MXPA98004734A

MXPA98004734A - Retrovi protease inhibitor compounds

Info

Publication number: MXPA98004734A
Application number: MXPA/A/1998/004734A
Authority: MX
Inventors: J Kempf Dale; W Norbeck Daniel; A Oliver Patricia; Liu Jihhua; Leung Sham Hing; J Cooper Arthur; Chen Xiaoqi; A Betebenner David; R Herrin Thomas; N Kumar Gondi; L Condon Stephen; A Dickman Daniel; M Hannick Steven; Kolaczkowski Lawrence; J Plata Daniel; J Stengel Peter; J Stoner Eric; Tien Jiehheh; M Patel Ketan
Original assignee: Abbott Laboratories
Priority date: 1995-12-13
Filing date: 1998-06-12
Publication date: 1999-01-11

Abstract

The present invention relates to describing a compound of the formula (I) as an inhibitor of HIV protease. Methods and compositions for inhibiting HIV infection are also described. (See Formula

Description

RETROVIRAL PROTEASE INHIBITORS COMPOUNDS This application is a continuation in part of the U.S. Patent Application. No. 08 / 572,226, filed on December 13, 1995.

TECHNICAL FIELD The present invention relates to novel compounds and a composition and method for inhibiting retroviral proteases and, in particular, for inhibiting human immunodeficiency virus (HIV) protease, a composition and method for inhibiting a retroviral infection and, in particular, an HIV infection, procedures for making the synthetic intermediates and compounds used in the procedures.

BACKGROUND OF THE INVENTION Retroviruses are those viruses that use an intermediate of ribonucleic acid (RNA) and a polymerase of deoxyribonucleic acid (DNA) dependent on RNA, reverse transcriptase, during its life cycle. Retroviruses include, but are not limited to, the RNA viruses of the Retroviridae family, and also the DNA viruses of the Hepadnavirus and Caulimovirus families. Retroviruses cause a variety of disease states in humans, animals and plants. Some of the most important retroviruses from a pathological point of view include human immunodeficiency viruses (HIV-1 and HIV-2), which cause the acquired immuno-deficiency syndrome (AIDS) in humans, viruses I, II, IV , and human T cell lymphotrophic V, which cause human acute cell leukemia, and bovine and feline leukemia virus, which cause leukemia in domestic animals. Proteases are enzymes that divide proteins into specific peptide bonds. Many biological functions are controlled. or mediated by proteases and their complementary protease inhibitors For example, the rennet of protease divides peptide angiotensinogen to produce angiotensin I peptide Angiotensin I is further divided by the protease angiotensin converting enzyme (ACE) to form angiotensin II hypotensive peptide Reniña and ACE inhibitors are known to reduce high blood pressure in vit An inhibitor of a retroviral protease will provide a therapeutic agent for diseases caused by retroviruses. The genomes of retroviruses encode a protease that is responsible for the proteolytic processing of one or more polyprotein precursors, such as the pol and gag gene products. See Wellink , Arch Virol 98 1 (1988) Retroviral proteases very commonly process the gag precursor to core proteins, and also process the precursor p__! to reverse transcpptase and retroviral protease In addition, retroviral proteases are of specific sequence See Pearl, Nature 328482 (1987) The correct processing of precursor polyproteins through the retroviral protease is necessary for the assembly of infectious virions. It has been shown that the in vitro mutagenesis that produces the defective protease virus leads to the production of immature nucleus forms, which lack infectious capacity. See Crawford, J. Virol. 53 899 (1985); Katoh, et al., Virology 145 280 (1985). Therefore, inhibition of retroviral protease provides an attractive target for antiviral therapy. See Mitsuya, Nature 325 775 (1987). Current treatments for viral diseases usually involve the administration of compounds that inhibit viral DNA synthesis. Current treatments for AIDS involve the administration of compounds such as 3'-azido-3'-deoxythymidine (AZT), 2 \ 3'-dideoxycytidine (DDC), 2 ', 3'-dideoxyinosine (DDI), d4T and 3TC and compounds that treat opportunistic infections caused by immunosuppression resulting from HIV infection. None of the current treatments for AIDS has proven to be totally effective in the treatment and / or reversal of the disease. In addition, many of the compounds currently used to treat AIDS cause adverse effects that include a low platelet count, renal toxicity, and bone marrow cytopenia. Recently, HIV protease inhibitors, ritonavir, saquinavir and indinavir, have been tested in the United States for the treatment of HIV infections. However, there is a continuing need for improved HIV protease inhibitors.

DESCRIPTION OF THE INVENTION According to the present invention, there is a compound of the formula I wherein R- and R2 are independently selected from the group consisting of lower alkyl, cycloalkylalkyl and aplakyl, R3 is lower alkyl, hydroxyalkyl or cycloalkylalkyl, R4 is aplo or a heterocyclic, R5 is b) and where n is 1, 2 or 3, m is 1, 2 or 3, m 'is 1 or 2, X is O, S or NH, Y is -CH2-, -O-, -S- or -N ( R5) -, wherein R6 is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, Y "is -CH2- or N (R6 ') -, where R6 • is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, Y 'is -N (R6), wherein R6 is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, and Z is O, S, or NH; a) -O-, b) -S-, c) -N (R7) -, wherein R7 is hydrogen, lower alkyl, cycloalkyl or cycloalkylalkyl, d) -O-alkylenyl-, e) -S-alkylenyl-, f) -S (O) -alkylenyl-, g) -S (O) 2-alkynyl-, h) -N (R7) -alkylenyl-, wherein R7 is as defined above, i) -alkylene-O- , j) alkylenyl-S-, k) alkylenyl-N (R7) -, wherein R7 is as defined above, I) alkylenyl or om) alkenylenyl; or a pharmaceutically acceptable salt, ester or prodrug thereof. Preferred compounds are compounds of formula I, wherein Ri and R2 are arylalkyl, R3 is lower alkyl, R is aryl, Rs is or wherein X, Y, Y ', Y ".A, R6-, n, m and m' are as defined above and Li is -O-alkylenyl The most preferred compounds are compounds of the formula I, wherein R and R2 are benzyl or R is benzyl and R2 is lower alkyl, R3 is lower alkyl, R4 is (a) phenyl, which is substituted with two lower alkyl groups and which is optionally substituted with a third substituent selected from the group consisting of lower alkyl, hydroxy, amino and halogen or (b) pyridyl or pyrimidinyl, any of which is substituted with two lower alkyl groups and which is optionally substituted with a third substituent selected from the group consisting of alkyl lower, hydroxy, amino and halogen, R5 is: where n is 1 or 2, X is O u S and Y is -CH2- or -NH-, X -? - ((CCHz b) where m is 1 or 2, X is O, Y is -CH2- and Z is O, where m 'is 1, X is O, Z is O and Y is -NH-, where m' is 1, X is I, Y "is -NH- and Y 'is -NH- or e) where X is O and R6 is hydrogen Still very preferred compounds are the compounds of the formula I, wherein R ^ and R2 are benzyl or R, is benzyl and R2 is isopropyl, R3 is lower alkyl, R is 2,6-dimethylphenyl, which is optionally substituted with a third substituent selected from the group consisting of lower alkyl and halogen, R5 is where n is 1 or 2, X is O u S and Y is -CH2 or -NH- m is 1 or 2, X is O, Y is -CH2- and Z is O, where m 'is 1, X is O, Z is O and Y is -NH- where m 'is 1, X is O, Y "is -NH- and Y' is -NH- where X is O and R6- is hydrogen LT is -O-CH2- The most preferred compounds are the compounds of formula I, wherein R, and R2 are benzyl or R1 is benzyl and R2 is isopropyl, R3 is lower alkyl, R4 is 2,6-dimethylphenyl, which is optionally substituted with a third substituent selected from the group consisting of lower alkyl and halogen, R5 is where n is 1 or 2, X is O or S and Y is -CH2 or -NH- where m 'is 1, X is O, Z is O and Y is -NH-. where m 'is 1, X is O, Y "is -NH- and Y' is -NH- where X is O and R6- is hydrogen LT is -O-CH2. Very highly preferred compounds are the compounds of formula I, wherein R * and R2 are benzyl or R < is benzyl and R2 is isopropyl, R3 is lower alkyl, R4 is 2,6-dimethylphenyl, which is optionally substituted with a third substituent selected from the group consisting of lower alkyl and halogen, R5 is where n is 1 or 2, X is O u S and Y is -CH2 or -NH- and L1 is -O-CH2. Examples of highly and very highly preferred compounds of the formula I are selected from the group consisting of: (2Sl3S, 5S) -2- (2,6-dimethylphenoxyacetyl) -amino-3-hydroxy-5- [2S- (1- tetrahydro-pyrimid-2-oneyl) -3-methylbutanoyl] -amino-1,6-diphenylhexane; (2S.3S 5S) -2- (2,6-d? Met? Lfenox? Acet? L) -am? No-3-hydroxy-5- (2S- (1-? M? Dazol? D? N- 2-on? L) -3,3-d? Met? Lbutane? L) -am? No-1,6-d? Phen? Hexane, (2S, 3S 5S) -2- (2,6-d? Methophenox? acet? l) -am? no-3-hydrox? -5- (2S- (1-? m? dazol? d? n-2-t? on? l) -3-met? lbutane? l) -am? no-1,6-d? phen? hexane, (2S, 3S, 5S) -2- (24,6-tr? met? lfenox? acet? l) -am? no-3 -h? drox? -5- (2S- (1 -? m? dazol? d? n-2-on? l) -3-met? lbutane? l) am? no-1,6-d? fen? lhexane, (2S, 3S, 5S) -2- (4-fluoro-2,6-d? met? lfenox? acet? l) am? no-3-hydroxy-5- (2S- (1-? m? dazol? d? n-2-on? l) -3-met? l-butane? l) -am? no-1,6-d? phen? hexane, (2S, 3S, 5S) -2- (2 , 6-d? Met? Lfenox? Acet? L) -am? No-3-h? Drox? -5- (2S- (1-p? Rrol? D? N-2- on? L) -3- methanol-butane?) am? no-1, 6-d? phenylhexane, (2S, 3S, 5S) -2- (2,6-d? met? lfenox? acet? l) -am? no- 3-hydroxy? -5- (2S- (1-pyrrolidone-2,5-d? On? L) -3-met? L-butane? L) -am? No-1 , 6-d? Phenylhexane, (2S, 3S, 5S) -2- (trans-3- (2,6-d? Met? Lfen? L) propenotl) am? No-3-hydrox? -5- (2S-1-tetrah? Drop? R? M? D? N-2-on? L) -3-met? L-butane? L) am? No-1, 6-d? Phen? Hexane, (2S , 3S) 5S) -2- (3- (2,6-d? Met? Lfen? L) propane? L) am? No-3-hydroxy-5- (2S- (1 -tetra h? Drop? R? M? D? N-2-on? L) -3-met? L-butane? L) am? No-1, 6-d? Phen? L hexane, (2S , 3S, 5S) -2- (2,6-d? Met? Lfenox? Acet? L) -am? No-3-h? Drox? -5- (2S- (1-tetra? Dro-p? R ? m? d-2,4-d? on? l) -3-met? lbutane? l) -am? no-1,6-d? phen? l-hexane, (2S, 3S, 5S) -2 - (2,6-d? Met? Lfenox? Acet? L) -am? No-3-h? Drox? -5- (2S- (4- aza-1-tetrah? Dro-p? R? M? d-2-on? l) -3-met? l-butane? l) am? no-1,6-d? phen? l-hexane, (2S, 3S, 5S) -2- (2,6- d? met? lfenox? acet? l) -am? no-3-hydrox? -5- (2S- (1-tetrahydro-pyrimid-2-oneyl) -3-methylbutanoyl) amino-1-phenyl-6 -methyl-heptane; (2S, 3S, 5S) -2- (2,6-Di-ethyl-phenoxyacetyl) amino-3-hydroxy-5- (2S- (1-tetrahydro-pyrimid-2,4-dionyl) -3-methylbutanoyl) amino-1 phenyl-6-methyl-heptane; and (2S, 3S, 5S) -2- (2,6-d.methylphenoxyacetyl) -amino-3-hydroxy-5- (2S- (4-aza-4,5-dehydro-1-pyrimid-2) -onyl) -3-methyl-butanoyl) amino-1,6-diphenyl-hexane; or a pharmaceutically acceptable salt, ester or prodrug thereof. The very highly preferred compound of the formula I is (2S, 3S, 5S) -2- (2,6-dimethyl-enoxyacetyl) -amino-3-h id roxy-5 [2S- (1-tetrahydro-pyrimid-2-2 onyl) -3-methylbutanoyl] -amino-1,6-diphenylhexane; or a pharmaceutically acceptable salt, ester or prodrug thereof. In some circumstances, it is preferred to be able to prepare (2S, 3S, 5S) -2- (2,6-dimethyl-enoxy acetyl) - my non-3-hydroxy-5- [2S- (1-tetrahydro-pyrimid-2-onyl) -3-me ti-l-butanoyl] -amin or-1,6-diphenylhexane (or a pharmaceutically acceptable salt, ester or prodrug thereof) as an amorphous solid. Said amorphous solid can be prepared by dissolving (2S, 3S, 5S) -2- (2,6-dimethylphenoxyacetyl) -amino-3-hydroxy-5- [2S- (1-tetrahydro-pyrimid-2-onyl) -3- methylbutanoyl] -amino-1,6-diphenylhexane in an organic solvent (eg, ethanol, isopropanol, acetone, acetonitrile and the like) and then adding the solution to water. Preferably, (2S, 3S, 5S) -2- (2,6-dimethyl-enoxy acetyl) -am- non-3-hydroxy-5- [2S- (1-tetrahydro-pyrimid-2-oneyl) -3-methylbutanoyl ] -amino-1,6-diphenylhexane is dissolved in ethanol (from about 2 to about 4 ml / g) and the ethanolic solution is added with stirring to water (from about 10 to about 100 ml / g) to give (2S, 3S, 5S) -2- (2,6-dimethylphenoxyacetyl) -amino-3-hydroxy-5- [2S- (1-tetrahydro-pyrimid-2-oneyl) -3-methylbutanoyl] -amino-1,6-diphenyl -hexane. Another embodiment of the present invention comprises an HIV protease inhibitor compound comprising a substituent of formula II: li wherein R3 is lower alkyl, hydroxyalkyl or cycloalkylalkyl; and R5 is b) Rß where n is 1 2 or 3, m is 1, 2 or 3, m 'is 1 or 2, X is O, S or NH, Y is -CH2-, -O-, -S-, or -N ( R6) -, wherein R6 is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aplo or aplakyl, and "is -CH2- or -N (R6) - wherein R6 is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aplo or aplaxyl , Y 'is -N (R6) -, wherein R6 is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aplo or aplakyl, and Z is O, S or NH Preferred compounds are HIV protease inhibitor compounds comprising a substituent of formula II, wherein R3 is lower alkyl and Rs is and) wherein X, Y, Y ', Y ", Z, R6-, n, mym' are as defined above The most preferred compounds are HIV protease inhibitor compounds comprising a substituent of formula II, wherein R3 is lower alkyl and Rs is where n is 1 or 2, X is O u S and Y is -CH2 or -NH-, where m is 1 or 2, X is O, Y is -CH2- and Z is O, where m 'is 1, X is O, Z is O and Y is -NH-, where m' is 1, X is O, Y "is -NH- and Y 'is -NH-, oe) where X is O and R6 is hydrogen The still highly preferred compounds are HIV protease inhibitor compounds comprising a substituent of formula II, wherein R3 is isopropyl and Rs is where n is 1 or 2, X is O u S and Y is -CH2 or -NH, where m is 1 or 2, X is O, Y is -CH2- and Z is O, where m 'is 1, X is O, Z is O and Y is -NH-, where m 'is 1, X is O, Y "is -NH- and Y' is -NH- where X is O and R6 •• is hydrogen. The highly preferred compounds are HIV protease inhibitor compounds comprising a substituent of formula II, wherein R3 is isopropyl and R5 is where n is 1 or 2, X is O u S and Y is -CH2 or -NH- b) where m 'is 1, X is O, Z is O and Y is -NH-, where m 'is 1, X is O, Y "is -NH- and Y' is -NH-, or where X is O and Re is hydrogen. Very highly preferred compounds are HIV protease inhibitor compounds comprising a substituent of formula II, wherein R3 is isopropyl and R5 is where n is 1 or 2, X is O u S and Y is -CH2 or -NH-. Examples of such HIV protease inhibitor compounds include: cis-N-tert-butyl-decahydro-2- [2 (R) -hydroxy-4-phenyl-3 (S) - (2S- (1-tetrahydropyrimid- 2-onyl) -3-methylbutanoyl) aminobutyl] - (4aS, 8aS) -isoquinolin-3 (S) -carboxyamide; cis-N-tert-butyl-decahydro-2- [2 (R) -hydroxy-4-thiof in yl-3 (S) - (2S- (1-tetrahydro-pyrimid-2-ynyl) -3-methylbutanoyl) aminobutyl ] - (4 aS, 8aS) -isoquinolin-3 (S) -carboxyamide; and 4-amino-N - ((2 syn, 3S) -2-hydroxy-4-phenyl-3- (2S- (1-tetrahydropyrimid-2-oneyl) -3-methylobutanoylamino) -butyl) -N-isobutyl -benzenesulfonamide; and the like; or pharmaceutically acceptable salts thereof. Said HIV protease inhibitor compounds comprising a substituent of the formula II can be prepared by JP 'coupling a suitable intermediate or precursor having an amino group (-NH2 or -NHR *, where R * is lower alkyl), a hydroxyl group (-OH) or a thiol group (-SH) to the compound of the formula III or an activated ester salt or derivative thereof: wherein R3 is lower alkyl, hydroxyalkyl or cycloalkylalkyl; Y R5 is where n is 1, 2 or 3, m is 1, 2 or 3, m 'is 1 or 2, X is O, S or NH, Y is -CH2-, -O-, -S- or -N ( R6) -, wherein R6 is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, Y "is -CH2- or -N (R6) - wherein R6- is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, Y 'is -N (R6) -, where R6' is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, and Z is O, S or NH.The preferred compounds are the compounds of the formula III or an activated ester derivative thereof, wherein R3 is lower alkyl and R5 is wherein X, Y, Y ', Y ", Z, R6-, n, mym' are as defined above, The most preferred compounds are the compounds of formula III or an activated ester derivative thereof, wherein R3 is lower alkyl and R5 is where n is 1 or 2, X is O u S and Y is -CH; NH-, where m is 1 or 2, X is O, Y is -CH2- and Z is O , where m 'is 1, X is O, Z is O and Y is -NH- where m' is 1, X is O, Y "is -NH- and Y 'is -NH- ? wherein X is O and R6 'is hydrogen. Still very preferred compounds are the compounds of the formula III or an activated ester derivative thereof, wherein R3 is isopropyl and R5 is where n is 1 or 2, X is O u S and Y is -CH2 or -NH- where m is 1 or 2, X is O, Y is -CH2- and Z is O, where m 'is 1, X is O, Z is O and Y is -NH- where m 'is 1, X is O, Y "is -NH- and Y' is -NH- where X is O and R6 is hydrogen. Most preferred compounds are the compounds of formula Ili or an activated ester derivative thereof, wherein R3 is isopropyl and R5 is where n is 1 or 2, X is O or S, and Y is -CH or - NH-, where m 'is 1, X is O, Z is O and Y is -NH- where m' is 1, X is O, Y "is -NH- and Y 'is -NH-, od) where X is O and R6 is hydrogen The highly highly preferred compounds are the compounds of the formula III or an activated ester derivative thereof, wherein R3 is isopropyl and R5 is where n is 1 or 2, X is O u S and Y is -CH2 or -NH-. The compounds of the invention may comprise asymmetrically substituted carbon atoms. As a result, all stereoisomers of the compounds of the invention means that they are included in the invention, including racemic mixtures, mixtures of diastereomers, as well as diastereomers of the compounds of the invention. The terms "S" and "R" configuration are as defined by IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Puré Appl. Chem. (1976) 45, 13-30. The term "N-protecting group" or "N-protected", as used herein, refers to those groups that purport to protect the N-terminus of an amino acid or peptide or protect an amino group against undesirable reactions during synthetic procedures. . The commonly used N-protecting groups are described by Greene and Wuts, "Protective Groups In Organic Synthesis", (John Wiley &Sons, New York, (1991)), which is incorporated herein by reference. The N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyl oxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-di methoxybenzyloxycarbonyl, 2,4-Di methoxy benzyloxycarbonyl, 4-m-ethoxy benzyloxycarbonyl, 2-nitro-4,5-di methoxy benzloxycarbonyl, 3, 4, 5-tri-methoxy benzyl oxocarbonyl, 1- (p-biphenylyl) -1-methylethoxycarbonyl, a, a-dimethyl-3,5-dimethoxy benzyloxycarbonyl, benzhydi loxycarbonyl, t- butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl, and the like; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like, and silyl groups such as trimethyl Isytite and the like. Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz). The term "activated ester derivative", as used herein, refers to acid halides such as acid chlorides, and activated esters including, but not limited to, anhydrides derived from formic and acetic acid, anhydrides derived from alkoxycarbonyl halides such as isobutyloxycarbonyl chloride and the like, esters derived from N-hydroxysuccinimide, esters derived from N-hydrophthalimide, esters derived from N-hydroxybenzotriazole, esters derived from N-hydroxy-5-norbornene-2,3-dicarboxyamide, esters derivatives of 2,4,5-trichlorophenol, esters derived from thiophenol, anhydrides derived from propylphosphonic acid and the like. The term "alkanoyl", as used herein, refers to R19C (O) -, wherein R? 9 is a lower alkyl group. The term "alkenylenyl", as used herein, refers to a divalent group derived from a straight or branched chain hydrocarbon containing from 2 to 10 carbon atoms and also containing at least one carbon-carbon double bond. Examples of alkenylene include -CH = CH-, -CH2CH = CH-, -C (CH3) = CH-, -CH2CH = CHCH2-, and the like. The terms "alkoxy" and "thioalkoxy", as used herein, refer to R5O- and R15S-, respectively, wherein R15 is a lower alkyl group. The term "alkoxyalkoxy", as used herein, refers to R22O-R23O-, wherein R22 is lower alkyl, as defined above, and R23 is an alkylenyl group. Representative examples of alkoxyalkoxy groups include methoxymethoxy, ethoxymethoxy, t-butoxymethoxy and the like. The term "alkoxyalkyl", as used herein, refers to an alkoxy group attached to a lower alkyl radical. The term "alkoxycarbonyl", as used herein, refers to R20C (O) -, wherein R20 is an alkoxy group. The term "alkylamino", as used herein, refers to -NHR? 6, wherein R16 is a lower alkyl group. The term "alkylaminocarbonyl", as used herein, refers to R2? C (O) -, wherein R21 is an alkylamino group. The term "alkylenyl", as used herein, refers to a divalent group derived from a straight or branched chain saturated hydrocarbon having from 1 to 10 carbon atoms through the removal of two hydrogen atoms, by example, methylene (-CH2-), 1,2-ethylene (-CH2CH2-), 1,1-ethylene = CH-CH3, 1,3-propylene (-CH2CH2CH2-), 2,2-dimethylpropylene (-CH2C ( CH3) 2CH2-), and the like. The term "aminocarbonyl", as used herein, refers to -C (O) NH2. The term "aryl", as used herein, refers to a mono- or bicyclic carbocyclic ring system comprising from 6 to 12 carbon atoms and having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like. The aryl groups may be unsubstituted or substituted with one, two or three substituents independently selected from lower alkyl, halogen, haloalkyl, haloalkoxy, alkoxy, alkoxycarbonyl, thioalkoxy, amino, alkylamino, dialkylamino, aminocarbonyl, mercapto, nitro, carboxyaldehyde, carboxy and hydroxy The term "aplakyl", as used herein, refers to an aplo group, as previously defined, attached to a lower alkyl radical, for example, benzyl and the like The term "cycloalkyl", as used in present, refers to a ring system having 3 to 8 carbon atoms including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, and the like The term "cycloalkylalkyl", as used herein, refers to a cycloalkyl group attached to a lower alkyl radical, including, but not limited to, cyclohexylmethyl The term "dialkylamino", as used herein , refers to -NR16R? 7, wherein R? 6 and R17 are independently selected from lower alkyl groups. The term "dialkylaminocarbonyl", as used herein, refers to R22C (O) -, wherein R22 is a dialkylamino group. The term "halo" or "halogen", as used herein, refers to -Cl, -Br, -I or -F. The term "haloalkoxy", as used herein, refers to R? BO-, wherein R18 is a haloalkyl group. The term "haloalkyl", as used herein, refers to a lower alkyl group, in which one or more hydrogen atoms are replaced by halogen, for example, chloromethyl, chloroethyl, trifluoromethyl, and the like. The term "heterocyclic ring" or "heterocyclic" or "heterocycle", as used herein, refers to any 3 or 4 member ring containing a heterogeneous atom selected from oxygen, nitrogen and sulfur; or a 5, 6 or 7 member ring containing one, two or three heterogeneous atoms independently selected from the group consisting of nitrogen, oxygen and sulfur or a 5 membered ring containing 4 nitrogen atoms; and includes a 5, 6 or 7 membered ring containing one, two or three nitrogen atoms; an oxygen atom; a sulfur atom; a nitrogen atom and a sulfur atom; a nitrogen atom and an oxygen atom; two oxygen atoms in non-adjacent positions; an oxygen atom and a sulfur atom in non-adjacent positions; two sulfur atoms in non-adjacent positions; two sulfur atoms in adjacent positions and one nitrogen atom; two adjacent nitrogen atoms and one sulfur atom; two non-adjacent nitrogen atoms and one sulfur atom; two non-adjacent nitrogen atoms and one oxygen atom. The 5-membered ring has 0-2 double bonds and the 6- and 7-membered rings have 0-3 double bonds. The heterogeneous nitrogen atoms may optionally be quaternized. The term "heterocyclic" also includes groups wherein any of the above heterocyclic ring is fused to a benzene ring or a cyclohexane ring or other heterocyclic ring (e.g., indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl, bistetrahydrofuranyl or benzothienyl, and the like) ). Heterocyclics include: azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolyl inyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, morpholinyl, thiazolyl, thiazolidinyl , isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, furyl, thienyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrimidyl and benzothienyl. Also included are heterocyclics of the formula: wherein X * is -CH2-, -NH- or -O-, Y * is -C (O) - or [-C (R ") 2.] v, wherein R" is hydrogen or C1-alkyl C and v is 1, 2 or 3 and Z * is -Oo -NH-; such as 1,3-benzodioxolyl, 1,4-benzodioxanyl and the like. Heterocyclics can be unsubstituted or substituted with one, two, three or four substituents independently selected from the group consisting of hydroxy, halo, oxo (= O), alkylimino (R * N =, wherein R * is a lower alkyl group ), amino, alkylamino, dialkylammo, alkoxy, alkoxyalkoxy, haloalkyl, cycloalkyl, aplo, aplaxyl, -COOH, -SO3H and lower alkyl. In addition, the nitrogen-containing heterocycles can be N-protected. The term "hydroxyalkyl", as used herein, refers to a lower alkyl radical to which it is attached to a hydroxy group. The term "lower alkyl", as used herein, it refers to a straight or branched chain alkyl radical containing from 1 to 6 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl , t-butyl, n-pentyl, 1-methyl butyl, 2,2-dimethyl-l-butyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like. The term "thioalkoxyalkyl", as used herein, refers to a thioalkoxy group attached to a lower alkyl radical. The compound of the invention of the formula I can be prepared as shown in Schemes I-IV. As summarized in Scheme I, intermediates 1_ and 2 (wherein P is an N-protecting group, eg, t-butyloxycarbonyl) can be coupled using standard peptide coupling and reagent methods, for example, the reaction of 1 and 2 in the presence of 1-hydroxubenzotriazole and a diimide such as dicyclohexylcarbodiimide (DCC) or N-ethyl-N'-dimethylaminopropyl-carbodiimide (EDAC) and the like to give Alternatively, a salt or an activated ester derivative of intermediate 1 (for example, the acid chloride, prepared through the reaction of the carboxylic acid with thionyl chloride) can be reacted with the intermediate 2 The compound 3 can be N-deprotected to give the compound 4 The N-deprotection of 3, wherein P ^ (especially where Pi is t-butyloxycarbonyl) is an acid-labile N-protecting group can lead to the formation of impurities resulting from the migration of the acyl group R4-L1-C (O) - of the amino group to the hydroxyl group La for This impurity can be minimized or eliminated by performing deprotection using (1) trifluoroacetic acid in methylene chloride or (2) concentrated hydrochloric acid (from about 2 molar equivalents to about 6 molar equivalents, preferably of about 2 equivalents molars at about 4 molar equivalents) in acetic acid at about room temperature A preferred N-deprotection method comprises reacting compound 3 (wherein P ^ is t-butyloxycarbonyl) with concentrated hydrochloric acid (from about 10 to about 20 molar equivalents ) in acetonite (from about 2 to about 10 liters / kilogram of compound 3) at a temperature from about 0 ° C to about 5 ° C. Compound 5 or an activated ester derivative thereof can then be coupled to compound 4 to give the compound of formula I (ie, 6_) An alternative procedure is In Scheme NA, Compound 7 (wherein P2 is an N-protecting group, eg, benzyloxycarbonyl) can be coupled to compound 5, or a salt or an activated ester derivative thereof (eg, acid chloride). , prepared through the reaction of the carboxylic acid with thionyl chloride), to give 8. The compound 8 can be N-deprotected to give 9. The compound 9_ can be coupled with the compound 1, or an activated ester derivative of same, to give the compound of formula I (ie, 6). Scheme IIB shows a preferred alternative procedure, wherein the N-protected amino alcohol 7a. (P3 is hydrogen and P4 is an N-protecting group or both P3 and P are N-protecting groups, preferably P3 and P are benzyl) is reacted with from about 1 to about 1.3 molar equivalents of carboxylic acid 5 or an activated ester salt or derivative thereof (for example, the acid chloride, prepared through the reaction of the carboxylic acid with thionyl chloride in ethyl acetate or THF or oxalyl chloride in toluene / DMF and the like) in the presence of about 1.0 to about 4.0 molar equivalents (preferably, from about 2.5 to about 3.5 molar equivalents) of an amine base organic (for example, imidazole, 1-methylimidazole, 2-methylimidazole, 2-isopropylimidazole, 4-methylimidazole, 4-nitroimidazil, pyridine, NN-dimethylaminopyridine, 1,2,4-triazole, pyrrole, 3-methylpyrrole, triethylamine or N -methylmorpholine and the like) or from about 1 to about 20 molar equivalents of an inorganic base (e.g., sodium carbonate or sodium bicarbonate and the like) in an inert solvent e (for example, ethyl acetate, dimethylformamide, THF, acetonitop, isopropyl acetate or toluene and the like) at a temperature from about 0 ° C to about 50 ° C to provide the compound 8_a. Preferred organic amine bases include imidazole and 1, 2,4-tr? Azol N-debenzylation of 8_a, for example, using hydrogen and a hydrogenation catalyst or Pd / C and a formic acid salt (for example, ammonium formate and the like) or Pd / C and formic acid and the like) provides 9 The compound 9 can be advantageously purified through crystallization with an organic carboxylic acid (for example, S-pyroglutamic acid, succinic acid or fumapco acid and the like) A preferred carboxylic acid is S-pyroglutamic acid Compound 9 (or an organic carboxylic acid salt of compound 9) is reacted with from about 10 to about 13 molar equivalents of carboxylic acid 1 or a salt or an active ester derivative. of the same (e.g., acid chloride) in the presence of (1) about 4 to about 8 molar equivalents (preferably, about 5 to about 7 molar equivalents) of an inorganic base (e.g., NaHCO3, Na2CO3, K2CO3, NaOH or KOH and the like) in an inert solvent (eg, 1 1 ethyl acetate / water or isopropyl acetate / water or toluene / water or THF / water, and the like) at about room temperature or (2) from about 10 to about 40 molar equivalents (preferably from about 2.5 to about 3.5 molar equivalents) of an organic amine base (e.g., imidazole, 1-methylimidazole, 2-methylimidazole, 2-isorpopilimidazole, 4-methylimidazole, -nitroimidazole, pyridine, N, N-dimethylaminopyridine, 1,4-triazole, pyrrole, 3-methylpyrrole, triethylamine or N-methylmorpholine and the like) in an inert solvent (for example, ethyl acetate, isopropyl acetate, THF) , toluene, acetonitrile, dimethyl formamide and the like) at a temperature from about 0 ° C to about 50 ° C to provide the compound 6. In a preferred embodiment of the invention (shown in Scheme III), intermediate compound 5 has the formula of compound 1_0 (R3 is as defined or the compound of formula I and is preferably isopropyl). The compound 1_0_ can be prepared in a variety of ways as shown in Scheme III. In one method, amino acid 11. (either as the free carboxylic acid or as the carboxylic acid ester (ie, lower alkyl ester) is converted to carbamate 12. (R "is phenyl, phenyl substituted lower alkyl, phenyl halo -substituted, nitro-substituted phenyl, trifluoromethylphenyl and the like) through the reaction with the appropriate chloroformate ester and the like The reaction of carbamate 12 with from about 1.0 to about 1.5 molar equivalents of the amine 1_3_ or an acid addition salt thereof (Q is a leaving group, for example, Cl, Br, or I, or a sulfonate such as methanesulfonate, triflate, p-toluenesulfonate, benzenesulfonate, and the like) in an inert solvent (eg, THF, methyl t-ether) butyl, dimethoxyethane, THF / water, dimethoxyethane / water, toluene or heptane and the like) in the presence of a base (for example, LiOH, NaOH, Li2CO3, Na2CO3, lithium phenoxide or sodium phenoxide and the like) in the amount of approximately 2.5 to about 3.5 molar equivalents provides urea 1_4. The urea 14 can be isolated and reacted further or can be converted in situ to cyclic urea 10 through the reaction in an inert solvent (for example, THF, dimethoxyethane, methyl t-butyl ether, toluene or heptane and the like) with a base (e.g., potassium t-butoxide, sodium hydride, potassium hydride or dimethylaminopyridine and the like) of the amount of from about 2.0 to about 5.0 molar equivalents. If the amino acid ester of 1_1 was the starting material, the ester is then hydrolyzed to provide the carboxylic acid 1_0. Alternatively, the amino acid 1 _ (either as the free carboxylic acid or as the carboxylic acid ester) is converted to the urea 1_4 through the reaction with from about 1.0 to about 1.5 molar equivalents of isocyanate 1_5 (Q is a group leaving, for example, Cl, Br or I, or a sulfonate such as methanesulfonate, triflate, p-toluenesulfonate, benzenesulfonate and the like) in an inert solvent (for example, THF, dimethoxyethane, methyl t-butyl ether, toluene or heptane and similar) in the presence of a base. In yet another alternative, the amino acid V? (Either as the free carboxylic acid or as the carboxylic acid ester) is converted to diamine 16. through the reaction with from about 10 to about 15 molar equivalents of amine 13 or an N-protected derivative thereof (Q is a leaving group, for example, Cl, Br or I, or a sulfonate such as methanesulfonate, tpflato, p-toluenesulfonate, benzenesulfonate and the like) in an inert solvent (e.g. , THF, dimethoxyethane, methyl t-butyl ether, toluene or heptane and the like) in the presence of a base (for example, NaH or potassium t-butoxide and the like) in the amount of about 10 to about 40 molar equivalents -desprotection is required if the N-protected derivative of 1_3 was used The reaction of diamine 1_6 with a carbonyl equivalent Y7_ (eg, phosgene, carbonyldiimidazole and the like, wherein Q 'and Q "are leaving groups such as Cl, Br , I, O-lower al, -O-aplo or imidazole and the like) in an inert solvent (for example, dimethoxyethane, methyl t-butyl ether, toluene or heptane and the like) in the presence of a base (for example, NaH or potassium t-butoxide and the like) in the amount of about 2 0 to about 40 molar equivalents provides cyclic urea 10. If the amino acid ester of H was the starting material, the ester is then hydrolyzed to provide the carboxylic acid 10. In another alternative more shown in Scheme IV, the compound V \ (either as the free carboxylic acid or as the carboxylic acid ester (ie, lower alkyl ester) is reacted with acylonitoplo according to J Am Chem Soc 72_, 2599 (1950) to give aminonitopol. Alternatively, the acylonitop can be replaced with 3-chloroproponotropyl to provide 18 aminonitoplo protection 1_8 as the carbamate (R30 is lower alkyl or phenyl or haloalkyl) (e.g., 2-chloroethyl, 2-bromoethyl, and the like) using normal conditions (e.g., the reaction of the amine with the chloroformate ester appropriate (CIC (O) OR 3o, wherein R 30 is lower alkyl, phenyl, haloalkyl and the like) clear or in an inert solvent (e.g., water, THF and the like) in the presence of an inorganic base (e.g., NaOH, KOH , K2CO3 and the like) or an organic base (e.g., an alkylamine or dialkatlamine and the like) provides the compound 1_9 The hydrogenation of 19 in the presence of a catalyst (e.g., Ni-Al alloy (basic) or Raney nickel (neutral or basic) or PtO2 (acid) and the like) in a solv inert carrier (e.g., water or methanol or ethanol or THF and the like) provides cyclic urea 10. In a preferred process, compound 1_9 is hydrogenated in the presence of an Ni-AI alloy catalyst in an inert solvent (e.g. , water or methanol or ethanol or THF and the like) in the presence of a base of a base (eg, KOH or NaOH or LiOH or an organic amine base and the like) in the amount of about 1 1 to about 5 molar equivalents to provide the cyclic urea 10. If the amino acid ester 1_1 was the starting material, the ester then hydrolyzed to provide the carboxylic acid 1_. Alternatively, the hydrogenation of compound 1_8 (as described above for compound 1_9) provides diamine 16, which can be converted to compound 10. As previously described, if amino acid ester 1_1 was the starting material, the ester is then hydrolyzed to provide the carboxylic acid 1_0.

SCHEME I SCHEME HAS UB SCHEME SCHEME lll SCHEME IV Ifi The key intermediates for the preparation of the compounds of the invention include compounds of the formula III as described above and compounds of the formula IV: or a salt thereof, wherein P3 and P4 are independently selected from hydrogen or an N-protecting group; * > Ri and R2 are independently selected from the group consisting of lower alkyl, cycloalkylalkyl and arylalkyl; R3 is lower alkyl, hydroxyalkyl or cycloalkylalkyl; and R5 is or where n is 1, 2 or 3, m is 1, 2 or 3, m 'is 1 or 2, X is O, S or NH, Y is -CH2-, -O-, -S- or -N ( R6) -, wherein R6 is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, Y "is -CH2- or -N (R6) -> wherein R6 is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, Y 'is -N (R6) -, wherein R6' is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, and Z is O, S or NH.The preferred compounds of formula IV, wherein P3 and P are hydrogen or benzyl, RT and R2 are arylalkyl, R3 is lower alkyl and R5 is b) wherein X, Y, Y ', Y ", Z, R6-, n, m and m' are as defined above The most preferred compounds are the compounds of formula IV, wherein Ri and R2 are benzyl or R < is benzyl and R2 is lower alkyl, R3 is lower alkyl and R5 is where n is 1 or 2, X is O u S and Y is -CH2 or -NH-, where m is 1 or 2, X is O, Y is -CH2- and Z is O, where m 'is 1, X is O, Z is O and Y is -NH- where m' is 1, X is O, Y "is -NH- and Y 'is -NH- e) where X is O and R6- is hydrogen The still highly preferred compounds are the compounds of the formula IV, wherein Ri and R2 are benzyl or R * is benzyl and R2 is isopropyl, R3 is lower alkyl and R5 is where n is 1 or 2, X is O u S and Y is -CH2 or -NH- where m is 1 or 2, X is O, Y is -CH2- and Z is O, where m 'is 1, X is o, Z is O and Y is -NH-, where m 'is 1, X is O, Y "is -NH- and Y' is -NH- where X is O and R6- is hydrogen. The most preferred compounds are the compounds of formula IV, wherein R and R2 are benzyl or R ^ is benzyl and R2 is isopropyl, R3 is lower alkyl and Rs is where n is 1 or 2, X is O u S and Y is -CH2 or -NH-, b) where m 'is 1, X is O, Z is O and Y is -NH-, where m 'is 1, X is O, Y "is -NH- and Y' is -NH-, or where X is O and R6- is hydrogen. The highly highly preferred compounds are the compounds of the formula IV, wherein Ri and R2 are benzyl or R < is benzyl and R2 is isopropyl, R3 is lower alkyl and R5 is where n is 1 or 2, X is O u S and Y is -CH or -NH-. Preferred salts of the compound of the formula are the organic carboxylic acid salts, especially the (S) -pyrglutamic acid salt. The following examples will serve to further illustrate the preparation of the novel compounds of the invention.

EXAMPLE 1 (2S.3S.5S) -2- (2,6-di methyne, cetyl) amino-3-hydroxy-5-f2S- (1-imide zolidin-2-or nyl) -3-methyl-butanoll amino -1.6 -difenilhexane A. Ester N.N-dibenzyl- (L) -benzylic phenylalanine A solution containing L-phenylalanine (161 kg, 975 moles), potassium carbonate (445 kg, 3220 moles), water (675 L), ethanol (340 L), and benzyl chloride (415 kg, 3275 moles) was heated at 90 + 15 ° C for 10-24 hours. The reaction mixture was cooled to 60 ° C and the lower aqueous layer was removed. Heptane (850 L) and water (385 L) were added to the organics, stirred and the layers separated. The organic products were then washed once more with a water / methanol mixture (150 L / 150 L). The organic products were then separated to give the desired product as an oil, which was carried out in the next step without purification. IR (net) 3090, 3050, 3030, 1730, 1495, 1450, 1160 cm "1, 1 H NMR (300 MHz, CDCl 3) d 7.5-7.0 (m, 20H), 5.3 (d, 1 H.) J = 13.5 Hz), 5.2 (d, 1 H, J = 13.5 Hz), 4.0 (d, 2H, J = 15 Hz), 3.8 (t, 2H, J = 8.4Hz), 3.6 (d, 2H, J = 15 Hz ), 3.2 (dd, 1H, J = 8.4.14.4 Hz), 13C NMR (300MHz, CDCI3) d 172.0, 139.2, 138.0, 135.98.2, 128.1, 128.1, 126.9, 126.2, 66.0, 62.3, 54.3, 35.6 . [a] D -79 ° (c = 0.9, DMF).

B. (4S) -4- (N, N-Dibenzylamino) -3-oxo-5-phenyl-pentanenitrile A solution containing the product of Example 1A (ie, benzyl ester) (about 0.45 moles) in 520 ml of tetrahydrofuran and 420 ml of acetonitrile was cooled to -40 ° C under nitrogen. A second solution containing sodium amide (48.7 g, 1.25 moles) and 850 L of tetrahydrofuran was cooled to -40 ° C. To the sodium amide solution was added slowly to 75 ml of acetonitrile and the resulting solution was stirred at -40 ° C for more than 15 minutes. The sodium / acetonitrile amide solution was then slowly added to the benzyl ester solution at -40 ° C. The combined solution was stirred at -40 ° C for one hour and then quenched with 1150 ml of a 25% citric acid (w / v) solution. The resulting slurry was heated to room temperature and the organics separated. The organics were then washed with 350 ml of a 25% solution of sodium chloride (w / v), then diluted with 900 ml of heptane. The organics were then washed three times with 900 ml of a 5% solution of sodium chloride (w / v), twice with 900 ml of a 10% solution of methanolic water, once with 900 ml of an aqueous solution. 15% methanolic water, and then once with 900 ml of a 20% methanolic water solution. The organics were distilled and the resulting material was dissolved in 700 ml of hot ethanol. After cooling to room temperature, the desired product was precipitated. Filtration gave the desired product in a 59% yield from L-phenylalanine. IR (CHCl3) 3090, 3050, 3030, 2250, 1735, 1600, 1490, 1450, 1370, 1300, 1215 cm "1, 1 H NMR (CDCl 3) d 7.3 (m, 15 H), 3.9 (d, 1 H, J = 19.5 Hz), 3.8 (d, 2H, J = 13.5 Hz), 3.6 (d, 2H, J = 13.5 Hz), 3.5 (dd, 1 H, J = 4.0, 10.5 Hz), 3.2 (dd, 1H, J = 10.5, 13.5 Hz), 3.0 (dd, 1H, J = 4.0, 13.5 Hz), 3.0 (d, 1H, J = 19.5 Hz), 13C NMR (300MHz, CDCI3) d 197.0, 138.4, 138.0, 129.5, 129.0 , 128.8, 128.6, 127.8, 126.4, 68.6, 54.8, 30.0, 28.4. [O] D -95 ° (c = 0.5, DMF).

C. (5S) -2-Amino-5- (N.N-dibenzylamino) -4-oxo-1,6-diphenylhex-2-ene To a solution at -5 ° C of the nitrile product of Example 1B (90 kg, 244 moles) in tetrahydrofuran (288 ml), benzylmagnesium chloride (378 kg, 2M in THF, 708 moles) was added. The solution was warmed to room temperature and stirred until the analysis showed no starting material. The solution was then re-cooled to 5 ° C and slowly transferred to a 15% citric acid solution (465 kg). Additional tetrahydrofuran (85 L) was used to rinse the original vessel and the rinse was added to the citric acid quench vessel. The organics were separated and washed with 10% sodium chloride (235 kg) and distilled to a solid. The product was distilled again from ethanol (289 L) and then dissolved in ethanol at 80 ° C (581 L). After cooling to room temperature and stirring for 12 hours, the resulting product was filtered and dried in a vacuum oven at 30 ° C to give approximately 95 kg of the desired product. Mp. 101-102 ° C, IR (CDCI3) 3630, 3500, 3130, 3060, 3030, 2230, 1620, 1595, 1520, 1495, 1450 cm "1, 1H NMR (300 MHZ, CDCI3) d 9.8 (br s , 1 H), 7.2 (m, 20H), 5.1 (s, 1 H), 4.9 (br s, 1 H), 3.8 (d, 2H, J = 14.7 Hz), 3.6 (d, 2H, J = 14.7 Hz), 3.5 (m, 3H), 3.2 (dd, 1t1, J = 7.5, 14.4 Hz), 3.0 (dd, 1H, J = 6.6.14.4 Hz), 13C NMR (CDCI3) d 198.0, 162.8, 140.2, 140.1, 136.0, 129.5, 129.3, 128.9, 128.7, 128.1,128.0, 127.3, 126.7, 125.6, 96.9, 66.5, 54.3, 42.3, 32.4. [A] D -147 ° (c = 0.5, DMF).

D. (2S.3S.5S) -5-Amino-2- (NN-dibenzylamino) -3-hydroxy-1.β-diphenylhexane i) A suspension of sodium borohydride (6.6 kg, 175 moles) in tetrahydrofuran (157 L) was cooled to -10 ± 5 ° C. Methanesulfonic acid (41.6 kg, 433 moles) was slowly added and the temperature was maintained at 0 ° C during the addition. After the addition was complete, a solution of water (6 L, 333 moles), the product of Example 1C (20 kg, 43 moles) and tetrahydrofuran (61 L) were added slowly while keeping the temperature below 0 ° C. during the addition. The mixture was stirred for not less than 19 hours at 0 ± 5 ° C. ii) Sodium borohydride (6.6 kg) was added to a separate flask., 175 moles) and tetrahydrofuran (157 L). After cooling to -5 ± 5 ° C, trifluoroacetic acid (24.8 kg, 218 moles) was added, while keeping the temperature below 15 ° C. The solution was stirred for 30 minutes at 15 ± 5 ° C and then added to the reaction mixture resulting from step i, keeping the temperature at less than 20 ° C. This was stirred at 20 ± 5 ° C until the reaction was The solution was then cooled to 10 ± 5 ° C and quenched with 3N NaOH (195 kg) After stirring with tert-butyl methyl ether, the organic layer was separated and washed once with 05N NaOH (200 kg) ), once with 20% aqueous ammonium chloride w / v (195 kg), and twice with 25% aqueous sodium chloride (160 kg) The organics were distilled to give the desired product as an oil, which was used directly in the next step IR (CHCl3) 3510, 3400, 3110, 3060, 3030, 1630, 1H NMR (300 MHz, CDCI3) d 72 (m, 20H), 4 1 (d, 2H, J = 135Hz) , 365 (m, 1H), 35 (d, 2H, J = 13 5 Hz), 3 1 (m, 2H), 2 8 (m, 1 H), 265 (m, 3H), 1 55 (m, 1 H), 1 30 (m, 1 H), 13 C NMR (300 MHz, CDCl 3) 81 408, 140 1, 1382, 1294, 1294, 1286, 1284, 128 3, 1282, 1268, 1263, 1257, 72 0 6 36, 549, 53 3, 462, 40 1, 302 E. (2S.3S.5S) -2- (NN-d-benzethylamino) -3-hydroxy-5-ft-butyloxycarbonylamino) -1,6-diphenylhexane To a solution of [2S, 3S, 5S] -2-N, Nd? Benc? Lam? No-3-hydroxy? -5-am? No-16, d? Phenol hexane (ca. 105 kg, 226 mol) in MTBE (1096 L), BOC anhydride was added ( 65 kg, 373 moles) and 10% potassium carbonate (550 kg) This mixture was stirred until the reaction was complete (approximately 1 hour) The lower layer was removed and the organics were washed with water (665 L) The solution it was then distilled to give the desired product as an oil. 300 MHz 1 H NMR (CDCl 3) d 1.40 (s, 9H), 1.58 (s, 2H), 2.45-2.85 (m, 4H), 3.05 (m, 1 H), 3.38 (d, 2H), 3.6 (m , 1 H), 3.79 (m, 1 H), 3.87 (d, 2 H), 4.35 (s, 1 H), 4.85 (s, broad, 1 H), 7.0-7.38 (m, 20 H).

F-1 (2S.3S, 5S) -2-Amino-3-hydroxy-5- (t-butyloxycarbonylamino) -1.β-diphenylhexane To a solution of [2S, 3S, 5S] -2-N, N-dibenzylamino-3 -hydroxy-5-t-butyloxycarbonylamino-1,6-diphenylhexane (12 g, 21.3 moles) in methanol (350 ml) was charged with ammonium formate (8.05 g, 128 mmol), 6.0 eq) and 10% palladium on carbon. % (2.4 g). The solution was stirred under nitrogen at 60 ° C for three hours and then at 75 ° C for 12 hours. An additional amount of ammonium formate (6 g) and 10% palladium on carbon (1.5 g) was added, as well as 1 ml of glacial acetic acid. The reaction was carried out in 2 hours at a reflux temperature. The reaction mixture was then cooled to room temperature and then filtered through a pad of celite. The filter cake was washed with methanol (75 ml) and the combined filters were concentrated under reduced pressure. The residue was taken in 1N NaOH (300 ml) and extracted into methylene chloride (2 X 200 ml). The combined organic layers were washed with brine (250 ml) and dried over sodium sulfate. The concentration of the solution under reduced pressure provided the desired product as a light colored oil, which crystallized slowly after standing (5 g). Further purification of the product can be achieved by flash chromatography (silica gel). , 5% methanol in methylene chloride) 300 MHz 1 H NMR (CDCl 3) d 1 42 (s, 9 H), 1.58 (m, 1 H), 1 70 (m, 1 H), 2.20 (s, broad, 2H ), 2 52 (m, 1 H), 2.76-2.95 (m, 4H), 350 (m, 1H), 3.95 (m, 1H), 480 (d, broad, 1H), 7 15-7.30 (m, 10H) F-2 Succinate salt of r2S.3S.5S1-2-Amino-3-hydroxy-5-t-butyloxycarbonylamino-1,6-diphenylhexane To a solution of [2S, 3S, 5S] -2-N, Nd? Benc? Lam ? no-3-hydrox? -5-t-butylox? carbonylamino-1,6-d? phen? hexane (approximately 127 kg, 225 mol) in methanol (437 L), a methanolic slurry (285 L) was added. L) of 5% palladium on carbon (24 kg) To this was added a solution of ammonium formate (84 kg, 1332 moles) in methanol (361 L). The solution was heated to 75 ° C for 6- 2 hours and then cooled to room temperature. The solids were filtered out of the reaction mixture using a filter coated with a filter aid (Celite) and the methanol was distilled from the mixture. of reaction using heat and vacuum (up to 70 ° C). The residue was dissolved in isopropyl acetate (4400 kg) with heat (40 ° C) and then washed with a 10% solution of sodium carbonate (725 kg), and finally with water (665 L). Both washes were made at 40 ° C to keep the product in the solution The solvent was removed under vacuum with heat (up to 70 ° C) Then isopropyl alcohol (475 L) was added and distilled to remove residual solvents. Isopropanol (1200 L) was added to the residue and stirred until homogeneous. To this solution was added a solution of succinic acid (15-40 kg) in isopropanol (1200 L). The solution jacket was heated to 70 ° C to dissolve all solids and then allowed to cool slowly to room temperature and stirred for 6 hours. The solution was then filtered to give the desired product as a white solid (55-80 kg). Mp: 145-146 ° C. 1H NMR: (Me2SO-d6, 300 MHz) d 0.97 (d, 3H, IPA), 1.20 (s, 9H), 1.57 (t, 2H), 2.20 (s, 2H, succinic acid), 2.55 (m, 2H ), 2.66 (m, 2H), 2.98 (m, 1 H), 3.42 (m, 1 H), 3.70 (m, 1 H), 3.72 (m, 1 H, IPA), 6.60 (d, 1 H, NH amide), 7.0-7.3 (m, 10H). 1H NMR: (CD3OD, 300 MHz) d 1.11 (d, 3H, J = 7 Hz, IPA), 1.29 (s, 9H), 1.70 (m, 2H), 2.47 (s, 2H, succinic acid), 2.65 ( m, 2H), 2.85 (m, 2H), 3.22 (m, 1 H), 3.64 (m, 1 H), 3.84 (m, 1 H), 7.05-7.35 (m, 10H).

G. 2,6-dimethylphenoxy ethyl acetate To a solution of 2,6-dimethyphenol (8.0 g, 66 mmol) in dioxane (600 ml) was added ethyl bromoacetate (18.2 ml, 164 mmol) and cesium carbonate (58 g). , 176 mmoles). The reaction mixture was refluxed for 18 hours, cooled to room temperature, filtered and concentrated in vacuo. Purification through silica gel column chromatography (5% to 20% ether in hexane) provided the desired compound (80%). 300 MHz 1 H NMR (CDCl 3) d 1.35 (t, J = 7.5 Hz, 3 H), 2.30 (s, 6 H), 4.31 (q, J = 7.5 Hz, 2 H), 4.40 (s, 2 H), 7.0 (m, 3H).

H. 2,6-Dimethylphenoxy acetic acid To a solution of the compound of Example 1G (5.15 g, 24.7 mmol) in methanol (170 ml) and water (56 ml) was added 5.3 g of lithium hydroxide at 0 ° C, The solution was stirred for 1.5 hours at room temperature and concentrated in vacuo. The residue was acidified with 0.5M HCl and extracted with ethyl acetate (300 ml). The organic layer was dried and concentrated to give a white solid (4.05 g, 91%). 300 MHz 1 H NMR (CDCl 3) d 1.35 (t, J = 7.5 Hz, 3 H), 2.30 (s, 6 H), 4.31 (q, J = 7.5 Hz, 2 H), 4.40 (s, 2 H), 7.0 (m, 3H).

I. (2S.3S.5S) -2- (2.β-Pimethylphenoxyacetyl) amino-3-hydroxy-5- (t-butyloxycarbonylamino) -1,6-diphenylhexane. Coupling of the amine of Example 1F with the acid of Example 1H, using a normal EDAC coupling procedure, provided the desired compound (78%). 300 MHz 1 H NMR (CDCl 3) d 1.40 (s, 9 H), 1.65 (m, 3 H), 2.18 (s, 6 H), 2.78 (m, 2 H), 2.98 (d, J = 9 Hz, 2 H), 3.75 ( m, 1 H), 3.90 (m, 1H), 4.15 (m, 1 H), 4.20 (s, 2H), 4.60 (m, 1 H), 7.0 (m, 3H), 7.25 (m, 10H). Mass spectrum: (M = H) + = 547.

J. 2-N- (Benzyloxycarbonyl) amino-acetaldehyde To a solution of 1.45 ml of DMSO in 20 ml of CH2Cl2 at -78 ° C was added dropwise 1.34 ml of oxalyl chloride. After 15 minutes at -78 ° C, a solution of N-Cbz-aminoethanol in 40 ml of CH2Cl2 was added After 15 minutes at -78 ° C and 2 minutes at 0 ° C, the solution was cooled to -78 ° C C and tetylamine (6 14 ml) was added dropwise. The solution was stirred at -78 ° C for 30 minutes and emptied into 50 ml of cold 10% aqueous citric acid and extracted with ether (150 ml). The combined organic was washed with brine and dried with anhydrous Na2SO4; it was filtered and concentrated in vacuo. Purification of the crude product through silica gel chromatography (10% EtOAc / CH 2 Cl 2) provided the desired compound (42%) 300 MHz 1 H NMR (CDCl 3) d 4 17 (d, J = 6 Hz, 2H), 5 15 (s, 2H), 540 (br s, 1 H), 736 (m, 5H), 9.66 (s, 1 H) Mass spectrum (M + NH4) + = 211 K. N- (Benzyloxycarbonylamino) -ethyl valine methyl ester To a solution of the aldehyde of Example 1J (0829 g, 429 mmol) in 17 ml of methanol was added valine methyl ester hydrochloride (072 g, 4.29 mmol), sodium acetate (0.7 g, 8 58 mmol) and sodium cyanoborohydride (0.54 g, 8 58 mmol). The mixture was stirred at room temperature overnight and the solvent was evaporated in vacuo. The residue was taken up in ethyl acetate (100 ml) and washed with saturated NaHCO3 (10 ml) and the aqueous layer was extracted with ethyl acetate (2 x 50 ml) The combined organic layer was washed with brine and dried with Anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified through silica gel column chromatography (20% EtOAc / CH2Cl2) to provide the desired compound (60%) 300 MHz 1H NMR (CDCl3) d 0.91 (d, J = 3 Hz, 3H), 0.94 (d, J = 3 Hz, 3H), 1.90 (m, 1 H), 2.55 (m, 1 H), 2.80 (m, 1 H). 2.98 (d, J = 6 Hz, 1 H), 3.20 (m, 1 H), 3.30 (m, 1 H), 3.71 (s, 3H), 5.10 (s, 2H), 5.27 (br s, 1 H), 7.37 (m, 5H). Mass spectrum: (M + H) + = 309.

L. 2S- (1-imidazolidin-2-ynyl) -3-methyl butanoic acid methyl ester The Cbz protection of the compound in Example 1K was removed through hydrogenolysis and the crude product was treated with an equivalent of 1, 1-carbonyldiimidazole in CH 2 Cl 2 to provide the desired compound (64%), 300 MHz 1 H NMR (CDCl 3) d 0.95 (d, J = 7.5 Hz, 3 H), 0.98 (d, J = 7.5 Hz, 3 H), 2.15 (m , 1 H), 3.47 (m, 3 H), 3.71 (s, 3 H), 3.73 (m, 1 H), 4.23 (d, J = 10.5 Hz, 1 H), 4.81 (br s, 1 H), Spectrum of mass: (M + H) + = 201.

M. 2S- (1-imidazolidin-2-ynyl) -3-methyl butanoic acid To a solution of the compound of Example 1L (151 mg, 0.75 mmol) in 2.5 ml of water and 5 ml of dioxane was added at 0 °. C lithium hydroxide monohydrate (2.0 eq.) The solution was stirred at 0 ° C for 1.5 hours at room temperature for 1 hour. Acidification with 1N HCl, extraction with EtOAc (100 ml + 2 x 50 ml), drying with sodium sulfate and evaporation of the filtered solution in vacuo provided the desired compound (88%). 300 MHz 1 H NMR (DMSO-d 5) d 0.85 (d, J = 12 Hz, 3 H), 0.92 (d, J = 12 Hz, 3 H), 2.05 (m, 1 H), 3.25 (m, 2 H), 3.30 (m, 1 H), 3.50 (m, 1 H), 3.90 (d, J = 15 Hz, 1 H), 6.40 (br s, 1 H), 12.60 (br s, 1 H). Mass spectrum: (M + H) + = 187.

N. (2S.3S.5S) -2- (2,6-Dimethylphenoxyacetyl) amino-3-hydroxy-5-amino-1,6-diphenylhexane To 4.5 g of the compound of Example 11 was added 40 ml of CH2Cl2 and trifluoroacetic acid . The solution was left at room temperature for one hour. Concentration of the solution in vacuo provided the desired compound (100%). 300 MHz 1 H NMR (CDCl 3) d 1.48 (m, 1 H), 1.62 (m, 1 H), 2.05 (m, 1 H), 2.24 (s, 6 H), 2.50 (m, 1 H), 2.80 (m , 1 H), 3.0-3.10 (m, 4H), 3.90 (d, J = 10 Hz, 1 H), 4.17 (m, 1H), 4.26 (ABq, J = 13.5 Hz, 2H), 7.0 (m, 3H), 7.10 (m, 2H), 7.30 (m, 7H), 7.41 (d, J = 10 Hz, 1 H). Mass spectrum: (M + H) + = 447.

O. (2S.3S.5S) -2- (2,6-Dimetitfenoxiacetil) amino-3-hydroxy-5-r2S-M-imidazolidin-2-onyl) -3-methyl-butanoin amino-1,6-diphenylhexane The coupling of the compound Example 1N amino with the acid of Example 1M, using the normal coupling procedure [1- (3-dimethylaminopropyl) -3-ethylcarbodiimide in DMF] provided the desired compound (80%). 300 MHz 1 H NMR (CDCl 3) d 0.83 (d, J = 6 Hz, 3 H), 0.86 (d, J = 6 Hz, 3 H), 1.75 (m, 2 H), 2.16 (m, 1 H), 2.18 (s, 6H), 2.76 (m, 2H), 2.97 (d, J = 7.5Hz, 2H), 3.14 (m, 2H), 3.30 (m, 2H), 3.70 (d, J = 1- Hz, 1 H), 3.75 (m, 1 H), 4.20 (m, 4H), 4.50 (br s, 1 H), 6.70 (d, J = 7.5 Hz, 1 H), 7.0 (m, 3H), 7.25 (m, 10H) . Mass spectrum: (M + H) + = 615.

EXAMPLE 2 (2S, 3S, 5S) -2- (2,6-Dimethylphenoxyacetin amino-3-hydroxy-5-r2S- (1-tetrahydro-pyrimid-2-oneyl) -3-methyl-butanoyl amino-1,6- diphenylhexane A. 2S- (1-Tetrahydro-pyrimid-2-ynyl) -3-methyl butanoic acid Using the procedures described in Examples 1J to 1M, but replacing the N-Cbz-aminoethanol in Example 1J with N-Cbz-3 -aminopropanol, the desired compound was provided. 300 MHz 1 H NMR (DMSO-d 6) d 0.82 (d, J = 7 Hz, 3 H), 0.93 (d, J = 7 Hz, 3 H), 1.77 (m, 2 H), 2.10 (m, 1 H), 3.10- 3.23 (m, 4H), 4.42 (d, J = 10.5 Hz, 1 H), 6.37 (br s, 1 H). Mass spectrum: (M + H) + = 201.

B. (2S.3S.5S) -2- (2,6-Dimethylphenoxyacetyl) amino-3-hydroxy-5-r 2 S- (1-tetrahydro-pyrimid-2-oneyl) -3-methyl-butanoin amino-1,6- diphenylhexane The coupling of the amino compound of Example 1N with the acid of Example 2A, using a standard procedure (EDAC in DMF), afforded the desired compound (70%). 300 MHz 1 H NMR (CDCl 3) d 0.80 (d, J = 4.5 Hz, 3 H), 0.83 (d, J = 4.5 Hz, 3 H), 1.50 (m, 1 H), 1.65-1.72 (m, 6 H), 2.20 ( s, 6H), 2.68 (m, 1H), 2.82 (m, 2H), 3.0 (d, J = 7.5 Hz, 1H), 3.05 (m, 4H), 3.77 (m, 1H), 4.07 (d, J = 4.5 Hz, 1H), 4.20 (m, 4H), 4.50 (br s, 1H), 6.78 (br d, 1H), 7.0 (m, 3H), 7.25 (m, 10H). Mass spectrum: (M + H) + = 629.

EXAMPLE 3 (2S.3S, 5S) -2- (2,6-Dimethyl-phenoxyacetyl) amino-3-hydroxy-5-r2S- (3-oxazolidin-2-oneyl) -3-methyl-butanoin amino-1-6- diphenylhexane A. 2S- (3-Oxazolidin-2-opyl) -3-methyl-butanoic acid methyl ester To a solution of L-valine methyl ester hydrochloride (7.6 mmol) was added a solution of ethylene oxide in ethanol (1.5 equivalents). The solution was kept at 0 ° C for 0.5 hours and then at room temperature for 18 hours, at which time 0.01 equivalents of BF3 »Et2O were added. Fresh ethylene oxide was bubbled directly into the solution for 3 to 4 minutes. After 8 hours, the solution was concentrated to dryness and the residue was dissolved in CH2Cl2 and cooled to 0 ° C. To this solution were added 1.2 equivalents of triethylamine and 1.0 equivalents of triphosgene. After 1 hourThe solvent was removed in vacuo and the residue was washed with water (30 ml) and extracted with CH2Cl2 (3 x 50 ml), dried and concentrated. Purification of the crude product through silica gel column chromatography (5% EtOAc / CH 2 Cl 2) provided the desired compound (42%, 2 steps). 300 MHz 1 H NMR (CDCb) d 0.98 (d, J = 4.0 Hz, 3 H), 1.0 (d, J = 4.0 Hz, 3 H), 2.16 (m, 1 H), 3.60 (m, 2 H), 3.73 (s, 3H), 4.20 (d, J = 10 Hz, 1H), 4.37 (m, 2H). Mass spectrum: (M + H) + = 202.

B. 2S- (3-Oxazolidin-2-ynyl) -3-methyl-butanoic acid The hydrolysis of the methyl ester of Example 3A, using the procedure described in Example 1M provided the desired compound 300 MHz 1H NMR (DMSO-d6) d 090 (d, J = 6 Hz, 3H), 095 (d, J = 6 Hz, 3H), 2 1 (m, 1H), 3 55 (m, 1H), 370 (m, 1H), 388 ( d, J = 9 Hz, 1 H), 430 (m, 2H), 130 (br s, 1 H) Mass spectrum (M + NH4) + = 205 C. (2S.3S.5S) -2- (2,6-DimethylphenoxyacetH) amino-3-hydroxy-5-r2S- (3-oxazolidin-2-oneyl) -3-methyl-butanoin amino-1,6-diphenylhexane The coupling the amine of Example 1N with the acid of Example 3B, using normal coupling procedures (EDAC in DMF), provided the desired compound 300 MHz 1 H NMR (CDCl 3) d 083 (d, J = 45 Hz, 3H), 087 (d, J = 45 Hz, 3H), 1 75 (m, 1H), 2 10 (m, 1H), 220 (s, 6H), 265 (m, 1H), 2 85 (m, 1H), 30 (m, 3H), 330 (m, 1H), 360 (m, 2H), 377 (m, 1H), 420 (m, 4H), 625 (br d, J = 6 Hz, 1H), 70 (m , 3H), 725 (m, 10H) Mass spectrum (M + H) + = 616 EXAMPLE 4 (2S.3S.5S) -2-r (3R. 3aS.6aR) -Bis-tetrahydrofuranyloxyl amino-3-hydroxy-5-r2S- (3-methyl-1-imidazolidin-2-onyl) 3-methyl-butane-amino-1,6-diflu nyl hexane A. 2S- (3-methyl-1-imidazolidin-2-oneyl) -3-methyl butanoic acid methyl ester To a suspension of 45 mg (60 mg) % oil dispersion) of sodium hydride in 0.5 ml of DMF was added a solution of 150 mg of the compound of Example 1L in 4.5 ml of DMF.After 20 minutes at room temperature, methyl iodide (1.5 equivalents) was added. 0.07 ml) The reaction was completed in 1 hour.The reaction was quenched with a saturated NH CI solution and extracted with ether (100 ml + 50 ml x 2), dried and concentrated in vacuo. purified by silica gel column chromatography (20% EtOAc / CH 2 Cl 2) to provide the desired compound (61%) 300 MHz 1 H NMR (CDCl 3) d 0.95 (d, J = 6 Hz, 3H), 0.97 (d, J = 6 Hz, 3H, 2.15 (m, 1H), 2.80 (s, 3H), 3.32 (m, 3H), 3.60 (m, 1 H), 3 .70 (s, 3H), 4.25 (d, J = 10.5 Hz, 1H). Mass spectrum: (M + H) + = 215.

B. 2S- (3-Methyl-1-imidazolidin-2-oneyl) -3-methyl butanoic acid The hydrolysis of the methyl ester of Example 4A using the procedure described in Example 1M provided the desired compound. 300 MHz 1 H NMR (DMSO-d 6) d 0.85 (d, J = 6 Hz, 3 H), 0.92 (d, J = 6 Hz, 3H), 2.05 (m, 1H), 2.65 (s, 3H), 3.25 (m, 3H), 3.42 (m, 1H), 3.90 (d, J = 10 Hz, 1H). Mass spectrum: (M + H) + = 201.

C. Carbonate of (3R.3aS.βaR) -Bis-tetrahydrofuranyl- (4-nitrophenyl) To a solution of 3R-h? Drox? - (3aS, 6aS) -b? S-tetrah? Drofuran [J Med Chem 37 , 2506-2508 (1994)] (200 mg, 544 mmol) in 10 ml of CH2Cl2 was added tetylamine (026 ml, 1.85 mmol), and p-nitrophenyl chloroformate (341 mg, 1.69 mmol) The solution it was kept at room temperature for 3 days, diluted with CH2CI (100 ml) and washed with saturated NaHCO3 (15 ml). The organic layer was dried and concentrated in vacuo. Purification through silica gel column chromatography ( 5% EtOAc / CH 2 Cl 2) provided the desired compound (42%) 300 MHz 1 H NMR (CDCl 3) d 2 0 (m, 1 H), 220 (m, 1 H), 3 18 (m, 1 H), 4 0 (m , 3H), 4 17 (m, 1H), 527 (m, 1H), 580 (d, J = 6 Hz), 740 (d, J = 7 5 Hz, 2H), 830 (d, J = 7 5 Hz, 2H) Mass spectrum (M + NH4) + = 313 D. (2S.3S.5S) -2-r (3R.3aS.6aR) -bis-tetrahydrofuranyloxyl amino-3-hydroxy-5- (t-butyloxycarbonyl) amino-1,6-diphenylhexane To one solution of the carbonate of Example 4C (100 mg, 0 34 mmol) in 34 ml of DMF was added the compound of Example 1F (130 mg, 034 mmol). The solution was kept at room temperature overnight and then concentrated in vacuo. Purification of the crude product through silica gel column chromatography (2% to 5% MeOH / CH 2 Cl 2) provided the desired compound (93%) 300 MHz 1 H NMR (CDCl 3) d 1 40 (s, 9H), 1 64 (m, 3H), 276 (m, 2H), 2 87 (m, 2H), 366-40 (m, 7H), 453 (m, 1H), 506 (m, 2H), 568 (d, J = 6 HZ, 1H), 7 10-728 (m, 10H) Mass spectrum (M + NH4) + = 558 E. (2S.3S.5S) -2-r (3R.3aS.6aR) -bis -tetrahydrofuranyl M amino-3-hydroxy-5-amino-1,6-diphenylhexane To a solution of the compound of Example 4D (170 mg, 0.31 mmol) in 5 ml of CH2Cl2 was added 5 ml of trifluoroacetic acid. After 0.25 hours, the solvent was removed in vacuo. The residue was dissolved in 100 mL EtOAc and washed with saturated NaHCO3 and then with brine, dried and concentrated to provide the desired compound (91%). 300 MHz 1 H NMR (CDCl 3) d 1.27-1.60 (m, 4 H), 1.75 (m, 2 H), 2.47 (m, 1 H), 2.80 (m, 1 H), 2.88 (, 2 H), 3.0 (m, 2 H) , 3.80 (m, 4H), 4.0 (m, 1H), 5.10 (m, 1H), 5.30 (d, J = 10.5 Hz, 1H), 5.70 (d, J = 6 Hz, 1H), 7.057.25 ( m, 10H). Mass spectrum: (M + H) + = 441.

F. (2S.3S.5S) -2-r (3R. 3aS.6aR) -Bis-tetrahydrofuranyloxy-amino-3-hydroxy-5-r2S- (3-methyl-1-imidazolidin-2-onyl) - 3-Methyl-butanoin amino-1.β-difnyl hexane The coupling of the carboxylic acid of Example 4B with the amino compound of Example 4E, using the normal procedure (EDAC in DMF) provided the desired compound. 300 MHz 1 H NMR (CDCl 3) d 0.82 (d, J = 3 H, 3 H), 0.85 (d, J = Hz, 3 H), 1.65 (m, 1 H), 2.77 (s, 3 H), 2.85 (m, 3 H) , 3.17 (m, 2H) 3.47 (m, 1H), 3.60 (m, 2H), 3.75 (m, 1H), 3.87 (m, 1H), 4.0 (m, 1H), 4.20 (m, 1H), 5.05 (m, 2H), 5.68 (d, J = 6 Hz, 1H), 6.45 (br d, J = 7.5 Hz, 1H), 7.20 (m, 10H). Mass spectrum: (M + H) + = 623.

EXAMPLE 5 (2S, 3S.5S) -2-r (3R. 3aS, 6aR) -Bis-tetrahydrofuranyloxy-1-amino-3-hydroxy-5-f2S- (1-imidazolidin-2-oneyl) -3-methyl- butanoill amino-1,6 diphenylhexane The coupling of the amino compound of Example 4E with the carboxylic acid of Example 1M, using the normal procedure (EDAC / DMF), provided the desired compound. 300 MHz 1 H NMR (CDCl 3) d 0.85 (d, J = 7 Hz, 3 H), 0.88 (d, J = Hz, 3 H), 1.70 (m, 2 H, 2.18 (m, 1 H), 2.80 (m, 3 H) , 2.95 (m, 1H), 3.20 (m, 4H), 3.60 (m, 3H), 3.75 (m, 2H), 4.0 (m, 1 H), 4.20 (m, 1H), 4.45 (s, 1H) , 5.10 (m, 2H), 5.67 (d, J = 6 Hz, 1H) 6.60 (d, J = 7.5 Hz, 1H), 7.20 (m, 10H) Mass spectrum: (M + H) + = 609 .

EXAMPLE 6 (2S.3S.5S) -2- (N - ((5-thiazolyl) methoxycarbonyl) amino) -5 - ((2S- (1-imidazolidin-2-onyl) -3-methyl-butanoyl) -amino) -3-hydroxy-1.6-diphenylhexane A.2-Chloro-2-formyl ethyl acetate To a 2-liter, round bottom, three-necked flask, loaded with potassium t-butoxide (0.5 mole, 500 ml of a 1M THF solution) and 500 ml of dry THF, cooled to 0 ° C, was added dropwise, from an addition funnel, a solution of ethyl chloroacetate (0.5 mole, 53.5 ml) and ethyl formate (0.5 mole, 40.4 ml), in 200 ml of THF for 3 hours. After the addition was complete, the reaction mixture was stirred for 1 hour and allowed to stand overnight. The resulting solid was diluted with diethyl ether and cooled in an ice bath. Then, the pH was reduced to about 3, using 6N HCl. The organic phase was separated and the aqueous layer was washed 3 times with diethyl ether. The combined ether portions were dried over NaSO, and concentrated in vacuo. The desired crude compound was stored at -30 ° C without further purification.

B. Ethyl thiazole-5-carboxylate To a round bottom flask was added 250 ml of dry acetone, 7.5 g (0.123 mole) of thioformamide and 18.54 g (0.123 mole) of ethyl 2-chloro-2-formylacetate. The reaction was heated to reflux for 2 hours. The solvent was removed in vacuo, and the residue was purified by chromatography (SiO2, column 6 cm, 100% CHCl3, Rf = 0.25) to provide 11.6 g (60%) of the desired compound as a light yellow oil. NMR (CDCl 3) d 1.39 (t, J = 7 Hz, 3H), 4.38 (q, J = 7 Hz, 2H), 8.50 (s, 1H), 8.95 (s, 1H).

C.5- (Hydroxymethyl) thiazole To a cooled 500 ml three-necked flask (ice bath) containing lithium aluminum hydride (2.89 g, 76 mmol) in 250 ml of THF was added thiazole-5 ethyl carboxylate (11.82 g, 75.68 mmole) in 100 ml of THF, dropwise, for 1.5 hours to avoid excessive foam formation. The reaction was stirred for an additional hour, and treated cautiously with 2.9 ml of water, 2.9 ml of 15% NaOH and 8.7 ml of water. The solid salts were filtered and the filtrate was discarded. The crude salts were heated to reflux in 100 ml of ethyl acetate for 30 minutes. The resulting mixture was filtered, and the two filtrates were combined, dried over Na2SO4 and concentrated in vacuo. The product was purified through silica gel column chromatography eluting sequentially with 0% -2% -4% methanol in chloroform, to provide the desired compound. Rf-0.3 (4% methanol in chloroform), which solidified after standing in a 75% yield. NMR (CDCl 3) d 4.92 (s, 2H), 7.78 (s, 1H), 8.77 (s, 1H). Mass spectrum: (M + H) + = 116.

P. ((5-thiazolyl) methyl) - (4-nitrophenyl) carbonate A solution of 3.11 g (27 mmol) of 5- (hydroxymethyl) thiazole and an excess of N-methyl morpholine in 100 ml of methylene chloride are added. cooled to 0 ° C and treated with 8.2 g (41 mmol) of 4-nitrophenyl chloroformate. After stirring for 1 hour, the reaction mixture was diluted with CHCl 3, washed successively with 1N HCl, saturated aqueous NaHCO 3, and saturated brine, dried over NaSO, and concentrated in vacuo. The residue was purified through silica gel chromatography (SiO2, 1-2% MeOH / CHCl3, Rf = 0.5 in 4% MeOH / CHCl3) to yield 5.9 g (78%) of the desired compound as a yellow solid. . NMR (CDCl 3) d 5.53 (s, 2H), 7.39 (dt, J = 9, 3 Hz, 2H), 8.01 (s, 1H), 8.29 (dt, J = 9, 3 Hz, 2H), 8.90 (s) , 1 HOUR). Mass spectrum: (M + H) + = 281.

E. (2S.3S.5S) -5-amino-2- (N-((5-thiazolyl) -methoxycarbonyl) amino-3-hydroxy-1,6-diphenylhexane The coupling of the amino compound of Example 1F with the carbonate of Example 6D, using the procedure of Example 4D, followed by removal of the Boc-protecting group, using TFA / CH2Cl2, provided the desired compound. 300 MHz 1 H NMR (CDCb) d 1.3-1.6 (m, 2H), 2.40 (dd, J = 14, 8 Hz, 1H), 2.78 (dd, J = 5 Hz, 1H), 2.88 (d, J = 7 Hz, 2H), 3.01 (m, 1H), 3.72 (br q, 1H), 3.81 (br d, J = 10 Hz, 1H), 5.28 (s, 2H), 5.34 (br d, J = 9 Hz, 1H), 7.07 (br d, J = 7 Hz, 2H), 7.15-7.35 (m, 8H), 7.87 (s, 1H), 8.80 (s, 1H). Mass spectrum: (M + H) + = 426.

F. (2S.3S.5S) -2- (N - ((5-thiazolyl) methoxycarbonyl) amino) -5 - ((2S- (1-imidazolidin-2-onyl) -3-methyl-butanoyl) -amino ) -3-hydroxy-1,6-diphenylhexane The coupling of the amino compound of Example 6E with the carboxylic acid of Example 1M, using a normal procedure (EDAC in DMF), provided the desired compound (52%). 300 MHz 1 H NMR (CDCb) d 0.82 (d, J = 7.5 Hz, 3 H), 0.85 (d, J = 7.5 Hz, 3 H), 1.65 (m, 2 H), 2 15 (m, 1 H), 270 (m , 3H), 2.85 (d, 7 5 Hz, 2H), 3.08 (m, 1H), 3 18 (m, 1H), 3.30 (M, 2H), 360 (m, 3H), 3 80 (m, 1H) ), 4 16 (m, 1H), 440 (s, 1H), 5.16 (d, J = 9 Hz, 1H), 524 (s, 2H), 660 (d, J = 9 Hz, 1H), 7 20 (m, 10H), 7.83 (s, 1H), 8.80 (s, 1H) Mass spectrum (M + H) + = 594 EXAMPLE 7 (2S, 3S.5S) -2- (N - ((5-thiazolyl) methoxycarbonyl) amino) -3-hydroxy-5- (2S- (1-imidazolidin-2-onyl) -3,3-dimethyl butanoyl) amino) - 1.6- diphenylhexane A. 2S- (1-imidazolidin-2-ynyl) -3,3-d-methyl butanoic acid Using the procedures described in Example 1J to 1M, but replacing L-valine methyl ester with Lt-butyl methyl ester leucine, the desired compound was provided 300 MHz * H NMR (DMSO-d6) d 1.0 (s, 9H), 3.22 (t, J = 7.5 Hz, 2H), 3.55 (q, J = 7.5 Hz, 1H), 3.65 (q, J = 7.5 Hz, 1H), 4.14 (s, 1H), 6.40 (s, 1H), 12.62 (brs, 1H) Mass spectrum: (M + H) + = 201.

B.sub.2S, 3S.5S) -2- (N - ((5-thiazolemethoxycarbonylamino) -3-hydroxy-5- (2S- (1-imidazolidin-2-onyl) -3,3-dimethylbutanoyl) amino) - 1.6- diphenylhexane Coupling the amino compound of Example 6E with the carboxylic acid of Example 7A, using a normal procedure (EDAC in DMF), provided the desired compound (77%) 300 MHz 1H NMR (CDCb) d 1.0 (s, 9H), 1.68 (m, 2H), 2.60-2.80 (m, 3H), 2.85 (d, J = 7.5 Hz, 1H), 3.10 (m, 1H), 3.30 (m, 1H), 3.50 (m, 1H) ), 4.56 (s, 1H), 5 15 (d, J = 7 5 Hz, 1H), 5.25 (ABq, 1H), 6.50 (d, J = 7 Hz, 1H), 7.20 (m, 10H), 7.83 (s, 1H), 8.80 (s, 1H). Mass spectrum: (M + H) + = 609 EXAMPLE 8 (2S.3S.5S) -2- (2,6-dimethylphenoxyacetyl) amino) -3-hydroxy-5- (2S- (1-imidazolidin-2-oneyl) -3,3-dimethylbutanoyl) amino) -1 , 6-diphenylhexane The coupling of the amino compound of Example 1N with the carboxylic acid of Example 7A, using a normal procedure (EDAC in DMF), provided the desired compound (80%). 300 MHz 1H NMR (CDCb) d 1.0 (s, 9H), 2.18 (s, 6H), 2.68 (m, 1H), 2.80 (m, 1H), 2.98 (m, 3H), 3.10 (m, 1H), 3.27 (q, J = 7 Hz, 1H), 3.53 (m, 1H), 3.77 (m, 1H), 4.0 (S, 1H), 4.20 (m, 4H), 6.72 (m, 1H), 7.0 (m , 3H), 7.10-7.25 (m, 10H). Mass spectrum: (M + H) + = 629.

EXAMPLE 9 (2S.3S.5S) -2- (2,6-dimethylphenoxyacetyl) amino) -3-hydroxy-5- (2S-M-imidazolidin-2-thienyl) -3-methyl butanoyl) amino) -1,6- diphenylhexane A. 2S- (1-lmidazolidin-2-thienyl) -3-methyl butanoic acid Using the same procedures described in Example 1J to 1M, but replacing 1, 1-carbon? Ld? M? Diazole with 1,1- thiocarbonyldnidazole, the desired compound was provided. 300 MHz 1 H NMR (DMSO-de) d 0 87 (d, J = 6 Hz, 3 H), 096 (d, J = 6 Hz, 3 H), 2 11 (m, 1 H), 345 (m, 2 H), 362 (m, 1H), 3 80 (q, J = 9 Hz, 1H), 480 (d, J = 10 Hz, 1H), 830 (s, 1H), 12 75 (br s, 1H) B. (2S.3S, 5S) -2- (2,6-dimethylphenyl oxalate) -3-hydroxy-5- (2S- (1-imidazolidin-2-phenyl) -3-methylbutanoyl) amino) -1 , 6-diphenylhexane The coupling of the amino compound of Example 1N with the carboxylic acid of Example 9A, using a normal procedure (EDAC in DMF), provided the desired compound (53%) 300 MHz 1 H NMR (CDCb) d 082 (d, J = 6 Hz, 3H), 0.93 (d, J = 6 Hz, 3H), 1 75 (m, 1H), 2 20 (s, 6H), 265 (m, 1H), 2.84 (m, 1H), 30 (m, 3H), 325 (m, 1H), 340 (m, 2H), 3 §4 (d, J = Hz, 1H), 3.78 (m, 1H), 422 (m, 4H), 456 ( d, J = 10.5 Hz, 1H), 5.65 (s, 1H), 6.60 (d, J = Hz, 1H), 7.0 (m, 3H), 725 (m, 10H). Mass spectrum: (M + H) + = 631.

EXAMPLE 10 (2S.3S.5S) -2- (4-am i non-2,6-dimethyl-enoxyacetyl) amino) -3-hydroxy-5- (2S-H-imidazolidin-2-onyl) -3- methyl-butanoyl) amino) -1.6- diphenylhexane A. Ethyl ester of 2,6-dimethyl-4-nitro-phenoxyacetic acid To a solution of 10.5 g (54.6 mmol) of ethyl 2,6-dimethylphenoxy acetate and 7.5 g (109 mmol) of sodium nitrite in 100 ml of sodium chloride. methylene was slowly added 50 ml of trifluoroacetic acid. The reaction mixture became solid after the addition. An additional 35 ml of trifluoroacetic acid was added. Then, the reaction mixture was stirred at room temperature for 3 hours, carefully divided between a saturated solution of sodium bicarbonate and methylene chloride. The combined organic extracts were washed with brine and dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. The residue was recrystallized from 30% ethyl acetate and hexanes to give 4.75 g (36%) of ethyl 2,6-dimethyl-4-nitro-phenoxyacetate as light yellow prisms. 300 MHz 1 H NMR (CDCb) d 1.34 (3 H, t, J = 7.5 Hz), 2.39 (6 H, s), 4.31 (2 H, q, J = 7.5 Hz), 7.93 (2 H, s).

B. 2,6-Dimethyl-4-nitro-phenoxyacetic acid To a solution of 0.962 g (4.06 mmol) of ethyl 2,6-dimethyl-4-nitro phenoxyacetate in 10 ml of methanol, 1 ml of 3N hydroxide was added. of sodium. Then, the reaction mixture was stirred at room temperature for 30 minutes, acidified with 3 N of HCl and partitioned between water and methylene chloride. The combined organic extracts were washed with brine and dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure to give 0.82 g (97%) of 2,6-dimethyl-4-nitro-phenoxyacetic acid as a solid. light yellow. 300 MHz 1 H NMR (d 3 -DMSO) d 2.35 (6H, s), 4.55 (2H, s) 7.97 (2H, s), 13.02 (1 H, bs).

C. (2S.3S.5S) -2- (t-Butyloxycarbonyl) amino) -3-hydroxy-5- (2S- (1-imidazolidin-2-ynyl) -3-methyl ethyl-butanoyl) amino) -1 , 6-diphenylhexane The coupling of (2S, 3S, 5S) -2- (t-butyloxycarbonyl) amino-3-hydroxy-5-amino-1,6-diphenylhexane with the carboxylic acid of Example 1M, using a normal procedure ( EDAC in DMF), provided the desired compound (100%). 300 MHz 1 H NMR (CDCb) d 0.83 (d, J = 6 Hz, 3 H), 0.87 (d, J = 6 Hz, 3 H), 1.40 (s, 9 H), 1.70 (m, 2 H), 2.16 (m, 1H), 2.58-2.80 (m, 4H), 3.10-3.30 (m, 4H), 3.65 (m, 2H), 4.20 (m, 1H), 4.38 (s, 1H), 4.83 (d, J = Hz, 1H), 6.53 (d, J = 9 Hz, 1H), 7.20 (m, 10H). Mass spectrum: (M + H) + = 553.

D. (2S.3S.5S) -2-Amino-3-hydroxy-5- (2S- (1-imidazole idin-2-oneyl) -3-methyl-butanoyl) amino-1,6-diphenylhexane Deprotection of the Boc group -protector of the compound of Example 10C through a normal procedure (TFA / C ^ C), provided the desired compound. 300 MHz 1H NMR (CDCb) d 0.87 (d, J = 6 Hz, 3H), 0.90 (d, J = 6 Hz, 3H), 1.33 (dd, J = 4.5, 9.0 Hz, 1H) 2.18 (m, 1H ), 2.50 (m, 1H), 2.80 (m, 5H), 3.20 (m, 4H) 3.72 (d, J = 10 Hz, 1H), 4.30 (m, 1H), 4.50 (s, 1H), 6.67 ( d, J = 7 Hz, 1H), 7.20 (m, 10H). Mass spectrum: (M + H) + = 453.

E. (2S.3S.5S) -2- (4-Nitro-2,6-dimethyl-enoxyacetyl) amino) -3-hydroxy-5- (2S- (1-imidazolidin-2-onyl) -3-methyl-butanoyl amino) -1.6- diphenylhexane The coupling of the amino compound of Example 10D with the carboxylic acid of Example 10B, using a normal procedure (EDAC in DMF), provided the desired compound. 300 MHz 1 H NMR (CDCb) d 0.83 (d, 7 = Hz, 3 H), 0.86 (d, J = 7 Hz, 3 H), 1.70 (m, 3 H), 2 18 (m, 2 H), 2.28 (s, 6H) 2.75 (m, 3H), 2.95-3.30 (m, 6H), 3.67 (d, J = 10.5 Hz, 1H), 3.75 (m, 1H), 3.82 (d, J = 4 Hz, 1H), 4.25 (m, 5H), 6 55 (d, J = 7 Hz, 1H), 7.20 (m, 10H), 7.92 (s, 2H). Mass spectrum: (M + H) + = 660.

F. (2S.3S.5S) -2- (4-am i non-2,6-dimethyl-enoxyacetyl) amino) -3-hydroxy-5- (2S- (1-imidazolidin-2-onyl) -3-methyl -butanoyl) amino) -1.β-diphenylhexane To a suspension of 7 mg of 10% Pd / C in 5 ml of methanol was added a solution of 69 mg of the compound of Example 10E. The reaction mixture was stirred vigorously under an atmosphere of hydrogen (a balloon filled with hydrogen attached to a 3-outlet tap). After 1 hour, the reaction was completed through TLC analysis; the catalyst was filtered and the filtrate was concentrated in vacuo. The crude product was purified through silica gel column chromatography (2% to 5% MeOH / CH 2 Cl 2) to provide the desired compound (65%). 300 MHz 1 H NMR (CDCb) d 0.82 (d, J = Hz, 3 H), 0.87 (d, J = 6 Hz, 3 H), 1.70 (m, 2 H), 2.10 (s, 6 H), 2.15 (m, 2 H) ), 2 72 (m, 2H), 2.97 (d, J = 7.5 Hz, 2H), 3.08 (m, 1H), 3.15 (m, 1H), 3 30 (m, 2H), 345 (br s, 2H) ), 3.66 (d, J = 10 Hz, 1H), 3.72 (m, 1H), 390 (d, J = 3 Hz, 1H), 4.10-4.20 (m, 4H), 4.30 (s, 1H), 6.33 (s, 2H), 6 57 (d, J = 9 Hz, 1H), 720 (m, 10H) Mass spectrum: (M + H) + = 630 EXAMPLE 11 (2S.3S, 5S) -2- (2.4.6-Tri-methyl-enoxy-acetyl) -amino) -3-hydroxy-5- (2S- (1-imidazolidin-2-oneyl) -3-methylbutanoyl) amino) -1.β-diphenylhexane A. 2,4,6-Trimethylphenoxyacetic Acid Using the procedures of Example 1G and 1H, but replacing 2,6-dimethylphenol with 2,4,6-trimethylphenol, the desired compound was provided. 300 MHz 1H NMR (CDCb) d 2.25 (s, 9H), 443 (s, 2H), 6.84 (s, 2H). Mass spectrum: (M + H) + = 195.

B. (2S.3S.5S -2- (2.4.6-Trimet-il-en-oxyacetyl) -amino) -3-hydroxy-5- (2S- (1-imidazole id i n-2-onyl) -3-methylbutanoyl) amino ) -1,6-diphenylhexane The coupling of the amino compound of Example 10D with the carboxylic acid of Example 11 A, using a normal procedure (EDAC in DMF), provided the desired compound (51%). 300 MHz 1 H NMR (CDCb) d 0.82 (d, J = 6 Hz, 3 H), 0.85 (d, J = 6 Hz, 3 H), 1.70 (m, 4 H), 2.13 (s, 6 H), 2.25 (s, 3H), 2.75 (m, 2H), 2.97 (d, J = 7 Hz, 1H), 3.13 (m, 2H), 3.28 (m, 2H), 3.68 (d, J = 10 Hz, 1H), 3.72 ( m, H), 4.16 (m, 4H), 4.40 (br s, 1H), 6.67 (d, J = 8 Hz, 1H), 6.80 (s, H), 7.20 (m, 10H). Mass spectrum: (M + H) + = 629.

EXAMPLE 12 (2S.3S, 5S) -2- (4-Fluoro-2,6-dimethylf-enoxyacetyl) amino) -3-hydroxy-5- (2S- (1-imidazole idin-2-onyl) -3-methyl- butan oil) amino) -1.6- diphenylhexane A. 4-Fluoro-2,6-dimethylphenoxyacetic acid Using the procedure of Example 1G and 1H, but replacing 2,6-dimethylphenol with 4-fluoro-2,6-dimethylphenol, the desired compound was provided. 300 MHz H NMR (CD3OD) d 2.26 (s, 6H), 4.37 (s, 2H), 6.73 (d, J = 9 Hz, 2H). Mass spectrum: M + = 198.

B. (2S.3 S.5S) -2- (4-Fluoro-2,6-dimethyl-enoxyacetyl) amino) -3-hydroxy-5- (2S- (1-imidazolidin-2-onyl) -3-methyl -butanoyl) amino) -1,6-diphenylhexane The coupling of the amino compound of Example 10D with the carboxylic acid of Example 12A provided the desired compound. 300 MHz 1H NMR (CDCb) d 0.83 (d, J = 6 Hz, 3H), 0.86 (d, J = 6 Hz, 3H), 1.72 (m, 2H), 2.15 (s, 6H), 2.20 (m, 1H), 2.76 (m, 2H), 2.98 (d, J = 7 Hz, 2H), 3.12 (m, 2H), 3.30 (m, 2H), 3.67 (d, J = 10Hz, 1H), 3.72 (m , 1H), 4.13 (AB q, J = 8, 9Hz, 2H), 4.20 (m, 2H), 4.37 (s, 1H), 6.64 (d, J = 9 Hz, 1H), 6.70 (d, J = Hz, 2H), 7.20 (m, 10H). Mass spectrum: (M + H) + = 633.

EXAMPLE 13 (2S, 3S, 5S) -2- (4,6-dimethyl-pyrimidin-5-oxy-acetyl) amino) -3-hydroxy-5- (2S- (1-imidazolidin-2-onyl) -3- methyl-butanoyl) amino) -1.β-diphenylhexane A. 4.6-Dimethyl-pyrimidin-5-oxy acetic acid Using the procedures of Example 1G and 1H, but replacing 2,6-dimethylphenol with 5-hydroxy-4,6-dimethylpyrimidine (prepared according to Chem. Ber. 93 p. 1998, 1960) the desired compound was provided. 300 MHz 1 H NMR (DMSO-d 6) d 2.45 (s, 6H), 4.55 (s, 2H), 8.50 (s, 1H). Mass spectrum: (M + H) + = 183.

B. (2S.3S.5S) -2- (4.6-Dimethyl-pyrimidin-5-oxy-acetyl) amino) -3-hydroxy-5- (2S- (1-imidazolidin-2-onyl) -3-methyl -butanoyl) amino) -1,6-diphenylhexane The coupling of the amino compound of Example 10D with the carboxylic acid of Example 13A provided the desired compound. 300 MHz 1 H NMR (CDCb) d 0.82 (d, J = 6 Hz, 3 H), 0.85 (d, J = 6 Hz, 3 H), 1.70 (m, 2 H), 2.15 (m, 1 H), 2.40 (s, 6H), 2.75 (m, 2H), 2.97 (d, J = 7 Hz, 2H), 3.12 (m, 2H), 3.30 (m, 2H), 3.66 (d, J = 10 Hz, 1H), 3.74 ( m, 1H), 3.88 (d, J = Hz, 1H), 4.20 (m, 4H, 6.62 (d, J = 9 Hz, 1H), 7.0 (d.J = 9 Hz, 1H), 7.20 (m, 10H), 8.70 (s, 1H). Mass spectrum: (M + H) + = 617.

EXAMPLE 14 (2S.3S.5S) -2- (2,4-dimethyl-pyridin-3-oxy-acetyl) amino) -3-hydroxy-5- (2S-M-imidazolidin-2-onyl) -3,3-dimethyl butanoyl ) amino) -1.6- diphenylhexane A. 2,4-Dimethyl-pyridin-3-oxy-acetic acid Using the procedures of Example 1G and 1H, but replacing 2,6-dimethylphenol with 2,4-dimethyl-3-hydroxypyridine (prepared according to J. Med. Chem. 35, pp. 3667-3671, 1992) the desired compound was provided. 300 MHz 1 H NMR (DMSO-d 6) d 2.26 (s, 3 H), 2.42 (s, 3 H), 4.44 (s, 2 H), 7.08 (d, J = 5 Hz, 1 H), 8.07 (d, J = 5 Hz, 1H). Mass spectrum: (M + H) + = 182.

B. (2S.3S.5S) -2- (2,4-dimethyl-pyridin-3-ox? -acetyl) amino) -3-hydroxy-5- (t-butyloxycarbonyl) amino) -1,6-diphenylhexane The coupling of the amino compound of Example 1F with the carboxylic acid of Example 14A, using a normal procedure (EDAC in DMF), provided the desired compound. 300 MHz 1H NMR (CDCb) d 1.40 (s, 9H), 1.70 (m, 2H), 2.18 (s, 3H), 2.40 (s, 3H), 2.77 (m, 2H), 2.98 (d, J = 7 Hz, 2H), 3.75-3.95 (m, 3H), 4.20 (s, 2H), 422 (m, 1H), 4.60 (br d, 1H), 7.0 (d, J = 5H, 1H), 7.10 (m , 3H), 7.25 (m, 7H), 816 (d, J = 5 Hz, 1H). Mass spectrum: (M + H) + = 548.

C. (2S, 3S.5S) -2- (2,4-dimethyl-pyridin-3-oxy-acetyl) amino) -3-hydroxy-5-mino-1,6-diphenylhexane Deprotection of the Boc group in the compound of Example 14B using a normal procedure (TFA / CH2Cl2) provided the desired compound. 300 MHz 1 H NMR (CDCb) d 1.45 (m, 1 H), 1.62 (m, 1 H), 223 (s, 3 H), 2.45 (s, 3 H), 2.50 (m, 1 H), 2.80 (m, 1 H), 3.0 (m, 2H), 3 12 (m, 1H), 3.90 (m, 1H), 4.18 (m, 1H), 4.25 (AB q, J = 9, 12Hz, 2H), 6.98 (d, J = 5Hz , 1H), 7.10 (m, 2H), 7.30 (m, 8H), 8.17 (d, J = 5 Hz, 1H). Mass spectrum: (M + H) + = 448.

D. (2S.3S.5S) -2- (2,4-dimethyl-pyridin-3-oxy-acetyl) amino) -3-hydroxy-5- (2S- (1-imidazolidin-2-onyl) -3,3 dimethyl butanoyl) amino) -1,6-diphenylhexane The coupling of the amino compound of Example 14C with the carboxylic acid of Example 7A, using a normal procedure (EDAC in DMF) provided the desired compound. 300 MHz 1H NMR (CDCb) d 1.0 (s, 9H), 1.70 (m, 3H), 2.18 (s, 3H), 2.42 (s, 3H), 2.75 (m, 2H), 30 (m, 4H), 3.30 (m, 1H), 3.55 (m, 1H), 3.80 (m, 1H), 4.05 (s, 1H), 4.20 (m, 4H), 4.60 (s, 1H), 6.70 (d, J = 7 Hz , 1H), 6.97 (d, J = 5Hz, 1H), 7.15 (m, 3H), 7.25 (m, 7H), 8.17 (d, J = Hz, 1H), Mass spectrum: (M + H) + = 630 EXAMPLE 15 (2S.3S, 5S) -2- (2,4-dimethyl-pyridin-3-oxy-acetyl) amino) -3-hydroxy-5- (2S- (1-imidazolidin-2-onyl) -3-methyl butanoyl) amino) -1.6- diphenylhexane The coupling of the amino compound of Example 14C with the carboxylic acid of Example 1M, using a normal procedure (EDAC in DMF), provided the desired compound. 300 MHz 1 H NMR (CDCb) d 0.82 (d, J = 6 Hz, 3 H), 0.86 (d, J = 6 Hz, 3 H), 1.75 (m, 3 H), 2.15 (m, 1 H), 2.18 (s, 3H), 2.40 (s, 3H), 2.75 (m, 2H), 2.97 (d, J = 7.5 Hz, 2H), 3.20 (m, 4H), 3.70 (d, J = 10 Hz, 1H), 3.75 ( m, 1H), 4.20 (m, 6H), 4.52 (s, 1H), 3.75 (m, 1H), 4.20 (m, 6H), 4.52 (s, 1H), 6.80 (d, J = 7 Hz, 1H ), 6.96 (d, J = 4.5 Hz, 1H), 7.20 (m, 10H), 8.17 (d, J = 4.5 Hz, 1H). Mass spectrum: (M + H) + = 616.

EXAMPLE 16 (2S.3S.5S) -2- (2,6-Dimethylthiophenopiacetyl) amino) -3-hydroxy-5- (2S- (1-imidazolidin-2-oneyl) -3-methyl-butanoyl) amino) -1, 6 -dif enyl hexane A. 2,6-dimethylthiophenoxy acetic acid Using the procedures of Example 1G and 1H, but replacing 2,6-dimethylphenol with 2,6-dimethylthiophenol provided the desired compound. 300 MHz 1H NMR (CDCb) d 2.56 (s, 6H), 3.40 (s, 2H), 7.10 (m, 3H). Mass spectrum: (M + H) + = 197.

B. (2S.3S, 5S) -2- (2,6-Dimethylthiofenoxyacetyl) amino) -3-hydroxy-5- (2S- (1-imidazolidin-2-oneyl) -3-methyl-butanoyl) a min) - 1,6-diphenyl hexane The coupling of the carboxylic acid of Example 16A with the amino compound of Example 10D provided the desired compound. 300 MHz 1 H NMR (CDCb) d 0.82 (d, J = 6 Hz, 3 H), 0.86 (d, J = 6 Hz, 3 H), 2.15 (m, 1 H), 2.52 (s, 6 H), 2.70 (m, 4H), 3.10 (m, 2H), 3.30 (m, 4H), 3.60 (m, 2H), 4.0 (m, 1H), 4.10 (m, 1H), 4.22 (s, 1H), 6.39 (d, J = 7 Hz, 1H), 6.58 (d, J = 9 Hz, 1H), 7.20 (m, 13H). Mass spectrum: (M + H) + = 631.

EXAMPLE 17 (2S.3S, 5S) -2- (2,6-Di-methyl-enoxyacetyl) -amino) -3-hydroxy-5- (2S- (1-irolidolid-2-oneyl) -3-methyl-butanoyl) amino) -1, 6-d phen i I hexane A. 4-Bromobutanoyl-L-valine methyl ester To a solution of 1.08 g (8.4 mmol) of L-valine methyl ester in 30 ml of CH2Cl2 was added 1.36 ml (16.8 mmol) of pyridine, cooled to 0 ° C and 1.55 g (8.4 mmol) of 4-bromobutanyl chloride was added. The solution was stirred at 0 ° C for 40 minutes and at room temperature for 1 hour. The solution was washed with saturated NaHCO3, brine and dried with anhydrous Na2SO; it was filtered and concentrated in vacuo. The crude product was purified through silica gel column chromatography (5% EtOAc / CH2Cl2) to provide 1.82 g (77%) of the desired product. 300 MHz 1H NMR (CDCb) d 0.92 (d, J = 6 Hz, 3H), 0.96 (d, J = 6 Hz, 3H) 2.20 (m, 3H), 2.46 (m, 2H), 3.50 (m, 2H) ), 3.76 (s, 3H), 4.58 (dd, J = 4.7 Hz, 1H), 5.97 (br d, J = 7 Hz, 1H). Mass spectrum: (M + H) + = 297.

B. 2S- (1-pyrrolidin-2-ynyl) -3-methyl-butanoic acid To a solution of 1.49 g (5.3 mmol) of the compound of Example 17A in a mixture of DMF / CH2Cl2, cooled to 0 ° C, they added 0.234 g (1.1 equivalents) of 60% sodium hydride in mineral oil. The mixture was slowly warmed to room temperature and stirred overnight. The mixture was poured into saturated ammonium chloride and extracted with ethyl acetate, dried or concentrated in vacuo. The crude product was hydrolyzed using lithium hydroxide as in Example 1H to provide the desired compound. 300 MHz 1 H NMR (CDCb) d 0.96 (d, J = 7 Hz, 3 H), 1.06 (d, J = 7 Hz, 3 H), 2.10 (m, 2 H), 2.40 (m, 1 H), 2.50 (t, J = 7 Hz, 2H), 3.56 (m, 2H), 4.14 (d, J = 10 Hz, 1H). Mass spectrum: (M + H) + = 186.

C. (2S.3S.5S) -2- (2,6-Dimethyl-phenoxyacetyl) amino) -3-hydroxy-5- (2S- (1-irolidolid-2-oneyl) -3-methyl-butanoyl) ami no) -1 .β-dif enyl hexane The coupling of the carboxylic acid of Example 17B with the amine of Example 1N, using a normal procedure (EDAC in DMF), provided the desired compound. 300 MHz 1H NMR (CDCb) d 0. 77 (d, J = 7 Hz, 3H), 0.83 (d, J = 7 Hz, 3H), 1.75 (m, 3H), 2.10 (m, 1H), 2.20 (s, 6H), 2.25 (m, 1H) ), 2.65 (m, 1H), 2.85 (m, 1H), 3.0 (d, J = 7 Hz, 2H), 3.20 (m, 1H), 3 77 (m, 2H), 3.88 (d, J = 10 Hz, 1H), 4.20 (m, 3H), 6.30 (d, J = 7 Hz, 1H), 698 (m, 3H), 7.20 (m, 10H). Mass spectrum (M + H) + = 614 EXAMPLE 18 (2S.3S.5S) -2- (2,6-Dimethyl-phenoxyacetyl) amino) -3-hydroxy-5- (2S-M-pyrrolidin-2,5-dionyl) -3-methyl-butanoyl) amino) -1.6 -diphenylhexane A. 2S- (1-pyrrolidin-2,5-dionyl) -3-methyl-butanoic acid benzyl ester To a solution of 700 mg (3.38 mmol) of L-valine benzyl ester in 6 ml of chloroform was added 1 equivalent of succinic anhydride. After 1 hour at room temperature, the solvent was removed in vacuo and the residue was dissolved in 20 ml of DMF. To this solution 0.52 g of N-hydroxy-benzotriazole was added. 0.68 g of EDAC and 0.52 ml of triethylamine. After 24 hours at room temperature, 20 mg of 4-dimethylaminopyridine was added. The solution was left at room temperature for 3 days. After normal processing, the crude product was purified through silica gel column chromatography to provide 0.25 g of the desired product (26%). 300 MHz 1 H NMR (CDCb) d 0.84 (d, J = 7 Hz, 3 H), 1.12 (d, J = 7 Hz, 3 H), 2.70 (m, 1 H), 2.71 (s, 4 H), 4.45 (d, J = 9 Hz, 1H), 5.15 (s, 2H), 7.30 (m, 5H).

B. 2S- (1-pyrrolidin-2,5-dionyl) -3-methyl-butanoic acid A mixture of 0.245 of the product of Example 18A, 30 mg of 10% palladium on carbon in 50 ml of methanol was stirred vigorously under one atmosphere of hydrogen (a balloon filled with hydrogen) for 1 hour. The catalyst was filtered and the solvent was removed under vacuum to provide 168 mg of the desired compound. 300 MHz 1H NMR (CDCb) d 0.84 (d, J = 6 Hz, 3H), 1.13 (d, J = 6 Hz, 3H), 2.65 (m, 1H), 2.80 (s, 4H), 4.45 (d, J = 8 Hz, 1H). Mass spectrum: (M + H) + = 200.

C. (2S.3S.5 S) -2- (2,6-Dimethyl-enoxyacetyl) amino) -3-hydroxy-5- (2S-f 1 -pyrrolidin-2,5-dionyl) -3-methyl-butanoyl) amino) - 1, 6-d ifenilhexa no The coupling of the carboxylic acid of Example 18B with the amine of Example 1N, using a normal procedure (EDAC in DMF) provided the desired product (75%). 300 MHz 1H NMR (CDCb) d 0.70 (d, J = 4 Hz, 3H), 0-72 (d, J = 4 Hz, 3H), 1.70 (m, 1H), 2.20 (s, 6H), 2.45 ( m, 2H), 2.60 (s, 4H), 2.80 (m, 2H), 3.0 (m, 2H), 3.76 (m, 1H), 4.20 (m, 6H), 7.0 (m, 3H), 7.20 (m , 10H). Mass spectrum: (M + H) + = 628.

EXAMPLE 19 (2S.3S.5S) -2- (Tra ns-3-f 2,6-dimethylphenyl) propenoyl) amino-3-hydroxy-5- (2S- (1-tetrahydropyrimidin-2-onyl) -3-methyl -butanoyl) amino-1,6-diphenylhexane A. 2.6-Dimethyl benzaldehyde The oxidation of 2,6-dimethylbenzyl alcohol through the normal Swern oxidation procedure (oxalyl chloride / DMSO) provided the desired compound. 300 1H NMR (CDCb) d 2. 62 (s, 6H), 7.10 (m, 2H), 7.33 (t, J = 7 Hz, 1H), 10.63 (s, 1H), Mass spectrum: (M + H) + = 135.

B. Trans-3- (2,6-dimethylphenyl) -propenoic acid methyl ester To a solution of trimethyl phosphonoacetate (149 mg, 0.82 mmol) in 15 ml of THF was added 36 mg of sodium hydride (60%). in oil). After 15 minutes, 100 mg of the compound of Example 19A in 2 ml of THF was added. After 2 hours, the reaction was carefully quenched with water and extracted with ethyl acetate (70 ml), dried and concentrated. Purification of the crude product through silica gel column chromatography (hexane / EtOAc 95: 5) provided the desired compound (75%). 300 MHz 1H NMR (CDCb) d 2.35 (s, 6H), 3.82 (s, 3H), 6.07 (d, J = 16 Hz, 1H). 7.10 (m, 3H), 7.85 (d, J = 16 Hz, 1H). Mass spectrum: (M + NH4) + = 191.

C. Trans-3- (2-dimethylphenyl) -propenoic acid The hydrolysis of the methyl ester of Example 19B, using lithium hydroxide in a mixture of methanol and water, provided the desired compound (84%). 300 MHz 1H NMR (CDCb) d 2.38 (s, 6H), 6.13 (d, J = 16 Hz, 1H), 7.10 (m, 3H), 7.96 (d, J = 16 Hz, 1H). Mass spectrum: (M + H) + = 194.

D. (2S.3S, 5S) -2- (Trans-3- (2,6-dimethylphenyl) propenoyl) amino-3-hydroxy -5- (t-butyloxycarbonyl) amino) -1,6-diphenylhexane The coupling of the acid carboxyl of Example 19C with the amine of Example 1F, using a normal procedure (EDAC / DMF), provided the desired compound (84%). 300 MHz 1H NMR (CDCb) d 1.40 (s, 9H), 1.68 (m, 1H), 2.34 (s, 6H), 2.75 (m, 2H), 2.96 (m, 2H), 3.72 (m, 1H), 3.85 (m, 1H), 4.08 (m, 2H), 4.60 (m, 1H), 5.88 (d, J = 10 Hz, 1H), 5.94 (d, J = 16 Hz, 1H), 7.10 (m, 5H) ), 7.25 (m, 8H), 7.72 (d, J = 16 Hz, 1H). Mass spectrum: (M + H) + = 543.

E. (2S.3S.5S) -2- (Trans-3- (2,6-dimethylphenyl) propenoyl) amino-3- h id roxy-5- (2S- (1-tetrahydropyrimidin-2-onyl) -3- methy1-butane-p-amino) -1,6-diphenylhexane Removal of the Boc protecting group from the compound of Example 19D (TFA / CH2CI2) and coupling of the resulting amine with the carboxylic acid of Example 2A, using a standard procedure (EDAC / DMF) provided the desired compound (73%). 300 MHz 1 H NMR (CDCb) d 0.82 (d, J = 6 Hz, 3 H), 0.87 (d, J = 6 Hz, 3 H), 1.50 (m, 1 H), 1.70 (m, 2 H), 2.20 (m, 1 H), 2.33 (s, 6H), 2.68 (m, 1H), 2.78 (m, 1H), 2.85 (m, 1H), 3.05 (m, 5H), 3.73 (m, 1H), 4.17 (m, 1H), 4.30 (d, J = 3 Hz, 1H), 4.60 (s, 1H), 5.95 (d, J = 15Hz, 1H), 6.0 (d, J = 9 Hz, 1H), 6.80 (d, J = 7 Hz, 1H), 7.25 (m, 13H), 7.70 (d, J = 15 Hz, 1H).

Mass spectrum: (M + H) + = 625.

EXAMPLE 20 (2S.3S.5S) -2- (3- (2,6-dimethylphenyl) propanoyl) amino-3-hydroxy-5- (2S (1-tetrahydropyrimidin-2-onyl) -3-methyl-butanoyl) a min 0-1.6- diphenylhexane A. 3- (2,6-Dimethylphenyl) propanoic acid methyl ester A solution of 400 mg of the compound of Example 19B in 25 ml of methanol and 40 mg of 10% Pd / C was vigorously stirred under a nitrogen atmosphere (pressure of balloon) for 3 hours. The catalyst was filtered and the concentration of the filtrate in vacuo afforded the desired compound (98%). 300 MHz 1 H NMR (CDCb) d 2.35 (s, 6H), 2.45 (m, 2H), 2.98 (m, 2H), 3.22 (s, 3H), 7.02 (s, 3H). Mass spectrum: (M + H) + = 210.

B. 3- (2,6-Dimethylphenyl) propanoic acid The hydrolysis of the methyl ester of Example 20A, using lithium hydroxide in methanol and water, provided the desired compound (93%). 300 MHz 1 H NMR (CDCb) d 2.36 (s, 6 H), 2.50 (m, 2 H), 3.0 (m, 2 H), 7.03 (s, 3 H). Mass spectrum: (M + NH4) + = 196.

C. (2S.3S.5S) -2- (3-2.6-dimethylphenyl) propanoyl) amino-3-hydroxy-5- (t-b uti lox i carbonyl) amino-1,6-diphenylhexane The coupling of the carboxylic acid of Example 20B with the amine of Example 1F, using a normal coupling procedure (EDAC / DMF), provided the desired compound. 300 MHz 1H NMR (CDCb) d 1.40 (s, 9H), 1.55 (m, 2H), 2.20 (m, 2H), 2.30 (s, 6H), 2.74 (m, 2H), 2.85 (m, 4H), 3.66 (m, 1H), 3.82 (m, 1H), 3.95 (m, 2H), 4.57 (br d, 1H), 5.66 (d, J = 9 Hz, 1H), 7.0 (s, 3H), 7.22 ( m, 10H). Mass spectrum: (M + H) + = 545.

D. (2S.3S.5S) -2- (3- (2,6-Dimethylphenyl) propanoyl) amino-3-hydroxy-5- (2S- (1-tetrahydropyrimidin-2-oneyl) -3-methyl-butanoyl) amino -1.6- Diphenylhexane Removal of the Boc protecting group from the compound of Example 20C, using trifluoroacetic acid in CH 2 Cl 2 and coupling of the resulting amine with the carboxylic acid of Example 2A, using a normal coupling procedure (EDAC / DMF), provided the desired compound. 300 MHz 1 H NMR (CDCb) d 0.82 (d, J = 6 Hz, 3 H), 0.86 (d, J = 6 Hz, 3 H), 1.55 (m, 2 H), 1.65 (ra, 1 H), 1.70 (s, 3H), 2.20 (m, 3H), 2.30 (s, 6H), 2.65 (m, 1H), 2.75 (m, 1H), 2.86 (m, 5H), 3.10 (m, 3H), 3.68 (m, 1H) ), 4.10 (m, 4H), 4.63 (s, 1H), 5.75 (d, J = 7 Hz, 1H), 6.76 (d, J = 7 Hz, 1H), 7.0 (m, 3H), 7.20 (m , 10H). Mass spectrum: (M + H) + = 627.

EXAMPLE 21 (2 S.3S.5S) -2- (2,6-di methyl-4-h idroxy-f enoxyacetyl) amino-3-hydroxy-5- (2S- (1-tetrahydropyrimidin-2-onyl) -3 -methyl-butanoyl) amino-1,6-diphenylhexane A. 2.6-Dimethyl-4-tert-butyldimethylsilyloxy phenol To a solution of 2.5 g (14.7 mmol) of 2,6-dimethylquinone in 5 ml of methanol was added 200 mg of Pd / C (20%). The reaction mixture was stirred under a hydrogen atmosphere overnight. The Pd / C was stirred on a pad of celite, and the solvent was evaporated to dryness under reduced pressure to give 2.0 g (100%) of 2,6-dimethylhydroquinone as a light yellow oil. To a solution of 2.0 g (14.7 mmoles) of 2,6-dimethyldihydroquinone in 10 ml of methylene chloride were added 1.2 g / 17.6 mmoles) of imidazole and 2.2 g (14.7 mmoles) of tert-butyldimethylsilyl chloride subsequently to 0 ° C. After the reaction was complete, as indicated by TLC, it was partitioned between methylene chloride and a mixture of 1N of 3N hydrogen chloride and brine. The organic layer was washed with brine, dried sodium sulfate, filtered and evaporated to dryness under reduced pressure. Silica gel chromatography using 5% ethyl acetate: hexanes gave 1.8 g (49%) of 2,6-dimethyl-4-tert-butyldimethylsilyloxy phenol as a white solid. 300 MHz 1 H NMR (CDCb) d 0.16 (s, 6H), 0.98 (s, 9H), 2.19 (s, 6H), 4.22 (s, 1H), 6.48 (s, 2H). Mass spectrum: (M + H) + = 253.

B. Ethyl 2,6-dimethyl-4-tert-butyldimethylsilyloxy phenoxyethyl acetate A solution of 1.8 g (7.1 mmol) of 2,6-dimethyl-4-tert-butyldimethylsilyloxy phenol in 5 ml of dimethylformamide was treated with 2.0 g (1.43 mmol) ) of potassium carbonate and 830 μl (7.5 mmol) of ethyl bromoacetate. The resulting solution was heated at 70 ° C for 4 hours. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate and 3N hydrogen chloride. The combined organic layer was washed with diluted brine, dried over magnesium sulfate, filtered and evaporated in vacuo. Silica gel chromatography, using 5% ethyl acetate: hexanes, gave 2.03 g (85%) of ethyl 2,6-dimethyl-4-tert-butyldimethylsilyloxy phenoxyethyl acetate as a light yellow oil. 300 MHz 1H NMR (CDCb) d 0.17 (s, 6H), (0.97 s, 9H), 1.33 (t, 3H, J = 6.3 Hz), 2.22 (s, 6H), 4.30 (q, 2H, J = 6.3 Hz), 4.35 (s, 2H), 6.57 (s, 2H). Mass spectrum: (M + H) + = 356.

C. 2,6-Dimethyl-4-hydroxyphenoxyacetic acid To a solution of 2.03 g (6.0 mmol) of ethyl 2,6-dimethyl-4-tert-butyldimethylsilyloxy phenoxy acetate in 10 ml of methanol was added 4 ml of methanol. N of sodium hydroxide. Then, the reaction mixture was stirred at room temperature for 30 minutes, acidified with 3N HCl. The reaction was allowed to stir for a further 1 hour, and then it was partitioned between water and methylene chloride. The combined organic extracts were washed with brine and dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. Titration with hexanes gave 910 mg (77%) of 2,6-dimethyl-4-hydroxy phenoxyacetic acid as a white solid. 300 MHz 1 H NMR (CD3OD) d 2.18 (s, 6H), 4.31 (s, 2H), 6.41 (s, 2H). Mass spectrum: (M + H) + = 214.

D. (2S.3S.5S) -2- (2,6-dimethyl-4-hydroxy-phenoxyacetyl) amino-3-hydroxy-5 - (t-butyloxycarb onyl) amino-1,6-diphenylhexane The coupling of the carboxylic acid of Example 21C with the amine of Example 1F, using a normal coupling procedure (EDAC / DMF), provided the desired compound. 300 MHz 1H NMR (CDCb) d 1.40 (s, 9H), 1.68 (m, 2H), 2.07 (s, 6H), 2.77 (d, J = 6 Hz, 2H), 2.98 (m, 2H), 3.74 ( m, 1H), 3.90 (m, 1H), 4.10 (m, 3H), 4.58 (m, 1H), 5.20 (m, 1H), 6.44 (s, 2H), 7.10-7.30 (m, 10H).

E. (2S.3S.5S) -2- (2,6-dimethyl-4-hydroxy-phenoxyacetyl) amino-3-hydroxy-5- (2S- (1-tetra hydropyrimidin-2-one) -3-methyl butane-amino-1,6-diphenylhexane Removal of the Boc protecting group from the compound of Example 21D using TFA / CH 2 Cl 2 and coupling of the resulting amine with the carboxylic acid of Example 2A, using a normal procedure (EDAC / DMF), provided the desired compound: 300 MHz 1 H NMR (CDCb) d 0.78 (d, J = 5 Hz, 3H), 0.81 (d, J = 5 Hz, 3H), 1.47 (m, 1H), 2.03 (s, 6H), 2.18 (m, 1H), 2.62 (m, 1H), 2.80 (m, 2H), 3.05 (m, 6H), 3.78 (m, 1H), 4.12 (M, 6H), 4.37 (M, 1H), 4.71. (s, 1H), 6.47 (s, 2H), 6.94 (br d, 1H), 7.20 (m, 10H), Mass spectrum: (M + H) '645.

EXAMPLE 22 (2S.3S.5S) -2- (cis (±) -1,1-dioxo-2-isopropyl-3-tetrahydrothiophenoxy) amino-3-hydroxy-5- (2S- (1-tetrahydropyrimid-2-onyl) -3-methyl-butanoyl) amino-1,6-diphenylhexane A. Cis (+) -2-isopropyl-3-hydroxy-tetrahydrothiophene To a solution of ethyl 3-mercaptopropionate (27.25 ml, 0. 246 moles) in 200 ml of ethanol was carefully added sodium ethoxide (16.75 g, 0.246 moles) in several portions. The resulting suspension was then cooled to -20 ° C and ethyl 2-bromoisovalerate (50 g, 0.239 mol) in 50 ml of ethanol was added dropwise over 2 hours. After the addition was complete, the reaction was warmed to room temperature and stirred for 3 hours. The mixture was poured into 600 ml of ethyl acetate and 600 ml of saturated NH 4 Cl. The ethyl acetate layer was removed and the aqueous layer was extracted (2 x 200 ml) with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give an orange oil. The oil was dissolved in 500 ml of toluene and sodium ethoxide (16.75 g, 0.246 moles) was added. The reaction mixture was heated to reflux for 6 hours, cooled to room temperature, and then emptied into a 1N ice-cold HCl solution (235 ml) and extracted with ethyl acetate (3 x 150 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated to an oil which was used in the next step without purification. The crude product was added to 500 ml of 10% aqueous sulfuric acid and the resulting mixture was heated to reflux for several hours, and then cooled to room temperature and neutralized with 6N sodium hydroxide and extracted with ethyl acetate. (3 x 300 ml). The combined organic layer was dried, filtered and concentrated in vacuo to give a dark red wine-colored oil. The crude product (ketone) was purified by vacuum distillation at 75 ° -80 ° C. 300 MHz 1H NMR (CDCb) d 0.93 (d, J = 9 Hz, 3H), 1.03 (d, J = 9 Hz, 3H), 2.32 (m, 1H), 2.55-2.70 (m, 2H), 2.93 (t, J = 7.5 Hz, 2H), 3.38 (d, J = 4 Hz, 1 HOUR). Mass spectrum: (M + H) + = 145. To a stirred solution of the above ketone in 125 ml of CH 2 Cl 2 at 0 ° C was added diisobutylaluminum hydride (86 ml, 1M in THF) dropwise over 20 minutes . The reaction mixture was allowed to warm to room temperature and then quenched through the careful addition of 1N HCl (255 ml). The reaction mixture was extracted with ether (3 x 150 ml) and the combined ether solution was washed with saturated sodium bicarbonate, brine and dried over magnesium sulfate. The solution was concentrated in vacuo and the resulting oil was purified through silica gel column chromatography (1 '% EtOAc / hexane). 300 MHz 1 H NMR (CDCb) d 1.03 (d, J = 7 Hz, 3 H), 1.08 (d, J = 7 Hz, 3 H), 1.80 (d, J = 9 Hz, 1 H), 1.90 (m, 2 H) , 2.24 (m, 1H), 2.90-3.10 (m, 3H), 4.36 (m, 1H). Mass spectrum (M + H) + = 147B. Cis (±) - (2-isopropyl-3-thiophenyl) -2 (2-pyridyl) carbonate To the product of example 22A (229 g, 157 mmol) in 40 ml of CH 2 Cl 2 was added dnsopropylethyl amine (465 ml , 267 mmoles) and d? - (2-pyridol carbonate) (542 g, 25 1 mmoles) After 18 hours at room temperature, the reaction mixture was diluted with chloroform and washed sequentially with 10% citric acid, saturated sodium bicarbonate, brine and then dried over sodium sulfate, filtered and concentrated in vacuo Purification of the crude product through silica gel column chromatography (20% EtOAc / hexane) provided the desired compound 300 MHz 1H NMR (CDCb) d 1 05 (d, J = 7 Hz, 3H), 1 08 (d, J = 7 Hz, 3H), 1 90 (m, 1H), 205 (m, 2H), 2 58 (dd, J = 6.15 Hz, 2H), 3 10 (m, 2H), 328 (dd, J = 3.12 Hz, 1H), 547 (m, 1H), 7 12 (m, 1H), 727 (m, 1H), 780 (m, 1 H), 841 (m, 1H) Mass spectrum (M + H) + = 268 C. (2S.3S.5S) -2- (cis (±) -2-isop rop-3-tetrahydrothiofenoxi) amino-3-hydroxy-5- (2S- (t-butyloxycarbonyl) amino-1,6 Diffusion of hexane To a solution of the compound of Example 22B (500 mg, 1.87 mmol) in 5 ml of CH 2 Cl 2 was added the amine of Example 1F (791 mg, 206 mmol). The reaction mixture was stirred at room temperature until all the compound of Example 22B was consumed The reaction mixture was diluted with chloroform and washed with 10% citric acid, saturated sodium bicarbonate, brine and then dried with sodium sulfate, filtered and concentrated in vacuo. Purification of the crude product through silica gel column chromatography (2% MeOH / CH 2 Cl 2) provided the desired compound (73%) 300 MHz 1 H NMR (CDCb) d 0.83-1.05 (m, 6H), 1.40 (s, 9H), 1.90 (m, 3H), 2.20 (m, 1H), 2.75 (m, 2H), 2.85 (m, 4H), 2.95-3.15 (m, 3H), 3.67-3.90 (m, 4H) ), 4.55 (m, 1H), 5.10 (m, 1H), 5.30 (m, 1H), 7.10-7.26 (m, 1 OH), Mass spectrum: (M + H) + = 557.

D. (2S.3S.5S) -2- (cis (±) -1,1-Dioxo-2-isopropyl-3-tetrahydrothiophenoxy) amino-3-hydroxy-5- (t-butyloxycarbonyl) amino-1,6-diphenylhexane To the compound of Example 22C (523 mg, 0.91 mmol) in 10 ml of acetone and 0.5 ml of water was added oxone (839 mg, 1.37 mmol) and sodium bicarbonate (152 mg, 1.82 mmol). The resulting solution was stirred for 2 hours, at which time a white precipitate appeared. The reaction was quenched with aqueous sodium bisulfite and extracted with ethyl acetate (2 x 100 mL), dried with sodium sulfate, filtered and concentrated in vacuo. The crude product was purified through silica gel column chromatography (2% MeOH / CH 2 Cl 2) to provide 422 mg of the product. 300 MHz 1H NMR (CDCb) d 1.20 (m, 6H), 1.40 (s, 9H), 1.60 (m, 4H), 2.10-2.32 (m, 4H), 2.67 (m, 2H), 2.75 (m, 2H) ), 2.85 (m, 2H), 3.15 (m, 2H), 3.70-3.90 (m, 3H), 4.56 (m, 1H), 5.30 (m, 2H), 7.10-7.30 (m, 10H).

E. (2S.3S.5S) -2- (cis (±) -1,1-Dioxo-2-isopropyl-3-tetrahydrothiophenoxy) amino-3-hydroxy-5- (2S- (1-tetrahydropyrimid-2- onyl) -3-methyl-butanoyl) amino-1,6-diphenylhexane Removal of the Boc protecting group from the compound of Example 22D using TFA / CH2CI2 and coupling of the resulting amine with the carboxylic acid of Example 2A provided the desired compound ( 82%) 300 MHz 1 H NMR (CDCb) d 082 (m, 6 H), 1 0-1 20 (m, 6 H), 1 60 (2 H), 207 (m, 1 H), 2 25 (m, 2 H), 265-320 (m, 12H), 370 (m, 1H), 390 (m, 1H), 4 10-420 (m, 2H), 507 (m, 1H), 537 (m, 1H), 587-598 (m, 1H), 695-705 (m, 1H), 720 (m, 10H) Mass spectrum (M + H) + = 671 EXAMPLE 23 (2S.3S.5S) -2- (2,6-Dimethyl-phenoxyacetyl) amino-3-hydroxy-5- (2S-M-dihydropyrimid-2,4-dionyl) -3-methyl-butanoyl) amino-1,6-diphenylhexane A. N- (2-Ethoxyacryloyl) -N '- (1S-carbomethoxy-2-methyl-propyl) -urea To 1 74 g (0013 moles) of 2-ethoxy? -acyloyl chloride in 18 ml of toluene was they added 390 g (0026 moles) of silver cyanate. The mixture was refluxed for 075 hours. The mixture was allowed to cool to room temperature and the precipitate was allowed to settle. The supernatant (96 ml) was removed and added to 18 ml of dry DMF and 5 ml of Et2O., it was cooled to -15 ° C for 45 minutes and left in a freezer overnight. The solvent was evaporated in vacuo and the residue was purified by silica gel column chromatography (2% MeOH / CH 2 Cl 2) provide 1 59 g of the desired compound (90.2%). 300 MHz 1 H NMR (CDCb) d 0.96 (d, J = 7 Hz, 3 H), 1.0 (d, J = 7 Hz, 3 H), 1.37 (t, J = 7.5 Hz, 3 H), 2.25 (m, 1 H) , 3.74 (s, 3H), 3.97 (q, J = 7.5 Hz, 2H), 4.42 (dd, J = 4.5.8.0 Hz, 1H), 5.25 (d, J = 12 Hz, 1H), 7.68 (d, J = 12 Hz, 1H), 8.55 (s, 1H), 9.10 (d, J = 8 Hz, 1H). Mass spectrum: (M + H) + = 273.

B. 2S- (1-Dihydropyrimid-2,4-donyl) -3-methyl butanoic acid A solution of 174 mg (0.64 mmol) of the compound of Example 23A in 10 ml of 2N sulfuric acid was brought to reflux for 2 hours, it was cooled to room temperature and left in a freezer overnight. The mixture was concentrated and the residue was extracted with ethyl acetate (2 x 100 ml), dried and concentrated in vacuo to give 122 mg of the desired compound. 300 MHz 1 H NMR (CDCb) d 1.06 (d, J = 7 Hz, 3 H), 1.13 (d, J = 7 Hz, 3 H), 2.25 (m, 1 H), 5.04 (d, J = 10 Hz, 1 H) , 5.74 (d, J = 7 Hz, 1H), 7.50 (d, J = 10 Hz, 1H), 8.43 (s, 1H).

C. (2S.3S.5S) -2- (2,6-Dimethyl-phenoxyacetyl) amino-3-hydroxy-5- (2S- (1-dihydropyrimid-2,4-dionyl) -3-methyl-butanoyl) amino-1,6-diphenylhexane coupling of the carboxylic acid of Example 23B with the amine of Example 1N using a normal coupling procedure (EDAC in DMF) provided the desired compound. 300 MHz 1H NMR (CDCb) d 0.81 (d, J = 7 Hz, 3H), 0.92 (d, J = 7 Hz, 3H), 2.18 (s, 6H), 2.23 (m, 1H), 2.63 (m, 1H), 2.85 (m, 1H), 3.0 (m, 2H), 3.78 (m, 1H), 420 (m, 4H), 458 (d, J = 10 Hz, 1H), 5.68 (dd, J = 1.5, 7.5 Hz, 1H), 70-725 (m, 13H), 7 50 (d, J = 75 Hz, 1H), 9 50 (s, 1H) Mass spectrum (M + H) + = 640 EXAMPLE 24 Alternate Preparation of (2S.3S.5S) -2- (2,6-Dimethylphenoxyacetyl) amino-3-hydroxy-5-r2S- (1-tetrahydro-pyrimid-2-oneyl) -3-methyl-butanoin amino -1, 6 -diphenylhexane A. 2,6-Dimethylphenoxyacetic Acid 2,6-Dimethylphenol (102.8 g, 0.82 mole) and chloroacetic acid (159.6 g, 1.68 mole) in 1000 mL of H2O were added to a three-neck, three-neck round bottom flask with mechanical stirring and a water-cooled condenser A solution of NaOH (134.9 g, 3.37 mol) dissolved in 500 ml of water was slowly added to the above mixture via an addition funnel and heated to reflux. After 2 hours, an additional solution of chloroacetic acid (79.4 g, 0.84 mol) and NaOH (67.2 g, 1.68 mol in 200 ml of water) was added to the reaction mixture. After 19 hours, an additional solution of chloroacetic acid (39.8 g, 0.42 mole) and NaOH (33.6 g, 0.84 mole in 100 ml of water) was added to the reaction mixture and the reflux was continued until the phenol game was consumed. The reaction flask was cooled in an ice-water bath and acidified to a pH = 1 with concentrated HCl, causing the formation of a precipitate. The resulting slurry was stirred in an ice bath for 1 hour and then filtered. The solid was dissolved in hot water (100 ° C) to crystallize the product as white plates, Mp = 136-137 ° C, yield = 78.8 g, 52%.

B. (2S.3S.5S) -2- (2,6-Dimethylphenoxyacetyl) amino-3-hydroxy-5- (t-butyloxycarbonylamino) -1,6-diphenylhexane Oxalyl chloride (36.3 ml, 0.2 moles) was added to a slurry. 2,6-dimethylphenoxyacetic acid (50 g, 0.28 moles) in 500 ml of toluene followed by the addition of 5 drops of DMF and stirred at room temperature for 30 minutes, then at 55 ° C for 1.5 hours. The toluene was stirred on a rotary evaporator and the remaining volatiles were removed under vacuum to provide 2,6-dimethyl-phenoxyacetyl chloride as an amber oil, 55 grams, 100%. [2S, 3S, 5S] -2-amino-3-hydroxy-5-t-butyloxycarbonyl-amino-1,6-diphenylhexane x 0.5 succinate (111.9 g, 0.25 moles) was charged to a 2-necked round neck flask. liters, three necks with mechanical agitation. NaHCO3 (106 g, 1.26 moles), 600 ml of H2O and 600 ml of EtOAc were added and stirred vigorously until all the solids dissolved (15 minutes). The stirring was reduced and a solution of the 2,6-dimethyl-phenoxyacetyl chloride and EtOAc (100 ml) was added in a narrow stream via an addition funnel. After 30 minutes of stirring, the starting materials were consumed (HPLC analysis) and the layers were separated. The aqueous layer was extracted with EtOAc, the organic layers were combined and washed with 200 ml of 1M NaOH, 200 ml of 10% HCl, 200 ml of brine, dried over MgSO 4, filtered and concentrated to provide the desired product as a white solid.

C. (2S.3S, 5S) -2- (2,6-Dimethylphenoxyacetyl) amino-3-hydroxy-5-amino-1,6-diphenylhexane Mixed with stirring (2S, 3S, 5S) -2- (2 , 6-dimethylphenoxy-α-cetyl) amino-3-hydroxy-5- (t-butyloxycarbonylamine) -1,6-diphenyl-n-hexane (175.1 g, 0.32 mol) and 500 ml of CH 2 Cl 2. CF3CO2H (249 ml, 3.2 moles) was added and stirred for 20-25 minutes, then the reaction mixture was emptied into a separatory funnel containing 1000 ml of water and 200 ml of CH2Cl2. The resulting mixture was stirred carefully and the layers separated. The organic layer was washed again with 500 ml of water, then 3 x 500 ml of NaHCO3 and finally 500 ml of brine. The organic solution was dried over MgSO, filtered and concentrated to a golden oil which was introduced into a foam. 300 ml of diethyl ether was added to the crude product and vigorously stirred to dissolve. Within a few minutes the solid began to crystallize and the mixture became thick. Enough diethyl ether was added to be able to stir the mixture, and the mixture was stirred at room temperature for 1 hour. The solid was filtered and dried with air to give the desired product as 115 g of white needles, yield 81%. A solution of HCl / diethyl ether was added to the filtrate to precipitate the remaining product as the HCl salt. This pink solid was collected by filtration, taking care to keep the solid flooded with N2, while it is moistened with water. When dried, the amine salt was transferred to a separatory funnel and extracted with CH2Cl2 and NaHCO3 (aqueous). The organic layer was washed with brine, dried over MgSO, concentrated and worked up as above to provide an additional 15 g of the desired product, the total yield is 91%.

D. N-Carbonylbenzyloxy-3-aminopropanol To a 12-liter, three-necked round bottom flask was added isopropyl acetate (6.5 L). The solvent was cooled to 0 ° C in an ice-water bath and 3-amino-1-propanol (1.14 kg, 15.1 moles, 2.15 eq.) Was added in one portion. To this rapidly stirred solution, benzyl chloroformate (1.20 kg, 7.03 moles, 1.0 eq.) Was added dropwise over 2 hours, while maintaining the internal temperature of the flask between 10 ° C and 15 ° C. After the addition was complete, the reaction mixture was allowed to stir at between 10 ° C and 15 ° C for an additional 0.3 hours, after which time water (3.5 L) was added in one portion. The solution was then divided and washed with 2 x 3.5 L more water. The organic layer was dried over potassium carbonate and concentrated to give a solid which was dissolved in excess ethyl acetate and precipitated from the solution by adding the compound to heptane. The solid was filtered under nitrogen to yield 1.20 kg (82%) of the desired product as a colorless solid.

E. N-Carbonylbenzyloxy-3-aminopropanal 335 ml of dimethyl sulfoxide and 9 L of methylene chloride were combined and cooled to -48 ° C. 313 ml of oxalyl chloride was added over 25 minutes so that the temperature remained below -40 ° C. It was cooled to -48 ° C, and 500 grams of N-Cbz-3-amino-1-propanol dissolved in 1 L of ethylene chloride was added so that the temperature remained below -40 ° C. It was stirred for an additional hour at -45 ° C. 1325 ml of triethylamine was added at such a rate that the temperature remained below -40 ° C. After further stirring for 15 minutes at -40 ° C, the mixture was allowed to warm to -30 ° C, then 2.5 L of 20% aqueous potassium dihydrogen phosphate was added. It was stirred for one hour, then the layers were separated, the organic layer was washed with brine, and dried with magnesium sulfate. The resulting aldehyde was maintained at 20 ° C until needed.

F. N- (N- (Benzyloxycarbonyl-3-amino) -propyl) valine methyl ester To a 5-liter, three-neck, round bottom flask was added the crude product (without chromatography) of Example 24E ( 115 g, 0.555 moles, 1.0 eq.) Followed by the addition of water (400 ml) and methanol (1600 ml). The reaction mixture was maintained at 25 ° C throughout the course of the reaction. After the solution became homogeneous, (S) -valine methyl ester hydrochloride (90.2 g, 0.538 moles, 0.97 eq.) was added in one portion followed by the rapid addition of sodium acetate trihydrate (151 g, 1.11 moles, 2.0 eq.) and sodium cyanoborohydride (73.2 g, 1.17 moles, 2.1 eq.) in said order. The reaction mixture was allowed to stir at room temperature for 0.5 hour and concentrated in vacuo to remove all the methanol present. To this solution, aqueous sodium bicarbonate (400 ml) was added and the mixture was extracted with isopropyl acetate (1 L). The organic layer was washed with water (2 x 400 ml), dried over sodium sulfate and concentrated to yield 150 g of the crude product, which was dissolved in isopropyl acetate (300 ml) and heptane (2400 ml). HCl was bubbled dry and an oily solid was precipitated out of the solution. The liquid was decanted away from the solid and dissolved in dichloromethane (3 L). The solution was washed with water (600 ml) and saturated aqueous sodium bicarbonate (600 ml) and dried over sodium sulfate. It was concentrated in vacuo to yield 105 g (59%) of the desired product as a light yellow oil.

G. N- (3-amino) -propyl) valine methyl ester To a 3 liter flask was added the product of Example 24F (120 g, 0.372 mol) and methanol (1 L). This solution was allowed to stir in the presence of Raney nickel (180 g) for 1 hour. After removal of the Raney nickel through filtration, Pd (OH) 2 (24 g) was added and the solution allowed to stir under 4,218 kg / cm 2 of a hydrogen atmosphere for 12 hours. The solution was purged with nitrogen and re-pressurized with 4,218 kg / cm 2 of hydrogen for an additional 1 hour. The solution was filtered and concentrated to give 63 g of an oil (90%). To this was added oily toluene (120 ml) and the solution was again concentrated in vacuo to give the desired product.

H. 2S- (1-Tetrahydro-pyrimid-2-oneyl) -3-methyl butanoic acid methyl ester To a 5-liter, 3-neck round bottom flask, with stirring bar was added the crude product of the Example 24G (150 mg, 0.8 moles) and dichloromethane (3.2 L). Carbonyldiimidazole (232 g, 1.44 moles, 1.8 eq.) Was added slowly in portions during minutes. The solution was allowed to stir at room temperature for 40 hours. Water (200 ml) was added for 1 hour with careful agitation until no evolution of gas occurred. A 35% solution of HCl was slowly added to the stirring solution until the solution became acidic. The solution was then partitioned and washed with water (2 x 300 ml). The organic layer was dried over sodium sulfate and concentrated to yield 126 g. (74%) of the desired product as a colorless solid.

I. 2S- (1-Tetrahydro-pyrimid-2-oneyl) -3-methyl butanoic acid methyl ester To a 12-liter, 3-neck round bottom flask, with stirring bar, was added the product of the Example 24H (126 g, 0.588 moles), water (1.3 L) and THF (3.9 L). The solution was cooled to 0 ° C in an ice-water bath and lithium hydroxide monohydrate (74 g, 1 76 mole, 30 eq) was added in one portion with rapid stirring. The solution was allowed to stir at 0 ° C during 14 hours After it was acidified to a pH of 11 through the slow addition of 50% aqueous phosphoric acid and the THF was removed in vacuo. The aqueous phase was washed with isopropyl acetate (2 L) and subsequently acidified to a pH through the slow addition of 35% aqueous HCl. The aqueous layer was then extracted with ethyl acetate (5 x 22 L). The combined organic layers were concentrated to give the desired product (105 g) as a white solid. it was purified through the addition of isopropyl acetate (500 ml) and ethanol (15 ml) and the solution was boiled with rapid stirring until 50 ml of the solvent was evaporated. The solution was cooled to 0 ° C and the filtered to give 92 g (75%) of the pure desired product J. (2S.3S.5S) -2- (2,6-Di methyl-enoxyacetyl) amino-3-hydroxy-5-r2S- (1-tetrahydro-pyrimid-2-oneyl) -3-methyl-butane amino-1,6-diphenylhexane In a 2-liter, 3-necked round bottom flask, the product of Example 24C (100 g, 022 mol), the product of Example 24I (448 g, 022 mol) and 750 were combined. ml of DMF and the mixture was cooled in an ice / water bath. HOBT (909 g, 067 mol), EDAC (86 g, 045 mol) and tetylamine (625 ml) 045 mol) were added and the ice bath was removed. , allowing to stir the reaction mixture with heating at room temperature for 5 hours. The reaction was diluted with 1000 ml of IPAC and quenched with 1000 ml of water. The mixture was stirred and separated, the aqueous layer was extracted 1 x 400 ml of water. IPAC, the organicox were washed with 1 x 400 ml of 10% HCl, 1 x 500 ml of NaHCO3, diluted with 100 ml of hexanes, then washed 4 x 500 ml of water, and 1 x 500 ml of brine, dried over MgSO4, filtered and concentrated to provide the product or desired as a white foam EXAMPLE 25 (2S .3S .5S) -2- (2.6-Di metilf in oxy acetyl) amino-3-hydroxy-5-r2S- (1 tetrahydro-pyrimid-2,4-dionyl) -3-methylbutane N amino-1,6-diphenylhexane A. T-butyl ester of N- (2-carbomethoxy) ethyl-L valine To a solution of 1 73 g of L-valine t-butyl ester in 10 ml of methanol was added 90 ml of methyl acrylate. The solution was heated to reflux for overnight Another 90 ml of ethyl acetate was added and the reflux continued for 24 hours. The solvent was evaporated in vacuo and the crude product was purified through silica gel column chromatography (20% ethyl acetate in hexane ) to provide 2435 g of the desired compound (939%) 300 MHz 1 H NMR (CDCb) d 091 (d, J = 35 Hz, 3H), 093 (d, J = 35 Hz, 3H), 1 47 (s, 9H), 1 85 (m, 1H), 247 (t, J = 7 Hz, 2H), 268 (m, 1H), 281 (d, J = 6 Hz, 1H), 295 (m, 1H), 368 (s, 3H) Mass spectrum: (M + H) + = 260.

B. N- (2-carboxyamido) ethyl-L-valine t-butyl ester To a solution of 1.86 g of the product of Example 25A in 5 ml of THF was added 0.415 g of lithium hydroxide monohydrate in 10.8 ml of Water. After 40 minutes, 10.8 ml of 1N HCl was added. The reaction mixture was evaporated to dryness and dry pyridine was added and evaporated to dryness twice. The residue was dissolved in 25 ml of acetonitrile and 0.62 ml of dry pyridine was added. To this solution was added 2.02 g of N, N'-disuccinimidyl carbonate. The reaction mixture was stirred for 3.5 hours. The solvent was removed under vacuum and 90 ml of THF were added followed by 1.43 ml of concentrated ammonium hydroxide. The reaction was allowed to continue overnight. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with sodium bicarbonate, brine and dried with anhydrous sodium sulfate. After filtering the drying agent, the filtrate was concentrated in vacuo and the crude product was purified through silica gel column chromatography (5% MeOH in CH 2 Cl 2) to give 1.19 g (68%) of the desired compound. 300 MHz H NMR (CDCb) d 0.95 (d, J = 7 Hz, 3H), 0.97 (d, J = 7 Hz, 3H), 1.48 (s, 9H), 1.93 (m, 1H), 2.37 (m, 2H), 2.65 (m, 1H), 2.95 (m, 2H), 5.30 (br s, 1H), 7.85 (br s, 1H). Mass spectrum: (M + H) + = 245.

C. 2S- (1-Tetrahydro-pyrimid-2,4-dionyl) -3-methylbutanoic acid t-butyl ester A solution of 0.92 g of the product of Example 25B in 10 ml of THF and 1.83 g of carbonyldiimidazole (CDI) was at reflux for 26 hours. Then, 1.83 g of CD1 was added again and the solution was refluxed for 72 hours. The solvent was evaporated in vacuo and the residue was dissolved in ethyl acetate and washed with water, saturated sodium bicarbonate, dilute hydrochloric acid and then brine. The organic layer was dried, filtered and concentrated in vacuo. The crude product was purified through silica gel chromatography (2% to 5% MeOH in CH 2 Cl 2) to give 0.54 g (52%) of the desired compound. 300 MHz 1H NMR (CDCb) d 0.96 (d, J = 7 Hz, 3H), 1.05 (d, J = 7 Hz, 3H), 1.48 (s, 9H), 2.20 (m, 1H), 2.66 (m, 2H), 3.43 (m, 1H), 3.75 (m, 1H), 4.63 (d, J = 9 Hz, 1H), 7.35TD * s, 1H).

Mass spectrum: (M + H) + = 271 D. 2S- (1-Tetrahydro-pyrimid-2,4-dionyl) -3-methylbutanoic acid A solution of 0.53 g of the compound of Example 25C in 5 ml of trifluoroacetic acid was stirred at 0 ° C for 1.25 hours. The solvent was evaporated in vacuo, dried and purified through silica gel column chromatography (2% MeOH / 4% HOAc in CH 2 Cl 2) to give 0.36 g of the desired compound. 300 MHz 1H NMR (DMSO-d6) d 0.86 (d, J = 7 Hz, 3H), 0.97 (d, J = 7 Hz, 3H), 2.15 (m, 1H), 3.40 (m, 4H), 4.39 ( d, J = 10 Hz, 1H). Mass spectrum: (M + H) + = 215.

E. (2S, 3S.5S) -2- (2,6-Dimethyl-enoxyacetyl) amino-3-hydroxy-5-f2S- (1-tetrahydro-pyrimid-2,4-dionyl) -3-methylbutanoin amino-1,6-diphenylhexane Coupling of the amino compound of Example 1N with the acid of Example 25D, using a normal coupling procedure (EDAC in DMF), provided the desired compound (86%). 300 MHz 1H NMR (CDCb) d 0.83 (d, J = 7Hz, 3H), 0.88 (d, J = 7Hz, 3H), 1.80 (m, 2H), 2.20 (s, 6H), 2.40 (m, 1H) , 2.58 (m, 1H), 2.80 (m, 1H), 2.92 (m, 1H), 3.05 (m, 3H), 3.65 (d, J = 5Hz, 1H), 3.83 (m, 1H), 4.20 (m , 5H), 6.18 (d, J = 9Hz, 1H), 7.0-7.38 (m, 14H). Mass spectrum: (M + H) + = 643.

EXAMPLE 26 (2S.3S.5S) -2- (2,6-Dimethyl-phenoxyacetyl) amino-3-hydroxy-5-r2S- (4-aza-1-tetrahydro-pyrimid-2-oneyl) -3-methyl-butanoyl-1-amino- 1.6- diphenylhexane A. N (1) -t-butyloxycarbonyl-N (2) -allyl hydrazine To a solution of 18.18 g of t-butyloxycarbonyl-protected hydrazine in 50 ml of acetonitrile was added 19.0 g of potassium carbonate, followed by 11.9 ml. of allyl bromide. The reaction mixture was refluxed for a total of 3 hours, filtered and concentrated in vacuo. The residue was dissolved in acetate and ethyl and washed with saturated sodium bicarbonate and dried with anhydrous sodium sulfate and filtered. After concentration in vacuo, the crude product was purified through silica gel column chromatography (20% EtOAc / hexane) to give 4.47 g of the desired compound. 300 MHz 1H NMR (CDCb) d 1.45 (s, 9H), 3.46 (m, 2H), 4.0 (br s, 1H), 5.10 (m, 2H), 5.83 (m, 1H), 6.0 (br s, 1H ). Mass spectrum: (M + H) + = 173.

B. N (1) -t-Butyloxycarbonyl-N (2) -allyl-NÍ2) -benzyloxycarbonyl hydrazine To a solution of 4.8 g of the compound of Example 26A in 15 ml of DMF was added 4.8 g of benzyloxycarbonyloxy-succinimide.

The reaction mixture was stirred at room temperature for 72 hours and the solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate and dried with anhydrous sodium sulfate. The crude product obtained after concentration was purified through silica gel column chromatography (20% to 50% EtOAc in hexane) and 5.27 g of the desired compound were provided. 300 MHz 1H NMR (CDCb) d 1.43 (br s, 9H), 4.15 (br s, 2H), 5.18 (s, 2H), 5.20 (m, 2H), 5.82 (m, 1H), 6.39 (br s, 1H), 7.36 (m, 5H). Mass spectrum: (M + H) + = 307.

C. N (1) -t-Butyloxycarbonyl-N (2) -formylmethyl-N (2) -benzyloxycarbonyl hydrazine A solution of 6.5 g of the compound of Example 26B in 100 ml of methanol was cooled with a dry ice / acetone bath . Ozone was bubbled for 1.75 hours until a pale blue color persisted. Air was passed through the solution for 10 minutes and then 15.6 ml of dimethyl sulfide was added and the reaction mixture was allowed to warm gradually to room temperature overnight. The solvent was evaporated in vacuo and the residue was dissolved in ethyl acetate and washed with water, then with brine several times. The organic layer was dried with anhydrous sodium sulfate, filtered and concentrated in vacuo to provide 7.2 g of the desired compound. 300 MHz 1H NMR (CDCb) d 1.40 (br s, 9H), 4.35 (m, 2H), 5.20 (s, 2H), 6.65 (br s, 1H), 7.36 (s, 5H), 9.70 (br s, 1 HOUR). Mass spectrum: (M + NH4) + = 326.

D. N-r2- (N- (2) -benzyloxycarbonyl-N- (1) -t-butyloxycarbonylhydrazinyl ethyl-L-valine methyl ester. To a solution of 7.2 g of the compound of Example 26C in 100 ml of methanol is They added 3.55 g of L-valine methyl ester hydrochloride, followed by 3.48 g of sodium acetate and 1.33 g of sodium cyanoborohydride, The reaction mixture was stirred at room temperature overnight. The crude product was purified through silica gel column chromatography (2% MeOH in CH 2 Cl 2) to provide 5.8 g of the desired compound 300 MHz 1 H NMR (CDCb) d 0.90 (d, d = 6Hz, 6H ), 1.43 (br s, 9H), 1.87 (m, 1H), 2.60-3.0 (m, 4H), 3.72 (s, 3H), 5.18 (s, 2H), 7.37 (m, 5H). : (M + H) + = 424.

E. 2S-r4-benzyloxycarbonylaza-1-tetrahydro-pyrimid-2-ynyl) -3-methyl-butanoic acid methyl ester A solution of 2.4 ml of the compound of Example 26D in 20 ml of HCl in dioxane was stirred at room temperature under argon for 1 hour. The solvent was evaporated in vacuo and the residue was washed with saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried, filtered and concentrated in vacuo. The crude product was dissolved in 28 ml of CH2Cl2 and 0.56 g of carbonyldiimidazole was added. The solution was left at room temperature for 48 hours. The solvent was removed and the residue was purified by silica gel column chromatography (10% to 30% EtOAc in CH 2 Cl 2) to give 0.78 g of the desired compound. 300 MHz 1H NMR (CDCb) d 0.90 (d, J = 7Hz, 3H), 0.98 (d, J = 7Hz, 3H), 2.17 (m, 1H), 3.34 (m, 1H), 3.61 (m, 2H) , 3.72 (s, 3H), 3.98 (m, 1 H), 4.71 (d, J = 10Hz, 1H), 5.20 (s, 2H), 6.72 (br s, 1H), 7.38 (m, 5H). Mass spectrum: (M + H) + = 350.

F. 2S- (4-benzyloxycarbonyl-1-tetrahydro-pyrim id-2-nyl) -3-methyl-butanoic acid Hydrolysis of 0.78 g of the compound of Example 26E using lithium hydroxide in dioxane aqueous solution provided 0.35 g of the desired compound. 300 MHz 1H NMR (CDCb) d 0.85 (d, J = 7Hz, 3H), 1.04 (d, J = 7Hz, 3H), 2.40 (m, 1H), 3.40 (m, 1H), 3.50 (m, 1H) , 3.80 (m, 2H), 3.95 (d, J = 10Hz, 1H), 5.20 (s, 2H), 7.30 (s, 1H), 7.36 (s, 5H). Mass spectrum: (M + H) + = 336.

G. (2S.3S.5S) -2- (2,6-Dimethyl-phenoxyacetyl) amino-3-hydroxy-5-r2S- (be ncyloxica rbo nilaza-1-tetrahydro-pyrimid-2-oneyl) -3-methyl-butanoyl-1 amino-1, 6-diphenylhexane The coupling of the amino compound of Example 1N with the acid of Example 26F, using a standard coupling procedure (EDAC / DMF), provided the desired compound (36%). 300 MHz 1H NMR (CDCb) d 0.72 (d, J = 7Hz, 3H), 0.83 (d, J = 7Hz, 3H), 2.20 (s, 6H), 2.65 (m, 1H), 2.83 (m, 1H) , 3.0-3.10 (m, 4H), 3.90 (m, 1H), 6.65 (m, 1H), 7.0-7.35 (m, 18H). Mass spectrum: (M + H) + = 764.

H. (2S.3S.5S) -2- (2,6-Dimetilf enoxyacetil) amino-3-hydroxy-5-r2S- (4-aza-1-tetrahydro-pyrimid-2-oneyl) -3-methyl-butane n-amino-1,6-diphenylhexane Removal of the benzyloxycarbonyl protecting group from the compound of Example 26G through hydrogenolysis using 10% palladium on carbon as a catalyst provided the desired compound. 300 MHz 1 H NMR (CDCb) d 0.83 (d, J = 4.5 Hz, 3 H), 0.86 (d, J = 4.5 Hz, 3 H), 1.80 (m, 1 H), 2.20 (s, 6 H), 2.58 (m; 1H), 2.67 (m, 1H), 2.90 (m, 2H), 3.0 (m, 2H), 3.80 (m, 1H), 4.20 (m, 3H), 6.72 (m, 1H), 7.0 (m, 2H) ), 7.20 (m, 11H). Mass spectrum: (M + H) + = 630.

EXAMPLE 27 (2S.3 S.5S) -2- (2.6-D imeti If enoxyacetyl) amino-3-hydroxy-5-r2S- (1-tetrahydro-pyrimid-2-oneyl) -3-methylbutane-amino-1 -phenyl-6-methylheptane A. (2S.3S.5S) -2-Amino-3-hydroxy-5- (t-butyloxycarbonylamino) -1-fe or I-6-methyl heptane Following the procedures described in Example 1A to Example 1F-1, but replacing isopropylmagnesium chloride for benzylmagnesium chloride in Example 1C, the desired compound was provided. 300 MHz 1H NMR (CDCb) d 0.88 (d, J = 7Hz, 3H), 0.92 (d, J = 7Hz, 3H), 1.43 (s, 9H), 1.50-1.80 (m, 4H), 2.55 (m, 1H), 2.90 (m, 1H), 3.0 (m, 1H), 3.54 (m, 2H), 4.62 (m, 1H), 7.30 (m, 5H). Mass spectrum: (M + H) + = 337.

B. (2S.3S.5S) -2- (2,6-D-methylphenoxyacetyl) amino-3-hydroxy-5- (t-butyloxycarbonylamino) -1-phenyl-6-methylheptane The coupling of the amino compound of Example 27A with the Example 1H acid, using a normal EDAC coupling procedure, provided the desired compound. 300 MHz 1H NMR (CDCb) d 0.85 (d, J = 7Hz, 3H), 0.90 (d, J = 7Hz, 3H), 1.43 (s, 9H), 1.70 (m, 2H), 2.20 (s, 6H) , 3.03 (d, J = 8Hz, 2H), 3.42 (m, 1H), 3.80 (m, 1H), 4.20 (m, 2H), 4.22 (s, 2H), 4.55 (m, 1H), 7.0 (m , 3H), 7.30 (m, 5H). Mass spectrum: (M + H) + = 499.

C. (2S.3S.5S) -2- (2,6-Dimethyl-phenoxyacetyl) amino-3-hydroxy-5-1-phenyl-6-methylheptane The removal of the t-butyloxycarbonyl protecting group from the compound of Example 27B, using the procedure of Example 1N, provided the desired compound. 300 MHz 1H NMR (CDCb) d 0.90 (d, J = 3Hz, 3H), 0.94 (d, J = 3Hz, 3H), 1.60 (m, 4H), 2.20 (s, 6H), 2.85 (m, 2H) , 3.0 (m, 1H), 3.85 (m, 1H), 4.20 (m, 2H), 7.0 (m, 2H), 7.35 (m, 6H). Mass spectrum: (M + H) + = 399.

D. (2S.3S.5S) -2- (2.6-D imeti If enoxyacetyl) amino-3-hydroxy-5-r2S-M-tetra hydro-pyrimid-2-onyl) -3-methylbutanoip amino-1 phenyl-6-methylheptane The coupling of the amino compound of Example 27C with the acid of Example 2A, using a normal coupling procedure (EDAC / DMF) provided the desired compound. 300 MHz 1H NMR (CDCb) d 0.88 (m, 12H), 1.67 (m, 2H), 1.90 (m, 1H), 2.20 (s, 6H), 3.0 (d, J = 8Hz, 2H), 3.22 (m , 4H), 3.67 (m, 1H), 3.77 (m, 1H), 4.20 (s, 2H), 4.40 (m, 1H), 4.76 (m, 1 H), 7.0 (m, 3H), 7.30 (m , 5H). Mass spectrum: (M + H) + = 581.

EXAMPLE 28 (2S.3S.5S) -2- (2,6-Dimethyl-phenoxyacetyl) amino-3-hydroxy-5-r 2 S-1-tetrahydro-pyrimid-2,4-dionyl) -3-methylbutanoin amino-1-phenyl-6-methylheptane Coupling of the amino compound of Example 27C with the acid of Example 25D, using a normal coupling procedure (EDAC / DMF) provided the desired compound. 300 MHz 1H NMR (CDCb) d 0.83 (d, J = 7Hz, 6H), 0.92 (t, J = 7Hz, 6H), 1.73 (m, 2H), 2.18 (s, 6H), 2.30 (m, 1H) , 2.62 (m, 2H), 3.03 (m, 2H), 3.45 (m, 1H), 3.55 (m, 1H), 4.72 (m, 2H), 4.20 (m, 4H), 6.40 (br d, J = 9Hz, 1H), 7.0 (m, 3H), 7.30 (m, 5H), 7.62 (br s, 1H). Mass spectrum: (M + H) + = 595.

EXAMPLE 29 (2S.3S.5S) -2- (2.6-D imet-ilphenoxyaceti I) amino-3-hydroxy-5-F2S-M-piperazine-2,3-dionyl) -3-methylbutanoi and amine -1, 6 -diphenylhexane A. 2S- (4-benzyloxycarbonyl-1-piperazin-2,3-dioni I) -3-methyl butanoic acid methyl ester To a solution of 0.77 g of N- (benzyloxycarbonylamino) -ethyl-L-valine methyl ester in 20 ml of toluene and 10 ml of acetonitrile were added 0.79 g of oxalyl diimidazole. The reaction mixture was maintained at 50 ° C for 24 hours and 0.2 g of oxalyl diimidazole was added. The reaction mixture was maintained at 50 ° C for another 72 hours. Evaporation of the solvent in vacuo and purification of the crude product through silica gel chromatography (10% EtOAc in CH 2 Cl 2) provided the desired compound. 300 MHz 1 H NMR (CDCb) d 0.95 (d, J = 7 Hz, 3 H), 1.03 (d, J = 7 Hz, 3 H), 2. 20 (m, 1H), 3.60 (m, 1H), 3.73 (s, 3H), 3.85 (m, 1H), 4.0 (m, 1H), 4. 10 (m, 1H), 4.90 (d, J = 10 Hz, 1H), 5.36 (s, 2H), 7.20 (m, 5H). Mass spectrum: (M + NH4) + = 380.

B. 2S- (1-piperazin-2,3-dionyl) -3-methylbutanoic acid methyl ester Removal of the benzyloxycarbonyl protecting group from the compound of Example 29A through hydrogenolysis using 10% Pd / C as a catalyst provided the compound wanted. 300 MHz 1 H NMR (CDCb) d 0.95 (d, J = 7 Hz, 3 H), 1.03 (d, J = 7 Hz, 3 H), 2.20 (m, 1 H), 3.50 (m, 3 H), 3.74 (s, 3H), 3.83 (m, 1H), 5.0 (d, J = 10 Jz, 1H), 7.30 (br s, 1H). Mass spectrum: (M + H) + = 229 C. (2S.3S.5S) -2- (2.6-Pi methylpinoxy acetyl I) amino-3-hydroxy-5-r2S-M-piperazin-2,3-dionyl) -3-methylbutanoin amino-1, 6- diphenylhexane The methyl ester of Example 29B was hydrolyzed using the procedure of Example 1M and the resulting acid was coupled to the amino compound of Example 1N, using a normal EDAC coupling procedure, to provide the desired compound. 300 MHz 1 H NMR (CDCb) d 0.82 (d, J = 6 Hz, 3 H), 0.85 (d, J = 6 Hz, 3 H), 1.80 (m, 2 H), 2.18 (m, 1 H), 2.20 (s, 6H), 2.65 (m, 1H), 2.82-3.0 (m, 4H), 3.3Q (m, 3H), 3.70 (m, 1H), 3.82 (m, 1H), 4.22 (m, 3H), 4.54 ( d, J = 10 Hz, 1H), 6.30 (br s, 1H), 6.65 (br d, 1H), 7.0-7.30 (m, 13H). Mass spectrum: (M + H) + = 643.

EXAMPLE 30 (2S.3S, 5S) -2- (2,6-Di methyl-enoxyacetyl) amino-3-hydroxy-5-y2S- (4-aza-4,5-dehydro-1-pyrimid-2-onyl) - 3-methyl-butanoin amino-1,6-diphenylhexane A. 2S- (4-aza-4,5-dehydro-1-pyrimid-2-onyl) -3-methyl-butanoic acid From the mixture of the hydrolysis product of Example 26F, the desired product was isolated after column chromatography (5% MeOH / 5% AcOH in CH 2 Cl 2) in a yield of 12.5%. 300 MHz 1H NMR (CD3OD) d 0.93 (d, J = 7Hz, 3H), 1.04 (d, d = 7Hz, 3H), 2.20 (m, 1H), 3.92 (dd, J = 15, 3 Hz, 1H) , 4.09 (dd, J = 15, 3 Hz, 1H), 4.50 (d, J = 10 Hz, 1H), 6.95 (t, J = 3 Hz, 1H). Mass spectrum: (M + H) + = 334.

B. (2S.3S.5S) -2- (2,6-Dimethyl-phenoxyacetyl) amino-3-hydroxy-5-r2S- (4-aza-4,5-dehydro-1-pyrimid-2-onyl) -3-methyl butane-p-amino-1,6-diphenylhexane Coupling of the compound of Example 1N with the acid of Example 30A, using a normal coupling procedure (EDAC / DMF), provided the desired compound (70%). 300 MHz 1H NMR (CDCb) d 0.80 (d, J = 7Hz, 3H), 0.85 (d, J = 7Hz, 3H), 1.75 (m, 2H), 2.15 (m, 1H), 2.20 (s, 6H) , 2.62 (m, 1H), 2.85 (m, 1H), 3.02 (m, 2H), 3.55 (m, 2H), 3.80 (m, 1H), 4.20 (m, 4H), 6.38 (br d, 1H) , 6.72 (t, J = 3 Hz, 1H), 7.0 (m, 3H), 7.22 (, 10H), 7.63 (s, 1H). Mass spectrum: (M + H) + = 628.

EXAMPLE 31 Cis-N-tert-butyl-decahydro-2-r 2 (R) -hydroxy-4-phenyl-3 S) - (2S-f 1 -tetrahydropyrimid-2-oneyl) -3-methylbutanoyl) aminobutyl- (4aS.8aS ) - isoquinolin-3 (S) -carboxyamide The title compound can be prepared by coupling the product of Example 2A with cis-N-tert-butyl-decahydro-2- [2 (R) -hydroxy-4-phenyl-3 (S) -aminobutyl] - (4aS, 8aS ) -isoquinolin-3 (S) -carboxy-amide (described in PCT patent application No. WO9426749 and US Patent No. 5,196,438, issued March 23, 1993, both incorporated herein by reference) using a method of Normal coupling (EDAC in DMF).

EXAMPLE 32 Cis-N-tert-butyl-decahydro-2-r2 (R) -hydroxy-4-thiophenyl-3 (S) - (2S- (1-tetrahydropyrimid-2-oneyl) -3-methylbutanoyl) aminobutyl- ( 4aS.8aS) - isoquinolin-3 (S) -carboxyamide The title compound can be prepared by coupling the product of Example 2A with cis-N-tert-butyl-decahydro-2- [2 (R) -hydroxy-4-thiophenyl-3 (S) -aminobutyl] - (4aS, 8aS ) -isoquinolin-3 (S) -carboxyamide (described in PCT patent application No. WO95 / 09843, published April 13, 1995 and US Patent No. 5,484,926, issued January 16, 1996) , both incorporated herein by reference) using a normal coupling procedure (EDAC in DMF).

EXAMPLE 33 4-Amino-N - ((2sin. 3S) -2-hydroxy-4-phenyl-3- (2S- (1-tetrahydropyrimid-2-oneyl) -3-methylbutanoylamino) -butyl) -N-isobutyl- benzene sulfonamide The title compound can be prepared by coupling the product of Example 2A with 4-amino-N - ((2 syn, 3S) -2-hydroxy-4-phenyl-3-amino) -butyl-N-isobutyl-benzenesulfonamide (described in PCT Patent Application No. WO94 / 05639, published March 17, 1994, which is incorporated herein by reference) using a standard coupling procedure (EDAC in DMF).

EXAMPLE 34 A. Alternate preparation of (2S.3S.5S) -2- (2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-amino-1,6-dipheniihexane To a 1 liter three-necked flask equipped with a mechanical stirrer , J-Kem® temperature probe, a dropping funnel, and a dry nitrogen line were charged 30.0 (54.87 mmol) of the product of Example 11 and 120 ml of acetonitrile. The resulting slurry was cooled to 0-5 ° C and 54.1 g (549 mmoles) of 37% aqueous hydrochloric acid were added slowly, maintaining an internal temperature of no more than + 5 ° C during the addition. The reaction mixture was stirred at 0-5 ° C and samples were taken periodically to analyze the consumption of the starting material by HPLC (Zorbax C-8 column, mobile phase = 1: 1 acetonitrile / 0.1% phosphoric acid aqueous, flow rate = 1.5 ml / minute, detection at 205 nm). After stirring for 3 hours, the reaction mixture was complete. The reaction was quenched by slowly adding 105 ml of 20% aqueous sodium hydroxide, again maintaining an internal temperature of no more than + 5 ° C during the addition. Once the pH of the reaction mixture was confirmed as basic, the solution was warmed to room temperature. Ethyl acetate (180 ml) was added with stirring and, after settling, the lower aqueous phase was separated and discarded. The organic phase was then flushed once with 105 ml of 10% aqueous sodium chloride.The title compound was catalyzed from 12 ml / g of 1: 2 ethyl acetate / heptane (yield 80-85). %).

B. Alternate Preparation of (2S, 3S, 5S) -2- (2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-amino-1,6-diphenylhexane To a 1 liter three-necked round bottom flask with a bar of bound mechanical stirring and thermometer, the product of Example 11 (51.6 g, 0.095 mol) and 100 ml of glacial acetic acid was added. To the resulting suspension was added 35% aqueous HCl (10.5 mL, 0.103 moles) in one portion. The solution was allowed to stir under an N2 atmosphere for 3 hours, at which time an additional 10.5 ml of 35% aqueous HCl was added. After a further 1.5 hours, the reaction flask was immersed in an ice bath and a solution of NaOH (16 ml, 0.198 mol) was added at a rate to maintain the internal temperature of the flask below 30 ° C. Water (200 ml) was added and the mixture was extracted with 4 x 200 ml ethyl acetate. The combined organic layers were washed with 2.5 M NaOH (2 x 200 mL), 100 mL H2O, brine, dried over Na2SO4, filtered and evaporated in vacuo to yield 39.7 g (94% crude) of a product as a colorless solid with a purity greater than 95% through HPLC. The product can be further purified by dissolving in 200 ml of isopropanol heated on a steam bath, cooled with stirring at 0-5 ° C to produce 32.2 g (76%) of the desired product, Mp = 131 ° C.

EXAMPLE 35 Alternate Preparation of 2S- (1-tetrahydro-pyrimid-2-onyl) -3 methyl butanoic acid A. N-Phenoxycarbonyl-L-valine N-Phenoxycarbonyl-L-valine can be prepared according to the procedures described in the U.S. Patent Application No. 08/08 / 671,893, filed June 28, 1996, which is incorporated herein by reference, and which includes the following method. In a reactor equipped with an overhead stirrer, cooler, pH probe and a thermocouple, lithium chloride (15.6 kg, 368 moles), L-valine (26.0 kg, 222 moles), neutral alumina (8.1 kg, 150 mesh) were added. , Aldrich) and 156 kg of distilled water. The heterogeneous mixture was stirred and cooled to -14 ° C ± 5 ° C. The pH was adjusted to 10.1 with 10% aqueous lithium hydroxide. Phenylchloroformate (36.6 kg, 234 mol) was added pre-cooled (-20 ° C), while maintaining a temperature of no more than -9 ° C and the pH was controlled during the reaction (keeping the pH within the range of 9.5 to 10.5 with a goal of 10.0) using a continuous addition of 10% aqueous lithium hydroxide. The reaction was stirred for 2 hours at about -14 ° C.

The reaction mixture was filtered through Celite and the filter cake was washed with 42 kg of distilled water. The aqueous filtrate was extracted with methyl t-butyl ether (65 kg) to remove residual phenol. The aqueous phase was then cooled to 0-5 ° C and mixed with 200 kg of toluene. The stirred biphasic solution was adjusted to a pH of 1.8-2.0 with 25% sulfuric acid (w / w). The toluene layer was concentrated to no more than 40 ° C to about 12 liters, filtered (30 kg of toluene rinse) and then concentrated again to no more than 40 ° C to about 120 liters. To the resulting solution was added 44.2 kg of heptane and the resulting solution was heated at 40 ° C ± 10 ° C for 15 minutes. The heat was removed and the solution was seeded and stirred overnight. The product was crystallized on the walls of the reactor and resuspended in 80 kg of toluene, re-concentrated at no more than 50 ° C to about 130 liters, then 45.2 kg of heptane was added. The resulting solution was then heated to 40 ° C ± 10 ° C for no more than 15 minutes and then cooled to no more than 20 ° C / hour at 18 ° C ± 5 ° C. After no more than 12 hours, the resulting white mud was cooled to 14 ° C ± 5 ° C and stirred for not more than 3 hours. The white mud was filtered and the solid was washed with 41 kg of 1: 1 toluene / heptane. The solid product was dried at no more than 50 ° C to provide the desired product (47.8 kg) as a white powder.

B. 2S- (1-Tetrahydro-pyrimid-2-oneyl) -3-methyl butanoic acid A mixture of N-phenoxycarbonyl-L-valine (25 kg, 0.106 moles) and 3-chloropropylamine hydrochloride (15.2 g, 0.116 moles) ) in THF (250 ml) was cooled to 2 ° C. Sodium hydroxide (12.7 g, 0.318 mol) was added to the stirring suspension. After approximately 35 minutes, a slow exotherm occurred at 10 ° C. The reaction was stirred at less than 10 ° C for 2 hours. A solution of potassium t-butoxide (29.6 g, 0.265 mole) in 125 mL of THF was added for 10 minutes, followed by a rinse in 20 mL of THF. The temperature of the reaction mixture was allowed to increase to 20 ° C during the addition. The reaction mixture was stirred at room temperature for 19 hours. The reaction mixture was quenched with 200 ml of distilled water and then acidified to a pH of 9 using 26.2 g of concentrated hydrochloric acid, keeping the temperature below 30 ° C. The aqueous layer was separated and washed with another 125 ml of THF. 3A ethanol (75 ml) was added to the separated aqueous layer and the mixture was acidified to a pH of < 3 with 12.3 g of concentrated hydrochloric acid, keeping the temperature below 25 ° C. The acidified mixture was extracted twice with ethyl acetate (250 ml and 150 ml). The combined organic layers were evaporated to dryness on a rotary evaporator at a temperature below 50 ° C. The residual solids were flooded with 250 ml of ethyl acetate. The residual solid was dissolved in 150 ml of 3A ethanol at reflux temperature and filtered through 5 g of a Darco-G60 bed on a filter aid, followed by rinsing 50 ml of ethanol. The filtrate was evaporated to dryness on a rotary evaporator at a temperature below 50 ° C. Ethyl acetate (75 ml) was added to the residue and refluxed for 30 minutes. The suspension was cooled to below 10 ° C for 2 hours. The solid was collected through filtration and washed with 20 ml of cold ethyl acetate (5-8 ° C). After drying at 40 ° C for 72 hours, the desired product was obtained as a white solid (15.6 g, 74%).

EXAMPLE 36 Alternate Preparation of 2S- (1-Tetrahydro-pyrimid-2-oneyl) -3-methyl butanoic acid A mixture of phenoxycarbonyl-L-valine (250 g, 1.05 moles, prepared according to the procedure described in US Patent Application No. 08 / 671,893, filed June 28, 1996, which is incorporated herein by reference ) and 3-chloropropylamine hydrochloride (151 g, 1.16 moles) in THF (2.5 L) was cooled to 2 ° C. Sodium hydroxide (127 g) was added, 3.2 moles) to the resulting suspension. After approximately 45 minutes, a rapid exotherm occurred at 10 ° C. The reaction was stirred at 1-5 ° C for 2 hours. Additional 3-chloropropylamine (10 g, 0.08 mol) was added and stirring was continued for 1 hour. A solution of potassium t-butoxide (296 g, 2.6 moles) in 1.25 L of THF was then added for 30 minutes, followed by a rinse of 100 ml of THF. The temperature of the reaction mixture was allowed to increase to 20 ° C during the addition. The reaction mixture was stirred at room temperature for 12-16 hours. The reaction mixture was quenched with 2 L of distilled water and cooled to 12 ° C and then acidified to a pH of 9 using 258 g (2.6 moles) of concentrated hydrochloric acid, keeping the temperature below 30 ° C. The aqueous layer was separated. 3A ethanol (625 ml) was added to the separated aqueous layer and the mixture was acidified to a pH of <3 with 116 g (1.2 moles) of concentrated hydrochloric acid, keeping the temperature below 25 ° C. The acidified mixture was extracted twice with ethyl acetate (2.5 L and 1.5 L). The combined organic layers were evaporated to dryness on a rotary evaporator at a temperature below 50 ° C. The residual solids were dried by repeated distillation with ethyl acetate (4 x 1 L). The residual solid was dissolved in 750 ml of methanol and treated with decolorization carbon (10 g of Darco-G60 bed) at room temperature overnight. The carbon was removed through filtration through diatomic soil. The filtrate was evaporated to dryness on a rotary evaporator at a temperature below 50 ° C. Ethyl acetate (1.5 L) was added to the residue and about 500 ml were stirred on a rotary evaporator. The suspension was cooled below 10 ° C during > 1 hour. The solid was collected through filtration and washed with 2 x 100 ml of cold ethyl acetate (5-8 ° C). After drying at 50 ° C for 72 hours, the desired product was obtained.

EXAMPLE 37 Alternate Preparation of 2S- (1-tetrahydro-pyrimid-2-oneyl) -3-methyl butanoic acid A. (S) - (-) - N-carboxymethyl-Nfß) cyanoethyl Valine To a 5-liter, three-necked round bottom flask with a mechanical stirring bar was added (S) -valin (170.1 g , 1.45 moles) and water (145 ml). The solution was cooled to 0 ° C with an ice-water bath and a solution of 1.0 equivalents of KOH (93 g of 88% solid KOH) in 180 ml of water was added dropwise over 20 minutes. After the addition was complete, 1.0 equivalents of acrylonitrile (95.5 ml) were added dropwise with vigorous stirring while maintaining the internal temperature of the flask below 5 ° C. The solution was allowed to stir at 0-5 ° C for 4.5 hours. Water (600 ml) was added and a pH meter was inserted into the solution. 1.0 equivalent of methyl chloroformate was added dropwise, while maintaining the pH of the solution between 9.5 and 10.5, with a 10% aqueous KOH solution. The addition took approximately 0.5 hours. Then, the solution was acidified with concentrated HCi and phosphoric acid to a pH of 2 and subsequently extracted with 2 L of ethyl acetate. The organic layer was concentrated under vacuum to give 201 g (60%) of a colorless oil which solidified on standing. Mp 65-66 ° C. Line D of sodium of optical rotation at 25 ° C -0.44 (c = 4.3, ethanol). IR (cm'1, CDCb) 2960, 1740, 1710, 1470. 1 H NMR (300 MHz, CDCb); (d TMS, 0.00) ppm 0.93 (d, 3H J = 7Hz); 1.07 (d, 3H J = 6Hz); 2.16-2.36 (m, 1H); 2.62-2.86 (m, 2H); 3.62 (t, 2H, J = 7.5 Hz); 3.77 (s, 1.2H rotamer); 3.82 (s, 1.8H rotamer); 4.15-4.30 (m, 1H); 9.76-9.96 (brs, 1H). ms (DCI / NH3) 246, 185, 146, 25. FAB hrms: cale, for (M + H +): 229.1188; It was found: 229.1185.

B. 2S- (1-Tetrahydro-pyrimid-2-oneyl) -3-methyl butanoic acid To a 2-L pressure flask was added the product of Example 37A (190 g, 0.833 moles), water (900 ml). and KOH (3 eq, 140 g). To this solution at room temperature was added a Nickel-Aluminum alloy (Raney type). Note that this is the non-activated form. The solution was sealed in a pressure pump and placed under 4,218 kg / cm 2 of hydrogen. The resulting solution was heated at 100 ° C for 4 hours. After cooling the solution to room temperature, it was filtered, washed with 900 ml of dichloromethane and subsequently acidified to a pH of 1. The aqueous solution was extracted with 2 x 900 ml of dichloromethane. The combined organic layers were concentrated to give 120 g of the crude product, which was made as a slurry in isopropyl acetate to give 70 g of the title compound.

EXAMPLE 38 Alternate Preparation of (2S, 3S.5S) -2- (2,6-Dimethylphenoxyacetyl) amino-3-hydroxy-5-r2S- (1-tetrahydro-pyrimid-2-oneyl) -3-methyl butanoill amino-1. 6 -diphenylhexane A-1 Chloride of 2S- (1-tetrahydro-pyrimid-2-oneyl) -3-methyl butanoyl Slurry 2S- (1-tetrahydro-pyrimid-2-onyl) -3-methyl butanoic acid (17.6 g, 87.9 mmol) in THF (240 mL) was made and cooled to < 5 ° C. Thionyl chloride (14.3 g, 120 mmol) was added over 5 minutes (extothermic). The slurry was stirred at 20 ° C for 70 minutes until complete by HPLC (the samples were quenched in methanol). The THF was removed through rotary evaporation; heptane (90 ml) was added and stirred through rotary evaporation, yielding a wet solid mass. The material was made as a slurry in DMF (85 ml).

A-2. Alternate Preparation of 2S-M -tetrahydro-pyrimid-2-oniH-3-methyl butanoyl chloride. 2S- (1-tetrahydro-pyrimid-2-oneyl) -3-methyl butanoic acid (39.6 g, 198) was made as a slurry. mmoles) in THF (590 ml) and cooled to 1 ° C. Thionyl chloride (28.3 g, 238 mmol) was added over 5 minutes (exothermic). The slurry was stirred at 20 ° C for 2 hours. The THF was removed on the rotary evaporator; THF (200 ml) was added and stirred on the rotary evaporator, yielding a wet solid mass. The material was made a slurry in DMF (225 ml).

B-1. (2S.3S.5S) -2-NN-dibenzylammon-3-hydroxy-5-r2S- (1-tetrahydropyrimid-2-oneyl) -3-methyl butanoyl amino-1,6-diphenylhexane (2S, 3S, 5S) -2-N, N-dibenzylamino-3-hydroxy-5-amino-1,6-diphenylhexane (approximately 83 mmoles; patent of E.U.A. No. 5,491,253, issued February 13, 1996, which is incorporated herein by reference) and imidazole (8.2 g, 120 mmol) were dissolved in ethyl acetate (350 ml, KF < 0.1%) and cooled to 2 g. ° C. The sludge product of Example 38A-1 was added (exothermic, maximum temperature of 10 ° C), followed by a rinse of DMF (15 ml). The reaction was initially cold-stirred, then allowed to warm slowly to room temperature and stirred overnight. The reaction was quenched with 100 ml of water and stirred for 30 minutes. The organic layer was separated and washed with 3 x 125 ml of 5% NaCl. The organic solution was filtered and concentrated on a rotary evaporator to a thick syrup, 62 g. Purity by HPLC of about 85 & (peak area). Approximate isomer content of 11.2%. CIMS (NH3) m / z 647 (M + H) +. 1 H NMR (300 MHz, CDC b) d 7.35-7.13 (m, 10 H), 7.13-7.06 (m, 1 H), 6.87 (br d, 1 H), 5.22 (br s, 1 H), 4.28 (d, 1 H), 4.20-4.05 (m, 1H), 3.95 (d, 2H), 3.65-3.56 (m, 1H), 3.37, (d, 2H), 3.12-2.89 (m, 5H), 2.83-2.53 (m, 4H) , 2.23-2.08 (m, 1H), 1.74-1.40 (m, 4H), 0.87-0.75 (m, 6H). 13C NMR (75 MHz, CDCb) d 170.0, 156.6, 140.2, 139.1, 138.4, 129.3, 129.1, 128.9, 128.4, 128.3, 128.0, 127.1, 126.0, 125.8, 69.1, 64.0, 63.1 (br), 54.2, 49.2, 41.2, 40.5, 40.0, 39.7, 31.5, 25.4, 21.6, 19.5, 18.6.

B-2 Alternate Preparation of (2S.3S.5S) -2-NN-dibenzylamino-3-hydroxy-5-r2S- (1-tetrahydro-pyrimid-2-oneyl) -3-methylbutane and II-amino-1,6-diphenylhexane ( 2S, 3S, 5S) -2-N, N-dibenzylamino-3-hydroxy-5-amino-1,6-diphenylhexane (approximately 180 mmol, US Patent No. 5,491,253, issued February 13, 1996, which incorporated herein by reference) and imidazole (38.1 g, 560 mmol) were dissolved in ethyl acetate (675 mL, KF <0.1%) and cooled to 1 ° C. The sludge form of Example 38A-2 was added slowly over 30 minutes (exothermic, maximum temperature of 6 ° C), followed by a rinse of ethyl acetate (225 ml). The reaction was stirred cold for 1.5 hours, then allowed to slowly warm to about 27 ° C and stirred for about 20 hours. The reaction was quenched with a dilute solution of HCl (36.75 g of concentrated HCl in 25 ml of water) and stirred for 20 minutes. The biphasic mixture was filtered with a 100 ml rinse of ethyl acetate. The organic layer was separated and washed with 3 x 125 ml of 5% NaCl. The organic layer was separated and washed with 3 x 225 ml of 5% NaCl and 2 x 225 ml of 5% NaHCO3. The organic solution was concentrated through rotary evaporation to provide the desired product as a thick syrup.

C. (2S.3S.5S) -2-Amino-3-hydroxy-5-r2S- (1-tetrahydro-pyrimid-2-oneyl) -3-methyl butanoyl amino-1,6-diphenylhexane The crude product of the Example 38B (approximately 83 mmol) was dissolved in methanol (260 ml). Pd / C (50% wet Pearleman catalyst, 10.4 g wet weight) and ammonium formate (15.1 g, 239 mmole) were added and the mixture was heated to 50 ° C. After 2.5 hours, the reaction was complete through TLC. The mixture was cooled to 35 ° C and the catalyst was removed by filtration through diatomaceous earth, followed by a methanol rinse (250 ml). The combined filtrate was concentrated on the rotary evaporator. The residue was dissolved in dioxane (150 ml) with heating. The dioxane was removed on the rotary evaporator to yield 60 g of a purity yellow oil by HPLC of approximately 882% (peak area). Isomer content > 79% (however, one isomer is not separated from the main peak) CIMS (NH3) m / z 467 (M + H) + 1H NMR (300 MHz, CD3OD) d 735-710 (m, 10H), 440-420 (m, 1H), 425 (d, 1H), 368-357 (m, 1H), 320-309 (m, 2H), 308-290 (m, 3H), 290-274 (m, 2H), 2.65 -249 (m, 2H), 220-204 (m, 1H), 1 92-178 (m, 1H), 1 78-160 (m, 2H), 160-145 (m, 1H), 088-077 ( m, 6H) 13C NMR (75 MHz, CD3OD) d 171.3, 158.4, 1405, 1398, 130.6, 1304, 1295, 1293, 1273, 1270, 71 5, 639, 57.1, 491, 41.8, 41.6, 41 4, 407, 40.5, 269, 225, 200, 189 1 H NMR (300 MHz, CDC b) d 7.35-7 13 (m, 10 H), 535 (s, 1 H), 440-423 (m, 2 H), 360-3.52 (m, 1 H), 325-265 (m, 8H), 2.58-2.45 (dd, 1H), 2.30-2 10 (m, 1H), 1.90-1 65 (m, 3H), 1.65-1.50 (m, 1H), 091 (d, 3H), 084 ( d, 3H) 13C NMR (75 MHz, CDCb) d 171 2, 1566, 139.1,1385, 129.3, 129.2, 1285, 1282, 1263, 1260, 71.6, 63 1 (br), 563, 487, 41 6, 41 0, 406 , 400, 396, 255, 21.7,19,7,187 D. (S) -pyroqlutamic acid salt of (2S.3S, 5S) -2-amino-3-hydroxy-5-r2S- (1-tetrahydro-pyrimid-2-oneyl) -3-methyl butanoyl) amino- 1.6- diphenylhexane The crude product of Example 38C was dissolved in dioxane (370 ml KF = 0.07% moisture). S-pyroglutamic acid (10.3 g, 80 mmol) was added and the suspension was heated to 50 ° C to give a clear solution. After stirring 1 hour, the solution was seeded with few crystals of the salt of the product. The salt precipitated slowly. The slurry was cooled slowly and stirred overnight at room temperature. The product was isolated through filtration and washed with dioxane (100 ml). The weight of the wet cake was 120 g. The product was dried at 60 ° C in a vacuum oven with a nitrogen purge. 35.2 g of a whitish powder was produced. Purity by HPLC: >98% (peak area including pyroglutamic acid). Isomer content approximately 1% (however, an isomer is not separated from the main peak). Mp = 135-14 ° C. [a] D25 = -21.9 ° (c = 2.5, CH3OH) CIMS (NH3) m / z 467 (M + H for base) \ 147 (M + NH for pyroglutamic acid) *, 130 (M + H for pyroglutamic acid ) * IR (KBr) 1586,1655,1682 cm " 1 H NMR (400 MHz, DMSO-d 6) d 7.62 (s, 1 H), 7.54 (d, 1 H), 7.32-7.06 (m, 10 H), 6.33 (s, 1 H), 4.26 (d, 1 H), 4.11- 3.99 (m, 1H), 3.82 (dd, 1H), 357-348 (m, 1H), 327-319 (m, 1H), 308-295 (m, 2H), 292-270 (m 5H), 253 -243 (m, 1H), 226-214 (m, 1H), 213-199 (m, 2H) 1 99-1 87 (m, 2H), 1 72-161 (m, 2H), 161-149 (m, 1H), 146-1 35 (m, 1H), 070 (d, 3H), 064 (d, 3H) 13C NMR (100 MHz, DMSO-d6) d 1769, 1761.1692, 1555, 1388, 1377 1293, 1293, 1283, 1278, 1264, 1255, 669, 61 5, 569, 553, 468, 402, 396, 394 , 388, 374, 298, 254, 253, 216, 196, 187 1 H NMR (300 MHz, CD 3 OD) d 732-703 (m, 10 H), 423-412 (m, 1 H), 412 (d, 1 H), 398 (dd, 1 H), 371-363 (m, 1 H), 346-337 (m, 1H), 311-298 (m, 2H), 297-280 (m, 4H), 270-259 (m, 1H), 249-238 (m, 1H), 238-212 (m , 3H), 207-1 92 (m, 2H), 175-163 (m, 2H), 163-150 (m, 1H), 145-132 (m, 1H), 074-065 (m, 6H) 13C NMR (75 MHz, CD3OD) d 1810, 1796, 1716, 1584, 1395, 1373, 1305, 1300, 1294, 1283, 1272, 681, 640, 596, 577, 488, 41 7, 41 1, 407, 406 , 379, 31 1, 269, 269, 225, 201,189 1 H NMR (300 MHz, D 2 O) d 730-697 (m, 10H), 416-403 (m, 1H), 399-391 (m, 2H) 371-363 (m, 1H), 343-335 (m, 1H), 300-268 (, 6H), 240-213 (m, 5H), 188-1 72 (m, 3H), 168-156 (m, 1H), 152-1 37 (m, 1H), 132 -1 18 (m, 1H), 060-052 (m, 6H) 13 C NMR (75 MHz, D 2 O) d 181.6, 180.1, 171.0, 157.3, 137.9, 135.2, 129.3, 129.2, 129.1, 128.4, 127.6, 126.4, 67.3, 62.6, 58.2, 56.7, 47.5, 40.1, 39.4, 39.2, 38.7, 35.7, 29.6, 25.3, 25.2, 20.5, 18.5, 17.6.

E. (2S.3 S.5S) -2-f 2.6-Di methyl-enoxyacetyl) amino-3-hydroxy-5-r2S-f 1-tetrahydro-pyrimid-2-oneyl) -3-methyl butane and II amino- 1,6-diphenylhexane The product from Example 1H (7.26 g, 40.3 mmol) was formed in a slurry in ethyl acetate (22 ml) and thionyl chloride (5.75 g, 48.3 mmol) was added, followed by a drop of DMF. The mixture was heated to 50 ° C and stirred for 5 hours. The resulting acid chloride solution was cooled to 22 ° C and maintained for the subsequent coupling reaction. The product of Example 38D (20 g, 31.7 mmol, corrected for the dioxane content), sodium bicarbonate (16.5 g, 197 mmol), ethyl acetate (150 mL) and water (150 mL) were combined in a flask and they were stirred until the product of Example 38D dissolved (some of the salt remained undissolved). The acid chloride solution prepared above was added for 5 minutes, followed by a rinse of ethyl acetate (5 ml). The addition was moderately exothermic (maximum temperature of 23 ° C). The mixture was stirred overnight. The organic layer was separated and washed with 5% sodium bicarbonate (100 ml) and water (100 ml). The solvent was stirred on the rotary evaporator. The residue was dissolved in ethyl acetate (100 ml) and filtered, rinsed with ethyl acetate (50 ml). The solvent was removed from the combined filtrate on the rotary evaporator. The residue was dissolved in hot ethyl acetate (105 ml) and heptapo (105 ml) was added; the product began to crystallize rapidly. The slurry was cooled and stirred at 20-23 ° C for 5 hours. The product was collected by filtration and washed with 1/1 (v / v) ethyl acetate / heptane (30 ml). The product was dried under a vacuum oven at 70 ° C to provide 18.8 g of the desired product as a white powder.

EXAMPLE 39 Preparation of (2S, 3S.5S) -2- (2,6-Dimethylphenoxyacetyl) amino-3-hydroxy-5-r2S- (1-tetrahydro-pyrimid-2-oneyl) -3-methylbutanoiH at mino-1, Amorphous 6-diphenylhexane A. The product of Example 38E (2.5 g) was dissolved in 8 ml of absolute ethanol. This solution was slowly added dropwise to 250 ml of cold water at 9 ° C with vigorous stirring. Immediately a white solid appeared. Stirring was continued for 15 minutes and the solids were collected through filtration. Vacuum drying at 50 ° C for 12 hours provided 2.32 g of the desired product as an amorphous solid. B. The product of Example 38R (2.5 g) was dissolved in 6 ml of absolute ethanol. This solution was added slowly drop dropwise to 31 ml of cold water at 7-9 ° C with vigorous stirring. A white solid appeared. Stirring was continued for 20 minutes and the solids were collected through filtration. Vacuum drying at 50 ° C for 12 hours provided 2.25 g of the desired product as an amorphous solid. C. The product of Example 38E (0.5 g) was dissolved in 8 ml of isopropanol. This solution was slowly added dropwise to 100 ml of cold water at 10-15 ° C with vigorous stirring. A white solid appeared. Stirring was continued for 20 minutes and the solids were collected through filtration. Air drying provided 0.48 g of the desired product as an amorphous solid. D. The product of Example 38E (0.5 g) was dissolved in 8 ml of acetone and 0.2 ml of absolute ethanol. This solution was slowly added dropwise to 100 ml of cold water at 10-15 ° C with vigorous stirring. A white solid appeared. Stirring was continued for 10 minutes and the solids were collected through filtration. Air drying provided 0.46 g of the desired product as an amorphous solid. E. The product of Example 38E (0.5 g) was dissolved in 2 ml of acetonitrile. This solution was slowly added dropwise to 100 ml of cold water at 10-15 ° C with vigorous stirring. A solid appeared. Stirring was continued for 20 minutes and the solids were collected by filtration. Air drying provided 0.46 g of the desired product as an amorphous solid.EXAMPLE 40 N- (3-Chloropropylaminocarbonyl) -valine methyl ester 3-Chloropropyl isocyanate (0.31 ml, 3.0 mmol) was added to a slurry of L-valine methyl ester hydrochloride (0.5 g, 3.0 mmol) and triethylamine (0.42 ml, 3.0 mmol) in THF (10 ml). The reaction mixture was stirred for 4 hours at room temperature and then quenched with the addition of aqueous sodium bicarbonate. The quenched reaction mixture was extracted with ethyl acetate. The organic layer was separated, dried and evaporated to give the desired product.

EXAMPLE 41 (2S.3 S.5S) -2- (2,6-Di methyl-enoxyacetyl) amino-3-hydroxy-5-f2S-M-tetra hydro-4-h idroxy-pyrimid-2-onyl) -3- methyl butane ill ami no -1.6- diphenylhexane Reaction of a solution of the product of Example 25E in methylene chloride with sodium borohydride provided the desired product.

EXAMPLE 42 (2S.3S.5S) -2- (2,6-Dimethyl-phenoxyacetyl) amino-3-hydroxy-5-r 2 S- (1-tetrahydro-6-hydroxy-pyrimid-2-oneyl) -3-methyl butanoill amino-1.6 - diphenylhexane An incubation of 300 ml of (2S, 3S15S) -2- (2,6-dimethyphenoxy-acetyl) am i-3-idroxy-5- [2S- (1-tetrahydro-6-hydroxy-pyrimid-2 -onyl) -3-methyl butanoyl] amino-1,6-diphenylhexane labeled with 14C in the carbonyl group of the acetyl portion (50 μM, 6.0 μCi) was carried out with rat liver microsomes (0.5 mg / ml microsomal protein) and a NADPH generation system for 60 minutes at 37 ° C. The metabolic reaction was stopped by adding 300 ml of acetonitrile. The supernatant obtained after centrifugation at 3000 ROM for 10 minutes was evaporated to dryness in vacuo. The residue was reconstituted in 2 ml of the HPLC mobile phase. Isolation of the desired product was carried out at room temperature with a Cie column of 10 x 150 mm, 5 μ Beckman Ultrasphere connected to a Cartridge Safety Column of Co., 5 μ Alltech Ultrasphere. A linear gradient of 25-55% acetonitrile in pH buffer (25 nM ammonium acetate, the pH was adjusted to 4.8 with formic acid) for 57 minutes was used as a column eluent at a flow rate of 2.8 ml /minute.

Fluorochemical Test to Classify P rotease Inhibitors of V l_H The inhibitory potency of the compound of the invention can be determined by the following method. The compound of the invention was dissolved in DMSO and a small aliquot was further diluted with DMSO at 100 times the final concentration desired for testing. The reaction was carried out in a 6 x 50 mm tube in a total volume of 300 microliters. The final concentrations of the components in the pH regulator of the reaction are: 125 mM sodium acetate, 1 M sodium chloride, 5 mM dithiothreitol, 0.5 mg / ml bovine serum albumin, 1.3 μM substrate Fluorogenic, 2% (v / v) of dimethyl sulfoxide, pH 4.5. After the addition of the inhibitor, the reaction mixture was placed in the fluorometer cell holder and incubated at 30 ° C for several minutes. The reaction was initiated through the addition of a small aliquot of cold HIV protease. The fluorescence intensity (excitation at 340 nM, emission 490 nM) was recorded as a function of time. The reaction rate was determined during the first six to eight minutes. The observed speed is directly proportional to the moles of the substrate divided by unit of time. The inhibition percentage is 100 x (1- (speed in the presence of inhibitor) / (velocity in the absence of inhibitor)). Fluorogenic substrate: Dabcyl-Gaba-Ser-GIn-Asn-Tyr-Pro-lle-Val-GIn-EDANS, where DABCYL = 4- (4-dimethylamino-phenyl) -azobenzoic acid, Gaba =? -aminobutyric acid and EDANS = 5 - ((2-aminoethyl) amino) -naphthalen-1-sulfonic acid.

TABLE 1 Composed of Concentration Percentage of Example Inhibition Inhibition (nanomolar) 1 P 92.6 0.5 2B 93.2 0.5 3C 86.9 0.5 4F 49.7 0.5 5 80.8 0.5 6F 61.4 0.5 7B 67.1 0.5 8 55.6 0.5 9B 62.6 0.5 10F 81.0 0.5 1 1 B 91.1 0.5 12B 76.8 0.5 13B 56.2 1.0 14D 52.7 0.5 15 48 0.5 17C 87.2 0.5 18C 57.8 0.5 19E 68.5 0.5 22E 71.8 0.5 23C 86.0 0.5 25E 100 0.5 26H 94.6 0.5 27D 92.9 0.5 28 86.6 0.5 29C 72.6 0.5 30B 91.0 0.5 Antiviral Activity The anti-HIV activity of the compound of the invention can be determined in MT4 cells according to the following procedure. The MT4 cells were infected with HIVIIIB cell-free supernatant (previously frozen with an infectious dose of 50% tissue culture known (TCID50) at 0.003 multitude of infection (MOI) for one hour. cells were washed twice to remove the residual viruses, resuspended in a culture medium and seeded in 96-well tissue culture plates at 1x10 4 cells per well with various dilutions of average compound record. Uninfected cells as toxicity and cell controls were used as culture media, RPIM 1640 media (Gibco) with 10% fetal bovine serum, various concentrations of human serum (Sigma) at 50%, 25% and 12.5%. %, were added to the culture medium resulting in a final concentration of 60%, 35% and 22.5% of total serum.All test plates were incubated in a 37 degree centrifuge incubator for 5 days. MTT (Sigma, 5 mg / ml of material in PBS) was added to all wells at 25 μl per well, incubated for 4 hours. 20% SDS was placed with 0.02 N of HCl in water at 50 ul per well to use the cells. Plates incubated overnight to complete lysis were read on a microliter plate reader at 570/650 nm wavelengths to determine the cell's optical density (OD). The baseline data were analyzed for percent inhibition. through the following formula.

O D. of test cavity - O.D. virus control x 100 O D cell control - O D. virus control The 50% effective concentration (EC50) was calculated through the medium effect equation (Chou, 1975, Proc. Int Cong Pharmacol 6th page 619) to determine the efficacy of the compound. The 50% lethal concentration (LC5o) was calculated using uninfected MT4 cells Under these conditions, the following data were obtained (n = 4 determinations in duplicate) TABLE 2 Compound of ICgo LC§ or Example (μM.% Of plasma) íuMl 1 P 0.01 41.32 2B 0.016 17.78 3C 0.025 49.5 4F 0.101 > 100 5 0.368 > 100 6F 0.193 > 100 7B 0.204 > 100 8 0.019 17.78 9B 0.272 19.33 10F 0.047 91.97 1 1 B 0.19 18.16 12B 0.093 19.1 1 14D 0.053 > 100 15 0.119 > 100 17C 0.051 18.96 18C 0.329 19.1 19E 0.395 17.95 20D 0.283 24.08 25E 0.012 22.88 26H 0.015 33.0 27D 0.03 56.23 28 0.011 72.2 29C 0.427 56 30B 0.003 18 The compounds of the present invention can be used in the form of salts derived from inorganic or organic acids. These salts include, but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphor sulfonate, digluconate, cyclopentanpropionate, dodecylsulfate, entansulfonate, glucoheptanoate, cerphosphate, hemisulfate, heptanoate , hexanoate, fumarate, hydrochloride, hydrobromide, iodhydrate, 2-hydroxy-ethanesulfonate (isethionate), lactate, maleate, methanesulfonate, ntcotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate. Also, groups containing basic nitrogen can be quaternized with agents such as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl chlorides, bromides and iodides, lauryl, myristyl and stearyl, aralkyl halides such as benzyl and phenethyl bromides, and others. can obtain water-soluble or dispersible products Examples of acids that can be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid and organic acids such as oxalic acid, malic acid, succinic acid and citric acid. Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium or with organic bases. The compounds of the invention include hydrochloride, methanesulfonate, sulfonate, phosphonate and isethionate. The compounds of the present invention can also be used in the form of esters. Examples of such esters include compounds wherein a hydroxyl group in the compound of this invention has been acylated with an N-protected or non-protected amino acid residue, a phosphate function, a hemisuccinimide residue, an acyl residue of the formula R * C (O) - or R * C (S) - wherein R * is hydrogen, lower alkyl, haloalkyl, alkoxy, thioalkoxy, alkoxyalkyl, thioalkoxyalkyl or haloalkoxy, or an acyl residue of the formula Ra-C (Rb) ) (Rd) -C (O) - or Ra-C (Rb) (Rd) -C (S) -, wherein Rb and Rd are independently selected from hydrogen and lower alkyl and Ra is -N (Re) (Rf) ), ORe or -SRe, wherein Re and Rf are independently selected from hydrogen, lower alkyl and haloalkyl, or an amino acyl residue of the formula R180NH (CH2) 2NHCH2C (O) - or R? ß0NH (CH2) 2? CH2C (O) -, wherein R1~0 is hydrogen, lower alkyl, arylalkyl, cycloalkylalkyl, alkanoyl, benzoyl or an a-amino acyl group. The amino acid esters of particular interest are glycine and Usin; however, other amino acid residues may also be used, including those in which the amino acyl group is -C (O) CH2RN2ooR2o ?, wherein R200 and R201 are independently selected from hydrogen and lower alkyl or the -NR20oR2o group? forms a heterocyclic ring containing nitrogen. These esters serve as pro-drugs of the compound of the present invention and serve to increase the solubility of these substances in the gastrointestinal tract. These esters serve to increase the solubility for intravenous administration of the compound. Other pro-drugs include compounds wherein a hydroxyl group of this invention is functionalized with a substituent of the formula -CH (Rg) OC (O) R? 8? or -CH (Rg) OC (S) R181, wherein R18? is lower alkyl, haloalkyl, alkoxy, thioalkoxy or haloalkoxy and Rg is hydrogen, lower alkyl, haloalkyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl. Said pro-drugs can be prepared according to the Schreiber procedure (Tetrahedron Lett, 1983, 24, 2363) by ozonolysis of the corresponding metalic ester in methanol followed by treatment with acetic anhydride. The pro-drugs of this invention are metabolized in vivo to provide the compound of this invention. The preparation of the pro-drug esters is carried out by reacting the compound of the invention with an activated amino acyl, phosphoryl, hemisuccinyl or acyl derivative, as defined above. The resulting product is then deprotected to provide the desired pro-drug ester. The pro-drugs of the invention can also be prepared through alkylation of the hydroxyl group with haloalkyl (esters), trans-acetylation with bis- (alkanoyl) acetals or condensation of the hydroxyl group with an activated aldehyde followed by acylation of the intermediate hemiacetal. The compounds of the invention are useful for inhibiting retroviral protease, in particular HIV protease, in vitro or in vivo (especially in mammals, and in particular in humans). The compounds of the present invention are also useful for the inhibition of retroviruses in vivo, especially the human immunodeficiency virus (HIV). The compounds of the present invention are also useful for the treatment or prophylaxis of diseases caused by retroviruses, especially the acquired immunodeficiency syndrome or an HIV infection in a human or other mammal. The total daily dose administered to a human or other mammalian host in individual or divided doses may be in amounts, for example, from 0.001 to 300 mg / kg of body weight daily, and very usually from 0.1 to 20 mg / kg of body weight. body weight daily. The unit dose compositions may contain amounts of their submultiples to make the daily dose. The amount of active ingredient that can be combined with the carrier materials to produce an individual dosage form will vary depending on the host treated and in particular the mode of administration. It will be understood, however, that the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed, age, body weight, general health status, sex, diet, the time of administration, the route of administration, the rate of excretion, the combination of drug, and the severity of the particular disease that is under therapy. The compounds of the present invention may be administered orally, parenterally, sublingually, by inhalation spray, rectally or topically, in dosage unit formulations containing conventional, non-toxic pharmaceutically acceptable carriers, auxiliaries and vehicles, as desired. Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. The term parenteral, as used herein, includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing agents or humectants and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic pharmaceutically acceptable diluent or solvent, for example, as a solution in 1,3-propanediol. Among the vehicles and acceptable solvents that can be used is water. The Ringer's solution and an isotonic sodium chloride solution. In addition, fixed, sterile oils are conventionally used as a solvent or suspension medium. For this purpose, any soft fixed oil may be employed, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectable solutions. Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable non-irritating excipient such as cocoa butter and polyethylene glycols, which are solids at ordinary temperatures but liquid at rectal temperature, and therefore , they will melt in the rectum and release the drug. Solid dosage forms for oral administration may include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound can be mixed with at least one inert diluent such as sucrose, lactose or starch. Said dosage forms may also comprise, as is normal in practice, additional substances other than inert diluents, for example, lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, dosage unit forms may also comprise pH regulating agents. Tablets and pills can also be prepared with enteric coatings. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water. Said compositions may also comprise auxiliaries, such as wetting agents, emulsifying and suspending agents, sweeteners, flavors and perfume-providing agents. The compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed through hydrated, mono- or multi-lamellar liquid crystals, which are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The compositions herein in liposome form may contain, in addition to the compound of the present invention, stabilizers, preservatives, excipients, and the like.

The preferred lipids are phospholipids and phosphatidyl hills (lecithins), both natural and synthetic. In the art, methods for forming liposomes are known. See, for example, Prescott, Ed., Methods in Cell Biology.

Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq. Some preferred dosage forms for the compounds of this invention are described in the U.S. Patent Application. No. 08 /, presented on November 21, 1996, in the name of J. Lipari, L A. Al-Razzak, S. Ghosh and R. Gao, and which has the title Pharmaceutical Composition, the which is incorporated herein by reference. A preferred dosage form for the compounds of this invention comprises a solution of (a) a compound of formula I in the amount of about% to about 50% (preferably, about 5% to about 30%) by weight of the total solution, and (b) polyoxyl castor oil 35 in the amount of from about 0% to about 20% (preferably from about 5% to about 10%) by weight of the total solution, in a pharmaceutically organic solvent acceptable, which comprises (i) oleic acid in the amount of from about 20% to about 99% (preferably from about 30% to about 70%, most preferably, from about 40% to about 65%) by weight of the solution total, or (ii) a mixture of (1) oleic acid in the amount of from about 20% to about 99% (preferably, from about 30% to about 70%, most preferably, about 40% to 65%) in pes or of the total solution, and (2) ethanol or propylene glycol or a mixture thereof in the amount of from about 0% to about 12% (preferably, about 10%) by weight of the total solution. In a yet still very preferred embodiment of the invention, the solution is encapsulated in a capsule (soft elastic gelatin (SEC) or a hard gelatin capsule.) A highly preferred composition of the invention comprises a solution of (a) a compound of the formula I in the amount of about 30% by weight of the total solution, and (b) polyoxyl castor oil 35 in the amount of about 10% by weight of the total solution, in a pharmaceutically acceptable organic solvent, which comprises a mixture of (1) olete acid in the amount of about 50% by weight of the total solution, and (2) ethanol in the amount of about 10% by weight of the total solution In a highly preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule and the solution also comprises an antioxidant (preferably BHT (butylated hydroxytoluene)) in the amount of approx. 0.001% to about 008% by weight of the total solution (preferably from about 0.01% to about 005% by weight of the total solution) An example of said composition and its preparation is given below Component% in Weight Compound of Example 2B (free base) 30 Ethanol (USP, 200 test) 10 Polyoxyl castor oil 35 (Cremophor® EL) 10 Oleic acid, 6321, NF 50 Butylated hydroxytoluene (BHT), NF 0.01 Preparation of the above composition: The mixing tank was purged with nitrogen. Ethereal acid (499.9 g) and ethanol (100 g) were mixed in the tank. The butylated hydroxytoluene (0.1 g) was charged to the tank and mixed until the solution became clear. The compound of Example 2B (300 g) was slowly charged to the tank and mixed until the solution became clear. The polyoxyl castor oil 35 (100 g) was added to the tank and mixed. The resulting solution was placed in soft elastic capsules (0.333 g of solution / SEC) to provide a dose of 100 mg of the compound of Example 2B / SEC or 0.667 g / SEC to provide a dose of 200 mg of the compound of Example 2B / SEC . Since the compound of the invention can be administered as an active pharmaceutical agent alone, it can also be used in combination with one or more immunomodulators, antiviral agents, other anti-infection agents or vaccines. Other antiviral agents that will be administered in combination with a compound of the present invention include AL-721, beta interferon, polyimanoacetate, reverse transcriptase inhibitors (e.g., dideoxycytidine (ddC); zalcitabine), dideoxy-inosine (ddl, didanosine), BCH-189, AzdU, carbovir, ddA, d4C, d4T (stavudine), 3TC (lamivudine) DP-AZT, FLT (fluorothymidine), BCH-189, 5-halo- 3'-thia-dideoxycytidine, PMEA, bis-POMPMEA, zidovudine (AZT), nevirapine, delviridin, MSA-300, trovirdine and the like), nucleoside reverse transcriptase inhibitors (e.g., R82193, L-697,661, BI-RG -587 (nevirapine), retroviral protease inhibitors (e.g., HIV protease inhibitors such as ritonavir, Ro 31-8959 (saquinavir), SC-52151, VX-478, AG1343 (nelfinavir), BMS 186,318, SC-55389a , BILA 1096 BS, DMP-323, DMP-450, KNI-227, KNI-272, U-140690, N- (2- (R) -hydroxy-1 (S) -indanil) -2 (R) - phenylmethyl-4 (S) -hydroxy-5- (1- (4- (3-pyridylmethyl) -2 (S) -N '- (t-butylcarboxyamido) -piperazinyl)) - pentanamide (MK-639; indavir), 5 (S) -Boc-amino-4 (S) -hydroxy-6-phenyl-2 (R) -phenylmethylhexanoyl- (L) -Val- (L) -Phe-morpholin-4-ylamide, 1-naphthoxyacetyl-beta -methylthio-Ala- (2S, 3S) -3-amino-2-hydroxy-4-butanoyl-1,3-thiazolidin-4-t-but ilamide (ie, 1-naphthoxyacetyl-Mta- (2S, 3S) -AHPBA-Thz-NH-tBu), 5-isoquinolinoxyacetyl-beta-methylthio-Ala- (2S, 3S) -3-amino-2-hydroxy- 4-butanoyl-1,3-thiazolidin-4-t-butyl-lamide (i.e. iQoa-Mta, Apns-Thz-NhtBu) and the like), compounds HEPT, L, 697, 639, R82150, U-87201E and similar), HIV integrase inhibitors (Zintevir and the like), TAT inhibitors (e.g., EO-24-7429 and the like), trisodium phosphonoformate, HPA-23, eflonitin, T-peptide, Reticulosa (nucleophosfoprotein), ansamycin LM 427 , trimetrexate, UA001, ribavirin, alpha interferon, oxetanocin, oxetanocin-Q, cilobut-G, cilobut-A, ara-M, BW882C87, foscarnet, BW256U87, B 348U87, L-693-989, Bv ara-U, triclonal antibodies of CMV, FIAC, HOE-602, HPMC, MSL-109, TI-23, trifluridine, vadarabine, famciclovir, penciclovir, acyclovir, ganciclovir, castanospermine, rCD4 / CD4-lgG, CD4-PE40, butyl-DNJ, hypericin, acid oxamyristic, dextran sulfate and pentosan polysulfate. Immunomodulators that can be administered in combination with the compound of the present invention include bropyrimine, Ampligen, anti-human alpha-interferon antibody, colony stimulation factor, CL246,738, lreg-1, lmreg-2.

Dietidithiocarbamate, interleukin-2, alpha-interferon, insin pronobex, methionine enkephalin, muramyl tripeptide, TP-5, erythropoietin, naltrexone, tumor necrosis factor, beta-interferon, gamma-interferon, interleukin-3, interleukin-4, infusion Autologous CD8 +, alpha-interferon immunoglobulin, IGF-1, anti-Leu-3A, autovaccination, biostimulation, extracoporal photopheresis, ciclosporin, rapamycin, FK-565, FK-506, G-CSF, GM-CDF, hyperthermia, isopinosin, IVIG, HIVIG, passive immunotherapy and hyperimmunization of polio vaccine. Other anti-infection agents that can be administered in combination with the compound of the present invention include pentamidine isethionate. Any of a variety of vaccines against HIV or AIDS (eg, gp 120 (recombinant), Env 2-3 (gp120), HIVAC-1e (gp120), gp160 (recombinant), CaxSyn HIV-1 (gp160), Immuno- Ag (gp160), HGP-30, HIV-lmmunogen, p24 (recombinant), VaxSyn HIV-1 (p24) can be used in combination with the compound of the present invention Other agents that can be used in combination with the compound of this invention are ansamycin LM 427, apurinic acid, ABPP, AI-721, carrisin, AS-101, avarol, azimexon, colchicine, compound Q, CS-85, N-acetyl cysteine (2-oxothiazolidin-4-carboxylate), D -penecylamine, diphenylhydantoin, EL-10, erythropoietin, fusidic acid, glucan, HPA-23, human growth hormone, hydroxychloroquine, iscador, L-ofloxacin or other quinolone antibiotics, lentinan, lithium carbonate, MM-1, monolaurin, MTP-PE, naltrezone, neurotrophin, ozone, PAI, panax ginseng, pentofilin, pentoxifylline, peptide T, pine pineapple extract, polyimanoacetate, reticu slab, retrogen, pbavirm, ribozymes, RS-47, Sdc-28, silicotungstate, THA, thymic humoral factor, thymopentin, thymosin fraction 5, alpha-one timosma, timoestimuhna, UA001, vitamin B12 and "wobemugos" Other agents that can to be used in combination with the compound of this invention are anti fungal agents such as amphoteme B, clotpmazole, flucytose, fluconazole, itraconazole, ketoconazole and nystatin, and the like. Other agents that can be used in combination with the compound of this invention are antibacterial such such as amikacin sulfate, azothromycin, ciprofloxacin, clarithromycin, clofazimine, ethambutiol, isoniazid, pyrazinamide, rifabutin, rifampin, streptomycin and TLC G-65 and the like. Other agents that can be used in combination with the compound of this invention are anti-neoplastic agents such as alpha-interferon, COMP (cyclophosphamide, vincristine, methotrexate and prednisone), etoposide, mBACOD (methotrexate, bleomycin, doxorubicin a, cyclophosphamide, vincristine and dexamethasone), PRO-MACE / MOPP (prednisone, methotrexate (w / leucovin rescue), doxorubicin, cyclophosphamide, taxol, etoposide / mechlorethamine, vincristine, prednisone and procarbazine), vincristine, vinblastine, angioinhibines, pentosan polysulfate, platelet factor 4 and SP-PG and the like. Other agents that can be used in combination with the compound of this invention are drugs for the treatment of neurological diseases such as T peptide, ritalin, lithium, elavil, phenytoin, carbamazipine, mexitetin, heparin and cytosine arabinoside, and the like. Other agents that can be used in combination with the compound of this invention are anti-protozoa, such as albendazole, zithromycin, clarithromycin, clindamycin, corticosteroids, dapsone, DIMP, aflornithine, 566C80, fansidar, furazolidone, L, 671, 329, latrazuril , metronidazole, paromycin, pefloxacin, pentamidine, piritresima, primaquine, pyrimethamine, somatostatin, spiramycin, sufadiazone, trimethoprim, TMP / SMX, trimetrexate and WR 6026 and the like. Preferred agents for inhibiting or treating HIV or AIDS in combination with the compound of this invention are reverse transcriptase inhibitors, especially AZT (zidovudine), ddl (didanosine), ddC (zalcitabine), d4T (stavudine), 3TC (lamivudine), nevirapine, delviridin, trovirdine, PMEA, bis-POMPMEA and MSA-300. Other preferred agents for the inhibition or treatment of HIV or AIDS in combination with the compound of this invention are HIV protease inhibitors, especially ABT-538 (ritonavir) and related compounds, described in US Pat. No. 5,541,206, issued July 20, 1996 and the patent of E.U.A. No. 5,491,253, issued February 13, 1996, which are incorporated herein by reference, N- (2 (R) -hydroxy-1 (S) -indanyl) -2 (R) -phenylmethyl-4 (S) - hydroxy-5- (1- (4- (3-pyridylmethyl) -2 (S) -N '- (t-butylcarboxyamido) -piperazinyl)) - pentanamide (i.e., indinavir) and related compounds, described in the Application European Patent No. EP541168, published May 12, 1993, and to the US patent No. 5,413,999, issued May 9, 1995, both incorporated herein by reference; N-tert-butyl-decahydro-2- [2 (R) -hydroxy-4-phenyl-3 (S) - [[N- (2-quinolylcarbonyl) -L-asparaginyl] amino] butyl] - (4aS, 8aS ) -isoquinolin-3 (S) -carboxyamide (i.e., saquinavir) and related compounds, described in U.S. Patent No. 5,196,438, issued March 23, 1993, which is incorporated herein by reference; 5 (S) -Boc-amino-4 (S) -hydroxy-6-phenyl-2 (R) -phenylmethylhexanoyl- (L) -Val- (L) -Phe-morpholin-4-ylamide and related compounds, described in European Patent Application No. EP532466, published March 17, 1993, which is incorporated herein by reference; t-naphthoxyacetyl-beta-methylthio-Ala- (2S, 3S) -3-amino-2-hydroxy-4-butanoyl-1,3-thiazolidine-4-t-butylamide (ie, 1-naphthoxyacetyl-Mta- ( 2S, 3S) -AHPBA-Thz-NH-tBu), 5-isoquinolinoxyacetyl-beta-methylthio-Ala- (2S, 3S) -3-amino-2-hydroxy-4-butanoyl-1,3-thiazolidin-4- t-butylamide (i.e. iQoa-Mta-Apns-Thz-NhtBu) and related compounds, described in European Patent Application No. EP490667, published June 17, 1992 and Chem. Pharm. Bull. 40 (8) 2251 (1992), which are incorporated herein by reference; [1"- [1R * (R *), 2S *]] - N1 [3 - [[[1,1-dimethylethyl) amino] carbonyl] (2-methylpropyl) -amino] -2-hydroxy-1- (phenylmethyl) propiQ-2 - [(2-quinCylincarbhenyl) amino] -butanediamine (ie, SC-52151) and related compounds, described in PCT Patent Application No. WO92 / 08701, published on 29 May 1992, and PCT Patent Application No. WO93 / 23368, published November 25, 1993, both incorporated herein by reference; (i.e., VX-478) and related compounds, described in PCT Patent Application No. WO94 / 05639, published March 17, 1994, which is incorporated herein by reference; (that is, DMP-323) or (ie, DMP-450), and related compounds, described in PCT Patent Application No. WO93 / 07128, published April 15, 1993, which is incorporated herein by reference: (ie, AG1343, (nelfinavir)), described in PCT Patent Application No. WO95 / 09843, published April 13, 1995 and the US patent. No. 5,484,926, issued January 16, 1996, which are incorporated herein by reference; Boc (ie, BMS 186,318), described in European Patent Application No. EP580402, published January 26, 1994, which is incorporated herein by reference; (ie, SC-55389a), described in 2pd National Conference on Human Retroviruses and Related Infections, (Washington, D.C., January 29 to February 2, 1995), Session 88; Y (ie, BILA 1096 BS) and related compounds described in European Patent Application No. EP560268, published September 15, 1993, which is incorporated herein by reference; Y (ie, U-140690) and related compounds described in PCT Patent Application No. WO 9530670, published November 16, 1995, which is incorporated herein by reference; or a pharmaceutically acceptable salt of any of the foregoing. In a highly preferred combination, a compound of this invention is administered in combination with ritonavir. Said combination is especially useful for inhibiting the HIV protease in a human being. Said composition is also especially useful for inhibiting or treating an HIV infection in a human being. When used in said combination, the compound of this invention and ritonavir can be administered as separate agents at the same time or at different times or can be formulated as an individual composition comprising both compounds. When administered in combination with a compound of this invention, ritonavir causes an improvement in pharmacokinetics (ie, increases the half-life, increases the peak plasma concentration time, increases blood levels) of the compound of this invention. Preferred dosage forms for ritonavir include, (a) a liquid dosage form for oral administration as described in U.S. Pat. No. 5,484,801, issued January 19, 1996, which is incorporated herein by reference, (b) a solid or semi-solid encapsulated form as described in the PCT Patent Application NO. WO95 / 07696, published March 23, 1995 and patent of E.U.A. Series No. 08 / 402,690, filed March 13, 1995, both incorporated herein by reference, and (c) an encapsulated solid dose form as described in PCT Patent Application No. WO95 / 09614, published on May 13, 1995. April 1995 and the US patent No. 5,559,158, issued September 24, 1996, both incorporated herein by reference. Other examples of preferred dosage forms for ritonavir are described in U.S. Patent Application No. 08 /, filed November 21, 1996, in the name of J. Lipari, L A. Al-Razzak, S. Gohsh and R. Gao and which has the title Pharmaceutical Composition, which is incorporated herein by reference. A preferred composition for ritonavir comprises a solution of (a) ritonavir in the amount of from about 1% to about 30% (preferably from about 5% to about 25%) by weight of the total solution, and (b) castor oil of polyoxyl 35 in the amount of from about 0% to about 20% (preferably, from about 5% to about 10%) by weight of the total solution, in a pharmaceutically acceptable solvent, which comprises (i) oleic acid in the amount from about 15% to about 99% (preferably from about 30% to about 70%; most preferably from about 40% to about 65%) by weight of the total solution, or (ii) a mixture of (1) oleic acid in the amount of from about 15% to about 99% (preferably about 30% by weight). about 70%, most preferably from about 40% to about 65%) by weight of the total solution, and (2) ethanol or propylene glycol or a mixture thereof in the amount of from about 0% to about 12% (preferably from about 0% to about 12% (preferably about 10%), by weight of the total solution In a still highly preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a capsule of hard gelatin and the solution also comprises an antioxidant (preferably, BHT (butylated hydroxytoluene)) in the amount of about 001% to about 008% by weight of the total solution (preferably about 001% to about 0.005% by weight of the total solution) Examples of said composition and its preparation are given below Component% in Weight Ritonavir (free base) 20 Ethanol (USP, 200 test) 10 Polyoxyl castor oil 35 (Cremphor® EL) 5 Oleic acid, 6321, NF 65 Butylated hydroxytoluene (BHT), NF 001 Preparation of the above composition: The mixing tank was purged with nitrogen. Oleic acid (649.9 g) and ethanol (100 g) were mixed in the tank. The solution was heated to about 33 ° C (29-37 ° C) and maintained at that temperature. The butylated hydroxytoluene (0.1 g) was charged to the tank and mixed until the solution became clear. Ritonavir (200 g) was slowly charged into the tank and mixed until the solution became clear. The polyoxyl castor oil 35 (50 g) was added to the tank and mixed. Heating was stopped and the solution allowed to cool to room temperature (20-30 ° C). The resulting solution was placed in soft elastic capsules (0.5 g of solution / SEC) to provide a dose of 100 mg of ritonavir / SEC or 0.1 g / SEC to provide a dose of 200 mg ritonavir / SEC.

Component% in Weight Ritonavir (free base) 20 Ethanol (USP, 200 test) 10 Polyoxyl castor oil 35 (Cremphor® EL) 10 Oleic acid, 6321, NF 60 Butylated hydroxytoluene (BHT), NF 0.01 Preparation of the above composition: The mixing tank was purged with nitrogen. Oleic acid (599.9 g) and ethanol (100 g) were added to the tank. This solution was heated to approximately 33 ° C (29-37 ° C) and maintained at that temperature. The butylated hydroxytoluene (0.1 g) was charged to the tank and mixed until the solution became clear. Ritonavir (200 g) was slowly charged to the tank and mixed until the solution became clear. The polyoxyl castor oil 35 (100 g) was added to the tank and mixed. The heating was stopped and the solution was allowed to cool to room temperature (20-30 ° C). The resulting solution was placed in soft elastic capsules (0.5 g of solution / SEC) to provide a dose of 100 mg of ritonavir / SEC or 1.0 g / SEC to provide a dose of 200 mg ritonavir / SEC. Examples of the preferred individual dose forms comprising both ritonavir and a compound of the formula I are also described in the co-pending US Patent Application Ser. No. 08 /, presented on November 21, 1996, on behalf of J.

Lapari, L.A. Al-Razzak, S. Ghosh and R. Gao and which has the title of Pharmaceutical Composition, which is incorporated herein by reference. A preferred composition for a single dose form comprising both ritonavir and a compound of formula I comprises a solution of (a) a mixture of ritonavir in the amount of about 1% to about 30% (preferably about 5%) to about 25%) by weight of the total solution and a compound of the formula I in the amount of about 1% to about 50% (preferably, about 5% to about 40%) by weight of the total solution and ( b) polyoxyl castor oil 35 in the amount of about 10% by weight of the total solution, in a pharmaceutically acceptable organic solvent, which comprises a mixture of (1) oleic acid in the amount of about 10% to about 88 % (preferably, from about 40% to about 65%) by weight of the total solution, and (2) ethanol in the amount of about 10% by weight of the total solution. In a highly preferred embodiment of the invention, the solution is encapsulated in a soft elastic capsule (SEC) or a hard gelatin capsule and the solution also comprises an antioxidant (preferably, BHT (butylated hydroxytoluene)) in the amount of about 0.01% to about 0.8% by weight of the total solution (preferably, from about 0.01% to about 0.05% by weight of the total solution). Examples of said composition and its preparation are given below.

Component% in Weight Ritonavir (free base) 5 Compound of Example 2B (free base) 30 Ethanol (USP, 200 test) 10 Polyoxyl castor oil 35 (Cremphor® EL) 10 Oleic acid, 6321, NF 45 Butylated hydropytoluene (BHT), NF 0.01 Component% by Weight Ritonavir (free base) 15 Compound of Example 2B (free base) 15 Ethanol (USP, 200 test) 10 Pohoxtlo castor oil 35 (Cremphor® EL) 10 Oleic acid, 6321, NF 50 Butylated hydroxytoluene (BHT) ), NF 001 Component% in Weight Ritonavir (free base) 15 Compound of Example 2B (free base) 15 Ethanol (USP, 200 test) 10 Polyoxtle castor oil 35 (Cremphor® EL) 5 Oleic acid, 6321, NF 55 Butylated hydroxytoluene (BHT), NF 001 Preparation of the above composition: The mixing tank was purged with nitrogen. Olether acid (5499 g) and ethanol (100 g) were added to the tank. The butylated htdroxtoluene (0 1 g) was charged to the tank and mixed until the solution was made transparent The ptonavir (150 g) was slowly charged to the tank and mixed until the solution became clear The compound of Example 2B (150 g) was slowly charged to the tank and mixed until the solution became clear Castor oil of polyoxyl 35 (100 g) was added to the tank and mixed. The resulting solution was placed in soft elastic capsules (10 g of solution / SEC) to provide a dose of 150 mg of ptonavir and the compound of Example 2B / SEC.

Component% in Weight Ritonavir (free base) 15 Compound of Example 2B (free base) 5 Ethanol (USP, 200 test) 10 Polyoxyl castor oil 35 (Cremphor® EL) 10 Oleic acid, 6321, NF 60 Butylated hydroxytoluene (BHT), NF 0.01 The total daily dose of ritonavir (administered in combination with a compound of this invention) which will be administered to a human or other mammalian host in individual or divided doses may be in amounts, for example, of 0.001 to 300 mg / kg of weight of the body and more usually 0.1 to 10 mg of ritonavir. The dosage unit compositions may contain said amounts of their. submultiples to form the daily dose. In the compositions comprising a mixture of ritonavir and the compound of Example 2B, the (w / w) ratio of ritonavir to the compound of Example 2B ranges from about 1:16 to about 5: 1 (preferably about 1: 6). at about 3: 1). In another highly preferred combination, a compound of this invention is administered in combination with ritonavir and one or more reverse transcriptase inhibitors (preferably, one or more compounds selected from the group consisting of AZT (zidovudine), ddl (didanosine), ddC (zalcitabine), d4T (stavudine) and 3TC (lamivudine)). Said composition is especially useful for inhibiting or treating an HIV infection in a human being. When used in said combination, the compound of this invention and ritonavir and one or more reverse transcriptase inhibitors may be administered as separate agents at the same time or at different times, or may be formulated as compositions comprising two or more of the compounds . A particularly preferred therapeutic combination comprises a compound of formula I (especially, the compound of Example 2B) in combination with ritonavir, AZT and 3TC. It will be understood that the agents which can be combined with the compound of the present invention for the inhibition, treatment or prophylaxis of AIDS or an HIV infection are not limited to those listed above, but also include in principle any agent useful for the treatment or prophylaxis of AIDS or an HIV infection. When administered as a combination, the therapeutic agents can be formulated as separate compositions, which are given at the same time or at different times, or the therapeutic agents can be given as an individual composition.

The foregoing is merely illustrative of the invention and is not intended to limit the invention to the disclosed compounds. The variations and changes that are obvious to those skilled in the art are within the scope and nature of the invention, which are defined in the appended claims.

Claims

CLAIMS A compound of the formula wherein Ri and R2 are independently selected from the group consisting of lower alkyl, cycloalkylalkyl and alkalkyl, R3 is lower alkyl, hydroxyalkyl or cycloalkylalkyl, R is aplo or a heterocyclic, Rs is i) where n is 1, 2 or 3, m is 1, 2 or 3, m 'is 1 or 2, X is O, S or NH, Y is -CH2-, -O-, -S- or - N (R6) -, wherein R6 is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl or aplakyl, and "is -CH2- or N (RS) -, wherein R6 is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aplo or "aplaxyl, Y 'is -N (R6), wherein R6 is hydrogen, lower alkyl, cycloalkyl, cycloalkyl-alkyl, aplo or aplakyl, and Z is O, S, or NH, and a) -O-, b) -Sc) -N (R7) -, wherein R is hydrogen, lower alkyl, cycloalkyl or cycloalkyl alkyl, d) -O-alk? lene-, e) -S- alkylenyl-, f) -S (O) -alkyl- len-, g) -S (O) 2 -alkenyl-, h) -N (R7) -alkyllene-, wherein R7 is as defined above, i) -alk? len? l-, j) alkylenyl-S-, k) alkylene? N (R7) -, wherein R7 is as defined above, I) alkylenyl or om) alkenylenyl , or a pharmaceutically acceptable salt, ester or prodrug thereof 2 - A compound according to claim 1, wherein R and R2 are arylalkyl, R3 is lower alkyl, R4 is aryl, R5 is: wherein X, Y, Y ', Y ".A, R6, n, m and m' are as defined above and Li is -O-alkylenyl, the most preferred compounds are the compounds of formula I, wherein R, and R2 are benzyl or RT is benzyl and R2 is isopropyl, R3 is lower alkyl, R4 is 2,6-dimethylphenyl, which is optionally substituted with a third substituent selected from the group consisting of lower alkyl halogen, R5 is where n is 1 or 2, X is O u S and Y is -CH2 or -NH-, and L is -O-CH2. 3 - A compound according to claim 1, wherein Ri and R2 are benzyl or R-, is benzyl and R2 is lower alkyl, R3 is lower alkyl, R4 is (a) phenyl, which is substituted with two alkyl groups lower and which is optionally substituted with a third substituent selected from the group consisting of lower alkyl, hydroxy, amino and halo, or (b) pyridyl or pyrimidinyl any of which is substituted with two lower alkyl groups and which is optionally substituted with a third substituent with a third substituent selected from the group consisting of lower alkyl, hydroxy, amino and halogen, R5 is: wherein n is 1 or 2, X is O or S and Y is -CH2- or -NH- in where m is 1 or 2, X is O, Y is -CH2- and Z is O, where m 'is 1, X is O, Z is O and Y is -NH-, d) where m' is 1, X is I, Y "is -NH- and Y 'is -NH- or where X is O and R6- is hydrogen 4 - . 4. A compound according to claim 1, wherein Ri and R2 are benzyl or Ri is benzyl and R2 is isopropyl, R3 is lower alkyl, R4 is 2,6-dimethylphenyl, which is optionally substituted with a selected third substituent. of the group consisting of lower alkyl and halogen, Rs is where n is 1 or 2, X is O u S and Y is -CH2 or -NH-, b) m is 1 or 2, X is O, Y is -CH2- and Z is O, where m 'is 1, X is O, Z is O and Y is -NH-, where m 'is 1, X is O, Y "is -NH- and Y' is -NH- or where X is O and R6- is hydrogen and L, is -O-CHz-. 5 - A compound according to claim 1, wherein RT and R2 are benzyl or Ri is benzyl and R2 is isopropyl, R3 is lower alkyl, R is 2,6-dimethylphenyl, which is optionally substituted with a selected third substituent. of the group consisting of lower alkyl and halogen, Rs is wherein n is 1 or 2, X is O u S and Y is -CH2 or -NH-, and 6 - A compound selected from the group consisting of: (2S, 3S, 5S) -2- (2,6-d-methylf-enoxyacetyl) -a -3-min-hydroxy-5- [2S- (1-tetrahydro-pyrimid-2-one) -3-methylbutanoyl) ] -amino-1,6-diphenylhexane; (2S, 3S, 5S) -2- (2,6-Dimethyl-enoxyaceti-l) -amino-3-hydroxy-5- (2S- (1-imidazolidin-2-ynyl) -3,3-dimethylbutanoyl) -amino- 1,6-diphenylhexane; (2S, 3S, 5S) -2- (2, 6-d imeti Iphenoxia ^ ceti l) -ami non-3-hydroxy-5- (2S- (1-imidazolidin-2-thienyl) -3-methylbutanoyl) - amine-1,6-diphenylhexane; (2S, 3S, 5S) -2- (2,4,6-trimethylphenoxyacetyl) -amino-3-hydroxy-5- (2S- (1-imidazolidin-2-oneyl) -3-methylbutanoyl) amino-1, 6-diphenylhexane; (2S, 3S, 5S) -2- (4-f luoro-2,6-dimethyl-enoxyacetyl) amino-3-hydroxy-5- (2S- (1-amidazolidin-2-onyl) -3-methyl- butanoyl) -amino-1,6-diphenylhexane; (2S, 3S, 5S) -2- (2,6-Dimethyl-enoxyacetyl) -amino-3-hydroxy-5- (2S- (1-pyrrolidin-2-oneyl) -3-methyl-butanoyl) amino-1 , 6-diphenylhexane; (2S, 3S, 5S) -2- (2,6-d? Met? Lfenox? Acet? L) -amino-3-h? Drox? -5- (2S- (1-p? Rrol? D? N -2.5-d? On? L) -3-met? L-butane? L) -am? No-1,6-diphenylhexane, (2S, 3S, 5S) -2- (trans-3- (2 , 6-dimethylphenyl?) Propene? L) amino-3-hydrox? -5- (2S-1-tetrahydro? Rim? D? N-2-on? L) -3-met? L-butane? l) amino-1, 6-d? phen? hexane, (2S, 3S, 5S) -2- (3- (2,6-d? met? lfen? l) propane? l) am? no -3 hydroxy-5- (2S- (1-tetrah? drop? r? m? d? n-2-on? l) -3-methyl-butane? l) amino-1,6-d? phenyl hexane, (2S , 3S, 5S) -2- (2,6-d? Methylphenol? Acet? L) -am? No-3-h? Drox? -5- (2S- (1-tetra hydro-p ir? M? D -2, 4-d? On? L) -3-methylobutanoyl) -a mino-1,6-d? Phenyl-hexane, (2S, 3S, 5S) -2- (2,6-d? Methylfenox acetyl) -amino-3-hydroxy-5- (2S- (4-aza-1-tetrahydro-pyr? m? d-2-onyl) -3-methyl-butanoyl) amino-1,6-d phenylhexane, (2S, 3S, 5S) -2- (2,6-dimethyl-enoxy acetyl) -amino-3-h idroxy-5- (2S- (1-tetrahydro-pyrim? d-) 2-onyl) -3-methylbutanoyl) amyl-1-f-enyl-6-methyl-heptane, (2S, 3S, 5S) -2- (2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5 - (2S- (1-tetrahydro-pyrimid-2,4-dionyl) -3-methylbutanoyl) amino-1-phenyl-6-methyl-hep tano and (2S, 3S, 5S) -2- (2,6-dimethyl-enoxyacetyl) -amino-3-hydroxy-5- (2S- (4-aza-4,5-dehydro-1-p? r? m? d-2-onyl) -3-methyl-butanoyl) amino-1,6-d? phenol-hexane; or a pharmaceutically acceptable salt, ester or prodrug thereof. 7. - The compound (2S, 3S, 5S) -2- (2,6-dimethylphenoxyacetyl) amino 3-hydroxy-5- (2S- (1-tetrahydro-pyrimid-2-oneyl) -3-methyl-butanoyl) amino- 1, 6-diphenylhexane; or a pharmaceutically acceptable salt, ester or prodrug thereof. 8 - A pharmaceutical composition for inhibiting protease of HIV comprising a pharmaceutical carrier and a therapeutically effective amount of the compound of claim 1. A pharmaceutical composition for inhibiting HIV protease comprising a pharmaceutical carrier and a therapeutically effective amount of the compound of claim 7. 10 - A method for inhibiting HIV protease comprising administering to a human, in need of such treatment, a therapeutically effective amount of the compound of claim 1. 11 - A method for inhibiting HIV protease comprising administering to a human, with the need of said treatment, a therapeutically effective amount of the compound of claim 7. 12 - A method for inhibiting an HIV infection comprising administering to a human, in need of such treatment, a therapeutically effective amount of the compound of claim 1 13 - A method to inhibit an HIV infection that co It comprises administering to a human being, in need of such treatment, a therapeutically effective amount of the compound of claim 7. 14. A method for inhibiting an HIV infection comprising administering to a human being, with the need for said treatment. , a therapeutically effective amount of the compound of claim 1 in combination with a therapeutically effective amount of a reverse transcriptase inhibitor or a combination of reverse transcriptase inhibitors. The method according to claim 14, wherein the reverse transcriptase inhibitor is selected from the group consisting of AZT (zidovudine), ddl (didanosine), ddC (zalcitabine), d4T (stavudine), 3TC (lamivudine), nevirapine, delviridin, troviridine, PMEA, bis-POMPMEA and MSA-300 or a combination thereof. 16 - A method for inhibiting an HIV infection comprising administering to a human, in need of such treatment, a therapeutically effective amount of the compound of claim 7 in combination with a therapeutically effective amount of a reverse transcriptase inhibitor or a combination of reverse transcriptase inhibitors. 17. The method according to claim 16, wherein the reverse transcriptase inhibitor is selected from the group consisting of AZT (zidovudine), ddl (didanosine), ddC (zalcitabine), d4T (stavudine), 3TC (lamivudine) , nevirapine, delviridin, troviridine, PMEA, bis-POMPMEA and MSA-300 or a combination thereof. 18. - A method for inhibiting an HIV infection comprising administering to a human, in need of such treatment, a therapeutically effective amount of the compound of claim 1 in combination with a therapeutically effective amount of another HIV protease inhibitor or a combination of HIV protease inhibitors. 19 - The method according to claim 18, wherein the other HIV protease inhibitor is selected from the group consisting of ritonavir, saquinavir, indinavir, 5 (S) -Boc-amino-4 (S) -hydroxy-6 -f eni-2 (R) -f-enyl methylhexanoyl- (L) -Val- (L) -Phe-morpholin-4-ylamide; 1-naphthoxyacetyl-beta-methylthio-Ala- (2S, 3S) -3-amino-2-hydroxy-4-butanoyl -1,3-thiazolidin-4-t-butylamide; 5-isoquinolinoxyacetyl-beta-methylthio-Ala- (2S, 3S) -3-amino-2-hydroxy-4-butanoyl-1,3-thiazolinid-4-t-butylamide; (1S- (1R * (R *), 2S *)) - N1 (3 - ((((1,1-dimethyletyl) amino) carbonyl) (2-methylpropyl) amino) -2-hydroxy -1- (phenylmethyl) propyl) -2 - ((2-quinolinylcarbonyl) amino) -butanediamide; or a pharmaceutically acceptable salt thereof, or a combination of two or more of these VI H protease inhibitors. twenty - . A method for inhibiting a VI H infection comprising administering to a human, in need of such treatment, a therapeutically effective amount of the compound of claim 7 in combination with a therapeutically effective amount of another HIV protease inhibitor. or a combination of HIV protease inhibitors 21 - The method according to claim 20, wherein the other protease inhibitor is selected from the group consisting of ptonavir, saquinavir, indinavir, 5 (S) -Boc-am? no -4 (S) -h? Drox? -6-phen? L- 2 (R) -fen? Lmeth? Lhexanoyl- (L) -Val- (L) -Phe-morph? N-4? -amide; 1 -naf tox? Acet? L-beta-met? Lt? O-Ala- (2S, 3S) -3-am i no-2-h? Drox? -4- butanoil -1, 3-t-azole d-n-4-t-butyl lamide, 5-? Soquinol? Noxyacet? L-beta-meththio-Ala- (2S, 3S) -3-am? no-2-hydroxy? -4-butane? -1,3-t? azolydin-4-t-butylamide, (1S- (1R * (R *), 2S *)) - N1 (3 - ((((1,1-d? Meth? Lethyl) amino) carbonyl) (2-met? L propyl) am? No) -2-hydroxy-1- (phenylmethyl) propyl) -2 - ((2- qu? nolin? lcarbonil) am? no) -butanod? am? da, or a pharmaceutically acceptable salt thereof, or a combination of two or more of these HIV protease inhibitors. 22 -. 22. A method for inhibiting an HIV infection comprising administering to a human, in need of such treatment, a therapeutically effective amount of the compound of claim 7 in combination with a therapeutically effective amount of ritonavir or a pharmaceutically acceptable salt of the same. 23. A compound for inhibiting HIV protease comprising a substituent of the formula: wherein R3 is lower alkyl, hydroxyalkyl or cycloalkylalkyl; and Rs is 10 6 where n is 1, 2 or 3, m is 1, 2 or 3, m 'is 1 or 2, X is O, S or NH, Y is -CH2-, -O-, -S-, or -N (R6) -, wherein R6 is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, Y "is -CH2- or -N (R6 ••) -, where R6- is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aplo or aplakyl, Y 'is -N (R6) -, wherein R6 is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aplo or aplakyl, and Z is O, S or NH 24 - A compound according to claim 23, wherein R3 is lower alkyl and R5 is and) wherein X, Y, Y ', Y ", Z, R6 ••, n, m and m' are as defined above 25. A compound according to claim 23, wherein R3 is lower alkyl and R5 is: where n is 1 or 2, X is O u S and Y is -CH2 or -NH- where m is 1 or 2, X is O, Y is -CH2- and Z is O, C) where m 'is 1, X is O, Z is O and Y is -NH-, where m 'is 1, X is O, Y "is -NH- and Y' is -NH-, or where X is O and R6- is hydrogen. 26 - A compound according to claim 23, wherein R3 is isopropyl and R5 is: where n is 1 or 2, X is O u S and Y is -CH2 or -NH, where m is 1 or 2, X is O, Y is -CH2- and Z is O, where m 'is 1 , X is O, Z is O and Y is -NH- where m 'is 1, X is O, Y "is -NH- and Y' is -NH-, oe) where X is O and R6- is hydrogen 27 - A compound according to claim 23, wherein R3 is isopropyl and R5 is: where n is 1 or 2, X is O u S and Y is -CH2 or -NH- where m 'is 1, X is O, Z is O and Y is -NH- I X C) (CH2) n, ' where m 'is 1, X is O, Y "is -NH- and Y' is -NH-, or X N - R6- * N d) where X is O and Re is hydrogen. 28 - A compound according to claim 23, wherein R3 is isopropyl and R5 is: where n is 1 or 2, X is O u S and Y is -CH2 or -NH-. 29 - A compound according to claim 23 selected from the group consisting of: cis-N -te r-bu ti l-decah idro-2- [2 (R) -h idroxy-4-f eni l-3 (S) - (2S- (1-tetrahydro-pyrimid-2 -onyl) - 3-me thiubutanoyl) aminobutyl] - (4aS, 8aS) -isoquinolin-3 (S) -carboxyamide; cis-N-tert-butyl-decahydro-2- [2 (R) -hydroxy-4-thiophenyl-3 (S) - (2S- (1-tetrahydropyrimid-2-oneyl) -3-methylbutanoyl) aminobutyl] - (4aS, 8aS) -isoquinolin-3 (S) -carboxyamide; Y 4-amino-N - ((2 syn, 3S) -2-hydroxy-4-phenyl-3- (2S- (1-tetrahydropyrimid-2-ynyl) -3-methylobutanoylamino) -butyl) -N-isobutyl-benzenesulfonamide; or pharmaceutically acceptable salts thereof. 30. A compound of the formula: Wherein R3 is lower alkyl, hydroxyalkyl or cycloalkylalkyl; and Rs is X y- { HZfm b) 10 where n is 1, 2 or 3, m is 1, 2 or 3, m 'is 1 or 2, X is O, S or NH, Y is -CH2-, -O-, -S- or -N ( R6) -, wherein R6 is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, Y "is -CH2- or -N (R6), wherein R6 is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl , Y 'is -N (R6) -, wherein R6 is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, and Z is O, S or NH, or a salt or an activated ester derivative thereof. - A compound according to claim 30, wherein R3 is lower alkyl and Rs is: wherein X, Y, Y ', Y ", Z, R6-, n, m and m' are as defined above 32. A compound according to claim 30, wherein R3 is lower alkyl and R5 is: wherein n is 1 or 2, X is O u S and Y is -CH2 or -NH- where m is 1 or 2, X is O, Y is -CH2- and Z is O, where m 'is 1, X is O, Z is O and Y is -NH-, d) where m 'is 1, X is O, Y "is -NH- and Y' is -NH-, or where X is O and R6- is hydrogen. 33 - A compound according to claim 30, wherein R3 is isopropyl and R5 is: where n is 1 or 2, X is O u S and Y is -CH2 or -NH- where m is 1 or 2, X is O, Y is -CH - and Z is O, where m 'is 1, X is O, Z is O and Y is -NH-, where m 'is 1, X is O, Y "is -NH- and Y' is -NH- where X is O and R6- is hydrogen. 34. A compound according to claim 30, wherein R3 is isopropyl and Rs is: a) where n is 1 or 2, X is O u S, and Y is -CH2 or -NH- where m 'is 1, X is O, Z is O and Y is -NH-, where m 'is 1, X is O, Y "is -NH- and Y' is -NH-, or where X is O and Re- is hydrogen. 35 - A compound according to claim 30, wherein R3 is isopropyl and Rs is: where n is 1 or 2, X is O u S and Y is -CH2 or -NH-. 36. The compound according to claim 30, which is 2S- (1-tetrahydro-pyrimid-2-oneyl) -3-methyl butanoic acid or a salt or an activated ester derivative thereof. 37 - A compound of the formula: wherein P3 and P are independently selected from hydrogen or an N-protecting group; R, and R2 are independently selected from the group consisting of lower alkyl, cycloalkylalkyl, and arylalkyl; R3 is lower alkyl, hydroxyalkyl or cycloalkylalkyl; and Rs is a) 6 where n is 1, 2 or 3, m is 1, 2 or 3, m 'is 1 or 2, X is O, S or NH, Y is -CH2-, -O-, -S- or -N ( R6) -, wherein R6 is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, Y "is -CH2- or -N (R6) -, wherein R6 is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, Y 'is -N (R6) -, where R6 is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, and Z is O, S or NH, or a salt thereof. with claim 37, wherein P3 and P4 are hydrogen or benzyl, R and R2 are arylalkyl, R3 is lower alkyl and R5 is to) where X, Y, Y ', Y ", Z, RS", n, m and m' are as defined above. 39. A compound according to claim 37, wherein P3 and P4 are hydrogen or benzyl, R * and R2 are benzyl or R is benzyl and R is lower alkyl, R3 is lower alkyl and Rs is to} where n is 1 or 2, X is O u S and Y is -CH; -NH- where m is 1 or 2, X is O, Y is -CH2- and Z is O, where m 'is 1, X is O, Z is O and Y is -NH-, where m' is 1, X is O, Y "is -NH- and Y 'is -NH-, or -R6- ß) wherein X is O and R6 is hydrogen 40 - A compound according to claim 37, wherein P3 and P4 are hydrogen or benzyl, R, and R2 are benzyl or R, is benzyl and R is isopropyl, R3 is lower alkyl and R5 is where n is 1 or 2, X is O u S and Y is -CH2 or -NH- where m is 1 or 2, X is O, Y is -CH2- and Z is O, where m 'is 1, X is o, Z is O and Y is -NH-, where m 'is 1, X is O, Y "is -NH- and Y' is -NH-, or where X is O and R6 • is hydrogen. 41 - A compound according to claim 37, wherein P3 and P are hydrogen or benzyl, Ri and R2 are benzyl or R is benzyl and R2 is isopropyl, R3 is lower alkyl and R5 is where n is 1 or 2, X is O u S and Y is -CH2 or -NH-, b) where m 'is 1, X is O, Z is O and Y is -NH-, where m 'is 1, X is O, Y "is -NH- and Y' is -NH- where X is O and R6- is hydrogen. 42. A compound according to claim 37, wherein P3 and P4 are hydrogen or benzyl, R1 and R2 are benzyl or Ri is benzyl and R2 is isopropyl, R3 is lower alkyl and R5 is where n is 1 or 2, X is O u S and Y is -CH2 or -NH-. 43 - A compound according to claim 37 selected from the group consisting of: (2 S, 3S, 5S) -2-N, N-dibenzylam i non-3-hydroxy-5- (2S- (1- tetrahydro-pyrimid-2-onyl) -3-methylbutanoyl) amino-1,6-diphenylhexane; and (2S, 3S, 5S) -2-amino-3-hydroxy-5- (2S- (1-tetrahydro-pyrimid-2-oneyl) -3-methylbutanoyl) amino-1,6-diphenylhexane; or a salt of it. 44. The compound according to claim 43, which is (2S, 3S, 5S) -2-amino-3-hydroxy-5- (2S- (1-tetrahydro-pyrimid) (p) -saloglutamic acid salt. -2-onyl) -3-methyl-butanoyl) -amino-1,6-di-faith nil-hexane. 45 - A process for the preparation of a compound of the formula: or a salt or ester thereof, wherein R3 is lower alkyl, hydroxyalkyl or cycloalkyl, which comprises: (a) reacting a compound of the formula: or a salt or ester thereof, wherein R3 is as defined above and Q is a leaving group with a base; or (b) reacting a compound of the formula: or a salt or ester thereof, wherein R3 is as defined above with one carbonyl equivalent; or (c) hydrogenating a compound of the formula: wherein R3 is as defined above and R3t > is lower alkyl, phenyl or haloalkyl. 46. The process according to claim 45, wherein R3 is lower alkyl. 47. The process according to claim 45, wherein R3 is isopropyl and Q is chloro. 48. The process according to claim 45, wherein R3 is lower alkyl and the carbonyl equivalent is Q'-C (O) -Q ", where Q 'and Q" are Cl, Br, I, -O -lower alkyl, -O-aryl or imidazolyl. 49 -. 49. The process according to claim 48, wherein R3 is isopropyl 50- The process according to claim 45, wherein R3 is lower alkyl and R30 is lower alkyl 51- The process according to claim 50, wherein wherein R3 is isopropyl and R30 is methyl 52 - A process for the preparation of a compound according to claim 1, which comprises reacting a compound of the formula wherein Ri, R2, R3 and R5 are as defined above with a compound of the formula or a salt or activated ester derivative thereof, wherein R4 and L ^ are as previously defined 53 - A process for the preparation of (2S, 3S, 5S) -2- (2,6-d? meth? acetyl) am-no-3-hydroxy? -5- (2S- (1-tetrahydro-p? r? mid-2- onyl) -3-methyl butanoyl) amino-1, 6- diphenylhexane; or a pharmaceutically acceptable salt, ester or prodrug thereof, which comprises reacting (2S, 3S, 5S) -2-amino-3-hydroxy-5- (2S- (1-tetrahydro-pyrimid-2-onyl) -3-methyl butanoyl) amino-1,6-diphenylhexane with 2,6-dimethylphenoxyacetic acid, or a salt or an activated ester derivative thereof. 54. The process according to claim 53, wherein (2S, 3S, 5S) -2-amino-3-hydroxy-5- (2S- (1-tetrahydro-pyrimid-2-oneyl) -3-methyl butanoyl ) amino-1,6-diphenylhexane is reacted with 2,6-dimethylphenoxyacetyl chloride. 55 - A process for the preparation of a compound according to claim 1, comprising: (a) reacting a compound of the formula: wherein P3 is hydrogen and P4 is an N-protecting group, or both P3 and P4 are N-protecting groups and Ri and R2 are as defined above with a compound of the formula: or a salt or activated ester derivative thereof, wherein R3 and R5 are as defined above, to provide a compound of the formula wherein P3, R, Ri, R2, R3 and Rs are as defined above (b) N-protect the product of step (a) to provide a compound of the formula wherein Ri, R2, R3 and Rs are as defined above; and (c) reacting the product of step (b) with a compound of the formula: or a salt or activated ester derivative thereof, wherein R4 and Li are as defined above. 56 - A process for the preparation of (2S, 3S, 5S) -2- (2,6-dimethylphenoxyacetyl) am i non-3-hydroxy-5- (2S- (1-tetrahydro-pyrimid-2-onyl) -3-methyl butanoyl) amino-1,6-diphenylhexane; or a pharmaceutically acceptable salt, ester or prodrug thereof, comprising, (a) reacting (2S, 3S, 5S) -2-N, N-dibenzylamino-3-hydroxy-5-amino-1, 6- diphenylhexane with 2S- (1-terahydro-pyrimid-2-oneyl) -3-methyl butanoic acid or an activated salt or ester derivative thereof to provide (2S, 3S, 5S) -2-dibenzylamino-3-hydroxy-5 - (2S- (1-tetrahydro-pyrimid-2-oneyl) -3-methylbutanoyl) amino-1,6-diphenylhexane; (b) debenzylate the product from step (a) to provide (2S, 3S, 5S) -2-amino-3-hydroxy-5- (2S- (1-tetrahydro-pyrimid-2-oneyl) -3-methyl butanoyl amino-1, 6-diphenylhexane; and (c) reacting the product of step (b) with 2,6-dimethylphenoxyacetic acid, or an activated salt or ether derivative thereof. 57. The process according to claim 56, wherein: (a) (2S, 3S, 5S) -2-N, N-dibenzylamino-3-hydroxy-5-amino-1,6-diphenylhexane is reacted with 2S- (1-tetrahydro-pyrimid-2-oneyl) -3-methyl butanoyl chloride to provide (2S, 3S, 5S) -2-N, N-dibenzylamino-3-hydroxy-5- (2S- (1-tetrahydro -pyrimid-2-onyl) -3-methyl butanoyl) amino-1,6-diphenylhexane; (b) the product from step (a) is hydrogenated to provide (2S, 3S, 5S) -2-amino-3-hydroxy-5- (2S- (1-tetrahydro-pyrimid-2-one) -3-methyl butanoyl) amino-1,6-diphenylhexane; Y (c) the product of step (b) is reacted with 2,6-dimethylphenoxyacetyl chloride. 58 -. 58 - A process for the preparation of (2S, 3S, 5S) -2- (2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-amino-1,6-diphenylhexane or a salt thereof, which comprises reacting (2S, 3S, 5S) -2- (2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-t-butyloxycarbon Mam ino-1, 6-diphenylhexane with trifluoroacetic acid in methylene chloride, aqueous hydrochloric acid in acetonitrile or aqueous hydrochloric acid in acetic acid. 59 - A process for the preparation of a compound of the formula: or a salt or ester thereof, wherein R3 is lower alkyl, hydroxyalkyl or cycloalkylalkyl, and Q is a leaving group, comprising: (a) reacting a compound of the formula: or a salt or ester thereof, wherein R3 is as defined above with a compound of the formula: OsC ^ N. where Q is as defined above; or (b) reacting a compound of the formula: or a salt or ester thereof, wherein R3 is as defined above and R "is phenyl, phenyl lower-substituted alkyl, substituted halogen phenyl, nitro-substituted phenyl or trifluoromethylphenyl with a compound of the formula: where Q is as defined above. 60 - The process according to claim 59, wherein R3 is lower alkyl and Q is chloro. 61.- The process according to claim 59, wherein R3 is isopropyl and Q is chloro. 62 - A process for the preparation of (2S, 3S, 5S) -2- (2,6-dimethyl-enoxy acetyl) amino-3-hydroxy-5- (2S- (1-tetrahydro-pyrimid-2-onyl) -3-methyl butanoyl) amino-1,6-diphenylhexane, or a pharmaceutically acceptable salt, ester or prodrug thereof, as an amorphous solid, comprising dissolving (2S, 3S, 5S) -2- (2.6 di-methyl-methyl-1-amino-3-hydroxy-5- (2S- (1-tetrahydro-pyrimid-2-oneyl) -3-methyl-butanoyl) amino-1, 6-diphenylhexane in an organic solvent, followed by the addition of the solution to water. 63.- The process according to claim 62, wherein (2 S, 3S, 5S) -2- (2,6-dimethyl-enoxyacetyl) amino-3-hydroxy-5- (2S- (1-tetrahydro-pyrimid) -2-onyl) -3-methyl butanoyl) amino-1,6-diphenylhexane is dissolved in ethanol (from about 2 to about 4 ml / g) and the ethanolic solution is added to water (from about 10 to about 100 ml / g).