AU1369001A - Retroviral protease inhibiting compounds - Google Patents

Description

S&F Ref: 421388D1

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

ORIGINAL

Name and Address of Applicant: Abbott Laboratories Patent and Trademark Department, D-377/AP6D-2, 100 Abbott Park Road Abbott Park Illinois 60064-6060 United States of America

S

S

Actual Inventor(s): Hing Leung Sham Daniel W Norbeck Xiaoqi Chen David A Betebenner Dale J Kempf Thomas R Herrin Gondi N Kumar Stephen L Condon Arthur J Cooper Daniel A Dickman Steven M Hannick Lawrence Kolaczkowski Patricia A Oliver Daniel J Plata Peter J Stengel Eric J Stoner Jieh-Heh J Tien Jih-Hua Liu Ketan M Patel Address for Service: Invention Title: The following statement is a full performing it known to me/us:- Spruson Ferguson St Martins Tower,Level 31 Market Street Sydney NSW 2000 Retroviral Protease Inhibiting Compounds description of this invention, including the best method of [R:\LIBF] 1253.doc:brv Retroviral Protease Inhibiting Compounds Technical Field O 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, processes for making the compounds and synthetic intermediates employed in the processes.

Background of the Invention Retroviruses are those viruses which utilise a ribonucleic acid (RNA) intermediate and a RNA-dependent deoxyribonucleic acid (DNA) polymerase, reverse transcriptase, during their 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 man, animals and plants. Some of the more important retroviruses from a pathological standpoint include human immunodeficiency viruses (HIV-1 and HIV-2), which cause acquired immune deficiency syndrome (AIDS) in man, human T-cell lymphotrophic viruses I, II, IV and V, which cause human acute cell leukemia, and bovine and feline leukemia viruses which cause leukemia in domestic animals.

Proteases are enzymes which cleave proteins at specific peptide bonds. Many 20 biological functions are controlled or mediated by proteases and their complementary protease inhibitors. For example, the protease renin cleaves the peptide angiotensiogen to produce the peptide angiotensin I. Angiotensin 3817:m IN:\LIBCI03817:mnr I is further cleaved by the protease angiotensin converting enzyme (ACE) to form the hypotensive peptide angiotensin 11. Inhibitors of renin and ACE are known to reduce high blood pressure in yvio. An inhibitor of a retroviral protease will provide a therapeutic agent for diseases caused by the retrovirus.

The genomes of retroviruses encode a protease that is responsible for the proteolytic processing of one or more polyprotein precursors such as the aQI and gag gene products. See Wellink, Arch. Virol. 9 1 (1988). Retrovirai proteases most commonly process the gag precursor into core proteins, and also process the pIj precursor into reverse transciptase and retroviral protease.

/O In addition, retroviral proteases are sequence specific. See Pearl, Nature 328 482 (1987).

The correct processing of the precursor polyproteins by the retroviral protease is necessary for the assembly of infectious virions. It has been shown that in yitro mutagenesis that produces protease-defective virus leads to the production of immature core forms which lack infectivity. See Crawford, J. Virol.

899 (1985); Katoh, et al., Virology 145 280 (1985). Therefore, retroviral protease inhibition provides an attractive target for antiviral therapy. See *Mitsuya, Nature 325 775 (1987).

S Current treatments for viral diseases usually involve administration of a.0 compounds that inhibit viral DNA synthesis. Current treatments for AIDS involve Sadministration of compounds such as 3'-azido-3'-deoxythymidine (AZT), dideoxycytidine (DDC), 2',3'-dideoxyinosine (DDI), d4T and 3TC and compounds which treat the opportunistic infections caused by the immunosuppression resulting from HIV infection. None of the current AIDS treatments have proven to be totally effective in treating and/or reversing the disease. In addition, many of the compounds currently used to treat AIDS cause adverse side effects including low platelet count, renal toxicity and bone marrow cytopenia.

Recently the HIV protease inhibitors ritonavir, saquinavir and indinavir 30o have been approved in the U.S. for treatment of HIV infections. However, there is a continuing need for improved HIV protease inhibitors.

W Disclosure of the Invention In accordance with the present invention, there is a compound of the formula 1: 0 RR 3

HH

OH R 2 0 t wherein R, and R 2 are independently sele~cted f rom the group consistino of loweralkyl, cycloalkylalkyl and arylaikyl:I

R

3 is loweralkyl, hydroxyalkyl or cycloalkylalkyil: R4is aryl or heterocyclic,-

R

5 is N a x N

(CCH)M

a) -4-

Y

C) x d)

(CH

2

Z

x

N'

Y

/Y

e) (CH2)m x

(CH

2 )mo 0 Uj-N r HO wherein nis1, 2 or3, mnis 1, 2or 3.m'is 1 or 2, X is0, SorNHY is -CH 2 -0or -N(R 6 wherein R 6 is hydrogen, loweralkyl, cycloalkyl, cycloalkylakyl, aryl or arylalkyl, Y" is -H or -N(R 6 wherein R 6 is hydrogen. loweralkyl.

cycloalkyl. cycloalkylalkyf, aryl or arylalkyl, Y' is wherein R 6 .i hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, and Z is 0, S or NH: and Li is a) b) c) -N(R 7 wherein R 7 is hydrogen, loweralkyl, cycloalkyl or cycloalkylalkyl, d) -0-alkylenyl-, e) -S-alkylenyl- 1) -S(O)-alkylenyl-, g) -S(O) 2 -alkylenyl-, h) -N(R7)-alkylenyl- wherein R 7 is defined as above, i) -alkylenyl-O-, j) -alkylenyl-S-, k) alkylenyl-N(R,)- wherein R 7 is defined as above, 1) alkylenyl or m) alkenylenyl; or a pharmaceutically acceptable salt, ester or prodrug thereof.

-6- Preferred compounds are compounds of the formula I wherein R 1 and R are arylalkyI, R 3 is loweralkyl, R 4 is aryl, R 5 is x y a) (C 2

)-J

x

(CH

2 )m b) 2 x N c) (CH2)m Z x N Y" d) (CH2)m or x

N

wherein X, Y, Z, R 6 n, m and m' are defined as above and

L

1 is -O-alkylenyl.

More preferred compounds are compounds of the formula I wherein R 1 and R 2 are benzyl or R 1 is benzyl and R 2 is loweralkyl, R 3 is loweralkyl, R 4 is phenyl which is substituted with two loweralkyl groups and which is optionally substituted with a third substituent selected from the group consisting of loweralkyl, hydroxy, amino and halo or pyridyl or pyrimidinyl either of which is substituted with two loweralkyl groups and which is optionally substituted with a third substituent selected from the group consisting of loweralkyl, hydroxy, amino and halo. R 5 is

X

N y a (CH 2 )n wherein n is 1 or 2, X is O or S and Y is -CH 2 or -NH-, o o o o o 00 00 0 0 00 0 o0 o (CH2)m b) 0 wherein m is 1 or 2, X is O, Y is -CH 2 and Z is O, o o 0 0 I 00 o o Sc) (CH2)m o wherein m' is 1, X is 0, Z is 0 and Y is -NH-, wherein m is 1 or 2, X is O, Y is -CH 2 and Z is O, c) (CH2)m. Z

X

C) (CH2)m d) (CH 2 )m' wherein m' is 1, X is O, Y" is -NH- and Y' is -NH- or

X

N..

N N R6"

II

e)

N

wherein X is 0 and R6" is hydrogen and L is -O-CH 2 Most preferred compounds are compounds of the formula I wherein R 1 and R 2 are benzyl or R, is benzyl and R 2 is isopropyl, R 3 is loweralkyl, R 4 is 2,6-dimethylphenyl which is optionally substituted with a third substituent selected from the group consisting of loweralkyl and halo, R 5 is

X

N" Y a) (CH2)n" wherein n is 1 or 2. X is 0 or S and Y is -CH 2 or -NH-, x b)

(CH

2

Z

wh~erein m'is 1, X is 0. Z is 0 and Y is -NH-, x N Y"

I

C) (C H2)mrn wherein mis 1, X is 0, Y" is -NH- and Y' is -NH- or x IN N N-R 6 d)N *wherein X is 0 and R 6 is hydrogen and LI is -O-CH 2 Most highly preferred compounds are compounds of the formula I wherein R 1 and R 2 are benzyl or R 1 is benzyl and R 2 is isopropyl, R 3 is *loweralkyl, R 4 is 2,6-dimethylphenyl which is optionally substituted with a third substituent selected from the group consisting of loweralkyl and halo, H 5 is N XK Y,

(CH

2

)J

Wwherein n is 1 or 2, Xis 0or Sand Yis -CH 2 or-NHand L, is -O-CH 2 Examples of highly and most highly preferred compounds of the formula I are selected from the group consisting of: (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-[2S-(1 tetrahydro-pyrimid-2-onyi)-3-methyl butanoyl] amino-i .6-diphenyihexane: to 2

S.

3

S,

5 S)-2-(26-Dimethylphenoxyacety)amino3hydroxy5(2S-(i !midazolidin-2-onyI)-3,3-dimethyI butanoyl)amino- 1 6-diphenylhexane: 2

S.

3

S,

5 S)-2-(2,6-dimethylphenoxyacetyl)amino3hydroxy5(2S-(I imidazolidin-2-thionyl>3-methyI butanoyi)amino-i .6-diphenylhexane: 2

S.

3

S,

5 S)-2-(2,4,6-trimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(1 imidazolidlin-2-onyi)-3-methylbutanoyl) amino-i ,6-diphenylhexane 2

S,

3 SSS)-2-(4-fluoro-2,6-dimethylphenoxyacety) amino-3-hydroxy-5-(2S-(1 .sees, i midazo lidi n-2 -o nyl)-3- met hyl butanoyl) amino-i .6-diphenylhexane; 2 S, 3S, 5S)-2- (2,6-di met hylp he noxyacetyl) amino-3-hydroxy-5-(2S-(i ::pyrrolidin-2-onyl) met hyl-butanoyl) amino- 1,6-diphenyihexane, AO 2 S.3S,5S)-2- (2,6 -di met hylphe no xyacetyl) amino-3-hydroxy-5-(2S-( 1pyrrolidin-2-5-dionyl).3-methyl-butanoyl) amino- 1 6-diphenylhexane; (2S. 3S,5S)-2- (trans- 3- (2,6-di meth ylphenyl) propenoyl) amino-3-hydroxy-5-(2S- 1 -tetrahydropyrimidin-2-onyl)-3-methyl.but'anoyl) amino- 1,6-diphenylhexane: (2S,3S,5S)-2-(3-(2,6-dimethytphenyl) propanoyl) amino-3-hydroxy-5-(2S-(1tetrahydropyri midin2onyl)-3-met hyl-butanoyt) amino- 1 6-diphenyihexane; 2 S.3S,5S)-2-(2,6-Dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(1 tetrahydro-pyri mid2,4diony)3-met hylbutanoyl)a mino- 1,6-di phe ny h exane: 2

S.

3 S. 5S)-2- (2,6 -Di met hyl phe nox yacetyl) amino-3-hydroxy-5-(2S-(4..azai- :tetrahydro-pyrimid-2onyl)3methyl-butanoyl)amino-1 .6-diphenyihexane; 2

S.

3 S.5S)-2-(2,6-Dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(1- Itetrahydro-pyrimid-2-onyl)3methylbutanoyi)amino-1 -phenyl-6-methyiheptane: (2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(1tetrahydro-pyrimid-2,4-dionyl)-3-methylbutanoyl)amino-1 -phenyl-6methylheptane; and (2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(4-aza-4,5- 1 dehydro-1 -pyrimid-2-onyl)-3-methyl-butanoyl)amino-1,6-diphenyihexane; or a pharmaceutically acceptable salt, ester or prodrug thereof.

The most highly preferred compound of the formula I is (2S, 3S, 5S)-2- (2,6-Dimethylphenoxyacetyl) amino-3-hydroxy-5-[2S-(1 -tetrahydro-pyrimid-2onyl)-3-methyl butanoyl] amino- 1,6-diphenylhexane; to or a pharmaceutically acceptable salt, ester or prodrug thereof.

In some circumstances it is preferred to be able to prepare (2S, 3S, SS)- 2-(2,6-Dimethylphenoxyacetyl) amino-3-hydroxy-5-[2S-(1 -tetrahydro-pyrimid-2onyl)-3-methyl butanoyl] amino-i ,6-diphenylhexane (or a pharmaceutically acceptable salt, ester or prodrug thereof) as an amorphous solid. Such an A 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-methyl butanoyl] amjno-1,6-diphenylhexane in an organic solvent (for example, ethanol, isopropanol, acetone, acetonitrile and the like) and then .adding the solution to water. Preferably, (2S, 3S, 5S)-2-(2,6o Dimethylphenoxyacetyl) amino-3-hydroxy-5-[2S-(1-tetrahydro-pyrimid-2-onyl)- S. 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 with stirring to water (from about 10 about 100 mL/g) to provide amorphous (2S, 3S, 5S)-2- (2,6-Dimethylphenoxyacetyl) amino-3-hydroxy-5-[2S-(1-tetrahydro-pyrimid-2onyl)-3-methyl butanoyl] amino-1 ,6-diphenylhexane.

~Another embodiment of the present invention comprises an HIV protease inhibiting compound comprising a substituent of the formula II: &see .00. R3

-C

II

0 wherein R. is loweraikyl, hydroxyalkyl or cycloaikylalkyi: and x y a)

(CH

2 )nx (CH2)m b) Z x N "kY ,H d) (C 26m x

Z

N l

Y

e) (CH 2 )m x f) (CH 2 )m x g)N 0 N N-R 6 h) OHor 0 N 'k N-R 6 i) HO *wherein n is 1, 2or 3, m is 1, 2or 3, m' is 1 or 2, X isO0, S or NH, Yis -CH 2 or -N(R 6 wherein R 6 is hydrogen, loweralkyl, cycloalkyl, cycloalkylaikyl, qF aryl or arylalkyl, Y" is -CH 2 or -N(R 6 wherein R15 is hydrogen. loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, Y' is -N(R 6 wherein R 6 is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl. and Z is 0, S or NH.

Preferred compounds are HIV protease inhibiting compounds comprising a substituent of the formula 11 wherein R 3 is loweralkyl and x a)

(CH

2 )n x

(CH

2 )m b) ZC2M x N KY" c) (CH2)m' or -16x e)

-N

wherein X, Y, Z, R 6 n, m and m1' are defined as above.

More preferred compounds are HIV protease inhibiting compounds comprising a substituent of the formula 11 wherein R 3 is loweralkyl and R 5 is x N y a) (CH 2 )nJ wherein n is 1 or 2, X is 0 or S and Y is -CH 2 or -NH-, x b) (CH2)m b) wherein m is 1 or 2, X is 0, Y is -CH 2 and Z isO0, x N C) (CH 2 )m wherein mis 1, X is 0, Z isO0 and Y is -NH-, IV x d) (CH 2 )m wherein mis 1, X is 0, Y" is -NH- and Y'is -NH- or x IN N -RV e)

-N

wherein X is 0 and R 6 is hydrogen.

Even more preferred compounds are HIV protease inhibiting compounds comprising a substituent of the formula I] wherein R 3 is isopropyl and R 5 is x a) (CH2) wherein n is 1 or 2. X is 0 or S and Y is -CH 2 or -NH-, V* b) z wherein m is 1 or 2. X is 0, Y is -CH 2 and Z is 0, x N Y C) (CH2)m'

Z

wherein m'is 1, X is 0, Z is 0 and Y is -NH-, x N Y

/Y

d) (CH 2 )m' wherein m'is 1, X is 0, Y" is -NH- and Y'is -NH- or x e)N wherein X is 0 and R 6 is hydrogen.

Most preferred compounds are HIV protease inhibiting compounds comprising a substituent of the formula 11 wherein R 3 is isopropyl and R. is a) (CH 2

)J

*wherein n is 1 or 2, X is 0or S and Y is -CH 2 or -NH-, x N Y (CH2)m Z -19wherein mis 1X is0, Z is 0and Yis -NH-, x N Y c) (CH2)m wherein mis X is 0, Y" is -NH- and Y is -NH- or x N1 RV" d) wherein X is 0 and R 6 is hydrogen.

Most highly preferred compounds are HIV protease inhibiting compounds comprising a substituent of the formula 11 wherein R3is isopropyl and R 5 is

X

~N y *t (CH2)]wherein n is 1 or 2, X is 0 or S and Y is -CH 2 or -NH-.

*2 Examples of such HIV protease inhibiting 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)isoquinoline-3(S)-carboxamide; S cis-N-tert-butyl-decahydro-2-[ 2(R)-hydroxy-4-thiophenyl-3(S)-(2S-(1 tetrahy dropyrimid-2-onyl)-3-methylbutanoyI)aminobutyl]-(4aS,8aS)isoquinoline-3(S)-carboxamide; and 4-Amino-N-(( 2syn, 3S)-2-hydroxy-4-phenyl-3-(2S-( 1 -tetrahydropyrimid-2onyl)-3-methylbutanoylamino)-butyl)-N-isobutyl-benzenesulfonamide; and the like; or pharmaceutically acceptable salts thereof Such HIV protease inhibiting compounds comprising a substituent of the formula 11 can be prepared by coupfing a suitable intermediate or precursor having an amino group (-NH 2 or -NHR* wherein R* is loweralkyl), a hydroxyl group or a thici group to the compound of the formula III or a salt or an activated ester derivative thereof:

*R

3 HO- C R 11 0

III

whferein R3is loweralkyl. hydroxyalkyl or cycloalkylalkyl; and

R

5 is x a) (CH2a) x N y

(CH

2 )m b) z N Y C)z x

(CH

2 )6< x N N" 1) (CH2)m x N *J N G 0 N)"N -R 6 h) OH or 0

HO'

wherein n is 1, 2 or 3, m is 1, 2 or 3, m' is 1 or 2, X is 0, S or NH, Y is -CH 2 or wherein R, is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, Y" is or -N(R 6 wherein is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, Y' is -N(R 6 wherein R 6 is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, and Z is 0, S or NH; or a salt or an activated derivative thereof; with the proviso that 1) when R 3 is hydroxyalkyl, then R 5 is other than x wherein n is 1, 2 or 3; and 2) when RO s loweralkyl, then R 5 is other than 0 Preferred compounds are compounds of the formula III or an activated ester derivative thereof wherein ROis loweralkyl and R, is x a) I ~N Y

(CI-

2 x b) N j Y (CH2).

R:\LIBC\03817.doc N "(Y C) (CH 2 )m Z x

N

d) (CH 2 )m' x

N

wherein X, Y, Z, R 6 n, m and m' are defined as above.

More preferred compounds are compounds of the formula III or an activated ester derivative thereof wherein is loweraikyl and RIs 0: a (CH2) %.000 wherein n is 1 or 2, X is 0 or S and Y is -CH 2 or -NH-, .0000 0: .*000 Ux (C H2)mr wein-,, is C2, X is 0. Y is and Z is 0.

\.;ern ,n m 0. Z s 0 and Y is -NH-.

x

Y,

d) (CH 2 )m' wherein m'is 1, X is 0, -NH- and Y is -NH- or x *to.:N N -R1 6 e)

N

wherein X isO0 and R 6 is hydrogen.

Even more preferred compounds are compounds of the formula III or an *activated ester derivative thereof wherein Ris isopropyl and Ris 3* x a) N (CH 2 )n wherein n is 1 or 2, X is 0 or S and Y is or -NH-, x b) N Y

,~(CH

2 1 z wherein in is 2. X is 0, Y is and Z is 0, x C) N Y

(CH

2

Z

wherein mn' is 1, X is 0, Z is 0 and Y is -NIH-, x d) "N il

(CH

2 wherein m' is 1, X is 0, Y" is -NH- and Y' is -NH- or e) *N N -R 6 l0 wherein X is 0 and R 6 is hydrogen.

6000 GV ao R:\LIBC\03817.doc -26- Most preferred compounds are compounds of the formula III or an activated ester derivative thereof wherein R 3 is isopropyl and R 5 is

X

N^y a) (CH2 )n wherein n is 1 or 2, X is 0 or S and Y is -CH, or -NH-,

X

N, Y b) (CH2)m'

Z

wherein m' is 1, X is O, Z is O and Y is -NH-, x N Y"

S/Y,

c) (CH2)m wherein m' is 1, X is 0, Y" is -NH- and Y' is -NH- or N R 6 d)

N

wherein X is 0 and R 6 is hydrogen.

Most highly preferred compounds are compounds of the formula III or an activated ester derivative thereof wherein R 3 is isopropyl and R 5 is -27-

X

Ny

(CH

2 )n S wherein n is 1 or 2, X is O or S and Y is -CH2 or -NH-.

The compounds of the invention can comprise asymmetrically substituted carbon atoms. As a result, all stereoisomers of the compounds of the invention are meant to be included in the invention, including racemic mixtures. mixtures of diastereomers, as well as single diastereomers of the compounds of the invention.

The terms and configuration are as defined by the JUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl.

Chem. (1976) 45, 13- The term "N-protecting group" or "N-protected" as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an. amino group against undersirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene and Wuts, "Protective Groups in Organic Synthesis," (John Wiley Sons, New York X0 (1991)), which is hereby incorporated by reference. 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-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3.4-dimethoxybenzyloxycarbonyl, 2.4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 0V.0.: 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1 -(p-biphenylyl)-l -methylethoxycarbonyl, -28benzhydryloxycarbonyl, 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 trimethylsilyl and the like. Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, 1-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) to 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, formic and acetic acid derived anhydrides, anhydrides derived from alkoxycarbonyl halides such as isobutyloxycarbonylchloride and the like, N-hydroxysuccinimide S derived esters, N-hydroxyphthalimide derived esters, N-hydroxybenzotriazole derived esters, N-hydroxy-5-norbornene-2,3-dicarboxamide derived esters, 2,4,5-trichlorophenol derived esters, thiophenol derived esters, propylphosphonic acid derived anhydrides and the like.

The term "alkanoyl" as used herein refers to R 19 wherein R 19 is a *P loweralkyl 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-, -CH 2 CH=CH-, -C(CH 3

S-CH

2

CH=CHCH

2 and the like.

m The terms "alkoxy" and "thioalkoxy" as used herein refer to R 15 0- and

R

1 5 respectively, wherein R15 is a loweralkyl group.

~The term "alkoxyalkoxy" as used herein refers to R 2 2 0-R 2 3 0- wherein S. R 22 is loweralkyl as defined above and R 2 3 is an alkylenyl group.

.i Representative examples of alkoxyalkoxy groups include methoxymethoxy, *O ethoxymethoxy, t-butoxymethoxy and the like.

-29- W The term "alkoxyalkyl" as used herein refers to an alkoxy group appended to a loweralkyl radical.

The term "alkoxycarbonyl" as used herein refers to R 20 wherein is an alkoxy group.

The term "alkylamino" as used herein refers to -NHR 16 wherein R 16 is a loweralkyl group.

The term "alkylaminocarbonyl" as used herein refers to R 2 1 wherein

R

21 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 carbon atoms by the removal of two hydrogen atoms, for example methylene

(-CH

2 1.2-ethylene (-CH 2

CH

2 1,1-ethylene =CH-CH 3 1,3-propylene

(-CH

2

CH

2

CH

2 2,2-dimethylpropylene (-CH 2

C(CH

3 2

CH

2 and the like.

The term "aminocarbonyl" as used herein refers to -C(O)NH 2 The term "aryl" as used herein refers to a mono- or bicyclic carbocyclic ring system comprising 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. Aryl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, halo, 0 haloalkyl, haloalkoxy, alkoxy, alkoxycarbonyl, thioalkoxy, amino, alkylamino, dialkylamino, aminocarbonyl, mercapto, nitro, carboxaldehyde, carboxy and hydroxy.

The term "arylalkyl" as used herein refers to an aryl group as previously defined, appended to a loweralkyl radical, for example, benzyl and the like.

The term "cycloalkyl" as used herein refers to an aliphatic 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 appended to a loweralkyl radical, including but not limited to cyclohexylmethyl.

L" The term "dialkylamino" as used herein refers to NR16R17 wherein R 1 6 and R17 are independently selected from loweralkyl groups.

o*oooo The term "dialkylaminocarbonyl" as used herein refers to R22C(O)wherein R 22 is a dialkylamino group.

The term "halo" or "halogen" as used herein refers to -CI, -Br, -I or -F.

The term "haloalkoxy" as used herein refers to R 18 0- wherein R 18 is a I haloalkyl group.

The term "haloalkyl" as used herein refers to a loweralkyl group in which one or more hydrogen atoms are replaced by halogen, for example, chloromethy), chloroethyl, trifluoromethyl and the like.

The term "heterocyclic ring" or "heterocyclic" or "heterocycle" as used to herein refers to any 3- or 4-membered ring containing a heteroatom selected from oxygen, nitrogen and sulfur; or a 6- or 7-membered ring containing one, two or three heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur or a 5-membered ring containing 4 nitrogen atoms; and includes a 6- or 7-membered ring containing one, two or three nitrogen is atoms; one oxygen atom; one sulfur atom; one nitrogen and one sulfur atom; one nitrogen and one oxygen atom; two oxygen atoms in non-adjacent positions; one oxygen and one 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 nono 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 6and 7-membered rings have 0-3 double bonds. The nitrogen heteroatoms can.

be optionally quaternized. The term "heterocyclic" also includes bicyclic groups in which any of the above heterocyclic rings is fused to a benzene ring or a cyclohexane ring or another heterocyclic ring (for example, indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl, bistetrahydorfuranyl or benzothienyl and the like). Heterocyclics include: azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, S30 pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, thienyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrimidyl and benzothienyl.

'Y.

Heterocyclics also include compounds of the formula z* wherein X' is -CH 2 -NH- or Y' is or 2 wherein R" is hydrogen or C1-C4-alkyl and v is 1, 2 or 3 and Z* is or such as 1,3benzodioxolyl, 1,4-benzodioxanyl and the like.

Heterocyclics can be unsubstituted or substituted with one, two. three or to four substituents independently selected from the group consisting of hydroxy, halo, oxo alkylimino wherein R* is a loweralkyl group), amino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, haloalkyl, cycloalkyl, aryl, arylalkyl, -COOH, -SO 3 H and loweralkyl. In addition, nitrogen containing heterocycles can be N-protected.

The term "hydroxyalkyl" as used herein refers to a loweralkyl radical to which is appended an hydroxy group.

The term "loweralkyl" as used herein 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, iso-butyl, sec-butyl, t-butyl, n- S pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, nhexyl and the like.

The term "thioalkoxyalkyl" as used herein refers to a thioalkoxy group appended to a loweralkyl radical.

The compound of the invention of formula I can be prepared as shown in ZS Schemes I-IV. As outlined in Scheme I, intermediates 1 and 2 (wherein P 1 is N-protecting group, for example, t-butyloxycarbonyl) can be coupled using o standard peptide coupling reagents and methods, for example, reaction of 1 and 2 in the presence of 1-hydroxybenzotriazole and a diimide such as S° dicyclohexylcarbodiimide (DCC) or N-ethyl-N'-dimethylaminopropyl S carbodiimide (EDAC) and the like to give 3. Alternatively, a salt or an activated ester derivative of intermediate 1 (for example, the acid chloride, prepared by S* reaction of the carboxylic acid with thionyl chloride) can be reacted with intermediate 2.

-32q Compound 3 can be N-deprotected to give compound 4. N-deprotection of 3 wherein P 1 (especially wherein P 1 is t-butyloxycarbonyl) is an acid labile N-protecting group can lead to formation of impurities resulting from migration of the acyl group R 4

-L

1 from the amino group to the hydroxyl group. The 4 formation of this impurity can be minimized or eliminated by performing the deprotection using trifluoroacetic acid in methylene chloride or (2) concentrated hydrochloric acid (from about 2 molar equivalents to about 6 molar equivalents, preferably, from about 2 molar equivalents to about 4 molar equivalents) in acetic acid at about room temperature. A preferred 0o N-deprotection method comprises reacting compound 3 (wherein P 1 is t-butyloxycarbonyl) with concentrated hydrochloric acid (from about 10 to about molar equivalents) in acetonitrile (from about 2 to about 10 liters/kilogram of compound 3) at a temperature of 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 the formula I 6).

An alternative process is shown in Scheme IIA. Compound Z (wherein P2 is an N-protecting group, for example, benzyloxycarbonyl) can be coupled to compound 5, or a salt or an activated ester derivative thereof (for example, the acid chloride, prepared by reaction of the carboxylic acid with thionyl chloride), U to give 8. Compound B can be N-deprotected to give 9. Compound 9 can be coupled with compound 1, or an activated ester derivative thereof, to give the compound of the formula I 6).

Scheme IIB shows a preferred alternative process wherein the o*moo N- protected amino alcohol 7a (P 3 is hydrogen and P 4 is an N-protecting group ±S or both P 3 and P 4 are N-protecting groups, preferably, P 3 and P 4 are benzyl) is reacted with from about 1 to about 1.3 molar equivalents of carboxylic acid 5 or a salt or an activated ester derivative thereof (for example, the acid chloride, prepared by 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 from about 1.0 to about 4.0 molar equivalents (preferably, from about 2.5 to about molar equivalents) of an organic amine base (for example, imidazole, 1-methylimidazole, 2-methylimidazole, 2-isopropylimidazole, ~4-methylimidazole, 4-nitroimidazole, pyridine, N,N-dimethylaminopyridine, 1,2.4-triazole, pyrrole, 3-methylpyrrole, triethylamine or N-methylmorpholine -33and the like) or from about 1 to about 20 molar equivalents of an inorganic base (for example, sodium carbonate or sodium bicarbonate and the like) in an inert solvent (for example, ethyl acetate, dimethylformamide, THF, acetonitrile, isopropyl acetate or toluene and the like) at a temperature of from about 0°C to 6 about 50'C to provide compound 8a. Preferred organic amine bases include imidazole and 1,2,4-triazole.

N-Debenzylation of 8a (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.

Compound 9 can be advantageously purified by crystallization with an organic carboxylic acid (for example, S-pyroglutamic acid, succinic acid or fumaric acid and the like). A preferred organic carboxylic acid is S-pyroglutamic acid.

Compound 2 (or an organic carboxylic acid salt of compound 9} is reacted with from about 1.0 to about 1.3 molar equivalents of carboxylic acid 1 1, or a salt or an activated ester derivative thereof (for example, the acid chloride) in the presence of from about 4 to about 8 molar equivalents (preferably, from about 5 to about 7 molar equivalents) of an inorganic base (for example, NaHCO 3 Na2CO 3

KHCO

3

K

2

CO

3 NaOH or KOH and the like) in an inert solvent (for example, 1:1 ethyl acetate/water or isopropyl acetate/water or ;LA toluene/water or THF/water and the like) at about room temperature or from about 1.0 to about 4.0 molar equivalents (preferably, from about 2.5 to about molar equivalents) of an organic amine base (for example, imidazole, 1-methylimidazole, 2-methylimidazole, 2-isopropylimidazole, 4-methylimidazole, 4-nitroimidazole, pyridine, N,N-dimethylaminopyridine, .C 1,2,4-triazole, pyrrole, 3-methylpyrrole, triethylamine or N-methylmorpholine and the like) in an inert solvent (for example, ethyl acetate, isopropyl acetate, THF, toluene, acetonitrile, dimethylformamide and the like) at a temperature of from about 0°C to about 50°C to provide compound 6.

In a preferred embodiment of the invention (shown in Scheme III), So intermediate compound 5 has the formula of compound 10 (R 3 is as defined for the compound of formula I and is preferably isopropyl). Compound 1Q can be prepared in variety ways as shown in Scheme III. In one method, amino acid 11 (either as the free carboxylic acid or as the carboxylic acid ester loweralkyl W ester)) is converted to carbamate 12 is phenyl, loweralkyl-substituted phenyl, halo-substituted phenyl, nitro-substituted phenyl, trifluoromethylphenyl and the like) by reaction with the appropriate chloroformate ester and the like.

Reaction of carbamate 12 with from about 1.0 to about 1.5 molar equivalents of J amine 12 or an acid addition salt thereof (Q is a leaving group, for example, CI, Br or I, or a sulfonate such as methanesulfonate, triflate, p-toluenesulfonate, benzenesulfonate and the like) in an inert solvent (for example, THF, methyl t-butyl ether, dimethoxyethane, THF/water, dimethoxyethane/water, toluene or heptane and the like) in the presence of a base (for example, LiOH.

to NaOH, Li 2 CO3, Na 2

CO

3 lithium phenoxide or sodium phenoxide and the like) in the amount of from about 2.5 to about 3.5 molar equivalents provides urea 14.

Urea 14 can be isolated and reacted further or can be converted in _u to cyclic urea 10 by reaction in an inert solvent (for example, THF, dimethoxyethane, methyl t-butyl ether, toluene or heptane and the like) with a base (for example, IC potassium t-butoxide, sodium hydride, potassium hydride or dimethylaminopyridine and the like) in the amount of from about 2.0 to about molar equivalents. If the amino acid ester of 11 was the starting material, the ester is then hydrolyzed to provide the carboxylic acid o. Alternatively, amino acid 11 (either as the free carboxylic acid or as the O.0 carboxylic acid ester) is converted to urea 14 by reaction with from about 1.0 to about 1.5 molar equivalents of isocyanate 15 (O 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 (for example, THF, dimethoxyethane, methyl t-butyl ether, toluene or heptane and the like) in the AS presence of a base.

In yet another alternative, amino acid 11 (either as the free carboxylic acid or as the carboxylic acid ester) is converted to diamine 16 by reaction with from about 1.0 to about 1.5 molar equivalents of amine 13 or an N-protected derivative thereof (Q is a leaving group, for example, CI, Br or I, or a sulfonate a6 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 the like) in the presence of a base (for example, NaH or potassium t-butoxide and the like) in the amount of from about 1.0 to W about 4.0 molar equivalents. N-deprotection is required if the N-protected derivative of 12 was used. Reaction of diamine 16 with a carbonyl equivalent 17 (for example, phosgene, carbonyldiimidazole and the like wherein Q' and Q" are leaving groups such as CI, Br, I, -O-loweralkyl, -O-aryl or imidazolyl and the like) in an inert solvent (for example, 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 and the like) in the amount of from about 2.0 to about 4.0 molar equivalents provides cyclic urea 10. If the amino acid ester of 11 was the starting material, the ester is then hydrolyzed to provide o1 the carboxylic acid In yet another alternative shown in Scheme IV, compound 11 (either as the free carboxylic acid or as the carboxylic acid ester loweralkyl ester)) is reacted with acrylonitrile according to J. Am. Chem. Soc. 72, 2599 (1950) to give aminonitrile 18. Alternatively, acrylonitrile can be replaced with

I

S 3-chloropropionitrile to provide 18. N-protection of aminonitrile 18 as the carbamate (R 30 is loweralkyl or phenyl or haloalkyl (for example, 2-chloroethyl, 2-bromoethyl and the like) and the like) using standard conditions (for example, reaction of the amine with the appropriate chloroformate ester (CIC(0)OR 3 0 wherein R 30 is loweralkyl, phenyl, haloalkyl and the like) neat or in an inert tJ solvent (for example, water, THF and the like) in the presence of an inorganic base (for example, NaOH, KOH, K 2

CO

3 and the like) or an organic base (for example, an alkylamine or dialkylamine and the like) and the like) provides compound 19. Hydrogenation of 19 in the presence of a catalyst (for example, 0 Ni-AI alloy (basic) or Raney nickel (neutral or basic) or PtO 2 (acidic) and the like) in an inert solvent (for example, water or methanol or ethanol or THF and the like) provides cyclic urea 10. In a preferred process, compound 19 is hydrogenated in the presence of a Ni-AI alloy catalyst in an inert solvent (for example, water or methanol or ethanol or THF and the like) in the presence of a base (for example, KOH or NaOH or LiOH or an organic amine base and the like) in the amount of from about 1.1 to about 5 molar equivalents to provide cyclic urea 10. If the amino acid ester of 11 was the starting material, the ester is then hydrolyzed to provide the carboxylic acid -36- Alternatively, hydrogenation of compound 18 (as described above for compound 19) provides diamine 1 which can be converted to compound 10 as previously described. If the amino acid ester of 11 was the starting material, the ester is then hydrolyzed to provide the carboxylic acid 1Q.

*o -37- Scheme I 0 Ll OH 0 Ll N

H

Rl

H

2 N

NP

OH R 2 2 OH R 2 R4,,Ll NNH 2 H--y OH R 2 4

R

3

HO

0 0O R R 3

H

OH R 2 0 Scheme IIA

NH

2

P

2 HN y OH R 2 OH R 2 0

R

1

R

3

H

N

H

2 N Y R OH R 2 0 0 Ll OH

HH

OH R 2 0 -39- Scheme 11B

P

3 N l-

H

P'

4 OH R 2 7a

P

3

=P

4 =benzyl

HO

R

0 Ri R 3

H

N

P

3

-N

P'

4 OH R 2 0 8a Ri R 3

H

N

H

2 N

R

OH R 2 0 0

R

4 L

OH

0

R

4 OH R 2 0 Scheme III

H

2 N y C0 2

H

R'O-(O)C-HN y C0 2

H

O=C=N Q J H 2 N 13

H

yN yC0 2

H

0

R

H

H

2 N Q

NH

2 HN y C0 2

H

R

3 16 0 17 HN yN yC0 2

H

0 R 3 -41- Scheme IV

CN

H

2 N y C0 2

H

R3 NH -rC0 2

H

R3 18

OR

30 N C0 2

H

fees *00* a *1 0 0: 4 4

NH

2 HN y C0 2

H

R

3 HNYNyCO 2

H

0 R 3 -42- N) 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: R1 R 3

P

3 N

R

P

4 OH R 2

O

IV

or a salt thereof, wherein P 3 and P 4 are independently selected from hydrogen or an N-protecting group;

R

1 and R 2 are independently selected from the group consisting of loweralkyl, cycloalkylalkyl and arylalkyl; R3 is loweralkyl, hydroxyalkyl or cycloalkylalkyl; and R* is *oo x y X x N Y Z (CH2)m

Z

-43w x N Y c) Z x d)

(CH

2 )m z x z N l (CH2)m N

Y

I

f) (CH2)m x

N

0 N N -R 6 h) OH' or 0 U) N R H) HO' wherein n Is 1, 2or 3, m is 1, 2or 3, mis 1 or 2, X isO0, S or NH, Yis -CH 2 -0- S- or -N(R 6 wherein R 6 is hydrogen, loweraikyl, cycloalkyl, cycloalkylaikyl.

aryl or arylalkyl, Y" is -CH 2 or -N(R 6 wherein RI.. is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, Y' is -N(R 6 wherein R 6 is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, and Z is 0, S

NH.

Preferred compounds are compounds of the formula IV wherein P 3 and

V.*

*P

4 are hydrogen or benzyl, R, and R 2 are arylalkyl, R 3 is loweralkyl and R 5 Is x a) (CH2)n N Y (CH2)m .41 1 Sx N 'KY C)

(CH

2 h z x N Y d) (CH 2 )mn or x \1KN R 6 ~e) whri X, YYYZ ,mad 'r eie saoe More preferred compounds are compounds of the formula IV wherein R, and R 2 are benzyl or R, is benzyl and R 2 is loweralkyl, R 3 is loweraikyl and R is x a) (CH 2 )nJ wherein n is 1 or 2, X is 0 or S and Y is -CH 2 or -NH-, -46x N Y (CH2)m b)

Z

wherein mn is 1 or 2, X is 0, Y is -OH 2 and Z is 0, x N "kY C) (CH2)m

Z

wherein m'is 1, X is 0, Z is 0 and Y is -NH-, x N Y" d) (CH2)m' wherein m' is 1, X is 0, Y' is -NH- and Y' is -NH- or x N N -R1 6 e)

N

wherein X is 0 and R 6 is hydrogen.

Even more preferred compounds are compounds of the formula IV wherein R 1 and R 2 are benzyl or R 1 is benzyl and R 2 is isopropyl, R 3 is loweralkyl and R 5 is x Nk

Y

J

a) (CH 2 )nJ wherein n is 1 or 2, X is 0 or S and Y is -CH 2 or -NH-, x

NAY

(CH2)m b)

Z

wherein m is 1 or 2, X is 0. Y is -CH 2 and Z is 0.

x N Y N

Y.

d) (CH 2 )m wherein mis 1, X is 0, YZis and Yis -NH- o x d) (CH2)mN wherein mX is 1,0 i ,Y s-H and R6. is -NH-ogor -48- Most preferred compounds are compounds of the formula IV wherein R and R 2 are benzyl or R, is benzyl and R 2 is isopropyl, R 3 is loweralkyl and R 5 is x N y a) (CH 2)n wherein n is 1 or 2, X is 0 or S and Y is -CH 2 or -NH-, x N Y b)

(CH

2 )m Z wherein m'is 1, X is 0, Z is 0 and Y is -NH-, x 0000

N

0

Y,

0c) (CH2)m wherein mis 1, X is 0, Y" is -NH- and Y is -NH- or 0.00d) -N wherein X is 0 and R 6 is hydrogen.

5 Most highly preferred compounds are compounds of the formula IV wherein R 1 and R 2 are benzyl or R, is benzyl and R 2 is isopropyl, R 3 is loweralkyl and R 5 is -49-

X

Nk

Y

(CH

2 )nJ wherein n is 1 or 2, X is O or S and Y is -CH 2 or -NH-.

Preferred salts of the compound of formula IV are organic carboxylic acid to salts, especially the (S)-pyroglutamic 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-dimethvlDhenoxvacetyl) amino-3-hvdroxv-5-[2S-(1imidazolidin-2-onvl)-3-methyl-butanovl] amino-1,6-diphenvlhexane.

A. N,N-Dibenzvl-(L)-phenvlalanine Benzyl Ester.

A solution containing L-phenylalanine (161 kg, 975 moles), potassium carbonate (445 kg, 3220 moles), water (675 ethanol (340 and benzyl chloride (415 kg, 3275 moles) was heated to 90+150C for 10-24 hours. The 4,0 reaction mixture was cooled to 600C and the lower aqueous layer was removed. Heptane (850 L) and water (385 L) were added to the organics, i stirred, and the layers separated. The organics were then washed once with a water/methanol mixture (150 L/150 The organics were then stripped to give the desired product as an oil,which was carried on in the next step without 4 purification.

IR (neat) 3090, 3050, 3030, 1730, 1495, 1450, 1160 cm 1 1 H NMR (300 MHz, CDC13) 6 7.5-7.0 20H), 5.3 1 H, J 13.5 Hz), 5.2 1 H, J 13.5 Hz), 2H, J 15 Hz), 3.8 2H, J 8.4 Hz), 3.6 2H, J 15 Hz), 3.2 (dd, 1H, J 8.4, 14.4 Hz), 13C NMR (300 MHz, CDCI3) 5 172.0, 139.2, 138.0, 135.98.2, s o 128.1, 128.1, 126.9, 126.2, 66.0, 62.3, 54.3, 35.6.

[alD -790 (c 0.9, DMF).

B. (4S)-4-(N.N-Dibenzvlamino)-3-oxo-5-phenyl-pentanonitrile.

A solution containing the product of Example 1A benzyl ester) (approx. 0.45 moles) in 520 mL tetrahydrofuran and 420 mL acetonitrile was cooled to -400C under nitrogen. A second solution containing sodium amide S (48.7g, 1.25 moles) in 850 mL tetrahydrofuran was cooled to -40 0 C. To the sodium amide solution was slowly added 75 mL acetonitrile and the resulting solution was stirred at -40oC for more than 15 minutes. The sodium amide/acetonitrile solution was then slowly added to the benzyl ester solution at -400C. The combined solution was stirred at -400C for one hour and then I0 quenched with 1150 mL of a 25% citric acid solution. The resulting slurry was warmed to ambient temperature and the organics separated. The organics were then washed with 350 mL of a 25% sodium chloride solution, then diluted with 900 mL heptane. The organics were then washed three times with 900 mL of a 5% sodium chloride solution, two times with 900 mL of a IC methanolic water solution, one time with 900 mL of a 15% methanolic water solution, and then one time with 900 mL of a 20% methanolic water solution.

The organics were stripped and the resulting material dissolved into 700 mL of hot ethanol. Upon cooling to room temperature, the desired product :precipitated. Filtration gave the desired product in 59% yield from the LsZ phenylalanine. IR (CHCI3) 3090, 3050, 3030, 2250, 1735, 1600, 1490, 1450, 1370, 1300, 1215 cm- 1 1 H NMR (CDCI3) 87.3 15H), 3.9 1H, J 19.5 Hz), 3.8 2H, J 13.5 Hz), 3.6 2H, J 13.5 Hz), 3.5 (dd, 1H, 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 1H, J 19.5 Hz), 1 3 C NMR (300MHz, CDCI3) 8 197.0, 138.4, 138.0, 129.5, 129.0, 128.8, 128.6, 127.8, 126.4, 68.6, 54.8, 30.0, 28.4. [aJD -950 (c 0.5, DMF).

i: C. (5S)-2-Amino-5-(N.N-dibenzylamino)-4-oxo-1.6-diohenylhex-2-ene.

To a -50C solution of the nitrile product of Example 1B (90 Kg, 244 moles) in tetrahydrofuran (288 was added benzylmagnesium chloride (378 Kg, 2M in THF, 708 moles). The solution was warmed to ambient temperature o and stirred until analysis showed no starting material. The solution was then recooled to 50C and slowly transferred to a solution of 15% citric acid (465 kg).

Additional tetrahydrofuran (85 L) was used to rinse out the original container and the rinse was added to the citric acid quench container. The organics were separated and washed with 10% sodium chloride (235 kg) and stripped to a solid. The product was stripped again from ethanol (289 L) and then dissolved in 800C ethanol (581 After cooling to room temperature and stirring for 12 hours, the resulting product was filtered and dried in a vacuum oven at 300C to C give approx. 95 kg of the desired product, mp 101-102 0 C, IR (CDCI 3 3630, 3500, 3110, 3060, 3030, 2230, 1620, 1595, 1520, 1495, 1450 cm- 1 1 H NMR (300 MHZ, CDCI 3 d 9.8 (br s, 1H), 7.2 20H), 5.1 1 4.9 (br s, 1H), 3.8 d, 2H, J 14.7 Hz), 3.6 2H, J 14.7Hz), 3.5 3H), 3.2 (dd, 1H, J 7.5, 14.4 Hz), 3.0 (dd, 1H, J 6.6, 14.4 Hz), 13C NMR (CDC13) d 198.0, 162.8, 140.2, /0 140.1, 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. [XaID -1470 (c 0.5, DMF).

D. (2S. 5S)-5-Amino-2-(N.N-dibenzvlamino)-3-hvdroxv-1.6-diDhenylhexane i) A suspension of sodium borohydride (6.6 kg, 175 moles) in tetrahydrofuran (157 L) was cooled to less than -10±5°C. Methanesulfonic acid S (41.6 kg, 433 moles) was slowly added and the temperature kept below 0°C during the addition. Once 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) was slowly added while maintaining the temperature below 0"C during the addition. The mixture was stirred for not less than 19h at 0+50C.

2 ii) To a separate flask was added sodium borohydride (6.6 kg, 175 moles) and tetrahydrofuran (157 After cooling to -5+50C, trifluoroacetic acid (24.8 kg, 218 moles) was added while maintaining the temperature below 150C. The solution was stirred 30 min at 15+50C and was then added to the reaction mixture resulting from step i, keeping the temperature at less than 200C. This was stirred at 20±50C until reaction was complete. The solution was then cooled to 10±5°C and quenched with 3N NaOH (195 kg). After agitating with tert-butyl methyl ether (162 the organic layer was separated and washed one time with 0.5N NaOH (200 kg), one time with 20% w/v aqueous ammonium chloride (195 kg), and two times with 25% aqueous sodium chloride 3 (160 kg). The organics were stripped to give the desired product as an oil which was used directly in the next step.

SIR (CHC13) 3510, 3400, 3110, 3060, 3030, 1630, 1 H NMR (300 MHz, CDCI3) 5 7.2 20H), 4.1 2H, J 13.5 Hz), 3.65 1H), 3.5 2H, J 13.5 Hz), 3.1 2H), 2.8 1H), 2.65 3H), 1.55 1H), 1.30 1H), 13 C NMR (300 MHz, CDCI3) 8 140.8, 140.1, 138.2, 129.4, 129.4, 128.6, 128.4, 128.3, S128.2, 126.8, 126.3, 125.7, 72.0, 63.6, 54.9, 53.3, 46.2, 40.1, 30.2.

E. (2S,3S,5S)-2-(N,N-Dibenzylamino)-3-hvdroxy-5-(t-butvloxycarbonvlamino)- 1.6-diphenylhexane.

To a solution of the [2S,3S,5S]-2-N,N-dibenzylamino-3-hydroxy-5-amino- 1,6-diphenylhexane (approx. 105 kg, 226 moles) in MTBE (1096 was added S BOC Anhydride (65 kg, 373 moles) and 10% potassium carbonate (550 kg).

This mixture was stirred until reaction was complete (approx. 1 hour). The bottom layer was removed and the organics were washed with water (665 L).

The solution was then stripped to give the desired product as an oil. 300 MHz 1 H NMR (CDCI3) 5 1.40 1.58 2H), 2.45-2.85 4H), 3.05 1H), S 3.38 2H), 3.6 1H), 3.79 1H), 3.87 2H), 4.35 1H), 4.85 broad, 1H), 7.0-7.38 20 H).

F-1. (2S.3S,5S)-2-Amino-3-hydroxy-5-(t-butyloxycarbonylamino)-1.6diphenylhexane.

To a stirred solution of [2S,3S,5S]-2-N,N-dibenzylamino-3-hydroxy-5-tbutyloxycarbonylamino-1,6-diphenylhexane (12 g, 21.3 mmol) in methanol (350 mL) was charged ammonium formate (8.05 g, 128 mmol, 6.0 eq) and 10% palladium on carbon (2.4 The solution was stirred under nitrogen at °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 driven to completion within 2 hours at a reflux temperature. The reaction mixture was then cooled to room temperature and then filtered through a bed of celite. The filter cake was washed with methanol (75 mL) and the combined filtrates were concentrated under reduced pressure. The residue was taken up in 1 N 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. Concentration -53of the solution under reduced pressure provided the desired product as a light colored oil which slowly crystallized upon standing (5 Further purification of the product could be accomplished by flash chromatography (silica gel, methanol in methylene chloride). 300 MHz 1 H NMR (CDCI3) 6 1.42 9H), 1.58 1H), 1.70 1H), 2.20 broad, 2H), 2.52 1H), 2.76-2.95 4H), 3.50 1H), 3.95 1H), 4.80 broad, 1H), 7.15-7.30 F-2. [2S.3S.5S1-2-Amino-3-hvdroxy-5-t-butvloxycarbonvlamino-16diphenvlhexane succinate salt To a solution of [2S,3S,5S]-2-N,N-dibenzylamino-3-hydroxy-5-tto butyloxycarbonylamino-1,6-diphenylhexane(approx. 127 kg, 225 moles) in methanol (437 was added a methanolic (285 L) slurry of 5% palladium on carbon (24 kg). To this was added a solution of ammonium formate (84 kg, 1332 moles) in methanol (361 The solution was heated to 750C for 6-12 hours and then cooled to room temperature. Solids were filtered from .the reaction mixture using a filter coated with filteraid (Celite) and the methanol was stripped from the reaction mixture using heat and vacuum (up to 700C). The residue was dissolved in isopropyl acetate (4400 kg) with heat (400C) and then 'washed with a 10% sodium carbonate solution (725 kg), and finally with water o(665 Both of the washes were performed at 400C to keep the product in o: solution. The solvent was removed under vacuum with heat (up to 700C).

Isopropyl alcohol (475 L) was then added and stripped off 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 The solution jacket was heated to 700C to dissolve all of the solids and then allowed to slowly cool to room temperature and stir for 6 hours. The solution was then filtered to give the desired product as a white solid (55-80 kg).

mn; 145-146 1 H NMR: (Me 2 SO-d 6 300 MHz) 5 0.97 3H, IPA), 1.20 (s, :i 9H), 1.57 2H), 2.20 2H, succinic acid), 2.55 2H), 2.66 2H), 2.98 (m, 3 1H), 3.42 1H), 3.70 1H), 3.72 1H, IPA), 6.60 1H, amide NH), 7.3 -54w 1 H NMR: (CD 3 OD, 300 MHz) 6 1.11 3H, J=7 Hz, IPA), 1.29 9H), 1.70 (m, 2H), 2.47 2H, succinic acid), 2.65 2H), 2.85 2H), 3.22 3.64 (m, 1H), 3.84 1H), 7.05-7.35 G. Ethyl 2,6-dimethylphenoxy acetate.

S To a solution of 2,6-dimethylphenol (8.0 g, 66 mmole) in dioxane (600 ml) was added ethyl bromoacetate (18.2 ml, 164 mmole) and cesium carbonate (58 g, 176 mmole). The reaction mixture was heated at reflux for 18 h, cooled to room temperature, filtered and concentrated in vacuo. Purification by silica gel column chromatography to 20% ether in hexane) provided the desired compound 300 MHz 1 H NMR (CDC13) 6 1.35 J 7.5 Hz, 3H), 2.30 (s, 6H), 4.31 J 7.5 Hz, 2H), 4.40 2H), 7.0 3H).

H. 2,6-Dimethylphenoxy acetic acid.

To a solution of the compound from Example 1G (5.15 g, 24.7 mmole) in methanol (170 ml) and water (56 ml) was added 5.3 g of lithium hydroxide at 0 0 C, the solution was stirred for 1.5 h at RT and concentrated in vacuo. The residue was acidified with 0.5M HCI and extracted with ethyl acetate (300 ml).

The organic layer was dried and concentrated to give a white solid (4.05 g, 300 MHz 1H NMR (CDCI3) 5 2.30 6H), 4.48 2H), 7.0 3H).

I. (2S, 3S. 5S) -2-(2.6-Dimethylphenoxyacetyl) .0 butyloxvcarbonylamino)-1.6-diphenylhexane.

Coupling of the amine from Example 1F with the acid from Example 1H using standard EDAC coupling procedure provided the desired compound 300 MHz 1 H NMR (CDCI3) 8 1.40 9H), 1.65 3H), 2.18 6H), 2.78 2H), 2.98 J 9 Hz, 2H), 3.75 1H), 3.90 1H), 4.15 1H), 4.20 2H), 4.60 1H), 7.0 3H), 7.25 10H). Mass spectrum: (M H)+ 547.

J. 2-N-(Benzyloxvcarbonyl) amino-acetaldehyde.

To a solution of 1.45 ml of DMSO in 20 ml of CH2CI2 at -78 0 C was added dropwise 1.34 ml of oxalyl chloride. After 15 minutes at -780C, a solution of W N-Cbz-aminoethanol in 40 ml of CH2CI 2 was added. After 15 minutes at -78°C and 2 minutes at 0°C, the solution was cooled to -780C and triethylamine (6.14 ml) was added dropwise. The solution was stirred at -78 0 C for 30 minutes and poured into 50 ml of cold 10% aq. citric acid and extracted with ether (150 ml).

The combined organic layer was washed with brine and dried with anhydrous Na2SO4; filtered and concentrated in vacuo. Purification of the crude product by silica gel column chromatography (10% EtOAc/CH 2 Cl 2 provided the desired compound 300 MHz 1 H NMR (CDC13) 8 4.17 J= 6 Hz, 2H).

5.15 2H), 5.40 (br s, 1 7.36 5H), 9.66 1H). Mass spectrum: 1 0

(M+NH

4 211.

K. N-(Benzyloxvcarbonvlamino)-ethyl valine methyl ester.

To a solution of the aldehyde from Example 1J (0.829 g, 4.29 mmole) in 17 ml of methanol was added valine methyl ester hydrochloride (0.72 g, 4.29 mmole), sodium acetate (0.7 g, 8.58 mmole), and sodium cyanoborohydride S (0.54 g, 8.58 mmole. The mixture was stirred at RT overnight and the solvent was evaporated in vacuo. The residue was taken up in ethyl acetate (100 ml) and washed with satd. NaHCO3 (10 ml) and the aq. layer was extracted with ethyl acetate (2 x 50 ml). The combined organic layer was washed with brine and dried with anhy. sodium sulfate, filtered and concentrated in vacuo. The t 0 residue was purified by silica gel column chromatography (20% EtOAc/CH2CI 2 to provide the desired compound 300 MHz 1H NMR (CDCI 3 5 0.91 J 3 Hz, 3H), 0.94 J 3 Hz, 3H), 1.90 1H), 2.55 1 2.80 1H). 2.98 S(d, J= 6Hz, 1H), 3.20 1H), 3.30 1H), 3.71 3H), 5.10 2H), 5.27 (br s, 1H), 7;.37 5H). Mass spectrum: 309.

L. 2S-(1-lmidazolidin-2-onvl)-3-methvl butanoic acid methyl ester.

The Cbz-protecting of the compound in Example 1K was removed by hydrogenolysis and the crude product was treated with one equivalent of 1,1,carbonyldiimidazole in CH2CI2 to provide the desired compound 300 S:°i MHz 1 H NMR (CDC13) 0.95 J 7.5 Hz, 3H), 0.98 J 7.5 Hz, 3H), 2.15 3b 1H), 3.47 3H), 3.71 3H), 3.73 1H), 4.23 J 10.5 Hz, 1H), 4.81 (br s, 1 Mass spectrum: 201.

-56- M. 2S-(1-lmidazolidin-2-onvl)-3-methyl butanoic acid.

To a solution of the compound from Example 1L (151 mg, 0.75 mmole) in ml of water and 5 ml of dioxane was added at 0°C lithium hydroxide monohydrate (2.0 The solution was stirred at 0°C for 1.5 h and RT for 1 h.

Acidification with 1N HCI, extraction with EtOAc (100 ml 2 x 50 ml), dried with sodium sulfate and evaporation of the filtered solution in vacuo provided the desired compound 300 MHz 1H NMR (DMSO-d 6 8 0.85 J 12 Hz, 3H), 0.92 J 12 Hz, 3H), 2.05 1 3.25 2H), 3.30 1H), 3.50 (m, 1H), 3.90 J= 15 Hz, 1H), 6.40 (br s, 1H), 12.60 (br s, 1H). Mass spectrum: lo (M+H) 187.

N. (2S, 3S, 5S) -2-(2,6-Dimethylphenoxyacetvl) amino-3-hvdroxy-5-amino-1,6diphenylhexane.

To 4.5 g of the compound from Example 11 was added 40 ml each of

CH

2

CI

2 and trifluoroacetic acid. The solution was left at RT for 1 h.

1* Concentration of the solution in vacuo provided the desired compound (100%).

300 MHz 1 H NMR (CDC13) 8 1.48 1H), 1.62 1H), 2.05 1H), 2.24 (s, 6H), 2.50 1H), 2.80 1H), 3.0-3.10 4H), 3.90 J 10 Hz, 1H), 4.17 1H), 4.26 (ABq, J 13.5 Hz, 2H), 7.0 3H), 7.10 2H), 7.30 7H), 7.41 J 10 Hz, 1H). Mass spectrum: 447.

O. (2S, 3S. 5S)-2-(2.6-Dimethvlphenoxvacetyl) amino-3-hvdroxv-5-[2S-(1imidazolidin-2-onyl)-3-methvl-butanovll amino-1,6-diphenvlhexane.

Coupling of the amino compound from Example 1N with the acid from Example 1M using standard coupling procedure [1-(3-dimethylaminopropyl)-3ethylcarbodiimide in DMF] provided the desired compound. 300 MHz 1H NMR (CDC13) 0.83 J 6 Hz, 3H), 0.86 J 6 Hz, 3H), 1.75 2H), 2.16 1H), 2.18 6H), 2.76 2H), 2.97 J 7.5 Hz, 2H), 3.14 2H), 3.30 2H), 3.70 J 1- Hz, 1 3.75 1 4.20 4H), 4.50 (br s, 1 H), 6.70 J 7.5 Hz, 1H), 7.0 3H), 7.25 10H). Mass Spectrum: 615.

W Examlle 2 (2S. 3S. 5S)-2-(2.6-Dimethvlphenoxvacetvl) amino-3-hvdroxy-5-r2S-(1 tetrahydro-pyrimid-2-onyl)-3-methyl butanovil amino-i .6-diphenvihexane.

A. 2S-(1 -Tetrahvdro-ovrimid-2-onvl)-3-methvl butanoic acid.

Using the procedures described in Examples 1 J to 1iM, but replacing the N-Cbz-aminoethanol in Example 1J with N-Cbz-3-aminopropanol provided the desired compound. 300 MHz 1 H NMR (DMSO-d 6 8 0.82 J 7 Hz, 3H), 0.93 J 7 Hz, 3H), 1.77 (in, 2H), 2.10 (mn, 1 3.10-3.23 (in, 4H), 4.42 J 10.5 Hz, 1 6.37 (br s, 1 Mass spectrum: =201.

B. (2S. 3S. 5S)-2-(2.6-Dimethvlohenoxvacetl) amino-3-hvdroxv-5-12S-(1 tetrahvdro-Dyriinid-2-onvl)-3-methvl butanoyll amino-i .6-diiohenvlhexane.

Coupling of the amino compound from Example 1 N with the acid from Example 2A using standard procedure (EDAC in DMF) provided the desired compound 300 MHz 1 H NMR (CDCI3) 8 0.80 J 4.5 Hz, 3H), 0.83 (d, I~ J 4.5 Hz, 3H), 1.50 (in, 1 1.65-1.72 (in, 6H), 2.20 6H), 2.68 (in, 1 2.82 (in, 2H), 3.0 J =7.5 Hz, 1 3.05 (in, 4H), 3.77 (in, 1 4.07 J 4.5 Hz, 1 4.20 (in, 4H), 4.50 (br s, 1 6.78 (br d, 1 7.0 (in, 3H), 7.25 (in, 1 OH).

Mass spectrum: 629.

Examole 3 (2S. 3S. 5S)-2-(2.6-Dimethvlphenoxvacetyfl amino-3-hvdroxy-5-f2S-(3oxazolidin-2-onyl)-3-methvl-butanoyl1 amino-i 6-diphenvlhexane.

A. 2S-(3-Oxazolidin-2-onvl)-3-methvl-butanoic acid methyl ester.

To a solution of L-valine methyl ester hydrochloride (7.6 inmole) was %*tooadded a solution of ethylene oxide in ethanol (1 .5 equivalent). The solution was kept at 000 for 0.5 h and then at FIT for 18 h, at which time 0.01 equivalent of

*.:BF

3 -Et 2 O was added. Fresh ethylene oxide was bubbled directly into the solution for 3 to 4 minutes. After 8 h the solution was concentrated to dryness and the residue was dissolved in CH 2

CI

2 and cooled to 0 0 C. To this solution was added 1 .2 equivalents of triethylamine and 1 .0 equivalent of triphosgene.

-58- After 1 h, the solvent was removed in vacuo and the residue was washed with water (30 ml) and extracted with CH 2

CI

2 (3x50 ml), dried and concentrated.

Purification of the crude product by silica gel column chromatography EtOAc/CH 2 C 12) provided the desired compound 2 steps). 300 MHz 1 H £NMR (CDCI3) 860.98 J 4.0 Hz, 3H), 1.0 J 4.0 Hz, 3H), 2.16 (in, 1 H), 3.60 (in, 2H), 3.73 3H), 4.20 J 10 Hz, 1iH), 4.37 (in, 2H). Mass spectrum.- 202.

B. 2S-(3-Oxazo li din -2-on yl)-3- met hyl-butano ic acid.

Hydrolysis of the methyl ester from Example 3A, using the procedure to described in Example 1 M provided the desired compound. 300 MHz 1 H NMR (DMSO-d 6 6 0.90 J 6 Hz, 3H), 0.95 J 6 Hz, 3H), 2.1 (in, 1 3.55 (in, 1 3.70 (in, 1 3.88 J 9 Hz, 1 4.30 (in, 13.0 (br s, 1 Mass spectrum: (M+NH 4 205.

C. (2S, 3S, 5 Di met hvlohenoxvacetvl) amino-3-hydroxy-5-[2S-(3- IC oxazolidin-2-onyl')-3-methyl-butanoyl1 amino-i .6-dio~henvlhexane.

Coupling of the amine from Example 1 N with the acid from Example 3B **using standard coupling procedures (EDAC in DMF) provided the desired compound. 300 MHz 1 H NMR (CDCI3) 6 0.83 J 4.5 Hz, 3H), 0.87 J 104.5 H z, 3 1. 75 (in, 1iH), 2.10 (in, 1iH), 2.20 6 2.6 5 (mn, 1iH), 2.8 5 (in, 1iH), 3. 0 (in, 3 3.3 0 (in, 1 3.6 0 (in, 2 3.7 7 (in, 1 4.2 0 (in, 4 6.2 5 (b r d, J= 6 Hz, 1 7.0 (in, 3H), 7.25 (in, 1 OH). Mass spectrum: 616.

Examole 4 (2S,3S,5S)-2-f(3R. 3aS. 6aR)-Bis-tetrahydrofuranloxv1 ainino-3-hvdroxy-5-f2Smet hyl-i1 -i midazolidin-2-onyl)-3-ineth yl butanoyll amnino-i .6-dio~henvlhexane.

A. 2S-(3-Methvl-l-iinidazolidin-2-onfl)-3-methyI butanoic acid methyl ester.

To a suspension of 45 mg (60% oil dispersion) of sodium hydride in ml of DMF was added a solution of 150 mg of the compound from Example 1 L in ml of DMF. After 20 minutes at RT, (1 .5 equivalent, 0.07 ml) methyl iodide SO was added. Reaction was complete in 1 h. The reaction was quenched with -59- W satd. NH 4 CI solution and extracted with ether (100 ml 50 ml x dried and concentrated in vacuo. The crude product was purified by silica gel column chromatography (20% EtOAc/CH2Cl 2 to provide the desired compound 300 MHz 1 H NMR (CDCI3) 0.95 J 6 Hz, 3H), 0.97 J 6 Hz, 3H, 2.15 S 1H), 2.80 3H), 3.32 3H), 3.60 1H), 3.70 3H), 4.25 J 10.5 Hz, 1H). Mass spectrum: 215.

B, 2S-(3-Methvl-1-imidazolidin-2-onvl)-3-methyl butanoic acid.

Hydrolysis of the methyl ester from Example 4A using the procedure described in Example 1M provided the desired compound. 300 MHz 1H NMR (DMSO-d6) 8 0.85 J 6 Hz, 3H), 0.92 J 6 Hz, 3H), 2.05 1 2.65 (s, 3H), 3.25 3H), 3.42 1H), 3.90 J 10 Hz, 1H). Mass spectrum: 201.

C. (3R.3aS.6aR)-Bis-tetrahvdrofuranvl-(4-nitrophenyl) carbonate.

To a solution of 3R-hydroxy-(3aS,6aR)-bis-tetrahydrofuran Med.

I Chem. 37, 2506-2508 (1994)] (200 mg, 1.54 mmole) in 10 ml of CH 2

CI

2 was added triethylamine (0.26 ml, 1.85 mmole), and p-nitrophenyl chloroformate (341 mg, 1.69 mmole). The solution was kept at RT for 3 days, diluted with

CH

2

CI

2 (100 ml) and washed with satd. NaHCO 3 (15 ml). The organic layer was dried and concentrated in vacuo. Purification by silica gel column 2- 0 chromatography EtOAc/CH 2

CI

2 provided the desired compound 300 MHz 1 H NMR (CDCI3) 2.0 1H), 2.20 1H), 3.18 1H), 4.0 (m, 3H), 4.17 1H), 5.27 1H), 5.80 J 6 Hz), 7.40 J 7.5 Hz, 2H), 8.30 J 7.5 Hz, 2H). Mass spectrum: (M+NH 4 313.

9**99* D. (2S,3S,5S)-2-[(3R.3aS.6aR)-Bis-tetrahvdrofuranvloxvy butvloxv carbonyl) amino-1.6-diphenvlhexane.

To a solution of the carbonate from Example 4C (100 mg, 0.34 mmole) in 3.4 ml of DMF was added the compound from Example 1F (130 mg, 0.34 mmole). The solution was kept at RT overnight and then concentrated in vacuo.

Purification of the crude product by silica gel column chromatography to MeOH/CH 2

CI

2 provided the desired compound 300 MHz 1H NMR (00013) 8 1.40 9H), 1.64 (in, 3H), 2.76 (in, 2H), 2.87 (in, 2H), 3.66-4.0 (in, 7H), 4.53 (in, 1 5.06 (in, 2 5.68 J 6 HZ, 1 7.1 0-7.28 (in, 10 OH). Mass spectrum: (M+NH 4 558.

E. (2S.3S.5S)-2-[(3R .3aS,6aR1-Bis-tetrahydrofuranloxyI amino-i .6-diphenvihexane.

To a solution of the compound from Example 40 (170 mng, 0.31 iniole) in ml of CH 2 01 2 was added 5 ml of trifluoroacetic acid. After 0.25 h, the solvent was removed in vacuo. The residue was dissolved in 100 ml of EtOAc and washed with said. NaHCO 3 and then brine, dried and concentrated to provide the desired compound 300 MHz 1 H NMR (00013) 51.27-1.60 (in, 4H), 1. 75 (in, 2 2.47 (in, 1 2.8 0 (in, 1 2.88 (in, 2 3. 0 (in, 2 3.8 0 (mn, 4 H).

(mn, 1 5. 10 (in, 1 5.30 J 10.5 Hz, 1 5.70 J =6 Hz, 1 7.05- 7.25 (in, 1 OH). Mass spectrum: 441.

F. (2S,3SSS)-2-[(3R, 3aS, 6aR)-Bis-tetrahydroturanvloxyl [f2S-(3-inethyl-l-imidazolidin-2-onyl)-3-methyI butanoyll amino-i .6diphenvlhexane.

Coupling of the carboxylic acid from Example 4B with the amino compundfro Exmpl 4Eusing standard procedure (EA in provided the desired compound. 300 MHz 1 H NMR (CDC1 3 8 0.82 J 3H, 3H), 0.85 J Hz, 3H), 1.65 (in, 1 2.77 3H), 2.85 (in, 3H), 3.17 (in, 2H) 3.47 (in, 1 3.60 (mn, 2H), 3.75 (mn, 1 3.87 (in, 1 4.0 (in, 1 4.20 (in, 1 H), 5.05 (in, 2H), 5.68 J 6 Hz, 1 6.45 (br d, J 7.5 Hz, 1 7.20 (in, 1 OH).

Mass spectrum: 623.

Exainole Ac 2S.3S.5S)-2-(3R.3aS.6aR)-Bis-tetrahvdrofuranloxyI anino-3-hvdroxy-5-f2S- (1 -imidazolidin-2-onl)-3-inethyI butanoyll amino-i .6-diphenylhexane.

Coupling of the amino compound from Example 4E with the carboxylic acid from Example 1 M using standard procedure (EDAC/DMF) provided the desired compound. 300 MHz 1 H NMR (00013) 6 0.85 J 7 Hz, 3H), 0.88 J Hz, 3H), 1.70 (in, 2H, 2.18 (in, 1 2.80 (in, 3H), 2.95 (in, 1 3.20 (in, -61- 4H), 3.60 3H), 3.75 2H), 4.0 1H), 4.20 1H), 4.45 1H), 5.10 (m, 2H), 5.67 J 6 Hz, 1H) 6.60 J 7.5 Hz, 1 7.20 10H). Mass spectrum: 609.

Example 6 (2S.3S.5S)-2-(N-((5-Thiazolyl)methoxvcarbonyl)amino)-5-((2S-(1-imidazolidin- 2-onvl)-3-methvl-butanovl)-amino)-3-hvdroxy-1 6-diphenvlhexane.

A. Ethyl 2-Chloro-2-formvlacetate.

To a three neck 2L round bottom flask charged with potassium t-butoxide mol, 500 mL of a 1 M solution in THF) and 500 mL of dry THF cooled to 0"C was added dropwise from an addition funnel a solution of ethyl chloroacetate i o (0.5 mol, 53.5 mL) and ethyl formate (0.5 mol, 40.4 mL), in 200 mL of THF over 3 hours. After completion of addition, the reaction mixture was stirred for i hour and allowed to stand overnight. The resulting solid was diluted with diethyl ether and cooled in an ice bath. Then, the pH was lowered to approximately 3 using. 6N HCI. The organic phase was separated, and the aqueous layer was SS washed 3 times with diethyl ether. The combined ethereal portions were dried over NaSO 4 and concentrated in vacuo. The crude desired compound was stored at -30 0 C and used without further purification.

B. Ethyl To a round bottom flask was added 250 mL of dry acetone, 7.5 g (0.123 2 mol) of thioformamide, and 18.54 g (0.123 mol) of ethyl 2-chloro-2formylacetate. The reaction was heated at reflux for 2 hours. The solvent was removed in vacuo, and the residue was purified by chromatography (SiO 2 6 cm o.d. column, 100% CHCI3, Rf 0.25) to provide 11.6 g of the desired compound as a light yellow oil. NMR (CDCI3 6 1.39 J 7 Hz, 3H), 4.38 J S 7 Hz, 2H), 8.50 1H), 8.95 1 H).

C. To a precooled (ice bath) three neck 500 mL flask containing lithium aluminum hydride (2.89 g, 76 mmol) in 250 mL of THF was added ethyl (11.82 g, 75.68 mmol) in 100 mL of THF dropwise over hours to avoid excess foaming. 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 set aside. The crude 6 salts were heated at reflux in 100 mL of ethyl acetate for 30 minutes. The resulting mixture was filtered, and the two filtrates were combined, dried over Na 2

SO

4 and concentrated in vacuo. The product was purified by silica gel chromatography eluting sequentially with 0% 2% 4% methanol in chloroform.

to provide the desired compound, Rf 0.3 methanol in chloroform), which to solidified upon standing in 75% yield. NMR (CDC13) 8 4.92 2H), 7.78 1 H).

8.77 1H). Mass spectrum: 116.

D. ((5-Thiazolyl)methyl)-(4-nitrophenyl)carbonate.

A solution of 3.11 g (27 mmol) of 5-(hydroxymethyl)thiazole and excess N-methyl morpholine in 100 ml of methylene chloride was cooled to 00C and treated with 8.2 g (41 mmol) of 4-nitrophenyl chloroformate. After being stirred for 1 h, the reaction mixture was diluted with CHCI 3 washed successively with 1N HCI, saturated aqueous NaHCO 3 and saturated brine, dried over NaS0 4 and concentrated in vacuo. The residue was purified by silica gel chromatography (Si02, 1-2% MeOH/CHCI 3 Rf 0.5 in 4% MeOH/CHCI 3 to O yield 5.9 g of the desired compound as a yellow solid. NMR (CDCl3) 6 5.53 2H), 7.39 (dt, J 9, 3 Hz, 2H), 8.01 1 8.29 (dt, J 9, 3 Hz, 2H), 8.90 1 Mass spectrum: 281.

E. (2S.3S.5S)-5-Amino-2-(N-((5-thiazolyl)-methoxycarbonyl)amino)-3-hydroxy- 1,6-diphenvlhexane.

Coupling of the amino compound from Example 1F with the carbonate from Example 6D using the procedure from Example 4D, followed by removal of the Boc-protecting group using TFA/CH 2

CI

2 provided the desired compound.

300 MHz 1 H NMR (CDCI3) 81.3-1.6 2H), 2.40 (dd, J 14, 8 Hz, 1H), 2.78 (dd, J 5 Hz, 1H), 2.88 J 7 Hz, 2H), 3.01 1H), 3.72 (br q, 1 3.81 (br d, 0 J 10 Hz, 1H), 5.28 2H), 5.34 (br d, J 9 Hz, 1 7.07 (br d, J 7 Hz, 2H), 7.15-7.35 8H), 7.87 1H), 8.80 1H). Mass spectrum: 426.

-63- F. -(2S.3S.S'-2-(N-((5-thiazolyl)methoxycarbonl)amino) -(2S -1imidazolidin-2-onyl)-3-methyl-butanol)-aminol-3-hvdroxv-1 .6-diohenvlhexane.

Coupling of the amino compound from Example 6E with the carboxylic acid.from Example 1iM using standard procedure (EDAC in DMF) provided the 57 desired compound 300 MHz 1 H NMR (CDCI3) 6i 0.82 J =7.5 Hz. 3H), 0.85( J 7.5 H z, 3 1. 65 (in, 2 2.15 (mn, 1 2.7 0 (mn, 3 2.8 5 7. 5 H z, 2H), 3.08 (mn, 1 3.18 (in, 1 3.30 2H), 3.60 (mn, 3H), 3.80 (mn, 1 4.16 (in, 1 4.40 1 5.16 J 9 Hz, 1 5.24 2H), 6.60 J =9 Hz, 1 H).

7.20 (in, 10OH), 7.83 1 8.80 1 Mass spectrum: 594.

.Exampole 7 ka(2S.3S,5S)-2-(N-((5-Thiazolvfl-iethoxvcarbonvl)amino)-3-hvdroxy-5-(2S-(1imidazolidin -2-onvl)-3,3-dimethyI butanoyl)ainino-1 .6-dirphenylhexane.

A. 2S-(1 -linidazolidin-2-onfl)-3,3-diinethyI butanoic acid.

.000 Using the procedures described in Example 1 J to 1iM, but replacing L- *valine methyl ester with L-t-butyl-leucine methyl ester provided the desired compound. 300 MHz 1 H NMR (DMSO-d6) 8 1.0 3.22 J 7.5 Hz, 2H), :000 3.55 J Hz, 1 3.65 J 7.5 Hz, 1 4.14 1 6.40 1 12.62 (br s, 1 Mass spectrum: 20 1.

000:B. (2S.3S.5S)-2-(N-((5-ThiazolvF)-iethoxycarbonflamino)-3-hydroxy-5-(2S- :oo~o(1 -imidazolidin-2-onfl-3.3-dimethyI butanoyl)amino-1 .6-diihenvihexane.

oo~o.Coupling of the amino compound from Example 6E with the carboxylic o o...:acid from Example 7A using standard procedure (EDAC in DMF) provided the :..00desired compound 300 MHz 1 H NMR (Cool 3 83 1.0 9H), 1.68 (in, .00* 2H), 2.60-2.80 (in, 3H), 2.85 J 7.5 Hz, 1 3.10 (in, 1 3.30 (in, 1 3.50 1 4.56 1 5.15 J 7.5 Hz, 1 5.25 (Alq, 1 6.50 J 7 Hz, 1 7:20 (in, 1 OH), 7.83 1 8.80 1 Mass spectrum: =609.

-64- Exam[?le 8 (2S,3S .5S'l-2-(2,6-Dimethyln~henoxyacetvl)amino-3-hydroxv-5-(2S-(i imidazolidin-2-onvl'l-3.3-dimethyI butanoyvbamino- 1 6-diphenvihexane, Couplin g of the amino compound from Example 1 N with the carboxylic acid from Example 7A using standard procedure (EDAC in DMF) provided the desired compound 300 MHz 1 H NMR (COCl 3 63 1 .0 9H), 2.18 6H), 2.68. (in, 1 2.8 0 (in, 1 2.9 8 (in, 3 3.10 (in, 1 3.2 7 J 7 H z, 1 H), 3 (in, 1 3.7 7 (mn, 1 4. 0 1 4.2 0 (in, 4 6.7 2 (mn, 1 7. 0 (in, 3 H), 7.10-7.25 (in, 10H). Mass spectrum: 629.

Exainle 9 (2S, 3S,5 S) Di met hvl henoxyacetvl) ami no-3-hvydrox 1imidazolidin-2-thionvl)-3-methyI butanoyl)amino-1 6-dio~henvihexane.

A. 2S-(1 -Imidazolidin-2-thionyl'l-3-inethyI butanoic acid.

Using the same procedures described in Example 1 J to 1iM, but replacing ~1 ,1 -carbon yl-diiinidazole with 1,1 ,-thiocarbonyidiimidazole provided the desired compound. 300 MHz 1 H NMR (DMSO-d 6 8 0.87 J 6 Hz, 3H), 0.96 J 6 Hz, 3H), 2.11 (in, 1 3.45 (in, 2H), 3.62 (in, 1 3.80 J 9 Hz, 1 4.80 (d, J 10 Hz, 1 8.30 1 12.75 (br s, 1 H).

B. (2S.3S.5S)-2-(2,6-Diinethlpthenoxvacetvflaino-3-hydroxv-5-(2S-(l- .2o imidazolidin-2-thionyl)-3-inethyI butanovbamino-1 .6-dio~henvihexane.

Coupling of the amino compound from Example 1 N with the carboxylic acid from-Example 9A using standard procedure (EDAC in DMF) provided the desired compound 300 MHz 1 H NMR (CDCl 3 5 0.82 J 6 Hz, 3H), 0.93. J 6 Hz, 3H), 1.75 (in, 1 2.20 6H), 2.65 (mn, 1 2.84 (in, 1 (in, 3H), 3.25 (in, 1 3.40 (in, 2H), 3.54 J Hz, 1 3.78 (in, 1 4.22 (in, 4H), 4.56 J 10.5 Hz, 1 5.65 1 6.60 J Hz, 1 7.0 (in, 3H), 7.25 (in, 1 OH). Mass spectrum: 631.

w Example (2S.3S.5S)-2-4-Amino-2.6-dimethylphenoxyacetyl) amino-3-hvdroxv-5-(2S-(1imidazolidin-2-onvl)-3-methyl-butanoyl) amino-1.6-diphenvlhexane.

A. 2,6-Dimethvl-4-nitro phenoxyacetic acid ethyl ester.

To a solution of 10.5 g (54.6 mmole) of ethyl 2,6-dimethylphenoxy acetate and 7.5 g (109 mmole) of sodium nitrite in 100 ml of methylene chloride was ml of trifluoroacetic acid slowly. The reaction mixture became solid after addition. Additional 35 ml of trifluoroacetic acid was added. After the reaction mixture was stirred at room temperature for 3 h, it was carefully tb partitioned between saturated sodium bicarbonate solution 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 recrystalized in 30% ethyl acetate and hexanes to give 4.75 g of ethyl 2,6-dimethyl-4-nitro phenoxyacetate as light yellow prisms. 300 MHz 1 H NMR (CDCI3) 5 1.34 (3H, t, J 7.5 Hz), 2.39 (6H, s),.4.31 (2H, q, J 7.5 Hz), 7.93 (2H, s).

B. 2.6-Dimethvl-4-nitro-phenoxvacetic acid.

To a solution of 0.962 g (4.06 mmole) of ethyl 2,6-dimethyl-4-nitro phenoxy acetate in 10 ml of methanol was added 1 ml of 3 N sodium hydroxide.

After the reaction mixture was stirred at room temperature for 30 minutes it was acidified with 3 N HCI 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 recduced pressure to give 0.82 g of 2,6-dimethyl-4-nitro phenoxy acetic acid as light yellow solid. 300 MHz 1 H NMR (d3-DMSO) 6 2.35 (6H, 4.55 (2H, s) 7.97 (2H, 13.02 (1H, bs).

ooooo Q. (2S.3S.5S)-2-(t-Butyloxycarbonl) amino-3-hvdroxy-5-(2S-(i mipzlimn2 only)-3-methyl-butpnoflamino- 1.6-diphenyihexane.

Coupling of (2S ,3S ,5S)-2-(t-butyloxycarbonyl) amino-i ,6-diphenylhexane with the carboxylic acid from Example 1 M using standard procedure (EDAC in DMF) provided the desired compound (100%).

300 MHz 1 H NMR (COG! 3 6 0.83 J 6 Hz, 3H), 0.87 J 6 Hz, 3H), 1 9H), 1.70 (in, 2H), 2.16 (mn, 1 2.58-2.80 (in, 4H), 3.10-3.30 (mn, 4H), 3.65 (in, 2 4.2 0 (in, 1 4.3 8 1 4,8 3 J H z, 1lH), 6.5 3 J 9 H z, 1 H), 7.20 (in,.lOH). Mass spectrum: 553.

to D. (2S,3S5S)-2-Anino-3-hydroxy-5-(2S-(1 -iinidazolidin-2:-nl)-3-inethvlbutanovi) amino-i .6-diphenvihexane.

Deprotection of the Boc-protecting group of the compound from Example by standard procedure (TFA/CH 2

CI

2 provided the desired compound. 300 MHz 1 H NMR (CDCI3) 6 0.87 J 6 Hz, 3H), 0.90 J 6 Hz, 3H), 1.33 (dd, J 15=4.5, 9. 0 H z, 1 H) 2.18 (in, 1 2.5 0 (in, 1 2.8 0 (mn, 5 3.2 0 (in, 4 H) 3.7 2 (d, J 10 Hz, 1 4.30 (in, 1 4.50 1 6.67 J 7 Hz, 1 7.20 (in, 10 OH).

Mass spectrum: 453.

(2S.3*S.5 Nitro- 2.6-diinethylphe noxvacetvl) anino-3-hydroxv-5-(2S- (1 -i midazo lidi n-2-o nyl)-3 -met hvl-buta noyl) amino- 1,6-dinhenvihexane.

OV. 0 Coupling of the amino compound from Exam'ple 100 with the carboxylic acid from Example 1OB using standard procedure (EDAC in DMF) provided the %0.0 desired compound. 300 MHz 1 H NMR (00013) 8 0.83 7 Hz, 3H), 0.86 J 0*0 7 Hz., 3H), 1.70 (in, 3H), 2.18 (in, 2H), 2.28 6H) 2.75 (in, 3H), 2.95-3.30 (in, 0: 6H), 3.67 J 10.5 Hz, 1 3.75 (mn, 1 3.82 J 4 Hz, 1 4.25 (in, 25 6.55'(d, J 7 Hz, 1 7.20 (in, 1 OH), 7.92 2H). Mass spectrum: 0 a -67- F (2S.3S.5S'l-2-(4-Ami no-2,6-di met hylphenoxyacetl) amino-3-hvdroxv-5-(2S- (1 -i mi dazo lidi n-2-o nyl'-3 -met hy -buta noll amino-i 1.6-di phe nvlhex ane.

To a suspension of 7 mg of 1 0% Pd/C in 5 ml of methanol was added a solution of 69 mg of the compound from Example 10E. The reaction mixture S was stirred vigorously under a hydrogen atmosphere (balloon filled with hydrogen attached to a 3-way stopcock). After 1 h, reaction was complete by TLC. analysis:, the catalyst was filtered off and the filtrate was concentrated in vacuo. The crude product was purified by silica gel column chromatography to 5% MeOH/CH 2

CI

2 to provide the desired compound 300 MHz VIC$ 1H NMR (CDCI 3 850.82 J Hz, 3H), 0.87 J 6 Hz, 3H), 1.70 (in, 2H), 2.10 6H), 2.15 (mn, 2H), 2.72 (in, 2H), 2.97 J 7.5 Hz, 2H), 3.08 (mn, 1 3.15 (mn, 1 3.3 0 (mn, 2 3.4 5 (b r s, 2 3.6 6 J 10 H z, 1 3.7 2 (mn, 1 3.9 0 J ±3 Hz, I1H), 4.10-4.20 (in, 4H), 4.30 1 6.33 2H), 6.57 J 9 9Hz, 1 7.20 (in, 1 OH). Mass spectrum: 630.

15Exainple 11 f(2S, 3S, (2,4,6-Tri met hylphenoxyacetvl) amino-3-hydroxy-5-(2S-(1 iinidazolidin-2-onyl)-3-methylbutanol) amino-i .6-diphenvlhexane.

A. 2.4.6-Triinethylphenoxyacetic acid.

Using the procedures from Example 1 G and 1 H, but replacing 2,6- 0 so.: 20 dimethylphenol with 2,4,6-trimethylphenol provided the desired compound. 300 MHz 1 H NMR (CDC13) 8 2.25 9H), 4.43 2H), 6.84 2H). Mass spectrum: 195.

B. (2S.3S.5S)-2-(2,4,6-Triinethylohenoxyacetl) amino-3-hydroxy-5-(2S-(1 irnidazo lid in -2-o nyl'-3- met hylbuta noyl) amino-i .6-dio~henvlhexane.

2SQoupling of the amino compound from Example 10D with the carboxylic *fo* acid from Example 11A using standard procedure (E DAC in DMF) provided the desired compound (51 300 MHz 1 H NMR (CDCI3) 8 0.82 J 6 Hz, 3H), 0.85 6 Hz, 3H), 1.70 (in, 4H), 2.13 6H), 2.25 3H), 2.75 (mn, 2H), 2.97 J 7 Hz, 1 3.13 (in, 2H), 3.28 (in, 2H), 3.68 J 10 Hz, 1 3.72 (in, -68- 0@S@

S

eq. is 0S 0e 4 *q S. S

S

S

95S5O* a

OSOS

C

*SSS

0@ S St 2.~S

C

a 1 4.16 (in, 4H), 4.40 br s, 1 6.67 J 8 Hz, 1 6.80 2H), 7.20 (in, 1OH). Mass spectrum: =629.

Example 12 (2S.3S,5S)-2-(4-Fluoro)-2,6-dimethylphenoxvacetl) amino-3-hvdroxv-5-(2S-(i imidazolidin-2-onyl)-3-methvl-butanovl) amino- 1,6-dio~henvihexane.

A. 4-Fluoro-2.6-dimethylghenoxvacetic acid.

Using the procedure from Example 1 G and 1 H, but replacing 2,6dliiethyiphenol with 4-f luoro-2,6-dimethylphenol provided the desired compound. 300 MHz 1 H NMR (CD3OD) 6 2.26 6H), 4.37 2H), 6.73 J 9 Hz, Mass spectrum: M+ 198.

B. (2S.3S.5S)-2-(4-Fluoro-2,6-dimethvlphenoxvacetl) amino-3-hvdroxy-5-(2S- (1 -imidazolidin-2-onyl)-3-methvl-butanofl) amino-i .6-diohenylhexane.

Coupling of the amino compound from Example 10D with the carboxylic acid from Example 1 2A provided the desired compound. 300 MHz 1 H NMR (CDCI3) 560.83 J 6 Hz, 3H), 0.86 J =6 Hz, 3H), 1.72 (in, 2H), 2.15 (s, 6H), 2.20 (in, 1 2.76 (mn, 2H), 2.98 J 7 Hz, 2H), 3.12 (in, 2H), 3.30 (mn, 2H), 3.67 J 10 Hz, 1 3.72 (in, 1 4.13 (AB q, J 8, 9 Hz, 2H), 4.20 (mn, 2H), 4.37 1 6.64 J 9 Hz, 1 6.70 J Hz, 2H), 7.20 (in, 1 OH).

Mass spectrum: 633.

Examole 13 (2S,3S.5S)-2-(4,6-DimethyI pyrimidin-5-oxv-acetfl) amino-3-hydroxy-5-(2S-O1imidazolidin-2-onyl)-3-inethl-butanol)l amino-i .6-diphenyihexane.

A. 4.6-Dimethyl 1ovrimidin-5-oxv-acetic acid.

Using the procedures from Example 1iG and 1 H, but replacing 2,6diinethylphenol with 5-hydroxy-4 ,6-dimethylpyri mi dine (prepared according to Chem. Ber. 93 pg. 1998, 1960) provided the desired compound. 300 MHz 1

H

NMVR (DMSO-d 6 8 2.45 6H), 4.55 2H), 8.50 1 Mass spectrum: 183.

-69- B. (2S,3S.5S)-2-(4,6-Dimethvl pvrimidin-5-oxv-acetyl) amino-3-hvdroxv-5-(2S- (1 -imidazolidin-2-onyl)-3-methvl-butanol) amino-i .6-diohenvlhexane.

Coupling of the amino compound from Example 10D with the carboxylic acid from Example 13A provided the desired compound. 300 MHz 1 H NMR (CDCI3) 6.0.82 J 6 Hz, 3H), 0.85 J 6 Hz, 3H), 1.70 (in, 2H), 2.15 (mn, 1 2.4 0 6 2.7 5 (mn, 2 2.9 7 J 7 H z, 2 3.12 (in, 2 3.3 0 (in. 2 H), 3.66 J 10 Hz, 1 3.74 (in. 1 3.88 J Hz, 1 4.20 (in. 4H, 6.62 J =9 H z, 1 7. 0 J 9 H z, 1 7.2 0 (in, 10 8.7 0 1 M a ss sp ec tr um: 617.

Example 14 D. (2S,3 S, 5S)-2- Dimet hvyl-pvridi n-3-oxy-acetvl) ainino-3-hydroxv-5-(2S-(1 iinidazolidin-2-onyl)-3,3-dimethvl butanoyl) amino- 1,6-diphenvihexane.

A. 2,4-Di met hyl-gyridi n-3-oxy-acetic acid.

Using the procedures from Example 1 G and 1 H, but replacing 2,6- 115 dimethylphenol with 2,4 diinethyl-3-hydroxypyridine (prepared according to J.

Med. -Chein. 35, pg. 3667-3671, 1992) provided the desired compound. 300 MHz 1 H NMR (DMSO-d6) 5 2.26 3H), 2.42 3H), 4.44 2H), 7.08 J Hz, 1 8.07 J 5 Hz, 1 Mass spectrum: 182.

B. (2S, 3 S.5S)-2- D imet hyl-pvridi n-3-ox y- acetyl) 20butyloxycarbonvl) amino-i .6-diphenvihexane.

Coupling of the amino compound from Examplel F with the carboxylic acid from Example 14A using standard procedure (EDAC in DMF) provided the d esi red compound. 300 MHz 1 H NMR (CDC1 3 8 1.40 9H), 1.70 (in, 2H), 2.18 3H), 2.40 3H), 2.77 (in, 2H), 2.98 J 7 Hz, 2H), 3.75-3.95 (in, 3H), 2-54.20 2H), 4.22 (in, 1 4.60 (br d, 1 7.0 J 5H, 1 7.10 (in, 3H), 7.25 S(in, 7H), 8.16 J 5 Hz, 1 Mass spectrum: =548.

C. (2S,3S.S5S)-2-(2,4- Dimet hvl-pvridin-3-oxy-acetyl) I1 .6-diphenylhexane.

Deprotection of the Boc-group in the compound from Example 1 4B using standard procedure (TFN/CH 2 C 12) provided the desired compound. 300 MHz 1H NMR (CDCI3) 8 1.45 (in, 1 1.62 (mn, 1 2.23 3H), 2.45 3H), 2.50 (in, 1 2.80 (in, 1 3.0 (mn, 2H), 3.12 (in, 1 3.90 (in, 1 4.18 (in, 1 4.25 (ABq, J 9, 12 Hz, 2H), 6.98 J 5 Hz, 1 7.10 (in, 2H), 7.30 (in. 8H), 8.17 J =5 Hz, 1 Mass spectrum: 448.

D. (2S ,3SSS)-2-(2,4-Dimethvl-pvridin-3-oxv-acetvl) amino-3-hvdroxy-5-(2S-(1 0 irnidazolidin-2-onyl)-3.3-diinethyI butanoyi) amino-i .6-dighenvihexane.

Coupling of the amino compound from Example 14C with the carboxylic acid from Example 7A using standard procedure (EDAC in DMF) provided the desired compound. 300 MHz 1 H NMR (C~DC 3 5 1.0 9H), 1.70 (in, 3H), 2.18 3 2.4 2 3 2.7 5 (in, 2 3. 0 (in, 4 3.3 0 (in, 1 3.5 5 (in, 1 3.8 0 (in, 1 4.05 1 4.20 (in, 4H), 4.60 1 6.70 J 7 Hz, 1 6.97 J Hz, 7.15 (in, 3H), 7.25 (in, 7H), 8.17 J Hz, 1 Mass spectrum: 630.

Exainole (2S,3S.5S)-2-(2 .4-Dimethyl-o~yridin-3-oxy-acetfl) ainino-3-hydroxy-5-(2S-(1 i 2..m idazo lidi n-2-onfl- 3- met hvl-butanovl) amino-i .6-diphenvihexane.

Coupling of the amino compound from Example 14C with the carboxylic acid from Example 1M using standard procedure (EDAC in DMF) provided the desired compound. 300 MHz 1 H NMR (CDCI3) 5 0.82 J 6 Hz, 3H), 0.86 (d, 1 6 Hz, 3H), 1.75 (in, 3H), 2.15 (in, 1 2.18 3H), 2.40 3H), 2.75 (in, 2H), J 7.5 Hz, 2H), 3.20 (in, 4H), 3.70 J 10 Hz, 1 3.75 (in, 1 4.20 6H), 4.52 1 3.75 (in, 1 4.20 (mn, 6H), 4.52 1 6.80 J 7 Hz, 1 6.96 J 4.5 Hz, 1 7.20 (in, 10 8. 17 J 4.5 Hz, 1 Mass :spectrum: 616.

-71- W Example 16 (2S,3S.5S)-2-(2.6-Dimethvlthioo~henoxyacetvl) amino-3-hvdroxv-5(2S-(1 i midlazo li din -2-o nyl)- 3- met hvl-butanovl) amino-i1 .6-dirohenylhexane.

A. 2.6-Dimethylthiocjhenoxv acetic acid.

Using the procedures from Example 1iG and 1 H, but replacing 2.6dlimethyiphenol with 2,6-dimethylthiophenol provided the desired compound.

300 MHz 1 H NMR (CDCI3) 82.56 6H), 3.40 2H), 7.10 (in. 3H). Mass spectrum: 197.

B. (2S.3S.5S)-2-(2,6-Dimethvlthiophenoxvacetvl) amino-3-hydroxv-5 irnidazolidi n-2-onvyl)- 3- met h l-butan oy1) amino- 1 6-diphenylhexane.

Coupling of the carboxylic acid from Example 16A with the amino compound from Example 100 provided the desired compound. 300 MHz 1 H NMR (CDCI3) 83 0.82 J =6 Hz, 3H), 0.86 J 6 Hz, 3H), 2.15 (in, 1 2.52 6H), 2.70 (mn, 4H), 3.10 (mn, 2H), 3.30 (mn, 4H), 3.60 (in, 2H), 4.0 (in, 1 4.10 (Tn, 1 4.2 2 1 6.3 9 J 7 H z, 1 6.5 8 J =9 H z, 1 7.2 0 (in, 13 3H).

Mass spectrum: 631.

Example 17 f 2 S,3S.5 Di met hvlphenoxyacetl) amino-3-hydroxv-5-(2S-(1 o~vrrolidin-2-onvP)-3-inethvl-butanofl) amino-i .6-diphenvlhexane.

A. 4-Bromobutanovl-L-valine methyl ester.

To a solution of 1.08 g (8.4 minole) of L-valine methyl ester in 30 ml of CH1 2

CI

2 was added 1.36 ml (16.8 minole) of pyridine, cooled to 0 0 C and 1.55 g (8.4 inmole) of 4-broinobutanoyl chloride added. The solution was stirred at 0 0 C for 40 minutes and at RT for 1 h. The solution was washed with satdl.

NaHCO 3 brine and dried with anhy. Na 2

SO

4 filtered and concentrated in :e :vacuo. The crude product was purified by silica gel column chromatography EtOAc/CH 2

CI

2 to provide 1 .82 g of desired product. 300 MHz 1 H NMR (C~DC 3 8 0.92 J 6 Hz, 3H), 0.96 J 6 Hz, 3H) 2.20 (in, 3H), 2.46 -72- (in, 2 3.5 0 (in, 2 3.7 6 3 4.5 8 (dd, J 4,7 H z, 1 5.9 7 (b r d. J 7 H z, 1 Mass spectrum: 297.

B. 2S-(1 -Pvrrolidin-2-onvO)-3-methyl-butanoic acid.

To a solution of. 1.49 g (5.3 mmole) of the compound from Example 1 7A in a mixture of DMF/CH 2

CI

2 cooled to 0OC was added 0.234 g equivalent) of 60% sodium hydride in mineral oil. The mixture was slowly warmed up to RT and stirred overnight. The mixture was poured into satd. ammonium chloride and extracted with ethyl acetate, dried and concentrated in vacuo. The crude product was hydrolyzed using lithuim hydroxide as in Example 1 H to provide %0 the desired compound. 300 MHz 1 H NMVR (CDCI3) 5 0.96 J =7 Hz, 3H), 1.06 J 7 Hz, 3H), 2.10 (in, 2H), 2.40 (in, 1 2.50 J 7 Hz, 2H), 3.56 (in. 2H), 4.14 J 10 Hz, 1 Mass spectrum: 186.

C. (2S.3S.5S)-2-(2,6-Dimethylr~henoxyacetvl) amino-3-hvdroxv-5-(2S-(1 pyrro lidi n-2-onfl)- 3- met hl-butanoy 1) amino-i .6-dirohenvlhexane.

Coupling of the carboxylic acid from Example 17B with the amine from Example, 1 N using standard procedure (EDAC in DMF) provided the desired compoun~d. 300 MHz 1 H NMR (CoDC 3 8 0.77 J 7 Hz, 3H), 0.83 J 7 Hz, 3H); 1.75 (in, 3H), 2.10 (in, 1 2.20 6H), 2.25 (in, 1 2.65 (in, 1 2.85 (in, 1 3.0 J 7 Hz, 2H), 3.20 (in, 1 3.77 (in, 2H), 3.88 J 10 Hz, 1 H), 2o 4.20 (in, 3H), 6.30 J 7 Hz, 1 6.98 (in, 3H), 7.20 (in, 10 Mass spectrum: 614.

Exainole 18 (2S.3S.5S)l-2-(2.6-D~methvlrhenoxyacetfl) ainino-3-hvdroxv-5-(2S-(1 Dvrrolidin-2.5-dionvl)-3-inethvl-butanofl) amino-i .6-diphe nvihexane.

A. 2S-(1-Pvrrolidin-2,5-dionvl)-3-inethvl-butanoic acid benzvl ester.

To a solution of 700 mng (3.38 iniole) of L-valine benzyl ester in 6 ml of chloroform was added 1 equivalent of succinic anhydride. After 1 h at RT, the OV 0 solvent was removed in vacuo and the residue was dissolved in 20 ml of DMF.

To this solution was added 0.52 g of N-hydroxy-benzotriazole, 0.68 g of EDAC -73and 0.52 ml of triethylamine. After 24 h at RT, 20 mg of 4-dimethylaminopyridine was added. The solution was left at RT for 3 days. After standard work-up, the crude product was purified by silica gel column chromatography to provide 0.25 g of desired product 300 MHz 1 H NMR (CDCI3) 8 0.84 J =7 Hz, 3H), 1. 12 J 7 Hz, 3 2.70 (in, 1 2.71 4H), 4.45 J 9 Hz, 1 5.15 (s, 2H), 7.30 (in, B. 2S-(l1-Pvrrolidin-2.5-dionyl'l-3-methyl-butanoic acid.

A mixture of 0.245 of the product from Example 18A, 30 mg of palladium on charcoal in 50 ml of methanol was stirred vigorously under hydrogen atmosphere (balloon filled with hydrogen) for 1 h. The catalyst was filtered off and the solvent was removed under vacuum to provide 168 mg of the desired compound. 300 MHz 1 H NMR (C~DC 3 6 0.84 J 6 Hz, 3H). 1. 13 (d, J 6 Hz., 3H), 2.65 (in, 1 2.80 4H), 4.45 J 8 Hz, 1 Mass spectrum: 200.

C. (2S'.3S.5S)-2-(2.6-Dimethylghenoxyacetyl) amino-3-hydroxy-5-(2S-(1- Dvrrolidin-2.5-dionyl')-3-methyl-butanovl) amino-i1 .6-dighenvlhexane.

Coupling of the carboxylic acid from Example 18B with the amine from Example 1N using standard procedure (EDAC in DMF) provided the desired 300 MHz 1 H NMR (CDCI3) 5 0.70 J =4 Hz, 3H), 0.72 J 4 Hz, 3H), 1.70 (in, 1 2.20 6H), 2.45 (in, 2H), 2.60 4H), 2.80 (in, 2H), 2H), 3.76 (in, 1 4.20 (in, 6H), 7.0 (in, 3H), 7.20 (in, 1 OH). Mass spectrum (M+H)4 628.

Example 19 (2S.3S.5S)-2-(Trahs-3-(2.6-dimethlohenfl) propenofl) (2S-1 -tetra hydroovrimidin-2-onfl)-3-m eth yl-butanol) amino-i .6dio~henvlhexane.

2.6-Dimethyl benzaldehvde.

Oxidation of 2,6-dimethyl benzyl alcohol by standard Swern oxidation procedure (oxalyl chloride/DMSO) provided the desired compound. 300 MHz -74- S1H NMR (CDCI 3 2.62 6H), 7.10 2H), 7.33 J 7 Hz, 1H), 10.63 (s, 1H), Mass spectrum: 135.

B. Trans-3-(2.6-dimethvlphenvl)-propenoic acid methyl ester.

To a solution of trimethyl phosphonoacetate (149 mg, 0.82 mmole) in S ml of THE was added 36 mg of sodium hydride (60% in oil). After 15 minutes 100 mg of the compound from Example 19A in 2 ml of THF was added. After 2 h, the reaction was quenched carefully with water and extracted with ethyl acetate (70 ml), dried and concentrated. Purification of the crude product by silica-gel column chromatography (hexane/EtOAc 95:5) provided the desired (0 compound 300 MHz 1H NMR (CDCI 3 8 2.35 6 3.82 3H), 6.07 J 16 Hz, 1H). 7.10 3H), 7.85 J 16 Hz, 1H). Mass spectrum:

(M+NH

4 191.

C. Trans-3-(2,6-dimethylphenyl)-propenoic acid.

Hydrolysis of the methyl ester from Example 19B using lithium hydroxide in a mixture of methanol and water provided the desired compound 300 se. MHz 1 H NMR (CDCl3) 2.38 6H), 6.13 J 16 Hz, 1 7.10 3H), 7.96 (d,J 16 Hz; 1H). Mass spectrum: 194.

D. (2S,3S,5S)-2-(Trans-3-(2.6-dimethvlDhenyl) propenoyl) (t-butvloxycarbonyl) amino-1,6-diphenvlhexane.

Coupling of the carboxylic acid from Example 19C with the amine from Examplel1 F using standard procedure (EDAC/DMF) provided the desired compound 300 MHz 1H NMR (CDC3) 5 1.40 9H), 1.68 1H), 2.34 6H), 2.75 2H), 2.96 2H), 3.72 1 3.85 1 4.08 2H), 4.60 5. 1H), 5.88 J 10 Hz, 1H), 5.94 J =16 Hz, 1H), 7.10 5H), 7.25 (m, e 8H), 7.72 J 16 Hz, 1H). Mass spectrum: 543 (2S.3S.5S'i-2-(Trans-3-(.2.6-dimethvlphenyfl propenovl) mn--hdols (2S-1-tetrahvdropyrimidin-2-onvl)-3-methvl-butanol) amino-i .6diphenvihexane.

Removal of the Boo-protecting group of the compound from Example 19D

(TFA/CH

2

CI

2 and coupling of the resulting amine with the carboxylic acid from Example 2A using standard procedure (EDAC/DMF) provided the desired compouind 300 MHz 1 H NMR (CDCI3) 5 0.82 J 6 Hz, 3H), 0.87 J 6 H z, 3 1. 50 (in, 1 1. 70 (in, 2 2.2 0 (in, 1 2.3 3 6 2.6 8 (mn. 1 H).

2.78 (mn, 1 2.85 (mn. 1 3.05 (in, 5H), 3.73 (mn, 1 4.17 (in, 1 4.30 J 3 Hz, 1 4.60 1 5.95 J =15 Hz, 1 6.0 d, J 9Hz, 1 6.80 J 7 Hz,-1 7.25 (in, 13H), 7.70 J 15 Hz, 1 Mass spectrum: 625.

Exmule 2Q (2S.3S.5S'l-2-(3-(2.6-Dimethvlphenyl) propanovf) arnino-3-hydroxY-5-(2S-(1 tetrahydropyrimidin-2-onyfl-3-methyl-butanoyfl amino-i .6-diphenvihexane.

A. 3-(2.6-Dimethylohenyh~ propanoic acid methyl ester.

000A solution of 400 mg of the compound from Example 1 9B in 25 ml of o methanol1 and 40 mg of 10% Pd/C was stirred vigorously under a hydrogen atmosphere (balloon pressure) for 3 h. The catalyst was filtered off and 2.0concentration of the filtrate in vacuo provided the desired compound o 300 MHz 1 H NMR (CDC13) 8 2.35 6H), 2.45 (mn, 2H), 2.98 (mn, 2H), 3.22 (s, 3H), 7.02 3H). Mass'spectrum: 210.

0 0 B. Di met hylphenvb) propanoic acid.

Hydrolysis of the methyl ester from Example 20A. using lithium hydroxide in methanol and water provided the desired compound 300 MHz 1 H 0 NMR (CDCI3) 5 2.36 6H), 2.50 (in, 2H), 3.0 (mn, 2H), 7.03 3H). Mass o o spectrum: (M+NH4)+ 196.

0 0:* C. (2S .3S .5S)-2-(3-2.6-Dimethylphenvl) propanofl) butyloxvcarbonfl) amino-i .6-diphenylhexane.

Coupling of the carboxylic acid from Example 20B with the amine from Example 1 F using standard coupling procedure (EDAC/DMF) provided the desired compound. 300 MHz 1 H NMVR (CDCI 3 8 1 .40 9H), 1 .55 (in, 2H), 2.20 (in, 2H), 2.30 6H), 2.74 (mn, 2H), 2.85 (in, 4H), 3.66 (in, 1 3.82 (in, 1 H): 3.95 (mn, 2H), 4.57 (br d, 1 5.66 J 9 Hz, 1 7.0 3H), 7.22 (in, I OH).

Mass spectrum: 545.

D. Dimethylohenvl' prooanovl) ainino-3-hvdroxv-5-(2S- (1 -tetrahydroovriinidin-2-onyl)-3-methvl-butanoyl) amino-i .6-di~henvihexane.

Removal of the Boc-protecting group of the compound from Example using trifluoroacetic acid in CH 2

CI

2 and coupling of the resulting amine with the carboxylic acid from Example 2A using standard coupling procedure (EDAC/DMF) provided the desired compound. 300 MHz 1 H NMR (CDCI 3 8~ 0:82 J 6 Hz, 3H), 0.86 J 6Hz, 3H), 1.55 (in, 2H), 1.65 (in, 1 1.70 (s, 3H), 2.20 (in. 3H), 2.30 6H), 2.65 (in, 1 2.75 (in, 1 2.86 (in, 5H), 3.10 (mn, 3H), 3..68 (in, 1 4.10 (in, 4H), 4.63 1 5.75 J 7 Hz, 1 6.76 J 7 Hz, 1 7.0 (in, 3 7.20 (in, 1 OH). Mass spectrum: 627.

Examole 21 .6-Diinethvl-4-hvdroxy-phenoxyacetvfl ainino-3-hvdroxv-5-(2S- (1 -tetrahvd ropy ri midi-2-onyl)- 3-meth yl-butanovl) amino-i .6-diphenylhexane.

A. 2 .6-Diinethyl-4-tert-butyldimethvlsilvloxy phenol To a solution of 2.5 g (114.7 mmole) of 2,6-dimethyiquinone in 5 ml of methanol was added 200 mg of Pd/C The reaction mixture was stirred under 1 atmosphere of hydrogen for overnight. The Pd/C was removed over a celite pad, and the solvent was evaporated to dryness under reduced pressure to give 2.0 g (100%) of 2,6-dimethyldihydroquinone as a light yellow oil.

To'a solution of 2.0 g (14.7 inmole) of 2,6-diinethyldihydroqui none in ml of methylene chloride was added 1 .2 g (17.6 mmole) of imidlazole and 2.2 g (14.7 inmol) of tert-butyldimethylsilyl chloride subsequently at 0 0 C. After the W reaction was complete as indicated by TLC, it was partitioned between methyjene chloride and 1:1 mixture of 3 N hydrogen chloride and brine. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure. Silica gel chromatography using 5% ethyl acetate:hexanes gave 1.8 g of 2,6-dimethyl-4-tertbutyldimethylsilyloxy phenol as a white solid. 300 MHz 1 H NMR (CDCI3) 6 0.16 6H), 0.98 9H), 2.19 6H), 4.22 1H), 6.48 2H). Mass spectrum: 253.

B. Ethyl 2.6-Dimethvl-4-tert-Butvldimethvlsilvloxv ohenoxvl acetate \I0 A solution of 1.8 g (7.1 mmole) of 2,6-dimethyl-4-tert-butyldimethylsilyloxy phenol in 5 ml of dimethylformamide was treated with 2.0 g (1.43 mmole) of potassium carbonate and 830 il (7.5 mmole) of ethyl bromoacetate. The resulting solution was heated at 70°C for 4 hr. After cooled to room temperature, the reaction mixture was partitioned between ethyl acetate and 3 N 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 of ethyl 2,6-dimethyl-4-tert-butyldimethylsilyloxy phenoxyl acetate as a light yellow oil.

300 MHz 1 H NMR (CDCl3) 0.17 6H), 0.97 s, 9H), 1.33 3H, J 6.3 Hz), t• 2.22 6H), 4.30 2H, J 6.3 Hz), 4.35 2H), 6.57 2H). Mass spectrum: 356.

C. 2.6-Dimethvl-4-Hydroxvl phenoxvacetic acid To a solution of 2.03 g (6.0 mmole) of ethyl 2,6-dimethyl-4-tertbutyldimethysilyloxy phenoxy acetate in 10 ml of methanol was added 4 ml of 3 N sodium hydroxide. After the reaction mixture was stirred at room temperature for 30,minutes it was acidified with 3 N HCI. The reaction was allowed to stir for additional 1 h, and then 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.

SO Tri.turation with hexanes gave 910 mg of 2,6-dimethyl-4-hydroxyl phenoxyacetic acid as a white solid. 300 MHz 1H NMR (CD30D) 8 2.18 6H), 4.31 2H), 6.41 2H). Mass spectrum: (M+H) 4 214.

-78- D. (2S.3S.5S)-2-(2.6-Dimethvl-4-hydroxy-ohenoxyacetvl) (t-butvboxvcarbonfl) amino-i .6-diohenvlhexane.

Coupling of the carboxylic acid from Example 21 C with the amine from Example 1 F using standard coupling procedure (EDAC/DMF) provided the desired compound. 300 MHz 1 H NMR (CDCI 3 6 1.40 9H), 1.68 (in, 2H), 2.07 6H), 2.77 J 6 Hz, 2H), 2.98 (mn, 2H), 3.74 (in, 1 3.90 (in, 1 4.10 (in, 3H), 4.58 (in, 1 5.20 (in, 1 6.44 2H), 7.10-7.30 (in, 1 OH).

E. (2S.3S.5Sl-2-(2.6-Dimethvl-4-hvdroxv-ohenoxyacetl) (2S-(1 -tetrahvdropvriinidin-2-onyl)-3-methvl-butpnol) amino-i .6diohenvlhexane.

Reinoval of the Boo-protecting group of the compound from Example 2 1 D using TFAICH 2

CI

2 and coupling of the resulting amine with the carboxylic acid from Example 2A using standard procedure (EDAC/DMF) provided the desired compound. 300 MHz 1 H NMR (CDCI3) 6 0.78 J 5 Hz, 3H), 0.81 J Hz, 1.47 (in, 1 2.03 6H), 2.18 (in, 1 2.62 (in, 1 2.80 (in, 2H), 3.05 (in, 6 3.78 (in, 1 4.12 6 4.37 1 4.71 1 6.47 2 6.9 4 (br d,-1 7.20 (in, 10OH). Mass spectrum: 645.

(2 S. 3 S S) 2-(ci s 1 -di oxo-2-i sop ropvl-3-tetrahvd rot hio 1heno xy~ami no-3hydroxv-5-(2S-(l-tetrahvdroovrimid-2-onyfl-3-inethyI butanovl)amino-1 .6diohenvihexane, C is soorop~yl-3-hyd roxy-tetrahyd rothioo~hene.

To a solution of ethyl-3-mercaptopropionate (27.25 ml, 0.246 mole) in 200. ml of ethanol was added carefully sodium ethoxide (16.75 g,.Q.246 mole) in ::::*several portions. The resulting suspension was then cooled to -200C and ethyl- 2-bromoisovalerate (50 g, 0.239 mole) in 50 ml of ethanol was added dropwise :over*2 h. After addition was complete, the reaction was warmed to ambient temperature and stirred for 3 h. The mixture was poured into 600 ml of ethyl go acetate and 600 ml of saturated NH 4 CI. The ethyl acetate layer was removed and the aqueous layer extracted (2 x 200 ml) with ethyl acetate. The combined 3 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 mole) was added. The reaction mixture was heated to reflux for 6 h, cooled to RT, and then poured into an ice-cold solution of 1N HCI (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 that was used in the next step without purification.

The crude product was added to 500 ml of aqueous 10% sulfuric acid and the.resulting mixture heated to reflux for several hours, and then cooled to RT 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 burgundy oil. The crude product (ketone) was purified by vacuum distillation at 75 0 -80 0 C. 300 MHz 1 H NMR (CDCI3) F 0.93 J 9 Hz, 1.03 J 9 Hz, 3H), 2.32 1 2.55-2.70 2H), 2.93 J S Hz, 2H), 3.38 J 4 Hz, 1 Mass spectrum: 145.

To a stirred solution of the above ketone in 125 ml of CH 2

CI

2 at 0°C was added diisobutylaluminum hydride (86 ml, 1M in THF) dropwise over minutes. The reaction mixture was allowed to warm to room temperature and then was quenched by cautious addition of 1N HCI (255 ml). The reaction 20 mixture was extracted with ether (3 x 150 ml) and the combined ether solution was washed with satd. sodium bicarbonate, brine and dried over magnesium sulfate. The solution was concentrated in vacuo and the resulting oil was purified by silica gel column chromatography (10% EtOAc/hexane). 300 MHz 1 H NMR (CDCI3) 6 1.03 J 7 Hz, 3H), 1.08 J 7 Hz, 3H), 1.80 J 9 2 5 Hz, 1H), 1.90 2H), 2.24 1 2.90-3.10 3H), 4.36 1H). Mass spectrum: 147.

B. Cis(+)-(2-isooroDvl-3-thioDhenvyl-2(2-vyridvylcarbonate.

To the product from Example 22A (2.29 g, 15.7 mmole) in 40 ml of

CH

2

CI

2 was added diisopropylethyl amine (4.65 ml, 26.7 mmole) and di-(2- 0 pyridyl)carbonate (5.42 g, 25.1 mmole). After 18 h at RT, the reaction mixture was diluted with chloroform and washed sequentially with 10% citric acid, satd.

0 sodium bicarbonate, brine and then dried over sodium sulfate; filtered and concentrated in vacuo. Purification of the crude product by silica gel column chromatography (20% EtOAc/hexane) provided the desired compound. 300 MHz 1 H NMR (CDCI3) 6 1.05 J 7 Hz, 3H), 1.08 J 7 Hz, 3H), 1.90 (m, 1H), 2.05 2H), 2.58 (dd, J 6, 15 Hz, 2H), 3.10 2H), 3.28 (dd, J 3, 12 Hz, 5.47 1H), 7.12 1H), 7.27 1H), 7.80 1H), 8.41 1H).

Mass spectrum: (M+H) 268.

C. (2S. 3S. 5S)-2-(cis(+)-2-lsoDropyl-3-tetrahydrothiophenoxvlamino-3hvdroxy-5-(t-butyloxvcarbonvylamino-1.6-diohenvlhexane tO To a solution of the compound from Example 22B (500 mg, 1.87 mmole) in 5 mi of CH 2

CI

2 was added the amine from Example 1F (791 mg, 2.06 mmole). The reaction was stirred at RT until all the compound from Example 22B was consumed. The reaction mixture was diluted with chloroform and washed with 10% citric acid, satd. sodium bicarbonate, brine and then dried 1$ with.sodium sulfate; filtered and concentrated in vacuo. Purification of-the crude product by silica gel column chromatography MeOH/CH 2

CI

2 provided the desired compound 300 MHz 1 H NMR (CDCI 3 8 0.83-1.05 6H), 1.40 9H), 1.90 3H), 2.20 1H), 2.75 2H), 2.85 4H), 2.95-3.15 3H), 3.67-3.90 4H), 4.55 1 5.10 1H), 5.30 1H), 7.10-7.26 2o Mass spectrum: 557.

D. (2S.3S.5S-2-(cis(+-1 .1-Dioxo-2-isopropyl-3-tetrahydrothioDhenoxy)amino- 3-hydroxv-5-(t-butvloxvcarbonvl)amino-1.6-diphenylhexane.

To the compound from Example 22C (523 mg, 0.91 mmole) in 10 ml of acetone and 0.5 ml of water was added Oxone (839 mg, 1.37 mmole) and sodium bicarbonate (152 mg, 1.82 mmole). The resulting solution was stirred for 2 h, 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 by silica gel column chromatography MeOH/CH 2 C1 2 to provide 422 mg of product. 300 MHz 1 H NMR (CDCI3) 6 1.20 6H), 1.40 (s, 9H), 1.60 4H), 2.10-2.32 4H), 2.67 2H), 2.75 2H), 2.85 2H), 3.15 2H), 3.70-3.90 3H), 4.56 1H), 5.30 2H), 7.10-7.30 -81- E. (2S.3S.5Sl-2-(cis(')-1 .1 -Dioxo-2-isonropvl-3-tetrahydrothioo~henoxv)amino- 3-hvydroxv-5-(2S- (I -tetrahvdro pvri md-2-o nyl)-3- met h l butanovf)amino- 1.6diohenyjhexane.

Removal of the Boc-protecting group of the compound from Example 221D using TFAICH 2

CI

2 and coupling of the resulting amine with the carboxylic acid from Example 2A provided the desired compound 300 MHz 1 H NMR (C 0.013) 8 0.8 2 (in, 6 1. 0 20 (in. 6 1. 60 2 2.0 7 (mn, 1 2.2 5 (mn, 2 H).

2.65-3.20 (in, 12H), 3.70 (in, 1 3.90 (in, 1 4.10-4.20 (in. 2H), 5.07 (in, 1lH): 5.37 (in, 1 5.87-5.98 (in, 1 6.95-7.05 (in, 1 7.20 (in, 1 OH). Mass (0 spectrum: 671.

(2 S,3S.5S)-2-(2,6-Di met hvfohenoxyacetvl' amnino-3-hvdroxv-5-(2S-(1 di hydropy ri id- 2.4-di onvl')-3- met hyI- butanoyfl amino-i .6-diohenylhexane.

A. N-(2-EthoxYacrvloyl)-N'-(1 S-carbo methox-2- methyl-1ropy 1) -ure a.

To 1 .74 g (0.013 mole) of 2-ethoxy-acryloyl chloride in 1 8 ml of -toluene was added 3.90 g (0.026 mole) of silver cyanate. The mixture was heated to reflux for 0.75 h. The mixture was allowed to cool to RT and the precipitate allowed to settle. The supernatant (9.6 ml) was withdrawn and added to 18 ml of dry DMF and 5 ml of Et 2 O, cooled to -1 500 for 45 minutes and left in freezer .000e 2-0overnight. The solvent was evaporated in vacuo and the residue was purified by si 'lica gel column chromatography MeOH/CH 2

CI

2 to provide 1 .59 g of desired compound 300 MHz 1 H NMR (CDC13) 8 0.96 J =7 Hz, 3H), 1.0 J 7 Hz, 3H), 1.37 J 7.5 Hz, 3H), 2.25 (in, 1 3.74 31H), 3.97 J Hz, 2H), 4.42 (dd, J 4.5, 8.0 Hz, 1 5.25 J 12 Hz, 1 7.68 J= 12 Hz, 1 8.55 1 9. 10 J 8 Hz, 1 Mass spectrum: 273.

B.2S-(1 -Dihvdropyrimid-2.4-dionyl)-3-inethyl butanoic acid.

:A solution of 174 mg (0.64 inmole) of the compound from Example 23A in ml of 2N sulfuric acid was refluxed for 2 h, cooled to RT and left in freezer overnight. The mixture was concentrated and the residue was extracted with 3o ethyl acetate (2 x 100 ml), dried and concentrated in vacuo to give 122 mg of -82- 1 desired compound. 300 MHz 1 H NMR (CDCI3) 5 1.06 J 7 Hz, 3H), 1.13 (d, J 7 Hz, 3H), 2.25 1H), 5.04 J 10 Hz, 1H), 5.74 J 7 Hz, 1H), 7.50 J 1.0 Hz, 1H), 8.43 1H).

C. (2S.3S.5S)-2-(2.6-Dimethylohenoxvacetyl) amino-3-hvdroxv-5-(2S-(1 5dihvdropvrimid-2.4-dionvyl-3-methyl-butanovl) amino-1 .6-diphenvlhexane.

Coupling of the carboxylic acid from Example 23B with the amine from Example 1N using standard coupling procedure (EDAC in DMF) provided the desired compound. 300 MHz 1 H NMR (CDCI 3 8 0.81 J 7 Hz, 3H), 0.92 (d, J =7 Hz, 3H), 2.18 6H), 2.23 1H), 2.63 1H), 2.85 1H), 3.0 2H), to 3.78 1H), 4.20 4H), 4.58 J 10 Hz, 1 5.68 (dd, J 1.5, 7.5 Hz, 1H), 7.0-7.25 13H), 7.50 J 7.5 Hz, 1H), 9.50 1H). Mass spectrum:

(M+H)

4 640.

Example 24 Alternate Preparation of (2S. 3S. 5S)-2-(2.6-DimethylDhenoxyacetyl) amino-3- SDhvydroxv-5-[2S-(1-tetrahvdro-pvrimid-2-onyl-3-methyl butanovll amino-1.6diohenvlhexane.

A. 2.6-Dimethvlphenoxvacetic acid 2,6-Dimethylphenol (102.8 g, 0.842 mol) and chloroacetic acid (159.6 g, S* 1.68 mol) in 1000 ml of H 2 0 was added to a 3-L, 3-necked 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 addition funnel and heat to reflux. After 2 hours, additional chloroacetic acid (79.4 g, 0.84 mol) and NaOH solution (67.2 g, 1.68 mol in in 200 ml water) was added to the reaction mixture. After 19 hours, additional chloroacetic acid (39.8 g, 0.42 mol) and NaOH solution (33.6 g, .84 mol in in 100 ml water) was added to the reaction mixture and refluxing was continued until starting phenol was consumed. The reaction flask was cooled in and icewater bath and acidified to pH=1 with conc. HCI, causing a precipitate to form.

The resulting slurry was stirred in the ice bath for 1 hour then filtered. The solid -83- O was dissolved in hot (100 0 C) water and cooled to crystallize the product as white plates, mp= 136-1370C, yield 78.8 g, 52%.

B, (2S. 3S. 5S) -2-(2.6-Dimethylohenoxvacetyl) butvloxvcarbonvlamino)- .6-diphenvlhexane.

Oxallyl chloride (36.3 ml, 0.42 mol) was added to a slurry of 2-6 dimethylphenoxyacetic acid (50 g, 0.28 mol) in 500 ml toluene followed by addition of 5 drops of DMF and stirred at room temperature for 30 min, then at 0 C for 1.5 hours. The toluene was removed on a rotary evaporator and remaining volatiles were removed in vacuo to afford 2,6-dimethyl- L phenoxyacetyl chloride as an amber oil, 55 grams, 100%.

2

S,

3 S,5S]-2-Amino-3-hydroxy-5-t-butyloxycarbonylamino-1,6diphenylhexane x 0.5 succinate (111.9 g, 0.25 mol) was charged to a 2L, 3necked round-bottomed flask with mechanical stirring. NaHCO 3 (106 g, 1.26 mol), 600 ml H 2 0 and 600 ml EtOAc were added and stirred vigorously until all solids were dissolved (15 minutes). Stirring was slowed and a solution of the 2,6-dimethyl-phenoxyacetyl chloride and EtOAc (100 ml) was added in a narrow stream via addition funnel. After 30 min of stirring, starting materials Ot': 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 1 M NaOH, 200 ml of 10% HCI, 200 ml of brine, dried over MgSO4, filtered and concentrated to provide the desired product as a white solid.

C. (2S. 3S. 5S) -2-(2.6-DimethvlDhenoxvacetvl) amino-3-hvdroxv-5-amino-1 ,6diohenvlhexane.

2(2S, 3S, 5S) -2-(2,6-Dimethylphenoxyacetyl) butyloxycarbonylamino)-1,6-diphenylhexane (175.1 g, 0.32 mol) and 500 ml CH2CI 2 were mixed with stirring. CF3CO2H (249 ml, 3.2 mol) was added and S. stirred 20-25 minutes, then the reaction mixture was poured into a separatory funnel containing 1000 ml of water and 200 ml of CH2CI2. The resulting -84mixture was shaken carefully and the layers were separated. The organic layer was washed again with 500 ml of water, then 3x 500 ml of NaHCO 3 and finally 500 ml of brine. The organic solution was dried over MgSO 4 filtered and concentrated to a golden oil that pulled into a foam 300 ml of diethyl ether was added to the crude product and shaken vigorously to dissolve. Within minutes solid began to crystallize and the mixture became thick. Enough diethyl ether was added to make the mixture stirrable and the mixture was stirred at room temperature for 1 hour. The solid was filtered and air dried to give the desired product as 115 g of white needles, 81% yield.

to A solution of HCI/diethyl ether was added to the filtrate to precipitate the remaining product as the HCI salt. This pinkish solid was collected by filtration, taking care to keep the solid flooded with N2 while it was wet with ether. When dry, transfered the amine salt to a separatory funnel and extracted with CH2CI2 and NaHCO3 The organic layer was washed with brine, dried over 3 MgSO4, concentrated and treated as above to afford an additional 15 g of the desired product, the total yield is 91%.

D. N-Carbonvlbenzyloxv-3-aminopropanol O o To a 12L 3-neck round bottom flask was added isopropyl acetate The solvent was cooled to 0oC in an ice-water bath and 3-amino-l-propanol S2 o (1.14Kg, 15.1mol, 2.15eq) was added in one portion. To this rapidly stirring solution, benzyl chloroformate (1.20Kg, 7.03mol, 1.0eq) was added dropwise over 2h while maintaining the internal temperature of the flask between 100C and.150C. After the addition was complete, the reaction mixture was allowed to stir between 100C and 150C for an additional 0.3h after which time water was added in one portion. The solution was then partitioned and washed with an additional 2X3.5L of water. The organic layer was dried over potassium carbonate and concentrated to give a solid that was dissolved in excess isopropyl acetate and precipitated from solution by adding the S* compound to heptane. The solid was filtered under nitrogen to yield 1.20Kg of the desired product as a colorless solid.

rwl E. N-Carbonvlbenzvloxv-3-aminopropanal 335 mL of dimethylsulfoxide and 9L of methylene chloride were combined and chilled to -480C. 313 mL of oxalyl chloride was added over minutes so that the temperature remained below -400C. Cooled to -480C, and added 500 grams of N-Cbz-3-amino-l-propanol dissolved in 1L of methylene chloride so that the temperature remained below -400C. Stirred for an additional hour at -450C. 1325 mL of triethylamine was added at such a rate that the temperature remained below -40oC. After stirring an additional minutes at -40 0 C, the mixture was allowed to warm to -300C, then added D0 of 20% aqueous potassium dihydrogen phosphate. Stirred for one hour, then separated the layers, washed the organic layer with brine, and dried with magnesium sulfate. The resulting aldehyde was kept in solution at -200C until needed.

F. N-(N-(Benzvloxvcarbonvl-3-amino)-oro yl) valine methyl ester.

To a 5L 3-neck round bottom flask was added the crude ~(unchromatographed) product of Example 24E (115g, 0.555mol, e followed by addition of water (400mL) and methanol (1600mL). The reaction mixture was maintained at 250C throughout the course of the reaction. After the solution became homogeneous, (S)-Valine methyl ester hydrochloride 20 (90.2g, 0.538mol, 0.97eq) was added in one portion followed by rapid addition of sodium acetate trihydrate (151g, 1.11mol, 2.0eq) and sodium cycanoborohydride (73.2g, 1.17mol, 2.1eq) in said order. The reaction mixture was allowed to stir at room temperature for 0.5h and was concentrated in vacuo to remove all methanol present. To this solution, saturated aq sodium 25- bicarbonate (400mL) was added and the mixture was extracted with isopropyl acetate (1 The organic layer was washed with water (2X400mL), dried over sodium sulfate, and concentrated to yield 150g of crude product, which was dissolved in isopropyl acetate (300mL) and heptane (2400mL). Dry HCI was bubbled in and an oily solid precipitated out of solution. The liquid was decanted away from the solid and was dissolved in dichloromethane The solution was washed with water (600mL) and saturated aq sodium bicarbonate -86- (600mL) and dried over sodium sulfate. It was concentrated in vacuo to yield 105g of the desired product as a light yellow oil.

G. N-(3-amino)-oroDvyl valine methyl ester.

To a 3L flask was added the product of Example 24F (120g, 0.372mol) 3 and methanol (1 This solution was allowed to stir in the presence of Raney Nickel (180g) for 1h After removal of Raney Nickel by filtration, Pd(OH)2 (24g) was added and the solution was allowed to stir under 60 psi of a hydrogen atmosphere for 12h. The solution was purged with nitrogen and repressurized with 60 psi of hydrogen for an additional 1h. The solution was filtered and \D concentrated to give 63g of an oil To this oil toluene (120mL) was added and the solution was again concentrated in vacuo to give the desired product.

H. 2S-(1-tetrahydro-pyrimid-2-onvl)-3-methvl butanoic acid methyl ester.

*.To a 5L 3-neck round bottom flask with stir bar was added the crude 5 product of Example 24G (150g, 0.8mol) and dichloromethane (3.2L).

Carbonyldiimidazole (232g, 1.44mol, 1.8eq) was added slowly in portions over 25 min. The solution was allowed to stir at ambient temperature for 40h. Water (200mL) was added over 1h with careful stirring until no more gas evolution occurred. A solution of 35% HCI was slowly added to the stirring solution until the solution became acidic. The solution was then partitioned and was washed with water (2X300mL). The organic layer was dried over sodium sulfate and was. concentrated to yield 126g of the desired product as a colorless solid.

I. 2S-(1-tetrahydro-Dvrimid-2-onyl)-3-methyvl butanoic acid methyl ester.

*i 25 To a 12L 3-neck round bottom flask with stir bar was added the product of Example 24H (126g, 0.588mol), water and THF(3.9L). The solution was cooled to 00C in an ice-water bath and lithium hydroxide monohydrate (74g, -87- 1.76mol, 3.0eq) was added in one portion with rapid stirring. The solution was allowed to stir at OOC for 14h. It was then acidified to pH 11 by slow addition of aq phosphoric acid and the THF was removed in vacuo. The aqueous phase was washed with isopropyl acetate (2L) and was subsequently acidified to pH by slow addition of 35% aq HCI. The aqueous layer was then extracted with ethyl acetate (5X2.2L). The combined organic layers were concentrated to give the desired product (105g) as a white solid. The compound was then purified by addition of isopropyl acetate (500mL) and ethanol (15mL) and bringing the solution to a boil with rapid stirring until 50mL of solvent had evaporated. The solution was cooled to 0 0 C and filered to give 92g of pure desired product.

J. (2S. 3S. 5S)-2-(2.6-Dimethvlohenoxvacetvl) amino-3hvdroxv-5-12S-(1-tetrahvdro-Dvrimid-2-onvyl-3-methyl butanovl] amino-1.6-diohenvlhexane.

In a 2L, 3-necked round-bottomed flask were combined the product of Example 24C (100 g, 0.22 mol), the product of Example 241 (44.8 g, 0.22 mol) and 750 ml DMF and the mixture was cooled in an ice/water bath. HOBT (90.9 g, 0.67 mol), EDAC (86 g, 0.45 mol) and triethylamine (62.5 ml, 0.45 mol) were added and the ice bath was removed, allowing the reaction mixture to stir with warming to room temperature for 5h. The reaction was diluted with 1000 ml of IPAG and quenched with 1000 ml of water. The mixture was shaken and separated, the aq. layer was extracted 1x 400 ml IPAC, the organics were washed with 1x 400 ml 10% HCI, 1x 500 ml NaHCO3, diluted with 100 ml hexanes, then washed 4x 500 ml water, and 1x 500 ml brine, dried over MgSO4, filtered and concentrated to provide the desired product as a white foam.

a.

a 2 o a a a a e go oooo -88- Example (2S.3S.5S)-2-(2.6-Dimethvlohenoxvacetvl) amino-3-hydroxy-5-[S-(1 tetrahydro-ovrimid-2.4-dionvl)-3-methylbutanovllamino- .6-diDhenylhYan A. N-(2-Carbomethoxy) ethyl-L-Valine t-butyl ester.

To a solution of 1.73 g of L-Valine t-butyl ester in 10 ml of methanol was ml of methyl acrylate. The solution was heated to reflux overnight.

Another 9.0 ml of methyl acrylate was added and continued the reflux for 24 h.

The solvent was evaporated in vacuo and the crude product was purified by silica gel column chromatography (20% ethyl acetate in hexane) to provide o 2.435 g of desired compound 300 MHz 1 H NMR (CDCI 3 0.91 (d, Hz, 3H), 0.93 J=3.5 Hz, 3H), 1.47 9H), 1.85 1H), 2.47 (t, J=7 Hz, 2H), 2.68 1H), 2.81 J=6 Hz, 1H), 2.95 1H), 3.68 3H).

Mass spectrum: 260.

B. N-(2-Carboxamido) ethvl-L-Valine t-butvl ester.

To a.solution of 1.86 g of the product from Example 25A in 5 ml of THF was-added 0.415 g of lithium hydroxide monohydrate in 10.8 ml of water. After min, 10.8 ml of 1N HCI was added. The reaction mixture was evaporated to dryness and dry pyridine was added and evaporated to dryness two times. The residue was dissolved in 25 ml of acetonitrile and 0.62 ml of dry pyridine added. To this solution was added 2.02 g of N,N'-disuccinimidyl carbonate.

The -reaction mixture was stirred for 3.5 h. The solvent was removed in vacuo and,90 ml of THF added followed by 1.43 ml of conc. ammonium hydroxide.

The reaction was allowed to go overnight. The reaction mixture was filtered and the filtrate concentrated in vacuo. The residue was dissolved in ethyl acetate -2 and washed with sodium bicarbonate, brine and dried with anhy. sodium sulfate. After filtering off the drying agent, the filtrate was conc. in vacuo and the crude product was purified by silica gel column chromatography MeOH in

CH

2

CI

2 to give 1.19 g of desired compound. 300 MHz 1H NMR (CDCI3) 8 0.95 J=7 Hz, 3H), 0.97 J=7 Hz, 3H), 1.48 9H), 1.93 (m, 1 2.37 2H), 2.65 1H), 2.95 2H), 5.30 (br s, 1H), 7.85 (br s, 1 H).

Mass spectrum: (M+H)+=245.

-89- C. 2S-(1-Tetrahydro-pvrimid-2.4-dionvl)-3-methylbutanoic acid t-butyl ester.

A solution-of 0.92 g of the product from Example 25B in 10 ml of THF and 1.83 g of carbonyldiimidazole (CDI) was refluxed for 26 h. Then 1.83 g of CDI was again added and the solution was refluxed for 72 h more. The solvent was evaporated in vacuo and the residue was dissolved in ethyl acetate and washed with water, satd. sodium bicarbonate, dilute hydrochloric acid and then brine. The organic layer was dried, filtered and conc. in vacuo. The crude product was purified by silica gel column chromatography to 5% MeOH in

C.H

2 C1 2 to give 0.54 g of desired compound. 300 MHz 1 H NMR tL (CDC13) 6 0.96 J=7 Hz, 3H), 1.05 J=7 Hz, 3H), 1.48 9H), 2.20 (m, 1H), 2..66 2H), 3.43 1H), 3.75 1H), 4.63 J=9 Hz, 1H), 7.35 (br s.

1H). Mass spectrum: (M+H)+=271.

2S-(1-Tetrahvdro-Dvrimid-2.4-dionvl)-3-methvlbutanoic acid.

A solution of 0.53 g of the compound from Example 25C in 5 ml of trifluoroacetic acid was stirred at 0°C for 1.25 h. Solvent was evaporated in vacuo, dried and purified by silica gel column chromatography MeOH/4% HOAQ in CH 2

CI

2 to give 0.36 g of desired compound. 300 MHz 1H NMR (DMSO-d 6 0.86 J=7 Hz, 3H), 0.97 J=7 Hz, 3H), 2.15 1 3.40 (m, 4H),.4.39 J=10 Hz, 1H). Mass spectrum: (M+H)+=215.

E. (2S.3S.5S)-2-(2.6-Dimethvlohenoxvacetvl) amino-3-hvdroxv-5-[2S-(1tetrahvdro-Dvrimid-2.4-dionvl)-3-methvlbutanovl amino-1.6-diDhenvlhexane.

Coupling of the amino compound from Example 1N with the acid from 9 Example 25D using standard coupling procedure (EDAC in DMF) provided the desired compound 300 MHz 1H NMR (CDCI 3 8 0.83 J=7Hz, 3H), 0.88 J=7Hz, 3H), 1.80 2H), 2.20 6H), 2.40 1 2.58 1 2.80 1H), 2.92 1H), 3.05 3H), 3.65 J=5Hz, 1H), 3.83 1H), 4.20 (m, 6.18 J=9Hz, 1H), 7.0-7.38 14H). Mass spectrum: (M+H)+=643.

Example 26 (2S.3S.5S)-2-(2.6-DimethylDhenoxvacetyl) amino-3-hydroxv-5[2S-(4-aza- tetrahvdro-ovrimid-2-onvy)-3-methvl-butanoyvlamino-1.6-diohenvlhexane A. N( )-t-butvloxvcarbonvl-N(2)-allyl hydrazine.

To a solution of 18.18 g of t-butyloxycarbonyl protected hydrazine in ml of acetonitrile was added 19.0 g of potassium carbonate, followed by 11..9 ml of allyl bromide. The reaction mixture was heated at reflux for a total of 3 b filtered and conc. in vacuo. The residue was dissolved in ethyl acetate and washed with satd. sodium bicarbonate and dried with anhydrous sodium sulfate and filtered. After concentration in vacuo, the crude product was purified by silica gel column chromatography (20% EtOAc/hexane) to give 4.47 g of desired compound. 300 MHz 1 H NMR (CDC13) 8 1.45 9H), 3.46 2H).

(br s, 1H), 5.10 2H), 5.83 1 6.0 (br s, 1H). Mass spectrum: (M+H)+=173.

6 B. N(1 -tbutvloxvcarbonvl-N(2-allvl-N(2)-benzyloxvcarbonyl hydrazine.

To a solution of 4.8 g of the compound from Example 26A in 15 ml of DMF was added 4.69 g of benzyloxycarbonyloxy-succinimide. The reaction mixture was stirred at RT for 72 h and the solvent was evaporated in vacuo.

•The residue was dissolved in ethyl acetate, washed with satd. sodium C bicarbonate and dried with anhydrous sodium sulfate. The crude product obtained after concentration was purified by silica gel column chromatography (20% to 50% EtOAc in hexane) and provided 5.27 g of desired compound.

300 MHz 1 H NMR (CDCI 3 6 1.43 (br s, 9H), 4.15 (br s, 2H), 5.18 2H), 5.20 i 2H), 5.82 1H), 6.39 (br s, 1 7.36 5H). Mass spectrum: 2-5 (M+H)+=307.

C. N(1 )-t-butvloxvcarbonvl-N(2)-formvlmethyl-N(2)-benzvloxvcarbonvl hvdrazine.

A solution of 6.5 g of the compound from Example 26B in 100 ml of methanol was cooled with a dry ice/acetone bath. Ozone was bubbled in for S1.75 h until a pale blue color persisted. Air was passed through the solution for min and then 15.6 ml of dimethyl sulfide was added and the reaction -91mixture was allowed to warm gradually to RT overnight. Solvent was evaporated in vacuo and the residue was dissolved in ethyl acetate and washed with water, then brine several times. The organic layer was dried with anhydrous sodium sulfate, filtered and conc. in vacuo to provide 7.2 g of the desired compound. 300 MHz 1 H NMR (CDCI 3 5 1.40 (br s, 9H), 4.35 (m, 2H), 5.20 2H), 6.65 (br s, 1H), 7.36 5H), 9.70 (br s, 1H). Mass spectrum:

(M+NH

4 )+=326.

D. N-f2-(N-(2)-benxvloxvcarbonvI-N-(1 -t-butyloxvcarbonvlhvdrazinvl] ethvl-L- Valine methyl ester, \o "To. a solution of 7.2 g of the compound from Example 26C in 100 ml of methanol was 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 RT overnight. The mixture was filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography MeOH in CH 2

CI

2 to provide 5.8 g of desired compound.

300 MHz 1H NMR (CDCI 3 6 0.90 J=6Hz, 6H), 1.43 (br s, 9H), 1.87 (m, 1H), 2.60-3.0 4H), 3.72 3H), 5.18 2H), 7.37 5H). Mass spectrum: (M+H)+=424.

E. 2S-[4-benzvloxvcarbonvlaza-1-tetrahydro-Dyrimid-2-onyl)-3-methvl-butanoic 2 4 acid methyl ester.

A solution of 2.4 g of the compound from Example 26D in 20 ml of HCI in dioxane was stirred at RT under argon for 1 h. Solvent was evaporated in va6uo and the residue was washed with satd. 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 CH2CI 2 and 0.56 g of carbonyldiimidazole was added. The solution was left at RT for 48 h. The solvent was removed and the residue was purified by silica gel column chromatography (10% to 30% EtOAc in CH2CI2) to give 0.78 g of de.sired compound. 300 MHz 1 H NMR (CDCI3) 0.90 J=7Hz, 3H), 0.98 (d, 3 J=7Hz, 3H), 2.17 1H), 3.34 1H), 3.61 2H), 3.72 3H), 3.98 1H), 4.71 J=10Hz, 1H), 5.20 2H), 6.72 (br s, 1H), 7.38 5H). Mass spectrum: (M+H)+=350.

-92- F. 2S-(4-Benzvloxvcarbonylaza-1 -tetrahydro-pvrimid-2-onvl)-3-methL -butpnoic acid.

Hydrol~sis of 0.78 g of the compound from Example 26E using lithium hydroxide in aqueous dioxane provided 0.35 g of desired compound.

300 MHz 1 H NMR (CDCI 3 8 0.85 J=7Hz, 3H), 1.04 J=7Hz, 3H), 2.40 (in, 1 3.40 (mn, 1 3.50 (mn, 1 3.80 (in, 2H), 3.95 J=1 0Hz, 1 5.20 2H), 7.30 1 7.36 5H). Mass spectrum:- (M+H)+=336.

G. (2S.3S.5S)-2-(2.6-Dimethylohenoxyacelyi ainino-3-hyvdroxy-5[2S- (ben z ylo xycarbo nylaza- 1 -tetra hvdro-p2yrim id-2-o nyl)- 3-meth I- butanY la ino- 1 .6-diphenylhexane.

Coupling of the amino compound from Example 1 N with the acid from ,Example 26F using standard coupling procedure (EDAC/DMF) provided the desired compound 300 MHz 1 H NMR (C~DC 3 8 0.72 J=7Hz, 3H), 0:83 J=7Hz, 3H), 2.20 6H), 2.65 (in, 1 2.83 (mn, 1 3.0-3.10 (in, 4H), 1573.90 (in, 1 6.65 (in, 1 7.0-7.35 (in, 1 8H). Mass spectrum: (M+H)+=764.

H. (2S.3S.5S)l-2-(2.6-Dimelhylphenoxyacetyl amino-3-hydroxv-5[2S-(4-aza-1 tetr hvdro-oyrimid-2-oxyl)-3-methyl-butanovllamino-1 .6-diphenvthexane.

Removal of the benzyloxycarbonyl protecting group of the compound from Ex~ample 26G by hydrogenolysis using 10% palladium on carbon as catalyst provided the desired compound. 300 MHz 1 H NMR (C~DC 3 8 0.83 (d, 3H), 0.86 J=4.5Hz, 3H), 1.80 (in, 1 2.20 6H), 2.58 (in, 1 H), 2.67 (in, 1 2.90 (in, 2H), 3.0 (in, 2H), 3.80 (in, 1 4.20 (in, 3H), 6.72 (in, 1 H), 7.0 (in, 2H), 7.20 (in, 11 Mass spectrum: (M+H)+=630.

-93- (2 S.3 S.5 Dim ethyvlohe noxyacetyl) amino-3-hvdroxv-5-f2S-(1 tet rahvydro-Qyr* mid-2-onyl) 3- met hvlbutan ovflpmi no- 1 -oahenvl-6-methvlheutane A. (2S.3S .5S)-2-Amino-3-hydroxv-5-(t-butloxycarbonlmno)-1 -phenvl-6- Following the procedures described in Example 1lA to Example 1iF-1.

but s *ubstituting isopropylmagnesium chloride for benzylmagnesium chloride in Example 1 C provided the desired compound. 300 MHz 1 H NMVR (CoDC 3 63 0.88 J=7Hz, 3H), 0.92 J=7Hz, 3H), 1.43 9H), -1.50-1 .80 (in, 4H), 2.55 1 2.90 (in, 1 3.0 (mn, 1 3.54 (in, 2H), 4.62 (mn, 1 7.30 (in, Mass, spectrum: (M+H)+=337.

B. (2S.3S.5S)-2-(2.6-Diinethylohenoxyacetl) butyloxycarbonylami no)l- -henyl-6-methvlheptane, Coupli~ng of the amino compound from Example 27A with the acid from Example 1 H using standard EDAC coupling procedure provided the desired compound. 300 MHz 1 H NMVR (CDCI 3 5 0.85 J=7Hz, 3H), 0.90 J=7Hz, 3H), 1:43 9H), 1.70 (in, 2H), 2.20 6H), 3.03 J=8Hz, 2H), 3.42 (mn, 1 H), 80 (in, 1 4.2 0 (in, 2 4.2 2 2 4.5 5 (in, 1 7. 0 (in, 3 7.3 0 (in, 5 H).

Mass spectrum: (M+H)+=499.

C. (2S.3S.5S2l-2-(2.6-Dimethylo~henoxyacetfl) anino-3-hvdroxy-5-amino-l1p henyl 6 -met hyl heptane, Removal. of the t-butyloxycarbonyl protecting group of the compound from Example 27B using the procedure of Example 1iN provided the desired compound. 300 MHz 1 H NMR (CoDC 3 8 0.90 J=3Hz, 3H), 0.94 J=3Hz, 3 1. 60 (in, 4 2.2 0 6 2.8 5 (in, 2 3. 0 (in, 1 3.8 5 (in, 1 4.2 0 (in, 2H), 7'0 (in, 2H), 7.35 (in, 6H). Mass spectrum: (M+H)+=399.

D. (2S.3S.5Sl-2-(2.6-Diinethylohenoxyacetfl) amino-3-hydroxy-5-f2SA( tetrahvdro-1ovrimid-2-onyl)-3-methvlbutanovllpmino-1 -ohenyl-6-methylheptpne.

3o Coupling of the amino compound from Example 27C with the acid from Example 2A using standard coupling procedure (EDAC/DMF) provided the -94- W desired compound. 300 MHz 1 H NMR (CoDC 3 8 0.88 (in, 12H), 1.67 (mn, 2H), 1.90 (in, 1 2.20 6H), 3.0 J=8Hz, 2H), 3.22 (in, 4H), 3.67 (mn, 1 3.77 1 4.20 2H), 4.40 (mn, 1 4.76 (in, 1 7.0 (in, 3H), 7.30 (in, 5H). Mass spectrum: (M+H)+=581.

Exam~le 28 (2S23S.5S-2-(2.6-Dimethvlphenoxvacetyl) amino-3-hydroxv-5-[2S-Litetra hvdro-Qy ri mid-2. 4-d io nvl-3- methvylbutanovll a ino- 1 -Dhenyl-6- Coupling of the amino compound from Example 270 with the acid from Example 25D using standard coupling procedure (EDAC/DMF) provided the desired compound. 300 MHz 1 H NMR (COCl 3 8 0.83 J=7Hz, 6H), 0.92 (t, J=7Hz, 6H), 1.73 (in, 2H), 2.18 6H), 2.30 (in, 1 2.62 (in, 2H), 3.03 (mn, 2H), 3.4.5 (in, 1 3.55 (in, 1 4.72 (in, 2H), 4.20 (mn, 4H), 6.40 (br d, J=9Hz, 1 H), (in, 3H), 7.30 (in, 5H), 7.62 (br s, 1 Mass spectrum: (M+H)+=595.

3S. .5S) Di met hylphe noxyacetyflai no-3-h yd roxy-5-[2S- (1 -pi Perazi n- 2 .3-di onvfl-3 -iethvlbutanolamli no- 1.6-di phe nvihexane, A. 2S- (4 -be nzvloxvcarbonyl- 1 -pipe razi n-2.3-dionyfl-3-methvlbutanoic acid mehy T ester, To a solution of 0.77 g of N-(benzyloxycarbonylamino)-ethyl-L-Valifle methyl ester in 20 ml of toluene and 10 ml of acetonitrile was added 0.79 g of oxalyl diimidazole. The reaction mixture was kept at 500C for 24 h and 0.2 g of oxalyl diimidlazole was added. The reaction mixture was kept at 5000 for another 72 h. Evaporation of solvent in vacuo and purification of the crude 25product by silica gel column chromatography (10% EtOAc in CH 2

CI

2 provided the desired compound. 300 MHz 1 H NMR (ODC1 3 5 0.95 J=7 Hz, 3H), 1.03 J=7Hz, 3H), 2.20 (in, 1 3.60 (in, 1 3.73 3H), 3.85 (in, 1 (in, 1 4.10 (in, 1 4.90 J=1 0 Hz, 1 5.36 2H), 7.20 (in, 5H). Mass spectrum: (M+NH 4 )+=380.

B. 2S-(l-piperazin-2.3-dionvW)3-inethylbutanoic acid methyl ester.

Removal of the benzyloxycarbonyl protecting group of the compound from Example 29A by hydrogenolysis using 10% Pd/C as catalyst provided the desired compound. 300 MHz 1 H NMR (C~DC 3 8 0.95 J=7 Hz, 3H), 1.03 J=7 Hz, 3H), 2.20 (in, 1 3.50 (in, 3H), 3.74 3H), 3.83 (in, 1 5.0 (d, 6J=1 0Jz, 1 7.30 (br s, 1 Mass spectrum: (M+H)+=229.

C. (2S5.3S.5S)-2-(2.6-Dimethylo~henoxvacetyfl amino-3-hvdroxy-5[2S-( 1piperazin-2.3-dionyfl-3-methvlbutanovllamino-1 .6-diQhenvlhexane, The methyl ester from Example 29B was hydrolyzed using the procedure of Example 1iM and the resulting acid was coupled to the amino compound to from Example 1 N using standard EDAC coupling procedure to provide the desired compound. 300 MHz 1 H NMR (C~DC 3 5 0.82 J=6 Hz, 3H), 0.85 J=6 Hz, 3H), 1.80 (in, 2H), 2.18 (in, 1 2.20 6H), 2.65 (mn, 1 2.82-3.0 (in, 4H), 3.30 (mn, 3H), 3.70 (in, 1 3.82 1 4.22 (in, 3H), 4.54 (d, J=1 0 Hz, 1 6.30 (br s, 1 6.65 (br d, 1 7.0-7.30 (in, 13H). Mass IC; spectrum: (M+H)+=643.

Exaple-3Q (2S.3S.5S)-2-(2.6-Dimethylohenoxvacetyfl ainino-3-hvdroxv-5f2S-(4-aza-4.5cl dhyd ro- 1 -ovyri m id- 2-o nvl) -3 -met hvl-b uta n oll am in o- 1. .6-dipohe nyl hex ane.

A. 2S-(4-Aza-4.5-dehydro-1-ovyrimid-2-onvl)-3-methvl-butanoic acid.

20 From the hydroysis product mixture of Example 26F, the desired product was isolated after column chromatography MeOH/5% AcOH in CH 2

CI

2 in 12.5% yield. 300 MHz 1 H NMR (CD 3 OD) 860.93 J=7Hz, 3H), 1.04 (d, J=7Hz, 2.20 (in, 1 3.92 (dd, J=1 5, 3 Hz,, 1 4.09 (dd, J=1 5, 3 Hz, 1 H), 4.50 J=1 0 Hz, 1 6.95 J=3Hz, 1 Mass spectrum: (M+H)+=334.

(2S.3s.5S)-2-(2.6-Dimethylphenoxyacetyfl amino-3-hydroxy 512S -(4-aza- 4 .5-dehvdro-1 -pvrimid-2-oxyl)-3-methyl-butanoylamino-1 .6-diohenvlhexane.

Coupling of the compound from Example 1N with the acid from Example using standard coupling procedure (EDAC/DMF) provided the desired compound 300 MHz 1 H NMR (C~DC 3 6 0.80 J=7Hz, 3H), 0.85 (dr- J=7Hz, 3H), 1.75 (in, 2.15 (in, 1 2.20 2.62 (in, 1 2.85 (in, 1 H), 3.02 (in, 2H), 3.55 (in, 2H), 3.80 (mn, 1 4.20 (in, 4H), 6.38 (bor d, 1 6.72 (t, J=3 Hz,1 7.0 (mn, 3H), 7.22 (in, 10OH), 7.63 1 Mass spectrum: (M+H)+=628.

Example 3 cis-N-tert-butyl-decahydro-2-f 2(R)-hydroxy-4-phenyl-3(S)-(23-(1let ra hvdroovri mid-2-o nvl)-3- met hvlbutanoyflami nobutyll- (4aS, 8aS)soouinoline-3(S)-carboxainide The title compound can be prepared by coupling the product of Example' 2A with cis-N-terl-butyl-decahydro-2-[ 2(R)-hydroxy-4-phenyl-3(S)-aininobutyl)- (4aS,8aS)-isoquinoline-3(S)-carboxamide (disclosed in PCT Patent Application No. W09426749 and U.S. Patent No. 5,196,438, issued March 23, 1993, both of which are incorporated herein by reference) using a standard coupling procedure-(EDAC in DMF).

Exml 32 cis-N-tert-butyl-decahvdro-2-1 2(R)-hvdroxy-4-thiophenyl-3(S)-(2S-(1 tetra hydrolo rmid-2-o nyl)- 3- methylbutanoyflainobutyll- (4aS 8aS)-.

*i soq ui n o i ne- 3 ca rbox am i de The title compound can be prepared by coupling the product of Example 2A with cis- N-te rt-butyl-decahydro-2-[ 2(R)-hydroxy-4-thiophenyl-3(S)aminobutyl)-(4aS,8aS)-isoquinoline-3(S)-carboxainide (disclosed in PCT Patent Application No. W095/09843, published April 13, 1995 and U.S. Patent No. 5,484,926, issued January 16, 1996, both of which are incorporated herein by reference) using a standard coupling procedure (EDAC in DMF).

2.4-Ainino-N-(( 2syn. 3S)-2-hydroxy-4-phenyl-3-(2S-( 1 -tetra hydropyri mid-2 onvl)-3-methylbutanoylainino)-butyl)kN-isobutyl-benzenesulfonamide The title compound can be prepared by coupling the product of Example 2A with 4-Amino-N-(( 2syn, 3S)-2-hydroxy-4-phenyl-3-anino)-butyl)-N-isobutylbenzenesulfonainide (disclosed in PCT Patent Application No. W094/05639, published March 17, 1994, which is incorporated herein by reference) using a standard coupling procedure (EDAC in DMF).

-97- Example 34 A. Alternative Preparation of (2S. 3S. 5S) -2-/2.6-DimethvlDhenoxvacetl) amino-3-hvdroxv-5-amino-1,6-diphenvlhexane To a 1 liter 3-necked flask equipped with a mechanical stirrer. J-Kem temperature probe, dropping addition funnel, and dry nitrogen line was charged 30.0 g (54.87 mmol) of the product of Example 11 and 120 mL of acetonitrile.

The resultant slurry was cooled to 0-5 0 C and 54.1 g (549 mmol) of 37% aqueous hydrochloric acid was slowly added, maintaining an internal temperature of not more than +5 0 C during the addition. The reaction mixture <o was stirred at 0-5 0 C and samples were taken periodically to analyze for consumption of starting material by HPLC (Zorbax C-8 column, mobile phase 1:1 acetonitile/0.1% aqueous phosphoric acid, flow rate 1.5 mL/minute.

detection at 205 nm).

After stirring for 3 hours the reaction was complete. The reaction was 5 quenched by the slow addition of 105 mL of 20% aqueous sodium hydroxide, again maintaining an internal temperature of not more than +5 0 C during the addition. Once the pH of the reaction mixture was confirmed to be basic, the solution was warmed to room temperature. Ethyl acetate (180 mL) was added o* with mixing and. after settling, the lower aqueous phase was separated and discarded. The organic phase was then washed once with 105 mL of aqueous sodium chloride.

The title compound was crystallized from 12 mL/g of 1:2 ethyl acetate/heptane (yield 80-85%).

B. Alternative Preparation of (2S, 3S, 5S) -2-(2.6-Dimethvylhenoxvacetvl) 'S amino-3-hvdroxv-5-amino- 1,6-diphenvlhexane To a round-bottom 3-neck 1L flask with attached mechanical stirbar and thermometer was added the product of Example 11 (51.6 g, 0.095 mol) and 100 mL of glacial acetic acid. To the resulting suspension was added 35% aqueous HCI (10.5 mL. 0.103 mol) in 1 portion. The solution was allowed to stir under a 3o N 2 atmosphere for 3h, at which time an additional 10.5 mL of 35% aqueous HCI was added. After an additional 1.5h. the reaction flask was immersed in an ice -98bath and a NaOH solution (16 mL, 0.198 mol) was added at a rate to maintain the internal temperature of the flask below 30 OC. Water (200 mL) was added and the mixture extracted with 4 x 200 mL of Isopropyl Acetate. The combined organic layers were washed with 2.5M NaOH (2 x 200 mL), 100 mL H 2 0, brine, dried over Na 2

SO

4 filtered and evaporated in vacuo to yield 39.7g (94% crude) of product as a colorless solid in greater than 95% purity by HPLC. The product could be further purified by dissolving in 200 mL isopropanol heated over a steam bath, allowed to cool with stirring to 0-5 OC to yield 32.2g of the desired product, m.p. 131 OC.

t1 Example Alternative Preparation of 2S-(1-Tetrahydro-pyrimid-2-onvl)-3-methvl butanoic acid A. N-phenoxycarbonyl-L-valine N-phenoxycarbonyl-L-valine may be prepared according to the iS procedures disclosed in U.S. Patent Application No. 08/08/671,893, filed June S28, 1996, which is incorporated herein by reference, and which include the following method.

Into a reactor equipped with an overhead stirrer, chiller, pH probe and thermocouple was added lithium chloride (15.6 kg, 368 moles), L-valine (26.0 o kg, 222 moles), neutral alumina (8.1 kg, 150 mesh, Aldrich) and 156 kg of distilled water. The heterogeneous mixture was stirred and cooled to -140C 5°C. The pH was adjusted to 10.1 with 10% aqueous lithium hydroxide. Precooled (-20 0 C) phenylchlorformate (36.6 kg, 234 moles) was added while maintaining a temperature of not more than -9 °C and the pH was controlled during the reaction (maintaining a pH within the range of 9.5 to 10.5 with a target 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 So water. The aqueous filtrate was extracted with methyl t-butyl ether (65 kg) to remove residual phenol. The aqueous phase was then cooled to 0-5oC and mixed with 200 kg of toluene. The stirred biphasic solution was adjusted to -99pH 1.8-2.0 with 25% sulfuric acid. The toluene layer was concentrated at not more than 40 °C to approximately 120 L, filtered (30 kg rinse of toluene) and then concentrated again at not more than 40 °C to approximately 120 L.

To the resulting solution was added 44.2 kg of heptane and the resulting solution was heated to 40 oC 10C for 15 minutes. The heat was removed and the solution was seeded and stirred overnight. The product crystallized on the walls of the reactor and was resuspended in 80 kg of toluene, reconcentrated at not more than 50 °C to approximately 130 L, then 45.2 kg of heptane was added. The resulting solution was then heated to 40 °C to for not less than 15 minutes and then cooled at not more than 20 °C/hour to 18 OC 50C. After not less than 12 hours, the resulting white slurry was cooled to 14 oC 5 0 C and stirred for not less than 3 hours. The white slurry was filtered and the solid washed with 41 kg of 1:1 toluene/heptane. The solid product was dried at not more than 50 oC to provide the desired producl (47.8 kg) as a white powder.

B. 2S-(1-Tetrahvdro-ovrimid-2-onvl)-3-methvl butanoic acid A mixture of N-phenoxycarbonyl-L-valine (25 g, 0.106 mol) and 3-chloropropylamine hydrochloride (15.2 g, 0.116 mol) in THF (250 mL) was cooled to 20C. Sodium hydroxide (12.7 g, 0.318 mol) was added to the stirring z0 suspension. After about 35 minutes, a slow exotherm to 10°C occurred. The reaction was stirred at less than 100C for 2 hours. A solution of potassium tbutoxide (29.6 g, 0.265 mol) in 125 mL of THF was added over 10 minutes, followed by a 20 mL THF rinse. The temperature of the reaction mixture was allowed to rise to 200C 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 pH 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. Ethanol 3A (75 mL) was added to the separated 3o aqueous layer and the mixture was acidified to pH 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 -100evaporator at a temperature below 50 0 C. The residual solids were flushed with 250 mL of ethyl acetate. The residual solid was dissolved in 150 mL of ethanol 3A at reflux temperature and filtered through a 5 g Darco-G60 bed over filteraid, followed by a 50 mL hot ethanol rinse. The filtrate was evaporated to dryness on a rotary evaporator at a temperature below 50 0 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 by filtration and washed with mL of cold ethyl acetate (5-8 0 After drying at 40 0 C for 72 hours the desired product was obtained as a white solid (15.6 g, 74%).

to Example 36 Alternative Preparation of 2S-(1-Tetrahvdro-pyrimid-2-onyl)-3-methvl butanoic acid A mixture of phenoxycarbonyl-L-valine (250 g, 1.05 mol; prepared according to the procedure disclosed in U.S. Patent Application No. 08/671,893, I; filed June 28, 1996, which is incorporated herein by reference) and 3chloropropylamine hydrochloride (151 g, 1.16 mol) in THF (2.5 L) is cooled to 2°C. Sodium hydroxide (127 g, 3.2 mol) is added to the stirring suspension.

After about 45 minutes, a rapid exotherm to 10 0 C occurrs. The reaction is stirred at 1-5oC for 2 hours. Additional 3-chloropropylamine (10 g, 0.08 mol) is added ee* and stirring is continued for 1 hour. A solution of potassium t-butoxide (296 g, 2.6 mol) in 1.25 L of THF is then added over 30 minutes, followed by a 100 mL THF rinse. The temperature of the reaction mixture was allowed to rise to 20 0

C

during the addition. The reaction mixture is stirred at room temperature for 12- 16 hours.

The reaction mixture is quenched with 2 L of distilled water and cooled to 12 0 C and then acidified to pH 9 using 258 g (2.6 mol) of concentrated hydrochloric acid, keeping the temperature below 30 0 C. The aqueous layer is separated. Ethanol 3A (625 mL) is added to the separated aqueous layer and -the mixture was acidified to pH 3 with 116 g (1.2 mol) of concentrated 3o hydrochloric acid, keeping the temperature below 25°C. The acidified mixture is extracted twice with ethyl acetate (2.5 L and 1.5 The combined organic layers are evaproated to dryness on a rotary evaporator at a temperature below -101- The residual solids are dried by repeated distillation with ethyi acetate (4 x 1 The residual solid is dissolved in 750 mL of methanol and treated with decolorizing carbon (10 g Darco-G60 bed) at room temperature overnight. The carbon is removed by filtration through diatomaceous earth. The filtrate is S evaporated to dryness on a rotary evaporator at a temperature below 500C.

Ethyl acetate (1.5 L) is added to the residue and approximately 500 mL is removed on tne rotary evaporator. The suspension is cooled to below 10°C foi 1 hour. The solid is collected by filtration and washed with 2 x 100 mL of cold ethyl acetate (5-80C). After drying at 50°C for 72 hours the desired product is o0 obtained.

Example 37 Alternative Pro-aration of 2S-(:-Tetrahdro-ovrimid-2-onvl'.-3-methv butanoic acid A. (S)-(-t-N-carboxvmethvl-N(Bcvyanoethyl Valine IS To a 5L 3-neck round bottom flask with a mechanical stirrer was added (S)-valine (170.1g, 1.45mol) and water 145mL. The solution was cooled to 00C with an ice-water bath and a solution of 1.0eq of KOH (93g of 88% solid KOH) in 180mL water was added dropwise over 20 minutes. After the addition was complete. acrylonitrile 1.0eq (95.5mL) was added dropwise with vigorous to stirring while maintaining the internal temperature of the flask below 50C. The solution was allowed to stir between 0-50C for 4.5h. Water (600mL) was added and a pH meter was inserted into the solution. Methyl chloroformate 1.Oeq (112mL) was added dropwise while maintaining the pH of the solution between 9.5 and 10.5, with solution of 10% aq KOH. The addition took place over 0.5h. The solution was then acidified with conc. HCI and phosphoric acid to pH 2 and was subsequently extracted with 2L of isopropyl acetate. The organic layer was concentrated under vacuum to give'201 g of a Scolorless oil that solidified on standing. mp 65-660C. Optical rotation sodium D line at 25cC -0.44 ethanol). IR (cm- 1 CDCI3) 2960, 1740, 1710,1470.

1 H NMR (300 MHz.CDCI 3 (6 TMS. 0.00) ppm 0.93 (d,3H J=7Hz); 1.07 (d,3H J=6Hz); 2.16-2.36 2.62-2.86 3.62 (t,2H, J=7.5Hz); 3.77 (s,1.2H -102rotamer); 3.82 (s,1.8H rotamer); 4.15-4.30 9.76-9.96 (brs,1H). ms (DCI/NH3) 246, 185, 146, 125. FAB hrms: cal for 229.1188: found: 229.1185.

B. 2S-(1-Tietrahydro-pyrimid-2-onvl)-3-methvl butanoic acid To a 2L pressure vial was added the product of Example 37A (190g, 0.833 mol), water (900mL) and KOH (3eq, 140g). To this solution at ambient temperature was added Nickel Aluminum alloy (Raney-Type) 75g. Note that this is the unactivated form. The solution was sealed in a pressure bomb and was placed under 60 psi of hydrogen. The resulting solution was heated to Io 1000C for 4h. After cooling the solution to ambient temperature, it was filtered.

washed with 900mL of dichloromethane and subsequently acidified to pH 1.

The aqueous solution was extracted with 2 X 900mL of dichloromethane. The combined organic layers were concentrated to give 120g of crude product which was slurried in isopropyl acetate to give 70g of the title compound.

19 Examole 38 Alternative Preparation of (2S. 3S. 5S)-2-(2.6-DimethvlDhenoxyacetvl) amino-3 hvdroxv-5-[2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyll amino-1.6- S* diphenvlhexane A-1. 2S-(1-Tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl chloride roo 2S-(1-Tetrahydro-pyrimid-2-onyl)-3-methyl butanoic acid (17.6 g, 87.9 mmole) was slurried in THF (240 mL) and cooled to <5 Thionyl chloride (14.3 g, 120 mmole) was added over 5 minutes (exothermic). The slurry was stirred at 20 °C for 70 min. until complete by HPLC (samples quenched into methanol). THF was removed by rotary evaporation; heptane (90 mL) was ZS added and removed by rotary evaporation, yielding a wet solid mass. The material was slurried in DMF (85 mL).

A-2. Alternative Preparation of 2S-(1-Tetrahydro-pvrimid-2-onyl)-3-methvl butanoyl chloride 2S-(1-Tetrahydro-pyrimid-2-onyl)-3-methyl butanoic acid (39.6 g, 198 ?o mmole) was slurried in THF (590 mL) and cooled to 1 Thionyl chloride -103- (28.3 g, 238 mmole) was added over 5 minutes (exothermic). The slurry was stirred at 20 °C for 2 hours. THF was removed on the rotary evaporator; THF (200 mL) was added and removed on the rotary evaporator, yielding a wet solid mass. The material was slurried in DMF (225 mL).

SB-1. (2S, 3S, 5S)-2-N.N-dibenzvlamino-3-hvdroxv-5-2S-(1-tetrahvdro-vyrirnid.

2-onvl)-3-methvl butanovll amino-1 6-diohenvlhexane (2S, 3S, 5S)-2-N,N-dibenzylamino-3-hydroxy-5-amino-1,6diphenylhexane (ca. 83 mmole; U.S. Patent No. 5,491.253, issued February 13, 1996, which is incorporated herein by reference) and imidazole (8.2 g. 120 io mmole) were dissolved in ethyl acetate (350 mL, KF and cooled to 2 OC. The slurried product of Example 38A-1 was added (exothermic, maximum temp. was 10 followed by a DMF rinse (15 mL). The reaction was stirred cold initially then allowed to slowly warm to room temperature and stirred overnight.

o The reaction was quenched with 100 mL water and stirred 30 minutes.

The organic layer was separated and washed with 3 x 125 mL 5% NaCI. The organic solution was filtered and concentrated on rotary evaporator to a thick Ssyrup, 62 g. HPLC purity approx. 85% (peak area). Isomer content approx.

11.2%.

-o CIMS (NH 3 m/z 647 (M o 1 H NMR (300 MHz, CDCI3) 8 7.35-7.13 10H), 7.13-7.06 1H), 6.87 (br d, 1 5.22 (br s, 1H), 4.28 1H), 4.20-4.05 1H), 3.95 2H), 3.65-3.56 (m, 1 3.37, 2H), 3.12-2.89 5H), 2.83-2.53 4H), 2.23-2.08 1H), 1.74-1.40 4H), 0.87-0.75 6H).

13C NMR (75 MHz, CDC13) 5 170.0, 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 54.2, 49.2, 41.2, 40.5, 40.0, 39.7. 31.5, 25.4, 21.6, 19.5, 18.6.

-104- B-2. Alternative Preparation of (2S. 3S. 5S)-2-NN-dibenzvlamino-3-hvdrox.y-.

[2S-(1-tetrahvdro-pvrimid-2-onvl)-3-methvl butanoyl] amino-1, 6 -diohenylhexane (2S, 3S. 5S)-2-N,N-dibenzylamino-3-hydroxy-5-amino-1,6diphenylhexane (ca. 180 mmole: U.S. Patent No. 5.491.253. issued February 5 13. 1996, which is incorporated herein by reference) and imidazole (38.1 o.

560 mmole) were dissolved in ethyl acetate (675 mL. KF and cooled to 1 The slurrieo product of Example 38A-2 was added slowly over minutes (exothermic. maximum temp. was 6 followed by an ethv! acetate rinse (225 mL). The reaction was stirred cold for 1. 5 hours, then allowed to

G

1 slowly warm to about 27'C and stirred for aoout 20 hours.

The reaction was quenched with a dilute solution of HCI (36.75 o concentrated HCI in 225 mL of water) and stirred 20 minutes. The bionasic mixture was filtered with a 100 mL ethy! acetate rinse. The organic aver was separated and washed with 3 x 125 mL 5% NaCI. The organic laver was (s separated and washed with 3 x 225 mL 5% NaCI and 2 x 225 mL 5% NaHCO, The organic solution was concentrated by rotary evaporation to provide the desired product as a thick syrup.

C. (2S. 3S. 5S-2-Amino-3-hvdroxv-5-f2S-1-tetrahvdro-pvrimid-2-onyl-3methyl butanoyll amino-1.6-diphenvlhexane "o The crude product of Example 38B (ca. 83 mmole) was dissolved in methanol (260 mL). Pd/C (50% wet Pearleman's catalyst, 10.4 g wet weight) and ammonium formate (15.1 g, 239 mmole) were added and the mixture was .i warmed to 50 OC. After 2.5 hours the reaction was complete by TLC. The mixture was cooled to 35 OC and catalyst was removed by filtration through 0s 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 warming. Dioxane was removed on the rotary evaporator to yield 60 a of yellow oil. HPLC purity approx. 88.2% (peak area).

Isomer content 27 9% (however. one isomer does not separate from the main 3o peak).

0 -105- CIMS (NH 3 nm.z 467 (M H)+ 1 H NMR (300 MHz. CD 3 0D) 5 7.35-7.10 10H), 4.40-4.20 1H). 4.25 (d, 1H), 3.68-3.57 1H). 3.20-3.09 2H), 3.08-2.90 3H), 2.90-2.74 2H), 2.65-2.49 2H), 2.20-2.04 1H), 1.92-1.78 1H), 1.78-1.60 2H).

1.60-1.45 1H), 0.88-0.77 6H) 1 3 C NMR (75 MHz. CD30D) 5 171.3. 158.4, 140.5. 139.8, ;30.6. 130.4. 129 129.3, 127.3. 127.0. 71.5. 63.9. 57.1. 49.1 41.8. 41.6. 41.4, 40.7. 40.5. 26.9.

22.5. 20.0. 18.9 H NMR (300 MHz. CDC133) 7.35-7.13 10H). 5.35 1 H) 4.40-4.23 (m.

to 2H), 3.60-3.52 1 3.25-2.65 8H). 2:58-2.45 (dd. 1H). 2.30-2.10 (mr 1H), 1.90-1.65 3H). 1.65-1.50 1H), 0. 91 3H), 0.84 3H) S: 13C NMR (75 MHz, CDC13) 5 171.2, 156.6. 139.1. 138.5, 129.3. 129.2. 128.5.

128.2, 126.3, 126.0, 71.6, 63.1 56.3, 48.7. 41.6, 41.0, 40.6, 40.0. 39.6, 25.5, 21.7, 19.7. 18.7 i5 D. (2S. 3S, 5S)-2-Amino-3-hvdroxv-5-r2S-(1-tetrahvdro-Dvrimid-2-onvl)-3methyl butanoyl] amino-1.6-diphenvlhexane (S)-Pvroqlutamic acid salt The crude product of Example 38C was dissolved in dioxane (370 mL.

KF 0.07% moisture). S-Pyroglutamic acid (10.3 g, 80 mmole) was added and the suspension was warmed to 50 °C to give a clear solution. After stirring 1 z hour the solution was seeded with a few crystals of the product salt. The salt slowly precipitated. The slurry was slowly cooled and stirred overnight at roorr temperature. The product was isolated by filtration and washed with dioxane (100 mL). Wet cake weight was 120 g. Product was dried at 60 'C in a vacuum oven with nitrogen purge. Yield 35.2 g off-white powder. HPLC purity: >98% (peak area including pyroglutamic acid). Isomer content approx. 1% (however.

one isomer does not separate from the main peak).

mo 135-141 °C 106- [a]D 2 5 -21.9- CH 3

OH)

CIMS (NH 3 m1z 467 (M +4 H for base)+, 147 (M NH 4 for Dyroolutamic acid), 1 30 (M H for pyroglutamic acid)+ IR (KEr) 1586. 1655. 1682 cm- 1 I H WAR (400 MHz. DMSO-d 6 3 7.62 1 7.54 11H). -7.32-7.06 (mn. I1 H- 6. 33 1 4.2 6 (d.1 1 4. 111- 3.9 9 (in, 1 H).1 3.8 2 (d d, 1 3.7 -3,48 (in. I H) 3.27 -3.19 (mn, 1 3.0 8- 2.9 5 (in. 2 2.9 2 -2.7 0 5 2.5 3 -2.4 3 (in. IH).

2.2 6 14 (in, 1 2.13 -1.9 9 (in. 2 1.9 9 87 (in, 2 H) 1.7 2 61 (in. 2 H) 1.61 -1.49 (in, 1 1.46-1.35 (in. 1 0.70 3H). 0.64. 3H).

30I NMR (100 MHz. DMSO-d 6 5 176.9. 176.1. 169.2, 155.5. 138.8, 137. 7.

129.3, 129.3. 128.3, 127.8, 126.4, 125.5, 66.9, 61.5. 56.9, 55.3. 46.8. 40.2, 39.6.

39.4. 38.8, 37.4, 29.8, 25.4, 25.3. 21-6, 19.6, 18.7.

IH NMR (300 MHz, CD 3 OD) 5 7.32-7.03 1 OH). 4.23-4.12 (in. 1 4.12 (d.

iH). 3.98 (dd, 1 3.71-3.63 (in, 1 3.46-3.37 (in, 1 3.1 1-2.98 (mn, 2H), 2.9 7 80 (in, 4 2.7 0 -2.5 9 (in, 1 H) 1 2.4 9 -2.3 8 (in. 1 2.3 8- 2.12 (in, 3 H), 2.07-1.92 (in, 2H), 1.75-1.63 (in, 2H), 1.63-1.50 (in. 1 1.45-1.32 (in, 1 H)j 0.74-0.65 (mn, 6H).

13 C NMR (75 MHz, CD 3 OD) 6 181.0, 179.6, 171.6, 158.4, 139.5, 137.3. 130J.5, 130.0, 129.4. 128.3, 127.2, 68.1, 64.0, 59.6, 57.7. 48.8, 41.7, 41.1, 40.7, 40.6, 37.9. 31.1, 26.9, 26.9. 22.5, 20.1, 18.9.

1 H NMR (300 MHz, D 2 0) 6 7.30-6.97 (in, 10H), 4.16-4.03 (in, 1H), 3.99-3.91 (mn. 2H). 3.71 -3.63 (in, 1 3.43-3.35 (in, 1 3.00-2.68 (mn, 6H), 2.40-2.13 (in, 1.88-1.72 (in, 3H), 1.68-1.56 (in, 1 1.52-1.37 (in. 1 1.32-1.18 (in. 1 H), 0.60-0.52 (mn. 6H).

-107- 13C NMR (75 MHz, D 2 0) 5 181.6. 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. 39.2 387, 35.7. 29.6. 25.3, 25.2, 20.5, 18.5, 17.6.

(2S, 3S. 5S)-2-(2,6-Dimethvlohenoxvacetvl) amino-3-hvdroxv-5-[2S- 1 tetrahvdro-ovrimid-2-onvyl-3-methvl butanoyl] amino-1.6-dipnenylhexane The product of Example 1H (7.26 g, 40.3 mmole) was slurried in ethyl acetate (22 mL) and thionyl chloride (5.75 g. 48.3 mmole) was added. followed by 1 drop DMF. The mixture was warmed to 50 °C and stirred 5 hours. The soiution of the resulting acid chloride was cooled to 22 'C and held for the to suosequent coupling reaction.

The product of Example 38D (20 c. 31.7 mmoie. corrected for dioxane content), sodium bicarbonate (16.5 g, 197 mmole). ethyl acetate (150 mL) and water (150 mL) were combined in a flask and stirred until the product of Example 38D had dissolved (some salt remains undissolved). The solution of 15 acid chloride prepared above was added over 5 minutes, followed by an ethyl acetate rinse (5 mL). Addition was mildly exothermic (maximum temperature 23 The mixture was stirred overnight.

The organic layer was separated and washed with 5% sodium bicarbonate (100 mL) and water (100 mL). Solvent was removed on the rotary to evaporator. The residue was dissolved in ethyl acetate (100 mL) and filtered, rinsing 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 heptane (105 mL) was added; product began to crystallize o: rapidly. The slurry was cooled and stirred at 20-23 oC for 5 hours. Product was 2-5 collected by filtration and washed with 1/1 ethyl acetate/heptane (30 mL).

Product was dried under vacuum oven at 70 OC to provide 18.8 g of the desired product as a white powder.

66* 6 Examole 39 -108- Preparation of Amorphous (2S, 3S. 5S)-2-(2.6-Dimethvlphenoxvacetvl) amino.

3-hvdroxv-5-12S-(1-tetrahvdro-pvrimid-2-onvyl)-3-methvl butanoyll amino-1 6diphenvlhexane A. The product of Example 38E (2.5 g) was dissolved in 8 mL of absolute S etnanol. This solution was added slowly dropwise to 250 mL of chilled water at 9'C with vigorous stirring. A white solid immediately appeared The stirrino w.as continued for 15 minutes and the solids were collected by filtration.

Vacuum drying at 50°C for 12 hours provided 2.32 g of the desired orocuct as an amorphous solid.

1 o 3. The product of Example 38E (2.5 g) was dissolved in 6 mL of absolute ethanol. This solution was added slowiy dropwise to 31 mL of chilled water at 7-9°C with vigorous stirring. A white solid appeared. The stirring was continued for 20 minutes and the solids were collected by filtration. Vacuum drying at 0 C for 12 hours provided 2.24 g of the desired product as an amorohous (S solid.

C. The product of Example 38E (0.5 g) was dissolved in 8 mL of isopropanol. This solution was added slowly dropwise to 100 mL of chilled Swater at 10-15cC with vigorous stirring. A white solid appeared. The stirring was continued for 20 minutes and the solids were collected by filtration. Air 2e 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 added slowly dropwise to 0 100 mL of chilled water at 10-15CC with vigorous stirring. A white solid appeared. The stirring was continued for 10 minutes and the solids were collected by filtration. Air drying provided 0.46 g of the desired product as an amorphous solid.

E. The proouct of Example 38E (0.5 g) was dissolved in 2 mL of acetonitrile. This solution was added slowly dropwise to 100 mL of chilled water *1 09at 10-1 5'C with vigorous stirring. A white solid appeared. The 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 S N-(3-Chloroproopviaminocarbonylp-valine methyl ester 3-Chloroproprylisocyanate (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 was then quenched with the addition of aqueous sodlium,ec bicarbonate. The quenched reaction mixture was extracted with ethyl acetate.

The organic layer was separated, dried and evaporated to give the desired Product.

Examole 41 (2S. 3S. 5S)-2-(2.6-Dimethvlohenoxyacetvl) amino-3-hvdroxy-5-r2S-(1 t etrah vdro-4- hyd roxy- 1yri mid- 2-onvyl)-3-met hyl butanoyll amino-i .6dilohenvlhexane Reaction of a solution of the product of Example 25E in methylene chloride with sodium borohydridle provides the desired product.

Examnle 42 (2S. 3S. 5S)-2-(2.6-Dimethvlnhenoxvacetvl) amino-3-hvdroxv-5-[2S-(l tetrahvdro-6-hvdroxv-ovyrimid-2-onyl)-3methyI butanoylI amino-i .6dinhenvihexane A 300-mL incubation of (2S, 3S, 5S)-2-(2,6- Dimethylphenoxyacetyl) amino-3-hydroxy-5-[2S-(l1-tetrahydro-6- *z S hydroxy-pyrimid-2-onyl)-3-methyl butanoyl] amino- 1,6-diphenylhexane labelled with 140 in the carbonyl group of the acetyl moiety (50 ltM, Ci) was performed with rat liver microsomes (0.5 mg/mL microsomal protein) and an NADPH-generating system for 60 minutes at 3700. The metabolic reaction was stopped by adding 300 mL of acetonitrile. The 36 supernatant obtained after centrifugation at 3000 RPM for 1 0 minutes -110was evaporated to dryness in vacuo. The residue was reconstituted in 2 mL of HPLC mobile phase. Isolation of the desired product was achieved at ambient temperature with a Beckman Ultrasphere 5 pm x 150 mm C 18 column connected to an Alltech Ultrasphere 5 um Cis cartridge guard column. A linear gradient of 25-55% acetonitrile in buhfer (25 mM ammonium acetate. pH adjusted to 4.8 with formic acid) over 57 minutes was used as column eluent at a flow rate of mL minute.

Fluorooenic Assay for Screening Inhibitors of HIV ProTease (0 The inhibitory potency of the compound of the invention can De determined by the followino method.

The compound of the invention is dissolved in DMSO and a small aliauol funner diluted with DMSO to 100 times the final concentration desired for testing. The reaction is carried out in a 6 X 50 mm tube in a total volume of 300 IS microliters. The final concentrations of the components in the reaction buffer are: 125 mM sodium acetate. 1 M sodium chloride, 5 mM dithiothreitol. mg/ml bovine serum albumin, 1.3 uM fluorogenic substrate, 2% (v/v) dimethylsulfoxide, pH 4.5. After addition of inhibitor, the reaction mixture is placed in the fluorometer cell holder and incubated at 30 0 C for several minutes.

The reaction is initiated by the addition of a small aliquot of cold HIV protease.

The fluorescence intensity (excitation 340 nM, emmision 490 nM) is recorded as a function of time. The reaction rate is determined for the first six to eight minutes. The observed rate is directly proportional to the moles of substrate cleaved per unit time. The percent inhibition is 100 X (1 (rate in presence of '2z. inhibitor)/(rate in absence of inhibitor)).

Fluorogenic substrate: Dabcyl-Gaba-Ser-Gln-Asn-Tyr-Pro-lle-Val-Gln- EDANS wherein DABCYL 4-(4-dimethylamino-phenyl)azobenzoic acid.

Gaba y-aminobutyric acid, and EDANS 5-((2-aminoethyl)amino)naphthalene-1-sulfonic acid.

-11 1- Table 1 Compound of Example iF 2B 3C 4F 6F 7B 8 9B loF 11iB 1 2B 13B 1 4D 15 170 18C 19E 22 E 23C

E

26H 27D 28 29C 30B Percent Inhibition 92.6 93.2 86.9 49.7/ 80.8 61.4 67:.1 55.6 62.6 81.0 91.1 76.8 56.2 52.7 48 87.2 57.8 68.5 71.8 86.0 1 00 94.6 92.9 86.6 72.6 91.0 inhibitor Concentration (nanomolar), 1 .0 0* -112- Antiviral Activity The anti-HIV activity of the compound of the invention can be determined in MT4 cells according to the following procedure. MT4 cells were infected with cell-free supernatant of HIVIIIB (previously frozen with known 50% tissue culture infectious dose (TCID 5 o) at 0.003 multiplicity of infection (MOI) for one hour.

After one hour infection, cells were washed twice to remove residual viruses.

resuspended in culture media and seeded into 96-well tissue culture olates at ixI0^4 cells per well with various half-log dilutions of compounds. Uninfected cells are included as toxicity and cell controls. RPMI 1640 media (Gibco with to fetal bovine serum were used as culture media. Various concentrations of human serum (Sigma) 50%. 25% and 12.5% were added to culture media resuting in final concentration of 60%. 35% and 22.5% total serum. All assay piaies were incubated in 37 deg. cent. incubator for 5 days. MTT (sigma. mg/.ml stock in PBS) was added to all wells at 25 ul per well, incubate for 4 IS hours. 20%SDS with 0.02 N HCI in water was added at 50 ul per well to lyse cellls. Plates incubated overnight for complete lyses were read on a microtitre plate reader at 570/650 nm wavelengths to determine ceil optical density Raw data were analysed for percent inhibition by the following formula: O,D. test well O.D. virus control x100 O.D. cell control virus control The 50% effective concentration (ECso) was calculated by the median effect equation (Chou. 1975,Proc. Int. Cong. Pharmacol. 6th p. 619) to determine the efficacy of compound. The 50% lethal concentration (LC50) was calculated using uninfected MT4 cells.

'2 Under these conditions. the following data were obtained (n 4 duplicate **determinations: oo -113- Table 2 Compound of Example 1P 2B 3C 4F 6F 7B 8 9B 11B 12B 14D 17C 18C 19E 26H 27D 28 29C IC50 (iM. 0% plasma) 0.01 0.016 0.025 0.101 0.368 0.193 0.204 0.019 0.272 0.047 0.19 0.093 0.053 0.119 0.051 0.329 0.395 0.283 0.012 0.015 0.03 0.011 0.427 0.003 (uM) 41.32 17.78 49.5 >100 >100 >100 >100 17.78 19.33 91.97 18.16 19.11 >100 >100 18.96 19.1 17.95 24.08 22.88 33.0 56.23 72.2 56 18 0 0* 0 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, camphorsulfonate, -114digluconate, cyclopentanepropionate. dodecylsulfate. ethanesulfonat.

glucoheptanoate, glycerophosphate, hemisulfate. heptanoate. hexanoate.

fumarate, hydrochloride. hydrobromide, hydroiodide. 2-hydroxyethanesulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate 2-naphthalenesulfonate. oxalate, pamoate, pectinate. persuizate.

3-ohenyipropionate, picrate, pivalate. propionate. succinate. :artrate.

th:ocyanate, p-toluenesuifonate and undecanoate. Also, the basic nitrogen- Contalning groups can be quaternized with such agents as ioweralkVI halides such as methyl, ethyl. propyl. and butyl chloride, bromides, and iodides: dialkyi suifates like dimethyl. diethyl. dibutyl, and diamyl sulfates. lcnc chain halides such as decyl, lauryl, myristyl and stearyl chlorides. bromides and iodides.

aralkyl halides like benzyl and phenethyl bromides. anc others. Water or oilscluble or dispersible products are thereby obtained.

Examples of acids which may be employed to form pnarmaceutically 1s acceptable acid addition salts include such inorganic acids as hydrochloric acid. sulphuric acid and phosphoric acid and such organic acids as oxalic acid.

maleic 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.

2 Preferred salts of 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 *99*9 in the compound of this invention has been acylated with an N-protected or *9*9 S unprotected amino acid residue, a phosphate function, a hemisuccinate residue, an acyl residue of the formula or wherein R' is hycrogen. loweralkyl, haloalkyl. alkoxy. thioalkoxy. alkoxyalkyl. thioalkoxyalkyl ~or naloalkoxy, or an acyl residue of the formula Ra-C(Rb)(Rd)-C(O)- or wherein Rb and Rd are independently selected from 30 hvarogen or loweralkyl and Ra is ORe or -SRe wherein Re and Rf are nscDendently selected from hydrogen. loweralkyl and haloalkyl. or an amino-acyl residue of the formula R18 0

NH(CH

2 2

NHCH

2 or RinroNH(CH 2 2 0CH 2 wherein R 18 0 is hydrogen, loweralkyl. arylalkyl.

cycloalkylalkyl, alkanoyl, benzoyl or an a-amino acyl group. The amino acid -115esters of paricular interest are giycine and lysine: however, other amino acid residues can also be used. including those wherein the amino acyl group is

-C(O)CH

2

NR

200 o 2 0 1 wherein R 2 0 0 and R 2 0 1 are independently selected from hydrogen and loweralkyl or the group -NR 200

R

2 0 1 forms a nitrogen containing heterocyclic ring. 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 also serve to increase solubility for intravenous administration of the compound. Other prodrugs include compounds wnerein a hydroxyl group in the compound of this invention is 1 0 functionalized with a substitueni of the formula -CH(Rg)OC(O)R 1 i 1 or -CH(Rg)OC(S)R 1 ia wherein Ris i is loweralkyl, haloalkyl, alkoxy. thioalkoxy or haloalkoxy and R, is hydrogen. ioweralkyl, haloalkyi, alkoxycarbonyl, aminocarbonyi. alkylaminocarbonyl or dialkylaminocarbonyl. Such prodrugs can be prepared according to the procedure of Schreiber (Tetrahedron Let.

IS 1983. 24, 2363) by ozonolysis of the corresponding methallyl ether in methanol followed by treatment with acetic anhydride.

The prodrugs of this invention are metabolized in vivo to provide the compound of this invention The preparation of the prodrug esters is carried out by reacting the comoound of the invention with an activated amino acyl, c phosphoryl. hemisuccinyl or acyl derivative as defined above. The resulting product is then deprotected to provide the desired pro-drug ester. Prodrugs of the invention can also be prepared by alkylation of the hydroxyl group with (haloalkyl)esters. transacetalization with bis-(alkanoyl)acetals or condensation of the hydroxyi group with an activated aldehyde followed by acylation of the 5 intermediate hemiacetal.

The compounds of the invention are useful for inhibiting retroviral protease, in panicular 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 human c immunodeficiency virus (HIV). The compounds of the present invention are also *e useful for the treatment or prophylaxis of diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection in a human or other mammal.

-116- Total daily dose administered to a human or other mammal host in sinole or divided doses may be in amounts, for example. from 0.001 to 300 mg/kg body weight daily and more usually 0.1 to 20 mg/kg body weight daily. Dosage unit compositions may contain such amounts of submultiples thereof to make UD the daily dose.

The amount of active ingredient that may be combineo with the carrier materiais to produce a single dosage form will vary depending upon the host treated and the panicu;ar mode of administration.

It will be understood. however, that the specific dose level for any 1o particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex.

diet. time of administration. route of administration, rate of excretion, drug combination. and the severity of the particular disease undergoing therapy.

The compounds of the present invention may be administered orally, (c parenteraliy, sublingually. by inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, 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 0 subcutaneous injections. intravenous. intramuscular, intrasternal injection, or infusion techniques.

e injectable preparations, for example, sterile injectable aqueous or oleagenous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile o z" injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1.3-propanediol. Among the acceptable vehicles and solvents that may be i employed are water. Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or 36 susoending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and -117polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore 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 .S may be admixed with at least one inert diluent such as sucrose lactose or starch. Such dosage forms may also comprise, as is normal oractice. additional substances other than iner diluents. lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pilis. the dosaoe forms may also comprise buffering agents. Tablets and pills can additionaiiv be iC prepared with enteric coatings.

Licuid dosage forms for oral administration may include pharmaceuticallv acceotabie emulsions, solutions, suspensions, syrups, and eiixirs containino inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants. such as wetting agents. emulsifying and suspending is agents, and sweetening, flavoring, and perfuming 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 by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous zo medium. Any non-toxic, physiologically aceptable and metabolizable lipid capabale of forming liposomes can be used. The present compositions in liposome form can contain, in addition to the compound of the present invention.

stabilizers, preservatives. excipients. and the like. The preferred lipids are the phospholipids and phosphatidyl cholines (lecithins), both natureal and -5 synthetic.

Methods to form liposomes are known in the art. 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 30 disclosed in U.S. Patent Application No. 08/ filed November 21.

1996. in the names of J. Lipari. L.A. AI-Razzak. S. Ghosh and R. Gao and which is entitled Pharmaceutical Composition, which is incorporated herein by reference.

A preferred dosage form for the compounds of this invention comprises -118a solution of a compound of the formula I in the amount of from about 1% to about 50% (preferably. from about 5% to about 30%) by weight of the total solution and polyoxyl 35 castor oil in the amount of from about 0% to about (preferably, from about 5% to about 10%) by weight of the total solution, in a pharmaceuticaliy acceptable organic solvent which comprises oleic acid in .ne amount of from about 20% to about 99% (preferably, from about 30% to aoout 70%: more preferably, from about 40% to about 65%) by weight of the .oali solution or (ii) a mixture of oleic acid in the amount of from about to aoout 99% (preferably. from about 30% to about 70%: more preferably. from aC acout 40% to about 65%) by weight of the total solution and ethanol or oDooyiene glycol or a mixture thereof in the amount of from aoout 0% to about (oreferably. about 10%) by weight of the total solution. In an even more preferred embodiment of the invention, the solution is encapsulated in a soiL eias-ic gelatin capsule (SEC) or a hard gelatin capsule.

ls A most preferred composition of the invention comprises a solution of a compound of the formula I in the amount of about 30% by weight of the total solution and polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution, in a pharmaceutically acceptable organic solvent wnhch comprises a mixture of oleic acid in the amount of about 50% by weight of the total solution and ethanol in the amount of about 10% by weight of the total solution. In a most 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 from about 0.01% to about 0.08% z by weight of the total solution (preferably. from about 0.01% to about 0.05% by weight of the total solution).

.i •11 i An example of such a composition and its preparation is provided below.

-119- Component By Weight compound of Example 2B (free base) Ethanol (USP, 200 proof) polyoxyl 35 castor oil (Cremophor® EL) S Oleic acid, 6321, NF Butylated hydroxy toluene (BHT). NF 0.01 "reparation of the above composition: The mixing tank was purged with nitrogen. Oleic acid (499.9 g) and ethanol (100g) were mixed in the tank. The butylated hydroxytoluene (0.1 g) t was charged into the tank and mixed until the solution was clear. The Compound of Example 2B (300 g) was slowly charged into the tank and mixed until the solution was clear. The polyoxyl 35 castor oil (100 g)was added to the tank and mixed. The resulting solution was filled into soft elastic caosules (0.333 g of solution/SEC) to provide a dosage of 100 mg of compound of K, Example 2B/SEC or 0.667 g/SEC to provide a dosage of 200 mg of compound of Example 2B/SEC.

While the compound of the invention can be administered as the sole active pharmaceutical agent, it can also be used in combination with one or more immunomodulators, antiviral agents, other antiinfective agents or z vaccines. Other antiviral agents to be administered in combination with a compound of the present invention include AL-721, beta interferon, polymannoacetate, reverse transcriptase inhibitors for example, dideoxycytidine (ddC; zalcitabine), dideoxyinosine (ddl; didanosine), BCH-189, AzdU, carbovir, ddA, d4C, d4T (stavudine), 3TC (lamivudine) DP-AZT, FLT 2. (fluorothymidine), BCH-189, 5-halo-3'-thia-dideoxycytidine, PMEA, bisi POMPMEA, zidovudine (AZT), nevirapine, delviridine, MSA-300, trovirdine and the like), non-nucleoside reverse transcriptase inhibitors (for example, R82193, L-697.661. BI-RG-587 (nevirapine), retroviral protease inhibitors (for example, HIV protease inhibitors such as ritonavir, Ro 31-8959 (saquinavir), SC-52151, 3o 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)-indanyl)- 2 (R)-phenylmethyl-4(S)-hydroxy-5-(1-(4-(3-pyridylmethyl)-2(S)-N'-(t- -120outylcarboxamido)-piperazlflyl))-pefltaneamide (MK-639: indinavir). amino-4(S)-hydroxy-6-phelyl-2(R)-plelymethyhexaloyl-(L)-Val-(L)-Phemoropholin-4 -ylamidle, 1 -Naphthoxyacetyl-beta-nlethylthio-Ala-(2S.3S)-3-amino- 2-hvdroxy-4-butanoyl-1 ,3-thiazolidine-4-t-butylamide 1 -Naphthoxyacetvi.

S Mta-(2S.3S)-AHPBA-Thz-NH-tBu), soqui no iinoxyacetyl -beta- met hvlt hio-AiLk2.3)-Iain--hydroxy-4-butafloYl-i .3-thiazciidine-4-t-butyiamide iQoa-M',a-APns-Thz- NHtBu) and the like). HEPT compounds. L.697,639, 7282150. U-B7201 E and the like), HIV integrase inhibitors (Zintevir and the like)' TAT inhibitors (for example. RO-24-7429 and the like), trisodium to ;Dhosphonoformate, HPA-23, eflonithine. Peptide T. Reticulose (nucieophosphoproiein). ansamycin LM 427, trimetrexate. UA001. ribavirin', aloPha interferon. oxetanocin, oxetanocin-C-. cylobut-G. cyclobut-A. ara-M.

BW882CB7. floscarnet. BW256U87. BW348U87, L-693.989, 3V ara-U. CMV ,icional antibodies, FlAG, HOE::-602. HPMP', MSL- 109. TI-23, trifluridine, vicarabine, 41amciclovir, penciciovir. acyclovir, ganciclovir. castanospermine.

r-CD4/04-lIG, CD4-PE40, butyl-DNJ. hypericin, oxamyristic acid, dextran sulfate and pentosan polysulfate. Immunomodulators that can be administered in combination with the compound of the present invention include bropirimine, Ampigen. anti-human alpha interferon antibody. colony stimulting factor, ****CL246,738. Imreg-1, lmreg-2, dliethydithiocarbamate, interleukin-2, alpha- :interferon, inosine pranobex. methionile enkephalin, murarnyltripeptide. interferon, interleukin-3, interleukin-4, autologous 008+ infusion, alpha interferon immunoglobulin, IGF-1. anti-Leu-3A, autovaccination, biostimulation, exiracorporeal photophoresis, cyclosporin, rapamycin, FK-565, FK-506, G-CSF, GM-CSF, hyperthermia, isopinosine. IVIG. HIVIG, passive immunotherapy and polio vacci 'ne hype ri mmu nizatio n. Other antiinfective agents that can be *administered in combination with the comp' ound of the present invention include pentamidine isethionate. Any of a variety of HIV or AIDS vaccines (for example, :30 gp12O (recombinant), Env 2-3 (gpl 20), HIVAC-le (gpl 20), gpl6O (recombinant), VaxSyn HIV-1 (gpl6O), Immuno-Ag (gp16O), HGP-30, HIV- Immunogen. p24 (recombinant), VaxSyn HIV-1 (p24) can be used in combination with the compound of the present invention.

-121- Other agents that can be used in combination with the compound of this invention are ansamycin LM 427. apurinic acid, ABPP, AI-72, carrisyn, AS-la,, avarol. azimexon. colchicine. compound 0. CS-85, N-acetyl cysteine. (2oxothiazoiidine-4-carboxvlate). D-penicillamine, diphenyihydantoin. s ervhropoieten, fusidic acid. glucan. HPA-23, human growth hormone, hvoroxchloroouine. iscador. L-ofloxacin or other ouinoione antibiotics. lentinan.

lithium carbonate. MMV-i monolaurin. MTP-PE, naitrexone. neurotroPin. ozone.

PAI. panax ginseng, pentofylline. pentoxifylline, Peotide T. pine cone extract, oolvmannoacetate. reTiculose, retrooen. ribavirin. ribozymes. -S-47 Sdc-28.

silicotunasiate. THA, thymic humorai factor. thymo'entin. thyrosin fraction tnvmosin aloha one, thvmostimulin. UA001, uridine. vitamin E12 and woboem ugos.

Other aoents that can be used in combination with the compound of this invention are antifungais such as amphotericin B. clotrimazoin. flucvtosine.

-fluconazole. itraconazoie. ketoconazole and nystatin and the like.

Other agents that can be used in combination with the compound of this invention are antibacterials such as amikacin sulfate, azithromycin, ciprofloxacin, tosufloxacin. clarithromycin, clofazimine, ethambutol, isoniazid, pyrazinamide. rifabutin. rifampin, streptomycin and TLC G-65 and the like.

-z0 Other aoents that can be used in combination with the compound of this invention are anti-neoplastics such as alpha interferon, COMP (cyclophosphamide, vincristine, methotrexate and prednisone). etoposide, o0.mBACOD (methotrexate. bleomycin, doxorubicin, cyclophosphamide. vincristine and dexamethasone), P RO-MACE/MOPP(prednisone, methotrexate (w/leucovin rescue), doxorubicin. cyclophosphamide, taxol, etoposide/mechiorethamine, vincristine, prednisone and procarbazine), vincristine, vinblastine, angioinhibins. pentosarn polysulfate, platelet factor 4 and SP-PG and the like.

0..Other agents that can be used in combination with the compound of this invention are drugs for treating neurological disease such as peptide T, ritalin, 3,C) lithium, elavil. phenytoin. carbamazipine, mexitetine. heparin and cytosine arabinoside and the like.

Other agents that can be used in combination with the compound of this invention are anti-protozoals such as albendazole. azithromycin. clarithromycin.

clindamycin. corticosteroids. dapsone, DIMP, eflornithine. 566C80, fansidar, -1 22furazolidone. L.671,329. letrazuri!. metronidazole. oparomvcin. Defloxacin, pentamidine. piritrexim. primaquine, pyrimethamine. somatostatin. spiramycin.

sulfadiazine, trimethoprim. TMP/ISMX. trimetrexate and WR 6026 and the like.

Among the Preferred agients for inhibition or treatment of HIV or AIDS in Combination with the compound of this invention are reverse 71rnscriptase ;nnibitors. especially, AZT (zidovudine). ddl (didanosine). ddC (zalcitabine). dJ4s-avudine). 3FC (lam ivudine). neviraoine. delviridine. trovird;ne PMEA. bis- POMPMEA and MSA-300- Other oreferred agents for inhibition or trea*tment of HA/ or AIDS in to ~ccMo i nation with the compound of this invention are HIV protease inhibitors.

esD=-cafy A-538 (riTonavir) ano related compounds, disciosed in U.S. Pateni No. 5.541.206. issued July 30. 1996 and U.S. Patent No. 5.491 .253. issued -:eoruary 13. 1996 which are both incoroorated by reference herein, N-(2(R)-hydroxy- 1 (S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5--( oyrldylmethyl)-2(S)-N'-(t-butvlcarboxamido)-piperazinyl))-pentaneamide ndinavir) and related compounds, disclosed in European Patent Application No. z.P541168, published May 12, 1993, and U.S. Patent No. 5.413.999, issued May 9. 1995 which are both incorporated herein by reference: N-te r!-butyl-decahydro-2-[2(R)- hydroxy-4-phe nyl-3 (S)-[[N-(2-quinolylcarbonyl)- ZC3 L--asoaraginyl]aminolbutyl]-(4aS.8aS)-isoquinoline-3(S)-carboxamide sao~uinavir) and related compounds. disclosed in U.S. Patent No. 5.196.438, issued March 23, 1 993. which is incorporated herein by reference; Sz(S)-Boc-amino-4(S)-hydroxy-6-Phenyl-2(R)-phe nylmethylhexanoyl-(L)- Val-(L) he-morpholin-4-yiamide and related compounds, disclosed in European Patent Application No. EP532466. published March 17, 1993, which is incorporated herein by reference: 1 .3-thiazolidine-4-t-butylamide 1 -Naphthoxyaicetyl-Mta-(2S.3S)-AHPBA- Thz-NH-tBu), 5-isoquinolinoxyacetyl-beta-methylthioAa-(2S.3S)3amino-2 0* 3 hycdroxy-4-butanoyl-1 ,3-thiazolidine-4-t-butylamide i~oa-Mta-Apns-Thz- NHtBu) and related compounds, disclosed in European Patent Application No.

EP490667, published June 17, 1992 and Chem. Pharm. Bull. 40 2251 (1992). which are both incorporated herein by reference; 1 23- Il S-[i 1 ,1 -di met hylIethyI) am ino] carbonyl](2methylpropyl)aminol-2-hydroxy- 1 -(phenylmethyl)propyl]-2-[(2quinolinylcarbonyl)amino]-butaflediamide SC-521 51) and related compounds, disclosed in PCT Patent Application No. W092/08701, publishec," May 29, 1992 and POT Patent Application No. W093/23368, published November 25, 1993, both of which are incorporated herein by reference-,

OH

0 Ph NH I N

S

0 0 4 .4 4*44 4 4

S.

444**4

S

VX-478) and related compounds, disclosed in POT Patent Application No.

W094/05639, published March 17, 1994. which is incorporated herein by reference; 0 HO J- N'OH 41 H O OIHI(i.e. D M P-323) or -124- 0- H2NNH H O O H .e D M P -4 5 0 and related comoounds, disclosed in PICT Patent APplication No. VW093/()' 28 puofIIshed April 15. 1993. which is incorporated herein by reference

OH

N

H

0 /C

N

PhS H AG1343, (nelfinavir)), disclosed in PCT Patent Application No. W095/09843, published April 13. 1995 and U.S. Patent No. 5.484,926. issued January 16, 1996. which are both incorporated herein by reference; OH

OH

E H BocNH NHBoc Ph~ 0 0

N

0ie, M 186.318) disclosed in European Patent Application No. EP580402. published January 1994. which is incorporated herein by reference; -125- 0

H

N

OH

H o 0 0 Dh 1

S

S.

S.

SC-55389a) disclosed at 2nd National Conference on Human Retroviruses and Related Infections. (Washington, Jan. 29 Feb. 2, 1995), Session 88: and

N

S

OHH

Val- NH

N

O O BILA 1096 BS) and related compounds disclosed in European Patent Application No. EP560268, published September 15, 1993, which is incorporated herein by reference; and

OH

Ph O O CF3

HNF

3 S N 0 O U-140690) and related compounds disclosed 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 above.

-126- In a most preferred combination, a compound of this invention is administered in combination with ritonavir. Such a combination is especially useful for inhibitino HIV protease in a human. Such a combination is also especially useful for inhibiting or treating an HIV infection in a human. When Is used in such a combination the compound of this invention and ritonavir can be administered as separate agents at the same or different times or they can be formulated as a single composition comprising both compounds.

When aoministered in combination with a compound of this invention r1tonavir causes an improvement in the pharmacokinetics increases half- 0 life. increases the time to peak plasma concentration, increases blood levels) o: Inhe com ound of this invention.

Preferred dosage forms for ritonavir include a liquid dosage form fo: ora; administration as disclosed in U.S. Patent No. 5,484.801. issued January 19. 1996. which is incorporated herein by reference, an encapsulated solid IS or semi-solid dosage form as disclosed in PCT Patent Application No.

W095/07696, published March 23, 1995 and U.S. Serial No. 08/402.690, filed March 13. 1995. both of which are incorporated herein by reference and an encapsulated solid dosage form as disclosed in PCT Patent Application No.

W095/09614. published April 13. 1995 and U.S. Patent No. 5.559.158. issued September 24. 1996, both of which are incorporated herein by reference Other examples of preferred dosage forms for ritonavir are disclosed in U.S. Patent Application No. 08/. filed November 21. 1996. in the names of J. Lipari. L.A. AI-Razzak, S. Ghosh and R. Gao and which is entitled Pharmaceutical Composition. which is incorporated herein by reference.

A preferred composition for ritonavir comprises a solution of 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 polyoxyl 35 castor oii in the amount of from about 0% to about 20% (preferably, from about 5% to about by weight of the total solution, in a pharmaceutically acceptable organic 3o solvent which comprises oleic acid in the amount of from about 15% to about 99% (preferably, from about 30% to about 70%; more preferably, from about 40% to about 65%) by weight of the total solution or (ii) a mixture of (1) oieic acid in the amount of from about 15% to about 99% (preferably. from -127about 30% to about more preferably, from about 40% to about 65%) by weight of the total solution and 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 an even more preferred embodiment of the S- invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) oi a hard gelatin capsule and the solution also comprises an antioxidant (preferabiy. BHT (butylated hydroxytoluene)) in the amount of from about 0.01% to about 0.08% by weight of the total solution (preferably. from about 0.01% to about 0.05% by weight of the totai solution).

to Examples of such a composition and its preparation are provided below Component By Weight ritonavir (free base) Ethanol (USP. 200 proof) polyoxyl 35 castor oil (Cremophor® EL) Oleic acid. 6321, NF Butylated hydroxy toluene (BHT), NF 0.01 Preparation of the above composition: The mixing tank was purged with nitrogen. Oleic acid (649.9 g) and ethanol (100g) were mixed in the tank. This solution was warmed to about 33°C (29-370C) and maintained at that temperature. The butylated hydroxytoluene iS (0.1 g) was charged into the tank and mixed until the solution was clear. The ritonavir (200 g) was slowly charged into the tank and mixed until the solution o o was clear. The polyoxyl 35 castor oil (50 g) was added to the tank and mixed.

Heating was discontinued and the solution allowed to cool to amibient temperature (20-30°C). The resulting solution was filled into soft elastic i z capsules (0.5 g of solution/SEC) to provide a dosage of 100 mg of ritonavir/SEC or 1.0 g/SEC to provide a dosage of 200 mg of ritonavir/SEC.

-128- Componen By Weight ritonavir (free base) Ethanol (USP. 200 proof) polyoxyl 35 castor oil (Cremophor' EL) Oleic acid. 6321, NF Butylated hycroxy toluene (BHT). NF 0.01 Preparatior c tine above composition: The mixing tank was purged with nitrogen. Oleic acid (599.9 g) and ethanol (10c)I were mixed in the tank. This solution was warmed to about 33"( (29-37C) ar.c maintained at that temperature. The outylated hydroxvroluene S (0.1 g) was cnarged into the tank and mixed until the solution was clear. The ntonavir (200 g) was slowly charged into the tank and mixed until the solution was clear. Tne poiyoxyl 35 castor oil (100 g)was added to the tank and mixed.

Heating was Discontinued and the solution allowed to cool to amibient temperature (20-300C). The resulting solution was filled into soft elastic co capsules (0.5 g of solution/SEC) to provide a dosage of 100 mg of ritonavir/SEC or 1.0 g/SEC to provide a dosage of 200 mg of ritonavir/SEC.

Examoles of preferred single dosage forms comprising both ritonavir and a compouno of the formula I are also disclosed in U.S. Patent Application No.

08/ .filed November 21, 1996, in the names of J. Lipari, L.A. Al- I1 Razzak. S. Ghosh and R. Gao and which is entitled Pharmaceutical Composition. which is incorporated herein by reference.

A preferred composition for a single dosage form comprising both ritonavir and a compound of the formula I comprises a solution of S. a mixture of ritonavir in the amount of from about 1% to about '0 (preferably. from about 5% to about 25%) by weight of the total solution and a compound oi :he formula I in the amount of from about 1% to about (preferably, from about 5% to about 40%) by weight of the total solution and (b) poiyoxyl 35 castor oil in the amount of about 10% by weight of the total solution, in a pharmaceutically acceptable organic solvent which comprises a mixture of -129oleic acid in the amount of from about 10% to about 88% (preferably frorn aoout 40% to about 65%) by weight of the total solution and ethanol in the amount of about 10% by weight of the total solution. In a most preferred embodiment of the invention, the solution is encapsulated in a soft elastic c gelatin capsule (SEC) or a hard gelatin capsule and the solution also comprises an antioxidant (preferably, BHT (butylated hydroxytoluene)) in the amount of from about 0.01% to about 0.08% by weight of the total solution (preferably, froabout 0.01% to about 0.05% by weight of the total solution).

Examoles of such a composition and its preparation are provided belov., tO Component ritonavir (free base) compound of Example 2B (free base) Ethanol (USP, 200 proof) polyoxyl 35 castor oil (Cremophor®

EL)

1 5 Oleic acid. 6321, NF Butylated hydroxy toluene (BHT), NF Component ritonavir (free base) compound Example 2B (free base) o t Ethanol (USP, 200 proof) polyoxyl 35 castor oil (Cremophor®

EL)

Oleic acid. 6321, NF Butylated hydroxy toluene (BHT), NF Component 2 ritonavir (free base) compound Example 2B (free base) Ethanol (USP. 200 proof) polyoxyl 35 castor oil (Cremophor®

EL)

Oleic acid. 6321, NF J3 Butylated hydroxy toluene (BHT), NF Byv Weight 0.01 By Weight 0.01 By Weiogh 0.01

S*

S

-130- Preparation of the above composition: The mixing tank was purged with nitrogen. Oleic acid (549.9 g) and ethanol (100g) were mixed in the tank. The butylated hydroxytoluene (0.1 g) was charged into the tank and mixed until the solution was clear. The ritonavir (150 g) was slowly charged into the tank and mixed until the solution was clear.

Compound Example 2B (150 g) was slowly charged into the tank and mixed until the solution was clear. The polyoxyl 35 castor oil (100 g) was added to the tank and mixed. The resulting solution was filled into soft elastic capsules (1.0 c of solution/SEC) to provide a dosage of 150 mg each of rironavir and compound foC Example 2B!SEC.

Component By Weight ritonavir (free base) compound Example 2B (free base) Ethanol (USP, 200 proof) polyoxyl 35 castor oil (Cremophor® EL) Oleic acid, 6321, NF Butylated hydroxy toluene (BHT). NF 0.01 9* 9O 9 S..Total daily dose of ritonavir (administered in combination with a compound of this invention) to be administered to a human or other mammal host in single or divided doses may be in amounts, for example, from 0.001 to 300 mg/kg body weight daily and more usually 0.1 to 10 mg of ritonavir.

Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose.

In the compositions which comprise a mixture of ritonavir and the compound of Example 2B, the ratio of ritonavir to the compound of Example 2B ranges from about 1:16 to about 5:1 (preferably. from about 1:6 to about 3:1).

0ll l -131- In another most 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 S(stavudine) and 3TC (lamivudine)). Such a combination is especially useful fo; inhibiting or treating an HIV infection in a human. When used in such a combination the compound of this invention and ritonavir and one or more reverse transcriptase inhibitors can be administered as separate agents at the same or different times or they can be formulated as compositions comprising (o two or more of the compounds. A particularly preferred therapeutic combination comprises a compound of the formula I (especially, the compound of Example 23' in combination with ritonavir. AZT and 3TC.

it will be understood that 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 include in principle any agents 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 20 different times, or the therapeutic agents can be given as a single composition.

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

oe

Claims (266)

1. 2. A compDound accordina to Claim I wherein R, and R 2 are arylalkyl, R., is loweralkyl, R 4 is aryl, R 5 is x y a (CH 2 )J N Y (CH2)m b) x d (CH2)m nr 136 X e) N e) .N N R6 wherein X, Y, Z, R6-, n, m and m' are defined as therein and L, is -O-alkylenyl.
2. 3. A compound according to claim 1 wherein R, and R 2 are benzyl or R, is benzyl and R 2 is loweralkyl, R 3 is loweralkyl, R 4 is phenyl which is substituted with two loweralkyl groups and which is optionally substituted with a third substituent selected from the group consisting of loweralkyl, hydroxy, amino and halo or pyridyl or pyrimidinyl either of which is substituted with two loweralkyl groups and which is optionally .o 00 0 0 o* o0 0 o0 0 o *0 0 0 0 o0 0 0 0 0 i R:\LIBC\03817.doc -138- x N-(IN 6 e)N wherein X is 0 and R 6 is hydrogen and is -0-C H 2
3. 4. A comp)ound according to Claim 1 wherein R 1 and are benzvl or R, s oenzvi and R 9 is isopropyl. is loweralkyl, R. is 2.6-dimethylphenvl which is co' tionallv substituted with a third substituen, seiected from the group consisting of !oweralkyl and halo, R. is x a) (C 2 )-J .*wherein n is 1 or 2, X is 0 or S and Y is -CH 2 or -NH-, N 0 o x C' (C(CH2)m -140-
4. 6. A compound selected from the aroup consisting of: (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-[2S-(i- tet rahydro -pyri m id-2 -ony1) -3-m ethyl butanoyl] amino-i .6-diphenyihexane- (2S, 3S,5S)-2- Dimet hylphe noxvacetyl) ami no-3- hydroxy- 5- (2S- (1 midazolidin-2-onyl)-3,3-dimethyI butanoyl)amino-1 .6-diphenyihexane;, (2S.3 S (2,6-dimethyiphenoxyacetyl)amino-3-hydroxy-5-(2S- (1 imidazoiidin-2-thionyl)-3-methyI butanoyi)amino-1,6-diphenvihexane:. (,2S.3S,5S),-2-(2.4,6-trimethyiphenoxyacetyl) amino-3-hydroxv-5-(2S-(1 midazolidin-2-onyl)-3-methyibutanov) amino-i 16-diphenyihexane: (2S.3S.5S3)-2-(4-fiuoro-2.6-dimethylphenoxyacel) amino-3-hvdroxv-5-(2S-( I. midazoiidin-2-onyl)-3-methyl-buianoyl) amino- 1,6-diphenyihexane: (.2S.3S.5S)-2-(2.6-dimethylphenoxyacetyl) amino-3-hvdroxy-5-(2S-(,I- pyrrolidin-2-onyl)-3-methyl-butLanoyl) amino-i .6-diohenvihexane: ('2S.3S.5S'!-2-(2.6-dimethylphenoxyacetyl) amino-3-hydroxv-5-(2S-( 1- pyrrohldin-2-'.5-dionyl)-3-methyi-butanoyl) amino-i ,6-diphenylhexane: (2S-.3S.5S)-2-(trans-3-(2,6-dimethylochenyl) propenoyl) amino-3-hydroxy-5-(2s- 1 -tetrahydropyrimidin-2-onyl)-3-methyl-butanoyl) amino-i ,6-diphenylhexane:- (2S.3-S.5S)-2-(3-(2,6-dimethytphenyl) propanoyl) amino-3-hydroxy-5-(2S-(1 tLet rahydro pyri midi n- 2-onyl)-3- met hyl-butanoyl) amino- 1,6-diphe nylhexane: (2S,3-S,5S)-2-(2,6-Dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(i tetrahydro-pyrimi-2,4-dionyl)-3-methylbutanoyiamino-1,6-diphenylhexane:- tetrahydro-pyrimid-2-onyl)-3-n-ethyl-butanoyl)amino- 1 6-diphenylhexane: (2S,3S.5S)-2-(2,6-Dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(i tetrahydro-pyrimid-2-onyl)-3-methylbutanoyl)amino-1 -phenyl-6-methylheptane; (2S,3-S,5S)-2-(2,6-Dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(i tetrahydro-pyrimid-2.4-dionyl)-3-methylbutanoyl)amino-i -phenyl-6- methyiheptane: and (2S,3S,5S)-2-(2.6-Dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S-(4-aza-4.5-- *dehydro-i1 -Pyri mid -2-onyl)- 3-methyl-butan oyl)amino-i 1.6-diphe n ylhexane: or a Pharmaceutically acceptable salt, ester or prodrug thereof. -141-
5. 7. The compound (2S, 3S, 5S)-2-(2.6-dimethylphenoxyacetyl) 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.
6. 8. A pharmaceutical composition for inhibiting HIV protease comprising a pharmaceutical carrier and a therapeutically effective amount of the compound of Claim 1.
7. 9. A pharmaceutical composition for inhibiting HIV protease comprising a pharmaceutical carrier and a therapeutically effective amount of the compound of Claim 7. A method for inhibiting HIV protease comprising administering to a human in need of such treatment a therapeuctially effective amount of the compound of Claim 1.
8. 11. A method for inhibiting inhibiting HIV protease comprising administering to a human in need of such treatment a therapeuctially effective amount of the compound of Claim 7.
9. 12. A method for inhibiting an HIV infection comprising administering to a human in need of such treatment a therapeuctially effective amount of the compound of Claim 1.
10. 13. A method for inhibiting an HIV infection comprising administering to a human in need of such treatment a therapeuctially effective amount of the compound of Claim 7.
11. 14. 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 a -142- reverse transcriotase inhibitor or a combination of reverse transcriptase inhibitors. The method of Claim 14 wherein the reverse transcriptase inhibitor i selected from the group consisting of AZT (zidovudine), ddl (didanosine), ddC (zaicitabine), d4T (stavudine), 3TC (lamivudine), nevirapine. delviridine, trovirdine. PMEA, bis-POMPMEA and MSA-300 or a combination thereof.
12. 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 Ciaim 7 in combination with a therapeutically effective amount of a reverse transcriptase inhibitor or a combination of reverse transcriptase inhibitors.
13. 17. The method of Claim 16 wherein the reverse transcriptase inhibitor is selected from the group consisting of AZT (zidovudine), dd! (didanosine). ddC (zalcitabine), d4T (stavudine), 3TC (lamivudine), nevirapine, delviridine, trovirdine, PMEA. bis-POMPMEA and MSA-300.
14. 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.
15. 19. The method of 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-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-thiazolidine-4-t-butylamide; 5-isoquinolinoxyacetyl-beta-methylthio-Ala-(2S,3S)-3-amino-2-hydroxy-4- butanoyl-1.3-thiazolidine-4-t-butylamide; -143- (1 S-(1 R-(R-)2S)-Nl -dimethylethiyl)amino)carbony)(2- met hylpropyl) am ino)-2-hydroxy-1 -(ph enylmethyl)propy1) qui noIi nylIca rbonyI) am ino)-butanediamide; OH NH 2 H 0 N s~ 0 0 0 0 P HO OH N N/ H2 NH* HO OH see* oboe H 2 N NH 2 -144- H, OH HO N 0- 0 N PhS H OH OH E H BocNH,,A,,.,N NHBoc Ph~ 0 N 0 I- 0 0 OH H H H N N< H- OHH and -145- Ph 0 ,-CF 3 S N 0 0 or a pharmaceutically acceptable salt thereof, or a combination Of two or more ot these HIV protease inhibitors. 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 o-; another HIV protease inhibitor or a combination of HIV protease inhibitors.
16. 21. The method of Claim 20 wherein the other HIV protease inhibitor is selected from the group consisting of ritonavir, saquinavir, indinavir, .Phe-morpholin-4-ylamide; 1-Naphthoxyacetyl-beta-methylthio-Ala-(2S,3S)-3-amino2hydroxy-4butanoyl- A: 0 ,3-th iaz oIid in e-4-t- buty lam ide; 5-isoquinolinoxyacety-beta-methylthio-Ala.(2S .3S)-3-amino-2-hydroxy-4- buta no ylI-1 .3-t h iazoIi d in butyIam id e; (1 S(1 R 2S*) -Nl1 ,1 -di methylethyl)amni no)carbon yl) (2- met hylpropyl)ami no)-2- hydroxy- 1 -(phenylmethyl)propyl)-2-((2- qunlnlcroy mio-uandaie -146- OH NH 2 0 ON ~N NI 0 0 0 9*9* 9* .9 9. 9 9. 9 9.*9 S 9 9*9* 999 9999** 9 S 6@ 9 90 *0 09 9 990995 9 NH 2 OH Nr ,H~N 0' -147- OH E H BocNH N Ph H NN H NHBoc 0' N 0 OH HH Ph C C C. C C C. C C C C C CC.. C *CC* C C C. C C C CC C S CCC.. C N S H ICF 3 and HN -148- w or a pharmaceutically acceptable salt thereof, or a combination of two or moij :f these HIV protease inhibitors.
17. 22. A method for inhibiting an HIV infection comprising administering io ;A human in need of such treatment a therapeutically effective amount of the compound of Claim 7 in combination with a therapeutically effective amount oi ritonavir or a pharmaceutically acceptable salt thereof.
18. 23. An HIV protease inhibiting compound comprising a substilueni of ii formula: R3 -c Rs 0 wherein R 3 is loweralkyl, hydroxyalkyl or cycloalkylalkyl; and R 5 is x K Y a) (C(H H2 SN Y *-(CH2)m x -149- y kc) z x K /Y d) (CH 2 m x Y e) (CH2)m 9 x 9N 9*90 99 NN R o 6 9 OH o -150- 0 ~N R iHO wherein n is 1, 2 or 3, m is 1, 2 or3, m'is 1 or 2, X is0. S or NH, Y is -CH 2 or -N(R 6 wherein R. is hydrogen. loweralkyi, cycloalkyl, cycloalkylalkyl. aryl or arylalkyl, Y' is -CH 2 or -N(R 6 wherein R 6 is hydrogen. loweralkyl, cycioalkyl, cycloalkylalkyi, aryl or arylalkyf, Y' is -N(R 6 wherein R 6 is hydrogen, loweralkyl, cycloalkyl. cycloalkylalkyl. aryl or arylalkyl, and Z is 0, S or NH.
19. 24. A compound according to Claim 23 wherein R 3 is loweralkyl andR. is 00SN Y a) N Y (CH2)m -151- x C) (CH)M' Z x N Y ZNy, d) (CH2)m or x N 6 e)N *0wherein X, Y, Z, R 6 n, m and m' are defined as therein. 0
20. 25. A compound according to Claim 23 wherein R 3 is loweralkyl and R is x a a) wherein n is 1 or 2, X is 0 or S and Y is -OH 2 or -NH-, -152- w x N Y (CH2)M wherein m is 1 or 2, X is 0. Y is -OH 2 and Z is 0, x N Y C) (CH2)m' Z wherein m'is 1, X is 0. Z is 0 and Y is -NH-. x (H6 wherein m'is 1. X is 0, Y' is -NH- and Yis -NH- or e) N wherein X is 0 and R 6 is hydrogen. 011 -153-
21. 26. A compound according to Claim 23 wherein R 3 ii.; isopropyl .n-d Rl is x y a) (CH 2 )n-J wherein n is 1 or 2, X is 0 or S and Y is -CH 2 or -NH-. x N y (CH 2 )m b) Z wherein mis 1 or 2, XisO0, Y is -CH 2 and ZisO0 x y (CH26m wherein m'is 1, X is 0, Z isO0 and Y is NH-, x N *K, d) (CH2)m wherein m'is 1, X is 0, Y" is -NH- and Yis -NH- or -154- IN (N RV e)N wherein X is 0 and R 6 is hydrogen.
22. 27. A compound according to Claim 23 wherein R, is iSopropyl;3ii ;3nd is x a) (C H2)n wherein n is 1 or 2. X is 0 or S and Y is -CH 2 or -NH-. x b) (CHm 61 wherein m is 1, X is 0, Z is 0 and Y is -NH-, x d) N -155- wherein X is 0 and R 6 11 is hydrogen.
23. 28. A compound according to Claim 23 wherein R 3 is isopropyl and R 5 is x (CH 2 )J wherein n is 1 or 2. X is 0 or S and Y is -CH 2 or -NI-V-
24. 29. A compound according to Claim 23 selected from the group consisting of: cis-N-tert-butyl-decahydro-2( 2(R)-hydroxy-4-phenyf-3(S)(25(1 tetrahydropyrimid-2onyl)3methylbutanoyl)aminobutyl)( 4 aS8aS)- isoquinoline-3(S)-carboxamide; cis-N.-tert-butyl-decahydro.2-( 2(R)-hydroxy-4.thlophenyli3(S)-(2S-(1. tetrahydropyri mid- 2 -onyl)-3-methylbutanoyl)aminobutyl)>(4aS .8aS)- isoquinoline-3(S)-carboxarnide; and 4-Amino-N-(( 2syn, 3S)-2-hydroxy-4-phenyl-3-(2S-( 1 -tetrahydropyrimid-2- onyl)- 3 -methylbutanoylamino)-butyl)>N-isobutyl-benzenesulfonamide or pharmaceutically acceptable salts thereof
25. 30. A compound of the formula: *HO-C R 0 wherein R 3 is loweralkyl. hydroxyalkyl or cycloalkylalkyl: and R is -156- w x ky (CH 2 )J a) x (CH2)m z x Z x N N Y -I, d) (CH 2 6m'Z 157 x N (CH 2 )M' x N "k N-R 6 g) 0 N "k N-R 6 h) or N N-R 6 0.00.HO 0 60 05 i) wherein n is 1, 2 or 3, m is 1, 2 or 3, mi' is 1 or 2, X is 0, S or NH, Y is -CL- 2 or 00.* -N(R 6 wherein R 6 is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl, or :arylalkyl, Y" is -CH 2 or 6 wherein R 6 is hydrogen, loweralkyl, cycloalkyl, *:000:cycloalkylalkyl, aryl or arylalkyl, Y' is -N(R 6 wherein R 6 is hydrogen, loweralkyl, I( cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, and Z is 0, S or NH; or a salt or an activated ester derivative thereof; with the proviso that 1) when R 3 is hydroxy-C, to -C 6 alkyl, then R 5 is other than [R:\LIBZZ]03498.doc:mff 1 57a (CH )n wherein n is 1, 2or 3; and 2) when R 3 is C 1-tO-C 6 -alkyl, then R 5 is other than 0 N [R:\LIBZZ]03498.doc:mff -158-
26. 31. A compound according to Claim 30 wherein R 3 is loweralkyl iand Rr, is x a) (CH2) x N y (CH 2 )M b) Z x (CH2) m'Z x 0.y.6 d) (CH2)m' o r Z*.N N -RV. e)N 159 wherein X, Y, Z, RV., n, mn and in' are defined as above.
27. 32. A compound according to claim 30 wherein R 3 is loweralkyl and R 5 is x Nk (CH 2 )nj a) wherein n is I or 2, X is 0 or S and Y is -CH 2 or -NH-, x N (CH 2 )M z b) wherein m is 2, X is 0, Y is -CH 2 and Z is 0, x N Y" 9* 1* (CH 2 m d *wherein m' is 1, X is 0, Y" is 0N andY is -NH- o [R:\LIBZZ]03498.doc:mrr 160 x N N-R 6 e) wherein X is 0 and R 6 is hydrogen. 3. A compound according to claim 30 wherein R 3 is isopropyl and R 5 is x N\ Y (CH 2 )n a) wherein n is 1 or 2, X is 0 or S and Y is -CH 2 or-NH-, x N x (CH 2 )M z b) Io wherein m is 2, X is 0, Y is -CH- 2 and Z is 0, x N Y N Y. (CH 2 )m *1 [R:\LIBZZ]03498.doc:mrr 4 -161- wherein m' is 1. X is O. Y" is -NH- and Y' is -NH- or X N N Re6 e) wherein X is O and R 6 is hydrogen.
28. 34. A compound according to Claim 30 wherein R 3 is isopropyl and is X N Y a) (CH2)n wherein n is 1 or 2, X is O or S and Y is -CH 2 or -NH-, N b) (CH2) Z wherein m' is 1, X is O, Z is 0 and Y is -NH-, *x Y* L I c) (CH2)m' wherein m' is 1, X is O, Y" is -NH- and Y' is -NH- or -162- x d) N wherein X is 0 and R6, is hydrogen. A compound according to Claim 30 wherein R3 is isopropyi and Rr is X N y (CH2)n-/ wherein n is 1 or 2. X is O or S and Y is -CH 2 or -NH-.
29. 36. The compound according to Claim 30 which is 2S-(1-Tetrahydro- pyrimid-2-onyl)-3-methyl butanoic acid or a salt or an activated ester derivative thereof.
30. 37. A compound of the formula: R R 3 P 3 N R P 4 OH R 2 O wherein P 3 and P 4 are independently selected from hydrogen or an N-protecting group; R 1 and R 2 are independently selected from the group consisting of loweralkyi, cycloalkylalkyl and arylalkyl; R3 is loweralkyl, hydroxyalkyl or cycloalkylalkyl; and R 5 is 0 -163- x a) (CH 2 )J x Y (CH2)m b) x Y c)z N x (CH 2 )m -164- \A. f) (CH2)m' x g)N 0 N N -R 6 h) OH or 0 I) HO wherein nis1, 2 or3, m is 1, 2or 3, mis 1 or 2, X is0, S orNH, Yis -CH 2 or -N(R 6 wherein R 6 is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, Y" is -OH 2 or -N(R 6 wherein is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, Y' is -N(R 6 wherein R 6 is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, and Z is 0, S or NH; or a salt thereof. -165-
31. 38. A compound according to Claim 37 wherein P 3 and P 4 are hydrogen or, benzyl, R, and R 2 are arytalkyl, R 3 is loweralkyI and x N ky J a) (CH 2 )nJ x (CH2)m b) Z x /Y d (CH2)m o x N -166- wherein X, Y, Z, R 6 n, mn and m are defined as therein,
32. 39. A compound according to Claim 37 wherein P 3 and P4 are hydrogen or benzyl, R 1 and R 2 are benzyl or R, is benzyl and R 2 is loweralkvl. R 3 is oweralkyl and R 5 is x a (CH 2 )nJ wherein n is 1 or 2. X is 0 or S and Y is or -NH-. x N y (CH 2 )m b) wherein m is 1 or 2. X is 0, Y is -OH- and Z isO0, x y H z c) (CH26m wherein mis 1, X is 0, Z is 0 and Y is -NH-, x KY, d) (CH 2 )m' wherein m'is 1. X is 0, Y" is -NH- and Y is -NH- or -167- x e) wherein X is 0 and R 6 is hydrogen. A compound according to Claim 37 wherein P 3 and P 4 are hydroqgenr or benzyl, R, and R 2 are benzyl or R, is benzyl and R 2 is isopropyl, R 3 is loweralkyl and R 5 is x Ay a) (CH 2 )nJ wherein n is 1 or 2, X is 0 or S and Y is -CH 2 or -NH-, x (CH2)m b) Z wherein m is 1 or 2, X is 0, Y is -CH 2 and Z is 0. x c) (CH 2 )m .:wherein m' isi1, X is 0, Z isO0 and Y is -NH-, -168- x N N-R wherein i1 X is 0 .Yis-H and R 6 .is hydrogen x (CH 2)n J wherein ni 2 X is 0 o and R6Y is -OHdroo-NH. x N V (CH 2 )vZ a) wherein m is 1 o X is 0 or iS0 and Y is -o -NH-, N H z -169- x C) (C H26m wherein m is 1, X is 0, Y 'is -NH- and Y is -NH- or x d) -N wherein X is 0 and R 6 is hydrogen.
33. 42. A compound according to Claim 37 wherein P 3 and P 4 are ~Iydrogeri or benzyl, R, and R 2 are benzyi or R, is benzyl and R 2 is isopropyl, R 3 is loweralkyl and R 5 is y (CH 2 )nJ wherein n is 1 or 2, X is 0 or S and Y is O-H 2 or -NH-.
34. 43. A compound according to Claim 37 selected from the group consisting of: (2S, 3S, 5S)-2-NN-dibenzylamino-3-hydroxy-5-(25..(1-tetrahydro-pyrimid-2- onyl)-3-methyl butanoyl) amino-i 16-diphenyihexane; andI (2S. 3S, 5S)-2-Amino-3-hydroxy-5-(2S-(1 -tetrahydro-pyrimid-2-onyl)-3.rnethyl butanoyl) amino-i ,6-diphenylhexane; :or a salt thereof.
35. 44. The compound according to Claim 43 which is (2S, 3S, 5S)-2- Amino-3-hydroxy-5-(2S-(1 -tetrahydro-pyrimid-2-onyl)3methyI butanoyl) amino-i .6-diphenyihexane (S)-Pyroglutamic acid salt. -170- A process for the preparation of a compound of the formula: HN N CO 2 H 0 R 3 or a salt or ester thereof, wherein R 3 is loweralkyl. hydroxyalkyl or cycloalkylalkyi, comprising reacting a compound of the formula: H H Q N N. CO 2 H 0 R 3 or a salt or ester thereof, wherein R 3 is as defined above and Q is a leaving group with a base; or reacting a compound of the formula: o NH 2 HN CO 2 H R or a salt or ester thereof, wherein R 3 is as defined above with a carbonyl equivalent; or hydrogenating a compound of the formula: R3 -171- wherein R 3 is as defined above and R 3 0 is loweralkyl, phenyl or haloalkyl.
36. 46. The process of Claim 45 wherein R 3 is loweralkyl.
37. 47. The process of Claim 45 wherein R 3 is isopropyl and Q is chloro.
38. 48. The process of Claim 45 wherein R 3 is loweralkyl and the carbonyl equivalent is wherein 0' and 0" are CI. Br, I. -O-loweralkyi. -O-aryl no imidazolyl.
39. 49. The process of Claim 48 wherein R 3 is isopropyl. The process of Claim 45 wherein R 3 is loweralkyl and R 30 is loweralkyl,
40. 51. The process of Claim 50 wherein R3 is isopropyl and R 30 is methyl.
41. 52. A process for the preparation of a compound of Claim 1 comprising reacting a compound of the formula: S R1 R3 .N H 2 N OH R 2 0 wherein R 1 R 2 R 3 and R 5 are as defined therein with a compound of the formula: R4 Li OH or a salt or activated ester derivative thereof, wherein R4 and L, are as defined therein. -172-
42. 53. A process for the preparation of (2S, 3S, 5S)-2-(2,6- dimethylphenoxyacetyl) 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, comprising reacting (2S, 3S, 5S)-2-amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl) methyl butanoyl) amino-1,6-diphenylhexane with 2 ,6-dimethylphenoxyacetic acid. or a salt of activated ester derivative thereof.
43. 54. The process according to Claim 53 wherein (2S, 3S, 5S)-2-amino.3- hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl) amino-1,6- diphenylhexane is reacted with 2.6-dimethylphenoxyacetyl chloride. A process for the preparation of a compound of Claim i comprisino reacting a compound of the formula: Ri P3" NH 2 Y" P4 OH R 2 ooft wherein P 3 is hydrogen and P 4 is an N-protecting group or both P 3 and P 4 are N-protecting groups and R 1 and R 2 are as defined therein with a compound of the formula: *o R 3 HO R O or a salt or activated ester derivative thereof, wherein R 3 and R 5 are as defined therein, to provide a compound of the formula: R1 R3 H P 3 N P 4 OH R 2 O -173- wherein P 3 P 4 R 1 R 2 R 3 and R 5 are as defined above; N-deprotecting the product of step to provide a compound of the for'mula. R1 R 3 H N H 2 N R, OH R 2 0 wherein R 1 R 2 R 3 and R 5 are as defined above; and reacting the product of step with a compound of the formula: 0 R41_I L OH or a salt or activated ester derivative thereof, wherein R 4 and L, are as defined therein.
44. 56. A process for the preparation of (2S, 3S, 5S)-2-(2,6- Sdimethylphenoxyacetyl) amino-3-hydroxy-5-(2%( 1 -tetra hyd ro-pyrim id2-on yl)- 3-methyl butanoyl) amino-i ,6-diphe nylhexane; or a pharmaceutically acceptable salt, ester or prodrug thereof, comprising reacting (2S, 3S, 5S)- 2 -N,N-dibenzylamino3hydroxy-5amino-1 ,6- diphenylhexane with 2S-(1 -tetrahydro-pyrimi-2-onyly3-methyl butanoic anid or a salt or activated ester derivative thereof to provide (2S, 3S, 5S)-2-N,N- dibenzylamino-3-hydroxy5(2S-(1 -tetrahydro-pyrimid-2-onyl).3-methyI butanoyl) amino- 1,6-diphenylhexane; debenzylating the product of step to provide (2S, 3S. 5S)-2-amino-3- hydroxy-5-(2S-(i -tetrahydro-pyrimid-2-onyl>3-methyI butanoyl) amino-i 6- diphenylhexane; and reacting the product of step with 2 6 -dimethylphenoxyacetic acid, or a salt of activated ester derivative thereof.
45. 57. The process according to Claim 56 wherein -174- (2S, 3S, 5S)-2-N,N-dibenzylamino-3-hydroxy-5-amino-i 6 -diphenylhexaiw'- is reacted with 2S-(1 -tetrahydro-pyrimid-2-onyl)-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; the product of step is hydrogenated to provide (2S, 3S. 5S)-2-amino-3- hydroxy-5-(2S-(1 -tetrahydro-pyrimid-2-onyl)-3-methy butanoyl) amino-i .6- diphenyihexane; and the product of step is reacted with 2,6-dimethyiphenoxyacetyl chloride.
46. 58. A process for the preparation of (2S, 3S, 5S) Dimethyiphenoxyacetyl) amino-3-hydroxy-5-amino-i 6-diphenylhexane or a salt thereof, comprising reacting (2S, 3S, 5S) 2 -(2,6-Dimethylphenoxyacelyi) amino-3-hydroxy-5-t-butyloxycarbonylamino-.1,6-diphenylhexane with trifiuoroacetic acid in methylene chloride, aqueous hydrochloric acid in acetonitrile or aqueous hydrochloric acid in acetic acid.
47. 59. A process for the preparation of a compound of the formula: H H N N C0 2 H 0 R3 or a salt or ester thereof, wherein R 3 is loweralkyl, hydroxyalkyl or cycloalkylalkyl and Q is a leaving group, comprising reacting a compound of the formula: H 2 N C0 2 H 0 or a salt or ester thereof, wherein R 3 is as defined above with a compound of the formula: 0=C=N Q
48. 175- wherein Q is as defined above; or reacting a compound of the formula: R"O-(O)C-HN CO 2 H R3 or a salt or ester thereof, wherein R3 is as defined above and R" is phenyl, loweralkyl-substituted phenyl, halo-substituted phenyl, nitro-substituted phenyl or trifluoromethylphenyl with a compound of the formula: H 2 N Q wherein 0 is as defined above. The process of Claim 59 wherein R 3 is loweralkyl and Q is chloro. 61. The process of Claim 59 wherein R 3 is isopropyl and 0 is chloro. 62. A process for the preparation of (2S, 3S, 5S)-2-(2,6- Dimethylphenoxyacetyl) 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-Dimethylphenoxyacetyl) amino-3-hydroxy-5-(2S- (1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl) amino-i ,6-diphenylhexane in an organic solvent followed by adding the solution to water. 63. The process according to Claim 62 wherein (2S, 3S, 5S)-2-(2,6- Dimethylphenoxyacetyl) 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 about 100 mL/g). 64. An HIV protease inhibiting compound, substantially as hereinbefore described with reference to any one of the Examples. A process for the preparation of a retroviral protease inhibiting 1, 4 -diamino-3- hydroxybutane derivative, substantially as hereinbefore described with reference to any one of the Examples. 66. A 1,4-diamino-3-hydroxybutane derivative when prepared by the process of claim 67. A process for the preparation of (2S, 3S, 5S)- 2 -(2,6-dimethylphenoxyacetyl) 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, substantially as hereinbefore described with reference to any one of Examples 2, 24, 38 or 39. 68. The compound (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy- 5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl) amino- 1,6-diphenylhexane. 69. A pharmaceutical composition for inhibiting HIV protease comprising a pharmaceutical carrier and a therapeutically effective amount of the compound of claim 68. 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 68. 71. 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 68. 72. 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 68 in combination with a therapeutically effective amount of a reverse transcriptase inhibitor or a combination of reverse transcriptase inhibitors. 73. The method of claim 72 wherein the reverse transcriptase inhibitor is selected from the group consisting of AZT (zidovudine), ddl (didanosine), ddC (zalcitabine), d4T (stavudine), 3TC (lamivudine), nevirapine, delaviridine, trovirdine, PMEA, bis- POMPMEA and MSA-300. 74. The method of claim 72 wherein the reverse transcriptase inhibitor is selected from the group consisting of AZT (zidovudine), ddl (didanosine), ddC (zalcitabine), d4T (stavudine), 3TC (lamivudine), nevirapine and delaviridine. 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 68 in combination with a therapeutically effective amount of another HIV protease inhibitor or a combination of HIV protease inhibitors. 76. The method of claim 75 wherein the other HIV protease inhibitor is selected from the group consisting of ritonavir, saquinavir, indinavir, [I:\DAYLIB\LIBC]03817.doc:SAK 1 77 (S)-Boc-amino-4(S)-hydroxy-6-pheny-2(R)-phenylmeffiylhexanoyl1(L)-.Val.(L)-Phe- morpholin-4-ylamide; 1 -Naphthoxyacetyl-beta-m'ethylthio-Ala-(2S 3S)-3 -amino-2-hydroxy-4-butanoy[- 1, 3- thiazolidine-4-t-butylamide; 5-isoquinolinoxyacetyl-beta-methylthioAla-(2S 3S)-3-amino-2-hydroxy-4-butanoyl- 1, 3- thiazol idine-4-t-butylamide; (1 ,2S 1 -dimethylethyl)amino)carbonyl)(2-methylpropyl)amino)-2 hydroxy- I (hnlehlpoy)2(2qioiycroy~mn)btndaie H NH 2 HS 0 0 0 Ph 00 HO OH 0 N N H 2 N NH 2 H, OHH H N HO 0 [I:\DAYLIB\LEBC]03817.doc:SAK 178 OH OH BocNH N NHBoc Ph ro 0 O 0 0 OH H H N H O O Ph Val-NH N 0" N H and OH CPh O O C F 3 HN S N O or a pharmaceutically acceptable salt thereof, or a combination of two or more of these HIV protease inhibitors. 77. 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 68 in combination with a therapeutically effective amount of ritonavir or a pharmaceutically acceptable salt thereof. 78. A method for inhibiting an HIV infection comprising administering to a human in need of such treatment the compound of claim 68 in combination with ritonavir [I:\DAYLIB\LBC]03817.doc:SAK or a pharmaceutically acceptable salt thereof in a ratio of the compound of claim 68 to ritonavir of from about 16:1 to about 79. A method for inhibiting an HIV infection comprising administering to a human in need of such treatment the compound of claim 68 in combination with ritonavir or a pharmaceutically acceptable salt thereof in a ratio of the compound of claim 68 to ritonavir of from about 6:1 to about 1:3. 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 68 in combination with ritonavir and one or more reverse transcriptase inhibitors. 81. The method of claim 80 wherein the reverse transcriptase inhibitor is selected from the group consisting of AZT (zidovudine), ddl (didanosine), ddC (zalcitabine), d4T (stavudine) and 3TC (lamivudine). 82. 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 68 in combination with ritonavir, AZT (zidovudine), and 3TC (lamivudine). 83. The method of any one of claims 72 to 74 wherein the compound of claim 68 and the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are administered as separate agents. 84. The method of any one of claims 72 to 74 wherein the compound of claim 68 20 and the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are administered as separate agents at the same time. 85. The method of any one of claims 72 to 74 wherein the compound of claim 68 and the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are administered as separate agents at different times. 86. The method of any one of claims 72 to 74 wherein the compound of claim 68 and the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are formulated as compositions comprising two or more of the compounds. 87. The method of either of claims 75 or 76 wherein the compound of claim 68 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are 30 administered as separate agents. 88. The method of either of claims 75 or 76 wherein the compound of claim 68 S* and the other HIV protease inhibitor or combination of other HIV protease inhibitors are administered as separate agents at the same time. 89. The method of either of claims 75 or 76 wherein the compound of claim 68 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are administered as separate agents at different times. The method of either of claims 75 or 76 wherein the compound of claim 68 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are formulated as compositions comprising two or more of the compounds. [I:\DAYLB\LIBC]03817.doc:SAK 180 91. The method of any one of claims 77 to 79 wherein the compound of claim 68 and the ritonavir are administered as separate agents. 92. The method of any one of claims 77 to 79 wherein the compound of claim 68 and the ritonavir are administered as separate agents at the same time. 93. The method of any one of claims 77 to 79 wherein the compound of claim 68 and the ritonavir are administered as separate agents at different times. 94. The method of any one of claims 77 to 79 wherein the compound of claim 68 and the ritonavir are formulated as a composition comprising two or more compounds. The method of any one of claims 80 to 82 wherein the compound of claim 68 and the ritonavir and the one or more reverse transcriptase inhibitors are administered as separate agents. 96. The method of any one of claims 80 to 82 wherein the compound of claim 68 and the ritonavir and the one or more reverse transcriptase inhibitors are administered as separate agents at the same time. 97. The method of any one of claims 80 to 82 wherein the compound of claim 68 and the ritonavir and the one or more reverse transcriptase inhibitors are administered as separate agents at different times. 98. The method of any one of claims 80 to 82 wherein the compound of claim 68 and the ritonavir and the one or more reverse transcriptase inhibitors are formulated as 20 compositions comprising two or more of the compounds. Sf: 99. Use of a compound according to claim 68 in the preparation of a medicament for inhibiting HIV protease. 100. Use of a compound according to claim 68 in the preparation of a medicament for inhibiting an HIV infection. 101. Use of a compound according to claim 68 in combination with one or more reverse transcriptase inhibitor(s) in the preparation of a medicament for inhibiting an HIV infection. 102. Use of a compound according to claim 68 in combination with one or more reverse transcriptase inhibitor(s) selected from the group consisting of AZT (zidovudine), 30 ddl (didanosine), ddC (zalcitabine), d4T (stavudine), 3TC (lamivudine), nevirapine, delaviridine, trovirdine, PMEA, bis-POMPMEA and MSA-300 in the preparation of a medicament for inhibiting an HIV infection. 103. Use of a compound according to claim 68 in combination with one or more reverse transcriptase inhibitor(s) selected from the group consisting of AZT (zidovudine), ddl (didanosine), ddC (zalcitabine), d4T (stavudine), 3TC (lamivudine), nevirapine and delaviridine in the preparation of a medicament for inhibiting an HIV infection. 104. Use of a compound according to claim 68 in combination with one or more other protease inhibitor(s) in the preparation of a medicament for inhibiting an HIV infection. [I:\DAYLB\LIC]03817.doc:SAK 181 105. Use of a compound according to claim 68 in combination with one or more other protease inhibitor(s) selected from the group consisting of ritonavir, saquinavir, indinavir, (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- thiazolidine-4-t-butylamide; -isoquinol inoxyacetyl-beta-methylthio-Ala-(2S ,3 S)-3-amino-2-hydroxy-4-butanoyl- 1,3 thiazolidine-4-t-butylamide; (1 S 1 2S 1 Adimethylethyl)amino)carbony1) (2-methy lp ropy I)ami no)-2- hiydroxy-l1-(phenylmethyl)propyl)-2-((2-quinolinylcarbonyl)amino)-butanediamide; OH 0 H 0 Ph NI1 N, S\ 0 0 9 H2N 9 0* 9* 9*99** OH H HO PhS [I:\DAYLIBkL1BCI03817.doc:SAK OH BocNH H Ph NHBoc N^O 0 H N N H 0 OH H N H y N 0 0 Ph N 0 N H U 0 U U. 0 and .CF 3 s in the preparation of a medicament for inhibiting an HIV infection. 106. Use of a compound according to claim 68 in combination with ritonavir or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting an HIV infection. 107. Use of the compound of claim 68 in combination with ritonavir or a pharmaceutically acceptable salt thereof in a ratio of the compound of claim 68 to ritonavir of from about 16:1 to about 1:5 in the preparation of a medicament for inhibiting an HIV infection. 108. Use of the compound of claim 68 in combination with ritonavir or a pharmaceutically acceptable salt thereof in a ratio of the compound of claim 68 to [I:\DAYLIB\LEBC]03817.doc:SAK 183 ritonavir of from about 6:1 to about 1:3 in the preparation of a medicament for inhibiting an HIV infection. 1 109. Use of the compound according to claim 68 in combination with ritonavir and one or more reverse transcriptase inhibitors for the preparation of a medicament for inhibiting an HIV infection. 110. Use of the compound according to claim 68 in combination with ritonavir and one or more reverse transcriptase inhibitors selected from the group consisting of AZT (zidovudine), ddl (didanosine), ddC (zalcitabine), d4T (stavudine) and 3TC (lamivudine) for the preparation of a medicament for inhibiting an HIV infection. 111. Use of the compound according to claim 68 in combination with ritonavir and AZT (zidovudine), and 3TC (lamivudine) for the preparation of a medicament for inhibiting an HIV infection. 112. The compound according to claim 68 when used for inhibiting an HIV infection. 113. The compound according to claim 68 when used for inhibiting HIV protease. 114. The compound according to claim 68 when used in combination with one or more reverse transcriptase inhibitor(s) for inhibiting an HIV infection. 115. The compound according to claim 68 when used in combination with one or more reverse transcriptase inhibitor(s) selected from the group consisting of AZT (zidovudine), ddl (didanosine), ddC (zalcitabine), d4T (stavudine), 3TC (lamivudine), nevirapine, delaviridine, trovirdine, PMEA, bis-POMPMEA and MSA-300 for inhibiting an HIV infection. 116. The compound according to claim 68 when used in combination with one or S' more reverse transcriptase inhibitor(s) selected from the group consisting of AZT (zidovudine), ddl (didanosine), ddC (zalcitabine), d4T (stavudine), 3TC (lamivudine), nevirapine and delaviridine for inhibiting an HIV infection. 117. The compound according to claim 68 when used in combination with one or more other HIV protease inhibitor(s) for inhibiting an HIV infection. 118. The compound according to claim 68 when used in combination with one or more other HIV protease inhibitor(s) selected from the group consisting of ritonavir, saquinavir, indinavir, (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- thiazolidine-4-t-butylamide; 5-isoquinolinoxyacetyl-beta-methylthio-Ala-(2S,3S)-3-amino-2-hydroxy-4-butanoyl-1,3- thiazolidine-4-t-butylamide; (1S-(1R*(R*),2S*))-N'(3-((((1,1-dimethylethyl)amino)carbonyl)(2-methylpropyl)amino)-2- hydroxy-l-(phenylmethyl)propyl)-2-((2-quinolinylcarbonyl)amino)butanediamide; [I:\DAYLIB\LIBC]03817.doc:SAK OH 0 HO Q NH 2 NOj 0 0 H 2 N *00 0 OH 0 H HO 0) PhSll OH OH BocNH H N H 0 H ,-NllN H OH 0 l (I:\DAYLIB\LEBC]03817.doc:SAK N N val-NH H N o A H and OH Ph 0 0 0 C F 3 HN S N O O for inhibiting an HIV infection. 119. The compound according to claim 68 when used in combination with ritonavir or a pharmaceutically acceptable salt thereof for inhibiting an HIV infection. 120. The compound of claim 68 when used in combination with ritonavir or a pharmaceutically acceptable salt thereof in a ratio of the compound of claim 68 to ritonavir of from about 16:1 to about 1:5 for inhibiting an HIV infection. 121. The compound of claim 68 when used in combination with ritonavir or a pharmaceutically acceptable salt thereof in a ratio of the compound of claim 68 to ritonavir of from about 6:1 to about 1:3 for inhibiting an HIV infection. 122. The compound according to claim 68 when used in combination with ritonavir and one or more reverse transcriptase for inhibiting an HIV infection. 123. The compound according to claim 68 when used in combination with ritonavir 15 and one or more reverse transcriptase inhibitors selected from the group consisting of AZT (zidovudine), ddl (didanosine), ddC (zalcitabine), d4T (stavudine) and 3TC (lamivudine) for inhibiting an HIV infection. 124. The compound according to claim 68 when used in combination with ritonavir and AZT (zidovudine), and 3TC (lamivudine) for inhibiting an HIV infection. 125. Use according to any one of claims 101 to 103 wherein the compound of claim 68 and the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are administered as separate agents. 126. Use according to any one of claims 101 to 103 wherein the compound of claim 68 and the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are administered as separate agents at the same time. [I:ADAYIB~LIBC]03817.doc:SAK 186 127. Use according to any one of claims 101 to 103 wherein the compound of claim 68 and the reverse transcriptase inhibitor or combination of reverse transcriptase O! inhibitors are administered as separate agents at different times. 128. Use according to any one of claims 101 to 103 wherein the compound of claim 68 and the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are formulated as compositions comprising two or more of the compounds. 129. Use according to either of claims 104 or 105 wherein the compound of claim 68 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are administered as separate agents. 130. Use according to either of claims 104 or 105 wherein the compound of claim 68 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are administered as separate agents at the same time. 131. Use according to either of claims 104 or 105 wherein the compound of claim 68 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are administered as separate agents at different times. 132. Use according to either of claims 104 or 105 wherein the compound of claim 68 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are formulated as compositions comprising two or more of the compounds. 133. Use according to any one of claims 106 to 108 wherein the compound of claim 68 and the ritonavir are administered as separate agents. ooo 134. Use according to any one of claims 106 to 108 wherein the compound of claim too 68 and the ritonavir are administered as separate agents at the same time. 135. Use according to any one of claims 106 to 108 wherein the compound of claim 68 and the ritonavir are administered as separate agents at different times. 25 136. Use according to any one of claims 106 to 108 wherein the compound of claim •e•°o 68 and the ritonavir are formulated as a composition comprising two or more compounds. 137. Use according to any one of claims 109 to 111 wherein the compound of claim 68 and the ritonavir and the one or more reverse transcriptase inhibitors are administered oooo as separate agents. 138. Use according to any one of claims 109 to 111 wherein the compound of claim t 68 and the ritonavir and the one or more reverse transcriptase inhibitors are administered as separate agents at the same time. 139. Use according to any one of claims 109 to 111 wherein the compound of claim 68 and the ritonavir and the one or more reverse transcriptase inhibitors are administered as separate agents at different times. 140. Use according to any one of claims 109 to 111 wherein the compound of claim 68 and the ritonavir and the one or more reverse transcriptase inhibitors are formulated as compositions comprising two or more of the compounds. [IADAYLB\LBC]03817.doc:SAK 187 141. The compound of claim 68 when used according to any one of claims 114 to 116 wherein the compound of claim 68 and the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are administered as separate agents. 142. The compound of claim 68 when used according to any one of claims 114 to 116 wherein the compound of claim 68 and the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are administered as separate agents at the same time. 143. The compound of claim 68 when used according to any one of claims 114 to 116 wherein the compound of claim 68 and the reverse transcriptase inhibitor or lo combination of reverse transcriptase inhibitors are administered as separate agents at different times. 144. The compound of claim 68 when used according to any one of claims 114 to 116 wherein the compound of claim 68 and the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are formulated as compositions comprising two or more-of the compounds. 145. The compound of claim 68 when used according to either of claims 117 to 118 wherein the compound of claim 68 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are administered as separate agents. 146. The compound of claim 68 when used according to either of claims 117 to 118 000 0 20 wherein the compound of claim 68 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are administered as separate agents at the same time. 147. The compound of claim 68 when used according to either of claims 117 to 118 wherein the compound of claim 68 and the other HIV protease inhibitor or combination of S• other HIV protease inhibitors are administered as separate agents at different times. 148. The compound of claim 68 when used according to either of claims 117 to 118 S• wherein the compound of claim 68 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are formulated as compositions comprising two or more of the compounds. o S 149. The compound of claim 68 when used according to any one of claims 119 to 121 wherein the compound of claim 68 and the ritonavir are administered as separate o .agents. S. 150. The compound of claim 68 when used according to any one of claims 119 to 121 wherein the compound of claim 68 and the ritonavir are administered as separate agents at the same time. 151. The compound of claim 68 when used according to any one of claims 119 to 121 wherein the compound of claim 68 and the ritonavir are administered as separate agents at different times. 152. The compound of claim 68 when used according to any one of claims 119 to 121 wherein the compound of claim 68 and the ritonavir are formulated as a composition comprising two or more compounds. (I:\DAYLIB\LIBC]03817.doc:SAK 188 153. The compound of claim 68 when used according to any one of claims 122 to 124 wherein the compound of claim 68 and the ritonavir and the one or more reverse transcriptase inhibitors are administered as separate agents. 154. The compound of claim 68 when used according to any one of claims 122 to 124 wherein the compound of claim 68 and the ritonavir and the one or more reverse transcriptase inhibitors are administered as separate agents at the same time. 155. The compound of claim 68 when used according to any one of claims 122 to 124 wherein the compound of claim 68 and the ritonavir and the one or more reverse transcriptase inhibitors are administered as separate agents at different times. 156. The compound of claim 68 when used according to any one of claims 122 to 124 wherein the compound of claim 68 and the ritonavir and the one or more reverse transcriptase inhibitors are formulated as compositions comprising two or more of the compounds. 157. A method for inhibiting HIV protease comprising administering to a human in need of such treatment the composition of claim 69. 158. A method for inhibiting an HIV infection comprising administering to a human in need of such treatment the composition of claim 69. 159. A method for inhibiting an HIV infection comprising administering to a human in need of such treatment the composition of claim 69 in combination with a o 20 therapeutically effective amount of a reverse transcriptase inhibitor or a combination of reverse transcriptase inhibitors. 160. The method of claim 159 wherein the reverse transcriptase inhibitor is selected from the group consisting of AZT (zidovudine), ddl (didanosine), ddC (zalcitabine), d4T (stavudine), 3TC (lamivudine), nevirapine, delaviridine, trovirdine, PMEA, bis- 25 POMPMEA and MSA-300. 161. The method of claim 159 wherein the reverse transcriptase inhibitor is selected from the group consisting of AZT (zidovudine), ddl (didanosine), ddC (zalcitabine), d4T i (stavudine), 3TC (lamivudine), nevirapine and delaviridine. 162. A method for inhibiting an HIV infection comprising administering to a human in need of such treatment the composition of claim 69 in combination with a therapeutically effective amount of another HIV protease inhibitor or a combination of HIV protease inhibitors. 163. The method of claim 162 wherein the other HIV protease inhibitor is selected from the group consisting of ritonavir, saquinavir, indinavir, 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-l,3- thiazolidine-4-t-butylamide; 5-isoquinolinoxyacetyl-beta-methylthio-Ala-(2S,3S)-3-amino-2-hydroxy-4-butanoyl-1,3- thiazolidine-4-t-butylamide; [I:\DAYLIB\LBC]03817.doc:SAK 189 (1 ,2S (3 1-dimethylethyl)amino)carbonyl)(2-methylpropyl)amino)-2- hydroxy- 1 -(phenylmethyl)propyl)-2-((2-quinolinylcarbonyl)amino)-butanediamide; NH 2 OH H-)N a. a a *aaa.. a a a a a. a a. a. OH BocN H, H Ph N- H IC 0 [I:\DAYLEB\ILIBC]03817.doc:SAK 190 0 OH H H H N H O Ph N O OH N0 Val- NH N 0 ON H and OH 0 O CF 3 HN S N 0 5 or a pharmaceutically acceptable salt thereof, or a combination of two or more of these HIV protease inhibitors. 164. A method for inhibiting an HIV infection comprising administering to a human in need of such treatment the composition of claim 69 in combination with a therapeutically effective amount of ritonavir or a pharmaceutically acceptable salt thereof. 10 165. A method for inhibiting an HIV infection comprising administering to a human in need of such treatment the composition of claim 69 in combination with ritonavir or a pharmaceutically acceptable salt thereof in a ratio of the compound of Sclaim 68 to ritonavir of from about 16:1 to about S: 166. A method for inhibiting an HIV infection comprising administering to a human in need of such treatment the composition of claim 69 in combination with ritonavir or a pharmaceutically acceptable salt thereof in a ratio of the compound of claim 68 to ritonavir of from about 6:1 to about 1:3. 167. A method for inhibiting an HIV infection comprising administering to a human in need of such treatment the composition of claim 69 in combination with ritonavir and one or more reverse transcriptase inhibitors. (I:\DAYLBu\LBC]03817.doc:SAK 191 168. The method of claim 167 wherein the reverse transcriptase inhibitor is selected from the group consisting of AZT (zidovudine), ddl (didanosine), ddC (zalcitabine), d4T b) (stavudine) and 3TC (lamivudine). 169. A method for inhibiting an HIV infection comprising administering to a human in need of such treatment the composition of claim 69 in combination with ritonavir, AZT (zidovudine), and 3TC (lamivudine). 170. The method of any one of claims 159 to 161 wherein the composition of claim 69 and the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are administered as separate agents. 171. The method of any one of claims 159 to 161 wherein the composition of claim 69 and the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are administered as separate agents at the same time. 172. The method of any one of claims 159 to 161 wherein the composition of claim 69 and the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are administered as separate agents at different times. 173. The method of any one of claims 159 to 161 wherein the composition of claim 69 and the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are formulated as compositions comprising two or more of the compounds. 174. The method of either of claims 162 or 163 wherein the composition of claim 20 69 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are administered as separate agents. 175. The method of either of claims 162 or 163 wherein the composition of claim 69 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are administered as separate agents at the same time. 25 176. The method of either of claims 162 or 163 wherein the composition of claim 69 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are administered as separate agents at different times.
49. 177. The method of either of claims 162 or 163 wherein the composition of claim 69 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are formulated as compositions comprising two or more of the compounds.
50. 178. The method of any one of claims 164 or 166 wherein the composition of claim 69 and the ritonavir are administered as separate agents.
51. 179. The method of any one of claims 164 or 166 wherein the composition of claim 69 and the ritonavir are administered as separate agents at the same time.
52. 180. The method of any one of claims 164 or 166 wherein the composition of claim 69 and the ritonavir are administered as separate agents at different times.
53. 181. The method of any one of claims 164 or 166 wherein the composition of claim 69 and the ritonavir are formulated as a composition comprising two or more compounds. [I:\DAYLIB\LIBCJO3817.doc:SAK
54. 182. The method of any one of claims 167 to 169 wherein the composition of claim 69 and the ritonavir and the one or more reverse transcriptase inhibitors are administered as separate agents.
55. 183. The method of any one of claims 167 to 169 wherein the composition of claim 69 and the ritonavir and the one or more reverse transcriptase inhibitors are administered as separate agents at the same time.
56. 184. The method of any one of claims 167 to 169 wherein the composition of claim 69 and the ritonavir and the one or more reverse transcriptase inhibitors are administered as separate agents at different times.
57. 185. The method of any one of claims 167 to 169 wherein the composition of claim 69 and the ritonavir and the one or more reverse transcriptase inhibitors are formulated as compositions comprising two or more of the compounds.
58. 186. Use of a composition according to claim 69 in the preparation of a medicament for inhibiting HIV protease.
59. 187. Use of a composition according to claim 69 in the preparation of a medicament for inhibiting an HIV infection.
60. 188. Use of a composition according to claim 69 in combination with one or more reverse transcriptase inhibitor(s) in the preparation of a medicament for inhibiting an HIV infection. 20 189. Use of a composition according to claim 69 in combination with one or more reverse transcriptase inhibitor(s) selected from the group consisting of AZT (zidovudine), ddl (didanosine), ddC (zalcitabine), d4T (stavudine), 3TC (lamivudine), nevirapine, delaviridine, trovirdine, PMEA, bis-POMPMEA and MSA-300 in the preparation of a medicament for inhibiting an HIV infection. 25 190. Use of a composition according to claim 69 in combination with one or more reverse transcriptase inhibitor(s) selected from the group consisting of AZT (zidovudine), ddl (didanosine), ddC (zalcitabine), d4T (stavudine), 3TC (lamivudine), nevirapine and delaviridine in the preparation of a medicament for inhibiting an HIV infection.
61. 191. Use of a composition according to claim 69 in combination with one or more other protease inhibitor(s) in the preparation of a medicament for inhibiting an HIV infection.
62. 192. Use of a composition according to claim 69 in combination with one or more other protease inhibitor(s) selected from the group consisting of ritonavir, saquinavir, indinavir, 5(S)-Boc-amino-4(S)-hydroxy-6-phenyl-2(R)-phenylmethylhexanoyl-(L)-Val-(L)-Phe- morpholin-4-ylamide; l-Naphthoxyacetyl-beta-methylthio-Ala-(2S,3S)-3-amino-2-hydroxy-4-butanoyl-1,3- thiazolidine-4-t-butylamide; -isoquinolinoxyacetyl-beta-methylthio-Ala-(2S,3S)- 3 -amino-2-hydroxy-4-butanoyl-1,3- thiazolidine-4-t-butylamide; [I:\DAYLIB\LIBC]03817.doc:SAK 1 93 (I 1 ,2S 1, -dimethylethyl)amino)carbonyl)(2methylpropyI)amino)- 2 ON hydroxy- -(phenylmethyl)propyl)-2-( 2 -quinolinylcarbony)amino)-butanediamjde; OH NN N s J O 0 0 Ph, 0 II)N N 01-1 0 0- 9 N [1 0 H* NH-) H N *o 0li 0 N H *OH O H BocNH H- NHBoc S. N [I:\DAYLIB\LIBC]038 17.doc:SAK 194 0 OH H N H Ph N 0 0 Val- NI-l N N 0I-i and OH HN K CF 3 S N O Sin the preparation of a medicament for inhibiting an HIV infection. 5
63. 193. Use of a composition according to claim 69 in combination with ritonavir or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting an HIV infection.
64. 194. Use of a composition according to claim 69 in combination with ritonavir or a pharmaceutically acceptable salt thereof in a ratio of the compound of claim 68 to 10 ritonavir of from about 16:1 to about 1:5 in the preparation of a medicament for inhibiting an HIV infection.
65. 195. Use of a composition according to claim 69 in combination with ritonavir or a pharmaceutically acceptable salt thereof in a ratio of the compound of claim 68 to ritonavir of from about 6:1 to about 1:3 in the preparation of a medicament for inhibiting an HIV infection.
66. 196. Use of a composition according to claim 69 in combination with ritonavir and one or more reverse transcriptase inhibitors for the preparation of a medicament for inhibiting an HIV infection.
67. 197. Use of a composition according to claim 69 in combination with ritonavir and one or more reverse transcriptase inhibitors selected from the group consisting of AZT [I:\DAYLIB\LIBC]03817.doc:SAK 195 (zidovudine), ddl (didanosine), ddC (zalcitabine), d4T (stavudine) and 3TC (lamivudine) for the preparation of a medicament for inhibiting an HIV infection.
68. 198. Use of a composition according to claim 69 in combination with ritonavir and AZT (zidovudine), and 3TC (lamivudine) for the preparation of a medicament for inhibiting an HIV infection.
69. 199. The composition according to claim 69 when used for inhibiting an HIV infection.
70. 200. The composition according to claim 69 when used for inhibiting HIV protease.
71. 201. The composition according to claim 69 when used in combination with one or more reverse transcriptase inhibitor(s) for inhibiting an I-IIV infection.
72. 202. The composition according to claim 69 when used in combination with one or more reverse transcriptase inhibitor(s) selected from the group consisting of AZT (zidovudine), ddl (didanosine), ddC (zalcitabine), d4T (stavudine), 3TC (lamivudine), nevirapine, delaviridine, trovirdine, PMEA, bis-POMPMEA and MSA-300 for inhibiting an HIV infection.
73. 203. The composition according to claim 69 when used in combination with one or more reverse transcriptase inhibitor(s) selected from the group consisting of AZT (zidovudine), ddl (didanosine), ddC (zalcitabine), d4T (stavudine), 3TC (lamivudine), 20 nevirapine and delaviridine for inhibiting an HIV infection.
74. 204. The composition according to claim 69 when used in combination with one or more other HIV protease inhibitor(s) for inhibiting an HIV infection.
75. 205. The composition according to claim 69 when used in combination with one or more other HIV protease inhibitor(s) selected from the group consisting of ritonavir, S 25 saquinavir, indinavir, 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- thiazolidine-4-t-butylamide; 5-isoquinolinoxyacetyl-beta-methylthio-Ala-(2S,3S)-3-amino-2-hydroxy-4-butanoyl- 1,3- thiazolidine-4-t-butylamide; (1 S-(1 -dimethylethyl)amino)carbonyl)(2-methylpropyl)amino)-2- hydroxy-1-(phenylmethyl)propyl)-2-((2-quinolinylcarbonyl)amino)-butanediamide; OH N NH 2 OPh 0Ph0 [I:\DAYLIB\LIBCj03817.doc:SAK 1 96 OH 110 [-kN OH 07 PhS 1 1H N O0 H- OH BocNI- N Ph~ N 1-Boc NO 0 0 0 OH N NN Ph II:\DAYLIB\LIBC]03817.doc:SAK OH 00J Val- NH N 0 N Sand 01-1 OH Ph C F3 NS N for inhibiting an HIV infection.
76. 206. The composition according to claim 69 when used in combination with ritonavir or a pharmaceutically acceptable salt thereof for inhibiting an HIV infection.
77. 207. The composition according to claim 69 when used in combination with ritonavir or a pharmaceutically acceptable salt thereof in a ratio of the compound of claim 68 to ritonavir of from about 16:1 to about 1:5 for inhibiting an HIV infection.
78. 208. The composition according to claim 69 when used in combination with o ritonavir or a pharmaceutically acceptable salt thereof in a ratio of the compound of claim 68 to ritonavir of from about 6:1 to about 1:3 for inhibiting an HIV infection.
79. 209. The composition according to claim 69 when used in combination with ritonavir and one or more reverse transcriptase for inhibiting an HIV infection.
80. 210. The composition according to claim 69 when used in combination with 15 ritonavir and one or more reverse transcriptase inhibitors selected from the group consisting of AZT (zidovudine), ddl (didanosine), ddC (zalcitabine), d4T (stavudine) and 3TC (lamivudine) for inhibiting an HIV infection.
81. 211. The composition according to claim 69 when used in combination with ritonavir and AZT (zidovudine), and 3TC (lamivudine) for inhibiting an HIV infection.
82. 212. Use according to any one of claims 188 to 190 wherein the composition of claim 69 and the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are administered as separate agents.
83. 213. Use according to any one of claims 188 to 190 wherein the composition of claim 69 and the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are administered as separate agents at the same time. [I:\DAYLIB\LIBC]03817.doc:SAK
84. 214. Use according to any one of claims 188 to 190 wherein the composition of claim 69 and the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are administered as separate agents at different times.
85. 215. Use according to any one of claims 188 to 190 wherein the composition of claim 69 and the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are formulated as compositions comprising two or more of the compounds.
86. 216. Use according to either of claims 191 or 192 wherein the composition of claim 69 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are administered as separate agents.
87. 217. Use according to either of claims 191 or 192 wherein the composition of claim 69 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are administered as separate agents at the same time.
88. 218. Use according to either of claims 191 or 192 wherein the composition of claim 69 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are administered as separate agents at different times.
89. 219. Use according to either of claims 191 or 192 wherein the composition of claim 69 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are formulated as compositions comprising two or more of the compounds.
90. 220. Use according to any one of claims 193 to 195 wherein the composition of 20 claim 69 and the ritonavir are administered as separate agents.
91. 221. Use according to any one of claims 193 to 195 wherein the composition of claim 69 and the ritonavir are administered as separate agents at the same time.
92. 222. Use according to any one of claims 193 to 195 wherein the composition of claim 69 and the ritonavir are administered as separate agents at different times.
93. 223. Use according to any one of claims 193 to 195 wherein the composition of claim 69 and the ritonavir are formulated as a composition comprising two or more compounds.
94. 224. Use according to any one of claims 196 to 198 wherein the composition of claim 69 and the ritonavir and the one or more reverse transcriptase inhibitors are administered as separate agents.
95. 225. Use according to any one of claims 196 to 198 wherein the composition of claim 69 and the ritonavir and the one or more reverse transcriptase inhibitors are administered as separate agents at the same time.
96. 226. Use according to any one of claims 196 to 198 wherein the composition of claim 69 and the ritonavir and the one or more reverse transcriptase inhibitors are administered as separate agents at different times.
97. 227. Use according to any one of claims 196 to 198 wherein the composition of claim 69 and the ritonavir and the one or more reverse transcriptase inhibitors are formulated as compositions comprising two or more of the compounds. [I:\DAYLIB\LIBC]03817.doc:SAK 199
98. 228. The composition of claim 69 when used according to any one of claims 201 to 203 wherein the composition of claim 69 and the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are administered as separate agents.
99. 229. The composition of claim 69 when used according to any one of claims 201 to s 203 wherein the composition of claim 69 and the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are administered as separate agents at the same time.
100. 230. The composition of claim 69 when used according to any one of claims 201 to 203 wherein the composition of claim 69 and the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are administered as separate agents at different times.
101. 231. The composition of claim 69 when used according to any one of claims 201 to 203 wherein the composition of claim 69 and the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are formulated as compositions comprising two or more of the compounds.
102. 232. The composition of claim 69 when used according to either of claims 204 to 205 wherein the composition of claim 69 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are administered as separate agents.
103. 233. The composition of claim 69 when used according to either of claims 204 to ooo 20 205 wherein the composition of claim 69 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are administered as separate agents at the same time.
104. 234. The composition of claim 69 when used according to either of claims 204 to 205 wherein the composition of claim 69 and the other HIV protease inhibitor or S 25 combination of other HIV protease inhibitors are administered as separate agents at different times.
105. 235. The composition of claim 69 when used according to either of claims 204 to 205 wherein the composition of claim 69 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are formulated as compositions comprising two or more of the compounds.
106. 236. The composition of claim 69 when used according to any one of claims 206 to 208 wherein the composition of claim 69 and the ritonavir are administered as separate agents.
107. 237. The composition of claim 69 when used according to any one of claims 206 to 208 wherein the composition of claim 69 and the ritonavir are administered as separate agents at the same time.
108. 238. The composition of claim 69 when used according to any one of claims 206 to 208 wherein the composition of claim 69 and the ritonavir are administered as separate agents at different times. II:\DAYLIB\LIBC]03817.doc:SAK 200
109. 239. The composition of claim 69 when used according to any one of claims 206 to 208 wherein the composition of claim 69 and the ritonavir are formulated as a 9 composition comprising two or more compounds.
110. 240. The composition of claim 69 when used according to any one of claims 209 to 211 wherein the composition of claim 69 and the ritonavir and the one or more reverse transcriptase inhibitors are administered as separate agents.
111. 241. The composition of claim 69 when used according to any one of claims 209 to 211 wherein the composition of claim 69 and the ritonavir and the one or more reverse transcriptase inhibitors are administered as separate agents at the same time.
112. 242. The composition of claim 69 when used according to any one of claims 209 to 211 wherein the composition of claim 69 and the ritonavir and the one or more reverse transcriptase inhibitors are administered as separate agents at different times.
113. 243. The composition of claim 69 when used according to any one of claims 209 to 211 wherein the composition of claim 69 and the ritonavir and the one or more reverse transcriptase inhibitors are formulated as compositions comprising two or more of the compounds.
114. 244. The compound (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy- 5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl) amino-l,6-diphenylhexane or a pharmaceutically acceptable salt, ester, or prodrug thereof when prepared by the process 20 of any one of claims 53, 54, 56, 57, 62, 63, and 67.
115. 245. 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 244.
116. 246. 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 244.
117. 247. 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 244 in combination with a therapeutically effective amount of a reverse transcriptase inhibitor or a combination of reverse transcriptase inhibitors.
118. 248. The method of claim 247 wherein the reverse transcriptase inhibitor is selected from the group consisting of AZT (zidovudine), ddl (didanosine), ddC (zalcitabine), d4T (stavudine), 3TC (lamivudine), nevirapine, delaviridine, trovirdine, PMEA, bis- 0 POMPMEA and MSA-300.
119. 249. The method of claim 247 wherein the reverse transcriptase inhibitor is selected from the group consisting of AZT (zidovudine), ddl (didanosine), ddC (zalcitabine), d4T (stavudine), 3TC (lamivudine), nevirapine and delaviridine.
120. 250. 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 244 in combination with a therapeutically effective amount of another HIV protease inhibitor or a combination of HIV protease inhibitors. [I:\DAYLIB\LIBC]03817.doc:SAK 201 1. The method of claim 250 wherein the other HIV protease inhibitor is selected from the group consisting of ritonavir, saquinavir, indinavir, -B oc-am ino-4(S) -hyd roxy-6 -phe ny1I-2(R)-phenylImethylIhexanoylI (L-Va 1-L) Pile- m-orphol in-4-ylamide; 1 -Naphithoxyacety I-beta-methylthio-Ala-(2S 3 S)-3-amino-2-hydroxy-4-butanoyl- 1, 3- thiazolid ine-4-t-butylamide; iiln xaey-eam tytioAl 2 ,S--mn y rx uao l1,3- tiazol idine-4-t-butylamide; (1 1Rk'(R* 1 1 -dimethy lethylI)ani no)carbony1)(2-methy lp ropy I)a-ino-2- lhydr-oxy-l1-(plhenylr-netlhyl)propyl)-2-((2-quinolinylcarbonyl)amiino)-butaniedianilde; NH1- 9 OH 9 l-1 2 N O H O H PhS Nj H [I:\DAYLIB\LIBC]038 17.doc:SAK 202 OH BocNH I- NHBoc NOj 0 N N N 0 OHH N N OH Val- NH N O NH H S S. j< and OH .CF 3 HN S 0 \0 or a pharmaceutically acceptable salt thereof, or a combination of two or more of these HIV protease inhibitors.
121. 252. 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 o1 claim 244 in combination with a therapeutically effective amount of ritonavir or a pharmaceutically acceptable salt thereof.
122. 253. A method for inhibiting an HIV infection comprising administering to a human in need of such treatment the compound of claim 244 in combination with ritonavir [I:\DAYLIB\LIBC]03817.doc:SAK 203 or a pharmaceutically acceptable salt thereof in a ratio of the compound of claim 244 to ritonavir of from about 16:1 to about
123. 254. A method for inhibiting an HIV infection comprising administering to a human in need of such treatment the compound of claim 244 in combination with ritonavir or a pharmaceutically acceptable salt thereof in a ratio of the compound of claim 244 to ritonavir of from about 6:1 to about 1:3.
124. 255. 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 244 in combination with ritonavir and one or more reverse transcriptase inhibitors.
125. 256. The method of claim 255 wherein the reverse transcriptase inhibitor is selected from the group consisting of AZT (zidovudine), ddl (didanosine), ddC (zalcitabine), d4T (stavudine) and 3TC (lamivudine).
126. 257. 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 1i claim 244 in combination with ritonavir, AZT (zidovudine), and 3TC (lamivudine).
127. 258. The method of any one of claims 247 to 217 wherein the compound of claim 244 and the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are administered as separate agents.
128. 259. The method of any one of claims 247 to 217 wherein the compound of claim 244 and the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are administered as separate agents at the same time.
129. 260. The method of any one of claims 247 to 217 wherein the compound of claim 244 and the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are administered as separate agents at different times.
130. 261. The method of any one of claims 247 to 217 wherein the compound of claim 244 and the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are formulated as compositions comprising two or more of the compounds.
131. 262. The method of either of claims 250 or 251 wherein the compound of claim S* 244 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are administered as separate agents.
132. 263. The method of either of claims 250 or 251 wherein the compound of claim *244 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are administered as separate agents at the same time.
133. 264. The method of either of claims 250 or 251 wherein the compound of claim 244 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are administered as separate agents at different times.
134. 265. The method of either of claims 250 or 251 wherein the compound of claim 244 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are formulated as compositions comprising two or more of the compounds. tI:\DAYLIB\LIBC]03817.doc:SAK 204
135. 266. The method of any one of claims 252 to 254 wherein the compound of claim 244 and the ritonavir are administered as separate agents. S267. The method of any one of claims 252 to 254 wherein the compound of claim 244 and the ritonavir are administered as separate agents at the same time.
136. 268. The method of any one of claims 252 to 254 wherein the compound of claim 244 and the ritonavir are administered as separate agents at different times.
137. 269. The method of any one of claims 252 to 254 wherein the compound of claim 244 and the ritonavir are formulated as a composition comprising two or more compounds.
138. 270. The method of any one of claims 255 to 257 wherein the compound of claim 244 and the ritonavir and the one or more reverse transcriptase inhibitors are administered as separate agents.
139. 271. The method of any one of claims 255 to 257 wherein the compound of claim 244 and the ritonavir and the one or more reverse transcriptase inhibitors are administered as separate agents at the same time.
140. 272. The method of any one of claims 255 to 257 wherein the compound of claim 244 and the ritonavir and the one or more reverse transcriptase inhibitors are administered as separate agents at different times.
141. 273. The method of any one of claims 255 to 257 wherein the compound of claim 20 244 and the ritonavir and the one or more reverse transcriptase inhibitors are formulated S: as compositions comprising two or more of the compounds.
142. 274. Use of a compound according to claim 244 in the preparation of a medicament for inhibiting HIV protease.
143. 275. Use of a compound according to claim 244 in the preparation of a medicament for inhibiting an HIV infection.
144. 276. Use of a compound according to claim 244 in combination with one or more reverse transcriptase inhibitor(s) in the preparation of a medicament for inhibiting an HIV infection.
145. 277. Use of a compound according to claim 244 in combination with one or more reverse transcriptase inhibitor(s) selected from the group consisting of AZT (zidovudine), ddl (didanosine), ddC (zalcitabine), d4T (stavudine), 3TC (lamivudine), nevirapine, delaviridine, trovirdine, PMEA, bis-POMPMEA and MSA-300 in the preparation of a medicament for inhibiting an HIV infection.
146. 278. Use of a compound according to claim 244 in combination with one or more reverse transcriptase inhibitor(s) selected from the group consisting of AZT (zidovudine), ddl (didanosine), ddC (zalcitabine), d4T (stavudine), 3TC (lamivudine), nevirapine and delaviridine in the preparation of a medicament for inhibiting an HIV infection.
147. 279. Use of a compound according to claim 244 in combination with one or more other protease inhibitor(s) in the preparation of a medicament for inhibiting an HIV infection. [I:\DAYLIB\LIBC]03817.doc:SAK 205
148. 280. Use of a compound according to claim 244 in combination with one or more other protease inhibitor(s) selected from the group consisting of ritonavir, saquinavir, indinavir, (S)-Boc-ainio-4( S)-hydroxy-6-phenyl-2(R)-plienylmethylhexanoyl-(L)-Val-(L)-Phe- mor-pholin-4-ylamnide; I -Naphthioxyacetyl-beta-r-nethylthiio-Ala-(2S,3S)-3-amino-2-hiydroxy-4-butanoyl- 1,3- tihiazolidine-4-t-butylamide; 5-isoquinolinoxyacetyl-beta-imetlhylthio-Ala-(2S,3S)-3-amiino-2-lhydr-oxy-4-butanioyl- 1,3- thiazol id ine-4-t-butylamide; (1 1R" 1-dimethiylethiyl )anino )car-boinyl)(2-miethiylpropyl)amiino)-2- hy)dr-oxy,- 1-(plheiylr-netlhyl)propyl)-2-((2-quinolinylcar-boniyl)ainio)-butaniediimide; 0- 01-i 0 I N 0h NO1- N, \O 0 0 Hi1N NH 2 OH 1-10 KJWK1, N H [I:\DAYLIB\LIBC]O38 17.doc:SAK 206 OH BocNH H Ph NHBoc NO 0 N OH 0-1 0 /N N 1-1 r I N N 0 I O Val-NH N H and S O'O S 1-1 a 0 OVOO: in the preparation of a medicament for inhibiting an HIV infection.
149. 281. Use of a compound according to claim 244 in combination with ritonavir or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting an HIV infection.
150. 282. Use of the compound of claim 244 in combination with ritonavir or a pharmaceutically acceptable salt thereof in a ratio of the compound of claim 244 to ritonavir of from about 16:1 to about 1:5 in the preparation of a medicament for inhibiting an HIV infection.
151. 283. Use of the compound of claim 244 in combination with ritonavir or a pharmaceutically acceptable salt thereof in a ratio of the compound of claim 244 to 1I:\DAYLIB\LIBC03817.doc:SAK 207 ritonavir of from about 6:1 to about 1:3 in the preparation of a medicament for inhibiting an HIV infection.
152. 284. Use of the compound according to claim 244 in combination with ritonavir and one or more reverse transcriptase inhibitors for the preparation of a medicament for inhibiting an HIV infection.
153. 285. Use of the compound according to claim 244 in combination with ritonavir and one or more reverse transcriptase inhibitors selected from the group consisting of AZT (zidovudine), ddl (didanosine), ddC (zalcitabine), d4T (stavudine) and 3TC (lamivudine) for the preparation of a medicament for inhibiting an HIV infection.
154. 286. Use of the compound according to claim 244 in combination with ritonavir and AZT (zidovudine), and 3TC (lamivudine) for the preparation of a medicament for inhibiting an HIV infection.
155. 287. The compound according to claim 244 when used for inhibiting an HIV infection.
156. 288. The compound according to claim 244 when used for inhibiting HIV protease.
157. 289. The compound according to claim 244 when used in combination with one or more reverse transcriptase inhibitor(s) for inhibiting an HIV infection.
158. 290. The compound according to claim 244 when used in combination with one or more reverse transcriptase inhibitor(s) selected from the group consisting of AZT 20 (zidovudine), ddl (didanosine), ddC (zalcitabine), d4T (stavudine), 3TC (lamivudine), nevirapine, delaviridine, trovirdine, PMEA, bis-POMPMEA and MSA-300 for inhibiting aan HIV infection. i 291. The compound according to claim 244 when used in combination with one or more reverse transcriptase inhibitor(s) selected from the group consisting of AZT (zidovudine), ddl (didanosine), ddC (zalcitabine), d4T (stavudine), 3TC (lamivudine), nevirapine and delaviridine for inhibiting an HIV infection.
159. 292. The compound according to claim 244 when used in combination with one or more other HIV protease inhibitor(s) for inhibiting an HIV infection.
160. 293. The compound according to claim 244 when used in combination with one or 30 more other HIV protease inhibitor(s) selected from the group consisting of ritonavir, saquinavir, indinavir, 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- thiazolidine-4-t-butylamide; 5-isoquinolinoxyacetyl-beta-methylthio-Ala-(2S,3S)-3-amino-2-hydroxy-4-butanoyl-1,3- thiazolidine-4-t-butylamide; (1S-(lR*(R*),2S*))-N'(3-((((1,1-dimethylethyl)amino)carbonyl)(2-methylpropyl)amino)-2- hydroxy- 1 -(phenylmethyl)propyl)-2-((2-quinolinylcarbonyl)amino)-butanediamide; [I:\DAYLIB\LIBCIO3817.doc:SAK 208 oHl 0 yN 0 1-10 N 0 0 N J-I,N D I-I 01-1 .4 4 4* 4 444* *4 4 4 4 44 4 444444 4 44*4 4 4444 *4.*44 4
161. 444. 4 .4.4 *4 4 4* 44 44~444 4 OH H 0PhS,_ N'_ H- OH NHBoc NO O OH N- NH H:0 0Ph,. JI:\DAYLIB\LIBCJ0381I7.doc:SAK 209 N H O H r 8 9Val-NH N N O0 and 1-1 HN O SO N for inhibiting an HIV infection. 294. The compound according to claim 244 when used in combination with ritonavir or a pharmaceutically acceptable salt thereof for inhibiting an HIV infection. 295. The compound according to claim 244 when used in combination with •ritonavir or a pharmaceutically acceptable salt thereof in a ratio of the compound of claim 244 to ritonavir of from about 16:1 to about 1:5 for inhibiting an HIV infection. 296. The compound according to claim 244 when used in combination with lo ritonavir or a pharmaceutically acceptable salt thereof in a ratio of the compound of claim 244 to ritonavir of from about 6:1 to about 1:3 for inhibiting an HIV infection. 297. The compound according to claim 244 when used in combination with ritonavir and one or more reverse transcriptase for inhibiting an HIV infection. 298. The compound according to claim 244 when used in combination with ritonavir and one or more reverse transcriptase inhibitors selected from the group consisting of AZT (zidovudine), ddl (didanosine), ddC (zalcitabine), d4T (stavudine) and 3TC (lamivudine) for inhibiting an HIV infection. 299. The compound according to claim 244 when used in combination with ritonavir and AZT (zidovudine), and 3TC (lamivudine) for inhibiting an HIV infection. 300. Use according to any one of claims 276 to 246 wherein the compound of claim 244 and the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are administered as separate agents. 301. Use according to any one of claims 276 to 246 wherein the compound of claim 244 and the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are administered as separate agents at the same time. [I:\DAYLIB\LIBC]o38 17.doc:SAK 210 302. Use according to any one of claims 276 to 246 wherein the compound of claim 244 and the reverse transcriptase inhibitor or combination of reverse transcriptase O inhibitors are administered as separate agents at different times. 303. Use according to any one of claims 276 to 246 wherein the compound of claim 244 and the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are formulated as compositions comprising two or more of the compounds. 304. Use according to either of claims 279 or 280 wherein the compound of claim 244 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are administered as separate agents. 305. Use according to either of claims 279 or 280 wherein the compound of claim 244 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are administered as separate agents at the same time. 306. Use according to either of claims 279 or 280 wherein the compound of claim 244 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are administered as separate agents at different times. 307. Use according to either of claims 279 or 280 wherein the compound of claim 244 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are formulated as compositions comprising two or more of the compounds. 308. Use according to any one of claims 281 to 283 wherein the compound of claim 20 244 and the ritonavir are administered as separate agents. 309. Use according to any one of claims 281 to 283 wherein the compound of claim 244 and the ritonavir are administered as separate agents at the same time. 310. Use according to any one of claims 281 to 283 wherein the compound of claim 244 and the ritonavir are administered as separate agents at different times. 311. Use according to any one of claims 281 to 283 wherein the compound of claim 244 and the ritonavir are formulated as a composition comprising two or more *pa" compounds. 312. Use according to any one of claims 284 to 286 wherein the compound of claim 244 and the ritonavir and the one or more reverse transcriptase inhibitors are administered 30 as separate agents. 313. Use according to any one of claims 284 to 286 wherein the compound of claim 244 and the ritonavir and the one or more reverse transcriptase inhibitors are administered as separate agents at the same time. 314. Use according to any one of claims 284 to 286 wherein the compound of claim 244 and the ritonavir and the one or more reverse transcriptase inhibitors are administered as separate agents at different times. 315. Use according to any one of claims 284 to 286 wherein the compound of claim 244 and the ritonavir and the one or more reverse transcriptase inhibitors are formulated as compositions comprising two or more of the compounds. [I:\DAYLIB\LIBC]03817.doc:SAK 316. The compound of claim 244 when used according to any one of claims 289 to 291 wherein the compound of claim 244 and the reverse transcriptase inhibitor or 1 combination of reverse transcriptase inhibitors are administered as separate agents. 317. The compound of claim 244 when used according to any one of claims 289 to 291 wherein the compound of claim 244 and the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are administered as separate agents at the same time. 318. The compound of claim 244 when used according to any one of claims 289 to 291 wherein the compound of claim 244 and the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are administered as separate agents at different times. 319. The compound of claim 244 when used according to any one of claims 289 to 291 wherein the compound of claim 244 and the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are formulated as compositions comprising two or more of the compounds. 320. The compound of claim 244 when used according to either of claims 292 to 293 wherein the compound of claim 244 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are administered as separate agents. 321. The compound of claim 244 when used according to either of claims 292 to 293 wherein the compound of claim 244 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are administered as separate agents at the S* same time. 322. The compound of claim 244 when used according to either of claims 292 to 293 wherein the compound of claim 244 and the other HIV protease inhibitor or 25 combination of other HIV protease inhibitors are administered as separate agents at different times. 323. The compound of claim 244 when used according to either of claims 292 to 293 wherein the compound of claim 244 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are formulated as compositions comprising 30 two or more of the compounds. 324. The compound of claim 244 when used according to any one of claims 294 to 296 wherein the compound of claim 244 and the ritonavir are administered as separate agents. 325. The compound of claim 244 when used according to any one of claims 294 to 296 wherein the compound of claim 244 and the ritonavir are administered as separate agents at the same time. 326. The compound of claim 244 when used according to any one of claims 294 to 296 wherein the compound of claim 244 and the ritonavir are administered as separate agents at different times. [I:\DAYLIB\LIBC]03817.doc:SAK 212 327. The compound of claim 244 when used according to any one of claims 294 to 296 wherein the compound of claim 244 and the ritonavir are formulated as a composition comprising two or more compounds. 328. The compound of claim 244 when used according to any one of claims 297 to 299 wherein the compound of claim 244 and the ritonavir and the one or more reverse transcriptase inhibitors are administered as separate agents. 329. The compound of claim 244 when used according to any one of claims 297 to 299 wherein the compound of claim 244 and the ritonavir and the one or more reverse transcriptase inhibitors are administered as separate agents at the same time. 330. The compound of claim 244 when used according to any one of claims 297 to 299 wherein the compound of claim 244 and the ritonavir and the one or more reverse iranscriptase inhibitors are administered as separate agents at different times. 331. The compound of claim 244 when used according to any one of claims 297 to 299 wherein the compound of claim 244 and the ritonavir and the one or more reverse transcriptase inhibitors are formulated as compositions comprising two or more of the compounds. 332. A process for the preparation of a pharmaceutical composition comprising a compound according to claim 68, said process substantially as hereinbefore described with reference to any one of Examples 43 to 333. A pharmaceutical composition when prepared by the process of claim 332. S"334. A pharmaceutical composition comprising a compound according to claim 68, substantially as hereinbefore described with reference to any one of the Examples. 335. A method for inhibiting HIV protease comprising administering to a human in need of such treatment the composition according to either of claims 333 or 334. S 25 336. A method for inhibiting an HIV infection comprising administering to a human in need of such treatment the composition according to either of claims 333 or 334. 337. A method for inhibiting an HIV infection comprising administering to a human in need of such treatment the composition according to either of claims 333 or 3o 334.in combination with a therapeutically effective amount of a reverse transcriptase inhibitor or a combination of reverse transcriptase inhibitors. 338. The method of claim 337 wherein the reverse transcriptase inhibitor is selected from the group consisting of AZT (zidovudine), ddl (didanosine), ddC (zalcitabine), d4T (stavudine), 3TC (lamivudine), nevirapine, delaviridine, trovirdine, PMEA, bis- POMPMEA and MSA-300. 339. The method of claim 337 wherein the reverse transcriptase inhibitor is selected from the group consisting of AZT (zidovudine), ddl (didanosine), ddC (zalcitabine), d4T (stavudine), 3TC (lamivudine), nevirapine and delaviridine. 340. A method for inhibiting an HIV infection comprising administering to a human in need of such treatment the composition according to either of claims 333 or 334 [I:\DAYLIB\LIBC]03817.doc:SAK 213 in combination with a therapeutically effective amount of another HIV protease inhibitor or a combination of HIV protease inhibitors. 341. The method of claim 340 wherein the other HIV protease inhibitor is selected from the group consisting of ritonavir, saquinavir, indinavir, 5(S)-lBoc-amino- 4 (S)hydroxy-6-phenyl2(R)phenylmethyllexanoy(L)Val(L)-Phe- rnorphol in-4-ylamide; 1 -Naplhtloxyacety I-beta-methylthio-Ala-('2S 3 S)-3-am-ino-2-hiydroxy-4-butainoyl-1 ,3- tiazolidine-4-t-butylamide; 5-isoqulinolinoxyacetyI-beta-methyltio-Ala-(2S,3S 3 -aino-2-hydr-oxy-4-butanoyl iazolidine-4-t-butylamide; I 1 l1-dinmetlhylethyl)amiino)car-bonyl)(2-ineth)lpropyl)aniii 0 hiydroxy- I -(leility~ioy)2(2q iiln la-oila-io-uaida ie NH-) 0 H- N 0 0 Ph 0 CO HO OH)I 0 0 0 .000 H* N 11 N. H,1 [I:\DAYLIB\LIBCIO38 17.doc:SAK OH BocN H1- N NHBoc NOj OH- 0 I IN N ~N I-I I Ph Ph N -1 0 N N HVal--NH N O N and 0 oo .o o. o 0 00 0 .:000: .CF 3 S O \O or a pharmaceutically acceptable salt thereof, or a combination of two or more of these HIV protease inhibitors. 342. A method for inhibiting an HIV infection comprising administering to a human in need of such treatment the composition according to either of claims 333 or 334 in combination with a therapeutically effective amount of ritonavir or a pharmaceutically acceptable salt thereof. 343. A method for inhibiting an HIV infection comprising administering to a human in need of such treatment the composition according to either of claims 333 or 334 [I:\DAYLIB\LIBC]03817.doc:SAK 215 in combination with ritonavir or a pharmaceutically acceptable salt thereof in a ratio of the compound of claim 68 to ritonavir of from about 16:1 to about 344. A method for inhibiting an HIV infection comprising administering to a human in need of such treatment the composition according to either of claims 333 or 334 in combination with ritonavir or a pharmaceutically acceptable salt thereof in a ratio of the compound of claim 68 to ritonavir of from about 6:1 to about 1:3. 345. A method for inhibiting an HIV infection comprising administering to a human in need of such treatment the composition according to either of claims 333 or 334 in combination with ritonavir and one or more reverse transcriptase inhibitors. 346. The method of claim 345 wherein the reverse transcriptase inhibitor is selected from the group consisting of AZT (zidovudine), ddl (didanosine), ddC (zalcitabine), d4T (stavudine) and 3TC (lamivudine). 347. A method for inhibiting an HIV infection comprising administering to a human in need of such treatment the composition according to either of claims 333 or 334 in combination with ritonavir, AZT (zidovudine), and 3TC (lamivudine). 348. The method of any one of claims 337 to 339 wherein the composition according to either of claims 333 or 334 and the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are administered as separate agents. 349. The method of any one of claims 337 to 339 wherein the composition according to either of claims 333 or 334 and the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are administered as separate agents at the same time. 350. The method of any one of claims 337 to 339 wherein the composition according to either of claims 333 or 334 and the reverse transcriptase inhibitor or 25 combination of reverse transcriptase inhibitors are administered as separate agents at different times. 351. The method of any one of claims 337 to 339 wherein the composition according to either of claims 333 or 334 and the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are formulated as compositions comprising 30 two or more of the compounds. 352. The method of either of claims 340 or 341 wherein the composition according to either of claims 333 or 334 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are administered as separate agents. 353. The method of either of claims 340 or 341 wherein the composition according to either of claims 333 or 334 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are administered as separate agents at the same time. 354. The method of either of claims 340 or 341 wherein the composition according to either of claims 333 or 334 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are administered as separate agents at different times. [I:\DAYLIB\LIBC]03817.doc:SAK 216 355. The method of either of claims 340 or 341 wherein the composition according to either of claims 333 or 334 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are formulated as compositions comprising two or more of the compounds. 356. The method of any one of claims 342 to 344 wherein the composition according to either of claims 333 or 334 and the ritonavir are administered as separate agents. 357. The method of any one of claims 342 to 344 wherein the composition according to either of claims 333 or 334 and the ritonavir are administered as separate agents at the same time. 358. The method of any one of claims 342 to 344 wherein the composition according to either of claims 333 or 334 and the ritonavir are administered as separate agents at different times. 359. The method of any one of claims 342 to 344 wherein the composition according to either of claims 333 or 334 and the ritonavir are formulated as a composition comprising two or more compounds. 360. The method of any one of claims 345 to 347 wherein the composition according to either of claims 333 or 334 and the ritonavir and the one or more reverse transcriptase inhibitors are administered as separate agents. 361. The method of any one of claims 345 to 347 wherein the composition according to either of claims 333 or 334 and the ritonavir and the one or more reverse transcriptase inhibitors are administered as separate agents at the same time. 362. The method of any one of claims 345 to 347 wherein the composition according to either of claims 333 or 334 and the ritonavir and the one or more reverse 25 transcriptase inhibitors are administered as separate agents at different times. 363. The method of any one of claims 345 to 347 wherein the composition according to either of claims 333 or 334 and the ritonavir and the one or more reverse transcriptase inhibitors are formulated as compositions comprising two or more of the compounds. 30 364. Use of a composition according to either of claims 333 or 334 in the preparation of a medicament for inhibiting HIV protease. 365. Use of a composition according to either of claims 333 or 334 in the preparation of a medicament for inhibiting an HIV infection. 366. Use of a composition according to either of claims 333 or 334 in combination with one or more reverse transcriptase inhibitor(s) in the preparation of a medicament for inhibiting an HIV infection. 367. Use of a composition according to either of claims 333 or 334 in combination with one or more reverse transcriptase inhibitor(s) selected from the group consisting of AZT (zidovudine), ddl (didanosine), ddC (zalcitabine), d4T (stavudine), 3TC [I:\DAYLIB\LIBC03817.doc:SAK I 217 (lamnivudine), nevirapine, delaviridine, trovirdine, PMEA, bis-POMPMEA and.MSA-300 in the preparation of a med icament for inhibiting an HIV infection. 368. Use of a composition according to either of claims 333 or 334 in combination with one or more reverse transcriptase inhibitor(s) selected from the group consisting of AZT (zidovuidine), ddl (didanosine), ddC (zalcitabine), d4T (stavudine), 3TC (laivudine), nevirapine and delaviridine in the preparation of a medicament for inhibiting an H-IV infection. 369. Use of a composition according to either of claims 333 or 334 in combination wvith one or more other protease inhibitor(s) in the preparation of a medicament for an HIV infection. 370. Use of a comnposition according to either of claims 333 or 334 in combination with one or more other protease inhibitor(s) selected from the group consisting of ritonavir, s aquinavir, indinavir, (S)-Boc-ami-ino-4(S)-hydr-oxy-6-pheny -2(R)-phenyli-ethyliexanoy -(L)-Vai-(L)-Phie- rnorpholin-4-ylamide; I -Naphithoxyacety l-beta-m-ethiylthio-Ala-(2S ,3S)-3-amiino-2-hiydr-oxy-4-butaioy 1-1 ,3- thiazolidine-4-t-butylamide; inoxyacetyl-beta-i-ethylthio-Ala-(2S ,3S)-3-amiino-2-hiydr-oxy-4-butanoy 1-1,3 tiazolidine-4-t-butylamide; (1S-(1 1-dimethylethyl)amino)carbonyl)(2-methiylpropyl)amino-2- hydiroxy,- 1-(phienylmethyl)propyl)-2-((2-quinolinylcarbonyl)amino)-butanediaide; N 1-12 OH 0 N NS 0 0 Ph 00 1-10 O 0H IH 00. [I:\DAYLIB\LIBC]038 17.doc:SAK 0-C 0 pi OH BocNl-1 1-1 is 2 G.H N I-1 0OH N NI-Boc 0 NO0 0 *.eg *fr* 6 6tp* 0 01-H H HN H N N H 0~ 0 l Ph OH 0 0 Val-NH N N 0 0 K) H ;and [I:\DAYLIB\LIBC]038 17.doc:SAK 219 OH HN N O N in the preparation of a medicament for inhibiting an HIV infection. 371. Use of a composition according to either of claims 333 or 334 in combination with ritonavir or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting an HIV infection. 372. Use of a composition according to either of claims 333 or 334 in combination with ritonavir or a pharmaceutically acceptable salt thereof in a ratio of the compound of claim 68 to ritonavir of from about 16:1 to about 1:5 in the preparation of a medicament for inhibiting an HIV infection. 373. Use of a composition according to either of claims 333 or 334 in combination with ritonavir or a pharmaceutically acceptable salt thereof in a ratio of the compound of claim 68 to ritonavir of from about 6:1 to about 1:3 in the preparation of a medicament for inhibiting an HIV infection. 374. Use of a composition according to either of claims 333 or 334 in combination with ritonavir and one or more reverse transcriptase inhibitors for the preparation of a medicament for inhibiting an HIV infection. 375. Use of a composition according to either of claims 333 or 334 in combination with ritonavir and one or more reverse transcriptase inhibitors selected from the group consisting of AZT (zidovudine), ddl (didanosine), ddC (zalcitabine), d4T (stavudine) and 20 3TC (lamivudine) for the preparation of a medicament for inhibiting an HIV infection. 376. Use of a composition according to either of claims 333 or 334 in combination with ritonavir and AZT (zidovudine), and 3TC (lamivudine) for the preparation of a medicament for inhibiting an HIV infection. 377. The composition according to either of claims 333 or 334 when used for 25 inhibiting an HIV infection. 378. The composition according to either of claims 333 or 334 when used for inhibiting HIV protease. 379. The composition according to either of claims 333 or 334 when used in combination with one or more reverse transcriptase inhibitor(s) for inhibiting an HIV infection. 380. The composition according to either of claims 333 or 334 when used in combination with one or more reverse transcriptase inhibitor(s) selected from the group consisting of AZT (zidovudine), ddl (didanosine), ddC (zalcitabine), d4T (stavudine), [I:\DAYLIB\LIBC]03817.doc:SAK 220 3TC (lamivudine), nevirapine, delaviridine, trovirdine, PMEA, bis-POMPMEA and MSA-300 for inhibiting an HIV infection. 381. The composition according to either of claims 333 or 334 when used in combination with one or more reverse transcriptase inhibitor(s) selected from the group of AZT (zidovudine), ddl (didanosine), ddC (zalcitabine), d4T (stavudine), 3TC (lamnivudine), nevirapine and delaviridine for inhibiting an HIV infection. 382. The composition according to either of claims 333 or 334 when used in combination with one Or more other HI1V protease inhibitor(s) for inhibiting an HIV infection. 383. The composition according to either of claimns 333 or 334 when used inl combinationl with one Or more other HIV protease inhibitor(s) selected from the group consisting of ritonavir, saquinavir, indinavir, 5()Bcaiio4S-iyrx--hnl2 )phnlieiyhxny-L)-Val-( L)-Phle- mnorphol in-.4-ylamide; 1 5 1 -Naphthioxyacetyl-beta-methyltflioAla-(2S.3 S)-3 -am-ino-2--hydroxy-4-butanoyl 1 ,3- thiiazol id ine-4-t-butylamide; -isoqulinol inoxyacetyl-beta-methylthioAla-(2S ,3 S)- 3 -amino-2-hydroxy-4butanoyl-1,3- th iazol idine-4--t-butylamide; l-dirnethyIethyI)amino)carbonyl)(27methylpropyI)amino)-2 hydrFoxy -I -(hn eh oy1 2(2q oIiFyIabn ~m1n)btndimi NH, 0 N N S 0 Ph,_, 0 1-10 01-I 0 l-1 9 N NN- tI:\DAYLIB\LlBCJ038 17.doc:SAK OH 17 N NIS IBocNH- 1-1 0 1-i IfI N H NHBoc 00 N O OH NH YN 0 N 0 ySO N H ;and OH CF 3 0-S-\ for inhibiting an HIV infection. 384. The composition according to either of claims 333 or 334 when used in combination with ritonavir or a pharmaceutically acceptable salt thereof for inhibiting an HIV infection. [1:\DAYLIB\LIBC]038 17.doc:SAK 385. The composition according to either of claims 333 or 334 when used in combination with ritonavir or a pharmaceutically acceptable salt thereof in a ratio (w/w) of the compound of claim 68 to ritonavir of from about 16:1 to about 1:5 for inhibiting an HIV infection. 386. The composition according to either of claims 333 or 334 when used in combination with ritonavir or a pharmaceutically acceptable salt thereof in a ratio (w/w) of the compound of claim 68 to ritonavir of from about 6:1 to about 1:3 for inhibiting an HIV infection. 387. The composition according to either of claims 333 or 334 when used in combination with ritonavir and one or more reverse transcriptase for inhibiting an HIV infection. 388. The composition according to either of claims 333 or 334 when used in combination with ritonavir and one or more reverse transcriptase inhibitors selected from the group consisting of AZT (zidovudine), ddl (didanosine), ddC (zalcitabine), d4T (stavudine) and 3TC (lamivudine) for inhibiting an HIV infection. 389. The composition according to either of claims 333 or 334 when used in combination with ritonavir and AZT (zidovudine), and 3TC (lamivudine) for inhibiting an HIV infection. 390. Use according to any one of claims 366 to 368 wherein the composition of either claim 333 or claim 334 and the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are administered as separate agents. 391. Use according to any one of claims 366 to 368 wherein the composition of either claim 333 or claim 334 and the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are administered as separate agents at the same time. 25 392. Use according to any one of claims 366 to 368 wherein the composition of either claim 333 or claim 334 and the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are administered as separate agents at different times. 393. Use according to any one of claims 366 to 368 wherein the composition of either claim 333 or claim 334 and the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are formulated as compositions comprising two or more of the compounds. 394. Use according to either of claims 369 or 370 wherein the composition of either claim 333 or claim 334 and the other HIV protease inhibitor or combination of "other HIV protease inhibitors are administered as separate agents. 35 395. Use according to either of claims 369 or 370 wherein the composition of either claim 333 or claim 334 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are administered as separate agents at the same time. 396. Use according to either of claims 369 or 370 wherein the composition of either claim 333 or claim 334 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are administered as separate agents at different times. [I:\DAYLB\LIBC]0387.doc:SAK 223 397. Use according to either of claims 369 or 370 wherein the composition of either claim 333 or claim 334 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are formulated as compositions comprising two or more of the compounds. 398. Use according to any one of claims 371 to 373 wherein the composition of either claim 333 or claim 334 and the ritonavir are administered as separate agents. 399. Use according to any one of claims 371 to 373 wherein the composition of either claim 333 or claim 334 and the ritonavir are administered as separate agents at the same time. 400. Use according to any one of claims 371 to 373 wherein the composition of either claim 333 or claim 334 and the ritonavir are administered as separate agents at different times. 401. Use according to any one of claims 371 to 373 wherein the composition of either claim 333 or claim 334 and the ritonavir are formulated as a composition comprising two or more compounds. 402. Use according to any one of claims 374 to 376 wherein the composition of either claim 333 or claim 334 and the ritonavir and the one or more reverse transcriptase inhibitors are administered as separate agents. 403. Use according to any one of claims 374 to 376 wherein the composition of either claim 333 or claim 334 and the ritonavir and the one or more reverse transcriptase inhibitors are administered as separate agents at the same time. 404. Use according to any one of claims 374 to 376 wherein the composition of either claim 333 or claim 334 and the ritonavir and the one or more reverse transcriptase inhibitors are administered as separate agents at different times. 25 405. Use according to any one of claims 374 to 376 wherein the composition of either claim 333 or claim 334 and the ritonavir and the one or more reverse transcriptase inhibitors are formulated as compositions comprising two or more of the compounds. 406. The composition of either claim 333 or claim 334 when used according to any one of claims 379 to 381 wherein the composition of either claim 333 or claim 334 and the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are administered as separate agents. 407. The composition of either claim 333 or claim 334 when used according to any one of claims 379 to 381 wherein the composition of either claim 333 or claim 334 and the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are 35 administered as separate agents at the same time. 408. The composition of either claim 333 or claim 334 when used according to any one of claims 379 to 381 wherein the composition of either claim 333 or claim 334 and the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are administered as separate agents at different times. [I:\DAYLIB\LIBC]03817.doc:SAK 224 409. The composition of either claim 333 or claim 334 when used according to any one of claims 379 to 381 wherein the composition of either claim 333 or claim 334 and the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are formulated as compositions comprising two or more of the compounds. 410. The composition of either claim 333 or claim 334 when used according to either of claims 382 or 383 wherein the composition of either claim 333 or claim 334 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are administered as separate agents. 411. The composition of either claim 333 or claim 334 when used according to either of claims 382 or 383 wherein the composition of either claim 333 or claim 334 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are administered as separate agents at the same time. 412. The composition of either claim 333 or claim 334 when used according to either of claims 382 or 383 wherein the composition of either claim 333 or claim 334 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are administered as separate agents at different times. 413. The composition of either claim 333 or claim 334 when used according to either of claims 382 or 383 wherein the composition of either claim 333 or claim 334 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are formulated as compositions comprising two or more of the compounds. 414. The composition of either claim 333 or claim 334 when used according to any one of claims 384 to 386 wherein the composition of either claim 333 or claim 334 and the ritonavir are administered as separate agents. 415. The composition of either claim 333 or claim 334 when used according to any 25 one of claims 384 to 386 wherein the composition of either claim 333 or claim 334 and the ritonavir are administered as separate agents at the same time. 416. The composition of either claim 333 or claim 334 when used according to any "i one of claims 384 to 386 wherein the composition of either claim 333 or claim 334 and *'the ritonavir are administered as separate agents at different times. 417. The composition of either claim 333 or claim 334 when used according to any one of claims 384 to 386 wherein the composition of either claim 333 or claim 334 and the ritonavir are formulated as a composition comprising two or more compounds. 418. The composition of either claim 333 or claim 334 when used according to any one of claims 387 to 389 wherein the composition of either claim 333 or claim 334 and 35 the ritonavir and the one or more reverse transcriptase inhibitors are administered as separate agents. 419. The composition of either claim 333 or claim 334 when used according to any one of claims 387 to 389 wherein the composition of either claim 333 or claim 334 and the ritonavir and the one or more reverse transcriptase inhibitors are administered as separate agents at the same time. [I:\DAYLIB\LIBC03817.doc:SAK 225 420. The composition of either claim 333 or claim 334 when used according to any one of claims 387 to 389 wherein the composition of either claim 333 or claim 334 and the ritonavir and the one or more reverse transcriptase inhibitors are administered as separate agents at different times. 421. The composition of either claim 333 or claim 334 when used according to any one of claims 387 to 389 wherein the composition of either claim 333 or claim 334 and the ritonavir and the one or more reverse transcriptase inhibitors are formulated as compositions comprising two or more of the compounds. 422. A medicament when prepared according to any one of claims 99 to 111, 186 lo to 198, 274 to 286, or 364 to 376. 423. A process for the preparation of a pharmaceutical composition comprising a compound according to claim 1, said process substantially as hereinbefore described with reference to any one of Examples 43 to 424. A pharmaceutical composition when prepared by the process of claim 423. 425. A pharmaceutical composition comprising a compound according to claim 1, substantially as hereinbefore described with reference to any one of the Examples. 426. Use of a compound according to any one of claims 1 to 8 or a composition of claim 9 in the preparation of a medicament for inhibiting HIV protease. 427. Use of a compound according to any one of claims 1 to 8 or a composition according to any one of claims 9, 424 or 425 in the preparation of a medicament for inhibiting HIV infection. S428. A medicament when prepared according to either claim 426 or claim 427. 429. The compound according to any one of claims 1 to 8 or a composition according to any one of claims 9, 424 or 425 when used in the inhibition of HIV protease. 25 430. The compound according to any one of claims 1 to 8 or a composition according to any one of claims 9, 424 or 425 when used in the inhibition of HIV infection. 431. A method according to any one of claims 14 to 22 wherein the compounds of the method are administered as separate agents. 432. A method according to any one of claims 14 to 22 wherein the compounds of the method are administered as separate agents at the same time. :433. A method according to any one of claims 14 to 22 wherein the compounds of the method are administered as separate agents at different times. 434. A method according to any one of claims 14 to 22 wherein the compounds of 35 the method are formulated as a single composition comprising two or more compounds. 435. A compound according to claim 1 when prepared by the process of any one of claims 52 to 57, 62 and 63. 436. A compound of the formula [I:\DAYLIB\LBCj03817.doc:SAK 226 r, HN N CO 2 H 0 R 3 or a salt or ester thereof, wherein R 3 is loweralkyl, hydroxyalkyl or cycloalkylalkyl when prepared by the process of any one of claims 45 to 51. 437. (2S, 3S, 5S)- 2 2 ,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-amino-1,6- diphenylhexane or a salt thereof when prepared by the process of claim 58. 438. A compound of the formula H H QN N CO 2 H 0 R3 or a salt or ester thereof, wherein R 3 is loweralkyl, hydroxyalkyl or cycloalkylalkyl and Q is a leaving group when prepared by the process of any one of claims 59 to 61. 439. 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, substantially as hereinbefore described with reference to any one of the Examples. 440. The compound (2S, 3S, 5S)-2-(2, 6 -dimethylphenoxyacetyl) amino-3-hydroxy- 5-amino-l,6-diphenylhexane or a salt thereof when prepared by the process of claim 439. 441. A compound according to any one of claims 23 to 29, substantially as hereinbefore described with reference to any one of Examples 31 to 33. 442. A process for the preparation of a compound according to any one of claims 23 to 29 substantially as hereinbefore described with reference to any one of the "Examples. 20 443. A compound according to any one of claims 23 to 29 when prepared according to claim 442. 444. A pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount of a compound according to any one of claims 23 to 44, 64, 66, 440, 441, or 443.
162. 445. A method for inhibiting HIV protease comprising administering to a human in need of such treatment a therapeutically effective amount of a compound according to any one of claims 23 to 44, 64, 66, 440, 441, or 443 or a composition according to claim 444.
163. 446. A method for inhibiting an HIV infection comprising administering to a 30 human in need of such treatment a therapeutically effective amount of a compound according to any one of claims 23 to 44, 64, 66, 440, 441, or 443 or a composition according to claim 444. II:\DAYLIB\LIBC]03817.doc:SAK
164. 447. Use of a compound according to any one of claims 23 to 44, 64, 66,.440, 441, or 443 or of a composition according to claim 444 in the preparation of a medicament for inhibiting HIV protease.
165. 448. Use of a compound according to any one of claims 23 to 44, 64, 66, 440, 441, or 443 or of a composition according to claim 444 in the preparation of a medicament for inhibiting HIV infection.
166. 449. A medicament prepared according to either claim 447 or claim 448.
167. 450. The compound according to any one of claims 23 to 44, 64, 66, 440, 441, or 443 or a composition according to claim 444 when used in the inhibition of HIV protease.
168. 451. The compound according to any one of claims 23 to 44, 64, 66, 440, 441, or 443 or a composition according to claim 444 when used in the inhibition of HIV infection.
169. 452. A method for inhibiting HIV protease comprising administering to a human in need of such treatment a therapeutically effective amount of a compound according to claim 1.
170. 453. A method for inhibiting an HIV infection comprising administering to a human in need of such treatment a therapeutically effective amount of a compound according to claim 1.
171. 454. A method for inhibiting an HIV infection comprising administering to a human in need of such treatment a therapeutically effective amount of a compound according to claim 1 in combination with a therapeutically effective amount of a reverse transcriptase inhibitor or a combination of reverse transcriptase inhibitors.
172. 455. The method of claim 454 wherein the reverse transcriptase inhibitor is selected from the group consisting of AZT (zidovudine), ddl (didanosine), ddC (zalcitabine), d4T 25 (stavudine), 3TC (lamivudine), nevirapine, delaviridine, trovirdine, PMEA, bis- POMPMEA and MSA-300.
173. 456. The method of claim 454 wherein the reverse transcriptase inhibitor is selected from the group consisting of AZT (zidovudine), ddl (didanosine), ddC (zalcitabine), d4T .(stavudine), 3TC (lamivudine), nevirapine and delaviridine.
174. 457. A method for inhibiting an HIV infection comprising administering to a human in need of such treatment a therapeutically effective amount of a compound according to claim 1 in combination with a therapeutically effective amount of another HIV protease inhibitor or a combination of HIV protease inhibitors.
175. 458. The method of claim 457 wherein the other HIV protease inhibitor is selected 35 from the group consisting of ritonavir, saquinavir, indinavir, 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, 3 S)- 3 -amino-2-hydroxy-4-butanoyl-1,3- thiazolidine-4-t-butylamide; [I:\DAYLB\LBC10387.doc:SAK 228 -isoquinol inoxyacetyl-beta-methylthio-Ala-(2S 3 S)-3-amino-2-hydroxy-4-butanoyl- 1, 3- thiazolI id ine-4-t-butylamide; (I1S-(l 1 -dimethylethyl)ar-nino)carbonyl)(2-methylpropyl)amino)-2 hyd roxy- 1 -(pheny i-nethyl)propyl)-2-((2-qu inolinylcarbonyl)amino)-butanediamjde; N01-I- N s H0 0 Ph 0 110)- N N al-I 0 0-L N1N CO N NH 00 140I- NNHc 0 NO- 0 [1:\DAYLIB\LIBC]038 17.doc:SAK N N N9 229 OH H I1- H P N Ph 01-1 Val--NI-I 0 N I-I and CF 3 S 5 or a pharmaceutically acceptable salt thereof, or a combination of two or more of these HIV protease inhibitors.
176. 459. A method for inhibiting an HIV infection comprising administering to a human in need of such treatment a therapeutically effective amount of a compound according to claim 1 in combination with a therapeutically effective amount of ritonavir or a pharmaceutically acceptable salt thereof.
177. 460. A method for inhibiting an HIV infection comprising administering to a human in need of such treatment a compound according to claim 1 in combination with ritonavir or a pharmaceutically acceptable salt thereof in a ratio of the compound of claim 1 to ritonavir of from about 16:1 to about
178. 461. A method for inhibiting an HIV infection comprising administering to a human in need of such treatment a compound according to claim 1 in combination with ritonavir or a pharmaceutically acceptable salt thereof in a ratio of the compound of claim I to ritonavir of from about 6:1 to about 1:3.
179. 462. A method for inhibiting an HIV infection comprising administering to a human in need of such treatment a therapeutically effective amount of a compound IA:\DAYLLB\LIBC03817.doc:SAK 230 according to claim 1 in combination with ritonavir and one or more reverse transcriptase inhibitors.
180. 463. The method of claim 462 wherein the reverse transcriptase inhibitor is selected from the group consisting of AZT (zidovudine), ddl (didanosine), ddC (zalcitabine), d4T (stavudine) and 3TC (lamivudine).
181. 464. A method for inhibiting an HIV infection comprising administering to a human in need of such treatment a therapeutically effective amount of a compound according to claim 1 in combination with ritonavir, AZT (zidovudine), and 3TC (lamivudine).
182. 465. The method of any one of claims 454 to 456 wherein the compound of claim 1 iand the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are administered as separate agents.
183. 466. The method of any one of claims 454 to 456 wherein the compound of claim 1 and the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are administered as separate agents at the same time.
184. 467. The method of any one of claims 454 to 456 wherein the compound of claim 1 and the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are administered as separate agents at different times.
185. 468. The method of any one of claims 454 to 456 wherein the compound of claim 1 and the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are formulated as compositions comprising two or more of the compounds.
186. 469. The method of either of claims 457 or 458 wherein the compound of claim 1 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are administered as separate agents. :o 25 470. The method of either of claims 457 or 458 wherein the compound of claim 1 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are administered as separate agents at the same time.
187. 471. The method of either of claims 457 or 458 wherein the compound of claim 1 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are 30 administered as separate agents at different times.
188. 472. The method of either of claims 457 or 458 wherein the compound of claim 1 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are formulated as compositions comprising two or more of the compounds.
189. 473. The method of any one of claims 459 to 461 wherein the compound of claim 1 35 and the ritonavir are administered as separate agents.
190. 474. The method of any one of claims 459 to 461 wherein the compound of claim 1 and the ritonavir are administered as separate agents at the same time.
191. 475. The method of any one of claims 459 to 461 wherein the compound of claim 1 and the ritonavir are administered as separate agents at different times. [I:\DAYLIB\LIBC]03817.doc:SAK 231
192. 476. The method of any one of claims 459 to 461 wherein the compound .of claim 1 and the ritonavir are formulated as a composition comprising two or more compounds. O 477. The method of any one of claims 462 to 464 wherein the compound of claim 1 and the ritonavir and the one or more reverse transcriptase inhibitors are administered as separate agents.
193. 478. The method of any one of claims 462 to 464 wherein the compound of claim 1 and the ritonavir and the one or more reverse transcriptase inhibitors are administered as separate agents at the same time.
194. 479. The method of any one of claims 462 to 464 wherein the compound of claim 1 io and the ritonavir and the one or more reverse transcriptase inhibitors are administered as separate agents at different times.
195. 480. The method of any one of claims 462 to 464 wherein the compound of claim 1 and the ritonavir and the one or more reverse transcriptase inhibitors are formulated as compositions comprising two or more of the compounds.
196. 481. Use of a compound according to claim 1 in the preparation of a medicament for inhibiting HIV protease.
197. 482. Use of a compound according to claim 1 in the preparation of a medicament for inhibiting an HIV infection.
198. 483. Use of a compound according to claim 1 in combination with one or more reverse transcriptase inhibitor(s) in the preparation of a medicament for inhibiting an HIV infection.
199. 484. Use of a compound according to claim 1 in combination with one or more reverse transcriptase inhibitor(s) selected from the group consisting of AZT (zidovudine), ddl (didanosine), ddC (zalcitabine), d4T (stavudine), 3TC (lamivudine), nevirapine, 25 delaviridine, trovirdine, PMEA, bis-POMPMEA and MSA-300 in the preparation of a medicament for inhibiting an HIV infection.
200. 485. Use of a compound according to claim 1 in combination with one or more reverse transcriptase inhibitor(s) selected from the group consisting of AZT (zidovudine), ddl (didanosine), ddC (zalcitabine), d4T (stavudine), 3TC (lamivudine), nevirapine and 30 delaviridine in the preparation of a medicament for inhibiting an HIV infection.
201. 486. Use of a compound according to claim 1 in combination with one or more other protease inhibitor(s) in the preparation of a medicament for inhibiting an HIV infection.
202. 487. Use of a compound according to claim 1 in combination with one or more 35 other protease inhibitor(s) selected from the group consisting of ritonavir, saquinavir, indinavir, 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-l,3- thiazolidine-4-t-butylamide; [I:\DAYLIB\LIBC03817.doc:SAK 232 5-isoquinolinoxyacetyl-beta-methylthio-Ala-(2S ,3S)-3-ar-nino-2-hydroxy-4-butanoyl- 1,3- th iazol id ine-4-t-buty lamide; (1 I 1-dimethylethyl)anino)carbonyI) (2-methy lp ropylI)ami no) 2- hyd roxy- 1 -(pheiiylmetlhyl)propyl)-2-((2-quinol inylcarbonyl)arnino)-butanlediamiide; NI- OH 0 NJ NI s 0 0 Ph 0 N N 0 000. .0 S. S 00 0 0000 *4 00 0 S 9 0 OS@e S. 9 so g. S .09 0 *909 OH H N PhS N H- 0OH BocN H- H N Ph 2 NHBoc too [I:\DAYLIB\LIBC]038 17.doc:SAK 233 I-I 1 H N H NN N N H 0 Ph N S Val-NH N N 0 I-I and OH HN CFJ O O in the preparation of a medicament for inhibiting an HIV infection. 5 488. Use of a compound according to claim 1 in combination with ritonavir or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting an HIV infection.
203. 489. Use of a compound according to claim 1 in combination with ritonavir or a pharmaceutically acceptable salt thereof in a ratio of the compound of claim 1 to 10 ritonavir of from about 16:1 to about 1:5 in the preparation of a medicament for inhibiting an HIV infection.
204. 490. Use of a compound according to claim 1 in combination with ritonavir or a pharmaceutically acceptable salt thereof in a ratio of the compound of claim 1 to i ritonavir of from about 6:1 to about 1:3 in the preparation of a medicament for inhibiting an HIV infection.
205. 491. Use of a compound according to claim 1 in combination with ritonavir and one or more reverse transcriptase inhibitors for the preparation of a medicament for inhibiting an HIV infection.
206. 492. Use of a compound according to claim 1 in combination with ritonavir and one or more reverse transcriptase inhibitors selected from the group consisting of AZT [I:\DAYLIB\LIBC]03817.doc:SAK 234. (zidovudine), ddl (didanosine), ddC (zalcitabine), d4T (stavudine) and 3TC (lamivudine) for the preparation of a medicament for inhibiting an HIV infection.
207. 493. Use of a compound according to claim I in combination with ritonavir and AZT (zidovudine), and 3TC (lamivudine) for the preparation of a medicament for inhibiting an HIV infection.
208. 494. A compound according to claim 1 when used for inhibiting an HIV infection.
209. 495. A compound according to claim 1 when used for inhibiting HIV protease.
210. 496. A compound according to claim 1 when used in combination with one or more reverse transcriptase inhibitor(s) for inhibiting an I-IIV infection.
211. 497. A compound according to claim 1 when used in combination with one or more reverse transcriptase inhibitor(s) selected from the group consisting of AZT (zidovudine), ddl (didanosine), ddC (zalcitabine), d4T (stavudine), 3TC (lamivudine), nevirapine, delaviridine, trovirdine, PMEA, bis-POMPMEA and MSA-300 for inhibiting an HIV infection.
212. 498. A compound according to claim 1 when used in combination with one or more reverse transcriptase inhibitor(s) selected from the group consisting of AZT (zidovudine). ddl (didanosine), ddC (zalcitabine), d4T (stavudine), 3TC (lamivudine), nevirapine and delaviridine for inhibiting an HIV infection.
213. 499. A compound according to claim 1 when used in combination with one or more Other HIV protease inhibitor(s) for inhibiting an HIV infection.
214. 500. A compound according to claim 1 when used in combination with one or more other I-IV protease inhibitor(s) selected from the group consisting of ritonavir, saquinavir, indinavir, (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- thiazolidine-4-t-butylamide; 5-isoquinolinoxyacetyl-beta-methylthio-Ala-(2S, 3S)-3-amino-2-hydroxy-4-butanoyl-1,3- thiazolidine-4-t-butylamide; (1S-(1 -dimethylethyl)amino)carbonyl)(2methylpropyl)amino)-2- hydroxy- 1 -(phenylmethyl I)propyl)- 2 -((2-quinolinyl Icarbonyl)amino)-butanediamide; SOH NH 2 N N 0 0 0 Ph2 [I:\DAYLIB\LIBC]03817.doc:SAK 235 0,-OO 0) 0 n I-kN 0 1-10 01-1 NH 9 k OH- H BH N Phh NHBoc NO 0 0 OH I- IH N H NNN 0 0 0 Ph 11I:\DA YLIB\LIBC]038 17.doc: SAK 236 N O OH 0 0 Val-NI-l N o0 ;and 01- o0 3 HNN S SO N for inhibiting an HIV infection.
215. 501. A compound according to claim 1 when used in combination with ritonavir or a pharmaceutically acceptable salt thereof for inhibiting an HIV infection.
216. 502. A compound according to claim 1 when used in combination with ritonavir or a pharmaceutically acceptable salt thereof in a ratio of the compound of claim 1 to ritonavir of from about 16:1 to about 1:5 for inhibiting an HIV infection.
217. 503. A compound according to claim 1 when used in combination with ritonavir or a pharmaceutically acceptable salt thereof in a ratio of the compound of claim 1 to ritonavir of from about 6:1 to about 1:3 for inhibiting an HIV infection.
218. 504. A compound according to claim 1 when used in combination with ritonavir and one or more reverse transcriptase for inhibiting an HIV infection.
219. 505. A compound according to claim 1 when used in combination with ritonavir 15 and one or more reverse transcriptase inhibitors selected from the group consisting of AZT (zidovudine), ddl (didanosine), ddC (zalcitabine), d4T (stavudine) and 3TC (lamivudine) for inhibiting an HIV infection.
220. 506. A compound according to claim 1 when used in combination with ritonavir and AZT (zidovudine), and 3TC (lamivudine) for inhibiting an HIV infection.
221. 507. Use according to any one of claims 483 to 485 wherein the compound of claim I and the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are administered as separate agents.
222. 508. Use according to any one of claims 483 to 485 wherein the compound of claim 1 and the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are administered as separate agents at the same time. [I:\DAYLIB\LIBC]03817.doc:SAK 237
223. 509. Use according to any one of claims 483 to 485 wherein the compound of claim I and the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are administered as separate agents at different times.
224. 510. Use according to any one of claims 483 to 485 wherein the compound of claim s 1 and the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are formulated as compositions comprising two or more of the compounds.
225. 511. Use according to either of claims 486 or 487 wherein the compound of claim 1 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are administered as separate agents.
226. 512. Use according to either of claims 486 or 487 wherein the compound of claim I and the other HIV protease inhibitor or combination of other HIV protease inhibitors are administered as separate agents at the same time.
227. 513. Use according to either of claims 486 or 487 wherein the compound of claim 1 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are administered as separate agents at different times.
228. 514. Use according to either of claims 486 or 487 wherein the compound of claim 1 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are formulated as compositions comprising two or more of the compounds.
229. 515. Use according to any one of claims 488 to 490 wherein the compound of claim 20 1 and the ritonavir are administered as separate agents.
230. 516. Use according to any one of claims 488 to 490 wherein the compound of claim 1 and the ritonavir are administered as separate agents at the same time.
231. 517. Use according to any one of claims 488 to 490 wherein the compound of claim 1 and the ritonavir are administered as separate agents at different times.
232. 518. Use according to any one of claims 488 to 490 wherein the compound of claim 68 and the ritonavir are formulated as a composition comprising two or more compounds.
233. 519. Use according to any one of claims 491 to 493 wherein the compound of claim 1 and the ritonavir and the one or more reverse transcriptase inhibitors are administered as separate agents.
234. 520. Use according to any one of claims 491 to 493 wherein the compound of claim 1 and the ritonavir and the one or more reverse transcriptase inhibitors are administered as separate agents at the same time.
235. 521. Use according to any one of claims 491 to 493 wherein the compound of claim 1 and the ritonavir and the one or more reverse transcriptase inhibitors are administered as separate agents at different times.
236. 522. Use according to any one of claims 491 to 493 wherein the compound of claim 1 and the ritonavir and the one or more reverse transcriptase inhibitors are formulated as compositions comprising two or more of the compounds. [I:\DAYLIB\LIBC]03817.doc:SAK 238
237. 523. A compound according to claim 1 when used according to any one of claims 496 to 498 wherein the compound of claim 1 and the reverse transcriptase inhibitor or 0 combination of reverse transcriptase inhibitors are administered as separate agents.
238. 524. A compound according to claim 1 when used according to any one of claims 496 to 498 wherein the compound of claim 1 and the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are administered as separate agents at the same time.
239. 525. A compound according to claim 1 when used according to any one of claims 496 to 498 wherein the compound of claim 1 and the reverse transcriptase inhibitor or o1 combination of reverse transcriptase inhibitors are administered as separate agents at different times.
240. 526. A compound according to claim 1 when used according to any one of claims 496 to 498 wherein the compound of claim 1 and the reverse transcriptase inhibitor or combination of reverse transcriptase inhibitors are formulated as compositions comprising two or more of the compounds.
241. 527. A compound according to claim 1 when used according to either of claims 499 to 500 wherein the compound of claim 1 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are administered as separate agents.
242. 528. A compound according to claim 1 when used according to either of claims 499 to 500 wherein the compound of claim 1 and the other HIV protease inhibitor or Scombination of other HIV protease inhibitors are administered as separate agents at the same time. S* 529. A compound according to claim 1 when used according to either of claims 499 to 500 wherein the compound of claim 1 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are administered as separate agents at •different times.
243. 530. A compound according to claim 1 when used according to either of claims 499 to 500 wherein the compound of claim 1 and the other HIV protease inhibitor or combination of other HIV protease inhibitors are formulated as compositions comprising two or more of the compounds.
244. 531. A compound according to claim 1 when used according to any one of claims 501 to 503 wherein the compound of claim 1 and the ritonavir are administered as separate agents.
245. 532. A compound according to claim 1 when used according to any one of claims 501 to 503 wherein the compound of claim 1 and the ritonavir are administered as separate agents at the same time.
246. 533. A compound according to claim 1 when used according to any one of claims 501 to 503 wherein the compound of claim 1 and the ritonavir are administered as separate agents at different times. [I:\DAYLIB\LIBC]03817.doc:SAK 239
247. 534. A compound according to claim 1 when used according to any one.of claims 501 to 503 wherein the compound of claim 1 and the ritonavir are formulated as a composition comprising two or more compounds.
248. 535. A compound according to claim 1 when used according to any one of claims 504 to 506 wherein the compound of claim 1 and the ritonavir and the one or more reverse transcriptase inhibitors are administered as separate agents.
249. 536. A compound according to claim 1 when used according to any one of claims 504 to 506 wherein the compound of claim 1 and the ritonavir and the one or more leverse transcriptase inhibitors are administered as separate agents at the same time.
250. 537. A compound according to claim 1 when used according to any one of claims 504 to 506 wherein the compound of claim 1 and the ritonavir and the one or more icv\erse transcriptase inhibitors are administered as separate agents at different times.
251. 538. A compound according to claim 1 when used according to any one of claims 504 to 506 wherein the compound of claim 1 and the ritonavir and the one or more reverse transcriptase inhibitors are formulated as compositions comprising two or more of the compounds.
252. 539. A process of preparing a compound according to claim 1, which process is substantially as herein described with reference to any one of the Examples.
253. 540. A compound according to claim 1 when prepared according to the process of 20 claim 539.
254. 541. A composition comprising the compound of claim 1 in combination with at least one reverse transcriptase inhibitor.
255. 542. A composition according to claim 541 wherein the reverse transcriptase inhibitor is selected from the group consisting of AZT (zidovudine), ddl (didanosine), ddC (zalcitabine), d4T (stavudine), 3TC (lamivudine), nevirapine, delaviridine, trovirdine, PMEA, bis-POMPMEA and MSA-300. ~543. A composition comprising the compound of claim 1 in combination with at least one other HIV protease inhibitor.
256. 544. A composition according to claim 543 wherein the other protease inhibitor is selected from the group consisting of ritonavir, saquinavir, indinavir, 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-l,3- thiazolidine-4-t-butylamide; 5-isoquinolinoxyacetyl-beta-methylthio-Ala-(2S,3S)-3-amino-2-hydroxy-4-butanoyl-1,3- thiazolidine-4-t-butylamide; 1,1 -dimethylethyl)amino)carbonyl)(2-methylpropyl)amino)-2- hydroxy- 1-(phenylmethyl)propyl)-2-((2-quinolinylcarbonyl)amino)-butanediamide; [I:\DAYLIB\LIBC]03817.doc:SAK 240 OH o Ph 0 0 N N 'S 0 0 N H2I a. a a~ a. 0 P1' OH BocNI- Ph' N H NI-Boc 0 1-H 01-I ENN Ph I! :\DAYLIB\LIBC]038 17 .doc: SAK N OH S Y Val-NH N N 0 N and OH Ph O O CF3 HNN 00 oS N or a pharmaceutically acceptable salt thereof.
257. 545. A composition comprising the compound of claim 1 in combination with ritonavir. ~546. A composition comprising the compound of claim 1 in combination with ritonavir and at least one reverse transcriptase inhibitor. 44
258. 547. A composition according to claim 546 wherein the reverse transcriptase S1io inhibitor is selected from the group consisting of AZT (zidovudine), ddl (didanosine), SddC (zalcitabine), d4T (stavudine) and 3TC (lamivudine).
259. 548. A pharmaceutical composition comprising a composition according to any one of claims 541 to 547 in combination with a pharmaceutically acceptable carrier.
260. 549. A process of preparing a pharmaceutical composition according to claim 548, wherein said process comprises mixing the composition of any one of claims 541 to 547 4 with a pharmaceutically acceptable carrier.
261. 550. A pharmaceutical composition when prepared by the process of claim 549. S. 551. A process of preparing a composition according to either claim 541 or claim 542, wherein said process comprises mixing a compound of claim 1 with at least one reverse transcriptase inhibitor.
262. 552. A process of preparing a composition according to either claim 543 or claim 544, wherein said process comprises mixing a compound of claim 1 with at least one other HIV protease inhibitor.
263. 553. A process of preparing a composition according to any one of claims 545 to 546, wherein said process comprises mixing a compound of claim 1 with ritonavir and at least one reverse transcriptase inhibitor. II:\DAYLIB\LIBCIO3S17.doc:SAK 242
264. 554. A composition when prepared according to any one of claims 551 to 553.
265. 555. A process of preparing a pharmaceutical composition wherein said process comprises mixing a composition according to claim 554 with a pharmaceutically acceptable carrier.
266. 556. A pharmaceutical composition when prepared according to the process of claim 555. .o [I:\DAYLIB\LIBC03817.doc:SAK 243 1. The compound (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy- 0 5-[2S-(1-tetrahydro-pyrimid-2-onyl)-3-methylbutanoyl]amino-1,6-diphenylhexane; or a pharmaceutically acceptable salt, ester or prodrug thereof. 2. The compound (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy- 5-[2S-(1-tetrahydro-pyrimid-2-onyl)-3-methylbutanoyl]amino-1,6-diphenylhexane. 3. A pharmaceutical composition for inhibiting HIV protease comprising a pharmaceutical carrier and a therapeutically effective amount of a compound, pharmaceutically acceptable salt, ester or prodrug of claim 1. 4. A pharmaceutical composition for inhibiting an HIV infection comprising a pharmaceutical carrier and a therapeutically effective amount of a compound, pharmaceutically acceptable salt, ester or prodrug of claim 1. A pharmaceutical composition for inhibiting HIV protease comprising a pharmaceutical carrier and a therapeutically effective amount of the compound of claim 2. 6. A pharmaceutical composition for inhibiting an HIV infection comprising a is pharmaceutical carrier and a therapeutically effective amount of the compound of claim 2. 7. A compound, pharmaceutically acceptable salt, ester or prodrug of claim 1 for use as a medicament. 8. Compound of claim 2 for use as a medicament. 9. Use of a compound, pharmaceutically acceptable salt, ester or prodrug of 20 claim 1 for manufacturing a medicament for inhibiting HIV protease. Use of a compound, pharmaceutically acceptable salt, ester or prodrug of claim 1 for manufacturing a medicament for inhibiting an HIV infection. 11. Use of the compound of claim 2 for manufacturing a medicament for inhibiting HIV protease. 12. Use of the compound of claim 2 for manufacturing a medicament for inhibiting an HIV infection. .i 13. A pharmaceutical composition for inhibiting HIV protease comprising a pharmaceutical carrier and a therapeutically effective amount of a combination of a compound, pharmaceutically acceptable salt, ester or prodrug of claim 1 and ritonavir. 14. A pharmaceutical composition for inhibiting an HIV infection comprising a pharmaceutical carrier and a therapeutically effective amount of a combination of a compound, pharmaceutically acceptable salt, ester or prodrug of claim 1 and ritonavir. A pharmaceutical composition for inhibiting HIV protease comprising a pharmaceutical carrier and a therapeutically effective amount of a combination of the compound of claim 2 and ritonavir. [R:\LIBM]39926.doc:mrr 244 16. A pharmaceutical composition for inhibiting an HIV infection comprising a pharmaceutical carrier and a therapeutically effective amount of a combination of the compound of claim 2 and ritonavir. 17. Use of a compound, pharmaceutically acceptable salt, ester or prodrug, of claim 1 in combination with ritonavir for manufacturing a medicament for inhibiting HIV protease. 18. Use of a compound, pharmaceutically acceptable salt, ester or prodrug of claim 1 in combination with ritonavir for manufacturing a medicament for inhibiting an HIV infection. 19. Use of the compound of claim 2 in combination with ritonavir for manufacturing a medicament for inhibiting HIV protease. Use of the compound of claim 2 in combination with ritonavir for manufacturing a medicament for inhibiting an HIV infection. 21. A process for the preparation of a compound of claim 1, comprising is reacting (2S,3 S,5S)-2-N,N-dibenzylamino-3-hydroxy-5-amino- 1,6- diphenylhexane with 2S-(1-tetrahydro-pyrimid-2-onyl)-3-methylbutanoic acid or a salt or activated ester derivative thereof to provide (2S,3S,5S)-2-N,N-dibenzylamino-3-hydroxy- 5-(2S-(1 -tetrahydro-pyrimid-2-onyl)-3-methylbutanoyl)amino- 1,6-diphenylhexane; debenzylating the product of step to provide (2S,3S,5S)-2-amino-3- 20 hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methylbutanoyl)amino-1,6- diphenylhexane; and reacting the product of step with 2,6-dimethylphenoxyacetic acid, or a salt or activated ester derivative thereof. 22. The process according to claim 21 wherein (2S,3 S,5 S)-2-N,N-dibenzylamino-3-hydroxy-5-amino- 1,6- diphenylhexane is reacted with 2S-(1-tetrahydro-pyrimid-2-onyl)-3-methylbutanoyl chloride to provide (2S,3S,5S)-2-N,N-dibenzylamino-3-hydroxy-5-(2S-(1-tetrahydro- ***pyrimid-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane; the product of step is hydrogenated to provide (2S,3S,5S)-2-amino- 3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methylbutanoyl)amino-1,6- diphenylhexane; and the product of step is reacted with 2,6-dimethylphenoxyacetyl chloride. 23. A process for the preparation of the compound of claim 2, comprising [R:\LIBM]39926.doc:mrr 245 reacting (2S, 3 S, 5 S)-2-N,N-dibenzylamino-3 -hydroxy-5 -amino- 1, 6- diphenyihexane with 2S-(1-tetrahydro-pyrimid-2-onyl)-3-methylbutanoic acid or a salt or activated ester derivative thereof to provide (2S,3S,5S)-2-N,N-dibenzylamino-3-hydroxy- I-tetrahydro-pyrimid-2-onyl)-3-methylbutanoyl)amino- 1,6-diphenylhexane; debenzylating the product of step to provide (2S,3S,5S)-2-amino-3- 1-tetrahydro-pyrimid-2-onyl)-3-methylbutanoyl)amino- 1,6- diphenyihexane; and reacting the product of step with 2,6-dimethyiphenoxyacetic acid, or a salt or activated ester derivative thereof. 24. The process according to claim 23 wherein (2S,3 S,5 S)-2-N,N-dibenzylamino-3 -hydroxy-5 -amino- 1,6- diphenyihexane is reacted with 2S-( 1-tetrahydro-pyrimid-2-onyl)-3 -methylbutanoyl chloride to provide (2S,3 S,5 S)-2-N,N-dibenzylamino-3 -hydroxy-5 1-tetrahydro- pyrimid-2-onyl)-3 -methylbutanoyl)amino- 1,6-diphenylhexane; the product of step is hydrogenated to provide (2S,3S,5S)-2-amino- 3-hydroxy-5-(2S-(I1-tetrahydro-pyrimid-2-onyl)-3 -methylbutanoyl)amino-l1,6- diphenylhexane; and the product of step is reacted with 2,6-dimethylphenoxyacetyl chloride. 20 25. A process for the preparation of a compound of claim 1, comprising reacting (2S,3 S,5 S)-2-amino-3 -hydroxy-5-(2S-( 1 -tetrahydro-pyrimid-2-onyl)-3 methylbutanoyl)amino- 1,6-diphenylhexane with 2,6-dimethyiphenoxyacetic acid, or a salt or activated ester derivative thereof. 26. The process according to claim 25 wherein (2S,3S,5S)-2-amino-3-hydroxy-5- (2 1-tetrahydro-pyrimid-2-onyl)-3-methylbutanoyl)amino- 1,6-diphenylhexane is reacted with 2,6-dimethylphenoxyacetyl chloride. 27. A process for the preparation of the compound of claim 2, comprising reacting (2S,3 S,5 S)-2-amino-3 -hydroxy-5 1 -tetrahydro-pyrimid-2-onyl)-3 methybutanoyl)amino- 1,6-diphenylhexane with 2,6-dimethylphenoxyacetic acid, or a salt or activated ester derivative thereof. 28. The process according to claim 27 wherein (2S,3S,5S)-2-amino-3-hydroxy-5- 1-tetrahydro-pyrimid-2-onyl)-3 -methylbutanoyl)amino-1I,6-diphenylhexaneis reacted with 2,6-dimethyiphenoxyacetyl chloride. 29. A process for the preparation of the compound of claim 2 as an amorphous solid, comprising dissolving (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy- IR:\LIBM]39926.doc:mrr 246 5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane in an organic solvent, followed by adding the solution to water. The process according to claim 29 wherein (2S,3S,5S)-2-(2,6- dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3- methylbutanoyl(amino-1,6-diphenylhexane is dissolved in ethanol, from about 2 to about 4mL/g, and the ethanolic solution is added to water, from about 10 to about 100mL/g. 31. A process for preparing a compound, pharmaceutically acceptable salt, ester or prodrug of claim 1, substantially as herein described with reference to any one of Examples 2, 24, 38 and 39. 32. A process for preparing the compound of claim 2, substantially as herein described with reference to any one of Examples 2, 24, 38 and 39. 33. A compound, pharmaceutically acceptable salt, ester or prodrug of claim 1 when prepared according to the process of any one of claims 21, 22, 25, 26, or 31. 34. The compound of claim 2 when prepared according to the process of any one s1 of claims 23, 24, 27 to 30 or 32. A pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount of a compound, pharmaceutically acceptable salt, ester or prodrug of claim 1. 36. A pharmaceutical composition comprising a pharmaceutical carrier and a 20 therapeutically effective amount of a compound, pharmaceutically acceptable salt, ester or prodrug of claim 1 and ritonavir. 37. A pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount of the compound of claim 2. 38. A pharmaceutical composition comprising a pharmaceutical carrier and a 25 therapeutically effective amount of the compound of claim 2 and ritonavir. 39. A compound, pharmaceutically acceptable salt, ester or prodrug according to claim 1 when used for inhibiting HIV protease. 40. A compound, pharmaceutically acceptable salt, ester or prodrug according to claim 1 when used for inhibiting an HIV infection. 41. The compound of claim 2 when used for inhibiting HIV protease. 42. The compound of claim 2 when used for inhibiting an HIV infection. 43. A compound, pharmaceutically acceptable salt, ester or prodrug according to claim 1 when used in combination with ritonavir for inhibiting HIV protease. 44. A compound, pharmaceutically acceptable salt, ester or prodrug according to claim 1 when used in combination with ritonavir for inhibiting an HIV infection. R:\LIBM]39926.doc:mrr 247 The compound of claim 2 when used in combination with ritonavir for inhibiting HIV protease. 46. The compound of claim 2 when used in combination with ritonavir for inhibiting an HIV infection. 547. A medicament when prepared according to any one of claims 9 to 12 or 19 to 48. A method for inhibiting HIV protease comprising administering to a human in need thereof a therapeutically effective amount of a compound, pharmaceutically acceptable salt, ester or prodrug of claim 1. o 49. A method for inhibiting an HIV infection comprising administering to a human in need thereof a therapeutically effective amount of a compound, pharmaceutically acceptable salt, ester or prodrug of claim 1. A method for inhibiting HIV protease comprising administering to a human in need thereof a therapeutically effective amount of the compound of claim 2. Is 51. A method for inhibiting an HIV infection comprising administering to a hunan in need thereof a therapeutically effective amount of the compound of claim 2. A method for inhibiting HIV protease comprising administering to a human in need thereof a therapeutically effective amount of a combination of a compound, pharmaceutically acceptable salt, ester or prodrug of claim 1 and ritonavir. 53. A method for inhibiting an HIV infection comprising administering to a human in need thereof a therapeutically effective amount of a combination of a ooooo •compound, pharmaceutically acceptable salt, ester or prodrug of claim 1 and ritonavir. 54. A method for inhibiting HIV protease comprising administering to a human in need thereof a therapeutically effective amount of a combination of the compound of claim 2 and ritonavir. A method for inhibiting an HIV infection comprising administering to a S• human in need thereof a therapeutically effective amount of a combination of the compound of claim 2 and ritonavir. 56. A method for the treatment of a disease caused by HIV comprising administering to a human in need thereof a therapeutically effective amount of a compound, pharmaceutically acceptable salt, ester or prodrug of claim 1. 57. A method for the treatment of a disease caused by HIV comprising administering to a human in need thereof a therapeutically effective amount of a compound of claim 2. [R:\LIBMj39926.doc:mrr 248 58. A method for the treatment of a disease caused by HIV comprising administering to a human in need thereof a therapeutically effective amount of a combination of a compound, pharmaceutically acceptable salt, ester or prodrug of claim 1 and ritonavir. 59. A method for the treatment of a disease caused by HIV comprising administering to a human in need thereof a therapeutically effective amount of a combination of a compound of claim 2 and ritonavir. The method according to any one of claims 56 to 59 wherein the disease is acquired immune deficiency syndrome. 61. A compound, pharmaceutically acceptable salt, ester or prodrug of claim 1 when used for the treatment of a disease caused by HIV. 62. A compound of claim 2 when used for the treatment of a disease caused by HIV. 63. A compound, pharmaceutically acceptable salt, ester or prodrug of claim 1 in combination with ritonavir when used for the treatment of a disease caused by HIV. 64. A compound of claim 2 in combination with ritonavir when used for the *I treatment of a disease caused by HIV. o 65. Use of a compound, pharmaceutically acceptable salt, ester or prodrug of claim 1 for the preparation of a medicament for the treatment of a disease caused by HIV. 20 66. Use of a compound, of claim 2 for the preparation of a medicament for the treatment of a disease caused by HIV. 67. Use of a compound, pharmaceutically acceptable salt, ester or prodrug of claim 1 in combination with ritonavir for the preparation of a medicament for the treatment of a disease caused by HIV. 68. Use of a compound of claim 2 in combination with ritonavir for the preparation of a medicament for the treatment of a disease caused by HIV. 69. The compound according to any one of claims 61 to 64 wherein the disease is acquired immunodeficiency syndrome. The use according to any one of claims 65 to 68 wherein the disease is acquired immunodeficiency syndrome. 71. A medicament when prepared according to any one of claims 65 to 68. 72. A pharmaceutical composition according to claim 36 comprising a pharmaceutical carrier and a therapeutically. effective amount of a combination of a compound, pharmaceutically acceptable salt, ester or prodrug of claim 1 and ritonavir. [R:\LIBM]39926.doc:mrr 249 73. A pharmaceutical composition according to claim 38 comprising a pharmaceutical carrier and a therapeutically effective amount of a combination of the com-pound of claim 2 and ritonavir. Dated 11 January, 2001 Abbott Laboratories Patent Attorneys for the Applicant/Nominated Person 0 SPRUSON FERGUSON (RALIBM]39926.doc:mff