this section describes the synthesis of several compounds and their prodrugs useful hiv aspartyl protease inhibitors . these examples are for the purpose of illustration only and are not to be construed as limiting the scope of the invention in any way . analytical thin layer chromatography ( tlc ) was carried out with 0 . 25 mm silica gel e . merck 60 f 254 plates and eluted with the indicated solvent systems . preparative chromatography was performed by flash chromatography , using silica gel 60 ( em science ) with the indicated solvent systems and positive air pressure to allow proper rate of elution . detection of the compounds was carried out by exposing eluted plates ( analytical or preparative ) to iodine , uv light and / or treating analytical plates with a 2 % solution of p - anisaldehyde in ethanol containing 3 % sulfuric acid and 1 % acetic acid followed by heating . alternatively , analytical plates can be treated with a 0 . 3 % ninhydrin solution in ethanol containing 3 % acetic acid and / or a cam solution made of 20 g ( nh 4 ) 6 mo 7 o 24 and 8 . 3 g ce ( so 4 ) 2 polyhydrate in water ( 750 ml ) containing concentrated sulfuric acid ( 90 ml ). preparative hplc were perform on a gilson apparatus equipped with a c18 column , a 215 liquid handler module and 25 ml / min capacity head pumps . the hplc is operated with a gilson unipoint system software . hplc system : 2 gilson # 305 - 25 ml pumps , gilson # 215 liquid handler for injection and collection and a gilson # 155 uv - vis absorbance detector , all controlled from a gilson unipoint v1 . 91 software column : alltech (# 96053 ) hyperprep pep , c - 18 , 100 åα , 8 μm , 22 × 250 mm the crude material dissolved in acetonitrile to a concentration of around 50 to 80 mg / 2 ml were injected in each run . fractions were collected in amounts of 9 ml pertaining absorbance was detected at the uv detector . unless otherwise indicated , all starting materials were purchased from a commercial source such as aldrich co . or sigma co . melting points ( mp ) were determined on a büchi 530 melting point apparatus in capillary tubes and were uncorrected . mass spectra were recorded on a hewlett packard lc / msd 1100 system using apci or electrospray sources either in negative mode or positive mode . nuclear magnetic resonance ( nmr ) spectra were recorded on a bruker amx - ii - 500 equipped with a reversed or qnp probe . samples were dissolved in deuterochloroform ( cdcl 3 ), deuteroacetone ( acetone - d 6 ), deuteromethanol ( cd 3 od ) or deuterodimethylsulfoxide ( dmso - d 6 ) for data acquisition using tetramethylsilane as internal standard . chemical shifts (*) are expressed in parts per million ( ppm ), the coupling constants ( j ) are expressed in hertz ( hz ) whereas multiplicities are denoted as s for singlet , d for doublet , 2d for two doublets , dd for doublet of doublets , t for triplet , q for quartet , quint . for quintet , m for multiplet , and br s for broad singlet . to the acid to be condensed ( 0 . 8 eq .) and 1 - hydroxybenzotriazole ( 25 mg , 0 . 18 mmol , 1 . 2 eq .) in solution in 1 ml of dichloromethane and few drops of dimethylformamide , the minimum as to solubilize the reagents , was added 1 -[ 3 -( dimethylamino ) propyl ]- 3 - ethylcarbodiimide hydrochloride ( edac ) ( 26 mg , 0 . 14 mmol , 0 . 9 eq ). the mixture was stirred for 15 min before addition of the amine (( 1s )- 4 - amino - n -( 4 - amino - 1 - hydroxymethyl - butyl )- n - isobutyl - benzenesulfonamide ( vii , example 1 , step f )) ( 50 mg , 0 . 15 mmol ) in 1 ml dmf . the resulting mixture was stirred for several hours , generally overnight , before pouring into an extraction funnel containing 15 ml hydrochloric acid 1 . 0 n and 30 ml ethyl acetate and extracted . the organic layers were washed with 20 ml of water , dried over magnesium sulfate , filtered and evaporated . the crude mixture was purified by reverse phase semi - preparative hplc under the conditions described in the materials and methods section . the fractions containing the desired compound were combined and evaporated . the residue was taken up in a minimal amount of acetonitrile , diluted with water and lyophilized . to a suitable vessel was added 100 mg n - substituted amino acids , and a 1 ml aliquot of dmf , 150 mg edac , 75 mg hobt were added . after 30 min at 40 ° c . 1 . 5 eq . of the amino amide / acid , ( 1s )- 4 - amino - n -( 5 - amino - 1 - carboxylamido - pentyl )- n - isobutyl - benzenesulfonamide ( step d ) was added along with 100 mg n - methyl morpholine . the solution was then stirred at 23 ° c . for 4 - 12 h . a 1m k 2 co 3 ( 20 ml aliquot ) is added and left for 1 h . then , etoac is added ( 50 ml ). the aqueous phase is separated and extracted with citric acid ( 10 %) 50 ml . the organic phase was separated and evaporated . the residue was purified by semi - preparative hplc and lyophilized . to the amine dissolved in dichloromethane and n , n - dimethylformamide ( dmf ), the minimum as to dissolve the product , were added 1 . 5 eq . of diisopropylethylamine and the mixture cooled in an ice bath under stirring for 10 - 15 min . the acid / sulphonyl chloride ( 1 . 1 eq .) was added dropwise and the reaction continued at 0 ° c . for 20 - 30 min and at room temperature an additional 2 - 4 hours . the reaction mixture was poured into an extraction funnel containing aqueous 1 . 0n sodium hydroxide and etoac and separated . the organic layer was washed with 1 . 0n hydrochloric acid , with brine , and then dried over magnesium sulfate . the crude product obtained after evaporation was generally purified by semi - preparative hplc as described earlier ( see materials and methods section ). d . alternative procedure for the preparation of amide derivatives from acid chloride in a dried flask and under nitrogen atmosphere , dry acetonitrile ( 1 ml ), triethylamine ( 4 eq .) and n - hydroxybenzotriazole ( 1 . 2 eq .) were added and stirred at room temperature . the corresponding acid chloride ( 1 . 1 eq .) was added slowly and the mixture was stirred for 30 minutes . the amine ( product of example 8 ( 1 eq .) or other appropriate amine ) was then added and the mixture was stirred until completion by tlc ( 100 % etoac ). the mixture was poured into an extracting funnel containing 50 ml of ethyl acetate . the organic layers were washed with water , saturated nahco 3 and brine , dried over sodium sulfate , filtered and evaporated . the crude mixture was purified by flash chromatography with 100 % acoet . e . general procedure for the preparation of amide derivatives from acid n - hydroxybenzotriazole ( 1 . 9 eq . ), 1 -[ 3 -( dimethylamino ) propyl ]- 3 - ethylcarbodiimide hydrochloride ( edac ) ( 2 . 5 eq .) and the corresponding carboxylic acid ( 0 . 8 eq .) were added to 1 ml of n , n - dimethylformamide and stirred at room temperature for 30 - 60 minutes . the amine ( product of example 8 ( 1 eq .) or other appropriate amine ) was then added and the mixture was stirred until completion by tlc ( 100 % etoac ). the mixture was poured into an extracting funnel with 50 ml of ethyl acetate . the organic layers were washed with water , saturated nahco 3 and brine , dried over sodium sulfate , filtered and evaporated . the crude mixture was purified by flash chromatography with 100 % etoac . f . general procedure for the preparation of secondary amine derivatives from aldehydes ( 5s )- 2 - amino - n -{ 5 -[( 4 - amino - benzenesulfonyl )- isobutyl - amino ]- 6 - hydroxy - hexyl }- 3 - naphthalen - 2 - yl - propionamide ( or the product of example 8 for the ornithine derivatives or other amine ) ( 1 . 0 eq .) was added to dichloromethane ( 1 ml ) and stirred at 0 ° c . the corresponding aldehyde ( 1 . 0 eq .) and acetic acid ( 1 . 0 eq .) were added to the mixture . after stirring for 10 minutes , sodium triacetoxyborohydride ( 1 . 5 eq .) was added and the mixture stirred until completion by tlc ( 100 % etoac ). the solvent was evaporated and the crude mixture was purified by reverse phase semi - preparative hplc under the conditions described in the materials and methods section . in a dried flask and under inert atmosphere , the alcohol was dissolved in dry dichloromethane ( 0 . 2m ) and dissuccinimidyl carbonate ( 1 . 0 eq .) was added . the mixture was stirred at room temperature for 2 - 3 hours before addition of the solid amine . the mixture was stirred an additional hour and then poured in an extraction funnel containing 1 . 0n sodium hydroxide and ethyl acetate and extracted . the organic layer was washed with a 1 . 0n hydrochloric acid solution ( if the alcohol moiety do not bear a basic site ) and with brine , dried with magnesium sulphate , filtered and evaporated to dryness . the crude residue was then purified by semi - preparative hplc using the conditions described in the materials and methods section . l - α - amino -,- caprolactam ( 22 . 0 g ) was dissolved in cold dichloromethane ( dcm , 200 ml ). isobutyraldehyde ( 12 . 6 g ) was added slowly and stirred until the heat evolved was dissipated ( water forms at the surface ). the cold solution was added to 46 . 5 g of powdered nabh ( oac ) 3 in dcm ( 0 . 5 l ). acoh ( 70 ml ) was added to the solution . the slightly turbid mixture was stirred at 20 ° c . for 4 h . a 500 ml solution of 2m naoh was added slowly to the turbid mixture and the ph adjust to 11 using a concentrated naoh solution , and then the mixture stirred for a further 20 min . after extraction , the dcm layer was dried with mgso 4 , filtered and evaporated . the oil thus obtained crystallizes slowly on standing ( 27 . 8 g , 85 %) and was used without further purification in the next step . 1 h nmr ( cdcl 3 ): δ 0 . 93 ( d , j = 6 . 5 , 3h ), 0 . 97 ( d , j = 6 . 5 , 3h ), 1 . 39 ( t , j = 9 . 8 , 1h ), 1 . 47 ( m , 1h ), 1 . 78 - 1 . 65 ( m , 2h ), 2 . 00 - 1 . 93 ( m , 2h ), 2 . 32 - 2 . 2 ( m , 2h ), 2 . 38 ( t , j = 9 . 7 , 1h ), 3 . 16 ( m , 3h ), 6 . 62 ( s , 1h ( nh )). mp 52 - 54 ° c . ( hexanes ). a small sample was converted to the s - methyl benzyl urea by adding the solid to a solution of s - methyl benzyl isocyanate in mecn . nmr gives 98 % ee nα - isobutyl - l - α - amino -,- caprolactam ( iv ) ( 4 . 1 g free base ) was dissolved in dcm ( 200 ml ) and treated with 4 . 0 g triethylamine , followed by 4 - acetamidobenzenesulfonyl chloride ( 5 . 2 g ). a 0 . 1 g portion of dimethylaminopyridine was added and the mixture was stirred 5 h . the resulting thick slurry was poured into 500 ml 0 . 5 m hcl and shaken vigorously . the solid in the biphasic solution was filtered out and washed with cold acetone to give 7 . 3 g ( 87 %) of clean product . 1 h nmr ( dmso - d 6 ): δ 0 . 93 ( d , j = 6 . 0 , 3h ), 0 . 96 ( d , j = 6 . 0 , 3h ), 1 . 39 ( t , j = 12 . 0 , 1h ), 1 . 85 - 1 . 65 ( m , 3h ), 2 . 08 - 2 . 18 ( m and s , 6h ), 2 . 90 - 2 . 97 ( m , 1h ), 3 . 00 - 3 . 06 ( m , 2h ), 3 . 35 ( dd , j = 14 . 2 , 8 . 5 , 1h ), 4 . 65 ( d , j = 8 . 7 , 1h ), 6 . 3 ( s , 1h ), 7 . 42 ( d , j = 8 . 8 , 2h ), 7 . 6 ( d , j = 8 . 8 , 2h ). mp 230 - 233 ° c . ( etoh ). step c . preparation of ( 3s )- 3 -{[ 4 -( acetyl - tert - butoxycarbonyl - amino )- benzenesulfonyl ]- isobutyl - amino }- 2 - oxo - azepane - 1 - carboxylic acid tert - butyl ester ( boc activation ) ( vi ) 4 . 2 g of nα - isobutyl - nα -( 4 - acetamidobenzenesulfonyl )- l - α - amino -,- caprolactam ( v ) was suspended in 30 ml mecn and briefly sonicated to break up any large chunks . to this white suspension was added 6 . 7 g ( 3 eq .) of di - tert - butyl pyrocarbonate in 10 ml mecn . the suspension was stirred with a magnetic bar and a 120 mg portion of dmap was added . the solution becomes a clear light yellow after a few minutes . tlc ( etoac ) reveals 1 product rf 0 . 9 ( starting material rf at 0 . 4 ). the solution is poured in distilled water 20 ml and extracted with ether , dried with na 2 so 4 and evaporated yielding 6 . 90 g . a sample was recrystallized from hexanes . 1 h nmr ( dmso - d 6 σ 0 . 68 ( d , j = 6 . 0 , 3h ), 0 . 85 ( d , j = 6 . 0 , 3h ), 1 . 39 ( s , 10h ), 1 . 47 ( s , 9h ), 1 . 85 - 1 . 65 ( m , 3h ), 2 . 15 ( s , 3h ), 2 . 80 ( q , j = 4 , 1h ), 3 . 10 - 3 . 36 ( m , 2h ), 4 . 01 ( d , j = 8 . 0 , 1h ), 4 . 85 ( d , j = 8 . 7 , 1h ), 7 . 32 ( d , j = 8 . 8 , 2h ), 7 . 87 ( d , j = 8 . 8 , 2h ). mp 123 - 124 ° c . step d . preparation of ( 1s )- 4 - amino - n -( 5 - amino - 1 - hydroxymethyl - pentyl )- n - isobutyl - benzenesulfonamide ( vii - deprotected ) ( reductive ring opening and deprotection ) a 3 . 0 g portion of ( 3s )- 3 -{[ 4 -( acetyl - tert - butoxycarbonyl - amino )- benzenesulfonyl ]- isobutyl - amino }- 2 - oxo - azepane - 1 - carboxylic acid tert - butyl ester ( vi , step c ) is dissolved in 40 ml etoh followed by 750 mg nabh 4 . brief heating with a heat gun gives a clear solution . tlc reveals one streaky spot after 20 min ( etoac ). the solution is concentrated to a paste , poured in 40 ml 1n naoh and extracted with ethyl acetate , the organic phase dried with naso 4 and evaporated to give 2 . 8 g of product intermediate ( vii ); ( 1s )-{ 4 -[( 5 - tert - butoxycarbonylamino - 1 - hydroxymethyl - pentyl )- isobutyl - sulfamoyl ]- phenyl }- carbamic acid tert - butyl ester ( vii ). the above product intermediate is dissolved in 5 ml etoh and 5 ml 12 n hcl is added . vigorous gas evolution is observed for a few minutes . after 2 h the solution is evaporated and rendered basic with concentrated koh and extracted with etoac yielding 1 . 75 g of a white powder . 1 h nmr ( dmso - d 6 ): σ 0 . 82 ( m , 6h ), 0 . 97 - 1 . 12 ( m , 2h ), 1 . 15 - 1 . 30 ( m , 3h ), 1 . 57 ( m , 1h ), 1 . 84 ( m , 1h ), 2 . 40 ( t , j = 7 . 8 , 2h ), 2 . 75 ( m , 1h ), 2 . 85 ( m , 1h ), 3 . 21 ( m , 1h ), 3 . 44 ( d , j = 6 . 4 , 2h ), 5 . 92 ( br s , 2h ), 6 . 59 ( d , j = 8 . 0 , 2h ), 7 . 39 ( d , j = 8 . 0 , 2h ). the preparation of the title is based on scheme 4 of this invention . ( 1s , 5s )-( 1 -{ 5 -[( 4 - amino - benzenesulfonyl )- isobutyl - amino ]- 6 - hydroxy - hexylcarbamoyl }- 2 - naphthalen - 2 - yl - ethyl )- carbamic acid tert - butyl ester ( 698 mg , 1 . 089 mmol ) was added to 6 ml of ethanol and 6 ml of hcl . the mixture was stirred at room temperature until completion by tlc . the ethanol was evaporated and the acidic mixture was poured into an extracting funnel containing 75 ml of ethyl acetate and 50 ml of hcl 1m and separated . the aqueous layer was washed with ethyl acetate . the aqueous phase was basified with pellets of naoh and poured into an extracting funnel . the organic layer was washed with naoh 1m and brine , dried over sodium sulfate , filtered , evaporated and dried under vacuum to give 544 mg ( 92 %) of a yellow solid ( rf = 0 , 100 % etoac , indicator : ninhydrin ). ( 2s )- 3 - isobutylamino - azepan - 2 - one ( example 28 , step a ) 1 . 0 g was dissolved in dcm ( 20 . 0 ml ) and treated with 2 ml triethylamine followed by the addition of 3 , 4 - methylenedioxybenzenesulfonyl chloride ( 900 mg ). a 0 . 05 g portion of dmap was added and the mixture was stirred 5 h . the resulting solution was poured into ml 0 . 5 m hcl and shaken vigorously . the organic phase was dried and evaporated to give ( 1 . 30 mg ) of clean product . 1 h nmr ( dmso - d 6 ): * 0 . 93 ( d , j = 6 . 0 , 3h ), 0 . 96 ( d , j = 6 . 0 , 3h ), 1 . 26 - 1 . 47 ( m , 1h ), 1 . 85 - 1 . 65 ( m , 3h ), 2 . 08 - 2 . 28 ( m and s , 6h ), 2 . 97 - 3 . 07 ( m , 1h ), 3 . 11 - 3 . 33 ( m , 3h ), 4 . 65 ( d , j = 9 . 0 , 1h ), 6 . 02 ( s , 2h ), 6 . 88 ( d , j = 6 . 6 , 1h ), 7 . 14 ( s , 1h ), 7 . 30 ( d , j = 6 . 7 1h ). the following prodrugs were prepared from l - lysine derivatives using the procedures summarized herein . 1 . 0 g l - 2 - bromophenylalanine ( peptech corp .) is dissolved in 6 ml 1m k 2 co 3 followed by 0 . 77 g methoxycarbonyloxysuccinimide in 20 ml acetone . the resulting clear biphasic solution is stirred for 4 h , then concentrated to 10 ml . the resulting basic solution is extracted with ether and the aqueous phase rendered acidic with 6 m hcl . the oily precipitate is extracted with etoac ( 2 × 20 ml ) and evaporated to yield 1 . 16 g of a clear oil which crystallizes upon standing . 1 h nmr ( cd 3 od ): δ 2 . 94 - 3 . 02 ( m , 1h ), 3 . 30 - 3 . 36 ( m , 1h ), 3 . 51 ( s , 3h ) 4 . 52 ( t , j = 7 . 6 , 1h ), 7 . 04 ( t , j = 6 . 8 1h ), 7 . 20 - 7 . 26 ( m , 2h ), 7 . 52 ( d , j = 7 . 0 , 2h ). this compound was prepared as for the preparation of the product of example 3 ( step d ) with 100 mg of l - moc - 2 - bromophenylalanine ( step a of this example ). the resulting precipitated residue was further purified by reverse phase preparative hplc . yields 25 mg of the title compound . 1 h nmr ( cd 3 od ): δ 0 . 89 - 0 . 98 ( m , 7h ), 1 . 00 - 1 . 15 ( m , 2h ), 1 . 26 - 1 . 35 ( m , 2h ), 1 . 45 - 1 . 52 ( m , 1h ), 1 . 62 - 1 . 70 ( m , 1h ), 1 . 88 - 1 . 95 ( m , 1h ), 2 . 74 - 2 . 98 ( m , 3h ), 2 . 98 - 3 . 16 ( m , 3h ), 3 . 20 - 3 . 29 ( m , 1h ), 3 . 56 ( s , 3h ), 3 . 67 - 3 . 74 ( m , 1h ), 3 . 81 - 3 . 89 ( m , 1h ), 3 . 99 - 4 . 05 ( m , 1h ), 4 . 39 ( t , j = 7 . 0 , 1h ), 6 . 75 ( d , j = 8 . 0 , 2h ), 7 . 10 - 7 . 17 ( m , 1h ), 7 . 24 ( s , 1h ), 7 . 50 ( d , j = 8 . 0 , 2h ), 7 . 58 - 7 . 61 ( m , 1h ). the title derivative was prepared as for the synthesis of the product of example 3 ( step d ) with 100 mg of 3 -( 2 - bromo - phenyl )- 2 -[( 2 - methyl - pyridine - 3 - carbonyl )- amino ]- propionic acid . yields 70 mg of the title compound . the 3 -( 2 - bromo - phenyl )- 2 -[( 2 - methyl - pyridine - 3 - carbonyl )- amino ]- propionic acid starting material was easily prepared from the coupling of l - 2 - bromophenylalanine ( peptech corp .) and 2 - methyl - nicotinoyl chloride . 1 h nmr ( cd 3 od ): δ 0 . 83 - 0 . 99 ( m , 8h ), 1 . 00 - 1 . 15 ( m , 2h ), 1 . 26 - 1 . 35 ( m , 2h ), 1 . 45 - 1 . 52 ( m , 1h ), 1 . 62 - 1 . 70 ( m , 1h ), 1 . 88 - 1 . 95 ( m , 1h ), 2 . 84 - 2 . 98 ( m , 2h ), 2 . 98 - 3 . 86 ( m , 3h ), 3 . 20 - 3 . 29 ( m , 1h ), 3 . 56 ( s , 3h ), 3 . 67 - 3 . 69 ( m , 1h ), 3 . 81 - 3 . 89 ( m , 1h ), 3 . 99 - 4 . 05 ( m , 1h ), 4 . 99 ( t , j = 7 . 0 , 1h ), 6 . 68 ( d , j = 8 . 0 , 2h ), 7 . 03 - 7 . 32 ( m , 4h ), 7 . 50 ( d , j = 8 . 0 , 1h ), 7 . 57 ( t , j = 7 . 8 , 1h ), 7 . 71 ( t , j = 7 . 8 , 1h ), 8 . 43 ( d , j = 7 . 8 1h ). this compound was done as for the preparation of the product of example 3 ( step d ) with 100 mg of l - 3 -( 2 - bromo - phenyl )- 2 -[( pyridine - 4 - carbonyl )- amino ]- propionic acid . the precipitated residue was further purified by reverse phase preparative hplc . yields 65 mg of the desired material . the l - 3 -( 2 - bromo - phenyl )- 2 -[( pyridine - 4 - carbonyl )- amino ]- propionic acid starting material was easily prepared from the combination of l - 2 - bromophenylalanine ( peptech corp .) and isonicotinoyl chloride mono hydrochloride ( aldrich ). 1 h nmr ( cd 3 od ): δ 0 . 83 - 0 . 99 ( m , 8h ), 1 . 00 - 1 . 15 ( m , 2h ), 1 . 26 - 1 . 35 ( m , 2h ), 1 . 45 - 1 . 52 ( m , 1h ), 1 . 62 - 1 . 70 ( m , 1h ), 1 . 88 - 1 . 95 ( m , 1h ), 2 . 84 - 2 . 98 ( m , 2h ), 2 . 98 - 3 . 86 ( m , 3h ), 3 . 20 - 3 . 29 ( m , 1h ), 3 . 56 ( s , 3h ), 3 . 67 - 3 . 69 ( m , 1h ), 3 . 81 - 3 . 89 ( m , 1h ), 3 . 99 - 4 . 05 ( m , 1h ), 4 . 99 ( t , j = 7 . 0 , 1h ), 6 . 68 ( d , j = 8 . 0 , 2h ), 7 . 03 - 7 . 32 ( m , 4h ), 7 . 50 ( d , j = 8 . 0 , 1h ), 7 . 70 ( d , j = 7 . 8 , 2h ), 8 . 73 ( d , j = 7 . 8 2h ). the title compound was synthesized as for the preparation of the product of example 3 ( step d ) with 100 mg of l - 3 -( 2 - fluoro - phenyl )- 2 - methoxycarbonylamino - propionic acid ( or l - moc - 2 - fluorophenylalanine ). yields 14 . 5 mg 35 % of the desired material . the l - 3 -( 2 - fluoro - phenyl )- 2 - methoxycarbonylamino - propionic acid starting material was easily prepared from the combination of l - 2 - fluorophenylalanine ( peptech corp .) and methoxycarbonyloxysuccinimide as in example 4 ( step a ). 1 h nmr ( cd 3 od ): δ 0 . 90 ( d , j = 3 . 5 , 6h ), 0 . 95 - 1 . 01 ( m , 1h ), 1 . 02 - 1 . 11 ( m , 1h ), 1 . 25 - 1 . 32 ( m , 2h ), 1 . 40 - 1 . 49 ( m , 1h ), 1 . 56 - 1 . 67 ( m , 1h ), 1 . 86 - 1 . 95 ( m , 1h ), 2 . 82 - 2 . 90 ( m , 1h ), 2 . 90 - 2 . 96 ( m , 2h ), 2 . 98 - 3 . 03 ( m , 1h ), 3 . 08 - 3 . 14 ( m , 2h ), 3 . 59 ( s , 3h ), 3 . 74 - 3 . 76 ( m , 1h ), 3 . 88 - 3 . 92 ( m , 1h ), 4 . 02 - 4 . 06 ( m , 1h ), 4 . 33 - 4 . 35 ( m , 1h ), 6 . 74 ( d , j = 8 . 2 , 2h ), 7 . 04 - 7 . 12 ( m , 2h ), 7 . 25 - 7 . 30 ( m , 2h ), 7 . 53 ( d , j = 8 . 2 , 2h ). this derivative was made as for the preparation of the product of example 3 ( step d ) with 100 mg of l - 3 -( 2 - chloro - phenyl )- 2 - methoxycarbonylamino - propionic acid ( or l - moc - 2 - chlorophenylalanine ). yields 71 mg of the desired material . the l - 3 -( 2 - chloro - phenyl )- 2 - methoxycarbonylamino - propionic acid starting material was easily prepared from the combination of l - 2 - chlorophenylalanine ( peptech corp .) and methoxycarbonyloxysuccinimide as in example 4 ( step a ). 1 h nmr ( cd 3 od ): δ 0 . 89 - 0 . 98 ( m , 8h ), 1 . 00 - 1 . 15 ( m , 2h ), 1 . 26 - 1 . 35 ( m , 2h ), 1 . 45 - 1 . 52 ( m , 1h ), 1 . 62 - 1 . 70 ( m , 1h ), 1 . 88 - 1 . 95 ( m , 1h ), 2 . 84 - 2 . 98 ( m , 2h ), 2 . 98 - 3 . 06 ( m , 3h ), 3 . 20 - 3 . 29 ( m , 1h ), 3 . 56 ( s , 3h ), 3 . 67 - 3 . 69 ( m , 1h ), 3 . 81 - 3 . 89 ( m , 1h ), 3 . 99 - 4 . 05 ( m , 1h ), 4 . 39 ( t , j = 7 . 0 , 1h ), 7 . 05 ( d , j = 8 . 0 , 2h ), 7 . 16 - 7 . 25 ( m , 3h ), 7 . 34 ( s , 1h ), 7 . 75 ( d , j = 8 . 0 , 2h ). this derivative was synthesized using the procedure described for the preparation of ( 1s , 5s )-[ 1 -{ 5 -[( 4 - amino - benzenesulfonyl )- isobutyl - amino ]- 6 - phosphonooxy - hexylcarbamoyl }- 2 -( 2 - bromo - phenyl )- ethyl ]- carbamic acid methyl ester ( example 4 , steps a and b ) using l - 4 - bromophenylalanine ( peptech corp .) instead of l - 2 - bromophenylalanine . the desired material was obtained in 28 % yield ( 25 mg ) 1 h nmr ( cd 3 od ): δ 0 . 90 ( d , j = 5 . 9 , 6h ), 1 . 00 - 1 . 17 ( m , 2h ), 1 . 20 - 1 . 30 ( m , 2h ), 1 . 39 - 1 . 50 ( m , 1h ), 1 . 55 - 1 . 69 ( m , 1h ), 1 . 86 - 1 . 99 ( m , 1h ), 2 . 79 - 2 . 90 ( m , 2h ), 2 . 91 - 3 . 11 ( m , 4h ), 3 . 59 ( s , 3h ), 3 . 75 - 3 . 79 ( m , 1h ), 3 . 86 - 3 . 92 ( m , 1h ), 4 . 02 - 4 . 08 ( m , 1h ), 4 . 20 - 4 . 30 ( m , 1h ), 6 . 76 ( d , j = 8 . 2 , 2h ), 7 . 15 ( d , j = 7 . 8 , 2h ), 7 . 42 ( d , j = 7 . 8 , 2h ), 7 . 54 ( d , j = 8 . 2 , 2h ). a 3 . 0 g portion of ( 3s )- 3 -{[ 4 -( acetyl - tert - butoxycarbonyl - amino )- benzenesulfonyl ]- isobutyl - amino }- 2 - oxo - azepane - 1 - carboxylic acid tert - butyl ester ( vi , step c ) is dissolved in 40 ml etoh followed by 1 ml nh 4 oh conc . brief heating with a heat gun gives a clear solution . tlc reveals one streaky spot after 20 min ( etoac ). the solution is concentrated to a paste , poured in 40 ml 1n naoh and extracted with ethyl acetate , the organic phase dried with naso 4 and evaporated to give 2 . 8 g of product intermediate ; ( 1s )-{ 4 -[( 5 - tert - butoxycarbonylamino - 1 - hydroxymethyl - pentyl )- isobutyl - sulfamoyl ]- phenyl }- carbamic acid tert - butyl ester ( vii ). the above product intermediate is dissolved in 5 ml etoh and 5 ml 12 n hcl is added . vigorous gas evolution is observed for a few minutes . after 2 h the solution is evaporated and rendered basic with concentrated koh and extracted with etoac yielding 1 . 75 g of a white powder . 100 mg portion of the above was added to a solution of 100 mg moc - dip in 2 ml dmf containing 2 eq of edac and 1 eq hobt . the solution was reacted for 30 min and poured into 1 m k2co3 . the turbid solution was extracted with etoac and the organic phase dried with na2so4 the evaporated to dryness . the residue was then purified by rp - hplc . the compound was prepared from general procedure a using ( 2s )- 2 - tert - butoxycarbonylamino - 2 - naphthyl - propionic acid and ( 1s )- 4 - amino - n -( 5 - amino - 1 - hydroxymethyl - pentyl )- n - isobutyl - benzenesulfonamide ( above ) but the product was purified by flash chromatography yielding 49 % of the boc derivative . this product was treated with trifluoroacetic acid to give the amine in 96 % yield using the same conditions as described for the preparation of ( 2s , 4s )- 2 - amino - n -{ 4 -[( 4 - amino - benzenesulfonyl )- isobutyl - amino ]- 5 - hydroxy - pentyl }- 2 - naphthyl - propionamide . the product was used without further purification . the product was reacted with benzene sulfonyl chloride using general procedure c . prepared as in example 11 using 2 - thiophene - sulphonyl chloride through general procedure c . the compound was prepared from general procedure a using ( 2s )- 2 - tert - butoxycarbonylamino - 2 - bromophenyl - propionic acid and ( 1s )- 4 - amino - n -( 5 - amino - 1 - hydroxymethyl - pentyl )- n - isobutyl - benzenesulfonamide ( above ) but the product was purified by flash chromatography . this product was treated with trifluoroacetic acid to give the amine in 96 % yield using the same conditions as described for the preparation of ( 2s , 4s )- 2 - amino - n -{ 4 -[( 4 - amino - benzenesulfonyl )- isobutyl - amino ]- 5 - hydroxy - pentyl }- 2bromophenyl - propionamide . the product was used without further purification . the product was reacted with 3 - hydroxy - 2 - methyl benzoic acid using general procedure e . as in example 18 using 6 - hydroxy - 2 - picolinic acid through general procedure e the compound was prepared from general procedure a using ( 2s )- 2 - tert - butoxycarbonylamino -( 2 - methyl - phenyl )- propionic acid and ( 1s )- 4 - amino - n -( 5 - amino - 1 - hydroxymethyl - pentyl )- n - isobutyl - benzenesulfonamide ( above ) but the product was purified by flash chromatography . this product was treated with trifluoroacetic acid to give the amine in 96 % yield using the same conditions as described for the preparation of ( 2s , 4s )- 2 - amino - n -{ 4 -[( 4 - amino - benzenesulfonyl )- isobutyl - amino ]- 5 - hydroxy - pentyl }-( 2 - methyl - phenyl ) propionamide . the product was used without further purification . the product was reacted with nicotinic acid using general procedure e . as in example 20 using 6 - methyl - nicotinic acid through general procedure e as in example 20 using 4 - picolinic acid through general procedure e as in example 20 using 2 - hydroxy - 3 - methyl benzoic acid through general procedure e the compound was prepared from general procedure a using ( 2s )- 2 - tert - butoxycarbonylamino -( cyclohexyl )- propionic acid and ( 1s )- 4 - amino - n -( 5 - amino - 1 - hydroxymethyl - pentyl )- n - isobutyl - benzenesulfonamide ( above ) but the product was purified by flash chromatography . this product was treated with trifluoroacetic acid to give the amine in 96 % yield using the same conditions as described for the preparation of ( 2s , 4s )- 2 - amino - n -{ 4 -[( 4 - amino - benzenesulfonyl )- isobutyl - amino ]- 5 - hydroxy - pentyl }-( cyclohexyl ) propionamide . the product was used without further purification . the product was reacted with methyl chloroformate using general procedure c . as in example 24 using nicotinic acid through general procedure e as in example 24 using 6 - methylnicotinic acid through general procedure e this compound was prepared from nα - isobutyl - nα -( 3 , 4 - methylenedioxybenzenesulfonyl )- l - α - amino -,- caprolactam ( step a ) in a three step reaction sequence ( boc activation , reductive ring opening and deprotection ) as described for the preparation of ( 1s )- 4 - amino - n -( 5 - amino - 1 - hydroxymethyl - pentyl )- n - isobutyl - benzenesulfonamide ( example 28 , steps c and d ). the final product was obtained in 75 % yield and was used as such in the next step . the compound was prepared from general procedure a using ( 2s )- 2 - tert - butoxycarbonylamino - 2 - chlorophenyl - propionic acid and ( 1s )- 4 - amino - n -( 5 - amino - 1 - hydroxymethyl - pentyl )- n - isobutyl - benzenesulfonamide ( above ) but the product was purified by flash chromatography . this product was treated with trifluoroacetic acid to give the amine in 96 % yield using the same conditions as described for the preparation of ( 2s , 4s )- 2 - amino - n -{ 4 -[( 4 - amino - benzenesulfonyl )- isobutyl - amino ]- 5 - hydroxy - pentyl }- 2 - chlorophenyl - propionamide . the product was used without further purification . the product was reacted with 4 - picolinic acid using general procedure e . as in example 29 using 2 - methylnicotinic acid through general procedure e preparation of ( 3s )- 3 -( 4 - pyridylmethyl ) lamino - azepan - 2 - one intermediate was effected as in the synthesis ( 3s )- 3 - isobutylamino - azepan - 2 - one using pyridine - 4 carbaldehyde . as in example 18 using 3 - methyl - 2 picolinic acid through general procedure e as in example 18 using 3 - hydroxy - 4 - methyl benzoic acid through general procedure e as in example 18 using 4 - pyridine carbinol acid through general procedure g as in example 18 using 2 - methyl nicotinic acid through general procedure e as in example 18 using 6 - methyl nicotinic acid through general procedure e as in example 18 using 3 , 4 methylene dioxybenzoic acid through general procedure e as in example 18 using 4 - picolinic acid through general procedure e as in example 18 using 5 - methyl - pyrazine carboxylic acid through general procedure e as in example 18 using 2 - pyrazine carboxylic acid through general procedure e as in example 18 using 2 - pyridine carboxylic acid through general procedure e as in example 18 using nicotinic acid through general procedure e enzymatic assay for determining the inhibition constant ( ki ) of synthetic compounds targeting the hiv protease this is a fluorometric assay based on the cleavage by protease of a substrate carrying a donor group ( edans ) and an acceptor group ( dabcyl ) on each side of the cleavage site , interacting together through fluorescence resonance energy transfer ( fret ) as described by matayoshi et al . ( science 247 : 954 - 954 , 1990 ). after calculation of vo and vi , the inhibition constant ( ki ) of the compound is determined using the equation of henderson : graphs are traced and the ki determined using graphpad prism software v . 3 . 0 . to evaluate the ec 50 of our compounds , various drug concentrations are incubated with the infected cell for six days and then the metabolic activity of the cells is monitored by the mtt assay . ( see a . j . japour et al ., antimicrobial agents and chemotherapy , 37 , 1095 - 1101 , 1993 and r . pauwels et al . journal of virological methods , 20 , 309 - 321 , 1988 ) we use the laboratory viral strain nl4 . 3 as wild type virus and the cell line used is mt - 4 which is a t - cell line highly sensitive to hiv - 1 . we also use some wt clinical strains . to address the resistance issue we assay the inhibitors with nl4 . 3 mutants which are designed to be resistant to specific commercially available inhibitors . the same mtt assay is used to evaluate the ccic 50 ( cell culture of ic 50 ) of our compounds except that the virus is omitted . the compounds listed in table 1 were prepared as indicated above . the numbers of the compounds listed in table 1 ( ex . no .) corresponds to the example numbers presented above . the activities of the compounds are listed in table 2 , demonstrating their potential usefulness . the ccic 50 are not shown in the table but it was found that the average ccic 50 for hiv protease inhibitors of the invention was 30 +/− 20 m with a range of 6 to 100 μm . ki , ic 50 and ec 50 results for compounds of formula i are presented in table 2 , illustrating their potential usefulness .