WO2001019783A1 - Synthesis of [3,5,7]-1h-imidazo[1,5-a]imidazol-2(3h)-one compounds - Google Patents

Abstract

Individual substituted [3,5,7]-1H-imidazo[1,5-a]imidazol-2(3H)-one compounds and their pharmaceutically-acceptable salts are disclosed, as are libraries of such compounds. Methods of preparing and using the libraries of compounds as well as individual compounds of the libraries are also disclosed.

Description

Synthesis of [3 , 5 , 7] -IH-imidazo [1 , 5-a] ιmιdazol-2 (3H) -one Compounds

Description

Technical Field

The present invention relates generally to the combinatorial synthesis of [3,5,7] -1H- lmidazo [1 , 5-a] ιmιdazol-2 (3H) -one derivatives. More specifically, the invention provides novel [3,5,7]- lH-imidazo [1 , 5-a] ιmιdazol-2 (3H) -one compounds as well as novel combinatorial libraries comprised of many such compounds, and methods of synthesizing the libraries .

Background Information

The process of discovering new therapeutically active compounds for a given indication involves the screening of all compounds from available compound collections. From the compounds tested one or more structure (s) is selected as a promising lead. A large number of related analogs are then synthesized to develop a structure- activity relation-ship and select one or more optimal compounds. With traditional one-at-a-time synthesis and biological testing of analogs, this optimization process is long and labor intensive.

Adding significant numbers of new structures to the compound collections used m the initial screening step of the discovery and optimization process cannot be accomplished with traditional one-at-a-time synthesis methods, except over a time frame of months or even years. Faster methods are needed that permit the preparation of up to thousands of related compounds m a matter of days or a few weeks. This need is particularly evident when it comes to synthesizing more complex compounds, such as the [3 , 5 , 7] -IH-imidazo [1 , 5-a] ιmιdazol-2 (3H) - one compounds of the present invention.

Solid-phase techniques for the synthesis of peptides have been extensively developed and combinatorial libraries of peptides have been prepared with great success . During the past four years there has been substantial development of chemically synthesized combinatorial libraries (SCLs) made up of peptides.

The preparation and use of synthetic peptide combinatorial libraries has been described for example by Dooley m U.S. Patent No. 5367.053; Huebner m U.S. Patent No. 5.182366; Appel et al m WO PCt 92/09300; Geysen m published European Patent Application 0 138 855 and Pimmg m U.S. Patent No. 5.143.854. Such SCLs provide the efficient synthesis of an extraordinary number of various peptides m such libraries and the rapid screening of the library that identifies lead pharmaceutical peptides.

Peptides have been, and remain, attractive targets for drug discovery. Their high affinities and specificities toward biological receptors as well as the ease with which large peptide libraries can be combmatorially synthesized make them attractive drug targets. The screening of peptide libraries has led to the identification of many biologically-active lead compounds. However, the therapeutic application of peptides is limited by their poor stability and bioavailability in vivo . Therefore, there is a need to synthesize and screen compounds that can maintain high affinity and specificity toward biological receptors, while exhibiting improved pharmacological properties relative to peptides.

Combinatorial approaches have recently been extended to "organic" or non-peptide libraries.

Significantly, many biologically active compounds contain the imidazole moiety. Such compounds are conformationally constrained scaffolds, are quite common in nature and many imidazole- containing natural products have been isolated encompassing a wide range of biological activities. The imidazole ring system is of particular importance because it is present in the essential amino acid histidine. The histidine residues are found at the active site of ribonuclease and several other enzymes. Drugs such as cimetidine were designed with histamine itself as the starting point [C.R. Ganellin, in Medicinal Chemistry, ed.S.M. Roberts and B.J. Price, Academic Press, London, 1985, p.93; G.J. Durant, Chem Soc . Rev. , 1985, 84, 375].

Several other classes of drugs are based on the imidazole ring. 2-Nitroimidazole (azomycin) is a naturally occurring antibiotic and some synthetic nitroimidazoles are active against intestinal infections (Reviews: Nitroimidazoles; Chemistry; Pharmacology and Clinical Applications, eds . A. Breccia, B. Cavalleri, and G. E. Adams, Plenum Press, New York, 1982; J. H. Boyer, Nitrazoles, VCH, Deerfield Beach, Florida, 1986) . Imidazole-containing moieties are found in many biologically active compounds and are known to have useful therapeutic implications. There is a need to further study and develop large numbers of [3,5,7] -IH-imidazo [1, 5-a] ιmιdazol-2 (3H) -one compounds and their binding to biological receptors. These compounds of the present invention are principally derived from the synthesis of dipeptides, but the dipeptides are substantially modified. In short, they are chemically modified through, acylation and cyclization via Bischler-Naprielski reaction into the subject [3,5,7] -IH-imidazo [1 , 5-a] ιmιdazol-2 (3H) -one, thus providing mixtures and individual compounds of substantial diversity.

Brief Summary of the Invention

The invention provides a rapid approach for combinatorial synthesis and screening of individual compounds and libraries of [3 , 5 , 7] -IH-imidazo [1 , 5- a] ιmιdazol-2 (3H) -one compounds. The present invention further provides libraries and individual compounds and their pharmaceutically-acceptable salts of Formula I. The present invention also relates to the preparation of synthetic combinatorial libraries of organic compounds and their pharmaceutically- acceptable salts of Formula I, wherein R¹ , R² and R³ have the meanings provided below.

The present invention has several benefits and advantages. One benefit is the provision of a new synthesis for bicyclic [3 , 5 , 7] -IH-imidazo [1 , 5- a] ιmιdazol-2 (3H) -one compounds. The present invention provides a large array of diverse [3,5,7]- lH-imidazo [1 , 5-a] imidazol-2 (3H) -one compounds that can be screened for biological activity, and as described below, are biologically active. An advantage of the invention is that individual compounds can be prepared or libraries containing a plurality of compounds can be prepared.

Another benefit of the invention is that the yield of bicyclic compound produced is relatively great compared to that obtained in prior syntheses of the parental compound.

Still further benefits and advantages of the invention will be apparent to the skilled worker from the discussion that follows.

Detailed Description of the Invention

The present invention relates to the preparation and use of synthetic combinatorial libraries and individual compounds of a [3,5,7] -1H- imidazo [1 , 5-a] imidazol-2 (3H) -one also referred to as a imidazo-imidizol-one that correspond in structure to Formula I, and their pharmaceutically-acceptable salts :

wherein :

R¹ and R² are independently selected from the group consisting of a hydrogen atom (hydrido) , C₁-C₁₀ alkyl, C₁-C₁₀ substituted alkyl, C7-C₁₆ phenylalkyl, C₇-C]_g substituted phenylalkyl, phenyl, substituted phenyl, C3-C7 cycloalkyl, and a C3-C7 substituted cycloalkyl group.

R3 is selected from the group consisting of a hydrido, C]_-C]_Q alkyl, C]_-C]_Q substituted alkyl, ^c2"^c10 alkenyl, C2-C]_o substituted alkenyl, C2-C10 alkynyl, C2-C10 substituted alkynyl, C3-C₇ substituted cycloalkyl, phenyl, C₇-Cη_g phenylalkyl, ^c7"^c ₁6 phenylalkenyl, C- -C^ζ phenylalkenyl and a C₇- C_]_g substituted phenylalkenyl group.

In one embodiment of the above bicyclic imidazo-imidizol-one of Formula I, wherein

R¹ and R² are independently selected from the group consisting of a hydrido, methyl, benzyl, 2- butyl, N,N-dimethylaminobutyl, N-methylaminobutyl, N- methyl -N-benzylaminobutyl , 2 -methylpropyl , methylsulfinylethyl , methylthioethyl , N,N- dimethylaminoethyl , N,N-dimethylaminopropyl , N ,N ,N - trimethylguanidinopropyl , N ,N ,N -tribenzyl- guanidinopropyl, N ,N -dibenzylguanidinopropyl, N - methylguanidinopropyl , hydroxy ethyl , 1 -hydroxyethyl , 2 -propyl, N-methyl-3 -indolylmethyl , 4-methoxybenzyl , 4-hydroxybenzyl , propyl, butyl, cyclohexylmethyl , phenyl, 2-naphthylmethyl , and a 4-imidazolylmethyl substituent; and

R3 is selected from the group consisting of a 1 -phenyl - 1 -cyclopropyl , 1-phenylbutyl , 2- phenylbutyl , 3 -fluorobenzyl , 3-bromobenzyl , ,α,α- trifluoro-m-xylyl , p-xylyl, 4-fluorobenzyl , 3- methoxybenzyl , 4 -bromobenzyl , 4-methoxybenzyl, 4- ethoxybenzyl , 4 -isobutyl -α-methyl -benzyl , 3,4- dichlorobenzyl , 3 , 5-bis- (trifluoromethyl) -benzyl , 2- (3 , 4-dimethoxyphenyl) -ethyl , 4-biphenylmethyl , β- methyl-styryl , 2 - (trifluoromethyl) -styryl , 3,4- dimethoxybenzyl , 3 , 4-dihydroxybenzyl , 2- methoxystyryl , 3 , 4 -dihydroxystyryl , 2 -hydroxystyryl , phenyl, 4-chlorostyryl , 3 -methoxyphenyl , 4- isopropylphenyl , 4-vinylphenyl , 4 -fluorophenyl , 4- bromophenyl , 3 , 4-dimethoxystyryl , 4 -hydroxypheny1 , trans-styryl , 3 , 4-dimethylphenyl , 3-fluoro-4- methylphenyl , 3 -bromo-4 -methyl -phenyl , 3-iodo-4- methyl -phenyl , 3 , 4-dichlorophenyl , 4-biphenyl, 3,4- difluorophenyl , m-tolyl, benzyl, phenethyl, 3- methoxy-4-methylphenyl , 3 -phenylpropyl , 4- butylphenyl , 3 , 5-dimethylphenyl , 3,5-bis-

(trifluoromethyl) -phenyl , 3 , 4-dimethoxyphenyl , 4- ethyl -4-biphenyl , 3 , 4 , 5-triethoxyphenyl , propyl, hexyl , isopropyl, 2 -butyl, isobutyl, 2-pentyl, isovaleryl, 3-heptyl, 1-propenyl, 2-propenyl, trans- 2-pentenyl, 1 -ethyl -1 -pentenyl , p-tolyl, p-anisyl, t- butyl , neopentyl , cyclohexyl, cyclohexylmethyl , dicyclohexylmethyl , cyclohexylpropyl , cycloheptyl, methyl, 2-methylcyclopropyl, cyclobutyl, cyclopentyl, cyclopentylethyl , 2-furyl, cyclohexylethyl , 4- methylcyclohexyl , 4-tert-butyl-cyclohexyl , 1- adamantyl , 4 -methylcyclohexylmethyl , 1 , 3 -pentadienyl , 2-buten-2 -yl , 2-norbornanemethyl , 1 -adamantanemethyl , and a 3-pentyl, 2 -thiophene substituent.

In one of the preferred embodiments of the present invention, the R groups are those as immediately defined above. In the above Formula the stereochemistry of the chiral R¹ group can independently be in the R or S configuration, or a mixture of the two. For instance, as will be described in further detail below, the R¹ group can be the side chain substituent of the α-carbon of various amino acids. The amino acids can be in the L-or D-configuration, resulting in the same R group varying only in its stereochemistry. As a consequence of an R¹ substituent being in one or both or two stereoconfigurations, the R^ group is usually illustrated bonded to the bicyclic ring by a wavy line .

It is also noted that a compound of Formula I can exist in two tautomeric forms; i.e., in the keto or enol forms. Those two tautomeric forms are illustrated in Formula IA, below.

For convenience, a contemplated compound of Formula I (IA) is usually depicted and discussed as being in the keto form (imidazo-imidizol-one) with the understanding that both keto and enol forms are present in equilibrium.

Formulas of the two tautomers in both stereoconfigurations are shown below.

In any of the Formulas herein, the term "Cι_-C_]_o alkyl" denotes a straight or branched chain radical such as a methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, amyl , tert-amyl, hexyl , heptyl , decyl group and the like. The term "lower alkyl" denotes a C1-C₄ alkyl group. A preferred "C_]_-Cτ_o alkyl" group is a methyl group. The term "C2-C_Q alkenyl" denotes a radical such as a vinyl, allyl, 2-butenyl, 3-butenyl, 2- pentenyl, 3 -pentenyl, 4 -pentenyl, 2-hexenyl, 3- hexenyl , 4-hexenyl, 5-hexenyl, 2-heptenyl, 3- heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl and a 2- decenyl group and the like, as well as dienes and trienes of straight and branched chains containing up to ten carbon atoms and at least one carbon-to-carbon (ethylenic) double bond.

The term "C2-C]_o alkynyl" denotes a radical such as ethynyl, propynyl , butynyl , pentynyl , hexynyl , heptynyl , decynyl and the like, as well as di- and tπynes of straight and branched chains containing up to ten carbon atoms and at least one carbon-to-carbon (acetylenic) triple bond. The term "C₁-C₁₀ substituted alkyl", "C₂-

C]_Q substituted alkenyl" and "C2-C10 substituted alkenyl" denote that the above C_]_-C]_Q alkyl group and C2~C_]_o alkenyl and alkynyl groups are substituted by one or more, and preferably one or two, halogen, hydroxy, protected hydroxy, C3-C7 cycloalkyl, C3-C7 substituted cycloalkyl, naphthyl, substituted naphthyl, adamantyl , abietyl , thiofuranyl , mdolyl , substituted mdolyl, ammo, protected ammo, (monosubstituted) ammo, protected (monosubstituted) ammo, (disubstituted) ammo, guanidmo, (monosubstituted) guanidmo, (disubstituted) guanidmo, (trisubstituted) guanidmo, lmidazolyl pyrolidmyl, C_]_-C₇ acyloxy, nitro, heterocycle, substituted heterocycle, C1-C4 alkyl ester, carboxy, protected carboxy, carbamoyl, carbamoyloxy, carboxamide, protected carboxamide, cyano, methylsulfonylammo, methylsulfonyl , sulfhydryl, C1-C4 alkylthio, 0^_^-04 alkyl sulfonyl or C₁-C₄ alkoxy groups. The substituted alkyl groups can be substituted once or more, and preferably once or twice, with the same or with different substituents.

Examples of the above substituted alkyl groups include the cyanomethyl , nitromethyl, chloromethyl , hydroxymethyl , tetrahydro- pyranyloxymethyl , tπtyloxymethyl , propionyloxymethyl , ammomethyl , carboxymethyl , allyloxycarbonylmethyl , allylcarbonyl -ammomethyl , carbamoyloxymethyl , methoxymethyl , ethoxy ethyl , t- butoxymethyl , acetoxymethyl , chloromethyl, bromomethyl , lodomethyl, 6 -hydroxy-hexyl , 2,4- dichloro (n-butyl) , 2 -ammo (isopropyl) , 2- carbamoyloxyethyl chloroethyl, bromoethyl, fluoroethyl, lodoethyl, chloropropyl , bromopropyl , fluoropropyl , lodopropyl and the like.

In preferred embodiments of the subject invention, C]_-C]_Q alkyl, C2~C_o alkenyl, C2"C_]__Q alkynyl, C]_-C]_Q substituted alkyl, C2~C]_o substituted alkenyl, or C2-C₁₀ substituted alkynyl, are more preferably C1-C7 or C2-C₇, respectively, and more preferably, C^-Cg or C2~Cg as is appropriate for unsaturated substituents. However, it should be appreciated by those of skill in the art that one or a few carbons usually can be added to an alkyl, alkenyl, alkynyl, substituted or unsubstituted, without substantially modifying the structure and function of the subject compounds and that, therefore, such additions would not depart from the spirit of the invention.

The term "C₁-C alkoxy" as used herein denotes groups that are ether groups containing up to four carbon atoms such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and like groups. A preferred C1-C₄ alkoxy group is methoxy.

The term "C1-C acyloxy" denotes a carboxy group-containing substituent containing up seven carbon atoms such as formyloxy, acetoxy, propanoyloxy, butanoyloxy, pentanoyloxy, hexanoyloxy, heptanoyloxy, benzoyloxy and the like.

Similarly, the term "C1-C7 acyl " encompasses groups such as formyl , acetyl , propionoyl, butyroyl, pentanoyl, hexanoyl, heptanoyl, benzoyl and the like.

The substituent term "C3-C7 cycloalkyl" includes the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl rings. The substituent term "C3-C7 substituted cycloalkyl" indicates an above cycloalkyl ring substituted by a halogen, hydroxy, protected hydroxy, phenyl, substituted phenyl, heterocycle, substituted heterocycle, C_]_-C}_o alkyl, C1-C₄ alkoxy, carboxy, protected carboxy, ammo, or protected ammo. The substituent term "C5-C₇ cycloalkenyl " indicates a substituent that is itself a 1-, 2-, or 3 -substituted cyclopentenyl ring, a 1-, 2- , 3- or 4- substituted cyclohexenyl ring or a 1-, 2-, 3-, 4- or 5 -substituted cycloheptenyl ring, whereas the term "substituted C3-C₇ cycloalkenyl" denotes the above

C3-C7 cycloalkenyl rings substituted by a C_]_-C_]__Q alkyl radical, halogen, hydroxy, protected hydroxy, C -C₄ alkoxy, carboxy, protected carboxy, ammo, or protected ammo, The term "heterocyclic ring" or

"heterocycle" denotes an optionally substituted 5- membered or 6-membered ring that has 1 to 4 heteroatoms, such as oxygen, sulfur and/or nitrogen, m particular nitrogen either alone or m conjunction with sulfur or oxygen ring atoms. These five- membered or six-membered rings can be fully unsaturated or partially unsaturated, with fully unsaturated rings being preferred.

Preferred heterocyclic rings include pyridmo, pyπmidmo, and pyraz o, furano, and thiofurano rings. The heterocyles can be substituted or unsubstituted as for example, with such substituents as those described m relation to substituted phenyl or substituted naphthyl . The term "C₇-C₁g phenylalkyl" or "C₇-C₁₆ aralkyl" denotes a C]_-C_]_Q alkyl group substituted at any position by a phenyl ring. Examples of such a group include benzyl, 2 -phenylethyl , 3 -phenyl (n-prop- 1-yl) , 4 -phenyl (hex- 1-yl) , 3-phenyl (n-am-2-yl) , 3- phenyl (sec-butyl ) , and the like. A preferred C₇-C_]_ phenylalkyl group is the benzyl group.

The term "C₇-C]_g substituted phenylalkyl" denotes an above C7~C]_ phenylalkyl group substituted on the C_-C_Q alkyl portion with one or more, and preferably one or two, groups selected from the group consisting of a halogen, hydroxy, protected hydroxy, keto, C2-C3 cyclic ketal phenyl, amino, protected amino, C1-C₇ acyloxy, nitro, carboxy, protected carboxy, carbamoyl, carbamoyloxy, cyano, N- (methyl - sulfonylamino) or C1-C4 alkoxy group, whose phenyl group portion can be substituted with 1 or 2 groups selected from the group consisting of a halogen, hydroxy, protected hydroxy, nitro, C]_-C]_o alkyl, C^- Cg substituted alkyl, C1-C₄ alkoxy, carboxy, protected carboxy, carboxymethyl , protected carboxymethyl, hydroxymethyl , protected hydroxymethyl , aminomethyl , protected ammomethyl, amino, (monosubstituted) amino, (disubstituted) amino, a N- (methylsulfonylamino) group, or a phenyl group that is itself substituted or unsubstituted. When either the C]_-C]_Q alkyl portion or the phenyl portion or both are mono- or di-substituted, the substituents can be the same or different.

Examples of "C7-C_]_g substituted phenylalkyl" include groups such as 2-phenyl-l- chloroethyl, 2- (4-methoxyphenyl) eth-l-yl , 2,6- dihydroxy-4 -phenyl (n-hex-2 -yl) , 5 -cyano-3 -methoxy-2 - phenyl (n-pent-3 -yl ) , 3- (2 , 6-dιmethylphenyl ) n-prop-1- yl , 4-chloro-3 -ammobenzyl , 6- (4-methoxyphenyl) -3- carboxy (n-hex-1-yl) , 5- (4 -ammomethyl -phenyl) -3- (ammomethyl) (n-pent-2-yl) , 5-phenyl-3 -keto- (n-pent- 1-yl), 4- (4-ammophenyl) -4- (I .4-oxetanyl) (n-but-1- yl) , and the like.

The term "C7-C_ phenylalkenyl" denotes a

C_]_-C^o alkenyl group substituted at any position by a phenyl ring. The term " C- -Ciζ substituted phenylalkenyl" denotes a C₇~C]_g arylalkenyl group substituted on the C^-C^o alkenyl portion. Substituents can the same as those as defined above m relation to C₇~C_]_ phenylalkyl and C7~C_]_ substituted phenylalkyl. A preferred C -C_]_g substituted phenylalkenyl is 3- (4-nιtrophenyl) -2 - propenyl .

The term "substituted phenyl" specifies a phenyl group substituted at one or more positions, preferably at one or two positions, with moieties selected from the group consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, C_]_-C_]__Q alkyl, C]_-C]_Q substituted alkyl, C1-C4 alkoxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, ammo, protected anilmo,

(monosubstituted) ammo, protected (monosubstituted) ammo, (disubstituted) ammo, trifluoromethyl, N- (methylsulfonylammo) , or phenyl that is itself substituted or unsubstituted such that, for example, a biphenyl group results. Illustrative substituents embraced by the term "substituted phenyl" include a mono- or di (halo) phenyl group such as 4-chlorophenyl , 2,6- dichlorophenyl , 2 , 5-dιchlorophenyl , 3,4- dichlorophenyl , 3-chlorophenyl , 3 -bro ophenyl , 4- bromophenyl , 3 , 4 -dibromophenyl , 3-chloro-4- fluorophenyl , 2 -fluorophenyl and the like; a mono or di (hydroxy) phenyl groups such as 4-hydroxyphenyl , 3- hydroxyphenyl , 2 , 4-dιhydroxyphenyl , the protected hydroxy derivatives thereof and the like; a nitrophenyl group such as 3- or 4 -nitrophenyl , a cyanophenyl group for example, 4-cyanophenyl; a mono- or di (lower alkyl) phenyl group such as 4 -methyl - phenyl, 2 , 4-dιmethylphenyl , 2-methylphenyl , 4- (ISO- propyl ) phenyl , 4-ethylphenyl, 3 - (n-prop-1-yl) phenyl and the like: a mono or di (alkoxyl) phenyl group for example, 2 , 6-dιmethoxyphenyl , 4-methoxyphenyl, 3-ethoxyphenyl , 4- (isopropoxy) phenyl , 4- (t-butoxy) - phenyl, 3 -ethoxy-4-methoxyphenyl , 3- (4 -methyl - phenoxy) phenyl , and the like; 3- or 4-trιfluoro- methylphenyl ; a mono- or dicarboxyphenyl or (protected carboxy) phenyl group such as 4- carboxyphenyl or 2 , 4-dι (protected carboxy) phenyl ; a mono-or di (hydroxymethyl) phenyl or (protected hydroxymethyl) phenyl such as 3- (protected hydroxymethyl) phenyl or 3 , 4 -di (hydroxymethyl) phenyl ; a mono- or di (ammomethyl) phenyl or (protected ammomethyl) phenyl such as 2- (ammomethyl) phenyl or 2 , 4- (protected ammomethyl) phenyl; or a mono- or di (N- (methylsulfonylamino) ) phenyl such as 3-(N- (methylsulfonylamino) ) phenyl . Also, the term "substituted phenyl" represents disubstituted phenyl groups wherem the substituents are different. For example, 3 -methyl -4 -hydroxyphenyl , 3-chloro-4- hydroxyphenyl , 2 -methoxy-4-bromophenyl , 4 -ethyl -2- hydroxyphenyl , 3 -hydroxy-4 -nitrophenyl , 2 -hydroxy- 4- chlorophenyl and the like are contemplated. The term "substituted naphthyl" specifies a naphthyl group substituted with one or more, and preferably one or two moieties selected from the group consisting of a halogen, hydroxy, protected hydroxy, cyano, nitro, C^-C^Q alkyl, C1-C alkoxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl , hydroxymethyl , protected hydroxymethyl, ammo, protected ammo, (monosubstituted) ammo, protected (monosubstituted) ammo, (disubstituted) ammo trifluoromethyl, or a N- (methylsulfonylamino) group. Examples of substituted naphthyl include 2- (methoxy) naphthyl and 4- (methoxy) naphthyl .

The term "substituted mdolyl" specifies a mdolyl group substituted, either at the nitrogen or carbon, or both, with one or more, and preferably one or two, moieties selected from the group consisting of a halogen, hydroxy, protected hydroxy, cyano, nitro, C]_-Cιo alkyl, C]_-C]_o substituted alkyl, C]_-C]_Q alkenyl, Cη - -^ζ phenylalkyl, C7-C]_ substituted phenylalkyl, Cχ-Cg alkoxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, ammo, protected ammo, monosubstituted ammo, or a disubstituted ammo group. Examples of the term "substituted mdolyl" includes such groups as 6-fluoro, 5-fluoro, 5-bromo, 5-hydroxy, 5 -methyl, 6 -methyl, 7 -methyl, 1 -methyl, 1- ethyl , 1 -benzyl, 1-napthylmethyl , and the like. An example of a disubstituted mdolyl is l-methyl-5- methyl mdolyl .

The terms "halo" and "halogen" refer to the fluoro, chloro, bromo, or iodo groups.

The term " (monosubstituted) ammo" refers to an ammo group with one substituent selected from the group consisting of phenyl, substituted phenyl, C_]_-

C_]_o alkyl, and C7-C]_g arylalkyl, wherem the latter three substituent terms are as defined above. The

(monosubstituted) ammo can additionally have an ammo-protecting group as encompassed by the term

"protected (monosubstituted) ammo . "

The term " (disubstituted) ammo" refers to am o groups with two substituents selected from the group consisting of phenyl, substituted phenyl, C_]_-

C_]_o alkyl, and C-J - CI _Q arylalkyl where the latter three substituent terms are as described above. The two substituents can be the same or different. The terms " (monosubstituted) guanidmo" ,

" (disubstituted) guanidmo . " and " (trisubstituted) - guanidmo" are used to mean that a guanidmo group is substituted with one, two, or three substituents, respectively. The substituents can be any of those as defined above m relation to (monosubstituted) - ammo and (disubstituted) ammo and, where more than one substituent is present, the substituents can be the same or different.

The terms "(monosubstituted) lmidizol-one imidazole, "(disubstituted) lmidizol-one imidazole." and "(trisubstituted) lmidizol-one imidazole " mean compounds which the lmidizol-one imidazole group is substituted with one, two, or three substituents, respectively. The substituents can be any of those as defined above in relation to a (monosubstituted) - amino or (disubstituted) amino group and where more than one substituent is present. The substituents can be the same or different.

The term "amino-protecting group" as used herein refers to one or more selectively removable substituents on the amino group commonly employed to block or protect the amino functionality. The term "protected (monosubstituted) amino" means there is an amino-protecting group on the monosubstituted amino nitrogen atom. In addition, the term "protected carboxamide" means there is an amino-protecting group present replacing the proton of the amido nitrogen so that di-N-alkylation.

Examples of such amino-protecting groups include the formyl ("For") group, the trityl group (Trt), the phthalimido group, the trichloroacetyl group, the chloroacetyl, bromoacetyl, and iodoacetyl groups. Urethane blocking groups, such as t-butoxy- carbonyl ("Boc"), 2- (4-biphenylyl) propyl (2 ) - oxycarbonyl ("Bpoc"), 2 -phenylpropyl (2) oxycarbonyl ("Poc"), 2- (4-xenyl) -isopropoxycarbonyl , 1,1- diphenylethyl (1) oxycarbonyl , 1,1- diphenylpropyl (1) oxycarbonyl , 2- (3 , 5-dimethoxyphenyl) propyl (2) oxycarbonyl ("Ddz"), 2- (p-5-toluyl) propyl - (2 ) oxycarbonyl , cyclo-pentanyloxycarbonyl , 1- methylcyclopentanyl -oxycarbonyl , eyelohexanyloxycarbonyl , 1 -methyl - cyclohexanyloxycarbonyl , 2 -methylcyclohexanyl - oxycarbonyl, 2- (4-toluylsulfonyl ) ethoxycarbonyl , 2- (methylsulfonyl) ethoxycarbonyl , 2- (triphenyl- phosphino) ethoxycarbonyl, 9-fluoroenylmethoxycarbonyl ("Fmoc") , 2- (trimethylsilyl) ethoxycarbonyl , allyloxycarbonyl , 1- (trimethylsilylmethyl) prop-1- enyloxycarbonyl , 5-benz-isoxalylmethoxycarbonyl , 4- acetoxybenzyloxycarbonyl , 2 , 2 , 2 -trichloro- ethoxycarbonyl , 2 -ethynyl (2 ) propoxycarbonyl , cyclopropylmethoxycarbonyl , isobornyloxycarbonyl , 1- piperidyloxycarbonyl , benzyloxycarbonyl ("Z"), 4- phenylbenzyloxycarbonyl , 2 -methylbenzyloxycarbonyl , α-2 , 4 , 5, -tetramethylbenzyloxycarbonyl ("Tmz"), 4- methoxybenzyl -oxycarbonyl , 4-fluorobenzyloxycarbonyl , 4-chloro-benzyloxycarbonyl , 3-chlorobenzyloxy- carbonyl , 2-chlorobenzyloxycarbonyl , dichloro- benzyloxycarbonyl , 4 -bromobenzyloxycarbonyl , 3- bromobenzyloxycarbonyl, 4 -nitrobenzyloxycarbonyl , 4- cyanobenzyloxycarbonyl , 4- (decyloxy) benzyloxy- carbonyl, and the like, the benzoylmethylsulfonyl group, dithiasuccinoyl ("Dts") group, the 2- (nitro) phenylsulfenyl group ("Nps'), the diphenyl- phosphine oxide group, and like amino-protecting groups. The species of amino-protecting group employed is usually not critical so long as the derivatized amino group is stable to the conditions of the subsequent reactions and can be removed at the appropriate point without disrupting the remainder of the compound. Preferred amino-protecting groups are Boc and Fmoc .

Further examples of amino-protecting groups embraced to by the above term are well known in organic synthesis and the peptide art and are described by, for example T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2^nd ed., John Wiley and Sons. New York., Chapter 7, 1991; M. Bodanzsky, Principles of Peptide Synthesis, 1^st and 2^nd revised eds . , Sprmger-Verlag, New York, 1984 and 1993; and Stewart and Young, Solid Phase Peptide Synthesis, 2^nd ed . , Pierce Chemical Co, Rockford. IL 1984.

The related term "protected ammo" defines an ammo group substituted with an ammo-protectmg group discussed above.

The term "carboxy-protectmg group" as used herein refers to one of the ester derivatives of the carboxylic acid group commonly employed to block or protect the carboxylic acid group while reactions are carried out on other functional groups on the compound. Examples of such carboxylic acid protecting groups include 4-nιtrobenzyl , 4-methoxybenzyl, 3 , 4-dιmethoxybenzyl , 2 , 4 -dimethoxybenzyl , 2,4, 6-trιmethoxybenzyl , 2,4, 6-trιmethylbenzyl , pentamethylbenzyl , 3 , 4-methylene-dιoxybenzyl , benzhydryl, 4 , 4 ' -methoxytπtyl , 4, 4 ',4''- trimethoxytrityl, 2 -phenylprop-2 -yl , trimethylsilyl, t-butyldimethylsilyl , 2,2,2 -tπchloroethyl , β- (trimethylsilyl) ethyl , β- [di (n-butyl) - methylsilyl] ethyl , p-toluenesulfonylethyl , 4- nitrobenzyl-sulfonylethyl , allyl, cmnamyl, 1- (trimethylsilylmethyl) -prop-l-en-3-yl, and like moieties. The species of carboxy-protectmg group employed is also usually not critical so long as the derivatized carboxylic acid is stable to the conditions of subsequent reactions and can be removed at the appropriate point without disrupting the remainder of the molecule.

Further examples of these groups are found m E. Haslam, Protective Groups m Organic Chemistry, J. G. W. McOmie Ed., Plenum Press, New York 1973, Chapter 5 and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis 2^nd ed. , John Wiley and Sons, New York, 1991, Chapter 5, each of which is incorporated herein by reference. A related term is "protected-carboxy" , which refers to a carboxy group substituted with one of the above carboxy-protectmg groups.

The term "hydroxy-protecting group" refers to readily cleavable groups bonded to hydroxyl groups, such as the tetrahydropyranyl, 2-methoxyprop- 2-yl, 1-ethoxyeth-l-yl , methoxymethyl , β-methoxy- ethoxymethyl , methylthiomethyl , t-butyl, t-amyl, trityl, 4-methoxytrιtyl , 4 , 4 ' -dimethoxytπtyl , 4 , 4 ', 4" -trimethoxytrityl , benzyl, allyl, trimethylsilyl, (t-butyl) dimethylsilyl and 2,2,2- tπchloroethoxycarbonyl groups, and the like. The species of hydroxy-protectmg groups is also usually not critical so long as the derivatized hydroxyl group is stable to the conditions of subsequent reaction (s) and can be removed at the appropriate point without disrupting the remainder of the compound.

Further examples of hydroxy-protectmg groups are described by C. B. Reese and E Haslam, Protective Groups Organic Chemistry, J. G. W. McOmie, Ed., Plentun Press, New York 1973, Chapters 3 and 4, respectively, and T. W. Greene and P. G. M. Wuts, Protective Groups m Organic Synthesis, 2^nd ed., John Wiley and Sons, New York, 1991, Chapters 2 and 3, whose disclosures are also incorporated by reference . The substituent term "C₁-C₄ alkylthio" refers to sulfide groups such as methylthio, ethylthio, n-propylthio, isopropylthio, -butylthio, t-butylthio and like groups. The substituent term " C1-C4 alkylsulfoxide" indicates sulfoxide groups such as methylsulfoxide, ethylsulfoxide, -propylsulfoxide, iso-propyl-sulfoxide, n-butylsulfoxide, sec- butylsulfoxide, and the like. The term "C1-C4 alkylsulfonyl " encompasses groups such as methylsulfonyl , ethylsulfonyl , n-propylsulfonyl , 1sopropylsulfonyl , α-butylsulfonyl , t-butylsulfonyl , and the like.

Phenylthio, phenyl sulfoxide, and phenylsulfonyl compounds are known m the art and these have their art-recognized definitions. By "substituted phenylthio", "substituted phenyl sulfoxide", and "substituted phenylsulfonyl " is meant that the phenyl can be substituted as described above m relation to "substituted phenyl."

The substituent terms "cyclic C2~C_]_o alkylene", "substituted cyclic C2-C10 alkylene", "cyclic C2-C10 heteroalkylene . " and "substituted cyclic C2~C]_o heteroakylene" defines a cyclic group bonded ("fused") to the phenyl radical. The cyclic group can be saturated or contain one or two double bonds. Furthermore, the cyclic group can have one or two methylene groups replaced by one or two oxygen, nitrogen or sulfur atoms. The cyclic alkylene or heteroalkylene group can be substituted once or twice by substituents selected from the group consisting of hydroxy, pro- tected-hydroxy, carboxy, protected-carboxy, keto, ketal, C_]_-C4 alkoxycarbonyl, C]_-C4 alkanoyl, C_]_-C_]_o alkyl, carbamoyl, C1-C4 alkoxy, C1-C4, alkylthio, C_]_- C4 alkylsulfoxide, C1-C alkylsulfonyl , halo, amino, protected-amino, hydroxymethyl and a protected- hydroxymethyl group .

A cyclic alkylene or heteroalkylene group fused onto the benzene radical can contain two to ten ring members, but it preferably contains four to six members. Examples of such saturated cyclic groups include a bicyclic ring system that is a 2,3- dihydroindanyl or a tetralin ring. When the cyclic groups are unsaturated, examples occur when the resultant bicyclic ring system is a naphthyl ring or indanyl .

An example of a cyclic group that can be fused to a phenyl radical that has two oxygen atoms and that is fully saturated is dioxanyl . Examples of fused cyclic groups that each contain one oxygen atom and one or two double bonds occur when the phenyl ring is fused to a furyl , pyranyl , dihydrofuryl or dihydropyranyl ring. Cyclic groups that each have one nitrogen atom and contain one or two double more double bonds are illustrated where the phenyl is fused to a pyridino or pyrano ring. An example of a fused ring system having one nitrogen and two phenyl radicals is a carbozyl group. Examples of cyclic groups that each have one sulfur atom and contain one or two double bonds occur where the benzene ring is fused to a thieno, thiopyrano, dihydrothieno, or dihydrothiopyrano ring. Examples of cyclic groups that contain two heteroatoms selected from sulfur and nitrogen and one or two double bonds occur where the phenyl ring is fused to a thiazolo, isothiazolo, dihydrothiazolo or dihydroisothiazolo ring. Examples of cyclic groups that contain two heteroatoms selected from oxygen and nitrogen and one or two double bonds occur where the benzene ring is fused to an oxazole, isoxazole, dihydroxazole or dihydroisoxazole ring. Examples of cyclic groups that contain two nitrogen heteroatoms and one or two double bonds occur where the benzene ring is fused to a pyrazolo, lmidazolo, dihydropyrazolo or dihydroimidazolo ring.

Examples of cyclic groups that each have one nitrogen atom and contain one or two double more double bonds occur when the phenyl is fused to a pyridmo or pyrano ring. An example of a fused ring system having one nitrogen and two phenyl radicals is a carbozyl group. Examples of cyclic groups that each have one sulfur atom and contain one or two double bonds occur when the phenyl is fused to a thieno, thiopyrano, dihydrothieno, or dihydrothiopyrano ring .

Examples of cyclic groups that contain two heteroatoms selected from sulfur and nitrogen and one or two double bonds occur when the phenyl ring is fused to a thiazolo, isothiazolo, dihydrothiazolo or dihydroisothiazolo r ng. Examples of cyclic groups that contain two heteroatoms selected from oxygen and nitrogen and one or two double bonds occur when the benzene ring, is fused to an oxazolo, isoxazolo, dihydroox-azolo or dihydroisoxazolo ring. Examples of cyclic groups which contain two nitrogen heteroatoms and one or two double bonds occur when the benzene ring is fused to a pyrazolo, Imidazolo, dihydropyrazolo or dihydroimidazolo ring.

Pharmaceutical Compositions

A pharmaceutical composition for treating infections, pa , or other indications treatable by a contemplated imidazo-imidazol-one is administered to a subject m need of the medication at dosage levels of about 0.7 to about 7000 mg per day, and preferably about 1 to about 500 mg per day, for a normal human adult of approximately 70 kg of body weight. This broadly translates into a dosage of about 0.01 to about 100 mg/kg of body weight per day of an lmidizo- lmidazol-one compound of Formula I as active ingredient. The specific dosages employed, however, can be varied depending upon the requirements of the patient, the severity of the condition being treated, and the activity of the compound being employed. The determination of optimum dosages for a particular situation is withm the skill of the art.

One or more of the lmidizo-imidazol-one compounds of Formula I can be present as a pharmaceutically-acceptable salt. The term "pharmaceutically-acceptable salt" encompasses those salts that form with the carboxylate anions or ammonium cations and include salts formed with the organic and inorganic cations and anions discussed below. Furthermore, the term includes salts that form by standard acid-base reactions with basic groups (such as ammo groups) and organic or inorganic acids. Such acids include hydrochloric, sulfuric, phosphoric, acetic, succmic, citric lactic, maleic, fumaric, palmitic, cholic, pamoic, mucic, D-glutamic, d-camphoric, glutaπc, phthalic, tartaric, lauπcc, steaπc, salicyclic, methanesulfonic, benzenesulfonic , sorbic, picric, benzoic, cmnamic, and like acids.

The term "organic or inorganic cation" refers to counterions for the carboxylate anion of a carboxylate salt. The counter- ions are chosen from the alkali and alkaline earth metals, (such as lithium, sodium, potassium, barium and calcium) : ammonium; and the organic cations such as (dibenzylammonium, benzylammonium, 2 -hydroxymethyl - ammonium, bis (2 -hydroxyethyl) ammonium, phenyl - ethylbenzyl ammonium, dibebenzylethylenediammoniurn, and like cations) . Other cations encompassed by the above term include the protonated form of procame, qumme and N-methylglucosamme, and the protonated forms of basic ammo acids such as glycme, ornithme, histidine, phenylglyc e, lysme and argmme . Furthermore, any zwitterionic form of the instant compounds formed by a carboxylic acid and an ammo group is referred to by this term. A preferred cation for the carboxylate anion is the sodium cation. A compound of Formula I can also be present as a solvate and hydrate. Thus, these compounds can crystallize with, for example, waters of hydration, or one, a number of, or any fraction thereof of molecules of the mother liquor solvent. The solvates and hydrates of such compounds are included withm the scope of this invention.

One or more of the contemplated compounds can be m the biologically active ester form, such as the non-toxic, metabolically-labile ester-form. Such ester forms induce increased blood levels and prolong the efficacy of the corresponding non-esterified forms of the compounds . Ester groups that can be used include the lower alkoxymethyl groups (C₁-C₄ alkoxymethyl ) for example, methoxymethyl , ethoxymethyl , isopropoxymethyl and the like; the (C1-C ) alkoxyethyl groups, for example methoxyethyl , ethoxyethyl , propxyethyl , iso-propoxyethyl , and the like, the 2 -oxo-1 , 3 -dioxolen-4 -ylmethyl groups such as 5-methyl-2 -oxo-1 , 3 -dioxolen-4 -ylmethyl , 5-phenyl- 2 -oxo-1 , 3 -dioxolen-4 -ylmethyl , and the like, the C_]_-

C3 alkylthiomethyl groups, for example methylthio- methyl , ethylthiomethyl, isopropylthiomethyl, and the like, the acyloxymethyl groups, for example pivaloyloxymethyl , pivaloyloxyethyl , α-acetoxymethyl , and the like, the ethoxycarbonyl -1 -methyl group, the α-acetoxyethyl , the 3-phthalidyl or 5 , 6-dimethyl- phtalidyl groups, the 1- (C1-C4 alkyloxycarbonyloxy) - ethyl groups such as the 1- (ethoxycarbonyloxy) ethyl group, and the 1-(C_-C4 alkylaminocarbonyloxy) ethyl groups such as the 1-methylaminocarbonyloxyethyl group .

For preparing pharmaceutical compositions containing compounds of the invention, inert, pharmaceutically acceptable carriers are used. The pharmaceutical carrier can be either solid or liquid.

Solid form preparations include, for example, powders, tablets, dispersible granules, capsules, cachets, and suppositories.

A solid carrier can be one or more substances that can also act as diluents, flavoring agents, solubilizers , lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material.

In powders, the carrier is generally a finely divided solid that is m a mixture with the finely divided active component. In tablets, the active compound is mixed with the carrier having the necessary binding properties m suitable proportions and compacted m the shape and size desired. For preparing pharmaceutical composition m the form of suppositories, a low-meltmg wax such as a mixture of fatty acid glyceπdes and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture is then poured into convenient-sized molds and allowed to cool and solidify.

Powders and tablets preferably contain between about 5% to about 70% by weight of the active ingredient. Suitable carriers include, for example, magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-meltmg wax, cocoa butter and the like. A pharmaceutical composition can include the formulation of the active compound with encapsulating material as a carrier providing a capsule m which the active component (with or without other carriers) is surrounded by a carrier, which is thus m association with it. In a similar manner, cachets are also included. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.

Liquid pharmaceutical compositions include, for example, solutions suitable for oral or parenteral administration, or suspensions, and emulsions suitable for oral administration. Sterile water solutions of the active component or sterile solutions of the active component m solvents comprising water, ethanol, or propylene glycol are examples of liquid compositions suitable for parenteral administration.

Sterile solutions can be prepared by dissolving the active component m the desired solvent system, and then passing the resulting solution through a membrane filter to sterilize it or, alternatively, by dissolving the sterile compound m a previously sterilized solvent under sterile conditions . Aqueous solutions for oral administration can be prepared by dissolving the active compound m water and adding suitable flavorants, coloring agents, stabilizers, and thickening agents as desired. Aqueous suspensions for oral use can be made by dispersing the finely divided active component m water together with a viscous material such as natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.

Preferably, the pharmaceutical composition is m unit dosage form. In such form, the composition is divided into unit doses containing appropriate quantities of the active urea. The unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparation, for example, packeted tablets, capsules, and powders in vials or ampules. The unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these packaged forms .

Library Synthesis and Use

As used herein, a chemical or combinatorial "library" is an intentionally created collection of a plurality of structurally similar, but different molecules. By "structurally similar", it is meant that the constituent compounds of a library have the same ring structure; i.e., a bicyclic imidizo- imidazol-one ring, and at least two positions at which substituents are bonded to the ring structure. It is preferred that the member compounds of the library also have the same substitution pattern of substituent groups; i.e., that the at least two substituents be bonded to the same ring positions in each member compound. The molecule members of the library are different in that each member has at least one different substituent group from the other members of the library. A library can contain two to thousands or millions of member compounds.

A particular library can also be comprised of members whose substituent groups are all different from each other. Thus, where the shared ring structure contains substituent groups at a plurality of positions, a library can be prepared in which the member molecules contain different groups at each position.

Alternatively, a plurality of sub-libraries or sets can also be prepared m which a first set has a first substituent that is held constant for all of the members (is present m all members) of the set, whereas the groups at the other substituent positions are different and constitute a mixture of groups at each substituent position. A second set of that plurality has a second, different, first substituent, and the same mixture of different groups at the other substituent positions. A third set of that plurality has a third, different first substituent, and the same mixture of different groups at the other substituent positions, and so on until one decides to stop making sets with different first substituents. Such set pluralities of structurally similar, but different compounds are also often referred to as libraries of libraries, and are particularly useful m ascertaining which compound or compounds of a library are active m an assay of choice.

A library can be prepared by the synthetic means discussed below or otherwise herein and screened for biological activity m a variety of formats (e.g. libraries of soluble molecules). Libraries of compounds can be attached to resin beads, silica chips or other solid supports) . The libraries can be screened m any variety of assays, such as those detailed below as well as others useful for assessing the biological activity of lmidazo- lmidazol-ones . The libraries typically contain at least one active compound and are generally prepared such that the compounds are equimolar quantities. The nonsupport -bound library mixtures prepared herein were screened m solution radio- receptor inhibition assays described m detail hereinafter. Deconvolution of highly active mixtures can then be carried out by iterative, or positional scanning methods. These techniques, the iterative approach or the positional scanning approach, can be utilized for finding other active compounds with the libraries of the present invention using any one of the below-described assays or others well known the art .

The iterative approach is well-known and is set forth m general m Houghten et al . , Nature, 354, 84-86 (1991) and Dooley et al . , Science, 266, 2019- 2022 (1994), both of which are incorporated herein by reference. In the iterative approach, for example, sub- libraries of a molecule havmg three variable groups are made wherem the first variable substituent is defined (known and held constant) withm the sub-library. Each of the compounds with the defined variable group is reacted separately with each of the other possibilities at the second variable group position and the third variable position is a mixture of all of the possible substituents to form a plurality of sub-libraries whose first two substituent groups are known. These sub-libraries are each assayed to define the identity of the second variable m the sub- library having the highest activity m the screen of choice. A new sub- library with the first two variable positions defined is separately reacted with each of the other possibilities at the remaining undefined variable position. As before, the identity of the third variable position m the sub-library having the highest activity is determined.

If more variables exist, this process is repeated for all variables, yielding the compound with each variable contributing to the highest desired activity the screening process. Promising compounds from this process can then be synthesized on larger scale m traditional single-compound synthetic methods for further biological investigation.

The positional -scanning approach has been described for various libraries as described, for example, R. Houghten et al . PCT/US91/08694 and U.S. Patent 5,556,762, both of which are incorporated herein by reference. The positional scanning approach is used as described below the preparation and screening of the libraries.

In the positional scanning approach, sub- libraπes are made defining only one variable substituent with each set of sub-libraries and all possible sub-libraries with each single variable substituent defined (and all other possibilities at all of the other variable positions) is made and tested. From the instant description one skilled m the art can synthesize libraries wherem two fixed substituent positions are defined at a time. From the assaying of each single-variable defined library, the optimum substituent at that position is determined, pointing to the optimum or at least a series of compounds having a maximum of the desired biological activity. Thus, the number of sub- libraπes for compounds with a single substituent position defined is the number of different substituents desired at that position, and the number of all the compounds m each sub-library is the product of the number of substituents at each of the other variables. The [3, 5, 7] -IH-imidazo [1, 5-a] lmidazol-

2 (3H) -one libraries and compounds of Formula I can be prepared according to the general reaction Scheme 1, which for ease of description is shown using single ammo acids. The reaction scheme shown forms a smgle compound or enantiomeric pair of compounds of Formula I. Where libraries are desired, a mixture of ammo acids (Boc-R^-aa-OH or Boc-R²aa-OH) , or carboxylic acids (R³-C02H) is used for at least one of the coupling steps. The individual compounds and libraries are prepared using solid-phase techniques. The solid- phase resin, here, p-methylbenzhydrylamme resm (p- MBHA) , is indicated m Scheme 1 by the large circle and dash.

Scheme 1

(1 ) POCI_3l Dioxane Reflux, 2 hours, Anion Exchange Resin AG^3-X4; or

Distilled POCI₃, Dioxane Reflux, 2 hours

(2) HF/ Anisole

Starting from p-methylbenzhydrylamine (MBHA) resin-bound N-tert-butyloxycarbonyl (Boc) amino acid 1 (Boc-R-'-aa-OH) , the Boc group was removed using a mixture of trifluoroacetic acid (TFA) and dichloromethane (DCM) . The resulting amine salt was neutralized, and the resulting primary amine was N- acylated with a second Boc-protected amino acid (Boc-

R²aa-OH) as before, to provide the resin bound- monopeptide 2.

Following removal of the Boc protecting group using 55% of trifluoroacetic acid in dichloromethane, the resulting free amine was acylated with a carboxylic acid 3 (R³-Cθ2H) m dimethylformamide (DMF) using diisopropylcarbodiimide (DICI) and hydroxybenzotπazole (HOBt) to effect coupling. The bicyclic [3 , 5 , 7] -IH-imidazo [1 , 5-a] - ιmιdazol-2 (3H) -one 4 was obtained via cyclization using the conditions of Bischler-Napieralski , with 25-fold excess of phosphorus oxychloπde (POCI3) m refluxmg 1,4 -dioxane m the presence of a 30-fold

® excess of anion exchange resm (AG 3-X4) [Bischler, A.; Napieralski, B. Chem . Ber . , (1893), 26, 1903; W. M. Whaley, T. R. Govmdachaπ, Org . React . , 6, 74 (1951); T. Kametani et al . , Tetrahedron, 27, 5367 (1971); G. Fodor et al . , Angew . Chem . Int . Ed . , 11, 919 (1972); G. Fodor, S. Nagubandi , Tetrahedron, 36, 1279 (1980); idem, Heterocycles , 15, 165 (1981)]. More recent syntheses using freshly distilled POCI3 m the absence of the anion exchange resm have provided yields m the range of about 80 percent. The desired products were readily obtained following cleavage from the resm with anhydrous HF m anisole to provide compound 4.

Following the strategy described m Scheme 1, with the parallel synthesis approach, commonly referred to as the "tea-bag" method [Houghten et al . , Na ture, 354: 84-86 (1991)], libraries are synthesized with 33 different ammo acids to provide the R group at R¹ , 33 different ammo acids to provide the R group at R² , and 92 different carboxylic acids to provide the R group at R^ , m which the individual building blocks were varied, while fixing the remaining two positions. Any variety of ammo acids can be used with the present invention as described above to prepare a vast array of bicyclic [3 , 5 , 7] -IH-imidazo [1 , 5-a] - ιmιdazol-2 (3H) -one with different R¹, R² and R³ groups. As described above, thirty-three first ammo acids were coupled to the resm, which ammo acids provide the R^ substituent group. The thirty-three am o acids included Ala, Phe, Gly, His (DNP) , lie, Lys(CBZ), Leu, Met, Arg(Tos), Nva, Ser(Bzl), Thr(Bzl), Val, Tyr(CHO), Tyr(BrZ), Nle, Cha, ala, phe, his (DNP), lie, lys (CBZ) , leu, met, arg(Tos), ser(Bzl), thr(Bzl), val, trp(CHO), tyr(BrZ), nle, nva , cha .

After the above-described 33 reactions and removal of the BOC protecting group, a single ammo acid (valme) was coupled as the second ammo acid, thereby providing the R² group. After removal of the second BOC group, a single carboxylic acid, acetic acid, was coupled to provide the R^ group for the 33 different compounds. Those compounds were thereafter cyclized to form compounds of Formula I and cleaved from the resm.

Another set or sub-library of 33 compounds was prepared by reacting a single ammo acid (valme) with the resm to provide one R¹ group. After removal of the BOC protecting group, each of the above 33 ammo acids was then separately coupled to provide 33 resm-l ked peptides with the same R¹ group and one of the 33 different R² groups. On removing the second BOC group, a single carboxylic acid (acetic acid) was bonded to the free ammo group to provide a single R³ group for the resm-lmked peptides. Theses compounds were also cyclized to form compounds of Formula I, and cleaved from the resm. In a third set or sub-library preparation, a single ammo acid (valme) was coupled to the resm to provide a single R¹ group, the BOC group was removed and a second ammo acid (valme) was coupled to provide a single R² group and form a dipeptide. After removal of the second BOC group, the dipeptide was separately reacted with each of the 92 carboxylic acids listed Table 2, below, to provide 92 different R³ groups. The acylated peptides were thereafter cyclized, cleaved from the solid support resm and recovered. Assays using those compounds are discussed hereinafter.

As used herein, abbreviations for the various ammo acid side-cham protecting groups are as follows: "Trt" for trityl, "tBu' for tert-butyl, "Boc" or "BOC" for tert-butoxycarbonyl , "Tos" for toluenesulfonyl or tosyl, "DNP" for d itrophenyl , "Bzl" for benzyl, "CHO" for formyl , "Brz" for 2- bromobenzyloxycarbonyl and "CBZ" for carbobenzoxy . As can be seen from the side chains exemplified m the table below, it should be appreciated from the above-described embodiments of R¹ and R² are merely illustrative of the R groups that can be present. Following usual notation, L-ammo acids are referred to with an initial capital letter as Val, whereas D-ammo acids are referred to with an initial lower case letter as m ala. Table 1

Amino acid name

Side chain R

Full 3-letter code (For R¹ and R²)

Glycine Gly

-^CH₃

Alanine Ala ^ CH(CH₃)₂

Valine Val ^ CH₂-CH(Cπ₃)₂

Leucine Leu

^ CH(CH₃)CH₂CH₃

Isoleucine lie

-^(CH₂)₄-NH₂

Lysine Lys

^CH₂-OH

Serine Ser

^CH(CH₃)-OH

Threonine Thr

^CH₂-^>

Phenylalanine Phe

Tyrosine Tyr

^(CH₂)₂-CH₃

Norvaline Nva

-^(CH₂)₃-CH₃

Norleucine Nle

Naphthylalanine Nal

Cyclohexylalanine Cha ^CH₂-<^ ^CH₂-CH₂-S-CH₃

Methionine Met

Phenylglycine Phg

A variety of carboxylic acids can also be used in the acylation step of the reaction of Scheme 1, thereby providing a wide array of substituents at the R³ position of the bicyclic [3,5,7] -1H- imidazo [1 , 5-a] imidazol-2 (3H) -one . Ninety-two carboxylic acids were used in preparing the [3,5,7]- 1H- imidazo [1 , 5-a] imidazol-2 (3H) -one libraries .

The ninety-two R³ groups were provided by the following carboxylic acids:

Table 2 Exemplary Carboxylic Acids

1 -Phenyl - 1 -Cyclopropanecarboxylic Acid 2-Phenylbutyric Acid 3 -Phenylbutyric Acid m-Tolylacetic Acid 3-Fluorophenylacetic Acid 3-Bromophenylacetic Acid α,α, -Trifluoro-m-tolyl-acetic Acid p-Tolylacetic Acid 4-Fluorophenylacetic Acid 3 -Methoxyphenylacetic Acid 4-Bromophenylacetic Acid 4 -Methoxyphenylacetic Acid 4-Ethoxyphenylacetic Acid 4- Isobutyl -α-methylphenylacetic Acid 3 , 4-Dichlorophenylacetic Acid 3 , 5 -Bis (Trifluoromethyl) phenylacetic Acid 3 - (3,4 -Dimethoxyphenyl ) propionic Acid 4-Biphenylacetic Acid α— ethylcinnamic Acid 2- (Trifluoromethyl ) cinnamic Acid (3 , 4 -Dimethoxyphenyl) acetic Acid 3,4- (Methylenedioxy) phenylacetic Acid 2 -Methoxyclnnamic Acid 3,4- (Methylenedioxy) cmnamic Acid

2 -Hydroxycmnamic Acid Benzoic Acid 4-Chlorocmnamιc Acid m-Anisic Acid 4-Isopropylbenzoιc Acid 4-Vmylbenzoιc Acid 4-Fluorobenzoιc Acid 4-Bromobenzoιc Acid

3 , 4-Dιmethoxycmnamιc Acid 4-Hydroxybenzoιc Acid trans-Cmnamic Acid

3 , 4-Dιmethylbenzoιc Acid

3-Fluoro-4-methylbenzoιc Acid

3-Bromo-4-methylbenzoιc Acid

3 -Iodo-4-methylbenzoιc Acid

3 , 4-Dιchlorobenzoιc Acid

4-Bιphenylcarboxylιc Acid

3 , 4-Dιfluorobenzoic Acid m-Toluic Acid

Phenylacetic Acid

Hydroc namic Acid

3 -Methoxy-4-methylbenzoιc Acid

4 -Phenylbutyπc Acid

4-Butylbenzoιc Acid

3 , 5-Dιmethylbenzoιc Acid

3 , 5 -Bis (Trifluoromethyl) benzoic Acid

3 , 4-Dιmethoxybenzoιc Acid

4 -Ethyl -4 -biphenylcarboxylic Acid 3 , 4 , 5-Trιmethoxybenzoιc Acid

3 , 4 , 5-Trιethoxybenzoιc Acid

Butyric Acid

Heptanoic Acid

Isobutyπc Acid

(+/-) -2-Methylbutyrιc Acid

Isovaleric Acid

3 -Methylvaleπc Acid

4-Methylvalerιc Acid

(+/- ) -2 -Ethylhexanoic Acid

Crotonic Acid

Vmylacetic Acid trans-3-Hexenoιc Acid

2-Ethyl-2-Hexenoιc Acid p-Toluic Acid p-Anisic Acid

Trimethylacetic Acid tert-Butylacetic Acid

Cyclohexanecarboxylic Acid

Cyclohexylacetic Acid

Dicyclohexylacetic Acid

Cyclohexanebutyric Acid

Cycloheptanecarboxylic Acid

Acetic Acid

2 -Methylcyclopropanecarboxylic Acid

Cyclobutanecarboxylic Acid

Cyclopentanecarboxylic Acid

3-Cyclopentylpropιonιc Acid

2-Furoιc Acid

Cyclohexanepropiomc Acid

4 -Methyl -1 -Cyclohexanecarboxylic Acid

4 -tert-Butyl -Cyclohexanecarboxylic Acid 1-Adamantanecarboxylic Acid 4-Methylcyclohexaneacetic Acid 2 , 4-Hexadienoic Acid Tiglic Acid

2 -Norbornaneacetic Acid 1-Adamantaneacetic Acid 2-Ethylbutyric Acid 2-Thiophenecarboxylic Acid

Example 1: Individual Syntheses of [3,5,7] -1H- imidazo [1, 5-a] -imidazol-2 (3H) -ones

The compounds listed below were prepared following the synthetic route illustrated and discussed in regard to Scheme 1, above. A total of

158 individual compound syntheses or pools were carried out, with 73 of those reactions yielding either no product, starting material or other than the expected product . The reason for the apparent failures is not completely understood, but is believed to be due to steric hindrance. Recent syntheses with about twenty compounds indicated yields of product in each synthesis when freshly distilled POCI3 was used in the synthesis. The reagent used for the preparation of each of the three "R" groups; i.e., the amino acid or carboxylic acid, is listed in the three columns labeled R¹, R² and R³ , respectively. Mass spectral data from the syntheses are shown in the right hand-most column of the table below.

Val Tyr Acetic 285.15 286.15 286..1

Val Trp Acetic 387. 16 388. 16

Val His Acetic 425. 14 426. 14 426. .2

Val Ala Acetic 193. 12 194. .12 194. .1

Val Val Acetic 221. 15 222. .15 222. .1

Val Leu Acetic 235. 17 236. .17 236. .1

Val lie Acetic 235. 17 236. 17 236. .2

Val Ser Acetic 209. 12 210. .12

Val Thr Acetic 223. 13 224. .13

Val Lys Acetic 250. 16 251. .16 251. .2

Val Arg Acetic 278. 19 279. ,19 279. .2

Val Met Acetic 253. 12 254. .12 254. .1

Val nle Acetic 235. 17 236. .17 236. .1

Val nva Acetic 221. 15 222. .15 222 .1

Val cha Acetic 275 .2 276, .20 276 .2

Val phe Acetic 269. 15 270. .15 270. .1

Val tyr Acetic 285. 15 286. .15 286. .1

Val trp Acetic 308. 16 309. .16

Val his Acetic 425. .14 426. .14 426 .1

Val val 1-Phenyl-l- 323 .2 324. .20 324 .2 cyclopropane- carboxylic

Val val 2 -Phenyl -butyric 325. 22 326. .22 326. .2

Val Val 3 -Phenyl-butyric 325. 22 326. .22 326. .2

Val Val m-Tolylacetic 311 .2 312 .20 312 .2

Val Val 3-Fluoro- 315. .17 316 .17 316 .2 phenylacetic

Val Val 3 -Bromo- 375. .11 376. .11 376. .2 phenylacetic

Val val (α,α,α- Trifluoro- 365. .17 366 .17 366 .2 m-Tolyl ) acetic

Val Val p-Tolylacetic 311 .2 312 .20 312 .2

Val val 4-Fluoro- 315. .17 316 .17 316 .1 phenylacetic

Val Val 3 -Methoxy327 .19 328 .19 328 .2 phenylacetic

Val Val 4 -Bromo- 375 .11 376 .11 376 .1 phenylacetic

Val Val 4 -Methoxy327 .19 328 .19 328 .2 phenylacetic

Val val 4-Ethoxy- 341 .21 342 .21 342 .2 phenylacetic

Val val 4 -Isobutyl - 367 .26 368 .26 368 .1 alpha- methylphenyl - acetic

Val Val 3 , 4-Dιchloro- 365 .11 366 .11 366 .2 phenylacetic

Val Val 3,5-Bιs- 433 .16 434 .16 434 .1

(Trifluoro- methyl ) - phenylacetic

Val Val 3- (3,4- 371 .22 372 .22 372 .2

Dimethoxy- phenyl) - propionic

Val Val 4-Bιphenyl- 373 .22 374 .22 374 .2 acetic

Val Val α-Methyl- 323 .2 324 .20 324 .2 cmnamic

Val Val 2- (Trifluoro377 .17 378 .17 378 .2 methyl ) cmnamic

Val Val (3 , 4-Dιmethoxy- 357 .21 358 .21 358 .2 phenyl) acetic

Val Val 3,4- (Methylene- 329 .17 330 .17 330 .2 -4(

dioxy ) phenyl - acetic

89 Val Val 2-Methoxy- 339.19 340.19 cinnamic

90 Val Val 3,4- (Methylene353.17 354.17 dioxy) cmnamic

91 Val Val 2- Hydroxy - 325.1, 326.1? cmnamic

92 Val Val Benzoic 283. 17 284 , .17 284 .2

93 Val Val 4-Chloro- 343. 15 344 .15 344 .2 cmnamic

94 Val Val m-Amsic 313. 18 314. .18

95 Val Val 4 -Isopropyl - 325. 22 326. .22 326 .2 benzoic

96 Val Val 4 -Vmylbenzoic 309. .18 310 .18

97 Val Val 4 -Fluoro- benzoic 301. ,16 302 .16 302 .2

98 Val Val 4 -Bromo-benzoic 361 .1 362 .10

99 Val Val 3 , 4-Dιmethoxy- 369. .21 370 .21 c namic

100 Val Val 4- Hydroxy - 299. .16 300 .16 benzoic

101 Val Val trans -Cmnamic 309. .18 310 .18 310 .2

102 Val Val 3 ,4 -Dimethyl - 311 .2 312 .20 312 .2 benzoic

103 Val Val 3-Fluoro-4- 315.17 316.17 methylbenzoic

104 Val Val 3 -Bromo-4- 375.11 376.11 376.1 me hylbenzoic

105 Val Val 3-Iodo-4- 423. 08 424 .08 methylbenzoic

106 Val Val 3 , 4-Dιchloro- 351. 09 352 .09 benzoic

107 Val Val 4-Bιphenyl- 373. 22 374 .22 374 .2 carboxylic

108 Val Val 3 , 4-Dιfluoro- 319. 15 320 .15 benzoic

109 Val Val m-Toluic 297. 18 298 .18 298 .2

110 Val Val Phenylacetic 297. 18 298 .18 298 .2

111 Val Val Hydrocmnamic 311 .2 312 .20 312 .2

112 Val Val 3 -Methoxy- 4 - 327. 42 328 .42 328 .2 methylbenzoic

113 Val Val 4-Phenylbutyrιc 325. 22 326 .22 326 .2

114 Val Val 4-Butylbenzoιc 339. 23 340 .23 340 .2

115 Val Val 3 , 5 -Dimethyl - 311 .2 312 .20 312 .2 benzoic

116 Val Val 3,5-Bιs- 419. 14 420 .14

(Tπfluoro- methyl ) benzoic

117 Val Val 3 , 4 -Dimethoxy- 343. 19 344 .19 benzoic 118 Val Val 4-Ethyl-4- 387. 23 388 .23 biphenyl- carboxylic

119 Val Val 3,4, 5-Trι- 373 .2 374 .20 methoxybenzoic 120 Val Val 3,4,5-Trι- 415. 25 416 .25 416 2 ethoxy-benzoic

121 Val Val Butyric 249. 18 250 .18 250 .2

122 Val Val Heptanoic 291. .23 292 .23 292 .2

123 Val Val Isobutyric 249. 18 250 .18 250 .2

124 Val Val (+/-) -2 -Methyl - 263 .2 264 .20 264 .2 butyric

125 Val Val Isovaleric 263 .2 264 .20 264 .2

126 Val Val 3 -Methyl al eric 277. .22 278 .22 278 .2

127 Val Val 4 -Methylvaleπc 277. .22 278 .22 278 .2 128 Val Val (+/-) -2-Ethyl- 305..25 306..25 306.2 hexanoic

129 Val Val Crotonic 247 17 248 .17

130 Val Val Vmylacetic 247. .17 248 .17 248 .2

131 Val Val trans-3-Hexenoιc 275 .2 276 .20 276 .3

132 Val Val 2-Ethyl-2- 303. .23 304 .23 304 .2 hexenoic

133 Val Val p-Toluic 297. .18 298 .18 298 .2

134 Val Val p-Anisic 313. .18 314 .18 314 .2

135 Val Val Tπmethylacetic 263 .2 264 .20 264 .1

136 Val Val tert-Butylacetic 277. ,22 278. .22 278 .2

137 Val Val Cyclohexane289. .22 290 .22 290 .2 carboxylic

138 Val Val Cyclohexyl- 303. .23 304. .23 304 .3 acetic

139 Val Val Dicyclohexyl- 385 31 386. .31 386 4 acetic

140 Val Val Cyclohexane - 331. .26 332. .26 332. .3 butyric

141 Val Val Cycloheptane- 303. .23 304. .23 carboxylic

142 Val Val Acetic 221. .15 222. .15 222. .2

143 Val Val 2-Methyl- 261. .18 262. .18 cyclopropane- carboxylic

144 Val Val Cyclobutane- 261. .18 262 .18 262 .2 carboxylic

145 Val Val Cyclopentane- 275 .2 276 .20 276 .2 carboxylic

146 Val Val 3 -Cyclopentyl - 303. .23 304 .23 304 .2 propionic

147 Val Val 2-Furoιc 273. .15 274 .15

148 Val Val Cyclohexane - 317. .25 318 .25 318. .3 propionic

149 Val Val 4-Methyl-l- 303. .23 304 .23 cyclohexane- carboxylic

150 Val Val 4-tert-Butyl- 345. .28 346 .28 cyclohexane- carboxylic

151 Val V Vaall 1-Adamantane- 355 26 356 .26 carboxylic

152 Val V Vaall 4 -Met ylcyclo- 317. .25 318. .25 318, .2 hexaneacetic

153 Val V Vaall 2 , 4-Hexadιenoιc 273. .18 274. .18

154 Val V Vaall Tiglic 261. .18 262. .18

155 Val V Vaall 2 -Norbornane- 315. .23 316. .23 316. ,2 acetic

156 Val Val 1-Adamantane- 355. .26 356. .26 356. .3 acetic

157 Val Val 2-Ethylbutyrιc 277 .22 278 .22 278. .2

158 Val Val 2-Thιophene- 351 09 352 .09 carboxylic

NMR product data for individual compounds from five syntheses carried out following the reaction route outlined above are provided below for compounds corresponding m structure to compound 4b of Scheme 1. Those compounds are referred to as compounds 4b^-"^.

4b 1-5

Product data:

4b¹: ^XH NMR (500 MHz,CD₃0D) δ 6.85-7.27 (m, 10H) , 5.25-5.35 (t, IH) , 3.75-3.85 (s, 2H) , 3.4-3.6 (dd, 2H) , 2.57 (s, 3H) ; HRMS (FAB) m/z 318.1590 found (M+H]⁺, 318.1606 calculated for C₂oH₂o ₃0⁺.

4b²: ^XH NMR (500 MHz,CD₃OD) δ 4.85-4.95 (m, IH) , 2.60 (s, 3H) , 2.54-2.59 (m, IH) , 2.23 (s, IH) , 1.25- 1.26 (d, 3H) , 0.89-0.90 (d, 3H) ; HRMS (FAB) m/z 193.1214 found (M]⁺, 193.1215 calculated for C₁₀H₁₅N₃O. 4b³: ^λrl NMR (500 MHz,CD₃OD) δ 7.15-7.41 (m, 5H) ,

4.8-5.0 (m, 2H) , 3.97 (s, 2H) 2.59 (s, 3H) , 1.27- 1.28 (d, 3H) , 0.90-0.92 (d, 3H) ; HRMS (FAB) m/z 269.1528 found (M]⁺, 269.1528 calculated for Cι₆H₁₉N₃0.

4b⁴: ^XH NMR (500 MHz,CD₃0D) δ 5.64 (s, IH) , 4.14 (s, 3H) , 3.30 (s, IH) , 2.43 (s, 3H) , 1.85-1.90 (dd, 6H) ; HRMS (FAB) m/z 193.1207 found (M]⁺, 193.1215 calculated for C₁₀Hι₅N₃O.

4b⁵: ^XH NMR (500 MHz,CD₃OD) δ 5.59-5.72 (m, 2H) , 5.18-5.20 (d, IH) , 2.68-2.85 (m, 3H) , 2.44 (d, 3H) , 2.37 (s, IH) , 1.0-1.1 (dd, 6H) . LCMS (ES) m/z 208.1 found [M+H]⁺, 208.14 calculated for CιιH₁₈N₃0⁺. Compound Rl R2 R

4b¹ benzyl benzyl methyl

4b² 2 -propyl methyl methyl

4b³ 2 -propyl benzyl methyl

4b⁴ methyl 2 -propyl methyl

4b⁵ benzyl benzyl 2 -propyl

Example 2 : Binding Inhibition of the Rat Brain Mu Receptor by [3 , 5 , 7] -IH- Imidazo [1 , 5-a] - ιmιdazol-2 (3H) -one Compounds

The previously prepared [3,5,7] -1H- lmidazo [1 , 5-a] -ιmιdazol-2 (3H) -one library of individual compounds was screened for the ability to inhibit the binding of [³H] [D-Ala², MePhe⁴ , Gly⁵- ol] enkephalm (DAMGO) that is known to bind specifically to the mu opiate receptor present m rat brain homogenates following literature procedures. [Dooley et al . , Science, 266:2019(1994); U.S. Patent No. 5,763,193.]

Preparation of rat brain membranes and the receptor binding assay were carried out as described m Dooley et al . , Life Sci . , 52:1509(1993). Each tube m the screening assay contained 0.08 mg of compound mixture per milliliter, 0.5 mL of membrane suspension (0.1 mg of protein), 7 nM ³H-labeled DAMGO [specific activity 36 Ci/mmol, obtained from the National Institute on Drug Abuse (NIDA) repository through Chiron Mimotopes PeptideSystems (San Diego, CA) and 50 mL of peptide mixture m 50 mM Tπs-HCl buffer (pH 7.4). The final volume was 0.65 mL . The results of these screenings are shown m the table, below, wherein the "R" groups are as discussed for

Val Val 1 - Phenyl - 1 - cyclo- 830 522.00 55 45 propanecarboxylic

Val Val 2 - Phenylbutyric 935.45 627 .45 66 34

Val Val 3 - Phenylbutyric 900.1 592 10 62 38

Val Val m-Tolylacetic 954.15 646 .15 68 32

Acid

Val Val 3-Fluoro- 853.7 545 70 57 43 phenylacetic Acid

Val Val 3-Bromo- 563 255 .00 27 73 phenylacetic Acid

Val Val (α,α,α,α- Trif luoro- 967.25 659 .25 69 31 m-tolyl ) acetic

Val Val p-Tolylacetic 858.65 550 .65 58 42

Val Val 4-Fluoro- 758.2 450 .20 47 53 phenylacetic Acid

Val Val 3 -Methoxy854 546 .00 57 43 phenylacetic Acid

Val Val 4-Bromo- 682.95 374 95 39 61 phenylacetic Acid

Val Val 4 -Methoxy775.2 467 .20 49 51 phenylacetic Acid

Val Val 4-Ethoxy- 929 1 621 .10 65 35 phenylacetic Acid

Val Val 3 , 4-Dιclhloro- 988.3 680 .30 71 29 phenylacetic Acid

Val Val 3,5-Bιs- 911.65 603 .65 63 37

(Tπfluoromethyl)

-phenylacetic

Val Val -Bιphenylacetιc 850.4 542 40 57 43

Val Val (3 , 4-Dιmethoxy- 870.35 562 .35 59 41 phenyl) acetic

Val Val 3,4-

(Methylenedioxy) - cmnamic Acid Val Val 4-Bιphenyl- 804.2 496. .20 52 48 carboxylic Acid

Val Val Phenylacetic Acid 818.7 510. .70 54 46

Val Val 4 - Phenylbutyric 716.3 408 30 43 57

Acid

Val Val Butyric Acid 826.45 518. .45 54 46

Val Val Heptanoic Acid 817.3 509. .30 53 47

Val Val Isobutyπc Acid 832 5 524. .50 55 45

Val Val (+/-)-2- 901.85 593. .85 62 38

Methylbutyric

Acid

Val Val Isovaleπc Acid 763 7 455 70 48 52

Val Val 3 -Methylvaleπc 918 7 610. .70 64 36

Acid

Val Val 4 -Methylvaleπc 909.6 601. 60 63 37

Acid

Val Val (+/-J-2- 881.35 573. 35 60 40

Ethylhexanoic

Acid

Val Val Trimethylacetic 931.85 623 85 65 35

Acid

Val Val tert-Butylacetic 991 683 00 72 28 137 Val Val Cyclohexane933.35 625.35 66 34 carboxylic Acid

138 Val Val Cycloexylacetic 877 .8 569 .80 60 40

Acid

139 Val Val Dicyclo- 928. 85 620 .85 65 35 hexylacetic Acid

140 Val Val Cycloheptane- 615. 55 307 .55 32 68 carboxyic Acid

142 Val Val Acetic Acid 946. 05 638 .05 67 33

144 Val Val Cyclobutane- 867 .3 559 .30 59 41 carboxylic Acid

145 Val Val Cyclopentane- 986 .9 678 .90 71 29 carboxylic Acid

146 Val Val 3 -Cyclopentyl - 945. 85 637. .85 67 33 propionic Acid

148 Val Val Cyclohexane - 890 .8 582. .80 61 39 propionic Acid

152 Val Val 4-Methyl -cyclo- 770 .1 462. .10 48 52 hexaneacetic Acid

155 Val Val 2-Norbornane- 918. 35 610. .35 64 36 acetic Acid

156 Val Val 1-Adamantane- 925. 85 617. .85 65 35 acetic Acid

157 Val Val 2-Thιophene- 930. 35 622. .35 65 35 carboxylic Acid

*NSB = ^■■ nnoonn--specific binding.

Example 3 : Binding Inhibition of the Guinea Pig Brain Kappa Receptor by [3,5,7] -1H-

Imidazo [1 , 5-a] imidazol-2 (3H) -one Compounds

The above-prepared library of individual compounds was screened for the ability to inhibit the binding of tritiated Compound U69,593 that is known to bind specifically to the kappa opiate receptor present in guinea pig brain homogenates following literature procedures. [Dooley et al . , J^". Biol .

Chem . , 273(30) 18848-18856 (1998)]

Briefly, guinea pig cortices and cerebella were homogenized in 40 mL of Buffer A [50 mM Tns-

HC1 , pH 7.4] at 4°C. Homogenates were centrifuged [Beckman^® J2-HC, 35,300 x g] for 10 minutes. The pellets were resuspended in fresh buffer and incubated at 37°C for 40 minutes. Following incubation, the suspensions were centrifuged as before, the resulting pellets resuspended in 100 volumes of Tris buffer, and the suspensions combined. Membrane suspensions were prepared and used on the same day. Protein content of the crude homogenates was determined by the method of Bradford, Anal . Biochem . , 72:248-252 (1976). Each assay tube contained 0.5 mL of membrane suspension, 3 nm of tπtiated Compound U69, 593 [ (5a,7a, 8b) - (-) -N-methyl-N- (7- (1- pyrrolidmyl) -1-oxaspιro (4,5)dec-8-yl)- benzeneacetamide ; Lahti et al . , European J. Pharmacol . , 109:281-284 (199-85) ] m a total volume of 0.65 mL . Assay tubes were incubated for 2.5 hours a

25°C. The assay was then filtered through GF-B filters on a Tomec™ harvester (Orange, CT) . The filters were subsequently washed with 6 mL of 50 mM Tπs-HCl, pH 7.4 at 4°C. Bound radioactivity was counted on a Wallace™ Beta-plate Liquid Scintillation Counter (Piscataway, NJ) . Unlabeled 1750,488 [ (trans- (dl) -3 , 4-dιchloro-N-methyl-N- [2- (1 -pyrrolldmyl) - cyclohexyl] -benzeneacetamide) methane sulfonate hydrate; Lahti et al . , Life Sci . , 31 : 2257-xx (1982) and Von Voightlander et al . , J. Pharmacol . Exp . Ther . , 224:7 (1983)] was used as a competitive inhibitor to generate a standard curve and determine nonspecific binding. The results of these assays are shown m the table, below, wherein the "R" groups are as discussed for Example 1. [3,5,7] -IH- Imidazo [1, 5-a] imidazol-2 (3H) -one Compound Binding Inhibition of [³H]U69,593

Pool Minus

# Mean NSB Bound Inhibi

3 Val Val Acetic Acid 1468.8 561. .80 54. .228 45 .772

4 Leu Val Acetic Acid 1895.55 988. .55 95. .420 4. 580

5 lieu Val Acetic Acid 1684.45 777. .45 75. .043 24 .957

11 Nle Val Acetic Acid 1736.15 829. .15 80. .034 19 .966

12 Nva Val Acetic Acid 1680.95 773. .95 74. .706 25 .294

18 Ala Val Acetic Acid 1818.85 911. .85 88. .016 11 .984

19 Val Val Acetic Acid 1783.25 876. .25 84. .580 15 .420

20 Leu Val Acetic Acid 1621.8 714. .80 68. .996 31 .004

21 lieu Val Acetic Acid 1496.7 589. .70 56. .921 43 .079

27 Nle Val Acetic Acid 1734.3 827. .30 79. .855 20 .145

28 Nva Val Acetic Acid 1607.35 700. .35 67. .601 32 .399

29 Cha Val Acetic Acid 1821.55 914. .55 88. .277 11 .723

30 Phe Val Acetic Acid 1682.8 775. ,80 74. .884 25 .116

34 Val Gly Acetic Acid 1726.65 819. .65 79. .117 20 .883

35 Val Ala Acetic Acid 1711.9 804. .90 77. .693 22 .307

36 Val Val Acetic Acid 1787.35 880. .35 84. .976 15 .024

37 Val Leu Acetic Acid 1559.4 652. .40 62. .973 37 .027

38 Val lieu Acetic Acid 1618.1 711. .10 68. .639 31 .361

39 Val Ser Acetic Acid 1723.65 816. .65 78. .827 21 .173

41 Val Lys Acetic Acid 1444.2 537. .20 51. .853 48 .147

42 Val Arg Acetic Acid 1406.35 499. .35 48. .200 51 .800

44 Val Nle Acetic Acid 2049.7 1142 .70 110 .299 -10 .299

45 Val Nv Acetic Acid 1790.45 883. .45 85. 275 14. .725

46 Val Ch Acetic Acid 2169 1262 .00 121 .815 -21 .815

47 Val Ph Acetic Acid 1989.3 1082 .30 104 .469 -4. .469

48 Val Tyr Acetic Acid 1784 877. .00 84. 653 15. .347

51 Val Ala Acetic Acid 1645.8 738. .80 71. 313 28. .687

52 Val Val Acetic Acid 1681.35 774. .35 74. 744 25. .256

53 Val Leu Acetic Acid 2008.85 1101 .85 106 .356 -6. .356

54 Val lieu Acetic Acid 1947.25 1040 .25 100 .410 -0. .410

59 Val Met Acetic Acid 1724.95 817. .95 78. 953 21. .047

60 Val Nle Acetic Acid 1755 4 848. .40 81. 892 18. .108

61 Val Nva Acetic Acid 1433.75 526. .75 50. 845 49. .155

62 Val Cha Acetic Acid 1776.3 869. .30 83. 909 16. .091

63 Val Phe Acetic Acid 1786.7 879. .70 84. 913 15. .087

64 Val Tyr Acetic Acid 1545.5 638. .50 61. 631 38. .369

67 Val Val 1 -Phenyl - 1-cyclo 1784.1 877. .10 84. 662 15. .338 propaneca:rboxylic

Acid

68 Val Val 2 -Phenylbutyric 2013.3 1106 .30 106 .786 -6. .786

Acid

69 Val Val 3 -Phenylbutyric 1602.75 695. .75 67. 157 32. .843

Acid

70 Val Val m-Tolylacetic Acid 2019.55 1112 .55 107 .389 -7. .389 71 Val Val 3-Fluoro- 1541.5 634.50 61.245 38.755 phenylacetic Acid

72 Val Val 3-Bromo- 1588.15 681.15 65.748 34.252 phenylacetic Acid

73 Val Val (α.α,α,α-Trιfluoro- 1717.2 810.20 78.205 21.795 m-tolyl ) acetic Acid

74 Val VVaall p-Tolylacetic Acid 1407.25 500.25 48.287 51.713

75 Val Val 4-Fluoro- 1643.95 736.95 71.134 28.866 phenylacetic Acid

76 Val Val 3-Methoxy- 1859.1 952.10 91.902 8.098 phenylacetic Acid

77 Val Val 4-Bromo- 1670 1 763.10 73.658 26.342 phenylacetic Acid

78 Val Val 4-Methoxy- 1812.05 905.05 87.360 12.640 phenylacetic Acid

79 Val Val 4-Ethoxy- 1842 9 935.90 90.338 9.662 phenylacetic Acid

81 Val Val 3,4-Dιclhloro 1831.35 924.35 89.223 10.777 phenylacetic Acid

82 Val Val 3,5-Bls- 1638.3 731.30 70.589 29.411 (Trifluoromethyl) - Phenylacetic Acid

84 Val Val 4-Bιphenylacetιc 1628.3 721.30 69.624 30.376 Acid

87 Val Val (3,4- 1749.65 842.65 81.337 18.663

Dimethoxyphenyl ) - acetic Acid 88 Val Val 3,4- 1739.6 832.60 80.367 19.633

(Methylenedioxy) - Cmnamic Acid 107 Val Val 4-Bιphenyl- 2089.6 1182.60 114.151 -14.151 carboxylic Acid

110 Val Val Phenylacetic Acid 1667.95 760.95 73.451 26.549

113 Val Val 4 -Phenylbutyric 1545.15 638.15 61.597 38.403 Acid

121 Val Val Butyric Acid 1533.45 626.45 60.468 39.532

122 Val Val Heptanoic Acid 1443.7 536.70 51.805 48.195

123 Val Val Isobutyπc Acid 1498.8 591.80 57.124 42.876

124 Val Val (+/-) -2-Methyl- 1555.85 648.85 62.630 37.370 butyric Acid

125 Val Val Isovaleπc Acid 1553.3 646.30 62.384 37.616

126 Val Val 3-Methylvalerιc 1666.5 759.50 73.311 26.689

127 Val Val 4-Methylvalerιc 1592.6 685.60 66.178 33.822 Acid

128 Val Val (+/-) -2-Ethyl- 1503.35 596.35 57.563 42.437 hexanoic Acid

135 Val Val Tπmethylacetic 1623.6 716.60 69.170 30.830

136 Val Val tert-Butylacetic 1741 9 834.90 80.589 19.411

137 Val Val Cyclohexane- 2249.85 1342.85 129.619 -29.619 carboxylic Acid

138 Val Val Cycloexylacetic 1639 3 732.30 70.685 29.315

139 Val Val Dicyclohexyl- 1515.95 608.95 58.779 41.221 acetic Acid

140 Val Val Cycloheptane- 1424 517.00 49.903 50.097 carboxyic Acid

142 Val Val Acetic Acid 1728.8 821.80 79.324 20 676

144 Val Val Cyclobutane- 1447.5 540.50 52 172 47.828 carboxylic Acid 145 Val Val Cyclopentane- 1544.15 637.15 61.501 38.499 carboxylic Acid 146 Val Val 3 -Cyclopentyl- 1622.75 715.75 69.088 30.912 propionic Acid

148 Val Val Cyclohexane- 1839.1 932.10 89.971 10.029 propionic Acid

152 Val Val 4-Methylcyclo- 1515.1 608.10 58.697 41.303 hexaneacetic Acid

155 Val Val 2-Norbornane- 1622.25 715.25 69.040 30.960 acetic Acid

156 Val Val 1-Adamantane- 1723.4 816.40 78.803 21.197 acetic Acid

157 Val Val 2-Thιophene- 1473.05 566.05 54.638 45.362 carboxylic Acid

Example 4: Preparation of Libraries of [3,5,7] -1H- Imidazo [1 , 5-a] imidazol-2 (3H) -one Compounds

Libraries of [3 , 5 , 7] -IH-imidazo [1 , 5- a] imidazol-2 (3H) -one compounds are prepared analogously to the preparation of individual compounds discussed in Example 1. However, whereas a single reagent was used to provide each of the R groups of the intermediates prepared in the syntheses of the individual compounds of Example 1, both single reactants and mixtures of reactants are used to provide the R¹ , R² and R³ groups for the different library pools of mixed compounds. As is discussed in treated detail below, 33 library pools are prepared in which R¹ is an individual amino acid side chain, with separate pools containing mixtures of 33 amino acids of different side chains (R²) and 92 different carboxylic acid chains (R³) .

Where individual reactants are used to provide a particular R group, the procedures of Example 1 are followed. Where mixtures are desired at a particular R group, the protected amino acids or carboxylic acids are provided in mixtures. The mixtures used to provide the various R groups are listed in the table, below, with the relative molar amount of each reactant being listed.

Table 4

Mixtures of Reactants Used to Prepare [3,5,7] -lH-Imιdazo[l,5-a] imidazol -2 (3H) -one Mixed Compound Library

1 2 3

R R R

Boc-amino Ratio Boc-amino Ratio Carboxylic acid Ratio acids Reagent acids Reagent Reagent

Boc-L-Ala 0.95 Boc-L-Ala 0.95 1-Phenyl-l- 1.00 cyclopropane - carboxylic Acid Boc-L-Phe 0.81 Boc-L-Phe 0.81 2 -Phenylbutyric 1.20 Boc-Gly 1.00 Boc-Gly 1.00 henylbutyric 2.60

Boc-L- 0.85 Boc-L-His (DNP) 0.85 m-Tolylacetic Acid 1.80

His (DNP) Boc-L-Ile 1.16 Boc-L- lie 1.16 3 -Fluorophenyl- 0.84 acetic Acid Boc-L- 1.05 Boc-L-Lys (CBZ) 1.05 3 -Bromophenyl - 0.61

Lys(CBZ) acetic Acid

Boc-L-Leu 1.08 Boc-L-Leu 1.08 (α,α,α-Tnfluoro-m- 0.61

Tolyl) acetic Acid Boc-L-Met 0.89 Boc-L-Met 0.89 p-Tolylacetic Acid 1.36 Boc-L- 1.42 Boc-L-Arg (Tos) 1.42 4 -Fluorophenyl - 1.04

Arg(Tos) acetic Acid

Boc-L- 1.30 Boc-L-Ser (Bzl) 1.30 3 -Methoxyphenyl - 1.17

Ser(Bzl) acetic Acid

Boc-L- 1.60 Boc-L-Thr (Bzl) 1.60 4 -Bromophenyl- 0.88

Thr(Bzl) acetic Acid

Boc-L-Val 1.14 Boc-L-Val 1.14 4 -Methoxyphenyl- 1.80 acetic Acid Boc-L- 0.89 Boc-L-Trp (CHO) 0.89 4 -Ethoxyphenyl- 1.40

Trp (CHO) acetic Acid

Boc-L- 1.26 Boc-L-Tyr(BrZ) 1.26 4 - Isobutyl -α- 1-70

Tyr(BrZ) methylphenylacetic

Boc-D-Ala 0.95 Boc-D-Ala 0.95 3 , 4 -Dichloro- 0.81 phenylacetic Acid Boc-D-Phe 0.81 Boc-D-Phe 0.81 3,5-Bιs- 0.50

(Trifluoromethyl) - phenylacetic Acid Boc-D- 0.85 Boc-D-His (DNP) 0.85 3 - ( 3 , 4 -Dimethoxy- 2.20

His (DNP) phenyl ) propionic Boc-D-Ile 1 16 Boc-D-Ile 1.16 ιphenylacetιc 1.40

Boc-D- 1.05 Boc-D-Lys(CBZ) 1.05 -Methylcmnamic 1-95

Boc-D-Leu 1.08 Boc-D-Leu 1.08 2- 1.03

( Trif luoromethyl ) - cmnamic Acid Boc -D-Met 0 . 89 Boc -D-Met 0 . 89 ( 3 , 4 -Dimethoxy- 1 . 44 phenyl ) acetic Acid

Boc -D- 1.42 Boc-D-Arg (Tos) 1.42 3,4- (Methylene- 1.27 Arg (Tos ) dioxy) phenylacetic

Acid

Boc-D- 1.30 Boc-D-Ser (Bzl) 1.30 2-Methoxycmnamιc 5.60 Ser (Bzl ) Acid Boc-D- 1.60 Boc-D-Thr (Bzl) 1.60 3,4- (Methylene- 10.40 Thr (Bzl ) dioxy) cmnamic Acid Boc -D-Val 1.14 Boc-D-Val 1.14 2 -Hydroxy- cmnaraic 4.90 Acid

Boc -D- 0.89 Boc-D-Trp(CHO) 0 89 Benzoic Acid 1.28

Trp ( CHO)

Boc -D- 1.26 Boc-D-Tyr(BrZ) 1.26 4-Chlorocmnamιc 2.95

Boc - L- 1.15 Boc-L- 1.15 -Anisic Acid 1.52

Norvaline Norval e

Boc -D- 1.15 Boc-D- 1.15 4- Isopropyl- 3.00

Norval e Norvaline benzoic Acid

Boc - L- 1.15 Boc-L- 1.15 4-Vmylbenzoιc 1.50

Norleucme Norleucme Acid

Boc -D- 1.15 Boc-D- 1.15 4-Fluorobenzoιc 1 22

Norleuc e Norleuc e Acid

Boc - L- 1.50 Boc-L- 1.50 4-Bromobenzoιc 0.59

Cyclohexyl - Cyclohexyl- Acid alamne alanme

Boc -D- 1.50 Boc-D- 1.50 3, 4 -Dimethoxy- 7.27

Cyclohexyl- Cyclohexyl- cmnamic Acid alanine alanme

4 -Hydroxybenzoic 7 , .61

trans-Cmnamic Acid 4 .20

3, 4-Dιmethyl- 2. .44 benzoic Acid

3-Fluoro-4-methyl- 0. .75 benzoic Acid

3 -Bromo-4 -methyl - 0 .86 benzoic Acid

3 - Iodo-4 -methyl - 0 84 benzoic Acid

3 , 4-Dιchloro- 0 .39 benzoic Acid

4-Bιphenyl- 5 .10 carboxylic Acid

3 , 4-Dιfluoro- 0. .45 benzoic Acid m-Toluic Acid 1 .60

Phenylacetic Acid 1 .00

Hydroc namic Acid 2 .50

3 -Methoxy- 4- 2 .10 methylbenzoic Acid

4 - Phenylbutyric 3 .00

Acid

4 -Butylbenzoic 2 60

3 , 5 -Dimethyl - 1 .94 benzoic Acid

3,5-Bιs- 0 .96

(Trifluoromethyl) -

Benzoic Acid

3 , 4 -Dimethoxy- 3 .08 benzoic Acid

4 -Ethyl-4- 0. .92 biphenylcarboxylic

3,4, 5-Tπmethoxy- 1 .46 benzoic Acid

3,4, 5-Tπethoxy- 2 .37 benzoic Acid

Butyric Acid 3 .39

Heptanoic Acid 3 .51

Isobutyπc Acid 3 .11

(+/-) -2 -Methyl - 6 .25 butyric Acid

Isovaleπc Acid 6 .36

3 -Methylvaleric 5 06 ethylvaleric 3 32

( + /-) - 2 -Ethyl - _* hexanoic Acid

Crotonic Acid 5 .26

Vinylacetic Acid 1 .30 trans - 3 -Hexenoic _*

2 -Ethyl -2 -hexenoic 11 .63

Acid p-Toluic Acid 2 28 p-Anisic Acid 5 .38

Tπmethylacetic 4 .24

tert-Butylacetic _*

Cyclohexane3 .51 carboxylic Acid

Cyclohexylacetic 3 .95

Dicyclohexylacetic _*

Cyclohexanebutyric 3 .33

Cycloheptane- 2. .60 carboxylic Acid

Acetic Acid 2 .65

2 -Methylcyclo2 .42 propanecarboxylic

Acid

Cyclobutane- 2 .77 carboxylic Acid

Cyclopentane- 3. .03 carboxylic Acid

3 -Cyclopentyl - 3, .71 propionic Acid

2-Furoιc Acid 4. .44

Cyclohexane- 2. .80 propionic Acid

4 -Methyl -1 -cyclo5 92 hexanecarboxylic

4-tert-Butyl- 6. .64 cyclohexane- carboxylic Acid

1-Adamantane- _* carboxylic Acid

4 -Methylcyclo- 4 79 hexaneacetic Acid

2 , 4 -Hexadienoic _*

Acid

Tiglic Acid 4 59

2-Norbornane- 5 45 acetic Acid 1-Adamantane- 11.16 acetic Acid

2-Ethylbutyrιc Acid

2-Thιophene- 1.16 carboxylic Acid

*-ratιo not determined

Each of the patents and articles cited herein is incorporated by reference. The use of the article "a" or "an" is intended to include one or more .

The foregoing description and the examples are intended as illustrative and are not to be taken as limiting. Still other variations within the spirit and scope of this invention are possible and will readily present themselves to those skilled in the art.

Claims

What is Claimed:

1. A library of compounds having a structure corresponding to that shown m Formula I, below, or a pharmaceutically acceptable salt thereof:

wherein:

R¹ and R^ are independently selected from the group consisting of a hydrido, C₁-C_]_o alkyl, C- - C_]__Q substituted alkyl, C7-C]_g phenylalkyl, C7-C₁5 substituted phenylalkyl, phenyl, substituted phenyl, C3-C7 cycloalkyl, and a C3-C7 substituted cycloalkyl group ; and R³ is selected from the group consisting of a hydrido, C]_-C_₀ alkyl, C_-C]_Q substituted alkyl, ^c2"^c10 alkenyl, C2-C]_o substituted alkenyl, C2-C10 alkynyl, C2- 10 substituted alkynyl, C3-C₇ substituted cycloalkyl, phenyl, C₇-C_]_g phenylalkyl, -C₁6 phenylalkenyl, C7-C15 phenylalkenyl and a C7- C_j_g substituted phenylalkenyl group.

2. The library according to claim 1 wherein R¹ and R² are independently selected from the group consisting of a hydrido, methyl, benzyl, 2- butyl , N, N-dimethylammobutyl , N-methylammobutyl , N- methyl -N-benzylammobutyl , 2 -methylpropyl , methylsulfmylethyl , methylthioethyl , N,N- dimethylammoethyl , N, N-dimethylammopropyl , N , N , N - tri ethylguanidinopropyl , N ,N , N -tπbenzyl- guanidinopropyl , N ,N -dibenzylguanidinopropyl, N - methylguanidmopropyl , hydroxymethyl, 1-hydroxyethyl, 2 -propyl, N-methyl-3 -mdolylmethyl , 4-methoxybenzyl, 4 -hydroxybenzyl , propyl , butyl , cyclohexylmethyl , phenyl, 2-naphthylmethyl , and a 4-ιmιdazolylmethyl substituent .

3. The library according to claim 1 wherem R³ is selected from the group consisting of a 1 -phenyl - 1 -cyclopropyl , 1-phenylbutyl , 2 -phenylbutyl , 3-fluorobenzyl , 3-bromobenzyl , α, α, α-tπfluoro-m- xylyl , p-xylyl, 4-fluorobenzyl , 3-methoxybenzyl , 4- bromobenzyl , 4-methoxybenzyl, 4-ethoxybenzyl , 4- lsobutyl-α-methylbenzyl , 3 , 4-dιchlorobenzyl , 3,5-bιs- (tπfluoromethyl) benzyl , 2- (3,4- dimethoxyphenyl) ethyl , 4-bιphenylmethyl , β- methylstyryl , 2 - (trifluoromethyl) -styryl , 3,4- dimethoxybenzyl , 3 , 4 -dihydroxybenzyl , 2- methoxystyryl , 3 , 4-dιhydroxystyryl , 2 -hydroxystyryl , phenyl, 4-chlorostyryl , 3 -methoxyphenyl , 4- lsopropylphenyl , 4-vmylphenyl , 4-fluorophenyl , 4- bromophenyl , 3 , 4 -dimethoxystyryl , 4 -hydroxyphenyl , trans- styryl , 3 , 4-dιmethylphenyl , 3-fluoro-4- methylphenyl , 3 -bromo-4 -methyl -phenyl , 3-ιodo-4- methyl -phenyl , 3 , 4-dιchlorophenyl , 4-biphenyl, 3,4- difluorophenyl , m-tolyl, benzyl, phenethyl, 3- methoxy-4-methylphenyl , 3-phenylpropyl , 4- butylphenyl , 3 , 5-dιmethylphenyl , 3,5-bιs-

(tπfluoromethyl) phenyl , 3 , 4-dimethoxyphenyl , 4- ethyl-4-bιphenyl , 3 , 4 , 5-tπethoxyphenyl , propyl, hexyl , isopropyl, 2 -butyl, isobutyl, 2-pentyl, isovaleryl, 3-heptyl, 1-propenyl, 2-propenyl, trans- 2-pentenyl, 1 -ethyl -1 -pentenyl , p-tolyl, p-anisyl, t- butyl , neopentyl , cyclohexyl, cyclohexylmethyl , dicyclohexylmethyl, cyclohexylpropyl, cycloheptyl, methyl, 2-methylcyclopropyl, cyclobutyl, cyclopentyl, cyclopentylethyl , 2-furyl, cyclohexylethyl , 4- methylcyclohexyl , 4 -tert -butyl -cyclohexyl , 1- adamantyl , 4 -methylcyclohexylmethyl , 1 , 3 -pentadienyl , 2-buten-2-yl , 2 -norbornanemethyl , 1 -adamantanemethyl , 3-pentyl, and a 2 -thiophene substituent.

4. The library according to claim 1 wherein the R¹ substituent is a side chain from an amino acid selected from the group consisting of Ala, Phe, Gly, His, lie, Lys, Leu, Met, Arg, Nva, Ser, Thr, Val, Tyr, Tyr, Nle, Cha, ala, phe, his, ile, lys, leu, met, arg, ser, thr, val, trp, tyr, nle, nva, and cha, wherein amino acids written in all lower case letters are D-amino acids.

5. The library according to claim 1 wherein the R² substituent is a side chain from an amino acid selected from the group consisting of Ala, Phe, Gly, His, Ile, Lys, Leu, Met, Arg, Nva, Ser, Thr, Val, Tyr, Tyr, Nle, Cha, ala, phe, his, ile, lys, leu, met, arg, ser, thr, val, trp, tyr, nle, nva, and cha, wherein amino acids written in all lower case letters are D-amino acids.

6. A library of compounds having a structure corresponding to that shown in the formula below, or a pharmaceutically acceptable salt thereof:

wherein:

R¹ and R² are independently benzyl, methyl or 2 -propyl and R³ is methyl or 2 -propyl.

7. A compound having a structure corresponding to that shown in Formula I, below, or a pharmaceutically acceptable salt thereof:

wherein :

Rl and R² are independently selected from the group consisting of a hydrido, C_-C]_Q alkyl, C_- C_]_o substituted alkyl, C7-C]_g phenylalkyl, C7-C_ substituted phenylalkyl, phenyl, substituted phenyl, C3-C7 cycloalkyl, and a C3-C7 substituted cycloalkyl group ; and

R³ is selected from the group consisting of a hydrido, C^-C^Q alkyl, C]_-C]_Q substituted alkyl, C2-C_o alkenyl, C₂-C₁₀ substituted alkenyl, C2-C10 alkynyl, C2-C]_Q substituted alkynyl, C3-C7 substituted cycloalkyl, phenyl, C7-C₁₆ phenylalkyl, C7-C phenylalkenyl, Cη - C±β phenylalkenyl and a C7- C_]_g substituted phenylalkenyl group.

8. The compound according to claim 7 wherein R¹ and R² are independently selected from the group consisting of a hydrido, methyl, benzyl, 2- butyl , N,N-dimethylaminobutyl , N-methylaminobutyl, N- methyl -N-benzylaminobutyl , 2-methylpropyl , methylsulfinylethyl , methylthioethyl , N,N- dimethylaminoethyl , N,N-dimethylaminopropyl , N ,N ,N - trimethylguanidinopropyl , N ,N ,N -tribenzyl- guanidinopropyl , N ,N -dibenzylguanidinopropyl, N - methylguanidinopropyl , hydroxymethyl, 1-hydroxyethyl, 2 -propyl, N-methyl-3 -mdolylmethyl , 4-methoxybenzyl, 4-hydroxybenzyl , propyl, butyl, cyclohexylmethyl , phenyl, 2 -naphthylmethyl , and a 4-imidazolylmethyl substituent .

9. The compound according to claim 7 wherein R^ is selected from the group consisting of a 1 -phenyl - 1 -cyclopropyl , 1-phenylbutyl , 2-phenylbutyl , 3 -fluorobenzyl , 3 -bromobenzyl , α, α, α-trifluoro-m- xylyl, p-xylyl, 4-fluorobenzyl , 3-methoxybenzyl, 4- bromobenzyl , 4-methoxybenzyl, 4-ethoxybenzyl , 4- isobutyl-α-methylbenzyl , 3 , 4-dichlorobenzyl , 3,5-bis- (trifluoromethyl) benzyl , 2-(3,4- dimethoxyphenyl) ethyl , 4-biphenylmethyl , β- methylstyryl , 2 - (trifluoromethyl) -styryl , 3,4- dimethoxybenzyl , 3 , 4-dihydroxybenzyl , 2- methoxystyryl , 3 , 4-dihydroxystyryl , 2-hydroxystyryl , phenyl, 4-chlorostyryl , 3 -methoxyphenyl , 4- isopropylphenyl , 4 -vinylphenyl , 4-fluorophenyl , 4- bromophenyl , 3 , 4 -dimethoxystyryl , 4-hydroxyphenyl , trans-styryl , 3 , 4 -dimethylphenyl , 3-fluoro-4- methylphenyl , 3 -bromo-4 -methyl -phenyl , 3-iodo-4- methyl -phenyl , 3 , 4-dichlorophenyl , 4-biphenyl, 3,4- difluorophenyl , m-tolyl, benzyl, phenethyl , 3- methoxy-4-methylphenyl , 3 -phenylpropyl , 4- butylphenyl , 3 , 5 -dimethylphenyl , 3,5-bis-

(trifluoromethyl) phenyl , 3 , 4-dimethoxyphenyl , 4- ethyl-4-biphenyl , 3 , 4 , 5-triethoxyphenyl , propyl, hexyl, isopropyl, 2 -butyl, isobutyl, 2-pentyl, isovaleryl, 3-heptyl, 1-propenyl, 2-propenyl, trans- 2-pentenyl, 1-ethyl-l-pentenyl, p-tolyl, p-anisyl, t- butyl , neopentyl , cyclohexyl, cyclohexylmethyl , dicyclohexylmethyl, cyclohexylpropyl, cycloheptyl, methyl, 2-methylcyclopropyl, cyclobutyl, cyclopentyl, cyclopentylethyl , 2-furyl, cyclohexylethyl , 4- methylcyclohexyl , 4 -tert-butyl-cyclohexyl , 1- adamantyl , 4 -methylcyclohexylmethyl , 1 , 3 -pentadienyl , 2-buten-2-yl , 2-norbornanemethyl , 1 -adamantanemethyl , 3-pentyl, and a 2 -thiophene substituent.

10. The compound according to claim 7 wherein the R^- substituent is a side chain from an amino acid selected from the group consisting of Ala, Phe, Gly, His, Ile, Lys, Leu, Met, Arg, Nva, Ser, Thr, Val, Tyr, Tyr, Nle, Cha, ala, phe, his, ile, lys, leu, met, arg, ser, thr, val, trp, tyr, nle, nva, and cha, wherein amino acids written in all lower case letters are D-amino acids.

11. The compound according to claim 7 wherein the R² substituent is a side chain from an amino acid selected from the group consisting of Ala, Phe, Gly, His, Ile, Lys, Leu, Met, Arg, Nva, Ser, Thr, Val, Tyr, Tyr, Nle, Cha, ala, phe, his, ile, lys, leu, met, arg, ser, thr, val, trp, tyr, nle, nva, and cha, wherein amino acids written in all lower case letters are D-amino acids.

12. A compound having a structure corresponding to that shown in the formula below, or a pharmaceutically acceptable salt thereof:

wherein:

R¹ and R² are independently benzyl, methyl or 2 -propyl and R^ is methyl or 2 -propyl.

13. The compound according to claim 12 wherein R-¹- and R² are benzyl and R^ is methyl.

14. The compound according to claim 12 wherein R¹ is 2 -propyl, and R² and R^ are methyl.

15. The compound according to claim 12 wherein R¹ is 2 -propyl, R² is benzyl and R- is methyl .

16. The compound according to claim 12 wherein R¹ is methyl, R² is 2 -propyl and R^ is methyl .

17. The compound according to claim 12 wherein R¹ and R² are benzyl and R³ is 2 -propyl.