BACKGROUNDINFORMATION The melanocortin (MC) receptors are a group of cell surface proteins that mediate a variety of physiological effects, including regulation of adrenal gland function such as production of the glucocorticoids cortisol and aldosterone; control of melanocyte growth and pigment production ; thermoregulation ; immunomodulation; analgesia; obesity; feeding disorders; and sexual dysfunction. Five distinct MC receptors have been cloned and are expressed in a variety of tissues, including melanocytes, adrenal cortex, brain, gut, placenta, skeletal muscle, lung, spleen, thymus, bone marrow, pituitary, gonads and adipose tissue (Tatro, Neuroimmunomodulation 3: 259-284 (1996)). Three MC receptors, MCR-1, MCR-3 and MCR-4, are expressed in brain tissue (Xia et al., Neuroreport 6: 2193-2196 (1995)).

A variety of ligands termed melanocortins function as agonists that stimulate the activity of MC receptors. The melanocortins include melanocyte-stimulating hormones (MSH) such as a-MSH, (3-MSH and Y-MSH, as well as adrenocorticotropic hormone

(ACTH). Individual ligands can bind to multiple MC receptors with differing relative affinities. The variety of ligands and MC receptors with differential tissue-specific expression likely provides the molecular basis for the diverse physiological effects of melanocortins and MC receptors. For example, a-MSH antagonizes the actions of immunological substances. such as cytokines and acts to modulate fever, inflammation and immune responses (Catania and Lipton, Annals N. Y. Acad.

Sci. 680: 412-423 (1993)).

More recently, the role of specific MC receptors in some of the physiological effects described above for MC receptors has been elucidated. For example, MCR-1 is involved in pain and inflammation. MCR-1 mRNA is expressed in neutrophils (Catania et al., Peptides 17 : 675-679 (1996)). The anti-inflammatory agent a-MSH was found to inhibit migration of neutrophils. Thus, the presence of MCR-1 in neutrophils correlates with the anti-inflammatory activity of a-MSH.

An interesting link of MC receptors to regulation of food intake and obesity has recently been described. The brain MC receptor MCR-4 has been shown to function in the regulation of body weight and food intake. Mice in which MCR-4 has been knocked out exhibit weight gain (Huszar et al., Cell 88: 131-141 (1997)). In addition, injecting synthetic peptides that mimic melanocortins and bind to MCR-4 into the brain of normal and mutant obese mice caused suppressed feeding (Fan et al., Nature 385: 165-168 (1997)). These results indicate that the brain MC receptor MCR-4 functions in regulating food intake and body weight.

Due to the varied physiological activities of MC receptors, high affinity ligands of MC receptors could be used to exploit the varied physiological responses of MC receptors by functioning as potential therapeutic agents or as lead compounds for the development of therapeutic agents. Furthermore, due to the effect of MC receptors on the activity of various cytokines, high affinity MC receptor ligands could also be used to regulate cytokine activity.

Thus, there exists a need for ligands that bind to MC receptors with high affinity for use in altering MC receptor activity.. The present invention satisfies this need and provides related advantages as well.

SUMMARY OF THE INVENTION The invention provides triamine derivative melanocortin receptor ligands of the formula : wherein R, to R8 and n have the meanings provided below.

The invention further provides methods of using the ligands to alter or regulate the activity of a melanocortin receptor.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows a general reaction scheme for synthesis of triamine derivatives.

Figure 2 shows a more specific reaction scheme for synthesis of triamine derivatives, wherein the R7 and R8 groups are further delineated.

Figure 3 shows another more specific reaction scheme for synthesis of triamine derivatives, wherein the R7 and Rg groups are further delineated.

Figure 4 shows the acute hypophagic effect of a triamine derivative (TRG 6603 #3) administered intraperitoneally (IP) to rats.

Figure 5 shows the acute hypophagic effect of a triamine derivative (TRG 6603 #3) administered intracerebroventricularly (ICV) to rats.

DETAILED DESCRIPTION OF THE INVENTION The invention provides triamine derivative compounds, as well as combinatorial libraries of such compounds. The invention further provides triamine derivative ligands for MC receptors and methods of using such ligands to alter the activity of a MC receptor. The invention also provides MC receptor triamine derivative ligands that are useful for regulating cytokine activity and treating sexual dysfunction or body weight in a subject.

Specifically, the invention provides compounds and combinatorial libraries of the formula:

wherein: the dotted lines indicate that the depicted ring is phenyl or cyclohexyl ; n is 0,1 or 2; # R1 to R. are, independently, a hydrogen atom, halo, hydroxy, protected hydroxy, nitro, Cl to C6 alkyl, Cl to C6 substituted alkyl, C7 to C12 phenylalkyl, C7 to C12 substituted phenylalkyl, C3 to C7 cycloalkyl, C3 to C7 substituted cycloalkyl, C-, to C7 cycloalkenyl, Cs to C7 substituted cycloalkenyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, Cl to C6 alkoxy, C1 to C6 substituted alkoxy, phenoxy, substituted phenoxy, Ci to C6 alkylthio, C1 to C6 substituted alkylthio, Ci to C6 alkylsulfonyl, C1 to C6 substituted alkylsulfonyl, phenylthio, substituted phenylthio, phenylsulfonyl, substituted phenylsulfonyl, amino, protected amino, (monosubstituted) amino, protected (monosubst. ituted) amino or (disubstituted) amino; and when any one of adjacent

position pairs Ri and R2, R2 and R3, and R3 and R4 and R4 and R5 together form one of the following groups: phenyl, substituted phenyl, heterocycle and substituted heterocycle, where such group is fused to the phenyl ring depicted in the above formula such that a bicyclic ring results ; R6 is a hydrogen atom, C1 to C6 alkyl, Ci to C6 substituted alkyl, C7 to C12 phenylalkyl-, C-, to C12 substituted phenylalkyl, Cll to C16 naphthylalkyl or Cl, to C16 substituted naphthylalkyl ; where R7 is absent, R8 together with the attached nitrogen depicted in the above formula form a substituted heterocycle or a substituted cyclic C3 to C7 heteroalkylene, wherein at least one of said substitution. is the formula-D-E, wherein D may be absent or present and, if present, is C1 to C6 alkylene or C1 to C6 substituted alkylene; and E is amino, protected amino, (monosubstituted) amino, protected (monosubstituted) amino or (disubstituted) amino group; and where R7 is a hydrogen atom, C1 to C6 alkyl or C1 to C6 substituted alkyl, R8 is the formula X-CH-Y, wherein the attached nitrogen depicted in the above formula is attached to the carbon atom of the formula X-CH-Y, and wherein X is a hydrogen atom, C1 to C6 alkyl, Ci to C6 substituted alkyl, C7 to C12 phenylalkyl, C7 to C12 substituted phenylalkyl, phenyl, substituted phenyl, naphthyl or substituted naphthyl, and Y is the formula- (CH2)n-Z, wherein n is 1 to 6 and Z is amino, protected amino, (monosubstituted) amino, protected (monosubstituted) amino or (disubstituted) amino; or a pharmaceutically-acceptable salt thereof.

In another embodiment, where R1 to R5 and R, are each hydrogen and R8 is the formula X-CH-Y, X is benzyl and Y is-CH2-amino, R6 is not benzyl.

In an additional embodiment, the ring depicted in the above formula is phenyl. In another embodiment, the ring is cyclohexyl.

. In a further embodiment, at least one of R1 to R5 is not hydrogen.

The invention also provides compounds and libraries wherein R6 is as described above, provided that R6 is not benzyl.

The invention further provides compounds and libraries wherein R1 to R5 are, independently, a hydrogen atom, halo, hydroxy, protected hydroxy, nitro, C1 to C6 alkyl, C1 to C6 substituted alkyl, phenyl, substituted phenyl, Ci to C6 alkylthio, Ci to C6 substituted alkylthio, Ci to C6 alkylsulfonyl, Ci to C6 substituted alkylsulfonyl, C1 to C6 alkoxy, C1 to C6 substituted alkoxy, phenoxy, substituted phenoxy, amino, (monosubstituted) amino or (disubstituted) amino.

The invention also provides compounds and libraries wherein R6 is Cl to C6 alkyl, Ci to C6 substituted alkyl, C7 to C12 phenylalkyl or C7 to Cl2 substituted phenylalkyl.

Also provided are compounds and libraries wherein R7 is absent and R, together with the attached nitrogen depicted in the above formula form a substituted heterocycle or a substituted cyclic C3 to C7 heteroalkylene, wherein at least one of said substitution

is the formula-D-E, wherein D is Cl to C6 alkylene and E is amino, (monosubstituted) amino or (disubstituted) amino.

In another embodiment, R, is a hydrogen atom and R, is the formula X-CH-Y, wherein the attached nitrogen depicted in the above formula is attached to the carbon atom of the formula X-CH-Y, and wherein X is C, to C6 alkyl, Cl to C6 substituted alkyl, C7 to Cl2 phenylalkyl or C7 to C12 substituted phenylalkyl and Y is the formula - (CH,) m-Z, wherein m is 1 or 2 and Z is amino, (monosubstituted) amino or (disubstituted) amino.

In an additional embodiment, Ri to Rs are, independently, a hydrogen atom, methyl, isopropyl, hydroxy, ethoxy, methoxy, butoxy, phenoxy, chloro, fluoro, bromo, nitro, trifluoromethyl, phenyl, methylthio, trifluoromethylthio, trifluoromethoxy, methylsulfonyl or dimethylamino.

The invention also provides compounds and libraries wherein R2 and R3 form a phenyl or substituted phenyl that is fused to the phenyl depicted in the above formula.

The invention additionally provides compounds and libraries wherein R6 is benzyl, 4- (iodophenyl) methyl, 4- (chlorophenyl) methyl, 4- (bromophenyl) methyl, 2- (methoxyphenyl) methyl, 3- (methoxyphenyl) methyl, 4- (ethoxyphenyl) methyl, 4- (propoxyphenyl) methyl, 4- (ethylphenyl) methyl, 4- (isopropylphenyl) methyl, 4- (isobutylphenyl) methyl, 4- (trifluoromethylphenyl) methyl, 3,4- (dimethoxyphenyl) methyl, 4- (t-butylphenyl) methyl, 4- (2- (l-piperidyl) ethoxy) phenylmethyl, 4- ( (3, 3-dimethyl) butoxyphenyl) methyl,

4- ( (3-methyl) butoxyphenyl) methyl, 4- ( (2-dimethylamino) ethoxyphenyl) methyl, 2-phenethyl, 2- (4-methoxyphenyl) ethyl, 3-indolylmethyl, 4- (biphenyl) methyl, 1-naphthylmethyl, 2-naphthylmethyl, diphenylmethyl, 3,4-dichlorophenylmethyl or 2-methoxyethyl.

In addition, the invention provides compounds and libraries wherein R7 is absent and R8 together with the nitrogen depicted in the above formula is 3- (aminomethyl)-7-hydroxyisoquinolyl, 3- (aminomethyl) isoquinolyl, 2- (aminomethyl) pyrrolidyl, trans-2-aminomethyl-4-hydroxypyrrolidyl, 4-aminomethylthiazolidin-3-yl or 2- (aminomethyl) piperidyl.

The invention further provides compounds and libraries wherein R7 is a hydrogen atom and 8 is the formula X-CH-Y, wherein Y is aminomethyl and X is 3-guanidinopropyl, 2-aminoethyl, 3- (methylamino) propyl, 4-aminobutyl, hydroxymethyl, 4-nitrophenylmethyl, benzyl, 3- (aminomethyl) phenylmethyl, 4- (aminomethyl) phenylmethyl, 4-hydroxyphenylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-thienylmethyl, butyl, 2- (ethylamino) ethyl, 2- (dimethylamino) ethyl, 3- (dimethylamino) propyl, 4- (dimethylamino) butyl, 1-hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl, 1-methylethyl, 1,1-dimethylethyl, methoxymethyl, 2-pyridylmethyl, 2-methylsulfonylethyl, thiomethyl, 2- (methylthio) ethyl, 1-methyl-l-thioethyl, ethyl, 4- (2, 2,2-trifluoroethylamino) butyl, aminomethyl, methylaminomethyl, dimethylaminomethyl, ethylaminomethyl, butylaminomethyl, 2,2-dimethylpropylaminoethyl, benzylaminoethyl, 2-phenethylaminomethyl, 3-phenylpropylaminomethyl, cyclohexylmethylaminomethyl, 2-cyclohexylethylaminomethyl, 4-hydroxybutylaminomethyl,

5-hydroxypentylaminomethyl, 2-methoxyaminoethylaminomethyl, 3-methoxypropylaminomethyl, 2-phenoxyethylaminomethyl, 2- (2-methoxy) ethoxyethylaminomethyl, 2-thienylsulfonylaminomethyl, 4- (methoxy) phenylsufonylaminomethyl, phenylsulfonylaminomethyl, 4- (butoxy) phenylsulfonylaminomethyl, methylsulfonylaminomethyl, 3- (4-morpholinyl) propyl, 3-cyclopropylaminopropyl, 3- (tetrahydofurfurylamino) propyl, 3- (4-hydroxypiperidinyl) propyl, 3- (l, l-dimethyl-2-hydroxyethylamino) propyl, 3- (N- (2-hydroxyethyl) methylamino) propyl, 3- (N- (cyclohexyl) methylamino) propyl, 2- (4-morpholinyl) ethyl, 2-cyclopropylaminoethyl, 2- (tetrahydrofurfurylamino) ethyl, 2- (4-hydroxypiperidinyl) ethyl, 2- (1, 1-dimethyl-2-hydroxyethylamino) ethyl, 2- (N- (2-hydroxyethyl) methylamino) ethyl, 2- (N- (cyclohexyl) methylamino) ethyl, 4-ethylaminobutyl, 4- (2-methoxyethylamino) butyl, 3-ethylaminopropyl, 3- (2-methoxyethylamino) propyl, 3-pyridylmethylaminomethyl, 3- (methylamino) propyl, 3- aminopropyl, 3- (butylamino) propyl, 3- (2, 2- dimethylpropylamino) propyl, 3- (phenylmethylamino) propyl, 3- (2-phenylethylamino) propyl, 3- (3- phenylpropylamino) propyl, 3- (2- cyclohexylethylamino) propyl, 3- (3- pridylmethylamino) propyl, 3- (3-methoxypropylamino) propyl, 3- (4-hydroxybutylamino) propyl, 3- (5- hydroxypentylamino) propyl, 3- (2- phenyoxyethylamino) propyl, 3-(methylamino) propyl, 4- aminobutyl, 4- (butylamino) butyl, 4- (2, 2- dimethylpropylamino) butyl, 4- (phenylmethylaminom) butyl,

4- (2-phenylethylamino) butyl, 4- (3- phenylpropylamino) butyl, 4- (cyclohexylmethylamino) butyl, 4- (2-cyclohexylethylamino) butyl, 4- (3- pridylmethylamio) butyl, 4- (3-methoxypropylamino) butyl, 4- (4-hydroxybutylamino) butyl, 4- (5- hydroxypentylamino) butyl, 4- (2-phenyoxyethylamino) butyl or 4- ( (2- (2-methoxy) ethoxy) ethylamino) butyl.

The invention also provides a method of altering the activity of a melanocortin receptor in a subject, comprising administering to the subject an effective amount of a melanocortin receptor ligand, wherein said melanocortin receptor ligand comprises one of the compounds described above.

The method includes increasing the activity of a melanocortin receptor. The method of the invention also includes decreasing the activity of a melanocortin receptor. Melanocortin receptors whose activity cn be increased or decreased include MC-1, MC-2, MC-3, MC-4 and MC-5.

Unless otherwise indicated, in the above formula the stereochemistry of chiral centers associated with-the RI through RI groups can independently be in the R or S configuration, or a mixture of the two.

As used herein, the term"ene" (such as alkylene) denotes that the"ene"group connects together two separate additional groups.

As used herein, the term"alkyl" (such as C1 to C9 alkyl or Cl to C6 alkyl) denotes such radicals as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, tert-amyl, hexyl and the like up to

chains of nine carbon atoms. Preferably, the compounds have Cl to Cs, more preferably Cl to C6 and even more preferably Cl to C3 carbon chains. Most preferred is methyl.

The term"alkenyl" (such as C2 to Cg alkenyl, C2 to C, alkenyl or C2 to C6 alkenyl) denotes such radicals as 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, as well as dienes and trienes of straight and branched chains.

The term"alkynyl" (such as C2 to Cg alkynyl or C2 to C7 alkynyl) denotes such radicals as ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, as well as di-and tri-ynes of straight and branched chains.

The terms"substituted alkyl,""substituted alkenyl,"and"substituted alkynyl,"denote that the above alkyl, alkenyl and alkynyl groups are substituted by one or more, and preferably one or two, halogen, hydroxy, protected hydroxy, oxo, protected oxo, cyclohexyl, naphthyl, amino, protected amino, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, guanidino, heterocyclic ring, substituted heterocyclic ring, imidazolyl, indolyl, pyrrolidinyl, Cl to C7 alkoxy, C1 to C7 acyl, Cl to C7 acyloxy, nitro, Ci to C7 alkyl ester, carboxy, protected carboxy, carbamoyl, carboxamide, protected carboxamide, N- (Cl to C6 alkyl) carboxamide, protected N- (Cl to C6 alkyl) carboxamide, N, N-di (Cl to C6alkyl) carboxamide, cyano, Cl to C6 alkylsulfonylamino, phenylsulfonylamino, Cl to C6 substituted alkylsulfonylamino, substituted phenylsulfonylamino, thio, Ci to C4 alkylthio, Cl to C6

alkylsulfonyl, Cl to C6 substituted alkylsulfonyl, phenylsulfonyl, substituted phenylsulfonyl, heterocyclic sulfonyl or substituted heterocyclic sulfonyl groups.

The substituted alkyl groups may 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 nitromethyl, chloromethyl, hydroxymethyl, tetrahydropyranyloxymethyl, trityloxymethyl, propionyloxymethyl, amino, methylamino, aminomethyl, dimethylamino, carboxymethyl, allyloxycarbonylmethyl, methoxymethyl, ethoxymethyl, t-butoxymethyl, acetoxymethyl, chloromethyl, bromomethyl, iodomethyl, trifluoromethyl, 6-hydroxyhexyl, 2,4-dichloro (n-butyl), 2-aminopropyl, chloroethyl, bromoethyl, fluoroethyl, iodoethyl, chloropropyl, bromopropyl, fluoropropyl, iodopropyl and the like.

Examples of the above substituted alkenyl groups include styrenyl, 3-chloro-propen-1-yl, 3-chloro- <BR> <BR> <BR> buten-1-yl, 3-methoxy-propen-2-yl, 3-phenyl-buten-2-yl, 1-cyano-buten-3-yl and the like. The geometrical isomerism is not critical, and all geometrical isomers for a given substituted alkenyl can be used.

Examples of the above substituted alkynyl groups include phenylacetylen-1-yl, 1-phenyl-2-propyn-1-yl and the like.

The term"oxo"denotes a carbon atom bonded to two additional carbon atoms substituted with an oxygen atom doubly bonded to the carbon atom, thereby forming a ketone moiety.

The term"protected oxo"denotes a carbon atom bonded to two additional carbon atoms substituted with two alkoxy groups or twice bonded to a substituted diol moiety, thereby forming an acyclic or cyclic ketal moiety.

The term''C1 to C6 alkoxy"as used herein denotes groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and like groups.

Preferred alkoxy groups are methoxy, ethoxy and propoxy.

The term''C1 to C6 substituted alkoxy"as used herein denotes a."C1 to C6 alkoxy"that is substituted as described above regarding a"C1 to C6 substituted alkyl." The terms"phenoxy"and"substittuted phenoxy"should be similarly understood.

The term"C1 to C-7 acyloxy"denotes herein groups such as formyloxy, acetoxy, propionyloxy, butyryloxy, pentanoyloxy, hexanoyloxy, heptanoyloxy and the like.

Similarly, the term"C1 to C7 acyl"encompasses groups such as formyl, acetyl, propionyl, butyryl, pentanoyl, pivaloyl, hexanoyl, heptanoyl, benzoyl and the like. Preferred acyl groups are acetyl and benzoyl.

The term"C3 to C7 cycloalkyl"includes the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl rings. The substituent term"C3 to C7 substituted cycloalkyl"indicates the above cycloalkyl rings substituted by one or two halogen, hydroxy, protected hydroxy, Ci to C6 alkyl, Ci to C7 alkoxy, oxo, protected oxo, (monosubstituted) amino, (disubstituted) amino, trifluoromethyl, carboxy, protected

carboxy, phenyl, substituted phenyl, amino, or protected amino groups.

The term t'C5 to C7 cycloalkenyl"indicates a 1, 2, or 3-cyclopentenyl ring, a 1,2,3 or 4-cyclohexenyl ring or a 1,2,3,4 or 5-cycloheptenyl ring, while the term "substituted C5 to C7 cycloalkenyl"denotes the above C5 to C7 cycloalkenyl rings substituted by a C1 to C6 alkyl radical, halogen, hydroxy, protected hydroxy, Ci to C7 alkoxy, trifluoromethyl, carboxy, protected carboxy, oxo, protected oxo, (monosubstituted) amino, protected (monosubstituted) amino (disubstituted) amino, phenyl, substituted phenyl, amino, or protected amino.

The term"heterocyclic ring"or"heterocycle" denotes optionally substituted five-membered, six- membered or seven-membered rings that have 1 to 4 heteroatoms, such as oxygen, sulfur and/or nitrogen, in particular nitrogen, either alone or in conjunction with sulfur or oxygen ring atoms. These five-membered, six- membered or seven-membered rings may be saturated, fully saturated or partially unsaturated, with fully saturated rings being preferred. An"aminoalkyl-substituted heterocyclic ring"means any one of the above-described heterocyclic rings is substituted with at least one aminoalkyl group. Preferred heterocyclic rings include morpholino, piperidinyl, piperazinyl, tetrahydrofurano, pyrrolo, tetrahydrothiophen-yl, diazapino, thiomorpholino, thiazapino-S, S-dioxide, thiomorpholino-S, S-dioxide and thiazolidino-S, S-dioxide.

The term"substituted heterocyclic ring"or "substituted heterocycle"means the above-described heterocyclic ring is substituted with, for example, one or more, and preferably one or two, substituents which

are the same or different and can be halogen, hydroxy, protected hydroxy, cyano, nitro, Cl to C6 alkyl, Cl to C7 alkoxy, Cl to C7 acyl, Cl to C7 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, carboxamide, protected carboxamide, N- (Ci to C6 alkyl) carboxamide, protected N- (Ci to C6 alkyl) carboxamide, N, N-di (Cl to C6 alkyl), trifluoromethyl, Ci to C6 alkylsulfonyl, Cl to C6 substituted alkylsulfonyl, phenylsulfonyl, substituted phenylsulfonyl, phenylthio, substituted phenylthio, Cl to C6 alkylthio, Cl to C6 substituted alkylthio, N- ( (Ci to C6 alkyl) sulfonyl) amino or N- (phenylsulfonyl) amino groups.

The term"aminoalkylsubstituted heterocyclic ring"is a heterocyclic ring substituted with at least one aminoalkyl group and the term"substituted aminoalkylsubstituted heterocyclic ring"is an aminoalkylsubstituted heterocyclic'ring substituted with one or more of the above identified substituents for a substituted heterocyclic ring.

The abbreviation"Ar"stands for an aryl group.

Aryl groups which can be used with present invention include phenyl, substituted phenyl, as defined above, heteroaryl, and substituted heteroaryl. The term "heteroaryl"means a heterocyclic aromatic derivative which is a five-membered or six-membered ring system having from 1 to 4 heteroatoms, such as oxygen, sulfur and/or nitrogen, in particular nitrogen, either alone or in conjunction with sulfur or oxygen ring atoms.

Examples of heteroaryls include pyridinyl, pyrimidinyl, and pyrazinyl, pyridazinyl, pyrrolo, furano, oxazolo, isoxazolo, thiazolo and the like.

The term"substituted heteroaryl"means the above-described heteroaryl is substituted with, for example, one or more, and preferably one or two, substituents which are the same or different which can be halogen, hydroxy, protected hydroxy, cyano, nitro, C1 to C6 alkyl, C1 to C-7 alkoxy, C1 to C7 acyl, C1 to C7 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino carboxamide, protected carboxamide, N- (Ci to C6alkyl) carboxamide, protected N- (Cl to C6 alkyl) carboxamide, N, N-di (C1 to C6 alkyl), trifluoromethyl, C1 to C6 alkylsulfonyl, Ci to C6 substituted alkylsulfonyl, phenylsulfonyl, substituted phenylsulfonyl, phenylthio, substituted phenylthio, C1 to C6 alkylthio, Ci to C6 substituted alkylthio, N-((C1 to C6 alkyl) sulfonyl) amino or N- (phenylsulfonyl) amino groups.

The terms"C-, to C12 phenylalkyl"and"C1l to C16 substituted naphthylalkyl"denotes a C1 to C6 alkyl group substituted at any position by a phenyl or naphthyl ring, respectively. Examples of such a group include benzyl, 2-phenethyl, 3-phenyl (n-propyl), 4-phenylhexyl, 3- phenyl (n-amyl), 3-phenyl (sec-butyl) and the like.

Preferred C7 to C12 phenylalkyl groups are benzyl and phenethyl.

The terms "C7 to C12 substituted phenylalkyl" and". C11 to C16 substituted naphthylalkyl"denotes such a group substituted on the C, to C6 alkyl portion with one or more, and preferably one or two, groups chosen from halogen, hydroxy, protected hydroxy, oxo, protected oxo, amino, protected amino, monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, guanidino, heterocyclic ring, substituted heterocyclic ring, Cl to C7

alkoxy, Cl to C7 acyl, Ci to C7 acyloxy, nitro, carboxy, protected carboxy, carbamoyl, carboxamide, protected carboxamide, N-(C1 to C6 alkyl) carboxamide, protected N- (Cl to C6 alkyl) carboxamide, N, N-(C1 to C6 dialkyl) carboxamide, cyano, N- (Ci to C6 alkylsulfonyl) amino, thiol, C1 to C4 alkylthio, Ci to C4 alkylsulfonyl groups; and/or the phenyl or naphthyl group may be substituted with one or more, and preferably one or two, substituents chosen from halogen, hydroxy, protected hydroxy, cyano, nitro, Ci to C6 alkyl, Cl to C7 alkoxy, Cl to C7 acyl, Cl to C7 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, carboxamide, protected carboxamide, N- (Ci to C6 alkyl) carboxamide, protected N- (Cl to C6 alkyl) carboxamide, N, N-di (Cl to C6 alkyl) carboxamide, trifluoromethyl, N-((Cl to C6 alkyl) sulfonyl) amino, N- (phenylsulfonyl) amino or a phenyl group, substituted or unsubstituted, for a resulting biphenyl group. The substituted alkyl or phenyl or naphthyl groups may be substituted with one or more, and preferably one or two, substituents which can be the same or different.

Examples of the term BIC7 to C12 substituted phenylalkyl"include groups such as 2-phenyl-1-chloroethyl, 2- (4-methoxyphenyl) ethyl, 4- (2, 6-dihydroxy phenyl)-n-hexyl, 2- (5-cyano-3-methoxyphenyl)-n-pentyl, 3- (2, 6-dimethylphenyl)-n-propyl, 4-chloro-3-aminobenzyl, 6- (4-met. hoxyphenyl)-3-carboxy (n-hexyl), 5- (4-aminomethylphenyl)-3- (aminomethyl)-n-pentyl, 5-phenyl-3-oxo-n-pent-1-yl and the like.

The term"substituted phenyl"specifies a phenyl group substituted with one or more, and preferably one or two, moieties chosen from the groups consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, Ci to C6 alkyl, C1 to C7 alkoxy, C1 to C, acyl, Cl to C-7 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, carboxamide, protected carboxamide, N- (Ci to C6 alkyl) carboxamide, protected N- (C1 to. C6 alkyl) carboxamide, N, N-di (C1 to C6alkyl) carboxamide, trifluoromethyl, N-. ( (C1 to C6 alkyl) sulfonyl) amino, N- (phenylsulfonyl) amino or phenyl, substituted or unsubstituted, such that, for example, a biphenyl results.

Examples of the term"substituted phenyl" include a mono-or di (halo) phenyl group such as 2,3 or 4-chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 2,3 or 4-bromophenyl, 3,4-dibromophenyl, 3-chloro-4-fluorophenyl, 2,3 or 4-fluorophenyl and the like ; a mono or di (hydroxy) phenyl group such as 2,3 or 4-hydroxyphenyl, 2,4-dihydroxyphenyl, the protected-hydroxy derivatives thereof and the like; a nitrophenyl group such as 2,3 or 4-nitrophenyl; a cyanophenyl group, for example, 2,3 or 4-cyanophenyl; a mono-or di (alkyl) phenyl group such as 2,3 or 4-methylphenyl, 2,4-dimethylphenyl, 2,3 or 4- (iso-propyl) phenyl, 2,3 or 4-ethylphenyl, 2,3 or 4- (n-propyl) phenyl and the like ; a mono or di (alkoxyl) phenyl group, for example, 2,6-dimethoxyphenyl, 2,3 or 4-methoxyphenyl, 2,3 or 4-ethoxyphenyl, 2,3 or 4- (isopropoxy) phenyl, 2,3 or 4- (t-butoxy) phenyl, 3-ethoxy-4-methoxyphenyl and the

like; 2,3 or 4-trifluoromethylphenyl; a mono-or dicarboxyphenyl or (protected carboxy) phenyl group such as 2,3 or 4-carboxyphenyl or 2,4-di (protected carboxy) phenyl; a mono-or di (hydroxymethyl) phenyl or (protected hydroxymethyl) phenyl such as 2,3, or 4- (protected hydroxymethyl) phenyl or 3,4-di (hydroxymethyl) phenyl; a mono-or di (aminomethyl) phenyl or (protected aminomethyl) phenyl such as 2,3 or 4- (aminomethyl) phenyl or 2,4- (protected aminomethyl) phenyl ; or a mono-or di (N- (methylsulfonylamino)) phenyl such as 2,3 or 4- (N- (methylsulfonylamino)) phenyl. Also, the term "substituted phenyl"represents disubstituted phenyl groups wherein 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.

Phenylthio, phenyl sulfoxide, phenylsulfonyl and phenylsulfonylamino compounds are known in the art and these terms have their art recognized definition. By "substituted phenylthio,""substituted phenyl sulfoxide," "substituted phenylsulfonyl"and"substituted phenylsulfonylamino"is meant that the phenyl can be substituted as described above in relation to "substituted phenyl." The term"substituted aniline"specifies an aniline group substituted with one or more, and preferably one or two, moieties chosen from the groups consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, Ci to C6 alkyl, Cl to C7 alkoxy, C1 to C7 acyl, C1 to C7 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected

hydroxymethyl, amino, protected amino, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, carboxamide, protected carboxamide, N- (Ci to C6 alkyl) carboxamide, protected N- (Ci to C6 alkyl) carboxamide, N, N-di (Cl to C6 alkyl) carboxamide, trifluoromethyl, N-((Cl to C6 alkyl) sulfonyl) amino and N- (phenylsulfonyl) amino.

Examples of substituted aniline include 2- fluoroanilinyl, 3-fluoroanilinyl, 4-fluoroanilinyl, 2- chloroanilinyl, 3-chloroanilinyl, 4-chloroanilinyl, 2- bromoanilinyl, 3-bromoanilinyl, 4-bromoanilinyl, 2- methoxyanilinyl, 3-methoxyanilinyl, 4-methoxyanilinyl, 2- hydroxyanilinyl, 3-hydroxyanilinyl, 4-hydroxyanilinyl, 2- carboethoxyanilinyl, 3-carboethoxyanilinyl, 4- carboethoxyanilinyl, 2-trifluoromethylanilinyl, 3- trifluoromethylanilinyl, 4-trifluoromethylanilinyl, 2- dimethylaminoanilinyl, 3-dimethylaminoanilinyl, 4- dimethylaminoanilinyl, 2-phenoxyanilinyl, 3- phenoxyanilinyl, 4-phenoxyanilinyl, 3,4- methylenedioxyanilinyl, 2,3-methylenedioxyanilinyl, 2,3- difluoroanilinyl, 2,3-dibromoanilinyl, 3,4-dibromoanilinyl, 2,3-dimethoxyanilinyl, 3,4-dimethoxyanilinyl, 1-amino-5,6,7,8-tetrahydronaphthyl, 2-hydroxy-3-amino-5,6,7,8-tetrahydronaphthyl, 2-aminonaphthyl, 1-amino-4-chloronaphthyl, 1-amino-4-bromonaphthyl, 5-amino-1-hydroxynaphthyl, 1-amino-2-hydroxynaphthyl, 5-aminoindanyl, 1-aminofluorenyl, 2-aminofluorenyl and N-methylanilinyl.

The term"substituted naphthyl"specifies a naphthyl group substituted with one or more, and preferably one or two, moieties either on the same ring or on different rings chosen from the groups consisting

of halogen, hydroxy, protected hydroxy, cyano, nitro, Cl to C6 alkyl, C, to C7 alkoxy, Cl to C7 acyl, Cl to C, acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, carboxamide, protected carboxamide, N- (Ci to C6 alkyl) carboxamide, protected N- (Ci to C6 alkyl) carboxamide, N, N-di (C1 to C6 alkyl) carboxamide, trifluoromethyl, N-((C1 to C6 alkyl) sulfonyl) amino or N- (phenylsulfonyl) amino.

Examples. of the term"substituted naphthyl" include a mono or di (halo) naphthyl group such as 1, 2,3, 4,5,6,7 or 8-chloronaphthyl, 2,6-dichloronaphthyl, 2, 5-dichloronaphthyl, 3,4-dichloronaphthyl, 1, 2,3,4,5, 6, 7 or 8-bromonaphthyl, 3,4-dibromonaphthyl, 3-chloro- 4-fluoronaphthyl, 1,2,3,4,5,. 6,7 or 8-fluoronaphthyl and the like; a mono or di (hydroxy) naphthyl group such as 1, 2,3,4,5,6,7 or 8-hydroxynaphthyl, 2,4- dihydroxynaphthyl, the protected-hydroxy derivatives thereof and the like; a nitronaphthyl group such as 3-or 4-nitronaphthyl; a cyanonaphthyl group, for example, 1, 2,3,4,5,6,7 or 8-cyanonaphthyl; a mono-or di (alkyl) naphthyl group such as 2,3,4,5,6,7 or 8- methylnaphthyl, 1, 2,4-dimethylnaphthyl, 1, 2,3,4,5, 6,7 or 8- (isopropyl) naphthyl, l, 2,3,4,5,6,7 or 8-ethylnaphthyl, l, 2,3,4,5,6,7 or 8- (n-propyl) naphthyl and the like; a mono or di (alkoxy) naphthyl group, for example, 2, 6-dimethoxynaphthyl, 1, 2, 3,4,5,6,7 or 8-methoxynaphthyl, 1, 2,3,4,5,6,7 or 8-ethoxynaphthyl, l, 2,3,4,5,6,7 or 8- (isopropoxy) naphthyl, 1, 2,3,4,5,6,7 or 8- (t-butoxy) naphthyl, 3-ethoxy-4-methoxynaphthyl and the

like; 1, 2,3,4,5,6,7 or 8-trifluoromethylnaphthyl; a mono-or dicarboxynaphthyl or (protected carboxy) naphthyl group such as 1, 2,3, 4,5,6,7 or 8-carboxynaphthyl or 2,4-di (-protected carboxy) naphthyl; a mono-or di (hydroxymethyl) naphthyl or (protected hydroxymethyl) naphthyl such as 1,2,3,4,5,6,7 or 8- (protected hydroxymethyl) naphthyl or 3,4-di (hydroxymethyl) naphthyl; a mono-or di (amino) naphthyl or (protected amino) naphthyl such as 1, 2,3,4,5,6,7 or 8- (amino) naphthyl or 2,4- (protected amino)-naphthyl, a mono-or di (aminomethyl) naphthyl or (protected aminomethyl) naphthyl such as 2,3, or 4- (aminomethyl) naphthyl or 2,4- (protected aminomethyl)-naphthyl; or a mono-or di- (N-methylsulfonylamino) naphthyl such as 1,2,3,4,5, 6,7 or 8- (N-methylsulfonylamino) naphthyl. Also, the term"substituted naphthyl."represents disubstituted naphthyl groups wherein the substituents are different, for example, 3-methyl-4-hydroxynaphth-1-yl, 3-chloro-4-hydroxynaphth-2-yl, 2-methoxy-4-bromonaphth-1-yl, 4-ethyl-2-hydroxynaphth-1-yl, 3-hydroxy-4-nitronaphth-2-yl, 2-hydroxy-4-chloronaphth-1-yl, 2-methoxy-7-bromonaphth-1-yl, 4-ethyl-5-hydroxynaphth-2-yl, 3-hydroxy-8-nitronaphth-2-yl, 2-hydroxy-5-chloronaphth-1-yl and the like.

The term"halo"or"halogen"refers to fluoro, chloro, bromo or iodo groups. Preferred halogens are bromo, fluoro and chloro.

The term"heterocyclic sulfonyl"refers to a sulfonyl group attached to a heterocycle. The term

"substituted heterocyclic sulfonyl"refers to where the attached heterocycle is substituted as described herein.

The term" (monosubstituted) amino" refers to an amino group with one substituent chosen from the group consisting of phenyl, substituted phenyl, Cl to C6 alkyl, Cl to C6 substituted alkyl, Cl to C7 acyl, C, to C7 alkenyl, C2 to C7 substituted alkenyl, Ca to C-7 alkynyl, C2 to C7 substitued alkynyl, C7 to C12 phenylalkyl, C7 to substituted phenylalkyl, heterocycle substituted heterocycle, C1 to C6 alkylsulfonyl, Cl to C6 substituted alkylsulfonyl, phenylsulfonyl, substituted phenylsulfonyl, heterocyclic sulfonyl and substituted heterocyclic sulfonyl. The (monosubstituted) amino can additionally have an amino-protecting group as encompassed by the term"protected ('monosubstituted) amino." Examples of the term (monosubstituted) amino include methylamino, ethylamino, cyclohexylamino, cyclohexylmethylamino, cyclohexylethylamino, cyclopentylamino, anilinyl, 2-methoxyanilinyl, benzylamino, 2-hydroxybenzylamino, phenethylamino, 2-methoxyphenethylamino and the like.

The term" (disubstituted) amino" refers to amino groups with two substituents chosen from the group consisting of phenyl, substituted phenyl, Ci to C6 alkyl, Cl to C6 substituted alkyl, C1 to C7 acyl, C2 to C7 alkenyl, C2 to C7 alkynyl, C7 to C12 phenylalkyl, and C7 to C12 substituted phenylalkyl. The two substituents can be the same or. different.

The term"protected amino"as used herein refers an amino group with a group commonly employed to

block or protect the amino functionality while reacting other functional groups of the molecule. 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 on the carboxamide nitrogen.

Examples of such amino-protecting groups include the formyl ("For") group, the trityl group, the phthalimido group, the trichloroacetyl group, the chloroacetyl, bromoacetyl, and iodoacetyl groups, urethane-type blocking groups, such as t-butoxycarbonyl ("Boc"), 2- (4-biphenylyl) propyl-2-oxycarbonyl ("Bpoc"), 2-phenylpropyl-2-oxycarbonyl ("Poc"), 2- (4-xenyl) isopropoxycarbonyl,<BR> l, l-diphenylethyl-1-oxycarbonyl,<BR> 1, 1-diphenylpropyl-1-oxycarbonyl, 2- (3, 5-dimethoxyphenyl) propyl-2-oxycarbonyl ("Ddz"), 2- (p-toluyl) propyl-2-oxycarbonyl, cyclopentanyloxycarbonyl, 1-methylcyclopentanyloxycarbonyl,<BR> cyclohexanyloxy-carbonyl, 1-methylcyclohexanyloxycarbonyl, 2-methylcyclohexanyloxycarbonyl, 2- (4-toluylsulfonyl) ethoxycarbonyl, 2- (methylsulfonyl) ethoxycarbonyl, 2- (triphenylphosphino)-ethoxycarbonyl, 9-fluorenylmethoxycarbonyl ("Fmoc"), 2- (trimethylsilyl) ethoxycarbonyl, allyloxycarbonyl, 1-(trimethylsilylmethyl) prop-1-enyloxycarbonyl, 5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl, cyclopropylmethoxycarbonyl,

isobornyloxycarbonyl, 1-piperidyloxycarbonyl, benzyloxycarbonyl ("Cbz"), 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxy-carbonyl, a-2, 4,5,-tetramethylbenzyloxycarbonyl ("Tmz"), 4-methoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl, 4- (decyloxy) benzyloxycarbonyl and the like; the benzoylmethylsulfonyl group, dithiasuccinoyl ("Dts"), the 2- (nitro) phenylsulfenyl group ("Nps"), the diphenyl-phosphine. oxide group and like amino-protecting groups. The species of amino-protecting group employed is not critical so long as the derivatized amino group is stable to the conditions of the subsequent reaction (S) and can be removed at the appropriate point without disrupting the remainder of the compounds. Preferred amino-protecting groups are Boc, Cbz and Fmoc. Further examples of amino-protecting groups embraced 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," 2nd ed., John Wiley and Sons, New York, NY, 1991, Chapter 7, M. Bodanzsky,"Principles of Peptide Synthesis,"1st and 2nd revised ed., Springer-Verlag, New York, NY, 1984 and 1993, and Stewart and Young,"Solid Phase Peptide Synthesis,"2nd ed., Pierce Chemical Co., Rockford, IL, 1984, each of which is incorporated herein by reference.

The related term"protected amino"defines an amino group substituted with an amino-protecting group discussed above. In addition, the term"protected carboxamide" means there is an amino-protecting group on the carboxamide nitrogen.

The term"carboxy-protecting groupas 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 t-butyl, 4-nitrobenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4-methylenedioxybenzyl, benzhydryl, 4,4'-dimethoxytrityl, 4,4', 4"-trimethoxytrityl, 2-phenylpropyl, trimethylsilyl, t-butyldimethylsilyl, phenyl, 2,2,2-trichloroethyl, (3- (trimethylsilyl) ethyl, ß-(ditn-butyl3methylsilyl) ethyl, p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl, cinnamyl, 1- (trimethylsilylmethyl)-propenyl and like moieties. The species of carboxy-protecting group employed is 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 in E. Haslam,"Protective Groups in Organic Chemistry,"J. G. W. McOmie, Ed., Plenum Press, New York, NY, 1973, Chapter 5, and T. W. Greene and P. G. M.

Wuts,"Protective Groups in Organic Synthesis,"2nd ed., John Wiley and Sons, New York, NY, 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- protecting groups.

The term"hydroxy-protecting group"refers to readily cleavable groups bonded to hydroxyl groups, with the hydroxy becoming a"protected hydroxy". In addition, the term"protected hydroxymethyl"means there is a

readily cleavable groups bonded to hydroxyl portion of the hydroxymethyl group. Examples of such readily cleavable groups bonded to hydroxyl groups include the tetrahydropyranyl, 2-methoxypropyl, 1-ethoxyethyl, methoxymethyl, 2-methoxyethoxymethyl, methylthiomethyl, t-butyl, t-amyl, trityl, 4-methoxytrityl, 4,4'-dimethoxytrityl, 4,4', 4"-trimethoxytrityl, benzyl, allyl, trimethylsilyl, (t-butyl) dimethylsilyl, 2,2,2-trichloroethoxycarbonyl groups and the like. The species of hydroxy-protecting groups is not critical so long as the derivatized hydroxyl group 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 hydroxy-protecting groups are described by C. B. Reese and E. Haslam, "Protective Groups in Organic Chemistry,"J. G. W. McOmie, Ed., Plenum Press, New York, NY, 1973, Chapters 3 and 4, respectively, and T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis,"2nd ed., John Wiley and Sons, New York, NY, 1991, Chapters 2 and 3.

The term"C1 to C6 alkylthio"refers to sulfide groups such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, t-butylthio and like groups.

The term''Cl to C6 alkylsulfoxide"indicates sulfoxide groups such as methylsulfoxide, ethylsulfoxide, n-propylsulfoxide, isopropylsulfoxide, n-butylsulfoxide, sec-butylsulfoxide and the like.

The term''C1 to C6 alkylsulfonyl"encompasses groups such as methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, t-butylsulfonyl and the like. Similarly, the term''C1 to C6 alkylsulfonylamino"encompasses groups such as

methylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino, isopropylsulfonylamino, n- butylsulfonylamino, t-butylsulfonylamino and the like.

The terms''C1 to C6 substituted alkylthio,""C1 to C6 substituted alkylsulfoxide,""Cl to C6 substituted alkylsulfonyl"and"C1 to C6 substituted alkylsulfonylamino"refer to such groups with one or more substitutions as described above regarding the term "substituted alkyl."An example of Ci to C6 substituted alkylsulfonyl includes trifluoromethylsulfonyl.

By"substituted phenylthio,""substituted phenyl sulfoxide,""substittued phenoxy"and"substituted phenylsulfonyl"is meant that the phenyl can be substituted as described above in relation to "substituted phenyl." The terms"cyclic C ? to C, alkylene," "substituted cyclic C2 to C7 alkylene,""cyclic C2 to C7 heteroalkylene,""substituted cyclic C2 to C7 heteroalkylene,""cyclic C3 to C-, alkylene,""substituted cyclic C3 to C7 alkylene,""cyclic C3 to C7 heteroalkylene,"and"substituted cyclic C3 to C7 heteroalkylene,"define such a cyclic group bonded ("fused") to the phenyl radical resulting in a bicyclic ring system. The cyclic group may be saturated or contain one or two double bonds. Furthermore, the cyclic group may have one or two methylene or methine groups replaced by one or two oxygen, nitrogen or sulfur atoms which are the cyclic C2 or C3 to C7 heteroalkylene.

The cyclic alkylene or heteroalkylene group may be substituted once or twice by the same or different substituents selected from the group consisting of the following moieties: hydroxy, protected hydroxy, carboxy,

protected carboxy, oxo, protected oxo, Cl to C4 acyloxy, formyl, Cl to C7 acyl, Cl to C6 alkyl, carbamoyl, C1 to C7 alkoxy, Cl to Cd alkylthio, C1 to C4 alkylsulfoxide, Cl to C4 alkylsulfonyl, halo, amino, protected amino, (monosubstituted) amino, protected (monosubstitued) amino, (disubstituted) amino, hydroxymethyl or a protected hydroxymethyl.

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

Examples of fused cyclic groups which-each contain one- nitrogen atom and one or more double bond, preferably one or two double bonds, are when the phenyl is fused to a i pyridino, pyrano, pyrrolo, pyridinyl, dihydropyrrolo, or dihydropyridinyl ring. Examples of fused cyclic groups which each contain one oxygen atom and one or two double bonds are when the phenyl ring is fused to a furo, pyrano, dihydrofurano, or dihydropyrano ring. Examples of fused cyclic groups which each have one sulfur atom and contain one or two double bonds are when the phenyl is fused to a thieno, thiopyrano, dihydrothieno or dihydrothiopyrano ring. Examples of cyclic groups which contain two heteroatoms selected from sulfur and nitrogen and one or two double bonds are when the phenyl ring is fused to a thiazolo, isothiazolo, dihydrothiazolo or dihydroi. sothiazolo ring. Examples of cyclic groups. which contain two heteroatoms selected from oxygen and nitrogen and one or two double bonds are when the benzene ring is fused to an oxazolo, isoxazolo, dihydrooxazolo 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 or pyrazinyl.

The term"amino acid"includes any one of the twenty naturally-occurring amino acids or the D-form of any one of the naturally-occurring amino acids. In addition, the term"amino acid"also includes other non- naturally occurring amino acids besides the D-amino acids, which are functional equivalents of the naturally- occurring amino acids. Such non-naturally-occurring amino acids include, for example, norleucine ("Nle".), norvaline ("Nva"), (3-Alanine, L-or D-naphthalanine, ornithine ("Orn"), homoarginine (homoArg) and others well known in the peptide art, such as those described in M. Bodanzsky,"Principles of Peptide Synthesis,"1st and 2nd revised ed., Springer-Verlag, New York, NY, 1984 and 1993, and Stewart and Young,"Solid Phase Peptide Synthesis,"2nd ed., Pierce Chemical Co., Rockford, IL, 1984, both of which are incorporated herein by reference.

Amino acids and amino acid analogs can-be purchased commercially (Sigma Chemical Co.; Advanced Chemtech; RSP; Bachem; or ChemImpex) or synthesized using methods known in the art.

The amino acids are indicated herein by either their full name or by the commonly known three letter code. Further, in the naming of amino acids,"D-" designates an amino acid having the"D"configuration, as opposed to the naturally occurring L-amino acids. Where no specific configuration is indicated, one skilled in the art would understand the amino acid to be an L-amino

acid. The amino acids can, however, also be in racemic mixtures of the D-and L-configuration.

As used herein, the phrase"any one of the twenty naturally-occurring amino acids"means any one of the following: Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val. As used herein, the language"the D-form of a naturally-occurring amino acid"means the D-isomer of any one of these naturally-occurring amino acids, with the exception of Gly, which does not occur as D or L isomers.

One or more of the triamine derivatives, even within a given library, may be present as a salt. The term"salt"encompasses those salts that form with the carboxylate anions and amine nitrogens and include salts formed with the organic and inorganic anions and cations discussed below. Furthermore, the term includes salts that form by standard acid-base reactions with basic groups (such as amino groups) and organic or inorganic acids. Such acids include hydrochloric, sulfuric, phosphoric, acetic, succinic, citric lactic, maleic, fumaric, palmitic, cholic, pamoic, mucic, D-glutamic, d- camphoric, glutaric, phthalic, tartaric, lauric, stearic, salicyclic, methanesulfonic, benzenesulfonic, sorbic, picric, benzoic, cinnamic, 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, aluminum and calcium) ; ammonium and mono-, di-and tri-alkyl amines such as trimethylamine, cyclohexylamine; and the organic cations, such as dibenzylammonium, benzylammonium, 2-hydroxyethylammonium,

bis (2-hydroxyethyl) ammonium, phenylethylbenzylammonium, dibenzylethylenediammonium, and like cations. See, for example,"Pharmaceutical Salts,"Berge et al., J. Pharm.

Sci., 66: 1-19 (1977), which is incorporated herein by reference. Other cations encompassed by the above term include the protonated form of procaine, quinine and N- methylglucosamine, and the protonated forms of basic amino acids such as glycine, ornithine, histidine, phenylglycine, lysine and arginine. Furthermore, any zwitterionic form of the instant compounds formed by a carboxylic acid and an amino group is referred to by this term. For example, a cation for a carboxylate anion will exist when R2 or R3 is substituted with a (quaternary ammonium) methyl group. A preferred cation for the carboxylate anion is the sodium cation.

The compounds of the above formula can also exist as solvates and hydrates. Thus, these ; compounds may 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 within the scope of this invention.

One or more triamine derivatives, even when in a library, can be in the biologically active carbamate form. Such a carbamate form can induce increased blood levels and prolong the efficacy of the corresponding non- carbamate form of the compound. Specific carbamates include methyl, ethyl and isobutyl carbamates.

A library prepared as described in Example I, below, can be useful for screening the library on the resin or alternatively can be cleaved from the resin as discrete compounds and screened in absence of resin.

Preferably, the methods described above further comprise

the step of cleaving the library from the resin to give discrete compounds.

As used herein, a chemical or combinatorial "library"is an intentionally created collection of differing molecules which can be prepared by the synthetic means provided below or otherwise and screened for biological activity in a variety of formats (e. g., libraries of soluble molecules, libraries of compounds attached to resin beads, silica chips or other solid supports). The libraries can be screened in any variety of melanocortin receptor and related activity assays, such as those detailed below as well as others known in the art. The libraries will generally have at least one active compound and are generally prepared in such that the compounds are in equimolar quantities.

Compounds disclosed in previous work that are not in an intentially created collection are not part of a"combinatorial library"of the invention. In addition, compounds that are in an unintentional or undesired mixture are not part of a"combinatorial library"of the invention.

"Combinatorial chemistry"or"combinatorial synthesis"refers to the parallel synthesis of diverse compounds by sequential addition of reagents which leads to the generation of large chemical libraries having molecular diversity. Combinatorial chemistry, therefore, involves the systematic and repetitive, covalent connection of a set of different"building blocks"of varying structures to yield large arrays of diverse molecular entities.

A combinatorial library of the invention can contain two or more of the above-described compounds.

The invention further provides a combinatorial library containing three or more, four or more or five or more of the above-described compounds. In another embodiment of the invention, a combinatorial library can contain ten or more of the above-described compounds. In yet another embodiment of the invention, a combinatorial library can contain fifty or more or 100 or more of the above-described compounds. If desired, a combinatorial library of the invention can contain 100,000 or more, or even 1,000,000 or more, of the above-described compounds.

By way of example, the preparation of the combinatorial libraries can use the"split resin approach."The split resin approach is described by, for example, U. S. Patent 5,010,175 to Rutter, WO PCT 91/19735 to Simon, and Gallop et al., J. Med. Chem., 37: 1233-1251 (1994), all of which are incorporated herein by reference.

Triamine derivative compounds of the present invention can be synthesized essentially as described in U. S. Patent Application Serial No. 09/018,173, WO 98/34113 and Ostresh et al., J. Org. Chem., 63: 8622-23 (1998), each of which is fully incorporated herein by reference. In addition, triamine derivative compounds of the present invention can be synthesized using the methods of synthesis described in Example I below.

The choice of chemical functional groups incorporated into specific positions on triamine derivatives will depend, in part, on the specific physical, chemical or biological characteristics required of the MC receptor ligand. Such characteristics are determined, in part, by the route by which the MC receptor ligand will be administered or the location in a subject to which the MC receptor ligand will be directed.

As used herein, the term"ligand"means a molecule that can selectively bind to a receptor. For example, a MC receptor ligand can selectively bind to a MC receptor. Those skilled in the art know what is meant by the term ligand. The triamine derivatives described herein are MC receptor ligands. A ligand can function as an agonist or antagonist. As used herein, the term "agonist"means that a ligand has the function of mimicking the physiological activity of another molecule.

For example, a MC receptor ligand that functions as an agonist mimics the physiological activity of a MC receptor ligand such as MSH, which stimulates MC receptor activity. Similarly, the term"antagonist"means that a ligand has the function of reducing the physiological activity of another molecule, for example, by preventing the activation or inhibiting the activity of a receptor.

For example, a MC receptor ligand that functions as an antagonist reduces the physiological activity of a MC- receptor. A reduction in MC receptor activity can be due to the antagonist binding to the MC receptor and inhibiting activation or to the antagonist preventing the binding of a ligand that stimulates MC receptor activity.

The invention provides methods for altering the activity of a MC receptor in a subject by administering to the subject an effective amount of a MC receptor ligand ; wherein the MC receptor ligand comprises an triamine derivative. The MC receptor ligands can be the triamine derivatives having the structures described above.

Some of the physiological effects of known MC receptor ligands on MC receptor activity are mediated by cytokines, and MC receptor ligands alter cytokine activity. Due to the effect of MC receptor signaling on cytokines, the MC receptor ligands of the invention can

function as cytokine regulatory agents by regulating the aberrant or altered expression of one or more cytokines that occurs in various conditions, including, for example, pathologies, immune responses and inflammatory responses. Such conditions are considered together for purposes of the present invention in that they are characterized, in part, by altered or aberrant cytokine activity and, therefore, are amenable to regulation by one or more cytokine regulatory agents such as the MC receptor ligands disclosed herein.

It should be recognized, however, that while the MC receptor ligands of the invention can function as cytokine regulatory agents, no specific mechanism of action is proposed as to how a MC receptor ligand acts to affect a condition. The MC receptor ligands of the invention can be used to treat conditions characterized by altered or aberrant cytokine activity. However, the conditions treatable with the MC receptor ligands of the invention are not restricted to those conditions or diseases involving altered cytokine activity. The MC receptor ligands are useful for treating a disease or condition if the MC receptor ligand prevents the disease or improves signs or symptoms of the disease, regardless of the mechanism causing the signs or symptoms of the disease.

The present invention provides a method of reducing a pathologically elevated cytokine activity in a subject by administering to the subject an effective amount of MC receptor ligands such as triamine derivatives. The pathologically elevated cytokine activity can be due, for example, to inflammation, cachexia, or a patho-immunogenic disease.

Aberrant cytokine expression can result in damage to healthy tissue in a subject and, in extreme cases, can lead to severe disability and death.

Cytokines can be expressed at a site of localized infection or can be expressed systemically, for example, in an immune response or in response to bacterial endotoxin-induced sepsis. Cytokine expression can induce pyrexia (fever) and hyperalgesia (extreme sensitivity to pain) in a subject, as well as macrophage and monocyte activation, which produces or further contributes to an inflammatory response in a subject.

Cytokines are well known in the art and include, but are not limited to the tumor necrosis factors (TNFs), colony stimulating factors (CSFs), interferons (INFs), interleukins (IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, and IL-15), transforming growth factors (TGFs), oncostatin M (OSM), leukemia inhibiting factor (LIF), platelet activating factor (PAF) and other soluble immunoregulatory peptides that mediate host defense responses, cell regulation and cell-differentiation (see, for example, Kuby, Immunology 3rd ed. (W. H. Freeman and Co., New York (1997); see Chapter 13, which is incorporated herein by reference).

A MC receptor ligand of the invention, such as a triamine derivative, can function as a cytokine regulatory agent and can be used to decrease the activity of a cytokine. For example, a particular pathological condition can cause an increase in the level or activity of a cytokine. A MC receptor ligand that functions to restrain cytokine activity can be used to lower the level or activity of the elevated cytokine. Such a reduction in cytokine activity can alleviate the symptoms of the pathological condition.

A MC receptor ligand such as one of the triamine derivatives disclosed herein can function as a cytokine regulatory agent and increase the levels of IL- 10 in a mammal such as a human. IL-10 can block the activation of some inflammatory cytokines, including TNF, IL-1 and IL-6, while up-regulating cytokines such as IL- 12. IL-10 also stimulates the proliferation of mast cells and thymocytes. IL-10 inhibits several monocyte and macrophage functions, including, for example, antigen presentation to T cells by depressing Class II MHC expression; synthesis of IL-1, IL-6, IL-8, CSF, and TNF; and microbicidal activities.

Administration of a MC receptor ligand can increase the plasma levels of IL-10 in mammals and, therefore, can be useful for modulating, for example, immunoresponsiveness in a subject.

The binding of a MC receptor ligand to a MC receptor results in a wide range of physiological responses. MC receptors are G protein-coupled receptors that activate adenylate cylcase and produce cAMP in response to binding of ligands such as MSH. Although many of the physiological effects of MC receptor signaling are mediated by cytokines, MC receptor ligands of the invention are not limited to those that regulate cytokine activity, as discussed above, but can be any MC receptor ligand that functions to alleviate the signs or symptoms of a disease or condition. Therefore, MC receptor ligands are useful for exploiting the various physiological responses mediated by MC receptor signaling.

The diversity of physiological responses to MC receptor signaling can be advantageously used to alter or regulate a physiological pathway that mediates or

moderates a pathological condition or disease. The recent elucidation of the role of specific MC receptors in particular physiological pathways supports the use of ligands that activate specific MC receptors to modulate a physiological effect that results in a a given condition or disease. Therefore, MC receptor ligands of the invention, which alter the activity of a MC receptor that mediates or moderates a given condition or disease, are useful for treating that condition or disease.

MC receptor ligands such as triamine derivatives are useful for reducing inflammation.

Administration of a triamine derivative can reduce inflammation in response to arachadonic acid administration. Thus compounds of the invention are useful for reducing inflammation.

Nitric oxide (NO) is induced during inflammation by a variety of proinflammatory cytokines. a-MSH was shown to inhibit production of NO through reduction of NO synthase and NO synthase mRNA (Star et al., Proc. Natl. Acad. Sci. USA 92: 8016-8020 (1995)).

Similarly, MC receptor ligands of the invention, such as triamine derivatives, can be used to inhibit NO production, thereby reducing inflammation.

Triamine derivative ligands of the invention that can alter the activity of an MC-3 receptor can be useful for treating sexual dysfunction and other conditions or conditions associated with MC-3 such as inflammation.

Other MC-3-associated conditions that can be treated with the MC-3 receptor ligands include disuse deconditioning; organ damage such as organ transplantation or ischemic injury; adverse reactions

associated with cancer chemotherapy; diseases such as atherosclerosis that are mediated by free radicals and nitric oxide action ; bacterial endotoxic sepsis and related shock; adult respiratory distress syndrome; and autoimmune or other patho-immunogenic diseases or reactions such as allergic reactions or anaphylaxis, rheumatoid arthritis, inflammatory bowel disease, ulcerative colitis, glomerulonephritis, systemic lupus erythematosus, transplant atherosclerosis and parasitic mediated immune dysfunctions such as Chagas's Disease.

The invention further provides a method for treating an MC-3-associated condition in a subject. The term"MC-3-associated condition"includes any condition or condition mediated by MC-3 or can be affected by binding an MC-3 ligand. Such conditions include inflammation and sexual dysfunction.

As used herein, the term"sexual dysfunction" means any condition that inhibits or impairs normal sexual function, including coitus. However, the term need not be limited to physiological conditions, but may include psychogenic conditions or perceived impairment without a formal diagnosis of pathology.

For the treatment of sexual dysfunction compounds of the present invention can be given in a dose range of 0. 001 milligram to about 100 milligram per kilogram of body weight, preferably as a single dose orally or as a nasal spray.

In males, sexual dysfunction includes erectile dysfunction. As used herein, the term"erectile dysfunction"or"impotence"means the inability or impaired ability to attain or sustain an erection that would be of satisfactory rigidity for coitus. Sexual

dysfunction in males can also include premature ejaculation and priapism, which is a condition of prolonged and sometimes painful erection unrelated to sexual activity, often associated with sickle-cell disease.

In females, sexual dysfunction includes sexual arousal disorder. The term"sexual arousal disorder" means herein a persistent or recurrent failure to attain or maintain the lubrication-swelling response of sexual excitement until completion of sexual activity. Sexual dysfunction in females can also include inhibited orgasm and dyspareunia, which. is painful or difficult coitus.

Sexual dysfunction can also be manifested as inhibited sexual desire or inhibited lordosis behavior in animals.

Triamine derivative compounds that activate MCR-4 are particularly useful for decreasing body weight.

MCR-4 has been shown to function in regulating food intake and weight gain. Targeted disruption of MCR-4 causes mice to develop a maturity onset obesity associated with hyperphagia, hyperinsulinemia and hyperglycemia (Huszar et al., supra). Further evidence for the role of MC receptors in regulating food intake and weight gain involves the function of the agouti-related protein, which is a MCR-4 antagonist. An agouti-related protein functions as a selective antagonist of MCR-3 and MCR-4 and causes obesity in transgenic mice expressing agouti-related protein (Ollman et al., Science 278: 135-137 (1997)). Furthermore, agouti analogs were injected into the brains of mice, and those analogs that functioned as MC receptor agonists inhibited feeding while those agouti analogs that functioned as antagonists increased feeding (Fan et al. supra). Thus, a functional role for MC receptors in regulating food intake and weight gain has been established. Therefore,

the MC receptor ligands of the invention such as triamine derivatives are useful for treating obesity by decreasing food intake and body weight gain.

As disclosed herein, administration of a triamine derivative to rats resulted in a significant decrease in the rate of body weight gain and a significant decrease in body weight (see Example IX). As used herein, the term"decrease in body weight"is used broadly to mean an actual decrease in body weight or a decrease in the rate of body weight gain over time, as compared to the normal weight gain expected in the period of time. Thus triamine derivatives are particularly effective at reducing body weight and food consumption.

These results indicate that a MC receptor ligand can cause a decrease in the rate of body weight gain and a decrease in food consumption.

An association between MC receptor signaling and body energy and metabolism has been reported (Huszar et al., supra). The MC receptor ligand HP 228 has been shown to modulate acute resting oxygen consumption (Omholt et al., The Pharmacologist, 39: 53 (1997)), which is incorporated herein by reference. Therefore, MC receptor ligands of the invention can also be used for modulating the metabolic rate or acute oxygen consumption in a subject. The modulated metabolic rate can lead to a decrease in body weight. Thus, MC receptor ligands that can modulate the metabolic rate or acute oxygen consumption in a subject are particularly useful for decreasing body weight in a subject. The MC receptor ligands of the invention can be used to treat obesity and can independently or in combination affect body weight by decreasing food consumption or modulating metabolic rate or oxygen consumption.

In addition to MC receptor ligands that function as agonists that stimulate MC receptor activity, the invention also provides MC receptor ligands, such as triamine derivatives, that function as antagonists that inhibit MC receptor activity. MC receptor antagonists can be used, for example, to increase food intake and body weight analogous to that observed with the MC receptor antagonist agouti-related protein and the agouti analogs that function as antagonists (Fan et al., supra).

MC receptor ligands that function as antagonists are particularly useful for increasing food intake and body weight in an individual suffering from cachexia, a general weight loss that occurs during chronic disease or emotional disturbance.

MC receptor ligands of the invention can also function as cytokine regulatory agents that are useful for treating diabetes. A link exists between obesity and non-insulin dependent diabetes mellitus (NIDDM) (Hotamisligil and Spiegelman, Diabetes 43: 1271-1278 (1994a)). Therefore, MC receptor ligands are useful for decreasing the weight of an obese subject to prevent or alleviate the symptoms associated with NIDDM. Increased TNF-a expression has been detected in the adipose tissue of obese individuals and has been suggested to have a role in the appearance of NIDDM in these individuals (Hotamisligil et al., J. Clin. Invest. 95: 2409-2415 (1995)). However, efforts to neutralize TNF activity using an antibody that binds the TNF receptor did not result in significant weight loss when examined in a rat obesity/diabetes model, the Zucker fa/fa rat model (Hotamisligil et al., J. Clin Invest. 94: 1543-1549 (1994b)). Therefore, MC receptor ligands of the invention that decrease TNF-a are particularly useful for treating diabetes and associated obesity.

When treating obesity, in conjunction with diabetes or hyperglycemia, or alone, generally satisfactory results are obtained when the compounds of the present invention are administered at a daily dosage of from 0.01 milligrams to about 100 milligrams per kilogram of subject body weight, preferably given in a single dose or in divided doses two to six times a day, or in sustained release form. In the case of a 70kg adult human, the total daily dose will generally be from about 0.7 milligrams to about 3500 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.

When treating diabetes mellitus or hyperglycemia, either alone or in combination, as well as when treating other diseases or disorders for which compounds of the present invention are useful, generally satisfactory results are obtained when the compounds of the present invention are administered at a daily dosage of from about 0.001 milligram to about 100 milligram per kilogram of animal body weight, preferably given in a single dose or in divided doses two to six times a day, or in sustained release form. In the case of a 70 kg adult human, for example, the total daily dose will generally be from about 0.07 milligrams to about 350 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.

The a-MSH analog MELANOTAN-II has been shown to cause penile erections in human subjects in pilot phase I clinical studies (Dorr et al., Life Sciences 58: 1777-1784 (1996)). Therefore, MC receptors ligands of the invention can be used to treat erectile dysfunction in a subject (see Example X).

Other conditions that can be treated with the MC receptor ligands of the invention such as triamine derivatives include, but are not limited to, disuse deconditioning; organ damage such as occurs in response to organ transplantation or ischemic injury such as that which can occur after reperfusion or stroke; adverse reactions associated with cancer chemotherapy; diseases such as atherosclerosis that are mediated by free radicals and nitric oxide action; bacterial endotoxic sepsis and related shock; adult respiratory distress syndrome; and autoimmune or other patho-immunogenic diseases or reactions such as allergic reactions or anaphylaxis, rheumatoid arthritis, inflammatory bowel disease, ulcerative colitis, glomerulonephritis, systemic lupus erythematosus, transplant atherosclerosis and parasitic mediated immune dysfunctions such as Chagas' Disease. Many of these conditions are characterized by altered or aberrant cytokine activity.--_ Other conditions that are treatable with melanocortin active compounds, such as the triamine derivatives of the present invention, include hypertension, fever, hypopigmentation, osteoarthritis, cancer, gall bladder disease, male and female sexual disorders, loss of libido, impotence, erectile dysfunction, cognitive and memory deficiencies, substance abuse, pain, sleep apnea, depression, anxiety, compulsion, neuroses, insomnia and other sleep disorders and Alzheimer's disease.

A variety of assays can be used to identify or characterize MC receptor ligands of the invention. For example, the ability of a triamine derivative to compete for binding of a known MC receptor ligand can be used to assess the affinity and specificity of a triamine derivative for one or more MC receptors. Any MC receptor

ligand can be used so long as the ligand can be labeled with a detectable moiety. The detectable moiety can be, for example, a radiolabel, fluorescent label or chromophore, or any detectable functional moiety so long as the MC receptor ligand exhibits specific MC receptor binding. A particularly useful detectable MC receptor ligand for identifying and characterizing other MC receptor ligands is'25I-HP 467, which has the amino acid sequence Ac-Nle-Gln-His- (p (I)-D-Phe)-Arg- (D-Trp)-Gly-NH2 and is described in Dooley et al.,"Melanocortin Receptor Ligands and Methods of Using Same,"U. S. patent application 09/027, 108, filed February 20,1998, which is incorporated herein by reference. HP 467 is a para- iodinated form of HP 228. Thus MC receptor ligands can be identified using a detectable MC receptor ligand.

Using assay methods such as those described above and in Example II, a melanocortin receptor binding assay, binding kinetics and competition with radiolabeled HP 467 confirmed that triamine derivatives of the invention bind to one or more MC receptors (see Examples II and IV). Furthermore, as shown in Tables 1 to 5 below, the assays revealed that triamine derivatives of the invention exhibited a range of affinities and specificity for various MC receptors: Table 1-selected MC receptor binding compounds Compound # MC-1 MC-3 MC4-MC-5 IC50 IC50 uM IC50 uM IC50 uM uM 6603 #1 6. 35 2. 35 5. 6 0. 7 6603 #3 2.2 0. 9 1. 9 0.2 6603 #6 4 4. 1 5. 2 0. 6 6603#16 5.8 2.8 1.8 0. 6 Table 2 Compounds with MC-1 receptor selectivity

Compound 4 MC-1 MC-3 MC4-MC-5 IC50 uM IC50 uM IC50 uM IC50 uM 6610 #19 0. 19 ND 6. 0 0. 3 6600 #9 0. 25 14.3 19.55 0.46 6601 #10 0.330. 81. 80. 7 Table 3 Compounds with MC-5 receptor selectivity Compound # MC-1 MC-3 MC4-MC-5 IC50 uM IC50 uM IC50 uM IC50 uM 6600 #4 0.3 0. 6 No fit 0.03 6600 #2 0. 27 1.34 1.2 0. 07 6600 #8 0. 42 1. 09 No fit 0. 04 6600 #23 0. 59 1. 79 No fit 0. 06 Table 4 MC agonistic compounds Compound # MC-1 MC-3 EC50 MC-4-MC-5 EC50 uM uM EC50 uM EC50 uM 6600 #1 0.4 No fit 0.9 0.35 6600 #3 0.6 No fit 0.3 0.15 Table 5 Compounds showing selective MC-1 agonism Compound # MC-1 MC-3 MC-4-MC-5 EC50 uM EC50 uM EC50 uM EC50 uM 6600 #19 0.24 Not 4.7 Not tested tested 6615 #11 0. 34 No fit 3. 2 No fit Tables 4 and 5 show compounds with MC agonism. The results from Tables 4 and 5 were generated as described below in Example III. The compounds listed in these Tables can be used, for example, to effect melanocortin receptor signaling (see Example V).

The invention provides MC receptor ligands that bind to several MC receptors with similar affinity (see Table 1). In addition, the invention also provides MC receptor ligands that show selectivity for one or more MC receptors (see Tables 2,3 and 5). As used herein, the term "selectivity" means that the affinity of a MC receptor ligand differs between one MC receptor and

another by about 10-fold, generally about 20-to 50-fold, and particularly about 100-fold. In some cases, a MC receptor ligand having broad specificity is desired. In other cases, it is desirable to use MC receptor ligands having selectivity for a particular MC receptor. For example, MCR-3 ligands are particularly useful for treating sexual dysfunction, whereas MCR-4 ligands are useful for treating obesity. The binding characteristics and specificity of a given MC receptor ligand can be selected based on the particular disease or physiological effect that is desired to be altered. i___ The invention also provides ligands with particular affinity for binding the MC-1 receptor (see Table 6 below). The invention further provides ligands with particular affinity for binding the MC-4 receptor (see Table 9 below).

In addition, the invention provides MC-1 agonists (see Table 7 below). Moreover, agonists particular for the MC-4 receptor is also provided (see Table 8 below).

Table 6 MC-1 Binders Pat R 1 Pat R 2 Pat R 3 Pat R 4 Pat R 5 ring N Pat R 6 Pat R 7 Pat R8 X Y H H H H H phenyl 2 (S) 4-chlorophenylmethyl H (S) X-CH-Y 3-guanidinopropyl aminomethyl H H Cl H H phenyl 1 (S) 4-methoxyphenylmethyl H (S) X-CH-Y 3-aminopropyl aminomethyl H H Cl H H phenyl 2 (S) 3,4-dimethoxyphenylmethyl H (S) X-CH-Y 3-aminoethyl aminomethyl H H OMe H H phenyl 2 (S) 4-ethoxyphenylmethyl) H (S) X-CH-Y (3-(aminomethyl)phenyl)methyl aminomethyl H H H H H Cyhex 0 (S) 4-chlorophenylmethyl H (S) X-CH-Y 3-guanidinopropyl aminomethyl H H H H H Cyhex 1 (S) 4-ethoxyphenylmethyl H (S) X-CH-Y (3-(aminomethyl)phenyl)methyl aminomethyl H H Cl H H phenyl 2 (S) 4-methoxyphenylmethyl H (S) X-CH-Y 3-aminopropyl aminomethyl H H Cl H H phenyl 0 (S) 3,4-dimethoxyphenylmethyl H (S) X-CH-Y 3-aminoethyl aminomethyl H H H H H phenyl 2 (S) 4-ethoxyphenylmethyl H (S) X-CH-Y (3-(aminomethyl)phenyl)methyl aminomethyl H H Cl H H phenyl 0 (S) 4-ethoxyphenylmethyl H (X) X-CH-Y 3-aminopropyl aminomethyl H H Cl H H Cyhex 1 (S) 4-iodophenylmethyl H (S) X-CH-Y 3-guanidinopropyl aminomethyl Table 7 MC-1 Agonists Pat R 1 Pat R 2 Pat R 3 Pat R 4 Pat R 5 Pat R 6 Pat R 7 Pat R8 X Y n= H H Cl H H (s) 4-iodophenylmethyl H (S) X-CH-Y 3-guanidinopropyl Aminomethyl 1 H H F H H (s) 4-iodophenylmethyl H (S) X-CH-Y 3-guanidinopropyl Aminomethyl 1 H H Cl H H (S) (4-ethoxyphenyl)methyl H (S) X-CH-Y 3-guanidinopropyl Aminomethyl 1 H H Ethoxy H H (R) (4-ethoxyphenyl)methyl H (R) X-CH-Y 3-guanidinopropyl Aminomethyl 1 H H Cl H H (S) (4-ethoxyphenyl)methyl H (S) X-CH-Y 2-aminoethyl Aminomethyl 1 H H F H H (S) (4-ethoxyphenyl)methyl H (S) X-CH-Y 3-guanidinopropyl Aminomethyl 1 G G Ck G G (S) (4-ethoxyphenyl)methyl H (S) X-CH-Y ethylaminomethyl aminomethyl 1 H H Cl H H (S) (4-ethoxyphenyl)methyl H (S) X-CH-Y butylamiomethyl aminomethyl 1 H H Cl H H (S) (4-ethoxyphenyl)methyl H (S) X-CH-Y 3-phenylpropylaminomethyl aminomethyl 1 H H Cl H H (S) (4-ethoxyphenyl)methyl H (S) X-CH-Y 4-hydroxybutylaminomethyl aminomethyl 1 H H Cl H H (S) (4-ethoxyphenyl)methyl H (S) X-CH-Y 5-hydroxypentylaminomethyl aminomethyl 1 H H Cl H H (S) (4-ethoxyphenyl)methyl (S) X-CH-Y 4-(phenylmethylamino)butyl aminomethyl 1 H H Cl H H (S) (4-ethoxyphenyl)methyl H (S) X-CH-Y 4-(2-phenylethylamino)butyl aminomethyl 1 H H Cl H H (S) (4-ethoxyphenyl)methyl H (S) X-CH-Y 2-(dimethylamino)ethyl aminomethyl 1 H H Cl H H (S) (4-ethoxyphenyl)methyl H (S) X-CH-Y 3-(dimethylamino)propyl aminomethyl 1 H H Cl H H (S) (4-ethoxyphenyl)methyl H (S) X-CH-Y 4-(dimethylamino)butyl aminomethyl 1 TABLE 8 R1 R2 R3 R4 R5 R6 R7 R8 X Y 1 H H Cl H H (S) (4-iodophenyl)methyl H (S) X-CH-Y 3-guanidinopropyl Aminomethyl 2 H H Cl H H (S) (4-ethoxyphenyl)methyl H (S) X-CH-Y 3-guanidinopropyl Aminomethyl 3 H H F H H (S) (4-iodophenyl)methyl H (S) X-CH-Y 3-guanidinopropyl Aminomethyl 4 H H F H H (S) (4-phenylphenyl)methyl H (S) X-CH-Y 3-guanidinopropyl Aminomethyl 5 H H Cl H H (S) (4-ethoxyphenyl)methyl H (S) X-CH-Y 2-aminoethyl Aminomethyl 6 H H Cl H H (S) (4-ethoxyphenyl)methyl H (S) X-CH-Y 2-aminoethyl Aminomethyl 7 H H Cl H H (S) (4-ethoxyphenyl)methyl H (S) X-CH-Y 3-(methylamino)propyl Aminomethyl 8 H H Cl H H (S) (4-ethoxyphenyl)methyl H (S) X-CH-Y 4-guanidinobutyl Aminomethyl 9 H H Cl H H (S) (4-ethoxyphenyl)methyl H (S) X-CH-Y hydroxymethyl Aminomethyl 10 H H Cl H H (S) (4-ethoxyphenyl)methyl H (S) X-CH-Y (3-aminomethyl)phenylmethyl Aminomethyl 11 H H Cl H H (S) (4-iodophenyl)methyl H (S) X-CH-Y 3-(methylamino)propyl Aminomethyl 12 H H Cl H H (S0 (4-iodophenyl)methyl H (S) X-CH-Y 4-guanidinobutyl Aminomethyl 13 H H Cl H H (S) (4-ethoxyphenyl)methyl H (S) X-CH-Y 2-ethylaminoethyl Aminomethyl 14 H H Cl H H (S) (4-ethoxyphenyl)methyl H (S) X-CH-Y 2-dimethylaminoethyl Aminomethyl 15 H H Cl H H (S) (4-ethoxyphenyl)methyl H (R) X-CH-Y 3-dimethylaminopropyl aminomethyl 16 H H Cl H H (S) (4-ethoxyphenyl)methyl H (R) X-CH-Y 3-dimethylaminopropyl aminomethyl 17 H H Cl H H (S) (4-ethoxyphenyl)methyl H (S) X-CH-Y 2-((2-hydroxyethyl)methyl)methylamino)ethyl Aminomethyl 18 H H Cl H H (S) (4-ethoxyphenyl)methyl H (S) X-CH-Y 3-hydroxypropyl Aminomethyl 19 H H Cl H H (S) (4-ethoxyphenyl)methyl absent (2-S, 4-R) trans-2-aminomethyl-4-hydroxypyrrolidine 20 H H Cl H H (S) (4-ethoxyphenyl)methyl H (R) X-CH-Y methylaminopropyl aminomethyl 21 H H Cl H H (S) (4-ethoxyphenyl)methyl H (R) X-CH-Y 3-(ethylamino)propyl aminomethyl 22 H H Cl H H (S) (4-ethoxyphenyl)methyl H (R)X-CH-Y 3-(butylamino)propyl aminomethyl 23 H H Cl H H (S) (4-ethoxyphenyl)methyl H (R) X-CH-Y 3-(2,2-dimethylpropylamino)propyl aminomethyl 24 H H Cl H H (S) (4-ethoxyphenyl)methyl H (R) X-CH-Y 3-(cyclohexylmethylamino)propyl aminomethyl 25 H H Cl H H (S) (4-ethoxyphenyl)methyl H (R) X-CH-Y 3-(3-pridyimethylamino)propyl aminomethyl 26 H H Cl H H (S) (4-ethoxyphenyl)methyl H (R) X-CH-Y 3-(2-methoxyethylamino)propyl aminomethyl 27 H H Cl H H (S) (4-ethoxyphenyl)methyl H (R) X-CH-Y 3-(3-methoxypropylamino)propyl aminomethyl 28 H H Cl H H (S) (4-ethoxyphenyl)methyl H (R) X-CH-Y 3-(4-hydroxybutylamino)propyl aminomethyl 29 H H Cl H H (S) (4-ethoxyphenyl)methyl H (R) X-CH-Y 3-(5-hydroxypentylamino)propyl aminomethyl 30 H H Cl H H (S) (4-ethoxyphenyl)methyl H (R) X-CH-Y 3-(2-phenyoxyethylamino)propyl aminomethyl 31 H H Cl H H (S) (4-ethoxyphenyl)methyl H (R) X-CH-Y 4-(ethylamino)butyl aminomethyl 32 H H Cl H H (S) (4-ethoxyphenyl)methyl H (R) X-CH-Y 4-(2-methoxyethylamino)butyl aminomethyl 33 H H Cl H H (S) (4-ethoxyphenyl)methyl H (R) X-CH-Y 4-(3-methoxypropylamino)butyl aminomethyl 34 H H Cl H H (S) (4-ethoxyphenyl)methyl H (R) X-CH-Y 4-(4-hydroxybutylamino)butyl aminomethyl 35 H H Cl H H (S) (4-ethoxyphenyl)methyl H (R) X-CH-Y 4-(5-hydroxypentylamino)butyl aminomethyl 36 H H Cl H H (S) (4-ethoxyphenyl)methyl H (R) X-CH-Y 4-(((2-(2-methoxy)ethoxy)ethylamino)butyl aminomethyl 37 H H F H H (S) (4-propoxyphenyl)methyl H (S) X-CH-Y 3-guanidinopropyl Aminomethyl 38 H H Cl H H (S) (4-t-butylphenyl)methyl H (R) X-CH-Y 2-(methylsulfonyl)ethyl aminomethyl 39 H H Cl H H (S) (4-propoxyphenyl)methyl absent (2-S, 4-R) trans-2-aminomethyl-4-hydroxypyrrolidine 40 H H Br H H (S) (4-propoxyphenyl)methyl absent (2-S, 4-R) trans-2-aminomethyl-4-hydroxypyrrolidine 41 H H Cl H H (S) (4-propoxyphenyl)methyl H (R) X-CH-Y 2-(methylsulfonyl)ethyl aminomethyl 42 H H Br H H (S) (4-propoxyphenyl)methyl H (R) X-CH-Y 2-(methylsulfonyl)ethyl aminomethyl 43 H H Br H H (S) (4-ethoxyphenyl)methyl H (S) X-CH-Y 2-aminoethyl Aminomethyl 44 H H Cl H H (S) (4-propoxyphenyl)methyl H (S) X-CH-Y 2-aminoethyl Aminomethyl 45 H H Br H H (S) (4-propoxyphenyl)methyl H (S) X-CH-Y 2-aminoethyl Aminomethyl 46 H H Br H H (S) (4-ethoxyphenyl)methyl H (R) X-CH-Y 3-aminopropyl aminomethyl 47 H H Cl H H (S) (4-propoxyphenyl)methyl H (R) X-CH-Y 3-aminopropyl aminomethyl 48 H H Br H H (S) (4-propoxyphenyl)methyl H (R) X-CH-Y 3-aminopropyl aminomethyl 49 H H Br H H (S) (4-ethoxyphenyl)methyl H (R) X-CH-Y 2-(methylsulfonyl)ethyl aminomethyl 50 H H Br H H (S) (4-ehoxyphenyl)methyl absent (2-S, 4-R) trans-2-aminomethyl-4-hydroxypyrrolidine 51 H H Cl H H (S) (4-ethoxyphenyl)methyl H (S) X-CH-Y 2-(cyclopropylamino)propyl Aminomethyl 52 H H Br H H (S) (4-ethoxyphenyl)methyl H (S) X-CH-Y 2-(cyclopropylamino)propyl Aminomethyl 53 H H Br H H (S) (4-ethoxyphenyl)methyl H (S) X-CH-Y 2-(3-methoxypropylamino)propyl Aminomethyl 54 H H Br H H (S) (4-ethoxyphenyl)methyl H (S) X-CH-Y 2-('4-hydroxypiperidin-1-yl)propyl Aminomethyl 55 H H Br H H (S) (4-ethoxyphenyl)methyl H (S) X-CH-Y 2-(2-hydroxy-1,1-dimethylethylamino)propyl Aminomethyl 56 H H Br H H (S) (4-propoxyphenyl)methyl H (S) X-CH-Y 2-(cyclopopylamino)propyl Aminomethyl 57 H H Br H H (S) (4-propoxyphenyl)methyl H (S) X-CH-Y 2-(tetrahydrofurfurylamino)propyl Aminomethyl 58 H H Br H H (S) (4-propoxyphenyl)methyl H (S) X-CH-Y 2-(tetrahydrofurfurylamino)propyl Aminomethyl 59 H H Br H H (S) (4-propoxyphenyl)methyl H (S) X-CH-Y 3-(3-methoxypropylamino)propyl Aminomethyl 60 H H Br H H (S) (4-propoxyphenyl)methyl H (S) X-CH-Y 2-(2-hydroxy-1,1-dimethylethylamino)propyl Aminomethyl 61 H H Br H H (S) (4-ethoxyphenyl)methyl H (S) X-CH-Y 2-hydroxyethyl Aminomethyl 62 H H Br H H (S) (4-propoxyphenyl)methyl H (S) X-CH-Y 2-('4-hydoxypiperidin-1-yl)ethyl Aminomethyl 63 H H Br H H (S) (4-propoxyphenyl)methyl H (S) X-CH-Y 2-(2-hydroxy-1,1-dimethylethylamno)ethyl Aminomethyl 64 H H Br H H (S) (4-ethoxyphenyl)methyl H (S) X-CH-Y 4-(ethylamino)butyl Aminomethyl 65 H H Br H H (S) (4-propoxyphenyl)methyl H (S) X-CH-Y 4-(ethylamino)butyl Aminomethyl 66 H H Br H H (S) (4-ethoxyphenyl)methyl H (S) X-CH-Y 4-(2-methoxyethylamino)butyl Aminomethyl 67 H H Br H H (S) (4-propoxyphenyl)methyl H (S) X-CH-Y 4-(2-methoxyethylamino)butyl Aminomethyl TABLE 8 68 H H Br H H (S) (4-ethoxyphenyl0methyl H (S) X-CH-Y 3-(ethylamino)propyl Aminomethyl 69 H H Br H H (S) (4-propoxyphenyl)methyl H (S) X-CH-Y 3-(ethylamino)propyl Aminomethyl 70 H H Br H H (S) (4-ethoxyphenyl)methyl H (S) X-CH-Y 3-(2-methoxyethylamino)propyl Aminomethyl 71 H H Br H H (SI) (4-propoxyphenyl)methyl H (S) X-CH-Y 3-(2-methoxyethylamino)upropyl Aminomethyl Table 9 MC-4 Binders Pat R1 Pat R2 Pat R3 Pat R4 Pat R5 n= Ring Pat R6 Pat R7 Pat R8 X Y H H Cl H H 1 Ph (S) (3,4-dimethoxyphenyl)methyl H (S) X-CH-Y 3-pyridylmethyl Aminomethyl H H Br H H 1 Ph (S) (4-trifluoromethlphenyl)methyl H (S) X-CH-Y 3-pyridylmethyl Aminomethyl H H Cl H H 1 Ph (S) (4-trifluoromethlphenyl)methyl H (S) X-CH-Y 3-pyridylmethyl Aminomethyl H H Cl H H 1 Ph (S) (4-trifluoromethlphenyl)methyl H (S) X-CH-Y 3-pyridylmethyl Aminomethyl H H Me H H 1 Ph (S) (4-trifluoromethlphenyl)methyl H (S) X-CH-Y 3-pyridylmethyl Aminomethyl H Cl H H H 1 Ph (S) (4-t-butylphenyl)methyl H (S) X-CH-Y 3-pyridylmethyl Aminomethyl H H Br H H 1 Ph (S) (4-t-butylphenyl)methyl H (S) X-CH-Y 3-pyridylmethyl Aminomethyl H H Cl H H 1 Ph (S) (4-t-butylphenyl)methyl H (S) X-CH-Y 3-pyridylmethyl Aminomethyl H H Cl H H 1 Ph (S) (4-t-butylphenyl)methyl H (S) X-CH-Y 3-pyridylmethyl Aminomethyl H H Me H H 1 Ph (S) (4-t-butylphenyl)methyl H (S) X-CH-Y 3-pyridylmethyl Aminomethyl Cl H Cl H H 1 Ph (S) (4-ethoxyphenyl)methyl H (S) X-CH-Y 3-pyridylmethyl Aminomethyl H H Br H H 1 Ph (S) (4-propoxyphenyl)methyl H (S) X-CH-Y 3-pyridylmethyl Aminomethyl H H Cl H H 1 Ph (S) (4-propoxyphenyl)methyl H (S) X-CH-Y 3-pyridylmethyl Aminomethyl H H Br H H 1 Ph (S) (4-methoxyphenyl)methyl H (S) X-CH-Y 3-pyridylmethyl Aminomethyl H H Cl H H 1 Ph (S) (4-methoxyphenyl)methyl H (S) X-CH-Y 3-pyridylmethyl Aminomethyl H H CF3 H H 1 Ph (S) (4-chlorophenyl)methyl H (S) X-CH-Y 3-guanidinopropyl Aminomethyl H H H H H 0 CyHex (S) (4-chlorophenyl)methyl H (S) X-CH-Y 3-guanidinopropyl Aminomethyl H H H H H 1 CyHex (S) (4-chlorophenyl)methyl H (S) X-CH-Y 3-guanidinopropyl Aminomethyl H H nAmyl H H 1 Ph (S) (4-phenylphenyl)methyl H (S) X-CH-Y 3-guanidinopropyl Aminomethyl H H F H H 1 Ph (S) (4-((3- H (S) X-CH-Y 3-guanidinopropyl Aminomethyl phenylpropylamino)phenyl)methyl H H CF3 H H 1 Ph (S) (4-chlorophenyl)methyl H (S) X-CH-Y (3- Aminomethyl aminomethyl)phenylmethyl H H OMe H H 2 Ph (S) (4-chlorophenyl)methyl H (S) X-CH-Y (3- Aminomethyl aminomethyl)phenylmethyl H H OEt H H 2 Ph (S) (4-chlorophenyl)methyl H (S) X-CH-Y (3- Aminomethyl aminomethyl)phenylmethyl H H H H H 0 CyHex (S) (4-chlorophenyl)methyl H (S) X-CH-Y (3- Aminomethyl aminomethyl)phenylmethyl H H H H H 1 CyHex (S) (4-chlorophenyl)methyl H (S) X-CH-Y (3- Aminomethyl aminomethyl)phenylmethyl H H H H H 2 Ph (S) (4-chlorophenyl)methyl H (S) X-CH-Y (3- Aminomethyl aminomethyl)phenylmethyl H H CF3 H H 1 Ph (S) (4-ethoxyphenyl)methyl H (S) X-CH-Y (3- Aminomethyl aminomethyl)phenylmethyl H Cl Cl H H 1 Ph (S) (4-t-butylphenyl)methyl absent (2-S, 4-R) trans-2-aminomethyl-4-hydroxypyrrolidine H H Cl H H 1 Ph (S) (4-t-butylphenyl)methyl absent (2-S, 4-R) trans-2-aminomethyl-4-hydroxypyrrolidine H Cl Cl H H 1 Ph (S) (3,4-dimethoxyphenyl)methyl H (S) X-CH-Y 3-aminopropyl Aminomethyl H Cl Cl H H 1 Ph (S) (4-trifluoromethylphenyl)methyl H (S) X-CH-Y 3-aminopropyl Aminomethyl H H Cl H H 1 Ph (S) (4-trifluoromethylphenyl)methyl H (S) X-CH-Y 3-aminopropyl Aminomethyl H H CF3 H H 1 Ph (S) (4-chlorophenyl)methyl H (S) X-CH-Y 3-aminopropyl Aminomethyl H H H H H 1 CyHex (S) (4-chlorophenyl)methyl H (S) X-CH-Y 3-aminopropyl Aminomethyl H H Cl H H 2 Ph (S) (4-t-butylphenyl)methyl H (S) X-CH-Y 3-aminopropyl Aminomethyl H Cl Cl H H 1 Ph (S) (4-t-butylphenyl)methyl H (S) X-CH-Y 3-aminopropyl Aminomethyl H H OCF3 H H 1 Ph (S) (4-t-butylphenyl)methyl H (S) X-CH-Y 3-aminopropyl Aminomethyl H H Cl H H 1 Ph (S) (4-t-butylphenyl)methyl H (S) X-CH-Y 3-aminopropyl Aminomethyl H H Me H H 1 Ph (S) (4-t-butylphenyl)methyl H (S) X-CH-Y 3-aminopropyl Aminomethyl H H Br H H 1 Ph (S) (4-methoxyphenyl)methyl H (S) X-CH-Y 3-aminopropyl Aminomethyl H H Cl H H 1 Ph (S) (4-methoxyphenyl)methyl H (S) X-CH-Y 3-aminopropyl Aminomethyl H Cl Cl H H 1 Ph (S) (4-methoxyphenyl)methyl H (S) X-CH-Y 3-aminopropyl Aminomethyl H H Br H H 1 Ph (S) (4-methoxyphenyl)methyl H (S) X-CH-Y 3-aminopropyl Aminomethyl H H Cl H H 1 Ph (S) (4-methoxyphenyl)methyl H (S) X-CH-Y 3-aminopropyl Aminomethyl H H Cl H H 1 Ph (S) (4-methoxyphenyl)methyl H (S) X-CH-Y 3-aminopropyl Aminomethyl H H H H H 1 CyHex (S) (4-chlorophenyl)methyl H (S) X-CH-Y 3-aminbutyl Aminomethyl H H Cl H H 2 Ph (S) (4-trifluoromethlphenyl)methyl H (S) X-CH-Y 2-methylsulfonylethyl Aminomethyl H Cl Cl H H 1 Ph (S) (4-trifluoromethlphenyl)methyl H (S) X-CH-Y 2-methylsulfonylethyl Aminomethyl H Cl H H H 1 Ph (S) (4-trifluoromethlphenyl)methyl H (S) X-CH-Y 2-methylsulfonylethyl Aminomethyl H H Cl H H 1 Ph (S) (4-trifluoromethlphenyl)methyl H (S) X-CH-Y 2-methylsulfonylethyl Aminomethyl H H Me H H 1 Ph (S) (4-trifluoromethlphenyl)methyl H (S) X-CH-Y 2-methylsulfonylethyl Aminomethyl H H Cl H H 2 Ph (S) (4-t-butylphenyl)methyl H (S) X-CH-Y 2-methylsulfonylethyl Aminomethyl H Cl H H H 1 Ph (S) (4-t-butylphenyl)methyl H (S) X-CH-Y 2-methylsulfonylethyl Aminomethyl H H Cl H H 1 Ph (S) (4-t-butylphenyl)methyl H (S) X-CH-Y 2-methylsulfonylethyl Aminomethyl H H Cl H H 1 Ph (S) (3-phenylphenyl)methyl H (S) X-CH-Y 2-methylsulfonylethyl Aminomethyl Cl H Cl H H 1 Ph (S) (4-ethoxyphenyl)methyl H (S) X-CH-Y 2-methylsulfonylethyl Aminomethyl H H Cl H H 2 Ph (S) (4-ethoxyphenyl)methyl H (S) X-CH-Y 2-methylsulfonylethyl Aminomethyl H H Cl H H 2 Ph (S) (4-methoxyphenyl)methyl H (S) X-CH-Y 2-methylsulfonylethyl Aminomethyl H H Br H H 1 Ph (S) (4-methoxyphenyl)methyl H (S) X-CH-Y 2-methylsulfonylethyl Aminomethyl H H Cl H H 1 Ph (S) (4-methoxyphenyl)methyl H (S) X-CH-Y 2-methylsulfonylethyl Aminomethyl H H Cl H H 1 Ph (S) (4-l-propylphenyl)methyl H (S) X-CH-Y 2-methylsulfonylethyl Aminomethyl Cl H Cl H H 1 Ph (S) (4-ethoxyphenyl)methyl H (S) X-CH-Y 2-methoxymethyl Aminomethyl H H Br H H 1 Ph (S) (4-methoxyphenyl)methyl H (S) X-CH-Y 2-methoxymethyl Aminomethyl H H Cl H H 1 Ph (S) (4-methoxyphenyl)methyl H (S) X-CH-Y 2-methoxymethyl Aminomethyl H H Cl H H 1 Ph (S) (4-methoxyphenyl)methyl H (S) X-CH-Y 2-methoxymethyl Aminomethyl H H Cl H H 1 Ph (S) (4-ethylphenyl)methyl H (S) X-CH-Y 2-methoxymethyl Aminomethyl H H Cl H H 1 Ph (S) (4-l-propylphenyl)methyl H (S) X-CH-Y hydroxymethyl Aminomethyl H Cl Cl H H 1 Ph (S) (4-trifluoromethlphenyl)methyl H (S) X-CH-Y hydroxymethyl Aminomethyl H H Br H H 1 Ph (S) (4-trifluoromethlphenyl)methyl H (S) X-CH-Y hydroxymethyl Aminomethyl H H Cl H H 1 Ph (S) (4-trifluoromethlphenyl)methyl H (S) X-CH-Y hydroxymethyl Aminomethyl H H Me H H 1 Ph (S) (4-trifluoromethlphenyl)methyl H (S) X-CH-Y hydroxymethyl Aminomethyl H Cl Cl H H 1 Ph (S) (4-t-butylphenyl)methyl H (S) X-CH-Y hydroxymethyl Aminomethyl H H OCF3 H H 1 Ph (S) (4-t-butylphenyl)methyl H (S) X-CH-Y hydroxymethyl Aminomethyl H H Br H H 1 Ph (S) (4-t-butylphenyl)methyl H (S) X-CH-Y hydroxymethyl Aminomethyl H H Me H H 1 Ph (S) (4-t-butylphenyl)methyl H (S) X-CH-Y hydroxymethyl Aminomethyl H H Cl H H 1 Ph (S) (4-phenylphenyl)methyl H (S) X-CH-Y hydroxymethyl Aminomethyl Cl H Cl H H 1 Ph (S) (4-ethoxyphenyl)methyl H (S) X-CH-Y hydroxymethyl Aminomethyl H H Cl H H 1 Ph (S) (4-ethylphenyl)methyl H (S) X-CH-Y hydroxymethyl Aminomethyl H H Cl H H 1 Ph (S) (4-l-propylphenyl)methyl H (S) X-CH-Y hydroxymethyl Aminomethyl H H OEt H H 1 Ph (S) (4-iodophenyl)methyl H (R) X-CH-Y 3-aminopropyl Aminomethyl H H H H H 0 CyHex (S) (4-iodophenyl)methyl H (R) X-CH-Y 3-aminopropyl Aminomethyl H H H H H 0 CyHex (S) (4-ethoxyphenyl)methyl H (R) X-CH-Y 3-aminopropyl Aminomethyl H H Br H H 1 Ph (S) (4-ethoxyphenyl)methyl H (S) X-CH-Y propylthiomethyl Aminomethyl H H Br H H 1 Ph (S) (4-ethoxyphenyl)methyl H (S) X-CH-Y isopropylthiomethyl Aminomethyl H H Cl H H 1 Ph (S) (4-ethoxyphenyl)methyl H (S) X-CH-Y isopropylthiomethyl Aminomethyl H H H H H 1 CyHex (S) (4-iodophenyl)methyl H (S) X-CH-Y 3-aminopropyl Aminomethyl H H Br H H 1 Ph (S) (4-ethoxyphenyl)methyl H (S) X-CH-Y (2,2,2-trifluoroethylthiomethyl Aminomethyl H H Cl H H 1 Ph (S) (4-ethoxyphenyl)methyl H (S) X-CH-Y (2-cyclohexylethylaminomethyl Aminomethyl H H Br H H 1 Ph (S) (3,4-dimethoxyphenyl)methyl H (S) X-CH-Y 2-aminoethyl Aminomethyl H H Cl H H 1 Ph (S) (3,4-dimethoxyphenyl)methyl H (S) X-CH-Y 2-aminoethyl Aminomethyl H H Cl H H 2 Ph (S) (4-trifluoromethlphenyl)methyl H (S) X-CH-Y 2-dimethylaminoethyl Aminomethyl H Cl Cl H H 1 Ph (S) (4-trifluoromethlphenyl)methyl H (S) X-CH-Y 2-dimethylaminoethyl Aminomethyl H H OCF3 H H 1 Ph (S) (4-trifluoromethlphenyl)methyl H (S) X-CH-Y 2-dimethylaminoethyl Aminomethyl H H Cl H H 1 Ph (S) (4-trifluoromethlphenyl)methyl H (S) X-CH-Y 2-dimethylaminoethyl Aminomethyl H H Me H H 1 Ph (S) (4-trifluoromethlphenyl)methyl H (S) X-CH-Y 2-dimethylaminoethyl Aminomethyl H H OCF3 H H 1 Ph (S) (4-t-butylphenyl)methyl H (S) X-CH-Y 2-dimethylaminoethyl Aminomethyl H H Br H H 1 Ph (S) (4-t-butylphenyl)methyl H (S) X-CH-Y 2-dimethylaminoethyl Aminomethyl H H Cl H H 1 Ph (S) (4-t-butylphenyl)methyl H (S) X-CH-Y 2-dimethylaminoethyl Aminomethyl H H Me H H 1 Ph (S) (4-t-butylphenyl)methyl H (S) X-CH-Y 2-dimethylaminoethyl Aminomethyl H Cl Cl H H 1 Ph (S) (4-methoxyphenyl)methyl H (S) X-CH-Y 2-dimethylaminoethyl Aminomethyl H H Br H H 1 Ph (S) (4-methoxyphenyl)methyl H (S) X-CH-Y 2-dimethylaminoethyl Aminomethyl H Cl Cl H H 1 Ph (S) (4-ethoxyphenyl)methyl H (S) X-CH-Y 2-dimethylaminoethyl Aminomethyl H H Me H H 1 Ph (S) (4-ethoxyphenyl)methyl H (S) X-CH-Y 2-dimethylaminoethyl Aminomethyl H H Cl H H 2 Ph (S) (4-methoxyphenyl)methyl H (S) X-CH-Y 2-dimethylaminoethyl Aminomethyl H Cl Cl H H 1 Ph (S) (4-methoxyphenyl)methyl H (S) X-CH-Y 2-dimethylaminoethyl Aminomethyl H H OCF3 H H 1 Ph (S) (4-methoxyphenyl)methyl H (S) X-CH-Y 2-dimethylaminoethyl Aminomethyl H H Cl H H 1 Ph (S) (4-((3-pyridyl)methylamino)phenyl)methyl

Another assay useful for identifying or characterizing MC receptor ligands measures signaling of MC receptors. MC receptors are G protein-coupled receptors that couple to adenylate cyclase and produce cAMP. Therefore, measuring cAMP production in a cell expressing a MC receptor and treated with a MC receptor ligand can be used to assess the function of the MC receptor ligand in activating a MC receptor. One method for measuring cAMP production in cells expressing a MC receptor ligand and treated with a triamine derivative of the invention is described in Example V. A variety of triamine derivatives that can activate MC receptors are shown in Tables 4 and 5.

The invention also relates to pharmaceutical compositions comprising a MC receptor ligand such as a triamine derivative and a pharmaceutically acceptable carrier. The term"composition", as in pharmaceutical composition, is intended to encompass a product comprising at least one active ingredient, and at least one inert ingredient making up the carrier, as well as any product which results, directly or indirectly, from combination of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.

Pharmaceutically acceptable carriers are well known in the art and include aqueous solutions such as physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil-or injectable organic esters.

A pharmaceutically acceptable carrier can contain physiologically acceptable compounds that act, for example, to stabilize the MC receptor ligand or increase the absorption of the agent. Such physiologically acceptable compounds include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. One skilled in the art would know that the choice of a pharmaceutically acceptable carrier, including a physiologically acceptable compound, depends, for example, on the route of administration of the MC receptor ligand and on the particular physico-chemical characteristics of the specific MC receptor ligand.

The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated.

Such dosage may be ascertained readily by a person skilled in the art.

The invention further relates to methods of administering a pharmaceutical composition comprising an MC receptor ligand such as a triamine derivative to a subject in order to restrain pathologically elevated cytokine activity in the subject, to treat inflammation or to treat obesity. For example, a triamine derivative can be administered to a subject as a treatment for inflammation, pain, obesity, cachexia, sexual dysfunction or syndrome X. As used herein,"syndrome X"is a set of conditions that result from or are associated with being overweight ; such set of conditions can include diabetes, high blood pressure, atherosclerosis, stroke and heart disease.

The invention also relates to methods of administering a pharmaceutical composition comprising an MC receptor ligand such as a triamine derivative to a subject in order to enhance a cytokine activity that restrains pathologically elevated cytokine activity in a subject. For example, IL-10 is known to decrease the activity of certain pathologically elevated cytokines such as TNF-a, IL-1, IL-6 and IL-8 (Platzer et al., International Immunol. 7: 517-523 (1995)). A normal range of IL-10 activity present in a specific tissue can be determined by sampling a statistically significant number of normal, healthy subjects in the population. A triamine derivative is administered to increase IL-10 activity above the normal range in order to restrain pathologically elevated cytokine activity. In particular, IL-10 cytokine activity is increased at least about one standard deviation above the normal, and can be two standard deviations or greater above the normal range.

A pharmaceutical composition comprising an MC receptor ligand such as a triamine derivative can be administered to a subject having pathologically elevated cytokine activity by various routes including, for example, orally, intravaginally, rectally, or parenterally, such as intravenously, intramuscularly, subcutaneously, intraorbitally, intracapsularly, intraperitoneally, intracisternally or by passive or facilitated absorption through the skin using, for example, a skin patch or transdermal iontophoresis, respectively. Furthermore, the composition can be administered by injection, intubation or topically, the latter of which can be passive, for example, by direct application of an ointment or powder, or active, for example, using a nasal spray or inhalant. An MC receptor ligand also can be administered as a topical spray, in

which case one component of the composition is an appropriate propellant. The pharmaceutical composition also can be incorporated, if desired, into liposomes, microspheres or other polymer matrices (Gregoriadis, Liposome Technology, Vols. I to III, 2nd ed., CRC Press, Boca Raton, FL (1993), which is incorporated herein by reference). Liposomes, for example, which consist of phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.

Since cytokine expression can be localized or systemic, one skilled in the art would select a particular route and method of administration of a triamine derivative based on the source and distribution of cytokines in a subject. For example, in a subject suffering from a systemic condition such as bacterial endotoxin-induced sepsis, a pharmaceutical composition comprising a triamine derivative can be administered intravenously, orally or by another method that distributes the compound systemically. However, in a subject suffering from a pathology caused by localized cytokine expression such as acute respiratory distress syndrome, a triamine derivative can be suspended or dissolved in the appropriate pharmaceutically acceptable carrier and administered directly into the lungs using a nasal spray or other inhalation device.

In order to restrain the biological activity of a cytokine, for example, a triamine derivative must be administered in an effective dose, which is about 0.0001 to 100 mg/kg body weight. The total effective dose can be administered to a subject as a single dose, either as a bolus or by infusion over a relatively short period of time, or can be administered using a fractionated treatment protocol, in which the multiple doses are

administered over a more prolonged period of time. One skilled in the art would know that the concentration of a triamine derivative required to obtain an effective dose in a subject depends on many factors including the age and general health of the subject as well as the-route of administration and the number of treatments to be administered. In view of these factors, the skilled artisan would adjust the particular dose so as to obtain an effective dose for altering the activity of a MC receptor.

Triamine derivative compounds of the present invention may be used in combination with other drugs that are used in the treatment, prevention, suppression or amelioration of the diseases or conditions for which such compounds are useful. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a triamine derivative compound of the present invention.

When such a triamine derivative compound is used contemporaneously with one or more other drugs, a pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients in addition to a triamine derivative compound of the present invention. Examples of other active ingredients that may be combined with a triamine derivative compound of the present invention, either administered separately or in the same pharmaceutical compositions, include, but are not limited to: (a) insulin sensitizers including (i) PPARy agonists such as the glitazones (e. g. troglitazone, pioglitazone, englitazone, MCC-555, BRL49653 and the like), and compounds disclosed in W097/27857,97/28115, 97/28137 and 97/27847; (ii) biguanides such as metformin and phenformin;

(b) insulin or insulin mimetics; (c) sulfonylureas such as tolbutamide and glipizide; (d) a-glucosidase inhibitors (such as acarbose); (e) cholesterol lowering agents such as (i) HMG- CoA reductase inhibitors (lovastatin, simbastatin and pravastatin, fluvastatin, atorvastatin, and other statins), (ii) sequestrants (cholestyramine, colestipos and a dialkylaminoalkyl derivatives of a cross-linked dextran), (ii) nicotinyl alcohol nicotinic acid or a salt thereof, (iii) proliferator-activator receptor a agonists such as fenofibric acid derivatives (gemfibrozil, 'clofibrat, fenofibrate and benzafibrate), (iv) inhibitors of cholesterol absorption for example beta-sitosterol and (acyl CoA: cholesterol acyltransferase) inhibitors for example melinamide, (v) probucol, (vi) vitamin E and (vii) thyromimetics; (f) PPAR5 agonists such as those disclosed in W097/28149 ; (g) anti-obesity compounds such as fenfluramine, dexfenfluramine, phentermine, sibutramine, orlistat, or P3 adrenergic receptor agonists; (h) feeding behavior modifying agents such as neuropeptide Y antagonists (e. g. neuropeptide Y5) such as those disclosed in WO 97/19682, WO 97/20820, WO 97/20821, WO 97/20822 and WO 97/20823;

(i) PPARa agonists such as described in WO 97/36579; (j) PPARy antagonists such as described in WO 97/10813 ; (k) serotonin reuptake inhibitors such as fluoxetine and sertraline; (1) growth hormone secretagogues such as MK- 0677; (m) agents useful in the treatment of male or female sexual dysfunction such as phosphodiester V inhibitors such as sildenafil, and a-2 adrenergic receptor antagonists; and (n) CCK agonists useful in the reduction of feeding such as SR146131, or the CCK agonists described in U. S. pat. nos. 5,859,007; 5,795,887; 5,731,340; 5,656,648; 5,889,182; 5,739,129; 5,508,432; 5,646,140; or 5, 534,530.

The following examples are intended to illustrate but not limit the invention.

EXAMPLE I This example provides methods for the synthesis of combinatorial libraries of the present invention.

Method 1. General protocol Step 1. Peptide synthesis Solid phase syntheses were carried out using the "tea-bag"methodology in which the resin is contained within polypropylene mesh packets. 100mg p-methylbenzhydrylamine (MBHA) resin (1. 3meq/g, 100-200 mesh) was neutralized by three 5mL washes with 5% diisopropylethylamine (DIEA) in dichloromethane (DCM).

Excess DIEA was removed by three 5mL DCM washes. The first amino acid was coupled by adding the resin packet to a solution of the N-a-tBoc protected amino acid (0.2M, 6x) and hydroxybenzotriazole (HOBt), 6x) in dimethyl formamide (DMF), followed by the addition of 0.2M diisopropylcarbodiimide (DIC, 6x) in DCM (see Step 1 of Figure 1).

The first amino acid can be non-cyclic, resulting in a triamine of the invention where R7 is present and R8 is the formula X-CH-Y, as discussed above.

When the non-cylic amino acid is N-alkylated, it results in R7 being an alkyl.

Alternatively, a cyclic amino acid can be used, resulting in R7 being absent and R8 and the adjacent nitrogen of the above depicted formula forming a heterocycle or substituted heterocycle, as discussed above. Commercially available cyclic amino acids such as, for example, proline, hydroxyproline, thioproline or tetrahydroisoquinoline carboxylate can be used. In

addition, both cyclic and non-cyclic amino acids can be made and are known to those skilled in the art.

Non-commercial amino acids can be prepared off resin from commercially available amino acids and used in this synthesis. For example the available N-BOC-O-allyl tyrosine can be hydrogenated by following the example by Fraile et al., Tetrahedron Asymmetry, 7: 2263-2276 (1996), to produce the N-BOC-0-propyl tyrosine, which can be incorporated into the solid phase synthesis. Cyclic derivatives can also be prepared off resin and incorporated in the syntheis. For example, 4-substituted proline derivatives can be prepared following the examples provided by Williams et al., J Org Chem, 59: 3616-3625 (1994); Hudlicky, M., J Fluorine Chem, 60: 193- 210 (1993); and Tanaka et al., Tetrahedron: Asymmetry, 9: 71-77 (1998). For examples of methods for thiazolidine S, S dioxide amino acids see Mata, E. G., Tetrahedron Lett, 38: 6335-6338 (1997); and Patek et al., Tetrahedron Lett, 36: 2227-2230 (1995).

The coupling reaction was allowed to proceed for 2h. The reaction solution was removed and the resin was washed once with 5mL DMF, and once with 5mL DCM. The N-a-tBoc protecting group was removed by washing the packet twice for 30 minutes with trifluoroacetic acid (TFA) in DCM. Excess TFA was removed by washing the packet twice with isopropanol, and twice with 5mL DCM (see Step 2 of Figure 1).

The resin-bound TFA salt was then neutralized, washed, and a second amino acid added in a manner identical to the first (see Step 3 of Figure 1).

Following removal of the second N-a-tBoc protecting group (see Step 4 of Figure 1), the resulting dipeptide was then N-acylated by adding the resin packet to a solution

of the carboxylic acid (0.2M, 6x) and HOBt (6x) (see Step 5 of Figure 1). DCI (0.2M in DCM, 6x) was then added and the coupling reaction allowed to proceed for 2h at room temperature. The resin was then washed once with 5mL DMF and once with 5mL DCM.

As shown at Step 5 of Figure 1, phenylacetic acid derivatives were coupled to make compounds of the invention. However, cyclohexylacetic acid derivatives were also used to make compounds of the invention, resulting in a cyclohexyl ring in the formula of the invention.

Step 2. Exhaustive reduction The exhaustive reduction of the three backbone functionalities of the N-acylated dipeptide (as well as any reducible side chain functionalities) was carried out in 50mL glass conical tubes under nitrogen (see Step 6 of Figure 1). To each tube was added the resin packet (0.13meq resin, 100mg of starting resin, 0.24 meq carbonyl) and boric acid (234mg, 15x). Trimethylborate (0.416mL, 15x) was added, followed by the slow addition of 10.8mL borane-THF complex (1M, 45x). Following cessation of hydrogen evolution, the capped tubes were heated at 65*C for 72h in a heating block. Following decantation of the reaction solution (quenched by the slow addition to isopropanol), the resin packet was washed three times with 5mL methanol, once with 5mL tetrahydrofuran and twice with 5mL piperidine. The amine-borane complex was then disproportionated by overnight treatment with lOmL piperidine (400x) at 65*C.

Following decantation of the resulting piperidine-borane solution, the resin packet was washed twice with 5mL DCM and twice with methanol. The resin was then dried under high vacuum.

Alternatively, the reduction was carried out with 10 mL 1M borane methylsulfide complex in dioxane at reflux for 24 hours. The steps for decantation, washing, piperidine treatment and washing remain the same.

Step 3: Resin cleavage The triamines were cleaved from resin by treatment with anhydrous HF, in the presence of 5% anisole, at 0*C for 9h (see Step 7 of Figure 1). The desired products were obtained following extraction from acetonitrile/water (1/1,2x5mL) and lyophilization.

Method 2. Protocol for synthesis of group X of R8 dimethylamine-triamine Solid phase syntheses were carried out using the"tea-bag"methodology in which the resin is contained within polypropylene mesh packets. 100mg MBHA resin (1. 3meq/g, 100-200 mesh) was neutralized by three 5mL washes with 5% DIEA in DCM. Excess DIEA was removed by three 5mL DCM washes.

Step 1: Coupling a-Boc-Diamino acid-amino-terminal- Fmoc-OH to resin (see Step 1 of Figure 2).

The resin packet was added to a solution of a- Boc-diamino (Fmoc)-OH (0.2M, 6x) and HOBt (0. 2M, 6x) in DMF, followed by the addition of DIC (0.2M, 6x) in DCM.

The coupling reaction was allowed to proceed for 2h. The reaction solution was removed and the resin was washed once with 5mL DMF, and once with 5mL DCM.

Step 2: Removal of Boc group (see Step 2 of Figure 2).

The N-a-tBoc protecting group was removed by

washing the packet twice for 30 minutes with 55tTFA/DCM.

Excess TFA was removed by washing the packet twice with 5mL IPA, twice with 5mL DCM, twice with 5mL 5% DIEA/DCM and twice with 5mL DCM.

Step 3: Addition of Boc-Tyr (OEt)-OH (see Step 3 of Figure 2).

The resin packet was added to a solution of Boc-Lys (OEt)-OH (0.1M, 6x) and DIC (0. 1M, 6x) in DCM.

The coupling reaction was allowed to proceed for 20h.

The reaction solution was removed and the resin was washed once with 5mL DMF, and once with 5mL DCM. The switch to DCM and exclusion of HOBt was to avoid any Fmoc deprotection.

Step 4: Removal of Boc group (see Step 4 of Figure 2).

The N-a-tBoc protecting group was removed by washing the packet twice for 30 minutes with 55% TFA/DCM.

Excess TFA was removed by washing the packet twice with 5mL IPA, twice with 5mL DCM, twice with 5mL 5% DIEA/DCM and twice with 5mL DCM.

Step 5: Addition of 4-chlorophenylacetic acid (see Step 5 of Figure 2).

The resin packet was added to a solution of 4-chlorophenylacetic acid (0. lM, 6x) and DIC (0. lM, 6x) in DCM. The coupling reaction was allowed to proceed for 3h. The reaction solution was removed and the resin was washed once with 5mL DMF, and once with 5mL DCM.

Step 6: Removal of Fmoc group (see Step 6 of Figure 2).

The N-b-Fmoc protecting group was removed by washing the packet for 30 minutes with 20%

piperidine/DMF. The packet was washed three times with 5mL DMF, three times with 5mL DCM, and once with 5mL MeOH.

Step 7: Methylation (see Step 7 of Figure 2).

The resin packet was added to a mixture of formaldehyde (lOmL ; 37taq) and formic acid (5mL) and heated at 80°C for 20 hours. After cooling to room temp the packet was washed twice with 5mL methanol, twice with 5mL DCM and once with methanol.

In an alternate procedure, the resin packet was added to a mixture of formaldehyde (lOmL) and formic acid (2.5mL) and heated at 80°C for 2 hours. A further portion of formic acid (2.5mL) was added and the mixture heated for a further 18 hours.

Step 8: Reduction (see last step of Figure 2).

The reduction was carried out in 50mL glass conical tubes under nitrogen. To each tube was added the resin packet (0.13meq resin, 100mg of starting resin, 0.24 meq carbonyl) and boric acid (234mg, 15x).

Trimethylborate (0.416mL, 15x) was added, followed by the slow addition of 10.8mL borane-THF complex (1M, 45x).

Following cessation of hydrogen evolution, the capped tubes were heated at 65°C for 72h in a heating block.

Following decantation of the reaction solution (quenched by the slow addition to isopropanol), the resin packet was washed three times with 5mL methanol, once with 5mL THF and twice with 5mL piperidine. The amine-borane complex was then disproportionated by overnight treatment with lOmL piperidine (400x) at 65°C. Following decantation of the resulting piperidine-borane solution, the resin packet was washed twice with 5mL DCM and twice

with methanol. The resin was then dried under high vacuum.

Alternatively, the reduction was carried out with 10 mL 1M borane methyl. sulfide complex in di-oxane at reflux for 24 hours. The steps for decantation, washing, piperidine treatment and washing remain the same.

Step 9: Cleavage (see last step of Figure 2).

The triamines were cleaved from resin by treatment, in the presence of 5% anisole, with anhydrous gas HF at room temperature or anhydrous liquid HF at 0°C for 9h. The desired products were obtained following extraction from acetonitrile/water (1/1,2x5mL) and lyophilization.

Method 3. Protocol for synthesis of group X of R8 providing monosubstituted alkylaminoalkyl Following method 2, as described above, except modifying step 7, as described below.

Step 7: Acylation providing group X The resin packet was added to a solution of a carboxylic acid (0.2M, 6x) and HOBt (0.2M, 6x) in DMF, followed by the addition of DIC (0.2M, 6x) in DCM. The coupling reaction was allowed to proceed for 2h. The reaction solution was removed and the resin was washed once with 5mL DMF, and once with 5mL DCM.

Step 7: Sulfonation providing group X Alternatively, the resin packet was added to a solution of a sulfonyl chloride (0.2M, 6x), base

(N-methyl imidazole or N-methyl morpholine (0.2M)) in DMF. The coupling reaction was allowed to proceed for 2h. The reaction solution was removed and the resin was washed once with 5mL DMF, and once with 5mL DCM.

Method 4. Protocol for synthesis of group X of R8 providing dialkylaminoalkyl Solid phase syntheses were carried out using the"tea-bag"methodology in which the resin is contained within polypropylene mesh packets. 150mg MBHA resin (1. 3meq/g, 100-200 mesh) was neutralized by three 5mL washes with 5% DIEA in DCM. Excess DIEA was removed by three 5mL DCM washes.

Step 1 : Couple Boc-aspartic acid (ß-Fmoc)-OH to resin (see Step 1 of Figure 3).

The resin packet was added to a solution of Boc-Asp (Fmoc)-OH (0.1M, 3x) and HOBt (0.1M, 3x) in DMF, followed by the addition of DIC to make 0. 1M. The coupling reaction was allowed to proceed for 24 hr. The reaction solution was removed and the resin was washed three times with 5mL DMF, and three times with 5mL DCM.

Step 2: Removal of Fmoc group (see Step 2 of Figure 3).

The (3-carboxy-Fmoc protecting group was removed by washing the packet for 2 hrs with 20% piperidine/DCM.

The packet was washed three times with 1% acetic acid in DCM, then three times with 5mL DCM.

Step 3: Addition of secondary amine to the P-carboxy group (see Step 3 of Figure 3).

The Boc-Asp on resin was treated with HOBt (0.1M, 5x) and the secondary amine (0. 1M, 5X) in DMF, followed by the addition of DIC (0. lM, 5x), and the reaction allowed to progress overnight. The packet was washed three times with 5mL DMF, three times with 5mL DCM.

Step 4: Removal of Boc group (see Step 4 of Figure 3).

The N-a-tBoc protecting group was removed by washing the packet for 30 minutes with 55% TFA/DCM.

Excess TFA was removed by washing the packet twice with 5mL DCM, twice with 5mL 5% DIEA/DCM and twice with 5mL DCM.

Step 5: Addition of Boc-Tyr (Et)-OH (see Step 5 of Figure 3).

The resin packet was added to a solution of Boc-Try (Et)-OH (0. 1M, 3x) and HOBt (0. 1M, 3x) in DMF, followed by the addition of DIC (0.1M, 3x). The coupling reaction was allowed to proceed for 20h. The reaction solution was removed and the resin was washed three times with 5mL DMF, and three times with 5mL DCM.

Step 6: Removal of Boc group (see Step 6 of Figure 3).

The N-a-tBoc protecting group was removed by washing the packet for 30 minutes with 55% TFA/DCM.

Excess TFA was removed by washing the packet twice with 5mL DCM, twice with 5mL 5% DIEA/DCM and twice with 5mL DCM.

Step 7: Addition of 4-chlorophenylacetic acid (see Step 7 of Figure-3).

The resin packet was added to a solution of 4-chlorophenylacetic acid (0. 1M, 3x), and HOBT (0. 1M, 3X) followed by DIC (0. 1M, 6x). The coupling reaction was allowed to proceed overnight. The reaction solution was removed and the resin was washed three times with 5mL DMF, and three times with 5mL DCM.

Step8 : Reduction (see Step 8 of Figure 3).

Resin in tea bags were suspended in anhydrous dioxane (40mL/mmole resin) under nitrogen, and BH3/Me2S (45 equiv. (final concentration ~1. 0M) was added. The mixture was heated to reflux for 24 hours, then cooled to room temperature. The solution was poured into methanol, and the tea bags were washed with THF and then treated with methanol for 10 minutes.

The resin packets where then washed three times with 5mL methanol, once with 5mL THF and twice with 5mL piperidine. The amine-borane complex was then disproportionated by overnight treatment with lOmL piperidine (400x) at 65°C. Following decantation of the resulting piperidine-borane solution, the resin packet was washed twice with 5mL DCM and twice with methanol.

The resin was then dried under high vacuum.

Step9 : Cleavage (see Step 9 of Figure 3).

The triamines were cleaved from resin by treatment with anhydrous gas HF at 20°C ; or liquid HF, in the presence of 5% anisole, at 0°C for 9h. The desired products were obtained following extraction from acetonitrile% water (1/1, 2x5mL) and lyophilization.

Based on these methods of synthesis, the following libraries and single compounds listed in Table

10 below were made, as designated by their R1 to R3 starting materials. Note that the R3 carobxylic acid starting material corresponds to the phenyl ring (and R1 to R5 phenyl substituents) of the claimed invention; the side chain of the R2 amino acid starting material corresponds to R6 of the claimed invention; and the side chain of the R1 amino acid starting material corresponds to R8 of the claimed invention (see equivalence at the bottom of Figure 1). Where R4 is listed (i. e., where it is not blank or hydrogen), it is a further modification of the R1 amino acid side chain and, therefore, contributes to R8 of the claimed invention (see, for example, step 7 of Figure 2 and step 3 of Figure 3).

6635 Boc- Boc- 4- Asp (OFm)-Tyr (Et bromophenylac 32 OH)-OH etic acid cyclopropylamine 503 38. 3 Boc-Boc-4- Asp (OFm) - Tyr (Et bromophenylac tetrahydrofurEur 33 OH)-OH etic acid ylamine 547 49. 6 Boc-Boc-4- Asp (OFm) - Tyr (Et bromophenylac methylcyclohexyl 34 OH )-OH etic acid amine 559 47. 9 Boc-Boc-4-3- AspAsp (OFm) - Tyr (Et bromophenylac methoxypropylami 35 OH )-OH etic acid ne 535 37.9 Boc-Boc-4-4- Asp (OFm)- Tyr (Et bromophenylac hydroxypiperidin 36 OH ) -OH etic acid e 547 46 3 Boc-Boc-4- Asp (OFm) - Tyr (Et bromophenylac 2-amino-2-methyl- 37 OH )-OH etic acid l-propanol 535 40. 2 Boc-Boc-4-2- Asp (OFm) - Tyr (Et bromophenylac (methylamino eth 38 OH )-OH etic acid anol 521 41 Boc-Boc-4- Asp (OFm) - Tyr (Pr bromophenylac 39 OH)-OH etic acid morpholine 547 53 Boc-Boc-4- Asp (OFm)- (Pr bromophenylac 40 OH)-OH etic acid cyclopropylamine 517 38.7 Boc- Boc- 4- Asp(OFm)- Tyr (Pr bromophenylac tetrahydrofurfur 41 OH)-OH etic acid ylamine 561 46.6 Boc-Boc-4-N- Asp(OFm)-Tyr (Pr bromophenylac methylcyclohexyl 42 OH )-OH etic acid amine 573 44.9 Boc-Boc-4-3- Asp (OFm)- Tyr (Pr bromophenylac methoxypropylami 43 OH )-OH etic acid ne 549 40. 2 Boc-Boc-4-4- Asp(OFm)- Tyr (Prbromophenylac hydroxypiperidin 44 OH)-OH etic acid e 561 43.6 Boc-Boc-4- Asp(OFm)- Tyr (Pr bromophenylac 2-amino-2-methyl- 45 OH )-Oh etic acid 1-propanol 549 38.3 Boc-Boc-4-2- Asp (OFm)- Tyr (Pr bromophenylac (methylamino) eth 46 OH)-OH etic acid anol 535 44.1 Boc-Boc-4- LYS(Fmoc) - Tyr (Et bromophenylac 47 OH )-OH etic acid Acetic acid 6635 Boc-Boc-4- LYS (Fmoc)- Tyr (Pr bromophenylac 48 OH)-OH etic acid Acetic acid 533 89.4 Boc- Boc- 4- 2- (2- LYS (Fmoc) - Tyr (Et bromophenylac methoxyethoxy) ac 49 OH)-OH etic acid etic acid 593 89. 5 Boc- Boc- 4- 2-(2- LYS (Fmoc)- Tyr (Pr bromophenylac methoxyethoxy) ac 50 OH )-OH etic acid etic acid 607 77.5 Boc-Boc-4- ORN (Fmoc)-Tyr (Et bromophenylac 51. OH)-OH etic acid Acetic acid 505 82.2 Boc-Boc-4- ORN(Fmoc)- Tyr (Pr bromophenylac 52 OH)-OH etic acid. Acetic acid 519 80.8 Boc- Boc- 4- 2- (2- ORN (Fmoc)- Tyr (Et bromophenylac methoxyethoxy) ac 53 OH)-OH etic acid etic acid 579 98. 9 Boc- Boc- 4- 2- (2- ORN (Fmoc)-Tyr (Pr bromophenylac methoxyethoxy) ac 54 OH)-OH etic acid etic acid 593 87.4 6600 TRG6600 p RI R2 R3 Fmoc-L-Fmoc-L-p-I-_ 1 Arg (Tos) phenylalanine Phenylacetic acid 523 4- Fmoc-L-Fmoc-L-p-I-Ethoxyphenylacetic 2 Arg (Tos) phenylalanine acid 567 4- Fmoc-L- Fmoc-L-p-I- Chlorophenylacetic 3 Arg (Tos) phenylalanine acid 558 4- Fmoc-L-Fmoc-L-p-I- (Trifluoromethyl)- 4 Arg (Tos) phenylalanine phenylacetic acid 591 3, 4- Fmoc-L-Fmoc-L-p-I- (Methylenedioxy)- 5 Arg (Tos) phenylalanine phenylacetic acid 567 4- Fmoc-L-Fmoc-L-Chlorophenylacetic 7 Arg (Tos) Tyrosine (OEt) acid 476 4- Fmoc-L-Fmoc-L- (Trifluoromethyl) p 8 Arg (Tos) Tyrosine (OEt) henylacetic acid 509 4- Fmoc-L-Fmoc-L-Nitrophenylacetic 9 Arg (Tos) Tyrosine (OEt) acid 486 3,5- Fmoc-L-Fmoc-L-Difluorophenylacet 10 Arg (Tos) Tyrosine (OEt) ic acid 477 Fmoc-L-Fmoc-L-2-Naphthylacetic 13 Arg (Tos) Tyrosine (OEt) acid 491 Fmoc-L-Fmoc-L-Cyclohexanecarboxy 15 Arg (Tos) Tyrosine (OEt) lic acid 433 4- Fmoc-D-Fmoc-D-Ethoxyphenylacetic 19 Arg (Tos) Tyrosine (OEt) acid 485 Fmoc-D-Fmoc-D-Cyclohexanecarboxy 22 Arg (Tos) Tyrosine (OEt) lic acid 433 Fmoc-D-Fmoc-D-p-I- 23 Arg (Tos) phenylalanine Phenylacetic acid 523 6600 3- Fmoc-D-Fmoc-D-p-I-Fluorophenylacetic 24 Arg (Tos) phenylalanine acid 541 7.4 Fmoc-D- Fmoc-D-p-I- Cyclohexylacetic 26 Arg (Tos) phenylalanine acid 529 5.5 4- Fmoc-D-Fmoc-D-Fluorophenylacetic 28 Arg (Tos) Tyrosine (OEt) acid 459 2.6 Fmoc-L- Fmoc-L-p-I- Fluorophenylacetic 29 Arg (Tos) phenylalanine acid 541 6.6 4- Fmoc-D- Fmoc-D-p-I- Fluorophenylacetic 30 Arg (Tos) phenylalanine acid 541 9.8 6601 6601 Rl R2 R3 Amt Amino Amino Acid Acid Carboxylic acid MM mg 3- Fmoc-L-Fmoc-L-p Fluorophenylacetic 6Arg (Tos) I-Phe acid 541 54. 9 Fmoc-L-Fmoc-L-p-4-Biphenylacetic 7 Arg (Tos) I-Phe acid 599 63.5 3. 4- Fmoc-L- Fmoc-L-p- Dimethoxyphenylacet 8 Arg (Tos) I-Phe ic acid 583 52 Fmoc-L- Fmoc-L-p- 3,5- 10 Arg (Tos) I-Phe Difluorophenylaceti 559 58. 2 Fmoc-L-Fmoc-L-p-Cyclohexylacetic 15 Arg (Tos) I-Phe acid 529 62.3 Fmoc-D-Fmoc-D- 30 Arg (Tos) Tyr (OEt) Phenylacetic acid 441 27. 2 3- Fmoc-D-Fmoc-D-Fluorophenylacetic 31 Arg (Tos) Tyr (OEt) acid 459 28.5 Fmoc-D-Fmoc-D-4-Biphenylacetic 32 Arg (Tos) Tyr (OEt) acid 517 28.4 Fmoc-D- Fmoc-D- Chlorophenylacetic 33 Arg (Tos) Tyr (OEt) acid 476 27.1 4- Fmoc-D-Fmoc-D- (Trifluoromethyl) ph 34 Arg (Tos) Tyr (OEt) enylacetic acid 509 29.6 3,4- Fmoc-D-Fmoc-D-Dimethoxyphenylacet 35 Arg (Tos) Tyr (OEt) ic acid 501 30.8 Fmoc-D- Fmoc-D- 37 Arg (Tos) Tyr (OEt) Difluorophenylaceti 477 31. 7 Fmoc-D- Fmoc-D-p- 4-Biphenylacetic 55 Arg (Tos) I-Phe acid 599 12 4- Fmoc-D-Fmoc-D-p Ethoxyphenylacetic 56 Arg (Tos) I-Phe acid 567 10.8 6601 4- Fmoc-D- Fmoc-D-p- Chlorophenylacetic 57 Arg (Tos) I-Phe acid 558 12. 6 4- Fmoc-D- Fmoc-D-p (Trifluoromethyl) ph 58 Arg (Tos) I-Phe enylacetic acid 591 17.4 3,4- Fmoc-D-Fmoc-D-p Dimethoxyphenylacet 59 Arg(Tos) I-Phe ic acid 583 12.6 Fmoc-D- Fmoc-D-p- @,@- 60 Arg (Tos) I-Phe Difluorophenylaceti 559 9.7 6602 ### R1 R2 R3 Amt Carboxylic Amino Acid Amino Acid acid MW mg Boc-L-4- 1Arg (Tos) Boc-L-Phenylglycine FPHCH Boc-L-4- 2 Arg (Tos) Boc-L-Phenylalanine FPhCH2CO2H 414 26 Boc-L- 4- 3 Arg (Tos) Boc-L-Homophenylalanine FPhCH2CO2H 428 16 Boc-L-Boc-L-p-4- 4 Arg (Tos) Fluorophenylalanine FPhCH2CO2H 432 28 Boc-L-Boc-L-p-4- 5 Arg (Tos) Chlorophenylalanine FPhCH2CO2H 448 28 Boc-L-Boc-L-p-4- 6 Arg (Tos.) Cyanophenylalanine FPhCH2CO2H 439 21 Boc-L-4-. 7 Arg (Tos) Boc-L-p-Biphenylalanine FPhCH2CO2H 490 38 Boc-L-Boc-L-3,4-4- 8 Arg (Tos) Dichlorophenylalanine FPhCH2CO2H 483 31 Boc-L-4- 9 Arg (Tos) Boc-L-3-Pyridylalanine FPhCH2CO2H 415 27 Boc-L-4- 10 Arg (Tos) Boc-L-4-Pyridylalanine FPhCH2CO2H 415 41 Boc-L-4- 11 Arg (Tos) Boc-L-Cyclohexylalanine FPhCH2CO2H 420 26 Boc-L-4- 12 Arg (Tos) Boc-L-Valine FPhCH2CO2H 366 27 Boc-L-4- 13 Arg (Tos) Boc-L-Tyrosine FPhCH2CO2H 430 37 Boc-L-4- 14 Arg (Tos) Boc-L-Tryptophan FPhCH2CO2H 453 41 Boc-L-4- 15 Arg (Tos) Boc-L-Histidine (Trt) FPhCH2CO2H 403 28 Boc-L-4- 16 Arg (Tos) Boc-L-Lysine (Z) FPhCH2CO2H 394 22 Boc-L-4- 17 Arg (Tos) Boc-L-Aminobutyric acid FPhCH2CO2H 352 13 6602 Boc-L-Boc-L-3-4- 18 Arg (Tos) (2naphthyl) alanine FPhCH2CO2H 464 24 Boc-L-4- 19 Arg (Tos) Boc-L-Aspartic acid FPhCH2CO2H 382 15 Boc-L-4- 20 Arg (Tos) Boc-L-Ornithine (Fmoc) FPhCH2CO2H 380 22 Boc-L- 22 Arg (Tos) Boc-D-Phenylalanine FPhCH2CO2H 414 26 Boc-L- 23 Arg (Tos) Boc-D-Homophenylalanine FPhCH2CO2H 428 28 Boc-L-Boc-D-p-4- 24 Arg(Tos) Fluorophenylalanine FPhCH2CO2H 432 23 Boc-L-Boc-D-p-4- 25 Arg (Tos) Chlorophenylalanine FPhCH2CO2H 448 30 Boc-L-Boc-D-p-4- Arg(Tos) Bromophenylalanine FPhCH2CO2H 493 31 Boc-L-4- 27 Arg (Tos) Boc-D-p-Iodophenylalanine FPhCH2CO2H 540 26 Boc-L-Fmoc-D-p-4- 28 Arg (Tos) Nitrophenylalaine FPhCH2CO2H 459 38 Boc-L-4- 29 Arg (Tos) Fmoc-D-p-Biphenylalanine FPhCH2CO2H 490 31 Boc-L-Fmoc-D-3, 4-4- 30 # Arg (Tos) Difluorophenylalanine FPhCH2CO2H 450 21 Boc-L-Fmoc-D-3-4- 31 Arg (Tos) (2naphthyl)alanine FPhCH2CO2H 464 39 Boc-L-4- 32 Arg (Tos) Boc-D-2-Naphthylalanine FPhCH2CO2H 464 28 Boc-L-4- 33 Arg (Tos) Boc-D-Valine FPhCH2CO2H 366 22 Boc-L-4- Arg(Tos) Fmoc-L-Leucine FPhCH2CO2H 380 29 Boc-L-4- 35 Arg (Tos) Boc-D-Tyrsine (OEt) FPhCH2CO2H 458 35 Boc-L-4- 36 Arg (Tos) Fmoc-D-Histidine (Trt) FPhCH2CO2H 403 57 6602 Boc-D-4- 37 Arg (Tos) Boc-L-Phenylglycine FPhCH2CO2H 400 28 Boc-D-4- 38 Arg (Tos) Boc-L-Phenylalanine FPhCH2CO2H 414 25 Boc-D- 4- 39 Arg (Tos) Boc-L-Homophenylalanine FPhCH2CO2H 428 24 Boc-D-Boc-L-p-4- 40 Arg (Tos) Fluorophenylalanine FPhCH2CO2H 432 27 Boc-D-Boc-L-p-4- 41 Arg (Tos) Chlorophenylalanine FPhCH2CO2H 448 34 Boc-D-4- 42 Arg (Tos) Boc-L-p-Iodophenylalanine FPhCH2CO2H 540 31 Boc-D-Boc-L-p-4- 43 Arg (Tos) Cyanophenylalanine FPhCH2CO2H 439 33 Boc-D-4- 44 Arg (Tos) Boc-L-p-Biphenylalanine FPhCH2CO2H 490 17 Boc-D-Boc-L-3, 4- 4- 45 Arg (Tos) Dichlorophenylalanine FPhCH2CO2H 483 17 Boc-D-4- 46 Arg (Tos) Boc-L-3-Pyridylalanine FPhCH2CO2H 415 25 Boc-D-4- 47 Arg (Tos) Boc-L-4-Pyridylalanine FPhCH2CO2H 415 31 Boc-D-4- 48 Arg (Tos) Boc-L-Cyclohexylalanine FPhCH2CO2H 420 14 Boc-D-4- 49 Arg (Tos) Boc-L-2-Naphthylalanine FPhCH2CO2H 464 26 Boc-D-Boc-L-3-4- 50 Arg (Tos) (2naphthyl) alanine FPhCH2CO2H 464 29 Boc-D-4- 51 Arg (Tos) Boc-L-Valine FPhCH2CO2H 366 22 Boc-D-4- 52 Arg (Tos) Fmoc-L-Leucine FPhCH2CO2H 380 32 Boc-D-4- 53 Arg (Tos) Boc-L-Tryptophan FPhCH2CO2H 453 27 Boc-D-4- 54 Arg (Tos) Boc-L-Tyrosine FPhCH2CO2H 430 36 6602 Boc-D-4- 55 Arg (Tos) Boc-L-Histidine(Trt) FPhCH2CO2H 403 15 Boc-D-4- 56 Arg (Tos) Boc-L-Aspartic acid FPhCH2CO2H 382 26 Boc-D-4- 57 Arg (Tos) Boc-L-Lysine (Z)- PhCH2CO2H 394 33 Boc-D-4- 58 Arg (Tos) Boc-L-Ornithine (Fmoc) FPhCH2CO2H 380 24 Boc-D-4- 59 Arg (Tos) Boc-L-Aminobutyric acid FPhCH2CO2H 352 15 Boc-D-4- 60 Arg (Tos) Boc-D-Phenylglycine FPhCH2CO2H 400 24 Boc-D-4- 61 Arg (Tos) Boc-D-Phenylalanine FPhCH2CO2H 414 14 Boc-D-4- 62 Arg(Tos) Boc-D-Homophenylalanine FPhCH2CO2H 428 22 Boc-D-Boc-D-p-4- 63 Arg (Tos) Fluorophenylalanine FPhCH2CO2H 432 30 Boc-D-Boc-D-p-4- 64 Arg (Tos) Chlorophenylalanine FPhCH2CO2H 448 38 Boc-D-Boc-D-p-4- 65 Arg (Tos) Bromophenylalanine FPhCH2CO2H 493 28 Boc-D-Boc-D-p-4- 66 Arg (Tos) Cyanophenylalanine FPhCH2CO2H 439 25 Boc-D-4- Arg (Tos) Fmoc-D-p-Biphenylalanine FPhCH2CO2H 490 29 Boc-D- Fmoc-D-3,4- 4- 68 Arg (Tos) Difluorophenylalanine FPhCH2CO2H 450 28 Boc-D- 69 Arg (Tos) Fmoc-D-Cyclohexylalanine FPhCH2CO2H 420 28 Boc-D-Fmoc-D-3-4- 70 Arg (Tos) (2naphthyl) alanine FPhCH2CO2H 464 26 Boc-D-4- 71 Arg (Tos) Boc-D-2-Naphthylalanine FPhCH2CO2H 464 35 Boc-D-4- 72 Arg (Tos) Boc-D-Valine FPhCH2CO2H 366 32 6602 Boc-D- 4- 73 Arg (Tos) Fmoc-D-Histidine(Trt) FPhCH2CO2H 403 33 6603 6603 RI R2 R3 MW Amt # Amino Acid Amino Acid Carboxylic acid (mg) N-a-Boc-N-g-Fmoc-L-Fmoc-L- 1 Diaminobutyric acid Tyr (OEt) 4-ClPhCH2CO2H 419 54 N-a-Boc-N-g-Fmoc-L-Fmoc-L- 2 Diaminobutyric acid Tyr (OEt) 4-ClPhCH2CO2H 433 47 Fmoc-L- 3 Fmoc-L-Arg (Me) 2-OH Tyr (OEt) 4-ClPhCH2CO2H 447 42 Fmoc-L-HomoArg (Pmc)- Fmoc-L- 4 OH Tyr (OEt) 4-ClPhCH2CO2H 447 38 Fmoc-L- 5 Boc-L-Ser-OH Tyr (OEt) 4-ClPhCH2CO2H 406 35 Boc-L-4-Fmoc-L- 6 Nitrophenylalanine Tyr (OEt) 4-ClPhCH2CO2H 511 36 Boc-L-3-Fmoc-L- 7 Cyanophenylalanine Tyr (OEt) 4-ClPhCH2CO2H 495 44 Boc-L-4-Fmoc-L- 8 Cyanophenylalanine Tyr(OEt) 4-ClPhCH2CO2H 495 45 Boc-L-3-Fmoc-L- 9 Pyridylalanine Tyr (OEt) 4-ClPhCH2CO2H 467 51 Boc-L-4-Fmoc-L- 10 Pyridylalanine Tyr (OEt) 4-ClPhCH2CO2H 467 58 N-a-Boc-N-g-Fmoc-L-Fmoc-L- 11 Diaminobutyric acid Tyr (OEt) 4-ClPhCH2CO2H 501 57 N-a-Boc-N-g-Fmoc-L-Fmoc-L- 12 Diaminobutyric acid Tyr (OEt) 4-ClPhCH2CO2H 515 55 Fmoc-L- 13 Fmoc-L-Arg (Me) 2-OH Tyr (OEt) 4-ClPhCH2CO2H 529 56 Fmoc-L-HomoArg (Pmc)- Fmoc-L- 14 OH Tyr (OEt) 4-ClPhCH2CO2H 529 60 Fmoc-L- 15 Boc-L-Ser-OH Tyr (OEt) 4-ClPhCH2CO2H 488 43 Fmoc-L- 16 Fmoc-L-His (Trt)-OH Tyr (OEt) 4-ClPhCH2CO2H 538 65 6603 Boc-L-3-Fmoc-L- 17 Cyanophenylalanine Tyr (OEt) 4-ClPhCH2CO2H 577 56 Boc-L-4-Fmoc-L- 18 Cyanophenylalanine Tyr (OEt) 4-ClPhCH2CO2H 577 57 Boc-L-3-Fmoc-L- 19 Pyridylalanine Tyr (OEt) 4-ClPhCH2CO2H 549 54 Boc-L-4-Fmoc-L- 20 Pyridylalanine Tyr (OEt) 4-ClPhCH2CO2H 549 69 6612 CmpdR1 R2 R3 R4 MW Yield 4-Cl- Boc-L-Boc-L-phenylaceti 1 Tic(OH)-OH Tyr(Oet) c acid 493 69.2 Boc-L- 4-Cl- Thienylala Boc-L-phenylaceti 2 nine Tyr (Oet) c acid 471 35.2 4-Cl- Boc-L-Boc-L-phenylaceti 3 Norleucine Tyr (Oet) c acid 431 38.5 Boc-L- 4-Cl- Boc-Tyr (OEt)- Phenylaceti Acetic 6 Dab (Fmoc) OH c acid anhydride 446 60.1 Boc-L-4-Cl- Boc-Tyr (OEt)- Phenylaceti Formaldehy 7 Dab (Fmoc) OH c acid de 446 58.2 Boc-L-4-Cl- Boc-Tyr (OEt)- Phenylaceti Formaldehy 8 Orn (Fmoc) OH c acid de 460 65.7 Boc-L- 4-Cl- Boc-Tyr (OEt) - Phenylaceti Formaldehy 9 Lys (Fmoc) OH c acid de 474 51.5 Boc-L- 4-Cl- Boc-Tyr (OEt)- Phenylaceti Formaldehy 10 Lys (Fmoc) OH c acid de 516 13.1 Boc-L- 4-Cl- Fmoc-Tyr (OEt)- Phenylaceti 11 Dap (Boc) OH c acid H 404 63.2 Boc-L- 4-Cl- Fmoc-Tyr (OEt)- Phenylaceti 12 Dap (Boc) OH c acid Fmoc 418 38.6 Boc-L- 4-Cl- Fmoc-Tyr (OEt)- Phenylaceti 13 Orn(Boc) OH c acid Fmoc 446 57.4 Boc-L-4-C1- Boc-Tyr (OEt)- Phenylaceti 15 Thr (Bzl) OH c acid 419 55.5 Boc-L- 4-Cl- Boc-Tyr (OEt)- Phenylaceti 16 Asp (Bzl) OH c acid 419 54.7 6612 Boc-L-4-Cl- Boc-Tyr (OEt)-Phenylaceti 17 Glu(Bzl) OH c acid 433 46.7 Boc-L-4-C1- Boc-Tyr (OEt) - Phenylaceti 18 Hyp(Bzl) OH c acid 431 62.7 Boc-L- 4-Cl- Tyr (OEt)- Phenylaceti 19 Boc-Val OH c acid 417 32.6 Boc-L- 4-Cl- Tyr (OEt) - Phenylaceti 20 Boc-tBuGly OH c. acid 431-36. 3 Boc-L- 4-Cl- Boc-Tyr (OEt) - Phenylaceti 21 Ser (Me) OH c acid 419 48.6 Boc-L-4-Cl- Boc-2-Tyr (OEt) - Phenylaceti 22 Pyrala OH c acid 466 58.4 Boc-L- 4-Cl- Boc-Tyr (OEt) - Phenylaceti 23 Met (0) 2 OH c acid 481 62.4 Boc- Boc-L- 4-Cl- Cys (MeOBzl Tyr(OEt) - Phenylaceti 24 OH c acid 421 54 Boc-L- 4-Cl- Tyr (OEt) - Phenylaceti 25 Boc-Met(O) OH c acid 449 55 Boc- Boc-L- 4-Cl- Pen (MeOBzl Tyr(OEt) - Phenylaceti 26) OH c acid 449 56.9 Boc-L- 4-Cl- Tyr (OEt) - Phenylaceti 27 Boc-aAbu OH c acid 403 36.4 Boc-L- 4-Cl- Boc-Tyr (OEt) - Phenylaceti 28 Lys (TFA) OH c acid 528 60. 6 Boc-L- 4-Cl- Tyr (OEt)- Phenylaceti 29 Boc-Phe OH c acid 465 50.1 6612 Boc-L-4-C1- Boc-Tyr (OEt)-Phenylaceti 30 Thiopro OH c acid 433 42.3 Boc-L- 4-Cl- Fmoc-Tyr (OEt)- Phenylaceti 31 Dab (Boc) OH c acid H 418 48. 2 Boc-L- 4-Cl- Fmoc-Tyr (OEt)- Phenylaceti 32 Dab (Boc) OH c acid Fmoc 432 43.3 Boc-L- 4-Cl- Fmoc-Tyr (OEt)- Phenylaceti 33 Orn (Boc) OH c acid H 432 31.0 Boc-L- 4-Cl- Fmoc-Tyr (OEt) - Phenylaceti 34 Lys (Boc) OH c acid H 446 20.2 Boc-L- 4-Cl- Boc-Tyr (OEt) - Phenylaceti 35 Dap (Fmoc) OH c acid H 404 50. 6 Boc-L- 4-Cl- Boc-Tyr (OEt) - Phenylaceti 36 Dap (Fmoc) OH c acid Fmoc 418 45.3 Boc-L-4-C1- Boc-Tyr (OEt)- Phenylacet : i Formaldehy 37 Dap (Fmoc) OH c acid de 432 20.8 Boc-L- 4-Cl- Boc-Tyr (OEt) - Phenylaceti Acetic 38 Dap (Fmoc) OH c acid anhydride 432 45.0 66t4 R3 : R4 : Rl : Diamino R2: Amino Carboxylic Carboxylic Cmpd acid acid acid acid MM Mg p-Cl- N-a-Boc-N-b- Boc-L- phenylacet 1 Fmoc-DAP Tyr (OEt) ic acid Me 419 67 p-Cl- N-a-Hoc-N-b Boc-L-phenylacet 2 Fmoc-DAP Tyr (OEt) ic acid H 405 67 p-Cl- N-a-Boc-N-b Boc-L-phenylacet 3 Fmoc-DAP Tyr (OEt) ic acid Acetic acid 433 66 p-Cl- N-a-Boc-N-b- Boc-L- phenylacet Butanoic 4 Fmoc-DAP Tyr (OEt) ic acid acid 461 64 p-Cl- N-a-Boc-N-b- Boc-L- phenylacet Pivalic 5 Fmoc-DAP Tyr (OEt) ic acid acid 475 47 p-Cl- N-a-Boc-N-b Boc-L-phenylacet Benzoic 6 Fmoc-DAP Tyr (OEt) ic acid acid 495 73 p-Cl- N-a-Boc-N-b- Boc-L- phenylacet Phenylaceti 7 Fmoc-DAP Tyr (OEt) ic acid c acid509 51 p-Cl- N-a-Boc-N-b- Boc-L- phenylacet Hydrocinnam 8 Fmoc-DAP Tyr (OEt) ic acid ic acid 523 51 p-Cl-Cyclohexane N-a-Boc-N-b- Boc-L- phenylacet carboxylic 9 Fmoc-DAP Tyr (OEt) ic acid acid 501 69 p-Cl- N-a-Boc-N-b- Boc-L- phenylacet Cyclohexyl 10 Fmoc-DAP Tyr (OEt) ic acid acetic acid 515 65 p-Cl- N-a-Boc-N-b- Boc-L- phenylacet Isonicotini 11 Fmoc-DAP Tyr (OEt) ic acid c acid 496 84 p-Cl- N-a-Boc-N-b- Boc-L- phenylacet Monomethyls 12 Fmoc-DAP Tyr (OEt) ic acid uccinate 477 68 6614 p-Cl- N-a-Boc-N-b Hoc-L-phenylacet Monomethylg 13 Fmoc-DAP Tyr (OEt) ic acid lutarate 491 91 L-Boc-p-Cl- Ornithine (F Boc-L-phenylacet 3 moc)-OH Tyr (OEt) ic acid Me 447 62 L-Boc-p-C1- Ornithine (F Boc-L-phenylacet 15 moc)-OH Tyr (OEt) ic acid H 433 59 L-Boc-p-Cl- Ornithine (F Boc-L-phenylacet 16 moc)-OH Tyr (OEt) ic acid Acetic acid, 461 47 L-Boc-p-Cl- Ornithine (F Boc-L-phenylacet Butanoic 17 moc)-OH Tyr (OEt) ic acid acid 489 63 L-Boc- p-Cl- Ornithine (F Boc-L-phenylacet Pivalic 18 moc)-OH Tyr (OEt) ic acid acid 503 76 L-Boc-p-Cl- Ornithine (F Boc-L-phenylacet Benzoic 19 moc)-OH Tyr (OEt) ic acid acid 523 74 L-Boc-p-Cl- Ornithine (F Boc-L-phenylacet Phenylaceti 20 moc)-OH Tyr (OEt) ic acid c acid 537 43 L-Boc- p-Cl- Ornithine (F Boc-L-phenylacet Hydrocinnam 21 moc)-OH Tyr (OEt) ic acid ic acid 551 73 L-Boc-p-Cl-Cyclohexane Ornithine (F Boc-L-phenylacet carboxylic 22 moc)-OH Tyr (OEt) ic acid acid529 63 L-Boc-p-Cl- Ornithine (F Boc-L-phenylacet Cyclohexyl 23 moc)-OH Tyr (OEt) ic acid acetic acid 543 84 L-Boc-p-Cl- Ornithine (F Boc-L-phenylacet Isonicotini 24 moc)-OH Tyr (OEt) ic acid c acid 524 73 L-Boc-p-Cl- Ornithine (F Boc-L-phenylacet Methoxyacet 25 moc)-OH Tyr (OEt) ic acid ic acid 491 58 6614 L-Boc- p-Cl- 3- Ornithine (F Boc-L-phenylacet Methoxyprop 26 moc)-OH Tyr (OEt) ic acid ionic acid 505 67 L-Boc-p-Cl- Ornithine (F Boc-L-phenylacet Monomethyls 27 moc)-OH Tyr (OEt) ic acid uccinate 505 71 L-Boc-p-Cl- Ornithine (F Boc-L-phenylacet Monomethylg 28 moc)-OH Tyr (OEt) ic acid lutarate 519 64 L-Boc-p-Cl- Ornithine (F Boc-L-phenylacet Phenoxyacet 29 moc)-OH Tyr (OEt) ic acid ic acid 553 71 L-Boc-p-Cl- Lysine (Fmoc Boc-L-phenylacet 30)-OH Tyr (OEt) ic acid Me 461 70 L-Boc-p-Cl- Lysine (Fmoc Boc-L-phenylacet 4)-OH Tyr (OEt) ic acid H 447 55 . L-Boc-p-Cl- Lysine (Fmoc Boc-L-phenylacet 32 )-OH Tyr(OEt) ic acid Acetic acid 475 49 L-Boc-p-Cl- Lysine (Fmoc Boc-L-phenylacet Butanoic 33)-OH Tyr (OEt) ic acid acid 503 60 L-Boc-p-Cl- Lysine (Fmoc Boc-L-phenylacet Pivalic 34)-OH Tyr (OEt) ic acid acid 517 69 L-Boc-p-Cl- Lysine (Fmoc Boc-L-phenylacet Benzoic 35)-OH Tyr (OEt) ic acid acid 537 77 L-Boc-p-Cl- Lysine (Fmoc Boc-L-phenylacet Phenylaceti 36)-OH Tyr (OEt) ic acid c acid 551 69 L-Boc- p-Cl- Lysine (Fmoc Boc-L-phenylacet Hydrocinnam 37 )-OH Tyr (OEt) ic acid ic acid 565 53 L-Boc--Cl-Cyclohexane Lysine (Fmoc Boc-L-phenylacet carboxylic 38 )-OH Tyr (OEt) ic acid acid 543 73 6614 L-Boc-p-Cl- Lysine (Fmoc Boc-L-phenylacet Cyclohexyl 39 )-OH Tyr (OEt) ic acid acetic acid 557 76 L-Boc-p-Cl- Lysine (Fmoc Boc-L-phenylacet Isonicotini 40)-OH Tyr (OEt) ic acid c acid 538 53 L-Boc-p-Cl- Lysine (Fmoc Boc-L-phenylacet Methoxyacet 41)-OH Tyr (OEt) ic acid ic acid 505 57 L-Boc-p-Cl-3- Lysine (Fmoc Boc-L-phenylacet Methoxyprop 42)-OH Tyr (OEt) ic acid ionic acid 519 48 L-Boc-p-Cl- Lysine (Fmoc Boc-L-phenylacet Monomethyls 43)-OH Tyr (OEt) ic acid uccinate 519 60 L-Boc-p-Cl- Lysine (Fmoc Boc-L-phenylacet Monomethylg 44)-OH Tyr (OEt) ic acid lutarate 533 63 L-Boc-p-Cl- Lysine (Fmoc Boc-L-phenylacet Phenoxyacet 45)-OH Tyr (OEt) ic acid ic acid 567 57 2- (2- L-Boc-p-Cl-methoxyetho Lysine (Fmoc Boc-L-phenylacet xy) acetic 46)-OH Tyr (OEt) ic acid acid 549 55 6615 R-groups Cmpd R1 R2 R3 MW Yield ApPur 1 Boc-Ser (Bzl)-OH Boc-Tyr (Et)-OH 4-FC6H4CH2CO2H 390 48 80 2 Boc-Ser (Bzl)-OH Boc-D-Tyr (Et)-OH 4-FC6H4CH2CO2H 390 49 90 3 Boc-D-Ser (Bzl)-OH Boc-Tyr (Et)-OH 4-FC6H4CH2CO2H 390 46 90 4 Boc-D-Ser (Bzl)-OH Boc-D-Tyr (Et)-OH 4-FC6H4CH2CO2H 390 48 85 5 Boc-3-PyAla Boc-Tyr (Et)-OH 4-FC6H4CH2CO2H 451 64 95 6 Boc-3-PyAla Boc-D-Tyr (Et)-OH 4-FC6H4CH2CO2H 451 67 95 7 8oc-D-3-PyAla Boc-Tyr (Et)-OH 4-FC6H4CH2CO2H 451 64 95 8 Boc-D-3-PyAla Boc-D-Tyr (Et)-OH 4-FC6H4CH2CO2H 451 59 95 9 Boc-Orn (Fmoc)-OH Boc-Tyr (Et)-OH 4-FC6H4CH2CO2H 431 52 70 10 Boc-Orn (Fmoc)-OH Boc-D-Tyr (Et)-OH 4-FC6H4CH2CO2H 431 50 75 11 Boc-D-Orn (Fmoc)-OH Boc-Tyr (Et)-OH 4-FC6H4CH2CO2H 431 69 80 12 Boc-D-Orn (Fmoc)-OH Boc-D-Tyr (Et)-OH 4-FC6H4CH2CO2H 431 46 75 6617 Tyrosine ethers by Mitsunobu CmpdR1 R2 R3 R4 MW Yield Boc-L-Boc-L-4- 1 Arg (Tos) Tyr FPhCH2CO2H ethanol 459 4.4 Boc-L-Boc-L-4- 2 Arg (Tos) Tyr FPhCH2CO2H propanol 473 21. 2 Boc-L- Boc-L- 4- 1-piperidine 3 Arg (Tos) Tyr FPhCH2CO2H ethanol 542 81. 1 Boc-L-Boc-L-4-3, 3-dimethyl-l- 4 Arg (Tos) Tyr FPhCH2CO2H butanol 515 13.8 Boc-L-Boc-L-4_ isoamyl 5 Arg(Tos) Tyr FPhCH2CO2H alcohol 501 23.4 N, N- Boc-L- Boc-L- 4- dimethylethano 6 Arg (Tos) Tyr FPhCH2CO2H 1 amine 502 20. 8 Tyrosine ethers from acylated tyrosine dipeptide on resin via Fukuyama Mitsunobu alkylation of the tyrosine phenol with the R4 alcohol's 6620 TRG6620 Cmpd Rl R2 R3 BOC-L-BOC-L- 1 Orn (FMOC) * Tyr (OEt) cyclohexylacetic acid 418 56 4- BOC-L-BOC-L- (Trifluoromethyl) phen 5 Orn (FMOC) * Tyr (OEt) ylacetic acid 481 63 BOC-L-BOC-L-4-Ethoxyphenylacetic 6 Orn (FMOC) * Tyr (OEt) acid 457 60 Boc-L- BOC-L-Homophenyl 7 Orn (FMOC) * alanine cyclohexylacetic acid 389 54 Boc-L-4- BOC-L-Homophenyl (Trifluoromethyl) phen 11 Orn (FMOC) * alanine ylacetic acid 450 60 Boc-L- BOC-L-Homophenyl 4-Ethoxyphenylacetic 12 Orn (FMOC) * alanine acid 426 58 BOC-L-Boc-L- 13 Orn (FMOC) * Tryptophan cyclohexylacetic acid 413 54 4- BOC-L-Boc-L- (Trifluoromethyl) phen 17 Orn (FMOC) * Tryptophan ylacetic acid 475 60 BOC-L-Boc-L-4-Ethoxyphenylacetic 18 Orn (FMOC) * Tryptophan acid 451 56 Boc-L-4- BOC-L-Chlorophen 19 Orn (FMOC) * ylalanine cyclohexylacetic acid 408 55 Boc-L-4-4- BOC-L-Chlorophen (Trifluoromethyl) phen 23 Orn (FMOC) * ylalanine ylacetic acid 470 63 6620 Boc-L-4- BOC-L-Chlorophen 4-Ethoxyphenylacetic 24 Orn (FMOC) * ylalanine acid 446 59 BOC-L-BOC-L- 14 Arg (Tos) Tyr (OEt) cyclohexylacetic acid 447 55 4- BOC-L-BOC-L- (Trifluoromethyl) phen 8 Arg (Tos) Tyr (OEt) ylacetic acid 509 63 BOC-L-BOC-L-4-Ethoxyphenylacetic 30 Arg (Tos) Tyr (OEt) acid485 59 Boc-L- BOC-L-Homophenyl 31 Arg (Tos) alanine cyclohexylacetic acid 416 58 Boc-L-4- BOC-L-Homophenyl (Trifluoromethyl) phen 35 Arg (Tos) alanine ylacetic acid478 59 Boc-L- BOC-L-Homophenyl 4-Ethoxyphenylacetic 36 Arg (Tos) alanine acid 454 63 BOC-L-Boc-L- 37 Arg (Tos) Tryptophan cyclohexylacetic acid 442 56 4- BOC-L-Boc-L- (Trifluoromethyl) phen 41 Arg (Tos) Tryptophan ylacetic acid 504 66 BOC-L-Boc-L-4-Ethoxyphenylacetic 42 Arg (Tos) Tryptophan acid 480 12 Boc-L-4- BOC-L-Chlorophen 43 Arg (Tos) ylalanine cyclohexylacetic acid 437 60 Boc-L-4-4- BOC-L-Chlorophen (Trifluoromethyl) phen 47 Arg (Tos) ylalanine ylacetic acid 499 68 6620 Boc-L-4- BOC-L-Chlorophen 4-Ethoxyphenylacetic 48 Arg (Tos) ylalanine acid 475 67 BOC-L- Lysine (FMO BOC-L- 49 C) Tyr (OEt) cyclohexylacetic acid 419 54 BOC-L-4- Lysine (FMO BOC-L- (Trifluoromethyl) phen 53 C) Tyr (OEt) ylacetic acid481 59 BOC-L- Lysine (FMO BOC-L-4-Ethoxyphenylacetic 54 C) Tyr (OEt) acid 457 57 BOC-L-Boc-L- Lysine (FMO Homophenyl 55 C) alanine cyclohexylacetic acid 389 48 BOC-L-Boc-L-4- Lysine (FMO Homophenyl (Trifluoromethyl) phen 59 C) alanine ylacetic acid 451 51 BOC-L-Boc-L- Lysine (FMO Homophenyl 4-Ethoxyphenylacetic 60 C) alanine acid 427 48 BOC-L- Lysine (FMO Boc-L- 61 C) Tryptophan cyclohexylacetic acid 414 48 BOC-L-4- Lysine (FMO Boc-L- (Trifluoromethyl) phen 65 C) Tryptophan ylacetic acid 476 53 BOC-L- Lysine (FMO Boc-L-4-Ethoxyphenylacetic 66 C) Tryptophan acid 452 52 BOC-L-Boc-L-4- Lysine (FMO Chlorophen 67 C) ylalanine cyclohexylacetic acid 409 56 BOC-L-Boc-L-4-4- Lysine (FMO Chlorophen (Trifluoromethyl) phen 71 C) ylalanine ylacetic acid 471 62 6620 BOC-L-Boc-L-4- Lysine (FMO Chlorophen 4-Ethoxyphenylacetic 72 C) ylalanine acid 447 60 BOC-L-3-BOC-L- 73 Cyanophe Tyr (OEt) cyclohexylacetic acid 467 72 4- BOC-L-3-BOC-L- (Trifluoromethyl) phen 77 Cyanophe Tyr (OEt) ylacetic acid 529 56 BOC-L-3-BOC-L-4-Ethoxyphenylacetic 78 Cyanophe Tyr (OEt) acid 505 57 Boc-L- BOC-L-3-Homophenyl 79 Cyanophe alanine cyclohexylacetic acid 437 61 Boc-L-4- BOC-L-3-Homophenyl (Trifluoromethyl) phen 83 Cyanophe alanine ylacetic acid 499 68 Boc-L- BOC-L-3-Homophenyl 4-Ethoxyphenylacetic 84 Cyanophe alanine acid 475 62 BOC-L-3-Boc-L- 85 Cyanophe Tryptophan cyclohexylacetic acid 462 66 4- BOC-L-3-Boc-L- (Trifluoromethyl) phen 89 Cyanophe Tryptophan ylacetic acid 524 49 BOC-L-3-Boc-L-4-Ethoxyphenylacetic 90 Cyanophe Tryptophan acid 500 55 Boc-L-4- BOC-L-3-Chlorophen 91 Cyanophe ylalanine cyclohexylacetic acid 457 74 Boc-L-4-4- BOC-L-3-Chlorophen (Trifluoromethyl) phen 95 Cyanophe ylalanine ylacetic acid 519 75 6620 Boc-L-4- BOC-L-3-Chlorophen 4-Ethoxyphenylacetic 96 Cyanophe ylalanine acid 495 67 BOC-L-3- Pyridylala BOC-L- 97 nine Tyr (OEt) cyclohexylacetic acid 439 53 BOC-L-3-4- Pyridylala BOC-L- (Trifluoromethyl) phen 101 nine Tyr (OEt) ylacetic acid 501 73 BOC-L-3- Pyridylala BOC-L-4-Ethoxyphenylacetic 102 nine Tyr (OEt) acid477 48 BOC-L-3-Boc-L- Pyridylala Homophenyl 103 nine alanine cyclohexylacetic acid 409 68 BOC-L-3-Boc-L-4- Pyridylala Homophenyl (Trifluoromethyl) phen 107 nine alanine ylacetic acid 471 53 BOC-L-3-Boc-L- Pyridylala Homophenyl 4-Ethoxyphenylacetic 108 nine alanine__ acid 447 56 BOC-L-3- Pyridylala Boc-L- 109. nine Tryptophan cyclohexylacetic acid 434 45 BOC-L-3-4- Pyridylala Boc-L- (Trifluoromethyl) phen 113 nine Tryptophan ylacetic acid 496 73 BOC-L-3- Pyridylala Boc-L-4-Ethoxyphenylacetic 114 nine Tryptophan acid 472 56 BOC-L-3-Boc-L-4- Pyridylala Chlorophen 115 nine ylalanine cyclohexylacetic acid 429 31 BOC-L-3-Boc-L-4-4- Pyridylala Chlorophen (Trifluoromethyl) phen 119 nine ylalanine ylacetic acid 491 65 6620 BOC-L-3-Boc-L-4- Pyridylala Chlorophen 4-Ethoxyphenylacetic 120 nine ylalanine acid 467 58 * The FMOC group on Ornithine was reduced to N-methyl on all Ornithine containing compounds (6620-1 through 6620-24) 6626 CmpdR1 R2 R3 MW Yield %Pur Boc-L-4- 1 Boc-L-Tic (OH) Tyr (OEt) ClPhCH2CO2H 478 31 90 Boc-L-4- 2 Boc-Pro-OH Tyr (OEt) ClPhCH2CO2H 416 35 90 Boc-L- 4- 3 Boc-HoPro-OH Tyr (OEt) CIPhCH2CO2H 430 21 75 Boc-N-Methyl-Boc-L-4- 4 Tyr (Bzl)-OH Tyr (OEt) ClPhCH2CO2H 496 22 65 Boc-4, 4- Biphenylal 4- 5 Boc-L-Tic (OH) anine ClPhCH2CO2H 510 27 90 Boc-4,4- Boc-L-Tic (OH) - Biphenyl 4- 6 OH anine ClPhCH2CO2H 526 46 95 Boc-4,4- Biphenylal 4- 7 Boc-Pro-OH anine ClPhCH2CO2H 448 35 90 Boc-4, 4- Biphenylal 4- 8 Boc-HoPro-OH anine ClPhCH2CO2H 462 27 70 Boc-4,4- Boc-Hyp(Bzl)- Biphenylal 4- 9 OH anine ClPhCH2CO2H 464 43 60 Boc-4,4- Biphenylal 4- 10 Boc-Phe-OH anine ClPhCH2CO2H 498 28 85 Boc-4,4- Boc-N-Methyl-Biphenylal 4- 11 Tyr (Bzl)-OH anine ClPhCH2CO2H 528 44 55 Boc-4- 12 Boc-L-Tic (OH) Glycine ClPhCH2CO2H 344 25 90 Boc-L-Tic (OH) - Boc- 4- 13 OH Glycine ClPhCH2CO2H 360 41 90 Boc-4- 14 Boc-Pro-OH Glycine ClPhCH2CO2H 282 22 90 Boc- 4- 15 Boc-HoPro-OH Glycine ClPhCH2CO2H 296 30 80 6626 Boc-Hyp (Bzl)- Boc- 4- 16 OH Glycine ClPhCH2CO2H 298 32 85 Boc- 4- 17 Boc-Phe-OH Glycine ClPhCH2CO2H 332 31 90 Boc-Tyr. (Bzl)- Boc- 4- 18 OH Glycine ClPhCH2CO2H 348 40 55 Boc-N-Methyl-Boc-4- 19 Tyr (Bzl)-OH Glycine CXlPhCH2CO2H 362 47 60 Boc-2- Naphthylal 4- 20 Boc-L-Tic(OH) anine ClPhCH2CO2H 484 46 90 Boc-2- Boc-L-Tic(OH)- Naphthylal 4- 21 OH anine ClPhCH2CO2H 500 61 90 Boc-2- Naphthylal 4- 22-Boc-Pro-OH anine ClPhCH2CO2H 422 30 85 Boc-2- Naphthylal 4- Boc-HoPro-OH anine ClPhCH2CO2H 436 35 80 Boc-2- Boc-Hyp (Bzl)- Naphthylal 4- 24 OH anine ClPhCH2CO2H 438 45 70 Boc-2- Naphthylal 4- 25 Boc-Phe-OH anine ClPhCH2CO2H 472 57 85 Boc-2- Boc-Tyr (Bzl)- Naphthylal 4- 26 OH anine ClPhCH2CO2H 488 68 55 Boc-2- Boc-N-Methyl-Naphthylal 4- 27 Tyr (Bzl)-OH anine ClPhCH2CO2H 502 28 55 6628 R1 : Amino R2 : Amino R3: Carboxylic Cpd acid acid acid MW Yield Boc-Boc-3, 4-Di-cl- 2 Ser (OBzl) Tyr (OEt) phenylacetic acid 440 26 Boc-Boc-3-Cl-phenylacetic 3 Ser (OBzl) Tyr (OEt) acid 406 19 Boc-Boc-4-Cl-phenylacetic 5 Ser (OBzl) Tyr (OEt) acid 406 24 Boc-Boc-4-Br-phenylacetic 6 Ser (OBzl) Tyr (OEt) aicd 450 19 Boc-Boc- 7 Ser (OBzl) Tyr (OEt) p-Tolylacetic acid 385 19 Boc- Boc-4-CF3- 3,4-Di-Cl- 9 Ser (OBzl) Phe phenylacetic acid 464 35 Boc-Boc-4-CF3-3-Cl-phenylacetic 10 Ser (OBzl) Phe acid 430 27 Boc- Boc-4-CF3- 4-Cl-phenylacetic 12 Ser (OBzl) Phe acid 430 24 Boc-Boc-4-CF3-4-Br-phenylacetic 13 Ser (OBzl). Phe aicd 474 31 Boc-Boc-4-CF3- 14 Ser (OBzl) Phe p-Tolylacetic acid 409 23 Boc-Boc-3,4-Di-3, 4-Di-Cl- 16 Ser (OBzl) OMe-Phe phenylacetic acid 456 23 Boc-Boc-3,4-Di-3-Cl-phenylacetic 17 Ser (OBzl) OMe-Phe acid 422 25 6628 Boc-Boc-3,4-Di-4-Cl-phenylacetic 19 Ser (OBzl) OMe-Phe acid 422 27 Boc-Boc-3,4-Di-4-Br-phenylacetic 20 Ser (OBzl) OMe-Phe aicd 466 15 Boc-Boc-3,4-Di- 21 Ser (OBzl) OMe-Phe p-Tolylacetic acid 401 29 Boc-Boc-4-tBu-3, 4-Di-Cl- 23 Ser (OBzl) Phe phenylacetic acid. 452 26 Boc-Boc-4-tBu-3-Cl-phenylacetic 24 Ser (OBzl) Phe acid 418 30 Boc-Boc-4-tBu-4-Cl-phenylacetic 26 Ser (OBzl) Phe acid 418 28 Boc-Boc-4-tBu-4-Br-phenylacetic 27 Ser (OBzl) Phe aicd 462 21 Boc-Boc-4-tBu- 28 Ser (OBzl) Phe p-Tolylacetic acid 397 36 Boc-Boc-N-Me-3, 4-Di-Cl- 30 Ser (OBzl) Tyr (Me) phenylacetic acid 440 29 Boc-Boc-N-Me-3-Cl-phenylacetic 31 Ser (OBzl) Tyr (Me) acid 406 29 Boc-Boc-N-Me-4-Cl-phenylacetic 33 Ser (OBzl) Tyr (Me) acid 406 28 Boc-Boc-N-Me-4-Br-phenylacetic 34 Ser (OBzl) Tyr (Me) aicd 450 20 Boc-Boc-N-Me- 35 Ser (OBzl) Tyr (Me) p-Tolylacetic acid 385 27 6628 Boc- Boc- 3, 4-Di-Cl- 37 Met (O) 2 Tyr (OEt) phenylacetic acid 516 51 Boc-Boc-3-Cl-phenylacetic 38 Met (O) 2 Tyr (OEt) acid 482 54 Boc-Boc-4-Cl-phenylacetic 40 Met (O) 2 Tyr (OEt) acid 482 52 Boc-Boc-4-Br-phenylacetic 41 Met (O) 2 Tyr (OEt) acid 526 43 Boc-Boc- 42 Met (0) 2 Tyr (OEt) p-Tolylacetic acid 461 45 Boc-Boc-4-CF3-3,4-Di-Cl- 44 Met (0) 2 Phe phenylacetic acid 540 47 Boc-Boc-4-CF3-3-Cl-phenylacetic 45 Met (O) 2 Phe acid 506 52 Boc-Boc-4-CF3-4-Cl-phenylacetic 47 Met (O) 2 Phe acid 506 46 Boc-Boc-4-CF3-4-Br-phenylacetic 48 Met (0) 2 Phe aicd 550 55 Boc-Boc-4-CF3- 49 Met (0) 2 Phe p-Tolylacetic acid 485 41 Boc- Boc-3,4-Di-3,4-Di-Cl- 51 Met (O) 2 OMe-Phe phenylacetic acid 532 63 Boc-Boc-3, 4-Di-3-Cl-phenylacetic 52 Met (0) 2 OMe-Phe acid 498 42 Boc-Boc-3, 4-Di-4-Cl-phenylacetic 54 Met (0) 2 OMe-Phe acid 498 51 Boc-Boc-3,4-Di- 4-Br-phenylacetic 55 Met(O) 2 OMe-Phe aicd 542 53 6628 Boc-Boc-3,4-Di- 56 Met (0) 2 OMe-Phe p-Tolylacetic acid 477 50 Boc-Boc-4-tBu-3, 4-Di-Cl- 58 Met (O) 2 Phe phenylacetic acid 528 63 Boc-Boc-4-tBu-3-Cl-phenylacetic 59 Met (0) 2 Phe acid 494 58 Boc- Boc-4-tBu- 4-Cl-phenylacetic 61 Met (0) 2 Phe acid 494 65 Boc- Boc-4-tBu- 4-Br-phenylacetic 62 Met(O) 2 Phe aicd 538 61 Boc-3,4-Di-3-Cl-phenylacetic 64 Boc-Hyp OMe-Phe acid 448 23 Boc-3,4-Di-4-Cl-phenylacetic 66 Boc-Hyp OMe-PHe acid 448 24 Boc-3, 4-Di-4-Br-phenylacetic 67 Boc-Hyp OMe-Phe aicd 492 29 Boc-3,4-Di- 68 Boc-Hyp OMe-Phe p-Tolylacetic acid 427 21 Boc-4-tBu- 3,4-Di-Cl- 70 Boc-Hyp Phe phenylacetic acid 478 43 Boc-4-tBu- 3-Cl-phenylacetic 71 Boc-Hyp Phe acid-444 30 Boc-4-tBu- 4-Cl-phenylacetic 73 Boc-Hyp Phe acid 444 28 Boc-4-tBu- 4-Br-phenylacetic 74 Boc-Hyp Phe aicd 488 31 Boc-4-tBu- 75 Boc-Hyp Phe p-Tolylacetic acid 423 28 6628 Boc-N-Me-3,4-Di-Cl- 77 Boc-Hyp Tyr(Me) phenylacetic acid 466 20 Boc-N-Me-3-Cl-phenylacetic 78 Boc-Hyp Tyr (Me) acid 432 18 Boc-N-Me-4-Cl-phenylacetic 80 Boc-Hyp Tyr (Me) acid 432 22 Boc-N-Me-4-Br-phenylacetic 81 Boc-Hyp Tyr (Me) aicd 476 25 Boc-N-Me- 82 Boc-Hyp Tyr (Me) p-Tolylacetic acid 411 20 Boc-3, 4-Di-Cl- 84 Boc-Hyp Tyr (OEt) phenylacetic acid 466 35 Boc-3-Cl-phenylacetic 85 Boc-Hyp Tyr (OEt) acid 432 19 Boc-4-Cl-phenylacetic 87 Boc-Hyp Tyr (OEt) acid 432 24 Boc-4-Br-phenylacetic 88 Boc-Hyp Tyr (OEt) aicd 476 16 Boc- 89 Boc-Hyp Tyr (OEt) p-Tolylacetic acid 411 20 Boc-3, 4-Di- 3, 4-Di-Cl- 90 Boc-Hyp OMe-Phe phenylacetic acid 482 31 Boc-Boc-4-tBu- 91 Met (O) 2 Phe p-Tolylacetic acid 473 57 Boc-Boc-N-Me-3, 4-Di-Cl- 93 Met (0) 2 Tyr (Me) phenylacetic acid 516 49 Boc-Boc-N-Me-3-Cl-phenylacetic 94 Met (O) 2 Tyr (Me) acid 482 38 6628 Boc- Boc-N-Me- 4-Cl-phenylacetic 96 Met (O) 2 Tyr (Me) acid 482 47 Boc-Boc-N-Me-4-Br-phenylacetic 97 Met (0) 2 Tyr (Me) aicd 526 41 Boc-Boc-N-Me- 98 Met (0) 2 Tyr (Me) p-Tolylacetic acid 461 44 Boc-3-Boc-4-Cl-phenylacetic 99 PyrAla Tyr (OPr) acid 481 36 Boc-3- Boc- 4-Br-phenylacetic 100 PyrAla Tyr (OPr) aicd 525 44 Boc-Boc-4-Cl-phenylacetic 101 Ser (OBzl) Tyr (OPr) acid 420 29 Boc-Boc-4-Br-phenylacetic 102 Ser (OBzl) Tyr (OPr) aicd 464 21 Boc-4-Cl-phenylacetic 103 Boc-Hyp Tyr (OPr) acid 446 28 Boc-4-Br-phenylacetic 104 Boc-Hyp Tyr (OPr) aicd 490 34 Boc-Boc-4-Cl-phenylacetic 105 Ser (Me) Tyr (OPr) acid 434 26 Boc-Boc-4-Br-phenylacetic 106 Ser (Me) Tyr (OPr) aicd 478 23 Boc- Boc- 4-Cl-phenylacetic 107 Met (0) 2 Tyr (OPr) acid 496 39 Boc-Boc-4-Br-phenylacetic 108 Met (O) 2 Tyr (OPr) aicd 540 44 6629 R1 : Amino R3: Carboxylic Cpd acid R2 : Amino acid acid MW Yield BOC-L- 1 Ser (Me)-OH BOC-1-Naphthyl-Ala 4-ClPhCH2CO2H 426 18 BOC-L- 2 Ser (Me)-OH BOC-2-Naphthy-Ala 4-ClPhCH2CO2H 426 17 BOC-L- BOC-Ala(3, 3- 3 Ser (Me)-OH diphenyl)-OH 4-ClPhCH2CO2H 452 21 BOC-L-BOC-L-3,4-Dichloro 4 Ser (Me)-OH Phe 4-ClPhCH2CO2H 445 18 BOC-L-BOC-L-4,4'- 5 Ser (Me)-OH Biphenylalanine 4-ClPhCH2CO2H 452 13 BOC-L-BOC-L-4- 6 Ser (Me)-OH Bromophenylalanine 4-ClPhCH2CO2H 455 15 BOC-L-4- BOC-L-Chlorophenylalanin 7 Ser (Me)-OH e 4-ClPhCH2CO2H 411 17 BOC-L-BOC-L-homo-SER (Me) 8Ser (Me)-OH OH 4-ClPhCh2CO2H 344 14 BOC-L- 9 Ser (Me)-OH BOC-L-Phe-OH 4-ClPhCH2CO2H 376 15 BOC-L-Fmoc-L-homo- 11 Ser (Me)-OH Tyr (Me)-OH 4-ClPhCH2CO2H 420 10 BOC-L- 12 Ser (Me)-OH Fmoc-L-m-Tyr (Me) 4-ClPhCH2CO2H 406 16 BOC-L- 13 Ser (Me)-OH Fmoc-L-o-Tyr (Me) 4-ClPhCH2CO2H 406 17 6629 BOC-L- 14 Ser (Me)-OH Fmoc-L-Phe (4-Et) 4-ClPhCH2CO2H 404 17 BOC-L- 15 Ser (Me)-OH Fmoc-L-Phe (4-iPr) 4-ClPhCH2CO2H 418 17 BOC-L- 16 Met (O) 2-OH BOC-1-Naphtnyl-Ala 4-ClPhCH2CO2H 488 31 BOC-L- 17 Met (0) 2-OH BOC-2-Naphthy-Ala 4-ClPhCH2CO2H 488 32 BOC-L-BOC-Ala (3,3- 18 Met (0) 2-OH diphenyl)-OH 4-ClPhCH2CO2H 514 31 BOC-L-BOC-L-3,4-Dichloro Met (0) 2-OH Phe 4-ClPhCH2CO2H @@@@@ 4-ClPhCH2CO2H 507 32 BOC-L- BOC-L-4,4'- 20 Met (O) 2-OH Biphenylalanine 4-ClPhCH2CO2H 514 32 BOC-L-BOC-L-4- 21 Met (O) 2-OH Bromophenylalanine 4-ClPhCh2CO2H 517 30 BOC-L-4- BOC-L-Chlorophenylalanin 22 Met (0) 2-OH e 4-ClPhCH2CO2H 473 30 BOC-L-BOC-L-homo-SER (Me) 23 Met (O) 2-OH OH 4-ClPhCh2CO2H 406 26 BOC-L- 24 Met (0) 2-OH BOC-L-Phe-OH 4-ClPhCH2CO2H 438 26 BOC-L-Fmoc-L-homo- 26 Met (0) 2-OH Tyr (Me)-OH 4-ClPhCH2CO2H 482 12 BOC-L- 27 Met (0) 2-OH Fmoc-L-m-Tyr (Me) 4-ClPhCH2CO2H 468 29 6629 BOC-L- 28 Met (0) 2-OH Fmoc-L-o-Tyr (Me) 4-ClPhCH2CO2H 468 29 BOC-L- Met (0) 2-OH Fmoc-L-Phe (4-Et) 4-ClPhCH2CO2H 466 28 BOC-L- 30 Met (O) 2-OH Fmoc-L-Phe (4-iPr) 4-ClPhCH2CO2H 480 32 BOC-L-3- 31 Pyridylala BOC-1-Naphthy-Ala 4-ClPhCH2CO2H 473 88 BOC-L-3- 32 Pyridylala BOC-2-Naphthy-Ala 4-ClPhCH2CO2H 473 74 BOC L-3-BOC-Ala (3,3- 33 Pyridylala diphenyl)-OH 4-ClPhCH2CO2H 499 80 BOC-L-3-BOC-L-3, 4-Dichloro 34 Pyridylala Phe 4-ClPhCH2CO2H 492 54 BOC-L-3-BOC-L-4,4'- 35 Pyridylala Biphenylalanine 4-ClPhCH2CO2H 499 82 BOC-L-3-BOC-L-4- 36 Pyridylala Bromophenylalanine 4-ClPhCH2CO2H 502 68 BOC-L-4- BOC-L-3-Chlorophenylalanin 37 Pyridylala e 4-ClPhCH2CO2H 458 66 BOC-L-3-BOC-L-homo-SER (Me) 38 Pyridylala OH 4-ClPhCH2CO2H 391 68 BOC-L-3- 39 Pyridylala BOC-L-Phe-OH 4-ClPhCH2CO2H 423 67 BOC-L-3-Fmoc-L-homo- 41 Pyridylala Tyr (Me)-OH 4-ClPhCH2CO2H 467 68 6629 BOC-L-3- 42 Pyridylala Fmoc-L-m-Tyr (Me) 4-ClPhCH2CO2H 453 72 BOC-L-3- 43 Pyridylala Fmoc-L-o-Tyr (Me) 4-ClPhCH2CO2H 453 64 BOC-L-3- 44 Pyridylala Fmoc-L-Phe (4-Et) 4-ClPhCH2CO2H 451 66 BOC-L-3- 45 Pyridylala Fmoc-L-Phe (4-iPr) 4-ClPhCH2CO2H 465 74 BOC-L- 46 Tic (OH)-OH BOC-1-Naphthyl-Ala 4-ClPhCH2CO2H 500 32 BOC-L- 21 Tic (OH)-OH BOC-2-Naphthy-Ala 4-ClPhCH2CO2H 500 31 BOC-L-BOC-Ala (3,3- 48 Tic (OH)-OH diphenyl)-OH 4-ClPhCH2CO2H 526 36 BOC-L-BOC-L-3,4-Dichloro 49 Tic (OH)-OH Phe 4-ClPhCH2CO2H 519 42 BOC-L-BOC-L-4,4'- 6 Tic (OH)-OH Biphenylalanine 4-ClPhCH2CO2H 526 86 BOC-L-BOC-L-4- 51 Tic (OH)-OH Bromophenylalanine 4-ClPhCH2CO2H 529 39 BOC-L-4- BOC-L-Chlorophenylalanin 52 Tic (OH)-OH e 4-ClPhCH2CO2H 485 33 BOC-L-BOC-L-homo-SER (Me) 53 Tic (OH)-OH OH 4-ClPhCH2CO2H 418 25 BOC-L- 54 Tic (OH)-OH BOC-L-Phe-OH 4-ClPhCH2CO2H 450 32 6629 BOC-L-Fmoc-L-homo- 55 Tic (OH)-OH Tyr (Me)-OH 4-ClPhCH2CO2H 494 35 BOC-L- 56 Tic (OH)-OH Fmoc-L-m-Tyr (Me) 4-ClPhCH2CO2H 480 36 BOC-L- 57 Tic (OH)-OH Fmoc-L-o-Tyr (Me) 4-ClPhCH2CO2H 480 39 BOC-L- 58 Tic (OH)-OH Fmoc-L-Phe (4-Et) 4-ClPhCH2CO2H 478 50 BOC-L- 59 Tic (OH)-OH Fmoc-L-Phe (4-iPr) 4-ClPhCH2CO2H 492 32 BOC-L- 60 Ser (OBzl) BOC-1-Naphthy-Ala 4-ClPhCH2CO2H 412 56 BOC-L- 61 Ser (OBzl) BOC-2-Naphthy-Ala 4-ClPhCH2CO2H 412 64 BOC-L-BOC-Al. a (3, 3- 62 Ser (OBzl) diphenyl)-OH 4-ClPhCH2CO2H 438 61 BOC-L-BOC-L-3, 4-Dichloro 63 Ser (OBzl) Phe 4-ClPhCH2CO2H 431 53 BOC-L-BOC-L-4,4'- 64 Ser (OBzl) Biphenylalanine 4-ClPhCH2CO2H 438 59 BOC-L-BOC-L-4- 65 Ser (OBzl) Bromophenylalanine 4-ClPhCH2CO2H 441 62 BOC-L-4- BOC-L-Chlorophenylalanin 66 Ser (OBzl) e 4-ClPhCH2CO2H 397 53 BOC-L-BOC-L-homo-SER (Me) 67 Ser (OBzl) OH 4-ClPhCH2CO2H 330 49 BOC-L- 68 Ser (OBzl) BOC-L-Phe-OH 4-ClPhCH2CO2H 362 56 BOC-L-Fmoc-L-homo- 70 Ser (OBzl) Tyr (Me)-OH 4-ClPhCH2CO2H 406 55 BOC-L- 71 Ser (OBzl) Fmoc-L-m-Tyr (Me) 4-ClPhCH2CO2H 392 42 6629 BOC-L- 72 Ser (OBzl) Fmoc-L-o-Tyr (Me) 4-ClPhCH2CO2H 392 56 BOC-L- 73 Ser (OBzl) Fmoc-L-Phe (4-Et) 4-clPhCH2CO2H 390 49 BOC-L- 74 Ser (OBzl) Fmoc-L-Phe (4-iPr) 4-ClPhCH2CO2H 404 47 BOC-L-Hyp- 76 OH BOC-1-Naphthy-Ala 4-ClPhCH2CO2H 438 23 BOC-L-Hyp- 77 OH BOC-2-Naphthyl-Ala 4-ClPhCH2CO2H 438 27 BOC-L-Hyp-BOC-Ala(3,3- 78 OH diphenyl)-OH 4-ClPhCH2CO2H 464 27 BOC-L-Hyp- BOC-L-3,4-Dichloro 79 OH Phe 4-ClPhCH2CO2H 457 30 BOC-L-Hyp BOC-L-4,4'- 80 OH Biphenylalanine 4-ClPhCH2CO2H 464 35 BOC-L-Hyp-BOC-L-4- 81 OH Bromophenylalanine 4-ClPhCH2CO2H 467 33 BOC-L-4- BOC-L-Hyp-Chlorophenylalanin 82 OH e 4-ClPhCH2CO2H 423 24 BOC-L-Hyp-BOC-L-homo-SER (Me) 83 OH OH 4-ClPhCH2CO2H 356 28 BOC-L-Hyp- 84 OH BOC-L-Phe-OH 4-ClPhCH2CO2H 388 31 BOC-L-Hyp-Fmoc-L-homo- 86 OH Tyr (Me) -OH 4-ClPhCH2CO2H 432 27 BOC-L-Hyp- 87 OH Fmoc-L-m-Tyr (Me) 4-ClPhCH2CO2H 418 31 BOC-L-Hyp- 88 OH Fmoc-L-o-Tyr (Me) 4-ClPhCH2CO2H 418 31 BOC-L-Hyp- 89 OH Fmoc-L-Phe (4-Et) 4-ClPhCH2CO2H 416 35 BOC-L-Hyp- 90 OH Fmoc-L-Phe (4-iPr) 4-ClPhCH2CO2H 430 16 BOC-L- Dimethyl- 91 Orn BOC-2-Naphtnyl-Ala 4-ClPhCH2CO2H 467 2 6629 BOC-L- Dimethyl- Orn BOC-2-Naphthyl-Ala 4-ClPhCH2CO2H 511 2 BOC-L- Dimethyl-BOC-L-3, 4-Dichloro 93 Orn Phe 4-ClPhCH2CO2H 486 3 BOC-L- Dimethyl-BOC-L-3, 4-Dichloro 94 Orn Phe 4-ClPhCH2CO2H 529 0 BOC-L- Dimethyl- BOC-L-4, 4'- 95 Orn Biphenylalanine 4-ClPhCH2CO2H 493 0 BOC-L- Dimethyl-BOC-L-4, 4'- 96 Orn Biphenylalanine 4-ClPhCH2CO2H 537 2 BOC-L- Dimethyl- 97 Orn Fmoc-L-Phe (4-Et) 4-ClPhCH2CO2H 445 3 BOC-L- Dimethyl- 98 Orn Fmoc-L-Phe (4-Et) 4-ClPhCH2CO2H 489 1 BOC-L- Dimethyl- 99 Orn Fmoc-L-Phe (4-iPr) 4-ClPhCH2CO2H 503 0 6630 RI : Amino R2: Amino R3: Carboxylic Cpd acid acid acid MW Yield 2, 4-di- BOC-L-3-Boc-Chlorophenylacetic 1 Pyridylala Tyr (Et)-OH acid 501 72 BOC-L-3-Boc-2-Cl-phenylacetic 2 Pyridylala Tyr (Et)-OH acid 467 82 3- BOC-L-3-Boc- (trifluoromethly) p 3 Pyridylala Tyr (Et)-OH henylacetic acid 500 68 3, 4-di- BOC-L-3-Boc-Methoxyphenylaceti 4 Pyridylala Tyr (Et)-OH c acid 492 74 3, 5-di- BOC-L-3-Boc- (trifuoromethyl) ph 5 Pyridylala Tyr (Et)-OH enylacetic acid 568 60 3, 5-di- BOC-L-3-Boc-fluoropenlacetic 6 Pyridylala Tyr (Et)-OH acid 468 73 3-Ethoxy-4- BOC-L-3-Boc-Hydroxyphenylaceti 7 Pyridylala Tyr (Et)-OH c acid 492 73 3- BOC-L-3-Boc-Methoxyphenylaceti 8 Pyridylala Tyr (Et)-OH c acid 462 65 4- BOC-L-3-Boc- (dimethylamino) phe 9 Pyridylala Tyr (Et)-OH nylacetic acid 475 67 4- BOC-L-3-Boc- (methylthio) phenyl 10 Pyridylala Tyr (Et)-OH acetic acid 478 67 BOC-L-3-Boc-4-biphenylacetic 12 Pyridylala Tyr (Et)-OH acid 508 70 4- BOC-L-3-Boc-Bromophenylacetic 13 Pyridylala Tyr (Et) -OH acid 511 71 6630 4- BOC-L-3-Boc-Fluorophenylacetic 14 Pyridylala Tyr (Et)-OH acid 450 56 4- BOC-L-3-Boc-Methoxyphenylaceti 15 Pyridylala Tyr (Et)-OH c acid 462 60 BOC-L-3-Boc- 16 Pyridylala Tyr (Et)-OH phenylacetic acid 432 64 2, 4-di- BOC-L-Boc-Chlorophenylacetic 18 Tic (OH)-OH Tyr (Et) -OH acid 528 43 BOC-L-Boc-2-Cl-phenylacetic 19 Tic (OH)-OH Tyr (Et) -OH acid 494 42 3- BOC-L-Boc- (trifluoromethly) p 20 Tic (OH)-OH Tyr (Et) -OH henylacetic-acid 527 48 3, 4-di- BOC-L- Boc- Methoxyphenylaceti 21 Tic (OH)-OH Tyr (Et) -OH c acid 519 34 3, 5-di- BOC-L-Boc- (trifuoromethyl) ph 22 Tic (OH)-OH Tyr (Et)-OH enylacetic acid 595 63 3, 5-di- BOC-L-Boc-fluoropenlacetic 23 Tic (OH) -OH Tyr (Et) -OH acid 495 37 3-Ethoxy-4- BOC-L- Boc- Hydroxyphenylaceti 24 Tic (OH)-OH Tyr (Et) -OH c acid 519 45 3- BOC-L-Boc-Methoxyphenylaceti 25 Tic (OH)-OH Tyr (Et)-OH c acid 489 40 4- BOC-L-Boc- (dimethylamino) phe 26 Tic (OH)-OH Tyr (Et) -OH nylacetic acid 502 45 6630- 4- BOC-L-Boc- (methylthio) phenyl 27 Tic (OH)-OH Tyr (Et) -OH acetic acid 505 47 4- BOC-L-Boc- (trifluoromethyl) p 28 Tic (OH)-OH Tyr (Et)-OH henylacetic acid 527 40 BOC-L-Boc-4-biphenylacetic 29 Tic (OH)-OH Tyr (Et)-OH acid 535 41 4- BOC-L- Boc- Bromophenylacetic 30 Tic (OH)-OH Tyr (Et) -OH acid 538 57 4- BOC-L-Boc-Fluorophenylacetic 31 Tic (OH)-OH Tyr (Et) -OH acid 4- BOC-L-Boc-Methoxyphenylaceti 32 Tic (OH)-OH Tyr (Et) -OH c acid 489 29 BOC-L-Boc- 33 Tic (OH)-OH Tyr (Et)-OH phenylacetic acid 459 34 2, 4-di- BOC-L-Boc-Chlorophenylacetic 35 Ser (OBzl) Tyr (Et) -OH acid 440 58 BOC-L-Boc-2-Cl-phenylacetic 36 Ser (OBzl) Tyr (Et) - OH acid 406 58 3- BOC-L-Boc- (trifluoromethly) p 37 Ser (OBzl) Tyr (Et)-OH henylacetic acid 439 66 3, 4-di- BOC-L-Boc-Methoxyphenylaceti 38 Ser (OBzl) Tyr (Et)-OH c acid 431 66 3, 5-di- BOC-L-Boc- (trifuoromethyl) ph 39 Ser (OBzl) Tyr (Et) - OH enylacetic acid 507 59 6630 3,5-di- BOC-L-Boc-fluoropenlacetic 40 Ser (OBzl) Tyr (Et)-OH acid 407 66 3-Ethoxy-4- BOC-L-Boc-Hydroxyphenylaceti 41 Ser (OBzl) Tyr (Et) -OH c acid 431 62 3- BOC-L-Boc-Methoxyphenylaceti 42 Ser (OBzl) Tyr (Et)-OH c acid 401 60 4- BOC-L-Boc- (dimethylamino) phe 43 Ser (OBzl). Tyr (Et)-OH nylacetic acid 414 61 BOC-L-Boc- (methylthio) phenyl 44 Ser (OBzl) Tyr (Et)-OH acetic acid 417 59 4- BOC-L-Boc- (trifluoromethyl) p 45 Ser (OBzl) Tyr (Et)-OH henylacetic acid 439 64 BOC-L-Boc-4-biphenylacetic 46 Ser (OBzl) Tyr (Et)-OH acid 447 66 4- BOC-L-Boc-Bromophenylacetic 47 Ser (OBzl) Tyr (Et)-OH acid 450 57 4- BOC-L-Boc-Methoxyphenylaceti 49 Ser (OBzl) Tyr (Et)-OH c acid 401 65 BOC-L-Boc- 50 Ser (OBzl) Tyr (Et)-OH phenylacetic acid 371 63 2,4-di- BOC-L-Boc-Chlorophenylacetic 52 Ser (Me)-OH Tyr (Et)-OH acid 454 26 BOC-L-Boc-2-Cl-phenylacetic 53 Ser (Me)-OH Tyr (Et)-OH acid 420 23 3- BOC-L-Boc- (trifluoromethly) p 54 Ser (Me)-OH Tyr (Et) -OH henylacetic acid 453 27 6630 3, 4-di- BOC-L-Boc-Methoxyphenylaceti 55 Ser (Me)-OH Tyr (Et)-OH c acid 445 25 3, 5-di- BOC-L-Boc- (trifuoromethyl) ph 56 Ser (Me)-OH Tyr (Et)-OH enylacetic acid 521 25 3, 5-di- BOC-L-Boc-fluoropenlacetic 57 Ser (Me)-OH Tyr (Et)-OH acid 421 30 3-Ethoxy-4- BOC-L-Boc-Hydroxyphenylaceti 58 Ser (Me) -OH Tyr (Et)-OH c acid 445 23 3- BOC-L-Boc-Methoxyphenylaceti 59 Ser (Me)-OH Tyr (Et) -OH c acid 415 22 4- BOC-L-Boc- (dimethylamino) phe 60 Ser (Me)-OH Tyr (Et)-OH nylacetic acid 428 27 4- BOC-L-Boc- (methylthio) phenyl 61 Ser (Me)-OH Tyr (Et) -OH acetic acid 431 31 4- BOC-L-Boc- (trifluoromethyl) p 62 Ser (Me)-OH Tyr (Et)-OH henylacetic acid 453 25 BOC-L-Boc-4-biphenylacetic 63 Ser (Me)-OH Tyr (Et) -OH acid 461 26 4- BOC-L-Boc-Bromophenylacetic 64 Ser (Me)-OH Tyr (Et)-OH acid 464 25 4- BOC-L-Boc-FluorophenylaceLic 65 Ser (Me)-OH Tyr (Et)-OH acid 403 19 4- BOC-L-Boc-Methoxyphenylaceti 66 Ser (Me)-OH Tyr (Et) -OH c acid 415 20 BOC-L-Boc- 67 Ser (Me)-OH Tyr (Et)-OH phenylacetic acid 385 21 6630 2, 4-di- BOC-L- Boc- Chlorophenylacetic 69 Met (O) 2-OH Tyr (Et)-OH acid 516 31 BOC-L-Boc-2-Cl-phenylacetic 70 Met(O)2-OH Tyr (Et)-OH acid 482 35 3- BOC-L-Boc- (trifluoromethly) p '7 Met (O) 2-OH Tyr (Et)-OH henylacetic acid 515 42 3, 4-di- BOC-L-Boc-Methoxyphenylaceti 72 Met (O) 2-OH Tyr (Et)-OH c acid 507 33 3, 5-di- BOC-L-Boc- (trifuoromethyl) ph 73 Met (0) 2-OH Tyr (Et)-OH enylacetic acid 583 38 3,5-di- BOC-L-Boc-fluoropenlacetic 74 Met (0) 2-OH Tyr (Et)-OH acid 483 27 3-Ethoxy-4- BOC-L- Boc- Hydroxyphenylaceti 75 Met (0) 2-OH Tyr (Et)-OH c acid 3- BOC-L--Boc-Methoxyphenylaceti 76 Met (O) 2-OH Tyr (Et)-OH c acid 477 29 4- BOC-L-Boc- (dimethylamino) phe 77 Met (O) 2-OH Tyr (Et)-OH nylacetic acid 490. 32 4- BOC-L-Boc- (methylthio) phenyl 78 Met (O) 2-OH Tyr (Et) -OH acetic acid 493 40 4- BOC-L-Boc- (trifluoromethyl) p 79 Met (0) 2-OH Tyr (Et) -OH henylacetic acid 515 31 BOC-L-Boc-4-biphenylacetic 80 Met (0) 2-OH Tyr (Et)-OH acid 523 35 6630 4- BOC-L-Boc-Bromophenylacetic 81 Met (0) 2-OH Tyr (Et)-OH acid 526 25 4- BOC-L-Boc-Fluorophenylacetic 82 Met (0) 2-OH Tyr (Et)-OH acid 465 30 4- BOC-L-Boc-Methoxyphenylaceti 83 Met (0) 2-OH Tyr (Et)-OH c acid 477 31 BOC-L-Boc- 84 Met (O) 2-OH Tyr (Et)-OH phenylacetic acid 447 21 2,4-Di- Boc-Chlorophenylacetic 86 BOC-L-Hyp-OH Tyr (Et)-OH acid 466 20 Boc-2-Cl-phenylacetic 87 BOC-L-Hyp-OH Tyr (Et)-OH acid 432 19 3- Boc- (Trifluoromethly) p 88 BOC-L-Hyp-OH Tyr (Et)-OH henylacetic acid 465 17 3, 4-Di- Boc-Methoxyphenylaceti 89 BOC-L-Hyp-OH Tyr (Et)-OH c acid 457 12 3, 5-Di- Boc- (trifuoromethyl) ph 90 BOC-L-Hyp-OH Tyr (Et)-OH enylacetic acid 533 18 3, 5-Di- Boc-fluoropenlacetic 91 BOC-L-Hyp-OH Tyr (Et)-OH acid 433 21 3-Ethoxy-4- Boc-Hydroxyphenylaceti 92 BOC-L-Hyp-OH Tyr (Et) -OH c acid 457 17 3- Boc-Methoxyphenylaceti 93 BOC-L-Hyp-OH Tyr (Et) -OH c acid 427 16 4- Boc- (Dimethylamino) phe 94 BOC-L-Hyp-OH Tyr (Et) -OH nylacetic acid 440 21 6630 4- Boc- (Methylthio) phenyl 95 BOC-L-Hyp-OH Tyr (Et)-OH acetic acid 443 18 Boc-4-Biphenylacetic 96 BOC-L-Hyp-OH Tyr (Et)-OH acid 473 18 4- Boc-Bromophenylacetic 97 BOC-L-Hyp-OH Tyr (Et)-OH acid 476 20 4- Boc-Fluorophenylacetic 98 BOC-L-Hyp-OH Tyr (Et)-OH acid 415 17 4- Boc-Methoxyphenylaceti 99 BOC-L-Hyp-OH Tyr (Et)-OH c acid 427 17 Boc- 100 BOC-L-Hyp-OH Tyr (Et)-OH Phenylacetic acid 397 17 4- BOC-L-Boc-Fluorophenylacetic 102 Dimethyl-Orn Tyr (Et)-OH acid 445 7 4- BOC-L-Boc-Fluorophenylacetic 103 Dimethyl-Orn Tyr (Et)-OH acid 489 1 4- BOC-L-Boc-Methoxyphenylaceti 104 Dimethyl-Orn Tyr (Et)-OH c acid 457 4 4- BOC-L-Boc-Methoxyphenylaceti 105 Dimethyl-Orn Tyr (Et)-OH c acid 501 2 BOC-L-Boc- 106 Dimethyl-Orn Tyr. (Et)-OH Phenylacetic acid 427 6 BOC-L-. Boc- 107 Dimethyl-Orn Tyr (Et)-OH Phenylacetic acid 471 1 BOC-L-Boc- 108 Dimethyl-Orn Tyr (Et)-OHp-Toluic acid 441 4 6630 BOC-L-Boc- 109 Dimethyl-Orn Tyr (Et) -OH p-Toluic acid 485 1 6634 R1 : R2 : R3: Amino Amino Carboxylic R4: Sulfonyl Cpd acid acid acid chloride MW Yield BOC-Boc-p-Cl- DAP (F Tyr (Et phenylacet 2-thiophenesulfonyl 1 MOC))-OH ic acid chloride 550 25.1 BOC-Boc-p-Cl-4- DAP (F Tyr (Et phenylacet methoxybenzenesulfo 2 MOC))-OH ic acid nyl chloride 574 22.6 BOC-Boc-p-Cl- DAP (F Tyr (Et phenylacet benzenesulfonyl 3 MOC))-OH ic acid chloride 544 28.7 BOC- Boc- p-Cl- DAP (F Tyr (Et phenylacet 4-butoxysulfonyl 4 MOC))-OH ic acid chloride 616 27., 0 BOC-Boc-p-Cl- DAP (F Tyr (Et phenylacet methanesulfonyl 5 MOC))-OH ic acid chloride 482 31.0 BOC-Boc-p-Cl- DAB (F Tyr (Et phenylacet 2-thiophenesulfonyl 6 MOC))-OH ic acid chloride 564 23.2 BOC-Boc-p-Cl-4- DAB (F Tyr (Et phenylacet methoxybenzenesulfo 7 MOC))-OH ic acid nyl chloride 588 30.2 BOC--Boc-p-Cl- DAB (F Tyr (Et phenylacet benzenesulfonyl 8 MOC))-OH ic acid chloride 558 21.5 BOC-Boc-p-Cl- DAB (F Tyr (Et phenylacet 4-butoxysulfonyl 9 MOC))-OH ic acid chloride 630 30.0 6634 BOC-Boc-p-Cl- DAB(F Tyr (Et phenylacet methanesulfonyl 10 MOC))-OH ic acid chloride 496 28. 8 BOC- Boc- p-Cl- Orn (F Tyr (Et phenylacet 2-thiophenesulfonyl 11 MOC) ) -OH ic acid chloride578 33.1 BOC- Boc- p-Cl- 4- Orn (F Tyr (Et phenylacet methoxybenzenesulfo 12 MOC))-OH ic acid nyl chloride 602 33.9 BOC-Boc-p-Cl- Orn (F Tyr (Et phenylacet benzenesulfonyl 13 MOC) ) -OH ic acid chloride 572 29.4 BOC-Boc-p-Cl- Orn (F Tyr (Et phenylacet 4-butoxysulfonyl 14 MOC))-OH ic acid chloride 644 35.8 BOC-Boc-p-Cl- Orn (F Tyr (Et phenylacet methanesulfonyl 15 MOC))-OH ic acid chloride 510 16.5 6635 CmpdR1 R2 R3 R4 MW Yield Boc-Boc-4- Glu (OFm)-Tyr (Et chlorophenyla 1 OH)-OH cetic acid morpholine 502 40 Boc-Boc-4- Glu(OFm)- Tyr (Et chlorophenyla 2 OH)-OH cetic acid cyclopropylamine 472 23 Boc-Boc-4- Glu (OFm) - Tyr (Et chlorophenyla tetrahydrofurfur 3 OH)-OH cetic acid ylamine 516 27 Boc-Boc-4-4- Glu (OFm)- Tyr (Et chlorophenyla hydroxypiperidin 4 OH)-OH cetic acid e 516 35 Boc-Boc-4- Glu(OFm) - Tyr (Et chlorophenyla 2-amino-2-methyl- 5 OH)-OH cetic acid 1-propanol 504 30 Boc-Boc-4-2- Glu (OFm)- Tyr (Et chlorophenyla (methylamino) eth 6 OH)-OH cetic acid anol 490 27 Boc-Boc-4-N- Glu (OFm)- Tyr (Et chlorophenyla met : hylcyclohexyl 7 OH)-OH cetic acid amine 528 35 Boc- Boc- 4- Asp (OFm) - Tyr (Et chlorophenyla 8 OH ) -OH cetic acid morpholine 488 53 Boc- Boc- 4- Asp (OFm) - Tyr (Et chlorophenyla 9 OH)-OH cetic acid cyclopropylamine 458 12 Boc-Boc-4- Asp (OFm) - Tyr(Et chlorophenyla tetrahydrofurfur 10 OH)-OH cetic acid ylamine 502 35 Boc-Boc-4-4- Asp (OFm) - Tyr(Et chlorophenyla hydroxypiperidin 11 OH)-OH cetic acid e 502 14 Boc-Boc-4- Asp (OFm)- Tyr (Et chlorophenyla 2-amino-2-methyl- 12 OH)-OH cetic acid 1-propanol 490 28 Boc-Boc-4-2- Asp (OFm)- Tyr (Et chlorophenyla (methylamino) eth 13 OH)-OH cetic acid anol 476 30.0 Boc-Boc-4-N- Asp (OFm) - Tyr(Et chlorophenyla methylcyclohexyl 14 OH)-OH cetic acid amine 514 26.0 Boc-Boc-4- Glu (OFm) - Tyr(Etbromophenylac 15 OH)-OH etic acid morpholine 547 64.3 6635 Boc-Boc-4- Glu(OFm)- Tyr (Et : bromophenylac 16 OH)-OH etic acid cyclopropylamine 517 62.3 Boc-Boc-4- Glu (OFm) - Tyr(Et bromophenylac tetrahydrofurfur 17 OH)-OH etic acid ylamine 561 70. 7. Boc-Boc-4-N- Glu(OFm) - Tyr(Et bromophenylac methylcyclohexyl 18 OH)-OH etic acid amine 573 70.9 Boc-Boc-4-3- Glu(OFm) - Tyr(Et bromophenylac methoxypropylami 19 OH)-OH etic acid ne 549 51.9 Boc-Boc-4-4- Glu (OFm)- (Et bromophenylac hydroxypiperidin 20 OH)-OH etic acid e 561 55.4 Boc-Boc-4- Glu (OFm)- (Et bromophenylac 2-amino-2-methyl- 21 OH ) -OH etic acid 1-propanol 549 51.9 Boc-Boc-4-2- Glu (OFm) - Tyr(Et bromophenylac (methylamino) eth 22 OH)-OH etic acid anol 535 51.9 Boc-Boc-4- Glu(OFm) - Tyr (Pr bromophenylac 23 OH)-OH etic acid morpholine 561 61.9 Boc-Boc-4- Glu(OFm) - Tyr (Pr bromophenylac 24 OH)-OH etic acid cyclopropylamine 531 64.5 Boc-Boc-4- Glu(OFm)-Tyr (Pr bromophenylac tetrahydrofurfur 25 OH ) -OH etic acid ylamine 575 42.7 Boc-Boc-4-N- Glu (OFm)- Tyr (Pr bromophenylac methylcyclohexyl 26 OH ) -OH etic acid amine 587 51 Boc-Boc-4-3- Glu(OFm)- Tyr (Pr bromophenylac methoxypropylami 27 OH)-OH etic acid ne 563 60.8 Boc-Boc-4-4- Glu (OFm)- Tyr (Pr bromophenylac hydroxypiperidin 28 OH ) -OH etic acid e 575 60.6 Boc- Boc- 4- Glu(OFm) - Tyr (Pr bromophenylac 2-amino-2-methyl- 29 OH ) - OH etic acid 1-propanol 563 54.3 Boc-Boc-4-2- Glu(OFm) - Tyr (Pr Bromophenylac (methylamino)eth 30 OH)-OH etic acid anol 549 48.1 Boc-Boc-4- Asp(OFm) - Tyr (Et bromophenylac 31 OH ) -OH etic acid morpholine 533 52.1

EXAMPLE II Melanocortin Receptor Assays This example describes methods for assaying binding to MC receptors.

A. Cell culture and preparation: HEK-293 cell lines were transfected with the human melanocortin receptors hMC1, hMC3, and hMC4 were obtained from Dr. Ira Gantz, as described in Gantz, I. et al., Biochem. Biophys. Res. Comm., 3: 1214-1220 (1994); Gantz et al., J. Biol. Chem., 268: 8246-8250 (1993); Gantz et al., J. Biol. Chem., 268: 15174-15179 (1993) ; and Haskell-Leuvano et al., Biochem. Biophys. Res. Comm., 204: 1137-1142 (1994).

Vectors for construction of an hMC-5 expressing cell line were also obtained from Dr. Ira Gantz, as described in the above references, and a line of HEK-293 cells expressing hMC-5 was constructed. HEK-293 cell lines were maintained in DMEM containing 25mM HEPES, sodium pyruvate, 10% Cosmic Calf serum, 100 units/ml penicillin, 100pg/ml streptomycin, 2 mM glutamine, non- essential amino acids, vitamins and 0.2 mg/ml G418 to maintain selection.

B. Membrane Preparation: HEK-293 cells stably expressing the MC Receptors were grown to confluency in 175 cm2 flasks.

3 flasks were washed in 30 ml room temperature phosphate buffered saline (Cellgro) per flask, and harvested using a rubber scraper in 5 ml ice-cold PBS per flask. The cells were combined into one test tube, homogenized using a Polytron homogenizer (3 bursts of 10 seconds) and centrifuged at 32,000x g for 20 min at 4°C.

Membranes were washed as follows: the pellet obtained after centrifugation was resuspended in 20 ml ice-cold hypotonic buffer, (20 mM Tris-HCl, 5 mM EDTA, pH 7.7 at 4°C), dispersed using a 8 strokes in a teflon/glass homogenizer and recentrifuged as decribed above. The final pellet was resuspended in 3 ml ice cold suspension buffer (20 mM HEPES, 10 mM NaCl, 1.26 mM Caca2, 0.81 mM MgSO4, 0.22 mM KH2PO4, 10% w/v Sucrose, pH 7.4), giving a protein concentration of approx. 2 mg/ml. Protein concentration was measured by a BCA assay (Pierce), using bovine serum albumin as standard. The crude membrane preparation was aliquoted, flash-frozen in liquid nitrogen and stored at-80°C.

Before use in assays, each membrane preparation was tested and the protein concentration to give 3000 counts of total binding is determined. Typically, 6 ug/ml for MC-1,1.5 ug/ml for MC-3,1.5 pg/ml for MC-4, and lpg/ml for MC-5 give 3000 counts in the assay.

C. Assays: Binding assays were performed in a total volume of 250 ul. Triamines and other compounds were dissolved in DMSO and diluted in PBS to give no more than 2.5t DMSO (0.25 % final in the assay), and 25 pl of test compound is added to each tube. 50,000 dpm of 1211 labeled HP 467 (Ac- Nle-Gln-His-(p (I)-D-Phe)-Arg-(D-Trp)-Gly-NH2, with the iodo group radioactively labeled; see WO 99/21571) (in 25 pl) prepared in 50mM Tris pH 7.4,2 mg/ml BSA, lOmM CaC12, 5mM MgCl2, 2mM EDTA were added to each tube. l25I-HP 467 was custom labeled by Amersham to a specific activity of 2000 Ci/mmol. Membranes were thawed and resuspended in ice-cold suspension buffer without sucrose at the protein concentration determined above, and 200 pi were added to each tube. Assays were incubated for 90 minutes at room temperature.

GF/B filter plates (Packard Instrument Co.) were prepared by soaking for at least one hour in 0.5% v/v polyethyleneimine. Assays were filtered using a Brandel 96-well cell harvester. The filters were washed four times with cold 50 mM Tris, pH 7.4. Filter plates were dehydrated for 2 hours and 35pl of Microscint (Packard Instrument Co.) added to each well. Filter plates were counted using a Packard Topcount and data analyzed in MDL Screen (MDL Information Systems, Inc.).

All cell culture media and reagents were obtained from GibcoBRL except for Cosmic Calf Serum from HyClone. Fine chemicals were obtained form Sigma, and GF/B plates and Microscint were obtained from Packard Instruments.

EXAMPLE III cAMP Assay for Melanocortin Receptor Agonism This example describes. methods for assaying cAMP production from G-protein coupled MC receptors.

HEK 293 cells expressing MCR-1, MCR-3, MCR-4 and MCR-5 were used (see Example II). Cells were plated at 20,000 cells per well in a 96-well plate coated with collagen Biocoat (Becton Dickinson). The next day, cells were pretreated with 75 pl of 0.4 mM 3-isobutyl-1- methylxanthine (IBMX) in low serum medium containing DMEM, 25 mM HEPES, non-essential amino acids, vitamins, 100 units/ml penicillin, 100 ug/ml streptomycin and 0.1% COSMIC CALF SERUM. IBMX is an inhibitor of cAMP phosphodiesterase. The pretreatment was carried out for 10 min at 37°C.

Following pretreatment, 25 pi of diluted triamine derivative was added to the wells, and cells were incubated for 15 min at 37°C. Cells were lysed by adding 25 pl saponin lysis buffer and incubating 2 to 5 min.

Plates were covered and stored at-20°C. cAMP concentration was determined by ELISA.

Briefly, 96 well ELISA plates were coated with goat anti- cAMP antibody (BabCo, Berkeley, CA) in PBS for 12 to 72 hr at 4°C. 50 pi of sample was mixed with 50 pl of cAMP ELISA buffer containing 1% bovine serum albumin, 10% heat inactivated donor horse serum, 1% normal mouse serum and 0.05% TWEEN-20 in PBS, and the diluted sample was added to the coated ELISA plate. Standards of known concentrations of cAMP were added to separate wells. 25 pl of 16 ng/ml cAMP-conjugated horse radish peroxidase (HRP) (cAMP-HRP)

was added to each well, and the plates were incubated hr at room temperature. Plates were washed and the binding of cAMP-HRP was detected with 3,3', 5,5'-tetramethylbenzidine (TMB) and hydrogen peroxide using standard immunoassay procedures.

EXAMPLE IV Melanocortin Receptor Binding Profile of Triamine derivatives This example describes MC receptor binding affinity and specificity for various triamine derivatives.

Various triamine derivatives were tested for in vitro binding activity to HEK 293 cells expressing MCR-1, MCR-3, MCR-4 or MCR-5 as described in'Example II.

Tables 1 to 3 above show the IC50 values, the concentration giving 50% inhibition of binding of l25I-HP 467, for various triamine derivatives. As shown in Tables 2 and 3, triamine derivatives exhibited a range of affinities to MCR-1 and MCR-5. Some triamine derivatives exhibited specificity of about 10-fold for at least one MC receptor over another MC receptor, for example, TRG 6600 #4 and &num 8.

Several triamine derivatives exhibited similar affinities between all four MC receptors whereas other triamine derivatives showed specificity for at least one MC receptor over another MC receptor (compare Table 1 with Tables 2. and 3).

These results show that triamine derivatives are MC receptor ligands.

EXAMPLE V Effect of Triamine derivatives on Melanocortin Receptor Signaling This example shows the effect of triamine derivatives on MC receptor signaling.

Various triamine derivatives were tested for their ability to activate MC receptor by measuring cAMP as described in Example III. Tables 4 and 5 show the EC50 values, the effective concentration for achieving 50% of maximal cAMP production, for various triamine derivatives administered to HEK 293 cells expressing MCR-1, MCR-3, MCR-4 or MCR-5. The EC50 values shown in Tables 4 and 5 are uM. Table 3 also shows the maximum amount (in pmol) of cAMP produced in response to a given triamine derivative. As shown in Tables 4 and 5, triamine derivatives were able to activate various MC receptors with a range of affinities.

These results show that triamine derivatives are MC receptor ligands that can activate MC receptors, both generally and selectively.

EXAMPLE VI Reduction of Lipopolysaccharide-Induced Tumor Necrosis Factor Levels in Mice This example describes the effectiveness of triamine derivatives for decreasing tumor necrosis factor (TNF) levels in lipopolysaccharide (LPS ; endotoxin) treated mice.

BALB/c female mice weighing approximately 20 g are placed into a control group and a treated group. Five mg/kg of LPS in 0.9% saline is administered (100 pi to give 100 pg LPS per mouse) by intraperitoneal (IP) injection to all mice. Mice in the treatment group receive either 30,100,300 or 600 pg of various triamine derivatives per mouse in a volume of 100 pi of PBS.

Control mice receive 100 pi of saline alone. One minute after initial injections all mice receive the LPS injection. As a positive control, 100 pg of HP 228 is injected per mouse.

Blood samples are collected from the orbital sinus of treated and control mice 90 minutes or 105 minutes after LPS administration. The plasma is separated by centrifugation at 3000 x g for 5 min and stored at -20°C. Samples are thawed and diluted, if TNF-a concentration is greater than 3200 pg/ml, with PBS containing 1% bovine serum albumin, 10% donor horse serum, 1% normal mouse serum, 0.05% TWEEN-20 and 0.05% thimerosal.

A 100 pl sample of plasma is assayed by ELISA for TNF-a. Briefly, ELISA plates are coated with hamster anti-mouse TNF-a antibody (Genzyme; Cambridge MA).

Samples or known concentrations of TNF-a are added to the coated plates and incubated for 2 hr at 37°C. Plates are washed and subsequently incubated with biotinylated rabbit anti-mouse TNG-a for 1 hr at 37°C. Plates are washed and incubated with streptavidin-HRP for 1 hr at 37°C, and HRP activity is detected with hydrogen peroxide and o-phenylenediamine (OPD) using standard immunoassay procedures. The mean ( SEM) TNF-a level in mice from each group is determined and the percent reduction in TNF- a levels calculated.

EXAMPLE VII Increasing Levels of IL-10 in Mice This example describes the effectiveness of triamine derivatives in increasing the levels of IL-10 in mammals.

Triamine derivatives are administered intraperitoneally to mice in doses of 30,100 or 300 pg/mouse or orally in doses of 300 or 600 pg/mouse.

Levels of IL-10 are measured 90 or 105 minutes after administration as indicated. Samples are collected and diluted, when appropriate, as described in Example VI. A 100 pi sample of plasma is assayed by ELISA for IL-10.

Briefly, ELISA plates are coated with rat anti-mouse IL-10 monoclonal antibody (Pharmingen; San Diego CA). Samples or known concentrations of IL-10 are added to the coated plates and incubated for 2 hr at 37°C. Plates are washed

and incubated with biotinylated rat anti-mouse IL-10 (R&D Systems Minneapolis MN) for 1 hr at 37°C. Plates are washed and incubated with streptavidin-HRP 30 min at 37°C, and HRP activity is detected with hydrogen peroxide and TMB using standard immunoassay procedures.

EXAMPLE VIII Effect of Triamine derivatives on Arachidonic Acid Induced Dermal Inflammation This example describes the effect of triamine derivatives on arachidonic acid induced dermal inflammation.

Female BALB/c mice (17-22 g) are used and administered the test triamine derivatives or positive control compounds 30 to 60 min prior to topical application of arachidonic acid. Indomethacin and HP 228 are used as positive controls. Compounds are administered orally (p. o.) or intraperitoneally (i. p.). Initial ear thickness (left and right) is measured using spring loaded micro-calipers. Arachidonic acid is applied to mice anesthetized with a cocktail of ketamine/xylazine (7.0 mg/ml and 0.6 mg/ml, respectively) administered i. p. (300 pl/mouse). Utilizing a micro-pipette, 20 ul of arachidonic acid solution (100 mg/ml ethanol or acetone) is applied to the right ear (10 pl to inner and 10 pi to outer surfaces of both ears for a total of 2 mg arachidonic acid per right ear), and 20 ul of vehicle (ethanol or acetone) is applied to the left ear. Mice are returned to their cages to recover. Mice are again

anesthetized 50 min after arachidonic acid application and their ears measured.

Dermal inflammation is determined by subtracting the difference of the vehicle treated left ear (L60-Lo) from the difference of the arachidonic acid treated right ear (R60-Ro) Ear thickness measurements are averaged for each group, and the responses in the vehicle treated control group (Cr ; saline or PBS) are subtracted from the response noted in the triamine derivative treated group (Tr) to give the relative inflammatory response for each treatment group compared to the control group. The percent inhibition is defined by the equation: % inhibition = (Cr-Tr)/ (Cr) x 100..

EXAMPLE IX Reduction in Body Weight Due to Administration of Triamine derivatives This example demonstrates that administration of an triamine derivative can cause a decrease in the body weight of a subject.

Described below are methods for determining the effects of novel compounds on food intake in rats over a 24-hour period. The MC-4 receptor is believed to be involved in the regulation of food intake and weight gain.

Thus, chronic MC-4 antagonism by agouti or AGRP is associated with hyperphagia and obesity (similarly for MC- 4 R knockout mice) and rats treated with a potent and prototypic MC-4 agonist, HP228, have demonstrated notable hypophagia and weight loss (IP, ICV). The triamine

compound used in this assay has demonstrated in vitro efficacy for binding to and agonizing the human melanocortin-4 (MC-4) receptor.

A. Assay Preparation 1. Materials and Buffers The triamine compounds was lyophilized and in the form of dry, powdery grains or a sticky substance.

HP228: (Ac-Nle-Gln-His-(D)-Phe-Arg-(D)-Trp-Gly-NH2 : (Multiple Peptide Systems, San Diego, California) Sibutramine: Novartis, Basel, Switzerland, or Meridia (prescription form) Dulbecco's Phosphate Buffered Saline (PBS): GibcoBRL Milli-Q Water: Double distilled water from Trega Biosciences, San Diego, California Polyethylene Glycol 400 (PEG400; 10% v/v for"PEG400"oral formulation) Propylene Glycol (1, 2 propane-diol; 30% v/v for"PEG400" oral formulation) 100% EtOH (10% v/v for"PEG400"oral formulation) Milli-Q water (50% v/v for"PEG400"oral formulation)

2. Compound Preparation a. Control Compounds: PBS (with up to 5% EtOH v/v) was used as the negative control for all treatments administered IP and ICV and PEG400'oral formulation is the standard vehicle for all treatments administered PO.

HP228 was the positive control for all intraperitoneal (IP) and intracerebroventricular (ICV) studies and Sibutramine the positive control for all perioral (PO) studies. HP228 and Sibutramine solutions were made up fresh either on the day of the assay (regular light cycle; 6pm-6am) or the previous afternoon (reverse light cycle; 9am-9pm). HP228 was dissolved in PBS to create a 5 mg/ml (1 ml/kg IP) or 1 mg/ml (10 pg/rat ICV) solution.

Sibutramine, a novel serotinin and noradrenaline re-uptake inhibitor, which is an approved weight loss treatment, was the positive control for all perioral (PO) studies. Sibutramine has been shown to lower body weight in various rodent models (normal, Zucker fatty and diet- induced obesity) by reducing food intake and increasing energy expenditure. Sibutramine was dissolved in the appropriate amount of"PEG400 oral formulation"to yield a 10 mg/kg treatment dose (2 ml/kg @ 5 mg/ml).

The triamine compound (TRG 6600 #3) was dissolved in (up to 5% v/v) EtOH/PBS (IP, ICV) or PEG400 (PO) to yield the appropriate concentration for treatment at a volume of 1 ml/kg (IP), 2 ml/kg (PO) or 10 ml/rat

(ICV) and was stored at 4°C. The triamine compound was administered IP (S 10 mg/kg), PO (£ 60 mg/kg) and ICV (£ 50 mg/rat).

3. Assay Protocol This protocol is designed for fed, non-obese rats as fasting induces several factors (e. g., leptin, neuropeptide Y, AGRP) that may serve to confound the interpretation of an acute, initial in vivo screen.

Adult, male rats (Sprague-Dawley ; 200-225 g upon arrival and 250-300 g at time of study) from Harlan Laboratories (San Diego, California) were acclimated in the study vivarium for at least one week with free access to food and water. Animals that will be experimentally monitored in the reverse light: dark cycle room were acclimated for approximately 9 days and/or until daily feeding has returned to control levels. Animals with an ICV cannula implanted into the lateral ventricles were allowed to recover and acclimate for 4-5 days after surgery and body weight and food consumption was tracked following surgery. Baseline body weight and food consumption measurements for studies with all routes of treatment administration (IP, PO, ICV) were taken for 2 days prior to the start of the study with animals in individual cages. On the study day, body weight measurements were taken and the animals were randomly divided into groups (n = 6-8) such that food consumption (from the previous day) was equivalent between all groups.

Four groups (n = 6-8) were run at one time: a negative and a positive control and two different novel compounds. Thus, animals were administered a single treatment of the following: Negative Vehicle Control: EtOH/PBS (1 ml/kg IP; 10 ml/rat ICV) Negative Vehicle Control: PEG400 Oral Formulation (2 ml/kg PO) Positive Control: HP228 (5 mg/kg IP; 50mg/rat ICV) Positive Control: Sibutramine (10 mg/kg PO) Triamine derivative compound: 5-10 mg/kg IP; 50mg/rat ICV; 30-60 mg/kg PO.

Treatments were administered approximately 1 hour before the beginning of the dark cycle (regular 6pm- 6am; reverse 9am-9pm) and the animals were returned to their individual cages with ad libitum access to food and water. Food consumption measurements were obtained 2,4, 6,18 and 24 hours after treatment (regular light cycle) or 2,4,6,8 and 24 hours after treatment (reverse light cycle) by weighing the cage lid with all remaining food and calculating the difference from baseline (time 0).

Measurements during the dark cycle were taken under red light conditions. Treatment solutions were administered ICV at room temperature over approximately 10 seconds by conscious injection of a 10 ml volume.

B. Data Analysis All data were reported as means standard error of the mean (SEM) and analyzed by one of the following appropriate statistical methods: one-way analysis of variance (ANOVA) with Student Newman-Keuls test for multiple comparisons, ANOVA for repeated measures, or a Student's t-test where appropriate.

Administration of the test triamine compound ICV caused a statistically significant decrease in the food intake of rats at 4 and 6 hours after injection (see Figure 5). In addition, administration of the test triamine compound IP caused a statistically significant reduction in the food intake of rats over the 24 hour test period (see Figure 4). These results indicate that a triamine derivative can decrease weight gain and food intake in subjects.

EXAMPLE X Penile Erection Due to Administration of Triamine Derivative Assay Method Adult male rats are housed 2-3 per cage and acclimated to the standard vivarium light cycle (12 hr. light, 12 hr. dark), rat chow and water for a least a week prior to testing. All experiments are performed between 9 a. m. and noon and rats are placed in cylindrical, clear plexiglass chambers during the 60 minute observation

period. Mirrors are positioned below and to the sides of the chambers to improve viewing.

Observations begin 10 minutes after an unstraperitoneal injection of either saline or compound.

An observer counts the number of grooming motions, stretches, yawns and penile erections (spontaneously occurring, not elicited by genital grooming) and records them every 5 minutes, for a total of 60 minutes. The observer is unaware of the treatment and animals are tested once, with n=6 in each group. HP 228 is used as a positive control for. penile erections. Differences between groups are determined by an overall analysis of variance and the Student Neunmann-Keuls post hoc test is used to identify individual differences between groups (p zu 0.05).

As recited in the claims below, amended or unamended as filed or later added, the term"comprising" is open-ended, regardless of where in the claim the term is recited.

All references cited herein are fully incorporated by reference.

Although the invention has been described with reference to the examples provided above, it should be understood that various modifications can be made without departing from the spirit of the invention. Accordingly, the invention is limited only by the following claims.