DIFLUOROSTATONE ANTIVIRAL AGENTS

Abstract: The present invention provides novel difluorostatone derivatives of general formula (I), which are useful as antiviral agents. More specifically, these novel compounds are useful as inhibitors of retroviral proteases required for replication, particularly the HIV-1 and HIV-2 viral proteases, in the prevention or treatment of infection by the human immunodeficiency virus (HIV), and in the treatment of consequent pathological conditions such as the acquired immunodeficiency syndrome (AIDS) in mammals capable of being infected with HIV virus.

Description: DIFLUOROSTATONE ANTIVIRAL AGENTS BACKGROUND OF THE INVENTION Retroviruses are a class of viruses which transport their genetic material as ribonucleic acid rather than as deoxyribonucleic acid. Retroviruses are associated with a wide variety of diseases in man, one of which is AIDS. Although there have been disclosures of other anti-viral agents useful in the treatment of AIDS, for example see patent applications EP 0 218 688, EP 0 352 000 and PCT/ϋS 91/09741, the compounds of the present invention have not been previously disclosed. PCT/US 91/09741 is hereby incorporated by reference. SUMMARY OF THE INVENTION The present invention relates to compounds having the following general formula (I); P2 Pi Rl—CNH-CH—CNH-CH—C—CF 2 —C NR 5 Rβ II II O O formula I and the stereoisomers, hydrates, isosteres and the pharmaceutically acceptable salts thereof wherein Pi i s wherein T is [(0)_.-W-R] and T' is [ (O) b '-W'-R * ] or hydrogen, wherein each of W and W are independently Cι_ 6 alkylene or nothing, provided that W is C 2 - 6 alkylene when W is directl attached to a nitrogen atom in R, provided that W* is C 2 - 6 alkylene when W is directly attached to a nitrogen atom in R', provided that W or W are each independently C__ 6 alkylene when R or R' are each independently an aryl; P 2 is C x _ 6 alkyl, cyclopentyl, hydroxy C j ^ g alkyl, phenyl, benzyl or 3-tetrahydrofuryl; R and R' are each independently -CH 2 CHO, hydroxy Cι_ 6 alkyl, C1-6 alkoxy C 1 - 6 alkyl, C__ 6 alkyl, C 1 - 6 alkenylene, piperazinyl, substituted piperazinyl, piperidyl, morpholinyl, pyridyl, pyrazinyl, pyrimidiny or phenyl wherein substituted piperazinyl is piperazinyl substituted on one nitrogen atom thereof with CHO, C(0)NHR' 4 , C_- 4 alkyl or C0 2 R 4 ; R l is R3 is Ci-6 allenyl Ci- 6 alkoxy, Ci- 6 alkylene, hydroxy C__6 alkyl, Ci- 6 alkyl or OH; R4 is Cι_ 6 alkyl, phenyl or benzyl; R' 4 is hydrogen or C__ 6 alkyl; R 5 is hydrogen, C 1 - 15 alkyl, OH, hydroxy C 1 - 15 alkyl -CH([(CH2)d-0-CH2]χ-R'8)2r ~CH 2 Si(CH3)2(R3) . ?DL, (Ci- 6 alkylene)-OR4, -CH(Y)(Z), C1-6 wherein PDL is -(CH 2 ) a - -r 3- or 4-pyridyl, or p- substituted benzyloxy, wherein the substitution is wit a nitro, OH, amino, C__ 6 alkoxy, hydroxy Ci-β alkylene, or halogen; Y is C 1 - 15 alkyl, hydroxy C 1 - 15 alkyl, Ci- 6 alkyl or -(CH 2 ) e -C6H4-(V) e 1 ; Z is -(CH 2 ) d -0-CHO, Cι- 6 alkylene-0-(CH 2 )d-(0-CH2-CH 2 )e-0-Cι-6 alkyl, CHO, CO2R4, CO2NHR4, -(CH 2 )d-0-(CH2)d , -H'7r -(CH 2 ) e -OR4 or wherein V is OR 4 or hydroxy C_- 6 alkylene; provided that d'=2 when R'7 is piperazinyl, substitute piperazinyl, piperidyl or morpholinyl; R 6 is as defined for R 5 with the proviso that Re is other than hydrogen when R 5 is hydrogen, or R 5 and Rβ are taken together with the nitrogen atom to which they are attached are selected from the group consisting of; (f) (g) ( ) R 7 is CH 2 OR4, C(0)NHR or CHO; R' is piperazinyl, substituted piperazinyl, piperidyl, morpholinyl, pyridyl, pyrazinyl, pyrimidinyl or phenyl, wherein substituted piperazinyl is piperazinyl substituted on one nitrogen atom thereof with CHO, C(0)NHR 4 , C 1 - 4 alkyl or CO 2 R 4 ; R 8 is (H, OH) or =0; R's is pyrimidyl, pyridyl, pyrazinyl or phenyl; a is zero , 1 , 2 or 3 ; b and b' are each independently zero or 1; d and d' are each independently 1 or 2; e and e 1 are each independently zero, 1 or 2; and x is zero or one. DETAILED DESCRIPTION OF THE INVENTION The terms "halo", "halogen" or "halide" refer to a chlorine, bromine or iodine atom. Isosteres of the compounds of Formula I include those wherein (a) the α-amino acid residues of the P- and P 2 substituents are in their unnatural configuration (when there is a natural configuration) or (b) when the normal peptide amide linkage is modified, such as for example, t form 0 II -CH 2 NH- (reduced), -C-N(CH 3 ) (N-methylamide) , -COCH 2 - (keto), -CH(OH)CH 2 - (hydroxy), -CH(NH 2 )CH 2 - (amino), -CH 2 CH 2 - (hydrocarbon). Preferably a compound of the invention should not be in an isosteric form. Unless otherwise stated the α-amino acids are preferably in thei L-con iguration. A compound of the invention may be in free form, e.g. amphoteric form, or in salt, e.g., acid addition or anion salt, form. A compound in free form may be converted into salt form in an art-known manner and vice-versa. The pharmaceutically acceptable salts of the peptide Formula I (in the form of water, or oil-soluble or dispersible products) include the conventional non-toxic salts or the quaternary ammonium salts of these peptides, which are formed, e.g., from inorganic or organic acids o bases. Examples of such acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethane- sulfonate, lactate, maleate, methanesulfonate, 2-naphthal- enesulfonate, nicotinate, oxalate, paemoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate. Base salts include ammonium salts, alkalimetal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl- D-glucamine, and salts with amino acids such as arginine, lysine, and so forth. Also, the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others. The hydrates of the compounds of Formula I are hydrated compounds having the partial structure and in their end-use application are generally the active forms. In general, as used herein, the term "alkyl" includes the straight, branched-chain and cyclized manifestations thereof unless otherwise indicated, particularly such moieties as methyl, ethyl, isopropyl, n-butyl, t-butyl, -CH--t-butyl, cyclopropyl, n-propyl, pentyl, cyclopentyl, n-hexyl, cyclohexyl and cyclohexylmethyl. The term "aralkyl", when used, includes those aryl moieties attache to an alkylene bridging moiety, preferably methyl or ethyl "Aryl" includes both carbocyclic and hetereocyclic moieties of which phenyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, indazolyl, furyl and thienyl are of primary interest; these moieties being inclusive of their position isomers such as, for example, 2-, 3-, or 4-pyridyl, 2- or 3-furyl and thienyl, 1-, 2-, or 3-indolyl or the 1- and 3 indazolyl, as well as the dihydro and tetrahydro analogs o the furyl and thienyl moieties. Also included within the term "aryl" are such fused carbocyclic moieties as pentalenyl, indenyl, naphthalenyl, azulenyl, heptalenyl, acenaphthylenyl, fluorenyl, phenalenyl, phenanthrenyl, anthracenyl, acephenanthrylenyl, aceanthrylenyl, triphenylenyl, pyrenyl, chrysenyl and naphthacenyl. Also included within the term "aryl" are such other heterocycli radicals as 2- or 3-benzo[b]thienyl, 2- or 3-naphtho[2, - bjthienyl, 2- or 3-thianthrenyl, 2H-pyran-3-(or 4- or 5-)yl, 1-isobenzo- furanyl, 2H-chromenyl-3-yl, 2- or 3- phenoxathiinyl, 2- or 3-pyrrolyl, 4- or 3-pyrazolyl, 2-pyrazinyl, 2-pyrimidinyl, 3-pyridazinyl, 2-indolizinyl, 1-isoindolyl, 4H-quinolizin-2-yl, 3-isoquinolyl, 2- quinolyl, 1-phthalazinyl, 1,8-naphthyridinyl, 2- quinoxalinyl, 2-quinazolinyl, 3-cinnolinyl, 2-pteridinyl, 4aH-carbazol-2-yl, 2-carbazolyl, β-carbolin-3-yl, 3-phenanthridinyl, 2-acridinyl, 2-perimidinyl, 1-phenazinyl, 3-isothiazolyl, 2-phenothiazinyl, 3-isoxazolyl, 2-phenoxazinyl, 3-isochromanyl, 7-chromanyl, 2-pyrrolin-3-yl, 2-imidazolidinyl, 2-imidazolin-4-yl, 2-pyrazolidinyl, 3-pyrazolin-3-yl, 2-piperidyl, 2-piperazinyl, 1-indolinyl, 1-isoindolinyl, 3-morpholinyl, benzo[b]isoquinolinyl and benzo[b]furanyl, including the position isomers thereof. Likewise the term "alkylene" includes straight or branched-chain moieties. Some examples of branched-chain alkylene moieties are ethylethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, and so on. For example, C 3 alkylene can mean CH, I 3 -CH 2 -CH 2 -CH 2 - or -C- or -CH 2 -CH- or -CH-CH-- . CH, CH, CH, All [ C 1 _ 6 ) moieties such as C-_ 6 alkyl, C λ _ 6 allenyl, C 1-6 alkoxy, and hydroxy C j ^ g alkyl, are more preferably λ _ 3 moieties (containing 1-3 carbon atoms instead of 1-6 carbon atoms) . The fluorenylmethyloxy moiety is that moiety generally called by its abbreviation FMOC, and is the fluorenyl moiety bearing -CH-0 attached to the 9-position of the fluo¬ renyl moiety. Other terms defined herein are piperazinyl or substituted piperazinyl the substitution (*) occurring only at one nitrogen atom which is not attached to the remainder of the molecule (attachment via a nitrogen atom). The substituents are one of CHO, C(0)NHR 4 , C χ _ 4 alkyl or CO_R 4 . The term "Bn" refers to a benzyl functionality of the formula; Pi inyl both bind to the rest of molecule via their respective nitrogen atoms while pyrimidinyl, pyridyl and pyrazinyl bind to the rest of the molecule anywhere except their respective nitrogen atoms. ,_ More specifically, in the instance wherein P 2 is either C χ _ 6 alkyl or hydroxy C 1-6 alkyl, such moieties as -C(CH 3 ) 3 , -CH(CH 3 ) 2 , -CH(CH 3 ) (C 2 H 5 ) , -C(OH)(CH 3 ) 2 and -CH(OH)CH 3 are preferred. The "hydroxy C-_ 6 alkyl" moiety is illustrated i one example by -CH 2 -OH, the "C-_ 6 alkoxy C 1-6 alkyl" moiety, _ 0 is illustrated in one example by -CH 2 -OCH 3 , (although in each instance the C 1-6 alkylene may be straight or branched and the hydroxy radical is not limited to the terminal carbon atom of the alkyl moiety). 25 As it is often quite advantageous to have what is termed an amino protecting group (Pg), the scope of those compounds of Formula I includes those R- moieties which, together with their adjacent carbonyl moiety form such groups as acetyl (Ac), succinyl (Sue), benzoyl (Bz), 30 t-butyloxycarbonyl (Boc), benzyloxycarbonyl (CBZ), tosyl (Ts), dansyl (DNS), isovaleryl (Iva), methoxysuccinyl (MeOSuc), 1-adamantanesulphonyl (AdS0 2 ), 1-adamantaneacetyl (AdAc), phenylacetyl, t-butylacetyl (Tba), bis[(l- naphthyl)methyl]acetyl (BNMA) and Rz wherein Rz is an aryl -- group as previously described suitably substituted by 1 to 3 members selected independently from the group consisting of fluoro, chloro, bromo, iodo, trifluoromethyl, hydroxy, alkyl containing from 1 to 6 carbons, alkoxy containing from 1 to 6 carbons, carboxy, alkylcarbonylamino wherein the alkyl group contains 1 to 6 carbons, 5-tetrazolo, and acylsulfonamido (i.e., acylaminosulfonyl and sulfonylamino- carbonyl) containing from 1 to 15 carbons, provided that when the acylsulfonamido contains an aryl, the aryl may be further substituted by a member selected from fluoro, chloro, bromo, iodo and nitro. Among the classes of amino protecting groups contemplated are: (1) acyl type protecting groups such as formyl, trifluoroacetyl, phthalyl, p-toluenesulfonyl (tosyl), benzenesulfonyl, nitrophenylsulfenyl, tritylsulfenyl, O-nitrophenoxyacetyl, and α-chlorobutyryl; (Ξ) aromatic urethane type protecting groups such as benzyloxycarbonyl and substituted benzyloxycarbonyls such as p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, l-(p-biphenylyl)-l-methylethoxycarbonyl, α-, α-dimethyl- 3,5-dimethoxybenzyloxycarbonyl, and benzhydryloxycarbonyl; (3) aliphatic urethane protecting groups such as tert- butyloxycarbonyl (Boc), diisopropylmethoxycarbonyl, iso- propyloxycarbonyl, ethoxycarbonyl, and allyloxycarbonyl; (M) cycloalkyl urethane type protecting groups such as cyclopentyloxycarbonyl, adamantyloxycarbonyl, and cyclo- hexyloxycarbonyl; (S) thio urethane type protecting groups such as phenylthiocarbonyl; (L) alkyl type protecting groups such as triphenylmethyl (trityl) and benzyl (Bn); (7) trialkylsilane protecting groups such as trimethyl- silane if compatible. The preferred α-amino protecting groups are tert-butyloxycarbonyl (Boc) or benzyloxycarbonyl (CBZ). The use of Boc as an α-amino protecting group for amino acids is described by Bodansky et al. in "The Practice of Peptide Synthesis", Springer-Verlag, Berlin (1984), p. 20. The term "stereoisomers" is a general term for all isomers of individuals molecules that differ only in the orientation of their atoms in space. It includes mirror image isomers (enantiomers) , geometric { cis/trans) isomers, and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereoisomers) . For amino-acids, the designations L/D, or R/S can be used as described in IUPAC-IUB Joint Commission on Biochemichal Nomenclature, Eur. J. Biochem. 138: 9-37 (1984). In general the compounds of this invention may be prepared using standard chemical reactions analogously known in the art. More specifically, the preparation of compounds of structure (3) is well known in the art and described generally by Schirlin, D. and Van Dorsselaer, V. in PCT/US91/09741 published July 23, 1992 with an international publication number of WO 92/12123. The compounds of formula (I) can be prepared as described in Reaction Schemes A, A', A", B, C and D. All the substituents, unless otherwise indicated, are previously defined. The reagents and starting materials are readily available to one of ordinary skill in the art. REACTION SCHEME A l '1 PgNHCH-CHO (a) PgNHCH-CHCF 2 COEt (d ) PgNHCH- < [H H --C C F P 2 --C , jj--OEt OH O OH (3) (4) (13) P' ^OH PgNH-CH-CH-CF,-CNR-R, (c) Pg_lH-CH-CH-CF--C-NR-R c PgNH-CH-CH-CF,-C-NRcR- I 2 II 5 6 | 2 II 5 6 I 2 II 5 6 OH O OH O OH O 15 ) 20 P' l x NH 2,-CH-C .H-CF, 2--C-NR I 5;R R 6 NH~ 2-CH-C iH-CF _,-C n-NR _ C -R # o- NH _,-CH-C IH-CF, _-C,,-NR- _R b- OH O OH OH O (7) (9) (15) 25 REACTION SCHEME A' (7) (9) (15) P' I 1 R , 1 C-NH-CH-C-NH-CH-CH-CF,-CNR « .R < - I 2 i, 5 6 .(c) R',C-NH-CH-C-NH-CH-CH-CF,-CNR-R Λ R* 1 C-NH-CH-C--IH-CH-CH-CF,-CNR-R- In II In II I 2 I, 5 6 j-n II I - II _ 6 OH OH O OH O (8) (10) (16) (c,) I 1 (g) i' i 1 R* 1 _-NH-CH-C-NH-CH-C-CF--CNR I -R, R M ,C-NH-CH-C-NH-CH-C-CF--CNRcR A x ll II II 2 II 5 6 — ► x ιι 1 ii 2 I 5 6 o o o o IA IA' REACTION SCHEME A' II (7) (9) (15) -NR 5 Rg R' ,C-NH-CH-C-CF-- 1|| II - 25 In Scheme A, step (a) the aldehyde of formula (3) is subjected to a condensation reaction under Reformatski conditions with an ester of bromodifluoroacetic acid, preferably the ethyl ester in the presence of zinc and in an anhydrous aprotic solvent, e.g., tetrahydrofuran, ether dimethoxyethane and the like under a nitrogen or argon inert atmosphere. The reaction is gently heated to about 60°C for about 1-12 hours or ultrasonicated to produce compounds (4). Alternatively, in Reaction Scheme A step (a), the condensation to produce compounds (4) can be achieved in greater yields and at lower reaction temperatures utilizin the following general method. Under an inert atmosphere, such as nitrogen, the aldehyde (3) is dissolved in a suitable anhydrous organic solvent. Examples of a suitabl anhydrous organic solvent are tetrahydrofuran, diethyl ether, t-butyl methyl ether and the like. The solution is cooled to approximately 0°C. To the solution is added abo 0.30 equivalents of silver acetate, about 2.1 equivalents of zinc dust, and about 2 equivalents of ethyl bromodifluoroacetate. About 0.34 equivalents of diethylaluminum chloride (as a solution in toluene) is added slowly to the reaction keeping the temperature of th reaction below 12°C. The reaction is allowed to stir for to 3 hours at about 0°C and then at room temperature for 4 to 12 hours. The reaction is then cooled to about 10°C an quenched with saturated aqueous ammonium chloride. The compound (4) is then isolated and purified by techniques well known in the art. For example a solution of sodium hydrogen tartrate is added and the reaction is allowed to warm from 10°C to room temperature. The mixture is filtered, the solids washed with a suitable organic solvent, such as ethyl acetate and the layers of the filtrate are separated. The aqueous layer is extracted with ethyl acetate, the organic layer and extracts are combined, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue is purified by flash chromatography on silica gel with a suitable eluent, such as cyclohexane/ethyl acetate to provide the compounds (4). In Scheme A, step (b) formation of compounds (5) or (14) may be effected directly or undirectly. In one method, the esters of formula (4) or (13) are de-esterified using a suitable base, such as LiOH, KOH, NaOH and the like, in the presence of water and a partially water miscible solvent (such as tetrahydrofuran, dimethoxyethane, dioxane) at about room temperature. The resulting acid can then be aminated with the appropriate R 5 R 6 -substituted amine using standard peptide-like coupling conditions. The selection of the appropriate coupling reaction procedure is within the skill of the art. The coupling reaction can be carried out using standard coupling procedures such as the azide method, mixed carbonic acid anhydride (isobutyl chloroformate) method, carbodiimide [dicyclohexylcarbodiimide, diisopropylcarbodiimide, or water-soluble carbodiimide,1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDC)] method, active ester (p-nitrophenyl ester, N-hydroxy-succinic imido ester) method, Woodward reagent K method, carbonyldiimidazole method, phosphorus reagents such as BOP-Cl, or oxidation- reduction methods. Some of these methods (especially the carbodiimide method) can be enhanced by adding hydroxybenzotriazole (HOBT), for example the mixed anhydride method may be employed, using DCC and hydroxybenzotriazole at room temperature in solvents such as CH 2 C1 2 , tetrahydrofuran or dimethylformamide. Alternatively the esters (4) or (13) may be directly subjected to a reaction with the appropriate R 5 R 6 _ substituted amine without or with a solvent (tetrahydro¬ furan) at a temperature of from 0 to 80 β C. Alternatively, an appropriate Rs,R 6 -substituted amine that is protected as necessary is dissolved in a suitable organic solvent, such as dichloromethane under an inert atmosphere, such as nitrogen. An equivalent of a 2M solution of trimethylaluminum in toluene is added dropwise to the solution. After approximately 15 minutes this solution is added to approximately 0.3 equivalents of ester (4) or (13) dissolved in a suitable organic solvent, such as dichloromethane. The reaction is allowed to stir for about 15 to 24 hours at about room temperature to 40°C. The product is then isolated using techniques well known in the art. For example cold dilute aqueous hydrochloric acid and ethyl acetate is added. The organic layer is separated and washed with water, brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the compounds (5) or (14). In Step (c) compounds (6), (8) or (11) are prepared by removal of the P'- protecting group using standard procedures well known in the art [see T.H. Green, "Protective Groups in Organic Synthesis", John Wiley and Sons, 1981], such as hydrogenation. The free phenol functionality is then reacted with an appropriate alkyl halide in an inert solvent (preferably anhydrous dioxane, anhydrous acetone or anhydrous dimethylformamide) in the presence of a base (potassium or cesium carbonate) with or without potassium iodide at room or reflux temperature. In Step (ci) compound (13) is prepared by removal of the P' j^ protecting group using standard procedures well known in the art[see T.H. Green, "Protective Groups in Organic Synthesis", John Wiley and Sons, 1981], such as, hydrogenation, POH being the compound obtained. POH being a free phenol. In Step (C 2 ) compounds (6), (8) or (11) are prepared from the PoHderivatives (14), (16) or (17) by reaction with an appropriate alkylhalide in an inert solvent, in the presence of a base. For example, the PoHderivative is dissolved in a suitable organic solvent, such as acetone. Approximately 1.2 equivalents of a suitable base, such as potassium carbonate, are added followed by addition of approximately 1.15 equivalents of the alkyl halide. A catalytic amount of potassium iodide is then added and the reaction is stirred for 1 to 3 days. The product is isolated and purified by techniques well known in the art, such as extractive methods and recrystallization. For example, the reaction is poured into a suitable solvent mixture, such as ethyl acetate/dilute aqueous sodium chloride and the organic layer is separated. The organic layer is then washed with dilute aqueous potassium hydroxide, brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue is purified by recrystallization from a suitable solvent mixture, such as cyclohexane/ethyl acetate to provide compounds (6), (8) or (11). In Step (d), for the preparation of Compounds (7), (9) and (15), the protecting groups Pg may readily be removed by standard procedures well known in the art [see T.H. Green, "Protective Groups in Organic Synthesis", John Wiley and Sons, 1981], preferably acid/base hydrolysis (e.g., formic acid at room temperature followed by extraction of the free base after treatment with sodium carbonate). In Step (e), Compounds (7), (9) or (15) are subjected to a peptide coupling procedure with an appropriately protected acid of the formula R'-CONHCH(P 2 )C0 2 H or R'-CO-H, using the herein-described procedures (or by any other coupling procedure well known in the art, or as described in European Patent Application, Serial Number 93 401 785.6) to produce compounds (8) and (11) (from compound (7)); (10) and (12) (from compound (9)); and (16) and (17) (from compound (15)). R'ι is defined as Ri except for those instances wherein protection of the R_ group may be requir as recognized by one of ordinary skill in the art. For example, a hydroxyl functionality on the alkyl portion of the R_ group must be protected prior to the oxidation in step (f). In Step (f), the oxidation of compounds (8) and (11) may be effected by methods well known in the art, such as the Swern oxidation procedure, or with 1,1,l-triacetoxy-1,1 dihydro-l,2-benziodoxol-3(lH)-one to provide compounds of formulas IA and IB. In general the Swern oxidation [see Synthesis, (1981) 165] is effected by reacting about 2 to 20 equivalents of dimethylsulfoxide (DMSO) with about 1 to 10 equivalents o trifluoroacetic anhydride [(CF 3 CO) 2 0] or oxalyl chloride [(C0C1) 2 ], said reactants being dissolved in an inert solvent, e.g., methylene chloride (CH 2 CI 2 ), said reaction being under an inert atmosphere (e.g., nitrogen or equivalently functioning gas) under anhydrous conditions temperatures of about -70°C to -30°C to form an in situ sulfonium adduct to which is added about 1 equivalent of the appropriate alcohols, i.e., compounds (8) and (11). Preferably, the alcohols are dissolved in an inert solven e.g., CH 2 CI 2 , tetrahydrofuran, or minimum amounts of DMSO, and the reaction mixture is allowed to warm to about -50° or -20°C (for about 20-60 minutes) and then the reaction completed by adding about 3 to 30 equivalents of a tertia amine, e.g., triethylamine, diisopropylethylamine, /-meth morpholine, etc. Alternatively the oxidation can be carried out with t Dess-Martin periodinane (i.e., 1,1,l-triacetoxy-1,1- dihydro-l,2-benziodoxol-3(lH)-one) , [see Dess Martin, J_;_ Orq. Chem. , 48, 4155, (1983)]. This oxidation is effected by contacting about 1 equivalent of the alcohol with 1 to 10 equivalents of periodinane (preferably greater than 5 equivalents) , said reagent being in suspension in an inert solvent (e.g., methylene chloride) under an inert atmosphere (preferably nitrogen) under anhydrous conditions at 0°C to 50°C (preferably room temperature) and allowing the reactants to interact for about 1 to 48 hours. Optional deprotection of the amine protecting groups may be effected as desired after the ketones have been isolated. In general, the modified Jones oxidation procedure may conveniently be effected by reacting the alcohols with pyridinium dichromate by contacting the reactants together in a water-trapping molecular sieve powder, e.g., a grounded 3 Angstrom molecular sieve), wherein said contact is in the presence of glacial acetic acid at about 0°C to 50°C, preferably at room temperature followed by isolation and then optionally removing amine protecting groups. Alternatively, 1 to 5 equivalents of a chromic anhydride-pyridine complex (i.e., a Sarett reagent prepared in situ ) [see Fieser and Fieser "Reagents for Organic Synthesis" Vol. 1, pp. 145 and Sarett, et al., J.A.C.S. 25, 422, (1953)] in an inert solvent (e.g., CH 2 CI 2 ) under an inert atmosphere under anhydrous conditions at 0°C to 50°C is treated with 1 equivalent of the alcohol. The reaction is allowed to stir for about 1 to 15 hours. The product is isolated and purified by techniques well known in the art followed by optionally removing amine protecting groups. In step (g) the compounds decribed by formulas IA and IB wherein R'_ is protected as required, are deprotected under conditions well known in the art [see T.H. Green, "Protective Groups in Organic Synthesis", John Wiley and Sons, 1981], to provide compounds of formula IA 1 and IB' wherein R"ι are those substituents which required protection as required. For example the protected compound is dissolved in a suitable organic solvent, such as methylene chloride and treated with TFA/H 2 0. The reaction is allowed to stir at room temperature for about 4 to 10 hours and then it is concentrated under vacuum. The residue is purified by techniques well known in the art, such as extractive methods followed by flash chromatograph (silica gel, hexane/ethyl acetate) to provide the deprotected compound. For the preparation of the necessary aldehydes of formula (3) and the acids which are to be coupled with the compounds (7), (9) or (15), alternative alkylation procedures are utilized depending upon whether the P- and/or the P 2 moieties are or are not residues of natural amino acids. For the preparation of these intermediates wherein the P- or P 2 moieties are residues of natural amino acids (or minor modifications thereof, e.g., P- or P 2 being a benzyl or methyl ether of tyrosine), the compounds are either known or are prepared by processes and techniques well known in the art. To prepare the intermediates of the formula PgHN-CHC0 2 R 9 wherein Pg is an amino protecting group, P 3 is either a P ' 1 or P' 2 moiety with P'- and P' 2 being as defined for P χ and P 2 respectively, except that they are other than residues of naturally occuring amino acids, and the R g moiety is an alkyl radical, preferably methyl when P 3 is P' ι , and ethyl when P 3 is P' 2 , alternative methods are available. To prepare the intermediates of formula P' I 2 PgHN-CHCHO PgHN-CHCOOH (10B) (10A) the following reaction scheme may be utilized REACTION SCHEME B PgNHCH 2 C0 2 R g (1) Base PgNHCHC0 2 R g (18) (2) P 3 X (19) wherein P 3 is as previously defined and X is a leaving group, preferably halo or triflate, R 9 is methyl when P 3 is P'-, and ethyl when P 3 is P' 2 . In essence, the preparation of compounds (19) utilizes the Krapcho method [Tetrahedron Letters, 2.6, 2205 (1976)] for alkylation wherein compounds (18) are treated with a base, e.g., LDA, (lithium diisopropylamide) , followed by reaction with the desired P 3 X in the presence of TMEDA (i.e. tetramethylethylenediamine) in a solvent (tetrahydro¬ furan) with or without HMPA (i.e. hepamethylphosphonamide) according to the standard Krapcho conditions. Following alkylation the compounds are then subjected to a reduction using diisobutyl alaminum hydride (Dibal) in a mixture of solvents, e.g., ether, toluene, hexane, tetrahydrofuran at about -78°C for about 1 hour. Following the preparation of the aldehydes of Formula (10B), the compounds are subjected to the processes of Reaction Schemes A, A' and/or A". Alternatively, the compounds of (19) may be prepared by a Malonate/Curtius type sequence of reactions, [see Yamada, et al., J. Amer. Chem. Soc, (1972) 9_4, 6203] as illustrated by the following reaction scheme REACTION SCHEME C t-Bu0 2 CCH 2 C0 2 R 9 ( 20 ) ?3 H0 2 CCH 2 C0 2 R 9 ( 22 ) (19) wherein t-Bu is t-butyl, although other selectively removable acid protecting groups may be utilized, and P 3 X is as previously defined. This reaction involves the alkylation of the malonate ester (20) followed by selecti removal of the t-butyl protecting group to produce compounds (22). These compounds are then transformed to (19) using the Curtius type rearrangement which entails their conversion to the protected amine via the intermediately formed acylazides and isocyanates. The resultant amines are then protected with standard amino protecting groups, preferentially being protected in situ . In the instance wherein P 3 represents a P'- moiety, t ester is transformed to the desired aldehydes of Formula (3) using standard Dibal reduction techniques, particularly in this situation (wherein P- is not a resid of a natural amino acid). Alternatively, (as is preferre when P χ is a residue of a natural amino acid) the ester i de-esterified to its corresponding acid, converted to it corresponding hydroxamate and the hydroxamate upon treatment with lithium aluminum hydride is converted to aldehyde. In the instance wherein P 3 represents a P' 2 moiety, the ethyl ester of compounds (19) are removed and the resulting compounds are ready for coupling as outlined in Reaction Scheme A'. In Scheme D an alternative procedure for preparation of compounds of formula IA is set forth. Reaction Scheme D (7) (a), Coupling Reaction P2 PgNH-CH CNH-CH— C — CF 2 — C NR5R6 II I II O (23) OH O (b), Deprotection P2 i H 2 N-CH CNH-CH—C—CF 2 —C NR 5 R 6 O 11 n(24a,) O • H (c), Coupling Reaction ,, (d), Oxidation P2 Pi R'lC—NH—CH CNH-CH—C—CF 2 —C NR5R6 II II IA In Scheme D, step (a) compounds of formula (7) are subjected to a coupling reaction in a manner analogous to that described previously in Scheme A' step (e) with a suitably protected acid of the formula PgNHCH(P 2 )Cθ 2 H to provide compound of formula (23). In Scheme D, step (b) compounds of formula (23) are deprotected in a manner analogous to that described in Scheme A, step (d) to provide compounds of formula (24). In Scheme D, steps (c) and (d) compounds of formula (24) are first subjected to a coupling reaction with an acid of the formula R'_Cθ 2 H in a manner analogous to that described in Scheme A' step (e) and the coupled product is then oxidized in a manner analogous to that described in Scheme A' step (f) to provide the compounds of formula IA. It is understood by one of ordinary skill in the art that compounds of formulas (9) and (15) may be manipulated in a manner analogous to formula (7) in Scheme D, in addition to the manipulations decribed in Schemes A' and A" to provide compounds of formulas IA, IA', IB and IB'. Having generically described the methods for the preparation of the compounds of this invention, the following specific examples illustrate the chemistry and techniques by which the synthesis may be effected. The following examples present typical syntheses as described in Schemes A, A', A" and D. These examples are understood to be illustrative only and are not intended to limit the scope of the present invention in any way. As used herein, the following terms have the indicated meanings: "g" refers to grams; "mmol" refers to millimoles; "ml" refers to milliliters; "bp" refers to boiling point; "mp" refers to melting point; » -c" refers to degrees Celsius; "mm Hg" refers to millimeters of mercury; "μL" refers to microliters; "μg" refers to micrograms; "μM" refers to micromolar; "Cbz" means carbobenzyloxy; "DMF" means dimethylformamide; "THF" means tetrahydrofuran; "TBAF" means tetrabutylammonium fluoride; "NMM" means N- methylmorpholine; "DMSO" means dimethylsulfoxide; "HOBT" means hydroxybenzotriazole and "EDC" means l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. Example 1 Preparation of α,α-Difluoro-γ-[ [ ( 2-(R)- [ [ (hydroxy)phenylacetyl]amino]-3-methyl-l-oxobutyl1amino] • B-oxo-4-(phenylmethoxy)-N-(phenylmethy1)-benzene- pentanamide. Step A Preparation of Q-benzyl-N-( tert-butoxycarbonyl)-L- tyrosinal; the starting material in Reaction Scheme A, ♦ [Following the procedure of Schirlin, D. and Van Dorsselaer, V. in PCT/US91/09741 published July 23, 1992 with an international publication number of WO 92/12123.] A mixture of N-tert-butoxycarbonyl-L-O-benzyltyrosine (37.1 g, 100 mmol), dicyclohexylcarbodiimide (20.6 g, 100 mmol), and N-hydroxybenzotriazole hydrate (15.3 g, 100 mmol) in anhydrous dichloromethane (350 mL) is stirred at 0°C for 10 minutes. To this is added at 0°C, N,0- dimethylhydroxylamine hydrochloride (9.75 g, 100 mmol) and N-methylmorpholine (10.1 g, 100 mmol). The temperature is allowed to warm to room temperature and stirring is continued for 15 hours. The white precipitate is then filtered off and rinsed with dichloromethane. The filtrate is concentrated under vacuum and the residue is purified by flash chromatography (silica gel, ethyl acetate/cyclohexane, 2:8) to provide the N-tert- butoxycarbonyl-L-0-benzyltyrosine-N,On-dimethyl-hydroxamate (34.3 g) as a white solid (R F =0.36 in ethyl acetate/cyclohexane, 1:1). The N-tert-butoxycarbony1-L-O-benzyltyrosine-N,0- dimethyl-hydroxamate (18.2 g, 44 mmol) is dissolved in a mixture of anhydrous diethyl ether/dimethoxyethane (300 mL, 4:1) and cooled to 0°C. To this is added lithium aluminum hydride (1.82 g, 48 mmol) portionwise. The reaction is stirred at 0°C for 1.5 hours. A 1M solution of potassium hydrogen sulfate (55 mL) is then added dropwise with stirring to the reaction. After addition is complete, the aqueous phase is decanted and extracted with ethyl acetate (2 x 200 mL). The combined organic layers are washed with 3N hydrochloric acid (250 mL), water (200 mL), saturated sodium bicarbonate (150 mL) and brine (200 mL). The organic layer is then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue is recrystallized from ethyl acetate/pentane to provide N-tert-butoxycarbonyl-L-O-benzyltyrosinal (13 g). Step B Preparation of 4-tert-butoxycarbonylamino-2,2-difluoro-3- hydroxy-5-(4-benzyloxy)phenylpentanoic acid, ethyl ester. Reaction Scheme A, step (a); To a stirred mixture of N-tert-butoxycarbonyl-L-O-benzyltyrosinal (13.0 g, 36.6 mmol), silver acetate (1.82 g, 10.9 mmol), activated zinc dust (5.02 g, 76.8 mg-atom, washed with 3N hydrochloric acid, water, acetone and ether) and ethyl bromodifluoroacetate (14.8 g, 72.9 mmol) in anhydrous tetrahydrofuran (120 mL) at 0°C is added diethylaluminum chloride (22.4 mL of a 1.8M solution in toluene) over 20 minutes. The temperature is kept below 12°C during the addition. The reaction is then allowed to stir at 0°C for 90 minutes and then at room temperature for 4 hours. The reaction is then cooled to 10°C and quenched with saturated aqueous ammonium chloride (200 mL). A 1M solution of sodium hydrogen tartrate (200 mL) is added and the reaction is allowed to warm to room temperature. The reaction is filtered and the solids rinsed with ethyl acetate. The filtrate layers are separated and the aqueous layer is extracted with ethyl acetate. The combined organic laye are dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue is purified by flash chromatography (cyclohexane/ethyl acetate, 4:1) to provide the title compound (8.34 g). The ratio of diastereomers is approximately 1:1. Step C Preparation of 4-tert-Butoxycarbonylamino-2,2-difluoro-3 hydroxy-5-(4-benzyloxy)phenyl-N-(phenylmethyl)pentanamid Reaction Scheme A step (b): To a solution of 4-tert butoxycarbonylamino-2,2-difluoro-3-hydroxy-5-(4- benzyloxy)phenylpentanoic acid, ethyl ester (5.5 g, 11.5 mmol) in anhydrous tetrahydrofuran (50 mL) is added at 0° benzylamine (6.15 g, 57.5 mmol). The reaction is stirre for 3 hours at 0°C, then at room temperature for 15 hours The reaction is then diluted with ethyl acetate (100 mL), washed with 0.1N aqueous hydrochloric acid (2 x 50 mL), water (50 mL), brine (50 mL) and dried over anhydrous magnesium sulfate. It is then filtered and concentrated under vacuum. The residue is recrystallized from ethyl acetate/pentane to provide the title compound (5.17 g) a white solid. Step D Preparation of 4-amino-2,2-difluoro-3-hvdroxy-5-(4- benzyloxy)phenyl-N-(phenylmethyl) entanamide. Reaction Scheme A, step (d): A solution of 4-tert- butoxycarbonylamino-2,2-difluoro-3-hydroxy-5-(4- benzyloxy)phenyl-N-(phenylmethyl)pentamide (5.1 g, 9.4 mmol) in trifluoroacetic acid (100 mL) is stirred at 0°C 1 hour. The solvent is then removed under vacuum and th residue dissolved in ethyl acetate (100 mL). The organi layer solution is washed with saturated sodium bicarbona (3 x 50 mL), brine, dried over anhydrous magnesium sulfa filtered and concentrate under vacuum to provide the tit compound as a white solid; R_=0.62 (silica gel, butanol/acetic acid/water, 6:2:2). Step E Preparation of N-(R)-[[[ (1,1- Dimethylethyl)dimethylsilyl]oxy]phenylacetyl]-L-valine. To a stirred solution of (R)-(-)-mandelic acid (5.6g, 37 mmol) and tert-butylchlorodimethylsilane (15.0 g, 99.5 mmol) in DMF (100 mL) is added imidazole (16.7 g, 245 mmol) in portions over 15 minutes while maintaining the reaction mixture near 25°C with a cool water bath. After 17 hours, the mixture is diluted with water and extracted with two portions of ether. The combined extracts are cooled to - 10°C and washed quickly with cold (-10°C) 1 N HC1, twice with cold water, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide 15.0 g of a yellow oil which is then dissolved in CH 3 OH (250 mL) and THF (80 mL). A solution of potassium carbonate (14 g, 100 mmol) in water (140 mL) is added with vigorous stirring. After 1 hour, the mixture is partially concentrated under vacuum and the remaining clear light yellow solution is diluted with brine (300 mL) . The cloudy mixture is cooled to -10°C and acidified to pH 5 with 1 M KHSO 4 . Extraction with cold (-10°C) ether and washing of the extracts with two portions of brine provides, after drying with anhydrous sodium sulfate, filtration and concentration under vacuum, 6.6 g (67%) of (R)-O-tert-butyldimethyl-silylmandelic acid as a yellow oil. This crude silylated acid (25 mmol) is dissolved in CH 3 CN (80 mL) and the resulting solution is cooled to -10°C. To the stirred solution is added NMM (2.52 g, 24.9 mmol), then isobutylchloroformate (3.72 g, 27.2 mmol). After 10 minutes, a solution of L-valine methyl ester hydrochloride (7.32 g, 43.7 mmol) and NMM (4.08 g, 40.3 mmol) in H 2 0 (20 mL) is added and stirring is continued at -10°C for 20 minutes. The reaction mixture is poured into ice-cold dilute HC1 containing some NaCl and extracted with two portions of ethyl acetate. The combined extracts are washed with water, aqueous saturated sodium bicarbonate, brine, dried over anhydrous magnesium sulfate filtered and concentrated under vacuum. Two flash chromatographies (12% ethyl acetate in cyclohexane) provid 4.4 g of coupled silylated ester (R f 0.4, 4/1 cyclohexane/ethyl acetate) contaminated with N- isobutyloxycarbonyl-L-valine methyl ester. The silylated ester (4.4 g, 12 mmol) is dissolved in THF (15 mL) with stirring and a solution of 1 M tetrabutylammonium fluorid (TBAF) in THF (11.6 mL) is added. After 1.25 hours, the solution is concentrated under vacuum and the residue is purified by flash chromatography (4/1 cyclohexane/ethyl acetate) to provide 2.4 g (37% overall from O-tert- butyldimethylsilylmandelic acid) of N-[ (R)-mandeloyl]-L- valine methyl ester as an oil. Following the procedures i a manner analogous to that described above, the material i reconverted to its O-tert-butyldimethylsilyl ether in 82% yield after flash chromatography (12% ethyl acetate in cyclohexane). To a stirred solution of this ester (13.5 mmol) in CH 3 OH (125 mL) and water (5 mL) is added LiOH«H (0.59 g, 14 mmol). After 17 hours an additional amount of LiOH-H 2 θ (0.06 g) is added and stirring is continued for 2 hours. The solution is concentrated under vacuum and the residue is diluted with water (100 mL) and washed with ether. The aqueous layer is acidified with ice-cold 6 N HC1 and extracted with two portions of ether. The combine extracts are washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the title compound in 48% yield as a white solid: mp 146-148°C; IR (CHCI 3 ) v ma χ 2957, 2932, 1718, 1678, 1516, 1096, 863, 840 cm "1 ; X H NMR (CDCI 3 ) 6 9.17 (bs, 1 H), 7.51 (d, 1 H, J=9.0 Hz), 7.43-7.40 (m, 2 H) , 7.32- 7.25 (m, 3 H), 5.15 (s, 1 H) , 4.51 (dd, 1 H, J=9.0, 4.3 Hz), 2.34-2.28 (m, 1 H), 1.00 (d, 3 H, J=6.9 Hz), 0.97 (d, 3 H, J=7.0 Hz), 0.94 (s, 9 H) , 0.11 (s, 3 H) , -0.08 (s, 3 H); 13 C NMR (CDCI 3 ) 6 175.49, 172.65, 139.36, 128.32, 128.21, 126.68, 75.66, 56.60, 31.04, 25.66, 19.01, 18.02, 17.44, -4.83, -5.31; mass spectrum, m/z 394 (M + + 29), 366 (M + + 1, 100), 350, 308; exact mass calcd for CιgH 32 N0 4 Si 366.2101, found 366.2099; [α] 20 D -56.6° (c 1.00, CH 3 OH) . Anal. Calcd for Ci 9 H 3 ιN0 4 Si: C 62.43; H, 8.55; N, 3.83. Found: C, 62.22; H, 8.61; N, 3.65. Step F Preparation of [3ζ,4(S,R) ]-2,4,5-Trideoxy-4-[ [2-[ [ [ [ (1-1- dimethylethyl)dimethylsilyl]oxy]phenylacetyl]amino]-3- methyl-1-oxobutyl]amino]-2,2-difluoro-5-[4- (phenylmethoxy)phenyl]-N-(phenylmethyl)-L-qlycero- pentanamide. Reaction Scheme A', step (e): N-(R)-[ [ [ (1,1- dimethylethyl)dimethylsilyl]oxy]phenylacetyl]-L-valine prepared above (25 mmol) is dissolved in CH 3 CN (80mL) and the resulting solution cooled to -10°C. To the stirred solution is added N-methylmorpholine (2.52 g, 24.9 mmol, NMM), followed by isobutylchloroformate (3.72 g, 27.2 mmol). After 10 minutes, a solution of 4-amino-2,2- difluoro-3-hydroxy-5-(4-benzyloxy)phenyl-N-(phenylmethyl) pentanamide (43.7 mmol, prepared in step (d) above) and NMM (4.08 g, 40.3 mmol) in H 2 O (20 mL) is added and stirring is continued at -10°C for 20 minutes. The reaction mixture is poured into ice-cold dilute HC1 containing some NaCl and is extracted with two portions of ethyl acetate. The combined extracts are washed with water, aqueous saturated sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The title compound is obtained in 76% yield as a clear colorless oil which crystallizes on standing after flash chromatography (6% acetone in CH C1 2 ): mp 117-120°C; IR (KBr) v max 3418, 1704, 1677, 1653, 1540, 1513, 1246, 1095, 839 cm-l; l K NMR (CDCI 3 ) δ 7.44-7.18 (m, 16 H), 6.96 (d, 3 H, J=8.7 Hz), 6.84 (d, 2 H, J=8.7 Hz), 6.10 (d, 1 H, J=8.1 Hz), 5.10 (s, 1 H) , 5.01 (s, 2 H), 4.69 (d, 1 H, J=6.9 Hz), 4.43 (dd, 1 H, J=14.7, 6.0 Hz), 4.34 (dd, 1 H, J=14.7, 6.0 Hz), 3.96 (dd, 1 H, J=8.5, 6.9 Hz), 3.91-3.82 ( , 2 H), 2.76 (dd, 1 H, J=13.8, 7.8 Hz), 2.66 (dd, 1 H, J=13.8, 7.8 Hz), 2.22-2.11 (m, 1 H), 0.94 (s, 9 H), 0.88 (d, 3 H, J=6.6 Hz), 0.86 (d, 3 H, J=6.9 Hz), 0.09 (S, 3 H), -0.06 (s, 3 H) ; 13 C NMR (CDCI 3 ) δ 173.37, 171.91, 163.92 (t, J=35 Hz), 159.01, 139.62, 137.40, 137.31, 130.47, 129.60, 129.16, 128.94, 128.80, 128.70, 128.37, 128.31, 128.22, 127.83, 126.63, 115.50 (t, J=257 Hz), 115.36, 76.21, 70.67 (t, J=25 Hz), 70.37, 58.79, 51.93, 43.76, 36.52, 29.97, 26.08, 19.80, 18.47, 17.96, - 4.41, -4.89; 19 F NMR (CDC13) δ -118.40 (s), -118.45 (s); mass spectrum, m/z 816 (M + + 29), 788 (M + + 1), 573, 469, 441, 423 (100); exact mass calcd for C 44 H 5 βF 2 3 θ 6 Si 788.3906 found 788.3932; [α] 20 D -74.6° (c 1.02, CH 3 OH) . Anal. Calcd for C 44 H 55 F 2 N 3 θ 6 Si: C, 67.06; H, 7.04; N, 5.33. Found: C, 67.07; H, 7.14; N, 5.18. Step G Preparation of final title compound. Reaction Scheme A', steps (f) and (g): The above prepared alcohol is oxidized under Swern conditions as follows: To a stirred solution of 2 M oxalyl chloride/CH 2 Cl (2.0mL) at -60°C under nitrogen is added dropwise anhydrous DMSO (0.42 mL, 5.9 mmol). After 10 minutes, a solution of [3ζ,4(S,R)]-2,4,5-Trideoxy-4-[ [2-[ [ [ [ (1-1- di ethylethylJdimethylsilyl]oxy]phenylacetyl]amino]-3- methyl-l-oxobutyl]amino]-2,2-difluoro-5-[4- (phenylmethoxy)phenyl]-N-(phenylmethyl)-L-glycero- pentonamide (0.50 mmol) in CH 2 CI 2 (3 mL) and anhydrous DMSO (1.5 mL) is added. The solution is allowed to stir at -65 to -55°C for 5 hours. It is then warmed to -20°C, followed by addition of triethylamine (1.39 mL, 10.0 mmol) over 5 minutes. The reaction mixture is then allowed to warm to room temperature overnight. It is then diluted with ethyl acetate (60 mL) and filtered, washing the solids with ethyl acetate. The filtrate is washed with 0.1 M HC1 (3 x 15 mL), brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide 375 mg of crude ketone. This is dissolved in 4/1 acetic acid/H 2 θ (50 mL). The stirred solution is heated at 80°C for 19 hours, allowed to cool to room temperature before being diluted with water and extracted with two portions of CH 2 CI 2 . The combined extracts are washed with water, brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. Flash chromatography of the residue (10% acetone in CH 2 CI 2 ) provides 180 mg title compound contaminated by residual silylated compound. The material is resubjected to the reaction conditions and purified by flash chromatography to provide 121 mg of final title compound. Two recrystallizations from ethyl acetate/pentane provide 30 mg (8.8%) of final title compound as a pale yellow solid: mp 144-150°C; IR (KBr) v max 3398, 3300, 1683, 1656, 1540, 1513, 1454, 1244, 698 cm -1 ; 1 H NMR (DMSO-d 6 ) δ 9.77-9.72 (m, 1 H) , 8.69 (d, 1 H, J=7.6 Hz), 7.80 and 7.73 (2d, 1 H total, J=9.3 Hz), 7.45-7.21 (m, 15 H), 7.12 and 7.10 (2d, 2 H total, J=8.7 Hz), 6.89 and 6.87 (2d, 2 H total, J=8.8, 8.4 Hz), 6.21 and 6.20 (2d, 1 H total, J=5.1 Hz), 5.05 (s, 2 H) , 5.02 and 5.00 (2s, 1 H total), 5.03-4.90 (m, 1 H) , 4.38 (d, 2 H, J=5.7 Hz), 4.23- 4.17 (m, 1 H), 3.14-3.07 and 2.65-2.57 (m, 2 H total), 1.97-1.88 and 1.78-1.73 (m, 1 H total), 0.73 and 0.71 (2d, 3 H total, J=6.7 Hz), 0.57 and 0.49 (2d, 3 H total, J=6.9, 6.7 Hz); 19 F NMR (DMSO-d 6 ) δ -110.31 (d, J=268 Hz), -110.54 (d, J=268 Hz), -112.21 (d, J=268 Hz), -112.25 (d, J=269 Hz); mass spectrum, m/z 700 (M + + 29), 672 (M + + 1, 100), 652, 439, 421, 402; exact mass calcd for C38H 40 F 2 N 3 O 6 672.2885, found 672.2842. Example 2 Preparation of [6S-(6R*, 9RA 13S*) ]-4,4,-Difluoro-9-( 1- methylethyl)-3,5,8,ll-tetraoxo-l,13-diphenyl-6-[ [4- (phenylmethoxy)phenyl ] ethyl ]-12-oxa-2,7,10- triazatetradecan-14-oic Acid, Methyl Ester. Step A Preparation of [3ζ,4(S) ]-2,4,5-Trideoxy-4-[ [ 2-[ [ (1,1- dimethylethoxy)carbonyl]amino]-3-methyl-l-oxobutyl ]amino- [4-(phenylmethoxy)phenyl]-N-(phenylmethyl)-L-qlycero- pentanamide. Reaction Scheme D, step (a): To an ice-cold stirred solution of 4-amino-2,2-difluoro-3-hydroxy-5-(4- benzyloxy)phenyl-N-(phenylmethyl)pentanamide (556 mg, 1.2 mmol, prepared in example 1, step D) in 2:1 dry CH 2 CI 2 /DM (13.5 mL) is added HOBT (0.19 g, 1.2 mmol), DCC (0.26g, 1 mmol) and N-t-Boc-L-valine (0.27 g, 1.2 mmol). The reaction mixture is allowed to warm to 25°C overnight, th diluted with ethyl acetate/cyclohexane, washed with dilut aqueous sodium bicarbonate, water, brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide a gummy solid. This is triturate with CH 2 CI2 and filtered to remove some of the dicyclohexylurea. The filtrate is concentrated under vacuum and the residue is purified by flash chromatograph (3:2 cyclohexane/ethyl acetate) to provide 694 mg (88%) o the title compound as an ivory solid. The major diastereomer is separated in 69% yield by recrystallizati from ether/CH2Cl2- Step B Preparation of the chloroformate of formula: To a stirred solution of triphosgene (6.65 g, 22.4 mmol) in CH 2 CI 2 (25 mL) under nitrogen is added (R)-(-)- methyl mandelate (5.36 g, 32.3 mmol) followed by the rapid addition of a solution of pyridine (2.66 mL, 32.9 mmol) in CH 2 CI 2 (2.5 mL). The reaction mixture is warmed to reflux and pyridinium chloride separated. After 17 hours at room temperature, the reaction mixture is partially concentrated under vacuum, diluted with ethyl acetate, and filtered. The filtrate is concentrated concentrated under vacuum and the residue is again dissolved in ethyl acetate and filtered. Concentration under vacuum provides 7.25 g of a pale yellow oil composed of approximately a 20:1:1 mixture of chloroformate: carbonate: methyl mandelate. For the chloroformate IR (neat) v max 1772, 1750 cm "1 ; X H NMR (CDCI 3 ) δ 7.5-7.37 (m, 5 H), 5.98 (s, 1 H), 3.78 (s, 3 H) . Step C Preparation of [5E,6S-(6R*, 9R*, 13S*) ]-4,4,-Difluoro-5- hydroxy-9-(1-methylethyl)-3,8,11-trioxo-1 ,13-diphenyl-6- [ [4-(phenylmethoxy)phenyl]methyl]-12-oxa-2,7,10- triazatetradecan-14-oic Acid, Methyl Ester. Reaction Scheme D, steps (b) and (c): A flask containing the major diastereomer of [3ξ,4(S) ]-2,4, 5- Trideoxy-4-[ [ 2-[ [ (l,l-dimethylethoxy)carbonyl]amino]-3- methyl-l-oxobutyl]amino-5-[ 4-(phenylmethoxy)phenyl]-N- (phenylmethyl)-L-glycero-pentonamide (403 mg, 0.630 mmol) is submersed in an ice bath and ice-cold trifluoroacetic acid (TFA) (5 mL) is added with stirring. After 30 minutes, the solution is concentrated under vacuum at 25°C and the residue is carefully partitioned between ethyl acetate and aqueous saturated sodium bicarbonate. The organic layer is separated, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide 334 mg (98%) of deprotected amine which is immediately suspended in CH 2 CI 2 (5 mL) at 0°C and treated with NMM (77 μL, 0.70 mmol) and the chloroformate prepared above (160 mg, 0.70 mmol) dissolved in CH 2 CI2 (1 mL). After stirring for 1.5 hours, the reaction mixture is poured into ethyl acetate/dilute aqueous ammonium chloride. The organic layer is separated, washed with dilute aqueous sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. Flash chromatography (4:1 CH 2 Cl 2 /ethyl acetate) of the residue provides 332 mg (72%) of a single diastereomer of the title compound as a white foam: 1 H NMR (CDCI 3 ) δ 7.44-7.26 (m, 15 H), 7.12 (d, 2 H, J=8.4 Hz), 6.89 (d, 2 H, J=8.4 Hz), 6.53 (d, 1 H, J=8.4 Hz), 5.89 (s, 1 H) , 5.40 (d, 1 H, J=7.9 Hz), 5.02 (s, 2 H), 4.70 (d, 1 H, J=7.0 Hz), 4.49 (apparent d, 2 H, J=5.8 Hz), 4.3-4.1 ( , 2 H), 3.85 (dd, 1 H, J=7.8, 5.5 Hz), 3.63 (s, 3 H), 3.05-2.87 (m, 2 H) , 2.2-2.04 (m, 1 H), 1 . 90 ( s , 1 H) , 0. 83 ( d , 3 H, J=6 .7 Hz ) , 0 . 71 ( d , 3 H, J=6 . 8 Hz ) ; 19 F NMR ( CDCI3 ) δ -116 . 60 ( dd , 1 F , J=259 , 9 Hz ) , - 118 .73 ( dd , 1 F , J=259 , 15 Hz ) . Step D Preparation of final title compound. Reaction Scheme A 1 , step (f): The above prepared alcohol is subjected to Swern Oxidation conditions in a manner analogous to that described previously in example 1, step G. The residue is purified by flash chromatography (4:1 CH 2 Cl 2 /ethyl acetate) to provide 52% of the final title compound. Precipitation with pentane from an ethyl acetate solution provides 29% of final title compound as a white powder: IR (KBr) v max 3399, 3316, 1745, 1699, 1668, 1534, 1513, 1241 cm -1 ; X H NMR (CDCI3) δ 5.89, 5.87, and 5.82 (3s in 6.0:1.8:1.0 ratio, 1 H); 5.05 and 5.03 (2s in 1:1.6 ratio, 2 H); 3.69, 3.67, and 3.65 (3s in 2.5:1.0:1.9 ratio, 3 H); --F NMR (CDC13) δ -112.53 (s), -112.60 (s), -116.25 (d, J=256 Hz), -117.00 (d, J=256 Hz), -120.21 (d, J=256 Hz), -120.78 (d, J=256 Hz), (s: d ratio 4:1); mass spectrum, m/z 770 (M + + 41), 758 (M + + 29), 731, 730 (M + + 1, 100); exact mass calcd for C 40 H 42 F 2 N 3 O 8 730.2940, found 730.2925; [α] 20 D -48.3° (c 1.22, CH 3 OH) . Anal. Calcd for C 4θ H 4 iF N 3 θ β : C, 65.83; H, 5.66; N, 5.76. Found: C, 65.16; H, 5.69; N, 5.79. Example 3 Preparation of α,α-Difluoro-γ-[ [3-methyl-l-oxo-2-[ [ (1- oxo-trans-3-phenyl-2-propenyl)amino]butyl]amino]-β-oxo-4- (phenylmethoxy)-N-(phenylmethyl)-benzene-pentanamide. Step A Preparation of N-(trans-Cinnamoyl)-L-valine To a stirred solution of L-valine methyl ester hydrochloride (1.97 g, 11.8 mmol) and NMM (1.10 g, 10.8 mmol) in CH 2 CI 2 (15 mL) and DMF (20 mL) is added a solution of 1-trans-cinnamoylimidazole (2.15 g, 10.8 mmol) in CH2CI2 (28 mL). After 18 h, additional L-valine methyl ester hydrochloride (0.36 g, 2.1 mmol) is added and the reaction mixture is stirred for 5 h before being diluted with water (100 mL) and extracted with CHCI 3 . The organic extract is washed with three portions of water, dried (MgSθ 4 ), and concentrated in vacuo. Filtration through a short silica gel column (1/1 ethyl acetate/cyclohexane) provides 2.0 g (71%) of N-(trans-cinnamoyl)-L-valine methyl ester. To a stirred solution of this ester (13.5 mmol) in CH 3 OH (125 mL) and water (5 mL) is added LiOH-H 2 θ (0.59 g, 14 mmol). After 17 hours an additional amount of LiOH-H 2 θ (0.06 g) is added and stirring is continued for 2 hours. The solutio is concentrated in vacuo and the residue is diluted with water (100 mL) and washed with ether. The aqueous layer acidified with ice-cold 6 N HC1 and extracted with two portions of ether. The combined extracts are washed with water and dried (MgS04). Concentration in vacuo provides 67% of the title compound as a white solid: mp 63-68°C; (CHC1 3 ) v max 3008, 2970, 1718, 1670, 1629, 1512, 1196, 66 cm "1 ; 1 H NMR (CDCI 3 ) δ 9.94 (bs, 1 H) , 7.65 (d, 1 H, J=15. Hz), 7.50-7.46 (m, 2 H) , 7.35-7.31 (m, 3 H) , 6.56 (d, 1 H J=8.7 Hz), 6.52 (d, 1 H, J=15.6 Hz), 4.75 (dd, 1 H, J=8.7 4.8 Hz), 2.34-2.28 (m, 1 H) , 1.02 (d, 3 H, J=6.9 Hz), 0.9 (d, 3 H, J=6.6 Hz); 13 C NMR (CDCI 3 ) δ 175.31, 166.66, 142.42, 134.50, 129.93, 128.79, 127.94, 119.75, 57.47, 31.19, 19.00, 17.78; mass spectrum, m/z 276 (M + + 29), 24 (M + + 1), 203, 131 (100); exact mass calcd for C 14 H 18 NO 3 248.1287, found 248.1290; [α] 20 D +24.1° (c 1.02, CH 3 OH) . Anal. Calcd for C 14 H 1 -/NO 3 O.1H 0: C, 67.51; H, 6.96; N, 5.62. Found: C, 67.30; H, 7.10; N, 5.57. Step B Preparation of [3ζ,4(S) ]-2,4,5-Trideoxy-2,2-difluoro-4-[ [ methyl-l-oxo-2-[ (l-oxo-trans-3-phenyl-2- propenyl)amino]butyl]amino]-5-[4-(phenylmethoxy)phenyl]-N (phenylmethyl)-L-qlycero-pentanamide. Reaction Scheme A', step (e): N-(trans-Cinnamoyl)-L- valine prepared above (25 mmol) is dissolved in CH 3 CN (80 and the resulting solution cooled to -10°C. To the stirr solution is added N-methylmorpholine (2.52 g, 24.9 mmol, NMM), followed by isobutylchloroformate (3.72 g, 27.2 mmol). After 10 minutes, a solution of 4-amino-2,2- difluoro-3-hydroxy-5-(4-benzyloxy)phenyl-N-(phenylmethyl) pentanamide (43.7 mmol, prepared in example 1, step D and NMM (4.08 g, 40.3 mmol) in H 2 O (20 mL) is added and stirr is continued at -10°C for 20 minutes. The reaction mixtu is poured into ice-cold dilute HC1 containing some NaCl a is extracted with two portions of ethyl acetate. The combined extracts are washed with water, aqueous saturated sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue is recrystallized from ethyl acetate/pentane to provide 61% of a 2:1 mixture of diastereomers of title compound as a light tan solid: mp 222-227°C; IR (KBr) v max 3410, 3287, 1682, 1652, 1620, 1540, 1512, 1243, 1217, 697 cm "1 ; X H NMR (DMSO-d 6 ) δ 9.17-9.11 (m, 1 H) , 8.05 and 8.01 (2d, 1 H total, J=9.1, 9.1 Hz), 7.85 and 7.71 (2d, 1 H total, J=9.1, 9.0 Hz), 7.59-7.22 (m, 16 H), 7.12 (d, 2 H, J=8.5 Hz), 6.94-6.85 (m, 3 H), 6.26 (d, 1 H, J=7.6 Hz), 5.04 and 4.96 (2s, 2 H total), 4.42-3.99 (m, 5 H), 2.79- 2.63 (m, 2 H), 2.09-1.98 and 1.92-1.85 (2m, 1 H total), 0.86 and 0.74 (2d, 3 H total, J=6.9 Hz), 0.83 and 0.64 (2d, 3 H total, J=6.9 Hz); 19 F NMR (DMSO-d 6 ) δ -111.11 (dd, J=255, 6 Hz), -112.12 (dd, J=254, 8 Hz), -120.35 (dd, J=254, 19 Hz), -122.04 (dd, J=255, 20 Hz); mass spectrum, m/z 698 (M + + 29), 670 (M + + 1, 100), 650, 441, 423. Anal. Calcd for C 39 H 41 F 2 N 3 O 5 : C, 69.94; H, 6.17; N, 6.27. Found: C, 68.59; H, 6.32; N, 5.90. Step C Preparation of the final title compound. Reaction Scheme A', step (f): The above prepared alcohol is oxidized under Swern conditions as follows: To a stirred solution of 2 M oxalyl chloride/CH 2 Cl 2 (2.0mL) at -60°C under nitrogen is added dropwise anhydrous DMSO (0.42 mL, 5.9 mmol). After 10 minutes, a solution of the above prepared alcohol (0.50 mmol) in CH 2 CI 2 (3 mL) and anhydrous DMSO (1.5 mL) is added. The solution is allowed to stir at -65 to -55°C for 5 hours. It is then warmed to -20°C, followed by addition of triethylamine (1.39 mL, 10.0 mmol) over 5 minutes. The reaction mixture is then allowed to warm to room temperature overnight. It is then diluted with ethyl acetate (60 mL) and filtered, washing the solids with ethyl acetate. The filtrate is washed with 0.1 M HC1 (3 x 15 mL), brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. Flash chromatography (6% acetone in CH 2 CI 2 ) followed by recrystallization from ethyl acetate/pentane provides 34 of the final title compound as a white solid: mp 187-194 IR (KBr) n, ax 3403, 3285, 1691, 1654, 1623, 1540, 1513, 1454, 1243, 1219, 1178, 697 cm "1 ; λ E NMR (DMSO-d 6 ) δ 9.77 9.68 (m, 1 H), 8.67-8.62 (m 1 H), 8.05-8.00 (m, 1 H) , 7. (d, 2 H, J=7.0 Hz), 7.50-7.21 (m, 14 H), 7.14 (d, 2 H, J=8.5 Hz), 6.91-6.83 (m, 3 H) , 5.04-4.95 (m, 3 H) , 4.42- 4.33 (m, 3 H), 3.14-3.05 (m, 1 H), 2.74-2.61 (m, 1 H) , 2.02-1.76 (m, 1 H) , 0.84 and 0.81 (2d, 3 H total, J=7.0, 6.9 Hz), 0.64 and 0.59 (2d, 3 H total, J=7.1, 6.9 Hz); 19 NMR (DMSO-d 6 ) δ -110.26 (d, J=269 Hz), -110.53 (d, J=268 Hz),-112.03 (d, J=269 Hz), -112.04 (d, J=268 Hz)-major diastereomer pair; -105.07 (d, J=265 Hz), -105.08 (d, J=266 Hz), -110.59 (d, J=265 Hz), -110.61 (d, J=266 Hz) minor diastereomer pair; mass spectrum, m/z 696 (M + + 29) 668 (M + + 1), 439, 230, 202, 131, 124, 91 (100); exact calcd for C39H40F2N3O5 668.2936, found 668.2953; [α] 0 D +7.23° (c 0.622, DMSO-d 6 ). Anal. Calcd for C 39 H 39 F 2 N 3 O 5 : 70.15; H, 5.89; N, 6.29. Found: C, 69.63; H, 5.85; N, 6.01. Example 4 Preparation of α,α-Difluoro-γ-[ [ 2-[ 2-hydroxy-l-oxo-4- (phenylbutyl)amino]-3-methyl-l-oxobutyl ]amino]-B-oxo~4- (phenylmethoxy)-N-(phenylmethyl)-benzene-pentanamide. Step A Preparation of(R)-[ [2-[ (1,1- Dimethylethyl)dimethylsilyl 1oxy]-4-phenylbutyryl]-L-valine. ι_ (R)-(-)-2-hydroxy-4-phenylbutyric acid is coupled with L-valine methyl ester hydrochloride under standard coupling conditions in a manner analogous to that described previously, such as example 2, step A, to provide (R)-(2- hydroxy-4-phenylbutyryl)-L-valine methyl ester as a yellow 20 solid in 89% yield. Treatment with tert-butyldimethylsilyl chloride in a manner analogous to that described previously in example 1 for the preparation of N-(R)-[ [ [ (1,1- dimethylethy1)dimethyIsily1]oxy]phenylacetyl]-L-valine provides the ester of the title compound as a colorless oil 25 in 83% yield after flash chromatography (9/1 cyclohexane/ethyl acetate) . The ester is hydrolyzed with LiOH»H2θ in a manner analogous to that described previously in example 1 for the preparation of N-(R)-[ [ [ (1,1- dimethylethyljdimethylsilyl ]oxy]phenylacetyl]-L-valine to 30 provide the title compound in 58% yield as a white solid: mp 110-113°C; IR (KBr) v max 3387, 2958, 2932, 2897, 2860, 1719, 1626, 1531, 1251, 1097, 839 cm "1 ; X H NMR (CDC1 3 ) δ 7.24-7.12 (m, 7 H) , 4.54 (dd, 1 H, J=8.7, 4.5 Hz), 4.32 (t, 1-H, J=4.8 Hz), 2.76-2.55 (m, 2 H) , 2.36-2.25 (m, 1 H) , 35 2.19-2.07 (m, 1 H), 2.02-1.90 (m, 1 H), 1.00 (d, 3 H, J=7.2 Hz), 0.97 (d, 3 H J=6.9 Hz), 0.97 (s, 9 H) , 0.13 (s, 3 H) , 0.10 (s, 3 H); 13 C NMR (CDCI 3 ) δ 175.64, 174.08, 141.69, 128.42, 128.30, 125.77, 72.73, 59.64, 36.98, 30.75, 30.02, 25.67, 19.05, 17.93, 17.54, -4.79, -5.15; mass spectrum, m/z 394 (M + + 1), 393 (M+), 378, 336 (100), 289, 117, 91, 73; [α] 20 D +13.7° (c 1.00, CH 3 OH) . Anal. Calcd for C 2 ιH 35 Nθ 4 Si: C, 64.08; H, 8.96; N, 3.56. Found: C 63.87; H, 9.07; N, 3.45. Step B Preparation of [ 3ζ,4(S,R) ]-2,4,5-Trideoxy-4-[ [2-[ [2-[ [ (1,1 dimethylethy1)dimethyIsilyl]oxy]-l-oxo-4- phenylbutyl1amino]-3-methyl-l-oxobutyl3amino]-5-[4- (phenylmethoxy)phenyl]-N-(phenylmethyl)-L-qlycero- pentanamide. Reaction Scheme A', step (e): (R)-[ [2-[ (1,1- Dimethylethyl)dimethylsilyl]ox ]-4-phenylbutyryl]-L-valine is coupled with 4-amino-2,2-difluoro-3-hydroxy-5-(4- benzyloxy)phenyl-N-(phenylmethyl)pentanamide prepared in example 1, step D under standard coupling conditions in a manner analogous to that described previously, such as in example 2, step A, to provide the title compound after flash chromatography (6% acetone in CH 2 CI 2 ) as a tan foam i 61% yield: mp 62-67°C; X H NMR (CDCI 3 ) δ 7.44-7.11 (m, 17 H) 7.04 (d, 2 H, J=8.7 Hz), 6.86 (d, 2 H, J=8.7 Hz), 6.11 (d, 1 H, J=8.1 Hz), 5.01 (s, 2 H) , 4.71 (d, 1 H, J=6.9 Hz), 4.52 (dd, 1 H, J=14.6, 6.5 Hz), 4.35 (dd, 1 H, J=14.4, 5.4 Hz), 4.28 (t, 1 H, J=4.8 Hz), 4.15-3.93 (m, 3 H) , 2.91 (d, 2 H, J=7.8 Hz), 2.72 (ddd, 1 H, J=13.2, 12.0, 4.8 Hz), 2.5 (ddd, 1 H, J=13.5, 12.3, 5.4 Hz), 2.15-1.90 (m, 3 H) , 0.98 (s, 9 H), 0.87 (d, 3 H, J=2.4 Hz), 0.85 (d, 3 H, J=2.1 Hz), 0.14 (s, 3 H), 0.10 (S, 3 H) ; 19 F NMR (CDCI 3 ) δ -117.17 (dd J=259, 15 Hz), -118.62 (dd, J=259, 10 Hz); mass spectrum, m/z 844 (M+ + 29), 816 (M+ + 1), 758, 469, 441, 423 (100), 91; [ot] 20 D -30.6° (c 0.547, CH 3 OH) . Anal. Calcd for C 46 H 59 F 2 N 3 0 6 Si: C, 67.70; H, 7.29; N, 5.15. Found: C, 67.32 H, 7.22; N, 5.15. Step C Preparation of final title compound. Reaction Scheme A', steps (f) and (g): The above prepared alcohol is oxidized under Swern conditions in a manner analogous to that described previously in example 1, step G to provide the protected ketone as a light brown oil in 72% yield after flash chromatography (6% acetone in CH 2 CI 2 ). Deprotection of the ketone (217mg) in a manner analogous to that described previously in example 1, step G provides the title compound after flash chromatography (6, 10, and finally 15% acetone in CH 2 CI 2 ), 104 mg (58%) as a light yellow glass. Crystallization from CH 2 Cl 2 /ether and three recrystallizations from ethyl acetate/pentane provides 34 mg (19%) of title compound as a white solid: IR (KBr) v max 3394, 3300, 1686, 1651, 1534, 1513, 1498, 1243, 698 cm "1 ; 1 H NMR (DMSO-d 6 ) δ 9.76-9.69 (m, 1 H) 8.70-8.66 (m, 1 H), 7.52-7.11 (m, 19 H) , 6.88 and 6.87 (2d, 2 H total, J=8.7 Hz), 5.73 (t, 1 H, J=5.8 Hz), 5.03 and 5.00 (2s overlapping m, 3H total, J=8.3 Hz), 4.35 (apparent d, 2 H, J=6.1 Hz), 4.26-4.20 (m, 1 H) , 3.94-3.87 (m, 1 H) , 3.15- 3.06 (m, 1 H), 2.73-2.58 (m, 2 H) , 1.96-1.66 (m, 3 H) , 0.77 and 0.76 (2d, 3 H total, J=6.7 Hz), 0.63 and 0.53 (2d, 3 H total, J=6.8, 6.6 Hz); 19 F NMR (DMSO-d 6 ) δ -110.35 (d, J=268 Hz), -110.47 (d, J=268 Hz), -112.14 (d, J=268 Hz), -112.20 (d, J=268 Hz); mass spectrum, m/z 700 (M + + 1), 680, 622, 439 (100), 421, 254, 91. Example 5 Preparation of N-[l-[ [ [3,3-Difluoro-4-[ [ 2-methyl-l- [ (phenylmethoxy)methyl]-propyl]amino]-2,4-dioxo-l-[ [4- (phenylmethoxy)phenyl ]-methyl]butyl]amino]carbonyl ]-2- methylpropyl]-8-oxo-4-morpholinepropanamide. Step A Preparation of [1 (R), 3 , 4(S) ]-2,4,5-Trideoxy-4-[ [ (1,1 dimethylethoxy)-carbonyl]amino]-2,2-difluoro-N-[2-methyl [ (phenylmethoxy)methyl]propyl1-5-[4-( henylmethoxy)pheny L-qlycero-pentanamide. Reaction Scheme A, step (b): To a stirred solution O-benzyl-D-valinol (5.42 g, 28.0 mmol) in CH 2 CI 2 (15 mL) added a 2 M solution of (CH 3 ) 3 Al/toluene (14.0 mL, 28.0 mmol) over 20 minutes. During the addition more CH 2 CI 2 mL) is added to convert the resulting paste to a thin slurry. As the addition proceeds, a solution again form with vigorous gas evolution as it warms to reflux. Afte the addition is complete, the solution is allowed to sti at reflux for 15 minutes as gas evolution subsides. The solution is allowed to cool to room temperature and a solution of 4-tert-butoxycarbonylamino-2,2-difluoro-3- hydroxy-5-(4-benzyloxy)phenylpentanoic acid, ethyl ester (5.38 g, 11.2 mmol, prepared in example 1) in CH 2 CI 2 (20 is added over 15 minutes with moderate gas evolution. T resulting solution is heated at reflux overnight. The reaction mixture is cooled to 0°C and carefully quenched with excess methanol. The resulting solution is washed with 1 N HC1. The aqueous layer is extracted with ether The combined organic extracts are washed with water, dri over anhydrous magnesium sulfate, filtered and concentra under vacuum to provide after flash chromatography (4:1 cyclohexane/ethyl acetate) 5.5 g (78%) of title compound as a beige powder. Step B Preparation of [1 (R), 3^, 4(S) ]-4-Amino-2,4,5-trideoxy- 2,2-difluoro-N-[2-methyl-l-[ (phenylmethoxy)methyl]propyl]- 5-[4-(phenylmethoxy)phenyl]-L-qlycero-pentanamide. Reaction Scheme A, step (d): A solution of the above prepared alcohol (3.6 g, 5.7 mmol) in HCO 2 H (50 mL) is allowed to stir at room temperature for 3 hours. The solution is then concentrated under vacuum at 35°C. The residue is dissolved in ethyl acetate and aqueous sodium bicarbonate is added with vigorous stirring. The layers are separated and the organic layer is washed with water. The combined aqueous layers are again extracted with ethyl acetate. The combined organic extracts are dried anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide 3.0 g (99%) of the title compound as an orange oil. Step C Preparation of [1 (R) , 3 , 4(S) ]-2,4,5-Trideoxy-4-[ [2- [ [ (l,l-dimethylethoxy)carbonyl]amino]-3-methyl-l- oxobutyl]amino]-2,2-difluoro-N-[2-methyl-l- [ (phenylmethoxy)methyl]propyl]-5-[4-( henyl¬ methoxy)phenyl]-L-qlycero-pentanamide. Reaction Scheme D, step (a): The above prepared amine is coupled under standard conditions in a manner analogous to that described previously, such as exmaple 2 , step A, with N-(tert-butoxycarbonyl)-L-valine (1.21 g, 5.61 mmol) to provide, after flash chromatography (9:1 CH 2 Cl 2 /ethyl acetate), 2.3 g (60%) of title compound as a yellow powder. Step D Preparation of [1 (R), 3ζ, 4(S) ]-4-[ [ 2-Amino-3-me hy1-1 oxobutyllaminol-2,4 ,5-trideoxy-2,2-difluoro-N-[2-methyl [ (phenylmethoxy)methyl]-propyl]-5-[4- (phenylmethoxy)phenyl]-L-qlycero-pentanamide. Reaction Scheme D, step(b): A solution of the above prepared amide (2.0 g, 2.8 mmol) in HC0 2 H (25 mL) is all to stir at room temperature for 6 hours. The solution concentrated under vacuum at 30°C and the residue is dissolved in ethyl acetate. Aqueous sodium bicarbonate added with vigorous stirring. White solids precipitate which are filtered and found to be the formate salt of (S)-amino alcohol. The organic layer of the filtrate i separated, washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under vacu to provide an amber oil containing some white solids; the (R)- and (S)-amino alcohol and the lactam by-produc are present. The residue is slurred in CHCI 3 for 1 hour the precipitated solids, again the formate salt of the ( amino alcohol, are collected. The filtrate is concentr under vacuum and the residue dissolved in CH 2 CI 2 and additional formate salt of the (S)-amino alcohol is collected. Flash chromatography of the residual oil (5: CH 2 Cl 2 /ethyl acetate to remove the lactam, then 9:1 CH 2 C CH 3 OH) provides a yellow semi-solid which is the (R)-ami alcohol contaminated with 5% of the formate of the (S)- amino alcohol. Yield: 800 mg (43%) of the formate salt the (S)-amino alcohol and 640 mg (37%) of the (R)-amino alcohol. To a stirred suspension of the formate salt of (S)-amino alcohol (800 mg, 1.19 mmol) in ethyl acetate added 10% aqueous sodium bicarbonate. After 2 hours at room temperature, the solids dissolve. The organic la is separated, washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under vacu to provide 712 mg (95%) of title compound as a white powder: mp 160-164°C; IR (KBr) umax 3383, 3327, 1676, 1530, 1514, 1244, 1109 cm "1 ; X H NMR (CDCI 3 ) δ 7.73 (d, J = 6.9 Hz), 7.43-7.29 (m, 10 H), 7.10 (d, 2 H, J = 8.4 Hz), 6.90 (d, 2 H, J = 8.7 Hz), 6.78 (d, 1 H, J = 9.0 Hz), 5.56 (bs, 1 H), 5.04 (s, 2 H) , 4.55 (d, 1 H, J = 12.0 Hz), 4.47 (d, 1 H, J = 12.0 Hz), 4.33-4.18 (m, 2 H), 3.92-3.83 (m, 1 H), 3.60 (dd, 1 H, J = 9.6, 3.6 Hz), 3.45 (dd, 1 H, J = 9.6, 3.6 Hz), 3.16 (d, 1 H, J = 3.9 Hz), 3.03-3.00 (m, 2 H), 2.18-1.93 (m, 2 H), 1.44 (bs, 2 H) , 0.94 (d, 6 H, J = 6.9 Hz), 0.85 (d, 3 H, J = 6.9 Hz), 0.53 (d, 3 H, J = 6.9 Hz); 19 F NMR (CDC1 3 ) δ -110.67 (dd, J = 259, 5 Hz), - 121.74 (dd, J = 258, 18 Hz); mass spectrum, m/z 654 (M + + 29), 626 (M + + 1), 325, 92, 91 (100), 72. Anal. Calcd for C 35 H 45 F 2 N 3 O 5 : C, 67.18; H, 7.25; N, 6.72. Found: C, 67.34; H, 7.21; N, 6.66. Step E Preparation of [1 (R) , 3E, 4(S) 1-2,4,5-Trideoxy-2,2- difluoro-4-[[3-methyl-2-[ [3-(4-morpholinyl)-l,3- dioxopropyl]amino3-l-oxobutyl]amino]-N-[2-methyl-l- [ (phenylmethoxy)methylJpropyl]-5-[4-(phenyl- methoxy)phenyl]-L-qlycero-pentanamide. Reaction Scheme D, step (c): The (R)-amino alcohol prepared above (169 mg, 0.270 mmol) is coupled under standard coupling conditions described previously, such as example 2, step A, with 2-(4-morpholinylcarbonyl)ethanoic acid (49 mg, 0.28 mmol, compound (B) prepared in example 5a) to provide, after flash chromatography (3% CH 3 OH/CHCI3) , 185 mg (88%) of title compound as a tan powder: mp 87-94°C; IR (KBr) v max 3428, 3325, 1651, 1535, 1512, 1454, 1238, 1115 cm "1 ; 19 F NMR (CDCI 3 ) δ -116.11 (d, J = 259 Hz), - 119.49 (dd, J = 259, 15 Hz); mass spectrum, m/z 809 (M + + 29), 781 (M + + 1) 509, 255, 243, 227, 88 (100). Step F Preparation of final title compound. Reaction Scheme D, step (d): The above prepared alcohol (177 mg, 0.283 mmol) is oxidized under Swern conditions in a manner analogous to that described in example 1, step G to provide 170 mg (100%)of the final title compound after flash chromatography (3% CH 3 OH/CHCI 3 Recrystallization from CH 2 Cl 2 /et er provides 49 mg (28%) final title compound as pale tan powder: mp 119-128°C; I (KBr) v max 3306, 1661, 1638, 1539, 1514, 1454, 1238, 111 cm "1 ; 1 H NMR (CDCI3) δ 7.77 and 7.75 and 7.61 and 7.47 (4 1 H total, J = 7.1, 7.1, 8.7, 8.9 Hz respectively), 7.4 7.29 (m, 10 H), 7.16-7.03 (m, 3H), 6.91-6.72 and 6.38-6. (2m, 3 H total), 5.74 and 5.53-5.46 and 5.24-5.17 (bs an 2m, 1 H total) 5.02 (s, 2 H), 4.56 and 4.48 (2d, 1 H tot J = 12.1 Hz), 4.55 and 4.47 (2d, 1 H total, J = 12.0 Hz 4.27 and 4.23 and 4.12 (3dd, 1 H total, J = 8.8, 5.3 and 8.7, 5.7 and 7.3, 5.1 Hz respectively), 3.89-3.80 (m, 1 3.69-3.59 (m, 7 H) , 3.52-3.40 (m, 3 H) , 3.32-3.21 (m, H), 2.94-2.75 (m, 1 H), 2.29-1.87 (m, 2 H) , 0.94 and 0.9 and 0.92 and 0.91 and 0.89 and 0.88 and 0.84 and 0.81 an 0.80 and 0.76 and 0.59 and 0.55 (12d, 12 H total, J = 6. and 7.0 and 7.0 and 6.9 and 6.9 and 7.0 and 7.0 and 7.0 6.8 and 6.8 and 6.9 and 6.8 Hz respectively); 19 F NMR (CDCI 3 ) δ -114.46 (d, J = 274 Hz), -112.74 (s), -113.47 ( J = 274 Hz), Hydrate: -114.43 (d, J - 253 Hz), -116.47 J = 254 Hz), -120.63 (d, J = 253 Hz), -122.73 (d, J = 25 Hz); mass spectrum, m/z 807(M + + 29), 779 (M + + 1), 401 361, 243 (100), 227; exact mass calcd for C 42 H 53 F 2 N 4 O8 779.3831, found 779.3878. Example 5a Preparation of 4-Morpholine acetic acid, trifluoroacetic acid salt (A) and 2-(4-Morpholinylcarbonyl)ethanoic acid _______ Preparation of 4-Morpholine acetic acid, 1,1-dimethylethyl ester. To a stirred solution of t-butyl bromoacetate (1.61 mL, 10.0 mmol) in tetrahydrofuran (25 mL) is added morpholine (1.74 mL, 20.0 mmol). The suspension is stirred for 1.5 hours and then concentrated under vacuum. The residue is dissolved in methylene chloride (50 mL) with saturated sodium carbonate (50 mL) . The layers are separated and the aqueous is extracted methylene chloride (2 x 25 mL). The organic extracts are combined, washed with saturated sodium carbonate (20 mL), brine (30 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue is triturated with ethyl acetate (15 mL), filtered and the filtrate concentrated under vacuum to provide the title compound (2.01 g) as a colorless oil; TLC R f = 0.45 (ethyl acetate, silica gel). Preparation of final title compound (A). Trifluoroacetic acid (15 mL) is added to the above prepared ester (1.00 g, 4.97 mmol). The solution is stirred for 5 hours and then concentrated under vacuum to provide a yellow oil. This is triturated with diethyl ether (25 mL) to provide the final title compound (A) (1.06 g, 82%) as an off white solid; mp 118-121°C. Preparation of 2-(4-Morpholinylcarbonyl)ethanoic acid, methyl ester. To a solution of methylmalonyl chloride (10.0 g, 73.2 mmol) in methylene chloride (200 L) at 0°C is added rapid dropwise a solution of morpholine (16.0 g, 0.183 mmol, 16. mL) in methylene chloride (50 mL) . The reaction is stirr for 4 hours at room temperature. The reaction is then filtered and the filtrate is diluted with additional methylene chloride (200 mL). This is then washed with 1 HC1, saturated sodium bicarbonate and brine. The organic is then concentrated under vacuum to provide a yellow oil, which is purified by flash chromatography (ethyl acetate, silica gel) to provide the title compound (9.7 g, 71%) as pale yellow oil; Rf = 0.28 (ethyl acetate). Preparation of final title compound (B). To a solution of the above prepared amide (1.70 g, 9. mmol) in methanol (45 mL) is added IN lithium hydroxide ( L, 9.99 mmol). The reaction is stirred at room temperature for 2.5 hours. The pH is adjusted to 3 with HCL and the reaction is concentrated under vacuum. The residue is recrystallized from acetonitrile to provide th title compound (B) (0.216 g, 14%) as a white solid. Example 6 [ 1R- ( 1R* , 2S* ) ] -α , α-Dif luoro-γ- [ [ 2- ( R) ~ [ [ (hydroxy)phenylacetyl]-amino]-3-methyl-l-oxobutyl]amino] ■ N-[2-methyl-l-[ (phenylmethoxy)methyl]propyl]-β-oxo-4- (phenylmethoxy)-benzenepentanamide. Step A Preparation of [1 (R) , 3E, 4(S) ]-2,4,5-Trideoxy-4-[ [2-[ [ 4- [ [2-[ [[[(I,1-dimethyl- ethy1)dimethylsilyl]oxyjphenylacetyl]amino]-3-methyl-l- oxobutyl]amino]-2 ,2-difluoro-N-[2-methyl-l- [ (phenylmethoxy)-methyl]propyl ]-5-[4-(phenylmethoxy)- phenyl]-L-qlycero-pentanamide. Reaction Scheme A', step (e): [1 (R), 3_, 4(S)]-4- Amino-2,4,5-trideoxy-2,2-difluoro-N-[2-methyl-l- [ (phenylmethoxy)methyl]propyl]-5-[4-(pheny1- methoxy)phenyl]-L-glycero-pentonamide (0.87 g, 1.6 mmol) prepared in example 5, step B, is coupled under standard coupling conditions in a manner analogous to that described previously, such as example 2, step A, with (R)-O-tert- butyldimethyl-silylmandelic acid (0.44 g, 1.2 mmol) prepared in example 1 to provide the title compound, after flash chromatography (3:2, then 1:1 hexane/ethyl acetate), 0.36 g (35%) as a yellow oil: IR (film) v max 3405, 3325, 2959, 2932, 2895, 2876, 2861, 1684, 1657, 1512, 1470, 1454, 1244, 1221, 1179, 1098, 864 cm "1 ; 19 F NMR (CDC1 3 ) δ -117.20 (d, J = 258 Hz), -118.99 (s), -120.55 (d, J = 262 Hz); mass spectrum (CI, 70 eV) , m/z 874 (M + + 1), 509, 221 (100); exact mass calcd for C 4 gH 66 2 N 3 θ Si 874.4638, found 874.4651. Step B Preparation of final title compound. Reaction Scheme A', steps (f) and (g): The above prepared alcohol(345 mg, 0.39 mmol) is oxidized under Swe conditions in a manner analogous to that described previously in example 1 to provide after flash chromatography (3:2 hexane/ethyl acetate), 154 mg ( 45%) the ketone as a yellow glass: IR (film) v roax 3408, 3298, 2961, 2932, 2861, 1655, 1613, 1514, 1470, 1454, 1246, 117 1098, 1072, 839 cm "1 ; 19 F NMR (CDCI 3 ) δ -112.68 (s), -117. (d, J = 253Hz), -120.03 (d, J = 253 Hz); mass spectrum (CI, 70 eV), m/z 872 (M+ + 1), 221 (100), 197; exact mas calcd for C 49 H 64 F 2 N 3 0 Si 872.4482, found 872.4500. To a stirred solution of ketone in CH 2 CI 2 (4 mL) is added TFA/H 2 O (9:1, 1 mL) . The reaction mixture is allow to stir at room temperature for 7 hours and then concentrated under vacuum. The residue is dissolved in CH 2 CI 2 and the solution is washed with saturated aqueous sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, filtered and concentrate under vacuum. The residue is purified by flash chromatography (1:1 hexane/ethyl acetate) to provide 85 mg (64%) of the final title compound as a white powder: IR (film) v max 3397, 331 2965, 2934, 2874, 1750, 1688, 1663, 1532, 1514, 1468, 145 1242, 1179, 1113, 826 cm "1 ; 19 F NMR (CDCI 3 ) δ -112.30 (d, = 271 Hz), -113.50 (d, J = 271 Hz), -117.54 (d, J = 254 Hz), -119.32 (d, J = 254 Hz); mass spectrum (CI, 70 eV) , m/z 758 (M + + 1), 107 (100), 91. Anal. Calcd for C 3 H 9 F 2 N 3 O 7 «0.6H 2 O: C, 67.19; H, 6.58; N, 5.47. Found: 67.11; H, 6.55; N, 5.39. Example 7 Preparation of N-[l-[ [ [3,3-Difluoro-4-[ [2-methyl-l- [ (phenylmethoxy)-methyl3-propyl]amino]-2,4-dioxo-l-[ [ 4- (phenylmethoxy)phenyl ]- methyl )-butyl]amino]carbonyl1-2- methylpropyl]-6-(4-morpholinyl-carbonyl)-3- pyridinecarboxa ide. Step A Preparation of 6-(4-Morpholinylcarbonyl)-3- pyridinecarboxylic Acid. To a stirred 1 M solution of 0-tert-butyl-N,N '- dicyclohexylisourea [see Mathias, L., Synthesis, 570, 1979, for preparation] in CH2CI 2 (20 mL) at 5°C under nitrogen is added 1.49 g (8.24 mmol) of 2-methyl isocinchomeronate [see Isagawa, K. , et al., Nippon Kaqaku Zasshi, 88, 553, 1967, for preparation] in portions over 2 minutes. After 15 minutes, the cold water bath is removed. As dicyclohexylurea begins to precipitate, the reaction mixture is again be placed in a cool water bath at 15-20°C. The mixture is diluted with CH 2 CI 2 (5 L) and allowed to stir at room temperature overnight. The mixture is then diluted with CH 2 CI 2 (30 mL), filtered, and the blue- green solids are washed with CH 2 CI 2 • The filtrate and washings are diluted with ether and washed with dilute aqueous sodium bicarbonate, water, brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide 1.36 g of light blue solids. Flash chromatography (55:45 cyclohexane/ethyl acetate) provides 1.01 g (52%) of the diester below as white crystals. Recrystallization from ether/pentane provides the above diester as matted white needles: mp 111 112°C; IR (KBr) v max 3420, 2984, 1711, 1379, 1310, 1290, 1246, 1134, 1126, 746 cm "1 ; X H NMR (CDC1 3 ) δ 9.26 (d, 1 H, = 2.1 Hz), 8.39 (dd, 1 H, J = 8.1, 2.1 Hz), 8.19 (dd, 1 H J = 8.1, 0.7 Hz), 4.04 (s, 3 H) , 1.63 (s, 9H) ; mass spectrum (El), m/z 238 (M+ + 1), 237 (M+), 182, 179, 164, 57, (100); CI m/z 238 (M+ + 1), 210, 182 (100). Anal. Cal for C 12 H 15 NO 4 : C, 60.75; H, 6.37; N, 5.90. Found: C, 60.80 H, 6.31; N, 5.75. A solution of the above diester (935 mg 3.94 mmol) and morpholine (2.0 mL, 23 mmol) in THF (6 mL) are stirred at reflux under nitrogen for 24 hours. Additional morpholine (2.0 mL, 23 mmol) is added and heating continued. After 3 more days, the solution is concentrated under vacuum and the residue is dissolved in ethyl acetate and the solution is washed twice with water. The organic layer is concentrated under vacuum to provide 1.01 g of light yellow solid. Two recrystallizations from ether/pentane, with filtration through filter aid, provide 542 mg (47%) of amide ester below as fine cream-colored crystals: mp 91-93°C; IR (KBr) v max 2984, 2965, 1707, 1634, 1370, 1317, 1287, 1169, 1132, 1117 cm "1 ; l E NMR (CDCI 3 ) δ 9.13 (dd, 1 H, J = 2.1, 1.0 Hz), 8.36 (dd, 1 H, J = 8.1, 2.1 Hz), 7.75 (dd, 1 H, J = 8.1, 0.9 Hz), 3.83 (s, 4 H) , 3.73-3.55 (m, 4 H) , 1.62 (s, 9 H) ; mass spectrum, m/z 293 (M + + 1), 292, 123, 86 (100). Ana Calcd for C 15 H 20 2 O 4 : C, 61.63; H, 6.90; N, 9.58. Found: C 61.62; H, 6.91; N, 9.64. HC1 gas is bubbled through a solution of the above amide ester (103.5 mg, 0.354 mmol) in CH 3 NO 2 (4-5 mL) for 20-25 minutes. After standing for an additional 20 minutes, the solution is concentrated under vacuum and the residue is triturated with acetone to provide the title compound (acid) as a pale yellow solid. The material is combined with crude acid from a similar experiment (from 502 mg 14) and recrystallized from acetone to provide (335 mg (69%) of title compound as short, thick white needles: mp 181-183°C; IR (KBr) v max 2928, 2872, 1717, 1601, 1285, 1262, 1111 cm "1 ; 1 H NMR (CD 3 OD) δ 9.26 (d, 1 H, J = 1.1 Hz), 8.78 (dd, 1 H, J = 8.1, 2.0 Hz), 8.0 (d, 1 H, J = 8.1, Hz), 3.80 (s, 4 H) , 3.67 (nm, 2 H) , 3.51 (nm, 2 H); mass spectrum, m/z 277 (M + + 41), 265 (M + + 29), 238, 237 (M + + 1, 100). Anal. Calcd for C 11 H 12 N 2 O4: C, 55.93; H, 5.13; N, 11.86. Found: C, 56.15; H, 5.32; N, 11.46. Step B Preparation of [1 (R) , 3ζ, 4(S) -2,4,5-Trideoxy-2,2- difluoro-4-[ [3-methyl-2-[ [ [6-(4-morpholinylcarbonyl)-3- pyridinyllcarbonyl]amino]-l-oxobutyl3-amino3-N-[2-methyl-l- [ (phenylmethoxy)methyl3-propyl]-5-[4- (phenylmethoxy)phenyl3-L-qlycero-pentanamide. Reaction Scheme D, step (c): The (S)-amino alcohol (185 mg, 0.296 mmol) prepared in example 5, step D, is coupled with the above prepared acid (77 mg, 0.33 mmol) under standard coupling conditions in a manner analogous to that described previously, such as example 2, step A, to provide after flash chromatography (5% CH 3 OH/CHCI 3 ), 227 mg (91%) of the title compound as a white powder: mp 218-220°C; IR (KBr) v max 3287, 1674, 1663, 1636, 1557, 1539, 1514, 1244, 1115 cm "1 ; X H NMR (CDCI 3 + DMSO-d 6 ) δ 9.05 (d, 1 H, J = 1.8 Hz), 8.29 (dd, 1 H, J = 8.1, 2.1 Hz), 8.03 (d, 1 H, J = 9.3 Hz) 7.70 (d, 1 H, J = 8.4 Hz), 7.46 (d, 1 H, J = 8.4 Hz), 7.37-7.22 (m, 11 H) , 7.09 (d, 2 H, J = 8.1 Hz), 6.67 (d, 2 H, J = 8.4 Hz), 5.89-5.85 (m, 1 H) , 4.88 (d, 1 H, J = 11.7 Hz), 4.83(d, 1 H, J = 11.7 Hz), 4.54 (d, 1 H, J = 12.0 Hz), 4.47 (d, 1 H, J = 12.0 Hz), 4.45-4.35 (m, 1 H) , 4.31 (t, 1 H, J = 9.0 Hz), 4.24-4.13 (m, 1 H) , 3.92-3.82 (m, 1 H), 3.77 (s, 4 H) , 3.64-3.48 (m, 6 H) , 3.08-3.02 (m, 1 H), 2.76 (dd, 1 H, J = 14.4, 10.5 Hz), 2.15-1.92 (m, 2 H), 0.94 (d, 6 H, J = 6.9 Hz), 0.88 (d, 6 H, J = 6.6 Hz); 19 F NMR (CDC1 3 + DMSO-d 6 ) δ -109.78 (d, J = 256 Hz), -122. (dd, J = 256, 19 Hz); mass spectrum, m/z 872 (M + + 29), 8 (M+ + 1), 509 (100), 418, 318, 290, 219. Anal. Calcd for C 46 H 55 F 2 N 5 O 8 : C, 65.47; H, 6.57; N, 8.30. Found: C, 65.0 H, 6.65; N, 9.12. Step C Preparation of final title compound. Reaction Scheme D, step (d): The above prepared alcohol (196 mg, 0.232 mmol) is oxidized under under Swer conditions in a manner analogous to that described previously in example 1, to provide 196 mg (100%) of crud final title compound as an orange oil after flash chromatography (3% CH 3 OH/CHCI 3 ) . Recrystallization from CH 2 Cl 2 /pentane, then CH 2 CI 2 / ether, provides 100 mg (51%) pure final title compound as cream granules: mp 108-135°C IR (KBr) v max 3422, 3306, 1638, 1535, 1514, 1454, 1115 cm l i l E NMR (CDCI 3 ) δ 8.95-8.87 (m, 1 H) , 8.16 and 8.13 and 8.12-8.08 (2dd and m, 1 H total, J = 2.2, 1.1 Hz), 7.74 a 7.71 eld 7.68-7.67 (2dd and m, 1 H total, J = 5.8, 0.7 Hz) 7.43-7.27 (m, 10 H) , 7.14-7.04 and 7.13 and 7.09 and 7.06 (m and 3d, 2 H total, J = 8.5, 8.8, 8.8 Hz respectively), 6.95-6.77 and 6.88 and 6.85 (m and 2d, 4H total, J = 8.7 Hz), 6.49 and 6.39 and 6.23 (3d, 1 H total, J = 7.2, 6.7, 9.0 Hz respectively), 5.60-5.56 and 5.46 and 5.33-5.21 (m and bs and , 1 H total), 5.02 and 4.98 and 4.93 (3s, 2 H total) 4.57-4.40 (m, 3H) , 3.81 (bs, 5 H), 3.67-3.59 (m, 5 H), 3.50-3.43 (m, 1H) , 3.36-3.27 (m, 1 H) , 2.95-2.76 (m, H), 2.17-1.91 (m, 2 H) , 0.96-0.88 and 0.83 and 0.82 and 0.71 and 0.59 (m and 4d, 12 H total, J = 6.8 Hz); 19F NMR (CDC13) d -111.54 (d, J = 270 Hz), -112.47 (A J = 269 Hz), -113.76 (d, J = 270 Hz), -114.62 (d, J = 270 Hz), Hydrate: -114.80 (d, J = 253 Hz), -118.53 (s), -118.68 (s), -122.82 (d, J = 254 Hz); mass spectrum, m/z 870 (M + + 29), 842 (M + + 1), 197, 194, 91 (100); exact mass calcd for C 46 H54F 2 N5O8 842.3940, found 842.3994. Anal. Calcd for 46 H 53 F 2 5 O 8 : C, 65.62; H, 6.35; N, 8.32. Found: C, 64.80; H, 6.46; N, 8.27. Example 8 Preparation of 7,7-Difluoro-4,12-bis(l-methylethyl)-6,8,11- trioxo-l-phenyl-9-[ [4-(phenylmethoxy)phenyl]methyl]-2-oxa- 5,10,13-triazatetradecan-14-oic Acid, 3-Pyridinylmethyl Ester. Step A Preparation of N-[ (3-Pyridinylmethoxy)carbonyl]-L-valine. To a stirred suspension of L-valine methyl ester hydrochloride (2.0 g, 12 mmol) in toluene (15 mL) is added triphosgene (1.78 g, 6 mmol) and DMF (0.15 mL, 2 mmol). The heterogeneous mixture is allowed to stir at room temperature for 30 minutes. To this mixture is added tributylamine (0.1 mL, 0.4 mmol) dropwise over 2 minutes. The reaction mixture is heated to reflux for 1 hour. Analysis by IR spectroscopy shows a strong signal at 2250 cm "1 , indicating the presence of isocyanate. The now homogeneous solution is cooled to 0°C and 3-pyridylcarbinol (0.9 mL, 9 mmol) is added dropwise over 10 minutes. A white precipitate forms during the addition. The reaction mixture is warmed to room temperature and is allowed to stir for 16 hours. Additional 3-pyridylcarbinol (1.8 mL, 18 mmol) is added and the cloudy mixture is heated to reflux for 3 hours. The solution is concentrated under vacuum, diluted with ethyl acetate and washed with three portions of water. The solution dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide an oil. Flash chromatography (8:1 CH 2 CI 2 /C 2 H 5 OH) of the oil provides 1.46 g (60%) of N-[(3- pyridinylmethoxy)carbonyl]-L-valine, methyl ester as a yellow oil: X H NMR (CDCI 3 ) δ 8.61 (s, 1 H), 8.56 (d, 1 H, = 6.5 Hz), 7.71 (d, 1 H, J = 10.2 Hz), 7.29 (dd, 1 H, J = 8.1, 6.6 Hz), 5.38 (bs, 1 H) , 5.13 (s, 2 H) , 4.29 (dd, 1 H, J = 8.2, 5.9 Hz), 2.12 (m, 1 H) , 0.92 (d, 3 H, J = 6.3 Hz), 0.88 (d, 3 H, J = 6.3 Hz); [α] 20 D +9.25° (c 0.85, CHCI 3 ). Anal. Calcd for C 13 H 18 N 2 O 4 : C, 58.65; H, 6.77; N, 10.53. Found: C, 57.62; H, 7.03; N, 10.47. Alternatively the N-[ (3-pyridinylmethoxy)carbonyl]-L- valine, methyl ester can be prepared as follows: L-valine methyl ester (4.25 g, 34 mmol, freshly prepared from the hydrochloride salt by neutralization with 50% aqueous NaOH) is added to a stirred mixture of 1,1 '-carbonyldiimidazole (4.86 g, 30 mmol) in CH 2 CI 2 (30 mL) over 15 minutes. After 15 more minutes, 3-pyridylcarbinol (5.0 mL, 51 mmol) is added dropwise to the homogeneous solution. The resulting solution is heated at 45°C for 3 hours and then allowed to stir at room temperature overnight. The CH2CI2 is removed under vacuum, and the residue is dissolved in toluene (70 mL). The solution is heated at 70°C for 6 hours, and then concentrated under vacuum. The residue is dissolved in CH 2 CI 2 and the resulting solution is washed three times with water, dried over anhydrous magnesium sulfate, filtered and concentrate to provide an oil, which is purified by flash chromatography to provide 4.6 g (51%) of the N-[ (3-pyridinylmethoxy)carbonyl]-L-valine, methyl ester as a yellow oil. To a stirred solution of the N-[(3- pyridinylmethoxy)carbonyl]-L-valine, methyl ester (1.4 g, 5.3 mmol) in CH 3 OH (6 mL) is added LiOH«H 2 0 (0.24 g, 5.8 mmol). The heterogeneous mixture is allowed to stir at room temperature for 16 hours. The reaction mixture is diluted with water until completely homogeneous, acidified with 0.5 N HC1 (11.6 mL, 5.8 mmol) and concentrated under vacuum to provide a white solid, which is crystallized from 8:1 CH 2 CI 2 /C 2 H 5 OH to the title compound 0.53 g (40%) as a white crystalline solid: mp 242-244°C; X H NMR (DMSO-d 6 ) δ 8.9 (m, 2 H), 8.5 (d, 1 H, J = 8 Hz), 8.05 (m, 1 H) , 7.7 (d, 1 H, J = 9 Hz), 5.22 (s, 2 H), 3.9 (m, 1 H) , 2.05 ( , 1 H), 0.85 (m, 6 H) . Step B Preparation of [1 (R) , 3ζ, 4(S) 3-2,4,5-Trideoxy-2,2- difluoro-4-[ [ 3-methyl-l-oxo-2-[ [ (3- pyridinylmethoxy)carbonyl]amino]butyl]amino]-N-[ 2-methyl-l- [ (phenylmethoxy)methyl1propyl]-5-[4-( henyl- methoxy)phenyl3-L-qlycero-pentanamide. The amino alcohol prepared in example 5, step D (0.28 g, 0.53 mmol) is coupled with the above prepared acid (0.19 g, 0.74 mmol) under standard coupling conditions described previously, such as example 2, step A to provide, after crystallization from ethyl acetate, 0.20 g (50%) of title compound as a white powder: mp 187-191°C; IR (KBr) v„, ax 3426, 3300, 2960, 1698, 1674, 1657, 1541, 1512, 1246, 1177, 1151, 1105, 1028, 698 cm "1 ; X H NMR (DMSO-d 6 ) - 8.58 (d, 1 H, J = 1.6 Hz), 8.49 (dd, 1 H, J = 4.7, 1.4 Hz), 7.76 (d, 1 H, J = 7.9 Hz), 7.46-7.24 (m, 13 H), 7.13-7.07 (2d, 2 H total, J = 8.8 Hz), 6.88 and 6.81 (2d, 2 H total, J = 8.8, 8.3 Hz), 8.34, 7.97, and 6.18 (3d, 1 H total), 5.08 and 5.03 (d and s, 2 H total, J = 5.7 Hz), 4.99 (d, 2 H, J = 2.2 Hz), 4.46 (d, 2 H, J = 3.8 Hz), 4.21 (m, 1 H), 4.06-3.92 (m, 1 H), 3.87-3.73 (m, 2 H) , 3.52 (d, 2 H, J = 6.9 Hz), 2.93 (d, 1 H, J = 12.2 Hz), 2.6 (m, 1 H) , 1.93-1.75 (m, 2 H), 0.87 (apparent t, 8 H, J = 6.6 Hz), 0.68 (dd, 4 H, J = 6.8, 6.6 Hz); 19 F NMR (DMSO-d 6 ) δ major diastereomer: -108.9 (d = 251, 7 Hz), -119.8 (dd, J = 245, 19 Hz), minor diastereomer: -111.6 (dd, J = 252, 8 Hz), -117.1 (dd, = 250, 18 Hz); mass spectrum, m/z 761 (M + + 1), 555, 13 121, 110, 92. Anal. Calcd for C 42 H 5 oF 2 N 4 θ 7 : C, 66.32; H, 6.58; N, 7.37. Found: C, 62.43; H, 6.36; N, 6.79. Step C Preparation of final title compound. Reaction Scheme D, step (d): In a manner analogous that described previously in example 1, the above prepar alcohol is oxidized under Swern conditions to provide af flash chromatography (8:1 CH 2 CI 2 /C 2 H 5 OH) , 100 mg (50%) of final title compound as a white powder: mp 108-111°C; I (KBr) v max 3416, 3308, 2963, 1696, 1660, 1537, 1514, 12 1115, 1028 cm "1 ; X H NMR (DMSO-d 6 ) δ 8.91 (d, 1 H, J = 8.8 Hz), 8.58-8.51 (m, 2 H), 7.75 (d, 1 H, J = 7.7 Hz), 7.45 7.23 (m, 12 H) , 7.16 (d, 1 H, J - 8.6 Hz), 6.90(d, 2 H, = 8.6 Hz), 5.06-4.99 (m, 5 H), 4.45 (d, 2 H, J = 3.1 Hz) 3.92-3.8 (m, 2 H), 3.52 (m, 2 H), 3.10 (dd, 1 H, J = 14. 3.1 Hz), 2.69 (dd, 1 H, J = 14.1, 9.9 Hz), 1.87 (m, 2 H) 0.84 and 0.78 (2dd, 10 H total, J = 10.8, 7.1 Hz and J = 6.4, 4.8 Hz respectively), 0.60 (dd, 2 H, J = 8.7, 6.9 H 13 C NMR (DMSO-d 6 ) δ 171.2 157.15, 155.8, 149.0, 148.95, 148.9, 138.3, 137.1, 135.5, 132.6, 130.2, 130.07, 128.8, 128.7, 128.37, 128.16, 127.75, 127.67, 127.6, 127.5, 127.44, 127.36, 123.43, 114.5, 71.9, 69.5, 69.45, 69.1, 69.0, 63.16, 59.6, 55.25, 54.76, 54.67, 33.8, 33.75, 30. 28.8, 28.77, 19.4, 19.33, 18.98, 18.59, 17.86; 19 F NMR (DMSO-d 6 ) δ -111.36 (d, J = 272 Hz), -114.36 (d, J = 270 Hz), -112.96 (s), -117.06 (d, J = 255 Hz), -120.00 (d, J 250 Hz); mass spectrum, m/z 759 (M+ + 1), 460, 110, 91. Anal. Calcd for C 42 H 48 F 2 N θ 7 «H 2 θ: C, 64.94; H, 6.44; N, 7 Found: C, 64.70; H, 6.36; N, 7.24. Example 9 Preparation of [lR-(IR*,2S*) 3-α,α-Difluoro-γ-[ [3-methyl-2- [[4-(4-morpholinylsulfonyl)benzoyl]amino]-l- oxobutyl]amino]-N-[2-methyl-l- [(phenylmethoxy)methyl]propyl]-8-oxo-4-(phenylmethoxy)- benzenepentanamide. Step A Preparation of [1 (R),3ζ, 4(S) ]-2,4,5-Trideoxy-2,2- difluoro-4-[ [3-methyl-2-[ [4-(4- orpholinylsulfonypbenzoyl]amino]-l-oxobutyl]-amino]-N-[2- methyl-1-[ (phenylmethoxy)methyljpropyl]-5-[4-(phenyl¬ methoxy)phenyl]-L-qlycero-pentanamide. Reaction Scheme D, step (c): The (S)-amino alcohol prepared in example 5, step D (161 mg, 0.26 mmol) is coupled with the acid (77 mg, 0.28 mmol) of the following structure [prepared as described by Sycheva, T.P. et al., Sbornik Statei Obshchei Khim, Akad. Nauk S.S.S.R., 1, 568-571 (1953)] under standard coupling conditions in a manner analogous to that described previously, such as example 2, step A, to provide after flash chromatography (1:1 ethyl acetate/CH2Cl2) , 140 mg (62%) of the title compound as a white solid. Recrystallization from ethyl acetate/cyclohexane provides the title compound as a white powder: mp 172.5-190.5°C (172.5-174, then 189.5-190.5°C) ; IR (KBr) v max 3420, 3322, 2965, 1643, 1534, 1514, 1171, 1113 cm" 1 ; X H NMR (CDC1 3 ) δ 7.90 (d, 2 H, J = 8.4 Hz), 7.79 (d 2 H, J = 8.3 Hz), 7.4-7.25 (m, 10 H) , 7.08 (d, 2 H, J = 8. Hz), 6.78 (d overlapping m, 4 H, J = 8.5 Hz), 6.65 (d, 1 H J = 8.6 Hz), 4.93 (s, 2 H) , 4.53 (d, 1 H, J = 12.0 Hz), 4.47 (d, 1 H, J = 12.0 Hz), 4.45-4.24 (m, 4 H), 3.82 (m, 1 H), 3.73-3.65 (n , 4 H), 3.62 (dd, 1 H, J = 9.7, 4.1 Hz), 3.46 (dd, 1 H, J = 10.0, 3.9 Hz), 3.1-2.85 (m, 6 H), 2.12 (m, 1 H), 1.98 (m, 1 H) , 0.97-0.89 (m, 12 H); 19 F NMR (CDCI 3 ) δ -110.18 (dd, J = 261, 4 Hz), -121.09 (dd, J = 261, 18 Hz); mass spectrum, m/z 879 (M + + 1, 100), 527, 325, 254. Anal. Calcd for C 46 H 56 F 2 N 4 O9S: C, 62.85; H, 6.4 N, 6.37. Found: C, 62.65; H, 6.43; N, 6.26. Step B Preparation of final title compound. Reaction Scheme D, step (d): In a manner analogous to that described in example 1 the above prepared alcohol (13 mg, 0.151 mmol) is oxidized under Swern conditions to provide 82 mg of a mixture of diastereomers of final title compound after flash chromatography (3:2 ethyl acetate/cyclohexane). The mixture partially crystallizes from cyclohexane/ethyl acetate upon evaporation of the solvent. The tacky pale yellow solid is triturated with ether to provide 59 mg (44%) of a single diastereomer of final title compound as a white powder: mp 114-116°C; IR (KBr) v max 3426, 2971, 1686, 1663, 1512, 1171, 1115 cm "1 ; X H NMR (CDCI 3 ) δ 7.92 (d, 2 H, J = 8.3 Hz), 7.81 (d, 2 H, = 8.3 Hz), 7.41-7.29 (m, 10 H) , 7.06 (d, 2 H, J = 8.6 Hz), 6.85 (d, 2 H, J = 8.6 Hz), 6.78 (d, 2 H, J = 8.6 Hz), 6.29 (d, 1 H, J = 6.7 Hz), 5.26 (m, 1 H) , 4.99 (s, 2 H, major peak), 4.55 (d, 1 H, J = 12.0 Hz), 4.48 (d, 1 H, J = 12.0 Hz), 4.43 (dd, 1 H, J = 8.4, 6.4 Hz), 3.84 (m, 1 H) , 3.72 (narrow m, 4 H) , 3.63 (dd, 1 H, J = 9.8, 3.8 Hz), 3.47 (dd 1 H, J = 9.7, 3.8 Hz), 3.31 (dd, 1 H, J = 14.4, 5.0 Hz), 3.00-2.87 (m, 5 H), 2.14 (m, 1 H) , 2.00 (m, 1 H) , 0.96 (d, 3 H, J = 6.7 Hz), 0.95 (d, 3 H, J = 6.7 Hz), 0.94 (d, 3 H, J = 6.7 Hz), 0.92 (d, 3 H, J = 6.7 Hz); 19 F NMR (CDCI 3 ) d - 112.45 (d, J = 270 Hz), -113.69 (d, J = 270 Hz),-117.94 (d, J = 255 Hz), -119.29 (d, J = 255 Hz); mass spectrum (CI), m/z 905 (M + + 29), 877 (M + + 1), 525, 507, 401, 353 (100), 197, 107. Anal. Calcd for C 46 H 5 F 2 N 4 θ9S«0.5 H 2 0: C, 62.36; H, 6.26; N, 6.32. Found: C, 62.24; H, 6.30; N, 6.27. Example 10 Preparation of [1R-(1R*,2S*) ]-α,α-Difluoro—y-[ [3-methyl-2- [ [4-(4-morpholinylcarbonyl)benzoyl]amino]-1- oxobutyl]amino]-N-[2-methyl-l- [ (phenylmethoxy)methyl3propyl]-β-oxo-4-(phenylmethoxy)- benzenepentanamide. Step A Preparation of [1 (R), 3ζ, 4(S) 3-2,4,5-Trideoxy-2,2- difluoro-4-[ [3-methyl-2-, f4-(4- morpholinylcarbonypbenzoyl]amino]-l-oxobutyl]-aminol-N-[2- methyl-1-[ (phenylmethoxy)methyl3propyl]-5-[4-(phenyl¬ methoxy)phenyl]-L-qlvcero-pentanamide. Reaction Scheme D, step (c): The (R) amino alcohol (171 mg, 0.274 mmol) prepared in example 5, step D is coupled with 4-(4-morpholinylcarbonylJbenzoic acid (68 mg, 0.29 mmol, prepared in example 10a) under standard coupling conditions, such as example 2, step A, in a manner analogous to that described previously to provide, after flash chromatography (3% CH 3 OH/CHCI 3 ) , 217 mg (94%) of the title compound as a yellow powder: IR (KBr) v max 3428, 3322, 1636, 1534, 1512, 1456, 1279, 1258, 1244, 1115 cm "1 ; 19 F NMR (CDCI3) δ -110.19 (d, J = 259 Hz), -117.26 (d, J = 259 Hz), -120.14 (d, J = 259 Hz), -121.40 (dd, J = 259, 20 Hz) + impurities; mass spectrum, m/z 871 (M + + 29), 843 (M + + 1), 527, 509, 329, 317 (100), 289, 250, 218. Step B Preparation of final title compound. Reaction Scheme D, step (d): The above prepared alcohol is oxidized under Swern conditions as follows: To stirred solution of the above prepared alcohol (215 mg, 0.255 mmol) in anhydrous CH 2 CI 2 (3 mL) and anhydrous DMSO (0.36 mL, 5.1 mmol) at -45°C is added 2 M oxalyl chloride/CH 2 Cl 2 (1.0 mL) over 5 minutes. The solution is allowed to stir at -40 to -30°C for 2.5 hours. The soluti is then cooled to -70°C and diisopropylethylamine (0.67 m 3.8 mmol) is added over 5 minutes. The solution is allow to warm to room temperature, diluted with CH 2 CI 2 , washed twice with water, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue is purified by flash chromatography (3% CH 3 OH/CHCI 3 ) to provi 210 mg (98%) of final title compound as an amber oil. Recrystallization from CH 2 Cl 2 /pentane provides 80 mg (37%) of final title compound as an amber powder: mp 87-92°C; I (KBr) v raax 3306, 1636, 1534, 1514, 1454, 1279, 1258, 1244, 1115 cm "1 ; 1 H NMR (CDCI 3 ) δ 7.82-7.75 (m, 2 H) , 7.48-7.30 (m, 12 H), 7.11-7.04 (m, 2 H) , 6.91-6.82 ( , 2 H) , 6.78 ( 1 H, J = 8.7 Hz), 6.68(d, 1 H, J = 8.7 Hz), 6.44 and 6.33 (2d, 1 H, J = 6.9 Hz), 5.31-5.22 (m, 1 H) , 5.05-4.94 (m, H), 4.57-4.38 (m, 3 H) , 3.88-3.28 (m, 12 H) , 2.94-2.81 (m, 1 H), 2.16-1.93 (m, 2 H) , 0.96-0.58 (m, 12 H) ; 19 F NMR (CDCI 3 ) δ -111.56 (d, J = 270 Hz), -112.56 (d, J = 270 Hz) -113.63 (d, J = 270 Hz), -114.54 (d, J = 270 Hz), Hydrate: -113.53 (d, J = 292 Hz), -114.85 (d, J = 252 Hz), -118.7 (d, J = 292 Hz), -122.88 (d, J = 252 Hz); mass spectrum, m/z 869 (M + + 29), 841 (M + + 1), 525, 317, 279, 218, 197, 157 (100); exact mass calcd for C 47 H 55 F 2 N 4 O 8 841.3988, found 841.4043. Anal. Calcd for C 47 H 5 F 2 N 4 O8: C, 67.13; H, 6.47; N, 6.66. Found: C, 65.80; H, 6.60; N, 6.69. Example 10a Preparation of 4- ( 4-morpholinylcarbonyp benzoic acid . Preparation of 4-(4-morpholinylcarbonyl)benzoic acid methyl ester. To a stirred suspension of monomethyl terephthalate (25.0 g, 0.14 mmol) in methylene chloride (500 mL) and dimethylformamide (4 mL) is added dropwise oxalyl chloride (12.1 mL, 0.14 mol) with vigorous gas evolution. After gas evolutions ceases, the reaction is stirred for 45 minutes and then cooled in an ice-water bath. Morpholine (48.4 mL, 0.56 mol) is then added resulting in an exotherm. After the addition is complete the reaction is allowed to warm to room temperature and stirred for 1 hour. The reaction mixture is then washed with 0.5 N HC1 (2 x 500 mL), half- saturated sodium bicarbonate (2 x 500 mL), water (2 x 500 mL) and brine (300 mL). The reaction is dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the title compound (33.8 g, 98%) as a white solid; mp 74-76°C. Preparation of final title compound. to a stirred solution of the above ester (50.1 g, 0.20 mmol) in methanol (800 mL) is added IN lithium hydroxide (241 mL, 0.24 mol) followed by water (160 mL) . After stirring at room temperature for 7 hours, additional water (100 mL) is added. The reaction is then stirred an additional 24 hours and then concentrated to remove the methanol. The aqueous is extracted with methylene chloride (2 x 100 mL) and diethyl ether (200 mL). The aqueous layer was then cooled in an ice-water bath and acidified to pH 1 with 12 N HC1 (ca. 20 L) . Filtration provides crude white solid. The solid material is suspended in methylene chloride (2 L) and heated to reflux. It is then cooled to room temperature, treated with anhydrous magnesium sulfa and filtered. The filtrate is concentrated under vacuum provide the final title compound (42.2 g, 89%) as a whit solid; mp 194-196°C. Example 11 Preparation of N-[l-[ [ [3,3-Difluoro-4-[ [2-methyl-l- [ (phenylmethoxy)methyl]-propyl]amino]-2,4-dioxo-l-[ [4- (phenylmethoxy)phenyl]-methyl3butyl]amino]carbony1]-2- methylpropyl]-4-morpholineacetamide. Step A Preparation off1 (R), 3ζ, 4(S) ]-2,4,5-Trideoxy-2,2- difluoro-4- [ [ 3-methyl-2- [ [ ( 4-morpholinypacetyl ] amino ] -l- oxobutyl]amino]-N-[2-methyl-l- [ (phenylmethoxy)methyl]propyl]—5—[4—(phenylmethoxy)phenyl]- L-qlycero-pentanamide. Reaction Scheme D, step (c): The (R,S)-amino alcohols (201 mg, 0.321 mmol) prepared in example 5, step D are coupled with 4-morpholine acetic acid, trifluoro acid salt (92 mg, 0.35 mmol, compound (A) prepared in example 5a) under standard coupling conditions in a manner analogous to that described previously [with the addition of 1.1 eq. of NMM] to provide after flash chromatography (4% CH 3 OH/CHCI 3 ) , 224 mg (92%) of title compound as a beige powder: mp 110- 117°C; IR (KBr) v max 3298, 2963, 1674, 1649, 1545, 1512, 1238, 1115, 698 cm "1 ; 19 F NMR (CDCI 3 ) δ major diastereomer- 110.56 (dd, J = 260, 5 Hz), -120.79 (dd, J = 260, 18 Hz); mass spectrum, m/z 781 (M+ + 29), 753 (M + + 1, 100), 752 (M + ), 291, 100, 91. Step B Preparation of final title compound. Reaction Scheme D, step (d): In a manner analogous to that described in example 1 the above prepared alcohol (206 mg, 0.274 mmol) is oxidized under Swern conditions to provide 170 mg (83%) of an orange glass after flash chromatography (3% CH 3 OH/CHCI 3 ) . Recrystallization from CH 2 Cl 2 /ether provides 70 mg (34%) of final title compound sticky amber crystals: mp 48-53°C; IR (CHCI 3 ) v max 2969, 1686, 1512, 1242, 1117, 760, 750, 731 cm "1 ; 1 H NMR (CDCI 3 ) δ 7.55-7.50 (m, 1 H), 7.43-7.29 (m, 10 H) , 7.14-7.07 (m, 2 H), 6.92-6.78 (m, 3 H), 6.52-6.49 and 6.40-6.37 (2m, 1 H total), 5.33-5.19 (m, 1 H), 5.03 (apparent d, J = 3.6 Hz), 4.55 (d, 1 H, J = 11.9 Hz), 4.48 and 4.47 (2d, 1 H total, = 11.9 Hz), 3.88-3.80 (m, 1 H) , 3.74-3.61 (m, 5 H) , 3.50- 3.44 (m, 1 H), 3.32-3.25 (m, 1 H) , 2.99-2.81 (m, 3 H), 2.49-2.46 (m, 4 H) , 2.14-1.95 (m, 2 H) , 1.28-1.24 and 0.95 0.70 and 0.50 (2m and d, 12 H total, J = 6.7 Hz); 19 F NMR (CDCI 3 ) δ -111.32 (d, J = 273 Hz), -112.96 (s), -114.64 (d J = 272 Hz); mass spectrum, m/z 779 (M + + 29), 751 (M + + 1), 226, 100 (100), 86; exact mass calcd for C 4 iHs 3 F 2 N 4 θ 7 751.3882, found 751.3892. Anal. Calcd for 4 iH 52 F 2 N θ 7 «1.3H 2 0: C, 63.60; H, 6.77; N, 7.24. Found: C 63.64; H, 6.80; N, 6.84. Example 12 Preparation of N-[l-[ [ [3,3-Difluoro-4-[ [2-methyl-l- [ (phenylmethoxy)methyl1-propyl1amino3-2,4-dioxo-l-[ [4- (phenylmethoxy)phenyl]methyl]-butyl]amino]carbony1]-2- methylpropyl]-lH-imidazole-1-acetamide. Step A Preparation of lH-Imidazole-1-acetic Acid*HCl. To a stirred solution of imidazole (1.50 g, 22.0 mmol) in CH 2 CI 2 (25 mL) at 0°C under nitrogen is added dropwise tert-butyl bromoacetate (1.62 mL, 10.0 mmol). The ice bat is removed and the solution is allowed to stir at room temperature for 22 hours. The solution is concentrated under vacuum and the residue is partitioned between ethyl acetate/ water. The organic layer is washed with water and concentrated under vacuum to provide 1.22 g (67%) of tert- butyl lH-imidazole-1-acetate as a white crystalline solid: mp 110-113°C; l E NMR (CDC1 3 ) δ 7.49 (s, 1 H) , 6.95 (s, 1 H), 4.59 (s, 2 H), 1.47 (s, 9 H). HC1 gas was bubbled through a solution of the tert-butyl lH-imidazole-1-acetate in CH 3 NO 2 (4-5 mL) for 20-25 minutes. After standing for 20 minutes more, the solution is concentrated under vacuum and recrystallized from CH 3 CN/CH 3 OH to provide the title compound in 70% yield: mp 206-209°C; l E NMR (DMSO-d 6 ) - 9.12(d, 1 H, J = 1.4 Hz), 7.73 (narrow m, 1 H) , 7.68 (d, 1 H, J = 1.4 Hz), 5.15 (s, 2 H) . Anal. Calcd for C 5 H 6 N 2 θ 2 »HCl: C, 36.94; H, 4.34; N, 17.23. Found: C, 37.21; H, 4.36; N, 17.39. Step B Preparation of[1 (R), 3 , 4(S) 3-2,4,5-Trideoxy-2,2- difluoro-4-[ [2-[ (lH-imidazol-l-ylacetyl)amino3-3-methyl-l- oxobutyl3amino3-N-[2-methyl-l- [ (phenylmethoxy)methyl3propyl3-5-[4-(phenylmethoxy)phenyl3~ L-qlycero-pentanamide. Reaction Scheme D, step (c): To a solution of the (R)- amino alcohol (205 mg, 0.328 mmol) prepared in example 5, step D in anhydrous CH 2 CI 2 (4 mL) and anhydrous DMF (7 mL) is added lH-imidazole-1-acetic acid«HCl(56 mg, 0.34 mmol) prepared above and NMM (35 μL, 0.32 mmol). Not all of the lH-imidazole-1-acetic acid dissolves. HOBT (53 mg, 0.34 mmol) and EDC (66 mg, 0.34 mmol) are then added and the resulting mixture is allowed to stir overnight at room temperature. The mixture is concentrated under vacuum and the residue is dissolved in ethyl acetate. The organic layer is washed with water, 10% aqueous sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide yellow solids which contain two major spots by TLC (10% CH 3 OH/CHCI 3 ) . The t compounds are separated by chromatography (the first is eluted with 4% CH 3 OH/CHCI 3 , the second with 1:1 CH 3 OH/CHCI 3 ) . The less polar material is the formamide of the starting material while the more polar material i the title compound (110 mg, 45%) which is isolated as a white powder: mp 190-193°C; IR (KBr) v max 3430, 3297, 16 1647, 1549, 1512, 1240, 1082 cm "1 ; 19 F NMR (CDCI 3 + DMSO- δ major diastereomer -115.66 (dd, J = 259, 7 Hz), -120.4 (dd, J = 259, 18 Hz); mass spectrum, m/z 762(M + + 29), (M + + 1), 91 (100). Step C Preparation of final title compound. Reaction Scheme D, step (d): In a manner analogous t that described in example 1 the above prepared alcohol ( mg, 0.138 mmol) is oxidized under Swern conditions to provide 101 mg (100%) of an orange oil after flash chromatography (2:1 CHCI 3 /CH 3 OH) . Recrystallization fro CH 2 Cl 2 /pentane provides 50 mg (50%) of final title compo as a beige solid: mp 112-116°C; IR (KBr) v max 3428, 3295 2963, 1647, 1551, 1512, 1240, 1113, 698 cm "1 ; X H NMR (DM d 6 ) δ 9.00 and 8.93 and 8.66 and 8.64 (4d, 1 H total, J 9.0, 9.0, 7.2, 7.2 Hz respectively), 8.16 (apparent triplet, 1 H, J = 8.4 Hz), 7.59 (bs, 1 H), 7.46-7.26 (m, H), 7.15 and 7.14 (2d, 1 H total, J = 8.6 Hz), 7.06 (bs, H), 6.90 and 6.89 (apparent 2d, 3 H, J = 8.7 Hz), 5.05 ( 2 H), 5.01 (dd, 1 H, J = 7.5, 3.4 Hz), 4.79-4.61 (m, 2 H 4.50-4.39 (m, 2 H), 4.30-4.20 (m, 1 H) , 3.85-3.76 (m, 1 3.54-3.50 (m, 2 H) , 3.20-3.08 (m, 1 H) , 2.72-2.57 (m, 1 2.00-1.72 (m, 2 H), 1.27-1.21 and 0.87-0.69 and 0.61-0.5 (m, 12 H total); 19 F NMR (DMSO-d 6 ) δ -108.87 (d, J = 267 Hz), -109.82 (d, J = 268 Hz), -111.37 (d, J = 268 Hz), - 112.32 (d, J = 254 Hz), 112.58 (d, J = 268 Hz), -117.61 J = 254 Hz); mass spectrum, m/z 760 (M + + 29), 732 (M + 1), 712, 180, 91 (100), 69; exact mass calcd for C 40 H 48 F 2 732.3573, found 732.3541. Anal. Calcd for C 4 oH 47 F 2 5 θ 6 «2 C , 62 . 57 ; H , 6 . 69 ; N , 9 . 12 . Found : C , 62 . 07 ; H , 6 . 49 ; N , 9. 05 . Example 13 Preparation of [l-[ [ [3,3-Difluoro-2,4-dioxo-l-[ [4- (phenylmethoxy)phenyl]-methyl]-4-[ (2- pyridinylmethvPamino3butyllamino1carbonyl]- 2- methylpropyll-carbamic Acid, 3-Pyridinylrr.ethyl Ester. Step A Preparation of [1 (R) , 3E3-2,4,5-Trideoxy-4-[ [ (1,1- dimethylethoxy)carbonyl]-amino3-2,2-difluoro-5-[4- (phenylmethoxy)-phenyl3-N-(2-pyridinylmethyl)-L-qlycero- pentanamide. Reaction Scheme A, step (b): To a stirred solution of 4-tert-butoxycarbonylamino-2,2-difluoro-3-hydroxy-5-(4- benzyloxy)phenylpentanoic acid, ethyl ester (1.5 g, 3.1 mmol) prepared in example 1 step B, in dry THF (16 mL) is added 2-(aminomethyl)pyridine (0.38 mL, 3.8 mmol). The homogeneous solution is heated at reflux for 4 hours and then allowed to cool to room temperature. A thick white precipitate forms upon cooling which is filtered and washed with ether to provide 0.80 g (48%) of title compound as a white powder: mp 166-170°C; 1 H NMR (DMSO-d 6 ) δ 9.23 (bs, 1 H), 8.51 (m, 1 H), 7.78 (t, 1 H, J = 7.5 Hz), 7.5-7.25 (m, 8 H), 7.12 (d, 2 H, J = 8.4 Hz), 6.91 (d, 2 H, J = 8.4 Hz), 6.69 (d, 1 H, J = 10.4 Hz), 6.19 (d, 1 H, J = 8.9 Hz), 5.08 (s, 2 H), 4.58-4.32 (m, 2 H) , 4.15-3.91 (m, 1 H), 3.82 (m, 1 H), 2.95 (d, 1 H, J = 10.9 Hz), 1.15 (s, 9 H); 19 F NMR (DMSO-d 6 ) δ major diastereomer: -103.30 (dd, J = 253, 9 Hz), -117.67 (dd, J = 252, 17 Hz), minor diastereomer: -111.37 (dd, J = 254, 8 Hz), -121.27 (dd, J = 256, 18 Hz). Step B Preparation of [3ζ, 4(S) ]-2,4,5-Trideoxy-2,2-difluoro-4- [ [3-methyl-l-oxo-2-[ [ (3- pyridinylmethoxy)carbonyl]amino]butyl]amino]-5-[4- (phenylmethoxy)phenyl]-N-(2-pyridinylmethyp-L-qlycero- pentanamide. Reaction Schemes A and A', steps (d) and (e): The above prepared amide (0.2 g, 0.4 mmol) is deprotected in manner analogous to that described previously in example step B by treatment with HCO 2 H. The free amine is then coupled with N-[(3-Pyridinylmethoxy)carbonyl3-L-valine (0.38 g, 1.5 mmol), prepared in example 8, under standard coupling conditions in a manner analogous to that describ previously to provide after recrystallization from ethyl acetate, 0.09 g (40%) of title compound as a white powder mp 201-210°C; 1 H NMR (DMSO-d 6 ) δ 9.48 (bs, 1 H) , 8.79 (m, H), 8.65 (m, 2 H), 8.02-7.85 (m, 3 H) , 7.39-7.65 (m, 9 H) 7.24 (d, 2 H, J = 8.5 Hz), 6.96 (d, 2 H, J = 8.5 Hz), 6.4 (d, 1 H, J = 10.4 Hz), 5.25 (d, 2 H, J = 3.8 Hz), 5.14 (s 2 H), 4.63-4.55 (m, 2 H) , 4.36 (m, 1 H) , 4.17 (m, 1 H), 3.91 (dd, 1 H, J = 7.8, 6.0 Hz) 3.14-3.03 (m, 1 H) , 2.81- 2.55 (m, 1 H) , 1.95 (m, 1 H), 0.81 (dd, 6 H, J = 9.1, 7.0 Hz); 1 F NMR (DMSO-d 6 ) δ -110.17 (dd, J = 254, 11 Hz), - 119.79 (dd, J = 247, 16 Hz). Step C Preparation of final title compound. Reaction Scheme A 1 , step (f): The above prepared alcohol (0.08 g, 0.1 mmol) is oxidized under Swern conditions in an analogous manner to that described previously, such as example 1, step G, from 2 M oxalyl chloride/CH 2 Cl 2 (0.6 mL, 1 mmol), DMSO (0.19 mL, 2.6 mmol) and diisopropylethylamine (0.41 mL, 2.4 mmol), 0.04 g (50 to provide the final title compound as a tan powder: mp 9 95°C; IR (KBr) v max 3401, 3306, 1699, 1599, 1437, 1298, 1242, 1178, 1113, 1026 cm "1 ; λ E NMR (CDC1 3 ) δ 8.63-8.52 (m, 2 H), 8.42 and 8.19, and 8.05 (3m, 2 H total), 7.77-7.62 (m, 2 H), 7.46-7.22 (m, 9 H), 7.18 (t, 1 H, J = 5.5 Hz), 7.05 (d, 2 H, J = 8.2 Hz), 6.89 (d, 2 H, J = 8.2 Hz), 5.35 and 5.22 (2d, 1 H total, J = 8.5 Hz), 5.10 (s, 2 H) , 5.05 (s, 2 H), 4.87-4.66 (m, 1 H), 4.60-4.48 (m, 1 H) , 3.81 (dd, 1 H, J = 9.2, 6.7 Hz), 3.32 and 3.27 (2d, 1 H total, J = 5.2 and 4.8 Hz), 3.18 and 3.13 (2d, 1 H total, J = 9.2 and 8.4 Hz) 1.91 (m, 1 H) , 1.31 (d, 1 H, J = 6.8 Hz), 0.73 and 0.78 and 0.82 (3d, 5 H total, J = 6.8 Hz); 19 F NMR (CDCI3) δ -110.48 (d, J = 276 Hz), -113.38 (s), -113.51 (d, J = 276 Hz), Hydrate: -118.75 (d, J = 254 Hz), -120.75 (d, J = 255 Hz); mass spectrum, m/z 674 (M + + 1), 460, 348, 280, 272, 252, 207, 138, 110 (100), 92. Example 14 Preparation of [l-[ [ [3,3-Difluoro-2,4-dioxo-l-[[4- (phenylmethoxy)phenyl]-methyl]-4-[ (3- pyridinylmethyl)amino]butyl]amino]carbonyl]-2- methylpropyl]-carbamic Acid, 3-Pyridinylmethyl Ester. Step A Preparation of [ 1 (R) , 3ζ ]-2 , 4 , 5-Trideoxy-4- [ [ (1 , 1- dimethylethoxy ) carbonyl ]-amino 3 -2 , 2-difluoro-5-[ 4- ( phenylmethoxy ) -phenyl ]-N- ( 3-pyridinylmethyp -L-qlycero- pentanamide. Reaction Scheme A, step (b): The title compound is prepared in a manner analogous to that described in example 13, step A from 4-tert-butoxycarbonylamino-2,2-difluoro-3- hydroxy-5-(4-benzyloxy)phenylpentanoic acid, ethyl ester (1.5 g, 3.1 mmol) prepared in example 1 step B, and 3-(aminomethyl)pyridine (0.38 mL, 3.8 mmol). The precipitated solids are washed with ether and are recrystallized from ethyl acetate to provide 0.80g (45%) of title compound as a white powder: mp 158-160°C; λ E NMR (CDC1 3 ) δ 8.55 (bs, 2 H) , 7.7 (d, 1 H, J = 7.2 Hz), 7.5-7.2 (m, 8 H), 7.1 (d, 2 H, J = 8.4 Hz), 6.9 (d, 2 H, J = 8.3 Hz), 5.0 (s, 2 H), 4.9 (d, 1 H, J = 9.8 Hz), 4.5 (d, 2 H, J = 2.6 Hz), 4.1-3.9 (m, 2 H) , 3.0-2.8 (m, 2 H) , 1.4 (s, 9 H); 19 F NMR (DMSO-d 6 ) δ -110.84 (d, J = 272 Hz), -122.56 (dd, J = 273, 21 Hz); mass spectrum, m/z 542 (M + + 1), 486, 442, 424, 344, 244, 224, 197, 109, 91. Step B Preparation of [3ζ,4(S) 3-2,4,5-Trideoxy-2,2-difluoro-4-[ [ 3- methyl-l-oxo-2-[ [ (3- pyridinylmethoxy)carbonyl]amino3butyl]amino3-5-[4-(phenyl¬ methoxy)phenyl]-N-(3-pyridinylmethyl)-L-qlycero- pentanamide. Reaction Schemes A and A', steps (d) and (e): The above prepared amide (0.27 g, 0.49 mmol) is treated with 97% HCO 2 H. The reaction mixture became homogeneous within 5 minutes. The solution is allowed to stir at room temperature for 3 hours. It is then concentrated under vacuum. The yellow oil is then dissolved in ethyl acetate, washed twice with aqueous 1 N sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the corresponding free amine as a yellow solid (0.18 g, 0.41 mmol). This is dissolved in a 1:1 mixture of CH2CI 2 / DMF (6 mL) . To this stirring solution at room temperature is added HOBT (0.07 g, 0.5 mmol), NMM (0.05 mL, 0.5 mmol), N-[(3- pyridinylmethoxy)carbonyl]-L-valine (0.13 g, 0.52 mmol), prepared in example 8 , and EDC (0.1 g, 0.5 mmol) in that order. After 16 hours, the mixture is diluted with CH 2 CI 2 and washed with water. A white precipitate separates, which is filtered, washed several times with ether, and recrystallized from ethyl acetate to provide 0.12 g (45%) of title compound as a white powder: mp 195-196°C; X H NMR (DMSO-d 6 ) δ 8.7-8.4 (m, 4 H) , 7.75 (d, 1 H, J = 10.4 Hz), 7.65 (d, 1 H, J = 11.2 Hz), 7.5-7.3 (m 7 H) , 7.15 (d, 2 H, J = 8.4 Hz), 6.9 (d, 2 H, J = 8.4 Hz), 5.12 (s, 2 H) , 5.08 (s, 2 H), 4.5-4.2 (m, 3 H) , 4.1-3.9 (m, 2 H), 2.8-2.6 (m, 2 H), 2.0 (m, 1 H), 0.8 (m, 6 H); 19 F NMR (DMSO-d 6 ) δ -111.2 (d, J = 257 Hz), -122.05 (dd, J = 250, 20 Hz); mass spectrum, m/z 676 (M + + 1), 567, 424, 150, 138, 110 (100), 92. Anal. Calcd for C 36 H 39 F 2 N 5 O 6 : C, 63.31; H, 5.87; N, 10.25. Found: C, 63.07; H, 5.90; N, 10.23. Step C Preparation of final title compound. Reaction Scheme A', step (f): The above prepared alcohol is oxidized under Swern conditions in a manner analogous to example 1 as follows: To a slightly cloudy solution of the above prepared alcohol (0.08 g, 0.12 mmol) in CH 2 C1 2 (2 mL) and DMSO (0.21 mL) at -45°C is added 2M oxalyl chloride/CH2Cl 2 (0.6 mL, 1 mmol) over 5 minutes. The solution is allowed to stir at -35 to -45°C for 2.5 hours and is then cooled to -78°C. Diisopropylethylamine (0.42 mL, 2.4 mmol) is added over 5 minutes. The solution is allowed to warm to room temperature over 1.5 hours, is diluted with CH 2 CI 2 and washed with water. The yellow precipitate which forms is filtered and washed three times with ether to provide 0.04 g (50%) of final title compound as a tan powder: mp 103-105°C; IR (KBr) v max 3422, 3295, 2965, 1697, 1649, 1537, 1512, 1244 cm -1 ; X E NMR (DMSO-d 6 ) δ 9.19 (bs, 1 H), 8.61-8.43 (m, 4 H) , 7.75-7.59 (m, 2 H), 7.45-7.28 (m, 7 H) , 7.09 (d, 2 H, J = 8.5 Hz), 6.81 (d, 2 H, J = 8.5 Hz), 5.09-4.98 (m, 4 H) , 4.50-4.26 (m, 3 H) , 3.90-3.61 (m, 2 H) , 3.12 (m, 2 H) , 2.55 (m, 1 H) , 1.79 (m, 1 H), 1.27 (t, 5 H, J = 8.6 Hz), 0.77 (t, 1 H, J = 6.2 Hz); 19 F NMR (DMSO-dβ) δ minor diastereomer: -111.34 (apparent doublet, J = 184 Hz), major diastereomer: -113.24 (d, J = 254 Hz), -117.56 (d, J = 254 Hz); mass spectrum, m/z 67 (M + + 1), 565, 460, 252, 207, 143, 138, 110 (100), 92. Anal. Calcd for C 3 6H 3 7F 2 5 θ 6 «2H 2 θ: C, 60.93; H, 5.78; N, 9.87. Found: C, 60.00; H, 6.15; N, 9.56. Example 15 Preparation of [l-[ [ [3,3-Difluoro-2,4-dioxo-l-[ [4- (phenylmethoxy)-phenyl3-methyl3-4-[ (2- pyridinylmethyl)amino3butyl3-amino]carbonyl3- 2- methylpropyP-carbamic Acid, 2-Pyridinylmethyl Ester. Step A Preparation of N-[ (2-Pyridinylmethoxy)carbonyl]-L-valine Methyl Ester. In a manner analogous to the preparation of N-[(3- pyridinylmethoxy)carbonyl]-L-valine in example 8, the ti compound is prepared from L-valine methyl ester hydrochloride (5.0 g, 30 mmol), triphosgene (4.66 g, 15. mmol), and (n-Bu) 3 N (0.05 mL, 0.4 mmol); however, 2-pyri carbinol (10.0 mL, 100 mmol, 3.3 equivalents) is added dropwise to the intermediate isocyanate. Flash chromatography as in example 8 provides 2.63 g (33%) of title compound as a yellow oil: IR (neat) v roax 3345, 29 1726, 1533, 1439, 1314, 1271, 1236, 1213, 1105 cm" 1 ; X H (CDC1 3 ) δ 8.61 (d, 1 H, J = 4.6 Hz), 7.7 (td, 1 H, J = 7. 1.8 Hz), 7.38 (d, 1 H, J = 7.7 Hz), 7.27 (dd, 1 H, J = 7. 4.6 Hz), 5.45 (d, 1 H, J = 8.9 Hz), 5.25 (s, 2 H) , 4.35 (dd, 1 H, J = 9.2, 4.7 Hz), 3.75 (s, 3 H), 2.24 (m, 1 H) , 1.0 (d, 3 H, J = 6.8 Hz), 0.9 d, 3 H, J = 6.8 Hz); 13 C NM (CDCI3) δ 172.4, 156.2, 155.9, 149.4, 136.7, 122.7, 121.6 67.4, 59.1, 52.1, 31.2, 18.9, 17.5; mass spectrum, m/z 267 (M + + 1, 100), 136, 110. Anal. Calcd for C 13 Hι 8 N 2 θ4 : C, 58.65; H, 6.77; N, 10.53. Found: C, 58.25; H, 6.86; N, 10.46. Step B Preparation of N-[ (2-Pyridinylmethoxy)carbonyl]-L-valine. Hydrolysis of the above ester (2.5 g, 9.4 mmol) with LiOH«H 2 θ (0.79 g, 18.8 mmol) in CH 3 OH in a manner analogous to that described previously in example 8 provides 2.0 g (85%) of the title compound as a white solid: IR (KBr) v raa χ 3366, 3065, 2963, 2936, 1722, 1616, 1602, 1577, 1526, 1433, 1279, 1250, 1219, 1109, 764, 627 cm '1 ; X H NMR (DMSO-d 6 ) δ 8.58 (d, 1 H, J = 4.7 Hz), 7.96 (t, 1 H, J = 8.0 Hz), 7.6 (d, 1 H, J = 8.0 Hz), 7.43 (d, 1 H, J = 7.5 Hz), 7.4 (dd, 1 H, J = 7.5, 5.2 Hz), 5.15 (s, 2 H) , 3.9 (dd, 1 H, J = 8.5, 5.9 Hz), 2.1 (m, 1 H), 0.92 (dd, 6 H, J = 6.6, 3.7 Hz); 13 C NMR (DMSO-d 6 ) δ 173.1, 156.3, 156.2, 148.6, 137.4, 123.0, 121.4, 65.9, 59.6, 29.5, 19.1, 18.0; mass spectrum, m/z 253 (M + + 1), 237, 209, 136 (100), 109, 92, 65. Step C Preparation of [3ζ, 4(S) ]-2,4, 5-Trideoxy-2,2-difluoro-4- [ [3-methyl-l-oxo-2-[ [(2- pyridinylmethoxy)carbonyl]amino]butyl]amino]-5-[ 4-(phenyl¬ methoxy)phenyl]-N-(2-pyridinylmethyl)-L-qlycero- pentanamide. Reaction Schemes A and A', steps (d) and (e): The [1 (R), 3ξ3-2,4,5-trideoxy-4-[[(l,l- dimethylethoxy)carbonyl]-amino]-2,2-difluoro-5-[4- (phenylmethoxy)-phenylJ-N-(2-pyridinylmethyl)-L-glycero- pentona ide (0.34 g, 0.63 mmol) prepared in example 13, step A, is deprotected as in example 13, step (d) and coupled with the above prepared acid (0.21 g, 0.82 mmol) under standard coupling conditions in a manner analogous to that described previously to provide 0.14g (30%) of title compound as a white powder: mp 224-225.5°C; IR (KBr) v max 3291, 1697, 1680, 1657, 1618, 1599, 1572, 1537, 1512, 1454 1439, 1398, 1341, 1300, 1244, 700 cm "1 ; 1 H NMR (DMSO-d 6 ) δ 9.31 (bs, 1 H), 7.82-7.71 (m, 3H) , 7.48-7.23 (m, 10 H) , 7.10 (d, 2 H, J » 8.6 Hz), 6.82 (d, 2 H, J = 8.6 Hz), 5.05 4.95 (m, 4 H), 4.47 (d, 2 H, J = 5.8 Hz), 4.23 (m, 1 H) , 4.04 (m, 1 H), 3.79 (t, 1 H, J = 6.0 Hz), 4.40 and 3.69 and 3.14 (3m, 1 H total), 2.94 (d, 1 H, J = 13.0 Hz), 2.63 (dd, 1 H, J = 14.6, 10.8 Hz), 1.83 (m, 1 H), 0.70 (dd, 5 H J = 9.2, 7.1 Hz), 0.57 and 0.47 (2d, 1 H total, J = 6.9 Hz); 13 C NMR (DMSO-d 6 ) δ 170.1, 157.4, 156.7, 156.6, 155.7, 148.97, 148.8, 137.2, 136.8, 130.76, 130.21, 128.4, 127.7, 127.5, 122.75, 122.25, 121.0, 120.8, 114.2, 69.0, 66.2, 60.38, 49.9, 44.1, 44.0, 34.0, 30.3, 19.2, 17.95; 19 F NMR (DMSO-d 6 ) δ major diastereomer: -110.07 (d, J = 248 Hz), - 119.9 ((d, J = 252 Hz), minor diastereomer: -110.03 (dm, = 250 Hz), -118.34 (dm, J = 250 Hz), -111.72 (dm, J = 250 Hz), -123.5 (dm, J = 250 Hz); mass spectrum, m/z 676 (M + + 1), 595, 567, 110, 92 (100) . Step D Preparation of final title compound. Reaction Scheme A', step (f): The above alcohol (0.13 g, 0.19 mmol) is oxidized under Swern condition in a manne analogous to that described previously in example 1 to provide after flash chromatography (8:1 CH 2 CI 2 /C 2 H 5 OH) 0.04 g (30%) of a 1:1 mixture of the final title compound as a tan powder: mp 140-142°C; IR (KBr) v max 3304, 1695, 1668, 1537, 1514, 1439, 1296, 1244, 1109, 1042 cm" 1 ; X H NMR (DMSO d 6 ) δ 9.09 and 8.85 and 8.09 (d, m, d, 1 H total), 8.56 (m, 1 H), 8.17 (m, 1 H) , 7.78-7.65 (m, 2 H) , 7.45-7.15 (m, 10 H), 7.05 (d, 2 H, J = 8.6 Hz), 6.89 (d, 2 H, J = 8.6 Hz), 5.56 and 5.43 (2d, 1 H total, J = 9.2, 9.2 Hz), 5.30-4.95 (m, 5 H), 4.84-4.45 (m, 2 H), 3.85-3.7 (m, 1 H), 3.32-3.27 (2d,l H, J = 4.9, 4.0 Hz), 3.16-2.80 (2m, 1 H), 1.90-1.70 (m, 1 H), 0.83-0.75 (m, 5 H) , 0.56 (d, 1 H, J = 6.8 Hz); 1 NMR (DMSO-d 6 ) δ -110.07 (d, J = 275 Hz), -113.25 (apparent d, J = 9 Hz), -113.45 (d, J = 276 Hz), Hydrate: -118.5 (d J = 257 Hz), -121.00 (d, J = 253 Hz); mass spectrum, m/z 674 (M + 1), 460, 143, 110, 92. Example 16 Preparation of [l-[ [ [3,3-Difluoro-2,4-dioxo-l-[ [4- (phenylmethoxy)-phenyl]-methyl]-4-[ (3- _ pyridinylmethyl)amino]butyl]-amino]carbonyl]- 2- methylpropyp-carbamic Acid, 2-Pyridinylmethyl Ester. Step A 5 Preparation of [3ζ, 4(S) ]-2,4,5-Trideoxy-2,2-difluoro-4- [ [3-methyl-l-oxo-2-[ [ (2- pyridinylmethoxy)carbonyl]amino]butyl]amino]-5-[ -(phenyl¬ methoxy)phenyl]-N-(3-pyridinylmethyl)-L-qlycero- pentanamide. 0 Reaction Schemes A and A', steps (d) and (e): The [1 (R) , 3ζ]-2,4,5-trideoxy-4-[ [ (1,1-dimethylethoxy)carbonyl]- amino]-2,2-difluoro-5-[4-(phenylmethoxy)-phenyl]-N-(3- pyridinylmethyl)-L-glycero-pentonamide (0.357 g, 0.709 mmol) prepared in example 14, step A, is 5 deprotected as in example 14, step (d) and coupled with N- [ (2-pyridinylmethoxy)carbonyl]-L-valine (0.157 g, 0.620 mmol) prepared in example 15, under standard coupling conditions described previously to provide after treating the crude material with hot CH 3 OH, filtering, and 0 concentrating under vacuum, 180 mg (54%) of title compound as a white powder: IR (KBr) v max 3298, 1697, 1680, 1659, 1537, 1512, 1298, 1244, 1103 cm "1 ; 1 H NMR (DMSO-d 6 ) δ 9.3 9.32 ( , 1 H), 8.52-8.46 (m, 3 H), 7.82-7.68 (m, 3 H) , 7.41-7.26 (m, 7 H) , 7.19 (d, 1 H, J = 9.6 Hz), 7.07 (d, 2 5 H, J = 8.4 Hz), 6.81 (d, 2 H, J = 8.4 Hz), 6.27 (d, 1 H, J = 7.2 Hz), 5.12 (d, 1 H, J = 13.5 Hz), 5.06 (d, 1 H, J = 13.5 Hz), 5.02 (d, 1 H, J = 12.0 Hz), 4.97 (d, 1 H, J = 12.0 Hz), 4.44 (dd, 1 H, J = 15.3, 6.0 Hz), 4.35 (dd, 1 H, J = 15.3, 5.7 Hz), 4.24-4.15 (m, 1 H) , 4.11 (dd, 1 H, J = 10.5, 5.1 Hz), 4.06-3.95 (m, 1 H) , 3.79 (dd, 1 H, J = 9.3, 6.9 Hz), 2.93-2.88 (m, 1 H) , 2.60 (dd, 1 H, J = 13.8, 11.1 Hz), 1.82-1.77 (m, 1 H), 0.71 (d, 3H, J = 6.9 Hz), 0.68 (d, 3H, J = 6.9 Hz); 19 F NMR (DMSO-d 6 ) δ -109.87 (dd, J = 252, 8 Hz), -120.07 (dd, J = 253, 17 Hz); mass spectrum, m/z 704 (M + + 29), 676 (M + + 1), 424, 241, 138, 110, 92 (100). Anal. Calcd for C 36 H 39 F 2 N 5 0 6 : C, 63.99; H, 5.82; N, 10.36. Found: C, 60.62; H, 5.97; N, 9.83. Step B Preparation of final title compound. Reaction Scheme A', step (f): In a manner analogous to that described previously in example 1, the above prepared alcohol (152 mg, 0.225 mmol) is oxidized under Swern conditions to provide after flash chromatography (19:1 CHCI 3 /CH 3 OH) 104 mg (68%) of final title compound which is recrystallized twice from CH 2 Cl 2 /pen ane to provide 34 mg (22%) of final title compound as a cream powder: mp 97- 102°C; IR (KBr) v max 3405, 3324, 1699, 1534, 1512, 1437, 1242, 1178, 1113 cm "1 ; X H NMR (CDCI3) δ 8.56-8.51 (m, 3H) , 7.71-7.62 (m, 2 H) , 7.43-7.19 (m, 10 H), 7.10-7.05 (m, 2 H), 6.91-6.83 (m, 2 H) , 6.48-6.37 (m, 1 H), 5.48-5.10 (m, 3H), 5.02 and 5.00 (2s, 2 H total), 4.61-4.46 (m, 2 H) , 3.90 and 3.87-3.81 (dd and m, 1 H total, J = 8.7, 6.1 Hz), 3.36-3.23 (m, 1 H) , 2.91-2.73 (m, 1 H total), 2.07-1.88 (m, 1 H), 0.86 and 0.79 and 0.76 and 0.75 and 0.61 and 0.59 (6d, 6 H total, J = 6.6 Hz); 19 F NMR (CDCI 3 ) δ -111.65 (d, J = 277 Hz), -111.73 (d, J = 276 Hz), -113.15 (d, J = 276 Hz), -113.20 (d, J = 277 Hz), Hydrate: -115.64 (d, J = 257 Hz), -116.55 (d, J = 256 Hz), -120.42 (d, J = 256 Hz), - 121.55 (d, J = 256 Hz); mass spectrum, m/z 702 (M + + 29), 674 (M + + 1), 138, 110, 92 (100). Anal. Calcd for C 3 6H37 2 5O6: C, 64.18; H, 5.54; N, 11.87. Found: C, 61.96; H, 5.80; N, 10.38. Example 17 Preparation of N-[4-(N-{2-pyridylmethyl)oxycarbonyl-L- valypamino-2,2-difluoro-1,3-dioxo-5-( 4-benzyloxy)phenyl- pentyl3-0-(3-pyridylmethyl)-D-valinol. Step A Preparation of N-trityl-D-valinol. A solution of D-valinol (4.95 g, 48.06 mmol), triethylamine (7.4 mL, 52.87 mmol) and trityl chloride (14.74 g, 52.87 mmol) in dry dichloromethane (75 mL) is stirred for 17 hours at room temperature. The organic solution is washed with water (2 x 75 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting oil is purified by flash chromatography (silica gel, ethyl acetate/petroleum ether, 15/85) to provide the title compound (13.5 g, 81%); R f =0.45 (ethyl acetate petroleum ether, 15/85). Step B Preparation of N-trityl-O-3-pyridylmethyl-D-valinol. Under a nitrogen atmosphere, to a suspension of sodium hydride (1.3 g, 30 mmol, 55% dispersion in oil, previously washed twice with pentane) in dry DMF (3 mL) is added with stirring, a solution of N-trityl-D-valinol (3.45 g, 10 mmol) in DMF (23 mL) . The reaction is stirred for 30 minutes at room temperature and then cooled to 0°C and tetrabutylammonium iodide (0.37 g, 1 mmol) is added. Then 3-picolyl chloride HC1 (1.81 g, 11 mmol) is added to the reaction in portions over 5 minutes. After addition is complete, the cooling bath is removed and the mixture allowed to stirr for 17 hours at room temperature. The reaction mixture is then cooled with an ice bath and hydrolyzed with water (100 mL). The mixture is then extracted with ethyl acetate (2 x 100 mL). The organic extracts are washed with water (2 x 50 mL), combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting yellow oil is purified by flash chromatography (silica gel, dichloromethane/ethyl acetate, 9/1, R_=0.42) to provide the title compound (3.4 g, 78%) as an oil. Step C Preparation of O-3-pyridylmethyl-D-valinol. A solution of N-trityl-O-3-pyridylmethyl-D-valinol (3.63 g, 8.3 mmol) in formic acid (30 mL) is kept for 5.5 hours at room temperature. The formic acid is removed under vacuum and the residue is dissolved in water (100 mL). The mixture is extracted with ethyl acetate (100 mL, 50 mL) to remove the trityl alcohol. The aqueous phase is then made basic with saturated sodium carbonate (50 mL) and 4N sodium hydroxide (3 mL). The aqueous mixture is then extracted with ethyl acetate (4 x 50 mL). The organic extracts are rinsed with brine (2 x 50 mL), combined, dried over sodium sulfate, filtered and concentrated under vacuum to provide the title compound (1.32 g, 82%) R_=0.12 (silica gel, dichloromethane/methanol, 8/2). Step D Preparation of N-[4-tert-butoxycarbonylamino-2,2-difluoro- 3-hydroxy-l-oxo-5-(4-benzyloxy)phenyl-pentyl]-O-(3- pyridylmethyl)-D-valinol. Reaction Scheme A, step (b); A solution of the ester (1.14 g, 2.38 mmol, prepared in example 1, step B) and of O-3-pyridylmethyl-D-valinol (1.32 g, 6.8 mmol, prepared in step C above) in dry tetrahydrofuran (1.5 mL) is heated for 2 days under reflux. After cooling, the reaction mixture is diluted with ethyl acetate (5 mL), pentane (10 mL) and the precipitate is collected by filtration. The filtrate is rinsed with pentane and recrystallized from dichloromethane/methanol/pentane to provide the title compound (0.8 g, 54%) as a white solid, R_=0.5 (silica gel ethyl acetate); mass spectrum, m/z 628 (MH + ). Step E Preparation of N-[4-amino-2,2-difluoro-3-hydroxy-l-oxo-5- ( -(benzyloxy)phenyl-pentyl]-O-(3-pyridylmethyl)-D-valinol Reaction Scheme A, step (d); The title compound is obtained in 91% yield following the deprotection procedure in an analogous manner described in Example 17, step C; mass spectrum, m/z 528 (MH + ). Step F Preparation of N-[4-(N-{2-pyridylmethyl}oxycarbonyl-L- valyl)amino-2,2-difluoro-3-hvdroxy-l-oxo-5-(4- benzyloxy)phenyl-pentyl3-Q-(3-pyridylmethyl)-D-valinol. Reaction Scheme A', step (e); To a solution of N-(2- pyridylmethyloxycarbonyl)-L-valine (0.101 g, 0.4 mmol, prepared in Example 15, step B), in anhydrous DMF (2 mL) are added under an atmosphere of nitrogen, N- hydroxybenztriazole hydrate (0.115 g, 0.4 mmol), 1-ethyl- 3(3-dimethylaminopropyl)carbodiimide (0.085 g, 0.44 mmol) and DMF (1 mL) . The reaction mixture is allowed to stir for 30 minutes at room temperature and N-[4-amino-2,2- difluoro-3-hydroxy-l-oxo-5-(N-(benzyloxy)phenyl-pentyl]-0- ( 3-pyridylmethyl)-D-valinol (0.211 g, 0.4 mmol, prepared above) in DMF (1 mL) is added. The reaction is allowed to stir for 15 hours, then diluted with ethyl acetate (80 mL) and washed with water (2 x 80 mL) . The aqueous rinses are extracted with ethyl acetate (80 mL) . The combined organic extracts are dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue is purified by flash chromatography (2χ, silica gel, dichloromethane/ethanol, 95/5, R_=0.15) to provide the title compound (0.170 g, 56%); mass spectrum, m/z 762 (MH + ). Step G Preparation of final title compound. Reaction Scheme A', step (f); To a solution of oxalyl chloride (0.195 mL, 2.23 mmol) in anhydrous dichloromethane (0.5 mL) at -60°C is added slowly under an atmosphere of nitrogen, freshly distilled dimethyl sulfoxide (0.316 mL, 4.46 mmol) in dichloromethane (1.5 mL). After 10 minutes of stirring at -60°C, the temperature is allowed to rise to -15°C. A mixture of a solution of the alcohol prepared above (0.170 g, 0.223 mmol) in dichloromethane (7 mL) and dimethylsulfoxide (0.5 mL) is added to the reaction dropwise. The reaction is then stirred for 1.75 hours at - 15°C and then cooled to -78°C. Diisopropylethylamine (0.93 mL, 6.69 mmol) is added and the reaction is stirred an additional 10 minutes. The reaction is then allowed to warm to room temperature and is diluted with dichloromethane (25 mL). The reaction mixture is washed with water (2 x 25 mL) . The aqueous washes are extracted with dichloromethane (25 mL) . The combined organic extracts are dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue is purified by flash chromatography (silica gel, ethyl acetate, R f =0.17) followed by recrystallization from dichloromethane/pentane to provide the title compound (0.120 g, 71%); mass spectrum, m/z 760 (MH + ); X E NMR (DMSO-d 6 ) δ 9.12-8.96 (m, IH), 8.66-8.55 (m, 2H), 7.96-7.85 (m, IH) , 7.85-7.75 (m, IH), 7.60-7.35 (m, 7H), 7.30-7.19 (m, 2H) , 7.08-6.83 (m, 2H), 5.20 (s, 2H), 5.17-5.05 (m, 3H) , 4.65-4.53 (m, 2H), 4.07-3.87 (2m, 2H) , 3.72-3.60 (m, 2H), 3.28-3.14 and 2.86- 2.78 (m, 2H), 2.09-1.83 (m, 2H) , 1.27-0.67 (m, 12H); 19 F NMR (DMSO-d 6 , T=60°C) δ (C 6 F 6 ) 52.94 (d, J=269 Hz), 52.30 (d, J=270 Hz), 51.25 (d, J=270 Hz), 50.35 (d, J=269 Hz). Anal. Calcd for C 41 H 4 7N 5 O7F 2 , 0.25 H 2 0: C, 64.43; H, 6.26; N, 9.16; Found C, 64.24; H, 6.25; N, 9.01. Example 18 Preparation N-[ 4-(N-{3-pyridylmethyl}oxycarbonyl-L- valypamino-2,2-dif luoro-l, 3-dioxo-5-( 4-benzyloxy ) phenyl- pentyl ]-0-( 3-pyr idylmethyl) -D-valinol. Step A Preparation of N-[4-(N-{3-pyridylmethyl)oxycarbonyl-L- valyl)amino-2,2-difluoro-3-hydroxy-l-oxo-5-(4- benzyloxy)phenyl-pentyl]-0-(3-pyridylmethyl)-D-valinol. Reaction Scheme A', step (e); The title compound is prepared in a manner analogous to the coupling procedure described in Example 17, Step F, utilizing the amine prepared in Example 17, Step E, and the acid prepared in Example 8, Step A. The title compound is obtained in 84% yield, Rf=0.43 (silica gel, dichloromethane/ethanol, 95/5 mass spectrum, m/z 762 (MH + ). Anal. Calcd for C 4 iH 49 N 5 O 7 F 2 «0.5 H 2 0: C, 63.88; H, 6.54; N, 9.08; Found C, 63.87; H, 6.47; N, 9.06. Step B Preparation of Final Title Compound. Reaction Scheme A', step (f); The title compound is prepared in a manner analogous to the Swern Oxidation described in Example 17, Reaction Scheme A', step (f), utilizing the above alcohol. The title compound is obtained in 50% yield, Rf=0.1 (silica gel, ethyl acetate) X H NMR (DMSO-d 6 ) δ 9.04-8.90 ( , IH) , 8.71-8.50 (m, 3H) , 7.90-7.70 (m, 2H) , 7.60-6.85 (m, 12H), 5.27-5.02 (m, 5H) , 4.50-4.66 (m, 2H) , 3.85-4.07 (m, 2H) , 3.72-3.57 (m, 2H) , 3.30-3.12 and 2.85-2.65 (m, 2H) , 2.05-1.8 (m, 2H) , 1.20- 0.59 (m, 12H); 19 F NMR (DMSO-d 6 ) δ (C 6 F 6 ) 52.93 (d, J=268 Hz), 52.15 (d, J=269 Hz), 50.92 (d, J=269 Hz), 49.68 (d, J=268 Hz); hydrates, 49.31 (d, J=254 Hz), 48.31 (d, J=254 Hz), 46.22 (d, J=254 Hz), 44.68 (d, J=254 Hz). Anal. Calcd for C41H47N5O7F2, H 2 0: C, 63.31; H, 6.35; N, 9.00; Found C, 62.56; H, 6.26; N, 8.66. Example 19 Preparation of N-[4-(N-{3-pyridylmethyl}oxycarbonyl-L- valypamino-2 , 2-dif luoro-1 , 3-dioxo-5- ( 4-benzyloxy)phenyl- pentyl]-Q-methyl -D-valinol. Step A Preparation of N-tert-butoxycarbonyl-D-valinol. A solution of D-valinol (5.1 g, 49.4 mmol) and di-tert- butyldicarbonate (10.9 g, 50 mol), in methanol (60 mL) is stirred for 17 hours at room temperature. The reaction is concentrated under vacuum and the residue is purified by flash chromatography (silica gel, ethyl acetate/petroleum ether, 3/7, R f =0.37) to provide the title compound in quantitative yield (10.07 g) as a colorless oil; mass spectrum, m/z 204 (MH + ). Step B Preparation of N-tert-Butoxycarbonyl-O-methyl-D-valinol. To a solution of N-tert-butoxycarbonyl-D-valinol (5.0 g, 25 mmol) and methyl iodide (27.5 mL of a 1M solution in tetrahydrofuran, 27.5 mmol) in dry tetrahydrofuran (45 mL) under an atmosphere of nitrogen at 0°C, is added with stirring, potassiu -tert-butoxide (3.086 g, 27.5 mmol) in portions. The reaction mixture is kept at room temperatur for 5.5 hours, then hydrolyzed with a saturated solution sodium chloride and extracted with ethyl acetate (2 x 300 mL) . The organic extracts are washed with brine (2 x 300 mL), combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue is purified by flash chromatography (silica gel, ethyl acetate/petroleum ether, 1/9, Rf=0.25) to provide the titl compound (2.93 g, 54%) as an oil. Step C Preparation of O-methyl-D-valinol. A solution of N-tert-butoxycarbonyl-O-methyl-D-valino (2.93 g, 13.5 mmol) in dry ether saturated with hydrogen chloride (11 mL) is stirred at room temperature for 3.5 hours. The reaction is then concentrated under vacuum. Pentane (50 mL) is added to the residue, followed by addition of diethylamine (7 mL) . The mixture is then stirred for 10 minutes and the solid is removed by filtration. The filtrate is concentrated under vacuum(150 bars) at room temperature to provide the title compound (1.30 g, 82%) as a colorless oil. Step D Preparation of N-[4-tert-butoxycarbonylamino-2,2-difluoro 3-hydroxy-l-oxo-5-(4-benzyloxy)phenyl-pentyl]-O-methyl-D- valinol. Reaction Scheme A, step (b); The title compound is prepared in a manner analogous to the procedure of Exampl 17, Step D, from the ester of Example 1, step B and the above prepared O-methyl-D-valinol followed by flash chromatography (78% yield); R_=0.19 (minor) and 0.09 (major) (silica gel, ethyl acetate/petroleum ether, 35/65); mass spectrum, m/z 551 (MH + ), 568 (MNH 4 + ). Step E Preparation of N-[4-amino-2,2-difluoro-3-hydroxy-l-oxo-5- (4-benzyloxy)phenyl-pentyl]-O-methyl-D-valinol. Reaction Scheme A, step (d); The title compound is prepared in a manner analogous to the deprotection procedure of Example 17, step C, from N-[4-tert- butoxycarbonylamino-2,2-difluoro-3-hydroxy-l-oxo-5-(4- butyloxy)phenyl-pentyl]-O-methyl-D-valinol prepared above (quantitative yield); mass spectrum, m/z 451 (MH + ). Step F Preparation of N-[4-(N-{3-pyridylmethyl)oxycarbonyl-L- valyl)amino-2,2-difluoro-3-hydroxy-l-oxo-5-(4- benzyloxy)phenyl-pentyl3-O-methyl-D-valinol. Reaction Scheme A 1 , step (e); The title compound is prepared in a manner analogous to the coupling method described in Example 17, step F, from N-[4-amino-2,2- difluoro-3-hydroxy-l-oxo-5-(4-benzyloxy)phenyl-pentyl]-O- methyl-D-valinol prepared above and the acid prepared in Example 8, Step A. Purification by crystallization (ethyl acetate plus 10% ethanol/pentane) provides the title compound in 58% yield; mass spectrum, m/z 685 (MH + ). Step G Preparation of final title compound. Reaction Scheme A', step (f); The final title compound is prepared in a manner analogous to the Swern Oxidation described in Example 17, step G from N-[4-(N-{3- pyridylmethyl}oxycarbonyl-L-valyl)amino-2,2-difluoro-3- hydroxy-l-oxo-5-(4-benzyloxy)phenyl-pentyl]-O-methyl-D- valinol prepared above (15% yield, R f =0.1, silica gel. dichloromethane/ethyl acetate, 4/6); l E NMR (DMSO-d 6 ) δ 9.07-8.93 (m, IH) , 8.87-8.50 (m, 2H) , 8.40-8.31 (m, IH), 7.94-7.81 ( , IH) , 7.60-6.59 (several m, 11H) , 5.29-5.01 (m, 5H), 4.10-3.78 (m, 2H) , 3.58-3.43 (m, 2H) , 3.35-3.25 (several s, 3H), 3.30-3.08 and 2.85-2.63 (m, 2H), 2.11- 1.72 (m, 2H), 1.04-0.48 (m, 12H); 19 F NMR (DMSO-d 6 ) δ (C 6 F 53.27 (d, J=267 Hz), 52.60 (d, J=269 Hz), 51.32 (d, J=269 Hz), 49.76 (d, J=267 Hz), 49.89 (d, J=254 Hz), 48.61 (d, J=254 Hz), 46.49 (d, J=254 Hz), 44.73 (J=254 Hz); mass spectrum, m/z 683 (MH + ) . Anal. Calcd for C 36 H 44 N 4 O7F 2 , H 2 0: C, 61.70; H, 6.62; N, 7.99; Found C, 62.07; H, 6.46; N, 7.84. Example 20 Preparation of N-{4-(N-{3-pyridylmethyl}oxycarbonyl-L- valyl)amino-2,2-difluoro-1,3-dioxo-5-(4-benzyloxy)phenyl- pentyl]-0-(2-pyridylmethyl)-D-valinol. Step A Preparation of N-trityl-O-2-pyridylmethyl-D-valinol. The title compound is prepared in a manner analogous to the procedure described in Example 17, step B from the alcohol of Example 17, step A and 2-picolyl chloride HC1, in 81% yield, R_=0.52 (silica gel, dichloromethane/ethyl acetate, 9/1). Step B Preparation of O-2-pyridylmethyl-D-valinol. The title compound is prepared in a manner analogous the procedure described in Example 17, step C from N- trityl-O-2-pyridylmethyl-D-valinol prepared above, in 80% yield. Step C Preparation of N-[4-tert-butoxycarbonylamino-2,2-difluoro- 3-hydroxy-l-oxo-5-(4-benzyloxy)phenyl-pentyl3-O-(2- pyridylmethyl)-D-valinol. Reaction Scheme A, step (b); The title compound is prepared in a manner analogous to the procedure described in Example 17, Step D, from the ester of Example 1, step B and O-2-pyridylmethyl-D-valinol, prepared above, in 63% yield, R_=0.65 (silica gel, ethyl acetate). Step D Preparation of N-[4-amino-2,2-difluoro-3-hydroxy-l-oxo-5- (4-benzyloxy)phenyl-pentyl]-Q-(2-pyridylmethyl)-D-valinol. Reaction Scheme A, step (d); The title compound is prepared in a manner analogous to the deprotection procedure described in Example 17, step C from N-[4-tert- butoxycarbonylamino-2,2-difluoro-3-hydroxy-l-oxo-5(4- benzyloxy)phenyl-pentyl]-0-(2-pyridylmethyl)-D-valinol, prepared above, in 91% yield which is used directly in the next step; mass spectrum, m/z 628 (MH + ) . Step E Preparation of N-[4-(N-{3-pyridylmethyl}oxycarbonyl-L- valyl)amino-2,2-difluoro-3-hydroxy-l-oxo-5-(4- benzyloxy)phenyl-pentyl]-0-(2-pyridylmethyl)-D-valinol. Reaction Scheme A', step (e); The title compound is prepared in a manner analogous to the procedure described in Example 17, step F from the amine prepared above and the acid prepared in Example 8, Step A, in 53% yield, R_=0.14 (major) and 0.08 (minor) (silica gel, dichloromethane/ethanol, 95/5); mass spectrum, m/z 762 (MH + ). Step F Preparation of final title compound. Reaction Scheme A', step (f); The final title compound is prepared in a manner analogous to the Swern Oxidation procedure described in Example 17, step G from the above prepared alcohol, in 72% yield, Rf=0.09 (silica gel, ethyl acetate); l H NMR (CDC1 3 ) δ 8.65-8.53 (m, IH) , 7.79-7.64 (m, 2H), 7.53-6.80 (several m, 14H) , 6.60-6.10 (several m, 2H), 5.57-5.33 (m, IH) , 5.30-5.10 ( , 3H) , 4.99 (s, 2H) , 4.68- 4.56 (m, 2H), 4.03-3.85 (m, 2H) , 3.85-3.34 (m, 2H) , 3.42- 3.24 and 2.97-2.75 (m, 2H) , 2.13-1.88 (m, 2H) , 1.05-0.57 (m, 12H); 19 F NMR (CDCI 3 ) δ (C 6 F 6 ) 50.26 (d, J=271 Hz), 49.97 (d, J=263 Hz), 49.18 (d, J=261 Hz), 48.60 (d, J=271 Hz), 45.17 (d, J=252 Hz), 45.10 (d, J=251 Hz), 41.77 (d, J=252 Hz), 40.91 (d, J=251 Hz); mass spectrum, m/z 760 (MH + ). Anal. Calcd for C41H47N 5 O7F 2 : C, 64.81; H, 6.23; N, 9.22; Found C, 62.91; H, 6.16; N, 8.66. Example 21 Preparation of N-[4-(N-{2-pyridylmethyl)oxycarbonyl-L- valvPamino-2,2-difluoro-1,3-dioxo-5-( 4-{3- pyridylmethyl}oxy)phenyl-pentyl]-0-(3-pyridylmethyl)-D- valinol. Step A Preparation of 4-tert-butoxycarbonylamino-2,2-difluoro-3- hydroxy-5-(4-hvdroxy)phenyl pentanoic acid, ethyl ester. Reaction Scheme A, step (c_); A solution of 4-tert- butoxycarbonylamino-2,2-difluoro-3-hydroxy-5-[ (4- benzyloxy)phenyl]pentanoic acid, ethyl ester (0.719 g, 1.5 mmol) in ethanol (50 mL) is kept for 7.5 hours under an atmosphere of hydrogen in the presence of 10% palladium on charcoal (0.074 g). The hydrogen atmosphere is then exchanged with a nitrogen atmosphere, the suspension is filtered and the filtrate is concentrated under vacuum to provide the title compound (0.500g, 83%), R_=0.51 (silica gel, petroleum ether/ethyl acetate, 1/1). Step B Preparation of N-[4-tert-butoxycarbonylamino-2,2-difluoro- 3-hydroxy-l-oxo-5-(4-hydroxy)phenyl-pentyl]-0-(3- pyridylmethyl)-D-valinol. Reaction Scheme A, step (b); The title compound is prepared in a manner analogous to the procedure described in Example 19, step D, from the above prepared ester and the amine prepared in Example 17, step C, in 82% yield, R f =0.46 (silica gel, ethyl acetate). Step C Preparation of N-[4-tert-butoxycarbonylamino-2,2-difluoro- 3-hydroxy-l-oxo-5-(4-hydroxy)phenyl-pentyl]-Q-(3- pyridylmethyl)-D-valinol. Reaction Scheme A, step (C 2 ); A mixture of N-[4-tert- butoxycarbonylamino-2,2-difluoro-3-hydroxy-l-oxo-5-(4- hydroxy)phenyl-pentyl]-0-(3-pyridylmethyl)-D-valinol (0.37 g, 0.7 mmol, prepared above), 3-picolyl chloride HCl (0.16 g, 0.98 mmol), cesium carbonate (0.775 g, 2.38 mmol) and potassium iodide (0.016 g, 0.098 mmol) in anhydrous DMF (7 mL) is stirred for 66 hours under an atmosphere of nitrogen. The reaction mixture is diluted with ethyl acetate (50 mL) and washed with water (2 x 50 mL) . The aqueous rinses are extracted with ethyl acetate (50 mL). The combined organic extracts are dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue is purified by flash chromatography (silica gel, ethyl acetate/methanol, 95/5, R f =0.25) to provide the title compound (0.245 g, 56%); mass spectrum m/z 629 (MH + ) Step D Preparation of N-[4-amino-2,2-difluoro-3-hydroxy-l-oxo-5- (4-{3-pyridylmethyl}oxy)phenyl-pentyl3-0-(3-pyridylmethyl) D-valinol. Reaction Scheme A, step (d); The title compound is prepared in a manner analogous to the deprotection procedure described in Example 17, step C from N-[4-tert- butoxycarbonylamino-2,2-difluoro-3-hydroxy-l-oxo-5-(4- hydroxy)phenyl-pentyl]-0-(3-pyridylmethyl)-D-valinol prepared above, in 84% yield; mass spectrum m/z 529 (MH + ). Step E Preparation of N-[4-{2-pyridylmethyl)oxycarbonyl-L- valyPamino-2,2-difluoro-3-hydroxy-l-oxo-5-(4-{3- pyridylmethyl}oxy)phenyl-pentyl)-Q-(3-pyridylmethyl)-D- valinol. Reaction Scheme A', step (e); The title compound is prepared in a manner analogous to the coupling procedure described in Example 17, step F, from the above prepared amine and the acid prepared in Example 15, step B, in 56% yield, R_=0.20 (silica gel, dichloromethane/ethanol, 95/5); mass spectrum m/z 763 (MH + ). Step F Preparation of final title compound. Reaction Scheme A', step (f); The final title compound is prepared in a manner analogous to the Swern Oxidation procedure described in Example 17, step G from the above prepared alcohol, in 70% yield, R_=0.19 (silica gel, ethyl acetate/acetone, 1/1); mass spectrum m/z 761 (MH + ); X H NMR (DMSO-d 6 ) δ 9.11-8.97 (m, IH) , 8.80-8.50 (m, 5H) , 8.50-8.30 (m, IH), 8.13-7.70 (m, 4H) , 7.69-6.60 (m, 8H), 5.40-5.00 (m, 5H), 4.71-4.49 (m, 2H) , 4.10-3.80 (m, 2H), 3.80-3.51 (m, 2H), 3.51-3.30 and 2.86-2.60 (m, 2H), 2.12-1.72 (m, 2H), 1.17-0.47 (m, 12H) ; 19 F NMR (DMSO-d 6 ) δ (C 6 F 6 ) 52.91 (d, J=268 Hz), 52.11 (d, J=269 Hz), 50.86 (d, J=269 Hz), 50.42 (d, J=268 Hz), 49.34 (d, J=254 Hz), 48.39 (d, J=254 Hz), 46.17 (d, J=254 Hz), 44.63 (d, J=254 Hz). Anal. Calcd for C 40 H 6 N 6 O 7 F 2 : C, 63.15; H, 6.09; N, 11.05; Found C, 62.26; H, 6.24; N, 10.76. Example 22 Preparation of N-[4-(N-{2-pyridylmethyl}oxycarbonyl-L- valy1)amino-2,2-difluoro-1,3-dioxo-5-(4-benzyloxy)phenyl- pentyl3-O-(2-pyridylmethyl)-D-valinol. Step A Preparation of N-[4-{2-pyridylmethyl)oxycarbonyl-L- valypamino-2,2-difluoro-3-hvdroxy-l-oxo-5-(4- benzyloxy)phenyl-pentyl3-0-(2-pyridylmethyl)-D-valinol. Reaction Scheme A 1 , step (e); The title compound is prepared in a manner analogous to the coupling procedure described in Example 17, step F from the amine prepared in Example 20, Reaction Scheme A, step (d) and the acid prepared in Example 15, step B, in 57% yield, R_=0.17 (major) and 0.12 (minor) (silica gel, dichloromethane/ethanol, 95/5); mass spectrum m/z 762 (MH + ) Step B Preparation of final title compound. Reaction Scheme A', step (f); The final title compound is prepared in a manner analogous to the Swern Oxidation procedure described in Example 17, step G from the above prepared alcohol, in 80% yield, R_=0.22 (silica gel, ethyl acetate); mass spectrum m/z 760 (MH + ); l E NMR (CDCI 3 ) δ 8.63-8.48 (m, 2H) , 7.77-7.60 (m, 2H) , 7.55-6.80 (several m, 13H), 6.49-6.02 (several m, 2H) , 5.55-5.30 (m, IH) , 5.30- 4.95 (several m, 5H), 4.72-4.52 (m, 2H), 4.05-3.82 (m, 2H), 3.82-3.35 (m, 2H) , 3.42-3.23 and 2.97-2.77 (m, 2H) , 2.13- 1.83 (m, 2H), 1.05-0.54 (m, 12H) ; 19 F NMR (CDCI 3 ) δ (C 6 F 6 ) 50.18 (d, J=271 Hz), 49.87 (d, J=277 Hz), 49.02 (d, J=271 Hz), 48.41 (d, J=271 Hz), 44.97 (d, J=252 Hz), 44.78 (d, J=252 Hz), 41.85 (d, J=252 Hz), 41.12 (d, J=252 Hz). Anal. Calcd for C 4 iH 47 5 0 7 F 2 , H 0; C, 63.31; H, 6.35; N, 9.00; Found C, 63.37; H, 6.19; N, 8.85. Example 23 Preparation of N-[4-(N-{2-pyridylmethyl}oxycarbonyl-L- valyl)amino-2,2-difluoro-1,3-dioxo-5-(4-benzyloxy)phenyl- pentyl3-O-methyl-D-valinol. Step A Preparation of N-[4-{2-pyridylmethyl)oxycarbonyl-L- valyl)amino-2,2-difluoro-3-hydroxy-l-oxo-5-(4- benzyloxy)phenyl-pentyl]-Q-methyl-D-valinol. Reaction Scheme A', step (e); The title compound is prepared in a manner analogous to the coupling procedure described in Example 17, step F from the amine prepared in Example 19, Reaction Scheme A, step (d) and the acid prepared in Example 15, step B, in 55% yield, R_=0.23 (silica gel, ethyl acetate); mass spectrum m/z 685 (MH + ). Anal. Calcd for C 36 H 46 N 4 O 7 F 2 , 0.5 H 2 0; C, 62.32; H, 6.83; N, 8.08; Found C, 62.36; H, 6.64; N, 7.91. Step B Preparation of the final title compound. Reaction Scheme A', step (f);The final title compound is prepared in a manner analogous to the Swern Oxidation procedure described in Example 17, step G from the above prepared alcohol, in 44% yield, R_=0.3 (silica gel, dichloromethane/ethyl acetate, 3/7); mass spectrum m/z 68 (MH + ); l E NMR (DMSO-d 6 ) δ 9.10-8.92 (m, IH) , 8.67-8.51 (m, 2H), 7.95-7.87 (m, IH) , 7.64-6.82 (several m, 11H) , 5.30- 5.03 (m, 5H), 4.10-3.93 (m, IH) , 3.93-3.78(m, IH) , 3.60- 3.37 (m,2H), 3.35-3.25 (several s, 3H) , 3.32-3.10 and 2.8 2.68 (m, 2H), 2.14-1.80 ( , 2H) , 1.10-0.60 (m, 12H) ; 19 NMR (DMSO-d 6 ) δ (C 6 F 6 ) 52.80 (d, J=267 Hz), 52.21 (d, J=26 Hz), 50.93 (d, J=269 Hz), 52.21 (d, J=269 Hz), 50.93 (d, J=269 Hz), 49.36 (d, J=267 Hz). Anal. Calcd for C 36 H 44 N 4 O 7 F 2 , 0.5 H 2 0; C, 62.51; H, 6.56; 8.10; Found C, 62.65; H, 6.50; N, 7.93. Example 24 Preparation of N-{4-(N-{2-pyridylmethyl}oxycarbonyl-L- valypamino-2,2-difluoro-1,3-dioxo-5-(4-benzyloxy)phenyl- pentyl3-O-benzyl-D-valinol. Step A Preparation of N-[4-(N-{2-pyridylmethyl)oxycarbonyl-L- valyl)amino-2,2-difluoro-3-hydroxy-l-oxo-5-(4- benzyloxy)phenyl-pentyl3-O-benzyl-D-valinol. Reaction Scheme A', step (e); The title compound is prepared in a manner analogous to the coupling procedure described in Example 17, step F from the amine prepared i Example 5, step B and the acid prepared in Example 15, st B in 52% yield, R_=0.28 (silica gel, petroleum ether/ethy acetate, 3/7) . Step B Preparation of the final title compound. Reaction Scheme A', step (f); The final title compound is prepared in a manner analogous to the Swern Oxidation procedure described in Example 17, step G from the above prepared alcohol, in 62% yield, R f =0.07 (Alumina neutral Act III, tetrahydrofuran/dichloromethane/water, 20/10/0.2), R f =0.27 (silica gel, ethyl acetate/petroleum ether,7/3); mass spectrum m/z 759 (MH + ); 1 H NMR (CDC1 3 ) δ 8.73-8.51 (m,lH), 7.79-7.65 (m, IH) , 7.42-6.45 (several m, 18H), 5.70-5.10 (m, 4H) , 5.06-4.93 (m, 2H), 4.58-4.40 (m, 2H) , 4.05-3.80 (m, 2H) , 3.74-3.58 and 3.55-3.40 (m, 2H) , 3.35- 3.20 and 3.00-2.80 (m, 2H) , 2.13-1.90 (m, 2H) , 1.10-0.50 (m, 12H); 19 F NMR (CDCI 3 ) δ (C 6 F 6 ) 50.67 (d, J=273 Hz), 49.50 (broad s), 48.35 (d, J=273 Hz), 47.24 (d, J=255 Hz), 45.70 (d, J=255 Hz), 42.01 (d, J=255 Hz) 40.00 (d, J=255 Hz). Anal. Calcd for C4 2 H 48 N 4 O7F 2 , 0.5 H 2 0: C, 65.70; H, 6.43; N, 7.30; Found C, 65.69; H, 6.25; N, 7.19. Example 25 Preparation of N-{4-(N-{3-pyridylmethyl}oxycarbonyl-L- valyl)amino-2,2-difluoro-1,3-dioxo-5-(4-benzyloxy)phenyl- pentyl]-0-[ 2-(2-methoxyethoxy)-1-ethyl]-D-valinol. Step A Preparation of N-trityl-Q-[2-(2-methoxyethoxy)-1-ethyl3~D~ valinol. The title compound is prepared in a manner analogous to the alkylation procedure described in Example 17, step B from the compound prepared in Example 17, step A and 2-(2- methoxyethoxy)ethyl-l-bromide in 86% yield, R f =0.74 (sili gel, acetone/petroleum ether, 2/8). Step B Preparation of Q-[2-( 2-methoxyethoxy)-l-ethyl]-D-valinol. A solution of N-trityl-0-[2-( 2-methoxyethoxy)-l-ethy D-valinol (1.0 g, 2.28 mmol, prepared above) in dry ether saturated with hydrogen chloride (20 mL) is kept for 2.5 hours at room temperature. The reaction is concentrated under vacuum and the residue is purified by flash chromatography (silica gel, dichloromethane first to elut the trityl alcohol and then dichloromethane/diethylamine, 95/5, R f =0.20) to provide the title compound (0.46 g, 100 as a colorless oil. Step C Preparation of N-[4-tert-butoxycarbonylamino-2,2-difluor 3-hydroxy-l-oxo-5-(4-benzyloxy)phenyl-pentyl]-O-[2-(2- methoxyethoxy)-1-ethyl3-D-valinol. Reaction Scheme A, step (b); The title compound is prepared in a manner analogous to the procedure describe in Example 19, step D from the ester of Example 1, step and 0-[2-(2-methoxyethoxy)-1-ethyl]-D-valinol, prepared above, in 51% yield, R f =0.37 (silica gel, petroleum ether/ethyl acetate, 3/7). Step D Preparation of N-[4-amino-2,2-difluoro-3-hydroxy-l-oxo-5- (4-benzyloxy)phenyl-pentyl]-Q-[2-( 2-methoxyethoxy)-l- ethyl ]-D-valinol. Reaction Scheme A, step (d); The title compound is prepared in a manner analogous to the deprotection procedure described in Example 17, step C from N-[4-tert- butoxycarbonylamino-2,2-difluoro-3-hydroxy-l-oxo-5-(4- benzyloxy)phenyl-pentyl]-0-[2-(2-methoxyethoxy)-1-ethyl]- valinol, prepared above, in 97% yield which is used directly in the next step; mass spectrum m/z 539 (MH + ) . Step E Preparation of N-[4-(N-(3-pyridylmethyl)oxycarbonyl-L- valyl)amino-2,2-difluoro-3-hydroxy-l-oxo-5-(4- benzyloxy)phenyl-pentyl]-O-[2-(2-methoxyethoxy)-1-ethyl ]-D- valinol. Reaction Scheme A 1 , step (e); The title compound is prepared in a manner analogous to the coupling procedure described in Example 17, step F from the amine prepared above and the acid prepared in Example 8, step A, in 52% yield, R_=0.18 (silica gel, ethyl acetate); mass spectrum m/z 773 (MH + ) . Step F Preparation of final title compound. Reaction Scheme A', step (f); The final title compound is prepared in a manner analogous to the Swern Oxidation procedure described in Example 17, step G from the above prepared alcohol, in 76% yield, R_=0.09 (silica gel, ethyl acetate); mass spectrum m/z 771 (MH + ); λ E NMR (DMSO-d 6 ) δ 9.05-8.88 (m, IH) , 8.77-8.55 (m, 2H) , 8.40-8.27 (m, IH) , 7.94-7.81 (m, IH) , 7.76-6.55 (several m, 11H), 5.31-4.97 (m, 5H), 4.10-3.79 (m, 2H) , 3.76-3.37 (m, 10H) , 3.32 (s, 3H), 3.29-3.11 and 2.89-2.60 (m, 2H), 2.09-1.79 (m, 2H) , 1.11-0.44 (m, 12H); 19 F NMR (DMSO-d 6 ) δ (C 6 F 6 ) 52.97 (d, J=267 Hz), 52.12 (d, J=269 Hz), 50.88 (d, J=269 Hz), 49.45 (d, J=254 Hz), 45.35 (d, J=267 Hz), 48.17 (d, J=254 Hz), 46.17 (d, J=254 Hz), 44.31 (d, J=254 Hz). Anal. Calcd for C 40 H 52 N 4 O 9 F 2 : C, 62.32; H, 6.80; N, 7.27; Found C, 61.78; H, 6.77; N, 7.12. Example 26 Preparation of N-[4-(N-{3-pyridylmethyl}oxycarbonyl-L- valypamino-2,2-difluoro-l,3-dioxo-5-(4-{2-N- morpholyl]ethyloxy)phenyl-pentyl3-O-methyl-D-valinol. Step A Preparation of N-[4-tert-butoxycarbonylamino-2,2-difluoro- 3-hydroxy-l-oxo-5-(4-hydroxy)phenyl-pentyl]-O-methyl-D- valinol. Reaction Scheme A, step (b); The title compound is prepared in a manner analogous to the procedure described in Example 17, Step D, from the ester of Example 21, step A and the amine prepared in Example 19, step C, in 83% yield, R f =0.15 (silica gel, petroleum ether/ethyl acetate, 6/4); mass spectrum m/z 461 (MH + ). Step B Preparation of N-[4-tert-butoxycarbonylamino-2,2-difluoro- 3-hydroxy-l-oxo-5-(4-{2-N-morpholyl}ethyloxy)phenyl- pentyl]-O-methyl-D-valinol. Reaction Scheme A, step (C 2 ); A mixture of N-[4-tert- butoxycarbonylamino-2,2-difluoro-3-hydroxy-l-oxo-5-(4- hydroxy)phenyl-pentyl]-0-methyl-D-valinol (1.117 g, 2.43 mmol, prepared above), N-(2-chloroethyl)morpholine HCl (0.633 g, 3.40 mmol), cesium carbonate (2.69 g, 8.26 mmol) and potassium iodide (0.056 g, 0.34 mmol) in dry DMF (20 mL) is stirred for 140 hours at room temperature. The reaction mixture is then diluted with ethyl acetate (100 mL) and washed with brine (2 x 100 mL). The aqueous washes are extracted with ethyl acetate (100 mL). The combined organic extracts are dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue is purified by flash chromatography (silica gel, ethyl acetate, R f =0.18) to provide the title compound (0.993 g, 71%). Step C Preparation of N-[4-amino-2,2-difluoro-3-hydroxy-l-oxo-5- (4-(2-N-morpholyl}ethyloxy)phenyl-pentyl]-O-methyl-D- valinol. Reaction Scheme A, step (d); The title compound is prepared in a manner analogous to the deprotection procedure described in Example 17, step C from N-[4-tert- butoxycarbonylamino-2,2-difluoro-3-hydroxy-l-oxo-5-(4-{2-N- morpholyl}ethyloxy)phenyl-pentyl3-O-methyl-D-valinol, prepared above, in 85% yield which is used directly in the next step. Step D Preparation of N-[4-(N-{3-pyridylmethyl}oxycarbonyl-L- valyl)amino-2,2-difluoro-3-hydroxy-l-oxo-5-(4-.2-N- morpholyl}ethyloxy)phenyl-pentyl3-O-methyl-D-valinol. Reaction Scheme A', step (e); The title compound is prepared in a manner analogous to the procedure described in Example 17, Step F from the amine prepared above and the acid prepared in Example 8, step A, in 80% yield, R_=0.19 (silica gel, ethyl acetate/methanol, 9/1); mass spectrum m/z 708 (MH + ). Step E Preparation of final title compound. Reaction Scheme A', step (f); A mixture of the above prepared alcohol (0.280 g, 0.396 mmol), 1,1,1-triacetoxy- l,l-dihydro-l,2-benziodoxol-3(lH)-one (0.672 g, 1.583 mmol, Dess-Martin periodinane) and tert-butanol (0.075 mL, 0.792 mmol) in freshly distilled dichloromethane (10 mL, distilled over P 2 O 5 ) is stirred for 15 minutes at room temperature. The reaction mixture is then hydrolyzed with isopropanol (1.2 mL) and concentrated under vacuum. The residue is suspended in dichloromethane (3 mL), filtered through a Fluropore filter which is rinsed with dichloromethane (2 l mL) . The filtrate is concentrated under vacuum and the residue purified by flash chromotagraphy (2 χ , silica gel, dichloromethane/methanol, 99/1 to remove the by-products of the Dess-Martin Reagent, then 98/2 and 96/4 to elute the title compound) to provide the title compound (0.112 g, 28%), Rf=0.11 (dichloromethane/methanol, 95/5); mass spectrum m/z 706 (MH + ); λ NMR (DMSO-d 6 ) δ 8.99-8.70 (m, IH) , 8.64-8.43 (m, 3H), 7.82-7.73 (m, IH), 7.47-6.70 (several m, 6H), 5.16- 4.92 (m, 3H), 4.08-3.95 (broad s, 2H), 3.95-3.71 (m, IH) , 3.71-3.65 ( , IH) , 3.60-3.48 (broad s, 4H) , 3.43-3.34 (m, 2H), 3.22-3.18 (2s, 3H), 3.24-3.03 and 2.77-2.56 (m, 2H) , 2.54-2.34 (m, 4H) , 2.02-1.70 (m, 2H) , 1.10-0.50 (m, 12H) ; 19 F NMR (DMSO-de) δ (C 6 F 6 ) 52.87 (d, J=267 Hz), 52.22 (d, J=269 Hz), 50.91 (d, J=269 Hz), 49.38 (d, J=267 Hz). Anal. Calcd for C 35 H 9 N 5 O8F 2 »0.5 H 2 0; C, 58.81; H, 7.05; N, 9.80; Found C, 58.61; H, 6.88; N, 9.93. In a further embodiment the present invention provides a method of treating a patient afflicted with a viral infection comprising the administration thereto of an effective antiviral amount of a compound of formula (I). The term "viral infection" as used herein refers to an abnormal state or condition characterized by viral transformation of cells, viral replication and proliferation. Viral infections for which treatment with a compound of formula (I) will be particularly useful include retroviruses such as but not limited to HTLV-I, HTLV-II, HTLV-III (HIV virus), murine leukemia virus, feline leukemia virus, cytomegalovirus(CMV) , avian sarcoma virus and the like. In addition treatment with a compound of formula (I) would be useful in treating a wide range of states of . HIV infection: AIDS, ARC (AIDS related complex), both symptomatic and asymptomatic, and actual or potential exposure to HIV. For example, the compounds of this invention are useful in preventing infection by HIV after suspected past exposure to HIV by, e.g., blood transfusion, accidental needle stick, or exposure to patient blood during surgery. An "effective antiviral amount" of a compound of formula (I) refers to an amount which is effective, upon single or multiple dose administration to the patient, in controlling the growth of the virus or in prolonging the survivability of the patient beyond that expected in the absence of such treatment. As used herein "controlling a viral infection" refers to slowing, interrupting, arresting or stopping the viral transformation of cells or the replication and proliferation of the virus and does not necessarily indicate a total elimination of the virus. The present invention further provides a method of inhibiting HIV protease in a patient in need thereof comprising administering to said patient an effective inhibitory amount of a compound of formula (I). It is understood that patients suffering from a retrovirus, such as HTLV-III are in need of an HIV protea inhibitor such as a compound of formula (I). As used herein, the term "patient" refers to a warm¬ blooded animal, such as a mammal, which is afflicted wit a particular viral infection. It is understood that humans, mice and rats are included within the scope of th term "patient". Administration of a compound of formula (I) to a patient results in inhibition of HIV protease in the patient. Thus, by treatment of a patient with a compound of formula (I) retroviruses, such as HTLV-III, are inhibited or suppressed. A patient is in need of treatment with an agent which inhibits HIV protease, such as a compound of formula (I), where the patient is suffering from certain viral infections for which HIV protease is implicated as a contributing factor in the progression of the disease. Based on standard clinical and laboratory tests and procedures, an attending diagnostician, as a person skill in the art, can readily identify those patients who are i need of treatment with an agent which inhibits HIV protease, such as a compound of formula (I). An "effective inhibitory amount" of a compound of formula (I) is that amount which is effective, upon singl or multiple does administration to a patient, in providin an inhibition of HIV protease. As used herein the term "effective amount" refers to an effective antiviral or inhibitory amount of a compound of formula (I). An effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances. In determining the effective amount or dose, a number of factors are considerec by the attending diagnostician, including, but not limited to: the species of mammal; its size, age, and general health; the specific viral infection involved; the degree of or involvement or the severity of the viral infection; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances. An effective amount of a compound of formula (I) is expected to vary from about 0.1 milligram per kilogram of body weight per day (mg/kg/day) to about 100 mg/kg/day. Preferred amounts are expected to vary from about 0.5 to about 10 mg/kg/day. In effecting treatment of a patient afflicted with a viral infection, a compound of formula (I) can be administered in any form or mode which makes the compound bioavailable in effective amounts, including oral and parenteral routes. For example, compounds of formula (I) can be administered orally, subcutaneously, intramuscularly, intravenously, transdermally, intranasally, rectally, and the like. Oral administration is generally preferred. One skilled in the art of preparing formulations can readily select the proper form and mode of administration depending upon the particular characteristics of the compound selected, the viral infection to be treated, the stage of the infection, and other relevant circumstances. The compounds of formula (I) can be administered alone or in the form of a pharmaceutical composition in combination with pharmaceutically acceptable carriers or excipients, the proportion and nature of which are determined by the solubility and chemical properties of the compound selected, the chosen route of administration, and standard pharmaceutical practice. The compounds of the invention, while effective themselves, may be formulated and administered in the form of their pharmaceutically acceptable salts for purposes of stability, convenience of crystallization, increased solubility and the like. In another embodiment, the present invention provides compositions comprising a compound of formula (I) in admixture or otherwise in association with one or more inert carriers. These compositions are useful, for example, as assay standards, as convenient means of making bulk shipments, or as pharmaceutical compositions. An assayable amount of a compound of formula (I) is an amount which is readily measurable by standard assay procedures and techniques as are well known and appreciated by those skilled in the art. Assayable amounts of a compound of formula (I) will generally vary from about 0.001% to about 75% of the composition by weight. Inert carriers can be any material which does not degrade or otherwise covalently react with a compound of formula (I). Examples of suitable inert carriers are water; aqueous buffers, such as those which are generally useful in High Performance Liquid Chromatography (HPLC) analysis; organic solvents, such as acetonitrile, ethyl acetate, hexane and the like; and pharmaceutically acceptable carriers or excipients. More particularly, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula (I) in admixture or otherwise in association with one or more pharmaceutically acceptable carriers or excipients. The pharmaceutical compositions are prepared in a manner well known in the pharmaceutical art. The carrier or excipient may be a solid, semi-solid, or liquid material which can serve as a vehicle or medium for the active ingredient. Suitable carriers or excipients are well known in the art. The pharmaceutical composition may be adapted for oral or parenteral use and may be administered to the patient in the form of tablets, capsules, suppositories, solution, suspensions, or the like. The compounds of the present invention may be administered orally, for example, with an inert diluent or with an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the compounds may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like. These preparations should contain" at least 4% of the compound of the invention, the active ingredient, but may be varied depending upon the particular form and may conveniently be between 4% to about 70% of the weight of the unit. The amount of the compound present in compositions is such that a suitable dosage will be obtained. Preferred compositions and preparations according to the present invention are prepared so that an oral dosage unit form contains between 5.0-300 milligrams of a compound of the invention. The tablets, pills, capsules, troches and the like may also contain one or more of the following adjuvants: binders such as microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch or lactose, disintegrating agents such as alginic acid, Primogel, corn starch and the like; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; and sweetening agents such as sucrose or saccharin may be added or a flavoring agent such as peppermint, methyl salicylate or orange flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or a fatty oil. Other dosage unit forms may contain other various materials which modify the physical form of the dosage unit, for example, as coatings. Thus, tablets or pills may be coated with sugar, shellac, or other enteric coating agents. A syrup may contain, in addition to the present compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors. Materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the amounts used. For the purpose of parenteral therapeutic administration, the compounds of the present invention may be incorporated into a solution or suspension. These preparations should contain at least 0.1% of a compound of the invention, but may be varied to be between 0.1 and about 50% of the weight thereof. The amount of the inventive compound present in such compositions is such that a suitable dosage will be obtained. Preferred compositions and preparations according to the present invention are prepared so that a parenteral dosage unit contains between 5.0 to 100 milligrams of the compound of the invention. The solutions or suspensions may also include the one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylene diaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampules, disposable syringes or multiple dose vials made of glass or plastic. The present invention is also directed to combinations of the HIV protease-inhibitory compounds with one or more agents useful in the treatment of AIDS, such as, for example, with known antiviral agents suitable for treating HIV 1 and HIV 2 viral infections, e.g., AZT, with or without a PNPase inhibitor, or in conjunctive therapy with DDI and a PNPase inhibitor. The compounds of this invention may be assayed fcr their HIV-protease inhibition using the following publishe techniques. Preparation of Retroviral Enzyme and Assay for Inhibition of the Protease A) Preparation of Retroviral Enzyme To prepare the recombinant protease, the HIV protease is expressed via E. Coli by the published work of C. Guenet, et al. , in European Journal of Pharmacology Molecular Pharmacology Section, 172 (1989) 443-451. B) Assay for Inhibition of Recombinant Viral Protease Inhibition of the reaction of the protease with a peptide substrate [Ser-Gln-Asn-Tyr-Pro-Ile-Val-NH 2 , Km = 1 mM] are in 50 mM Na acetate, 10% glycerol, 5% ethyleneglycol, pH 5.5, at 37°C for 1 hour. Various concentrations of inhibitor in 10 μl DMSO are added to 80 μl of assay solution and the reaction is initiated by the addition of 10 μl (1.6 μg) of recombinant protease. The reaction is quenched with 16 μl of 4 M perchloric acid. Products of the reaction are separate by HPLC (VYDAC wide pore 5 cm C-18 reverse phase, acetonitrile gradient, 0.1% trifluoroacetic acid). The extent of inhibition of the reaction is determined fro the peak heights of the products. HPLC of the products independently synthesized, provide quantitation standards and confirmation of the product composition. By following the techniques referenced above, as well as by utilization of other known techniques, as well as by comparison with compounds known to be useful for treatment of the above-mentioned disease states, it is believed that adequate material is available to enable one of ordinary skill in the art to practice the invention. As is true for most classes of compounds found to be useful in the pharmceutical industry, certain subgeneric groups and certain specific compounds are more preferred such as those exemplified and shown in the following charts. Rι R 6 =H » R 6 2-pyridylmethyloxy isopropyl 4-[ (2-pyridyl)methyloxy] benzyl 3-pyridylmethyloxy isopropyl 4-[ (3-pyridyl)me hyloxy ' benzyl 2-pyridylmethyloxy isopropyl 4-[2-(N-morpholyl)ethyloxy) benzyl 3-pyridylmethyloxy isopropyl 4-[2-(N-morpholyl)ethyloxy] benzyl 25 R, R5» 3-pyridylmethyloxy isopropyl 4-[ 2-(N-morpholyl)ethyloxy] benzyl 2-pyridylmethyloxy isopropyl 4-(benzyloxy)benzyl 2-pyridylmethyloxy t-butyl 4-[ (3-pyridyl)methyloxy] benzyl 2-pyridylmethyloxy isopropyl 4-[ (3-pyridyl)methyloxy] benzyl 20 25 20 25 The following list illustrates compounds according to the present invention; 1. α,α-difluoro-γ-[ [ (2-(R)- [ [ (hydroxy)phenylacetyl]amino]-3-methyl-l-oxobutyl]amino]- β-oxo-4-(phenylmethoxy)-N-(phenylmethyl)-benzene- pentanamide; 2. [6S-(6R*, 9R*, 13S*)]-4,4,-difluoro-9-(l- methylethyl)-3,5,8,ll-tetraoxo-l,13-diphenyl-6-[ [4- (phenylmethoxy)phenyl]methyl]-12-oxa-2,7,10- triazatetradecan-14-oic acid, methyl ester; 3. α,α-difluoro-γ-[ [3-methyl-l-oxo-2-[ [ (l-oxo-trans-3 phenyl-2-propenyl)amino]butyl]amino]-β-oxo-4- (phenylmethoxy)-N-(phenylmethyl)-benzene-pentanamide; 4. α,α-difluoro-γ-[ [2-[2-hydroxy-l-oxo-4- (phenylbutyl)amino]-3-methyl-l-oxobutyl]amino]-β-oxo-4- (phenylmethoxy)-N-(phenylmethyl)-benzene-pentanamide; 5. N-[1-[ [ [3,3-difluoro-4-[ [2-methyl-l- [ (phenylmethoxy)methy1]-propyl]amino]-2, -dioxo-l-[ [4- (phenylmethoxy)phenyl]-methyl]butyl]amino]carbony1]-2- methylpropyl]-β-oxo-4-morpholinepropanamide? 6. [1R-(1R*,2S*) ]-α,α-difluoro-γ-[[2-(R)- [ [ (hydroxy)phenylacetyl]-amino]-3-methyl-l-oxobutyl3amino] N-[2-methyl-l-[ (phenylmethoxy)methy13propyl]-_-oxo-4- (phenylmethoxy)-benzenepentanamide; 7. N-[l-[ [ [3,3-difluoro-4-[ [2-methyl-l- [ (phenylmethoxy)-methyl3-propyl]amino]-2,4-dioxo-l-[ [4- (phenylmethoxy)phenyl]- methyl]-butyl]amino]carbonyl]-2- methylpropyl]-6-(4-morpholinyl-carbonyl)-3- pyridinecarboxamide; 8. 7,7-difluoro-4,12-bis(l-methylethyl)-6,8,ll-trioxo- l-phenyl-9-[ [ -(phenylmethoxy)phenyl]methyl]-2-oxa-5,10,13- triazatetradecan-14-oic acid, 3-pyridinylmethyl ester; 9. [1R-(1R*,2S*) ]-α,α-difluoro-γ-[ [3-methyl-2-[ [4-(4- morpholinylsulfonyl)benzoyl]amino]-1-oxobutyl]amino3-N-[ 2- methyl-1-[ (phenylmethoxy)methyl]propylJ-β-oxo-4- (phenylmethoxy)-benzenepentanamide; 10. [1R-(1R*,2S*) ]-α,α-difluoro-γ-[ [3-methyl-2-[ [4-(4- morpholinylcarbonyl)benzoyl]amino]-1-oxobutyl]amino]-N-[ 2- methyl-l-[ (phenylmethoxy)methyl]propyl]-β-oxo-4- (phenylmethoxy)-benzenepentanamide; 11. N-[l-[[[3,3-difluoro-4-[ [2-methyl-l- [ (phenylmethoxy)methyl]-propyl]amino]-2,4-dioxo-l-[ [4- (phenylmethoxy)phenyl]-methyl]butyl]amino]carbonyl]-2- methylpropyl3-4-morpholineacetamide; 12. N-[l-[[[3,3-difluoro-4-[[2-methyl-l- [ (phenylmethoxy)methyl]-propyl3amino3-2,4-dioxo-l-[ [4- (phenylmethoxy)phenyl3methyl]-butyl]amino]carbonyl]-2- methylpropyl]-lH-imidazole-l-acetamide; 13. [l-[[ [3,3-difluoro-2,4-dioxo-l-[[4- (phenylmethoxy)phenyl]-methyl]-4-[ (2- pyridinylmethyl)amino)butyl]amino]carbonyl]- 2- methylpropyl3-carbamic acid, 3-pyridinylmethyl ester; 14. [l-[[ [3,3-difluoro-2,4-dioxo-l-[ [4- (phenylmethoxy)phenyl ]-methyl]-4-[ ( 3- pyridinylmethyl)amino3butyl]amino]carbonyl]-2- methylpropyl]-carbamic acid, 3-pyridinylmethyl ester; 15. [l-[ [ [3,3-difluoro-2,4-dioxo-l-[ [4-(phenylmethox phenyl]-methyl]-4-[ (2-pyridinylmethyl)amino]butyl ]- amino]carbonyl]- 2-methylpropyl]-carbamic acid, 2- pyridinylmethyl ester; 16. [1-[ [ [3,3-difluoro-2,4-dioxo-l-[ [ -(phenylmethox phenyl]-methyl]-4-[ (3-pyridinylmethyl)amino]butyl]- amino]carbonyl]- 2-methylpropyl]-carbamic acid, 2- pyridinylmethyl ester; 17. N-[4-(N-{2-pyridylmethyl)oxycarbony1-L-valyl)ami 2,2-difluoro-1,3-dioxo-5-(4-benzyloxy)phenyl-pentyl]-O-(3 pyridylmethyl)-D-valinol; 18. N-[4-(N-{3-pyridylmethyl}oxycarbonyl-L-valyl)ami 2, 2-difluoro-1,3-dioxo-5-( -benzyloxy)phenyl-pentyl ]-0-(3 pyridylmethyl)-D-valinol; 19. N-[4-(N-{3-pyridylmethyl}oxycarbony1-L-valyl)ami 2,2-difluoro-1,3-dioxo-5-(4-benzyloxy)phenyl-pentyl]-0- methyl-D-valinol; 20. N-{4-(N-{3-pyridylmethyl}oxycarbonyl-L-valyl)amin 2,2-difluoro-1,3-dioxo-5-(4-benzyloxy)phenyl-pentyl]-0-(2 pyridylmethyl)-D-valinol; 21. N-[4-(N-{2-pyridylmethyl}oxycarbony1-L- valyl)amino-2,2-difluoro-1,3-dioxo-5-(4-{3- pyridylmethyl}oxy)phenyl-pentyl]-0-( 3-pyridylmethyl)-D- valinol; 22. N-[ 4-(N-{2-pyridylmethyl}oxycarbony1-L-valyl)amino- 2,2-difluoro-1,3-dioxo-5-( 4-benzyloxy)phenyl-pentyl]-0-( 2- pyridylmethyl)-D-valinol; 23. N-[4-(N-{2-pyridylmethyl)oxycarbonyl-L- valyl)amino-2, 2-difluoro-1,3-dioxo-5-(4-benzyloxy)phenyl- pentyl]-O-methyl-D-valinol; 24. N-{4-(N-{2-pyridylmethyl}oxycarbonyl-L-valyl)amino- 2,2-difluoro-1,3-dioxo-5-( 4-benzyloxy)phenyl-pentyl]-0- benzyl-D-valinol; 25. N-{4-(N-{3-pyridylmethyl}oxycarbony1-L-valyl)amino- 2,2-difluoro-1,3-dioxo-5-(4-benzyloxy)phenyl-pentyl]-0-[2- ( 2-methoxyethoxy)-1-ethyl]-D-valinol; and 26. N-[4-(N-{3-pyridylmethyl}oxycarbonyl-L-valyl)amino- 2,2-difluoro-1,3-dioxo-5-(4-{2-N-morpholyl]ethyloxy)phenyl- pentyl]-O-methyl-D-valinol.

Claims: WHAT IS CLAIMED IS: A compound of the formula: P2 Pi R l -t-CNH-CHf-CNH-CH—C- -CF 2 —C- -NR5R6 II II o O and the stereoisomers, hydrates, isosteres and the pharmaceutically acceptable salts thereof wherein Pi is Ci-6alkylene wherein T is [(0) b -W-R] and T 1 is [ (0)_'-W*-R * ] or hydrogen, wherein each of W and W are independently Ci- 6 alkylene or nothing, provided that W is C 2 - 6 alkylene when W is directly attached to a nitrogen atom in R, provided that W 1 is C 2 - 6 alkylene when W' is directly attached to a nitrogen atom in R 1 , provided that W or W are each independently Ci-e alkylene when R or R' are each independently an aryl; P 2 is C 1 _ 6 alkyl, cyclopentyl, hydroxy C 1 _ 6 alkyl, phenyl, benzyl or 3-tetrahydrofuryl; R and R' are each independently -CH 2 CHO, hydroxy Ci-6 alkyl, Ci- 6 alkoxy C__ 6 alkyl, C_-e alkyl. Ci- 6 alkenylene, piperazinyl, substituted piperazinyl, piperidyl, morpholinyl, pyridyl, pyrazinyl, pyrimidinyl or phenyl wherein substituted piperazinyl is piperazinyl substituted on one nitrogen atom thereof with CHO, C(0)NHR* , C_- alkyl or CO 2 R 4 ; R l is R 3 is Cι_ 6 allenyl Ci- 6 alkoxy, Cι_ 6 alkylene, hydroxy C_- 6 alkyl, Cι_ 6 alkyl or OH; R is Ci- 6 alkyl, phenyl or benzyl; R* 4 is hydrogen or Cι_ 6 alkyl; R 5 is hydrogen, C 1 - 15 alkyl, OH, hydroxy C___ 5 alkyl, C_. 6 alkoxy, -CH( [ (CH2)d-0-CH2] x -R' 8)2/ "CH 2 Si(CH 3 ) 2 (R3) . PDL, -(Ci-6 alkylene)-OR , -CH(Y)(Z), Ci-e wherein PDL is -(CH 2 ) a -2-, 3- or 4-pyridyl, or p- substituted benzyloxy, wherein the substitution is with a nitro, OH, amino, Cι_β alkoxy, hydroxy Ci-β alkylene, or halogen; Y is C 1 - 15 alkyl, hydroxy C 1 - 15 alkyl, C__6 alkyl or -(CH 2 ) e -C6H4-(V) e * ; Z is -(CH 2 )d-0-CHO, Cι- 6 alkylene-0-(CH2)d-(0-CH2-CH 2 ) e -0-Cι-6 alkyl, CHO, CO2R4 t CO2NHR4, -(CH 2 )d-0-(CH 2 )d , -R , 7, -(CH 2 )e-OR or wherein V is OR 4 ( o c r H2 h , y < -drCoxy_Ci-β alkyle : ne; provided that d'=2 when R'7 is piperazinyl, substituted piperazinyl, piperidyl or morpholinyl; Re is as defined for R 5 with the proviso that R is other than hydrogen when R 5 is hydrogen, or R 5 and Re are taken together with the nitrogen atom to which th are attached are selected from the group consisting o () (g) (h) R 7 is CH 2 OR 4 , C(0)NHR 4 or CHO; R' 7 is piperazinyl, substituted piperazinyl, piperidy morpholinyl, pyridyl, pyrazinyl, pyrimidinyl or pheny wherein substituted piperazinyl is piperazinyl substituted on one nitrogen atom thereof with CHO, C(0)NHR 4 , C 1 - 4 alkyl or CO 2 R 4 ; R 8 is (H, OH) or =0; R'β is pyrimidyl, pyridyl, pyrazinyl or phenyl; a is zero , 1 , 2 or 3 ; b and b' are each independently zero or 1; d and d' are each independently 1 or 2; e and e 1 are each independently zero, 1 or 2; and x is zero or one. 2. A comp juouuunud a Qc_cι.υorιdiιnιιgy t _o_■ c tlxaα uimu is 3. A compound according to claim 2 wherein x is one and P 2 is isopropyl. 4. A compound according to claim 3 wherein Ri is 5. A compound according to claim 3 wherein Ri is 6. A compound according to claim 3 wherein R 5 is hydrogen and Re is 7. A compound according to claim 3 wherein R 5 is hydrogen and Rε is 8. A compound according to claim 3 wherein --. 5 is hydrogen and Re is 9. A compound according to claim 3 wherein R 5 is hydrogen and R & is 10. A compound according to claim 1 wherein the compound is α,α-difluoro-γ-[ [ (2-(R)- [ [ (hydroxy)phenylacetyl]amino]-3-methyl-l-oxobutyl]amino] β-oxo-4-(phenylmethoxy)-N-(phenylmethyl)-benzene¬ pentanamide. 11. A compound according to claim 1 wherein the compound is [6S-(6R*, 9R*, 13S*) ]-4,4,-difluoro-9-(1- methylethyl)-3,5,8,ll-tetraoxo-l,13-diphenyl-6-[ [4- (phenylmethoxy)phenyl]methyl]-12-oxa-2,7,10- triazatetradecan-14-oic acid, methyl ester. 12. A compound according to claim 1 wherein the compound is α,α-difluoro-γ-[ [3-methyl-l-oxo-2-[ [ (1-oxo- trans-3-phenyl-2-propenyl)amino]butyl]amino]-β-oxo-4- (phenylmethoxy)-N-(phenylmethyl)-benzene-pentanamide. 13. A compound according to claim 1 wherein the compound is α,α-difluoro-γ-[ [2-[2-hydroxy-l-oxo-4- (phenylbutyl)amino]-3-methyl-l-oxobutyl]amino]-β-oxo-4- (phenylmethoxy)-N-{phenylmethyl)-benzene-pentanamide. 14. A compound according to claim 1 wherein the compound is N-[l-[ [ [3,3-difluoro-4-[ [2-methyl-l- [ (phenylmethoxy)methyl]-propyl]amino]-2,4-dioxo-l-[ [4- (phenylmethoxy)phenyl]-methylJbutyl]amino3carbonyl3-2- methylpropyl3-β-oxo-4-morpholinepropanamide. 15. A compound according to claim 1 wherein the compound is [1R-(1R*,2S*) ]-α,α-difluoro-γ-[ [ 2-(R)- [ [ (hydroxy)phenylacetyl]-amino]-3-methyl-l-oxobutyl)amino3- N-[2-methyl-l-[ (phenylmethoxy)methyl]propyl3-β-oxo-4- (phenylmethoxy)-benzenepentanamide. 16. A compound according to claim 1 wherein the compound is N-[l-[ [ [3,3-difluoro-4-[ [2-methyl-l- [ (phenylmethoxy)-methyl]-propyl]amino]-2 ,4-dioxo-l-[ [4- (phenylmethox )phenyl]- methyl]-butyl]amino]carbonyl]-2- methylpropyl)-6-(4-morpholinyl-carbonyl)-3- pyridinecarboxamide. 17. A compound according to claim 1 wherein the compound is 7,7-difluoro-4,12-bis(l-methylethyl)-6,8,11- trioxo-l-phenyl-9-[ [4-(phenylmethoxy)phenyl]methyl3-2-oxa- 5,10,13-triazatetradecan-14-oic acid, 3-pyridinylmethyl ester. 18. A compound according to claim 1 wherein the compound is [IR-(IR*,2S*) ]-α,α-difluoro-γ-[ [3-methyl-2-[ [ 4- (4-morpholinylsulfonyl)benzoyl]amino]-1-oxobutyl]amino]-N- [2-methyl-l-[ (phenylmethoxy)methyl]propyl}-β-oxo-4- (phenylmethoxy)-benzenepentanamide. 19. A compound according to claim 1 wherein the compound is [lR-(1R*,2S*) ]-α,α-difluoro-γ-[ [3-methyl-2-[ [4- (4-morpholinylcarbonyl)benzoyl ]amino]-1-oxobutyl]amino)-N- [ 2-methyl-l-[ (phenylmethoxy)methylJpropyl3-β-oxo-4- (phenylmethoxy)-benzenepentanamide. 20. A compound according to claim 1 wherein the compound is N-[l-[ [[3,3-difluoro-4-[ [2-methyl-l- [ (phenylmethoxy)methyl3-propyl1amino3-2,4-dioxo-l-[ [4- (phenylmethoxy)phenyl]-methy1]butyl]amino]carbonyl]-2- methylpropyl]-4-morpholineacetamide. 21. A compound according to claim 1 wherein the compound is N-[l-[ [[3,3-difluoro-4-[ [2-methyl-l- [ (phenylmethoxy)methyl]-propyl]amino]-2,4-dioxo-l-[ [ - (phenylmethoxy)phenyl]methyl]-butyl]amino]carbonyl]-2- methylpropyl]-lH-imidazole-l-acetamide. 22. A compound according to claim 1 wherein the compound is [1-[ [ [3,3-difluoro-2,4-dioxo-l-[ [4- (phenylmethoxy)phenyl]-methyl]-4-[ (2- pyridinylmethyl)amino]butyl]amino]carbonyl]- 2- methylpropyl]-carbamic acid, 3-pyridinylmethyl ester. 23. A compound according to claim 1 wherein the compound is [l-[ [[3,3-difluoro-2,4-dioxo-l-[ [4- (phenylmethoxy)phenyl]-methyl]-4-[ (3- pyridinylmethyl)amino]butyl]amino]carbonyl]-2- methylpropylj-carbamic acid, 3-pyridinylmethyl ester. 24. A compound according to claim 1 wherein the compound is [l-[ [[3,3-difluoro-2,4-dioxo-l-[ [4- (phenylmethoxy)-phenyl]-methyl ]-4-[ (2- pyridinylmethyl)amino]butyl ]-amino]carbonyl]- 2- methylpropyl3-carbamic acid, 2-pyridinylmethyl ester. 25. A compound according to claim 1 wherein the compound is [l-[ [ [3,3-difluoro-2,4-dioxo-l-[ [4- (phenylmethoxy)-phenyl}-methyl]-4-[ (3- pyridinylmethyl)amino]butyl3-amino3carbonyl3- 2- methylpropyl]-carbamic acid, 2-pyridinylmethyl ester. 26. A compound according to claim 1 wherein the compound is N-[4-(N-{2-pyridylmethyl}oxycarbonyl-L- valyl)amino-2,2-difluoro-1,3-dioxo-5-(4-benzyloxy)phenyl- pentyl]-0-(3-pyridylmethyl)-D-valinol. 27. A compound according to claim 1 wherein the compound is N-[4-(N-{3-pyridylmethyl}oxycarbonyl-L- valyl)amino-2,2-difluoro-1,3-dioxo-5-(4-benzyloxy)phenyl- pentyl ]-0-(3-pyridylmethyl)-D-valinol. 28. A compound according to claim 1 wherein the compound is N-[4-(N-{3-pyridylmethyl}oxycarbonyl-L- valy1)amino-2,2-difluoro-1,3-dioxo-5-(4-benzyloxy)phenyl- pentyl]-O-methyl-D-valinol. 29. A compound according to claim 1 wherein the compound is N-{4-(N-{3-pyridylmethyl)oxycarbonyl-L- valy1)amino-2,2-difluoro-1,3-dioxo-5-(4-benzyloxy)phenyl- pentyl]-0-(2-pyridylmethyl)-D-valinol. 30. A compound according to claim 1 wherein the compound is N-[4-(N-{2-pyridylmethyl}oxycarbonyl-L- valy1)amino-2,2-difluoro-1,3-dioxo-5-(4-{3- pyridylmethyl}oxy)phenyl-pentyl]-0-(3-pyridylmethyl)-D- valinol. 31. A compound according to claim 1 wherein the compound is N-[4-(N-{2-pyridylmethyl}oxycarbonyl-L- valyl)amino-2,2-difluoro-1,3-dioxo-5-(4-benzyloxy)phenyl- pentyl3~0-( 2-pyridylmethyl)-D-valinol. 32. A compound according to claim 1 wherein the compound is N-[4-(N-{2-pyridylmethyl}oxycarbonyl-L- valyl)amino-2,2-difluoro-1,3-dioxo-5-(4-benzyloxy)phenyl- pentyl3-O-methyl-D-valinol. 33. A compound according to claim 1 wherein the compound is N-{4-(N-{2-pyridylmethyl}oxycarbonyl-L- valyl)amino-2,2-difluoro-1,3-dioxo-5-(4-benzyloxy)phenyl- pentyl]-O-benzyl-D-valinol. 34. A compound according to claim 1 wherein the compound is N-{4-(N-{3-pyridylmethyl}oxycarbonyl-L- valy1)amino-2,2-difluoro-1,3-dioxo-5-(4-benzyloxy)phenyl- pentyl]-O-[2-(2-methoxyethoxy)-1-ethyl]-D-valinol. 35. A compound according to claim 1 wherein the compound is N-[4-(N-{3-pyridylmethyl}oxycarbonyl-L- valyl)amino-2,2-difluoro-1,3-dioxo-5-(4-{2-N- morpholyl]ethyloxy)phenyl-pentyl3-O-methyl-D-valinol. 36. A method of treating a patient suffering from a viral infection comprising administering to said patient an effective antiviral amount of a compound according to claim 1. 37. A method of controlling a viral infection in a patient afflicted therewith comprising administering thereto an effective antiviral amount of a compound according to claim 1. 38. A method of inhibiting HIV protease in a patient in need thereof comprising administering to said patient an effective inhibitory amount of a compound according to claim 1. 39. A pharmaceutical composition comprising an assayable amount of a compound of claim 1 in admixture or otherwise in association with an inert carrier. 40. A pharmaceutical composition according to claim 39 for the treatment of a viral infection. 41. A compound according to claim 1 for use in the treatment of a viral infection. 42. A compound according to claim 1 for use in inhibiting HIV protease. 43. Use of a compound of claim 1, optionally in combination with a pharmaceutically acceptable carrier, for the preparation of a pharmaceutical composition for the treatment of a viral infection. 44. Use of a compound of claim 1, optionally in combination with a pharmaceutically acceptable carrier, for the preparation of an HIV protease inhibitor. 45. A process for the preparation of a compound of formula: 2 Pi Rτ-r-CNH-CH-1-CNH-CH—C—CF 2 —C NR 5 Re and the stereoisomers, hydrates, isosteres and the pharmaceutically acceptable salts thereof wherein Pi is Ci-ealkylene wherein T is [(0) b -W-R] and T' is [ (O) b '-W'-R' ] or hydrogen, wherein each of W and W' are independently Ci- 6 alkylene or nothing, provided that W is C 2 - 6 alkylene when W is direct attached to a nitrogen atom in R, provided that W 1 is C 2 - 6 alkylene when W' is directly attached to a nitrogen atom in R' , provided that W or W' are each independently Ci- 6 alkylene when R or R 1 are each independently an aryl; P 2 is C-_ 6 alkyl, cyclopentyl, hydroxy C 1 _ 6 alkyl, phenyl, benzyl or 3-tetrahydrofuryl; R and R' are each independently -CH 2 CHO, hydroxy C_- 6 alkyl, Ci-e alkoxy Ci-β alkyl, Ci-6 alkyl, Ci-e alkenylene, piperazinyl, substituted piperazinyl, piperidyl, morpholinyl, pyridyl, pyrazinyl, pyrimidinyl or phenyl wherein substituted piperazinyl is piperazinyl substituted on one nitrogen atom thereof with CHO, C(0)NHR * 4 , C 1 - 4 alkyl or CO 2 R4; R l is R3 is Ci-e allenyl Ci-β alkoxy, Ci-β alkylene, hydroxy Ci-β alkyl, Ci-6 alkyl or OH; R4 is Ci-6 alkyl, phenyl or benzyl; R* 4 is hydrogen or Ci- 6 alkyl; R 5 is hydrogen, Ci- 15 alkyl, OH, hydroxy Ci- 15 alkyl, C_. 6 alkoxy, -CH( [ (CH 2 )d-0-CH 2 *-R'8)2, -CH 2 Si(CH 3 ) 2 (R3) . PDL, -(Ci-e alkylene)-OR , -CH(Y)(Z), wherein PDL is -(CH 2 ) a -2-, 3- or 4-pyridyl, or p- substituted benzyloxy, wherein the substitution is with a nitro, OH, amino, C__ 6 alkoxy, hydroxy C -s alkylene, or halogen; Y is Ci- 15 alkyl, hydroxy Cι_ιs alkyl, Ci- 6 alkyl or -(CH2) e -C6H4-(V) e ' ; Z is -(CH 2 ) d -0-CHO, Cι_ 6 alkylene-0-(CH 2 )d-(0-CH 2 -CH2)e-0-Cι-6 alkyl, CHO, CO2R4, CO2NHR4, -(CH2)d-0-(CH 2 )d , -R , 7, -(CH 2 ) e -OR4 or wherein V is OR 4 or hydroxy Ci- 6 alkylene; provided that d'=2 when R'7 is piperazinyl, substituted piperazinyl, piperidyl or morpholinyl; Rβ is as defined for R 5 with the proviso that Re is other than hydrogen when R 5 is hydrogen, or R 5 and Re are taken together with the nitrogen atom to which the are attached are selected from the group consisting of R 7 is CH 2 OR 4 , C(0)NHR 4 or CHO; R' is piperazinyl, substituted piperazinyl, piperidyl, morpholinyl, pyridyl, pyrazinyl, pyrimidinyl or phenyl wherein substituted piperazinyl is piperazinyl substituted on one nitrogen atom thereof with CHO, C(0)NHR 4 , C 1 - 4 alkyl or CO 2 R 4 ; R B is (H, OH) or =0; R'β is pyrimidyl, pyridyl, pyrazinyl or phenyl; a is zero, 1, 2 or 3; b and b' are each independently zero or 1; d and d 1 are each independently 1 or 2; e and e' are each independently zero, 1 or 2; and x is zero or one, comprising oxidizing a compound of formula: Pi Rr CNH-CH-HCNH-CH—C—CF 2 —C NR5 6 OH wherein all the substituents are defined as above. 46. A process for the preparation of a compound of the formula: 2 Pi R l -f-CNH-CH -CNH-CH—C- -CF 2 —C -NR5R6 II II O O and the stereoisomers, hydrates, isosteres and the pharmaceutically acceptable salts thereof wherein Pi is C1-6alkylene wherein T is [(0)_.-W-R] and T' is [ (O) b '-W'-R' ] or hydrogen, wherein each of W and W are independently Ci- 6 alkylene or nothing, provided that W is C 2 - 6 alkylene when W is directly attached to a nitrogen atom in R, provided that W' is C - 6 alkylene when W' is directly attached to a nitrogen atom in R' , provided that W or W are each independently Ci- 6 alkylene when R or R' are each independently an aryl; P 2 is C 1 _ 6 alkyl, cyclopentyl, hydroxy C 1 _ 6 alkyl, phenyl, benzyl or 3-tetrahydrofuryl; R and R' are each independently -CH 2 CHO, hydroxy Ci- 6 alkyl, Ci- 6 alkoxy Ci- 6 alkyl, Ci-β alkyl, Ci- 6 alkenylene, piperazinyl, substituted piperazinyl, piperidyl, morpholinyl, pyridyl, pyrazinyl, pyrimidinyl or phenyl wherein substituted piperazinyl is piperazinyl substituted on one nitrogen atom thereof with CHO, C(0)NHR * 4 , C 1 -4 alkyl or CO 2 R 4 ; R 3 is Ci-e allenyl Cι_ 6 alkoxy, Ci- 6 alkylene, hydroxy Ci-β alkyl, Ci- 6 alkyl or OH; 30 R 4 is Ci-e alkyl, phenyl or benzyl; R' 4 is hydrogen or Ci- 6 alkyl; 35 R 5 is hydrogen, Ci- 15 alkyl, OH, hydroxy Ci- 15 alkyl, Ci¬ ts alkoxy, -CH( [ (CH2)d-0-CH 2 ] x -R'8)2, "CH 2 Si(CH 3 ) 2 (R3) . PDL, -(Ci- 6 alkylene)-OR 4 , -CH(Y)(Z), C1-6 wherein PDL is -(CH 2 ) a -2-, 3- or 4-pyridyl, or p- substituted benzyloxy, wherein the substitution is with a nitro, OH, amino, Ci- 6 alkoxy, hydroxy Ci- 6 alkylene, or halogen; Y is Ci- 15 alkyl, hydroxy Ci- 15 alkyl, Ci- 6 alkyl or -(CH 2 ) e -C6H4-(V)e' ; Z is -(CH 2 ) d -0-CHO, Cι_ 6 alkylene-0-(CH 2 ) d -(0-CH 2 -CH 2 ) e -0-Cι- 6 alkyl, CHO, CO 2 R 4 , CO2NHR4, -(CH 2 )d-0-(CH 2 )d , -R , 7, -(CH 2 ) e -OR4 or provided that d'=2 when R'7 is piperazinyl, substituted piperazinyl, piperidyl or morpholinyl; Rβ is as defined for R 5 with the proviso that Rε is other than hydrogen when R 5 is hydrogen, or R 5 and Re are taken together with the nitrogen atom to which the are attached are selected from the group consisting of R 7 is CH 2 OR 4 , C(0)NHR 4 or CHO; R' 7 is piperazinyl, substituted piperazinyl, piperidyl morpholinyl, pyridyl, pyrazinyl, pyrimidinyl or phenyl wherein substituted piperazinyl is piperazinyl substituted on one nitrogen atom thereof with CHO, C(0)NHR 4 , C 1 - 4 alkyl or CO 2 R 4 ; R 8 is (H, OH) or =0; R'β is pyrimidyl, pyridyl, pyrazinyl or phenyl; a is zero , 1 , 2 or 3 ; b and b 1 are each independently zero or 1; d and d' are each independently 1 or 2; e and e' are each independently zero, 1 or 2; and x is zero or one, comprising; a) oxidizing a compound of formula: P2 Pi R'1-f-CNH-CH -CNH-CH—C—CF 2 —C NR 5 R 6 OH wherein R'- is a protected R- group and the remaining substituents are defined as above; b) subsequently deprotecting the oxidized product of step a.

Inventors: CREGGE ROBERT J, FARR ROBERT A, JANOWICK DAVID A, KOHLMAN DANIEL T, SCHIRLIN DANIEL G, TARNUS CELINE, VAN DORSSELAER VIVIANE, CREGGE, ROBERT, J., FARR, ROBERT, A., JANOWICK, DAVID, A., KOHLMAN, DANIEL, T., SCHIRLIN, DANIEL, G., TARNUS, CELINE, VAN DORSSELAER, VIVIANE
Applicants: MERRELL PHARMA INC, MERRELL PHARMACEUTICALS INC.
Application year: 1995
Main classification: C07C271
IPC codes: A61K31, A61P31, A61P43, C07C231, C07C237, C07C269, C07C271, C07D213, C07D295, C07D521, C07F7, C07K5