Antipicornaviral compounds, their preparation and use

Abstract: Peptido and peptidomimetic compounds of formula (I) wherein the formula variables are as defined in the disclosure, advantageously inhibit or block the biological activity of the picornaviral 3C protease. These compounds, as well as pharmaceutical compositions containing these compounds, are useful for treating patients or hosts infected with one or more picornaviruses, such as RVP. Intermediates and synthetic methods for preparing such compounds are also provided.

Description: FIELD AND INDUSTRIAL APPLICABILITY OF THE INVENTION The invention pertains to peptide-like and peptidomimetic compounds that advantageously inhibit the enzymatic activity of picornaviral 3C proteases, especially rhinovirus 3C proteases (RVPs), and that retard viral growth in cell culture. The invention also relates to the use of such compounds in pharmaceutical compositions and therapeutic treatments for rhinoviral infections. The invention further relates to processes for synthesizing such compounds and compounds useful in such syntheses. BACKGROUND OF THE INVENTION The picornaviruses are a family of tiny non-enveloped positive-stranded RNA-containing viruses that infect humans and other animals. These viruses include the human rhinoviruses, human polioviruses, human coxsackieviruses, human echoviruses, human and bovine enteroviruses, encephalomyocarditis viruses, meningitis virus, foot and mouth viruses, hepatitis A virus, and others. The human rhinoviruses are a major cause of the common cold. To date, there are no effective therapies on the market that cure the common cold, only treatments that relieve the symptoms. Picornaviral infections may be treated by inhibiting the proteolytic 3C enzymes. These enzymes are required for the natural maturation of the picornaviruses. They are responsible for the autocatalytic cleavage of the genomic, large polyprotein into the essential viral proteins. Members of the 3C protease family are cysteine proteases, where the sulfhydryl group most often cleaves the glutamine-glycine amide bond. Inhibition of 3C proteases is believed to block proteolytic cleavage of the polyprotein, which in turn can retard the maturation and replication of the viruses by interfering with viral particle production. Therefore, inhibiting the processing of this cysteine protease with selective small molecules that are specifically recognized should represent an important and useful approach to treat and cure viral infections of this nature and, in particular, the common cold. Some small-molecule inhibitors of the enzymatic activity of picornaviral 3C proteases (i.e., antipicornaviral compounds) have been recently discovered. WO 97/43305 discloses inhibitors of picornavirus 3C proteases. WO 98/43950 discloses antipicornaviral compounds. WO 99/31122 discloses picornaviral 3C protease inhibitors. Peter John Murray et. al. disclose in Tetrahedron Letters 39 (1958), 6721 - 6724 the enantiospecific synthesis of novel lysine analogues. S. W. Kaldor et al. disclose in Bioorganic and Medicinal Chemistry Letters, Vol. 5, No. 17, 2021-2026 (1995) glutamine derived aldehydes for the inhibition of human rhinovirus 3C protease. There is still a desire to discover small-molecule compounds that are especially potent antipicornaviral agents. SUMMARY OF THE INVENTION Thus, an object of this invention is to discover small-molecule compounds that are especially potent antipicornaviral agents. A further object of the invention is to provide intermediates useful for the synthesis of said protease-inhibiting compounds and synthetic methods useful for such syntheses. A yet further object of the invention is to achieve pharmaceutical compositions that are highly effective for treating maladies mediated by inhibition of picornaviral 3C proteases, such as the common cold. Such objects have been attained through the discovery of compounds of the invention, which are picornaviral 3C protease inhibitors displaying particularly strong antiviral activity. It has surprisingly been discovered that peptido and peptidomimetic compounds containing a five-membered heterocyclic group have high rhinoviral-protease-inhibiting activity. It has further been surprisingly found that the rhinoviral-protease-inhibiting activity of peptido and peptidomimetic compounds may be significantly enhanced by replacing a glutamine-like moiety found in some known rhinoviral-protease-inhibiting compounds with a side-chain comprising a gamma- or delta-lactam. The inhibitors of the present invention are of the following general formula (I): wherein the residues are as defined in claim 1. Preferred embodiments are defined in claims 2 to 64. The invention also pertains to prodrugs, pharmaceutically acceptable salts, pharmaceutically active metabolites, and pharmaceutically acceptable solvates of compounds of the formula I. In preferred embodiments of the compounds of the formula I, R 2 and R 3 are each independently H; or where n is an integer from 0 to 5, each R 41 is independently H or lower alkyl, and the stereochemistry at the carbon denoted with an asterisk may be R or S; provided that at least one of R 2 and R 3 is Preferably, R 9 is a five-membered heterocycle having one to three heteroatoms selected from O, N, and S. In other preferred embodiments, the variables of formula I are as follows. Z and Z 1 are each independently selected from H, F, lower alkyl, -CO 2 R 21 , and -C(O)NR 21 R 22 , provided that Z and Z 1 are not both H, where R 21 and R 22 are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an acyl group, or a thioacyl group, or R 21 and R 22 , together with the atom(s) to which they are bonded, form a heterocycloalkyl group. At least one of R 2 or R 3 is and the other is H. R 5 and R 6 are each independently selected from H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, and a heteroaryl group, more preferably one of R 5 and R 6 is H and the other is alkyl or aryl (e.g., unsubstituted or substituted phenylmethyl). R 7 and R 8 are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group; and more preferably one of R 7 and R 8 is H and the other is alkyl (e.g., 2-propyl, 2-methyl-2-propyl, or 2-methyl-1-propyl) or arylmethyl (e.g., unsubstituted or substituted phenylmethyl or naphthylmethyl). R 9 is a five-membered heterocycle having from one to three heteroatoms selected from O, N, and S, more preferably a five-membered heterocycle having at least one nitrogen heteroatom and at least one oxygen heteroatom (e.g., unsubstituted or substituted 1,2-oxazolyl (i.e., isoxazolyl), 1,3-oxazolyl (i.e., oxazolyl), or oxadiazolyl (1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, or 1,2,5-oxadiazolyl). When R 9 is oxadiazolyl, unsubstituted and monomethyl-substituted 1,2,4-oxadiazolyl are preferred. In especially preferred embodiments, R 9 is 3-isoxazolyl or 5-isoxazolyl, either unsubstituted or substituted with one or two methyl groups and/or halogens, with chlorine and fluorine being preferred halogen substituents. In a preferred embodiment, the compounds, prodrugs, pharmaceutically acceptable salts, pharmaceutically active metabolites, and solvates have an antipicornaviral activity with an EC 50 less than or equal to 100 µM in the H1-HeLa cell culture assay, and more preferably an antirhinoviral activity with an EC 50 less than or equal to 10 µM in the H1-HeLa cell culture. The invention also relates to pharmaceutical compositions containing a therapeutically effective amount of at least one compound of the formula I, or a pharmaceutically acceptable salt, or solvate thereof. Additionally, the invention relates to methods of inhibiting picornaviral 3C protease by administering a therapeutically effective amount of at least one compound of the formula I, or a pharmaceutically acceptable salt, or solvate thereof. DETAILED DESCRIPTION AND PREFERRED EMBODIMENTS The present invention relates to compounds of the formula I: wherein Y, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , Z, and Z 1 are as defined above, and to pharmaceutically acceptable salts, and solvates thereof. Preferably, such compounds, pharmaceutically acceptable salts, and solvates have antipicornaviral activity, more preferably antirhinoviral activity, corresponding to an EC 50 less than or equal to 100 µM in the H1-HeLa cell culture assay, more preferably corresponding to an EC 50 less than or equal to 10 µM in the H1-HeLa cell culture assay. The present invention additionally relates to preferred compounds of the formulas I-A, I-B, and I-C: wherein R y (in formula I-A) is H or lower alkyl, and R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , Z, and Z 1 are as defined above, and to pharmaceutically acceptable salts, and solvates thereof. The inventive compounds of formulas I-A, which are referred to herein as "peptide-like" compounds, I-B, which are referred to herein as "ketomethylene-type" compounds, and I-C, which are referred to herein as "depsipeptide" compounds, differ in their backbones, which may affect the specific biodistribution or other physical properties; nonetheless each possesses a strong rhinoviral-protease-inhibiting activity. In preferred embodiments of compounds of formulas I-A, I-B, and I-C above: R 1 is H, F, or an alkyl group; R y (in formula I-A) is H or methyl; R 3 , R 5 , and R 8 are each H; R 2 is R 6 is an alkyl group, which has as a preferred optional substituent an aryl group; R 7 is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group; R 9 is a five-membered heterocycle having from one to three heteroatoms selected from O, N, and S, preferably where at least one of the heteroatoms is nitrogen, that is unsubstituted or substituted, where the optional substituents are preferably halogen or lower alkyl, and more preferably mono-chloro or -fluoro or a methyl group; and Z and Z 1 are each independently H, F, an alkyl group, a cycloalkyl group, a heterocycioaikyi group, an aryl group, a heteroaryl group, -C(O)R 21 , -CO 2 R 21 , -CN, -C(O)NR 21 R 22 , -C(O)NR 21 OR 22 , -C(S)R 21 , -C(S)NR 21 R 22 , -NO 2 , -SOR 21 , -SO 2 R 21 , -SO 2 NR 21 R 22 , -SO(NR 21 )(OR 22 ), -SONR 21 , -SO 3 R 21 , -PO(OR 21 ) 2 , -PO(R 21 )(R 22 ), -PO(NR 21 R 22 )(OR 23 ), -PO(NR 21 R 22 )(NR 23 R 24 ), -C(O)NR 21 NR 22 R 23 , or -C(S)NR 21 NR 22 R 23 , where Z and Z 1 are not both H, and where R 21 , R 22 , R 23 , and R 24 are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an acyl group, or a thioacyl group, or where any two of R 21 , R 22 , R 23 , and R 24 , together with the atom(s) to which they are bonded, form a heterocycloalkyl group, or Z and Z 1 (both as defined above), together with the atoms to which they are attached, form a heterocycloalkyl group. In preferred embodiments, the RVP-inhibiting agents of the invention are compounds of any of the stereospecific formulas I-A", I-B", and I-C": wherein R y , R 1 , R 2 , R 6 , R 7 , R 9 , Z, and Z 1 are as defined above, and pharmaceutically acceptable salts, prodrugs, active metabolites, and solvates thereof. In preferred embodiments of compounds of the formula I-A", I-B", or I-C": R 1 is H, F, or methyl; R y (in formula I-A') is H or methyl; R 2 is R 6 is arylmethyl or arylthiomethyl, where aryl is preferably an optionally substituted phenyl group; R 7 is an alkyl group, more preferably selected from 2-propyl, 2-methyl-2-pronyl, 2-methyl-1-propyl, and arylmethyl, where the aryl group is preferably phenyl or naphthyl; R 9 is isoxazolyl, oxazolyl, or oxadiazolyl, optionally substituted with one or two lower alkyl groups and/or halogens; and Z is H, and Z 1 is -CO 2 R 21 , -CN, or -C(O)NR 21 R 22 , where R 21 and R 22 are as defined above, or Z and Z 1 together form a cyclic ester or amide. In accordance with a convention used in the art, is used in structural formulas herein to depict the bond that is the point of attachment of the moiety or substituent to the core or backbone structure. Where chiral carbons are included in chemical structures, unless a particular orientation is depicted, both stereoisomeric forms are intended to be encompassed. As used herein, the term "alkyl group" is intended to mean a straight- or branched-chain monovalent radical of saturated and/or unsaturated carbon atoms and hydrogen atoms, such as methyl (Me), ethyl (Et), propyl, isopropyl, butyl, isobutyl, t-butyl, ethenyl, pentenyl, butenyl, propenyl, ethynyl, butynyl, propynyl, pentynyl, hexynyl, and the like, which may be unsubstituted (i.e., containing only carbon and hydrogen) or substituted by one or more suitable substituents as defined below (e.g., one or more halogens, such as F, Cl, Br, or I, with F and Cl being preferred). A "lower alkyl group" is intended to mean an alkyl group having from 1 to 4 carbon atoms in its chain. A "cycloalkyl group" is intended to mean a non-aromatic monovalent monocyclic, bicyclic, or tricyclic radical containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon ring atoms, each of which may be saturated or unsaturated, and which may be unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more heterocycloalkyl groups, aryl groups, or heteroaryl groups, which themselves may be unsubstituted or substituted by one or more substituents. Illustrative examples of cycloalkyl groups include the following moieties: A "heterocycloalkyl group" is intended to mean a non-aromatic monovalent monocyclic, bicyclic, or tricyclic radical, which is saturated or unsaturated, containing 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, or 18 ring atoms, which includes 1, 2, 3, 4, or 5 heteroatoms selected from nitrogen, oxygen, and sulfur, where the radical is unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more cycloalkyl groups, aryl groups, or heteroaryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents. Illustrative examples of heterocycloalkyl groups include the following moieties: An "aryl group" is intended to mean an aromatic monovalent monocyclic, bicyclic, or tricyclic radical containing 6, 10, 14, or 18 carbon ring atoms, which may be unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more cycloalkyl groups, heterocycloalkyl groups, or heteroaryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents. Illustrative examples of aryl groups include the following moieties: A "heteroaryl group" is intended to mean an aromatic monovalent monocyclic, bicyclic, or tricyclic radical containing 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 ring atoms, including 1, 2, 3, 4, or 5 heteroatoms selected from nitrogen, oxygen, and sulfur, which may be unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more cycloalkyl groups, heterocycloalkyl groups, or aryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents. Illustrative examples of heteroaryl groups include the following moieties: A "heterocycle" is intended to mean a heteroaryl or heterocycloalkyl group (each of which, as defined above, are optionally substituted). An "acyl group" is intended to mean a -C(O)-R radical, where R is a substituent as defined below. A "thioacyl group" is intended to mean a -C(S)-R radical, where R is a substituent as defined below. A "sulfonyl group" is intended to mean a -SO 2 R radical, where R is a substituent as defined below. A "hydroxy group" is intended to mean the radical -OH. An "amino group" is intended to mean the radical -NH 2 . An "alkylamino group" is intended to mean the radical -NHR a , where R a is an alkyl group. A "dialkylamino group" is intended to mean the radical -NR a R b , where R a and R b are each independently an alkyl group. An "alkoxy group" is intended to mean the radical -OR a , where R a is an alkyl group. Exemplary alkoxy groups include methoxy, ethoxy, propoxy, and the like. An "alkoxycarbonyl group" is intended to mean the radical -C(O)OR a , where R a is an alkyl group. An "alkylsulfonyl group" is intended to mean the radical -SO 2 R a , where R a is an alkyl group. An "alkylaminocarbonyl group" is intended to mean the radical -C(O)NHR a , where R a is an alkyl group. A "dialkylaminocarbonyl group" is intended to mean the radical -C(O)NR a R b , where R a and R b are each independently an alkyl group. A "mercapto group" is intended to mean the radical -SH. An "alkylthio group" is intended to mean the radical -SR a , where R a is an alkyl group. A "carboxy group" is intended to mean the radical -C(O)OH. A "carbamoyl group" is intended to mean the radical -C(O)NH 2 . An "aryloxy group" is intended to mean the radical -OR c , where R c is an aryl group. A "heteroaryloxy group" is intended to mean the radical -OR d , where R d is a heteroaryl group. An "arylthio group" is intended to mean the radical -SR c , where R c is an aryl group. A "heteroarylthio group" is intended to mean the radical -SR d , where R d is a heteroaryl group. The term "suitable organic moiety" is intended to mean any organic moiety recognizable, such as by routine testing, to those skilled in the art as not adversely affecting the inhibitory activity of the inventive compounds. Illustrative examples of suitable organic moieties include, but are not limited to, hydroxy groups, alkyl groups, oxo groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, acyl groups, sulfonyl groups, mercapto groups, alkylthio groups, alkoxy groups, carboxy groups, amino groups, alkylamino groups, dialkylamino groups, carbamoyl groups, arylthio groups, heteroarylthio groups, and the like. The term "substituent" or "suitable substituent" is intended to mean any suitable substituent that may be recognized or selected, such as through routine testing, by those skilled in the art. Illustrative examples of suitable substituents include hydroxy groups, halogens, oxo groups, alkyl groups, acyl groups, sulfonyl groups, mercapto groups, alkylthio groups, alkoxy groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, carboxy groups, amino groups, alkylamino groups, dialkylamino groups, carbamoyl groups, aryloxy groups, heteroaryloxy groups, arylthio groups, heteroarylthio groups, and the like. The term "optionally substituted" is intended to expressly indicate that the specified group is unsubstituted or substituted by one or more suitable substituents, unless the optional substituents are expressly specified, in which case the term indicates that the group is unsubstituted or substituted with the specified substituents. As defined above, various groups may be unsubstituted or substituted (i.e., they are optionally substituted) unless indicated otherwise herein (e.g., by indicating that the specified group is unsubstituted). A "solvate" is intended to mean a pharmaceutically acceptable solvate form of a specified compound that retains the biological effectiveness of such compound. Examples of solvates include compounds of the invention in combination with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine. A "pharmaceutically acceptable salt" is intended to mean a salt that retains the biological effectiveness of the free acids and bases of the specified compound and that is not biologically or otherwise undesirable. Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycollates, tartrates, methane-sulfonates, propanesulfonates, naphthalene-I-sulfonates, naphthalene-2-sulfonates, and mandelates. If an inventive compound is a base, a desired salt may be prepared by any suitable method known to the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid; hydrobromic acid; sulfuric acid; nitric acid; phosphoric acid; and the like, or with an organic acid, such as acetic acid; maleic acid; succinic acid; mandelic acid; fumaric acid; malonic acid; pyruvic acid; oxalic acid; glycolic acid; salicylic acid; pyranosidyl acid, such as glucuronic acid or galacturonic acid; alpha-hydroxy acid, such as citric acid or tartaric acid; amino acid, such as aspartic acid or glutamic acid; aromatic acid, such as benzoic acid or cinnamic acid; sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid; or the like. If an inventive compound is an acid, a desired salt may be prepared by any suitable method known to the art, including treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary); an alkali metal or alkaline earth metal hydroxide; or the like. Illustrative examples of suitable salts include organic salts derived from amino acids such as glycine and arginine; ammonia; primary, secondary, and tertiary amines; and cyclic amines, such as piperidine, morpholine, and piperazine; as well as inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium. In the case of compounds, salts, or solvates that are solids, it is understood by those skilled in the art that the inventive compounds, salts, and solvates may exist in different crystal forms, all of which are intended to be within the scope of the present invention and specified formulas. The inventive compounds may exist as single stereoisomers, racemates, and/or mixtures of enantiomers and/or diastereomers. All such single stereoisomers, racemates, and mixtures thereof are intended to be within the broad scope of the present invention. Preferably, however, the inventive compounds are used in optically pure form. As generally understood by those skilled in the art, an optically pure compound is one that is enantiomerically pure. As used herein, the term "optically pure" is intended to mean a compound comprising at least a sufficient activity. Preferably, an optically amount of a single enantiomer to yield a compound having the desired pharmacological pure compound of the invention comprises at least 90% of a single isomer (80% enantiomeric excess), more preferably at least 95% (90% e.e.), even more preferably at least 97.5% (95% e.e.), and most preferably at least 99% (98% e.e.). Preferably in the compounds of the formula I (or of any of the subgeneric formula), R 1 is H or F. In the compounds of formula I, preferably R 9 is an unsubstituted or substituted isoxazolyl group, where the optional substituents are preferably one or two methyl groups and/or halogens. Especially preferred embodiments of the invention are described below in reference to the following formula I-A": Preferred compounds of the present invention include peptido (peptide-like) Compounds (A-1) - (A-8) of the formula I-A'' above, wherein R 1 is H, Z is H, R y is H, and R 2 , R 6 , R 7 , Z 1 , and R 9 are as respectively defined below: (A-1) R 2 is CH 2 CH 2 C(O)NH 2 , R 6 is CH 2 Ph, R 7 is CH 2 CH(CH 3 ) 2 , Z 1 is CO 2 CH 2 CH 3 , and R 9 is (A-2) R 2 is CH 2 CH 2 C(O)NH 2 , R 6 is CH 2 Ph, R 7 is CH 2 CH(CH 3 ) 2 , Z 1 is CO 2 CH 2 CH 3 , and R 9 is (A-3) R 2 is CH 2 CH 2 C(O)NH 2 , R 6 is R 7 is C(CH 3 ) 3 , Z 1 is CO 2 CH 2 CH 3 , and R 9 is (A-4) R 2 is CH 2 CH 2 C(O)NH 2 , R 6 is R 7 is C(CH 3 ) 3 , Z 1 is CO 2 CH 2 CH 3 , and R 9 is (A-6) R 2 is CH 2 CH 2 C(O)NH 2 , R 6 is R 7 is CH(CH 3 ) 2 , Z 1 is CO 2 CH 2 CH 3 , and R 9 is Preferred peptide-like compounds of the formula I-A'''' further include Compounds (A-9) - (A-13) below, wherein R 1 is H, Z is H, Z 1 is CO 2 CH 2 CH 3 , R y is CH 3 , and R 2 , R 6 , R 7 , and R 9 are as respectively defined below: (A-9) R 2 is CH 2 CH 2 C(O)NH 2 , R 6 is R 7 is and R 9 is (A-10) R 2 is CH 2 CH 2 C(O)NH 2 , R 6 is CH 2 Ph, R 7 is CH 2 CH(CH 3 ) 2 , and R 9 is (A-11) R 2 is CH 2 CH 2 C(O)NH 2 , R 6 is R 7 is and R 9 is (A-12) R 2 is CH 2 CH 2 C(O)NH 2 , R 6 is R 7 is CH 2 CH(CH 3 ) 2 , and R 9 is (A-13) R 2 is CH 2 CH 2 C(O)NH 2 , R 6 is R 7 is and R 9 is Other preferred peptide-like compounds include the following: Preferred ketomethylene-type Compounds (B-1) - (B-4) of the invention are described below in reference to the following formula I-B": (B-1) R 2 is CH 2 CH 2 C(O)NH 2 , R 6 is R 7 is CH(CH 3 ) 2 , Z is H, Z 1 is CO 2 CH 2 CH 3 , and R 9 is Preferred depsipeptide-type Compounds (C-1) and (C-2) of the invention are described below in reference to the following formula I-C", where R 1 is H: (C-1) Z is H, R 2 is CH 2 CH 2 C(O)NH 2 , R 6 is R 7 is CH(CH 3 ) 2 , Z 1 is CO 2 CH 2 CH 3 , and R 9 is Additional compounds may be prepared in reference to formula I by selecting the variables from the following substituents: R y = H or CH 3 ; R 1 = H or CH 3 ; R 2 = R 6 = or phenylmethyl (i.e., benzyl), where the aryl group is optionally substituted with one, two, or three substituents each independently selected from halogens, methoxy and methyl; R 7 = 2-methyl-1-propyl, 2-propyl, 2-methyl-2-propyl, benzyl, or and R 9 = The present invention is also directed to a method of inhibiting picornaviral 3C protease activity, comprising contacting the protease with an effective amount of a compound of formula I, or a pharmaceutically acceptable salt, prodrug, pharmaceutically active metabolite, or solvate thereof. For example, picornaviral 3C protease activity may be inhibited in mammalian tissue by administering a compound of formula I or a pharmaceutically acceptable salt, prodrug, pharmaceutically active metabolite, or solvate thereof. More preferably, the present method is directed at inhibiting rhinoviral protease activity. "Treating" or "treatment" is intended to mean at least the mitigation of a disease condition in a mammal, such as a human, that is alleviated by the inhibition of the activity of one or more picornaviral 3C proteases, such as human rhinoviruses, human poliovirus, human coxsackieviruses, encephalomyocarditis viruses, meningitis virus, and hepatitis A virus, and includes: (a) prophylactic treatment in a mammal, particularly when the mammal is found to be predisposed to having the disease condition but not yet diagnosed as having it; (b) inhibiting the disease condition; and/or (c) alleviating, in whole or in part, the disease condition. The activity of the inventive compounds as inhibitors of picornaviral 3C protease activity may be measured by any of the suitable methods known to those skilled in the art, including in vivo and in vitro assays. An example of a suitable assay for activity measurements is the antiviral H1-HeLa cell culture assay described herein. Administration of the compounds of the formula I and their pharmaceutically acceptable prodrugs, salts, active metabolites, and solvates may be performed according to any of the accepted modes of administration available to those skilled in the art. Illustrative examples of suitable modes of administration include oral, nasal, parenteral, topical, transdermal, and rectal. Intranasal delivery is especially preferred. An inventive compound of formula I or a pharmaceutically acceptable salt, prodrug, active metabolite, or solvate thereof may be administered as a pharmaceutical composition in any pharmaceutical form recognizable to the skilled artisan as being suitable. Suitable pharmaceutical forms include solid, semisolid, liquid, or lyophilized formulations, such as tablets, powders, capsules, suppositories, suspensions, liposomes, and aerosols. Pharmaceutical compositions of the invention may also include suitable excipients, diluents, vehicles, and carriers, as well as other pharmaceutically active agents, depending upon the intended use. In preferred embodiments, the inventive pharmaceutical compositions are delivered intranasally in the form of suspensions. Acceptable methods of preparing suitable pharmaceutical forms of the pharmaceutical compositions are known or may be routinely determined by those skilled in the art. For example, pharmaceutical preparations may be prepared following conventional techniques of the pharmaceutical chemist involving steps such as mixing, granulating, and compressing when necessary for tablet forms, or mixing, filling, and dissolving the ingredients as appropriate, to give the desired products for oral, parenteral, topical, intravaginal, intranasal, intrabronchial, intraocular, intraaural, and/or rectal administration. Solid or liquid pharmaceutically acceptable carriers, diluents, vehicles, or excipients may be employed in the pharmaceutical compositions. Illustrative solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, pectin, acacia, magnesium stearate, and stearic acid. Illustrative liquid carriers include syrup, peanut oil, olive oil, saline solution, and water. The carrier or diluent may include a suitable prolonged-release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax. When a liquid carrier is used, the preparation may be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid (e.g., solution), or a nonaqueous or aqueous liquid suspension. A dose of the pharmaceutical composition contains at least a therapeutically effective amount of the active compound (i.e., a compound of formula I or a pharmaceutically acceptable salt, prodrug, active metabolite, or solvate thereof), and preferably is made up of one or more pharmaceutical dosage units. The selected dose may be administered to a mammal, for example, a human patient, in need of treatment mediated by inhibition of picornaviral 3C protease activity, by any known or suitable method of administering the dose, including topically, for example, as an ointment or cream; orally; rectally, for example, as a suppository; parenterally by injection; or continuously by intravaginal, intranasal, intrabronchial, intraaural, or intraocular infusion. A "therapeutically effective amount" is intended to mean the amount of an inventive compound that, when administered to a mammal in need thereof, is sufficient to effect treatment for disease conditions alleviated by the inhibition of the activity of one or more picornaviral 3C proteases, such as human rhinoviruses, human poliovirus, human coxsackieviruses, encephalomyocarditis viruses, menigovirus, and hepatitis A virus. The amount of a given compound of the invention that will be therapeutically effective will vary depending upon factors such as the particular compound, the disease condition and the severity thereof, the identity of the mammal in need thereof, which amount may be routinely determined by artisans. By way of illustration, a formulation for nasal delivery of the inventive compounds for treatment of rhinoviral infections can be prepared as follows, where all percentages are weight/weight and the suspension is prepared in purified water. A formula-I compound is micronized to a reduced particle size such that D 90 < 10 µm. A suspension is prepared to contain a final concentration of from about 0.01 % to about 2% of the active compound, preferably about from 0.2% to 2%. An appropriate preservative selected from those known in the art may be included, for example, benzalkonium chloride/EDTA, in appropriate final-concentration ranges, e.g., about 0.02%/0.01%. A suspending agent, such as mixture of microcrystalline cellulose (final concentration of about 1% - 1.5%, preferably about 1.2%) and sodium carboxymethylcellulose cellulose (final concentration of about 0.1% - 0.2%, preferably about 0.13%) may be included. A surfactant such as polysorbate 80 may be included in a final concentration of about from 0.05% to 0.2%, preferably about 0.1 %. A tonicity modifier such as dextrose may be included to give a final concentration of about from 4% to 6%, preferably about 5%. The pH of the final solution is adjusted as appropriate to a physiological range, e.g., 4-6, using non-toxic acid and/or base, such as HCl and/or NaOH. An exemplary formulation for nasal delivery of the inventive compound of Example 17 has the following composition, where all percentages are weight/weight and the suspension is prepared in purified water: Active Compound (B-2) 0.2 - 2 % Preservative Benzalkortium chloridelEDTA 0.02 % / 0.01 % Suspending Agent Microcrystalline cellulose/Nacarboxymethylcellulose 1.2%/0.13% Surfactant Polysorbate 80 0.1 % Tonicity Modifier Dextrose 5% pH Adjustment NaOH/HCl pH 4 - 6 GENERAL SYNTHESES The inventive compounds of formula (I) may be advantageously prepared by the methods of the present invention, including the general methods described below. In each of these general methods, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R y , Z, and Z 1 are as defined above, and R 4 is used (as a shorthand representation) to mean: where R 7 , R 8 , and R 9 are as defined above. In General Method I, useful for synthesis of peptide-like compounds of formula I-A, an amino acid A , where P 1 is an appropriate protecting group for nitrogen, is subjected to an amide-forming reaction with amino alcohol (or salt thereof) B to produce amide C . Compound C is then deprotected to give free amine (or salt thereof) D . Amine D and amino acid E , which may incorporate either an R 4 group or a protecting group for nitrogen (P 2 ), are subjected to a bond-forming reaction generating compound F . Compound F is oxidized to intermediate G , which is then transformed into unsaturated product H . If protecting groups have been used on amino acid E , or on any R groups (R 1 -R 9 ) and/or on R y and/or on Z and/or Z 1 , product H is deprotected and/or further modified to yield deprotected or modified H . An alternative method to prepare intermediate F is described as follows. Amino acid E and amino acid (or salt thereof) I, where P 3 is an appropriate protecting group for oxygen, are subjected to a bond-forming reaction to produce intermediate J. Molecule J is deprotected to yield free carboxylic acid K, which is subsequently subjected to an amide-forming reaction with amino alcohol (or salt thereof) B to genérate intermediate F. In General Method II, which is also useful for synthesizing peptide-like compounds of formula I-A, an amino acid L, where P 1 is an appropriate protecting group for nitrogen, is converted to a carbonyl derivative M, where "Lv" is a leaving group. Compound M is subjected to a reaction where Lv is replaced by R 1 to give derivative N. Derivative N is then transformed into unsaturated product O . Unsaturated compound O is deprotected to give free amine (or salt thereof) P, or modified at Z or Z 1 first to give O' and then deprotected to P. Intermediate P is subsequently subjected to an amide-forming reaction with carboxylic acid K to give final product H. If protecting groups have been used on any R group (R 1 -R 9 ) and/or on R y and/or on Z and/or Z 1 , product H is deprotected and/or further modified to yield deprotected or modified H. An alternative method to prepare intermediate N is described as follows. Compound M is subjected to a reaction where "Lv" is reduced to protected amino alcohol Q . Intermediate Q is subsequently oxidized to derivative N . In General Method III, useful for synthesis of peptide-like compounds of formula I-A, an amino acid L, where P 1 is an appropriate protecting group for nitrogen, is converted to a carbonyl derivative M , where "Lv" is a leaving group. Compound M is deprotected to give free amine (or salt thereof) R , which subsequently is subjected to an amide-forming reaction with carboxylic acid K to give intermediate S . Compound S is then either directly converted to carbonyl intermediate G , or successively reduced to alcohol F first, which is oxidized to G . Compound G is subjected to a reaction to yield the unsaturated final product H . If protecting groups have been used on any R groups (R 1 -R 9 ) and/or on R y and/or on Z and/or Z 1 , product H is deprotected and/or further modified to yield deprotected or modified H . In General Method IV, useful for synthesis of peptide-like compounds of formula I-A, free amine (or salt thereof) P , prepared from intermediate O as described in General Method II, is converted to amide T by reaction with amino acid A , where P 1 is an appropriate protecting group for nitrogen. Compound T is further deprotected to free amine (or salt thereof) U , which is subsequently converted to H with amino acid E . If protecting groups have been used on any R groups (R 1 -R 9 ) and/or on R y and/or on Z and/or Z 1 , product H is deprotected and/or further modified to yield deprotected or modified H. In General Method V, useful for synthesis of ketomethylene compounds of formula I-B, optically active lactone AA , where P 4 is an appropriate protecting group for nitrogen, and R 5 and R 8 are H (which may be prepared by the method described below and by various literature methods, including: (a) Herold et al., J Org. Chem. 1989 , 54 , 1178; (b) Bradbury et al., Tetrahedron Lett . 1989, 30, 3845; (c) Bradbury et al., J. Med Chem. 1990, 33, 2335; (d) Wuts et al., J. Org. Chem. 1992 , 57 , 6696; (e) Jones et al., J. Org. Chem. 1993 , 58 , 2286; (f) Pégorier et al., Tetrahedron Lett . 1995 , 36 , 2753; and (g) Dondoni et al., J. Org. Chem. 1995, 60 , 7927) is transformed by a two-step procedure (basic hydrolysis and subsequent oxidation) into carboxylic acid BB . This material is not isolated, but is subjected to an amide-forming reaction with amine (or salt thereof) P to provide final product CC . The P 4 protecting group, along with any additional protecting groups that have been used on any R groups (R 1 , R 2 , R 3 , R 6 , and/or R 7 ) and/or on Z and/or on Z 1 , is subsequently deprotected and/or further modified to yield deprotected or modified CC . Lactone AA may be prepared in optically active form by the following General Method VI (see: Herold et al., J. Org. Chem . 1989 , 54, 1178; Bradbury et al., Tetrahedron Lett . 1989, 30 , 3845; and Bradbury et al., J. Med. Chem . 1990, 33, 2335). A γ,δ-unsaturated carboxylic acid DD, which incorporates R 7 , is transformed into the corresponding acid chloride (not shown). This acid chloride is subjected to an amide-forming reaction with a chiral amine or a chiral oxazolidone to provide derivative EE (in which X 1 is a chiral amine or a chiral oxazolidone). Compound EE is subsequently deprotonated, and the resulting enolate is diastereoselectively alkylated with an electrophile corresponding to R 6 to provide compound FF, where R 5 is H . This material is then subjected to a halolactonization reaction to provide halo-lactone GG , in which R 5 and R 8 are H and "hal" is Br or I. Halo-lactone GG is subsequently transformed into azide HH, and this material is then converted into lactone AA, where P 4 is an appropriate protecting group for nitrogen. γ,δ-Unsaturated carboxylic acid DD may be prepared by the following General Method VII (see: Herold et al., J. Org. Chem . 1989 , 54 , 1178). An aldehyde II , which incorporates R 7 , is coupled with vinylmagnesium bromide to give alcohol JJ. Alcohol JJ is then transformed into γ,δ-unsaturated carboxylic acid DD by a three-step procedure as follows: (i) treatment with diethyl malonate and catalytic Ti(OEt) 4 at 160°C for 1 hour, (ii) heating at 190°C for 4 hours, and (iii) hydrolysis with ethanolic KOH at reflux. Carboxylic acid BB may also be prepared by General Method VIII (see Hoffman et al., Tetrahedron , 1997 , 53, 7119). An amino acid KK, which incorporates R 7 and where P 4 is an appropriate protecting group for nitrogen, is transformed into β-ketoester LL. Compound LL is deprotonated and the resulting anion is condensed with triflate MM, which incorporates R 6 . The coupling product thus obtained is treated with trifluoroacetic acid to provide ketoester NN, and this material is subsequently hydrolyzed to afford carboxylic acid BB . If basic hydrolysis results in epimerization, ketoester NN can be transesterified (allyl alcohol, Ti(O i -Pr) 4 ) and subsequently deprotected under neutral conditions (Pd(PPh 3 ) 4 , morpholine) to give carboxylic acid BB. Triflate MM, in turn, may be prepared from the corresponding alcohol by treatment with trifluoromethanesulfonic anhydride and 2,6-lutidine. Lactone AA may also be prepared by General Method IX (see: Askin et al., J. Org. Chem. 1992, 57 , 2771; and McWilliams et al., J. Am. Chem. Soc. 1996, 118 , 11970). An amino acid KK, which incorporates R 7 and where P 4 is an appropriate protecting group for nitrogen, is transformed into epoxide OO (single diastereomer) by the method described in Luly et al., J Org. Chem. 1987, 52 , 1487. Epoxide OO is condensed with the anion derived from compound PP, which incorporates R 6 and in which X 2 is a chiral auxiliary (including (1 S ,2 R )-1-aminoindan-2-ol acetonide) to afford coupling product QQ. This material is subsequently cyclized under acidic conditions to provide lactone AA. Compound PP may be prepared from the corresponding carboxylic acid (not shown) by the method outlined in Askin et al., J. Org. Chem. 1992, 57 , 2771. General Method X, useful in preparation of depsipeptide compounds of the formula I-C, illustrates a method to prepare intermediate TT. Amino acid E and alcohol RR, where P 5 is an appropriate protecting group for oxygen, are subjected to an ester bond-forming reaction to produce intermediate SS . Molecule SS is deprotected to yield free carboxylic acid TT, which may be utilized in lieu of carboxylic acid K in any of the general methods described above. SPECIFIC SYNTHESES The following specific methods may also be used to prepare various compounds according to the invention. Specific Method I describes the preparation of specific intermediate O1 , which may be utilized as intermediate O in the general methods described above. Thus, ester A1 (prepared as described in Chida et al., J. Chem. Soc., Chem. Commun . 1992, 1064) is hydrolyzed to give acid B1 , which, in tum, is transformed into oxazolidinone C1 . Compound C1 is subsequently deprotonated, and the resulting enolate is diastereoselectively alkylated to give allyl intermediate D1 . This entity is oxidized via ozonolysis, and the resulting aldehyde (not shown) is subjected to a reductive amination reaction producing lactam E1 . Acid-catalyzed methanolysis of E1 then affords alcohol F1 . This intermediate is oxidized via the method of Swern (or other suitable oxidation conditions) to the resulting aldehyde (not shown), which is subsequently subjected to an olefin-forming reaction to provide specific intermediate O1 . Specific Method II describes the preparation of specific intermediate O2 , which may be utilized as intermediate O in the general methods described above. Allyl intermediate D1 is subjected to a hydroboration/oxidation sequence to afford a primary alcohol (not shown). This entity is oxidized via the method of Swern (or other suitable oxidation conditions), and the resulting aldehyde (not shown) is subjected to a reductive-amination reaction, producing lactam G1 . Acid-catalyzed methanolysis of G1 then affords alcohol H1 . This intermediate is oxidized via the method of Swern (or other suitable oxidation conditions) to the resulting aldehyde (not shown), which is subsequently subjected to an olefin-forming reaction to provide specific intermediate O2. The following intermediates P1, P2, and P3 may be used in the above general methods in place of intermediate O, to vary the substituent group in the R 2 position. A synthesis of intermediate P1 is described below. Intermediate C1 (described above) is deprotonated, and the resulting enolate is trapped with an appropriate disulfide (symmetrical or mixed) to give sulfide p1 (P is a suitable protecting group for oxygen). The oxygen-protecting group is then removed to give alcohol p2 . This intermediate is oxidized via the method of Swern (or using other suitable oxidation.conditions), and the resulting aldehyde (not shown) is subjected to a reductive amination reaction to give lactam p3 . Acid-catalyzed methanolysis of p3 then affords alcohol p4 . This intermediate is oxidized via the method of Swern (or using other suitable oxidation conditions) to the resulting aldehyde (also not shown), which is subsequently subjected to an olefin-forming reaction to provide intermediate p5. This compound may be utilized in place of intermediate O in the above general synthetic methods; alternatively, the lactam-protecting group may be removed to give intermediate P1 . To synthesize intermediate P2, intermediate C1 is deprotonated, and the resulting enolate is trapped with an appropriate source of electrophilic oxygen (e.g., an oxaziridine) to give alcohol p6. This intermediate is alkylated with a suitably functionalized alkyl halide or triflate to give ether p7 (P is an appropriate protecting group for nitrogen). The nitrogen-protecting group is then removed, and the resulting amine (not shown) is subjected to cyclization conditions to give lactam p8 . Acid-catalyzed methanolysis of p8 then affords alcohol p9 . This intermediate is oxidized via the method of Swern (or using other suitable oxidation conditions) to the resulting aldehyde (also not shown), which is subsequently subjected to an olefin-forming reaction to provide intermediate P2 . A synthesis of specific intermediate P3 is now described. Intermediate D1 (described above) is ozonized, and the resulting aldehyde (not shown) is reduced to the corresponding alcohol (also not shown). This intermediate is then protected to afford compound p10 (P 1 is an appropriate protecting group for oxygen). The imide functionality present on p10 is hydrolyzed to carboxylic acid p11 , and this intermediate is coupled with a suitably protected hydroxylamine derivative to give amide p12 (P 2 is an appropriate protecting group for oxygen that is stable to conditions which will remove P 1 ). The P 1 protecting group is then removed, and the resulting alcohol (p13) is transformed into an appropriate leaving group (halide or triflate, not shown). The P 2 protecting group is then removed, and the resulting hydroxamic acid is cyclized to give intermediate p14. Acid-catalyzed methanolysis of p14 then affords alcohol p15 . This intermediate is oxidized via the method of Swern (or using other suitable oxidation conditions) to the resulting aldehyde (not shown), which is subsequently subjected to an olefin-forming reaction to provide intermediate P3. Specific Method III describes the preparation of intermediates Q1, Q2, and Q3, which may be utilized in the general methods described above. The known compound I1 is transformed into the literature molecule J1 by a modification of a published procedure (Ikuta et al., J. Med. Chem. 1987, vol. 30, p. 1995). Independently, the amino acid ester K1 is protected to afford silyl ether L1 . The ether is reduced with DIBAL (or using other suitable reduction conditions), and the resulting aldehyde (not shown) is subjected to an olefin-forming reaction with intermediate J1 , producing M1 . Silyl deprotection of M1 then affords alcohol N1 . This intermediate is subjected to a variety of hydrogenation conditions to provide intermediates Q1, Q2, and Q3. These intermediates may be transformed into intermediates analogous to intermediate O1 (see Specific Method I above) by oxidation and subsequent olefination. The artisan will recognize that various compounds of the invention may be made by following the above-described general and specific methods as well as teachings in the art, including the references cited herein, the disclosures of which are hereby incorporated by reference. Additionally, the artisan may prepare various compounds of the invention according to the example described below or through routine modifications to the syntheses described herein. EXAMPLES Examples of various preferred compounds of formula I are set forth below. The structures of the compounds of the following examples were confirmed by one or more of the following: proton magnetic resonance spectroscopy, infrared spectroscopy, elemental microanalysis, mass spectrometry, thin layer chromatography, melting-point determination, and boiling-point determination. Where there is any discrepancy between the given structural formula shown for a compound and its chemical name provided, the structural formula applies. Proton magnetic resonance ( 1 H NMR) spectra were determined using a Varian UNITY plus 300 spectrometer operating at a field strength of 300 megahertz (MHz). Chemical shifts are reported in parts per million (ppm, δ) downfield from an internal tetramethylsilane standard. Alternatively, 1 H NMR spectra were referenced to residual protic solvent signals as follows: CHCl 3 = 7.26 ppm; DMSO = 2.49 ppm; C 6 HD 5 = 7.15 ppm. Peak multiplicities are designated as follows: s = singlet; d = doublet; dd = doublet of doublets; t = triplet; q = quartet; br = broad resonance; and m = multiplet. Coupling constants are given in Hertz. Infrared absorption (IR) spectra were obtained using a Perkin-Elmer 1600 series FTIR spectrometer. Elemental microanalyses were performed by Atlantic Microlab Inc. (Norcross, GA) and gave results for the elements stated within ±0.4% of the theoretical values. Flash column chromatography was performed using Silica gel 60 (Merck Art 9385). Analytical thin layer chromatography (TLC) was performed using precoated sheets of Silica 60 F 254 (Merck Art 5719). Melting points (abbreviated as mp) were determined on a Mel-Temp apparatus and are uncorrected. All reactions were performed in septum-sealed flasks under a slight positive pressure of argon, unless otherwise noted. All commercial reagents were used as received from their respective suppliers with the following exceptions: tetrahydrofuran (THF) was distilled from sodium-benzophenone ketyl prior to use; dichloromethane (CH 2 Cl 2 ) was distilled from calcium hydride prior to use; anhydrous lithium chloride was prepared by heating at 110°C under vacuum overnight. The following abbreviations are used herein: Et 2 O refers to diethyl ether; DMF refers to N,N -dimethylformamide; DMSO refers to dimethylsulfoxide; and MTBE refers to tert -butyl methyl ether. Other abbreviations include: CH 3 OH (methanol), EtOH (ethanol), EtOAc (ethyl acetate), DME (ethylene glycol dimethyl ether), Ac (acetyl), Me (methyl), Ph (phenyl), Tr (triphenylmethyl), Cbz (benzyloxycarbonyl), Boc ( tert -butoxycarbonyl), TFA (trifluoroacetic acid), DIEA ( N , N -diisopropylethylamine), DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), HOBt (1-hydroxybenzotriazole hydrate), PyBOP (benzotriazolel-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate), HATU ( O -(7-azabenzotriazol-1-yl)- N , N , N' , N' -tetramethyluronium hexafluorophosphate), EDC (1-(3-dimethylaminopropyl)-3-ethylcarbarbodiimide hydrochloride), DCC (dicyclohexylcarbodiimide), DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone), DMAP (4-dimethylaminopyridine), Gln (glutamine), Leu (leucine), Phe (phenylalanine), Val (valine), His (histidine), 1-Naphth (1-naphthlyalanine), 2-Naphth (2-naphthylalanine), α-t-Butyl-Gly (tert-butyl glycine), ( S )-Pyrrol-Ala ((2 S ,3' S )-2-amino-3-(2'-oxopyrrolidin-3'-yl)-propionic acid), and ( S )-Piper-Ala ((2 S ,3' S )-2-amino-3-(2'-oxo-piperidin-3'-yl)-propionic acid). Additionally, "L" represents naturally occurring amino acids. A simplified naming system employing amino acid abbreviations is used to identify some intermediates and final products. When naming compounds, italicized amino acid abbreviations represent modifications at the C-terminus of that residue where the following apply: (1) acrylic acid esters are reported as "E" (trans) propenoates; (2) substituted 3-methylene-dihydrofuran-2-ones are reported as "E" (trans) 2-(α-vinyl-γ-butyrolactones); and (3) 5-vinylisoxazoles are reported as "E" (trans) propenisoxazoles. In addition, the terminology "AA 1 Ψ[COCH 2 ]-AA 2 " indicates that, for any peptide sequence, two amino acids (AA 1 and AA 2 ) usually linked by an amide bond are replaced by a ketomethlyene dipeptide isostere moiety. The terminology "AA 1 -NCH 3 -AA 2 " indicates that, for any peptide sequence, the amide bond that usually connects the two amino acids (AA 1 and AA 2 ) is replaced by an N -methyl amide linkage. The terminology "AA 1 -O-AA 2 " indicates that, for any peptide sequence, the amide bond that usually connects the two amino acids (AA 1 and AA 2 ) is replaced by an ester linkage. Examples of embodiments in accordance with the invention are described below. Example 1 - Preparation of Comparison Compound #1: 5-(3'-(Cbz-L-Leu-L-Phe-L- Gln )-E-Propene)-isoxazole Preparation of Intermediate Cbz-L-(Tr-Gln)-OMe Cbz-L-(Tr-Gln) (0.26 g, 0.50 mmol, 1 equiv.) was added to a solution of acetyl chloride (0.25 mL, 3.52 mmol, 7.0 equiv.) in CH 3 OH (5 mL), and stirring was continued at 23°C for 1 h (hour). The solvent was removed under reduced pressure, and the residue was dissolved in CH 2 Cl 2 (100 mL) and washed with water (100 mL), saturated NaHCO 3 (100 mL), and brine (100 mL). The organic layer was dried over Na 2 SO 4 and was concentrated. The residue was purified by flash column chromatography (20% EtOAc in hexanes) to afford Cbz-L-(Tr-Gln)-OMe (0.23 g, 84% yield) as a white solid: mp = 139-140°C; IR (cm -1 ) 1742, 1207; 1 H NMR (DMSO- d 6 ) δ 1.16 (t, 1H, J = 7.0), 1.77 (m, 1H), 1.97 (m, 1H), 3.61 (s, 3H), 4.99 (m, 1H), 5.03 (s, 2H), 7.02-7.55 (m, 20H), 7.69 (d, 1H, J = 7.7), 8.59 (s, 1H); Anal. (C 33 H 32 N 2 O 5 ) C, H, N. Preparation of Intermediate Cbz-L-(Tr-Glutaminol) Lithium chloride (0.24 g, 5.66 mmol, 2.0 equiv.) was added to a solution of Cbz-L-(Tr-Gln)-OMe (1.50 g, 2.79 mmol, 1 equiv.) in 2:1 THF:EtOH (30 mL), and the mixture was stirred at 23°C until all solids had dissolved (10 minutes). Sodium borohydride (0.21 g, 5.55 mmol, 2.0 equiv.) was added, and the reaction mixture was stirred overnight at 23°C. The solvents were removed under reduced pressure, the residue was taken up in water (50 mL), and the pH was adjusted to 2-3 with 10% HCl. The product was extracted with EtOAc (50 mL), and the organic layer was washed with water (50 mL) and brine (50 mL) before drying over MgSO 4 . The organic layer was concentrated, and the residue was purified by flash column chromatography (gradient elution, 20→50% EtOAc in benzene) to give Cbz-L-(Tr-glutaminol) (1.02 g, 72% yield) as a white glassy solid: mp = 66-70°C; IR (cm -1 ) 3318, 1699, 1510, 1240; 1 H NMR (DMSO- d 6 ) δ 1.40 (m, 1H), 1.72 (m, 1H), 2.26 (m, 2H), 3.17-3.50 (m, 3H), 4.64 (t, 1H, J = 5.0), 5.00 (s, 2H), 7.00-7.40 (m, 20H), 6.96 (d, 1H, J = 8.5), 8.54 (s, 1H); Anal. (C 32 H 32 N 2 O 4 ) C, H, N. Preparation of Intermediate L-(Tr-Glutaminol) A suspension of Cbz-L-(Tr-glutaminol) (1.93 g, 3.79 mmol) in CH 3 OH (25 mL) and Pd/C (10%, 0.19 g) was stirred under a hydrogen atmosphere (balloon) for 4 hours, then was filtered through a layer of Celite. The filtrate was concentrated under reduced pressure to give L-(Tr-glutaminol) as a white amorphous solid (1.38 g, 98% yield): mp = 191-193°C; IR (cm -1 ) 3255 (br), 1642, 1527; 1 H NMR (DMSO- d 6 ) δ 1.29 (m, 1H), 1.53 (m, 1H), 2.29 (m, 2H), 3.08 (m, 1H), 3.18 (m, 2H), 3.38 (s, br, 2H), 4.43 (s, br, 1H), 7.14-7.28 (m, 15H), 8.62 (s, 1H). Preparation of Intermediate Cbz-L-Leu-L-Phe-L-(Tr-Glutaminol) Carbonyldiimidazole (0.17 g, 1.05 mmol, 1.0 equiv.) was added to a solution of Cbz-L-Leu-L-Phe-OH (0.41 g, 1.0 mmol, 0.95 equiv.) in THF (10 mL), and the reaction mixture was stirred at 23°C for 1 hour. L-(Tr-Glutaminol) (0.39 g, 1.05 mmol, 1 equiv.) was then added, and the resulting solution was stirred overnight. The volatiles were removed under reduced pressure, and the residue was purified by flash column chromatography (gradient elution, 2→4% CH 3 OH in CHCl 3 ) to give Cbz-L-Leu-L-Phe-L-(Tr-glutaminol) (0.47 g, 62% yield) as a white amorphous solid: mp = 92-95°C; IR (cm -1 ) 3302, 1657, 1520, 1238; 1 H NMR (DMSO- d 6 ) δ 0.79 (t, 6H, J = 7.0), 1.30 (m, 2H), 1.44 (m, 2H), 1.75 (m, 1H), 2.22 (m, 2H), 2.82 (m, 1H), 2.97 (m, 1H), 3.14 (m, 1H), 3.25 (m, 1H), 3.63 (m, 1H), 3.95 (m, 1H), 4.48 (m, 1H), 4.65 (t, 1H, J = 5.0), 4.96 (d, 1H, J = 13.0), 5.02 (d, 1H, J = 13.0), 7.07-7.33 (m, 25H), 7.42 (d, 1H, J = 8.0), 7.66 (d, 1H, J = 8.5), 7.86 (d, 1H, J = 8.0), 8.52 (s, 1H); Anal. (C 47 H 52 N 4 O 6 •0.5H 2 O) C, H, N. Preparation of Intermediate Cbz-L-Leu-L-Phe-L-(Tr-Gln)-H o -Iodoxybenzoic acid (0.63 g, 2.25 mmol, 3.0 equiv.) was added to a solution of Cbz-L-Leu-L-Phe-L-(Tr-glutaminol) (0.58 g, 0.75 mmol, 1 equiv.) in DMSO (7.5 mL) at 23°C. After stirring for 2 hours, the DMSO was removed under reduced pressure. The residue was twice diluted with CH 2 Cl 2 , and the solvent evaporated to remove any remaining DMSO. The residue was diluted with EtOAc (30 mL) and filtered, and the filtrate was washed with 5% Na 2 S 2 O 3 /5% NaHCO 3 solution (30 mL), water (30 mL), and brine (30 mL), and then dried over Na 2 SO 4 . The solvent was removed under reduced pressure to give Cbz-L-Leu-L-Phe-L-(Tr-Gln)-H (0.53 g, 92% yield) as a white glassy solid, which was used immediately without further purification: 1 H NMR (DMSO- d 6 ) δ 0.79 (m, 6H), 1.00-1.98 (m, 5H), 2.27 (m, 2H), 2.84 (m, 1H), 3.02 (m, 1H), 3.98 (m, 2H), 4.58 (m, 1H), 4.99 (s, 2H), 7.14-7.32 (m, 25H), 7.39 (d, 1H, J = 8.1), 7.97 (d, 1H, J = 8.5), 8.38 (d, 1H, J = 8.0), 8.60 (s, 1H), 9.20 (s, 1H). Preparation of Intermediate 5-{3'-(Cbz-L-Leu-L-Phe-L-(Tr- Gln ))-E-Propene}-Isoxazole A solution of KN((CH 3 ) 3 Si) 2 (0.95 mL of a 0.5 M solution in THF, 0.477 mmol, 1.0 equiv.) was added to a suspension of isoxazol-5-ylmethyl-triphenylphosphonium bromide (0.222 g, 0.525 mmol, 1.1 equiv) in THF (20 mL) at 0°C, and the reaction was stirred at 0°C for 30 minutes. A solution of Cbz-L-Leu-L-Phe-L-(Tr-Gln)-H (0.366 g, 0.477 mmol, 1 equiv.) in THF (10 mL) was added, and the reaction mixture was then stirred overnight at 23°C. The solvent was removed in vacuo , and the residue was diluted with EtOAc (30 mL), washed with water (30 mL), and then dried over MgSO 4 . The solvent was removed under reduced pressure and the residue purified by flash silica gel chromatography (gradient elution, 0→1% CH 3 OH in CHCl 3 ) to give 5-{3'-(Cbz-L-Leu-L-Phe-L-(Tr- Gln ))-E-propene}-isoxazole (0.307 g, 70% yield) as an amorphous solid: IR (cm -1 ) 3423, 1678, 1568, 1265, 1043, 711; 1 H NMR (DMSO- d 6 ) δ 0.77-0.81 (m, 6H), 1.21-1.36 (m, 2H), 1.40-1.55 (m, 1H), 1.60-1.80 (m, 2H), 2.34-2.45 (m, 2H), 2.82-2.87 (m, 1H), 2.91-3.04 (m, 1H), 3.95-4.00 (m, 1H), 4.41-4.50 (m, 1H), 4.53-4.60 (m, 1H), 4.99 (q, 2H, J = 6.0), 6.19 (d, 1H, J = 15.0), 6.36 (dd, 1H, J = 15.0, 6.0), 6.46 (s, 1H), 7.15-7.33 (m, 20H), 7.42 (d, 1H, J = 9.0), 7.56-7.63 (m, 5H), 7.96 (d, 1H, J = 9.0), 8.08 (d, 1H, J = 9.0), 8.51 (s, 1H), 8.58 (s, 1H); HRMS calcd. for C 51 H 53 N 5 O 6 +Cs 964.3050 (M+Cs), found 964.3018. Preparation of Product: 5-(3'-(Cbz-L-Leu-L-Phe-L- Gln )-E-Propene)-Isoxazole Trifluoroacetic acid (1 mL) was added to a solution of 5-{3'-(Cbz-L-Leu-L-Phe-L-(Tr- Gln ))-E-propene}-isoxazole (0.214 g, 0.257 mmol) in CH 2 Cl 2 (10 mL), and the reaction mixture was stirred at 23°C overnight. The solvent was removed in vacuo and the residue purified by flash silica gel chromatography (gradient elution, 0→1% CH 3 OH in CHCl 3 ) to give 5-(3'-(Cbz-L-Leu-L-Phe-L- Gln )-E-propene)-isoxazole as a white solid (0.054 g, 36% yield): 1 H NMR (DMSO- d 6 ) δ 0.77-0.83 (m, 6H), 1.26-1.46 (m, 2H), 1.47-1.62 (m, 1H), 1.69-1.79 (m, 2H), 2.04-2.29 (m, 2H), 2.83-2.88 (m, 1H), 2.97-3.10 (m, 1H), 3.99-4.12 (m, 1H), 4.37-4.43 (m, 1H), 4.48-4.57 (m, 1H), 5.01 (q, 2H, J = 6.0), 6.20 (d, 1H, J = 15.0), 6.36 (dd, 1H, J = 15.0, 6.0), 6.45 (d, 1H, J = 3.0), 6.75 (s, 1H), 7.14-7.29 (m, 6H), 7.31-7.40 (m, 5 H), 7.45 (d, 1H, J = 9.0), 8.04 (d, 1H, J = 9.0), 8.07 (d, 1H, J = 9.0), 8.51 (d, 1H, J = 3.0); Anal. (C 32 H 39 N 5 O 6 ) C, H, N. Example 2 - Preparation of Compound A-1: Ethyl-3-((5'-Methylisoxazole-3'-carbonyl)-L-Leu-L-Phe-L- Gln )-E-Propenoate Preparation of Intermediate Boc-L-(Tr-Gln)-N(OMe)Me Isobutyl chloroformate (4.77 mL, 36.8 mmol, 1.0 equiv.) was added to a solution of Boc-L-(Tr-Gln)-OH (18.7 g, 36.7 mmol, 1 equiv.) and 4-methylmorpholine (8.08 mL, 73.5 mmol, 2.0 equiv.) in CH 2 Cl 2 (250 mL) at 0°C. The reaction mixture was stirred at 0°C for 20 min. (minutes), then N,O -dimethylhydroxylamine hydrochloride (3.60 g, 36.7 mmol, 1.0 equiv.) was added. The resulting solution was stirred at 0°C for 20 min. and at 23°C for 2 hours (h), and then was partitioned between water (150 mL) and CH 2 Cl 2 (2 x 150 mL). The combined organic layers were dried over Na 2 SO 4 , and were concentrated. Purification of the residue by flash column chromatography (gradient elution, 40→20% hexanes in EtOAc) provided Boc-L-(Tr-Gln)-N(OMe)Me (16.1 g, 82% yield) as a white foam: IR (cm -1 ) 3411, 3329, 3062, 1701, 1659; 1 H NMR (CDCl 3 ) δ 1.42 (s, 9H), 1.63-1.77 (m, 1H), 2.06-2.17 (m, 1H), 2.29-2.43 (m, 2H), 3.17 (s, 3H), 3.64 (s, 3H), 4.73 (s, br, 1H), 5.38-5.4 (m, 1H), 7.20-7.31 (m, 15H); Anal. (C 31 H 37 N 3 O 5 ) C, H, N. Preparation of Intermediate Boc-L-(Tr-Gln)-H Diisobutylaluminum hydride (50.5 mL of a 1.5 M solution in toluene, 75.8 mmol, 2.5 equiv.) was added to a solution of Boc-L-(Tr-Gln)-N(OMe)Me (16.1 g, 30.3 mmol, 1 equiv.) in THF at -78°C, and the reaction mixture was stirred at -78°C for 4 hours. Methanol (4 mL) and 1.0 M HCl (10 mL) were added sequentially, and the mixture was warmed to 23°C. The resulting suspension was diluted with Et 2 O (150 mL), and was washed with 1.0 M HCl (3 x 100 mL), half-saturated NaHCO 3 (100 mL), and water (100 mL). The organic layer was dried over MgSO 4 , filtered, and concentrated to give crude Boc-L-(Tr-Gln)-H (13.8 g, 97% yield) as a white solid: mp = 114-116°C; IR (cm -1 ) 3313, 1697, 1494; 1 H NMR (CDCl 3 ) δ 1.44 (s, 9H), 1.65-1.75 (m, 1H), 2.17-2.23 (m, 1H), 2.31-2.54 (m, 2H), 4.11 (s, br, 1H), 5.38-5.40 (m, 1H), 7.11 (s, 1H), 7.16-7.36 (m, 15H), 9.45 (s, 1H). Preparation of Intermediate Ethyl-3-(Boc-L-(Tr- Gln ))-E-Propenoate Sodium bis(trimethylsilyl)amide (22.9 mL of a 1.0 M solution in THF, 22.9 mmol, 1.0 equiv.) was added to a solution of triethyl phosphonoacetate (5.59 g, 22.9 mmol, 1.0 equiv.) in THF (200 mL) at -78°C, and the resulting solution was stirred for 20 minutes at that temperature. Crude Boc-L-(Tr-Gln)-H (10.8 g, 22.9 mmol, 1 equiv.) in THF (50 mL) was added via cannula, and the reaction mixture was stirred for 2 hours at -78°C, warmed to 0°C for 10 minutes, and then partitioned between 0.5 M HCl (150 mL) and a 1:1 mixture of EtuAc and hexanes (2 x 150 mL). The combined organic layers were dried over Na 2 SO 4 and were concentrated. Purification of the residue by flash column chromatography (40% EtOAc in hexanes) provided ethyl-3-[Boc-L-(Tr- Gln )]-E-propenoate (10.9 g, 88% yield) as a white foam: IR (cm -1 ) 3321, 1710; 1 H NMR (CDCl 3 ) δ 1.27 (t, 3H, J = 7.2), 1.42 (s, 9H), 1.70-1.78 (m, 1H), 1.80-1.96 (m, 1H), 2.35 (t, 2H, J = 7.0), 4.18 (q, 2H, J = 7.2), 4.29 (s, br, 1 H), 4.82-4.84 (m, 1H), 5.88 (dd, 1H, J = 15.7, 1.6), 6.79 (dd, 1H, J = 15.7, 5.3), 6.92 (s, 1H), 7.19-7.34 (m, 15H); Anal. (C 33 H 38 N 2 O 5 ) C, H, N. Preparation of Intermediate Ethyl-3-(Boc-L-Phe-L-(Tr- Gln ))-E-Propenoate A solution of HCl in 1,4-dioxane (4.0 M, 15 mL), was added to a solution of ethyl-3-(Boc-L-(Tr- Gln ))-E-propenoate (3.26 g, 6.01 mmol, 1 equiv.) in the same solvent (15 mL) at 23°C. After 2 h, the volatiles were removed under reduced pressure to afford ethyl-3-(H 2 N-L-(Tr- Gln ))-E-propenoate•HCl. This material was dissolved in CH 2 Cl 2 (60 mL) and Boc-L-Phe-OH (1.59 g, 6.01 mmol, 1.0 equiv.), HOBt (1.22 g, 9.02 mmol, 1.5 equiv.), 4-methylmorpholine (1.98 mL, 18.03 mmol, 3 equiv.), and EDC (1.73 g, 9.02 mmol, 1.5 equiv.) were added sequentially. The reaction mixture was stirred at 23°C overnight, and then was partitioned between water (100 mL) and CH 2 Cl 2 (2 x 100 mL). The combined organic layers were dried over Na 2 SO 4 , concentrated, and the residue was purified by flash column chromatography (40% EtOAc in hexane) to afford ethyl-3-(Boc-L-Phe-L-(Tr- Gln ))-E-propenoate (3.55 g, 85%) as white foam: IR (cm -1 ) 3306, 1706, 1661; 1 H NMR (CDCl 3 ) δ 1.29 (t, 3H, J = 7.2), 1.38 (s, 9H), 1.65-1.76 (m, 1H), 1.87-1.99 (m, 1H), 2.25-2.27 (m, 2H), 2.94-3.01 (m, 2H), 4.14-4.26 (m, 3H), 4.48-4.53 (m, 1H), 4.95 (s, br, 1H), 5.64 (d, 1H, J = 15.8), 6.29 (d, 1H, J = 8.1), 6.64 (dd, 1H, J = 15.8, 5.4), 6.80 (s, br, 1H), 7.14-7.32 (m, 20H); Anal. (C 42 H 47 N 3 O 6 ) C, H, N. Preparation of Intermediate Ethyl-3-(Boc-L-Leu-L-Phe-L-(Tr- Gln ))-E-Propenoate A solution of HCl in 1,4-dioxane (4.0 M, 15 mL) was added to a solution of ethyl-3-(Boc-L-Phe-L-(Tr- Gln ))-E-propenoate (6.40 g, 9.28 mmol, 1 equiv.) in the same solvent (15 mL) at 23°C. After 2 hours, the volatiles were removed under reduced pressure. The residue was dissolved in CH 2 Cl 2 (100 mL), and Boc-L-Leu-OH (2.58 g, 11.1 mmol, 1.2 equiv.), HOBt (1.88 g, 13.9 mmol, 1.5 equiv.), 4-methylmorpholine (3.06 mL, 27.8 mmol, 3 equiv.), and EDC (2.67 g, 13.92 mmol, 1.5 equiv.) were added sequentially. The reaction mixture was stirred at 23°C overnight, and then was partitioned between water (100 mL) and CH 2 Cl 2 (2 x 100 mL). The combined organic layers were dried over Na 2 SO 4 and concentrated, and the residue was purified by flash column chromatography (2% CH 3 OH in CH 2 Cl 2 ) to afford ethyl-3-(Boc-L-Leu-L-Phe-L-(Tr- Gln ))-E-propenoate (6.46 g, 87% yield) as white foam: IR (cm -1 ) 3284, 1651, 1515; 1 H NMR (CDCl 3 ) δ 0.86 (d, 3H, J = 6.0), 0.89 (d, 3H, J = 6.0), 1.29 (t, 3H, J = 7.2), 1.34 (s, 9H), 1.38-1.60 (m, 3H), 1.62-1.89 (m, 1H), 1.95-1.97 (m, 1H), 2.28-2.30 (m, 2H), 3.06-3.08 (m, 2H), 3.92-3.94 (m, 1H), 4.17 (q, 2H, J = 7.2), 4.48-4.51 (m, 2H), 4.67 (m, 1H), 5.66 (d, 1H, J = 15.9), 6.51-6.57 (m, 2H), 6.69 (dd, 1H, J = 15.6, 5.1), 7.10-7.33 (m, 21H); Anal. (C 48 H 58 N 4 O 7• 0.33H 2 O) C, H, N. Preparation of Intermediate Ethyl-3-((5'-Methylisoxazole-3'-carbonyl)-L-Leu-L-Phe-L-(Tr- Gln ))-E-Propenoate A solution of HCl in 1,4-dioxane (4.0 M, 3 mL), was added to a solution of ethyl-3-(Boc-L-Leu-L-Phe-L-(Tr- Gln ))-E-propenoate (0.216 g, 0.27 mmol, 1 equiv.) in the same solvent (3 mL) at 23°C. After 2 hours, the volatiles were removed under reduced pressure. The residue was dissolved in CH 2 Cl 2 (15 mL), cooled to 0°C, and triethylamine (0.112 mL, 0.81 mmol, 3.0 equiv.) and 5-methylisoxazole-3-carbonyl chloride (0.058 g, 0.40 mmol, 1.5 equiv.) were added sequentially. The reaction mixture was stirred at 0°C for 30 minutes, and then was partitioned between water (50 mL) and CH 2 Cl 2 (2 x 50 mL). The combined organic layers were dried over Na 2 SO 4 and concentrated, and the residue was purified by flash column chromatography (2% CH 3 OH in CH 2 Cl 2 ) to afford ethyl-3-((5'-methylisoxazole-3'-carbonyl)-L-Leu-L-Phe-L-(Tr- Gln ))-E-propenoate (0.199 g, 91% yield) as a white foam: IR (cm -1 ) 3286, 1650, 1541; 1 H NMR (CDCl 3 ) δ 0.86 (d, 3H, J = 5.4), 0.89 (d, 3H, J = 5.7), 1.28 (t, 3H, J = 7.2), 1.43-1.59 (m, 2H), 1.67-1.75 (m, 1H), 1.95-1.99 (m, 2H), 2.28 (t, 2H, J = 7.2), 2.41 (s, 3H), 2.97-3.04 (m, 1H), 3.06-3.13 (m, 1H), 4.17 (q, 2H, J = 7.2), 4.31-4.33 (m, 1H), 4.48-4.52 (m, 2H), 5.72 (d, 1H, J = 15.9), 6.19 (s, 1H), 6.41 (d, 1H, J = 7.5), 6.59 (d, 1H, J = 8.1), 6.71 (dd, 1H, J = 15.3, 6.0), 6.95 (d, 1H, J = 6.6), 7.09-7.21 (m, 21 H); Anal. (C 48 H 53 N 5 O 7• H 2 O) C, H, N. Preparation of Product Ethyl-3-((5'-Methylisoxazole-3'-carbonyl)-L-Leu-L-Phe-L- Gln) -E-Propenoate Triisopropylsilane (0.077 mL, 0.376 mmol, 1.8 equiv.) and trifluoroacetic acid (3 mL) were added sequentially to a solution of ethyl-3-((5'-methylisoxazole-3'-carbonyl)-L-Leu-L-Phe-L-(Tr- Gln ))-E-propenoate (0.185 g, 0.21 mmol, 1 equiv.) in CH 2 Cl 2 (3 mL) at 23°C, producing a bright yellow solution. The reaction mixture was stirred for 30 minutes at 23°C, during which time it became colorless. The volatiles were removed under reduced pressure, and the resulting white solid was triturated with Et 2 O (10 mL), filtered, and air-dried to give ethyl-3-((5'-methylisoxazole-3'-carbonyl)-L-Leu-L-Phe-L- Gln )-E-propenoate (0.87 g, 81% yield) as white solid: mp = 223-225°C; IR (cm -1 ) 3298, 1662, 1544, 1457, 1278; 1 H NMR (DMSO- d 6 ) δ 0.81 (d, 3H, J = 6.0 ), 0.85 (d, 3H, J = 6.3), 1.23 (t, 3H, J = 6.9), 1.38-1.42 (m, 1H), 1.48-1.77 (m, 4H), 2.04 (t, 2H, J = 7.2), 2.46 (s, 3H), 2.78-2.86 (m, 1H), 2.93-3.00 (m, 1H), 4.11 (q, 2H, J = 7.2), 4.36-4.54 (m, 3H), 5.63 (d, 1 H, J = 15.6), 6.56 (s, 1H), 6.68 (dd, 1H, J = 15.9, 5.4), 6.76 (s, br, 1H), 7.19 (m, 6H), 8.09 (d, 1H, J = 8.1), 8.14 (d, 1H, J = 7.8), 8.58 (d, 1H, J = 7.5); Anal. (C 29 H 39 N 5 O 7 ) C, H, N. Example 3 - Preparation of Compound A-2: Ethyl-3-((Isoxazole-5'-carbonyl)-L-Leu-L-Phe-L- Gln )-E-Propenoate Preparation of Intermediate Ethyl-3-((Isoxazole-5'-carbonyl)-L-Leu-L-Phe-L-(Tr- Gln ))-E-Propenoate This compound was prepared from ethyl-3-(Boc-L-Leu-L-Phe-L-(Tr- Gln ))-E-propenoate and isoxazole-5-carbonyl chloride using the procedure described above (Example 2) for the preparation of ethyl-3-((5'-methylisoxazole-3'-carbonyl)-L-Leu-L-Phe-L-(Tr- Gln ))-E-propenoate: IR (cm -1 ) 3282, 1643, 1530; 1 H NMR (CDCl 3 ) δ 0.87 (t, 6H, J = 6.6), 1.29 (t, 3H, J = 7.2), 1.49-1.64 (m, 3H), 1.69-1.80 (m, 1H), 1.90-1.96 (m, 1H), 2.30 (t, 2H, J = 7.2), 2.92-2.96 (m, 1H), 3.02-3.09 (m, 1H), 4.17 (q, 2H, J = 7.2), 4.42-4.48 (m, 3H), 5.69 (d, 1H, J = 15.3), 6.65 (s, br, 1H), 6.66 (dd, 1H, J = 15.9, 5.4), 6.76-6.79 (m, 2H), 7.00-7.31 (m, 22H), 8.24 (s, 1H); Anal. (C 47 H 51 N 5 O 7 •0.75 H 2 O) C, H, N. Preparation of Ethyl-3-((Isoxazole-5'-carbonyl)-L-Leu-L-Phe-L- Gln )-E-Propenoate The title compound was prepared from ethyl-3-((isoxazole-5'-carbonyl)-L-Leu-L-Phe-L-(Tr- Gln ))-E-propenoate using a procedure analogous to that described above (Example 2) for the preparation of ethyl-3-((5'-methylisoxazole-3'-carbonyl)-L-Leu-L-Phe-L- Gln )-E-propenoate: mp = 217-220°C; IR (cm -1 ) 3302, 1655, 1541; 1 H NMR (DMSO- d 6 ) δ 0.81 (d, 3H, J = 6.0), 0.86 (d, 3H, J = 6.0), 1.21 (t, 3H, J = 7.2), 1.42-1.75 (m, 5H), 2.04 (t, 2H, J = 7.2), 2.78-2.87 (m, 1H), 2.94-3.01 (m, 1H), 4.11 (q, 2H, J = 7.2), 4.37 (m, 1H), 4.41-4.52 (m, 2H), 5.64 (d, 1H, J = 15.6), 6.68 (dd, 1H, J = 15.9, 5.4), 6.76 (s, br, 1H), 7.12-7.19 (m, 7H), 8.02 (d, 1H, J = 8.1), 8.20 (d, 1H, J = 8.1), 8.74 (d, 1H, J = 1.8), 8.94 (d, 1H, J = 7.8); Anal. (C 28 H 37 N 5 O 7 ) C, H, N. Example 4 - Preparation of Compound A-3: Ethyl-3-((5'-Methylisoxazole-3'-carbonyl)-L-α-(t-Butyl-Gly)-L-(4-Me-Phe)-L- Gln )-E-Propenoate Preparation of Intermediate Ethyl-3-(Boc-L-(4-Me-Phe)-L-(Tr- Gln ))-E-Propenoate Ethyl-3-(H 2 N-L-(Tr- Gln ))-E-propenoate•HCl (prepared as described in Example 2 above, 1.37 g, 3.10 mmol) was dissolved in DMF (10 mL) at 23°C. Diisopropylethylamine (1.08 mL, 6.20 mmol) was added, followed by Boc-L-(4-Me-Phe)-OH (0.87 g 3.10 mmol). The reaction was cooled to 0°C. HATU (1.18 g, 3.10 mmol) was added, and the reaction allowed to warm to room temperature. The DMF was removed in vacuo . The residue was dissolved in EtOAc (30 mL), and the organic phase was washed sequentially with 10% HCl solution (25 mL), saturated NaHCO 3 solution (25 mL), H 2 O (25 mL), and brine (25 mL). The solvent was dried (MgSO 4 ) and filtered, and the residue purified by flash column chromatography (gradient elution, 0→0.75% CH 3 OH in CHCl 3 ) to give ethyl-3-(Boc-L-(4-Me-Phe)-L-(Tr- Gln ))-E-propenoate (1.48 g, 68% yield) as a white amorphous solid: IR (cm -1 ) 1713, 1655, 1491, 1175; 1 H NMR (DMSO-d 6 ) δ 1.20 (t, 3H, J = 7.0), 1.30 (s, 9H), 1.62-1.66 (m, 2H), 2.23 (s, 3H), 2.32 (m, 2H), 2.72 (m, 1H), 2.84 (m, 1H), 4.07-4.09 (m, 1H), 4.10 (q, 2H, J = 7.0), 4.38 (m, 1H), 5.64 (d, 1H, J = 15.5), 6.72 (dd, 1H, J = 15.5, 5.5), 6.88 (d, 1H, J = 8.0), 7.04 (d, 2H, J = 7.7), 7.10 (d, 2H, J = 7.7), 7.14-7.28 (m, 15H), 8.02 (d, 1H, J = 8.0), 8.53 (s, 1H); Anal. (C 43 H 49 N 3 O 6 ) C, H, N. Preparation of Intermediate Ethyl-3-(Boc-L-α-(t-Butyl-Gly)-L-(4-Me-Phe)-L-(Tr- Gln ))-E-Propenoate Ethyl-3-(Boc-L-(4-Me-Phe)-L-(Tr- Gln ))-E-propenoate (1.45 g, 2.06 mmol) was dissolved in 1,4-dioxane (27 mL), and a solution of HCl in 1,4-dioxane (4.0 M, 14 mL) was added. The reaction was stirred at room temperature for 4 hours. The solvent was removed by evaporation, and the residue taken up in EtOAc (50 mL). The organic phase was washed with saturated NaHCO 3 solution (50 mL) and then brine (50 mL), dried (MgSO 4 ), and the solvent removed under reduced pressure to give 1.23 g of an off-white amorphous solid. This material was coupled with Boc-L-α-(t-Butyl-Gly)-OH using the procedure described for the synthesis of ethyl-3-(Boc-L-(4-Me-Phe)-L-(Tr- Gln ))-E-propenoate above to afford ethyl-3-(Boc-L-α-(t-Butyl-Gly)-L-(4-Me-Phe)-L-(Tr- Gln ))-E-propenoate (49% yield) as a white amorphous solid: IR (cm -1 ) 1655, 1507, 1248, 1171; 1 H NMR (DMSO- d 6 ) δ 0.81 (s, 9H), 1.21 (t, 3H, J = 7.0), 1.37 (s, 9H), 1.52-1.70 (m, 2H), 2.22 (s, 3H), 2.26-2.28 (m, 2H), 2.73-2.91 (m, 2H), 3.86 (d, 1H, J = 9.6), 4.05-4.14 (m, 2H), 4.31-4.36 (m, 1H), 4.47-4.55 (m, 1H), 5.54 (d, 1H, J = 15.4), 6.37 (d, 1H, J = 9.6), 6.65 (dd, 1H, J = 15.8, 5.5), 7.01 (d, 2H, J = 8.1), 7.07 (d, 2H, J = 7.7), 7.11-7.32 (m, 15H), 8.03 (d, 1H, J = 8.1), 8.10 (d, 1H, J = 7.7), 8.49 (s, 1H); Anal. (C 49 H 60 N 4 O 7• 0.4H 2 O) C, H, N. Preparation of Intermediate Ethyl-3-((5'-Methylisoxazole-3'-carbonyl)-L-α-(t-Butyl-Gly)-L-(4-Me-Phe)-L-(Tr- Gln ))-E-Propenoate Ethyl-3-(Boc-L-α-(t-Butyl-Gly)-L-(4-Me-Phe)-L-(Tr- Gln ))-E-propenoate was deprotected using the procedure described for the deprotection of ethyl-3-(Boc-L-(4-Me-Phe)-L-(Tr- Gln ))-E-propenoate above, and the resulting amine (0.22 g, 0.30 mmol) was dissolved in CH 2 Cl 2 (3 mL). Pyridine (0.025 mL, 0.32 mmol) was added, and the reaction was cooled to 0°C. 5-Methylisoxazole-3-carbonyl chloride (0.046 g, 0.32 mmol) was added. The reaction was allowed to warm to room temperature, and was stirred for one hour. The solvent was removed in vacuo , and the residue subjected to flash column chromatography (gradient elution, 0→1% CH 3 OH in CH 2 Cl 2 ) to afford ethyl-3-((5'-methylisoxazole-3'-carbonyl)-L-α-(t-Butyl-Gly)-L-(4-Me-Phe)-L-(Tr- Gln ))-E-propenoate (0.19 g, 77% yield) as a white amorphous solid: IR (cm -1 ) 1651, 1518; 1 H NMR (DMSO-d 6 ) δ 0.88 (s, 9H), 1.20 (t, 3H, J = 7.0), 1.55-1.67 (m, 2H), 2.14 (s, 3H), 2.18-2.28 (m, 2H), 2.45 (s, 3H), 2.70-2.77 (m, 1H), 2.86-2.93 (m, 1H), 4.07-4.14 (m, 2H), 4.46 (d, 1H, J = 9.6), 4.50-4.55 (m, 1H), 5.54 (d, 1H, J = 15.8), 6.59 (s, 1H), 6.65 (dd, 1H, J = 15.8, 5.5, 15.8), 6.95 (d, 2H, J = 8.1), 7.05 (d, 2H, J = 8.1), 7.13-7.28 (m, 15H), 7.60 (d, 1H, J = 9.6), 8.13 (d, 1H, J = 8.1), 8.41 (d, 1H, J = 8.1), 8.51 (s, 1H); Anal. (C 49 H 55 N 5 O 7 ) C, H, N. Preparation of Product Ethyl-3-((5'-Methylisoxazole-3'-carbonyl)-L-α-(t-Butyl-Gly)-L-(4-Me-Phe)-L- Gln )-E-Propenoate Ethyl-3-((5'-methylisozazole-3'-carbonyl)-L-α-(t-Butyl-Gly)-L-(4-Me-Phe)-L-(Tr- Gln ))-E-propenoate (0.17 g, 0.20 mmol) was dissolved in CH 2 Cl 2 (4 mL) at 23°C. Trifluoroacetic acid (0.4 mL) was added, and the reaction was stirred at room temperature for six hours. The solvents were removed in vacuo , and the residue was subjected to flash column chromatography (gradient elution, 0→2% CH 3 OH in CH 2 Cl 2 ) to afford ethyl-3-((5'-methylisoxazole-3'-carbonyl)-L-α-(t-Butyl-Gly)-L-(4-Me-Phe)-L- Gln )-E-propenoate (0.085 g, 73% yield) as a white amorphous solid: IR (cm -1 ) 1661, 1541, 1206; 1 H NMR (DMSO- d 6 ) δ 0.88 (s, 9H), 1.21 (t, 3H, J = 7.0), 1.60-1.73 (m, 2H), 2.01-2.06 (m, 2H), 2.14 (s, 3H), 2.50 (s, 3H), 2.70-2.77 (m, 1H), 2.86-2.93 (m, 1H), 4.07-4.14 (m, 2H), 4.34-4.37 (m, 1H), 4.45 (d, 1H, J = 9.6), 4.50-4.55 (m, 1H), 5.57 (d, 1H, J = 15.8), 6.60 (s, 1H), 6.66 (dd, 1H, J = 15.8, 5.5), 6.75 (s, br, 1H), 6.96 (d, 2H, J = 8.1), 7.06 (d, 2H, J = 7.7), 7.17 (s, br, 1H), 7.6.5 (d, 1H, J = 9.6), 8.14 (d, 1H, J = 8.1), 8.40 (d, 1H, J = 7.7); Anal. (C 30 H 41 N 5 O 7 ·0.5TFA•0.5H 2 O) C, H, N. Example 5 - Preparation of Compound A-4: Ethyl-3-((5'-Methylisoxazole-3'-carbonyl)-L-α-(t-Butyl-Gly)-L-(4-F-Phe)-L- Gln )-E-Propenoate Preparation of Intermediate Ethyl-3-(Boc-L-(4-F-Phe)-L-(Tr- Gln ))-E-Propenoate Boc-L-(4-F-Phe)-OH (1.41 g, 5.0 mmol) was dissolved in THF (50 mL). Ethyl-3-(H 2 N-L-(Tr- Gln ))-E-propenoate•HCl (prepared as described in Example 2 above, 1.0 g, 5.0 mmol) was added, followed by Et3N (0.70 mL, 5.0 mmol). Carbonyldiimidazole (0.81 g, 5.0 mmol) was added, and the reaction was stirred at room temperature for 20 hours. The solvent was removed in vacuo , and the residue subjected to flash column chromatography (gradient elution, 0→1% CH 3 OH in CH 2 Cl 2 ) to afford ethyl-3-(Boc-L-(4-F-Phe)-L-(Tr- Gln ))-E-propenoate (1.13 g, 32% yield) as a white amorphous solid: IR (cm -1 ) 1712, 1666, 1510, 1169; 1 H NMR (DMSO-d 6 ) δ 1.20 (t, 3H, J = 7.0), 1.29 (s, 9H), 1.61-1.70 (m, 2H), 2.27-2.34 (m, 2H), 2.74-2.78 (m, 1H), 2.86-2.90 (m, 1H), 4.06-4.13 (m, 3H), 4.36-4.40 (m, 1H), 5.58 (d, 1H, J = 15.6), 6.71 (dd, 1H, J = 15.6, 5.5), 6.98 (d, 1H, J = 8.1), 7.03-7.09 (m, 2H), 7.14-7.28 (m, 17H), 8.06 (d, 1H, J = 8.1), 8.53 (s, 1H); LRMS (M+Na) 730. Preparation of Intermediate Ethyl-3-(Boc-L-α-(t-Butyl-Gly)-L-(4-F-Phe)-L-(Tr- Gln ))-E -Propenoate Ethyl-3-(Boc-L-(4-F-Phe)-L-(Tr- Gln ))-E-propenoate was deprotected and coupled with Boc-L-α-(t-Butyl-Gly)-OH using the procedures described above to prepare ethyl-3-(Boc-L-α-(t-Butyl-Gly)-L-(4-Me-Phe)-L-(Tr- Gln ))-E-propenoate, to provide ethyl-3-(Boc-L-α-(t-Butyl-Gly)-L-(4-F-Phe)-L-(Tr- Gln ))-E-propenoate (54% yield) as a white amorphous solid: IR (cm -1 ) 1720, 1651, 1506, 1168; 1 H NMR (DMSO- d 6 ) δ 0.80 (s, 9H), 1.20 (t, 3H, J = 7.0), 1.36 (s, 9H), 1.53-1.67 (m, 2H), 2.23-2.28 (m, 2H), 2.79-2.94 (m, 2H), 3.85 (d, 1H, J = 9.9), 4.09 (q, 2H, J = 7.0), 4.31-4.35 (m, 1H), 4.53-4.55 (m, 1H), 5.46 (d, 1H, J = 15.8), 6.36 (d, 1H, J = 9.2), 6.64 (dd, 1H, J = 15.8, 5.5), 6.97-7.03 (m, 2H), 7.13-7.28 (m, 17H), 8.08 (d, 1H, J = 8.1), 8.14 (d, 1H, J = 8.1), 8.49 (s, 1H); Anal. (C 48 H 57 N 4 O 7 F) C, H, N. Preparation of Intermediate Ethyl-3-((5'-Methylisoxazole-3'-carbonyl)-L-α-(t-Butyl-Gly)-L-(4-F-Phe)-L-(Tr- Gln ))-E-Propenoate Ethyl-3-(Boc-L-α-(t-Butyl-Gly)-L-(4-F-Phe)-L-(Tr- Gln ))-E-propenoate was deprotected and coupled with 5-methylisoxazole-3-carbonyl chloride using the procedures described above to prepare ethyl-3-((5'-methylisoxazole-3'-carbonyl)-L-α-(t-Butyl-Gly)-L-(4-Me-Phe)-L-(Tr- Gln ))-E-propenoate to afford ethyl-3-((5'-methylisoxazole-3'-carbonyl)-L-α-(t-Butyl-Gly)-L-(4-F-Phe)-L-(Tr- Gln ))-E-propenoate (74% yield) as a white amorphous solid: IR (cm -1 ) 1659, 1535, 15 10; 1 H NMR (DMSO-d 6 ) δ 0.88 (s, 9H), 1.20 (t, 3H, J = 7.4), 1.52-1.67 (m, 2H), 2.23-2.28 (m, 2H), 2.45 (s, 3H), 2.75-2.82 (m, 1H), 2.89-2.96 (m, 1H), 4.09 (q, 2H, J = 7.0), 4.32-4.36 (m, 1H), 4.45 (d, 1H, J = 9.6), 4.50-4.55 (m, 1H), 5.44 (d, 1H, J = 15.6), 6.58 (s, 1H), 6.63 (dd, 1H, J = 15.6, 5.5, 15.6), 6.93-6.99 (m, 2H), 7.13-7.28 (m, 17H), 7.64 (d, 1H, J = 9.6), 8.16 (d, 1H, J = 8.5), 8.46 (d, 1H, J = 8.1), 8.51 (s, 1H); Anal. (C 48 H 52 N 5 O 7 F) C, H, N. Preparation of Ethyl-3-((5'-Methylisoxazole-3'-carbonyl)-L-α-(t-Butyl-Gly)-L-(4-F-Phe)-L- Gln )-E-Propenoate Ethyl-3-[(5'-methylisoxazole-3'-carbonyl)-L-α-(t-Butyl-Gly)-L-(4-F-Phe)-L-(Tr- Gln )]-E-propenoate was deprotected using a procedure analogous to that described above for the preparation of ethyl-3-((5'-methylisoxazole-3'-carbonyl)-L-α-(t-Butyl-Gly)-L-(4-Me-Phe)-L- Gln )-E-propenoate to provide ethyl-3-((5'-methylisoxazole-3'-carbonyl)-L-α-(t-Butyl-Gly)-L-(4-F-Phe)-L- Gln )-E-propenoate (80% yield) as a white amorphous solid: IR (cm -1 ) 1653, 1543, 1223; 1 H NMR (DMSO-d 6 ) δ 0.88 (s, 9H), 1.21 (t, 3H, J = 7.0), 1.59-1.75 (m, 2H), 2.01-2.06 (m, 2H), 2.46 (s, 3H), 2.75-2.82 (m, 1H), 2.89-2.96 (m, 1H), 4.09 (q, 2H, J = 7.0), 4.33-4.36 (m, 1H), 4.44 (d, 1H, J = 9.6), 4.50-4.58 (m, 1H), 5.47 (d, 1H, J = 15.8), 6.59 (s, 1H), 6.64 (dd, 1H, J = 15.8, 5.5), 6.75 (s, br, 1H), 6.94-7.00 (m, 2H), 7.16 (s, br, 1H), 7.18-7.23 (m, 2H), 7.69 (d, 1H, J = 9.6), 8.16 (d, 1H, J = 8.1), 8.44 (d, 1H, J = 8.1); Anal. (C 29 H 38 N 5 O 7 F) C, H, N. Example 7 - Preparation of Compound A-6: Ethyl-3-[(5'-Methylisoxazole-3'-carbonyl)-L-Val-L-(4-F-Phe)-L- Gln ]-E-Propenoate Preparation of Intermediate Ethyl-3-{Boc-L-(4-F)-Phe-L-(Tr- Gln )}-E-Propenoate This compound was prepared from ethyl-3-(Boc-L-(Tr- Gln ))-E-propenoate and Boc-L-(4-F)-Phe-OH using a procedure like that described above (Example 2) for the preparation of ethyl-1-(Boc-L-Phe-L-(Tr- Gln ))-E-propenoate: IR (cm -1 ) 3328, 1707, 1506, 1168; 1 H NMR (CDCl 3 ) δ 1.29 (t, 3H, J = 7.2), 1.37 (s, 9H), 1.66-1.78 (m, 1H), 1.88-1.98 (m, 1H), 2.32 (t, 2H, J = 6.6), 2.85-2.92 (m, 1H), 2.97-3.04 (m, 1H), 4.18 (q, 2H, J = 7.2), 4.52 (m, 1H), 4.96 (m, 1H), 5.60 (d, 1H, J = 15.6), 6.56 (d, 1H, J = 8.1), 6.66 (dd, 1H, J = 15.6, 5.1), 6.80 (s, br, 1H), 6.92-6.98 (m, 2H), 7.08-7.12 (m, 2H), 7.17-7.23 (m, 6H), 7.24-7.33 (m, 10H); Anal. (C 42 H 46 FN 3 O 6 ) C, H, N. Preparation of Intermediate Ethyl-3-{Boc-L-Val-L-(4-F)-Phe-L-(Tr-Gln)}-E-Propenoate This compound was prepared from ethyl-3-{Boc-L-(4-F)-Phe-L-(Tr- Gln )}-E-propenoate and Boc-L-Val-OH in the manner described above (Example 2) for the preparation of ethyl-3-{Boc-L-Leu-L-Phe-L-(Tr- Gln )}-E-propenoate: IR (cm -1 ) 3319, 1657, 1511, 1172; 1 H NMR (CDCl 3 ) δ 0.78 (d, 3H, J = 6.9), 0.87 (d, 3H, J = 6.9), 1.29 (t, 3H, J = 7.2), 1.37 (s, 9H), 1.69-1.79 (m, 1H), 1.93-2.06 (m, 2H), 2.33 (t, 2H, J = 7.2), 2.97-3.04 (m, 1H), 3.73-3.77 (m, 1H), 4.18 (q, 2H, J = 7.2), 4.42-4.54 (m, 2H), 4.80 (d, 1H, J = 6.9), 5.61 (dd, 1H, J = 15.6, 1.5), 6.44 (d, 1H, J = 7.8), 6.69 (dd, 1H, J = 15.9, 5.4), 6.71 (s, br, 1H), 6.92-6.98 (m, 2H), 7.07-7.13 (m, 2H), 7.18-7.31 (m, 16H), 8.02 (s, 1H); Anal. (C 47 H 55 FN 4 O 7 ) C, H, N. Preparation of Intermediate Ethyl-3-{(5'-Methylisoxazole-3'-carbonyl)-L-Val-L-(4-F)-Phe-L-(Tr- Gln )}-E-Propenoate This compound was prepared from ethyl-3-{Boc-L-Val-L-(4-F)-Phe-L-(Tr- Gln )}-E-propenoate and 5-methylisoxazole-3-carbonyl chloride in a manner like that described above (Example 2) for the preparation of ethyl-3-{(5'-methylisoxazole-3'-carbonyl)-L-Leu-L-Phe-L-(Tr- Gln )}-E-propenoate: IR (cm -1 ) 3319, 1657, 1511, 1172; 1 H NMR (CDCl 3 ) δ 0.84 (d, 3H, J = 6.9), 0.89 (d, 3H, J = 6.9), 1.30 (t, 3H, J = 7.2), 1.68-1.80 (m, 1H), 1.95-2.06 (m, 1H), 2.08-2.17 (m, 1H), 2.34 (t, 2H, J = 7.2), 2.44 (s, 3H), 2.87-2.94 (m, 1H), 3.01-3.08 (m, 1H), 4.18 (q, 2H, J = 7.2), 4.48-4.56 (m, 2H), 5.68 (dd, 1H, J = 15.6, 1.8), 6.23 (s, 1H), 6.39 (d, 1H, J = 7.8), 6.70 (dd, 1H, J = 15.9, 5.4), 6.84-6.90 (m, 3H), 7.04-7.08 (m, 4H), 7.17-7.30 (m, 16H); Anal. (C 47 H 50 N 5 O 7 ) C, H, N. Preparation of Product Ethyl-3-{(5'-Methylisoxazole-3'-carbonyl)-L-Val-L-(4-F)-Phe-L - Gln }-E-Propenoate Ethyl-3-{(5'-Methylisoxazole-3'-carbonyl)-L-Val-L-(4-F)-Phe-L-(Tr- Gln )}-E-propenoate was deprotected using the procedure described above (Example 2) for the preparation of ethyl-3-{(5'-methylisoxazole-3'-carbonyl)-L-Leu-L-Phe-L- Gln }-E-propenoate: IR (cm -1 ) 3284, 1652, 1542; 1 H NMR (DMSO- d 6 ) δ 0.76 (d, 3H, J = 6.9), 0.79 (d, 3H, J = 6.9), 1.20 (t, 3H, J = 7.2), 1.57-1.76 (m, 2H), 1.96-2.06 (3H), 2.46 (s, 3H), 2.75-2.83 (m, 1H), 2.89-2.96 (m, 1H), 4.09 (q, 2H, J = 7.2), 4.13-4.25 (m, 1H), 4.35 (m, 1H), 4.49-4.56 (m, 1H), 5.53 (d, 1H, J = 15.6), 6.57 (s, 1H), 6.66 (dd, 1H, J = 15.6, 5.4), 6.75 (s, br, 1H), 6.97-7.03 (m, 2H), 7.17-7.24 (m, 3H), 8.1 (d, 1H, J = 7.8), 8.24 (d, 1H, J = 8.7), 8.32 (d, 1H, J = 8.1); Anal. (C 28 H 36 N 5 O 7 ) C, H, N. Example 10 - Preparation of Compound B-1: Ethyl-3-{(5'-Methylisoxazole-3'-carbonyl)-L-ValΨ(COCH 2 )-L-(4-F-Phe)-L- Gln }-E-Propenoste Preparation of Intermediate trans-6-Methyl-hept-4-enoic Acid. A solution of isobutyraldehyde (9.59 g, 133 mmol, 1 equiv.) in THF (50 mL) was added dropwise via addition funnel to a solution of vinylmagnesium bromide (133 mL of a 1.0 M solution in THF, 133 mmol, 1.0 equiv.) in THF (300 mL) at 0°C. Upon completion of the addition, the reaction mixture was stirred for 30 min. at 0°C, and then ethyl malonyl chloride (17.0 mL, 133 mmol, 1.0 equiv.) was added. After stirring for 1 h at 0°C, the reaction mixture was partitioned between saturated NH 4 Cl (150 mL) and a 1:1 mixture of EtOAc and hexanes (2 x 200 mL). The combined organic layers were dried over Na 2 SO 4 and were concentrated. Purification of the residue by filtration through silica gel (eluting with 5% EtOAc in hexanes) afforded the intermediate malonate ester (11.5 g, 40% yield). This material was not characterized, but was combined (neat) with Ti(OEt) 4 (1.13 mL, 5.39 mmol, 0.10 equiv.) and was heated to 190°C for 4 h, and then was cooled to 60°C. EtOH (50 mL) and 6.0 M KOH (50 mL) were added sequentially, and the brown reaction mixture was refluxed for 4 h. After cooling to 23°C, the reaction mixture was filtered through a medium frit, and the filtrate was partitioned between water (150 mL) and Et 2 O (2 x 150 mL). The aqueous layer was then acidified to pH = 2 (as indicated by pH paper) with concentrated HCl and was extracted with a 1:1 mixture of EtOAc and hexanes (2 x 150 mL). The combined organic layers were dried over Na 2 SO 4 , concentrated, and the residue was distilled at reduced pressure to afford trans-6-methyl-hept-4-enoic acid (3.58 g, 47%) as a colorless liquid: bp 107-112°C (1 Torr); IR (cm -1 ) 2960, 1711; 1 H NMR (CDCl 3 ) δ 0.96 (d, 6H, J = 6.5), 2.18-2.45 (m, 5H), 5.31-5.50 (m, 2H); Anal. (C 8 H 14 O 2 ) C, H. Preparation of Intermediate trans-6-Methyl-hept-4-enoic Acid (2 R -hydrox-y-1 R -methyl-2-phenyl-ethyl)-methyl Amide. Oxalyl chloride (2.25 mL, 25.8 mmol, 1.05 equiv.) was added to a solution of trans-6-methyl-hept-4-enoic acid (3.50 g, 24.6 mmol, 1 equiv.) and N,N -dimethylformamide (0.03 mL, 0.39 mmol, 0.016 equiv.) in benzene (60 mL) at 23°C. The reaction mixture was stirred at 23°C for 2 h, and then was concentrated under reduced pressure. The resulting oil was dissolved in THF (20 mL) and was added via cannula to a solution of (1 R ,2 R )-(-)-pseudoephedrine (3.87 g, 23.4 mmol, 1 equiv.) and triethylamine (3.92 mL, 28.1 mmol, 1.2 equiv.) in THF (150 mL) at 0°C. The reaction mixture was stirred at 0°C for 30 min., then was partitioned between half-saturated NH 4 Cl (150 mL) and EtOAc (2 x 150 mL). The combined organic layers were dried over Na 2 SO 4 , concentrated, and the residue purified by flash column chromatography (gradient elution 40→50% EtOAc in hexanes) to afford trans-6-methyl-hept-4-enoic acid (2 R -hydroxy-1 R -methyl-2-phenyl-ethyl)-methyl amide (6.31 g, 93%) as a viscous oil: R f = 0.35 (50% EtOAc in hexanes); IR (cm -1 ) 3382, 1622; 1 H NMR (CDCl 3 , mixture of rotamers) δ 0.96 (d, J = 6.8), 0.97 (d, J = 6.5), 1.11 (d, J = 6.9), 2.18-2.59 (m), 2.82 (s), 2.92 (s), 3.99-4.04 (m), 4.32-4.42 (m), 4.44-4.49 (m), 4.55-4.62 (m), 5.32-5.49 (m), 7.24-7.42 (m); Anal. (C 18 H 27 NO 2 ) C, H, N. Preparation of Intermediate trans-6-Methyl-2 S -(4-fluorobenzyl)-hept-4-enoic Acid (2 R -Hydroxy-1 R -methyl-2-phenylethyl)methyl Amide. n -Butyllithium (32.5 mL of a 1.6 M solution in hexanes, 52.0 mmol, 3.1 equiv.) was added to a suspension of anhydrous lithium chloride (7.18 g, 169 mmol, 10 equiv.) and diisopropylamine (7.80 mL, 55.7 mmol, 3.3 equiv.) in THF (250 mL) at -78°C. The reaction mixture was stirred for 30 min. at -78°C, was maintained at 0°C for 5 min., and subsequently cooled again to -78°C. trans-6-Methyl-hept-4-enoic acid (2 R -hydroxy-1 R -methyl-2-phenylethyl)-methyl amide (4.91 g, 17.0 mmol, 1 equiv) in THF (50 mL) was added via cannula, and the resulting solution was stirred at -78°C for 1.75 h, maintained at 0°C for 20 min., stirred at 23°C for 5 min., and then was cooled again to 0°C. A solution of 4-fluorobenzyl bromide (6.34 mL, 50.9 mmol, 3 equiv.) in THF (15 mL) was added and the reaction mixture was stirred at 0°C for 30 min., which was then partitioned between half-saturated NH 4 Cl (230 mL) and a 1:1 mixture of EtOAc and hexanes (200 mL, 2 x 150 mL). The combined organic layers were dried over Na 2 SO 4 and were concentrated. Purification of the residue by flash column chromatography (gradient elution 20→40% EtOAc in hexanes) provided trans-6-methyl-2 S -(4-fluorobenzyl)-hept-4-enoic acid (2 R -hydroxy-1 R -methyl-2-phenylethyl)methyl amide (6.33 g, 94%) as a viscous oil: R f = 0.38 (40% EtOAc in hexanes); IR (cm -1 ) 3378, 1614; 1 H NMR (CDCl 3 , mixture of rotamers) δ 0.85-0.95 (m), 0.96 (d, J = 6.8), 2.10-2.32 (m), 2.34-2.46 (m), 2.58 (s), 2.67-2.79 (m), 2.82-2.94 (m), 3.00-3.18 (m), 3.94 (br), 4.37-4.52 (m), 5.24-5.42 (m), 5.44-5.56 (m), 6.89-7.01 (m), 7.08-7.14 (m), 7.19-7.38 (m); Anal. (C 25 H 32 FNO 2 ) C, H, N. Preparation of Intermediate 5 S -(1 R -Bromo-2-methylpropyl)-3 R -(4-fluorobenzyl)dihydrofuran-2-one. N -Bromosuccinimide (2.93 g, 16.5 mmol, 1.05 equiv.) was added in small portions over 10 minutes to a solution of trans-6-methyl-2 S -(4-fluorobenzyl)-hept-4-enoic acid (2 R -hydroxy-1 R -methyl-2-phenylethyl)methyl amide (6.24 g, 15.7 mmol, equiv.) and glacial acetic acid (4.49 mL, 78.4 mmol, 5 equiv.) in a 4:1 mixture of THF and H 2 O (165 mL) at 0°C. The resulting yellow solution was stirred for 15 min. at 0°C, and then was warmed to 23°C and subsequently refluxed for 45 min. After cooling to 23°C, the reaction mixture was partitioned between half-saturated NaHCO 3 (200 mL) and a 1:1 mixture of EtOAc and hexanes (2 x 200 mL, 100 mL). The combined organic layers were dried over Na 2 SO 4 and were concentrated. Flash chromatographic purification of the residue (gradient elution 4→10% EtOAc in hexanes) gave 5 S -(1 R -bromo-2-methylpropyl)-3 R -(4-fluorobenzyl)dihydrofuran-2-one (4.14 g, 80%) as a pale yellow oil (containing approximately 5-10% unidentified impurities by 1 H NMR): R f = 0.56 (25% EtOAc in hexanes); IR (cm -1 ) 1772; 1 H NMR (CDCl 3 , major isomer) δ 0.94 (d, 3H, J = 6.5), 1.00 (d, 3H, J = 6.8), 2.05-2.35 (m, 3H), 2.83 (dd, 1H, J = 13.6, 8.4), 2.92-3.03 (m, 1H), 3.11 (dd, 1H, J = 13.6, 4.7), 3.90 (dd, 1H, J = 9.0, 3.7), 4.33-4.40 (m, 1H), 6.98-7.06 (m, 2H), 7.14-7.20 (m, 2H); Anal. (C 15 H 18 BrFO 2 ) C, H. Preparation of Intermediate 5 S -(1 S -Azido-2-methylpropyl)-3 R -(4-fluorobenzyl)dihydrofuran -2-one. A suspension of sodium azide (1.90 g, 29.2 mmol, 2.5 equiv.) and 5 S -(1 R -bromo-2-methylpropyl)-3R-(4-fluorobenzyl)dihydrofuran-2-one (3.85 g, 11.7 mmol, 1 equiv.) in N,N -dimethylformamide (40 mL) was heated at 50°C for 67 hours. The reaction mixture was cooled to 23°C and was partitioned between half-saturated NaCl (200 mL) and a 1:1:1 mixture of EtOAc, hexanes and acetone (2 x 200 mL, 100 mL). The combined organic layers were dried over Na 2 SO 4 , concentrated, and the residue purified by flash column chromatography (gradient elution 9→17% EtOAc in hexanes) to give 5 S -(1 S -azido-2-methylpropyl)-3 R -(4-fluorobenzyl)dihydrofuran-2-one (2.10 g, 62%) as a white solid (containing approximately 5-10% unidentified impurities by 1 H NMR): mp 91-96°C; R f = 0.44 (25% EtOAc in hexanes); IR (cm -1 ) 2097, 1772; 1 H NMR (CDCl 3 , major isomer) δ 0.99 (d, 3H, J = 6.5), 1.02 (d, 3H, J = 6.8), 1.95-2.20 (m, 3H), 2.78-2.88 (m, 1H), 2.94 (dd, 1H, J = 7.0, 4.2), 3.03-3.17 (m, 2H), 4.37-4.43 (m, 1H), 6.97-7.09 (m, 2H), 7.14-7.21 (m, 2H). Preparation of Intermediate {2-Methyl-1 S -(4 R -(4-fluorobenzyl)-5-oxotetrahydrofuran-2 S -yl)propyl}-carbamic Acid tert -Butyl Ester. A suspension of 5 S -(1 S -azido-2-methylpropyl)-3 R -(4-fluorobenzyl)dihydrofuran-2-one (2.02 g, 6.93 mmol, 1 equiv.), di- tert -butyl dicarbonate (2.12 g, 9.71 mmol, 1.4 equiv.) and Pd/C (10%, 0.20 g) in CH 3 OH (100 mL) was stirred under a hydrogen atmosphere (balloon) for 16 hours. The reaction mixture was vacuum filtered through Whatman #3 paper and concentrated. Purification of the residue by flash column chromatography (15% EtOAc in hexanes) provided {2-methyl-1 S -(4 R -(4-fluorobenzyl)-5-oxotetrahydrofuran-2 S -yl)propyl}-carbamic acid tert -butyl ester (1.58 g, 62%) as a white foam: R f = 0.80 (5% MeOH in CH 2 Cl 2 ); IR (cm -1 ) 3331, 1766, 1702; 1 H NMR (CDCl 3 ) δ 0.93 (d, 3H, J = 6.8), 0.95 (d, 3H, J = 6.5), 1.41 (s, 9H), 1.71-1.83 (m, 1H), 1.95-2.06 (m, 1H), 2.16-2.27 (m, 1H), 2.80 (dd, 1H, J = 13.5, 8.6), 2.88-2.99 (m, 1H), 3.09 (dd, 1H, J = 13.5, 4.4), 3.32-3.40 (m, 1H), 4.42-4.48 (m, 2H), 6.95-7.03 (m, 2H), 7.11-7.18 (m, 2H); Anal. (C 20 H 28 FNO 4 ) C, H, N. Preparation of Intermediate Ethyl-3-{Boc-L-ValΨ(COCH 2 )-L-(4-F-Phe)-L-(Tr- Gln )}-E-Propenoate. Lithium hydroxide (9.62 mL of a 1 M aqueous solution, 9.62 mmol, 5 equiv.) was added to a solution of {2-methyl-1 S -(4 R -(4-fluorobenzyl)-5-oxotetrahydrofuran-2 S -yl)propyl}-carbamic acid tert -butyl ester (0.703 g, 1.92 mmol, 1 equiv.) in DME (25 mL) at 23°C. The resulting suspension was stirred at 23°C for 30 min., and then was partitioned between 10% KHSO 4 (50 mL) and CH 2 Cl 2 (3 x 100 mL). The combined organic layers were dried over Na 2 SO 4 , concentrated, and the residue dissolved in CH 2 Cl 2 (30 mL). Powdered 4A molecular sieves (0.70 g), 4-methylmorpholine N -oxide (0.451 g, 3.85 mmol, 2 equiv.), and tetrapropylammonium perruthenate (0.068 g, 0.19 mmol, 0.10 equiv.) were added sequentially. The resulting dark reaction mixture was stirred for 1.33 hours at 23°C, then was vacuum filtered through Whatman #3 paper and then through Whatman #5 paper. The filtrate was concentrated under reduced pressure to provide a dark residue, which was dissolved in CH 2 Cl 2 (30 mL). Crude ethyl-3-(H 2 N-L-(Tr- Gln ))-E-propenoate•HCl (2.30 mmol, 1.2 equiv., prepared as described in Example 2 for the preparation of ethyl-3-{(5'-methylisoxazole-3'-carbonyl)-L-Leu-L-Phe-L- Gln }-E-propenoate), 4-methylmorpholine (0.846 mL, 7.69 mmol, 4 equiv.), HOBt (0.390 g, 2.89 mmol, 1.5 equiv.), and EDC (0.553 g, 2.88 mmol, 1.5 equiv.) were added sequentially, and the reaction mixture was stirred for 19 hours at 23°C and then was partitioned between brine (100 mL) and CH 2 Cl 2 (3 x 100 mL). The combined organic layers were dried over Na 2 SO 4 and were concentrated. Purification of the residue by flash column chromatography (gradient elution 35→40% EtOAc in hexanes) provided ethyl-3-{Boc-L-ValΨ(COCH 2 )-L-(4-F-Phe)-L-(Tr- Gln )}-E-propenoate (0.820 g, 53%) as a tan foam: R f = 0.50 (50% EtOAc in hexanes); IR (cm -1 ) 3307, 1708, 1666; 1 H NMR (CDCl 3 ) δ 0.67 (d, 3H, J = 6.8), 0.92 (d, 3H, J = 6.8), 1.28 (t, 3H, J = 7.2), 1.40 (s, 9H), 1.53-1.67 (m, 1H), 1.91-2.04 (m, 2H), 2.32-2.41 (m, 2H), 2.46-2.55 (m, 1H), 2.63 (dd, 1H, J = 12.1, 5.9), 2.69-2.80 (m, 1H), 2.83 (dd, 1H, J = 12.1, 8.2), 3.03 (dd, 1H, J = 17.7, 10.0), 4.05-4.11 (m, 1H), 4.17 (q, 2 H, J = 7.2), 4.40-4.50 (m, 1H), 4.84 (d, 1H, J = 8.4), 5.38 (d, 1H, J = 15.7), 6.01 (d, 1H, J = 8.4), 6.60 (dd, 1H, J = 15.7, 5.0), 6.92-6.99 (m, 2H), 7.03-7.12 (m, 3H), 7.17-7.30 (m, 15H); Anal. (C 48 H 56 FN 3 O 7 ) C, H, N. Preparation of Product Ethyl-3-{(5'-Methylisoxazole-3'-carbonyl)-L-ValΨ(COCH 2 )-L-(4-F-Phe)-L- Gln }-E-Propenoate Ethyl-3-{Boc-L-ValΨ(COCH 2 )-L-(4-F-Phe)-L-(Tr- Gln )}-E-propenoate was converted to product ethyl-3-{(5'-methylisoxazole-3'-carbonyl)-L-ValΨ(COCH 2 )-L-(4-F-Phe)-L- Gln }-E-propenoate in a manner analogous to that described in Example 2 above for the conversion of ethyl-3-{Boc-L-Leu-L-Phe-L-(Tr- Gln )}-E-propenoate to product ethyl-3-{(5'-methylisoxazole-3'-carbonyl)-L-Leu-L-Phe-L- Gln }-E-propenoate: mp = 220°C (dec); R f = 0.35 (10% CH 3 OH in CH 2 Cl 2 ); IR (cm -1 ) 3277, 1715, 1643; 1 H NMR (DMSO- d 6 ) δ 0.81 (d, 3H, J = 6.2), 0.87 (d, 3H, J = 6.9), 1.21 (t, 3H, J = 6.5), 1.59-1.67 (m, 2H), 2.03 (s, br, 2H), 2.21-2.24 (m, 1H), 2.46 (s, 3H), 2.57-2.68 (m, 3H), 2.80-2.95 (m, 2H), 4.09 (q, 2H, J = 6.5), 4.30-4.34 (m, 2H), 5.41 (d, 1H, J = 15.5), 6.55 (s, 1H), 6.61 (dd, 1H, J = 15.5, 5.5), 6.73 (s, 1H), 6.99-7.16 (m, 5H), 8.01 (d, 1H, J = 7.8), 8.69 (d, 1H, J = 8.7); Anal. (C 29 H 37 FN 4 O 7 ) C, H, N. Example 11 - Preparation of Compound A-10: Ethyl-3-((5'-Methylisoxazole-3'-carbonyl)-L-Leu-NCH 3 -L-Phe-L- Gln }-E-Propenoate Preparation of Intermediate Boc-L-Leu-NCH 3 -L-Phe-OCH 3 NCH 3 -L-Phe-OCH 3 •HCl (1.4 g) was dissolved in CH 2 Cl 2 (50 mL) and poured into a combination of aqueous (aq) 1 N NaOH (7 mL) and saturated aqueous NaHCO 3 (25 mL). After mixing, the organic phase was separated and the aqueous phase was washed with CH 2 Cl 2 (3 x 50 mL). The combined organic phases were dried over Na 2 SO 4 and evaporated to give the free amine as a clear colorless oil (1.14 g, 5.90 mmol). A solution of this amine and (iPr) 2 NEt (1.13 mL, 6.49 mmol) in DMF (10 mL) was added dropwise to a 0°C solution of Boc-L-Leu-OH (1.50 g, 6.49 mmol) and HOBt (0.877 g, 6.49 mmol) in DMF (10 mL). DCC (1.47 g, 7.12 mmol) was added. The reaction mixture was stirred at 0°C for 1 h, and was then stirred at 23°C for 48 h. The mixture was filtered to remove the precipitate (ppt) and the filtrate was evaporated. The residue was dissolved in CH 2 Cl 2 (200 mL), washed with saturated aqueous NaHCO 3 (40 mL), dried over Na 2 SO 4 and evaporated. The residue was purified by flash column chromatography (25% EtOAc in hexanes) to give Boc-L-Leu-NCH 3 -L-Phe-OCH 3 as a white solid (2.04 g, 85%): mp = 126-127°C; IR (cm -1 ) 3401, 3319, 1743, 1708, 1649; 1 H NMR (CDCl 3 ) (major isomer) δ 0.92 (d, 3H, J = 6.8), 0.95 (d, 3H, J = 6.5), 1.32-1.48 (m, 2H), 1.41 (s, 9H), 1.61-1.77 (m, 1H), 2.90 (s, 3H), 3.04 (dd, 1H, J = 14.5, 10.5), 3.37 (dd, 1H, J = 14.5, 5.5), 3.72 (s, 3H), 4.48-4.57 (m, 1H), 4.98-5.04 (m, 1H), 5.20 (dd, 1H, J = 10.5, 5.5), 7.16-7.32 (m 5H); Anal. (C 22 H 34 N 2 O 5 ) C, H, N. Preparation of Intermediate Boc-L-Leu-NCH 3 -L-Phe-OH Boc-L-Leu-NCH 3 -L-Phe-OCH 3 (0.625 g, 1.54 mmol) was dissolved in CH 3 OH (20 mL) and cooled to 0°C. Aqueous NaOH (6.15 mL of a 2N solution, 12.3 mmol) was added dropwise. The reaction mixture was stirred for 3 h at 23°C, and then poured into 10% aqueous KHSO 4 (150 mL). This mixture was extracted with CH 2 Cl 2 (3 x 100 mL), and the combined organic phases were dried over Na 2 SO 4 and evaporated to give Boc-L-Leu-NCH 3 -L-Phe-OH as a white foam (0.617 g, quant.), which was used without purification. Preparation of Intermediate Ethyl-3-{Boc-L-Leu-NCH 3 -L-Phe-L-(Tr- Gln )}-E-Propenoate This intermediate was prepared from Boc-L-Leu-NCH 3 -L-Phe-OH and ethyl-3-{H 2 N-L-(Tr- Gln )}-E-propenoate•HCl (prepared as described in Example 2) in a manner analogous to that described for the preparation of ethyl-3-{Boc-L-Leu-L-Phe-L-(Tr- Gln )}-E-propenoate in Example 2 above: IR (cm -1 ) 3295, 1713, 1672, 1649; 1 H NMR (CDCl 3 )(mixture of isomers) δ 0.65 (d, J = 6.2), 0.66 (d, J = 6.5), 0.84 (d, J = 6.5), 0.88 (d, J = 6.5), 1.02-1.22 (m), 1.23-1.38 (m), 1.33 (s), 1.41 (s), 1.55-1.82 (m), 1.89-2.07 (m), 2.23-2.30 (m), 2.90 (s), 2.94 (s), 3.01 (dd, J = 14.6, 10.9), 3.03-3.13 (m), 3.26-3.37 (m), 3.27 (dd, J = 14.6, 3.4), 3.42-3.54 (m), 4.00-4.22 (m), 4.37-4.73 (m), 4.82-4.89 (m), 5.63-5.70 (m), 5.95 (dd, J = 15.9, 1.2), 6.23-6.28 (m), 6.66-6.75 (m), 6.79-6.89 (m), 7.09-7.34 (m), 8.14 (d, J = 8.7); Anal. (C 49 H 60 N 4 O 7 ) C, H, N. Preparation of Product Ethyl-3-{(5'-Methylisoxazole-3'-carbonyl)-L-Leu-NCH 3 -L-Phe-L- Gln }-E-Propenoate Ethyl-3-{Boc-L-Leu-NCH 3 -L-Phe-L-(Tr- Gln )}-E-propenoate was converted to product ethyl-3-{(5'-methylisoxazole-3'-carbonyl)-L-Leu-NCH 3 -L-Phe-L- Gln }-E-propenoate in a manner analogous to that described in Example 2 above for the conversion of ethyl-3-{Boc-L-Leu-L-Phe-L-(Tr- Gln )}-E-propenoate to product ethyl-3-{(5'-methylisoxazole-3'-carbonyl)-L-Leu-L-Phe-L- Gln }-E-propenoate: R f = 0.23 (5% CH 3 OH in CH 2 Cl 2 ); IR (cm -1 ) 3295, 1713, 1666, 1637; 1 H NMR (CDCl 3 ) (mixture of isomers) δ 0.65 (d, J = 6.5), 0.71 (d, J = 6.5), 0.93 (d, J = 6.5), 0.94 (d, J = 6.5), 1.30 (t, J = 7.2), 1.24-1.73 (m), 1.81-2.22 (m), 2.45 (s), 2.48 (s), 2.86-2.93 (m), 2.96 (s), 2.97 (s), 3.03-3.14 (m), 3.21-3.31 (m), 3.48 (dd, J = 14.0, 5.9), 4.19 (q, J = 7.2), 4.20 (q, J = 7.2), 4.38-4.45 (m), 4.52-4.70 (m), 4.74-4.81 (m), 5.62-5.67 (m), 5.73-5.79 (m), 5.81 (dd, J = 15.6, 1.6), 5.99 (dd, J = 15.6, 1.6), 6.03-6.09 (m), 6.35 (s), 6.39 (s), 6.40-6.45 (m), 6.77-6.94 (m), 7.42 (d, J = 7.2), 8.13 (d, J = 7.8). Example 12 - Preparation of Compound C-1: Ethyl-3-{(5'-Niethylisoxazole-3'-carbonyl)-L-Val-O-L-(4-F-Phe)-L- Gln }-E-Propenoate Preparation of Intermediate Allyl ( S )-I-Hydroxy-3-(4-fluorophenyl)propionate In a flask fitted with a thermometer and a reflux condenser was dissolved methyl ( S )-1-hydroxy-3-(4-fluorophenyl)propionate (prepared from L-H 2 N-(4-F-Phe)-OCH 3 by the method described in Hoffman et al., Tetrahedron 1992 , vol. 48, 3007) (0.99 g, 5.0 mmol) in allyl alcohol (50 mL). Titanium tetraisopropoxide (1.53 mL, 5.0 mmol) was added, and the reaction brought to 90°C for 3.5 h. The reaction was cooled to room temperature and poured into 250 mL of 1:1 EtOAc/saturated NH 4 Cl solution. The organic phase was separated and washed with water (100 mL), brine (100 mL), dried (MgSO 4 ), and the solvent removed. The residue was subjected to flash column chromatography eluting with a gradient of 5-10% EtOAc/hexanes to afford 0.77 g (68%) of allyl ( S )-1-hydroxy-3-(4-fluorophenyl)propionate as a clear liquid: R f = 0.21 (15% EtOAc/hexanes); IR (neat) 3470 (broad), 1734, 1510, 1221 cm -1 ; 1 H NMR (DMSO-d 6 ) δ 1.24-1.27 (m, 1H), 2.92-2.99 (m, 1H), 3.09-3.15 (m, 1H), 4.43-4.47 (m, 1H), 4.65 (d, 2H, J = 5.9), 5.28-5.37 (m, 2H), 5.86-5.95 (m, 1H), 6.95-7.01 (m, 2H), 7.16-7.21 (m, 2H). Preparation of Intermediate Boc-L-Val-O-L-(4-F-Phe)-OCH 2 CH=CH 2 Allyl ( S )-1-hydroxy-3-(4-fluorophenyl)propionate (0.070 g, 0.31 mmol) was dissolved in CH 2 Cl 2 (20 mL). Boc-L-Val-OH (0.068 g, 0.31 mmol) was added, followed by DMAP (0.004 g, 0.03 mmol) and DCC (0.067 g, 0.33 mmol). The reaction was stirred at room temperature overnight, and the solvent was removed in vacuo . The residue was subjected to flash column chromatography eluting with a gradient of 3-5% EtOAc/hexanes. The Boc-L-Val-O-L-(4-F-Phe)-OCH 2 CH=CH 2 product was obtained as 0.12 g (90%) of a clear oil: R f = 0.18 (10% EtOAc/hexanes); IR (neat) 1752, 1717 1510 cm -1 ; 1 H NMR (DMSO- d 6 ) δ 0.80-0.85 (m, 6H), 1.36 (s, 9H), 1.97-2.04 (m, 1H), 3.07-3.15 (m, 2H), 3.89-3.94 (m, 1H), 4.51-4.55 (m, 2H), 5.17-5.30 (m, 3H), 5.75-5.84 (m, 1H), 7.06-7.17 (m, 3H), 7.27-7.32 (m, 2H); Anal. (C 22 H 30 NO 6 F) C, H, N. Preparation of Intermediate Ethyl-3-{Boc-L-Val-O-L-(4-F-Phe)-L-(Tr- Cln )}-E-Propenoate Boc-L-Val-O-L-(4-F-Phe)-OCH 2 CH=CH 2 (0.65 g, 1.52 mmol) was dissolved in THF (15 mL). Tetrakis(triphenylphosphine)palladium(0) (0.035 g, 0.03 mmol) was added, and the reaction stirred 5 min. at 23°C. Morpholine (0.16 mL, 1.83 mmol) was added dropwise, and the reaction stirred at room temperature for 2 h. The solvent was removed in vacuo , and the residue taken up in 50 mL of 4:1 hexanes/Et 2 O. The product was extracted into sat. NaHCO 3 solution (50 mL), and the organic phase discarded. The aqueous phase was acidified to pH = 1-2 with solid KHSO 4 , and the product re-extracted into EtOAc (50 mL). The organic phase was washed with brine (50 mL), dried (MgSO 4 ), and concentrated to give 0.50 g (86%) of the free acid as a clear oil. This material was dissolved in DMF (6 mL). Diisopropylethylamine (0.43 mL, 2.50 mmol) was added, followed by ethyl-3-{H 2 N-L-(Tr- Gln )}-E-propenoate•HCl (prepared as described in Example 2 above, 0.55 g, 1.25 mmol). The reaction was cooled to 0°C. HATU (0.48 g, 1.25 mmol) was added, and the reaction allowed to warm to room temperature. The DMF was removed in vacuo . The residue was dissolved with EtOAc (30 mL), and the organic phase washed consecutively with 10% HCl solution (25 mL), saturated NaHCO 3 solution (25 mL), H 2 O (25 mL), and brine (25 mL). The organic layer was dried (MgSO 4 ), filtered, and concentrated, and the residue was purified by flash column chromatography (0→1.0% MeOH/CH 2 Cl 2 ) to give 0.40 g (39%) of ethyl-3-{Boc-L-Val-O-L-(4-F-Phe)-L-(Tr- Gln )}-E-propenoate as a white amorphous solid: R f = 0.25 (3% MeOH/CHCl 3 ); IR(KBr) 1691, 1512, 1159 cm -1 ; 1 H NMR (DMSO- d 6 ) δ 0.78-0.83 (m, 6H), 1.20 (t, 3H, J = 7.0), 1.35 (s, 9H), 1.58-1.66 (m, 2H), 1.96-2.02 (m, 1H), 2.19-2.33 (m, 2H), 2.99-3.02 (m, 2H), 3.82-3.87 (m, 1H), 4.09 (q, 2H, J = 7.0), 4.33-4.37 (m, 1H), 5.03-5.08 (m, 1H), 5.60 (d, 1H, J = 15.8), 6.67 (dd, 1H, J = 15.8, 5.5), 7.02-7.08 (m, 2H), 7.14-7.28 (m, 18H), 8.12 (d, 1H, J = 8.1), 8.59 (s, 1H); Anal. (C 47 H 54 N 3 O 8 F) C, H, N. Preparation of Product Ethyl-3-{(5'-Methylisoxazole-3'-carbonyl)-L-Val-O-L-(4-F-Phe)-L- Gln }-E-Propenoate Ethyl-3-{Boc-L-Val-O-L-(4-F-Phe)-L-(Tr- Gln )}-E-propenoate was converted to product ethyl-3-{(5'-methylisoxazole-3'-carbonyl)-L-Val-O-L-(4-F-Phe)-L- Gln }-E-propenoate in a manner analogous to that described in Example 2 above for the conversion of ethyl-3-{Boc-L-Leu-L-Phe-L-(Tr- Gln )}-E-propenoate to product ethyl-3-{(5'-methylisoxazole-3'-carbonyl)-L-Leu-L-Phe-L- Gln }-E-propenoate: R f = 0.05 (3% MeOH/CHCl 3 ); IR (KBr) 1746, 1719, 1661, 1549 cm -1 ; 1 H NMR(DMSO- d 6 ) δ 0.87 (d, 3 H, J = 6.6), 0.92 (d, 3H, J = 6.6), 1.20 (t, 3H, J = 7.0), 1.61-1.74 (m, 2H), 1.96-2.01 (m, 2H), 2.15-2.22 (m, 1H), 2.46 (s, 3H), 3.00-3.03 (m, 2H), 4.10 (q, 2H, J = 7.0), 4.27-4.32 (m, 1H), 4.33-4.38 (m, 1H), 5.06-5.11 (m, 1H), 5.63 (d, 1H, J = 15.6), 6.54 (s, 1H), 6.68 (dd, 1H, J = 15.6, 5.5), 6.78 (s, br, 1H), 6.95-7.00 (m, 2H), 7.20-7.24 (m, 3H), 8.06 (d, 1H, J = 8.1), 8.87 (d, 1H, J = 7.7); Anal. (C 28 H 35 N 4 O 8 F) C, H, N. Example 13 - Preparation of Compound A-11: Ethyl-3-{(5'-Methylisoxazole-3'-carbonyl)-L-(2-Naphth)-NCH 3 -L-(4-F-Phe)-L- Gln }-E-Propenoate Preparation of Intermediate Ethyl-3-{Boc-NCH 3 -L-(4-F-Phe)-L-(Tr- Gln )}-E-Propenoate Boc-(4-F-Phe)-OH (4.46 g, 15.75 mmol, 1 equiv.) and CH 3 I (7.84 mL, 126 mmol, 8 equiv.) were dissolved in dry THF (100 mL) and cooled to 0°C. NaH (1.89 g, 47.25 mmol, 3 equiv.) was added to this solution with vigorous stirring. After stirring at 23°C for 24 h, EtOAc (3 mL) and H 2 O (3 mL) were added carefully to the mixture, and the resulting suspension was evaporated to dryness. After dissolving in H 2 O (100 mL), the reaction mixture was washed with Et 2 O (2 x 100 mL). The aqueous layer was acidified to pH = 3 with 10% citric acid solution, and then extracted with EtOAc (2 x 100 mL). The combined EtOAc extracts were washed successively with half-saturated NaHCO 3 (150 mL), 5% Na 2 S 2 O 3 (150 mL), and H 2 O (150 mL), dried over Na 2 SO 4 , and concentrated to give Boc-NCH 3 -(4-F-Phe)-OH as a pale yellow foam (4.37 g, 80%), which was used without further purification: 1 H NMR (CDCl 3 , mixture of isomers) δ 1.35 (s), 1.40 (s), 2.69 (s), 2.75 (s), 2.96-3.13 (m), 3.23-3.33 (m), 4.54-4.58 (m), 4.76-4.81 (m), 6.96-7.01 (m), 7.15-7.17 (m). A solution of HCl in 1,4-dioxane (4.0 M, 15 mL) was added to a solution of ethyl-3-(Boc-L-(Tr- Gln ))-E-propenoate (prepared as described in Example 2 above, 3.57 g, 6.73 mmol, 1 equiv.) in the same solvent (15 mL) at 23°C. After 2 h, the volatiles were removed under reduced pressure. The residue was dissolved in CH 2 Cl 2 (50 mL), and Boc-NCH 3 -(4-F-Phe)-OH (prepared as in the preceding paragraph, 2.0 g, 6.73 mmol, 1.0 equiv.), HOBt (1.23 g, 9.09 mmol, 1.5 equiv), 4-methylmorpholine (2.0 mL, 18.19 mmol, 3 equiv.), and EDC (1.74 g, 9.09 mmol, 1.5 equiv.) were added sequentially. The reaction mixture was stirred at 23°C overnight, and then was partitioned between water (100 mL) and CH 2 Cl 2 (2 x 100 mL). The combined organic layers were dried over Na 2 SO 4 , concentrated, and the residue was purified by flash column chromatography (30% EtOAc in hexane) to afford ethyl-3-{Boc-NCH 3 -L-(4-F-Phe)-L-(Tr- Gln )}-E-propenoate (4.07 g, 84%) as white foam: IR(cm -1 ) 1666, 1510, 1167; 1 H NMR (CDCl 3 , mixture of isomers) δ 1.29 (t, J = 7.2), 1.37 (s), 1.65-1.75 (m), 1.95-2.06 (m), 2.29-2.33 (m), 2.66 (s), 2.91-2.99 (m), 3.22-3.29 (m), 4.18 (q, J = 7.2), 4.52-4.58 (m), 5.68 (d, J = 15.9), 6.45 (d, J = 8.4), 6.74 (dd, J = 15.6, 5.4), 6.91-6.99 (m), 7.11-7.33 (m); Anal. (C 43 H 48 FN 3 O 6 ) C, H, N. Preparation of Intermediate Ethyl-3-{Boc-L-(2-Naphth)-NCH 3 -L-(4-F-Phe)-L-(Tr- Gln )}-E-Propenoate A solution of HCl in 1,4-dioxane (4.0 M, 3 mL), was added to a solution of ethyl-3-{Boc-NCH 3 -L-(4-F-Phe)-L-(Tr- Gln )}-E-propenoate (0.388 g, 0.54 mmol, 1 equiv.) in the same solvent (3 mL) at 23°C. After 2 h, the volatiles were removed under reduced pressure. The residue was dissolved in DMF (10 mL), cooled at 0°C, and DIEA (0.188 mL, 1.08 mmol, 2 equiv.), Boc-L-(2-Naphth)-OH (0.170 g, 0.54 mmol, 1.0 equiv.) and HATU (0.205 g, 0.54 mmol, 1 equiv.) were added sequentially. The reaction mixture was stirred at 23°C for 1 h. The volatiles were removed under reduced pressure, and the resulting residue was taken into EtOAc (50 mL), and washed with 0.5 N HCl (50 mL), saturated NaHCO 3 (50 mL) and brine (50 mL). The organic layer was dried over Na 2 SO 4 , concentrated, and the residue was purified by flash column chromatography (40% EtOAc in hexane) to afford ethyl-3-{Boc-L-(2-Naphth)-NCH 3 -L-(4-F-Phe)-L-(Tr- Gln )}-E-propenoate (0.437 g, 88%) as white foam: IR (cm -1 ) 1656, 1509, 1162; 1 H NMR (CDCl 3 , mixture of isomers) δ 0.88 (t, J = 7.2), 1.27 (s), 1.30 (s), 1.48-1.58 (m), 1.64-1.67 (m), 1.97-2.11 (m), 2.23-2.28 (m), 2.42-2.50 (m), 2.62-2.69 (m), 2.80 (s), 2.90 (s), 3.00-3.07 (m), 3.15-3.20 (m), 3.25-3.32 (m), 4.18 (q, J = 7.2), 4.42-4.46 (m), 4.53-4.56 (m), 4.61-4.66 (m), 4.72-4.82 (m), 5.94-5.00 (m), 5.63 (d, J = 15.6), 6.12 (d, J = 15.6), 6.60 (dd, J = 15.6, 5.4), 6.75-6.89 (m), 6.70-7.08 (m), 7.19-7.30 (m), 7.41-7.50 (m), 7.70-7.82 (m), 8.80 (d, J = 8.4); Anal. (C 56 H 59 FN 4 O 7 ) C, H, N. Preparation of Product Ethyl-3-{(5'-Methylisoxazole-3'-carbonyl)-L-(2-Naphth)-NCH 3 -L-(4-F-Phe)-L- Gln }-E-Propenoate Ethyl-3-{Boc-L-(2-Naphth)-NCH 3 -L-(4-F-Phe)-L-(Tr- Gln )}-E-propenoate was converted to product ethyl-3-{(5'-methylisoxazole-3'-carbonyl)-L-(2-Naphth)-NCH 3 -L-(4-F-Phe)-L- Gln }-E-propenoate in a manner analogous to that described in Example 2 above for the conversion of ethyl-3-{Boc-L-Leu-L-Phe-L-(Tr- Gln )}-E-propenoate to product ethyl-3-{(5'-methylisoxazole-3'-carbonyl)-L-Leu-L-Phe-L- Gln }-E-propenoate IR (cm -1 ) 3296, 1654, 1510; 1 H NMR (DMSO- d 6 , mixture of isomers) δ 1.17-1.24 (m), 1.62-1.78 (m), 2.04-2.15 (m), 2.38 (s), 2.42 (s), 2.71-2.79 (m), 2.84 (s), 2.87-2.92 (m), 3.03 (s), 3.15 (d, J = 7.5), 3.98-4.06 (m), 4.08-4.12 (m), 4.38-4.42 (m), 4.94 (m), 5.03-5.07 (m), 5.09-5.18 (m), 5.66-5.82 (m), 6.42 (s), 6.43 (s), 6.66-6.81 (m), 6.88-6.94 (m), 7.01-7.06 (m), 7.13-7.17 (m), 7.24-7.34 (m), 7.43-7.46 (m), 7.56 (s), 7.76-7.84 (m), 8.08 (d, J = 7.8), 8.60 (d, J = 8.4), 9.01 (d, J = 7.2); Anal. (C 37 H 40 FN 5 O 7• 0.75H 2 O) C, H, N. Example 14 - Preparation of Compound A-9: Ethyl-3-{(5'-Methylisoxazole-3'-carbonyl)-L-His-NCH 3 -L-(4-F-Phe)-L- Gln }-E-Propenoate Ethyl-3-{Boc-NCH 3 -L-(4-F-Phe)-L-(Tr- Gln )}-E-propenoate (described in Example 13 above) was converted to product ethyl-3-{(5'-methylisoxazole-3'-carbonyl)-L-His-NCH 3 -L-(4-F-Phe)-L- Gln }-E-propenoate in a manner analogous to the preparation of product ethyl-3-{(5'-methylisoxazole-3'-carbonyl)-L-(2-Naphth)-NCH 3 -L-(4-F-Phe)-L- Gln }-E-propenoate described in Example 13 above (utilizing Boc-L-(Tr-His)-OH in lieu of Boc-L-(2-Naphth)-OH): IR (cm -1 ) 3302, 1665, 1202; 1 H NMR (DMSO-d 6 , mixture of isomers) δ 1.21 (t, J = 7.2), 1.70-1.78 (m), 2.05-2.09 (m), 2.41 (s), 2.44 (s), 2.69-3.26 (m), 4.11 (q, J = 7.2), 4.38-4.53 (m), 5.07-5.19 (m), 6.51-5.84 (m), 6.44 (s), 6.48 (s), 6.63-6.86 (m), 6.89-7.01 (m), 7.09-7.19 (m), 7.23-7.42 (m), 8.02 (d, J = 8.7), 8.15 (d, J = 8.1), 8.59 (d, J = 8.7), 8.94 (s), 9.04 (s), 9.14 (d, J = 6.9); Anal. (C 30 H 36 FN 7 O 7 •TFA•H 2 O) C, H, N. Example 15 - Preparation of Compound A-12: Ethyl-3-{(5'-Methylisoxazole-3'-carbonyl)-L-Leu-NCH 3 -L-(4-F-Phe)-L- Gln }-E-Propenoate Ethyl-3-{Boc-NCH 3 -L-(4-F-Phe)-L-(Tr- Gln )}-E-propenoate (described in Example 13 above) was converted to product ethyl-3-{(5'-methylisoxazole-3'-carbonyl)-L-Leu-NCH 3 -L-(4-F-Phe)-L- Gln }-E-propenoate in a manner analogous to the preparation of product ethyl-3-{(5'-methylisoxazole-3'-carbonyl)-L-(2-Naphth)-NCH 3 -L-(4-F-Phe)-L- Gln }-E-propenoate described in Example 13 above (utilizing Boc-L-Leu-OH in lieu of Boc-L-(2-Naphth)-OH): IR (cm -1 ) 3325, 1663, 1171; 1 H NMR (DMSO- d 6 , mixture of isomers) δ 0.64-0.67 (m), 0.86-0.88 (m), 1.17-1.23 (m), 1.32-1.40 (m), 1.59-1.75 (m), 1.98-2.07 (m), 2.42 (s), 2.45 (s), 2.08 (s), 2.86-2.93 (m), 2.99 (s), 3.12-3.20 (m), 4.05-4.15 (m), 4.41-4.50 (m), 4.82-5.07 (m), 5.62 (d, J = 15.9), 5.86 (d, J = 15.9), 6.51 (s), 6.53 (s), 6.68-6.73 (m), 6.93-6.99 (m), 7.09-7.21 (m), 7.26-7.31 (m), 8.03 (d, J = 7.8), 8.08 (d, J = 7.8), 8.41 (d, J = 8.1), 8.94 (d, J = 7.2); Anal. (C 30 H 40 FN 5 O 7 •1.25CH 2 Cl 2 ) C, H, N. Example 16 - Preparation of Compound A-13: Ethyl-3-{(5'-Methylisoxazole-3'-carbonyl)-L-(1-Naphth)-NCH 3 -L-(4-F-Phe)-L- Gln }-E-Propenoate Ethyl-3-{Boc-NCH 3 -L-(4-F-Phe)-L-(Tr- Gln )}-E-propenoate (described in Example 13 above) was converted to product ethyl-3-{(5'-methylisoxazole-3'-carbonyl)-L-(1-Naphth)-NCH 3 -L-(4-F-Phe)-L- Gln }-E-propenoate in a manner analogous to the preparation of product ethyl-3-{(5'-methylisoxazole-3'-carbonyl)-L-(2-Naphth)-NCH 3 -L-(4-F-Phe)-L- Gln }-E-propenoate described in Example 13 above, but utilizing Boc-L-(1-Naphth)-OH in lieu of Boc-L-(2-Naphth)-OH: IR (cm -1 ) 3308, 1659, 1169; 1 H NMR (DMSO- d 6 , mixture of isomers) δ 1.16-1.23 (m), 1.61-1.78 (m), 1.98-2.02 (m), 2.07-2.12 (m), 2.41 (s), 2.43 (s), 2.77 (s), 2.78 (s), 2.84-2.87 (m), 2.93-3.03 (m), 3.08-3.14 (m), 3.31-3.38 (m), 4.00-4.15 (m), 4.27-4.32 (m), 4.40-4.46 (m), 4.58-4.64 (m), 5.07-5.17 (m), 5.57-5.73 (m), 6.45 (s), 6.57-6.61 (m), 6.71-6.88 (m), 6.89-6.91 (m), 7.11-7.19 (m), 7.31-7.38 (m), 7.50-7.58 (m), 7.73-7.78 (m), 7.83-7.94 (m), 8.08 (d, J = 8.1), 8.13 (d, J = 8.7), 8.62 (d, J = 8.1), 9.14 (d, J = 8.1); Anal. (C 37 H 40 FN 5 O 7 ) C, H, N. Examples 21 through 30 For Examples 21-30, the following Compounds (A-14) through (A-23) , respectively, were prepared using synthetic methods analogous to those described above for compounds of the formula I-A: Example 31 - Preparation of Comparison Compound #2: Ethyl-3-(Cbz-L-Leu-L-Phe-L - Gln )-E-Propenoate Preparation of Intermediate [Boc-L-(Tr-Gln)]-N(OMe)Me Isobutyl chloroformate (4.77 mL, 36.8 mmol, 1.0 equiv.) was added to a solution of N -α-Boc-γ-trityl-L-glutamine (18.7 g, 36.7 mmol, 1 equiv.) and 4-methylmorpholine (8.08 mL, 73.5 mmol, 2.0 equiv.) in CH 2 Cl 2 (250 mL) at 0°C. The reaction mixture was stirred at 0°C for 20 minutes, and then N,O -dimethylhydroxylamine hydrochloride (3.60 g, 36.7 mmol, 1.0 equiv.) was added. The resulting solution was stirred at 0°C for 20 minutes and at 23°C for 2 hours, and then was partitioned between water (150 mL) and CH 2 Cl 2 (2 x 150 mL). The combined organic layers were dried over Na 2 SO 4 and were concentrated. Purification of the residue by flash column chromatography (gradient elution 40→20% hexanes in EtOAc) provided {Boc-L-(Tr-Gln)}-N(OMe)Me (16.1 g, 82%) as a white foam: IR (cm -1 ) 3411, 3329, 3062, 1701, 1659; 1 H NMR (CDCl 3 ) δ 1.42 (s, 9H), 1.63-1.77 (m, 1H), 2.06-2.17 (m, 1H), 2.29-2.43 (m, 2H), 3.17 (s, 3H), 3.64 (s, 3H), 4.73 (s, br, 1H), 5.38-5.41 (m, 1H), 7.20-7.31 (m, 15H); Anal. (C 31 H 37 N 3 O 5 ) C, H, N. Preparation of Intermediate {Boc-L-(Tr-Gln)}-H Diisobutylaluminum hydride (50.5 mL of a 1.5 M solution in toluene, 75.8 mmol, 2.5 equiv.) was added to a solution of {Boc-L-(Tr-Gln)}-N(OMe)Me (16.1 g, 30.3 mmol, 1 equiv.) in THF at -78°C, and the reaction mixture was stirred at -78°C for 4 h. Methanol (4 mL) and 1.0 M HCl (10 mL) were added sequentially, and the mixture was warmed to 23°C. The resulting suspension was diluted with Et 2 O (150 mL) and was washed with 1.0 M HCl (3 x 100 mL), half-saturated NaHCO 3 (100 mL), and water (100 mL). The organic layer was dried over MgSO 4 , filtered, and was concentrated to give crude {Boc-L-(Tr-Gln)}-H (13.8 g, 97%) as a white solid: mp = 114-116°C; IR (cm -1 ) 3313, 1697, 1494; 1 H NMR (CDCl 3 ) δ 1.44 (s, 9H), 1.65-1.75 (m, 1H), 2.17-2.23 (m, 1H), 2.31-2.54 (m, 2H), 4.11 (s, br, 1H), 5.38-5.40 (m, 1H), 7.1 (s, 1H), 7.16-7.36 (m, 15H), 9.45 (s, 1H). Preparation of Intermediate Ethyl-3-{Boc-L-(Tr- Gln )}-E-Propenoate Sodium bis(trimethylsilyl)amide (22.9 mL of a 1.0 M solution in THF, 22.9 mmol, 1.0 equiv.) was added to a solution of triethyl phosphonoacetate (5.59 g, 22.9 mmol, 1.0 equiv.) in THF (200 mL) at -78°C, and the resulting solution was stirred for 20 minutes at that temperature. Crude {Boc-L-(Tr-Gln)}-H (10.8 g, 22.9 mmol, 1 equiv.) in THF (50 mL) was added via cannula, and the reaction mixture was stirred for 2 hours at -78°C, warmed to 0°C for 10 minutes, and partitioned between 0.5 M HCl (150 mL) and a 1:1 mixture of EtOAc and hexanes (2 x 150 mL). The combined organic layers were dried over Na 2 SO 4 and were concentrated. Purification of the residue by flash column chromatography (40% EtOAc in hexanes) provided ethyl-3-{Boc-L-(Tr- Gln )}-E-propenoate (10.9 g, 88%) as a white foam: IR (cm -1 ) 3321, 1710; 1 H NMR (CDCl 3 ) δ 1.27 (t, 3H, J = 7.2), 1.42 (s, 9H), 1.70-1.78 (m, 1H), 1.80-1.96 (m, 1H), 2.35 (t, 2H, J = 7.0), 4.18 (q, 2H, J = 7.2), 4.29 (s, br, 1H), 4.82-4.84 (m, 1H), 5.88 (dd, 1H, J = 15.7, 1.6), 6.79 (dd, 1H, J = 15.7, 5.3), 6.92 (s, 1H), 7.19-7.34 (m, 15H); Anal. (C 33 H 38 N 2 O 5 ) C, H, N. Preparation of Intermediate Ethyl-3-{Cbz-L-Leu-L-Phe-L-(Tr- Gln )}-E-Propenoate A solution of HCl in 1,4-dioxane (4.0 M, 20 mL), was added to a solution of ethyl-3-{Boc-L-(Tr- Gln )}-E-propenoate (1.00 g, 1.84 mmol, 1 equiv.) in the same solvent (20 mL) at 23°C. After 3 hours, the volatiles were removed under reduced pressure. The residue was dissolved in CH 2 Cl 2 (50 mL) and Cbz-L-Leu-L-Phe-OH (0.759 g, 1.84 mmol, 1.0 equiv.), HOBt (0.373 g, 2.76 mmol, 1.5 equiv.), 4-methylmorpholine (0.809 mL, 7.36 mmol, 4.0 equiv.), and EDC (0.529 g, 2.76 mmol, 1.5 equiv.) were added sequentially. The reaction mixture was stirred at 23°C for 18 hours, and then was partitioned between water (150 mL) and EtOAc (2 x 150 mL). The combined organic layers were dried over Na 2 SO 4 and were concentrated. Flash chromatographic purification of the residue (5% CH 3 OH in CH 2 Cl 2 ) afforded ethyl-3-{Cbz-L-Leu-L-Phe-L-(Tr- Gln )}-E-propenoate (1.25 g, 83%) as a white solid: mp = 192-194°C; IR (cm -1 ) 3295, 1696, 1678, 1655, 1519; 1 H NMR (CDCl 3 ) δ 0.84 (d, 3H, J = 6.5), 0.86 (d, 3H, J = 6.5), 1.24-1.32 (m, 1H), 1.28 (t, 3H, J = 7.2), 1.43-1.75 (m, 3H), 1.91-2.06 (m, 1H), 2.20-2.38 (m, 2H), 2.93-3.02 (m, 1H), 3.07-3.18 (m, 1H), 3.95-4.02 (m, 1H), 4.17 (q, 2H, J = 7.2), 4.43-4.55 (m, 2H), 4.82-4.95 (m, 2H), 5.69 (d, 1H, J = 15.7), 6.46 (d, 1H, J = 7.5), 6.60 (d, 1H, J = 8.1), 6.69 (dd, 1H, J = 15.7, 5.1), 7.09-7.38 (m, 27H); Anal. (C 51 H 56 N 4 O 7 ) C, H, N. Preparation of Product Ethyl-3-(Cbz-L-Leu-L-Phe-L- Gln )-E-Propenoate Trifluoroacetic acid (20 mL) was added to a solution of ethyl-3-{Cbz-L-Leu-L-Phe-L-(Tr- Gln )}-E-propenoate (1.25 g, 1.49 mmol, 1 equiv.) and triisopropylsilane (1.53 mL, 7.47 mmol, 5.0 equiv.) in CH 2 Cl 2 (20 mL) at 23°C, producing a bright yellow solution. The reaction mixture was stirred for 20 minutes at 23°C, during which time it became colorless. Carbon tetrachloride (20 mL) was added, and the volatiles were removed under reduced pressure. The residue was triturated with Et 2 O (20 mL), and the resulting white solid was collected by vacuum filtration, washed with Et 2 O (3 x 50 mL), and air-dried to afford ethyl-3-(Cbz-L-Leu-L-Phe-L- Gln )-E-propenoate (0.717 g, 81%): mp = 219-221°C; IR (cm -1 ) 3300, 1672, 1535; 1 H NMR (DMSO- d 6 ) δ 0.78 (d, 3H, J = 6.8), 0.82 (d, 3H, J = 6.5), 1.21 (t, 3H, J = 7.0), 1.25-1.37 (m, 2H), 1.42-1.54 (m, 1H), 1.58-1.80 (m, 2H), 2.02-2.09 (m, 2H), 2.84 (dd, 1H, J = 13.2, 8.9), 2.97 (dd, 1H, J = 13.2, 5.8), 3.93-4.01 (m, 1H), 4.11 (q, 2H, J = 7.0), 4.33-4.52 (m, 2H), 4.97 (d, 1H, J = 12.3), 5.04 (d, 1H, J = 12.3), 5.64 (d, 1H, J = 15.9), 6.69 (dd, 1H, J = 15.9, 5.4), 6.76 (s, 1H), 7.13-7.37 (m, 11H), 7.43 (d, 1H, J = 7.8), 7.99 (d, 1H, J = 8.1), 8.04 (d, 1H, J = 8.1); Anal. (C 32 H 42 N 4 O 7 ) C, H, N. Example 32 - Preparation of Comparison Compound #3: Ethyl-3-(Cbz-L-Val-L-Phe-L - Gln )-E-Propenoate Preparation of Intermediate Ethyl-3-{Boc-L-Phe-L-(Tr- Gln )}-E-Propenoate A solution of HCl in 1,4-dioxane (4.0 M, 10 mL) was added to a solution of ethyl-3-{Boc-L-(Tr- Gln )}-E-propenoate (prepared as described in Example 31, 3.05 g, 5.62 mmol, I equiv.) in the same solvent (20 mL) at 23°C. After 3 hours, the volatiles were removed under reduced pressure. The residue was dissolved in CH 2 Cl 2 (50 mL), and Boc-L-Phe-OH (1.49 g, 5.62 mmol, 1.0 equiv.), HOBt (0.911 g, 6.74 mmol, 1.2 equiv.), 4-methylmorpholine (1.85 mL, 16.8 mmol, 3.0 equiv.) and EDC (1.29 g, 6.73 mmol, 1.2 equiv.) were added sequentially. The reaction mixture was stirred at 23°C for 18 hours, and was then partitioned between water (150 mL) and EtOAc (2 x 150 mL). The combined organic layers were dried over Na 2 SO 4 and were concentrated. Flash chromatographic purification of the residue (gradient elution, 40→50% EtOAc in hexanes) afforded ethyl-3-{Boc-L-Phe-L-(Tr- Gln )}-E-propenoate (2.77 g, 71%) as a white foam: IR (cm -1 ) 3306, 1706, 1661; 1 H NMR (CDCl 3 ) δ 1.29 (t, 3H, J = 7.2), 1.38 (s, 9H), 1.65-1.76 (m, 1H); 1.87-1.99 (m, 1H), 2.25-2.27 (m, 2H), 2.94-3.01 (m, 2H), 4.14-4.26 (m, 3H), 4.48-4.53 (m, 1H), 4.95 (s, br, 1H), 5.64 (d, 1H, J = 15.8), 6.29 (d, 1H, J = 8.1), 6.64 (dd, 1H, J = 15.8, 5.4), 6.80 (s, br, 1H), 7.14-7.32 (m, 20H); Anal. (C 42 H 47 N 3 O 6 ) C, H, N. Preparation of Intermediate Ethyl-3-{Cbz-L-Val-L-Phe-L-(Tr- Gln )}-E-Propenoate A solution of HCl in 1,4-dioxane (4.0 M, 8 mL) was added to a solution of ethyl-3-{Boc-L-Phe-L-(Tr- Gln )}-E-propenoate (0.296 g, 0.429 mmol, 1 equiv.) in the same solvent (10 mL) at 23°C. After 3 hours, the volatiles were removed under reduced pressure. The residue was dissolved in CH 2 Cl 2 (10 mL), and then Cbz-L-Val-OH (0.108 g, 0.430 mmol, 1.0 equiv.), HOBt (0.070 g, 0.518 mmol, 1.2 equiv.), 4-methylmorpholine (0.142 mL, 1.29 mmol, 3.0 equiv.) and EDC (0.099 g, 0.516 mmol, 1.2 equiv.) were added sequentially. The reaction mixture was stirred at 23°C for 4 hours, and then was partitioned between water (100 mL) and EtOAc (2 x 100 mL). The combined organic layers were dried over Na 2 SO 4 and were concentrated. Flash chromatographic purification of the residue (3% CH 3 OH in CH 2 Cl 2 ) afforded ethyl-3-{Cbz-L-Val-L-Phe-L-(Tr- Gln )}-E-propenoate (0.220 g, 62%) as a white solid: mp = 195-198°C; IR (cm -1 ) 3284, 1689, 1646; 1 H NMR (CDCl 3 ) δ 0.69 (d, 3H, J = 6.9), 0.82 (d, 3H, J = 6.5), 1.28 (t, 3H, J = 7.2), 1.63-1.74 (m, 1H), 1.96-2.02 (m, 2H), 2.22-2.35 (m, 2H), 2.93 (dd, 1H, J = 14.0, 7.6), 3.10 (dd, 1H, J = 14.0, 6.7), 3.81-3.85 (m, 1H), 4.17 (q, 2H, J = 7.2), 4.48-4.58 (m, 2H), 4.87 (d, 1H, J = 12.0), 4.94 (d; 1H, J = 12.0), 5.06 (d, 1H, J = 6.9), 5.67 (d, 1H, J = 15.6), 6.43 (d, 1H, J = 7.5), 6.63-6.72 (m, 2H), 7.10-7.40 (m, 26H); Anal. (C 50 H 54 N 4 O 7 ) C, H, N. Preparation of Product Ethyl-3-(Cbz-L-Val-L-Phe-L- Gln )-E-Propenoate Trifluoroacetic acid (5 mL) was added to a solution of ethyl-3-{Cbz-L-Val-L-Phe-L-(Tr- Gln )}-E-propenoate (0.188 g, 0.229 mmol, 1 equiv.) and triisopropylsilane (0.300 mL, 1.46 mmol, 6.4 equiv.) in CH 2 Cl 2 (10 mL) at 23°C, producing a bright yellow solution. The reaction mixture was stirred for 20 min. at 23°C, during which time it became colorless. Carbon tetrachloride (10 mL) was added, and the volatiles were removed under reduced pressure. The residue was triturated with Et 2 O (20 mL), and the resulting white solid was collected by vacuum filtration, washed with Et 2 O (3 x 50 mL), and air-dried to afford ethyl-3-(Cbz-L-Val-L-Phe-L- Gln )-E-propenoate (0.094 g, 71%): mp = 240°C (dec); IR (cm -1 ) 3263, 1686, 1640; 1 H NMR (DMSO- d 6 ) δ 0.73 (d, 6H, J = 6.9), 1.21 (t, 3H, J = 7.2), 1.60-1.75 (m, 2H), 1.83-1.90 (m, 1H), 2.03-2.08 (m, 2H), 2.83 (dd, 1H, J = 13.6, 8.6), 2.96 (dd, 1H, J = 13.6, 6.2), 3.79-3.84 (m, 1H), 4.10 (q, 2H, J = 7.2), 4.37-4.49 (m, 1H), 4.51-4.56 (m, 1H), 4.99 (d, 1H, J = 12.5), 5.06 (d, 1H, J = 12.5), 5.61 (d, 1H, J = 15.5), 6.67 (dd, 1H, J = 15.5, 5.5), 6.76 (s, 1H), 7.13-7.36 (m, 12H), 8.06 (d, 2H, J = 8.1); Anal. (C 31 H 40 N 4 O 7 ) C, H, N. Results of biochemical and biological tests conducted using various compounds of the invention are described below. BIOCHEMICAL AND BIOLOGICAL EVALUATION Inhibition of Rhinovirus 3C Protease Stock solutions (50 mM, in DMSO) of various compounds were prepared; dilutions were in the same solvent. Recombinant rhinovirus 3C proteases (see Birch et al., "Purification of recombinant human rhinovirus 14 3C protease expressed in Escherichia coli," Protein Expr. Pur . 1995, 6(5), 609-618) from serotypes 14, 16, and 2 were prepared by the following standard chromatographic procedures: (1) ion exchange using Q Sepharose Fast Flow from Pharmacia; (2) affinity chromatography using Affi-Gel Blue from Biorad; and (3) sizing using Sephadex G-100 from Pharmacia. Each assay sample contained 2% DMSO, 50 mM tris pH 7.6, 1 mM EDTA, a test compound at the indicated concentration, approximately 1µM substrate, and 50-100 nM protease. The k obs/I values were obtained from reactions initiated by addition of enzyme rather than substrate. RVP. activity was measured in the fluorescence resonance energy transfer assay. The substrate was (N-terminal) DABCYL-(Gly-Arg-Ala-Val-Phe-Gln-Gly-Pro-Val-Gly)-EDANS. In the uncleaved peptide, the EDANS fluorescence was quenched by the proximal DABCYL moiety. When the peptide was cleaved, the quenching was relieved, and activity was measured as an increase in fluorescence signal. Data were analyzed using standard non-linear fitting programs (Enzfit), and are shown in Tables 1 and 2 below. In Table 1, all data are for rhinovirus 3C protease from HRV serotype-14 (produced from the infectious cDNA clone constructed by Dr. Robert Rueckert, Institute for Molecular Virology, University of Wisconsin, Madison, Wisconsin). Table 2 shows protease-inhibiting activity of compounds against proteases from several rhinovirus of serotype other than RVP serotype-14. The data in the column designated k obs /[I] were measured from progress curves in enzyme start experiments. Antirbinoviral H1-HeLa Cell Culture Assay In this cell protection assay, the ability of compounds to protect cells against HRV infection was measured by the XTT dye reduction method, which is described in Weislow et al., J. Natl. Cancer Inst . 1989, vol. 81, 577-586. H1-HeLa cells were infected with HRV-14 at a multiplicity of infection (m.o.i.) of 0.13 (virus particles/cell) or mock-infected with medium only. Infected or mock-infected cells were resuspended at 8 x 10 5 cells per mL, and incubated with appropriate concentrations of the compounds to be tested. Two days later, XTT/PMS was added to test plates and the amount of formazan produced was quantified spectrophotometrically at 450/650 nm. The EC 50 value was calculated as the concentration of compound that increased the percentage of formazan production in compound-treated, virus-infected cells to 50% of that produced by compound-free, mock-infected cells. The 50% cytotoxic dose (CC 50 ) was calculated as the concentration of compound that decreased the percentage of formazan produced in compound-treated, mock-infected cells to 50% of that produced by compound-free, mock-infected cells. The therapeutic index (TI) was calculated by dividing the CC 50 value by the EC 50 value. All strains of human rhinovirus (HRV) for use in this assay were purchased from American Type Culture Collection (ATCC), except for HRV serotype-14 (produced from the infectious cDNA clone constructed by Dr. Robert Rueckert, Institute for Molecular Virology, University of Wisconsin, Madison, Wisconsin). HRV stocks were propagated and viral assays were performed in H1-HeLa cells (ATCC). Cells were grown in minimal essential medium with 10% fetal bovine serum, available from Life Technologies (Gaithersburg, MD). The compounds were tested against control compounds WIN 51711, WIN 52084, and WIN 54954 (obtained from Sterling-Winthrop Pharmaceuticals), Pirodavir (obtained from Janssen Pharmaceuticals), and Pleconaril (prepared according to the method described in Diana et al., J. Med. Chem 1995 , vol. 38, 1355). Antiviral data obtained for the test compounds are shown in Tables I and 3, where all data are for HRV serotype-14 unless otherwise noted in parentheses. The designation "ND" indicates that a value was not determined for that compound.

Claims: A compound of the formula I: wherein: Y is -N(R y )-, -C(R y )(R y )-, or -O-, where each R y is independently H or C 1 -C 4 alkyl; R 1 is H, F, an alkyl group, OH, SH, or an O-alkyl group; R 2 and R 3 are each independently H; where n is an integer from 0 to 5, A 1 is CH or N, A 2 and each A 3 are independently selected from C(R 41 )(R 41 ), N(R 41 ), S, S(O), S(O) 2 , and O, and A 4 is NH or NR 41 , where each R 41 is independently H or C 1 -C 4 alkyl, provided that no more than 2 heteroatoms occur consecutively in the ring formed by A 1 , A 2 , (A 3 ) n , A 4 and C=O; and provided that at least one of R 2 and R 3 is R 5 and R 6 are each independently H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group; R 7 and R 8 are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, -OR 17 , -SR 17 , -NR 17 R 18 , -NR 19 NR 17 R 18 , or -NR 17 OR 18 , where R 17 , R 18 , and R 19 are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or an acyl group; R 9 is a five-membered heterocycle having from one to three heteroatoms selected from O, N, and S; and Z and Z 1 are each independently H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, -C(O)R 21 , -CO 2 R 21 , -CN, -C(O)NR 21 ,R 22 , -C(O)NR 21 OR 22 , -C(S)R 21 , -C(S)NR 21 R 22 , -NO 2 , -SOR 21 , -SO 2 R 21 , -SO 2 NR 21 R 22 , -SO(NR 21 )(OR 22 ), -SONR 21 , -SO 3 R 21 , -PO(OR 21 ) 2 , -PO(R 21 )(R 22 ), -PO(NR 21 R 22 )(OR 23 ), PO(NR 21 R 22 )(NR 23 R 24 ), -C(O)NR 21 NR 22 R 23 , or -C(S)NR 21 NR 22 R 23 , where R 21 , R 22 , R 23 , and R 24 are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an acyl group, or a thioacyl group, or any two of R 21 , R 22 , R 23 , and R 24 , together with the atom(s) to which they are bonded, form a heterocycloalkyl group, provided that Z and Z 1 are not both H; or Z 1 and R 1 , together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group; or Z and Z 1 , together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group; or a pharmaceutically acceptable salt, or solvate thereof, under the proviso that the following compounds are excluded: wherein R 3 , Z, Z 1 , R 41 and R 44 are as follows: R 3 is CH 2 (p-F)Ph, Z is H, Z 1 is CO 2 CH 2 CH 3 , R 41 is CH(CH 3 ) 2 , and R 44 is R 3 is CH 2 ( p -F)Ph, Z is H, Z 1 is R 41 is CH(CH 3 ) 2 , and R 44 is R 3 is CH 2 ( p -F)Ph, Z is H, Z 1 is CO 2 CH 2 CH 3 , R 41 is CH(CH 3 ) 2 , and R 44 is and wherein R 4 is: A compound, pharmaceutically acceptable salt, or solvate according to claim 1, wherein R 2 and R 3 are each independently H; where n is an integer from 0 to 5, each R 41 is independently H or lower alkyl, and the stereochemistry at the carbon denoted with an asterisk (*) may be R or S; provided that at least one of R 2 and R 3 is A compound, pharmaceutically acceptable salt, or solvate according to claim 1, wherein Y is -N(R y )-, where R y is H or C 1 -C 4 alkyl. A compound, pharmaceutically acceptable salt, or solvate according to claim 3, wherein: Z and Z 1 are each independently selected from H, F, C 1 -C 4 alkyl, -CO 2 R 21 , and -C(O)NR 21 R 22 , where R 21 and R 22 are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an acyl group, or a thioacyl group, or R 21 and R 22 , together with the atom(s) to which they are bonded, form a heterocycloalkyl group, provided that Z and Z 1 are not both H; or Z 1 and R 1 , together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group; or Z and Z 1 , together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group. A compound, pharmaceutically acceptable salt, or solvate according to claim 3, wherein R 1 is H, F, or methyl. A compound, pharmaceutically acceptable salt, or solvate according to claim 3, wherein at least one of R 2 or R 3 is A compound, pharmaceutically acceptable salt, or solvate according to claim 6, wherein one of R 5 and R 6 is H and the other is alkyl or aryl. A compound, pharmaceutically acceptable salt, or solvate according to claim 3, wherein one of R 5 and R 6 is H and the other is alkyl or aryl. A compound, pharmaceutically acceptable salt, or solvate according to claim 3, wherein one of R 5 and R 6 is H and the other is unsubstituted or substituted phenylmethyl. A compound, pharmaceutically acceptable salt, or solvate according to claim 3, wherein R 7 and R 8 are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group. A compound, pharmaceutically acceptable salt, or solvate according to claim 3, wherein one of R 7 and R 8 is H and the other is alkyl or aryl. A compound, pharmaceutically acceptable salt, or solvate according to claim 3, wherein one of R 7 and R 8 is H and the other is 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, phenylmethyl, or naphthylmethyl. A compound, pharmaceutically acceptable salt, or solvate according to claim 3, wherein R 9 is a five-membered heterocycle having at least one nitrogen heteroatom and one oxygen heteroatom. A compound, pharmaceutically acceptable salt, or solvate according to claim 3, wherein R 9 is selected from substituted and unsubstituted 1,2-oxazolyl, 1,3-oxazolyl, and 1,2,4-oxadiazolyl.. A compound, pharmaceutically acceptable salt, or solvate according to claim 3, wherein R 9 is 3-isoxazolyl or 5-isoxazolyl unsubstituted or substituted with one or two substituents selected from methyl and halogens. A compound according to claim 3 of the formula I-A": wherein R 1 , R 2 , R 6 , R 7 , R 9 , R y , Z, and Z 1 are as defined in claim 3, or a pharmaceutically acceptable salt, or solvate thereof. A compound, pharmaceutically acceptable salt, or solvate according to claim 16, wherein R 2 is A compound, pharmaceutically acceptable salt, or solvate according to claim 16, wherein: R y is H or methyl; R 1 is H, F, or methyl; Z and Z 1 are each independently selected from H, F, -CO 2 R 21 , -CN, and -C(O)NR 21 ,R 22 , where R 21 and R 22 are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an acyl group, or a thioacyl group, or R 21 and R 22 , together with the atom(s) to which they are bonded, form a heterocycloalkyl group, provided that Z and Z 1 are not both H; or Z 1 and R 1 , together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group; or Z 1 and R 1 , together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group; or Z and Z 1 , together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group; R 2 is R 6 is unsubstituted or substituted phenylmethyl; R 7 is alkyl or aryl; and R 9 is 3-isoxazolyl or 5-isoxazolyl unsubstituted or substituted with one or two substituents selected from methyl and halogens. A compound, pharmaceutically acceptable salt, or solvate according to claim 18, wherein R 7 is selected from 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, phenylmethyl, and naphthylmethyl. A compound, pharmaceutically acceptable salt, or solvate according to claim 16, wherein R y , R 1 , and Z are each H, and: R 2 is CH 2 CH 2 C(O)NH 2 , R 6 is CH 2 Ph, R 7 is CH 2 CH(CH 3 ) 2 , Z 1 is CO 2 CH 2 CH 3 , and R 9 is R 2 is CH 2 CH 2 C(O)NH 2 , R 6 is CH 2 Ph, R 7 is CH 2 CH(CH 3 ) 2 , Z 1 is CO 2 CH 2 CH 3 , and R 9 is R 2 is CH 2 CH 2 C(O)NH 2 , R 6 is R 7 is C(CH 3 ) 3 , Z 1 is CO 2 CH 2 CH 3 , and R 9 is R 2 is CH 2 CH 2 C(O)NH 2 , R 6 is R 7 is C(CH 3 ) 3 , Z 1 is CO 2 CH 2 CH 3 and R 9 is R 2 is CH 2 CH 2 C(O)NH 2 , R 6 is R 7 is CH(CH 3 ) 2 , Z 1 is CO 2 CH 2 CH 3 , and R 9 is A compound, pharmaceutically acceptable salt, or solvate according to claim 16, wherein R y is CH 3 , R 1 and Z are each H, and: R 2 is CH 2 CH 2 C(O)NH 2 , R 6 is R 7 is Z 1 is CO 2 CH 2 CH 3 , and R 9 is R 2 is CH 2 CH 2 C(O)NH 2 , R 6 is CH 2 Ph, R 7 is CH 2 CH(CH 3 ) 2 , and R 9 is R 2 is CH 2 CH 2 C(O)NH 2 , R 6 is R 7 is and R 9 is R 2 is CH 2 CH 2 C(O)NH 2 , R 6 is R 7 is CH 2 CH(CH 3 ) 2 , and R 9 is or R 2 is CH 2 CH 2 C(O)NH 2 , R 6 is R 7 is and R 9 is A compound, pharmaceutically acceptable salt, or solvate according to claim 16 selected from the group consisting of: A compound, pharmaceutically acceptable salt, or solvate according to claim 1, wherein Y is -CH 2 -. A compound, pharmaceutically acceptable salt, or solvate according to claim 23, wherein Z and Z 1 are each independently selected from H, F, C 1 -C 4 alkyl, -CO 2 R 21 , and -C(O)NR 21 ,R 22 , where R 21 and R 22 are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an acyl group, or a thioacyl group, or R 21 and R 22 , together with the atom(s) to which they are bonded, form a heterocycloalkyl group, provided that Z and Z 1 are not both H; or Z 1 and R 1 , together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group; or Z and Z 1 , together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group. A compound, pharmaceutically acceptable salt, or solvate according to claim 23, wherein R 1 is H, F, or methyl. A compound, pharmaceutically acceptable salt, or solvate according to claim 23, wherein at least one of R 2 and R 3 is A compound, pharmaceutically acceptable salt, or solvate according to claim 26, wherein one of R 3 and R 6 is H and the other is alkyl or aryl. A compound, pharmaceutically acceptable salt, or solvate according to claim 23, wherein one of R 5 and R 6 is H and the other is alkyl or aryl. A compound, pharmaceutically acceptable salt, or solvate according to claim 23, wherein one of R 5 and R 6 is H and the other is unsubstituted or substituted phenylmethyl. A compound, pharmaceutically acceptable salt, or solvate according to claim 23, wherein R 7 and R 8 are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group. A compound, pharmaceutically acceptable salt, or solvate according to claim 23, wherein one of R 7 and R 8 is H and the other is alkyl or aryl. A compound, pharmaceutically acceptable salt, or solvate according to claim 23, wherein one of R 7 and R 8 is H and the other is 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, phenylmethyl, or naphthylmethyl. A compound, pharmaceutically acceptable salt, or solvate according to claim 23, wherein R 9 is a five-membered heterocycle having at least one nitrogen heteroatom and one oxygen heteroatom. A compound, pharmaceutically acceptable salt, or solvate according to claim 33, wherein R 9 is unsubstituted or substituted 1,2-oxazolyl, 1,3-oxazolyl, or 1,2,4-oxadiazolyl. A compound, pharmaceutically acceptable salt, or solvate according to claim 34, wherein R 9 is 3-isoxazolyl or 5-isoxazolyl unsubstituted or substituted with one or two substituents selected from methyl and halogens. A compound according to claim 23 of the formula I-B": wherein R 1 , R 2 , R 6 , R 7 , R 9 , Z, and Z 1 are as defined in claim 23, or a pharmaceutically acceptable salt, or solvate thereof. A compound, pharmaceutically acceptable salt, or solvate according to claim 36, wherein R 2 is A compound, pharmaceutically acceptable salt, or solvate according to claim 36, wherein: R 1 is H, F, or methyl; Z and Z 1 are each independently selected from H, F, -CO 2 R 21 , -CN, and -C(O)NR 21, R 22 , where R 21 and R 22 are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an acyl group, or a thioacyl group, or R 21 and R 22 , together with the atom(s) to which they are bonded, form a heterocycloalkyl group, provided that Z and Z 1 are not both H; or Z 1 and R 1 , together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group; or Z and Z 1 , together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group; R 2 is R 6 is unsubstituted or substituted phenylmethyl; R 7 is alkyl or aryl; and R 9 is 3-isoxazolyl or 5-isoxazolyl unsubstituted or substituted with one or two substituents selected from methyl and halogens. A compound, pharmaceutically acceptable salt, or solvate according to claim 38, wherein R 7 is selected from 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, phenylmethyl, and naphthylmethyl. A compound, pharmaceutically acceptable salt, or solvate according to claim 36, wherein R 1 is H and: R 2 is CH 2 CH 2 C(O)NH 2 , R 6 is R 7 is CH(CH 3 ) 2 , Z is H, Z 1 is CO 2 CH 2 CH 3 , and R 9 is A compound, pharmaceutically acceptable salt, or solvate according to claim 1, wherein Y is -O-. A compound, pharmaceutically acceptable salt, or solvate according to claim 41, wherein Z and Z 1 are each independently selected from H, F, C 1 -C 4 alkyl, -CO 2 R 21 , and -C(O)NR 21 ,R 22 , where R 21 and R 22 are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an acyl group, or a thioacyl group, or R 21 and R 22 , together with the atom(s) to which they are bonded, form a heterocycloalkyl group, provided that Z and Z 1 are not both H; or Z 1 and R 1 , together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group; or Z and Z 1 , together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group. A compound, pharmaceutically acceptable salt, or solvate according to claim 41, wherein R 1 is H, F, or methyl. A compound, pharmaceutically acceptable salt, or solvate according to claim 41, wherein at least one of R 2 and R 3 is A compound, pharmaceutically acceptable salt, or solvate according to claim 44, wherein one of R 5 and R 6 is H and the other is alkyl or aryl. A compound, pharmaceutically acceptable salt, or solvate according to claim 41, wherein one of R 5 and R 6 is H and the other is alkyl or aryl. A compound, pharmaceutically acceptable salt, or solvate according to claim 41, wherein one of R 5 and R 6 is H and the other is unsubstituted or substituted phenylmethyl. A compound, pharmaceutically acceptable salt, or solvate according to claim 41, wherein R 7 and R 8 are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group. A compound, pharmaceutically acceptable salt, or solvate according to claim 41, wherein one of R 7 and R 8 is H and the other is alkyl or aryl. A compound, pharmaceutically acceptable salt, or solvate according to claim 42, wherein one of R 7 and R 8 is H and the other is 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, phenylmethyl, or naphthylmethyl. A compound, pharmaceutically acceptable salt, or solvate according to claim 41, wherein R 9 is a five-membered heterocycle having at least one nitrogen heteroatom and one oxygen heteroatom. A compound, pharmaceutically acceptable salt, or solvate according to claim 41, wherein R 9 is selected from substituted and unsubstituted 1,2-oxazolyl, 1,3-oxazolyl, and 1,2,4-oxadiazolyl. A compound, pharmaceutically acceptable salt, or solvate according to claim 41, wherein R 9 is 3-isoxazolyl or 5-isoxazolyl unsubstituted or substituted with one or two substituents selected from methyl and halogens. A compound according to claim 41, of the formula I-C": wherein R 1 , R 2 , R 6 , R 7 , R 9 , Z, and Z 1 are as defined in claim 42, or a pharmaceutically acceptable salt, or solvate thereof A compound, pharmaceutically acceptable salt, or solvate according to claim 54, wherein R 2 is A compound, pharmaceutically acceptable salt, or solvate according to claim 54, wherein: R 1 is H, F, or methyl; Z and Z 1 are each independently selected from H, F, -CO 2 R 21 , -CN, and -C(O)NR 21 ,R 22 , where R 21 and R 22 are each independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an acyl group, or a thloacyl group, or R 21 and R 22 , together with the atom(s) to which they are bonded, form a heterocycloalkyl group, provided that Z and Z 1 are not both H; or Z 1 and R 1 , together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, or Z and Z 1 , together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group; R 2 is R 6 is unsubstituted or substituted phenylmethyl; R 7 is alkyl or aryl; and R 9 is 3-isoxazolyl or 5-isoxazolyl unsubstituted or substituted with one or two substituents selected from methyl and halogens. A compound, pharmaceutically acceptable salt, or solvate according to claim 56, wherein R 7 is selected from 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, phenylmethyl, and naphthylmethyl. A compound, pharmaceutically acceptable salt, or solvate according to claim 54, wherein R 1 is H, Z is H, and R 2 is CH 2 CH 2 C(O)NH 2 , R 6 is R 7 is CH(CH 3 ) 2 , Z 1 is CO 2 CH 2 CH 3 , and R 9 is A compound, pharmaceutically acceptable salt, or solvate according to claims 1 or 58, having an antipicornaviral activity corresponding to an EC 50 less than or equal to 100 µM in an H1-HeLa cell culture assay. A compound, pharmaceutically acceptable salt, or solvate according to claims 1 or 58, having an antirhinoviral activity corresponding to an EC 50 less than or equal to 10 µM in an H1-HeLa cell culture assay. A pharmaceutical composition comprising: (a) a therapeutically effective amount of at least one antipicornaviral agent that is a compound, pharmaceutically acceptable salt, of solvate as defined in any of claims 1 to 60; and (b) a pharmaceutically acceptable carrier, diluent, vehicle, or excipient. Use of a compound, pharmaceutically acceptable salt, or solvate as defined in any of claims 1 to 60 for the preparation of a medicament for the treatment of a mammalian disease condition mediated by picornaviral protease activity. The use according to claim 62 for inhibiting the activity of a picornaviral 3C protease. The use according to claim 63, wherein the picornaviral 3C protease is a rhinoviral protease.

Inventors: DRAGOVICH PETER S, JOHNSON THEODORE O JR, MARAKOVITS JOSEPH T, PRINS THOMAS J, TIKHE JAYASHREE GIRISH, WEBBER STEPHEN E, ZHOU RU, DRAGOVICH, PETER S., JOHNSON, THEODORE O.,JR., MARAKOVITS, JOSEPH T., PRINS, THOMAS J., TIKHE, JAYASHREE GIRISH, WEBBER, STEPHEN E., ZHOU, RU
Applicants: AGOURON PHARMA, AGOURON PHARMACEUTICALS, INC.
Application year: 1999
Main classification: C07K5
IPC codes: A61P31, C07K5, C07D261, A61K31, A61K38, C07D413, C07D207