RETROVIRAL PROTEASE INHIBITING COMPOUNDS

This is a continuation-in-part of U.S. patent application Serial No. 286,380, filed August 9, 1994.

Technical Field

The present invention relates to novel compounds and a composition and method for inhibiting retroviral proteases and in particular for inhibiting human immunodeficiency virus (HIV) protease, a composition and method for treating a retroviral infection and in particular an HIV infection, processes for making such compounds and synthetic intermediates employed in these processes.

Background of the Invention

Retroviruses are those viruses which utilize 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, hepatitis B virus, which causes hepatitis and hepatic carcinomas 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 biological functions are controlled or mediated by proteases and their complementary protease inhibitors. For example, the protease renin cleaves the peptide angiotensinogen to produce the peptide angiotensin I. Angiotensin I is further cleaved by the protease angiotensin converting enzyme (ACE) to form the hypotensive peptide angiotensin II. Inhibitors of renin and ACE are known to reduce high blood pressure in vivo. 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 QQ[ and gaa gene products. See Wellink, Arch. Virol. Sfi 1 (1988). Retroviral proteases most commonly process the gag precursor into core proteins, and also process the βoj precursor into reverse transciptase and retroviral protease. 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 vitro mutagenesis that produces protease-defective virus leads to the production of immature core forms which lack infectivity. See Crawford, J. Virol. £2.899 (1985); Katoh, et al., Virology 14≤ 280 (1985). Therefore, retroviral protease inhibition provides an attractive target for antiviral therapy. See Mitsuya, Nature 225 775 (1987).

Current treatments for viral diseases usually involve administration of compounds that inhibit viral DNA synthesis. Current treatments for AIDS involve administration of compounds such as 3'-azido-3'-deoxythymidine (AZT), 2',3'- dideoxycytidine (ddC), 2',3'-dideoxyinosine (ddl) and 2',3'-didehydro-3'- deoxythymidine (d4T) 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.

Disclosure of the Invention

In accordance with the present invention, there are compounds of the formula A:

wherein R*ι is selected from:

R ₂ is R _2a -C(0)- or R _2a -S(0) - wherein R _2a is selected from:

R3 and R4 are independently selected from:

(xlvii) carboxyalkoxyalkyl,

(xlviii) (alkoxycarbonyl)alkoxyalkyl,

(xlix) (amino)carboxyalkyl,

(I) ((N-protected)amino)carboxyalkyl,

(li) (alkylamino)carboxyalkyl,

(Hi) ((N-protected)alkylamino)carboxyalkyl,

(liii) (dialkylamino)carboxyalkyl,

(liv) (amino)alkoxycarbonylalkyl,

(Iv) ((N-protected)amino)alkoxycarbonylalkyl,

(Ivi) (alkylamino)alkoxycarbonylalkyl,

(Ivii) ((N-protected)alkylamino)alkoxycarbonylalkyl,

(Iviii) (dialkylamino)alkoxycarbonylalkyl,

(lix) (polyalkoxy)alkyl,

(Ix) (hydroxyamino)alkyl,

(Ixi) (alkoxyamino)alkyl,

(Ixii) dihydroxyalkyl,

(Ixiii) (alkoxy)(alkyl)aminoalkyl and

(Ixiv) arylalkoxycarbonylalkyl; and

X is

(i) -C(=Y)- wherein Y is O, S or N(R ₅ ) wherein R ₅ is loweralkyl, hydroxy, amino, alkylamino, dialkylamino, alkoxy, benzyloxy, cyano or nitro; (ii) -S(O)- or (iii) -S(0) ₂ -; or a pharmaceutically acceptable salt, ester or prodrug thereof.

Preferred compounds of the invention are compounds of the formula B:

B

wherein R _{1 f} R ₂ , R ₃ , R and X are defined as above.

Preferred compounds of the invention are compounds of the formula A or B wherein R ₁ is loweralkyl or arylalkyi; R ₂ is R _a -C(0)- wherein R _2a is loweralkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, aryl or arylalkyi; R ₃ and R ₄ are independently selected from loweralkyl, loweralkenyl, cycloalkylalkyl, arylalkyi or (heterocyclic)alkyl; and X is -C(=0)-, -C(=N-OH)-, -C(=N-CN)- or -S(0) ₂ -.

More preferred compounds of the invention are compounds of the formula A or B wherein R ₁ is loweralkyl, benzyl, alkoxy-substituted benzyl or halo-substituted benzyl; R ₂ is R _2a -C(0)- wherein R _2a is loweralkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, aryl or arylalkyi; R ₃ and R ₄ are independently selected from loweralkyl, loweralkenyl, cycloalkylalkyl, benzyl, hydroxy- substituted benzyl, hydroxyalkyl-substituted benzyl, alkoxy-substituted benzyl, amino-substituted benzyl, disubstituted benzyl wherein the substitutents are hydroxy and alkoxy or (heterocyclic)methyl wherein the heterocyclic is thiazolyl, oxazolyl, isoxazolyl or furanyl; and X is -C(=0)-, -C(=N-OH)-, -C(=N-CN)- or -S(0) ₂ -.

Even more preferred compounds of the invention are compounds of the formula A or B wherein R ₁ is isobutyl, benzyl, methoxy-substituted benzyl or fluoro-substituted benzyl; R ₂ is R _2a -C(0)- wherein R _2a is CH ₃ -, CH ₃ -(CH ₂ ) ₂ -. (CH ₃ ) ₂ CHCH ₂ -, CH ₃ (CH ₂ ) ₃ -, (CH^CHg^CH-, cyclopentyl, HOCH ₂ (CH ₂ ) ₃ -, HOCH ₂ (CH ₂ )2- or HOCH ₂ -; R ₃ and R ₄ are independently selected from loweralkyl, allyl, cyclopropylmethyl, benzyl, hydroxy-substituted benzyl,

methoxy-substituted benzyl, hydroxymethyl-substituted benzyl, amino- substituted benzyl, disubstituted benzyl wherein the substituents are hydroxy and methoxy or (heterocyclic)methyl wherein the heterocyclic is thiazolyl, oxazolyl, isoxazolyl or furanyl; and X is -C(=0)- or -S(0) ₂ -.

Even more highly preferred compounds of the invention are compounds of the formula A or B wherein R ₁ is isobutyl, benzyl, methoxy-substituted benzyl or fluoro-substituted benzyl; R ₂ is R _2a -C(0)- wherein R _2a is CH ₃ -, CH ₃ -(CH ₂ ) ₂ -, (CH ₃ ) ₂ CHCH ₂ -, CH ₃ (CH ₂ ) ₃ -, (CH ₃ (CH ₂ ) ₂ ) ₂ CH-, cyclopentyl, HOCH ₂ (CH ₂ ) ₃ -, HOCH ₂ (CH ₂ ) ₂ - or HOCH ₂ -; R ₃ and R ₄ are independently selected from loweralkyl, allyl, cyclopropylmethyl, benzyl, hydroxy-substituted benzyl, methoxy-substituted benzyl, hydroxymethyl-substituted benzyl, amino- substituted benzyl, disubstituted benzyl wherein the substituents are hydroxy and methoxy or (heterocyclic)methyl wherein the heterocyclic is thiazolyl, oxazolyl, isoxazolyl or furanyl; and X is -C(=0)-.

Most highly preferred compounds of the invention are compounds of the formula A or B wherein R ₁ is benzyl, methoxy-substituted benzyl or fluoro- substituted benzyl; R ₂ is R _2a -C(0)- wherein R _2a is CH ₃ -, CH ₃ -(CH ₂ ) ₂ -, (CH ₃ ) ₂ CHCH ₂ -. CH ₃ (CH ₂ ) ₃ -, (CH ₃ (CH ₂ ) ₂ ) ₂ C -* cyclopentyl, HOCH ₂ (CH ₂ ) ₃ - ₍ HOCH ₂ (CH ₂ ) ₂ - or HOCH ₂ -; R ₃ and R are independently selected from loweralkyl, allyl, cyclopropylmethyl, benzyl, hydroxy-substituted benzyl, methoxy-substituted benzyl, hydroxymethyl-substituted benzyl, amino- substituted benzyl, disubstituted benzyl wherein the substituents are hydroxy and methoxy or (heterocyclic)methyl wherein the heterocyclic is thiazolyl, oxazolyl, isoxazolyl or furanyl; and X is -C(=0)-.

The especially preferred compounds of the invention are compounds of the formula A or B wherein R ₁ is benzyl, methoxy-substituted benzyl or fluoro- substituted benzyl; R ₂ is R _2a -C(0)- wherein R _2a is (CH ₃ ) ₂ CHCH ₂ -; R ₃ and R ₄ are independently selected from 4-hydroxybenzyl, 4-aminobenzyl and 3-aminobenzyl; and X is -C(=0)-.

The compounds of the invention comprise asymmetrically substituted centers (i.e., asymmetrically substituted carbon atoms). The present invention is intended to include all stereoisomeric forms of the compounds, including

racemic mixtures, mixtures of diastereomers, as well as single diastereomers of the compounds of the invention. The terms "S" and "R" configuration are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13 - 30.

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 undesirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, "Protective Groups In Organic Synthesis," (John Wiley & Sons, New York (1981)), which is hereby incorporated herein by reference. N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyi, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-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, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1 -(p-biphenylyl)-l -methylethoxycarbonyl, α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, 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, pivaloyi, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).

The term "O-protecting group" as used herein refers to a substituent which protects hydroxyl groups against undesirable reactions during synthetic

procedures such as those O-protecting groups disclosed in Greene, "Protective Groups In Organic Synthesis," (John Wiley & Sons, New York (1981 )). O-protecting groups comprise substituted methyl ethers, for example, methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, t-butyl, benzyl and triphenylmethyl; tetrahydropyranyl ethers; substituted ethyl ethers, for example, 2,2,2- trichloroethyl; silyl ethers, for example, trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl; and esters prepared by reacting the hydroxyl group with a carboxylic acid, for example, acetate, propionate, benzoate and the like.

The term "loweralkyl" as used herein refers to straight or branched chain alkyl radicals containing from 1 to 10 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like.

The term "alkylene" as used herein refers to a straight or branched chain carbon diradical containing from 1 to 6 carbon atoms including, but not limited to, -CH ₂ -, -CH2CH2-, -CH(CH ₃ )CH ₂ -, -CH2CH2CH2- and the like.

The term "loweralkenyl" as used herein refers to a loweralkyl radical which contains at least one carbon-carbon double bond including, but not limited to, propenyl, butenyl and the like.

The term "aryl" as used herein refers to a Cβ monocyclic aromatic ring system or a Cg or C10 bicyclic carbocyclic ring system 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, haloalkyi, alkoxy, thioalkoxy, alkoxycarbonyl, alkanoyl, hydroxy, halo, mercapto, nitro, cyano, amino, alkylamino, dialkylamino, carboxaldehyde, carboxy, carboxamide, arylalkyi, arylalkoxy, (heterocyclic)alkyl, (heterocyclic)alkoxy, (heterocyclic)carbonylalkoxy, aminoalkyl, aminoalkoxy, alkylaminoalkyl, alkylaminoalkoxy, dialkylaminoalkyl, dialkylaminoalkoxy, (alkoxyalkyl)aminoalkyl, (alkoxyalkyl)aminoalkoxy, di-(alkoxyalkyl)aminoalkyl, di-(alkoxyalkyl)aminoalkoxy, (alkoxyalkyl)(alkyl)aminoalkyl, (alkoxyalkyl)(alkyl)aminoalkoxy, hydroxyalkyl, hydroxyalkoxy, carboxyalkyl,

carboxyalkoxy, alkoxyalkyl, thioalkoxyalkyl, polyalkoxyalkyl and dialkoxyalkyl. In addition, substituted aryl groups include tetrafluorophenyl and pentafluorophenyl.

The term "arylalkyi" as used herein refers to an aryl group appended to a loweralkyl radical including, but not limited to, benzyl, 4-hydroxybenzyl, 1 - naphthylmethyl and the like.

The term "aminoalkyl" as used herein refers to -NH ₂ appended to a loweralkyl radical.

The term "hydroxyalkyl" as used herein refers to -OH appended to a loweralkyl radical.

The term "dihydroxyalkyl" as used herein refers to a loweralkyl radical disubstituted with -OH groups.

The term "polyhydroxyalkyl" as used herein refers to a loweralkyl radical substituted with more than two -OH groups.

The term "mercaptoalkyl" as used herein refers to a loweralkyl radical to which is appended a mercapto (-SH) group.

The term "hydroxyaminoalkyl" as used herein refers to a hydroxyamino group (-NHOH) appended to a loweralkyl radical.

The term "alkoxyaminoalkyl" as used herein refers to -NHR20 (wherein R20 is an alkoxy group) appended to a loweralkyl radical.

The term "(alkoxy) (alkyl)aminoalkyl" as used herein refers to (R2 _. )(R22)N- wherein R21 is alkoxy and R22 is loweralkyl appended to a loweralkyl radical.

The term "alkylamino" as used herein refers to a loweralkyl radical appended to an NH radical.

The term "cycloalkyl" as used herein refers to an aliphatic ring having 3 to 7 carbon atoms including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl and the like. Cycloalkyl groups can be unsubstituted or substituted with one or two substituents independently selected from loweralkyl, haloalkyi, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, carboalkoxy and carboxamide.

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

The term "cycloalkenyl" as used herein refers to an aliphatic ring having 5 to 7 carbon atoms and a carbon-carbon double bond including, but not limited to, cyclopentenyl, cyclohexenyl and the like. Cycloalkenyl groups can be unsubstituted or substituted with one or two substituents independently selected from loweralkyl, haloalkyi, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, carboalkoxy and carboxamide.

The term "cycloalkenylalkyl" as used herein refers to a cycloalkenyl group appended to a loweralkyl radical, including but not limited to cyclohexenylmethyl.

The term "alkylaminocycloalkyl" as used herein refers to an alkylamino group appended to a cycloalkyl radical.

The term "dialkylaminocycloalkyl" as used herein refers to a dialkylamino group appended to a cycloalkyl radical.

The terms "alkoxy" and "thioalkoxy" as used herein refer to R gO- and R gS-, respectively, wherein R _2g is a loweralkyl group.

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

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

The term "guanidinoalkyl" as used herein refers to a guanidino group (-NHC(=NH)NH2) appended to a loweralkyl radical.

The term "alkenyloxy" as used herein refers to R O- wherein R ₃₂ is a loweralkenyl group.

The term "hydroxyalkoxy" as used herein refers to -OH appended to an alkoxy radical.

The term "dihydroxyalkoxy" as used herein refers to an alkoxy radical which is disubstituted with -OH groups.

The term "arylalkoxy" as used herein refers R33O- wherein R ₃₃ is a arylalkyi group as defined above.

The term "(heterocyclic)alkoxy" as used herein refers to R ₃₄ 0- wherein R ₃₄ is a (heterocyclic)alkyl group.

The term "aryloxyalkyl" as used herein refers to a R35O- group appended to a loweralkyl radical, wherein R ₃ 5 is an aryl group.

The term "dialkylamino" as used herein refers to -NRggRg wherein R ₃₆ and R ₃₇ are independently selected from loweralkyl groups.

The term "N-protected aminoalkyl" as used herein refers to -NHR _4Q appended to a loweralkyl group, wherein R _4Q is an N-protecting group.

The term "alkylaminoalkyl" as used herein refers to -NHR ₄₁ appended to a loweralkyl radical, wherein R ₄₁ is a loweralkyl group.

The term "(N-protected)(alkyl)aminoalkyl" as used herein refers to -NR ₄₂ R ₄₃ , which is appended to a loweralkyl radical, wherein R ₄₂ is an N-protecting group and R ₄₃ is loweralkyl.

The term "dialkylaminoalkyl" as used herein refers to -NR ₄₄ R ₄₅ which is appended to a loweralkyl radical wherein R ₄₄ and R _4c are independently selected from loweralkyl.

The term "carboxyalkyl" as used herein refers to a carboxylic acid group (-COOH) appended to a loweralkyl radical.

The term "alkoxycarbonylalkyl" as used herein refers to a R ₄₆ C(0)- group appended to a loweralkyl radical, wherein R _4β is an alkoxy group .

The term "carboxy alkoxyalkyl" as used herein refers to a carboxylic acid group (-COOH) appended to an alkoxy group which is appended to a loweralkyl radical.

The term "alkoxycarbonylalkoxyalkyl" as used herein refers to an alkoxycarbonyl group (R ₄₇ C(0)- wherein R ₄₇ is an alkoxy group) appended to an alkoxy group which is appended to a loweralkyl radical.

The term "(amino)carboxyalkyl" as used herein refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and an amino group (-NH ₂ ).

The term "((N-protected)amino)carboxyalkyl" as used herein refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and -NHR ₄₈ wherein R _4g is an N-protecting group.

The term "(alkylamino)carboxyalkyl" as used herein refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and an alkylamino group.

The term "((N-protected)alkylamino)carboxyalkyl" as used herein refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and an -NR ₄ gR ₄₉ wherein R ₄ « is as defined above and R _4g is a loweralkyl group.

The term "(dialkylamino)carboxyalkyl" as used herein refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and -NR ₄ gR ₄₉ wherein R _4g is as defined above.

The term "(amino)alkoxycarbonylalkyl" as used herein refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as defined above and an amino group (-NH ₂ ).

The term "((N-protected)amino)alkoxy-carbonylalkyl" as used herein refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as defined above and - HRg _Q wherein R is an N-protecting group.

The term "(alkylamino)alkoxycarbonylalkyl" as used herein refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as defined above and an alkylamino group as defined above.

The term "((N-protected)alkylamino)alkoxy-carbonylalkyl" as used herein refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as defined above and -NR ₅₁ R _g2 wherein R _g1 is an N-protecting group and R ₅₂ is a loweralkyl group.

The term "(dialkylamino)alkoxycarbonylalkyl" as used herein refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as defined above and ~ ^NR 53 ^R 54 wherein Rg ₃ and R54 are independently selected from loweralkyl.

The term "aminocycloalkyl" as used herein refers to an NH ₂ appended to a cycloalkyl radical.

The term "((alkoxy)alkoxy)alkyl" as used herein refers to an alkoxy group appended to an alkoxy group which is appended to a loweralkyl radical.

The term "polyalkoxyalkyl" as used herein refers to a polyalkoxy residue appended to a loweralkyl radical.

The term "polyalkoxy" as used herein refers to -ORg ₇ wherein R _g7 is a straight or branched chain containing 1 -5, C _n ,-0-C _n „ linkages wherein n' and n" are independently selected from 1 to 3, including but not limited to methoxyethoxymethoxy, methoxymethoxy and the like.

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

The term "haloalkyi" as used herein refers to a loweralkyl radical in which one or more of the hydrogen atoms are replaced by halogen including, but not limited to, chloromethyl, trifluoromethyl, 1-chloro-2-fluoroethyl and the like.

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

The term "alkylsulfonyl" as used herein refers to R _g3 S0 ₂ - wherein R _g3 is loweralkyl group.

The term "alkylsulfonylalkyl" as used herein refers to an alkylsufonyl group appended to a loweralkyl radical.

The term "arylthioalkyl" as used herein refers to Rg ₄ -S-Rg5- wherein Rg ₄ is an aryl group and Rgs is an alkylene group.

The term "aryloxyalkyl" as used herein refers to Rg ₄ -0-Rg5- wherein Rg is an aryl group and Rgs is an alkylene group.

The term "arylsulfonylalkyl" as used herein refers to Rg6-S(0)2-Rg7- wherein Rg$ is any aryl group and Rg7 is an alkylene group.

The term "(heterocyclic)oxyalkyl" as used herein refers to Rg ₃ -0-Rgg- wherein Rgs is a heterocyclic group and Rgg is an alkylene group.

The term "(heterocyclic)thioalkyl" as used herein refers to R100-S-R101- wherein R100 is a heterocyclic group and R101 is an alkylene group.

The term "(heterocyclic)sulfonylalkyl" as used herein refers to R*i02-S(O)2-Ri03- wherein R102 is a heterocyclic group and R103 is an alkylene group.

The "arylalkoxyalkyl" as used herein refers to R104-O-R-105- wherein R*ιo ₄ is an arylalkyi group and R105 is an alkylene group, for example, benzyloxymethyl and the like.

The "arylthioalkoxyalkyl" as used herein refers to R1 ₀₆ -S-R ₁₀₇ - wherein R1 ₀₆ is an arylalkyi group and R ₁₀ 7 is an alkylene group.

The "arylalkylsulfonylalkyl" as used herein refers to Rιo8-S(0) ₂ -Rιo ₉ - wherein R ₁ 08 is an arylalkyi group and R*ιog is an alkylene group.

The term "(heterocyclic)alkoxy" as used herein refers to R-no-O- wherein R110 is a (heterocyclic)alkyl group, for example, 2-(morpholin-1-yl)ethoxy and the like.

The term "(heterocyclic)alkoxyalkyl" as used herein refers to R ₁ 10-O-R1 ₁ 1- wherein R-MO is a (heterocyclic)alkyl group and R111 is an alkylene group.

The term "(heterocyclic)thioalkoxyalkyl" as used herein refers to R-ιi ₂ -S-R*ιι ₃ - wherein R112 is a (heterocyclic)alkyl group and R*ιι ₃ is an alkylene group.

The term "(heterocyclic)alkylsulfonylalkyl" as used herein refers to Rιι ₄ -S(0) ₂ -R*ιi5- wherein R*ιι ₄ is a (heterocyclic)alkyl group and R ₁ 15 is an alkylene group.

The term "cycloalkyloxyalkyl" as used herein refers to R ₁ 16-O-R-117- wherein Rue is a cycloalkyl group and R117 is an alkylene group.

The term "cycloalkylthioalkyl" as used herein refers to Rnβ-S-Rng- wherein Rue is a cycloalkyl group and Rug is an alkylene group.

The term "cycloalkylsulfonylalkyl" as used herein refers to Ri20-S(O)2-Ri2i- wherein R120 is a cycloalkyl group and R-12 ₁ is an alkylene group.

The term "cycloalkylalkoxyalkyl" as used herein refers to R122-O-R123- wherein R122 is a cycloalkylalkyl group and R123 is an alkylene group.

The term "cycloalkylthioalkoxyalkyl" as used herein refers to R124-S-R ₁₂ 5- wherein Ri ₂₄ is a cycloalkylalkyl group and R ₁₂ 5 is an alkylene group.

The term "cycloalkylalkylsulfonylalkyi" as used herein refers to R ^* i26-S(0)2-Ri27- wherein R126 is a cycloalkylalkyl group and R ₁ 27 is an alkylene group.

The term "alkanoyl" as used herein refers to Rκ-C(O)- wherein Rk is a loweralkyl group.

The term "aminocarbonyl" as used herein refers to

-C(0)NH ₂ .

The term "aminocarbonylalkyl" as used herein refers to an aminocarbonyl group appended to a loweralkyl radical.

The term "alkylaminocarbonyl" as used herein refers to -C(0)NHR*i28 wherein R128 is loweralkyl.

The term "alkylaminocarbonylalkyl" as used herein refers to an alkylaminocarbonyl group appended to a loweralkyl radical.

The term "dialkylaminocarbonyl" as used herein refers to -C(O)NRi2gRi30 wherein R129 and R130 are independently selected from loweralkyl.

The term "dialkylaminocarbonylalkyl" as used herein refers to a dialkylaminocarbonyl group appended to a loweralkyl group.

The term "aroylalkyl" as used herein refers to Rι ₃ -|-C(0)-R-| ₃ 2- wherein R-131 is an aryl group and R-| ₃ 2 is an alkylene group.

The term "(heterocyclic)carbonylalkyl" as used herein refers to R _. 33-C(0)-Ri3 - wherein R133 is a heterocyclic group and R134 is an alkylene group.

The term "aminoalkoxy" as used herein refers to an alkoxy radical to which is appended an amino (-NH2) group.

The term "alkylaminoalkoxy" as used herein refers to an alkoxy radical to which is appended an alkylamino group.

The term "dialkylaminoalkoxy" as used herein refers to an alkoxy radical to which is appended a dialkylamino group.

The term "(alkoxyalkyl)aminoalkyl" refers to a loweralkyl radical to which is appended an (alkoxyalkyl)amino group.

The term "(alkoxyalkyl)aminoalkoxy" as used herein refers to an alkoxy radical to which is appended an (alkoxyalkyl)amino group.

The term "(alkoxyalkyl)(alkyl)aminoalkyl" refers to a loweralkyl radical to which is appended an (alkoxyalkyl)(alkyl)amino group.

The term "(alkoxyalkyl)(alkyl)aminoalkoxy" as used herein refers to an alkoxy radical to which is appended an (alkoxyalkyl)(alkyl)amino group.

The term "di-(alkoxyalkyl)aminoalkyl" refers to a loweralkyl radical to which is appended an di-(alkoxyalkyl)amino group.

The term "di-(alkoxyalkyl)aminoalkoxy" as used herein refers to an alkoxy radical to which is appended an di-(alkoxyalkyl)amino group.

The term "carboxyalkoxy" as used herein refers to an alkoxy radical to which is appended a carboxy (-COOH) group.

The term "aminocarbonylalkyl" as used herein refers to a loweralkyl radical to which is appended an aminocarbonyl (H2NC(0)-) group.

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

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

The term "(heterocyclic)carbonylalkoxy" as used herein refers to R-ι ₃₅ -C(0)-R ₁₃₆ -0- wherein R ₁₃₅ is a heterocyclic group and R ₁₃₆ is an alkylene group, for example, 2-(morpholin-1 -yl-carbonyl)ethoxy and the like.

The term "arylalkoxycarbonylalkyl" as used herein refers to R ₁₃₇ -0-C(0)- R ₁₃₈ - wherein R ₁₃₇ is an arylalkyi group and R ₁₃₈ is an alkylene group.

The term "alkanoyl" as used herein refers to R ₁₃₉ -C(0)- wherein R ₁₃₉ is a loweralkyl group.

The term "aroyl" as used herein refers to R- _{) Q} -C(0)- wherein R ₁₄₀ is an aryl group.

The term "alkylsulfonyl" as used herein refers to R ₁₄₁ -S(0) ₂ - wherein R ₁₄₁ is a loweralkyl group.

The term "arylsulfonyl" as used herein refers to R ₁₄₂ -S(0) ₂ - wherein R ₁₄₂ is an aryl group.

At each occurrence, the term "heterocyclic ring" or "heterocyclic" as used herein independently refers to a 3- or 4-membered ring containing a heteroatom selected from oxygen, nitrogen and sulfur; or a 5-, 6- or 7-membered ring containing one, two or three nitrogen 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; or two sulfur atoms in non-adjacent positions. The 5- membered ring has 0-2 double bonds and the 6-membered ring has 0-3 double bonds. The nitrogen heteroatoms can be optionally quaternized or N-oxidized. The sulfur heteroatoms can be optionally S-oxidized. 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. Heterocyclics include: pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, isoxazolyl, isoxazolinyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazoHdinyl, indolyl, quinoHnyl, tetrahydroqumolyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzofuranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl, pyranyl, dihydropyranyl, tetrahydropyranyl, dioxanyl, dioxolanyl, thienyl and benzothienyl. Heterocyclics also include:

Preferred heterocyclics are pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, tetrahydrofuranyl, tetrahydrothienyl and tetrahydropyranyl.

Heterocyclics can be unsubstituted or monosubstituted or disubstituted with substituents independently selected from hydroxy, halo, oxo (=0), alkylimino (R ^* N= wherein R ^* is a loweralkyl group), amino, (N-protected)amino, alkylamino, (N-protected)alkylamino, dialkylamino, alkoxy, polyalkoxy, haloalkyi, cycloalkyl, cycloalkylalkyl, aryl, arylalkyi,

-COOH, -S0 ₃ H, loweralkenyl, loweralkyl, hydroxyalkyl, aminoalkyl and alkoxyalkyl. Heterocyclics can also be substituted with a heterocycle selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorphoHnyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl, each of which can be unsubstituted or substituted with a substituent selected from halo, loweralkyl, hydroxy, alkoxy and thioalkoxy.

In addition, nitrogen containing heterocycles can be N-protected.

The term "(heterocyclic)alkyl" as used herein refers to a heterocyclic group appended to a loweralkyl radical, including but not limited to imidazolylmethyl, thiazolylmethyl, oxazolylmethyl, furanylmethyl, isoxazolylmethyl and the like.

The term "naturally occurring α-amino acid" as used herein refers to alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, glycine, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine or histidine.

In the compounds of the invention, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

Most preferred compounds of the invention are selected from the group consisting of:

(5R ,6R)-2 ,4-Bis-(4-hydroxybenzyl)-1 -(3-methylbutyryl)-5-benzyl- 6-hydroxy-3-oxo-1 ,2,4-triazacycloheptane;

(5R,6R)-2,4-Bis-(3-aminobenzyl)-1 -(3-methylbutyryl)-5-benzyl-6- hydroxy-3-oxo-1 ,2,4-triazacycloheptane; and

(5R,6R)-2,4-Bis-(4-aminobenzyl)-1 -(3-methylbutyryl)-5-benzyl-6- hydroxy-3-oxo-1 ,2,4-triazacycloheptane; or a pharmaceutically acceptable salt, ester or prodrug thereof.

Compounds useful as intermediates for the preparation of the compounds of formula A include the compound of the formula C:

NH - R 10

(v) diphenylmethyl,

(vi) di-(methoxyphenyl)methyl and

(vii) triphenylmethyl;

R ₈ is hydrogen or an O-protecting group; and

Rg and R-io are independently selected from hydrogen and an N-protecting group; or an acid addition salt thereof.

Preferred compounds of the formula C are those wherein R*ι is loweralkyl or arylalkyi and R2 is benzyl, nitrobenzyl, dimethoxybenzyl, diphenylmethyl, di-(methoxyphenyl)methyl or triphenylmethyl.

A preferred N-protecting group Rg is t-butyloxycarbonyl or benzyloxycarbonyl.

A preferred N-protecting group R-io is t-butyloxycarbonyl or benzyloxycarbonyl.

More preferred compounds are compounds of the formula C wherein R., is loweralkyl, benzyl, alkoxy-substituted benzyl or halo-substituted benzyl; and R _2b is benzyl, nitrobenzyl, dimethoxybenzyl, diphenylmethyl, di-(methoxyphenyl)methyl or triphenylmethyl.

Even more preferred compounds of the formula C are those wherein R ₁ is isobutyl, benzyl, methoxy-substituted benzyl or fluoro-substituted benzyl; R ₂ is benzyl, nitrobenzyl, dimethoxybenzyl, diphenylmethyl, di-(methoxyphenyl)methyl or triphenylmethyl.

Even more highly preferred compounds are compounds of the formula C wherein R ₁ is isobutyl, benzyl, methoxy-substituted benzyl or fluoro-substituted benzyl; and R _2b is benzyl, nitrobenzyl, dimethoxybenzyl, diphenylmethyl, di-(methoxyphenyl)methyl or triphenylmethyl.

Most highly preferred compounds are compounds of the formula C wherein R ₁ is benzyl, methoxy-substituted benzyl or fluoro-substituted benzyl; and R ₂ is R _2b is benzyl, nitrobenzyl, dimethoxybenzyl, diphenylmethyl, di-(methoxyphenyl)methyl or triphenylmethyl.

Preferred compounds of the formula C also include compounds of the formula D:

(iv) dimethoxybenzyl,

(v) diphenylmethyl,

(vi) di-(methoxyphenyl)methyl and

(vii) triphenylmethyl;

R ₈ is hydrogen or an O-protecting group; and

Rg and R10 are independently selected from hydrogen and an N-protecting group; or an acid addition salt thereof.

Preferred compounds of the formula D are those wherein Ri is loweralkyl or arylalkyi and R2b is benzyl, nitrobenzyl, dimethoxybenzyl, diphenylmethyl, di-(methoxyphenyl)methyl or triphenylmethyl.

A preferred N-protecting group Rg is t-butyloxycarbonyl or benzyloxycarbonyl.

A preferred N-protecting group R10 is t-butyloxycarbonyl or benzyloxycarbonyl.

More preferred compounds are compounds of the formula D wherein R ₁ is loweralkyl, benzyl, alkoxy-substituted benzyl or halo-substituted benzyl; R2 is benzyl, nitrobenzyl, dimethoxybenzyl, diphenylmethyl, di-(methoxyphenyl)methyl or triphenylmethyl.

Even more preferred compounds of the formula D are those wherein R ₁ is isobutyl, benzyl, methoxy-substituted benzyl or fluoro-substituted benzyl; R2b is benzyl, nitrobenzyl, dimethoxybenzyl, diphenylmethyl, di-(methoxyphenyl)methyl or triphenylmethyl.

Even more highly preferred compounds are compounds of the formula D wherein R ₁ is isobutyl, benzyl, methoxy-substituted benzyl or fluoro-substituted benzyl; and R2b is benzyl, nitrobenzyl, dimethoxybenzyl, diphenylmethyl, di-(methoxyphenyl)methyl or triphenylmethyl.

Most highly preferred compounds are compounds of the formula D wherein R ₁ is benzyl, methoxy-substituted benzyl or fluoro-substituted benzyl; and R2b is benzyl, nitrobenzyl, dimethoxybenzyl, diphenylmethyl, di-(methoxyphenyl)methyl or triphenylmethyl.

Other compounds which are useful as intermediates for the preparation of the compounds of formula A include the compound of the formula E:

wherein Ri is selected from:

Rg is hydrogen or an O-protecting group; and

X is

(i) -C(=Y)- wherein Y is O, S or N(R ₅ ) wherein R ₅ is loweralkyl, hydroxy, amino, alkylamino, dialkylamino, alkoxy, benzyloxy, cyano or nitro;

(ii) -S(O)- or

(iii) -S(0) ₂ -; or a salt thereof.

Preferred compounds of the formula E are those wherein Ri is loweralkyl or arylalkyi; R2b is benzyl and R ₈ is an O-protecting group.

More preferred compounds are compounds of the formula E wherein R ₁ is loweralkyl, benzyl, alkoxy-substituted benzyl or halo-substituted benzyl and X is -C(=0)-.

Even more preferred compounds of the formula E are those wherein R ₁ is isobutyl, benzyl, methoxy-substituted benzyl or fluoro-substituted benzyl and X is -C(=0)-.

Preferred compounds of formula E also include compounds of the formula F:

R ₈ is hydrogen or an O-protecting group; and

X is

(') -C(=Y)- wherein Y is O, S or N(R ₅ ) wherein R ₅ is loweralkyl, hydroxy, amino, alkylamino, dialkylamino, alkoxy, benzyloxy, cyano or nitro;

(ϋ) -S(O)- or (iii) -S(0) ₂ -; or a salt thereof.

Preferred compounds of the formula F are those wherein Ri is loweralkyl or arylalkyi; R2 is benzyl and R ₈ is an O-protecting group.

More preferred compounds are compounds of the formula F wherein R ₁ is loweralkyl, benzyl, alkoxy-substituted benzyl or halo-substituted benzyl and X is -C(=0)-.

Even more preferred compounds of the formula F are those wherein R ₁ is isobutyl, benzyl, methoxy-substituted benzyl or fluoro-substituted benzyl and X is -C(=0)-.

The compounds of the invention can be prepared as shown in Schemes 1 - 5. The schemes outline the preparation of the compounds of the invention having the preferred stereochemistry. However, other stereoisomers of the compounds of the invention can be prepared by starting with the aminoalcohol

having the opposite stereochemistry to that shown for compound 1 in Scheme 1. As outlined in Scheme 1 , oxidation (for example, Swern oxidation) of (D)-aminoalcohol 1 (R ₉ is an N-protecting group, for example, benzyloxycarbonyl and R ₁ is defined as above) provides aldehyde 2. Olefination (for example, by Wittig reaction) of N-protected aldehyde 2 provides olefin 3. Epoxidation of olefin 3 (for example, with m-chloroperbenzoic acid (MCPBA)) provides a mixture of epoxides 4 and 5. Separation of the epoxides (for example, by chromatography) provides the desired epoxide isomer 4.

As outlined in Scheme 2, reaction of N-protected hydrazine 6 (R ₁₀ is an N-protecting group, for example, benzyloxycarbonyl) with an aldehyde or ketone derivative of substituent R2b provides hydrazone 7. Reduction of hydrazone 7 (for example, by hydrogenation) provides hydrazine 8.

Alternatively, the appropriate hydrazine R _2b -NH-NH ₂ can be N-protected to provide 8.

As outlined in Scheme 3, reaction of epoxide 4 with hydrazine 8 provides hydroxy hydrazine 9. Protection of the hydroxyl group with an O-protecting group (for example, trimethylsilylethoxymethyl, methoxyethoxymethyl or methoxymethyl and the like) provides 10. Removal of N-protecting groups provides 11.

As outlined in Scheme 4, reaction of 11 with Q-X-Q' (Q and Q' are activating groups and X is defined as above) provides 12. When X is -C(=0)- or -C(=S)-, Q and Q" are, for example, independently selected from imidazolyl, N-succinimidyloxy, -O-phenyl, halogen and the like. When X is -C(=N-CN)-, Q-X-Q' is, for example, MeS-C(=N-CN)-SMe and the like. When X is -S(O)- or -S(0) ₂ -, Q and Q' are, for example, imidazolyl and the like. Compounds wherein X is -C(=N-R ₅ )- wherein R ₅ is loweralkyl, hydroxy, amino, alkylamino, dialkylamino, alkoxy or benzyloxy can be prepared by reacting the appropriate amine with the corresponding cyclic thiourea.

Alkylation of 12 with R ₃ -Z and R ₄ -Z' wherein Z and Z' are independently selected from leaving groups, for example, a sulfonate (mesylate, tosylate, triflate and the like) or a halogen and the like, provides 13. When R ₃ and R ₄ are the same, the alkylation can be done in one step. When R ₃ and R ₄ are different, the alkylations are done sequentially (the R ₄ substituent being introduced first,

followed by the R ₃ substituent). Deprotection of the hydroxyl group then provides 14.

As outlined in Scheme 5, various substituents R ₂ can be introduced by first removing the N-protecting group R _2b from compound 12 (by hydrogenation or other suitable N-debenzylation method) to give 13. Acylation or sulfonylation of 13 with R -Z wherein R -Z is a carboxylic acid halide or sulfonyl halide and the like provides 14.

Alkylation of 14 with R ₃ -Z' and R ₄ -Z" wherein 71 and Z" are independently selected from leaving groups, for example, a sulfonate (mesylate, tosylate, triflate and the like) or a halogen and the like, provides 15. When R ₃ and R ₄ are the same, the alkylation can be done in one step. When R ₃ and R ₄ are different, the alkylations are done sequentially (the R ₄ substituent being introduced first, followed by the R ₃ substituent). Deprotection of the hydroxyl group then provides 16.

Scheme 1

Scheme 2

R∑b II R∑b R M,O~' _^ NH, -► R ,N

10^ -► R

NH NH 10" NH

NH

6 8

Scheme 3

9 10

deprotect R9/R10

11

Scheme 4

Scheme 5

The following examples will serve to further illustrate the preparation of the novel compounds of the invention.

Exgm le ι

A. N-(rBenzyloxvtearbonvn-D-Dhenvlalaninal.

To a solution of 1.8 ml of dimethyl sulfoxide in 20 ml of dichloromethane cooled to -78°C was added slowly 1.65 ml of oxalyl chloride. The solution was stirred for 10 min at -78°C and a solution of 3.6 g (0.012 mole) of N-((benzyloxy)carbonyl)-D-phenylalaninol in 45 ml of dichloromethane was added slowly. The resulting solution was stirred at -78°C for 15 min, then 1 min at 0°C; recooling to -78°C and 7.6 ml of triethylamine was added over 10 min. After stirring at -78°C for 25 min, 20 ml of cold 10% aq. citric acid solution was added. After warming to 0°C, 200 ml of ether and 55 ml of cold 10% citric acid were added. The organic layer was separated by separatory funnel and washed repeatedly (5 x 60 ml) with water and finally with satd. NaCI solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo at RT to give 3.51 g of the desired compound as an off-white solid.

B. N«Benzvloxy arbonvn-2R-amino-1-phenyl-but-3-ene.

To a dry 250 ml 3-neck flask was added 14.34 g of triphenylmethylphosphonium bromide. To this was added 70 ml of THF, cooled to 0°C and 4.42 g of 35% potassium hydride dispersion in oil was added. The mixture was stirred at RT for 24 h. To this mixture was added 30 ml of toluene and let stand for 30 min. The supernatant was cannulated over into a solution of 3.37 g of N-((benzyloxy)carbonyl)-D-phenylalaninal in 50 ml of toluene at -78°C. The reaction mixture was stirred at -78°C for 2 h, followed by 0.5 h at RT. Satd. ammonium chloride (50 ml) was added. The layers were separated and the aqueous layer was extracted with ethyl acetate (3 x 100 ml). The combined organic layer was washed with satd. NaCI solution and dried over anhydrous sodium sulfate, filtered and concentrated to a yellow oil which was purified by silica gel column chromatography (30% ether/hexane) to provide 3.02 g (89%) of desired compound as a white solid. ¹ H NMR (CDCI ₃ ): δ 2.88 (d, 2H), 4.50 (m, 1 H), 4.70 (m, 1 H), 5.10 (m, 3H), 5.80 (m, 1 H), 7.10- 7.40 (m, 10H). Mass spectrum: (M+1)+ ^• ___ 282.

C. N-((Benzvloxy)carbonyn-2R-amino-3S-3.4-epoxvbutane.

According to the procedure of Luly, et al. (J. Org. Chem. £2, 1487 (1987)), to a solution of 2.97 g of the product of Example 1 B in 75 ml of dichloromethane at 0°C was added 9 g of MCPBA. The solution was stirred at 0°C for 1 h and then at RT overnight. It was added to 250 ml of ether and washed successively with cold 10% sodium thiosulfate, 10% sodium carbonate and then satd. NaCI solution. The organic layer was dried and concentrated to a colorless oil which was purified by silica gel column chromatography (20% EtOAc/hexane) to provide 2.7 g of the desired product containing a small amount of the 3R diastereomer. ¹ H NMR (CDCI ₃ ): 5 2.57 (m, 1 H), 2.70 (t,

J=4.5 Hz, 1 H), 2.90 - 3.05 (m, 1 H), 4.20 (m, 1 H), 4.70 (br d, 1 H), 7.20- 7.38 (m, 10H). Mass spectrum: (M+H)+ ___ 298.

P. Nm-Benzyloxycarbonyl-N(2>-benzyl hydrazine.

To a solution of 5 g of benzylhydrazine dihydrochloride in 50 ml of THF was added 5.9 ml of N-methylmorpholine and 7.6 g of CBz-NOS at 0°C. After 1 h, the reaction mixture was warmed to RT and stirred at RT overnight. After filtering off the solid formed and concentration of the filtrate; silica gel column chromatography (10% acetone/90% hexane) provided 2.6 g of desired product. 1 H NMR (CDCI ₃ ): δ 3.25 (br s, 1 H), 4.05 (s, 2H), 5.16 (s, 2H), 6.23 (br s, 1 H), 7.25 (m, 10H).

2-rBenzvloxycarbonvnamino-4R-hydroxv-5R-

(bgnzylpχycart?pnyl)amino-1.β-cilphenyi-2-azahexane,

To a solution of 1.2 g of the product of Example 1 C in 36 ml of isopropanol was added 1.03 g of the hydrazine from Example 1 D. The solution was heated at reflux for 24 h; cooled to RT and concentrated in vacuo. Silica gel column chromatography (10% to 20% acetone/hexane) provided 1.5 g of desired product. ¹ H NMR (CDCI3): δ 2.55 (m, 1 H), 2.80 (m, 1 H), 2.95 (d, 2H), 3.60 (m, 2H), 3.70 - 4.00 (m, 3H), 4.30 (s, 1 H), 5.03 (s, 2H), 5.05 (s, 2H), 5.30 (m, 1 H), 5.48 (s, 1 H), 7.30 (m, 20H).

F. 2-fbenzyloxvcarbonvhamino-4R- trimethvlsilvl-ethoxv-methoxy)- 5R-fbenzvloxvcarbonvnamino-1.6-diDhenvl-2-azahexane.

To a solution of the product from Example 1 E in 12 ml of dimethylformamide was added 1.8 ml of diisopropyl ethyl amine and then 1.14 ml of trimethylsilyl ethoxymethyl chloride. The reaction mixture was stirred at RT for 19 h. The DMF was removed in vacua. The residue was extracted with EtOAc (3 x 80 ml) and washed with satd. NaCI solution. The organic layer was dried with anhy. sodium sulfate, filtered and the solvent evaporated in vacuo. Purification of the residue by silica gel column chromatography (20% acetone/hexane) provided 1.23 g (83%) of the desired compound. 1 H NMR (CDCI ₃ ): δ θ.1 (s, 9H), 0.95 (t, 2H), 2.80 (m, 3H), 3.10 (m, 1 H), 3.65 (m, 3H), 3.97 (m, 1 H), 4.26 (m, 1 H), 4.70 (m, 2H), 5.00 (m, 4H), 5.30 (m, 1 H), 7.25 (m, 20H).

G. 2-Amino-4R-ftrimethvlsilvl-ethoxvmethoxv^5R.amino-1.6- diphenvl-2-azahexane.

To a suspension of 100 mg of 10% Pd/C in 20 ml of methanol was added 1.2 g of the product from Example 1 F. The mixture was stirred vigorously under a hydrogen atmosphere (balloon filled with hydrogen) for 1 h. The catalyst was filtered off and the filtrate was concentrated in vacuo to provide 0.70 g of crude product. ¹ H NMR (CDCI ₃ ): δ 0.2 (s, 9H), 0.95 (t, 2H),

2.10 (m, 4H), 2.70 (m, 2H), 2.90 (m, 2H), 3.39 (m, 1 H), 3.70 (m, 4H), 3.90 (m, 1 H), 4.80 (m, 2H), 7.30 (m, 10H).

H. (5R.6R .5-Dibenzvl-3-oxo-6-(tr.methylsilylethoxy-methoxyi-

1.2.4-triazacvcloheptane.

To 120 ml of dichloromethane with stirring was added 300 mg of carbonyldiimidazole (in 5 ml of CH2CI2) and 0.7 g of the product of

Example 1 G (in 5 ml of CH2CI2) over a period of 2 h via a syringe pump. The solution was kept at RT for 72 h; concentration in vacuo and purification by silica gel column chromatography (20% EtOAc/CH2Cl2) provided 400 mg of desired compound. ¹ H NMR (CDCI ₃ ): δ 0.20 (s, 9H), 0.90 (t, 2H), 2.96 (m,

2H), 3.17 (m, 2H), 3.70 (m, 3H), 4.10 (m, 3H), 5.52 (br s, 1 H), 4.75 (m, 2H),

5.70 (br s, 1 H), 7.30 (m, 10H).

I. (5R.βR 5-benzyl-6-Mrimethvlsilvlethoxvmethoxv}-3- oxo-1.2.4-triazacyc I o heptane.

To a suspension of 72 mg of 20% palladium hydroxide on carbon in 36 ml of methanol was added 360 mg of the product of Example 1H. The mixture was stirred vigorously under a hydrogen atmosphere (balloon filled with hydrogen) for 1 h. The catalyst was filtered off and the filtrate was concentrated in vacuo to provide 285.0 mg of the desired product. 1H NMR (CDCI3) δ 0.01 (s, 9H), 0.92 (m, 2H), 2.92 (m, 3H), 3.33 (dd, 1H), 3.57-3.70 (m, 4H), 4.17 (br d, 1H), 4.32 (br s, 1H), 4.87 (dd, 2H), 5.95 (br s, 1H), 7.18-7.33 (m, 5H). Mass spectrum: (M+H)+ = 352.

J. (5R.6R)-1-benzoyl-5-benzyl-6-(trimethylsilylethoxy- methoxy)-3-oxo-1.2.4-triazacvcloheptane.

To a solution of 88 mg (0.25 mmol) of the product of Example 11 in 10 ml of CH2CI2 was added 24.0 μl (0.30 mmol) of anhydrous pyridine and 32.0 μl (0.28 mmol) of benzoyl chloride. After being stirred at RT for 0.5 h, the mixture was treated with 2 ml of water, extracted with CH2CI2 (4 X 5 ml). The combined organic solution was dried over Na2Sθ4, filtered and concentrated. The residue was purified by silica gel column chromatography using 5% MeOH in CH2CI2, provided 108.4 mg (95%) of desired product. Mass spectrum: (M+H)+ = 456.

K. (5R.6R)-2.4-Bis-(2-propen-1-yh-1-benzoyl-5-benzyl- 6-hvdroxy-3-oxo-1.2.4-triazacycloheptane.

To a suspension of 71 mg (2.4 mmol) of NaH (80% oil dispersion) in 0.5 ml of DMF was added a solution of 108.0 mg (0.24 mmol) of the product of Example U in 1.5 ml of DMF. After stirring at RT for 30 min, 123 μl (1.4 mmol) of allyl bromide was added. The reaction mixture was stirred at RT for 1h and quenched at 0°C with 5 ml of satd. NH4CI solution and extracted with CH2CI2 (4 X 5 ml). The combined CH2CI2 solution was washed with brine and dried. Concentration in vacuo and purification by silica gel column chromatography using 25% EtOAc in hexane, provided 110.4 mg of product. It was then deprotected by dissolving in 5 ml of MeOH, stirred with 125 μl of trimethylsilyl chloride at RT for 4 h. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography using 5% MeOH in CH2CI2, provided 81.4 mg (85%) of desired product. Mass spectrum: (M+H)+ = 406.

L. (5R.6R)-2.4-Bis-M-propyn-1-benzoyl-5-benzyl-6- hvdroxy-3-oxo-1.2.4-triazacvcloheptane.

To a suspension of 25 mg of 10% Pd/C in 10 ml of EtOAc was added 50 mg of the product of Example 1K. The reaction mixture was stirred vigorously under a hydrogen atmosphere (hydrogen filled balloon) for 1.5 h. Filtration, concentration in vacuo and purification by silica gel column chromatography using 50% EtOAc in hexane provided 45.4 mg (90%) of desired product as a white foam. ^"■ H NMR (CDCl3) δ 0.69-1.10 (six t, 6H), 1.24-1.45 (m, 2H), 1.55-2.01 (m, 2H), 2.42-2.93 (m, 1H), 3.00-3.28 (m, 3H), 3.33-3.54 (m, 2H), 3.60-3.72 (m, 2H), 3.92-4.13 (m, 2H), 4.26-4.86 (m, 1H), 7.17-7.55 (m, 10H). Mass spectrum: (M+H)+ = 410.

Example 2 A. ⁽ 5R.6RΪ-1-acetyl-5-benzyl-6-rtrimethylsilylethoxv- methoxy.-3-oxo-1.2.4-triazacvcloheptane.

Using the procedure of Example U, but replacing the benzoyl chloride with the acetyl chloride, provided the desired compound. ¹ H

NMR (CDCI3) δ 0.04 (s, 9H), 0.95 (m, 2H), 2.19 (s, 3H), 2.79 (dd, 1H), 2.96 (m, 1H), 3.69 (m, 4H), 4.04 (m, 1H), 4.40 (br s, 1H), 4.70 (d, 1H), 4.83 (dd, 1H), 4.85 (d, 1H), 6.84 (s, 1H), 7.18-7.39 (m, 5H). Mass spectrum: (M+H)+ = 394.

B. (5R.6R)-2.4-Bis-(2-propen-1-vn-1-acetyl-5- benzyl-6-hvdroxv-3-oxo-1.2.4-triazacvclo heptane.

Using the procedure of Example 1K, but replacing the product of Example U with the product of Example 2A , provided the desired compound. ^" Η NMR (CDCI3) δ 1.99 (s, 3H), 2.33 (d, 1H), 2.48 (dd, 1H), 2.80 (dd, 1H), 2.98 (dd, 1H), 3.15 (dd, 1H), 3.43 (dt, 1H), 3.73 (dd, 1H), 3.95 (m, 1H), 4.06 (ddt, 1H), 4.47 (dd, 1H), 4.69 (dd, 1H), 4.88 (d, 1H), 5.00 (d, 1H), 5.32 (d, 1H), 5.39 (d, 1H), 5.47 (m, 1H), 6.04 (m, 1H), 7.18-7.34 (m, 5H). Mass spectrum: (M+H)+ - 344.

C. (5R.6Ri-2.4-Bis-M-Dropvn-1-acetvl-5- benzvl-6-hvdroxv-3-oxo-1.2.4-triazacvclo heptane.

Using the procedure of Example 1L, but replacing the product of Example 1K with the product of Example 2B, provided the desired compound. 1H NMR (CDCI3) δ 0.68 (t, 3H), 1.02 (t, 3H), 1.21 (m, 2H), 1.77 (q, 2H), 1.91 (m, 1H), 2.00 (s, 3H), 2.86 (dd, 1H), 2.98-3.07 (m, 3H), 3.14 (dd, 1H), 3.39 (dt, 1H), 3.50 (m, 1H), 3.98 (m, 1H), 4.07 (m, 1H), 4.53 (dd, 1H), 7.19-7.32 (m, 5H). Mass spectrum: (M+H)+ = 348.

Anal. Calcd. for C19H29N3O3O.5H2O: C, 64.84; H, 8.45; N, 11.94; Found: C, 64.73; H, 8.23; N, 11.70.

Example 3 A. ⁽ 5R.6R -1- ^p ropionyl-5-benzyl-6-Hr_methylsilyl- ethoxy-methoxyϊ-3-oxo-1.2.4-triazacvcloheptane.

Using the procedure of Example U, but replacing the benzoyl chloride with propionyl chloride, provided the desired compound. Mass spectrum: (M+H)+ - 408.

~c <~ Uu i _ -•

B. (5R.6Ri-2.4-Bis-(2-propen-1-vn-1-propionyl-5- benzyl-β-hvdroxy-3-oxo-1.2.4-triazacvcloheptane.

Using the procedure of Example 1K, but replacing the product of Example U with the product from Example 3A, provided the desired compound. Mass spectrum: (M+H) ⁺ = 358.

C. (5R.6Ri-2.4-Bis-M-propvn-1-propionvl-5- benzyl-6-hvdroxy-3-oxo-1.2.4-triazacvclo heptane.

Using the procedure of Example 1L, but replacing the product of Example 1K with the product of Example 3B, provided the desired compound. ¹ H NMR (CDCI3) δ 0.66 (t, 3H), 1.03 (t, 3H), 1.08 (t, 3H), 1.14-1.27 (m, 2H), 1.76 (m, 2H), 1.82 (ddd, 1H), 2.23 (m, 1H), 2.33 (m, 2H), 2.86 (dd, 1H), 3.00 (m, 1H), 3.13 (dd, 2H), 3.37 (dt, 1H), 3.48 (dt, 1H). 3.96-4.03 (m, 1H), 4.06-4.12 (m, 1H), 4.54 (dd, 1H), 7.19-7.34 (m, 5H). Mass spectrum: (M+H)+ = 362.

Anal. Calcd. for C20H31N3O3: C, 66.45; H, 8.64; N, 11.62; Found: C, 66.36; H, 8.61; N, 11.55.

Example 4 A. (5R.6R)-1-(2-methylpropionvn-5-benzvt-β- (trimethyl-silylethoxymethoxyϊ-3-oxo-1.2.4- triazacvcloheptane.

Using the procedure of Example 1J, but replacing the benzoyl chloride with isobutyryl chloride, provided the desired compound. 1 H NMR (CDCI3) δ 0.03 (s, 9H), 0.96 (t, 2H), 1.12 (d, 6H), 2.79 (m, 1H), 2.94 (m, 1H), 3.11 (m, 1H), 3.21 (m, 1H), 3.70 (m, 3H), 4.08 (m, 1H), 4.41 (br s, 1H), 4.71 (d, 1H), 4.77 (m, 1H), 4.85 (d, 1H), 6.74 (br s, 1H), 7.18 (m, 2H), 7.25-7.35 (m, 3H). Mass spectrum: (M+H)+ - 422.

yty

B. (5R.6 )-2.4-Bis-(2-propen-1-vn-1-(2- methylpropionvπ-5-benzyl-6-hvdroxy-3-oxo-1.2.4- triazacvcloheptane.

Using the procedure of Example 1K, but replacing the product of Example U with the product of Example 4A, provided the desired compound.

C. (5R.6Ri-2.4-Bis-M- ^p ro ^p yn-1-(2-methylpropionyl.-5- benzyl-6-hvdroxy-3-oxo-1.2.4-triazacvcloheptane.

Using the procedure of Example 1L, but replacing the product of Example 1K with the product of Example 4B , provided the desired compound. 1H NMR (CDCI3) δθ.65 (t, 3H), 0.99 (d, 3H), 1.03 (t, 3H), 1.14 (d, 3H),1.22 (m, 2H), 1.78 (m, 2H), 1.91 (m, 1H), 2.74 (m, 1H), 2.88 (dd, 1H), 3.03 (m, 3H), 3.15 (m, 1H), 3.41 (m, 1H), 3.92 (m, 1H), 4.06 (ddd, 1H), 4.58 (dd, 1H), 7.19-7.33 (m, 5H). Mass spectrum: (M+H)+ = 376.

Anal. Calcd. for C21H33N3O3: C, 67.17; H, 8.86; N, 11.19; Found: C, 67.29; H, 9.14; N, 11.15.

Example 5 A. (5R.6R)-1-(2.2-dimethylpropionvn-5-benzyl-6- (trimethyl-silylethoxymethoxy)-3-oxo-1.2.4- triazacvcloheptane.

Using the procedure of Example 1J, but replacing the benzoyl chloride with pivaloyi chloride, provided the desired compound. Mass spectrum: (M+H)+ = 436.

B. (5R.6R)-2.4-Bis-(2-propen-1-vn-1-(2.2- dimethylpropionvπ-5-benzyl-β-hvdroxy-3-oxo-1.2.4- triazacvcloheptane.

Using the procedure of Example 1K, but replacing the product of Example U with the product of Example 5A, provided the desired compound.

C. f5R.6R)-2.4-Bis-M-propvn-1-f2.2-dimethvl- propionvπ-5-benzyl-6-hvdroxy-3-oxo-1.2.4- triazacvcloheptane.

Using the procedure of Example 1L, but replacing the product of Example 1K with the product of Example 5B, provided the desired compound. Mass spectrum: (M+H) ⁺ = 390.

Anal. Calcd. for C22H35N3O3: C, 67.83; H, 9.06; N, 10.79; Found: C, 67.73; H, 9.19; N, 10.66.

Example 6

A. (5R.6Ri-1-methanesulfonyl-5-benzyl-6-(trimethvl- silyl-ethoxymethoxy.-3-oxo-1.2.4-triazacvcloheptane.

To a solution of 100 mg (0.28 mmol) of the product of Example 11 in 5 ml of CH2CI2 was added 95.2 μl (0.68 mmol) of triethylamine and 48.4 μl (0.64 mmol) of methanesulfonyl chloride. The mixture was stirred at 0°C for 2 h and then at RT for 5 h. Evaporated the solvent. The residue was purified by silica gel column chromatography using 70% EtOAc in hexane, provided 68.6 mg (57%) of desired product. ¹ H NMR (CDCI3) δ 0.04 (s, 9H), 0.97 (m, 2H), 2.89 (dd, 1H), 3.00 (dd, 1H), 3.14 (s, 3H), 3.36 (br d, 1H), 3.64-3.85 (m, 4H), 4.35 (br d, 1H), 4.38 (br s, 1H), 4.74 (d, 1H), 4.88 (d, 1H), 6.57 (d, 1H), 7.20-7.28 (m, 5H). Mass spectrum: (M+H)+ = 430.

B. (5R.6RΪ-2.4-Bis-(2-propen-1-vπ-1-methane- sulfonyl-5-benzyl-6-hvdroxy-3-oxo-1.2.4- triazacvcloheptane.

Using the procedure of Example 1K, but replacing the product from Example 1J with the product from Example 6A, provided the desired compound. ¹ H NMR (CDCI3) 1.93 (d, 1H), 2.58 (dd, 1H), 2.88 (dd, 1H), 3.00 (s, 3H), 3.09 (dd, 1H), 3.25 (dd, 1H), 3.47 (dt, 1H), 3.96 (m, 2H), 4.14 (m, 2H), 4.58 (dd, 1H), 4.94 (d, 1H), 5.03 (d, 1H), 5.33 (d,

1H), 5.39 (d, 1H), 5.56 (m, 1H), 6.04 (m, 1H), 7.15-7.32 ( , 5H). Mass spectrum: (M+H)+ - 380.

Anal. Calcd. for C18H25N3O4S: C, 56.97; H, 6.64; N, 11.07; Found: C, 56.93; H, 6.73; N, 10.94.

Example 7 A. (5R.6R)-1-bromoacetyl-5-benzyl-6-(trimethylsilvl- ethoxy-methoxy)-3-oxo-1.2.4-triazacvcloheptane.

Using the procedure of Example U, but replacing the benzoyl chloride with the bromoacetyl chloride, provided the desired compound. ¹ H NMR (CDCI3) δ 0.03 (s, 9H), 0.95 (m, 2H), 2.79 (dd, 1H), 2.94 (m, 1H), 3.73 (m, 4H), 4.06 (m, 1H), 4.23 (br s, 2H), 4.49 (br s, 1H), 4.71 (m, 2H), 4.86 (br d, 1H), 7.18-7.39 (m, 6H). Mass spectrum: (M+NH4) ⁺ = 491, 489.

B. (5R.6R)-1-(N.N-dimethylqlvcyl.-5-benzyl-6- (trimethylsilylethoxymethoxy)-3-oxo-1.2.4- triazacvcloheptane.

To a solution of 60 mg (0.13 mmol) of the product of Example 7A in 3 ml of CH2CI2 was added 0.5 ml (0.64 mmol) of 1.3 M dimethylamine in ether. The mixture was stirred at RT for 2 h and then treated with 3 ml of water, extracted with CH2CI2 (4 X 5 ml). The combined organic solution was dried over Na2Sθ4, filtered and concentrated. The residue was purified by silica gel column chromatography using 10% MeOH in CH2CI2, provided 55.4 mg (100%) of desired product. ¹ H NMR (CDCI3) δ0.03 (s, 9H), 0.97 (m, 2H), 2.32 (s, 6H), 2.88 (dd, 1H), 3.00 (dd, 1H), 3.09 (m, 1H), 3.27 (m, 1H), 3.67 (m, 2H), 3.79 (m, 2H), 3.92 (br s, 1H), 4.14 (br s, 1H), 4.40 (br s, 1H), 4.73 (d, 1H), 4.91 (d, 1H), 7.19-7.37 (m, 5H), 8.94 (br s, 1H). Mass spectrum: (M+H)+ = 437.

C. (5R.6R)-2.4-Bis-cvclopropylmethyl-1-(N.N- dimethylαlvcvh-5-benzyl-6-hvdroxy-3-oxo-1.2.4- triazacvcloheptane.

Using the procedure of Example 1L, but replacing the product from Example 1K with the product of Example 7B and replacing the allyl bromide with bromomethyl cyclopropane, provided the desired compound. ¹ H NMR (CDCI3) δθ.36 (m, 4H), 0.67 (m, 4H), 1.12 (m, 1H), 1.87 (dd, 1H), 2.32 (s, 6H), 2.86 (dd, 1H), 2.91-3.34 (m, 8H), 3.57 (m, 1H), 3.79 (m, 1H), 3.95 (dd, 1H), 4.07 (m, 1H), 4.55 (dd, 1H), 7.20-7.33 (m, 5H). Mass spectrum: (M+H) ⁺ = 415.

Example 8 A. f5R.6R)-1-r2-furovn-5-benzyl-6-(trimethylsilyl- ethoxymethoxy)-3-oxo-1.2.4-triazacvcloheptane.

Using the procedure of Example U, but replacing the benzoyl chloride with 2-furoyl chloride, provided the desired compound. Mass spectrum: (M+H)+ = 446.

B. (5R.6R -2.4-Bis-(4-hvdroxybenzvn-1-(2-fur0vn-5- benzyl-6-hvdroxy-3 -oxo-1.2.4 -triazacvcloheptane.

Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 8A and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound. Mass spectrum: (M+H) ⁺ = 528.

Anal. Calcd. for C30H29N3O6O.5H2O: C, 67.15; H, 5.64; N, 7.83; Found: C, 66.99; H, 5.49; N, 7.74.

Example 9 (5R.6R -2.4-Bis-(4-hvdroxybenzvh-1-acetyl-5-benzyl-6* hvdroxy- 3-OXO-1.2.4-triazacvcloheptane.

Using the procedure of Example 1K, but replacing the product of Example U with the product of Example 2A and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride,

provided the desired compound. ¹ H NMR (DMSO-Dβ) (mixture of three rotamers) δ 1.83, 1.87 and 2.03 (three s, 3H), 2.33-2.45 (m, 1H), 2.60 (m, 1H), 2.73 (m, 1H), 2.83 (m, 1H), 3.13-3.23 (m, 1H), 3.55-3.68 (m, 1H), 3.95, 4.17 and 4.25 (three d, 1H), 4.28, 4.36 and 4.55 (three d, 1H), 4.89, 4.92 and 4.96 (three d, 1H), 5.36, 5.38 and 5.48 ( three d, 1H), 6.63 (m, 4H), 6.78 (m, 2H), 7.02 (m, 2H), 7.17-7.34 (m, 5H), 9.29, 9.34, 9.35, 9.39, 9.47 and 9.52 (six s, 2H). Mass spectrum: (M+H)+ = 528.

Anal. Calcd. for C27H29N3O5-O.75H2O: C, 66.31; H, 6.29; N, 8.59; Found: C, 66.35; H, 6.16; N, 8.59.

Example 10 (5R.6R)-2.4-Bis-(4-hvdroxybenzvn-1-(2-methvl- propionvh-5-benzyl-6-hvdroxy-3-oxo-1.2.4- triazacvcloheptane.

Using the procedure of Example 1K, but replacing the product of Example U with the product of Example 4A and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound. ¹ H NMR (DMSO-dβ) (mixture of three rotamers) 0.86-1.09 (six d, 3H), 2.33-2.46, (m, 1H), 2.66-3.03 (m, 4H), 3.24 (m, 1H), 3.42-3.78 (three m, 1H), 3.98-4.08 (m, 1H), 4.28, 4.46 and 4.60 (three d, 1H), 4.81, 4.83 and 5.03 (three d, 1H), 5.12, 5.16 and 5.28 (three d, 1H), 6.60-6.80 (m, 6H), 6.98-7.33 (m, 7H), 9.03-9.23 (six s, 2H). Mass spectrum: (M+H)+ = 521.

Anal. Calcd. for C29H33N3O5O.5H2O: C, 67.95; H, 6.69; N, 8.20; Found: C, 67.87; H, 6.60; N, 8.11.

Example 11 A. (5R.6R)-1-(butyrvn-5-benzyl-6-πrimethylsilvl- ethoxy-methoxy)-3-oxo-1.2.4-triazacvcloheptane.

Using the procedure of Example U, but replacing the benzoyl chloride with butyryl chloride, provided the desired compound. Mass spectrum: (M+H)+ = 422.

B. (5R.6R)-2.4-Bis-(4-hvdroxybenzvh-1-(butyrvn-5- benzyl-6-hvdroxy-3-oxo-1.2.4-triazacvcloheptane.

Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 11 A and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound. ¹ H NMR (DMSO-d6) (mixture of three rotamers) 0.81 and 0.94 (three t, 3H), 1.44-1.57, (m, 2H), 2.34-2.67 (m, 1H), 2.73-2.97 (m, 2H), 3.22 (m, 1H), 3.63-3.72 (m, 1H), 3.98 (m, 1H), 4.12-4.23 (m, 1H), 4.22-4.56 (three d, 1H), 4.85-4.98 (three d, 1H), 5.33-5.47 (three d, 1H), 6.60-6.79 (m, 6H), 6.98-7.35 (m, 7H), 9.33 (br s, 1H), 9.46 (br s, 1H). Mass spectrum: (M+H)+ = 504.

Example 12

A. (5R.6Ri-1-(3-methylbιιtyrvn-5-benzyl-6- (trimethylsilyl-ethoxymethoxy)-3-oxo-1.2.4- triazacvcloheptane.

Using the procedure of Example U, but replacing the benzoyl chloride with isovaleryl chloride, provided the desired compound. ^" -H NMR (CDCI3) δ 0.03 (s, 9H), 0.96 (m, 8H), 2.15 (m, 1H), 2.36 (m, 2H), 2.77 (m, 1H), 2.95 (m, 1H), 3.71 (m, 3H), 4.06 (m, 1H), 4.36 (br s, 1H), 4.72 (d, 1H), 4.81 (m, 1H), 4.87 (d, 1H), 6.50 (br s, 1H), 7.16-7.35 (m, 5H). Mass spectrum: (M+H)+ = 436.

B. (5R.6Ri-2.4-Bis- ⁽ 4-hvdroxybenzvn-1-(3- methylbutyrvn-5-benzyl-6-hvdroxy-3-oxo-1.2.4- triazacvcloheptane.

Using the procedure of Example 1K, but replacing the product of Example U with the product of Example 12A and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound. ¹ H NMR (DMSO-d6) (mixture of three rotamers) 0.81-0.95 (four d, 6H), 1.72-2.45 (m, 4H), 2.56-2.86 (m, 1H), 3.03-3.25 (m, 1H), 3.63 (m, 1H), 4.18 (m, 1H), 4.25, 4.38 and 4.53 (three d, 1H), 4.94 (m, 1H), 5.33, 5.38 and 5.46 (three d, 1H), 6.61-

6.79 (m, 6H), 6.98-7.32 (m, 7H), 9.33, 9.39 and 9.47 (three br s, 2H). Mass spectrum: (M+H)+ = 518.

Example 13 A. (5 R.6R)-1-valeryl-5-benzyl-6-ftri met h vis il vl- ethoxy-methoxy)-3-oxo-1 ,2.4-triazacvcloheptane.

Using the procedure of Example U, but replacing the benzoyl chloride with valeryl chloride, provided the desired compound. Mass spectrum: (M+H)+ _* 436.

B. (5R.6R)-2.4-Bis-(4-hvdroxybenzvn-1-valeryl-5- ben zyl-6-hvdro xy -3-OXO-1.2.4-triazacvcloheptane.

Using the procedure of Example 1K, but replacing the product of Example U with the product of Example 13A and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound. ¹ H NMR (DMSO-Dε) (mixture of three rotamers) δθ.81, 0.87 and 0.92 (three t, 3H), 1.19, 1.37 and 1.52 ( three m, 4H), 1.90, 2.13 and 1.32 (three m, 2H), 2.39 (m, 1H), 2.62- 2.97 (m, 3H), 3.07-3.22 (m, 1H), 3.60-3.65 (m, 1H), 3.92, 3.96 and 4.03 (three d, 1H), 3.97, 4.16 and 4.21 (three d, 1H), 4.29, 4.38 and 4.52 (three d, 1H), 4.83, 4.89 and 4.95 (three d, 1H), 5.35, 5.38 and 5.47 (three d, 1H), 6.61 (m, 4H), 6.76 (m, 2H), 7.03(m, 2H), 7.16-7.33 (m, 5H), 9.30, 9.35, 9.39 and 9.47 (four br s, 2H). Mass spectrum: (M+H)+ = 518.

Anal. Calcd. for C30H35N3O5O.5H2O: C, 68.42; H, 6.89; N, 7.98; Found: C, 68.54; H, 6.79; N, 7.72.

SUBSΪ,7o~ES-ΕEι Γ ^{' '} -I 2C

Examole 14 A. (5R.6R)-1-(2-ethylbutyrvn-5-benzyl-6- ⁽ trimethvl- silyl-ethoxymethoxy)-3-oxo-1.2.4-triazacvcloheptane.

Using the procedure of Example U, but replacing the benzoyl chloride with 2-ethylbutyryl chloride, provided the desired compound. Mass spectrum: (M+H)+ = 450.

B. (5R.6RΪ-2.4-Bis-(4-hvdroxvbenzvn-1-<2-ethvl- butyrvh-5-benzyl-6-hvdroxy-3-oxo-1.2.4- triazacvcloheptane.

Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 14A and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound. ¹ H NMR (DMSO-D6) (mixtures of three rotamers) δ 0.75-0.96 (three m, 6H), 1.25-1.58 (three m, 4H), 2.36-2.46 (m, 1H), 2.65-2.85 (m, 3H), 3.15-3.25 (m, 2H), 3.68 (m, 1H), 3.95 (d, 1H), 4.10 (m, 1H), 4.38 (d, 1H), 4.95, 5.06 and 5.13 (three d, 1H), 5.38, 5.40 and 5.44 (three d, 1H), 6.57-6.63 (m, 4H), 6.87 (dd, 2H), 6.90 (dd, 1H), 7.12 (dd, 1H), 7.22-7.32 (m, 5H), 9.28, 9.32, 9.38, 9.40, 9.48 and 9.51 ( six s, 2H). Mass spectrum: (M+NH4)+ = 549.

Anal. Calcd. for C31H37N3O5O.5H2O: C, 68.87; H, 7.08; N, 7.77; Found: C, 68.88; H, 7.09; N, 7.68.

Example 15 A. (5R.6Ri-1-(2-(1-propylvalervm-5-benzyl-6- (trimethylsilyl-ethoxymethoxyϊ-3-oxo-1.2.4- triazacvcloheptane.

Using the procedure of Example U, but replacing the benzoyl chloride with 2-(1-propylvaleryl) chloride, provided the desired compound. Mass spectrum: (M+H) ⁺ = 478.

SU ST,

B. (5R.6R1-2.4-Bis-(4-hvdroxybenzyn-1-f2-π- propylvalervm-5-benzyl-6-hvdroxy-3-oxo-1.2.4- triazacvcloheptane.

Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 15A and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound. ¹ H NMR (DMSO-D6) (mixtures of three rotamers) δ 0.72, 0.85 and 0.87 (three t, 6H), 1.18-1.57 (m, 8H), 2.28-2.38 (m, 1H), 2.58-3.18 (m, 5H), 3.67 (dd, 1H), 3.97 (d, 1H), 4.03, 4.07 and 4.11 (three d, 1H), 4.12, 4.37 and 4.58 (three d, 1H), 4.94, 5.08 and 5.15 (three d, 1H), 5.35, 5.40 and 5.42 (three d, 1H), 6.52-6.63 (m, 4H), 6.74-6.79 (m, 2H), 6.87 (m, 1H), 7.09-7.16(m, 2H), 7.23-7.36 (m, 4H), 9.26, 9.31, 9.36, 9.37, 9.46 and 9.48 (six s, 2H). Mass spectrum: (M+NH4)+ = 577.

Anal. Calcd. for C33H41N3O5O.5H2O: C, 69.69; H, 7.44; N, 7.39; Found: C, 69.95; H, 7.37; N, 7.31.

Example 16 A. (5R.6R)-1-cvclopentanecarbonyl-5-benzyl-6- {trimethvl-silvlethoxvmethoχy}-3-oxo-1.2.4- triazacvcloheptane.

Using the procedure of Example U, but replacing the benzoyl chloride with cyclopentanecarbonyl chloride, provided the desired compound. Mass spectrum: (M+H)+ = 448.

B. ⁽ 5R.6R)-2.4-Bis-U-hvdroxybenzvh-1-cvclopentane- carbonyl-5-benzyl-6-hvdroxy-3-oxo-1.2.4- triazacvcloheptane.

Using the procedure of Example 1K, but replacing the product of Example U with the product of Example 16A and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound. ¹ H NMR (DMS0-D6) (mixtures of three rotamers) δ 1.94-1.85 (m, 8H), 2.23-2.30 (m, 1H), 2.61-3.18 (m, 5H), 3.66 (d, 1H), 3.98, 4.01 and 4.03 (three d, 1H), 4.08, 4.17 and

SU BSTUUT f r,

4.22 (three d, 1H), 4.30, 4.42 and 4.57 (three d, 1H), 4.82, 4.84 and 5.01 (three d, 1H), 5.31, 5.35 and 5.46 (three d, 1H), 6.58-6.66 (m, 4H), 6.73-6.79 (m, 2H), 6.97-6.99 (m, 1H), 7.09-7.15 (m, 2H), 7.19- 7.34 (m, 4H), 9.29, 9.34, 9.37 and 9.45 (four br s, 2H). Mass spectrum: (M+NH4) ⁺ = 547.

Anal. Calcd. for C31H35N3O5O.75H2O: C, 68.55; H, 6.77; N, 7.74; Found: C, 68.51; H, 6.47; N, 7.52.

Example 17 (5R.6R)-2.4-Bis-(4-hvdroxybenzvn-1-(N.N- dimethylαlvcvh-5-benzyl-6-hvdroxy-3-oxo-1.2.4- triazacvcloheptane.

Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 7B and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound. ^" -H NMR (DMSO-d6) (mixture of three rotamers) 2.17 (s, 3H), 2.22, (s, 3H), 2.27-2.44 (m, 1H), 2.55-3.03 (m, 5H), 3.18 (m, 1H), 3.78-4.00 (m, 2H), 4.23 (m, 1H), 4.33-4.41 (m, 1H), 4.92 (m, 1H), 5.32, 5.39 and 5.50 (three d, 1H), 6.57-6.66 (m, 4H), 6.76 (m, 2H), 7.03 (m, 2H), 7.17-7.32 (m, 5H), 9.28-9.52 (six s, 2H). Mass spectrum: (M+H)+ = 519.

Example 18 A. (5R.6R}-1-(4-morpholinylacetvπ-5-benzyl-6- (trimethyl-silylethoxymethoxy)-3-oxo-1.2.4-

Using the procedure of Example 7B, but replacing the dimethylamine with morpholine, provided the desired compound. Mass spectrum: (M+NH4) ⁺ = 479.

B. (5R.6R)-2.4-Bis-(4-hvdroxybenzvn-1-(4- morpholinylacetvh-5-benzyl-6-hvdroxy-3-oxo-1.2.4- triazacvcloheptane.

Using the procedure of Example 1K, but replacing the product of Example U with the product of Example 18A and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound. ^" -H NMR (DMSO-d6) (mixture of three rotamers) 2.37-2.47 (m, 5H), 2.63-3.14 (m, 5H), 3.24 (m, 1H), 3.47- 3.59 (m, 2H), 3.82 (m, 1H), 4.00 (m, 1H), 4.25 (m, 1H), 4.34-4.43 (m, 1H), 4.91 (m, 1H), 5.32, 5.40, 5.47 (three d, 1H), 6.58-6.77 (m, 6H), 7.01-7.34 (m, 7H), 9.29-9.51 (six s, 2H). Mass spectrum: (M+H)+ = 561.

Anal. Calcd. for C31H36N4O6O.75H2O: C, 64.85; H, 6.58; N, 9.76; Found: C, 64.58; H, 6.47; N, 9.61.

Example 19 A. _5R.6R)-1-methoxyacetyl-5-benzyl-6-(trimethvl- silyl-ethoxymet ho xy_-3-oxo-1.2.4 -triazacvcloheptane. Using the procedure of Example U, but replacing the benzoyl chloride with methoxyacetyl chloride, provided the desired compound. ^" -H NMR (CDCI3) δ 0.04 (s, 9H), 0.95 (m, 2H), 2.80 (dd, 1H), 2.96 (dd, 1H), 3.45 (s, 3H), 3.66-3.76 (m, 3H), 4.03 (m, 1H), 4.20 (dd, 2H), 4.41 (s, 1H), 4.72 (d, 1H), 4.88 (d, 1H), 6.95 (br s, 1H), 7.18-7.36 (m, 5H). Mass spectrum: (M+H) ⁺ = 441.

B. (5R.6Ri-2.4-Bis-(4-hvdroxvbenzvl)-1-methoxy- acetyl-5-benzyl-6-hvdroxy-3-oxo-1.2.4- triazacvcloheptane. Using the procedure of Example 1K, but replacing the product of Example U with the product of Example 19A and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound. Mass spectrum: (M+H)+ = 523.

Anal. Calcd. for C28H31N3O6O.75H2O: C, 64.79; H, 6.31; N, 8.09; Found: C, 64.99; H, 6.16; N, 8.00.

SU35T. I * Ji

Examole 20 A. (5R.6Ri-1-(t-butoxvcarbonvn-5-benzvl-6- (trimethyl-silylethoxymetho xy >-3-oxo-1.2.4- triazacvcloheptane.

To a solution of 50 mg (0.14 mmol) of the product of Example 11 in 3 ml of CH2CI2 was added 46.6 mg of di-terf-butyl dicarbonate, 4 mg of DMAP and 40 μl of triethylamine. The mixture was stirred at RT for 20 h and then treated with 3 ml of water, extracted with CH2CI2 (5 X 5 ml). The combined organic solution was dried over Na2Sθ4, filtered and concentrated. The residue was purified by silica gel column chromatography using 50% EtOAc in hexane, provided 53.7 mg (84%) of desired product. Mass spectrum: (M+H) ⁺ = 452.

B. (5R.6Ri-2.4-Bis-(4-hvdroxybenzvn-1-(t- butoxycarbonyl.-5-benzyl-6-hvdroxy-3-oxo-1.2.4- triazacvcloheptane.

Using the procedure of Example 1K, but replacing the product of Example 1J with the product of Example 20A and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound. Mass spectrum: (M+H)+ = 534.

Example 21 A. f5R.6R)-1-f4-methoxvcarbonylbutyrvn-5- benzyl-6-(trimethylsMylethoxymethoxy>-3-oxo-1.2.4- triazacvcloheptane.

Using the procedure of Example U, but replacing the benzoyl chloride with methyl glutaryl chloride, provided the desired compound. Mass spectrum: (M+NH)+ = 480.

SUB51 IT 0 : __

B. (5R.6R)-1-(5-hvdroxyvalervπ-5-benzyl-6- (trimethyl-silylethoxymethoxy)-3-oxo-1.2.4- triazapygiQhgp ane.

To a solution of 261.3 mg (0.54 mmol) of the product of Example 21 A in 30 ml of THF was added 1.6 ml of IJBH4 (2.0 M in THF). The mixture was stirred at RT for 20 h. It was then treated with 10 ml of 10% citric acid solution at OOC and extracted with CH2CI2 (5 x 20 ml). The combined organic solution was dried over Na2Sθ4, filtered and concentrated. The residue was purified by silica gel column chromatography using 5% MeOH in CH2CI2, provided 164.5 mg (67%) of desired product. Mass spectrum: (M+NH) ⁺ = 452.

C. ■f5R.6R)-1-(5-trimethylsilylethoxymethoxv- valervn-5-benzyl-β-(trimethylsilylethoxymethoxy)- 3-0x0-1.2.4-triazacvc 10 heptane.

Using the procedure of 1F, but replacing the product of Example 1E with the product of Example 21 B, provided the desired compound. Mass spectrum: (M+NH)+ ^• = 582.

D. (5R.6Ri-2.4-Bis-(4-hydroxybenzvn-1-(5- hvdroxvvalervn-5-benzvl-6-hvdroxv-3-oxo-1.2.4- tπagacyclQheptane.

Using the procedure of Example 1K, but replacing the product of Example U with the product of Example 21 C and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound. ¹ H NMR (DMSO-Dβ) (mixtures of three rotamers) δ 1.34-1.61 (m, 4H), 2.07-2.47 (m, 2H), 2.55-2.96 (m, 3H), 3.16-3.24 (m, 3H), 3.38-3.46 (m, 1H), 3.60-3.65 (m, 1H), 3.94- 4.02 (m, 1H), 4.09, 4.10 and 4.12 (three d, 1H), 4.15, 4.23 and 4.25 (three d, 1H), 4.37, 4.40 and 4.46 (three t, 1H), 4.54, 4.90 and 4.97 (three d, 1H), 5.34, 5.37 and 5.46 (three d, 1H), 6.60-6.62 (m, 4H), 6.75-6.78 (m, 2H), 6.98-7.10 (m, 2H), 7.17-7.32 (m, 5H), 9.28, 9.32, 9.34, 9.38, 9.46 and 9.49 (six s, 2H). Mass spectrum: (M+H)+ = 534.

■ ςJiw \~ ϋwc ^~ 1~ 1; i _ IT _Γ-

Anal. Calcd. for C30H35N3O6H2O: C, 65.32; H, 6.76; N, 7.62; Found: C, 65.46; H, 6.62; N, 7.46.

Example 22

A. (5R.6RΪ-1-(3-ethoxycarbonylpropionvn-5- benzyl-6-.trimethylsilylethoxymethoxy.-3-oxo-1.2.4- triazacvcloheptane.

Using the procedure of 1J, but replacing the benzoyl chloride with ethyl succinyl chloride, provided the desired compound. Mass spectrum: (M+NH)+ = 480.

B. (5R.6R)-1-(4-hvdroxybutyrvπ-5-benzyl-6- (trimethyl-silyletho xy methoxy 1-3-0X0-1.2.4- triazacvcloheptane.

Using the procedure of 21 A, but replacing the product of Example 21 A with the product of Example 22A, provided the desired compound. Mass spectrum: (M+NH) ⁺ = 438.

C. (5R.6Ri-1-(4-trimethylsilylethoxymethoxv- butyrvn-5-benzyl-6-(trimethylsilylethoxymethoxvϊ- 3-0x0-1.2.4-triazacvclo heptane.

Using the procedure of Example 1F, but replacing the product of Example 1E with the product of Example 22B, provided the desired compound. Mass spectrum: (M+NH)+ = 568.

D. <5R.6Ri-2.4-Bis-(4-hvdroxybenzvn-1-(4- hvdroxybutyrvh-5-benzyl-6-hvdroxy-3-oxo-1.2.4- triazacvcloheptane. Using the procedure of Example 1K, but replacing the product of Example U with the product of Example 22C and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound. ¹ H NMR (DMSO-Dβ) (mixture of three rotamers) δ 1.57-1.75 (m, 2H), 2.32-2.47 (m, 2H), 2.56-2.90 (m, 3H), 3.15-3.22 (m, 3H), 3.42-3.47 (m, 1H), 3.63 (m, 1H), 3.97 (m, 1H),

;_. J BST I I 0 it

4.08, 4.10 and 4.13 (three d, 1H), 4.15, 4.24 and 4.38 (three d, 1H), 4.48, 4.54 and 4.56 (three t, 2H), 4.894.93 and 5.02 (three d, 1H), 5.36, 5.38 and 5.44 (three d, 1H), 6.61 (m, 4H), 6.76-6.79 (m, 2H), 7.02-7.06 (m, 2H), 7.18-7.31 (m, 5H), 9.28, 9.33,9.34, 9.39, 9.47 and 9.49 (six s, 2H). Mass spectrum: (M+H)+ = 520.

Anal. Calcd. for C29H33N3O6H2O: C, 64.79; H, 6.56; N, 7.82; Found: C, 64.83; H, 6.38; N, 7.72.

Example 23 A. (5 R.6R)-1-( benzyl oxyacetvh-5-benzyl-6-rtri met hvl - silylethoxymetho xy )-3-oxo-1.2.4 -triazacvcloheptane.

Using the procedure of U, but replacing the benzoyl chloride with benzyloxyacetyl chloride, provided the desired compound. Mass spectrum: (M+NH)+ = 500.

B. (5 R .6 R1-1-fhvd roxyacetvn-5-benzyl-6-( trimethyl¬ silyl et ho xy-met ho xy )-3-oxo-1.2.4-triazacvclo heptane

To a suspension of 150 mg of 10% palladium on carbon in 10 ml of ethanol (95%) was added 143.8 mg of the product of Example 23A. The mixture was stirred vigorously under a hydrogen atmosphere (balloon filled with hydrogen) for 2 days. The catalyst was filtered off and the filtrate was concentrated in vacuo to provide 103.2 mg of the desired product. Mass spectrum: (M+NH4)+ = 427.

C. (5R.βR)-1-(trimethylsilylethoxymethoxyacetyl.-5- benzyl-6-(trimethylsilylethoxymethoxy)-3-oxo-1.2.4- triazacvcloheptane.

Using the procedure of Example 1F, but replacing the product of 1 E with the product of Example 23B, provided the desired compound. Mass spectrum: (M+NH)+ = 540.

D. (5 .6R 2.4-Bis-(4-hvdroxybenzvh-1-hvdroxv- acetyl-5-benzyl-6-hvdroxy-3-oxo-1.2.4- triazacvcloheptane.

Using the procedure of Example 1K, but replacing the product of Example U with the product of Example 23C and replacing the allyl bromide with 4-(2-trimethylsilylethoxymethoxy)benzyl chloride, provided the desired compound. ^"■ H NMR (DMSO-D6) (mixture of three rotamers) δ 2.58-2.79 (m, 3H), 3.10-3.25 (m, 2H), 3.39-3.48 (m, 1H), 3.65 (m, 1H), 3.87 (m, 1H), 4.08 (d, 1H), 4.33, 4.39 and 4.46 (three d, 2H), 4.80, 4.94 and 4.95 (three d, 1H), 5.43, 5.46 and 5.61 (three d, 1H), 6.64-6.76 (m, 6H), 7.03-7.33 (m, 7H), 7.73, 7.98 and 8.12 (three s, 1H), 9.30,9.33, 9.35, 9.43, 9.47 and 9.50 (six s, 2H). Mass spectrum: (M+NH4)+ = 509.

Example 24 (5R.6Rϊ-2.4-Bis-(3-nitrobenzvn-1-f3-methvl- butyrvn-5-benzyl-6-hvdroxy-3-oxo-1.2.4- triazacvcloheptane. Using the procedure of Example 1K, but replacing the product of Example U with the product of Example 12A and replacing the allyl bromide with 3-nitrobenzyl bromide, provided the desired compound. ¹ H NMR (DMSO-d6) (mixture of three rotamers) 0.65-0.94 (six d, 6H), 1.54-2.37 (m, 4H), 2.64-3.22 (m, 3H), 3.32-4.18 (m, 3H), 4.26-4.32 (m, 1H), 4.48-4.60 (m, 1H), 5.14, 5.17 and 5.18 (three d, 1H), 5.46, 5.50 and 5.51 (three d, 1H), 6.86-8.41 (m, 13H). Mass spectrum: (M+ H)+ =576.

Anal. Calcd. for C30H33N5O7O.5H2O: C, 61.63; H, 5.86; N, 11.98; Found: C, 61.70; H, 5.65; N, 11.72.

Example 25 (5R.6R)-2.4-Bis-(3-aminobenzvn-1-(3-methvl- butvrvn-5-benzyl-6-hvdroxv-3-oxo-1.2.4- triazacvcloheptane. To a suspension of 150 mg of Raney-Ni (50% in water) in 15 ml of MeOH/THF (1:1) was added 150 mg of the product of Example 24.

SUBS: I I i c

The reaction mixture was stirred vigorously under a hydrogen atmosphere (hydrogen filled balloon) for 2 h. Filtration, concentration in vacuo and purification by silica gel column chromatography using 5% MeOH in CH2CI2 provided 119.0 mg (89%) of desired product as a white foam. ¹ H NMR (DMSO-d6) (mixture of three rotamers) 0.84-0.97 (six d, 6H), 1.82-2.63, (m, 4H), 2.80-4.04 (m, 6H), 3.92, 4.06 and 4.13 (three d, 1H), 4.24, 4.39 and 4.52 (three d, 1H), 4.87-5.11 (m, 5H), 5.30, 5.32 and 5.38 (three d, 1H), 5.95-6.03 (m, 2H), 6.37-7.32 (m, 11H). Mass spectrum: (M+H)+ = 516.

Anal. Calcd. for C30H37N5O3O.25H2O: C, 69.27; H, 7.27; N, 13.46; Found: C, 69.34; H, 7.21; N, 13.34.

Example 26 (5R.6 )-2.4-Bis-U-nitrobenzvn-1-(3-methylbutyrvn-5- benzyl-6-hvdroxy-3-oxo-1.2.4 -triazacvcloheptane.

Using the procedure of Example 1K, but replacing the product of Example U with the product of Example 12A and replacing the allyl bromide with 4-nitrobenzyl bromide, provided the desired compound. ¹ H NMR (DMSO-d6) (mixture of two rotamers) 0.68-0.94 (four d, 6H), 1.57-2.38, (m, 4H), 2.63-3.20 (m, 3H), 3.31-4.16 (m, 3H), 4.25 and 4.31 (two d, 1H), 4.49 and 4.57 (two dd, 1H), 5.15 and 5.16 (two d, 1H), 5.44 and 5.49 (two d, 1H), 6.86-8.32 (m, 13H). Mass spectrum: (M+ H)+ =576.

Anal. Calcd. for C30H33N5O7O.5H2O: C, 61.63; H, 5.86; N, 11.98; Found: C, 61.70; H, 5.65; N, 11.72.

Example 27 (5R.6R)-2.4-Bis-(4-aminobenzvn-1-(3-methylbutyrylι-5 benzyl-6-hvdroxy-3-oxo-1.2.4 -triazacvcloheptane.

Using the procedure of Example 25, but replacing the product of Example 24 with the product of Example 26, provided the desired compound. H NMR (DMSO-dβ) (mixture of three rotamers) 0.85-0.99 (four d, 6H), 1.81-2.58, (m, 4H), 2.63-3.98 (m, 6H), 3.90, 4.04 and

4.12 (three d, 1 H), 4.18, 4.32 and 4.51 (three d, 1 H), 4.81-5,09 (m, 5H), 5.28, 5.31 and 5.40 (three d, 1 H), 6.38-6.56 (m, 6H), 6.98-7.31 (m, 7H). Mass spectrum: (M+ H)+ =516.

Anal. Calcd. for C30H37N5O3 O.5H2O: C, 68.68; H, 7.30; N, 13.35; Found: C, 68.80; H, 7.15; N, 13.17.

Using the methods described above, the compounds shown in Tables 1-128 can be prepared. In the tables, Ph represents phenyl.

TABLE 1 TABLE 2

R ₂ R ₂ benzoyl acetyl propionyl

2-methylpropionyl

2,2-dimethylpropionyl butyryl butyryl

3-met ylbutyryl 3-methylbutyryl

2-et ylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4- hydroxy butyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N,N-dimet ylglycyl N.N-dimethylglycyl

3-(N,N-dimethylamino)propionyl 3-(N,N-dimethylamino)propionyl

4-(N,N-dimet ylamino)butyryl 4-(N,N-dimethylamino)butyryl

5-(N,N-dimet ylamino)valeryl 5-(N,N-dimethylamino)valeryl

6-(N,N-dimet ylamino) exanoyl 6-(N , N-dimethylami no)hexanoy I

7-(N ,N-dimethylamino)heptanoyl 7-(N,N-dimethylamino)heptanoyl

4-mo holinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl

acety propionyl propionyl

2-methylpropionyl

2,2-dimethylpropionyl

2,2-dimethylpropionyl butyryl

3-methylbutyryl

2-ethylbutyryl valeryl

2-propylvaleryl cyclopropanoyl cyclobutanoyl cyclopentanoyl cyclobutanoyl cyclohexanoyl cyclopentanoyl cyclohexanoyl

2-hydroxyacetyl

3-hydroxypropionyl

4-hydroxybutyryl 3-hydroxypropionyl

5-hydroxyvaleryl

6-hydroxyhexanoyl

7-hydroxyheptanoyl 6-hydroxyhexanoyl 7-hydroxyheptanoyl

3-(N,N-dimethylamino)propionyl

4-(N,N-dimethylamino)butyryl 3-(N,N-dimethylamino)propionyl

5-(N , N-dimethylamino)valeryl 4-(N,N-dimethylamino)butyryl

6-(N,N-dimethylamino)hexanoyl 5-(N , N-dimethylamino)valeryl

7-(N,N-dimethylamino)heptanoyl 6-(N,N-dimethylamino)hexanoyl

4-moφholinylacetyl 7-(N,N-dimethylamino)heptanoyl methoxyacetyl t-butoxycarbonyl

2-furoyl

3-furoyl methanesulfonyl 3-furoyl methanesulfonyl

HfeO xy TABLE 5 TABLE 6

R ₂ R2 benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dimethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4-hydroxybutyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N,N-dimethylglycyl N,N-dimethylglycyl

3-(N , N-dimethylamino)propionyl 3-(N,N-dimethylamino)propionyl

4-(N,N-dimethylamino)butyryl 4-(N,N-dimethylamino)butyryl

5-(N,N-dimethylamino)valeryl 5-(N,N-dimethylamino)valeryl

6-(N , N-dimethylamino)hexanoyl 6-(N,N-dimethylamino)hexanoyl

7-(N,N-dimethylamino)heptanoyl 7-(N,N-dimethylamino)heptanoyl

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

TABLE 7

R2 R ₂ benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dimethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4-hydroxybutyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N,N-dimethylglycyl N,N-dimethylglycyl

3-(N,N-dimethylamino)propionyl 3-(N,N-dimethylamino)propionyl

4-(N,N-dimethylamino)butyryl 4-(N,N-dimethylamino)butyryl

5-(N,N-dimethylamino)valeryl 5-(N ,N-dimethylamino)valeryl

6-(N,N-dimethylamino)hexanoyl 6-(N,N-dimethylamino)hexanoyl

7-(N,N-dimethylamino)heptanoyl 7-(N,N-dimethylamino)heptanoyl

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

R ₂ R ₂ benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dimethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4-hydroxybutyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N,N-dimethylglycyl N,N-dimethylglycyl

3-(N,N-dimethylamino)propionyl 3-(N,N-dimethylamino)propionyl

4-(N,N-dimethylamino)butyryl 4-(N,N-dimethylamino)butyryl

5-(N,N-dimethylamino)valeryl 5-(N,N-dimethylamino)valeryl

6-(N,N-dimethylamino)hexanoyl 6-(N,N-dimethylamino)hexanoyl

7-(N,N-dimethylamino)heptanoyl 7-(N,N-dimethylamino)heptanoyl

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4-hydroxybutyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N,N-dimethylglycyl N,N-dimethylglycyl

3-(N,N-dimethylamino)propionyl 3-(N,N-dimethylamino)propionyl

4-(N,N-dimethylamino)butyryl 4-(N,N-dimethylamino)butyryl

5-(N,N-dimethylamino)valeryl 5-(N,N-dimethylamino)valeryl

6-(N,N-dimethylamino)hexanoyl 6-(N,N-dimethylamino)hexanoyl

7-(N,N-dimethylamino)heptanoyl 7-(N,N-dimethylamino)heptanoyl

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

TABLE 13 R2

R2 benzoyl benzoyl acetyl acetyl propionyl propionyl 2-methylpropionyl

2-methylpropionyl 2,2-dimethylpropionyl

2,2-dimethylpropionyl butyryl butyryl 3-methylbutyryl

3-methylbutyryl 2-ethylbutyryl

2-ethylbutyryl valeryl valeryl 2-propytvaleryl

2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl 2-hydroxyacetyl

2-hydroxyacetyl 3-hydroxypropionyl

3-hydroxypropionyl 4-hydroxybutyryl

4-hydroxybutyryl 5-hydroxyvaleryl

5-hydroxyvaleryl 6-hydroxyhexanoyl

6-hydroxyhexanoyl 7-hydroxyheptanoyl

7-hydroxyheptanoyl N.N-dimethylglycyl

N,N-dimethylglycyl 3-(N,N-dimethylamino)propionyl

3-(N,N-dimethylamino)propionyl 4-(N,N-dimethylamino)butyryl

4-(N,N-dimethylamino)butyryl 5-(N,N-dimethylamino)valeryl

5-(N ,N-dimethylamino)valeryl 6-(N,N-dimethylamino)hexanoyl

6-(N,N-dimethylamino)hexanoyl 7-(N,N-dimethylamino)heptanoyl

7-(N,N-dimethylamino)heptanoyl 4-moφholinylacetyl

4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl 2-furoyl

2-furoyl 3-furoyl

3-furoyl methanesulfonyl methanesulfonyl

TABLE 15 TABLE 16

R2 R ₂ benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dimethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4-hydroxybutyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N,N-dimethylglycyl N,N-dimethylglycyl

3-{N,N-dimethylamino)propionyl 3-(N,N-dimethylamino)propionyl

4-(N,N-dimethylamino)butyryl 4-(N,N-dimethylamino)butyryl

5-(N ,N-dimethylamino)valer l 5-(N,N-dimethylamino)valeryl

6-(N,N-dimethylamino)hexanoyl 6-(N,N-dimethylamino)hexanoyl

7-(N,N-dimethylamino)heptanoyl 7-(N,N-dimethylamino)heptanoyl

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

TABLE 17 TABLE 18

R ₂ R ₂ benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dimethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4- hydroxy butyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N,N-dimethylglycyl N,N-dimethylglycyl

3-(N,N-dimethylamino)propionyl 3-(N,N-dimethylamino)propionyl

4-(N,N-dimethylamino)butyryl 4-(N,N-dimethylamino)butyryl

5-(N,N-dimethylamino)valeryl 5-(N,N-dimethylamino)valeryl

6-(N,N-dimβthylamino)hexanoyl 6-(N,N-dimethylamino)hexanoyl

7-(N ,N-dimethylamino)heptanoyl 7-(N,N-dimethylamino)heptanoyl

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

TABLE 19 TABLE 20

R ₂ R ₂ benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dimethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4-hydroxybutyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N.N-dimethylglycyl N.N-dimethylglycyl

3-(N,N-dimethylamino)propionyl 3-(N,N-dimethylamino)propionyl

4-(N,N-dimethylamino)butyryl 4-(N,N-dimethylamino)butyryl

5-(N,N-dimethylamino)valeryl 5-(N,N-dimethylamino)valeryl

6-(N,N-dimethylamino)hexanoyl 6-(N,N-dimethylamino)hexanoyl

7-(N,N-dimethylamino)heptanoyl 7-(N,N-dimethylamino)heptanoyl

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

TABLE 21 TABLE 22

R ₂ U benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dimethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4-hydroxybutyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N.N-dimethylglycyl N.N-dimethylglycyl

3-(N,N-dimethylamino)propionyl 3-(N,N-dimethylamino)propionyl

4-(N,N-dimethylamino)butyryl 4-(N,N-dimethylamino)butyryl

5-(N,N-dimethylamino)valeryl 5-(N ,N-dimethylamino)valery I

6-(N,N-dimethylamino)hexanoyl 6-(N,N-dimethylamino)hexanoyl

7-(N,N-dimethylamino)heptanoyl 7-(N,N-dimethylamino)heptanoyl

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

methanesulfonyl

TABLE 25 TABLE 26 benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dimethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4-hydroxybutyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N.N-dimethylglycyl N.N-dimethylglycyl

3-(N , N-dimethylamino)propionyl 3-(N,N-dimethylamino)propionyl

4-(N , N-dimethylamino)butyryl 4-(N,N-dimethylamino)butyryl

5-(N,N-dimethylamino)valeryl 5-(N,N-dimethylamino)valeryl

6-(N , N-dimethylamino)hexanoyl 6-(N,N-dimethylamino)hexanoyl

7-(N,N-dimethylamino)heptanoyl 7-(N,N-dimethylamino)heptanoyl

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

TABLE 27 28

R ₂ R ₂ benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dimethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4-hydroxybutyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N.N-dimethylglycyl N.N-dimethylglycyl

3-(N,N-dimethylamino)propionyl 3-(N,N-dimethylamino)propionyl

4-(N,N-dimethylamino)butyryl 4-(N,N-dimethylamino)butyryl

5-(N,N-dimethylamino)valeryl 5-(N ,N-dimethylamino)valeryl

6-(N , N-dimethylamino) hexanoyl 6-(N,N-dimethylamino)hexanoyl

7-(N,N-dimethylamino)heptanoyl 7-(N,N-dimethylamino)heptanoyl

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

R2 R ₂ benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dimethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4-hydroxybutyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N.N-dimethylglycyl N.N-dimethylglycyl

3-(N,N-dimethylamino)propionyl 3-(N,N-dimethylamino)propionyl

4-(N,N-dimethylamino)butyryl 4-(N,N-dimethylamino)butyryl

5-(N,N-dimethylamino)valeryl 5-(N,N-dimethylamino)valeryl

6-(N,N-dimethylamino)hexanoyl 6-(N,N-dimethylamino)hexanoyl

7-(N,N-dimethylamino)heptanoyl 7-(N,N-dimethylamino)heptanoyl

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

TABLE 31 TABLE 32

R2 R ₂ benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dimethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4- hydroxy butyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N.N-dimethylglycyl N.N-dimethylglycyl

3-(N,N-dimethylamino)propionyl 3-(N,N-dimethylamino)propionyl

4-(N,N-dimethylamino)butyryl 4-(N,N-dimethylamino)butyryl

5-(N _r N-dimethylamino)valeryl 5-(N,N-dimethylamino)valeryl

6-(N,N-dimethylamino)hexanoyl 6-(N,N-dimethylamino)hexanoyl

7-(N,N-dimethylamino)heptanoyl 7-(N,N-dimethylamino)heptanoyl

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

TABLE 35 TABLE 36

R ₂ R ₂ benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dimethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4-hydroxybutyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N.N-dimethylglycyl N.N-dimethylglycyl

3-(N,N-dimethylamino)propionyl 3-(N,N-dimethylamino)propionyl

4-(N,N-dimethylamino)butyryl 4-(N,N-dimethylamino)butyryl

5-(N , N-dimethylamino )valeryl 5-(N,N-dimethylamino)valeryl

6-(N,N-dimethylamino)hexanoyl 6-(N,N-dimethylamino)hexanoyl

7-(N,N-dimethylamino)heptaπoyl 7-(N,N-dimethylamino)heptanoyl

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

TABLE 37 TABLE 38

32. R ₂ benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dimethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4-hydroxybutyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hyd roxy hexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N.N-dimethylglycyl N.N-dimethylglycyl

3-(N,N-dimethylamino)propionyl 3-(N,N-dimethylamino)propionyl

4-(N,N-dimethylamino)butyryl 4-(N,N-dimethylamino)butyryl

5-(N,N-dimethylamino)valeryl 5-(N,N-dimethylamino)valeryl

6-(N,N-dimethylamino)hexanoyl 6-(N,N-dimethylamino)hexanoyl

7-(N,N-dimethylamino)heptanoyl 7-(N,N-dimethylamino)heptanoyl

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

TABLE 39 TABLE 40

R ₂ R ₂ benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dimethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4-hydroxybutyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N.N-dimethylglycyl N.N-dimethylglycyl

3-(N,N-dimethylamino)propionyl 3-(N,N-dimethylamino)propionyl

4-(N,N-dimethylamino)butyryl 4-(N ,N-dimethylamino)butyryl

5-(N,N-dimethylamino)valeryl 5-(N,N-dimethylamino)valeryl

6-(N,N-dimethylamino)hexanoyl 6-(N,N-dimethylamino)hexanoyl

7-(N ,N-dimethylamino)heptanoyl 7-(N,N-dimethylamino)heptanoyl

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dimethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4-hydroxybutyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N.N-dimethylglycyl N.N-dimethylglycyl

3-(N,N-dimethylamino)propionyl 3-(N,N-dimethylamino)propionyl

4-(N,N-dimethylamino)butyryl 4-(N,N-dimethylamino)butyryl

5-(N,N-dimethylamino)valeryl 5-(N,N-dimethylamino)valeryl

6-(N .N-dimethylamino) hexanoyl 6-(N,N-dimethylamino)hexanoyl

7-(N,N-dimethylamino)heptanoyl 7-(N,N-dimethylamino)heptanoyl

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

TABLE 43 TABLE 44

R ₂ R benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dimethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propyrvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4-hydroxybutyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N.N-dimethylglycyl N.N-dimethylglycyl

3-(N,N-dimethylamino)propionyl 3-(N,N-dimethylamino)propionyl

4-(N,N-dimethylamino)butyryl 4-(N,N-dimethylamino)butyryl

5-(N ,N-dimethylamino)valery I 5-(N,N-dimethylamino)valeryl

6-(N,N-dimethylamino)hexanoyl 6-(N,N-dimethylamino)hexanoyl

7-(N,N-dimethylamino)heptanoyl 7-(N,N-dimethylamino)heptanoyl

4-moφholinylacetyl 4-moφho linylacety I methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-turoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

TABLE 45 TABLE 46

R2 R2 benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dimethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4-hydroxybutyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N.N-dimethylglycyl N.N-dimethylglycyl

3-(N,N-dimethylamino)propionyl 3-(N,N-dimethylamino)propionyl

4-(N,N-dimethylamino)butyryl 4-(N,N-dimethylamino)butyryl

5-(N,N-dimethylamino)valeryl 5-(N,N-dimethylamino)valeryl

6-(N,N-dimethylamino)hexanoyl 6-(N,N-dimethylamino)hexanoyl

7-(N ,N-dimethylamino)heptanoyl 7-(N,N-dimethylamino)heptanoyl

4-moφholinylacβtyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

TABLE 47 48

R ₂ R2 benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dimethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4-hydroxybutyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N.N-dimethylglycyl N.N-dimethylglycyl

3-(N,N-dimethylamino)propionyl 3-(N,N-dimethylamino)propionyl

4-(N , N-dimethylamino)butyryl 4-(N,N-dimethylamino)butyryl

5-(N,N-dimethylamino)valeryl 5-(N ,N-dimethylamino)valeryl

6-(N,N-dimethylamino)hexanoyl 6-(N,N-dimethylamino)hexanoyl

7-(N,N-dimethylamino)heptanoyl 7-(N , N-dimethylamino) heptanoy I

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dimethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4-hydroxybutyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N.N-dimethylglycyl N.N-dimethylglycyl

3-(N,N-dimethylamino)propionyl 3-(N , N-dimethylamino)propio nyl

4-(N , N-dimethylamino)butyryl 4-(N,N-dimethylamino)butyryl

5-(N,N-dimethytamino)valeryl 5-(N ,N-dimethylamino)valeryl

6-(N,N-dimethylamino)hexanoyl 6-(N ,N-dimethylamino)hexanoyl

7-(N,N-dimethylamino)heptanoyl 7-(N , N-dimethylamino) heptanoy I

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

TABLE 51 TABLE 52

R ₂ R ₂ benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dimethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propyh aleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4-hydroxy butyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxy heptanoy I

N.N-dimethylglycyl N.N-dimethylglycyl

3-(N , N-dimethylamino )propiony I 3-(N,N-dimethylamino)propionyl

4-(N,N-dimethylamino)butyryl 4-(N,N-dimethylamino)butyryl

5-(N,N-dimethy1amino)valeryl 5-(N,N-dimethylamino)valeryl

6-(N , N-dimethylamino)hexanoy I 6-(N,N-dimethylamino)hexanoyl

7-(N,N-dimethylamino)heptanoyl 7-(N,N-dimethylamino)heptanoyl

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

TABLE 57 TABLE 58

.52. benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dimethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4- hydroxy butyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N.N-dimethylglycyl N.N-dimethyiglycyl

3-(N,N-dimethylamino)propionyl 3-(N,N-dimethylamino)propionyl

4-(N ,N-dimethylamino)butyryl 4-(N,N-dimethylamino)butyryl

5-(N, N-dimethylamino )valeryl 5-(N,N-dimethylamino)valeryl

6-(N,N-dimethylamino)hexanoyl 6-(N,N-dimethylamino)hexanoyl

7-(N,N-dimethylamino)heptanoyl 7-(N,N-dimethylamino)heptanoyl

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

TABLE 59 TABLE 60

R ₂ R ₂ benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dimethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxy acetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4-hydroxybutyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N.N-dimethylglycyl N.N-dimethylglycyl

3-(N,N-dimethylamino)propionyl 3-(N,N-dimethylamino)propionyl

4-(N,N-dimethylamino)butyryl 4-( N ,N-dimethy lamino)butyryl

5-(N , N-dimethylamino)valery I 5-(N,N-dimethylamino)valeryl

6-(N , N-dimethylamino)hexanoyl 6-(N,N-dimethylamino)hexanoyl

7-(N,N-dimethylamino)heptanoyl 7-(N,N-dimethylamino)heptanoyl

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

TABLE 61 TABLE 62

R ₂ R ₂ benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dimethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4-hydroxybutyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N.N-dimethylglycyl N.N-dimethylglycyl

3-(N,N-dimethylamino)propionyl 3-(N,N-dimethylamino)propionyl

4-(N,N-dimethylamino)butyryl 4-(N,N-dimethylamino)butyryl

5-(N , N-dimethylamino )valeryl 5-(N,N-dimethylamino)valeryl

6-(N,N-dimethylamino)hexanoyl 6-(N, N-dimet hylamino)hexanoyl

7-(N,N-dimethylamino)heptanoyl 7-(N, N-dimet hylamino)heptanoyl

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

TABLE 63 TABLE

R2 64 benzoyl R2 acetyl benzoyl propionyl acetyl

2-methylpropionyl propionyl

2,2-dimethylpropionyl 2-methylpropionyl butyryl 2,2-dimethylpropionyl

3-methylbutyryl butyryl

2-ethylbutyryl 3-methylbutyryl valeryl 2-ethylbutyryl

2-propylvaleryl valeryl cyclopropanoyl 2-propylvaleryl cyclobutanoyl cyclopropanoyl cyclopentanoyl cyclobutanoyl cyclohexanoyl cyclopentanoyl

2-hydroxyacetyl cyclohexanoyl

3-hydroxypropionyl 2-hydroxyacetyl

4-hydroxybutyryl 3-hydroxypropionyl

5-hydroxyvaleryl 4- hydroxy butyryl

6-hydroxyhexanoyl 5-hydroxyvaleryl

7-hydroxyheptanoyl 6-hydroxyhexanoyl

N.N-dimethylglycyl 7-hydroxyheptanoyl

3-(N,N-dimethylamino)propionyl N.N-dimethylglycyl

4-(N , N-dimethylamino)butyryl 3-(N,N-dimethylamino)propionyl

5-(N,N-dimethylamino)valeryl 4-(N,N-dimethylamino)butyryl

6-(N,N-dimethylamino)hexanoyl 5-(N,N-dimethylamino)valeryl

7-(N ,N-dimethylamino)heptanoyl 6-(N,N-dimethylamino)hexanoyl

4-moφholinylacetyl 7-(N,N-dimethylamino)heptanoyl methoxyacetyl 4-moφholinylacetyl t-butoxycarbonyl methoxyacetyl

2-furoyl t-butoxycarbonyl

3-furoyl 2-furoyl methanesulfonyl 3-furoyl methanesulfonyl

TABLE 65

32, 3ι. benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dimethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4-hydroxybutyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N.N-dimethylglycyl N.N-dimethylglycyl

3-(N,N-dimethylamino)propionyl 3-(N,N-dimethylamino)propionyl

4-(N,N-dimethylamino)butyryl 4-(N,N-dimethylamino)butyryl

5-(N , N-dimethylamino)valery I 5-(N,N-dimethylamino)valeryl

6-(N,N-dimethylamino)hexanoyl 6-(N,N-dimethylamino)hexanoyl

7-(N,N-dimethylamino)heptanoyl 7-(N , N-d imethylamino) heptanoyi

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

TABLE 67 TABLE 68

32, R2_ benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2.2-dimethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4-hydroxybutyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N.N-dimethylglycyl N.N-dimethylglycyl

3-(N,N-dimethylamino)propionyl 3-(N,N-dimethylamino)propionyl

4-(N,N-dimethylamino)butyryl 4-(N,N-dimethylamino)butyryl

5-(N,N-dimethylamino)valeryl 5-(N ,N-dimethylamino)valeryl

6-(N,N-dimethylamino)hexanoyl 6-(N,N-dimethylamino)hexanoyl

7-(N,N-dimethylamino)heptanoyl 7-(N,N-dimethylamino)heptanoyl

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

R ₂

32- benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl

2-methylpropionyl

2,2-dimethylpropionyl

2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl

3-methylbutyryl

2-ethylbutyryl

2-ethylbutyryl valeryl valeryl

2-propylvaleryl

2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl

2-hydroxyacetyl

3-hydroxypropionyl

3-hydroxypropionyl

4-hydroxybutyryl

4-hydroxybutyryl

5-hydroxyvaleryl

5-hydroxyvaleryl

6-hydroxyhexanoyl

6-hydroxyhexanoyl

7-hydroxyheptanoyl

7-hydroxyheptanoyl

N.N-dimethylglycyl

N.N-dimethylglycyl

3-(N,N-dimethylamino)propionyl

3-(N,N-dimethylamino)propionyl

4-(N,N-dimethylamino)butyryl

4-(N,N-dimethylamino)butyryl

5-(N ,N-dimethylamino)valeryl

5-(N,N-dimethylamino)valeryl

6-(N,N-dimethylamino)hexanoyl

6-(N , N-dimethylamino)hexanoyl

7-(N,N-dimethylamino)heptanoyl

7-(N,N-dimethylamino)heptanoyl

4-moφholinylacetyl

4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl

2-furoyl

3-furoyl

3-furoyl methanesulfonyl methanesulfonyl

TABLE 77 TABLE 78

R 32. benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dimethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4-hydroxybutyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxy heptanoyi

N.N-dimethylglycyl N.N-dimethylglycyl

3-(N,N-dimethylamino)propionyl 3-(N,N-dimethylamino)propionyl

4-(N, N-dimethylamino)butyryl 4-(N,N-dimethylamino)butyryl

5-(N,N-dimethylamino)valeryl 5-(N,N-dimethylamino)valeryl

6- (N, N-dimethylamino) hexanoyl 6-(N,N-dimethylamino)hexanoyl

7-(N,N-dimethylamino)heptanoyl 7-{N,N-dimethylamino)heptanoyl

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

TABLE 79 TABLE 80

R ₂ R2 benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dimethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxy acetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4-hydroxybutyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxy heptanoyi

N.N-dimethylglycyl N.N-dimethylglycyl

3-(N,N-dimethylamino)propionyl 3-(N,N-dimethylamino)propionyl

4-(N,N-dimethylamino)butyryl 4-(N,N-dimethylamino)butyryl

5-(N, N-dimethylamino )valeryl 5-(N ,N-dimethylamino)valeryl

6-(N,N-dimethylamino)hexanoyl 6-(N,N-dimethylamino)hexanoyl

7-(N,N-dimethylamino)heptanoyl 7-(N,N-dimethylamino)heptanoyl

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

TABLE 81 TABLE 82

R2 R ₂ benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropioπyl

2,2-dimethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4-hydroxybutyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N.N-dimethylglycyl N.N-dimethylglycyl

3-(N,N-dimethylamino)propionyl 3-(N,N-dimethylamino)propionyl

4-(N,N-dimethylamino)butyryl 4-(N,N-dimethylamino)butyryl

5-(N ,N-dimethylamino)valeryl 5-(N,N-dimethylamiπo)valeryl

6-(N,N-dimβthylamino)hexanoyl 6-(N,N-dimethylamino)hexanoyl

7-(N,N-dimethylamino)heptanoyl 7-(N,N-dimethylamino)heptanoyl

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dimethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4-hydroxybutyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N.N-dimethylglycyl N.N-dimethylglycyl

3-(N,N-dimethylamino)propionyl 3-(N,N-dimethylamino)propionyl

4-(N,N-dimethylamino)butyryl 4-(N ,N-dimethylamino)butyryl

5-(N,N-dimethylamino)valeryl 5-(N , N-dimethylamino )valeryl

6-(N , N-dimethylamino)hexanoyl 6-(N, N-dimet hylamino)hexanoyl

7-(N,N-dimethylamino)heptanoyl 7-(N,N-dimethylamino)heptanoyl

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

TABLE 87 88

R2 R2 benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dimethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4- hydroxy butyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N.N-dimethylglycyl N.N-dimethylglycyl

3-(N,N-dimethylamino)propionyl 3-(N , N-di methylamino)propio ny I

4-(N,N-dimethylamino)butyryi 4-(N,N-dimethylamino)butyryl

5-(N, N-dimethylamino )valeryl 5-{N , N-dimethy lamino)valeryl

6- (N , N-dimethylamino) hexanoy I 6-(N,N-dimethylamino)hexanoyl

7-(N,N-dimethylamino)heptanoyl 7-(N,N-dimethylamino)heptanoyl

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

TABLE 90

R2 R2 benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dimethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4-hydroxybutyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N.N-dimethylglycyl N.N-dimethylglycyl

3-(N,N-dimethylamino)propionyl 3-(N,N-dimethylamino)propionyl

4-(N,N-dimethylamino)butyryl 4-(N,N-dimethylamino)butyryl

5-(N,N-dimethylamino)valeryl 5-(N,N-dimethylamino)valeryl

6-(N,N-dimethylamino)hexanoyl 6-(N,N-dimethylamino)hexanoyl

7-(N,N-dimethylamino)heptanoyl 7-(N,N-dimethylamino)heptanoyl

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dimethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4-hydroxybutyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N.N-dimethylglycyl N.N-dimethylglycyl

3-(N,N-dimethylamino)propionyl 3-(N,N-dimethylamino)propionyl

4-(N,N-dimethylamino)butyryl 4-(N,N-dimethylamino)butyryl

5-(N,N-dimethylamino)valeryl 5-(N,N-dimethylamino)valepyl

6-(N , N-dimethylamino)hexanoyl 6-(N,N-dimethylamino)hexanoyl

7-(N,N-dimethylamino)heptanoyl 7-(N,N-dimethylamino)heptanoyl

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

TABLE 97 TABLE 98

32. 32- benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dimethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4-hydroxybutyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N.N-dimethylglycyl N.N-dimethylglycyl

3-(N,N-dimethylamino)propionyl 3-(N, N-dimet hylamino)propionyl

4-(N,N-dimethylamino)butyryl 4-(N,N-dimethylamino)butyryl

5-(N,N-dimethylamino)valeryl 5-(N,N-dimethylamino)valeryl

6-(N,N-dimethylamino)hexanoyl 6-(N,N-dimethylamino)hexanoyl

7-(N,N-dimethylamino)heptanoyl 7-(N , N-dimethylamino)heptanoyl

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

TABLE 99 TABLE 100

R ₂ R ₂ benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dimethylpropιonyl 2,2-dimethylpropionyl butyryl butyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4-hydroxybutyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N.N-dimethylglycyl N.N-dimethylglycyl

3-(N,N-dimethylamino)propionyl 3-(N,N-dimethylamino)propionyl

4-(N,N-dimethylamino)butyryl 4-(N,N-dimethylamino)butyryl

5-(N,N-dimethylamino)valeryl 5-(N ,N-dimethylamino)valeryl

6-{N,N-dimethylamino)hexanoyl 6-(N, N-dimethylamino) hexanoyl

7-(N,N-dimethylamino)heptanoyl 7-(N,N-dimethylamino)heptanoyl

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

R ₂ R ₂ benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dimethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4-hydroxybutyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N.N-dimethylglycyl N.N-dimethylglycyl

3-(N,N-dimethylamino)propionyl 3-(N,N-dimethylamino)propionyl

4-(N,N-dimethylamino)butyryl 4-(N,N-dimethylamino)butyryl

5-(N, N-dimethylamino )valeryl 5-(N ,N-dimethylamino)valeryl

6-(N,N-dimethylamino)hexanoyl 6-(N,N-dimethylamino)hexanoyl

7-(N,N-dimethylamino)heptanoyl 7-(N,N-dimethylamino)heptanoyl

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

TABLE 107 TABLE 108

R2 R ₂ benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dimethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4- hydroxy butyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N.N-dimethylglycyl N.N-dimethylglycyl

3-(N,N-dimethylamino)propionyl 3-(N,N-dimethylamino)propionyl

4-(N,N-dimethylamino)butyryl 4-(N,N-dimethylamino)butyryl

5-(N,N-dimethylamino)valeryl 5-(N,N-dimethylamino)valeryl

6-(N , N-dimethylamino)hexanoyl 6-(N,N-dimethylamino)hexanoyl

7-(N,N-dimethylamino)heptanoyl 7-(N,N-dimethylamino)heptanoyl

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

TABLE 114

R ₂ R ₂ benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dimethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl

2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl

2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl

4-hydroxybutyryl

5-hydroxyvaleryl

5-hydroxyvaleryl

6-hydroxyhexanoyl

6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N.N-dimethylglycyl

N.N-dimethylglycyl

3-(N,N-dimethylamino)propionyl

3-(N,N-dimethylamino)propionyl

4-(N,N-dimethylamino)butyryl

4-(N,N-dimethylamino)butyryl

5-(N,N-dimethylamino)valeryl

5-(N,N-dimethylamino)valeryl

6-(N,N-dimethylamino)hexanoyl

6-(N,N-dimethylamino)hexanoyl

7-(N,N-dimethylamino)heptanoyl

7-(N,N-dimethylamino)heptanoyl

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

TABLE 116

R ₂ R ₂ benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dimethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4- hydroxy butyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N.N-dimethylglycyl N.N-dimethylglycyl

3-(N,N-dimethylamino)propionyl 3-(N,N-dimethylamino)propionyl

4-(N,N-dimethylamino)butyn/l 4-(N,N-dimethylamino)butyryl

5-(N,N-dimethylamino)valeryl 5-(N,N-dimethylamino)valeryl

6-(N,N-dimethylamino)hexanoyl 6-(N,N-dimethylamino)hexanoyl

7-(N ,N-dimethylamino)heptanoyl 7-(N,N-dimethylamino)heptanoyl

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

TABLE 117 TABLE 118

R ₂ R2 benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dimethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4-hydroxybutyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N.N-dimethylglycyl N.N-dimethylglycyl

3-(N,N-dimethylamino)propionyl 3-(N,N-dimethylamino)propionyl

4-(N,N-dimethylamino)butyryl 4-(N,N-dimethylamino)butyryl

5-(N,N-dimethylamino)valeryl 5-(N,N-dimethylamino)valeryl

6-(N,N-dimethylamino)hexanoyl 6-(N,N-dimethylamino)hexanoyl

7-(N,N-dimethylamino)heptanoyl 7-(N,N-dimethylamino)heptanoyl

4-moφhoiinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

TABLE 119 TABLE 120

R ₂ R2 benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dimethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4-hydroxybutyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N.N-dimethylglycyl N.N-dimethylglycyl

3-(N,N-dimethylamino)propionyl 3-(N,N-dimethylamino)propionyl

4-(N,N-dimethylamino)butyryl 4-(N,N-dimethylamino)butyryl

5-(N,N-dimethylamino)valeryl 5-(N,N-dimethylamino)valeryl

6-(N,N-dimethylamino)hexanoyl 6-(N,N-dimethylamino)hexanoyl

7-(N,N-dimethylamino)heptanoyl 7-(N,N-dimethylamino)heptanoyl

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dιmethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4-hydroxybutyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N.N-dimethylglycyl N.N-dimethylglycyl

3-(N,N-dimethylamino)propionyl 3-(N,N-dimethylamino)propionyl

4-(N , N-dimethylamino)butyryl 4-{N,N-dimethylamino)butyryl

5-(N,N-dimethylamino)valeryl 5-(N,N-dimethylamino)valeryl

6-(N,N-dimethylamino)hexanoyl 6-(N,N-dimethylamino)hexanoyl

7-(N,N-dimethylamino)heptanoyl 7-(N,N-dimethylamino)heptanoyl

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycaΦonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dimethylpropionyl 2,2-dimethyipropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2- hydroxy acetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4-hydroxybutyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N.N-dimethylglycyl N.N-dimethylglycyl

3-(N,N-dimethylamino)propionyl 3-(N,N-dimethylamino)propionyl

4-(N , N-dimethylamino)butyryl 4-(N,N-dimethylamino)butyryl

5-(N ,N-dimethylamino)valeryl 5-(N,N-dimethylamino)valeryl

6-(N , N-dimethylamino)hexanoy I 6-(N,N-dimethylamino)hexanoyl

7-(N ,N-dimethylamino)heptanoyl 7-(N,N-dimethylamino)heptanoyl

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycaΦonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

TABLE 125 TABLE 126

R ₂ R ₂ benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dimethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4-hydroxybutyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N.N-dimethylglycyl N.N-dimethylglycyl

3-(N,N-dimethylamino)propionyl 3-(N,N-dimethylamino)propionyl

4-(N , N-dimethylamino)butyryl 4-(N,N-dimethylamino)butyryl

5-(N,N-dimethylamino)valeryl 5-(N,N-dimethylamino)valeryl

6-(N,N-dimethylamino)hexanoyl 6-(N,N-dimethylamino)hexanoyl

7-(N,N-dimethylamino)heptanoyl 7-(N,N-dimethylamino)heptanoyl

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

TABLE 129 TABLE 130

R ₂ R ₂ benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dimethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2- hydroxy acetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4- hydroxy butyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N.N-dimethylglycyl N.N-dimethylglycyl

3-(N,N-dimethylamino)propionyl 3-(N,N-dimethylamino)propionyl

4-(N,N-dimethylamino)butyryl 4-(N,N-dimethylamino)butyryl

5-(N,N-dimethylamino)valeryl 5-(N , N-dimethylamino) valeryl

6-(N,N-dimethylamino)hexanoyl 6-(N,N-dimethylamino)hexanoyl

7-(N,N-dimethylamino)heptanoyl 7-(N,N-dimethylamino)heptanoyl

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

R2_ R ₂ benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dimethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2- hydroxy acetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4-hydroxybutyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N.N-dimethylglycyl N.N-dimethylglycyl

3-(N,N-dimethylamino)propionyl 3-(N,N-dimethylamino)propionyl

4-(N,N-dimethylamino)butyryl 4-(N,N-dimethylamino)butyryl

5-(N,N-dimethylamino)valeryl 5-(N,N-dimethylamino)valeryl

6-(N,N-dimethylamino)hexanoyl 6-(N,N-dimethylamino)hexanoyl

7-(N,N-dimethylamino)heptanoyl 7-(N,N-dimethylamino)heptanoyl

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

R ₂ R ₂ benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dimethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4-hydroxybutyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N.N-dimethylglycyl N.N-dimethylglycyl

3-(N, N-dimethylamino )propionyl 3-(N,N-dimethylamino)propionyl

4-(N,N-dimethylamino)butyryl 4-(N,N-dimethylamino)butyryl

5-(N,N-dimethylamino)valeryl 5-(N,N-dimethylamino)valeryl

6-(N,N-dimethylamino)hexanoyl 6-(N,N-dimethylamino)hexanoyl

7-(N,N-dimethylamino)heptanoyl 7-(N,N-dimethylamino)heptanoyl

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

TABLE 137 TABLE 138

R ₂ R ₂ benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dimethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4-hydroxybutyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N.N-dimethylglycyl N.N-dimethylglycyl

3-(N,N-dimethylamino)propionyl 3-(N,N-dimethylamino)propionyl

4-(N,N-dimethylamino)butyryl 4-(N,N-dimethylamino)butyryl

5-(N,N-dimethylamino)valeryl 5-(N,N-dimethylamino)valeryl

6-(N,N-dimethylamino)hexanoyl 6-(N,N-dimethylamino)hexanoyl

7-(N,N-dimethylamino)heptanoyl 7-(N,N-dimethylamino)heptanoyl

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

TABLE 139 TABLE140

R ₂ R ₂ benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dimethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4-hydroxybutyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N.N-dimethylglycyl N.N-dimethylglycyl

3-(N,N-dimethylamino)propionyl 3-(N,N-dimethylamino)propionyl

4-(N,N-dimethylamino)butyryl 4-(N,N-dimethylamino)butyryl

5-(N,N-dimethylamino)valeryl 5-(N, N-dimethylamino) valeryl

6-(N,N-dimethylamino)hexanoyl 6-(N,N-dimethylamino)hexanoyl

7-(N ,N-dimethylamino)heptanoyl 7-(N,N-dimethylamino)heptanoyl

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycaΦonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dimethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4-hydroxybutyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N.N-dimethylglycyl N.N-dimethylglycyl

3-(N,N-dimethylamino)propionyl 3-(N,N-dimethylamino)propionyl

4-(N,N-dimethylamino)butyryl 4-(N,N-dimethylamino)butyryl

5-(N,N-dimethylamino)valeryl 5-(N,N-dimethylamino)valeryl

6-(N,N-dimethylamino)hexanoyl 6-(N,N-dimethylamino)hexanoyl

7-(N,N-dimethylamino)heptanoyl 7-(N,N-dimethylamino)heptanoyl

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

TABLE 146

R ₂ R ₂ benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dimethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2- hydroxy acetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4-hydroxybutyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N.N-dimethylglycyl N.N-dimethylglycyl

3-(N,N-dimethylamino)propionyl 3-(N,N-dimethylamino)propionyl

4-(N , N-dimethylamino)butyryl 4-(N,N-dimethylamino)butyryl

5-(N,N-dimethylamino)valeryl 5-(N,N-dimethylamino)valeryl

6-(N,N-dimethylamino)hexanoyl 6-(N,N-dimethylamino)hexanoyl

7-(N,N-dimethylamino)heptanoyl 7-(N,N-dimethylamino)heptanoyl

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

TABLE 148

TABLE 147

R ₂

R ₂ benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl

2-methylpropionyl

2,2-dimethylpropionyl

2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl

3-methylbutyryl

2-ethylbutyryl

2-ethylbutyryl valeryl valeryl

2-propylvaleryl

2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl

2-hydroxyacetyl

3-hydroxypropionyl

3-hydroxypropionyl

4-hydroxybutyryl

4-hydroxybutyryl

5-hydroxyvaleryl

5-hydroxyvaleryl

6-hydroxyhexanoyl

6-hydroxyhexanoyl

7-hydroxyheptanoyl

7-hydroxyheptanoyl

N.N-dimethylglycyl

N.N-dimethylglycyl

3-(N , N-dimethylamino)propionyl 3-(N,N-dimethylamino)propionyl

4-(N,N-dimethylamino)butyryl

4- (N , N-dimethylamino)butyryl

5-(N,N-dimethylamino)valeryl

5-(N,N-dimethylamino)valeryl

6-(N,N-dimethylamino)hexanoyl 6-(N,N-dimethylamino)hexanoyl

7-(N,N-dimethylamino)heptanoyl 7-(N,N-dimethylamino)heptanoyl

4-moφholinylacetyl

4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl

2-furoyl

3-furoyl

3-furoyl methanesulfonyl methanesulfonyl

TABLE 149 TABLE 150

R ₂ R ₂ benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dimethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4-hydroxybutyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N.N-dimethylglycyl N.N-dimethylglycyl

3-(N,N-dimethylamino)propionyl 3-(N,N-dimethylamino)propionyl

4-(N,N-dimethylamino)butyryl 4-(N,N-dimethylamino)butyryl

5-(N,N-dimethylamino)valeryl 5-(N,N-dimethylamino)valeryl

6-(N,N-dimethylamino)hexanoyl 6-(N,N-dimethylamino)hexanoyl

7-(N,N-dimethylamino)heptanoyl 7-(N,N-dimethylamino)heptanoyl

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

R ₂ 32, benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dimethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4-hydroxybutyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N.N-dimethylglycyl N.N-dimethylglycyl

3-(N,N-dimethylamino)propionyl 3-(N,N-dimethylamino)propionyl

4-(N , N-dimethylamino)butyryl 4-(N,N-dimethylamino)butyryl

5-(N,N-dimethylamino)valeryl 5-(N,N-dimethylamino)valeryl

6-(N,N-dimethylamino)hexanoyl 6-(N,N-dimethylamino)hexanoyl

7-(N,N-dimethylamino)heptanoyl 7-(N,N-dimethylamino)heptanoyl

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

R ₂ R ₂ benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dimethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4-hydroxybutyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N.N-dimethylglycyl N.N-dimethylglycyl

3-(N,N-dimethylamino)propionyl 3-(N,N-dimethylamino)propionyl

4-(N , N-dimethylamino)butyryl 4-(N,N-dimethylamino)butyryl

5-(N,N-dimethylamino)valeryl 5-(N,N-dimethylamino)valeryl

6-(N,N-dimethylamino)hexanoyl 6-(N,N-dimethylamino)hexanoyl

7-(N,N-dimethylamino)heptanoyl 7-(N,N-dimethylamino)heptanoyl

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycaΦonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

TABLE 157 TABLE 158

R ₂ R ₂ benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dimethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4-hydroxybutyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N.N-dimethylglycyl N.N-dimethylglycyl

3-(N,N-dimethylamino)propionyl 3-(N,N-dimethylamino)propionyl

4-(N,N-dimethylamino)butyryl 4-(N,N-dimethylamino)butyryl

5-(N,N-dimethylamino)valeryl 5-(N,N-dimethylamino)valeryl

6-(N,N-dimethylamino)hexanoyl 6-(N,N-dimethylamino)hexanoyl

7-(N,N-dimethylamino)heptanoyl 7-(N,N-dimethylamino)heptanoyl

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

TABLE 159 TABLE 160

R ₂ R ₂ benzoyl benzoyl acetyl acetyl propionyl propionyl

2-methylpropionyl 2-methylpropionyl

2,2-dimethylpropionyl 2,2-dimethylpropionyl butyryl butyryl

3-methylbutyryl 3-methylbutyryl

2-ethylbutyryl 2-ethylbutyryl valeryl valeryl

2-propylvaleryl 2-propylvaleryl cyclopropanoyl cyclopropanoyl cyclobutanoyl cyclobutanoyl cyclopentanoyl cyclopentanoyl cyclohexanoyl cyclohexanoyl

2-hydroxyacetyl 2-hydroxyacetyl

3-hydroxypropionyl 3-hydroxypropionyl

4-hydroxybutyryl 4-hydroxybutyryl

5-hydroxyvaleryl 5-hydroxyvaleryl

6-hydroxyhexanoyl 6-hydroxyhexanoyl

7-hydroxyheptanoyl 7-hydroxyheptanoyl

N.N-dimethylglycyl N.N-dimethylglycyl

3-(N,N-dimethylamino)propionyl 3-(N,N-dimethylamino)propionyl

4-(N,N-dimethylamino)butyryl 4-(N,N-dimethylamino)butyryl

5-(N ,N-dimethylamino)valeryl 5-(N,N-dimethylamino)valeryl

6-(N,N-dimethylamino)hexanoyl 6-(N,N-dimethylamino)hexanoyl

7-(N,N-dimethylamino)heptanoyl 7-(N,N-dimethylamino)heptanoyl

4-moφholinylacetyl 4-moφholinylacetyl methoxyacetyl methoxyacetyl t-butoxycarbonyl t-butoxycarbonyl

2-furoyl 2-furoyl

3-furoyl 3-furoyl methanesulfonyl methanesulfonyl

Fluoroαenic Assay for Screening Inhibitors of HIV Protease

The inhibitory potency of the compounds of the invention can be determined by the following method.

A compound of the invention is dissolved in DMSO and a small aliquot further 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 microliters. The final concentrations of the components in the reaction buffer are: 125 mM sodium acetate, 1 M sodium chloride, 5 mM dithiothreitol, 0.5 mg/ml bovine serum albumin, 1.3 μM 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°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 inhibitor)/(rate in absence of inhibitor)).

Fluorogenic substrate: Dabcyl-Ser-Gln-Asn-Tyr-Pro-lle-Val-Gln-EDANS wherein DABCYL - 4-(4-dimethylamino-phenyl)azobenzoic acid and EDANS = 5-((2-aminoethyl)amino)-naphthalene-1 -sulfonic acid.

Table I shows the inhibitory potencies of compounds of the invention against HIV-1 protease.

Antiviral Activity

The anti-HIV activity of the compounds of the invention can be determined in MT4 cells according to the procedure of Kempf, et. al. (Antimicrob. Agents Chemother. 1991 , 35, 2209). The IC50 is the concentration of compound that gives 50% inhibition of the cytopathic effect of HIV. The LC50 is the concentration of compound at which 50% of the cells remain viable.

Table II shows the inhibitory potencies of compounds of the invention against HIV-I 3B in MT4 cells.

23D 3.0 71.6

24 0.86 >100

25 0.037 59.5

26 5.12 10

27 0.15 77.1

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, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy- ethanesulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate. Also, the basic nitrogen- containing groups can be quaternized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Water or oil- soluble or dispersible products are thereby obtained.

Examples of acids which may be employed to form pharmaceutically 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.

The compounds of the present invention can also be used in the form of esters. Examples of such esters include a hydroxyl-substituted compound of formula A or B which has been acylated with a naturally occurring α-amino acid residue which is optionally N-protected, a phosphate function, a hemisuccinate

residue, an acyl residue of the formula R ^* C(0)- or R ^* C(S)- wherein R ^* is hydrogen, loweralkyl, haloalkyi, alkoxy, thioalkoxy, alkoxyalkyl, thioalkoxyalkyl or haloalkoxy, or an acyl residue of the formula Ra-C(Rb)(Rd)-C(0)- or R _a - C(Rb)(Rd)-C(S)- wherein R and R are independently selected from hydrogen and loweralkyl and R _a is -N(R _e )(Rf), -OR _e or -SR _e wherein R _e and Rf are independently selected from hydrogen, loweralkyl and haloalkyi, or an amino- acyl residue of the formula R ₁₈ oNH(CH ₂ ) ₂ NHCH ₂ C(0)- or RιβoNH(CH ₂ ) OCH ₂ C(0)- wherein R-iβo is hydrogen, loweralkyl, arylalkyi. cycloalkylalkyl, alkanoyl, benzoyl or a naturally occurring α-amino acyl group. The amino acid esters of particular interest are those derived from the naturally occurring α-amino acids, however, other amino acid residues can also be used, including those wherein the amino acyl group is -C(0)CH NR ₂ ooR ₂ oι wherein R oo and R ₂ oι are independently selected from hydrogen and loweralkyl or the group -NR ₂ ooR ₂ oι forms a nitrogen containing heterocyclic ring. These esters serve as pro-drugs of the compounds of the present invention and also serve to increase the solubility of these substances in the gastrointestinal tract. These esters also serve to increase solubility for intravenous administration of the compounds. Other prodrugs include a hydroxyl-substituted compound of formula A or B wherein the hydroxyl group is functionalized with a substituent of the formula -CH(R _g )OC(0)Ri8i or -CH(R _g )OC(S)R ₁₈ ι wherein R ₁₈ ι is loweralkyl, haloalkyi, alkoxy, thioalkoxy or haloalkoxy and R _g is hydrogen, loweralkyl, haloalkyi, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl. Such prodrugs can be prepared according to the procedure of Schreiber (Tetrahedron Lett. 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 hydroxyl-substituted compound of formula A or B. The preparation of the prodrug esters is carried out by reacting a hydroxyl-substituted compound of formula A or B with an activated amino acyl, phosphoryl, hemisuccinyl or acyl derivative as defined above. The resulting product is then deprotected to provide the desired pro-drug ester. 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 hydroxyl group with an activated aldehyde followed by acylation of the intermediate hemiacetal.

The compounds of the invention are useful for inhibiting retroviral protease, in particular HIV protease, in vitro or in vivo (especially in mammals and in particular in humans). The compounds of the present invention are also useful for the inhibition of retroviruses in vivo, especially human immunodeficiency virus (HIV). The compounds of the present invention are also 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.

Total daily dose administered to a human or other mammal host in single or divided doses may be in amounts, for example, from about 0.001 to about 1000 mg/kg body weight daily and more usually from about 0.1 to about 50 mg/kg body weight daily. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose.

The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.

It will be understood, however, that the specific dose level for any 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, parenterally, 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 subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques.

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 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 employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending 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 polyethylene 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 may be admixed with at least one inert diluent such as sucrose lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending 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 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 a compound of the present invention,

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

Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Bioloαv. Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.

While the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more immunomodulators, antiviral agents, other antiinfective agents or 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, zalcitabine (ddC), didanosine (ddl), BCH-189, AzdU, carbovir, DDA, D4C, stavudine (d4T), DP-AZT, FLT (fluorothymidine), BCH-189, 5-halo-3'-thia-dideoxycytidine, PMEA, zidovudine (AZT) 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 Ro 31 -8959, SC-52151 , KNI-227, KNI-272 and the like), HEPT compounds, L,697,639, R82150, U- 87201 E and the like), TAT inhibitors (for example, RO-24-7429 and the like), trisodium phosphonoformate, HPA-23, eflonithine, Peptide T, Reticulose (nucleophosphoprotein), ansamycin LM 427, trimetrexate, UA001 , ribavirin, alpha interferon, oxetanocin, oxetanocin-G, cylobut-G, cyclobut-A, ara-M, BW882C87, foscamet, BW256U87, BW348U87, L-693,989, BV ara-U, CMV triclonal antibodies, FIAC, HOE-602, HPMPC, MSL-109, TI-23, trifluridine, vidarabine, famciclovir, penciclovir, acyclovir, ganciclovir, castanospermine, rCD4/CD4-lgG, CD4-PE40, butyl-DNJ, hypericin, oxamyristic acid, dextran sulfate and pentosan polysulfate. Immunomodulators that can be administered in combination with a compound of the present invention include bropirimine, Ampligen, anti-human alpha interferon antibody, colony stimulting factor, CL246,738, lmreg-1 , lmreg-2, diethydithiocarbamate, interleukin-2, alpha- interferon, inosine pranobex, methionine enkephalin, muramyl-tripeptide, TP-5, erythropoietin, naltrexone, tumor necrosis facator, beta interferon, gamma interferon, interleukin-3, interleukin-4, autologous CD8+ infusion, alpha interferon immunoglobulin, IGF-1 , anti-Leu-3A, autovaccination, biostimulation, extracorporeal photophoresis, FK-565, FK-506, G-CSF, GM-CSF, hyperthermia,

isopinosine, IVIG, HIVIG, passive immunotherapy and polio vaccine hyperimmunization. Other antiinfective agents that can be administered in combination with a compound of the present invention include pentamidine isethionate. Any of a variety of HIV or AIDS vaccines (for example, gp120 (recombinant), Env 2-3 (gp120), HIVAC-1 e (gp120), gp160 (recombinant), VaxSyn HIV-1 (gp160), Immuno-Ag (gp160), HGP-30, HIV-lmmunogen, p24 (recombinant), VaxSyn HIV-1 (p24) can be used in combination with a compound of the present invention.

Other agents that can be used in combination with the compounds of this invention are ansamycin LM 427, apurinic acid, ABPP, AI-721 , carrisyn, AS-101 , avarol, azimexon, colchicine, compound Q, CS-85, N-acetyl cysteine, (2- oxothiazolidine-4-carboxylate), D-penicillamine, diphenylhydantoin, EL-10, erythropoieten, fusidic acid, glucan, HPA-23, human growth hormone, hydroxchloroquine, iscador, L-ofloxacin or other quinolone antibiotics, lentinan, lithium carbonate, MM-1 , monolaurin, MTP-PE, naltrexone, neurotropin, ozone, PAI, panax ginseng, pentofylline, pentoxifylline, Peptide T, pine cone extract, polymannoacetate, reticulose, retrogen, ribavirin, ribozymes, RS-47, Sdc-28, silicotungstate, THA, thymic humoral factor, thymopentin, thymosin fraction 5, thymosin alpha one, thymostimulin, UA001 , uridine, vitamin B12 and wobemugos.

Other agents that can be used in combination with the compounds of this invention are antifungals such as amphotericin B, clotrimazole, flucytosine, fluconazole, itraconazole, ketoconazole and nystatin and the like.

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

Other agents that can be used in combination with the compounds of this invention are anti-neoplasties such as alpha interferon, COMP (cyclophosphamide, vincristine, methotrexate and prednisone), etoposide, mBACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine and dexamethasone), PRO-MACE/MOPP(prednisone, methotrexate (w/leucovin rescue), doxorubicin, cyclophosphamide, etoposide/mechlorethamine,

vincristine, prednisone and procarbazine), vincristine, vinblastine, angioinhibins, pentosan polysulfate, platelet factor 4 and SP-PG and the like.

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

Other agents that can be used in combination with the compounds of this invention are anti-protozoals such as albendazole, azithromycin, clarithromycin, clindamycin, corticosteroids, dapsone, DIMP, eflomithine, 566C80, fansidar, furazolidone, L, 671 , 329, letrazuril, metronidazole, paromycin, pefloxacin, pentamidine, piritrexim, primaquine, pyrimethamine, somatostatin, spiramycin, sulfadiazine, trimethoprim, TMP/SMX, trimetrexate and WR 6026 and the like.

Among the preferred agents for treatment of HIV or AIDS in combination with the compounds of this invention are reverse transcriptase inhibitors.

It will be understood that agents which can be combined with the compounds of the present invention for the 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 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.