA in 90% methanol/10% H.sub.2O

(1189) Condition 3

(1190) Column=HPLC XTERRA C18 3.0×50 mm S7

(1191) Start % B=0

(1192) Final % B=100

(1193) Gradient time=3 min

(1194) Stop time=4 min

(1195) Flow Rate=4 mL/min

(1196) Wavelength=220 nm

(1197) Solvent A=0.1% TFA in 10% methanol/90% H.sub.2O

(1198) Solvent B=0.1% TFA in 90% methanol/10% H.sub.2O

(1199) Condition M1

(1200) Column: Luna 4.6×50 mm S10

(1201) Start % B=0

(1202) Final % B=100

(1203) Gradient time=3 min

(1204) Stop time=4 min

(1205) Flow rate=4 mL/min

(1206) Solvent A: =95% H.sub.2O: 5% CH.sub.3CN, 10 mm Ammonium acetate

(1207) Solvent B: =5% H.sub.2O: 95% CH.sub.3CN; 10 mm Ammonium acetate

(1208) TABLE-US-00077 Exam- ple Compound Name RT (LC-Cond.); % homogeneity index; MS data; .sup.1H NMR data M1 7,7′-(4,4′- biphenyldiylbis(1H- imidazole-5,2-diyl(2S)-2,1- pyrrolidinediyl(2-oxo-1- phenyl-2,1- ethanediyl)))bis(7- azabicyclo[2.2.1]heptane)   (Cap-77a) 1.04 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.54H.sub.59N.sub.8O.sub.2: 851.48; found 851.55; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.54H.sub.59N.sub.8O.sub.2: 851.4761; found 851.4780 M2 7,7′-(4,4′- biphenyldiylbis(1H- imidazole-5,2-diyl(2S)-2,1- pyrrolidinediyl(2-oxo-1- phenyl-2,1- ethanediyl)))bis(7- azabicyclo[2.2.1]heptane) 0   (Cap-77b) 1.13 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.54H.sub.59N.sub.8O.sub.2: 851.48; found 851.57; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.54H.sub.59N.sub.8O.sub.2: 851.4761; found 851.4792 M3 N,N′-(4,4′- biphenyldiylbis(1H- imidazole-5,2-diyl(2S)-2,1- pyrrolidinediyl((1R)-(2-oxo- 1-phenyl-2,1- ethanediyl)))bis(N- ethylcyclopropanamine)   (Cap-78) 1.13 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.52H.sub.59N.sub.8O.sub.2: 827.48; found 827.69; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.52H.sub.59N.sub.8O.sub.2: 827.4761; found 827.4782 M4 ethyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-(N- (ethoxycarbonyl)-D-alanyl)- 2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)-1- methyl-2-   (Cap-59a) 1.20 min (Cond. 1); >97%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.38H.sub.47N.sub.8O.sub.6: 711.36; found 711.46; HRMS: Anal. Calcd. for [M + H].sup.+ oxoethyl)carbamate C.sub.38H.sub.47N.sub.8O.sub.6: 711.3619; found 711.3638 M5 ethyl ((1S)-2-((2S)-2-(5-(4′- (2-((2S)-1-(N- (ethoxycarbonyl)-L-alanyl)- 2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)-1- methyl-2-   (Cap-59b) 1.16 min (Cond. 1); 97%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.38H.sub.47N.sub.8O.sub.6: 711.36; found 711.48; HRMS: Anal. Calcd. for [M + H].sup.+ oxoethyl)carbamate C.sub.38H.sub.47N.sub.8O.sub.6: 711.3619; found 711.3621 M6 dimethyl (4,4′- biphenyldiylbis(1H- imidazole-5,2-diyl(2S)-2,1- pyrrolidinediylcarbonyl-1,1- cyclopropanediyl))biscar- bamate   (Cap-60) 1.12 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.38H.sub.43N.sub.8O.sub.6: 707.33; found 707.45; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.38H.sub.43N.sub.8O.sub.6: 707.3306; found 707.3309 M7 methyl (2-((2S)-2-(5-(4′-(2- ((2S)-1-(2- ((methoxycarbonyl)amino)- 2-methylpropanoyl)-2- pyrrolidinyl)-1H-imidazol- 5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-1,1-dimethyl-   (Cap-61) 1.21 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.38H.sub.47N.sub.8O.sub.6: 711.36; found 711.53; HRMS: Anal. Calcd. for [M + H].sup.+ 2-oxoethyl)carbamate C.sub.38H.sub.47N.sub.8O.sub.6: 711.3619; found 711.3652 M8 (2R,2′R)-1,1′-(4,4′- biphenyldiylbis(1H- imidazole-5,2-diyl(2S)-2,1- pyrrolidinediyl))bis(N,N- dimethyl-1-oxo-2- propanamine)   (Cap-83) 0.91 min (Cond. 1); >80%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.36H.sub.47N.sub.8O.sub.6: 623.38; found 623.46; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.36H.sub.47N.sub.8O.sub.2: 623.3822; found 623.3819 M9 (2R,2′R)-1,1′-(4,4′- biphenyldiylbis(1H- imidazole-5,2-diyl(2S)-2,1- pyrrolidinediyl))bis(N,N- diethyl-1-oxo-2- propanamine)   (Cap-69a) 1.00 min (Cond. 1); >95%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.55N.sub.8O.sub.2: 623.38; found 679.67; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.55N.sub.8O.sub.2: 679.4448; found 679.4432 M10 (2R,2′R)-1,1′-(4,4′- biphenyldiylbis(1H- imidazole-5,2-diyl(2S)-2,1- pyrrolidinediyl))bis(N,N- diethyl-3-methyl-1-oxo-2- butanamine)   (Cap-72) 1.03 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.44H.sub.63N.sub.8O.sub.2: 735.51; found 735.76; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.44H.sub.63N.sub.8O.sub.2: 735.5074; found 735.5060 M11 methyl ((1S)-1-(((2S)-2-(5- (4′-(2-((2S)-1-((2S)-2- ((methoxycarbonyl)(methyl) amino)-3-methylbutanoyl)- 2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H-imidazol- 2-yl)-1- pyrrolidinyl)carbonyl)-2-   (Cap-62) 1.46 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.55N.sub.8O.sub.2: 767.42; found 767.38; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.55N.sub.8O.sub.2: methylpropyl)methylcar- 767.4245; found bamate 767.4252 M12 dimethyl (4,4′- biphenyldiylbis(1H- imidazole-5,2-diyl(2S)-2,1- pyrrolidinediyl((1S)-2-oxo- 1-phenyl-2,1- ethanediyl)))biscarbamate 0   (Cap-82) 1.32 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.46H.sub.47N.sub.8O.sub.6: 807.36; found 807.32; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.46H.sub.47N.sub.8O.sub.6: 807.3619; found 807.3651 M13 N,N′-(4,4′- biphenyldiylbis(1H- imidazole-5,2-diyl(2S)-2,1- pyrrolidinediyl((2R)-1-oxo- 1,2-propanediyl)))bis(N- propyl-1-propanamine)   (Cap-70a) 1.09 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.44H.sub.63N.sub.8O.sub.2: 735.51; found 735.46; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.44H.sub.63N.sub.8O.sub.2: 735.5074; found 735.5063 M14 methyl ((1S)-2-hydroxy-1- (((2S)-2-(5-(4′-(2-((2S)-1- ((2S)-3-hydroxy-2- ((methoxycarbonyl)amino)- 3-methylbutanoyl)-2- pyrrolidinyl)-1H-imidazol- 5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate   (Cap-65) 1.13 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.51N.sub.8O.sub.8: 771.38; found 771.21 M15 methyl ((1S,2R)-2-hydroxy- 1-(((2S)-2-(5-(4′-(2-((2S)-1- ((2S,3R)-3-hydroxy-2- ((methoxycarbonyl)amino) butanoyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol- 2-yl)-1- pyrrolidinyl)carbonyl)pro-   (Cap-66) 1.10 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.38H.sub.47N.sub.8O.sub.8: 743.35; found 743.23; .sup.1H NMR (DMSO-d.sub.6, δ = 2.5 ppm, 400 MHz), ~14.5 (br s, pyl) carbamate 4H), 8.15 (s, 2H), 7.97 (d, J = 8.5, 4H), 7.89 (d, J = 8.4, 4H), 7.10/7.05 (two overlapping d, J = 8.0, 8.4, 1.82H), 6.57 (app br s, 0.18H), 5.78 (br d, J = 7.9, 0.18H), 5.16 (m, 1.82H), 4.27 (dd, J = 8.0, 5.3, 1.82H), 4.10 (m, 0.18H), 3.96-3.81 (m, 6H), 3.55 (s, 5.46H), 3.37 (s, 0.54H), 2.41 (m, 2H), 2.17-2.00 (m, 6H), 1.10 (d, J = 6.3, 0.54H), 1.04 (d, J = 6.3, 5.46H). M16 methyl ((1S,2S)-2-hydroxy- 1-(((2S)-2-(5-(4′-(2-((2S)-1- ((2S,3S)-3-hydroxy-2- ((methoxycarbonyl)amino) butanoyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol- 2-yl)-1- pyrrolidinyl)carbonyl)pro-   (Cap-67) 1.11 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.38H.sub.47N.sub.8O.sub.8: 743.35; found 743.23 pyl) carbamate M17 methyl ((1S)-2-((2S)-2-(5- (4′-(2-((2S)-1-(N- (methoxycarbonyl)-L- alanyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)-1- methyl-2-   (Cap-52) 1.64 min (Cond. 2); 99%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.36H.sub.43N.sub.8O.sub.6: 683.33; found 683.30; HRMS: Anal. Calcd. for [M + H].sup.+ oxoethyl)carbamate C.sub.36H.sub.43N.sub.8O.sub.6: 683.3306; found 683.3305. M18 methyl ((1R)-2-((2S)-2-(5- (4′-(2-((2S)-1-(N- (methoxycarbonyl)-D- alanyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)-1- methyl-2-   (Cap-85) 1.70 min (Cond. 2); 97%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.36H.sub.43N.sub.8O.sub.6: 683.33; found 683.32; HRMS: Anal. Calcd. for [M + H].sup.+ oxoethyl)carbamate C.sub.36H.sub.43N.sub.8O.sub.6: 683.3306; found 683.3318. M19 (2S,2′S)-1,1′-(4,4′- biphenyldiylbis(1H- imidazole-5,2-diyl(2S)-2,1- pyrrolidinediyl))bis(N,N- dimethyl-1-oxo-2- propanamine)   (Cap-13) 1.43 min (Cond. 2); >99%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.36H.sub.47N.sub.8O.sub.2: 623.38; found 623.43; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.36H.sub.47N.sub.8O.sub.2: 623.3822; found 623.3837. M20 dimethyl (4,4′- biphenyldiylbis(1H- imidazole-5,2-diyl(2S)-2,1- pyrrolidinediyl((2R)-1-oxo- 1,2- butanediyl)))biscarbamate   (Cap-53a) 1.82 min (Cond. 2); >99%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.38H.sub.47N.sub.8O.sub.6: 711.36; found: 711.35; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.38H.sub.47N.sub.8O.sub.6: 711.3619; found 711.3649. M21 dimethyl (4,4′- biphenyldiylbis(1H- imidazole-5,2-diyl(2S)-2,1- pyrrolidinediyl((2S)-1-oxo- 1,2- butanediyl)))biscarbamate   (Cap-53b) 1.81 min (Cond. 2); >99%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.38H.sub.47N.sub.8O.sub.6: 711.36; found 711.35; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.38H.sub.47N.sub.8O.sub.6: 711.3619; found 711.3643. M22 dimethyl (4,4′- biphenyldiylbis(1H- imidazole-5,2-diyl(2S)-2,1- pyrrolidinediyl((1R)-1- cyclopropyl-2-oxo-2,1- ethanediyl)))biscarbamate 0   (Cap-54a) 1.83 min (Cond. 2); >99%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.47N.sub.8O.sub.6: 735.36; found 735.44; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.47N.sub.8O.sub.6: 735.3619; found: 735.3614. M23 dimethyl (4,4′- biphenyldiylbis(1H- imidazole-5,2-diyl(2S)-2,1- pyrrolidinediyl((1S)-1- cyclopropyl-2-oxo-2,1- ethanediyl)))biscarbamate   (Cap-54b) 1.81 min (Cond. 2); >99%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.47N.sub.8O.sub.6: 735.36; found 735.43; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.47N.sub.8O.sub.6: 735.3619; found 735.3651. M24 methyl ((1S)-1-(((2S)-2-(5- (4′-(2-((2S)-1-((2S)-2- ((methoxycarbonyl)amino)- 3,3-dimethylbutanoyl)-2- pyrrolidinyl)-1H-imidazol- 5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-2,2- 2.11 min (Cond. 2); >99%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.55N.sub.8O.sub.6: 767.42; found 767.58; HRMS: Anal. Calcd. for dimethylpropyl)carbamate C.sub.42H.sub.55N.sub.8O.sub.6: 767.4245; found 767.4230. M25 dimethyl (4,4′- biphenyldiylbis(1H- imidazole-5,2-diyl(2S)-2,1- pyrrolidinediyl((4S)-5-oxo- 1-pentene-5,4- diyl)))biscarbamate   (Cap-55) 1.91 min (Cond. 2); 98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.47N.sub.8O.sub.6: 735.36; found 735.47; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.47N.sub.8O.sub.6: 735.3619; found 735.3630. M26 methyl ((1S)-2-((2S)-2-(5- (4′-(2-((2S)-1-(N- (methoxycarbonyl)-O- methyl-L-seryl)-2- pyrrolidinyl)-1H-imidazol- 5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-1- (methoxymethyl)-2- oxoethyl)carbamate   (Cap-56) 1.72 min (Cond. 2); 97%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.38H.sub.47N.sub.8O.sub.8: 743.35; found 743.49; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.38H.sub.47N.sub.8O.sub.8: 743.3517; found 743.3489. M27 methyl ((1S)-1-(((2S)-2-(5- (4′-(2-((2S)-1-((2S)-2- ((methoxycarbonyl)amino) pentanoyl)-2- pyrrolidinyl)-1H-imidazol- 5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)butyl) carbamate   (Cap-57) 1.98 min (Cond. 2); 98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.51N.sub.8O.sub.6: 739.39; found 739.52; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.51N.sub.8O.sub.6: 739.3932; found 739.3904.

Example M28

methyl ((1S)-1-(((2R)-2-(5-(4′-(2-((2R)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

(1209) ##STR01266##

Example M28

Step a

(1210) ##STR01267##

(1211) Bromide M28a was prepared from D-Proline according to the procedure described for its enantiomer 28b.

Example M28

Step b

(1212) ##STR01268##

(1213) Boronate ester M28b was prepared from bromide M28a according to the procedure described for intermediate 1c. LC: RT=1.57 min (Cond. 1); LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.27H.sub.33BN.sub.3O.sub.4: 474.26. found 474.24.

Example M28

Step c

(1214) ##STR01269##

(1215) Biphenyl M28c was prepared from bromide M28a and boronate M28b according to the procedure described for intermediate 1d. LC: RT=1.43 min (Cond. 1); LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.42H.sub.41N.sub.6O.sub.4: 693.32. found 693.38.

Example M28

Step d

(1216) ##STR01270##

(1217) Pyrrolidine M28d was prepared from carbamate M28c according to the procedure described for intermediate 28d. .sup.1H NMR (DMSO-d.sub.6, δ=2.5 ppm, 400 MHz): δ 11.83 (br s, 2H), 7.80 (d, J=8.3, 4H), 7.66 (d, J=8.3, 4H), 7.46 (br s, 2H), 4.16 (app t, J=7.2, 2H), 3.00-2.94 (m, 2H), 2.88-2.82 (m, 2H), 2.10-2.01 (m, 2H), 1.94-1.85 (m, 2H), 1.82-1.66 (m, 4H). [Note: in the region between 3.2-2.6 ppm there is a broad base-line signal that is believed to be that of the pyrrolidine NH].

(1218) LC: RT=1.02 min (Cond. 1); LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.26H.sub.29N.sub.6: 425.25. found 425.27.

Example M28

(1219) Example M28 was prepared as TFA salt from intermediate M28d and Cap-51 according to the procedure described for Example 1. LC: RT=1.33 min (Cond. 1); 96% homogeneity index; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.40H.sub.51N.sub.8O.sub.6: 739.32. found 739.43. HRMS: Anal. Calcd. for [M+H].sup.+ C.sub.40H.sub.51N.sub.8O.sub.6: 739.3932. found 739.3907.

Example M28-1

(1220) ##STR01271##

(1221) The TFA salt of Example M28-1 was prepared as a mixture of three stereoisomers from intermediate M28d and racemic version of Cap-51 according to the procedure described for Example 1. Three peaks with a retention time of 21.74 min, 22.62 min, and 23.40 min, and exhibiting the correct molecular weight, were observed when the sample was analyzed under the following condition:

(1222) Waters Acquity HPLC with Micromass ZQ MS (electrospray probe) and Waters 2996 PDA detection. (UV detection @ 315 nm)

(1223) Column: Acquity UPLC; BEH C18; 1.7 um; 100×2.1 mm ID; (at approx. 30 C)

(1224) Mobile phase A: water, 25 mM ammonium acetate at pH=5

(1225) Mobile phase B: acetonitrile

(1226) Flow rate: 0.50 ml/min

(1227) 10-50% B 0-35.0 min

(1228) 50-98% B 35.0-45.0 min

(1229) Hold 98% B 45.0-48.0 min

(1230) 98% B-100% B 48.0-48.5 min

(1231) Hold 100% B 48.5-50.0 min

Example M28-2

methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2R)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

(1232) ##STR01272##

Example M28-2

Step a

(1233) ##STR01273##

(1234) Carbamate M28-2a was prepared from boronate ester M28b and bromide 28b according to the procedure described for intermediate 1d. .sup.1H NMR (DMSO-d.sub.6, δ=2.5 ppm, 400 MHz): δ 12.25/12.01/11.93 (three br s, 2H), 7.86-6.98 (m, 20H), 5.13-4.88 (m, 6H), 3.63 (m, 2H), 3.47 (m, 2H), 2.35-1.84 (M, 8H). LC: RT=1.46 min (Cond. 1); LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.42H.sub.41N.sub.6O.sub.4: 693.32. found 693.34.

Example M28-2

Step b

(1235) ##STR01274##

(1236) Pyrrolidine M28-2b was prepared from carbamate M28-2a according to the procedure described for intermediate 28d. .sup.1H NMR (DMSO-d.sub.6, δ=2.5 ppm, 400 MHz): δ 11.84 (br s, 2H), 7.80 (d, J=8.3, 4H), 7.66 (d, J=8.3, 4H), 7.46 (br s, 2H), 4.87 (m, 0.05H), 4.16 (app t, J=7.2, 1.95H), 3.00-2.94 (m, 2H), 2.88-2.82 (m, 2H), 2.10-2.01 (m, 2H), 1.94-1.85 (m, 2H), 1.82-1.66 (m, 4H). [Note: in the region between ˜3.1-2.6 ppm there is a broad base-line signal that is believed to be that of the pyrrolidine NH]. LC: RT=0.96 min (Cond. 1); LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.26H.sub.29N.sub.6: 425.25. found 425.28.

Example M28-2

(1237) Example M28-2 was prepared as TFA salt from intermediate M28-2b and Cap-51 according to the procedure described for Example 1. LC: RT=1.96 minutes (Cond. 2); 98% homogeneity index; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.40H.sub.51N.sub.8O.sub.6 739.39. found 739.47.

Example M28-3

(1238) ##STR01275##

(1239) The TFA salt of Example M28-3 was prepared as a mixture of four stereoisomers from intermediate M28-2b and racemic version of Cap-51 according to the procedure described for Example 1. Three peaks with a retention time of 21.28 min, 22.19 min, and 23.01 min, and exhibiting the correct molecular weight, were observed when the sample was analyzed under the LC/MS condition described for Example M28-1.

Example M29

dimethyl (4,4′-biphenyldiylbis(H-imidazole-5,2-diyl(2R)-2,1-pyrrolidinediyl((R)-1-cyclopropyl-2-oxo-2,1-ethanediyl)))biscarbamate

(1240) ##STR01276##

(1241) Example M29 was prepared as TFA salt from intermediate M28d and Cap-54a according to the procedure described for Example 1. LC: RT=1.21 min (Cond. 1); >98% homogeneity index; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.40H.sub.47N.sub.8O.sub.6: 735.36. found 735.42. HRMS: Anal. Calcd. for [M+H].sup.+ C.sub.40H.sub.47N.sub.8O.sub.6: 735.3619. found 735.3598.

Example M30-M62

(1242) ##STR01277##

(1243) Example M30-M62 were prepared as TFA salts from CJ-24 and the respective caps using the same method described for Example 28.

(1244) TABLE-US-00078 Exam- ple Compound Name RT (LC-Cond.); % homogeneity index; MS data M30 ethyl ((1R)-2-((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2-(diethylamino)- 2-phenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)-1-methyl-2- oxoethyl)carbamate   (Cap-59a) 1.13 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.44H.sub.53N.sub.8O.sub.4: 757.42; found 757.50; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.44H.sub.53N.sub.8O.sub.4: 757.4190; found 757.4181 M31 ethyl ((1S)-2-((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2-(diethylamino)- 2-phenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)-1-methyl-2- oxoethyl)carbamate 0   (Cap-59b) 1.07 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.44H.sub.53N.sub.8O.sub.4: 757.42; found 757.55; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.44H.sub.53N.sub.8O.sub.4: 757.4190; found 757.4225 M32 (5S)-5-(((2S)-2-(5-(4′-(2-((2S)-1- ((2R)-2-(diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)carbonyl)-2- 1.02 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.43H.sub.49N.sub.8O.sub.3: 725.39; found 725.48; pyrrolidinone HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.43H.sub.49N.sub.8O.sub.3: 725.3928; found 725.3926 M33 methyl (1-(((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2-(diethylamino)- 2-phenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)carbonyl)cyclo- propyl)carbamate   (Cap-60) 1.12 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.44H.sub.51N.sub.8O.sub.4: 755.40; found 755.61; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.44H.sub.51N.sub.8O.sub.4: 755.4033; found 755.4066 M34 methyl (2-((2S)-2-(5-(4′-(2-((2S)- 1-((2R)-2-(diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)- 1H-imidazol-2-yl)-1- pyrrolidinyl)-1,1-dimethyl-2- oxoethyl)carbamate   (Cap-61) 1.16 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.44H.sub.53N.sub.8O.sub.4: 757.42; found 757.63; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.44H.sub.53N.sub.8O.sub.4: 757.4190; found 757.4164 M35 (2R)-1-((2S)-2-(5-(4′-(2-((2S)-1- ((2R)-2-(diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)- 1H-imidazol-2-yl)-1- pyrrolidinyl)-N,N-diethyl-1- oxo-2-propanamine   (Cap-69a) 1.06 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.45H.sub.57N.sub.8O.sub.2: 741.46; found 741.64; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.45H.sub.57N.sub.8O.sub.2: 741.4604; found 741.4597 M36 (2S)-1-((2S)-2-(5-(4′-(2-((2S)-1- ((2R)-2-(diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)- 1H-imidazol-2-yl)-1- pyrrolidinyl)-N,N-diethyl-1- oxo-2-propanamine   (Cap-69b) 1.04 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.45H.sub.57N.sub.8O.sub.2: 741.46; found 741.63; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.45H.sub.57N.sub.8O.sub.2: 741.4604; found 741.4581 M37 (1R)-N,N-diethyl-2-((2S)-2-(5- (4′-(2-((2S)-1-(1,3-oxazol-2- ylcarbonyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)- 1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1- phenylethanamine 1.11 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.45N.sub.8O.sub.3: 709.36; found 709.51; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.45N.sub.8O.sub.2: 709.3615; found 709.3615 M38 (1R)-N,N-diethyl-2-oxo-1- phenyl-2-((2S)-2-(5-(4′-(2-((2S)- 1-(3-pyridinylcarbonyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)- 4-biphenylyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)ethanamine 1.09 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.44H.sub.47N.sub.8O.sub.2: 719.38; found 719.51; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.44H.sub.47N.sub.8O.sub.2: 719.3822; found 719.3829 M39 (2R)-1-((2S)-2-(5-(4′-(2-((2S)-1- ((2R)-2-(diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)- 1H-imidazol-2-yl)-1- pyrrolidinyl)-1-oxo-2-propanol 1.09 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.48N.sub.7O.sub.3: 686.38; found 686.58; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.48N.sub.7O.sub.3: 686.3819; found 686.3843 M40 (2S)-1-((2S)-2-(5-(4′-(2-((2S)-1- ((2R)-2-(diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)- 1H-imidazol-2-yl)-1- pyrrolidinyl)-1-oxo-2-propanol 1.09 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.48N.sub.7O.sub.3: 686.38; found 686.57; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.48N.sub.7O.sub.3: 686.3819; found 686.3832 M41 methyl (1-(((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2-(diethylamino)- 2-phenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)- 1H-imidazol-2-yl)-1- pyrrolidinyl)carbonyl)cyclobutyl) carbamate 0   (Cap-64) 1.19 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.45H.sub.53N.sub.8O.sub.4: 769.42; found 769.66; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.45H.sub.53N.sub.8O.sub.4: 769.419; found 769.4155 M42 methyl (1-(((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2-(diethylamino)- 2-phenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)- 1H-imidazol-2-yl)-1- pyrrolidinyl)carbonyl)cyclo- pentyl)carbamate   (Cap-63) 1.25 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.46H.sub.55N.sub.8O.sub.4: 783.43; found 783.69; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.46H.sub.55N.sub.8O.sub.4: 783.4346; found 783.4357 M43 N-((1S)-2-((2S)-2-(5-(4′-(2-((2S)- 1-((2R)-2-(diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)- 1H-imidazol-2-yl)-1- pyrrolidinyl)-1-methyl-2- oxoethyl)-N-propyl-1- propanamine   (Cap-70b) 1.10 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.47H.sub.61N.sub.8O.sub.2: 769.49; found 769.69; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.47H.sub.61N.sub.8O.sub.2: 769.4917; found 769.4925 M44 (4S)-4-(((2S)-2-(5-(4′-(2-((2S)-1- ((2R)-2-(diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)- 1H-imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-1,3- oxazolidin-2-one   (Cap-81) 1.08 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.47N.sub.8O.sub.4: 727.37; found 727.56; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.47N.sub.8O.sub.4: 727.3720; found 727.3740 M45 (2R)-1-((2S)-2-(5-(4′-(2-((2S)-1- ((2R)-2-(diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)- 1H-imidazol-2-yl)-1- pyrrolidinyl)-N,N-diethyl-3- methyl-1-oxo-2-butanamine   (Cap-72) 1.08 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.47H.sub.61N.sub.8O.sub.2: 769.49; found 769.73; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.47H.sub.61N.sub.8O.sub.2: 769.4917; found 769.4898 M46 N-((1R)-2-((2S)-2-(5-(4′-(2-((2S)- 1-((2R)-2-(diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-1- methyl-2-oxoethyl)-N-propyl-1- propanamine   (Cap-70a) 1.12 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.47H.sub.61N.sub.8O.sub.2: 769.49; found 769.45; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.47H.sub.61N.sub.8O.sub.2: 769.4917; found 769.4915 M47 methyl ((1R)-2-((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2-(diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2- oxo-1-phenylethyl)carbamate   (Cap-4) 1.85 min (Cond. 2); 97%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.48H.sub.53N.sub.8O.sub.4: 805.42; found 805.4; HRMS: Anal. Calcd. for [M + H].sup.+: C.sub.48H.sub.53N.sub.8O.sub.4 805.4190; found 805.4196. M48 (1R)-N,N-diethyl-2-((2S)-2-(5- (4′-(2-((2S)-1-((2R)-2-(4- morpholinyl)-2-phenylacetyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)- 4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)-2-oxo-1- phenylethanamine   (Cap-6) 1.69 min (Cond. 2); 98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.50H.sub.57N.sub.8O.sub.3: 817.45; found 817.48; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.50H.sub.57N.sub.8O.sub.3: 817.4554; found 817.4589. M49 methyl ((1S)-2-((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2-(diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-1- methyl-2-oxoethyl)carbamate   (Cap-52) 1.67 min (Cond. 2); 92%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.43H.sub.51N.sub.8O.sub.4: 743.40; found 743.42; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.43H.sub.51N.sub.8O.sub.4: 743.4033; found 743.4053. M50 methyl (2-((2S)-2-(5-(4′-(2-((2S)- 1-((2R)-2-(diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-2- oxoethyl)carbamate 1.63 min (Cond. 2); 99%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.49N.sub.8O.sub.4: 729.39; found 729.39; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.49N.sub.8O.sub.4: 729.3877; found 729.3888. M51 (1R)-N,N-diethyl-2-((2S)-2-(5- (4′-(2-((2S)-1-(4- morpholinylcarbonyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)- 4-biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)-2-oxo-1- phenylethanamine 00 1.67 min (Cond. 2); 99%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.43H.sub.51N.sub.8O.sub.3: 727.41; found 727.40; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.43H.sub.51N.sub.8O.sub.3: 727.4084; found 727.4117. M52 (1R)-2-((2S)-2-(5-(4′-(2-((2S)-1- ((2R)-2-(diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4-biphenylyl)- 1H-imidazol-2-yl)-1- pyrrolidinyl)-N,N-dimethyl-2- oxo-1-phenylethanamine 01   (Cap-1) 1.65 min (Cond. 2); 92%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.48H.sub.55N.sub.8O.sub.2: 775.44; found 775.48; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.48H.sub.55N.sub.8O.sub.2: 775.4448; found 775.4433. M53 methyl ((1R)-2-((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2-(diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1-pyrrolidinyl)-1- methyl-2-oxoethyl)carbamate 02   (Cap-85) 1.68 min (Cond. 2); 98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.43H.sub.51N.sub.8O.sub.4: 743.40; found 743.42; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.43H.sub.51N.sub.8O.sub.4: 743.4033; found 743.4055. M54 methyl ((1R)-1-(((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2-(diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonylpropyl)car- bamate 03   (Cap-53a) 1.78 min; (Cond. 2); >99%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.44H.sub.53N.sub.8O.sub.4: 757.42; found 757.42; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.44H.sub.53N.sub.8O.sub.4: 757.4190; found 757.4216. M55 methyl ((1S)-1-(((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2-(diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)propyl)car- bamate 04   (Cap-53b) 1.74 min (Cond. 2); >99%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.44H.sub.53N.sub.8O.sub.4: 757.42; found 757.41; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.44H.sub.53N.sub.8O.sub.4: 757.4190; found 757.4212. M56 methyl ((1R)-1-cyclopropyl-2- ((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2- (diethylamino)-2-phenylacetyl)- 2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)-2- oxoethyl)carbamate 05   (Cap-54a) 1.74 min (Cond. 2); >99%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.45H.sub.53N.sub.8O.sub.4: 769.42; found 769.52; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.45H.sub.53N.sub.8O.sub.4: 769.4190; found 769.4188. M57 methyl ((1S)-1-cyclopropyl-2- ((2S)-2-(5-(4′-(2-((2S)-1-((2R)-2- (diethylamino)-2-phenylacetyl)- 2-pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)-2- oxoethyl)carbamate 06   (Cap-54b) 1.72 min (Cond. 2); >99%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.45H.sub.53N.sub.8O.sub.4: 769.42; found 769.53; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.45H.sub.53N.sub.8O.sub.4: 769.4190; found 769.4218. M58 methyl ((1S)-1-(((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2-(diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate 07   (Cap-51) 1.76 min (Cond. 2); >99%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.45H.sub.55N.sub.8O.sub.4: 771.43; found 771.54; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.45H.sub.53N.sub.8O.sub.4: 771.4346; found 771.4379. M59 methyl ((1S)-1-(((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2-(diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-2,2- dimethylpropyl)carbamate 08 1.92 min (Cond. 2); 99%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.46H.sub.57N.sub.8O.sub.6: 785.45; found 785.63; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.57N.sub.8O.sub.4: 785.4503; found 785.4515. M60 methyl ((1S)-1-(((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2-(diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-3-buten-1- yl)carbamate 09   (Cap-55) 1.81 min (Cond. 2); 99%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.45H.sub.53N.sub.8O.sub.4: 769.42; found 769.55; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.45H.sub.53N.sub.8O.sub.4: 769.4190; found 769.4157. M61 methyl ((1S)-2-((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2-(diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-1-(methoxymethyl)- 2-oxoethyl)carbamate 0   (Cap-56) 1.73 min (Cond. 2); 99%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.44H.sub.53N.sub.8O.sub.5: 773.41; found 773.55; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.44H.sub.53N.sub.8O.sub.5: 773.4139; found 773.4107. M62 methyl ((1S)-1-(((2S)-2-(5-(4′-(2- ((2S)-1-((2R)-2-(diethylamino)-2- phenylacetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)butyl)car- bamate   (Cap-57) 1.73 min (Cond. 2); 99%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.45H.sub.55N.sub.8O.sub.4: 771.43; found 771.56 (M + H).sup.+; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.45H.sub.55N.sub.8O.sub.4: 771.4346; found 771.4315.

Example M63-M66

(1245) ##STR01312##

(1246) Example M63-M66x were prepared from 28f and the respective acids using the method described for Example 28. Products were prepared as TFA salts unless noted otherwise.

(1247) TABLE-US-00079             Example             Compound Name     RT (LC- Cond.); % homogeneity index; MS data M63 methyl ((1R)-2-((2S)-2-(5-(4′-(2- ((2S)-1-(N,N-diethyl-D-alanyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate 1.17 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.43H.sub.51N.sub.8O.sub.4: 743.40; found 743.41; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.43H.sub.51N.sub.8O.sub.4: 743.4033; found 743.4017 M64 methyl ((1R)-2-((2S)-2-(5-(4′-(2- ((2S)-1-(N,N-dipropyl-D-alanyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate 1.22 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.45H.sub.55N.sub.8O.sub.4: 771.43; found 771.39; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.45H.sub.55N.sub.8O.sub.4: 771.4346; found 771.4361 M65 methyl ((1R)-2-((2S)-2-(5-(4′-(2- ((2S)-1-(1H-imidazol-5-ylcarbonyl)- 2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate 1.15 min (Cond. 1); >90%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.40N.sub.9O.sub.4: 710.32; found 710.31; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.40N.sub.9O.sub.4: 710.3203; found 710.3180 M66a & M66b M66a: methyl ((1R)-2-((2S)-2-(5-(4′- (2-((2S)-1-(4-(diethylamino)-2- ((methoxycarbonyl)amino)butanoyl)- 2-pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate Two fractions enriched with one of two compounds exhibiting very similar spectral data were isolated. M66a: 1.19 min (Cond. 1); 97%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.46H.sub.56N.sub.9O.sub.6: 830.44; found 830.39 M66b: 1.21 min (Cond. 1); >97%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.46H.sub.56N.sub.9O.sub.6: 830.44; found 830.39; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.46H.sub.56N.sub.9O.sub.6: 830.4354; found 830.4316 M66x (AcOH) methyl ((1R)-2-((2S)-2-(5-(4′-(2-((2S)- 1-((2R)-2-(diethylamino)butanoyl)-2- pyrrolidinyl)-1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)-1- pyrrolidinyl)-2-oxo-1- phenylethyl)carbamate 1.80 minutes (Cond. 2); (98%); LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.44H.sub.53N.sub.8O.sub.4 757.42; found 757.48; HRMS: Anal. Calcd for [M + H].sup.+ C.sub.44H.sub.53N.sub.8O.sub.4: 757.4190; found 757.4156

Example M67-M91

(1248) ##STR01319##

(1249) Example M67-M91y were prepared from 28d and the respective acids using the method described for Example 28. Final products were prepared as TFA salts, unless noted otherwise.

(1250) TABLE-US-00080             Example             Compound Name 0         RT (LC-Cond.); % homogeneity index; MS data M67a & M67b M67a: methyl ((1S)-1- (((2S)-2-(5-(4′-(2-((2S)-1-(4- (diethylamino)-2- ((methoxycarbonyl)amino) butanoyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)carbonyl)- 2-methylpropyl)carbamate Two fractions enriched with one of two compounds exhibiting very similar spectral data were isolated M67a: 1.16 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.43H.sub.58H.sub.9O.sub.6: 796.45; found 796.40 M67b: 1.17 min (Cond. 1); >96%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.43H.sub.58N.sub.9O.sub.6: 796.45; found 796.40; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.43H.sub.58N.sub.9O.sub.6: 796.4510; found 796.4537 M68 (.AcOH) methyl ((1S)-1-(((2S)-2-(5- (4′-(2-((2S)-1-((2S)-2- ((methoxycarbonyl)amino)- 3-methylbutanoyl)-2- pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-3-(4- morpholinyl)propyl)carbamate 1.10 min (Cond. 1); >96%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.43H.sub.56N.sub.9O.sub.7: 810.43; found 810.44; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.43H.sub.56N.sub.9O.sub.7: 810.4303; found 810.4333 M69 methyl ((1S)-1-(((2S)-2-(5- (4′-(2-((2S)-1-(N,N-diethyl- L-alanyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)carbonyl)- 2-methylpropyl)carbamate 1.72 min (Cond. 2); 98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.53N.sub.8O.sub.4: 709.42; found 709.56; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.53N.sub.8O.sub.4: 709.4190; found 709.4219. M70 methyl ((1S)-1-(((2S)-2-(5- (4′-(2-((2S)-1-(N,N-diethyl- D-alanyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)carbonyl)- 2-methylpropyl)carbamate 1.75 min (Cond. 2); 99%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.53N.sub.8O.sub.4: 709.42; found 709.55; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.53N.sub.8O.sub.4: 709.4190; found 709.4184. M71 methyl ((1S)-2-((2S)-2-(5- (4′-(2-((2S)-1-(N- (methoxycarbonyl)-L-valyl)- 2-pyrrolidinyl)-1H-imidazol- 5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)-1- (methoxymethyl)-2- oxoethyl)carbamate 1.81 min (Cond. 2); 97%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.39H.sub.49N.sub.8O.sub.7: 741.37; found 741.48; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.39H.sub.49N.sub.8O.sub.7: 741.3724; found 741.3738. M72 methyl ((1S)-1-(((2S)-2-(5- (4′-(2-((2S)-1-((2S)-2- ((methoxycarbonyl)amino)- 3,3-dimethylbutanoyl)-2- pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-2- 2.07 min (Cond. 2); 97%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.53N.sub.8O.sub.6: 753.41; found 753.53; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.53N.sub.8O.sub.6: 753.4088; found 753.4111. methylpropyl)carbamate M73 methyl (2-((2S)-2-(5-(4′-(2- ((2S)-1-((2S)-2- ((methoxycarbonyl)amino)- 3-methylbutanoyl)-2- pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H- 1.80 min (Cond. 2); 97%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.37H.sub.45N.sub.8O.sub.6: 697.35; found 697.32; HRMS: Anal. Calcd. for imidazol-2-yl)-1- [M + H].sup.+ C.sub.37H.sub.45N.sub.8O.sub.6: pyrrolidinyl)-2- 697.3462; found 697.3443. oxoethyl)carbamate M74 methyl ((1S)-1-(((2S)-2-(5- (4′-(2-((2S)-1-((2S)-2- ((methoxycarbonyl)amino) butanoyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)carbonyl)- 2-methylpropyl)carbamate 1.90 min (Cond. 2); 98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.39H.sub.49N.sub.8O.sub.6: 725.37; found 725.36; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.39H.sub.49N.sub.8O.sub.6: 725.3775; found 725.3742. M75 methyl ((1S)-1-(((2S)-2-(5- (4′-(2-((2S)-1-((2S)-2- ((methoxycarbonyl)amino)- 3-methylbutanoyl)-2- pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)butyl) carbamate 1.96 min (Cond. 2); 98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.51N.sub.8O.sub.6: 739.39; found 739.37; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.51N.sub.8O.sub.6: 739.3932; found 739.3953. M76 methyl ((1S)-1-(((2S)-2-(5- (4′-(2-((2S)-1-((2S)-2- ((methoxycarbonyl)amino)- 3-methylbutanoyl)-2- pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-3- buten-1-yl)carbamate 0 1.91 min (Cond. 2); 98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.49N.sub.8O.sub.6: 737.38; found 737.38; HRMS: Anal. Calcd. C.sub.40H.sub.49N.sub.8O.sub.6: 737.3775; found 737.3744. M77 methyl ((1S)-1-(((2S)-2-(5- (4′-(2-((2S)-1-((2S)-2- cyclopropyl-2- ((methoxycarbonyl)amino) acetyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)carbonyl)- 2-methylpropyl)carbamate 1.90 min (Cond. 2); 98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.49N.sub.8O.sub.6 737.38; found 737.34; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.49N.sub.8O.sub.6 737.3775; found 737.3764. M78 methyl ((1S)-1-(((2S)-2-(5- (4′-(2-((2S)-1-((2R)-2- (ethyl(methyl)amino)-2- phenylacetyl)-2- pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate 1.82 min (Cond. 2); 98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.44H.sub.53N.sub.8O.sub.4 757.42; found 757.42; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.44H.sub.53N.sub.8O.sub.4 757.4190; found 757.4188. M79 methyl ((1S)-1-(((2S)-2-(5- (4′-(2-((2S)-1-(N,N-diethyl- D-valyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2- yl)-1-pyrrolidinyl)carbonyl)- 2-methylpropyl)carbamate 1.78 min (Cond. 2); 94%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.57N.sub.8O.sub.4 737.45; found 737.45; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.57N.sub.8O.sub.4 737.4503; found 737.4488. M80 methyl ((1S)-1-(((2S)-2-(5- (4′-(2-((2S)-1-((2R)-2- ((methoxycarbonyl)amino)- 2-phenylacetyl)-2- pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate 2.05 min (Cond. 2); 99%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.43H.sub.49N.sub.8O.sub.6 773.37; found 773.40; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.43H.sub.49N.sub.8O.sub.6 773.375; found: 773.3759. M81 methyl ((1S)-2-methyl-1- (((2S)-2-(5-(4′-(2-((2S)-1-(3- methylbutanoyl)-2- pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- 2.05 min (Cond. 2); 99%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.38H.sub.48N.sub.7O.sub.4 666.38; found 666.37; HRMS: Anal. Calcd. for pyrrolidinyl)carbonyl) [M + H].sup.+ C.sub.38H.sub.48N.sub.7O.sub.4 propyl)carbamate 666.3768; found 666.3785. M82 methyl ((1S)-2-methyl-1- (((2S)-2-(5-(4′-(2-((2S)-1- ((4-methyl-1- piperazinyl)carbonyl)-2- pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- 1.75 min (Cond. 2); 98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.39H.sub.50N.sub.9O.sub.4 708.40; found 708.38; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.39H.sub.50N.sub.9O.sub.4 pyrrolidinyl)carbonyl) 708.3986; found 708.3974. propyl)carbamate M83 methyl ((1S)-1-(((2S)-2-(5- (4′-(2-((2S)-1-(N,N- dipropyl-D-alanyl)-2- pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate 1.81 min (Cond. 2); 98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.57N.sub.8O.sub.4 737.45; found 737.47; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.57N.sub.8O.sub.4 737.4503; found 737.4480. M84 methyl ((1S)-1-(((2S)-2-(5- (4′-(2-((2S)-1-(N,N- dipropyl-L-alanyl)-2- pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate 1.78 min (Cond. 2); 99%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.57N.sub.8O.sub.4 737.45; found 737.47; HRMS: [M + H].sup.+ C.sub.42H.sub.57N.sub.8O.sub.4 737.4503; found 737.4491. M85 methyl ((1S)-1-(((2S)-2-(5- (4′-(2-((2S)-1-((2R)-2- (diethylamino)butanoyl)-2- pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate 1.76 min (Cond. 2); 98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.55N.sub.8O.sub.4 723.43; found 723.47; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.55N.sub.8O.sub.4 723.4346; found 723.4335. M86 methyl ((1S)-1-(((2S)-2-(5- (4′-(2-((2S)-1-((2S)-2- (diethylamino)butanoyl)-2- pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate 0 1.73 min (Cond. 2); 98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.55N.sub.8O.sub.4 723.43; found 723.47; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.55N.sub.8O.sub.4 723.4346; found 723.4343. M87 methyl ((1S)-1-(((2S)-2-(5- (4′-(2-((2S)-1-(1H-imidazol- 4-ylcarbonyl)-2- pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-2- 1.67 min (Cond. 2); 99%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.37H.sub.42N.sub.9O.sub.4 676.34; found 676.45; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.37H.sub.42N.sub.9O.sub.4 methylpropyl)carbamate 676.3360; found 676.3344. M88 methyl ((1S)-1-(((2S)-2-(5- (4′-(2-((2S)-1-(N,N-diethyl- O-methyl-L-seryl)-2- pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate 1.67 min (Cond. 2); 97%; LCMS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.55N.sub.8O.sub.5 739.43; found 739.54; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.55N.sub.8O.sub.5 739.4295; found 739.4327. M89 methyl ((1S)-1-(((2S)-2-(5- (4′-(2-((2S)-1-(N.sup.2,N.sup.2- diethyl-D-asparaginyl)-2- pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate 1.76 min (Cond. 2); 97%; LCMS: Anal. Calcd. for for [M + H].sup.+ C.sub.41H.sub.54N.sub.9O.sub.5 752.42; found 752.43; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.54N.sub.9O.sub.5 752.4248; found 752.4263. M90 methyl ((1S)-1-(((2S)-2-(5- (4′-(2-((2R)-1-((2R)-2- ((methoxycarbonyl)amino)- 3-methylbutanoyl)-2- pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate 2.00 min (Cond. 2); 98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.51N.sub.8O.sub.6 739.39; found 739.46; HRMS: Anal. Calcd for [M + H].sup.+ C.sub.40H.sub.51N.sub.8O.sub.6 739.3932; found 739.3901. M91 methyl ((1S)-1-(((2S)-2-(5- (4′-(2-((2S)-1-(N,N-diethyl- O-methyl-D-seryl)-2- pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate 1.73 min (Cond. 2); 99%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.55N.sub.8O.sub.5 739.43; found 739.39; HRMS: Anal. Calcd for [M + H].sup.+ C.sub.41H.sub.55N.sub.8O.sub.5 739.4295; found 739.4277.  M91x methyl ((1S)-1-(((2S)-2-(5- (4′-(2-((2S)-1-(N,N-diethyl- 3-methyl-D-valyl)-2- pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate 1.78 minutes (Cond. 2); (97%); LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.43H.sub.59N.sub.8O.sub.4 751.47; found 751.50; HRMS: Anal. Calcd for [M + H].sup.+ C.sub.43H.sub.59N.sub.8O.sub.4: 751.4659; found: 751.4648.  M91y methyl ((1S)-3-amino-1- (((2S)-2-(5-(4′-(2-((2S)-1- ((2S)-2- ((methoxycarbonyl)amino)- 3-methylbutanoyl)-2- pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H- imidazol-2-yl)-1- pyrrolidinyl)carbonyl)-3- oxopropyl)carbamate (non- preferred name) 1.92 min (Cond. 2); (>97%); LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.39H.sub.48N.sub.9O.sub.7 754.37; found 754.42; HRMS: Anal. Calcd for [M + H].sup.+ C.sub.39H.sub.48N.sub.9O.sub.7: 754.3677; found: 754.3676.

Example M92-M103

(1251) Example M92-M103 were prepared from 28d and the respective acids using the method described for Example 28. Final products were prepared as TFA salts, unless noted otherwise.

(1252) ##STR01348##

(1253) TABLE-US-00081 Example Compound Name R (Source) Analytical Data M92 methyl ((1S)-1-methyl-2-((2S)- 2-(5-(4′-(2-((2S)-1-(1,3-oxazol- 2-ylcarbonyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)-2- oxoethyl)carbamate 1.70 min (Cond. 2); 95%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.35H.sub.37N.sub.8O.sub.5 649.29; found 649.41; HRMS: Anal. Calcd for [M + H].sup.+ C.sub.35H.sub.37N.sub.8O.sub.5 649.2887; found 649.2867 M93 methyl ((1S)-1-cyclopropyl-2- ((2S)-2-(5-(4′-(2-((2S)-1-(N- (methoxycarbonyl)-L-alanyl)-2- pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)-2- oxoethyl)carbamate 0 1.76 min (Cond. 2); 98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.38H.sub.45N.sub.8O.sub.6 709.35; found 709.50; HRMS: Anal. Calcd for [M + H].sup.+ C.sub.38H.sub.45N.sub.8O.sub.6 709.3462; found 709.3478 M94 methyl ((1S)-1-(((2S)-2-(5-(4′- (2-((2S)-1-((2S)-2- ((methoxycarbonyl)amino) propanoyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)- 1H-imidazol-2-yl)-1- pyrrolidinyl)carbonyl)butyl) carbamate 1.84 min (Cond. 2); 99%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.38H.sub.47N.sub.8O.sub.6 711.36; found 711.54; HRMS: Anal. Calcd for [M + H].sup.+ C.sub.38H.sub.47N.sub.8O.sub.6 711.3619; found 711.3590. M95 methyl ((1S)-1-(((2S)-2-(5-(4′- (2-((2S)-1-(N- (methoxycarbonyl)-L-alanyl)-2- pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)carbonyl)- 2,2-dimethylpropyl)carbamate 1.91 min (Cond. 2); 99%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.39H.sub.49N.sub.8O.sub.6 725.37; found 725.54; HRMS: Anal. Calcd for [M + H].sup.+ C.sub.39H.sub.49N.sub.8O.sub.6 725.3775; found 725.3809. M96 methyl ((1S)-2-((2S)-2-(5-(4′- (2-((2S)-1-(N,N-diethyl-D- alanyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)- 1H-imidazol-2-yl)-1- pyrrolidinyl)-1-methyl-2- oxoethyl)carbamate 1.61 min (Cond. 2); 99%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.38H.sub.49N.sub.8O.sub.4 681.39; found 681.54; HRMS: Anal. Calcd for [M + H].sup.+ C.sub.38H.sub.49N.sub.8O.sub.4 681.3877; found 681.3867. M97 methyl ((1S)-2-((2S)-2-(5-(4′- (2-((2S)-1-(7- azabicyclo[2.2.1]hept-7- yl(phenyl)acetyl)-2- pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)-1-methyl- 2-oxoethyl)carbamate 1.72 min (Cond. 2); 98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.45H.sub.51N.sub.8O.sub.4 767.40; found 767.59; HRMS: Anal. Calcd for [M + H].sup.+ C.sub.45H.sub.51N.sub.8O.sub.4 767.4033; found 767.4067. M98 methyl ((1S)-2-((2S)-2-(5-(4′- (2-((2S)-1-((2R)-2-hydroxy-2- phenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)-1-methyl-2- oxoethyl)carbamate 1.80 min (Cond. 2); 99%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.39H.sub.42N.sub.7O.sub.5 688.32; found 688.48; HRMS: Anal. Calcd for [M + H].sup.+ C.sub.39H.sub.42N.sub.7O.sub.5 688.3247; found 688.3263. M99 methyl ((1S)-2-((2S)-2-(5-(4′- (2-((2S)-1-((2R)-2- (ethyl(methyl)amino)-2- phenylacetyl)-2-pyrrolidinyl)- 1H-imidazol-5-yl)-4- biphenylyl)-1H-imidazol-2-yl)- 1-pyrrolidinyl)-1-methyl-2- oxoethyl)carbamate 1.70 min (Cond. 2); 99%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.49N.sub.8O.sub.4 729.39; found 729.56; HRMS: Anal. Calcd for [M + H].sup.+ C.sub.42H.sub.49N.sub.8O.sub.4 729.3877; found 729.3887. M100  methyl ((1S)-2-((2S)-2-(5-(4′- (2-((2S)-1-(N- (methoxycarbonyl)-L-alanyl)-2- pyrrolidinyl)-1H-imidazol-5- yl)-4-biphenylyl)-1H-imidazol- 2-yl)-1-pyrrolidinyl)-1- (methoxymethyl)-2- oxoethyl)carbamate 1.75 min (Cond. 2); 99%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.37H.sub.45N.sub.8O.sub.7 713.34; found 713.34; HRMS: Anal. Calcd for [M + H].sup.+ C.sub.37H.sub.45N.sub.8O.sub.7 713.3411; found 713.3386. M101  methyl ((1S)-2-((2S)-2-(5-(4′- (2-((2S)-1-(N,N-diethyl-D- valyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)- 1H-imidazol-2-yl)-1- pyrrolidinyl)-1-methyl-2- oxoethyl)carbamate 1.66 min (Cond. 2); 94%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.53N.sub.8O.sub.4 709.42; found: 709.42; HRMS: Anal. Calcd for [M + H].sup.+ C.sub.40H.sub.53N.sub.8O.sub.4 709.4190; found 709.4166. M102  methyl ((1S)-2-((2S)-2-(5-(4′- (2-((2S)-1-(N,N-dipropyl-D- alanyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)- 1H-imidazol-2-yl)-1- pyrrolidinyl)-1-methyl-2- oxoethyl)carbamate 1.71 min (Cond. 2); 98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.53N.sub.8O.sub.4 709.42; found 709.48; HRMS: Anal. Calcd for [M + H].sup.+ C.sub.40H.sub.53N.sub.8O.sub.4 709.4190; found 709.4191. M103  methyl ((1S)-2-((2S)-2-(5-(4′- (2-((2S)-1-(N,N-dipropyl-L- alanyl)-2-pyrrolidinyl)-1H- imidazol-5-yl)-4-biphenylyl)- 1H-imidazol-2-yl)-1- pyrrolidinyl)-1-methyl-2- oxoethyl)carbamate 0 1.66 min (Cond. 2); 98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.53N.sub.8O.sub.4 709.42; found 709.42; HRMS: Anal. Calcd for [M + H].sup.+ C.sub.40H.sub.53N.sub.8O.sub.4 709.4190; found 709.4198.

Example M104

methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-(3-hydroxy-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

(1254) ##STR01361##

Example M104

Step a

(1255) ##STR01362##

(1256) Pyrrolidine M104a was prepared from intermediate 28d and Cap-51 according to the procedure described for the synthesis of pyrrolidine 28f.

Example M104

(1257) HATU (96.3 mg, 0.253 mmol) was added to a DMF (5.0 mL) solution of pyrrolidine M104a (150 mg, 0.217 mmol), (S)-2-(tert-butoxycarbonylamino)-3-hydroxy-3-methylbutanoic acid (65.8 mg, 0.282 mmol) and i-Pr.sub.2EtN (180 uL, 1.03 mmol), and the reaction mixture was stirred at ambient condition for 35 min. The volatile component was removed in vacuo, and the residue was purified with a reverse phase HPLC (MeOH/H.sub.2O/TFA), and the fractions were concentrated in vacuo. The resultant residue was treated with 25% TFA/CH.sub.2Cl.sub.2 (6.0 mL) and stirred for 3.25 hr. The volatile component was removed in vacuo and the residue was free-based (MCX; MeOH wash; 2.0 M NH.sub.3/MeOH elution) to afford Example M104 as an off-white foam (107 mg). LC (Cond. 2): RT=1.03 min; >95% homogeneity index; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.38H.sub.49N.sub.8O.sub.5=697.38. found 697.28.

Example M105

methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-3-hydroxy-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

(1258) ##STR01363##

(1259) Methyl chloroformate (20 μL, 0.258 mmol) was added to a THF (2.0 mL) solution of Example M104 (82.9 mg, 0.119 mmol) and i-Pr.sub.2EtN (50 uL, 0.287 mmol) and stirred for 65 min. The mixture was then treated with 2.0 M NH.sub.3/MeOH (3 mL), stirred for 2.75 hr, and the volatile component was removed in vacuo. The resultant residue was purified with a reverse phase HPLC (MeOH/H.sub.2O/TFA) to afford the TFA salt of Example M105 as a white foam (64.1 mg). LC (Cond. 2): RT=1.17 min; >98% homogeneity index; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.40H.sub.51N.sub.8O.sub.7=755.39. found 755.25.

Example M106

methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S,3R)-4-hydroxy-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

(1260) ##STR01364##

(1261) HATU (69 mg, 0.181 mmol) was added to a DMF (3.0 mL) solution of pyrrolidine M104a (101 mg, 0.173 mmol), Cap-80b (55.9 mg, ˜0.183 mmol) and i-Pr.sub.2EtN (90 μL, 0.515 mmol), and the reaction mixture was stirred at ambient condition for 70 min. The volatile component was removed in vacuo and the residue was purified with a reverse phase HPLC (H.sub.2O/MeOH/TFA) to retrieve the dominant signal. The collected fraction was allowed to stand at ambient condition for a few hours and then the volatile component was removed in vacuo, at which time total desilylation of the coupled product was achieved. The resultant product was submitted to a reverse phase HPLC purification (ACN/H.sub.2O/NH.sub.4OAc) to afford Example M106 as an off-white foam (32.2 mg). LC (Cond. 2): RT=1.19 min; >95% homogeneity index; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.40H.sub.51N.sub.8O.sub.7=755.39. found 755.85.

Example M107

methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S,3S)-4-hydroxy-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

(1262) ##STR01365##

(1263) Example M107 was prepared from pyrrolidine M104a and Cap-80a according to the procedure described for the synthesis of Example M106. LC (Cond. 2): RT=1.20 min; ˜95% homogeneity index; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.40H.sub.51N.sub.8O.sub.7=755.39. found 755.78.

Example M108

methyl ((1S)-2-methyl-1-(((2S)-2-(5-(4′-(2-((2S)-1-L-valyl-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate

(1264) ##STR01366##

(1265) HATU (70.1 mg, 0.184 mmol) was added to a DMF (3.0 mL) solution of pyrrolidine M104a (100.7 mg, 0.173 mmol), (L)-Boc-Valine (49.6 mg, 0.228 mmol) and i-Pr.sub.2EtN (70 uL, 0.40 mmol), and the reaction mixture was stirred at ambient condition for 65 min. The volatile component was removed in vacuo and the residue was purified with a Biotage (60-100% EtOAc/hexanes) to afford 116.6 mg of the coupled product.

(1266) The above product (112 mg) was treated with 25% TFA/CH.sub.2Cl.sub.2 (2 mL) and the reaction mixture was stirred for 6 hr. The volatile component was removed in vacuo and the crude material was purified with a combination of MCX resin (MeOH wash; 2.0 M NH.sub.3/MeOH elution) and reverse phase HPLC (H.sub.2O/MeOH/TFA) to afford the TFA salt of Example M108 as a white foam (98.5 mg). LC (Cond. 2): RT=1.14 min; >98% homogeneity index; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.38H.sub.49N.sub.8O.sub.4=681.39. found 681.36. HRMS Calcd. for [M+H].sup.+ C.sub.38H.sub.49N.sub.8O.sub.4: 681.3877. found 681.3865.

Example M109 (R=Bn) & M110 (R=Me)

M109: benzyl (3S)-3-((methoxycarbonyl)amino)-4-((2S)-2-(5-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-4-oxobutanoate

M110: methyl (3S)-3-((methoxycarbonyl)amino)-4-((2S)-2-(5-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-4-oxobutanoate

(1267) ##STR01367##

(1268) HATU (109 mg, 0.287 mmol) was added to DMF (1.5 ml) solution of pyrrolidine M104a (151 mg, 0.260 mmol), Cap-68 (109 mg, 387 mmol), and i-Pr.sub.2EtN (100 μl, 0.574 mmol), and the reaction mixture was stirred at ambient condition for 3 hr. The volatile component was removed in vacuo and crude material was purified with a combination of MCX resin (MeOH wash; 2.0 M NH.sub.3/MeOH elution) and reverse phase HPLC (H.sub.2O/MeOH/TFA) to afford the TFA salt Example M109 (88.0 mg) and Example M110 (90.2 mg). Example M109: LC (Cond. 2): RT=2.16; 97% homogenity index; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.46H.sub.53N.sub.8O.sub.8: 845.40. found 845.51. HRMS Calcd. for [M+H].sup.+ C.sub.46H.sub.53N.sub.8O.sub.8: 845.3986. found 845.3983. Example M110: LC (Cond. 2): RT=1.92; 97% homogenity index.

(1269) LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.40H.sub.49N.sub.8O.sub.4: 769.47. found 769.46. HRMS Calcd. for [M+H].sup.+ C.sub.40H.sub.49N.sub.8O.sub.4: 769.3673. found 769.3682.

Example M111

(3S)-3-((methoxycarbonyl)amino)-4-((2S)-2-(5-(4′-(2-((2S)-1-(N-(methoxycarbonyl)-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-4-oxobutanoic acid

(1270) ##STR01368##

(1271) A mixture of Example M109 (69.7 mg, 0.082 mmol) and 10% Pd/C (10 mg) in methanol (5 ml) was stirred at room temperature under a balloon of H.sub.2 for 1.5 h. The reaction was filtered through diatomaceous earth (Celite®) and concentrated in vacuo, and the resultant material was purified with a reverse phase HPLC (H.sub.2O/MeOH/TFA) to afford the TFA salt of Example M111 as an off-white foam (54.0 mg). LC (Cond. 2): RT=1.18; 99% homogenity index; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.39H.sub.47N.sub.8O.sub.8: 755.35. found 755.32. HRMS Calcd. for [M+H]+C.sub.39H.sub.47N.sub.8O.sub.8: 755.3517. found 755.3525.

Example M112

methyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-4-(4-methyl-1-piperazinyl)-4-oxobutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

(1272) ##STR01369##

(1273) HATU (30.6 mg, 0.080 mmol) was added to a DMF (1.5 ml) solution of Example M111 (55.3 mg, 0.0733 mmol), N-methyl piperazine (11.0 mg, 0.11 mmol) and i-Pr.sub.2EtN (25 μl, 0.14 mmol), and the reaction mixture was stirred at ambient condition for 1.5 h. All volatile components were removed in vacuo, and the residue was purified with a combination of MCX resin and a reverse phase HPLC (H.sub.2O/MeOH/TFA) to afford the TFA salt of Example M112 as an off-white foam (51.4 mg). LC (Cond. 2): RT=1.75; 91% homogenity index; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.44H.sub.57N.sub.10O.sub.7: 837.44. found 837.59. HRMS Calcd. for [M+H].sup.+ C.sub.44H.sub.57N.sub.10O.sub.7: 837.4412. found 837.4453.

Example M113

methyl ((1S)-3-(dimethylamino)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-3-oxopropyl)carbamate

(1274) ##STR01370##

(1275) Example M118 was prepared from Example M111 and Me.sub.2N.HCl according to the procedure described for Example M112. LC (Cond. 2): RT=1.89; 99% homogenity index. LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.41H.sub.52N.sub.9O.sub.7: 782.40. found 782.47. HRMS Calcd. for [M+H].sup.+ C.sub.41H.sub.52N.sub.9O.sub.7: 782.3990. found 782.4008.

Example M114

4,4′-bis(2-((2S)-1-(N-(methoxycarbonyl)-L-valyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-2-biphenylcarboxylic acid

(1276) ##STR01371##

Example M114

Step a

(1277) ##STR01372##

(1278) DMF (20 mL) was added to mixture of KHCO.sub.3 (1.84 g, 18.4 mmol) and 2-bromo-5-iodobenzoic acid (4.99 g, 15.3 mmol) and the resulting mixture was stirred for 15 min. Benzyl bromide (2.4 mL, 20.2 mmol) was added drop-wise over 5 min and stirring was continued at ambient condition for ˜20 hr. Most of the volatile component was removed in vacuo and the residue was partitioned between CH.sub.2C.sub.12 (50 mL) and water (50 mL), and the organic layer was washed with water (50 mL), dried (MgSO.sub.4), filtered, and concentrated. The resulting crude material was purified with flash chromatography (7% EtOAc/hexanes) to afford ester M114a as a colorless viscous oil (6.01 g). .sup.1H NMR (DMSO-d.sub.6, δ=2.5 ppm, 400 MHz): δ 8.07 (d, J=2.0, 1H), 7.81 (dd, J=8.4, 2.1, 1H), 7.53 (d, J=8.4, 1H), 7.48 (m, 2H), 7.43-7.34 (m, 3H), 5.34 (s, 2H). LC (Cond. 1): RT=2.1 min; LC/MS: Anal. Calcd. for [M+Na].sup.+ C.sub.14H.sub.10BrINaO.sub.2: 438.88. found 438.83.

Example M114

Step b-d

(1279) ##STR01373##

(1280) Ester M114a was elaborated to ester M114d by employing a three step protocol employed in the synthesis of bromide 121c from 1-bromo-4-iodo-2-methylbenzene. M114d: .sup.1H NMR (DMSO-d.sub.6, δ=2.5 ppm, 400 MHz): δ 12.04/11.97 (br s, 1H), 8.12 (d, J=2.0, 0.92H), 7.99 (app br s, 0.08H), 7.81 (dd, J=8.3, 2.0, 0.92H), 7.74-7.62 (m, 2.08H), 7.50 (app br d, J=7.0, 2H), 7.44-7.35 (m, 3H), 5.38 (s, 2H), 4.79 (m, 1H), 3.52 (app br s, 1H), 3.36 (m, 1H), 2.24-1.79 (m, 4H), 1.39/5.11 (two s, 9H). LC (Cond. 1): RT=1.66 min; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.26H.sub.29BrN.sub.3O.sub.4: 526.13. found 526.16.

Example M114

Step e

(1281) ##STR01374##

(1282) Ester M114e was prepared from bromide M114d and boronate 1c according to the preparation of dimer 1d. .sup.1H NMR (DMSO-d.sub.6, δ=2.5 ppm, 400 MHz): δ 12.18/12.00/11.91/11.83 (four br s, 2H), 8.11-7.03 (m, 14H), 5.10 (s, 2H), 4.85-4.78 (m, 2H), 3.55 (app br s, 2H), 3.37 (m, 2H), 2.29-1.80 (m, 8H), 1.41/1.16 (two s, 18H). LC (Cond. 1): RT=1.54 min; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.44H.sub.51N.sub.6O.sub.6: 759.39. found 759.63.

Example M114

Step f

(1283) ##STR01375##

(1284) A mixture of benzyl ester M114e (1.005 g, 1.325 mmol) and 10% Pd/C (236 mg) in MeOH (20 mL) was stirred under a balloon of H.sub.2 for 5 hr. The reaction mixture was then treated with a 1:1 mixture of MeOH and CH.sub.2C.sub.12, filtered through a pad of diatomaceous earth (Celite®-521), and the filtrate was rotervaped to afford acid M114f (840 mg), contaminated with Ph.sub.3PO which was a carryover from the Suzuki coupling step. .sup.1H NMR (DMSO-d.sub.6, δ=2.5 ppm, 400 MHz): δ 12.17/11.98/11.89/11.81 (four app br s, 2H), 8.04-7.31 (m, 9H), 4.85-4.78 (m, 2H), 3.55 (app br s, 2H), ˜3.37 (m, 2H, overlapped with water signal) 2.27-1.84 (m, 8H), 1.41/1.16 (two s, 18H). LC (Cond. 1): RT=1.37 min; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.37H.sub.45N.sub.6O.sub.6: 669.34. found 669.53.

Example M114

Step g

(1285) ##STR01376##

(1286) 4N HCl/dioxane (8.0 mL) and CH.sub.2Cl.sub.2 (2.0 mL) were sequentially added to carbamate M114f (417 mg, 0.623 mmol), the mixture was vigorously stirred 5.5 hr, and then the volatile component was removed in vacuo to afford the HCl (0.4×) salt of pyrrolidine M114g (487 mg), contaminated with Ph.sub.3PO impurity. .sup.1H NMR (DMSO-d.sub.6, δ=2.5 ppm, 400 MHz) after D.sub.2O exchange: δ 8.23 (d, J=1.7, 1H), 8.09-8.04 (m, 3H), 7.92 (d, J=8.3, 2H), 7.53 (d, J=8.1, 1H), 7.48 (d, J=8.3, 2H), 5.00 (app br t, J=8.3, 1H), 4.90 (app br t, J=8.4, 1H), 3.6-3.3 (m, 4H), 2.5-1.99 (m, 8H). LC (Cond. 1): RT=0.92 min; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.27H.sub.29N.sub.6O.sub.2: 469.24. found 469.31.

Example M114

(1287) HATU (79.9 mg, 0.21 mmol) was added to a DMF (3.0 mL) solution of pyrrolidine M114 g.4HCl (80 mg, 0.13 mmol), Cap-51 (92.4 mg, 0.527 mmol) and i-Pr.sub.2EtN (160 μL, 0.919 mmol), and the reaction mixture was stirred at ambient condition for 2 hr. The volatile component was removed in vacuo and the residue was purified with a combination of MCX (MeOH wash; 2.0 M NH.sub.3/MeOH elution) and a reverse phase HPLC (CH.sub.3CN/H.sub.2O/NH.sub.4OAc) to afford the acetic acid salt of Example M114. LC (Cond. 1): RT=1.20 min; >98 homogeneity index. LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.41H.sub.51N.sub.8O.sub.8: 783.38. found 783.34. HRMS Calcd. for [M+H].sup.+ C.sub.41H.sub.51N.sub.8O.sub.8: 783.3830. found 783.3793.

Example M115-M116

(1288) Examples M115-M116 were prepared using the same method as described for Example M114 and by substituting the appropriate acids for Cap-51. The products were isolated as either the acetic acid or TFA salt depending on the nature of the mobile phase of the HPLC purification step.

(1289) ##STR01377##

(1290) TABLE-US-00082             Example             Compound Name         RT (LC-Cond.); % homogeneity index; MS data M115 (AcOH) 4,4′-bis(2-((2S)-1-((2R)- 2-cyclopropyl-2- ((methoxycarbonyl) amino)acetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-2- biphenylcarboxylic acid 1.17 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.47N.sub.8O.sub.8: 779.35; found 779.33; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.47N.sub.8O.sub.8: 779.3517; found 779.3498 M116 (2.TFA) 4,4′-bis(2-((2S)-1-((2S)- 2-cyclopropyl-2- ((methoxycarbonyl) amino)acetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-2- biphenylcarboxylic acid 0 1.13 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.47N.sub.8O.sub.8: 779.35; found 779.33; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.41H.sub.47N.sub.8O.sub.8: 779.3517; found 779.3551 M117 (2.TFA) 4,4′-bis(2-((2S)-1-((2R)- 2-((methoxycarbonyl) amino)-2-phenylacetyl)-2- pyrrolidinyl)-1H- imidazol-5-yl)-2- biphenylcarboxylic acid 1.29 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.47H.sub.47N.sub.8O.sub.8: 851.35; found 851.33; HRMS: Anal. Calcd. for [M + H].sup.+ C.sub.47H.sub.47N.sub.8O.sub.8: 851.3517; found 851.3480

Example M118

methyl ((1S)-1-(((2S)-2-(5-(2′-carbamoyl-4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

(1291) ##STR01382##

Example M118

Step a

(1292) ##STR01383##

(1293) Et.sub.3N (300 μL, 2.15 mmol) was added to a mixture of acid M114f (198.3 mg, 0.297 mmol), HOBt (94.2 mg, 0.697 mmol), EDCI (0.66 mmol), NH.sub.4Cl (101 mg, 1.89 mmol) in DMF (8.0 mL) and stirred for 17 hr at ambient condition. The reaction mixture was filtered through 0.45 μm filter, the volatile component was removed in vacuo and the residue was partitioned between CH.sub.2Cl.sub.2 and water. The organic layer was concentrated and the resulting crude material was purified with a reverse phase HPLC (MeOH/H.sub.2O/TFA).

(1294) The above product was treated with 25% TFA/CH.sub.2Cl.sub.2 (4.0 mL) and the reaction mixture was stirred for 2.5 hr at ambient condition. The volatile component was removed in vacuo and the residue was free-based (MCX; MeOH wash; 2.0 M NH.sub.3/MeOH elution) to afford amide M118a (67.2 mg). .sup.1H NMR (DMSO-d.sub.6, δ=2.5 ppm, 400 MHz): δ 11.83 (br s, 2H), 7.81-7.80 (m, 2H), 7.73 (d, J=8.3, 2H), 7.65 (br s, 1H), 7.52 (br S, 1H), 7.44 (br s, 1H), 7.41 (d, J=8.3, 2H), 7.36 (d, J=8.3, 1H), 7.31 (br s, 1H), 4.16 (app t, J=7.2, 2H), 3.00-2.94 (m, 2H), 2.88-2.82 (m, 2H), 2.10-2.01 (m, 2H), 1.94-1.85 (m, 2H), 1.83-1.66 (m, 4H). LC (Cond. 1): RT=0.89 min; >95 homogeneity index. LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.27H.sub.30N.sub.7O: 468.25. found 468.24.

Example M118

(1295) The TFA salt of Example M118 was prepared from intermediate M118a and Cap-51 according to the procedure described for Example 1. LC (Cond. 1): RT=1.16 min; 97% homogeneity index. LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.41H.sub.52N.sub.9O.sub.7: 782.40. found 782.40. HRMS: Anal. Calcd. for [M+H].sup.+ C.sub.41H.sub.52N.sub.9O.sub.7: 782.3990. found 782.3979.

Example M119

methyl ((1S)-1-(((2S)-2-(5-(2-(hydroxymethyl)-4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

(1296) ##STR01384##

Example M119

Step a

(1297) ##STR01385##

(1298) DIBAL-H (8.0 mL of 1.0 M/CH.sub.2Cl.sub.2, 8.0 mmol) was added drop-wise to an ice-water cooled CH.sub.2Cl.sub.2 (20 mL) solution of benzyl ester M114e (1.216 g, 1.60 mmol), and the reaction mixture was stirred for 1 hr and an additional DIBAL-H (0.5 mL of 1.0 M/CH.sub.2Cl.sub.2, 0.5 mmol) was added and stirring was continued for ˜2.5 hr. The reaction was quenched with excess saturated NH.sub.4Cl solution and the mixture was diluted with water and extracted with CH.sub.2Cl.sub.2 (3×). The combined organic phase was dried (MgSO.sub.4), filtered, and concentrated in vacuo. The resulting crude material was purified with a Biotage (100 g silica gel; 2-6% MeOH/EtOAc) to afford alcohol M119a as an off-white foam (610 mg). .sup.1H NMR (DMSO-d.sub.6, δ=2.5 ppm, 400 MHz): δ 12.23 (br s, 0.19H), 12.17 (br s, 0.19H), 11.89 (br s, 0.81H), 11.82 (br s, 0.81H), 7.97 (s, 0.81H), 7.84 (s, 0.19H), 7.78 (d, J=8.1, 1.62H), 7.69-7.20 (m, 6.38H), 5.21-5.15 (m, 1H), 4.86-4.78 (m, 2H), 4.49-4.45 (m, 2H), ˜3.54 (m, 2H), 3.40-3.34 (m, 2H), 2.30-1.80 (m, 8H), 1.41/1.17 (two s, 18H). LC (Cond. 1): RT=1.36 min. LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.37H.sub.47N.sub.6O.sub.5: 655.36. found 655.34.

Example M119

Step b

(1299) ##STR01386##

(1300) 25% TFA/CH.sub.2Cl.sub.2 (3.0 mL) was added to carbamate M119a (105 mg, 0.160 mmol) and the mixture was stirred at ambient condition for 4.5 hr. The volatile component was removed in vacuo and the residue was free-based (MCX; MeOH wash; 2.0 M NH.sub.3/MeOH elution) to afford pyrrolidine M119b, contaminated with its trifluoroacetylated derivative of unknown regiochemistry. The sample was dissolved in MeOH (1.5 mL) and treated with 1.0 M NaOH/H.sub.2O (300 μL, 0.3 mmol) and the mixture was stirred for 2.75 hr. It was then directly submitted to MCX purification (MeOH wash; 2.0 M NH.sub.3/MeOH elution) to afford M119b as a film of white solid (63.8 mg). .sup.1H NMR (DMSO-d.sub.6, δ=2.5 ppm, 400 MHz): δ 11.82 (br s, 2H), 7.96 (s, 1H), 7.77 (d, J=8.0, 2H), 7.66 (d, J=8.0, 1H), 7.46 (br s, 1H), 7.42 (br s, 1H), 7.36 (d, J=8.0, 2H), 7.21 (d, J=8.0, 1H), 5.16 (app br s, 1H), 4.46 (s, 2H), 4.16 (app t, J=7.1, 2H), 3.00-2.82 (two m, 4H; there is a broad base line signal in this region from the pyrrolidine NH that was not included in the integration), 2.10-2.01 (m, 2H), 1.94-1.85 (m, 2H), 1.83-1.67 (m, 4H). LC (Cond. 1): RT=0.78 min. LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.27H.sub.31N.sub.6O: 455.26. found 455.27.

Example M119

(1301) Example M119 was prepared from M119b and Cap-51 according to the procedure described for Example 1, with the exception that a reverse phase HPLC with ACN/H.sub.2O/NH.sub.4OAC solvent system was employed for the purification step. LC (Cond. 1): RT=1.15 min; 98% homogeneity index. LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.41H.sub.53N.sub.8O.sub.7: 769.40. found 769.40. HRMS: Anal. Calcd. for [M+H].sup.+ C.sub.41H.sub.53N.sub.8O.sub.7: 769.4037. found 769.4023.

Example M120

methyl ((1S)-1-(((2S)-2-(5-(2-((dimethylamino)methyl)-4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

(1302) ##STR01387##

Example M120

Step a

(1303) ##STR01388##

(1304) CH.sub.2Cl.sub.2 (6.0 mL) was added to a mixture alcohol M119a (501 mg, 0.765 mmol), TPAP (29.1, 0.083 mmol) and 4-methylmorpholine N-oxide (135.8 mg, 1.159 mmol), and the resultant heterogeneous mixture was vigorously stirred at ambient condition for 14.5 hr. Additional TPAP (11.0 mg, 0.031 mmol) and 4-methylmorpholine N-oxide (39 mg, 0.33 mmol) were added and stirring was continued for an additional 24 hr. The mixture was filtered through diatomaceous earth (Celite®) the filtrate was rotervaped and the resulting crude material was purified with a Biotage (2% MeOH/EtOAc) to afford aldehyde M120a as a yellow viscous oil (195.6 mg). LC (Cond. 1): RT=1.37 min. LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.37H.sub.45N.sub.6O.sub.5: 653.35. found 653.40.

Example M120

Step b

(1305) ##STR01389##

(1306) NaCNBH.sub.3 (33 mg, 0.50 mmol) was added in one batch to a MeOH (3.0 mL) solution of aldehyde M120a (195.6 mg, 0.30 mmol) and Me.sub.2NH (200 μL of 40% solution in H.sub.2O), and the reaction mixture was stirred for 4 hr. The volatile component was removed in vacuo and the residue was purified with a flash chromatography (sample was loaded as a silica gel mesh; 3-15% MeOH/CH.sub.2Cl.sub.2) to afford amine M120b as an off-white foam (120 mg). LC (Cond. 1): RT=1.32 min.

(1307) LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.39H.sub.52N.sub.7O.sub.4: 682.41. found 682.42.

Example M120

Step c

(1308) ##STR01390##

(1309) Carbamate M120b was converted to M120c by employing the protocol described for the preparation of 1e from 1d. .sup.1H NMR (DMSO-d.sub.6, δ=2.5 ppm, 400 MHz): δ 11.82 (br s, 2H), 7.87 (s, 1H), 7.77 (d, J=8.0, 2H), 7.65 (d, J=7.8, 1H), 7.45/7.43 (overlapping two br s, 2H), 7.37 (d, J=7.8, 2H), 7.21 (d, J=7.8, 1H), 4.87 (m, 0.1H), 4.17 (m, 1.90H), ˜3.3 (signal of Me.sub.2NCH.sub.2 overlapped with that of water), 3.01-2.94 (m, 2H), 2.89-2.83 (m, 2H), 2.10 (s, 6H), 2.10-2.01 (m, 2H), 1.94-1.85 (m, 2H), 1.81-1.67 (m, 4H). LC (Cond. 1): RT=0.79 min. LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.29H.sub.36N.sub.7: 482.30. found 482.35.

Example M120

(1310) The TFA salt of Example M120 was prepared from pyrrolidine M120c and Cap-51 according to the procedure described for Example 1. LC (Cond. 1): RT=1.06 min; 96% homogeneity index. LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.43H.sub.58N.sub.9O.sub.6: 796.45. found 796.48. HRMS: Anal. Calcd. for [M+H].sup.+ C.sub.43H.sub.58N.sub.9O.sub.6: 796.4510. found 796.4515.

Example M121

dimethyl ((2-((dimethylamino)methyl)-4,4′-biphenyldiyl)bis(1H-imidazole-5,2-diyl(2S)-2,1-pyrrolidinediyl((1R)-2-oxo-1-phenyl-2,1-ethanediyl)))biscarbamate

(1311) ##STR01391##

(1312) The TFA salt of Example M121 was prepared from M120c and Cap-4 according to the procedure described for Example 1. LC (Cond. 1): RT=1.15 min; >98% homogeneity index. LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.49H.sub.54N.sub.9O.sub.6: 796.45. found 864.46. HRMS: Anal. Calcd. for [M+H].sup.+ C.sub.49H.sub.54N.sub.9O.sub.6: 864.4197. found 864.4222.

Example M122

methyl ((1S)-1-(((1S,3S,5S)-3-(5-(4′-(2-((1S,3S,5S)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate

(1313) ##STR01392##

Example M122

Step a

(1314) ##STR01393##

(1315) Diisopropyl ethylamine (1.81 mL, 10.4 mmol) was slowly added to acetonitrile (20 mL) solution of (1S,3S,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (2.36 g, 10.4 mmol) and (2-(4′-(2-bromoacetyl)biphenyl-4-yl)-2-oxoethyl)bromonium (2.0 g, 5.05 mmol), and the reaction mixture was stirred at ambient conditions for 16 hr. The solvent was evaporated and the residue was partitioned between ethyl acetate and water (1:1, 40 mL each). The organic layer was washed with Sat. NaHCO.sub.3 (2×10 mL), brine, dried (Na.sub.2SO.sub.4), filtered, and concentrated in vacuo to afford ketoester M122a (3.58 g) as a viscous amber oil, which solidified upon storage in a refrigerator. .sup.1H NMR (DMSO-d.sub.6, δ=2.5 ppm, 400 MHz): δ 8.20 (m, 4H), 7.97 (d, J=8.5, 4H), 5.71-5.48 (m, 4H), 4.69 (m, 2H), 3.44 (m, 2H), 3.3 (m, 2H), 2.76-2.67 (m, 2H), 2.27 (m, 2H), 1.60 (m, 2H), 1.44/1.38 (two s, 18H), 0.78 (m, 2H), 0.70 (m, 2H). LC (Cond. 1): RT=1.70 min; LC/MS: the molecular ion was not picked up.

Example M122

Step b

(1316) ##STR01394##

(1317) Ammonium acetate (2.89 g, 37.5 mmol) was added to a toluene (20 mL) solution of ketoester M122a (2.58 g, 3.75 mmol), and the resulting mixture was heated at 120° C. for 4.5 hr, while azaetroping the water that is formed with a Dean-Stark set-up. The reaction mixture was cooled to room temperature and the volatile component was removed in vacuo. Sat. NaHCO.sub.3 solution (10 mL) was added to the solid and the mixture was stirred for 30 min, and the solid was filtered, dried in vacuo and submitted to a Biotage purification (28-100% EtOAc/hexanes) to afford imidazole M122b as light yellow solid (0.6 g). LC (Cond. 1): RT=1.52 min;

(1318) LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.38H.sub.45N.sub.6O.sub.4: 649.35. found 649.78.

Example M122

Step c

(1319) ##STR01395##

(1320) 4 N HCl in dioxane (5 mL) was added to a ice-water cooled dioxane (16 mL) solution of carbamate M122b (0.8 g, 1.2 mmol), the ice-water bath was removed and the mixture was stirred at ambient condition for 4 hr. Big chunks of solid that formed during the reaction were broken up with a spatula. Removal of the volatile component in vacuo afforded pyrrolidine M122c (0.4 HCl) as yellow solid (0.73 g). .sup.1H NMR (DMSO-d.sub.6, δ=2.5 ppm, 400 MHz): δ 7.90 (d, J=8.3, 4H), 7.84 (br s, 2H), 7.79 (d, J=8.3, 4H), 5.24 (m, 2H), 3.38 (m, 2H), 2.71 (m, 2H), ˜2.50 (2H, overlapped with solvent signal), 1.93 (m, 2H), 1.38 (m, 2H), 0.96 (m, 2H). LC (Cond. 1): RT=1.03 min; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.28H.sub.29N.sub.6: 449.25. found 449.59.

Example M122

(1321) The TFA salt of Example M122 was prepared from M122c and Cap-51 according to the procedure described for Example 1. LC (Cond. 1): RT=1.34 min;

(1322) LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.42H.sub.51N.sub.8O.sub.6: 763.39. found 763.73.

Example M123-M130

(1323) Example M123-M130 were prepared according to the procedure described for Example M122. Example M123-M129 were prepared as TFA salts, where as Example M130 was prepared as a free base.

(1324) ##STR01396##

(1325) TABLE-US-00083             Example             Compound Name         RT (LC-Cond.); % homogeneity index; MS data M123 methyl ((1R)-1-(((1S,3S,5S)-3-(5- (4′-(2-((1S,3S,5S)-2-((2R)-2- ((methoxycarbonyl)amino)-3- methylbutanoyl)-2- azabicyclo[3.1.0]hex-3-yl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-2- azabicyclo[3.1.0]hex-2- yl)carbonyl)-2- methylpropyl)carbamate 1.372 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.51N.sub.8O.sub.6: 763.39; found 763.73 M124 dimethyl (4,4′-biphenyldiylbis(1H- imidazole-5,2-diyl(1S,3S,5S)-2- azabicyclo[3.1.0]hexane-3,2- diyl((1R)-2-oxo-1-phenyl-2,1- ethanediyl)))biscarbamate 2.28 minutes (Cond. M1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.48H.sub.47N.sub.8O.sub.6: 831.36; found 831.36 M125 methyl ((1S)-2-hydroxy-1- (((1S,3S,5S)-3-(5-(4′-(2- ((1S,3S,5S)-2-((2S)-3-hydroxy-2- ((methoxycarbonyl)amino)-3- methylbutanoyl)-2- azabicyclo[3.1.0]hex-3-yl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-2- azabicyclo[3.1.0]hex-2- yl)carbonyl)-2- methylpropyl)carbamate 00 1.76 minutes (Cond. M1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.51N.sub.8O.sub.8: 795.38; found 795.37 M126 dimethyl (4,4′-biphenyldiylbis(1H- imidazole-5,2-diyl(1S,3S,5S)-2- azabicyclo[3.1.0]hexane-3,2- diyl((2S)-1-oxo-1,2- butanediyl)))biscarbamate 01 1.25 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.40H.sub.47N.sub.8O.sub.6: 735.36; found 735.68 M127 dimethyl (4,4′-biphenyldiylbis(1H- imidazole-5,2-diyl(1S,3S,5S)-2- azabicyclo[3.1.0]hexane-3,2- diyl((1S)-1-cyclopropyl-2-oxo-2,1- ethanediyl)))biscarbamate 02 1.27 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.42H.sub.47N.sub.8O.sub.6: 759.36; found 759.72 M128 methyl ((1S)-1-(((1S,3S,5S)-3-(5- (4′-(2-((1S,3S,5S)-2-((2S)-2- ((methoxycarbonyl)amino)-3,3- dimethylbutanoyl)-2- azabicyclo[3.1.0]hex-3-yl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-2- azabicyclo[3.1.0]hex-2- yl)carbonyl)-2,2- dimethylpropyl)carbamate 03 2.48 minutes (Cond. M1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.44H.sub.55N.sub.8O.sub.6: 791.42; found 791.41 M129 methyl (2-((1S,3S,5S)-3-(5-(4′-(2- ((1S,3S,5S)-2- (((methoxycarbonyl)amino)acetyl)- 2-azabicyclo[3.1.0]hex-3-yl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-2- azabicyclo[3.1.0]hex-2-yl)-2- oxoethyl)carbamate 04 1.10 minutes (Cond.1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.36H.sub.39N.sub.8O.sub.6: 679.74; found 679.77 M130 methyl ((1S)-2-((1S,3S,5S)-3-(5- (4′-(2-((1S,3S,5S)-2-(N- (methoxycarbonyl)-L-alanyl)-2- azabicyclo[3.1.0]hex-3-yl)-1H- imidazol-5-yl)-4-biphenylyl)-1H- imidazol-2-yl)-2- azabicyclo[3.1.0]hex-2-yl)-1- methyl-2-oxoethyl)carbamate 05 1.16 minutes (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M + H].sup.+ C.sub.38H.sub.43N.sub.8O.sub.6: 707.33; found 707.69

Example M131

methyl ((1S)-1-(((1R,3R,5R)-3-(5-(4′-(2-((1R,3R,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclol[3.1.0]hex-3-yl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate

(1326) ##STR01406##

(1327) Example M131 was prepared according to the procedure described for its disatereomer Example M122 starting from (1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid, which was in turn synthesized by employing a literature protocol (Hanessian et al., Angew. Chem., Int. Ed. Engl. 1997, 36, 1881-1884). LC (Cond. I): RT=1.273 min; LC/MS: Anal. Calcd. for [M+H].sup.+ C.sub.42H.sub.50N.sub.8O.sub.6: 763.39. found 763.94.

Biological Activity

(1328) An HCV Replion assay was utilized in the present disclosure, and was prepared, conducted and validated as described in commonly owned PCT/US2006/022197 and in O'Boyle et. al. Antimicrob Agents Chemother. 2005 April; 49(4):1346-53.

(1329) HCV 1b-377-neo replicon cells were used to test the currently described compound series as well as cells resistant to compound A due to a Y2065H mutation in NS5A (described in application PCT/US2006/022197). The compounds tested were determined to have more than 10-fold less inhibitory activity on cells resistant to compound A than wild-type cells indicating a related mechanism of action between the two compound series. Thus, the compounds of the present disclosure can be effective to inhibit the function of the HCV NS5A protein and are understood to be as effective in combinations as previously described in application PCT/US2006/022197 and commonly owned WO/04014852. Further, the compounds of the present disclosure can be effective against the HCV 1b genotype. It should also be understood that the compounds of the present disclosure can inhibit multiple genotypes of HCV. Table 2 shows the EC50 values of representative compounds of the present disclosure against the HCV 1b genotype. In one embodiment compounds of the present disclosure are active against the 1a, 1b, 2a, 2b, 3a, 4a, and 5a genotypes. EC50 ranges against HCV 1b are as follows: A=1-10 μM; B=100-999 nM; C=1-99 nM; and D=10-999 pM.

(1330) The compounds of the present disclosure may inhibit HCV by mechanisms in addition to or other than NS5A inhibition. In one embodiment the compounds of the present disclosure inhibit HCV replicon and in another embodiment the compounds of the present disclosure inhibit NS5A.

(1331) TABLE-US-00084 TABLE 2 Example Range 1 D 24-4e C 24-4f B 24-4g A 25-1 D 25-2 D 25-3 D 25-4 D 25-5 D 25-6 C 25-7 C 25-8 D 24-4h D 120-9 D 120 D 120-5 C 120-6 C 120-7 D 120-8 C 103-3 D 103-4 D 103-1 D 103-2 D 103-5 D 103-6 C 103-8 D 103-7 D 151 isomer 1 C 151 isomer 2 B 152j-9 C 152j-10 C 152j-1 C 152j-2 D 153c-5 C 153c-6 C 153c-2 C 153c-1 C 152j-7 C 152j-8 D 153c-3 A 153c-4 A 152j-11 D 152j-12 D 152j-15 D 152j-28 D 152j-13 C 152j-14 C 152j-19 D 152j-16 D 152j-3 D 152j-20 C 152j-17 D 152j-18 D 152j-3 D 152j-5 D 152j-6 D 152l-2 D 152l-1 D 152j-24 D 152j-23 D 153c-7 C 152j-22 D 24-18-2 D 24-18-1 D 24-18-4 D 24-18-5 D 24-18-6 D 24-18-3 D 152j-21 D 152l-3 D 131.1-2 D 131.1-1 D 24-4a D 120-1 D 120-2 D 120-3 D 120-4 D 24-10 D 24-9 D 24-8 D 24-11 C 24-12 C 11 C 24-16 D 24-18 D 24-17 D 24-15 C 24-13 B 24-14 C 24-4b C 24-4c D 24-4d D 148 C 149 D 150 C 24-5 D 24-6 D 24-7 D 24-1 D 24-2 D 24-3 D 28-1 D 28-2 D 28-3 D 28-4 D 28-5 D 84-1 D 84-2 D 84-3 D 84-4 D 84-7 C 84-10 C 84-12 D 84-14 C 84-15 C 84-17 D 84-18 C 84-19 C 84-20 C 84-24 D 84-26 D 84-27 D 84-28 D 84-32 D 84-33 D 84-34 C 84-35 D 84-36 D 84-38 D 84-39 D 84-40 D 84-44 D 84-46 D 84-47 D 84-48 D 84-49 D 84-50 D 84-51 D 84-52 D 84-53 D 84-54 D 84-55 D 84-56 D 84-57 D 84-58 D 84-59 D 84-60 D 84-61 D 84-62 D 84-63 D 84-64 D 84-65 C-D 84-66 C-D 84-67 D 84-68 C 84-69 D 84-70 C 84-71 C 84-72 C 84-73 C 84-74 D 84-75 C 84-76 D 84-77 D 84-78 D 84-79 D 84-80 D 84-81 D 84-82 D 84-83 D 84-84 D 84-85 D 84-86 D 84-87 D 94-1 D 94-2 C 94-3 D 94-6 C-D 94-9 D 94-10 D 94-12 C 94-13 D 94-17 D 94-19 D 94-20 C 94-24 D 94-25 D 94-26 D 94-27 C 94-30 D 94-32 C 94-33 C 94-34 C 94-36 D 94-37 C 94-38 D 94-42 D 94-44 D 94-45 D 94-46 D 94-47 D 94-48 D 94-49 D 94-50 D 94-51 D 94-52 D 94-53 D 94-54 D 94-55 D 94-56 D 107-1 D 107-2 D 107-3 D 107-4 D 107-5 D 107-6 D 107-7 D 107-8 D 107-9 D 107-10 D 107-11 D 107-12 D 107-13 D 107-14 D 107-15 D 107-16 D 107-17 D 107-18 D 107-19 D 107-20 D 107-21 D 107-22 D 107-23 D 107-24 D 107-25 D 107-26 D 107-27 D 107-28 D 107-29 D 107-30 D 107-31 D 107-32 D 107-33 D 107-34 D 107-35 D 107-36 D 107-37 D 107-38 D 107-39 D 107-40 D 107-41 D 107-42 D 107-43 D 107-44 D 2 D 3 D 4 D 5 C 6 C 7 D 8 D 24-23 D 9 C 10 C 11 C 12 C 13 C 14 B 15 C 16 C 17 D 18 D 19 D 20 C 21 D 22 D 23 D 24 C 25 D 26 C 27 C 28 C 29 D 30 C 31 D 32 C 33 D 34 D 35 D 36 D 37 D 38 D 39 D 40 D 41 D 42 D 43 D 44 D 45 D 46 D 47 D 48 D 49 D 50 B 51 D 52 D 53 D 54 D 55 D 56 D 57 D 58 D 59 D 60 D 61 D 62 D 63 D 64 D 65 C 67 D 68 D 69 D 70 C 71 D 72 C 73 D 74 D 75 D 76 D 77 D 78 D 79 D 80 D 81 D 82 D 83 D 84 D 85 D 86 D 87 D 88 D 89 D 90 D 91 D 92 D 93 D 94 D 95 D 96 D 97 D 98 D 99 D 100 D 101 D 102 D 103 D 104 D 105 D 106 D 107 D 108 D 109 C 110 D 111 D 112 D 113 D 114 D 115 D 116 D 117 D 118 D 119 D 120 D 121 D 122 D 123 D 124 D 125 D 126 D 127 D 128 D 129 D 130 D 131 D 132 D 133 C 134 D 135 D 136 D 138 D 139 D 140 D 141 D 142 C 143 D 144 D 145 D 146 D 147 D LS2 C LS3 C LS4 C LS16 C LS6 B LS11 A LS14 D LS20 D LS21 D LS22 D LS23 D LS24 D LS25 D LS26 D LS27 D’mer D 1 LS27 D’mer D 2 LS36 D LS37 D F5 D F6 D F7 D F8 D F14 D F15 D F16 D F17 D F20 B F21 B F22 B F25 D F26 C F27 C F28 C F29 C F30 C F32 B F33 B F34 C F35 B F37 B F38 D F39 D Diastereomers F41 D F43 D F48 D F49 C F51 D F52 D F53 D F54 D F55 D F56 D F57 D F58 D F60 D F61 C F62 C F63 D F64 C F65 B F66 C F67 C F69 B F70 B F71 D cj-48 B cj-49 C cj-50 D cj-51 D cj-52 D cj-53 D cj-54 D cj-55 D cj-56 D cj-57 D ci-58 D cj-59 D cj-60 D cj-61 D ci-62 D ci-63 D cj-64 D cj-65 D cj-66 D cj-67 D cj-68 D cj-69 D cj-70 D cj-71 D cj-72 D ci-73 D cj-74 C ci-75 D cj-76 D ci-77 D cj-78 D ci-79 D cj-80 D cj-81 D cj-82 D ci-83 D cj-84 D cj-85 D cj-86 D ci-87 D cj-88 D cj-89 D cj-90 D cj-91 D cj-92 C cj-93 D cj-94 D ci-95 D cj-96 D cj-97 D cj-98 D cj-99 D cj-100 D cj-101 D cj-102 D cj-103 D cj-104 D cj-105 D ci-106 D cj-107 D ci-108 D ci-109 D cj-110 D cj-111 D cj-112 D cj-113 D cj-114 D cj-115 D cj-116 D cj-117 D cj-118 D cj-119 D cj-120 D cj-121 D cj-122 D cj-45 D ci-41 D cj-47 C ci-43 D cj-44 D cj-40 D ci-46 D cj-42 D cj-36 D cj-37 D cj-38 D ci-39 D cj-32 D ci-33 D cj-34 D cj-35 C cj-136 D cj-137 C cj-138 A cj-139 C cj-140 B cj-141 A cj-142 A cj-143 A cj-144 D cj-145 C cj-146 B cj-147 C cj-148 C ci-149 C cj-150 C cj-151 C ci-152 C cj-153 D cj-154 D cj-155 C cj-156 D cj-126 D cj-127 C cj-128 D cj-129 D cj-130 D cj-131 C cj-132 B cj-133 C ci-134 C cj-135 C cj-125 C cj-15c D ci-20c D cj-20b D cj-20a D ci-17 D cj-16 D cj-20d D cj-20 D cj-15a D cj-15 D cj-15d D cj-11n C cj-11o C cj-11p D cj-11m C cj-11h D cj-11i D cj-11j D cj-11k D cj-11e A cj-11f C cj-11g C cj-11d D cj-11b D cj-11 D cj-11a D cj-11c D JG-3 D JG-4 C JG-5 D JG-6 C JG-7 D JG-8 D JG-9 D JG-10 C JG-12 D JG-13 C JG-14 D JG-15 D JG-16 D JG-17 D OL-1 D OL-2 D OL-3 C OL-4 D OL-5 D OL-6 D OL-7 D OL-8 D O1-9 D OL-10 D OL-11 D OL-12 D OL-13 D OL-19 D OL-20 C OL-21 D D73 D D74 D D75 D D76 D D77 D J16 D J17 D J18 D J19 D J20 D J21 D J22 D J23 D J24 D J25 D J26 D J27 D J28 C J29 D J30 C J31 D J37 D J38 D J39 D J40 D J41 D J42 D J42.a D J45 D J46 D J47 D J48 D J49 D J50 D J51 C D33 D D34 D D35 D D36 D D37 D D38 D D39 D D40 D D41 D D42 D D43 D D44 D D45 D D46 D D47 D D48 D D49 D D50 D D51 D D52 D D53 D D54 D D55 D D56 D D57 D D58 D D59 D D60 D D61 D D62 D D63 D D64 D D65 D D66 D D67 D D68 D D69 D D70 D M1 >A M2 C M3 C M4 B M5 A M6 A M7 >A M8 A M9 B M10 >A M11 C M12 C M13 B M14 B M15 B M16 A M17 B M18 A M19 >A M21 C M22 A M23 C M24 C M25 C M26 B M27 C M28 A M28-2 B M29 >A M30 C M31 C M32 B M33 C M34 C M35 C M36 C M37 C M38 C M39 C M40 C M41 C M42 C M43 C M44 B M45 C M46 C M47 C M48 C M49 C M50 C M51 C M52 C M53 C M54 C M55 C M56 C M57 C M58 C M59 C M60 C M61 C M62 C M63 C M64 C M65 C M66a B M66b B M66x C M67a B M67b B M68 B M69 B M70 C M71 C M72 C M73 B M74 C M75 C M76 C M77 C M78 C M79 C M80 C M81 B M82 C M83 C M84 C M85 C M86 C M87 C M88 C M89 C M90 A M91 C M91x C M91y B M92 A M93 C M94 C M95 C M96 B M97 C M98 C M99 C M100 C M101 B M102 C M103 B M104 B M105 C M106 C M107 C M108 C M109 C M110 C M111 A M112 C M113 C M114 >A M115 >A M116 >A M117 >A M118 >A M119 B M120 B M121 B M122 C M123 A M124 C M125 C M126 C M127 C M128 C M129 A M130 C

(1332) It will be evident to one skilled in the art that the present disclosure is not limited to the foregoing illustrative examples, and that it can be embodied in other specific forms without departing from the essential attributes thereof. It is therefore desired that the examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing examples, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

(1333) The compounds of the present disclosure may inhibit HCV by mechanisms in addition to or other than NS5A inhibition. In one embodiment the compounds of the present disclosure inhibit HCV replicon and in another embodiment the compounds of the present disclosure inhibit NS5A. Compounds of the present disclosure may inhibit multiple genotypes of HCV.